TREATMENTS ACCESS

9th CONFERENCE ON RETROVIRUSES AND OPPORTUNISTIC INFECTIONS. SEATTLE, 24-28 FEBRUARY 2002

PATHOPHYSIOLOGY

OTHER NEWS

TRIAL NEWS – ONGOING UK STUDIES

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APPENDIX

 

 

TREATMENTS ACCESS

South Africa finds 1 billion Rand to treble HIV budget, after Mandela confronts Mbeki

Graham McKerrow, HIV i-Base

The South African government has announced a trebling of spending on HIV prevention and treatment to 1 billion Rand (£62m) next year, and a further rise to R1.8bn (£111m) the following year. The announcement in the finance minister’s give-away budget in February represents a turnaround in government thinking on HIV, and follows a high profile intervention by former president Nelson Mandela.

However, several organisations have said the money is still far too little, and that the government has yet to seriously address the issue of treatment for people with HIV.

The cash announcement coincides with a decision to launch a programme of treatment with nevirapine to cut mother to child transmission of the virus. South Africa has been the target of international condemnation for refusing to adequately combat HIV, and central to the controversy have been statements by President Thabo Mbeki questioning whether HIV is the cause of AIDS and quoting in evidence AIDS dissidents such as Professor Peter Duesberg.

Political pressure inside the country for a change of policy became unstoppable as several provincial governments, including the Western Cape and KwaZulu Natal, announced nevirapine programmes to combat vertical transmission of the virus.

The latest wave of pressure started in January when treatment activists illegally imported generic drugs from Brazil. In early February The Nelson Mandela Awards for Health and Human Rights 2002 were awarded to Prof James McIntyre and Dr Glenda Gray of Chris Hani Baragwanath Hospital “in recognition of outstanding contributions to the medical science and practical implementation of drug therapies for the prevention of HIV transmission to newborns”.

A week later the ANC’s flagship province, Gauteng, which surrounds Johannesburg, announced that all its public hospitals would dispense nevirapine by the end of the year — a move seen as wrecking national government policy on HIV. This was followed on 18 February by a well-publicised meeting between Mr Mandela and President Mbeki to discuss the health crisis. Both men are on record as having sharply different views on the issue but an ANC statement said the two had reached an understanding “and reaffirmed the correctness of the positions taken by the ANC and the government.”

However, the ANC leadership was reported in local media as accusing Mr Mandela of basing his criticism on media reports that did not accurately reflect the Mbeki government’s position on AIDS.

Finance minister Trevor Manuel said in his budget speech at the end of the month: “The Budget contains significant measures to strengthen the national HIV/AIDS programme. In addition to an estimated R4bn currently spent by provincial health departments on AIDS-related illnesses, funding for prevention programmes in schools and communities, hospital treatment and community care programmes will amount to R1bn next year, rising to 1.8bn in 2004/5.”

“This includes a progressive roll-out of a programme to prevent mother to child transmission at the conclusion of the current trials.”

Most of the new money will pay for life skills education in schools, voluntary testing, home-based care and community-based support for people with HIV, as well as paying for antiretrovirals. Some of it will be used to provide medication to prevent TB and pneumonia in people with HIV.

Mr Manuel’s department said widespread use of triple combination therapy is still considered unaffordable but “continues to be the subject of various research projects”.

There is evidence that South Africa’s prevention programmes are beginning to work, but have a long way to go. Government statistics show that HIV infection rates in the under-20s declined from 21% in 1998 to 16.1% in 2000. The health department distributed 310 million condoms last year, and that figure will rise by 16% this year, said Mr Manuel.

Non-governmental bodies welcomed the announcement of new money as a step in the right direction, but said that a budget that included huge tax cuts and increases in spending could have done more to pay for anti-HIV treatment. The budget included R15bn (£1bn) in tax cuts.

Mark Heywood of the South African Treatment Action Campaign told journalists that the increase in the AIDS budget should be seen as a serious commitment to tackling the epidemic, but that it was insufficiently aimed at improving the lives of people with HIV.

He said: “The question is, do we spend our resources to keep our people well, or just to pay the price of creating facilities where they can die? It will be much more cost-effective to invest in health services and medicines so that people can stay alive and be productive.”

He called for an urgent investigation by the government into the cost implications of the health crisis, and said: “We need to work out how we can cut expenditure through a more effective targeting of treatment resources.”

A recent study showed that providing home-based care alone would cost the country about R1.8bn a year, Mr Heywood said. He urged the government to issue compulsory licences to cut the cost of combination drug therapy.

Dr Saadiq Kariem, of the Networking AIDS Community of South Africa, said that while this new budget was an improvement, people with HIV had hoped more would be allocated for treatment. He said more money was needed to care for children orphaned by AIDS, and called for more to be spent on home-based care for people with HIV.

The scale of South Africa’s AIDS crisis has been illustrated in many ways and has caused major skills shortages and thousands of orphans. The latest measure of the disaster is that the country now has a crisis in its cemeteries, which are having to turn away the dead because there is no more room to bury them. There is now a problem caused by the number of so-called “informal burials”. One province alone, KwaZulu Natal, is recording nearly 200 HIV-related deaths every day.

comment

The new South African AIDS budget may be too small and it may be too late for many of that country’s citizens – but it represents an important change of direction by the South African government and is to be welcomed as a sign that official policy is at last moving in the right direction.

The government must now be urged to cooperate closely with NGOs working in the field to find effective ways not only to expand prevention programmes but also to provide vital treatment and care. South Africa is not a rich country but it is one that can afford a R15bn give-away budget, and in that context it is not impossible to find R1.8bn for a proper home-care programme for people with HIV. This virus does not discriminate but it does attack the economically productive section of the population and such a programme would keep vital workers well: it would allow those who make the wealth to continue to do so, it would allow teachers to continue training the next generation, it would keep parents fit enough to raise their children. In short, antiretroviral treatment is an investment, not an expenditure — and the tax cuts in this latest budget show that South Africa is one African nation that can afford the bill.

Then, in association with Europe and North America, that country can turn its attention to the long-awaited ‘Renaissance of Africa’ — in the form of Mr Mbeki and Mr Blair’s joint project to boost aid to the continent and encourage democracy and stability — which must also prioritise the fight against HIV.
HIV Treatment Bulletin Vol 3 No 3 April 2002

   

9th CONFERENCE ON RETROVIRUSES AND OPPORTUNISTIC INFECTIONS (CROI)

SEATTLE, FEBRUARY 24-28 2002

Study results shed light on cardiovascular risks: Role of antiretrovirals and metabolism of lipids and sugars

Simon Collins, HIV i-Base

It is clear that current antiretroviral strategies result in changes in lipid and sugar metabolism to some extent in nearly all patients and to a serious degree in a significant number. That these symptoms overlap with risk factors for Cardiovascular Disease (CVD) are such a growing concern that several large prospective data collection studies have already been established and are posting early results. [1]

A more precise and practical estimate of the implications for these risk factors was proposed by Matthias Egger at the 2nd Workshop on Lipodystrophy in Toronto (Oct 2000) and was widely reported [2, 3]. It is unlikely and unfortunate that his recommendations to consider HAART as an additional risk factor for CVD in the decision to initiate therapy have not been fully integrated in clinical practice, although references to CVD risk are now included in US treatment guidelines. Even simple web-based resources for calculating CVD risk would benefit from being used. [4]

Several presentations at this conference looked to provide more detailed information about the rates of CVD in HIV patients and the risk factors associated with specific antiretroviral treatments. While follow up periods are impressive for HIV disease, the general feeling is that these are still too short to pick up CVD events which usually result from 30 years of cumulative risk factors.

Cardiovascular and cerebrovascular (CV-CV) events recorded on the databases of the Veterans Association from both post and pre-HAART era were reported by Sam Bozzette as a late breaker oral presentation. [5] Data was presented biannually from 1993-2001 for almost 40,000 veterans (98% male, 41% white, 7% prior vascular disease) covering 122,000 patient years. Antiretroviral (ARV) use from the >1.4 million prescriptions was included in the analysis).

There were 1764 hospital admissions and 521 attributable deaths to CV-CV, but these decreased despite a six-fold increase in use of antiretrovirals from all classes. Approximately 15,000 total all cause deaths occurred over this period.

All cause mortality reduced by 75% over this period, but as CV-CV events dropped less dramatically by 10-20%, this meant CV-CV events accounted for a greater proportion of all deaths. However, even when looking at those people at higher risk, the incidence per 100 patient years fell by approximately 50% (from 14 to 7 in the 2428 patients with a previous history of vascular disease; and from seven down to three in the 4051 patients >55 years old) in the pre- and post-HAART years respectively. (see Figure 1)

Fig 1. CV-CV events and ARV exposure recorded in VA databases

Year exposure/100 patient yrs   Events /100 patient yrs
  1993 1995 1997 1999 2001     1993 1995 1997 1999 2001
Anu ARV 23.1 23.1 56.1 57.9 60.1   CV-CV related admission 1.6 1.7 11.3 1.3 0.9
RTI 23.1 23.1 53.9 54.1 56.0   CV-CV admission or death 2.0 2.2 1.8 1.8 -
PI - - 33.0 40.1 35.9   All cause mortality 18.0 21.3 9.3 6.9 5.0
NNRTI - - 2.9 16.5 22.9              

Fig 2: Prevalence of established risk factors by study group

CHD risk factors
HIV +ve cases
HIV -ve controls
P-value
US Nat Data
 
(n=2526)
(n=23,541)
(HIV +ve vs HIV -ve) (general population)
Hypertension
18.0%
24.0%
<0.0001
24%
Hyperlipidemia
21.5%
16.0%
<0.0001
17%
Diabetes mellitus
7.2%
8.8%
<0.002
5%
Current smoker
18.8%
9.5%
<0.0001
26%

Seven year follow-up is a good basis for continuing to collect data from subsequent years, but this may still be too early to see an increase in incidence of events. Additional concern was indicated that patients would be missed from the database if, as often happens with CV-CV events, healthcare was accessed by VA patients at other clinics. The results, while interesting, should not in themselves lower overall concern for the overlap of metabolic changes and risk factors for cardiovascular disease.

A similar trend was reported from another large US cohort following 55,000 patients from 1992-2000 and reporting 7,188 deaths (68% of pre-HAART). Compared with the pre-HAART period, proportions of deaths decreased for TB, non-TB mycobacterial infections, PCP and toxoplasmosis. Proportions of deaths increased for liver, non-Hodgkins lymphoma, cachexia/wasting, kidney disease and sepsis. Although not reaching statistical significance, the trend for ischemic heart disease (OR 1.9; CI 0.99-3.62) was suggestive of an increase in proportion of deaths.

Whilst a similar rate of incidence and lack of association with specific drugs or ARV drugs in general was reported by Klein and colleagues from the Kaiser Permanente programme in California, this team were more cautious about the implications. [7] This group collected results for up to 5.5 years from men aged 34-65. The study reported a significant 6.5 against 3.8 CHD events/1000 patient years, adjusted for age in over 4100 HIV positive patients compared to 40,000 HIV negative controls (p=0.003), and a trend towards increased risk of myocardial infarction (4.3 vs 2.9, p=0.07). So whilst an increase in CHD could not be matched to ARV use, the risk of heart disease remained higher in HIV-positive patients.

Risk factors for CHD were common among HIV positive patients hospitalised for CHD: hypertension (27%), diabetes mellitus (16%), hypercholesterolemia (72%) and current smoker (29%). However differences between the HIV positive and the HIV negative control group, and indeed differences between the control group and incidence in US national data were not explained by traditional risk factors. (see Figure 2)

Holmberg and colleagues from the HOPS cohort reported higher incidence of myocardial infarction (but not of angina or cerebrovascular events) among patients using protease inhibitors. [8] The number of MI were small but the difference between the groups was significant; 13 in 3013 patients on PI compared to 2 in 2663 non-PI-using patients (p=0.012). This association remained in multivariate models controlling for hypertension, smoking, diabetes, age, gender, and evidence of dyslipidemia although the confidence intervals were relatively wide.

An interesting and potentially optimistic study looking at increased lipid levels was presented in a poster by Stefan Mauss. [9] This study looked more carefully at increases in cholesterol in 187 consecutively seen patients at a clinic in Düsseldorf, 45% of whom had hypercholesterolemia >200mg/dl. Hypercholesterolemia in these patients was due to increases in LDL in 14% cases, to high LDL and VLDL in 16% cases, to VLDL in 66% cases and in 4% cases due to increases in HDL alone. Further analysis of the VLDL composition revealed large triglyceride-rich particles associated with low risk familial hypertriglyceridaemia. The possibility that many HIV positive patients with high triglycerides may be at a lower risk than previously thought, perhaps supports the lower incidence seen in the cohorts reported above, and lipid profiles in lipodystrophic patients should be included in larger studies.

References:

  1. Studies underway on metabolic side effects of antiretrovirals. HTB Vol2No2.
    http://www.i-base.info/publications/bulletins/htb2-2/htb2-2p.html
  2. Egger M – Metabolic complications of HAART - Second workshop on lipodystrophy and adverse events. Toronto, Oct 2000. Oral presentation 023.
  3. Egger M - HAART and the heart: lipodystrophy & cardiovascular risk: need for perspective. PRN Notebook Vol6 No2.
    http://www.prn.org/_frms/vol6/num2/egger_frm.htm
  4. Web based resources to calculate CVD risk:
    http://www.livingheart.com/main/riskmain.asp
    http://www.intmed.mcw.edu/clincalc/heartrisk.html
  5. Bozzette S et al - Cardio- and Cerebrovascular Outcomes with Changing Process of Anti-HIV Therapy in 36,766 US Veterans. 9th CROI. Late Breaker LB9
  6. Wolfe M et al - Deaths from Non-AIDS-Related Diseases Have Increased as a Proportion of Deaths of HIV-Infected Persons since the Advent of HAART. 9th CROI. Oral abstract 14
  7. Klein D et al - Hospitalisations for Coronary Heart Disease and Myocardial Infarction among HIV+ Patients in the HAART Era, 9th CROI. Abstract 696.
  8. Holmberg S - Protease Inhibitor Use and Adverse Cardiovascular Outcomes in Ambulatory HIV Patients. 9th CROI. Abstract 698 - P
  9. Mauss S - Differentiating Hypercholesterolemia Associated with Antiretroviral Therapy (ART). 9th CROI. Abstract 689. P
HIV Treatment Bulletin Vol 3 No 3 April 2002

   

Switch to abacavir improves lipoatrophy

Simon Collins, HIV i-Base

Any study that shows an improvement in lipoatrophy, the most difficult of lipodystrophy symptoms to reverse, is worth studying closely. This study is particularly important as it is an independent study run by Andrew Carr and David Cooper, two of the leading and earliest researchers in lipodystrophy.

This study randomised 111 patients (98% male) with moderate to severe lipoatrophy to either continue with their current regimen or switch zidovudine (ZDV) (16%) or stavudine (d4T) (84%) to abacavir.

After six months there was a significant increase in limb fat in the group that switched to abacavir compared to those who didn’t switch their nucleoside (0.39kg and 0.08 kg, respectively; p=0.016). There were also significant relative increases in subcutaneous thigh and abdominal fat areas (p<0.02). Although these changes were small - and patients did not report subjective improvements - the results are important. In this study, use of MRI and DEXA scans provided the sensitivity of monitoring that is required for research - and arguably for treatment - in this area.

It was interesting that patients continuing without a nucleoside switch did not continue to lose fat, although it is difficult to know whether this stabilisation occurred because lipoatrophy was advanced, and that an earlier switch in people with mild lipoatrophy would also prevent further loss. It may be that switching to drugs with a more beneficial lipid profile is one part of a multi-structured approach.

Hypersensitivity reactions to abacavir occurred in five (10%) patients and there was no significant effect on intra-abdominal fat, lipid or glycaemic parameters. Previous studies have highlighted that switching to abacavir is associated with higher risk of viral rebound in patients with previous nucleoside exposure in failing or suboptimal combinations. Switching d4T or ZDV to abacavir and tenofovir may be a more appropriate choice for these patients. Although the effect of such a switch on lipoatrophy remains unknown.

Reference: Carr A - Switching Stavudine or Zidovudine to Abacavir for HIV Lipoatrophy: A Randomised, Controlled, Open-Label, Multicentre, 24-Week Study. Abstract 32.
HIV Treatment Bulletin Vol 3 No 3 April 2002

   

Potential use of niacin to reduce intra-abdominal fat

Simon Collins, HIV i-Base

Interesting results were presented by Fessel and colleagues from the Kaiser Permanente Care Programme in San Francisco on the use of open label high dose niacin (otherwise known as nicotinic acid or vitamin B3) for 48 weeks, to reverse intra-abdominal fat (IAF) accumulation. As with the other studies reported above, the interest here is in a treatment which reports benefits for otherwise untreatable symptoms.

High dose niacin is not without serious toxicity risks itself although it increases HDL-C (high-density lipoprotein cholesterol) to a much greater extent than the statins. The ACTG panel recommends avoiding niacin because it may cause insulin resistance even in people without diabetes.

Nevertheless, this study reported decreases in IAF measured by single slice CT scan (L2) in 13/16 patients. Dosing was gradually increased over several weeks in order to reach optimal dose of 3000mg/day. Median baseline IAF was 227 (CI 173-266) and median duration of treatment was 364 days (294-400). IAF decreased in 13 and increased in 3 patients. Results reported were: overall in 16 patients IAF decreased by 16.9% (CI -33% to -0.8%) (p = 0.01). For those 13 in whom IAF decreased, the mean loss was 26.9% (CI -39.1% to -14.8%). Nine patients had decreased IAF >20% (mean 35.5%, CI -50.5% to -18.5%). Percentage decrease of IAF was associated with both the rise in HDL (p = 0.002) and decreased ratio of total cholesterol (TC/HDL (p = 0.003). Decrease of IAF was also associated with the duration of niacin treatment (p < 0.0001). Initial and final plasma lipids for all 16 patients were: TC, 258 and 235 mg/dL (NS); HDL, 35.4 and 43.1 mg/dL (p = 0.002); TC/HDL ratios, 7.3 and 5.6 (p = 0.008).

Side effects from high dose niacin include flushing (managed by 325 mg aspirin 20 minutes prior to niacin dosing). One patient experienced acanthosis nigricans - a black furry rash on the chest and underarms, which can result from insulin resistance, and which resolves after discontinuation/dose reduction. Diabetes can be exacerbated and require dose adjustments for diabetes medication. Liver function also requires careful monitoring. Niacin can also increase levels of growth hormone and this may explain some of the benefits seen in this study. Two patients entered the study with large buffalo humps and although not accurately measured, this was reported to soften and shrink considerably in one patient over the study period.

Niacin is reported to appear in human milk and may cause serious side effects in nursing infants.

Fessel J - Effects of Niacin upon Fat Expansion in HIV-Positive Patients Who Have the Fat Redistribution Syndrome (FRS). Abstract 703-T

 
HIV Treatment Bulletin Vol 3 No 3 April 2002

   

Further benefits shown with New-Fill for facial atrophy

Simon Collins, HIV i-Base

Positive results were reported from the use of New-Fill to treat HIV-related facial lipoatrophy from Lafaurie and colleagues from St Louis Hopital, Paris. New-Fill is a hydrogel of Polylactic Acid which stimulates natural collagen and produces dermal thickening as a correction to facial wasting which appears to be sustained following treatment with three to seven sessions of intradermal injections. See also the report in the last issue of HTB from the i-Base meeting held in January on this subject.[1]

This study reported on seven of sixteen patients who had completed treatment with four to five cycles of treatment. Results were presented using analysis from tri-dimentional photographs which calculated mean surface area and volume gain at the sites of injection, together with mean analogue visual scale satisfaction index (AVSI) and quality of life questionnaire.

Mean AVSI increased from 1/10 at baseline to 8/10 following the third treatment. Mean surface gain was 0.3 - 0.4 mm2 and mean volume gain was 13 - 15 mm3. The range represented slightly different results reported for each side of the face. No serious complication was reported, two patients reported malaise after the first injection. Surprisingly, quality of life only showed a trend to improvement, although this may be a result of such a small study.

References:

  1. http://www.i-base.info/publications/bulletins/vol3/htb3-2/index.html#Forum

  2. Lafaurie M et al - Treatment of HIV-Associated Lipoatrophy of the Face with Intradermal Injections of Polylactic Acid Abstract 704-T.

 
HIV Treatment Bulletin Vol 3 No 3 April 2002

   

Lipodystrophy associated with lower CD4+ T cell counts

Brian Boyle, MD for HIV&hepatitis.com

Lipodystrophy is one of the most distressing problems many HIV-infected patients confront. Unfortunately, despite intensive research in the past 6 years, the exact mechanism and aetiology of lipodystrophy have yet to be settled upon.

Still, there has been no shortage of theories in this regard, many of which have been proved to be either partially or fully erroneous. One thing that is clear at this point is that lipodystrophy is likely to be multifactorial in origin, with host, disease, and treatment factors all having some role. Further, it may be that the two aspects of lipodystrophy, peripheral fat loss (lipoatrophy) and central fat gain, have different causes or patient-specific predisposing factors.

In a study presented at the 9th Conference on Retroviruses and Opportunistic Infections, Lichtenstein and colleagues involved in the HOPS study evaluated the potential causes of lipoatrophy. This study involved a prospective cohort analysis of 337 HIV-1-infected patients who had no evidence of lipoatrophy at the start of the study and either did or did not develop lipoatrophy over the ensuing 21 months.

The diagnosis of lipoatrophy in this study was based upon a standardised interview and physician assessment and the incidence of fat loss in the extremities, hips or buttocks and sunken cheeks - without total body weight loss - was analysed in stratified and multivariate analyses for their relationship to immunologic, virologic, clinical and drug treatment data for each patient.

Of the 337 patients, 44 (13.1%) developed lipoatrophy during the follow-up period. Using multivariate analysis, the significant risk factors for developing lipoatrophy were white race (OR 5.17), CD4+ T cell count at the follow-up survey of less than 100 cells/mm3 (OR 4.15), and body mass index less than 24 kg/m2 (OR 2.43). Notably, there was no association found between lipoatrophy and duration of use, initiation, continuation, or discontinuation of any antiretroviral medication.

The most significant factor found to be associated with lipoatrophy in this study was the patients CD4+ T cell count, and patients who consistently had a CD4+ T cell count >350 cells/mm3 had a very low rate of lipoatrophy (3.3%) whereas patients with a CD4+ T cell count consistently <200 cells/mm3 had a relatively high rate of lipoatrophy (30.8%).

The authors conclude, “Factors associated with severity of HIV-1 infection, especially CD4+ T-lymphocyte cell count, appeared to have the strongest association with the development of lipoatrophy.” These data, which indicate that progression of HIV disease affects the risk of lipoatrophy, are other factors that physicians and patients must consider when deciding the appropriate time to start antiretroviral therapy.

Ref: K. Lichtenstein and others. Incidence and Risk Factors for Lipoatrophy (Abnormal Fat Loss) in Ambulatory HIV-1-Infected Patients. Abstract 684a.

Copyright 2002 by HIV and Hepatitis.com. All Rights Reserved.
HIV Treatment Bulletin Vol 3 No 3 April 2002

   

Treatment interruptions

Mike Youle, MD, Royal Free HIV Clinic, London, for NATAP

Treatment interruption, stopping therapy pre-term and fixed period intermittent on-off therapy schedules have all been proposed, discussed and to some degree studied over the past couple of years. A number of things about these strategies are clear, much more is less so. When treatment is stopped viral load rebounds usually to around the level pre-treatment and over the next few months CD4 cell counts decline at a variable rate that appears to have little predictability. Some small studies (none randomised) have hinted that this strategy is more successful in those people who were treated at seroconversion and that the further along in HIV disease you go the more risky interrupting therapy that has suppressed HIV, will be. Tantalizing data, first shown at the 8th European Conference on Clinical Aspects and Therapy in HIV in Athens in October 2001 appeared in the Giga-HAART study, from Christine Katlama’s group in Paris. This was the first controlled data to build on work by our group, that of Steve Deeks from UCSF and of Veronica Miller formerly of Frankfurt that showed that potential benefits existed in short term treatment interruptions in salvage patients who then recommenced a new regimen.

So this conference was always going to be a forum for synthesizing new data into the idea that interruption of antiviral suppression may be a double-edged sword. What you gain by lower toxicity and lack of pills may be offset by physical and laboratory changes showing that HIV was once more attacking the immune system. The fundamental question of course still stands - do you gain any delay in disease progression by treatment that is not available if you delay treatment until the risk of disease occurrence is higher? So the “treat now or treat later” discussion is intricately linked to the question of treatment interruption. An in-depth meeting convened by The Forum for Collaborative Research will be held later this month in Montreal to discuss the multifarious aspects of treatment interruption. In addition there is now a large clinical endpoint study called Optima that will examine 1300 patients who are triple class failures and who will be randomised to have a three to six month treatment interruption versus immediate switch to a salvage regimen (similar to the giga-HAART approach). Also they will be randomised to take a standard three drug optimised HAART regimen or a mega-HAART five or more drug regimen. This trial is now open to recruitment in the US through VA hospitals, across Canada and the UK and should provide some more definitive answer as to the utility of this approach in later stage disease.

More information can be obtained at the following website:

http://www.optimatrial.org

Does an interruption encourage risk for neurocognitive dysfunction?

Overall there were 26 presentations on the topic of STIs, including two late-breakers in Seattle. They fell into a number of subject groups. The first were those that examined the effects on the viral populations and immune function in different tissues when treatment was ceased. Andrew Leigh Brown from the University of Edinburgh worked with a group from UCSD led by Ellis to examine the dynamics of viral rebound in the cerebrospinal fluid (CSF) [1, 2].

In two of nine patients studied where sufficient data points were available (understandably, repeat lumbar punctures are not popular with patients), there was a difference between CSF and plasma viral kinetics. A rise in white cells (pleocytosis) in four subjects was seen following the viral burst (viral load increase) in the CSF, suggesting that this is a response rather than a cause of viral turnover in the central nervous system. This work also appears to shed light on the issue that reducing viraemia systemically may limit the entry of lymphocytes and linked virus into the CSF.

Further work to evaluate the source of virus when treatment is suspended came from the group of Lydia Ruiz and Martinez-Picardo in Barcelona, Spain. They extensively examined the env sequences for 12 subjects over up to four sequential structured treatment interruptions (SSTI) [3]. Genetic analysis was performed for portions of the envelope genome of the virus in DNA, plasma RNA and PBMCs. In some patients there was little shift in the genetic structure of emerging populations whilst in others there was a marked alteration. This may limit the ability of treatment interruptions to strengthen the HIV-specific cell-mediated immune responses since the exposed viral antigens keep changing during each SSTI. A single subject was more extensively studied and examination of plasma samples revealed that the HIV populations that emerged over successive interruptions probably reflect a combination of reactivation of archived populations and ongoing selection due to the effect of cytotoxic T-lymphocyte responses [4]. The role of neutralising antibodies in treatment interruptions was examined by a group of investigators working on the Swiss Spanish Intermittent Therapy Trial, where subjects had four cycles of two weeks off/eight weeks on therapy [5]. In 10 subjects at week two and 25 subjects after week 42 virus was isolated from PBMCs and examined for replicative capacity and for neutralising antibodies. Although neutralising antibody levels did not increase over the cycles of the study during the four to six treatment free periods, after the four cycles there was a significant increase in these antibodies (90% inhibition titres >1/1000). This occurred especially in the subgroup of subjects who had maintained control of viraemia throughout the study.

Risk of HIV progression in therapy interruptions in EuroSIDA patient group

Next were those studies that evaluated the effects of treatment interruption of three months or more on the progression of disease in patients who either interrupted or did not interrupt therapy. The largest of these came form the EuroSIDA cohort that represents large clinical centres across Europe and is a long established study that has been prospectively followed for many years [6]. This study received much attention and discussion by attendees at the Conference.

8,530 patients are followed in EuroSIDA. Jens Lundgren from Copenhagen presented data on 565 (16%) subjects who interrupted therapy in a cohort of 5385 patients representing 15,312 person years of follow-up after commencing HAART up to the first interruption or last follow-up visit. There were 10,637 person years of follow-up from the start of HAART to the first new AIDS event/death or last follow-up visit, to assess the risk of disease progression.

Characteristics of the patients when they started HAART: 80% were male; average age 37; transmission risk: 48% MSM, 24% heterosexual; HIV viral load 25,000; CD4+ count 200; nadir (lowest ever) CD4+ count 138; 31% previously had AIDS; on average patients started HAART in March 1997 (October 1996 through December 1998). Over the course of 60 months the number of patients interrupting therapy increased. By the 60 month time point a total of 20% of patients had interrupted therapy.

What were the risk factors for patients who interrupted therapy?

More females than men interrupted therapy (p=0.02). More IVDUs interrupted therapy than MSM (P<0.001). Patients from South (p<0.001) or Eastern Europe (p=0.005) tended to interrupt less frequently than patients from Central or Northern Europe. Patients tended to interrupt therapy the longer they were on therapy (p<0.001), with a 30% increase per calendar year. Patients with higher viral load on HAART tended to interrupt therapy more often (p<0.001). If a patient previously had AIDS that did not seem to indicate a propensity to interrupt therapy. Patients with higher CD4+ tended to interrupt therapy (p=0.07).

At the time of interruption the median CD4+ cell count was 228 and viral load was 4000. Patients lost about 30 cells on average over the first three months following the interruption. Viral load increased on average about 1 log during the first three months.

What is the pattern of disease progression observed (patients taking interruptions of three months or more)?

There were 408 clinical events for patients while on HAART and 37 for patients off HAART. The death rate was 25% for the patients on HAART and was about 37% for patients off HAART. NHL was mentioned as occurring more often for patients on HAART. For patients off HAART pulmonary TB, PCP, and oesophageal candidiasis occurred. At the time of these events the average CD4+ count was 111 in the on HAART group (23-239), and 23% of the events occurred when CD4+ were above 250. Average viral load was 8000 (400 to 126,000). The average CD4+ count off HAART when events occurred was 52 (12-120). The maximum CD4+ count at which an event occurred was 250. Average viral load was 158,000 (20,000 to 500,000).

What was the incidence of clinical disease progression (interruptions of 3 months or more)?

The rate (number of new AIDS events or deaths per 100 person years of follow up) for patients who interrupted therapy was 20.3 (37/182) vs 3.9 (408/1054). Patients with less than 50 CD4+ had a dramatically worse rate of disease progression to AIDS or death (80% [14/18] vs 35.5% [117/331), if they were off HAART. This suggests that being on HAART had a benefit regardless of CD4+ count. For patients with 50-199 CD4+ cells on their latest blood test, the rate of disease progression was also greater for patients off HAART (32.3% [18/56] vs 7.3% [163/2241]). Again, this suggests an independent benefit from being on HAART regardless of CD4+ count. Interestingly, for patients with more than 200 CD4+ there did not appear to be a difference in disease progression whether they interrupted or stayed on HAART (2.8 rate for interrupters vs 1.6 rate when staying on HAART). This suggests that an interruption may be safer if CD4+ are higher. This question is a bone of contention. Some doctors feel it is relatively safe to take an interruption if CD4+ are high enough. They feel if CD4+ are too low a patient should be placed on prophylaxis medication for opportunistic infections. Other doctors feel an interruption is risky even if CD4+ are higher and the uncertainties about what may happen during an interruption concern them. As seen in the Ellis study, viral load in the CSF increases significantly during an interruption. It is assumed that viral load increases in many parts of the body and reservoirs after an interruption. The long-term effects of re-populating reservoirs with HIV and the gyrations in viral load in reservoirs are unknown. Will this wear out the immune system and reduce its long-term ability to control HIV? No one knows the answer to this question.

Lundgren reported that age, being off HAART, and having had previous AIDS diagnosis was associated with a hazard for experiencing an AIDS event or death. The risk of death/AIDS was increased five-fold if a patient was off HAART, and was the greatest risk factor for AIDS/death. A lower CD4 count and a higher viral load were also associated with risk for developing AIDS/death whether the patient was on or off HAART. But the risk was greater if the patient was off HAART.

Lungren mentioned the limitations of his study. The interruptions were not structured therapy interruptions. There may be some biased reasons why some patients interrupted therapy. For example, a patient may have been terminally ill. The implications from taking interruptions of less than three months were not studied. He summarised that the risk of interruptions in this study were closely linked to the latest CD4+ count. Interruption is risky if you have a low CD4 count. Interruption does not appear unsafe if CD4s do not fall below 200 to 250. HAART appears to have a benefit not explained by its effect on CD4+ and viral load. However, this benefit disappears once you stop drugs so Lundgren raised concern about interrupting therapy in patients with low CD4+ and high viral load.

Royal Free Cohort

Lampe and co-workers followed all 237 people from the Royal Free Hospital Clinic who were naive to antiretrovirals when they started a HAART regimen and who reached a viral load < 400 copies/mL (within 32 weeks) or who reached a viral load < 50 copies/mL without viral rebound [7]. Twenty one percent of subjects were female; main HIV exposures were homosexual (60%) and heterosexual (34%) sex. The median age at start of HAART was 35 years. HAART was started on a median date of Dec 98 (IQR Sep 96 - Nov 00). Baseline median (IQR) viral load was 5.3 (4.8 - 5.7) log copies/mL and CD4 count 193 (75 - 302). Nucleoside drugs in the initial regimen were zidovudine/3TC 126 (53%), stavudine/3TC 76 (32%) and other 35 (15%). Other drugs were nevirapine 58 (25%), efavirenz 44 (19%), indinavir 56 (24%), ritonavir 21 (9%), nelfinavir 50 (21%) and ritonavir boosted PI 29 (12%).

Median time from start of HAART to first measured value <50 copies/ml was 180 days. 1342 viral load measures were made over a total 347 person-years of follow-up after the first viral load < 50 cps/ml - a median of one measure per 13.5 weeks (median over all patients of 3.8 per year). Maximum follow-up was 4.4 years. Overall 13 people (5.4%) experienced viral rebound on therapy (rate 0.037 per person-year) representing one person with viral rebound per 26.7 person-years of follow-up. There was a (non-significant) trend towards lower rebound rate with increasing time from start of HAART.

Treatment interruption before intensification

The Barcelona group also presented a prospective randomised study of subjects with multiple exposure to antiretrovirals who were randomised to a three month treatment interruption or an immediate switch to a new salvage regimen that consisted of Lopinavir/ritonavir plus saquinavir soft-gel, 3TC, ddI and abacavir [8]. In the 22 subjects who had the treatment interruption (Group A) 13 (64%) showed a reversion to wild-type virus during this period, perhaps raising the question as to whether the period off treatment was long enough. The outcome in this group were compared to the 24 subjects from Group B who had an immediate switch to the salvage regimen. They showed no significant differences. Within three months after restarting therapy the CD4+ count in this group was about the same as the patients who did not take a break in therapy. Longer-term follow-up in greater numbers of patients may however be required to show such differences. The other major Catalan research group of Jose Gatell evaluated the use of mycophenalate mofetil (MMF) and the cytostatic drug hydroxyurea in groups of patients who had started HAART close to seroconversion [9, 10]. These were small studies 15 and 20 patients respectively but did show that blunting of viral load rebound occurred under both agents that appeared not to be related to decrease in cell turnover or from increase in apoptosis. Further larger studies would be valuable for each of these agents perhaps combined with another approach.

Therapeutic vaccination

Therapeutic vaccination to maintain the benefits accrued during antiretroviral therapy has become an area of intense interest with several studies currently reaching a degree of fruition. For instance, the Quest study is currently evaluating the utility of a canarypox vaccine, Remune, or both prior to cessation of HAART in subjects who have been treated just after seroconversion. The group of Franco Lori and Juliana Lisziewicz presented data evaluating the utility of a novel topical DNA immunisation (DermaVir) in preventing viral rebound during treatment interruptions in macaques [11]. Ten animals with late-stage disease were studied and randomised to continuous HAART, STI-HAART (three weeks on three weeks off) and after six cycles were also given DermaVir (a composition of HIV DNA plus Langerhans cell stimulant called polyethylenimine-mannose designed to stimulate recognition of the DNA by the animals’ immune system). All the macaques on HAART alone were dead by month seven whereas only one on STI-HAART had succumbed. Of the three monkeys who were then treated with DermaVir, median viral load decrease during each subsequent interruption occurred until control at <200copies/mL was achieved. Clearly if this were possible to replicate in humans it would be highly significant and could open the door to combination HAART and immunotherapy combination studies.

Other studies also seemed to suggest this trend with different vaccinations. An NIH study using NYVAC-SIV in macaques showed similar blunting of viral rebound in immunised animals versus controls [12]. A pilot study nested within a Remune protocol evaluated the rise in viral RNA in subjects who stopped therapy for 6 weeks after suppressing to undetectable for at least 6 months [314-W]. In the 20 Remune patients the slope of the rise was 0.16 log10 copies/mL versus 0.21 in the eight control subjects who were only treated with the adjuvant IFA (p<0.05). The difference between the post-interruption viral load level between the groups was not significant but the numbers of patients in the study precluded this being properly evaluated.

So many approaches are being taken to the treatment interruption scenario, using HAART, immunotherapy, cytostatic treatments and immune enhancing agents. This once again suggests that a combination of different interventions may be the best way to continue to support the inherent immune response to HIV.

Additional information on STIs reported at the Conference

Douek and colleagues from the NIH Vaccine Research Center added a cautionary note about therapy interruptions [13]. They identified populations of T cells responding (ie. producing interferon gamma) to either HIV antigens or (as a control) CMV antigens, and sorted these cells by flow cytometry in patients during a treatment interruption. Then using a novel PCR technique, they compared the amount of proviral HIV DNA within the two cell populations. The proportion of either population that was infected, as evidenced by the presence of HIV DNA within them, was low. However, HIV-specific memory CD4 cells were significantly more likely to be infected. This could be looked at as bad news, or no news. In responding to sites of HIV replication, like a fire fighter these cells place themselves at risk. Douek concluded that this phenomenon of HIV specifically infecting the very cells that respond to it adds a cautionary note to the practice of STIs.

The overall question that remains to be answered is whether HIV replication can be controlled by novel strategies that pairs cycles of antiviral therapy with cycles of immunotherapy, or whether slow but relentless infection of responding antiviral cells eventually erodes the immune response. Research so far has shown no evidence that therapy interruptions in persons chronically infected with HIV result in improved control of HIV when off HAART. Current studies continue to examine whether a drug holiday before initiation of salvage therapy improves response, whether early treatment within the first few months of therapy allows treatment of limited duration with better control of HIV replication, or whether immunotherapies such as HIV vaccines given during HAART allow HAART interruption with better control of viral replication. This study illustrates at the single-cell level the cost of unrestrained viral replication resulting from an interruption.

Two additional studies add cautionary notes about treatment interruptions. If a patient takes repeated interruptions (obviously) over time their average viral load will increase and their average CD4 count will decline. The studies below take a broad view cautioning about risks associated with this.

Total HIV viral load over time predicts death and AIDS events

In an interesting study from the Swiss HIV Cohort Study [Eggar, 14], researchers looked at the amount of viral load a patient has over time and how that might predict disease progression. Eggar examined the area under the viral load curve (AUC) as a measure of average viral burden and assessed its value as a predictor of clinical progression. They also examined cumulative drug exposure. A total of 2,324 patients who started HAART between 1st September 1995 and 30th November 1998, who had a CD4 count and viral load measurement within three months before starting HAART and at least one follow-up visit were included. The median viral burden over time was 2.80 log (630 copies/mL) copies (interquartile range 2.67 to 3.37).

The risk of progression to a new AIDS event or death was strongly related to viral burden over time. Kaplan-Meier probabilities at five years were:

  • 7.2% for patients with viral burdens of less than 3.0 log copies/mL per year
  • 20.6% for viral burdens of 3.0 log to 3.99 log
  • 38.7% for viral burdens of 4.0 log to 4.99 log
  • 79.1% for patients with viral burdens of 5 log or greater

Baseline CD4 cell count, a history of IVDU, and older age also predicted disease progression, but baseline viral load, clinical stage, treatment history, and sex did not. Drug exposure increased with increasing viral burden.

Viral burden over time was a stronger determinant of clinical progression than viral response in the first year after initiating HAART. Kaplan-Meier probabilities at five years:

  • 11.0% for patients who achieved and maintained undetectable viral loads
  • 15.9% for patients who achieved undetectable concentrations but had a viral rebound
  • 51.5% for patients who never achieved undetectable concentrations
    Probability of Progression to New AIDS Event or Death, using Kaplan-Meier curves:
  • 22 times greater if average viral load was 100,000 or higher compare to 0 to 2.9 log (1000 copies)
  • 6.5 times if average viral load was 10,000 to 100,000, compared to 0 to 2.9 log
  • 3.3 times greater if average viral load was 1,000 to 10,000, compared to 0-2.9 log

Long term effect of therapy interruptions on average CD4+ counts and viral load

Over 2000 patients in the Swiss HIV Cohort study were analysed over four years to see how interruptions affected their CD4+ count and viral load over time [15]. They looked at patients who either took or did not take interruptions, after starting HAART in 1996/1997. After four years, researchers found that 64% had <400 copies/mL of viral load, but only 50% on patients who interrupted therapy had undetectable viral load compared to 82% of patients who did not interrupt therapy. Average CD4+ increased from 200 before therapy to 357. But again, CD4+ increased only to 300 in patients who interrupted therapy compared to 420 for patients who did not interrupt therapy. After four years patients who interrupted therapy were more likely to have less than 200 CD4+ and less likely to have greater than 500 CD4+, compared to patients who did not interrupt therapy. 47% of patients who did not interrupt therapy vs 24% who interrupted therapy had greater than 500 CD4s. CD4 counts remained below 200 in 6% of patients who did not interrupt therapy vs 29% of patients who interrupted therapy. These differences were all statistically significant.

References

  1. R. J. Ellis, S. Letendre, S. D. W. Frost et al - Dynamics of HIV Rebound in Cerebrospinal Fluid (CSF) after Interruption of Antiretroviral Therapy (ART). 9TH CROI Abstract 49

  2. R. W. Price, A. Nilsson, S. G. Deeks et al - Relationship of Cerebrospinal Fluid (CSF) White Blood Cells (WBCs) to CSF and Systemic HIV Infection: Cross-Sectional and Longitudinal Analysis. 9th CROI Abstract 62

  3. J. Martinez-Picado, S. D. W. Frost, S. Marfi et al - Viral Populations Emerging in Plasma during Sequential Structured Treatment Interruptions in Chronically HIV-Infected Individuals Are Genetically Distinct between Time-Points and Tissues. 9th CROI Abstract 50

  4. B. Joos, M. Fischer, A. Trkol1 et al - Long-Term Multicompartment Evolutionary Study of HIV-env in a Chronically HIV-Infected Patient before and during HAART Followed by 5 Structured Treatment Interruptions (STI). 9th CROI Abstract 531-M

  5. A. Trkola, H. Kuster, C. Ruprecht et al -The Role of Patient Virus Properties and Neutralizing Antibody Responses in Structured Treatment Interruption Therapy. 9th CROI Abstract 243-T

  6. J. D. Lundgren, S. Vella, L. Paddam et al - Interruption/Stopping Antiretroviral Therapy and the Risk of Clinical Disease: Results from the EuroSIDA Study. 9th CROI Abstract 48

  7. F. Lampe, M. A. Johnson, C. Loveday et al -Viral Rebound after Suppression with HAART: Experience from 237 People with Viral Load < 50 copies/mL Followed for up to 4.4 Years. 9th CROI Abstract 536-M

  8. L. Ruiz, E. Ribera, A. Bonjoch et al -Virological and Immunological Benefit of a Salvage Therapy that Includes Kaletra plus Fortovase Preceded or not by Antiretroviral Therapy Interruption (TI) in Advanced HIV-Infected Patients (6-Month-Follow-up). 9th CROI Abstract 421-W

  9. F. García, M. Plana, M. Brunet et al - Effect of Associating an Immunosuppressive Therapy (Mycophenolate Mofetil: MMF)+HAART during STI and Holding the MMF Drug after Definitive Interruption of HAART on Viral Replication. 9th CROI Abstract 534-M

  10. M. Plana, L. Lopalco, F. García et al -Effect of Associating a Cytostatic Drug+HAART and Holding the Cytostatic Drug after STI and a Definitive Interruption of HAART on HIV-1-Specific Immune Responses. 9th CROI Abstract 535-M

  11. J. Lisziewicz, J. Xu, J. Trocio et al - Control of Viral Load Rebound during Treatment Interruptions in Macaques with AIDS Induced by a Novel Topical DNA Immunization (DermaVir). 9th CROI Abstract 312-W

  12. E. Tryniszewska, M. G. Lewis, Z. Hel et al - Containment of Viral Rebound after Antiretroviral Therapy Suspension in Macaques Chronically Infected with SIV following Vaccination with NYVAC-SIV Recombinant Vaccines. 9th CROI Abstract 313-W

  13. D. Douek, J. Brenchley, M. Betts et al -HIV Preferentially Infects HIV-Specific CD4 T Cells. 9th CROI Abstract LB7

  14. M. Egger, B. Ledergerber, P. Grob et al - Viral Replication and Long-Term Clinical Progression in Patients Treated with Potent Antiretroviral Therapy. 9th CROI Abstract 471-M

  15. G. Kaufmann, L. Perrin, G. Pantaleo et al - CD4 T-Lymphocyte Recovery in Individuals with Advanced HIV-1 Infection Receiving Potent Antiretroviral Therapy for 4 Years: The Swiss HIV Cohort Study. 9th CROI Abstract LB8
HIV Treatment Bulletin Vol 3 No 3 April 2002

   

 

Analysis of cells from long term non-progressors points the way to using vaccines and STIs to restore immune response to HIV

Graham McKerrow, HIV i-Base

Dr Brigitte Autran, one of the world’s leading researchers into immune reconstitution with highly active antiretroviral therapy (HAART), told the 9th Conference on Retroviruses and Opportunistic Infections of the ground-breaking research that she and colleagues are conducting at the Hôpital Pitié-Salpêtrière in Paris [1]. She summarised current thinking on immune reconstitution and suggested how immunity to HIV might be enhanced so as to improve the treatment and control of infection.

Dr Autran, a professor at the University of Paris, observed that it is widely accepted that HAART, when initiated during chronic infection, leads to the restoration of both naïve and memory CD4+ and CD8+ T-cells. Nevertheless, immunity to HIV is not usually restored even with prolonged fully suppressive HAART. HIV-specific CD4+ T cells are lost early in infection and HIV-specific CTLs (cytotoxic lymphocytes) are not generated or are less effective because of the loss of CD4+ T cell help and – as a result of antiretroviral therapy – low levels of HIV antigen.

However, there is an exception to this: when therapy is started during acute infection HIV-specific CD4+ T cells are preserved and the development of HIV-specific CTLs is delayed, but they are still capable of responding.

“The most important thing is not only to reconstitute the numbers of cells but, obviously, to reconstitute the defences of the patient against opportunistic pathogens and against HIV itself,” Dr Autran told delegates. The reconstitution of the host’s defences during antiretroviral therapy (ART) is antigen-driven. With opportunistic pathogens, the load and antigen production is not directly influenced by HAART, she said, whereas HIV load and antigen production are reduced by HAART.

Dr Autran was one of the first scientists to describe the process of immune reconstitution with HAART [2]. She told a plenary of the Seattle conference: “What we can call a suppressive HAART, although we know it is not completely suppressive, has several drawbacks in the context of HIV-specific immunity mediated by CTLs; and if it is introduced in chronic infection it will reduce the levels of pre-existing CTLs.”

“Concerning HIV-specific CD4+ cells: if the treatment is introduced at the time of primary infection it is good for the system, it is preserving the number and function of these HIV-specific CD4+ cells. But when it is introduced at time of chronic infection the low level of HIV antigens will not be able to restimulate appropriate CD4+ cells against HIV and it will prevent their restoration.”

“So it is considered that the major factor responsible for these abnormalities in reconstitution is reduced exposure to HIV, despite — we know it is persisting — some viral replication in many tissues.”

“It is probable, also, that an inappropriate presentation of HIV antigens due to persistent alteration in the network of dendritic cells might play a role. But obviously the amount of antigen produced might represent a major factor limiting reconstitution of immunity.”

“So it became clear that we could very simply restimulate the immune system simply by re-presenting HIV antigens to the T cells and the simplest way to do that was to interrupt the treatment.”

Dr Autran said that a few years ago treatment holidays “seemed to work, a little bit at least” so more research was devoted to analysing the implications.

“We concluded that indeed it is feasible to boost immunity with structured treatment interruptions but, at least in the context of chronic infection, it might be extraordinarily difficult to maintain a good equilibrium between the numbers of HIV-specific CD8+ and CD4+ cells and the virus; while, perhaps, in the context of primary infection… it might be easier to restimulate appropriate T cell response to the virus, capable to control the virus and maintain a long time off therapy.”

“So we were looking for other strategies to restimulate the immune system and we felt that perhaps the virus itself could be aprogenic [immuno-stimulating] and that we should use some therapeutic immunisation programmes to restimulate the T cells while the patient was still on therapy and before interrupting the treatment.”

So, ‘suppressive’ HAART delays HIV-specific CTL in primary infection, and reduces pre-existing CTLs in chronic infection. It also preserves HIV-specific CD4+ T cells in primary infection and prevents their restoration in chronic stages. There is reduced exposure to HIV despite persistent minimal virus replication, and inappropriate exposure to HIV antigens is due to persistent alterations of dendritic cell defects.

The Paris researchers followed a cohort of 70 long-term non-progressors (LTNPs) for five years, evaluating viral and host factors and comparing them with other chronically infected individuals [3].

Dr Autran said: “We concluded that the CD4+ T helper 1 responses, as characterised both by their capacity to produce interferon gamma and also by their numbers of cells producing interferon gamma negatively correlates with the plasma HIV and the provirus HIV and this is independently of the CD4+ counts and of any genetic factors. In summary, it is not because those patients are genetically protected against virus replication that their CD4+ cells are also protected and it appears that those cells might play a direct, active control on virus replication.”

“The new thing,” she added, “is that antibodies might also play a role in the control of established infections.” The researchers measured the levels of antibodies and measured the isotypes in immunoglobulins, particularly IgG1 and IgG2 against any pathogens. Analysis found high levels of IgG2 in LTNPs only. IgG2 directed against gag and gp41 antigens depended on Th1 rather than Th2 function CD4+ cells.

It was found that the level in the plasma of the IgG2 directed against gag and gp41 was negatively associated with HIV viral load. Multivariate analysis found that only the combination of the Th1 response measured by the numbers and the IgG2 phenotype was significantly correlated to the maintenance of the LTNP status.

Dr Autran reported: “IgG2 against gp41 was associated with 100% capacity to remain LTNPing while having low Elispot response despite IgG2 [being] associated with a poor maintenance of the LTNP status. So, obviously this Th1 function is extremely important in the control of the virus.”

She said that the goal of therapeutic vaccination strategies should be that when used to treat people with either primary or chronic infection, they should boost immunity to HIV while people are on treatment and provide strong immunity to the virus when treatment is interrupted by controlling virus replication and thus prolonging the time the patient can be off therapy.

Several clinical trials in France and elsewhere in Europe have been started in the last three years to investigate safe, well tolerated therapeutic vaccines, Dr Autran reported. The French investigators are using canary pox virus, which is recombinant for gag, envelope, protease and part of the RT and Nef gene. They can stimulate both specific CTL and CD4+ T cells. Trials are looking at the use of canary pox alone in chronic infection, canary pox plus lipopetides plus IL-2 in chronic and primary infections, and VCP plus inactivated virus in primary infection. The methods used in the trials are the same: once the patients are undergoing HAART they have several immunisations followed by therapeutic interruptions.

Dr Autran said: “Inactivated virus particles will also be able to play a role by activating the Th1 cells, and perhaps, by a complex mechanism, activate CTLs.”

None of the trials have yet finished but Dr Autran reported “very encouraging” intermediary results in terms of immunogenicity. “We know that these vaccine approaches are truly capable of inducing strong CD4+ T cell responses of the Th1 phenotype directed against the various antigens present in the vaccines. The CD8+ cells are currently being evaluated and we are now designing new trials involving new vaccines for the coming years and this is done in the context of a huge international effort.”

References

  1. Autran B. Immune reconstitution and immunologic responses to antiretroviral therapies: implications for therapeutic strategies. Program and abstracts of the 9th Conference on Retroviruses and Opportunistic Infections; February 24-28, 2002; Seattle, Washington. Abstract L3.

  2. Autran B, Carcelain G, Li TS, et al. Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease. Science. 1997;277:112-116.

  3. Condotti D, Costagliola D, Joberty C, et al. Status of long-term asymptomatic HIV-1 infection correlates with viral load but not with viral replication properties and cell tropism. French ALT Study Group. J Med Virol. 1999;58:256-263.

A webcast of Dr Autran’s presentation with slides and further references is at:

http://63.126.3.84/2002/frame.htm

HIV Treatment Bulletin Vol 3 No 3 April 2002

   

Symposiumon T cell turnover and thymic function

By Ross Hewitt, MD for HIVandhepatitis.com

Why do CD4+ T cells decline over time in HIV infection? This very basic question generated a difference opinion among expert presenters at the symposium on T Cell Turnover and Thymic Function held at the 9th Annual Retrovirus Conference.

Viral and CD4+ T Cell turnover

David Ho led off the discussion by reviewing data collected over the past six years involving the dynamics of HIV replication and of both CD4+ and CD8+ T cells. Since the advent of potent antiretroviral (ARV) therapy, measurements have determined the half-life of an HIV virion to be only 30 minutes. Such techniques also have calculated the half-life of a productively infected CD4+ T cell to be approximately 1.5 days. So, if CD4+ T cells turnover so rapidly and vigorously, why does the CD4+ T cell count decline over time?

Models for T cell decline

The simplest model of what happens to T cells is that the total pool is contributed to with new T cells from several sources, such as the thymus and the bone marrow, and by proliferation of cells within the pool, and taken away by death or destruction of these cells. This simple model does not take into account that both CD4+ and CD8+ cells are at first naïve (not committed to a particular immune response target) and then become activated (committed to a target). So, the T cell pool must be split between both naïve and activated cells for CD4+ and CD8+ T cells alike. So, possible explanations for overall decline in T cells are: 1) fewer T cells are produced from the sources; 2) high rates of proliferation and death in HIV infection result in fewer T cells; and 3) T cells are destroyed at greater rates in HIV infection. Each presenter offered their unique take on these possible causes of T cell decline.

Perelson: CD4+ T cell decline is due to increased destruction

Alan Perelson, a collaborator of Dr. Ho, discussed results of experiments that used deuterated (“heavy”) glucose and measured its incorporation in the DNA of newly dividing, proliferating CD4+ and CD8+ T cells. His mathematical predictions assumed that the rate of new cells supplied by the sources and the rate of cell death or destruction was pretty much equal because CD4+ and CD8+ T cell counts do not change much over a short period of time. In HIV+ persons, the proliferation rates of CD4+ and CD8+ T cells were shown to be six-fold and eight-fold higher than in HIV negative persons. For CD4+ T cells, the source rate was four-fold higher while death rate was three-fold higher than in HIV-negative controls, but was unchanged for CD8+ T cells. He also noted that there is very rapid exchange between tissue compartments and the blood because labelled cells appear in the blood within 12 hours. After a year of HAART, a decrease of 50% in turnover occurs, practically normalizing turnover rates. He concluded that CD4+ T cell declines occur over time as a result of HIV destruction and not reduced sources since turnover is so high.

Kovacs: CD4+ T cell decline is due to increased destruction and decreased production

Joseph Kovacs presented data from another experimental technique to measure T cell turnover, incorporation of BrdU into the DNA of proliferating CD4+ and CD8+ T cells.

Like Dr.Perelson, he also found high turnover of both types of cells. He took his analysis one step further by studying whether the cells were naïve (or “resting”) or activated (“memory”). He found that the naïve cells were slowly proliferating and that the activated cells were rapidly proliferating.

Similar to Dr. Perelson, he found that HAART reduced the turnover of the activated cells but not the naïve cells. He also studied monocytes and found that while their rate of death or destruction was not affected by HIV infection or HAART, the source (bone marrow) was inhibited by HIV infection and improved with HAART.

He concluded that HIV destruction of CD4+ T cells could not account solely for the decline in these cells over time because the turnover is so high.

Miedema: CD4+ T cells decline due to increased destruction of naïve T cells

Frank Miedema offered a different perspective on the issue of the high T cell turnover that all of the presenters acknowledged did occur. His hypothesis is that the high T cell turnover had no direct relation to the issue of T cell decline over time. He noted that HIV infected cells express high levels of the activation marker Ki67. He studied a cohort of seroconverters over time and observed that people with lower CD4+ T cell counts prior to HIV infection have faster progression to AIDS, as do people with high immune activation.

Because naïve CD4+ T cells are activated as a result of HIV infection, he concluded that increased activation leads to increased consumption of naïve (resting) cells. Because naïve cells are the most difficult to regenerate, chronic activation will ultimately cause T cell depletion. This theory is further supported by the observed faster CD4 cell decline that occurs once a switch to syncytial inducing (SI) phenotype occurs. Such SI viruses, which predominately use CXCR4 as a co-receptor, are able to infect naïve resting cells as well as activated cells whereas non-syncytial inducing (NSI) viruses infect primarily activated cells.

He concluded that the natural pathway for the fate of a CD4+ or CD8+ T cell, thymus to naïve to activated (memory effector) to cell death, is accelerated because immune hyperactivation causes increased recruitment of naïve T cells along this pathway, resulting in T cell decline over time.

McClune: CD4+ T cells decline due to increased destruction and failure of compensatory mechanisms

Mike McClune offered the most unique perspective by reassessing what turnover experiments are actually measuring and then looked for other mechanisms to explain T cell decline.

Turnover experiments that assess the fractional changes in rates of turnover fail to take into consideration the size of the entire pool of cells. So while fractional rate of turnover is high, the total size of the cell pool is low and results in absolute turnover rates that are unchanged in HIV infection. The pool of naïve resting cells is maintained through division of progenitor cells.

In HIV infection, there is destruction of microenvironments for progenitor cell differentiation, namely in the bone marrow and the thymus. Surprisingly, the thymus is very abundant in some HIV+ adults (especially under age 39, with 350-500 CD4+ T cells) but thymic size is diminished in adults with late stage HIV disease.

Patients with an abundant thymus have enhanced T cell reconstitution upon treatment with HAART. This begs the question: Could the thymus be responsive to T cell loss and result in upregulation of T cell production? Two lines of evidence support this theory.

First, the cytokine IL-7, which is known to be important in thymic function, stimulates proliferation and inhibits apoptosis of lineage restricted progenitor cells. Levels of IL-7 rise when the CD4+ T cell count drops; IL-7 production is increased in lymph nodes in CD4+ T cell depleted patients; and the pre-HAART level of IL-7 predicts how high the CD4+ T count goes after HAART is administered.

Growth hormone also positively regulates T cell production. In five patients receiving growth hormone with HAART, all had an increase in thymic density and volume over six to 12 months. Growth hormone also increased the percentage of naïve circulating CD4+ T cells. He concluded that HIV causes accelerated destruction of T cells. Compensatory feedback pathways may help to sustain T cell counts but these pathways fail and T cells are not replaced. T cell decline over time occurs as a result of two sequential lesions: accelerated destruction of mature cells and then failure to regenerate.

Summary

So, why do CD4+ T cells decline over time in HIV infection? When looking again at the three possible explanations of reduced T cell production, high T cell turnover and increased T cell destruction, the data presented indicated that while turnover is high and probably the result of immune hyperactivation, turnover itself does not fully explain T cell decline.

HIV infection appears to result in hyperactivation, which results in increased rate of destruction of T cells. The lower T cell counts trigger feedback mechanisms which themselves become damaged by HIV infection and supply of new T cells dwindles resulting in overall decline of T cell counts over time. An important lesson from the session appeared to be that unless experiments directly measure the phenomenon in question, experiments that measure surrogate or indirect phenomenon depend upon assumptions about the relation to the phenomenon in question which may ultimately be incorrect and lead to erroneous interpretation.

Copyright 2002 by HIV and Hepatitis.com. All Rights Reserved.

HIV Treatment Bulletin Vol 3 No 3 April 2002

   

Newdrugs: perhaps some genuine excitement this time

Graham Moyle, MD, MBBS, Chelsea & Westminster Hospital, London, for NATAP

For the first time in a number of years the majority of presentations in the new drugs session at the Retrovirus conference focused on genuinely novel compounds. Several companies have lead compounds with adequate pharmacological characteristics and in some cases demonstrated short-term clinical activity focusing on the novel targets of viral integration and viral entry. Additionally in more advanced development are compounds from currently available drug classes which have genuine activity in people with HIV infection against viruses with significant resistance to currently approved drugs within those drug classes.

NNRTIs

Two second generation non-nucleoside reverse transcriptase inhibitors (NNRTIs) reported clinical trials data. The more novel of these compounds from Tibotec is TMC 125. In a short-term study in treatment naive individuals previously presented, this agent demonstrated reductions in viral load of around 2 log in seven days. The study presented at this meeting was a proof of concept study to test drug activity in individuals with virus resistant to efavirenz and nevirapine. In vitro panels (test tube studies) demonstrate that virus with greater than 100-fold shifts in sensitivity [resistance] to efavirenz have generally less than 10-fold and often less than four-fold shifts in sensitivity to TMC 125. Specifically viruses with mutations typically selected for by nevirapine and efavirenz remain sensitive to TMC 125. However, resistance to this drug can be observed in the presence of multiple non-nucleoside binding site mutations.

The study evaluated 16 HIV-infected male individuals with viral load detectable above 2000 copies/mL while receiving triple drug regimens containing either efavirenz or nevirapine. Individuals were required to have virus with shifts in sensitivity of greater than 10-fold to efavirenz or nevirapine as assessed by Virco’s Antivirogram. The median baseline characteristics included CD4 cell count of 389 cells/mm3 and viral load of 10,753 copies/mL. The median fold change in sensitivity to efavirenz and nevirapine was greater than 100-fold whereas changes in sensitivity to TMC 125 range from <1 to 8.3-fold with the median of a 2.6-fold shift in sensitivity. The study included individuals who had single, double and triple mutations typically associated with non-nucleoside resistance. Patients entering the study discontinued the NNRTIs which they were failing substituting TMC 125 at baseline. Patients were then followed for eight days before being offered a new regimen. Viral load fell rapidly with all patients at day eight having viral load below baseline values and the median change in viral load of -0.89 log. The majority (75 percent) of participants had a viral load declined of at least 0.5 log. Only one patient discontinued, this was due to non-adherence. No grade three or four adverse events were reported, the most common adverse events being diarrhoea and headache. This agent is now advancing to larger phase 2 and phase 3 studies.

A second non-nucleoside currently in phase 2 clinical development is DPC-083, an agent related to efavirenz. This drug has an elimination half life approaching 100 hours and in vitro has less than ten-fold shifts in sensitivity in the presence of virus resistant to efavirenz and nevirapine with single and some double codon substitutions. Data from a phase 2 study evaluated 100 and 200 mg of this agent in 51 individuals failing nevirapine or efavirenz was reported. Baseline genotypes in these patients included individuals with both single and double mutations including at codon is 101 (44 percent), 103 (52 percent), 181 (17 percent), and 190 (25 percent). Patients discontinued their failing NNRTI and when available changed NRTIs, although 10 individuals did not change nucleoside analogues and 17 individuals only changed a single nucleoside analogue.

Individuals who did not change nucleoside analogues responded less well to DPC-083. Whilst 72 percent and 67 percent of individuals changing one or two nucleoside analogues, respectively, achieved viral load less than 400 copies/ml, only 40 percent of individuals who did not modify nucleoside responded.

Adverse events included central nervous system effects similar to those reported with efavirenz, and skin rash which was only seen in the 100 mg population. A second study of this agent in treatment naive individuals in combination with ZDV/3TC provided comparative data across different doses of DPC-083 and efavirenz. The study compared groups of around 30 treatment naive individuals who received either DPC 083 at doses of 50, 100, and 200 mg per day compared with standard 600 mg dosing of efavirenz. Baseline characteristics included viral load of 4.52 (33,000) log copies/ml and CD4 of 402 cells/mm3. Response rates as assessed by ITT non completer = failure analysis did not demonstrate differences between treatment groups with between 65 and 72 percent of individuals having a viral load less than 50 copies at week 16. This is unlikely to represent peak response. Adverse events leading to discontinuation were most common in the 200 mg DPC-083 dosing group, with 20 percent of individuals discontinuing predominantly due to skin rash. Discontinuation rates for efavirenz were 15%, and 12% with 100 mg DPC-083. Central nervous system effects appeared less common amongst individuals receiving DPC-083 at least at the 50 and 100 mg dosing groups relative to efavirenz. For example, dizziness was reported in 30 percent of efavirenz recipients but only 4 percent of 100 mg DPC-083 recipients. Based on these results the 100 mg dose is the likely candidate dose for further development of this product.

Protease inhibitors

The conference also saw new information presented with regards to candidate agents from the protease inhibitor class. The drugs of most interest in this regard are atazanavir and tipranavir.

Atazanavir

Atazanavir is a two pills once a day agent which in studies in naive populations has indicated efficacy at least as good as nelfinavir with an absence of lipid disturbances. This conference saw a presentation addressing the potential for this agent in individuals with a history of prior protease inhibitor use. The study compared the dual PI combination of atazanavir 400 or 600mg QD plus saquinavir soft gel (1200 mg QD) to saquinavir / ritonavir each dosed at 400 mg BID plus two nucleoside analogue RTIs.. Atazanavir is known to boost saquinavir exposures, and the dose of saquinavir chosen for the study was based on pharmacokinetic data.

The study randomised 85 individuals with prior protease inhibitor experience and viral loads between 1000 and 100,000 copies/mL and CD4+ T cell counts >100/mm3. Discontinuations for adverse events were most common in the ritonavir/saquinavir group (30 percent) compared with the atazanavir dosing groups (9 -11 percent). Viral load as a proportion of individuals less than 50 or less than 400 copies/mL were not reported. The mean change in viral load at week 48 was -1.44 log, -1.19 log and -1.66 log in the atazanavir 400 mg, 600 mg and saquinavir/ritonavir dosing groups. Changes in total cholesterol, HDL cholesterol and fasting triglycerides significantly favoured the atazanavir/saquinavir dosing group. Analysis by baseline genotypes and response were not reported. Pharmacokinetic data were also not reported. There remain a number of gaps in our knowledge about atazanavir. Studies in naive individuals evaluating its relative efficacy to standard of care agents such as efavirenz are currently ongoing.

More information about the clinical utility of atazanavir on specific viral genotypes are required before the agent can be confidently used in PI experienced individuals. Although this agent has advantages with regards to metabolic disturbances relative to other protease inhibitors, the most common adverse event is increases in indirect bilirubin which in a small proportion of individuals lead to clinical jaundice. This adverse event is typically seen in individuals with a specific genetic variation and availability of a test to select out those individuals at greatest risk of hyperbilirubinaemia would help eliminate the principal obstacle to use of this drug. Wider availability of atazanavir is expected over the course of this year. A patient expanded access program is being planned.

Tipranavir

Tipranavir is a new protease inhibitor currently in phase 2b/3 clinical development. It has a different chemical structure to currently available protease inhibitors. The drug has a number of formulation and pharmacokinetic issues and the final development dose is currently still under investigation. Due to extensive first-pass metabolism, tipranavir will require boosting with ritonavir. Data reported at this meeting evaluated tipranavir 500 or 1000 mg BID plus ritonavir 100 or 200mg BID in 41 individuals who had previously received currently approved protease inhibitors. Response was reported by baseline genotype and the number of mutations to approved PIs present at entry. Individuals with less than five baseline protease mutations experienced reductions in viral load of -2.21, -2.39 and -2.10 log at weeks 24, 48 and 80, respectively. Corresponding response is for individuals with more than five protease mutations were -2.37, -2.24, and -1.52 log. Specifically the presence of mutations known to affect approved protease inhibitors such as positions 82, 84 and 90 did not influence virological response to tipranavir. The data indicate that tipranavir is active against viruses with diminished susceptibility to currently approved protease inhibitors. Formulation issues must now be urgently addressed with tipranavir to enable its potential as a salvage drug in persons resistant to currently available protease inhibitors can be fulfilled.

Nucleoside analogues

Identification of several new candidates in the nucleoside analogue drug class were reported. Drugs from this class remain the backbone of HAART regimens although concerns exist regarding the potential of some of these drugs to trigger a range of toxicities particularly through inhibition of mitochondrial DNA polymerase gamma. Data with DPC 817 was reported. This agent demonstrated in vitro activity against viruses with resistance to ZDV and 3TC and with as many as 10 nucleoside analogue mutations. However this agent appeared to have diminished activity in the presence of the 151M and the 69S insertion multidrug resistance viral genotypes. Information on the potential of this drug to inhibit mitochondrial DNA polymerase gamma and other human DNA polymerase is what is not reported. However, animal and in vitro toxicity data have led to the discontinuation of this agent’s development.

Researchers responsible for the discovery of 3TC at Shire Biochem reported the anti-viral activity of a new nucleoside analogue known as BCH13520. This drug appears active against viral strains with phenotypic resistance to ZDV and/or 3TC although larger shifts in sensitivity were reported in the presence of 151M (20-fold) or 69 SS insertion (4.4-fold) multidrug resistant viruses. Selection experiments with this agent suggested it may select mutations at positions 75 and 65 although novel mutations including some in the NNRTIs minding region were also described. This agent appears to remain some distance from human clinical development.

Entry inhibitors

Several targets for inhibition of HIV early in its life cycle are being investigated. These include molecules which affect viral attachment to CD4 and to co-receptors and drugs which affect the fusion process. The drug in most advanced development in this regard is T20. This agent is an injectable fusion inhibitor currently requiring twice daily subcutaneous dosing. The study reported included 71 PI-experienced patients randomised to three T20 doses (50 mg BID n=16, 75 mg BID n=20, 100 mg BID n=16 plus a fixed regimen of abacavir 300 mg BID, amprenavir 1200 mg BID and ritonavir 200 mg BID, and efavirenz 600 mg qd). The comparator group (n=19) received only the fixed antiretroviral regimen.

A dose dependent treatment effect was observed. Patients in the control group experienced a viral load reduction of -1.87 whereas reductions of -2.10, -2.62, and -2.39 log were observed in the 50, 75 and 100 mg T20 dosing groups. By ITT analysis, the percentage of patients reaching <400 copies/mL was 37% (7/19) in the control arm and 55% (28/51) in the combined T20 group and for patients reaching <50 copies/mL was 37% (7/19) in control and 47% (24/51) in the combined T20 group.

At week 48, the observed median CD4 + T cell increase was +90/mm3 in the control group and +92, +147, +124/mm3 in the 3 T20 groups. Adverse events attributable to T- 20 were limited to injection site reactions with no adverse laboratory or clinical events observed. The data support the need for the urgent introduction of T20 for use in the salvage setting.

Other agents with oral bioavailability, acting at different sites of virus attachment or entry were also reported during the conference. Many of these drugs are entering phase I human studies or phase 2 studies where proof of principal will be demonstrated or not in HIV-infected individuals. Schering Plough are investigating a series of drugs which are antagonists of the CCR5 co-receptor. The development names for these drugs are SCH C and D. SCH C is active in vitro in the nMol range and has demonstrated oral bioavailability in healthy volunteers. A small phase 2 study of 12 HIV positive individuals not currently receiving antiretroviral therapy and with CD4 cell counts about 250/mm3 was reported. Patients were given 25 mg of SCH see every 12 hours for 10 days. No important adverse events were reported during the study. Pharmacokinetic data indicated that trough values of 90 nMol were achieved, into the estimated therapeutic range. A lag time before reductions in viral load began was noted, such that no change in viral load occurred in the group before Day 3. After that time, declines in the mean maximal viral load at day 10 of dosing was approximately 0.7 log with 10 of 12 individuals experiencing a reduction in viral load of at least 0.5 log. After treatment cessation viral load was noted to only gradually return to baseline suggesting a residual affect. It is not clear whether this agent will go forward in clinical development although a dose finding study at doses of 200 mg of this agent was reported to be ongoing. Concern has been expressed regarding prolongation of the QT interval (on EKG) observed in healthy volunteers given single doses of 600 mg or multiple doses of 400 mg per day of this agent. This study however provides an excellent proof of concept that the CCR5 receptor antagonists represent candidates for clinical evaluation.

An inhibitor of CXCR4 inhibitor known as AMD 3100 also reported proof of concept data. This drug has now been discontinued. The study involved ten-day continuous infusion is of this inhibitor into 40 individuals at a range of doses. Reductions in viral load were observed in some subjects in the study the most impressive responses were observed in individuals with SI virus, the strain that uses the CXCR4 receptor. In some cases individuals with mixed populations of SI and NSI virus experienced disappearance of SI virus during the infusion period. CXCR4 antagonists, are not currently commercially available. These data therefore provide a starting point for further investigation of the potential of drugs in this class.

Bristol-Myer Squibb reported the identification of an entry inhibitor class with activity in vitro against a wide range of HIV strains with activity in the nanomolar range. The activity of this agent appears to relate to binding to surface by HIV in the in the GP41 or GP120 region. Passage of virus in the presence of this drug can select for mutations in either GP41 or GP120 at or near where the virus binds to CD4. Importantly the drug does not appear to be highly protein bound and has demonstrated viral bioavailability in rats, dogs and monkeys. Bioavailability in the primates was in the range of 25 to 30 percent and may be considered the best guide to future bioavailability in the humans. This drug is now poised to undergo safety and bioavailability evaluations in healthy human volunteers before proceeding studies in people with HIV infection.

Integrase inhibitors

Both Merck and Shionogi/GlaxoSmithKline have reported integrase inhibitors which are small molecular weight compounds with the potential for oral administration. The Shionogi compounds have entered clinical development. The lead compound is currently known as S-1360. These drugs are of the same chemical class and may select for similar mutations within the integrase genome. S-1360 demonstrates activity in a high nanomolar range and has an acceptable preclinical safety and animal pharmacokinetic profile to warrant clinical investigation. This drug is now entering into phase I/II activity studies. No new information on the Merck integrase inhibitors were presented during the conference.

Conclusions

There appears to be a wealth of new drugs in development for people with HIV infection. These agents include genuinely novel members of currently approved drug classes, which appear to have activity against many of the viruses commonly selected for by current agents. Several of these drugs have demonstrated short term evidence of their activity in both treatment naive and treatment experienced individuals including those with documented resistance to currently approved agents. Additionally agents from a range of new drug classes are poised to enter clinical development or are currently in early phase clinical development promising a range of different drugs to help manage individuals who cannot establish adequate viral control on the currently available drugs.

HIV Treatment Bulletin Vol 3 No 3 April 2002

   

T20 and beyond: Inhibition of HIV attachment and fusion at the 9th CROI

Christopher D. Pilcher, M.D. UNC at Chapel Hill Center for AIDS Research for NATAP

The need for new drug classes

One of the chief obstacles currently facing patients with previous heavy treatment experience is the fact that all available agents work in similar ways, interfering in one way or another with one of two viral enzymes: HIV reverse transcriptase (RT) — which the virus uses to replicate itself within the cell, and HIV protease — which the virus uses to package itself for export out of an infected cell, to begin new rounds of destruction. The similar modes of action mean that when the virus adapts to one drug’s presence by developing genetic resistance mutations, these mutations can impair the activity of some or all of the other drugs in that drug class (a phenomenon called “cross-resistance”). As resistance mutations accumulate, patients’ future treatment options quickly shrink.

In contrast to RT and protease, the processes by which the virus mounts its initial assault on the cell membrane (virus entry) are not assailable by any current drugs. For this reason, treatments targeting these points in the viral life cycle would be expected to have excellent activity against even highly protease or RT inhibitor-resistant strains of HIV. At this time last year, there was a widespread enthusiasm concerning developments in the quest to develop medicines targeting viral entry. At the 9th Conference, the difficulties of moving these compounds forward have become more apparent and the celebration has become muted.

Virus entry: Attachment, then fusion

The events of virus entry into cells occur in several steps: the first step in the HIV-cell interaction that leads to virus entry is “attachment”, followed by “fusion” that is necessary for entry into the cell: The virus’ gp120 surface molecule fits into the CD4 receptor on the cell surface like a key in a lock and the virus becomes attached, but is left hanging loosely from the cell surface by this gp120-CD4 connection.

Once it is attached, gp120 is bound to another receptor (either one of the “co-receptors” for gp120, called CCR5 or CXCR4). Thus doubly bound, the gp120 molecule flips around to expose HIV’s previously hidden “harpoon” molecule, gp41.

Once the free end of gp41 spears the cell membrane, solidifying HIV’s attachment, gp41 doubles itself up into a tight coiled-coil structure. This brings the two ends of gp41 (one holding HIV, and one holding the cell membrane) very close together. The cell membrane and virus envelope come into contact and fuse. Fusion results in the virus’ contents getting dumped into the interior of the cell. Virus 1, Cell 0.

Potential advantages to entry inhibitors

It is important to remember that all of these processes occur on the cell surface, so that drugs targeting them can work “outside the cell” without any requirement for intracellular accumulation or metabolism. It is thus possible that entry inhibitors could evade possible “cellular resistance”. Different from viral resistance, cellular resistance can occur when host cells perceive drugs as toxins and adapt by pumping them quickly back out into the extracellular space. This has been proposed as one potential explanation for why potent HAART sometimes fails to control virus replication in patients, and might thus represent a potential additional advantage to using entry inhibitors.

It is also likely that “synergy” could be seen among the different classes of molecules targeting HIV entry when used together. As first explained by Robert Doms at last year’s Retrovirus conference, by delaying the process of attachment and fusion, coreceptor or CD4 antagonists can keep the uncoiled gp41 molecule exposed for longer than normal-opening up this target to attack by gp41 blockers like T20 or T1249. This provides a theoretical basis for hope that an even higher level of potency can be obtained by fusion and entry inhibitors in the future, and that these so far troubled drugs may have an important place in HIV treatment.

Potential hazards

Researchers have traditionally been wary of any drugs blocking CCR5 in particular because although viruses usually start by using CCR5 preferentially, they tend to mutate to use CXCR4 around the time of the onset of clinical AIDS. The fear has been that by purposely blocking CCR5 use, the so-called “X4 switch” could be induced and patients hastened on the road to AIDS. At least in the few mice and humans treated with CCR5-blocking drugs so far, this has not been shown to happen, but remains a central concern.

There are other unanswered questions about general safety for coreceptor (CCR5 and CXCR4) blockers. Coreceptors themselves are extremely common on the surfaces of all kinds of cells in the body, not just infected cells, but healthy cells. They may play key roles in embryogenesis and proper immune function as well as numerous other body processes. The consequences of blocking these receptors for the body are not known and an extra note of caution is probably warranted (see notes on SCH-C, below).

Fusion inhibitors: T20 and T1249

For inhibitors of fusion such as T20 and T1249, no such general safety concerns have been forwarded. These compounds are protein molecules (T20 has 36 amino acids) that basically bind to gp41 and prevent it from coiling up to reel the cell and virus together-preventing fusion. With T20 nearing completion of its phase III development and T1249 showing no red flags in phase II, the availability of these drugs to patients sometime soon seems likely. And although both agents have shown significant activity with little evidence of systemic toxicity in clinical trials to date, they are seriously limited by the fact that they are large peptides that cannot be absorbed from the gut. They must therefore be injected (twice daily) and can result in sometimes troubling injection site reactions.

In a 48 week update of T20-206 [1] a study comparing abacavir, ritonavir-boosted amprenavir and efavirenz to the same regimen + three separate doses of T20 in a total of 71 patients failing PIs at baseline, Roche-Trimeris presented data confirming previous impressions. Over 48 weeks, approximately 70% of subjects across T20 arms experienced injection site reactions. Of the subjects with reactions, about half in each T20 arm reported that these were mild; half reported at least some that were moderate in severity or worse (only 3 of 54 T20 treated patients discontinued the drug as a result). So while the tolerability of long term T20 for widespread clinical use is an open question, there were still no notable differences in systemic toxicity between the T20 and no-T20 groups over the full 48 weeks of T20-206, and activity of the combinations with or without T20 reported last year at 16 weeks, slightly favouring the T20 arms, appeared sustained over 48 weeks.

Attachment inhibitors

Focus at this year’s conference shifted to the progress in clinical development of two candidate attachment inhibitors that block the attachment of HIV gp120 to CCR5 or CXCR4. These were first introduced to a general audience at last year’s conference: Schering-Plough’s SCH-C and AMD-3100 from AnorMed.

CCCR5: SCH-C toxicity

Unlike most other attachment and entry inhibitors, SCH-C is a small molecule that has excellent absorption from the gut (60-90% bioavailability), low protein binding and a prolonged effect after ingestion (~25 hours) in addition to potent antiviral properties. SCH-C had previously shown potent activity in its first phase I trial but had also been noted to cause significant QT prolongation (an electrocardiographic abnormality that, when extreme, can herald life-threatening cardiac arrhythmias). In an oral session on Monday [2], M. Laughlin from the Aaron Diamond AIDS Research Center presented detailed results of another phase I experiment in using a range of lower doses of the drug that was somewhat if not entirely reassuring. The doses tested delivered 25 to 200 mg every 12 hours (as compared to the 400mg/day that was toxic in the first trial) to 12 ART-naive patients with NSI or CCR5 using virus. Treatment was monotherapy. Laughlin reported data on the initial low dose group (25 mg). Activity was potent over 10 days with 10/12 patients achieving a 0.5 log (three-fold) drop in viral load and 4/12 dropping more than 1.0 log, or 10-fold. Two patients had no response at all, for reasons that were not clear. Tolerability was better than at higher doses, however three patients had headache and two complained of bad taste. Most significantly, there was consistent and progressive QT prolongation, to a mean of 11 msec at 10 days of therapy. While this degree of prolongation did not cause the trial to be prematurely terminated for safety, it is clinically meaningful and might represent a serious problem for this particular drug to go forward. These results were taken to indicate that CCR5 is a “valid target” for inhibition; however the potential safety concerns remain very troubling and are very likely to limit progress of this particular compound.

Another CCR5 blocker named PRO140 is an antibody molecule that specifically targets CCR5, and showed impressive activity in a mouse model; some Merck compounds are also undergoing preclinical development and the results of these studies will be the subject of future meetings.

CXCR-4: AMD-3100 stumbles

Among the CXCR4 inhibitors, the granddaddy of compounds is AnorMed’s AMD3100, a bicyclam compound that had appeared highly potent in pre-clinical studies but like T20, has to be given by either subcutaneous or intravenous injection. In a poster presentation [3], Hendrix and colleagues presented data from a trial in which 40 subjects with stable or no ART were treated in a dose-ranging study to a maximum dose of 160 mcg/day. Antiviral effect was minimal, with no patients reaching the 1.0 log drop definition of successful activity and only five having a greater than 0.5 log drop. Despite this, side effects were significant with a majority of patients in all cohorts developing numbness or tingling, atrial and ventricular arrhythmias; two developed low platelet counts. The trial was stopped early and the drug is not likely to move forward in its current formulation.

A number of surprising studies showed that predictions as to how viruses might adapt to attachment inhibitors may be wrong. For instance, Xu and colleagues [4] presented evidence that laboratory viruses that evolve high-level resistance to SCH-C in cell cultures are not associated with a switch to CXCR4, but rather simply attach more firmly to CCR5. The possible results of this kind of adaptation on disease course are completely unknown. In another poster, Van Rij and colleagues from the Netherlands [5] showed that CXCR-4-using “SI” variants that occurred naturally in a patient with AIDS were actually less sensitive than earlier viruses from the same patient that could use both CXCR-4 and CCR5. This may suggest that even CXCR4 inhibitors could lead to an “X4 switch”-a somewhat scary possibility if these were to be used in patients with early infection. All in all, the 1st generation of attachment inhibitors have not fared very well in their early trials, and the future of both CCR5 and CXCR4 inhibition remain clouded by doubt.

Other candidate entry inhibitors

The “holy grail” of entry inhibition is the search for small molecule entry inhibitors that may be given orally. For now, clinicians are trying to figure out ways that injectable fusion and entry inhibitors may be used for instance as part of “deep salvage” therapy for treatment experienced patients, “induction” therapy for treatment naive patients, or in eradication protocols. If “cellular resistance” proves to be important as some people think (with cells actively pumping drug out of the interior), then drugs working on the outside of the cell may ultimately be critical tools in our armamentarium. Interest in attachment and fusion inhibitors appears to be here to stay.

References

  1. J. Lalezari, E. DeJesus, D. Northfelt et al - A Week 48 Assessment of a Randomized, Controlled, Open-Label Phase II Trial (T20-206) Evaluating 3 Doses of T-20 in PI-Experienced, NNRTI-Naïve Patients Infected with HIV-1. 9th CROI ABSTRACT 418-W

  2. J. Reynes, R. Rouzier, T. Kanouni et al - SCH C: Safety and Antiviral Effects of a CCR5 Receptor Antagonist in HIV-1- Infected Subjects. 9th CROI ABSTRACT 1

  3. C. Hendrix, A. C. Collier, M. Lederman et al - AMD-3100 CXCR4 Receptor Blocker Fails to Reduce HIV Viral Load by > 1 Log following 10-Day Continuous Infusion. 9th CROI ABSTRACT 391-T

  4. S. Xu, L. Wojcik, and J. Strizki - Antagonism of the CCR5 Receptor by SCH-C Leads to Elevated beta-Chemokine Levels and Receptor Expression in Chronically Treated PBMC Cultures. 9th CROI ABSTRACT 398-T

  5. C. Boggiano and S. E. Blondelle - Identification of HIV-1 Fusion Inhibitors Derived from Synthetic Combinatorial Peptide Libraries. 9th CROI ABSTRACT 394-T
HIV Treatment Bulletin Vol 3 No 3 April 2002

   

Pharmacogenetics predict abacavir hypersensitivity

In a demonstration of the potential clinical applications of recent progress in pharmacogenetics, two research teams have separately identified a genetic marker that may predict which HIV-infected patients are at risk of a hypersensitivity reaction to abacavir [Ziagen].

Patients with the HLA-B*5701 allele were more than 100 times more likely to experience a hypersensitivity reaction when treated with abacavir, a potent HIV-1 nucleoside reverse transcriptase inhibitor, according to lead investigator Dr. Simon Mallal, of the Royal Perth Hospital in Australia, who presented the first report at the 9th Conference on Retroviruses and Opportunistic Infections. Dr. Mallal’s study is also published in the March 2nd issue of The Lancet.

The Australian researchers evaluated data for 581 participants in the Western Australian HIV Cohort Study. Of these patients, 200 were treated with abacavir.

In general, “about 5% of patients treated with abacavir develop a severe, potentially life-threatening hypersensitivity reaction,” Dr. Mallal explained to conference participants. The prevalence ranges from 0% to 14%, and symptoms usually develop within the first six weeks of treatment. His team hypothesized that there may be a genetic basis for this hypersensitivity.

Eighteen of the 200 Australian patients developed abacavir hypersensitivity. The results of MHC region typing indicated that HLA-B*5701 was present in 14 of these 18 patients (78%). However, four of the 167 patients (2.3%) considered to be abacavir-tolerant also had this allele.

Furthermore, the HLA-DR7 and HLA-DQ3 combination was identified in 13 (72%) hypersensitive and in five (3%) abacavir-tolerant patients. Overall, 13 (72%) hypersensitive patients had the HLA-B*5701, HLA-DR7, HLA-DQ3 combination.

“All patients with the full haplotype had abacavir hypersensitivity,” Dr. Mallal told conference participants. He estimates that avoiding abacavir therapy in patients with this haplotype could significantly reduce the development of this potentially life-threatening drug reaction from 9% to 2.5% in his patient population.

Based on these findings, “we have now changed our clinical practice,” he continued. At his clinic, they now plan to withhold abacavir from patients with the HLA-B*5701, -DR7, -DQ3 haplotype. However, he cautioned that the current findings are not yet generally applicable. The patients he studied were all Caucasians, and the findings may not apply to patients of other races or to patients having a different genetic make-up.

Dr. Mallal is also concerned that the findings, if misinterpreted, “may do more harm than good.” Specifically, he cautioned that this is not yet a diagnostic test to confirm hypersensitivity, as testing for the haplotype was only 72% sensitive.

Also, “four out of the 18 hypersensitive patients developed classical abacavir hypersensitivity, but did not have the haplotypes.” Therefore, anyone who develops signs of abacavir sensitivity should stop the drug immediately.

“A negative test for the haplotype must not be used as evidence to rechallenge a patient” who shows signs of abacavir hypersensitivity, he added.

The second presentation, by Dr. Seth Hetherington, of GlaxoSmithKline of Research Triangle Park, North Carolina, involved a retrospective case-control study. This proof-of-principle study evaluated HIV-infected patients for polymorphisms associated with abacavir hypersensitivity. Data were available for 200 patients from whom allele frequencies for 114 candidate gene markers were analysed.

The cohort consisted primarily of men (92%) and caucasians (74%). Dr. Hetherington’s group found that 85 subjects developed abacavir sensitivity, while 115 (controls) did not.

Several polymorphisms within the HLA region were identified that were associated with susceptibility to hypersensitivity. Of the markers evaluated thus far, they found that the HLA-B57 gene allele was most highly associated with the reaction. In the 197 subjects with available data, HLA-B57 was present in 39 of 84 patients who developed hypersensitivity reactions (46%) compared with 4 of 113 controls (3.5%).

“These findings demonstrate the potential of pharmacogenetics in selecting drug treatment and improving treatment response,” Dr. Hetherington told conference participants.

He too cautioned that these findings may not necessarily apply to other patient populations. For example, there were a few cases of abacavir hypersensitivity in black patients who did not have the marker. Also, other genetic factors cannot be ruled out as causing or contributing to hypersensitivity.

Abacavir sensitivity usually starts with severe GI symptoms, followed by fever, rash, shortness of breath and myalgia, Dr. Mallal said. About 50% of hypersensitive patients begin to get symptoms by day 11.

Discontinuation of the drug reverses symptoms. However, without discontinuation, symptoms increase over time and the condition can be fatal. Rechallenge with abacavir can be especially dangerous, Dr. Mallal pointed out, because second reactions are usually more severe and more rapid.

References

S Hetherington and others (GlaxoSmithKline, Research Triangle Park, NC). HLA-B57 and TNF-alpha Variants Associated with Hypersensitivity Reactions to Abacavir among HIV-1 Positive Subjects. Abstract 92 (oral).

S Mallal and others (Center for Clinical Immunology and Biomedical Statistics, Royal Perth Hospital; Royal Perth Hospital; and University of Western Australia). The Presense of HLA-B 5701, -DRB1 and -DQ3 is Highly Predictive of Hypersensitivity to the HIV Reverse Transcriptase Inhibitor Abacavir. Abstract 91 (oral).

S Mallal and others. The Presense of HLA-B 5701, -DRB1 and -DQ3 is Highly Predictive of Hypersensitivity to the HIV reverse Transcriptase Inhibitor Abacavir. The Lancet. 359: 727-732. March 2, 2002.
HIV Treatment Bulletin Vol 3 No 3 April 2002

   

Pregnancy: growing body of evidence supports treating maternal disease

Polly Clayden, HIV I-Base

The 9th CROI provided an impressive volume of research into maternal/child health and managing pregnancy and mother to child transmission (MTCT) across a diverse range of access levels and resources (we will also include reports on paediatrics and women-specific research in the next issue of HTB). For those living in countries with access to treatment, the body of data continues to grow supporting the treatment of maternal disease, appropriately with fully suppressive therapy, to offer the best outcome to mother and baby.

As part of a symposium entitled ‘Controversies in Antiretroviral Therapy’, Judith Currier gave an overview of the state-of the-art ‘Challenges to managing antiretroviral therapy during pregnancy’ [1]. She began by reminding us that HIV continues to have a major impact on women of childbearing age worldwide, and explained that the “need to treat a woman for her HIV infection both in the short term and over the course of her lifetime, must be balanced with the goals of preventing infection”. Globally however only a small fraction of women with HIV have access to treatment and the primary use of antiretrovirals in settings where they are available has been for prevention of transmission and not for maternal benefit. Dr Catherine Wilfert from the Elizabeth Glaser Pediatric AIDS Foundation made this the subject of her plenary talk in which she outlined the programmes that this organisation have sponsored in Africa [2]. She spoke encouragingly of the work emphasising that prevention of MTCT should be the “…gateway to international care and support to entire families” and that “health of mothers needs to be optimal to enhance their lives and provide the best care for their children.”

Dr Currier also stressed that efforts to expand access to triple therapy must include provision of this treatment to pregnant women worldwide. Within settings with access to antiretrovirals she summarised the goals of care as: an uncomplicated pregnancy, a healthy uninfected baby and a healthy mother who has not compromised her future treatments for the management of her own disease.

Antiretroviral use during pregnancy

Enormous progress has been made since reduction of transmission from 25% to 8.3% using ZDV monotherapy prophylaxis and caesarean section was demonstrated in the 1994 076 trial [3]. Today since the introduction of potent HAART this rate has dropped to less than 2% [4, 5].

Two posters evaluated the pharmacokinetics of protease inhibitors used in pregnancy. Scott and colleagues from the PACTG 354 team looked at ritonavir in combination with ZDV and 3TC [6]. They found a dose of 600mg BID to provide therapeutic maternal levels at delivery but the drug was poorly tolerated and this would certainly be an unlikely combination to use in real life clinical practice.

Bryson and colleagues studied the PK of nelfinavir in combination with ZDV and 3TC. This drug has been used quite widely in pregnancy [7]. Anecdotally it appears that the gastrointestinal changes that occur in pregnant women may make this drug more tolerable as far as nelfinavir-induced diarrhoea is concerned, compared to non-pregnant patients [8]. The investigators reported that a dose of 750mg TID failed to reach optimal levels (only 3/9 women achieved the target AUC), and that a dose of 1250 BID met target AUC in 14/17 women. They also reported suboptimal levels in 5/18 (28%) of infants at a 40mg/kg BID dose.

The importance of reporting any adverse events associated with antiretroviral use was stressed in a presentation from Dr Markus describing the FDA’s Adverse Event Reporting System (AERS) [9]. Following a report to the FDA from BMS in November 2000 of two maternal and one infant death due to lactic acidosis that occurred during a clinical trial in which both patients were receiving ddI and d4T, the AERS database was searched for maternal adverse events. 10 reports of any maternal drug toxicity were found, of which two cases of lipodystrophy were excluded. 7/8 cases of lactic acidosis had received d4T and ddI and 1/8 received d4T and 3TC. There were three maternal and three infant deaths. All cases occurred after 32 weeks of pregnancy and the duration of ARV use was approximately five to eight months. This led to labelling changes for both d4T and ddI recommending that this combination only be used if the benefits clearly outweigh the maternal risks, and a ‘Dear Healthcare Provider’ letter was sent.

In addition Dr Currier also included a description of the Antiretroviral Pregnancy register focusing on an analysis assessing the teratogenic potential of antiretroviral drugs [10]. These data did not indicate an increase risk of birth defects with exposure to ARV overall or for the first trimester ZDV or 3TC exposures. Both presentations emphasise the continual critical importance of reporting exposure to antiretrovirals during pregnancy and the outcomes.

C-section – controversy still rages

Two reports from this meeting looked at mode of delivery. Dr Patel and colleagues examined the ‘Role of combination antiretroviral therapy and mode of delivery in perinatal HIV transmission’ for the Pediatric Spectrum of Disease Project in the US from 1995 to 2000 [11]. This large study collected prospectively data from 6274 HIV-exposed infants (amongst which HIV status was known for 5009) in six areas of the US.

They reported that in 1998 the number of elected caesarean section (ECS) deliveries began to increase as results from studies showing benefit in reducing MTCT were presented for women receiving either no antiretrovirals or ZDV monotherapy. They assessed the added benefit of C-section for women receiving combination therapy. During the study period there were significant increases in both interventions: 1.3% to 65.5% in use of combination therapy and 18.9% to 46.8% increase in C-section.

Overall the rate of MTCT was found to be lower in those receiving combination therapy than monotherapy, 4.9% and 9.4% (p<0.001). In addition the rate of transmission was lower with C-section than vaginal delivery, 13.0% vs 15.9% (p=0.676). With vaginal delivery the rate of transmission was lower in those receiving combination therapy than monotherapy, 5.5% vs 9.6% (p=0.015). The rates of transmission with C-section or vaginal delivery were similar in women receiving combination therapy ie 4.5% vs 5.5% (p=0.676). They also reported no significant benefit from C-section for women receiving no antiretroviral therapy but these data do not indicate whether these interventions were scheduled before onset of ruptured membranes and labour.

The investigators concluded that from this database that “…no additional benefits of caesarean section in women were noted in reducing transmission risk’. They also noted that further analyses are needed to better understand the role of maternal viral load, CD4+ T cell count and indication for C-section.

In addition, in an oral presentation, Dr Shapiro from Harvard presented data from PACTG 367, which analysed transmission rates from 2087 pregnancies according to antiretroviral therapy, mode of delivery and viral load [12]. In this study data from 67 US clinical sites resulting in live births between January 1998 and August 2000 were reviewed, from which 76 babies were HIV positive giving an overall transmission rate of 3.6% (95% CI [2.9%-4.5%]).

Dr Shapiro reported a reduction in transmission rate during the study period from 4.3% in 1998 to 1.6% in 2000 (p=0.03), during which time the use of multi-agent therapy in the third trimester and ECS both rose (from 76% in 1998 to 86% in 2000; p<0.001 and from 12% in 1998 to 29% in 2000; p<0.001 respectively). He also reported that with use of multi-agents the association with mode of delivery was “weaker”.

This observation provoked the comment from Dr Karen Beckerman from San Francisco General, that she was, “…glad that you concluded that the association with mode of delivery is “weaker” whereas I would conclude that it is absent”, and continued by emphasising the importance of counselling women to take care of their own disease as this will also have the most significant impact on their babies’ outcome. However, in the written abstract the authors conclude that “Over time, transmission rates decreased and multi-agent use and ECS increased. Transmission rates were significantly lower with more intensive ART and lower plasma HIV RNA level, but did not differ according to delivery mode…” In her overview Judith Currier also reminded us that, “clearly there is morbidity associated with this procedure”. Use of C-section remains controversial and as long as transmission rates remain as low as 2% or less, as has been demonstrated with appropriate use of complex therapy, it is unlikely that data to demonstrate either maternal or neonatal benefit with this procedure within this setting will be generated.

Resistance

Two further reports from the HIVNet 012 (012) study were presented at this meeting. Previous results from this study performed in Uganda demonstrated that an intrapartum and postpartum single dose of nevirapine given to the mother and infant respectively, significantly reduced the rate of MTCT and was more effective than a short course ZDV regimen [13]. In an oral presentation Mary Glenn Fowler described transmission rates from a subgroup of 583 women stratified by their high viral loads (>50, 000 RNA copies/mL) and low CD4 (<200) [14].

Although this analysis demonstrated significantly lower transmission rates among women receiving nevirapine than those receiving ZDV (24.9% vs 44.6%), and the investigators concluded that “these data support the efficacy of the simple NVP 2-dose peripartum regimen even among the women with the most advanced HIV disease.” However, these transmission rates are still rather alarming. This analysis did not include any resistance data for this high viral load group. Previous studies have shown that this strategy rapidly selected for nevirapine mutations, which was somewhat sobering after the original excitement that this trial generated. Several of us were poised to comment on this as the question time ran out. There remain huge concerns about the risk of using nevirapine monotherapy in this setting particularly for someone with very advanced disease.

A second report combined data from the 012 and HIVNet 023 to characterise the effect of single dose nevirapine on MTCT and on the selection for resistance in women infected with HIV-1 subtype C, n=36 (the majority of women in 012 were subtype A or D) [15]. HIVNet 023 is a phase I/II study conducted in South Africa and Zimbabwe — where C is the predominant subtype, which evaluates the safety and plasma concentrations of various prophylaxis dosing regimens given to breastfeeding infants. As part of the protocol, women found to be HIV positive at screening were offered the 012 regimen for prevention of MTCT.

At 24 weeks 31/121 (36%) of the infants were infected by MTCT across all subtypes and the investigators report no difference between subtypes in rates of transmission. Nevirapine mutations were present at 8 weeks in 27/121 (22%) of the women studied and higher rates of mutations were detected in subtype C 10/36 (28%) and D 11/37 (30%) compared to subtype A 6/48 (13%). Patterns of resistance were similar between groups; viral load and CD4 stratifications were not included in the analysis. The investigators concluded that different selections of resistance between subtypes ‘…could potentially limit the use of nevirapine or other NNRTIs for treatment of HIV-1 infection in certain circumstances and may have implications on therapy selection.’

In addition resistance data was reported from the PETRA study performed in South Africa, Tanzania and Uganda, which investigated different ZDV/3TC regimens [16]. Early analysis at 6 weeks showed that arm A reduced transmission by 50% and arm B by 37%.

PETRA Study design:

  Prepartum
from week 36		 Intrapartum Postpartum
1 week, mother + child
ARM A
ZDV+3TC
ZDV+3TC
ZDV+3TC
ARM B
Placebo
ZDV+3TC
ZDV+3TC
ARM C
Placebo
ZDV+3TC
Placebo

Women from arms A and B were studied from one participating site. 64 (32 from each treatment arm) samples were collected from mothers at one week, 82% were sequenced. In 2/24 (8.3%) of samples from women in arm A the M184V mutation was detected one week after delivery. In both cases this mutation was not detected at enrolment and disappeared after three months. In one further sample the M41L was detected at week one and was still present after three months. No NRTI mutations were detected in samples from arm B or in the infected infants.

Rapid testing

Although almost no one would dispute the paramount importance of antenatal care in an ideal setting, many women present in early stages of labour with their HIV status unknown. Two studies evaluated rapid HIV-1 testing presenting in early stages of labour in different settings. A study from Santos and colleagues in Brazil analysed the first 1729 rapid tests using the Determine test from Abbott Laboratories for determining HIV1/2 antibodies in plasma [17]. They looked at sensitivity, specificity, positive predictive value, negative predictive value and acceptability of the test.

All but one woman (0.6%) offered testing accepted and 61 (3.5%) tests were positive. In addition there were two (0.1%) false positives, one indeterminate and no false negatives. The sensitivity of the rapid test was 100%; specificity 99%; positive predictive value 99.3% and negative predictive value 100%. They also report a high rate of acceptance by pregnant women unaware of their HIV status in their cohort. Based on their findings the investigators also reported that they felt confirmatory tests for those who test negative according to this assay to be unnecessary due to the high negative predictive value. Despite these encouraging findings for the accuracy of the test, they also stressed that “Patients would benefit most if HIV testing occurred during antenatal care, when a better pre and post test counselling can be done in a much more caring environment.”

The second study, performed in Lima, Peru also evaluated the Abbott Determine and in addition a saliva test called OraQuick from Orasure [18]. 3,543 women were tested and from this group 26 (0.7%) had positive results and two (0.06%) were invalid using the Determine assay. Using the OraQuick saliva test the results were 26 (0.7%) positive and five (0.14%) invalid. The combined results were – 25 positive using both assays, one positive saliva/negative blood and one positive blood/invalid saliva.

This study also looked at the women’s opinion as to the acceptability of these tests. They report that with the Determine, 0.7% felt the test caused a lot of pain, 94% a little and 4.4% none. With the OraQuick, 0.1% reported a lot of discomfort, 2.1% a little and 97% no discomfort. Overall 33% found the saliva test more comfortable, 66% felt it made no difference, 0.6% preferred the blood test and 0.1% found neither acceptable. Overall the investigators concluded that “While HIV counselling and testing at the beginning of pregnancy is preferable, rapid testing in labour is feasible and allows for intervention prior to delivery to prevent maternal child HIV transmission.”

Breast milk

Breastfeeding increases the risk of mother to child transmission by approximately 14%. Therefore understanding the mechanism of breastfeeding transmission is important in the establishment of effective interventions to prevent postpartum MTCT.

Since CTL responses have been shown to have a role in controlling HIV levels in peripheral blood, in an oral abstract, Dr Sabbaj from the University of Alabama presented findings from a study in which it was sought to determine the presence of CD8+ T cells in breast milk from HIV positive women [19].

Colostrum was obtained from five HIV positive and four HIV negative women. Breast milk cells (BMC) were stimulated with clade B peptides spanning gag, pol, nef and env and they used responses to tetanus toxoid (TT), CMV and PHA as positive controls. All women in the study were reported as having strong responses to PHA and the HIV negative women had responses to CMV but not to any of the HIV peptides. All five of the HIV positive women had responses to gag, four to pol, three to nef and two to env.

This is the first study to demonstrate HIV-specific MHC class 1 restricted CD8+ T cell responses to HIV antigens in breast milk from HIV positive women and to show antigen-specific CD8+ T cell response. The investigators noted that “Their presence suggests that they play a role in limiting transmission and provide a rationale for vaccine studies enhancing these responses.”

Christine Rousseau and colleagues from the Fred Hutchinson Cancer Research Centre reported findings from a study conducted in Nairobi where almost 50% of cases of vertical transmission are attributed to breastfeeding [20].

Analysis of 648 samples from 273 women (collected at birth, six weeks, 14 weeks, and at three month intervals for up to two years) found increased breast milk viral load levels to be associated with frequency of MTCT through feeding. They also found breast milk viral load to correlate with that in plasma and the genital tract.

They observed that the range of breast milk viral load among those that transmitted was similar to those that did not, indicating that, as with maternal plasma viral load, there is no low level at which transmission never occurs. This, they report, demonstrates that there are other factors involved such as protective maternal antibodies, viral factors and/or host genetic factors.

In addition they reported that the “…SDFI 3’A allele is shown to be associated with increased breast milk viral levels, indicating that the allele might have an effect on viral replication in breast milk, providing a potential explanation for the increased risk of late transmission” (more than two months after delivery).

Conclusion

This conference provided further insights into the treatment of maternal health and the prevention of mother to child transmission. But as emphasised at the start of this article – programmes for access to HAART worldwide must also include pregnant women. No amount of mother to child transmission data alone will tackle the continuing global increase of orphans.

References

  1. Currier JS. Challenges to managing antiretroviral therapy during pregnancy. Abstract.S19. 9th CROI.

  2. Wilfert CM. Prevention of mother-to-child-transmission: Implementation, programs and treatment of mothers and children. Abstract.S26. 9th CROI

  3. Connor EM, Sperling RS, Gelber R et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. PACTG 076. N Engl J Med 1994; 1173-1180

  4. Blattner WA, Cooper E, Charurat M et al. Effectiveness of potent antiretroviral therapies on reducing perinatal transmission of HIV-1. Abstract LBOr4. 13th International conference on AIDS, July 9-14, 2000; Durban, South Africa

  5. Beckerman KP, Shannon M et al. The impact of combination antiretroviral therapy on maternal health and pregnancy outcome [Abstract MoPeB2198]. 13th International conference on AIDS, July 9-14, 2000; Durban, South Africa

  6. Scott G, Rodman J, Scott W et al. Pharmacokinetic and virologic response to ritonavir in combination with zidovudine and Lamivudine in HIV-1 infected pregnant women and their infants. Abstract 794-w 9th CROI

  7. Bryson Y, Stek A, Mirochnick M et al. Pharamacokinetics, antiviral activity and safety of nelfinavir with ZDV/3TC in pregnant HIV-infected women and their infants. Abstract 795-w. 9th CROI

  8. Beckerman KP. Principles of management of HIV disease during pregnancy. Topics in HIV Med 2000 vol8, issue 7,18-25

  9. Marcus K, Truffa M, Boxwell D. Cases from the FDA’s adverse event reporting system (AERS). Abstract LB 14 9th CROI

  10. Garcia P, Beckerman KP, Watts HW et al. Assessing the teratogenic potential of antiretroviral drugs. Abstract 1325, ICAAC, Dec 2001

  11. Patel J, Melville S, Heath C et al. Role of combination antiretroviral therapy and mode of delivery in perinatal HIV transmission. Abstract 798-w 9th CROI

  12. Shapiro D, Tuomala R, Samelson R et al. Mother-to-child HIV transmission rates according to antiretroviral therapy, mode of delivery and viral load. Abstract 114 9th CROI

  13. Jackson JB, Mracna M, Guay L et al. Selection of nevirapine resistance mutations in Ugandan women and infants receiving NVP prophalaxis to prevent HIV-1 vertical transmission. Abstract LBOr 13. 13th International conference on AIDS, July 9-14, 2000; Durban, South Africa

  14. Fowler MG, Mwatha A, Guay L et al. Effect of nevirapine for perinatal HIV prevention appears greatest among women with most advanced disease. Abstract 120. 9th CROI

  15. Kantor R, Lloyd R, Shafer R et al. Comparison of mother-to-child- transmission and genotypic resistance in HIV-1 subtypes A,C and D after single dose nevirapine in Africa. Abstract 801-w 9th CROI

  16. GiulianoM, Galluzzo T, Amici R et al. Selection of resistance mutations in pregnant women receiving short-course antiretroviral regimens with ZDV and 3TC to prevent perinatal transmission. Abstract 802-w 9th CROI

  17. Santos BR, Canti IT, Guerin YLS et al. Evaluation of an anti-HIV rapid test (Determine/Abbott) offered to pregnant women not tested before delivery in a large public hospital in Porto Alegre, Brazil. Abstract 788-w 9th CROI

  18. Melvin AJ, Alarcon J, Velasquez C et al. Rapid HIV-1 testing of pregnant women presenting in labour with unknown HIV status in Lima, Peru. Abstract 789-w 9th CROI

  19. Sabbaj S, Edwards B, Ghosh M et al HIV-specific CD8+ T cells are present at a high frequency in breast milk from HIV-infected women. Abstract 117 9th CROI

  20. Rousseau C, Richardson B, Steele M et al. Breastmilk HIV-1 viral load is associated with viral load in other compartments, host genotype and perinatal transmission. Abstract 792-w. 9th CROI
HIV Treatment Bulletin Vol 3 No 3 April 2002

   

Peripheral neuropathy update

Paul Blanchard, HIV i-Base

Sensory neuropathy is the most common neurological complication of HIV-infection. In the pre-HAART era approximately 30% of inpatients with AIDS suffered some degree of this form of neuropathy. The clinical features of HIV sensory neuropathy and neuropathy induced by nucleoside analogue toxicity overlap. Both present as a length-dependent sensory neuropathy (ie feet affected first) manifested by pain in the soles of the feet in over 60% of individuals and paresthesias in 40%. Weakness is almost never a presenting symptom. Neurological examination shows abnormal sensory thresholds in up to 85% of individuals and reduced or absent ankle reflexes in up to 96%. Motor findings are uncommon, with only a third of patients having distal weakness.

The prevalence of sensory neuropathy since the introduction of effective antiretroviral therapy has not been well described. Dr Catherine Cherry of Monash University, Melbourne, Australia presented data at the 9th CROI from a study of HIV-infected outpatients compared to an historical control. Prevalence and risk factors for sensory neuropathy were determined using a standardised screening and multivariate analysis performed over 4 months up to March 2001. Comparisons were made with an historical control of outpatients screened for sensory neuropathy in 1993.

There was found to be a significant increase in both the symptoms and signs of neuropathy in the 2001 cohort compared to the 1993 cohort (p<0.0001). In 1993 symptoms of neuropathy were present in 19% (18/94) of the out-patient population compared to 60% (84/140) in 2001. Clinical screening revealed at least one sign of sensory neuropathy in 14% of the 1993 cohort compared to 44% in the 2001 cohort. This represents a huge rise in the prevalence of both signs and symptoms of peripheral neuropathy since the introduction of HAART.

Cherry and colleagues went on to attempt to determine the risk factors for the development of sensory neuropathy in these cohorts and examined age, duration of HIV-infection, AIDS classification, CD4 count, nadir CD4, viral load, antiretroviral use and dideoxynucleoside (ddI, d4T, ddC) use in both univariate and multivariate analysis.

Univariate analysis revealed that those patients with sensory neuropathy tended to be older, to have been infected with HIV longer, to be more likely to have received both any antiretrovirals and dideoxynucleosides specifically and to have had lower CD4 nadirs (all p <0.05). AIDS diagnosis, median HIV viral load and median CD4 count were not found to be predictive of sensory neuropathy.

Multivariate analysis revealed only age (odds ratio 1.1) and dideoxynucleoside use (odds ratio 26) as significant predictors of the presence of neuropathy. Further analysis was performed to try and determine if either duration of dideoxynucleoside exposure increased risk or if any particular dideoxynucleosides were associated with increased risk.

Univariate analysis revealed significant risk factors for the presence of peripheral neuropathy to be:

  • Longer duration of dideoxynucleoside use
  • Longer duration of ddC use
  • Longer duration of d4T use
  • Longer duration of ddI use
  • Longer duration of dual dideoxynucleoside use

Independent predictors from multivariate analysis were history of exposure to d4T ever (odds ratio 7.4) or ddI ever (odds ratio 3.2).

Cherry concluded that there had been an increased prevalence of clinical sensory neuropathy since the introduction of HAART and that increased age and having used a dideoxynucleoside were independent risk factors for sensory neuropathy. Moreover d4T and ddI use were independently associated with sensory neuropathy, but not cumulative exposure. Additionally use of dual dideoynucleosides (ie. d4T + ddI) was not independently associated with neuropathy in this cohort.

Ref: Cherry C, McArthur J, Costello K et al. Increasing Prevalence of Neuropathy in the Era of Highly Active Antiretroviral Therapy (HAART). 9th Conference on Retroviruses and Opportunistic Infections; February 24-28, 2002; Seattle, Washington. Abstract 69.

http://63.126.3.84/2002/Abstract/13450.htm
HIV Treatment Bulletin Vol 3 No 3 April 2002

   

Further Retroconference reports and data on the web

The official conference Web site.
http://www.retroconference.org

The most useful information on this site is:

Audio, video, and slides from the major plenary and symposium overview talks and panels (but not from the many technical sessions where new data were presented).

Searchable abstracts of both oral and poster talks. You can search for all abstracts that contain any given word — including an author’s last name, a drug name or medical term, or the abstract number if you know it. To search the abstracts, first make sure you are at the 9th Conference on Retroviruses and Opportunistic Infections (the site will change for next year’s meeting), and select ‘Search Program and Abstracts.’

Many of the presentations will also have posters online. The posters have much more information than the abstracts, but there is no software available to search on them. These posters are usually formatted for display in a poster hall, but it is possible to read them online.

http://www.thebody.com/confs/retro2002/retro2002.html

The Body has many expert summaries of different research areas presented at the Retroviruses conference.

http://www.hivandhepatitis.com

This site has many conference articles, along with other news reports.

http://www.medscape.com/conference/retrovirus2002

Medscape has dozens of expert reviews. (The first time you use the Medscape site you need to register, but registration is free.)

http://www.natap.org/2002/9retro/ndx9retro.htm

Reports from the National AIDS Treatment Advocacy Project.

http://hivinsite.ucsf.edu/

A major HIV site run by the University of California San Francisco Medical Center. The Retroviruses coverage is currently at

http://hivinsite.ucsf.edu/InSite.jsp?page=cf9croi-00-00

http://www.medadvocates.org/news/main10818.html#Conf

Medical Advocates, a nonprofit organization, has grouped some of the abstracts and posters by drug or other topic.

Source: AIDS Treatment News
HIV Treatment Bulletin Vol 3 No 3 April 2002

   

PATHOPHYSIOLOGY

Passive transfer of scrub typhus plasma linked to reduced HIV viral load and clinical improvement

Graham McKerrow, HIV i-Base

A clinical study by US army doctors and a local hospital in Thailand has found that the passive transfer of scrub typhus plasma to people with HIV, who were not receiving antiretroviral drugs, was associated with reduced viral load, clinical improvement, a change of phenotype and decreases in CD8+ T cells and IL-6 levels.

Dr George Watt and colleagues safety tested individual 500 mL units of plasma from donors with mild scrub typhus, and subjected the plasma to virucidal heat treatment before administering it to 10 HIV-1 infected recipients. HIV copy numbers fell threefold or more in two recipients, and virus burden was reduced for eight weeks in 70% (7/10) of recipients of a single plasma infusion, compared with the mean of three pre-infusion measurements.

Dr Watt and colleagues from the Retrovirology Department of the US Armed Forces Research Institute of Medical Sciences in Bangkok, the Changrai Regional Hospital, and Human Plasma Product Services in Lille, France, report in the Quarterly Medical Journal of November 2001 [1] that: “In the clearest in vivo response, reduction in viral load was accompanied by clinical improvement, a switchback from the syncytia-inducing to the non-syncytia-inducing phenotype, and decreases in CD8+ T cells and IL-6 levels.

“Scrub typhus infections can generate heat-stable transferable plasma factors that exert prolonged anti-HIV effects. Whether variability in the results is due to different scrub typhus infections, different HIV infections or different individual responses, is unclear”, say the authors.

They also found that scrub typhus donor plasma inhibited HIV-1 in vitro compared with normal human plasma and media controls.

They transferred plasma from patients mildly infected with Orientia tsutsugamushi, the causative agent of scrub typhus, and with no other medical problems. It was given to HIV positive individuals who were not taking antiretrovirals and had <200 CD4+ cells/mm3. Recipients were given slow intravenous infusions of the plasma over two hours, and were monitored closely in hospital for the following 24 hours.

At the same time, complement inactivated plasma from scrub typhus donors was assessed for in vitro inhibition of HIV using cryopreserved peripheral blood mononuclear cells infected with a non-laboratory-adapted Thai strain of clade E virus (NP1668). HIV replication was assessed at three, seven, 10, and 14 days after infection by measuring the amount of p24 antigen in the culture supernatant.

In the in vivo study, the total viral burden during the two months following plasma transfer was established in the five men and five women who received plasma. No significant side effects were reported. The mean increase in bodyweight at one month was 0.8kg and at two months was 1.4kg. One month after infusing, CD4+ T cell counts and haematocrit (volume of red cells in the blood) were significantly higher than pre-infusion values, while white blood cell count was significantly lower.

The authors report that there were no significant changes to CD8+ T cell counts for the 10 plasma recipients as a group. However, there were changes in CD8+ T cell counts at the individual level; one person’s count fell from 1,065 cells/mL before the infusion, to 977 a month after infusion and then to 808 at two months.

Viral load fell dramatically in two recipients. In one the copy number fell from 173,412 copies/mL pre-infusion average to 34,772 at 28 days. In another, the viral load fell from a pre-infusion average of 44,833 to 12,963 at day 35.

In their discussion, the authors report that, “The data from this clinical study support and extend earlier findings [2] that showed HIV-inhibitory effects associated with scrub typhus infection.”

And they write: “The total viral burden during the two months after each plasma transfer was approximated by the AUC (area under the copy number curve). The AUC was less than half that predicted had viral load remained at the pre-infusion level in 7/10 patients.”

Dr Watt and colleagues conclude: “These finding suggest that some scrub typhus plasma contained HIV-inhibitory factors. It is also possible that all plasma contained HIV-suppressor factors but that, for whatever reason, not all subjects responded to them.”

They also draw attention the recipient of plasma whose viral load fell from a pre-infusion average of 166,404 copies/mL to a median value during the two months following plasma infusion of 58,666. This recipient experienced a further threefold fall in viral load following a second plasma infusion. There was also a switchback to the less pathogenic non-syncytia-inducing phenotype, in isolates from this recipient. “One month after receiving the first plasma infusion [this recipient] was able to return to her job in a fruit orchard. A subjective increase in appetite was accompanied by a gain in body weight from 57.0kg pre-infusion to 58.0kg at day 28 and 59.5kg at day 56. IL-6 concentrations fell after plasma was transferred to [her] as occurs with effective antiretroviral therapy.” report Dr Watt and colleagues.

The authors also draw attention in their discussion to the fact that there was no lowering of viral load after plasma transfer to one recipient. And in contrast to the recipient mentioned above, this other recipient experienced an increase in CD8+ T cells.

The authors write that their data suggest that some scrub typhus infections generate heat stable plasma factors capable of exerting anti-HIV effects even in late-stage HIV infection.

And they add: “O. tsutsugamushi infection is common. An estimated one billion people live in endemic areas, and seroprevalence rates of up to 69% have been reported in Thailand. There is therefore a large potential pool of research material with which to further explore possible anti-HIV effects associated with scrub typhus. All scrub typhus plasma were HIV-inhibitory in vitro but, as in natural infection, only some inhibited in vivo.

“The modest increases in weight and haematocrit after the first infusion suggest that the recipients were not harmed and might have benefited from receiving scrub typhus plasma. Plasma with clearly defined in vivo HIV suppressive activity can be used to try to optimise in vitro HIV inhibitory tests and identify an appropriate marker of HIV inhibitory effect. Elucidation of the inhibitory mechanism could generate new tools for the prevention and treatment of HIV infection.”

References

Watt G, Kantipong P, Jongsakul K et al. Passive transfer of scrub typhus plasma to patients with AIDS: a descriptive clinical study. Q J Med 2001;94:599-607.

Watt G, Kantipong P, deSouza M et al. HIV-1 suppression during acute scrub typhus infection. Lancet 2000; 356:475-9.
HIV Treatment Bulletin Vol 3 No 3 April 2002

   

OTHER NEWS

Rivals Robert Gallo and Luc Montagnier launch joint vaccine project

Graham McKerrow, HIV i-Base

Rival researchers Robert Gallo and Luc Montagnier – who fought a long battle over recognition for discovering HIV and the resulting blood tests – have buried their past differences and agreed to collaborate on developing an HIV vaccine.

Dr Montagnier, 69, formerly of the Pasteur Institute in Paris, approached Dr Gallo, 64, a few years ago and cynics point out that the timing of their agreement suits Dr Gallo by distracting attention from a damning new book called ‘Science Fictions: A Scientific Mystery, a Massive Cover-Up, and the Dark Legacy of Robert Gallo’, by Chicago Tribune journalist John Crewdson.

However, the two men had other explanations for their collaboration. Dr Gallo, who heads the Institute of Human Virology in Baltimore, USA, said: “A whole lot of people say ‘why can’t you guys collaborate? Why can’t you work together to try to solve the problem?’ It will stop a lot of that.”

Dr Montagnier, president of the World Foundation for AIDS Research and Prevention, said: “If we join our efforts it will be more credible for fund-raising.”

Dr Gallo says he finally took up Dr Montagnier’s invitation to collaborate because the Frenchman’s organisation had established testing sites in the Cameroon and Côte d’Ivoire and he saw collaboration as a way of speeding up the testing of vaccines his laboratory is developing.

The two scientists fell out after the discovery in 1983 of HIV, for which both claimed credit. Eventually they agreed to share recognition but it is thought the row deprived both men of winning the Nobel Prize for Medicine because the prize committee dislikes controversy.

The scientists still have their professional differences with Dr Gallo developing vaccines by attaching HIV genes to salmonella bacteria, while Dr Montagnier believes the best way to develop a useful vaccine is to make it out of pieces of HIV’s proteins.

Key to the rapprochement has been the Italian researcher Vittorio Colizzi at the University of Rome, who has worked with both men and whose lab will be used for much of their joint enterprise.

Dr Montagnier insisted that the pair have the highest motives for their collaboration, and went on to dismiss claims that they were trying to soothe the Nobel Prize Committee: “If the prize comes, it will come too late. I would have preferred it to have come earlier, and then I think it could have given us more influence to do something in Africa.”

The new project will be called the Programme for International Viral Collaboration and will be co-directed by the two scientists. It will be created under Dr Montagnier’s foundation, which itself works under the auspices of UNESCO. It will develop an international research network involving laboratories in the United States, Canada, and Nigeria, as well as Italy, Cameroon and the Côte d’Ivoire.

AIDS is now seen as the greatest epidemic and deadliest disease in history, surpassing the bubonic plague of the 14th Century. Dr Montagnier said: “HIV/AIDS is presently the greatest of threats to mankind and, unlike the plague, it will not go away. This will occur only when medical science develops a treatment accessible to all and a successful vaccine to prevent infection.”
HIV Treatment Bulletin Vol 3 No 3 April 2002

   

Abbott announces therapeutic drug monitoring scheme for lopinavir/r

Graham McKerrow, HIV i-Base

Abbott Laboratories has announced the introduction of a therapeutic drug monitoring (TDM) scheme for its second generation protease inhibitor lopinavir/r (KaletraTM), a coformulation of lopinavir and ritonavir. The scheme is being run in association with the Liverpool University TDM Service.

Kaletra capsules each contain 133.3mg of lopinavir and 33.3mg of ritonavir. Dr Ian Hitchcock, Abbott’s HIV medical adviser, says in a letter to doctors: “At the recommended dosage (400/100mg bd in adults) ritonavir has no antiretroviral activity but acts as a pharmacokinetic enhancer – slowing the clearance of lopinavir. This novel formulation gives rise to high and sustained plasma levels of lopinavir, which contribute towards durability and potentially provides a pharmacologic barrier to the emergence of viral resistance.”

Dr Hitchcock says that high plasma levels of lopinavir are generally achieved, but that on some occasions drug level monitoring may be considered appropriate to optimise antiretroviral therapy with lopinavir/r.

Abbott will sponsor analysis of blood samples by the Liverpool TDM Service for three types of patients: paediatric patients; patients receiving concomitant amprenavir with lopinavir/r; and patients receiving concomitant NNRTI therapy with lopinavir/r.

Dr Hitchcock tells physicians: “There will be no charge to your HIV treatment centre for the TDM analysis for lopinavir for patients meeting the required criteria. However, postage and packing costs will be the responsibility of the centre requesting the analysis, as will the cost of any additional assays requested with lopinavir (unless covered by other schemes).”

Request forms, and details of the service and how to request analysis are available from the Liverpool TDM Service website:

http://www.delphicdiagnostics.com/index.htm

Information about lopinavir/r is available at Abbott’s site:

http://www.kaletra.com/

Health professionals seeking information about the service can contact Sara Gibbons at the Liverpool TDM Service on 0151 794 5553, email: hivgroup@liv.ac.uk or Dr Hitchcock on 01628 773355.

comment

This programme is welcomed. A TDM form is also included on page 38 of this HTB, together with background information about the service and sample collection on pages 36-37.

 
HIV Treatment Bulletin Vol 3 No 3 April 2002

   

Johnson & Johnson to acquire Tibotec-Virco

Johnson & Johnson have announced it has signed a definitive agreement to acquire all of the assets of Tibotec-Virco NV, a privately held biopharmaceutical company focused on developing anti-viral treatments, with several promising compounds in development for the treatment of infectious diseases including HIV. The transaction is valued at approximately $320 million in cash and debt.

Johnson & Johnson is expected to incur a one-time charge of approximately $145 million, or $0.05 per share, upon closing, reflecting the write-off of in-process research and development costs. The transaction is anticipated to close in the second quarter of 2002 subject to customary closing conditions and regulatory approvals. Excluding one-time charges, the acquisition is not expected to impact earnings for 2002 or 2003.

“Tibotec-Virco will provide a good strategic fit with our current pharmaceutical research and development operations,” said Dr. Per Peterson, chairman, Research & Development for the pharmaceuticals group of Johnson & Johnson. “By combining Tibotec-Virco’s expertise with our own research and development activities, we will expand our drug discovery and development capabilities, particularly in the field of anti-viral therapies.”

Headquartered in Mechelen, Belgium, Tibotec-Virco applies the latest techniques in ultra-high throughput screening, pharmacogenomics, molecular biology and artificial intelligence to discovering and developing new drugs. The company has drug discovery and development programs focusing on potential new drugs that are active against drug-resistant strains of HIV, including two products in early clinical development. Tibotec-Virco also has early stage research programs concentrating on the development of treatments for hepatitis C and other infectious diseases. In addition to its drug discovery operations, Tibotec-Virco provides HIV drug resistance testing and other analytical services under the name of Virco. The company has operations in Mechelen, Belgium, Durham, North Carolina, and Dublin, Ireland.
HIV Treatment Bulletin Vol 3 No 3 April 2002

   

Increased Selenium intake may protect HIV positive patients from mycobacterial disease

Dietary selenium supplementation in patients with HIV appears to lower their risk of mycobacterial disease, Florida researchers have discovered.

In a study of 259 HIV-infected drug users assigned to receive placebo or selenium supplements 200 µg/day, Dr. Gail Shor-Posner and colleagues, of the University of Miami School of Medicine, identified 12 subjects who developed infections of Mycobacterium tuberculosis or atypical mycobacterial species during a two year follow up. They were compared with 32 matched controls.

All subjects had plasma selenium levels considered to be normal, but those with levels of 135 µg/L or less were 13 times more likely to develop mycobacterial disease, the investigators report in the Journal of Acquired Immune Deficiency Syndromes for February 1. Furthermore, receiving placebo rather than selenium supplements doubled the risk.

Dr. Shor-Posner’s group notes that selenium is recognized as a suppressor of tumour necrosis factor-alpha and an aid in maintaining T cell function. The researchers also suggest that selenium modulates viral expression and acts as an antioxidant. Thus, “higher than normal levels of selenium may be necessary to maintain a functional immune system in HIV-infected subjects,” they maintain.

Ref: J Acquir Immune Defic Syndr 2002; 29:169-173.

Source: Reuters Health
HIV Treatment Bulletin Vol 3 No 3 April 2002

   

HIV protease inhibitors have potent antiangiogenesis, antitumor effects

Kaposi’s sarcoma (KS) affects 20% of patients living with AIDS who are not receiving any form of anti-HIV therapy. It leads to the formation of small blood vessels, which in turn form small tumours that manifest as lesions on the skin, mouth and lymph nodes.

Recent observations have demonstrated that HIV-patients treated with highly active antiretroviral therapy (HAART), a drug regimen that constitutes at least one protease inhibitor (PI) such as indinavir or saquinavir, displayed a reduced incidence and increased regression of KS. Since protease inhibitors have also demonstrated a role in angiogenic and inflammatory processes and tumour growth, Barbara Ensoli and colleagues hypothesized that the lower incidence and regression of KS observed in PI-treated patients was, in part, attributable to the direct anti-KS and anti-angiogenic effects of these agents.

To explore this further, preclinical models to evaluate the efficacy of protease inhibitors as potential anti-angiogenic agents, were employed. Using nude mice (devoid of T cells) and the chorioallantoic membrane (Cam) assay (an established in vivo assay that is used to measure angiogenesis), the researchers set out to investigate the effects of indinavir and saquinavir in KS development.

Nude mice were treated with either indinavir or saquinavir and subsequently inoculated with different strains of KS cells. These cells were found to promote the development of KS-like lesions in 100% of mice that had remained untreated. By contrast, in mice that had received either indinavir or saquinavir, lesion development was significantly reduced with only 43% and 25% of these mice displaying macroscopic lesions, respectively. This provided the first evidence of the involvement of PIs in the inhibition of KS development.

To ascertain whether this effect was direct, PIs were tested in another system in which the inflammatory cytokines, bFGF and VEGF – potent angiogenic agents – were used to induce lesions. Using bFGF alone, 71% of the untreated mice developed lesions whereas those that received indinavir and saquinavir, lesion formation was inhibited to 28% and 25%, respectively. Similarly, using a combination of VEGF and bFGF, PI treatment led to a reduction in lesion formation from 83% in untreated mice to 33% and 17% in indinavir and saquinavir-treated mice, respectively. These results further supported the ability of PIs to mediate direct anti-angiogenic effects.

Current anti-angiogenic and anti-tumour therapies are based on blocking endothelial cell invasion, a process that requires the degradation of the basement membrane by matrix metalloproteinase-2. To elucidate the mechanism underlining PI-mediated KS inhibition, gel-activity assays were performed to determine whether these PIs exerted an effect on MMP-2 activity. Although little effect was observed on MMP-2 synthesis, both indinavir and saquinavir were found to block the conversion of MMP-2 into its active form.

All these results serve to strengthen the role of protease inhibitors as promising anti-angiogenic and anti-tumour agents in the treatment of KS and other HIV-associated tumours.

Source: Nature Medicine 2002; 8:225–232
HIV Treatment Bulletin Vol 3 No 3 April 2002

   

PRO 542: Reduced viral loads in patients failing conventional therapy

Progenics Pharmaceuticals reported that its novel investigational drug, PRO 542, produced a significant antiviral response in HIV-infected individuals who were no longer responding to currently available antiretroviral medications. In treatment-experienced patients, a single dose of PRO 542 reduced viral concentrations by 60% to 80% on average for up to four weeks. PRO 542 belongs to a new class of drugs, viral-entry inhibitors, which are designed to prevent HIV from entering and infecting cells. The findings were presented today at the 15th International Conference on Antiviral Research in Prague, The Czech Republic.

“PRO 542 showed important reductions in viral load in those patients who were most in need of new treatment options,” said Jeffrey M. Jacobson, M.D., Director, AIDS Center, Mount Sinai School of Medicine, New York City and Principal Investigator of the PRO 542 study in adults. “Conventional therapy is unable to control HIV long-term due to mutation of the virus. All currently available HIV drugs inhibit just two enzymes involved in viral replication after infection has occurred. PRO 542 is a viral-entry inhibitor which may provide clinical advantages over the current armamentarium. This novel antibody-like fusion protein is designed to work against all strains of HIV and to minimise the emergence of viral resistance. PRO 542 may prove particularly valuable for salvage therapy of patients failing conventional drug regimens.”

In clinical studies, PRO 542 was well tolerated and produced statistically significant (p=0.007) acute reductions in viral load across all seven patients who received a single 25 mg/kg intravenous infusion of the drug. These findings extend previous studies of four intravenous doses ranging to 10 mg/kg. In addition, an analysis of data from 22 adults treated with single-dose PRO 542 in a Phase I/II study identified a subgroup of patients who were the most highly responsive to therapy. These patients were failing conventional therapies and had evidence of advanced disease as measured by low numbers of CD4+ T cells (<200 cells/mm3) and/or high viral loads (>100,000 copies/mL) before treatment with PRO 542. CD4+ T cells are key components of the immune system and the major targets of HIV infection. The viral load reductions in these patients ranged from 0.4 to 0.8 log10 copies/mL, were dose-dependent, and were sustained for two to four weeks.

Viruses that are broadly resistant to currently available antiretroviral medications represent a growing challenge for HIV therapy. A study presented at the most recent Interscience Conference on Antimicrobial Agents and Chemotherapy reported that in the U.S. approximately 78% of HIV-infected individuals harbour virus that is resistant to one or more classes of antiretroviral agents, thus reducing their treatment options. An estimated one million Americans will be infected with HIV by the end of 2002.

“We have identified a group of patients who were not responding to currently available therapies but who did exhibit a significant antiviral response to PRO 542,” said Robert J. Israel, MD, Vice President of Medical Affairs at Progenics. “These findings are being incorporated into our Phase II clinical program. The company is also developing subcutaneous and intramuscular formulations of PRO 542 that may afford simplified dosing regimens.”

PRO 542 is an antibody-like molecule which is designed to neutralise HIV by directly binding to gp120, a protein on the surface of the virus, thereby preventing HIV attachment to healthy cells within the immune system. Whereas current antiretroviral medications are active only against virus that has already infected immune system cells, PRO 542 is designed to neutralize HIV before the virus can enter and infect cells. In previously reported Phase I/II studies in HIV-infected patients, intravenously administered PRO 542 mediated dose-dependent and statistically significant reductions in plasma HIV RNA, a measure of HIV viral load. PRO 542 is currently in Phase II clinical testing.

Source: PRNewsWire
HIV Treatment Bulletin Vol 3 No 3 April 2002

   

Researchers uncover possible drug approach to attack HIV-infected cells

A drug being tested as a cancer treatment also appears to be effective in the laboratory against HIV, say medical centre researchers. The findings suggest the drug may benefit patients by targeting infected cells without harming the healthy cells the body needs to defend itself against disease. Plans are under way to test the drug in people with HIV-infection.

HIV devastates the body’s immune system by taking over and killing a particular class of white blood cells known as CD4+ helper T cells. These cells coordinate the body’s defence against foreign invaders. Without the normal array of T cells, HIV-infected patients have weakened immune systems, leaving them susceptible to infections.

Stanford researchers have now found that low doses of the drug called motexafin gadolinium (or Gd-Tex) selectively kills HIV-infected CD4+ T cells. “Gd-Tex worked in vitro,” said Leonard Herzenberg, PhD, professor emeritus of genetics and senior author of the study reported in the 18th February issue of the Proceedings of the National Academy of Sciences. “It selectively killed the HIV-infected cells when they were in a mixture with healthy white blood cells. And to our surprise, only the infected CD4+ T cells were killed.”

Gd-Tex is now being tested in humans as a cancer treatment. The drug acts by accumulating in tumour cells and attacking the molecules that normally protect the cells from one type of stress. The cells therefore die more readily during radiation treatment.

When Herzenberg and his wife, Leonore Herzenberg, PhD, professor of genetics, learned about Gd-Tex, they had a hunch that the drug might also be effective in controlling HIV. Earlier studies had shown that the HIV virus attacks the cell’s natural defences against harmful molecules by reducing levels of a protective molecule called glutathione. When glutathione drops below a certain level, the weakened cell gives in to the stress and dies. Because HIV-infected cells are already under stress, additional stress induced by Gd-Tex could be enough to push weakened cells over the edge, the Herzenbergs reasoned.

To test the hypothesis, graduate student Omar Perez, primary author of the study, began treating HIV-infected blood samples with Gd-Tex. He then scanned individual cells and found that high levels of Gd-Tex were toxic to all T cells because of the attack on glutathione. Lower levels of Gd-Tex, on the other hand, were fatal only to HIV-infected CD4+ T cells.

“The first clue that Gd-Tex worked was that the CD4+ T cells were disappearing,” said Perez. Subsequent work showed that the CD4+ T cells were committing a kind of “cell suicide.” Since other blood cells were not as compromised by the HIV infection, they survived at the low doses of Gd-Tex that were fatal to HIV-infected helper T cells.

The drug’s effectiveness for HIV treatment remains an open question, and the Stanford team plans to proceed with caution. “We want to be careful in a clinical trial and start with a low dose,” said Herzenberg. For the drug to work as an HIV therapy, infected cells would have to take up Gd-Tex in an amount sufficient to kill them in patients, he said. In addition, the drug may have other ill effects. Herzenberg cautioned that the rapid destruction of infected CD4+ T cells could release harmful toxins into the body, and further testing will be required to know for sure.

Andrew Zolopa, MD, director of the Stanford Positive Care Clinic (which focuses on HIV/AIDS), is coordinating with the Herzenbergs and Pharmacyclics, California based pharmaceutical company that makes Gd-Tex, to begin clinical trials of the drug in HIV patients. They anticipate the trials will begin within the next few months

Source

http://www.stanford.edu
HIV Treatment Bulletin Vol 3 No 3 April 2002

   

Leptin reverses lipodystrophy in diabetic patients

Researchers have successfully used the hormone leptin to treat patients suffering from lipodystrophy. The findings by scientists at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the University of Texas Southwestern Medical Center appear in the 21st February 2002, issue of the New England Journal of Medicine. “This is the first example of leptin’s use in a therapeutic role in a rare form of diabetes,” says NIDDK’s Phillip Gorden, MD, the study’s senior investigator.

People with lipodystrophy have few or no fat cells and thus lack leptin, a hormone produced by and stored in fat cells. Because they have no fat cells, people with the condition usually store huge amounts of lipids (fat) in inappropriate places like muscle or liver, and they have extremely high levels of lipids in their blood. These patients are likely to be insulin resistant, meaning their bodies don’t readily respond to insulin, the hormone that allows muscle and fat cells to use glucose properly. The condition can be congenital or acquired.

Eight of the nine female patients who participated in the study had diabetes and were taking either insulin or a diabetes drug, or a combination of the two. During the four-month study, most patients experienced significant improvements in levels of fasting glucose, haemoglobin A1c, which measures a person’s average blood glucose over the three previous months, and triglycerides. Patients were able to reduce or stop using insulin and drugs to control their diabetes, and they reported eating less following treatment. The findings suggest that leptin reduces insulin resistance and prevents the body from accumulating fat in the wrong places.

“It is too soon to make the assumption that leptin will be useful in typical type 2 diabetes,” says Gorden. Although people with lipodystrophy and type 2 diabetes can develop some of the same complications when blood glucose is uncontrolled, the two conditions differ in fundamental ways. Most people with typical type 2 diabetes are overweight and not deficient in leptin. In fact, their leptin levels are usually high, and they may be resistant to leptin’s effects, says Gorden.

The rationale for treating lipodystrophy with leptin comes from classical endocrinology. “The idea is that if people have a hormone deficiency and they are given replacement hormone, they should respond,” says Gorden.

“What we have shown is that in a leptin-deficient state, we can correct many of the abnormalities that come with it,” adds Elif Arioglu Oral, MD, the paper’s lead author and a former research fellow at NIDDK. The results also suggest that leptin deficiency may explain the insulin resistance seen in people with lipodystrophy. “For the first time, we’re seeing leptin working as an insulin-sensitising agent,” adds Oral, now an assistant professor at the University of Michigan in Ann Arbor. Earlier leptin studies showed that lack of the hormone caused obesity in mice; resistance to leptin likewise contributed to obesity in mice and humans.

For all patients, average fasting triglyceride levels dropped by approximately 60% and liver volume dropped by 28%. The normal range for plasma triglycerides is 35 to 155 mg/dL. The level for patients at the start of the study ranged from 445 to 9,560. At the study’s conclusion, the range was 123 to 1,214.

The change in the patient with the highest triglyceride level was dramatic, says Oral. No medications had worked for this patient. The extra lipid had deposited in the skin, causing a lot of pain, and her liver was very enlarged. To remove the triglycerides, every week she had to go through aphaeresis, a process where blood is removed, components are separated out, and the blood is returned to the body. “Within three months of leptin therapy her liver had shrunk, and she was off aphaeresis,” says Oral. “Treatment made a difference in her quality of life.”

Ref: Oral EA, Simha V, Ruiz E et al. Leptin-replacement therapy for lipodystrophy. N Engl J Med 2002 Feb 21;346(8):570-8.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd =Retrieve&db=PubMed&list_uids=11856796&dopt=Abstract

Source: NIH press release

comment

Estrada and colleagues have previously described significantly lower plasma leptin levels in HIV-infected lipoatrophic patients than in healthy control individuals (J Acquir Immune Defic Syndr 2002 Jan 1;29(1):32-40). Perhaps leptin therapy in these individuals might also be of benefit?
HIV Treatment Bulletin Vol 3 No 3 April 2002

   

TRIAL NEWS – ONGOING UK STUDIES

Entry criteria changed for Optima study and treatment options for Salvage Therapy

Simon Collins, HIV i-Base

Optima (OPTions for Management with Antiretrovirals) is an international collaboration between the Veterans Administration in the USA, CIHR in Canada and the MRC in the UK. The study looks at two key questions in multi-drug experienced patients on a failing regimen: whether there is a benefit to a treatment interruption prior to adoption of a new regimen, and the possible additional benefit from using more than 4 drugs in a salvage setting. After a resistance test, patients are randomised to either an immediate treatment change or to a drug free period (ideally three months, but flexible depending on individual patient response). They are also randomised to using up to 4 drugs (NOT including small doses of ritonavir if used as a PK booster for a second PI) or to a Mega-ART regimen using at least 5 drugs. Investigational and expanded access drugs are allowed within the Optima protocol, and can be added as they become available.

Several important changes have now been made that broaden the entry criteria:

  1. Failure of at least two regimens including drugs from each of the three drug classes have been broadened to include evidence of resistance from a resistance test, even if these drugs have never been used by a patient. This now covers people infected with drug resistant HIV or those with cross-resistance.
  2. the upper cut-off for entry to the study has been raised from 200 cells/mm3 to 300 cells/mm3
  3. reducing the viral load entry criteria to 2500* copies/ml (from 5,000-10,000 copies/ml )

The previous exclusion of patients with a history of low adherence has now been dropped.

* by Roche Amplicor Monitor/COBAS v1.5 (<50 cut-off assay), or Bayer v3.0/Chiron v3.0 bDNA ‘ultrasensitive’ assays; or to >5000 copies using the older Roche Amplicor, v 1.0.

Twelve UK sites are currently enrolling patients include Belfast, Cambridge, Edinburgh, Oxford, Sheffield, Brighton, Colchester, Peterborough and in London (at the Chelsea and Westminster, St Marys, Central Middlesex and the Royal Free Hospitals). With a further ten sites soon to receive approval.

Enquiries from doctors wishing to run this study at their hospital should be made to Douglas Newberry, trial manager for Optima at the MRC Clinical Trials Unit on 020 7670 4813 (d.newberry@ctu.mrc.ac.uk)

General information is also available on the trial website:

http://www.optimatrial.org

comment

These changes are welcomed as they open the study to patients at an earlier stage of treatment failure, and before the CD4 count has fallen too low. Optima is a management study, with a large degree of flexibility in individually managing patient care in this difficult population.

Choice of individual drugs, including changes of drugs over time (as long as the intention is to keep to the allocation of either ‘up to 4 drugs’ or ‘5 or more drugs’) and flexibility to extend or reduce the period of treatment interruption, all remain with the individual patient/doctor. Where more frequent monitoring is preferred this is also possible (although funded as part of the study).

It is hoped that accurate targeting of suitable patients will answer these important questions in a timely manner.
HIV Treatment Bulletin Vol 3 No 3 April 2002

   

IL-2 still available in UK in ESPRIT Study, safety management guidelines expanded

Simon Collins, HIV i-Base

ESPRIT is large randomised international NIH (UD)-lead study using the immune modulating cytokine IL-2 together with HAART with 24 UK sites and is the largest ever HIV clinical trial. Randomisation to IL-2 or no IL-2 is 1:1. The study aims to follow 4000 patients using doses of 1.5 - 7.5 MIU BID in multiple 5 day cycles with follow up to 2007. A minimum of three cycles are recommended, many people benefit from a fourth cycle in the first year. Preliminary reports from previous studies indicate that a single ‘top-up’ cycle every 2-3 years may continue to extend this benefit and sustain this raised CD4. Patients in the study retain the option to access subsequent IL-2 cycles until 2007.

The UK has been allocated about 300 places on this study, and current enrolment stands at just over 200.

Updated toxicity management guidelines to increase awareness of psychiatric, cardiac, hepatic and renal disease in both new and currently enrolled patients have now been issued. These additional guidelines are to be welcomed.

General information and the management guidelines are available from Mary Pearson, UK trial manager for ESPRIT, at the MRC on 020 7670 4781 (m.pearson@ctu.mrc.ac.uk). The website for this study:

http://www.espritstudy.org

comment

Although IL-2 is available on a named patient basis in the UK the cost for this has severely limited access. This study therefore provides the only opportunity to access to this treatment for the near future. The UK is not included in the parallel SILCAAT study in patients with CD4 50-300. IL-2 treatment is expected to approximately double the baseline CD4 count over the first year of treatment and might be of particular interest to patients looking to boost their CD4 count prior to a treatment interruption.

Previous research indicates that IL-2 causes an increase of both naive and memory CD4 cells. Previously, this increase was thought to be mainly due to an increased rate of division of CD4 cells but recent research has shown that that IL-2 can dramatically extend the half life of these cells even in the few patients who generate only a minimal CD4 increase. This may be the main explanation for the sustained increase in CD4 cells long after taking IL-2.
HIV Treatment Bulletin Vol 3 No 3 April 2002

   

ON THE WEB

Controlling PI resistance like a switch: MDR1 and p-glycoprotein

 

One specific gene in a person’s body could literally be a drug-resistance switch — it may turn on and off a person’s ability to develop resistance to some protease inhibitors. GMHC Treatment Issues reports.

It’s well understood that unwavering adherence to one’s antiretroviral therapy (ART) regimen gives the best chance of keeping drug levels high enough to sustain suppression of viral replication and allow immune recovery to take root. Yet perfect performance is not a sure bet. Some people who never miss a dose fail to see their T-cells rise — even though their viral load stays within moderate levels. Others have all the luck: their virus goes undetectable and stays there for years while their CD4 counts hover near quadruple digits — all with side effects no more serious than occasional diarrhoea. Many clinicians have long thought that some genetic advantage must be at work, but there’s been little proof and no way to tell who’s drawn the lucky DNA.

http://www.thebody.com/gmhc/issues/jan02/gene.html

 

How do proteins cause drug resistance?

Proteins for dummies: GMHC Treatment Issues provides a primer on how proteins work in the body — and in HIV — and how mutations can cause drug resistance.

http://www.thebody.com/gmhc/issues/jan02/proteins.html

 

HE2000

Hollis-Eden, a small biotech company in San Diego, California, is developing a new class of drugs derived from a master hormone that helps run the immune system.

The first of these is called HE2000. A university study in Thailand shows it can help cure malaria. There is good reason to think it could also treat HIV illness, but we may never know because unlike an antiviral, there is no laboratory test that can be used to show the FDA that the drug is effective.

http://www.thebody.com/sfac/he2000.html

 

Updated HIV InSite Knowledge Base chapter: Mycobacterium avium complex

Mycobacterium Avium Complex and HIV by M. Jacobson, MD, HIV InSite Knowledge Base chapter, updated 2/02.

Mycobacterium avium complex (MAC) consists of several related species of mycobacterium that are ubiquitous in the environment. MAC rarely causes disease in individuals with a normal immune system. In patients with AIDS, however, it is one of the most common serious opportunistic infections.

http://hivinsite.ucsf.edu/InSite.jsp?page=kb-05-01-05
HIV Treatment Bulletin Vol 3 No 3 April 2002

   

APPENDIX: TDM Service at Liverpool University

 

See form on following page - For further information contact

Sara Gibbons: Tel: +44 (0) 151 794 5553 Fax: +44 (0) 151 794 5656/5540

 

email: hivgroup@liv.ac.uk

http://www.hiv-druginteractions.org

Drug Analysis Available

Protease Inhibitors – Saquinavir, Ritonavir, Indinavir, Nelfinavir, Amprenavir, Lopinavir/r.

NNRTIs – Delavirdine, Nevirapine, Efavirenz

Others – Sildenafil, Methadone, M8 (nelfinavir metabolite)

Samples - To aid us in the clinical interpretation of the results, it is helpful to have both a trough and a peak sample whenever possible. A trough sample should be taken as close to the end of the dosing interval as possible (i.e. at 12 h for bd regimens or 8 h for tds regimens). A peak sample should be taken approximately 1 h post dose for indinavir alone and 2 h post dose for indinavir with ritonavir and all other drugs. The dosing schedule for efavirenz makes it difficult to obtain trough and peak samples so we will try to give a clinical interpretation for samples from any known time point.

Blood samples should be collected in lithium-heparin tubes (or EDTA if heparinised tubes are unavailable) and plasma obtained by centrifugation within 2 h of collection. The minimum plasma sample volume required is 1 ml per drug analysed, e.g. if a single sample is analysed for saquinavir and ritonavir 2 ml of sample is required. Please do not overfill tubes and allow for expansion on freezing.

Sample Storage - If collection and transport of samples is to occur on the same day, the samples should be kept in a fridge at 4°C prior to transport. If transport is to be later than 24 hours after collection plasma may be stored at –20°C (or lower) and packed whilst frozen and allowed to thaw in transit.

Sample Details - Please complete the sample requisition form with as much information as possible to aid us in the interpretation of the results. Please ensure that samples are anonymised and the full name of the patient does not appear on the form or sample tube. The form is available as a Word 97 document or an Acrobat pdf file.

Transportation - Studies have shown that samples may remain at room temperature for 48 h with no effect on drug levels allowing overnight transportation without the need for packing on dry ice. Please notify us of your intention to send samples so we can ensure prompt handling on their arrival.

Samples may be sent First Class using the Royal Mail so long as all the requirements for the packing of pathological specimens are met. Please post early in the week (Monday–Wednesday) so packages do not remain in the University's mail room over the weekend. UN 602 packaging will be returned to the sender for reuse.

We are a member of the Hays DX system and samples may be sent using the PathPak service (Monday–Thursday). There is no charge to the sending laboratory as all inbound mail on this account is charged to us. This allows departments who are not members of an exchange to send samples from another department without incurring any cost to that department. Packaging will be returned to Hays for redistribution to exchanges.

Cost - The cost of analysis per sample is given below. When samples are analysed for saquinavir and nelfinavir under the scheme sponsored by HIV Focus (Roche Products Ltd), Roche will be invoiced directly for such samples.

Single PI or PI + low dose ritonavir = £40
Multiple PIs = £60
Single PI + single NNRTI = £60
Single NNRTI = £40
Multiple PIs + NNRTI = £90

Please note that when low dose ritonavir is given as a pharmacoenhancer (i.e. <400 mg), no clinical interpretation of the result will be provided and ritonavir will not be classed as PI for charging purposes. When given for antiretroviral activity (i.e.>/=400 mg), a clinical interpretation will be provided and ritonavir will be classed as a PI for charging purposes.

For full pharmacokinetic profiles or large numbers of samples, reduced costs may be available. Please contact Sara Gibbons or David Back to discuss rates.

Results - Samples will be analysed as soon as possible; we aim to send results out within two weeks of receiving the samples. When a fax number is given, results will be faxed and the original sent by second class post. In the absence of a fax number, results will be sent by first class post.

Delivery Address - See delivery address at bottom of form page.

 
HIV Treatment Bulletin Vol 3 No 3 April 2002