HIV Treatment Bulletin Volume 3 No.9

Shipments of cut-price anti-HIV drugs were diverted from Africa to Europe by unscrupulous importers organising a multi-million dollar scam that undermines efforts to treat people in poor countries.

GlaxoSmithKline sold Combivir (AZT and 3TC), Epivir (3TC) and Trizivir (AZT, 3TC and abacavir) to Senegal, Ivory Coast, the Republic of Congo, Togo and Guinea-Bissau at only 10% to 20% of the European prices. The 28 shipments would have sold for about $18m in Europe but were sold to Africa for about $3m, which GSK said was cost-price. Within three weeks of arriving at African airports, the drugs were back in Europe going via Paris and Brussels to Antwerp on their way to European pharmacies for sale at European prices. The products were mainly sold in Holland and Germany, but some were distributed in Britain and Switzerland.

GSK told this journal that the profiteers got away with the scam for several months before the authorities in Antwerp noticed discrepancies in July. They seized shipping records and computer files that revealed the scam, which involved two Dutch wholesalers. The Dutch government’s health care inspectorate and the Dutch police are expected to bring charges against a number of European traders in connection with the case.

“The batches are numbered and we now know they all went down to Africa. We will deliver to a wholesaler or airport named by a purchaser,” said Alan Chandler of GSK. He said the drugs were sent back to Europe before they even left the destination airports.

The drugs in question were mostly made in France and were in French packaging. The company is seeking permission from the European Medicines Evaluation Agency to have special packaging for preferentially priced drugs to make it harder to sell them in rich countries.

“As a company we are asking all the authorities, the regulatory authorities, customs etc, to be ever more vigilant in the handling of these products. We are asking people to be more vigilant in getting these drugs to people who need them. The people who lose out [from profiteers reimporting preferentially priced drugs] are poor people in Africa.

“However,” he said, “this hasn’t shaken our resolve to supply these drugs at preferential prices.”

The Dutch authorities have recalled all illegally distributed medicines to rule out any health risks.

Pharmaceutical companies long argued against preferential pricing for poor countries. One of their arguments was that it would be impossible to stop cheap drugs being hijacked and resold in rich countries at enormous profit for unscrupulous traders.

comment

GSK tells the truth but is ingenuous when it says “the people who lose out” from scams to reimport preferentially priced drugs are poor Africans. Clearly such scams eat into the very considerable profits the pharmacos can make in rich countries. If all the drugs involved in this case were sold in Europe – and most were – it would have denied sales to GSK that would have given them $15m in profits.

“Defend the pharmaceutical companies’ profits!” may not be a popular slogan, but major pharmacos need to be encouraged to offer low-priced drugs to poor countries, just as generic manufacturers should also be encouraged. The more people selling drugs to the developing world, the cheaper they will become and so more people with HIV will be able to receive treatment.

Governmental and international authorities operating in rich and poor countries have to show they are as vigilant as the customs officers of Antwerp.

HIV Treatment Bulletin Vol3 No9 November 2002

Activists win court battle in campaign for generic production of ddI

Thai activists campaigning to reduce the cost of antiretrovirals won an important victory in October when a Bangkok judge ruled invalid part of a patent held by Bristol-Myers Squib (BMS).

Two people with HIV and two non-governmental organisations, the Thai Organisation of People Living with HIV/AIDS and AIDS ACCESS, took the case to court. They said the American company improperly sought to extend its patent on ddI (didanosine, Videx) to cover dosages beyond those for which it originally applied. The ruling on the antiretroviral ddI EC allows activists to proceed with a lawsuit seeking to completely overturn BMS’s patent on the drug in Thailand and let other companies manufacture generic versions. This could halve the price of ddI in Thailand.

Thailand’s Central Intellectual Property Court ruled that BMS’s patent covers only pills containing between 5 and 100mg of ddI and paves the way for other drug makers to market pills with dosages above 100mg. Judge Kornkanya Suwanpanich’s ruling also affirmed that non-governmental organisations and individuals could challenge patents on social grounds, such as public health. Previously, only companies with a commercial interest in such cases had been complainants.

Thai activists welcomed the court verdict, which was detailed in a statement.

“This is the first court victory of HIV/AIDS patients,” said Nimit Tienudom, executive director of AIDS ACCESS. “We expect this ruling will set a precedent for other AIDS advocacy groups and patients to follow.”

The two Thai PWAs and the organisations said in their complaint to the court that giving BMS exclusive rights to make the drug prevented other firms producing cheaper remedies for Thai PWAs.

The plaintiffs told the court that BMS’s ddI currently cost 40 baht (£0.59) a pill, but the state-owned drugs firm could sell it at half that price if BMS’s rights were limited.

BMS had argued that the AIDS foundation could not act on behalf of PWAs in Thailand and the patent it was holding was valid in other countries.

The company has 30 days to appeal to the country’s Supreme Court. A BMS spokesperson said he would not comment on the case until the company had seen details of the ruling.

The ruling has “opened a new chapter of debate with regard to access to treatment” for people with HIV/AIDS in Thailand, Mukdawan Sakboon writes in an opinion piece for Thailand’s Nation.

Sakboon states that the ruling is significant because it is the first case of its kind to be decided by the court and has “set a precedent” for the second case. Whatever the outcome of the court cases, the consequences “will have great impact on a country hard hit by the AIDS epidemic where access to drug[s] is a big issue,” and will serve as a measure of how governments should balance intellectual property protection with public health needs, Sakboon concludes.

Thailand has around 700,000 PWHIV and sees 20,000 to 25,000 new cases of infection each year.

More than 40 million people are living with HIV/AIDS, most of them in developing nations. The United Nations estimates AIDS will kill 70 million people over the next 20 years unless there are more treatment and prevention initiatives.

Sources: AEGiS, CDC HIV/STD/TB Prevention News Update and kaisernetwork.org

http://ww2.aegis.org/news/re/2002/RE021001.html

Kaisernetwork.org, is a free service of the Kaiser Family Foundation

http://www.kaisernetwork.org

HIV Treatment Bulletin Vol3 No9 November 2002

Global AIDS fund facing bankruptcy

The Global Fund to fight AIDS, the UN-backed scheme launched last year to combat major infectious diseases, could be bankrupt within months if billions of dollars are not added to it, an activist group said on Wednesday.

The Washington-based Global AIDS Alliance said cash pledged so far for next year was little over a quarter of the $4.25 billion Fund officials feel will be necessary.

“The Fund faces de facto bankruptcy in just four months when new requests for funds will pour in,” Alliance global director Paul Zeitz said in a statement.

The Fund, which has so far amassed pledges and donations totalling $2.1 billion from governments and private donors, is already committed to paying out around $1.6 billion over the next five years to help countries fight AIDS, malaria and tuberculosis.

But a second round of requests for help from countries worst affected has been submitted for approval by experts of the Geneva-based Fund, which was set up at the instigation of United Nations Secretary-General Kofi Annan.

No figures have yet been released, but sources close to the Fund told Reuters that the requests were likely to be even greater than in the first round which was held earlier this year.

In launching the Fund, Annan said some $7 to 10 billion would be needed each year from all sources, not solely the Global Fund, to keep the AIDS pandemic in che

Next year, the Fund would require a further $4.6 billion, of which only $300 million had so far been promised in the multi-year donations.

Fund officials declined to comment on figures.

“This data makes clear that the Fund faces a severe financial shortfall. If this shortfall is not rectified, there will be a failure of many (AIDS) programmes,” the Alliance said.

The activists said it was up to the G7 group of the world’s most industrialised states, along with other rich states, to shoulder the bulk of the financial burden.

The United States, which has so far pledged $500 million, must boost its contribution to $3 billion over the coming two years, or 35% of the total, they said.

Source: Reuters Health

HIV Treatment Bulletin Vol3 No9 November 2002

CONFERENCE REPORT

THE 42ND INTERSCIENCE CONFERENCE ON ANTIMICROBIAL AGENTS AND CHEMOTHERAPY (ICAAC)

San Diego 27-30 September 2002

Immunology and treatment interruption data presented at the 42nd ICAAC

Mark Dybul MD, National Institutes of Health (NIH) for HIVandhepatitis.com

All references are to the Programme and Abstracts of the 42nd ICAAC.

The immunological discussions regarding HIV at the 42nd ICAAC in San Diego focused largely on mechanisms of immune control of HIV, potential mechanisms to enhance immune control of HIV, and the possibility of interrupting HAART in certain patients who may have relatively intact immune systems as determined by CD4+ T cell counts.

Immunological Control of HIV

The biggest news regarding HIV during the conference was David Ho’s presentation describing his lab’s recently published work identifying alpha-defensins -1, -2 and -3 as the elusive CD8 antiviral factor (CAF), soluble factors produced by CD8+ T cells that are responsible for the suppression of HIV in vitro that cannot be attributed to beta-chemokines (MIP 1- alpha and beta and RANTES). (Symposium 139 (H), abstract 1192)

Alpha-defensins are commonly used by the immune system to suppress the activity of extra-cellular bacteria. Levy’s group was the first to describe the existence of CAF in 1986, and in 1995 Gallo’s laboratory identified the beta-chemokines as the major soluble suppressor factor for HIV species that utilise the chemokine coreceptor CCR5, the coreceptor utilised by most viral strains until late in disease.

However, the beta-chemokines had no effect against HIV species that utilise the chemokine receptor CXCR4, and several groups have reported that beta-chemokines do not account for all of the CAF activity of CD8+ T cells against CCR5-utilizing HIV.

In this context, Ho presented his lab’s work identifying the alpha-defensins as the allusive CAF that is not beta-chemokine. Ho studied the CD8+ T cell CAF of three patients in the Aaron Diamond cohort of long term non-progressors (LTNP) who exhibited strong CAF activity in vitro. They then evaluated the supernatants of activated CD8+ T cells from these three patients, four progressors and 15 HIV-uninfected controls by protein chip analysis ; this analysis allows for the identification of small, highly charged proteins that could not be studied easily by technology that was previously available.

Upon identifying alpha-defensins by protein chip analysis, Ho described the experiments whereby antibodies to the alpha-defensins nearly eliminated the ability of CD8+ T cells obtained from LTNPs to suppress CXCR4-utilising HIV in vitro. In addition, antibodies to alpha-defensins, when combined with antibodies to the beta-chemokines, nearly eliminated the ability of CD8+ T cells obtained from LTNPs HIV-infected individuals to suppress CCR5-utilising HIV.

Ho then described experiments in which the alpha-defensins were added in vitro to try to block the ability of six isolates of CXCR4 and CCR5- utilising HIV, and while the results were less impressive, Ho commented that this was likely due to the alpha-defensins currently available not being highly purified. In these experiments, antibodies to the alpha-defensins eliminated the suppressive activity; as was seen in the previous experiments.

Ho noted that the clinical applicability of his findings is unclear; this may be the case because of the difficulty of producing these proteins in a highly purified form, and the potential difficulty of giving the proteins in a high enough concentration to have clinical effect.

In addition, there may be other CAF-related factors that remain to be identified, particularly CAF that may be identified in patients with chronic HIV infection. However, from the data presented it seems the alpha-defensins may play a significant role in suppressing HIV replication in vivo.

Enhancing immune control of HIV

DC-SIGN - gp120 interactions

Although not a mechanism of control of HIV infection in vivo, Kooyk presented her lab’s work elucidating the early events in HIV infection with the hope that therapeutic strategies could be developed to prevent certain means by which HIV seems to co-opt the immune system (abstract 1193). Kooyk et al have previously demonstrated that DC-SIGN, a C-type lectin found on dendritic cells (DC), plays a key role in binding HIV and may therefore be responsible for transporting HIV on DC from the mucosa (vaginal or rectal) to the lymph nodes to disseminate infection. However, DC-SIGN also participates in the regulation of interactions between T cells and DC through ICAM-3, and this interaction is important for inducing an immune response.

Kooyk reported that DC-SIGN has different binding sites for gp120 of HIV and ICAM-3. Therefore, it may be possible to design specific therapies to block the DC-SIGN - gp120 interaction without adversely affecting the beneficial immunologic effects of DC-SIGN - ICAM-3 interactions. In this regard, Kooyk presented data on the identification of antibodies against gp120 that block its interactions with DC-SIGN; this could be a novel vaccine strategy based on a better understanding of HIV immunopathogenesis.

Effects of HAART on immune responses

Smith et al (abstract H-1743) presented their work evaluating thymus size and CD4+ T cell reconstitution following HAART. The authors have previously demonstrated a relationship between a larger thymus size and recovery of naive CD4+ T cells following short term HAART.

In this study, 23 patients underwent thymus CT scans at one and three years of HAART. In 12 patients there was a decrease in size, in nine there was no change, and in two the size increased. However, patients with abundant thymic tissue (five patients) at year three had significantly more naive CD4+ T cells (240) than those with minimal thymic tissue (105, P = 0.007). In addition, 86% of patients had a decrease in IL-7 levels from year one to year three; IL-7 has been associated with T cell depletion in HIV disease.

The authors conclude that IL-7 levels and the thymus appear to be important for T cell restoration in patients receiving HAART.

Forcina et al (abstract H-1747) reported on the positive effects of HAART on the ability of CD4+ and CD8+ T cells to produce the beta-chemokines MIP-1 alpha and beta and RANTES (see above). Six HAART naive, six complete HAART responders and six patients failing HAART were evaluated by stimulating cells with PHA in vitro.

The patients receiving an effective HAART regimen produced a higher level of all three chemokines by both CD4+ and CD8+ T cells compared to HAART-naive patients and those failing HAART, and the levels approximated those of HIV-negative donors. IL-15 enhanced the production of only MIP-1- beta in the drug naive and failing patients, while it increased levels of all three chemokines in patients receiving effective HAART and in healthy donors.

These data lend further support to the potential role of IL-15 as an immunotherapeutic agent, particularly in patients treated effectively with HAART.

Loss of CD4+ T cells during treatment interruptions

There is a growing interest in the clinical safety of discontinuing HAART in patients with < 50 copies/ml of plasma HIV RNA and relatively high CD4+ T cell counts to spare potential toxicity of the drugs and to improve the quality of life of patients.

Seminari (abstract H-1745) presented results from 62 patients with CD4+ T cell counts > 300 and viral load < 50 c/ml in patients who had received a PI-containing regimen for > 6 months. These patients received an intermittent regimen of one month on HAART followed by one month off HAART for six-12 months (76% had reached 12 months). Patients were required to resume therapy if the CD4+ T cell count went below 200; five of the 62 patients met this criterion and all had a nadir CD4+ T cell count < 50 prior to HAART.

Although 12 patients with the same nadir CD4 count did not have drops to < 50 cells, there was a significant risk of reaching the CD4 endpoint for patients with that nadir CD4 count (P=0.005).

These data suggest that patients with low nadir CD4 counts may not be good candidates for treatment discontinuation or intermittent therapy approaches.

References

All references are to the Program and Abstracts of the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy (42nd ICAAC). September 27-30, 2002. San Diego, California.

Copyright 2002 by HIV and Hepatitis.com. All Rights Reserved. Reproduction of articles for personal or educational use is encouraged and does not require permission from the publisher. Permission to re-print copyrighted articles is almost always granted, but does require written permission from the publisher (email webmaster@HIVandHepatitis.com)

Link:

http://www.icaac.org/

HIV Treatment Bulletin Vol3 No9 November 2002

Treatment interruptions may result in poor T-cell recovery in patients with nadir CD+ count <50 cells/mm3

HIVandhepatitis.com report

Treatment interruptions have the potential to decrease the toxicity of highly active antiretroviral therapy (HAART) and improve the immune response to HIV, although the likelihood of the latter appears dubious in chronically-infected patients.

However, they also carry some risk since CD4+ counts can fall significantly in some patients and opportunistic infections and other adverse events can occur. Several studies presented at the 42nd ICAAC examined the safety of treatment interruptions.

One study by Maserati and colleagues evaluated treatment interruptions in 122 patients who had been on PI-containing HAART for more than six months, with a CD4+ count of at least 300 cells/mm3 and a viral load <50 copies/mL on therapy.

The enrolled patients were randomised to continue HAART or to undergo a series of treatment interruptions (TI), with an alternating one month on and one month off HAART for one year. If a patient in the TI arm had a CD4+ T cell count <200 cells/mm3 after an “on” month, he or she had to be dropped from the study.

Pursuant to the protocol five patients in the TI arm had to stop therapy due to a failure of their CD4+ count to recover to >200 cells/mm3 at the end of an on therapy month. All of these patients had a nadir CD4+ cell count <50 cells/mm3. Twelve patients in the TI arm who also had a nadir CD4+ count <50 did not have to stop the TI protocol, and none of the patients with a CD4+ nadir >50 had to do so.

The nadir CD4+ count of the three groups (TI discontinuations with nadir <50 cells/mm3, TI completers with CD4+ count nadir <50 cells/mm3, and TI completers with CD4+ count nadir >50 cells/mm3) revealed differences among the groups in median baseline CD4+ count at therapy discontinuation, 427, 473 and 607 cells/mm3, respectively, but the three groups had similar values regarding age, time on HAART, and duration of HIV-RNA suppression.

Relative to patients who never had a CD4+ count <50 cells/mm, patients with a CD4+ count nadir <50 cells/mm3 had a 17.9 fold increased risk of having to discontinue the TI due to a CD4+ count decrease to <200 cells/mm3 at the end of an on month.

The authors conclude: “The loss of CD4 cells below 200 cells/mm3 was associated with a nadir <50 cells/mm3 and in most cases it is associate to a poor CD4+ cell recovery after ‘off’’ periods.”

Ref: R Maserati and others. CD4+ Cell Loss During STIs (Structured Treatment Interruption). Abstract 1745. 42nd ICAAC

http://www.hivandhepatitis.com/2002conf/iccac2002/main.html

Reproduction of articles for personal or educational use is encouraged and does not require permission from the publisher. Permission to re-print copyrighted articles is almost always granted, but does require written permission from the publisher (webmaster@HIVandHepatitis.com)

HIV Treatment Bulletin Vol3 No9 November 2002

Treatment interruptions are safe in patients with CD4+ count between 300 to 500 cells/mm3 and viral loads lower than 70,000 copies/mL

Brian Boyle MD, for HIVandhepatitis.com

Treatment interruptions are of great interest to patients and clinicians, especially those patients who have been on antiretroviral medications for some time or who started highly active antiretroviral therapy (HAART) when their CD4+ count was still relatively high.

The primary reasons for considering treatment interruptions (TI) are to decrease the toxicity of HAART and improve the immune response to HIV, although the likelihood of the latter appears dubious in chronically-infected patients, but TI carries some risk, including significant declines in CD4+ counts and the risk of opportunistic infections and other adverse events that can occur.

Several studies presented at the 42nd ICAAC examined the safety of treatment interruptions.

In an observational study by Molina and colleagues, HAART was discontinued in a cohort of 49 patients who started antiretroviral therapy with CD4+ counts between 300 to 500 cells/mm3 and viral loads between 10,000 and 70,000 copies/mL. Nineteen of the patients were on dual antiretroviral therapy and 30 were on HAART at the time of discontinuation.

At the time ART was discontinued, the patients’ mean CD4+ count was 769 cells/mm3 and viral load was 704 copies/mL. Four months after stopping therapy, the mean CD4+ count was slightly less than 600 cells/mm3 and the viral load was approximately 35,000 copies/mL.

At the end of follow up (about 16 months), the mean CD4+ count in patients continuing off therapy was approximately 500 cells/mm3 and the viral load was approximately 45,000 copies/mL. Of 10 patients who restarted therapy the only difference between these patients and those who remained off therapy was their time of maintaining a viral load <200 copies/mL, 27.7 and 15 months, respectively (p=0.006).

The patients who restarted the same therapy that they had discontinued did well, with overall a significant recovery in CD4+ count and decrease in viral load, with seven of 10 reaching <20 copies/mL and the other three being ≤500 copies/mL.

The authors conclude: “Discontinuation of HAART in asymptomatic HIV-infected patients with baseline values of CD4+ greater than 350 cells/mm3 and viral loads lower than 70,000 copies/mL is a safe practice that may improve quality of life, avoid drug side-effects and save money. It did not seem to compromise the activity of ART in the future.

Ref: M Molina et al. Discontinuation of Highly Active Antiretroviral Therapy (HAART) in Asymptomatic HIV-Infected patients with CD4+ Counts Greater Than 350 and Viral Load Lower Than 70.000 Copies. Abstract 1082. 42nd ICAAC, September 27 - 30, 2002, San Diego, CA.

http://www.hivandhepatitis.com/2002conf/iccac2002/main.html

comment

Multiple studies have shown that patients who were not treated too early in the HAART euphoria in the late 90s will loose CD4-cells and will have a viral rebound.

The concept of structured treatment interruptions (off and on) is currently flawed by the fact that resistance can occur and that the concept is often not so attractive to patients. Currently the concept of drug holidays limited by CD4 and/or viral load end points (e.g. <300 CD4, >100.000 copies/ml) appear to be gaining favour. These may lead to clinically relevant periods without drug toxicity.

The prerequisite of this approach is that you have enough CD4’s to sacrifice and that you have no AIDS related disease which may worsen (CMV-retinitis, systemic KS etc.).

HIV Treatment Bulletin Vol3 No9 November 2002

Topical transdermal testosterone gel offers significant clinical benefits in hypogonadal HIV-infected patients

By Brian Boyle MD, for HIVandhepatitis.com

Testosterone deficiency is common in HIV infected men. Several studies have shown that testosterone replacement can alleviate symptoms associated with hypogonadism, including loss of libido, fatigue and depression.

Testosterone injections are not easy, however, especially since they may be given by weekly or biweekly deep intramuscular injections of testosterone esters, which are painful, cause wide, non-physiologic variations in serum testosterone levels and may lead to morbidities such as deep abscesses.

Fortunately, a daily topical transdermal testosterone formulation (AndroGel®) is available which provides sustained levels of serum testosterone; however, there are few trials comparing AndroGel to IM testosterone.

In a study by Cohan and associates, the tolerability of a topical testosterone formulation and its effect on quality-of-life were evaluated in 30 hypogonadal HIV-infected male patients on stable regimens of 200-300 mg intramuscular testosterone cypionate (IMT). These patients were recruited from a large HIV treatment centre in Los Angeles.

All subjects were evaluated for eight weeks on IMT and then switched to a daily transdermal application of 5.0-10.0 gm AndroGel. The follow-up period was eight weeks and study outcome variables included serum free (FT) and total testosterone concentrations, body composition analysis (BIA), and quality of life and patient perception surveys. Compliance and adverse events were evaluated at each study visit.

The pharmacologic data collected indicates that the daily application of AndroGel provides a more stable steady state serum testosterone concentration than does IMT, with a mean difference trough to peak FT with AndroGel of 2.2 pg/ml and with IMT of 15.6 pg/ml. In addition, both the mean peak FT of AndroGel (22.7 pg/ml) and of IMT (42.2 pg/ml) were within the normal range for males 20-49 years of age of 13.0-40.0 pg/ml.

The BIA remained stable in both groups. No adverse events were reported at a preliminary interim analysis of 12 patients and results suggested that AndroGel is well tolerated. Quality of life surveys for patients treated with AndroGel showed a trend toward greater physical and emotional well-being and cognitive function.

The authors conclude that topical transdermal testosterone gel used for testosterone replacement therapy in hypogonadal HIV infected patients offers significant clinical benefits and improved patient acceptance versus IM testosterone ester injections.

This study confirms the findings of many clinicians who use AndroGel in their practices but longer-term data regarding comparability of outcomes and improved patient satisfaction are still needed.

Ref: GR Cohan et al. A Prospective Study of the Safety and Efficacy of a Topical Transdermal Testosterone Gel versus Intramuscular Injections of Testosterone for the Treatment of Testosterone Deficiency in Male HIV-Infected Patients. Abstract 1912. 42nd ICAAC, September 27 - 30, 2002, San Diego, CA.

Links:

http://www.icaac.org/

http://www.hivandhepatitis.com/2002conf/iccac2002/main.html

http://www.hivandhepatitis.com/aboutus2.html#brian

HIV Treatment Bulletin Vol3 No9 November 2002

BMS experimental PI atazanavir shows potency comparable to NNRTI efavirenz among treatment-naïve HIV patients

Brian Boyle MD and Ronald Baker PhD , for HIVandhepatitis.com

A HAART regimen containing the experimental protease inhibitor (PI) atazanavir produces an anti-HIV effect comparable to an efavirenz -based HAART regimen, according to data presented at the 42nd ICAAC in San Diego in September.

Atazanavir (ATV) is a once-daily protease inhibitor (PI) that has low pill burden (two pills once daily), a favourable lipid profile with virtually no effect on lipids, and a favourable resistance profile with 150L, a mutation that does not appear to affect the other PIs, being the signature mutation in PI-naïve patients treated with ATV.

More details on the metabolic effects at week 24 of the study

In a double-blind, multinational, randomised trial, 810 ARV-naïve patients (mean viral load ~4.85 log10 copies/mL; mean CD4 ~320 cells/mm3) the potency of ATV was compared to efavirenz (EFV, Sustiva, Stocrin) in combination with fixed-dose AZT (zidovudine, ZDV, Retrovir) + 3TC (lamivudine, Epivir). The efficacy results at week 48 are depicted below

	<400 c/mL *	<50 c/mL *	CD4
ATV	70%	32%	+176
EFV	64%	37%	+160
P	NS	NS	<.05

* ITT (NC=F)

There was no significant difference in either arm between patients of different gender or with a viral load higher or lower than 100,000 copies/mL at baseline.

“These results are promising and important in that atazanavir, if approved, may provide physicians with another first-line treatment option for individuals with HIV and AIDS,” said Kathleen Squires MD, associate professor of medicine, Keck School of Medicine at the University of Southern California, in a press release from Bristol-Myers Squibb. Dr Squires presented the data at the ICAAC meeting in San Diego.

Both medications appeared safe and relatively well tolerated. Rash was more common in the efavirenz arm and jaundice (5%) more common in the ATV arm. In the ATV arm, 33% of patients experienced a grade 3 or 4 bilirubin increase, but only 5% dose reduced and only 1% discontinued ATV due to this side effect.

The study authors concluded: “ATV once daily has similar antiviral efficacy to a standard of care regimen with efavirenz through [48 weeks]. Both were safe, well tolerated. ATV was associated with decreases or minimal increases in lipid parameters.”

While the results for the efavirenz arm are lower than seen in some prior studies, there are several potential explanations for this. These include the multinational nature of the study, the disallowance of nucleoside analogue switches (which led to more patient discontinuations), the use of a very strict analysis of the data (with treatment failure defined as any noncompleter, any disease progression to CDC category C, 2 sequential HIV RNA levels >50, or 1 HIV RNA level >50 if no subsequent value available or if present at the 48 week time point), and the use of a more sensitive viral assay (Amplicor 1.5) than has been used in prior studies.

Still, the net effect of this trial is to find that ATV did just as well as efavirenz in combination with AZT and 3TC.

In May 2002, Bristol-Myers Squibb filed for the registration of atazanavir with the European Medicines Evaluation Agency. The company plans to file for the registration of atazanavir with the United States Food and Drug Administration later this year.

Sources

K Squires and others. Atazanavir (ATV) QD and Efavirenz (EFV) QD with Fixed-Dose ZDV+3TC: Comparison of Antiviral Efficacy and Safety Through Wk 24 (AI424-034). Abstract 1076. 42nd ICAAC Abstracts, September 27 - 30, 2002, San Diego, CA.

Bristol-Myers Squibb. Data show Bristol-Myers Squibb’s investigational protease inhibitor atazanavir provided antiviral effect comparable to Sustiva in treatment-naïve HIV/AIDS patients. Press Release. September 28, 2002.

Personal Communication. David Rosen. September 29, 2002.

comment

These results are still somewhat disappointing considering a success rate of 70-80% (<50 copies) in the recent efavirenz containing studies (TDF 903, FTC both presented as late breaker at ICAAC).

Both studies were multinational and both studies used Amplicor with <50 copies.

An intent to treat analysis which includes patients switching or discontinuing the study drug would be interesting, because if the above explanations are true the success rate should be much higher in this approach.

HIV Treatment Bulletin Vol3 No9 November 2002

Adverse drug reactions and lipodystrophy in children

Polly Clayden, HIV i-Base

Growth hormone deficiency in children

A poster at ICAAC evaluated the role of human growth Hormone (HGH) deficiency in childhood development and HIV related lipodystrophy [1].

Ezeanolue and colleagues described three African-American male children (two HIV-positive and one HIV-negative born to an HIV-positive mother), with growth failure, HGH deficiency and low insulin like growth factor 1 (ILGF-1) serum concentrations. The investigators noted that reports of growth hormone (GH) deficiency in HIV positive children are rare. HIV positive children with growth failure are usually found to have opportunistic infections (OI) and low CD4+ T-cell counts but normal GH and ILGF-1 serum concentrations.

All three children had delayed bone development, height and weights below two standard deviation scores. Two children had small pituitary glands on magnetic resonance imaging (MRI) but with replacement GH therapy they have shown good response and regained their growth velocity.

The investigators speculated on the link between this phenomenon and the exposure to nucleoside analogues in utero, since their mothers had all received AZT during pregnancy.

Thyroid dysfunction in children receiving HAART

Although a high rate of thyroid disorders has recently been described in HIV-infected adults treated with HAART, data on children are lacking.

A poster from Vignano and colleagues, whose group in Milan produce consistently excellent work on paediatric metabolic disorders, presented at the lipodystrophy meeting preceding ICAAC. They evaluated 52 HAART treated children from their cohort over six months for signs of thyroid dysfunction [2].

The investigators found that 19/52 (36.5%) overall showed thyroid abnormalities. They reported that their findings suggested that these abnormalities occurred frequently in HAART-treated children with long lasting immune recovery of viral replication. They identified three associated features: isolated low free thyroxin (FT4) syndrome, sub-clinical hypothyroidism and autoimmune thyroiditis.

The investigators recommend the need for regular monitoring of thyroid function in children receiving HAART.

Therapeutic drug monitoring of efavirenz in pretreated HIV-infected children

It is now fairly well documented that plasma concentrations of antiretrovirals in paediatric patients are extremely variable.

A poster from Breilh and colleagues evaluated the effect of antiretroviral regimens, including the non nucleoside reverse transcriptase inhibitor efavirenz (EFV) on viral load and CD4 cell count in heavily pretreated HIV-infected children, in association with plasma therapeutic drug monitoring (TDM) of EFV.

Sixteen children were assessed over a period of at least two years. Simultaneous PK, virological and immunological parameters were evaluated and plasma EFV concentrations were measured. The target concentration for the EFV trough plasma concentration (C12h) was > 3 µg/ml.

Thirty-two blood samples were obtained 12 hours post dose of EFV. The mean plasma EFV concentration at 12 hours was 1.92 µg/ml and 3.98 µg/ml respectively before and after TDM. Mean doses of EFV were 421 mg/day and 564 mg/day respectively before and after TDM. 13/16 children received 600 mg/day. In comparison with baseline, the children’s viral load decreased by 4.06 log10 and CD4 cell count increased of 267/mm3. 10/16 children achieved a viral load of HIV RNA< 50 copies/ml.

The investigators concluded that: “These results showed the fundamental part of TDM of EFV.” And they continued: “The dose of EFV calculated from the weight of child was not sufficient to obtain an efficacy plasma through (C12h) EFV plasma concentration and could be responsible in the future [for] virological failure.”

Improvement in lipid levels after switching to EFV from PI containing regimens

In an oral presentation McComsey reported the 48 week results of the first PI-switch study in HIV-infected children.

The investigators noted that children might have greater difficulties maintaining viral suppression due to non-adherence and palatability of the drugs. They also pointed out that lipid levels in healthy children vary enormously in age, race and gender. Seventeen children, aged 24-156 months (median 120) were evaluated. All were originally taking a PI-based regimen for 7-50 months (median 35) with HIV-RNA <400 c/ml for 4-55 months (median 13). All children were NNRTI naïve. The PI was switched to EFV while NRTIs were maintained.

All children were heavily pretreated; 88% had prior NRTIs and 41% had prior PI use. The duration of prior ARV therapy was between 21-123 months (median 88). Following the switch to EFV16/17 patients had HIV-1 RNA levels of <50 (in one HIV-1 RNA was 61 c/mL) at wk 48 and CD4% remained stable. Fasting triglycerides, LDL cholesterol levels significantly decreased. There were no significant changes in diet during the study.

The investigators concluded: “Switching to an EFV-containing regimen is safe and well tolerated in children. Fasting triglyceride, total and LDL cholesterol levels decreased significantly.”

References

Ezeanolue E, Hardy SL, Nunlee-Bland G et al. Growth Hormone Deficiency in Children with Perinatally Acquired Human Immunodeficiency Virus Infection. Abstract H-1913. Program and Abstracts 42nd Interscience Conference on Antimicrobial Agents and chemotherapy 27-30 September 2002
Vigano A, Riboni S, Bianchi R et al. High rate of thyroid dysfunction in HIV-infected children receiving highly active antiretroviral therapy. Abstract 96. Program and abstracts 4th International workshop on adverse drug reactions and lipodystrophy in HIV 22-25 September 2002
Breilh D, Pellegrini I , Douard D. Therapeutic Drug Monitoring of Efavirenz in Pretreated HIV-Infected Children. Abstract H-1710 Program and Abstracts 42nd Interscience Conference on Antimicrobial Agents and chemotherapy 27-30 September 2002
McComsey G, Bhumbra A, Maa J. Significant Improvement in Lipid Levels Upon Substitution of Protease Inhibitor Therapy with Efavirenz (EFV) in HIV-infected Children. Abstract. H-1081 Program and Abstracts 42nd Interscience Conference on Antimicrobial Agents and chemotherapy 27-30 September 2002

HIV Treatment Bulletin Vol3 No9 November 2002

suggests Kaletra/Combivir is better tolerated PEP than Combivir/nelfinavir

Graham McKerrow, HIV i-Base

Lopinavir/ritonavir (LPV, Kaletra) and AZT/3TC (zidovudine and lamivudine, Combivir) is “significantly” better tolerated as a post-exposure prophylaxis (PEP) than AZT/3TC plus nelfinavir, according to French researchers.

Dr Christian Rabaud, of the Service des Maladies Infectieuses et Tropicales, Vandoeuvre-les-Nancy, France, presented the preliminary findings of a study at the 42nd ICAAC. Rabaud says the improved tolerance could be because the intrinsic gut tolerance of LPV is better than that of nelfinavir.

The researchers conducted a prospective study of patients seeking HIV prophylaxis at six hospitals in eastern France. Ninety-eight patients were prescribed LPV and AZT/3TC over a 12-month period. The patients were 21 healthcare workers, 56 people who were exposed through sexual contact, two intravenous drug users, and 19 who were exposed to HIV by other means.

The HIV serological status of the source person could be determined in 30 (28.5%) cases; the source person was recognised as seropositive in 16 (53.5%) of these cases. Three people had not begun the prescribed PEP. Nine people were lost to follow-up. Tolerability could be evaluated in 86 people.

In 17 cases, PEP was discontinued before Day Five because the source person was recognised as HIV-seronegative or because the injury was reassessed as “low-risk”. In three (18%) of these cases, side effects were noted before this discontinuation. In 17 other cases, PEP was discontinued for adverse effects (median treatment period = seven days). Fifty-two people completed the 28 days of AZT/3TC plus LPV PEP and 27 (52%) experienced at least one adverse effect: diarrhoea (78%), nausea (63%), asthenia (48%) and/or skin rash (15%). Finally, in the 69 people who should have completed PEP, 44 (64%) experienced at least one side effect.

The researchers conclude: “Tolerability of [AZT/3TC plus LPV] PEP appeared significantly better when compared with [AZT/3TC plus nelfinavir] PEP (side effects : 64% vs 85%; p < 0,003).

Ref: C Rabaud, C Burty, F Truchetet et al. Tolerability of Post-Exposure Zidovudine/Lamivudine + Lopinavir/Ritonavir Prophylaxis of HIV Infection. Presentation Number: H-177. Poster Board Number: 177

comment

Although encouraging it has to be emphasised that this was a single arm study compared to an historical control.

This limits the conclusions which can be drawn from the study markedly.

HIV Treatment Bulletin Vol3 No9 November 2002

Novel approaches to the inhibition of HIV

Andrew T. Pavia, M.D., for theBody.com

HIV has several accessory genes that differentiate it from other lentiviruses. These include tat, rev, vif, vpr, vpu and nef. Of these, only tat and rev are absolutely required for the virus to function and replicate, making them potential treatment targets. Tat is a powerful transactivator of viral transcription. What that means is that the tat protein feeds back into the nucleus and accelerates the production of HIV RNA by more than 100 fold. This, in part, leads to feedback that lets the virus switch from making a small amount of regulatory proteins to making large amounts of structural proteins so it can assemble new virus. Rev is required to make multiple spliced RNA — an essential step in making structural proteins. Both tat and rev have multiple other proven or postulated functions.

Tat antagonists have been explored as potential drugs, as have antagonists of the complex that tat creates with cellular proteins. Work continues, but no promising candidates have emerged. Dr. Cullen’s presentation looked at a totally new and different way of blocking tat and therefore blocking virus.

He focused on two phenomena found in nature, RNA interference and micro RNAs, that destroy target RNA and are used to control protein production. RNA interference occurs when a double-stranded RNA is introduced that can bind to a target mRNA (the RNA used as a template for protein synthesis). These double-stranded RNAs are cleaved by a protein called “dicer” into 22 nucleotide RNAs which inactivate the target mRNA and block protein synthesis. It turns out that RNA interference is a major antiviral defence within plants. Experimentally, he showed that this can block HIV replication if one uses RNA interference to target tat. The problem so far is that there is no practical way to introduce long double-stranded RNA into cells.

Micro RNA is a somewhat similar process. It was discovered during basic science work on development, using the worm C. elegans. Micro RNAs are used in development to turn off the production of proteins at the appropriate time. These micro RNAs are produced as complex 70 nucleotide structures called “stem loop structures.” The fun begins when dicer (the same enzyme as described above) cuts the stem loops into 22 nucleotide RNA segments that target and inactivate the specific mRNA. Dr. Cullen described research in which a transfection vector was created that led to the production of custom designed stem loop structures that created the micro RNA of interest. This allows you to specifically target and knock out protein production by one gene.

He showed preliminary experiments in which this transfection vector was used to introduce micro RNA targeted at tat into HIV-infected cells. HIV production was almost totally blocked! This is one of the most exciting and practical ideas to date for using gene therapy to stop HIV production! Keep that in mind next time you wonder why the US National Institutes of Health funds worm research.

Of course many steps are necessary to prove this is safe and effective. A practical and safe way of transfecting a huge number of cells in an intact animal or person must be found. Nonetheless, this is beautiful science that may lead to exciting and new approaches to controlling HIV over the coming years.

Ref: ICAAC abstract 1784

Source

http://www.thebody.com/confs/icaac2002/pavia6.html

HIV Treatment Bulletin Vol3 No9 November 2002

Lipodystrophy and adverse drug reaction data presented at the 42nd ICAAC

Graeme Moyle, MD, for HIVandhepatitis.com

The last hours of the 42nd ICAAC conference in San Diego was the somewhat disappointing timing for the poster session that covers what is to many patients the most important aspect of the long-term management of HIV disease. However, over the course of the other days there was a range of presentations that included valuable information on lipid abnormalities, morphological change and mitochondrial disease.

Lipid Disturbances

Differentiation of drugs on the basis of lipid abnormalities remains challenging. Within the protease inhibitor class there are a number of comparative studies that enable differentiation between drugs. Kaletra causes greater rises in triglycerides and cholesterol than nelfinavir (Abbott M98-863 study), nelfinavir causes greater rises in cholesterol and triglycerides than the experimental protease inhibitor atazanavir (atazanavir 008 study).

The effect of Lopinavir (Kaletra) on lipid elevation may be exposure specific. Two studies evaluating lopinavir pharmacokinetics and changes in lipids and body composition demonstrated an association between higher lopinavir trough or mean exposures and higher cholesterol or triglycerides elevation.

In one study of 21 individuals where pre- and four hour post-observed dose levels of lopinavir were evaluated in individuals stable on Kaletra based therapy for at least three months, the lopinavir Cmin was higher (4.13 mg/ml) in individuals with triglycerides above 400 mg/dl compared with the Cmin in individuals with triglycerides values below this value (Cmin in 2.64 mg/ml) (p = 0.05)(Abstract H. 1916).

In a second study of 22 individuals receiving Kaletra there was a correlation demonstrated between the mean lopinavir plasma concentration and risk of developing elevated fasting cholesterol, the percent increase in cholesterol from baseline and the percent increase in triglycerides from baseline. No significant correlation was observed between changes in body fat as assessed by CT scan at multiple body sites and plasma lopinavir concentration (abstract H. 1920).

These data raise the possibility that therapeutic drug monitoring of lopinavir levels may have some value in managing dyslipidaemia in individuals receiving Kaletra who do not have other protease inhibitor options. The difficulty however is that the majority of these individuals are likely to be individuals in the salvage setting where higher levels of lopinavir are required to overcome pre-selected protease inhibitor resistance and where reducing drug exposure is likely to impact therapeutic efficacy. Additionally, the fixed dose packaging of Kaletra makes dose adjustment challenging.

New information from the MaxCmin study indicated that not all ritonavir-boosted protease inhibitor-based regimens have the same impact on lipids. This was a randomised open-label comparative study of ritonavir 100 mg twice daily boosting either saquinavir 1000 mg twice daily or indinavir 800 mg twice daily in individuals with a range of different treatment backgrounds.

Total cholesterol and LDL cholesterol rose only modestly (less than 10%) in individuals who received saquinavir but increased 15-20% in those who received indinavir. These differences were statistically significant. Triglyceride increases were also significantly smaller in the saquinavir treated group. Efficacy data from the study favoured saquinavir, as fewer individuals discontinued this agent due to adverse events.

Agouron and Efavirenz: effect on fasting lipids

Two studies compared the effect of nelfinavir with efavirenz on fasting lipid levels over 16 to 24 weeks of follow-up. In study AG 1127, a randomised comparison of nelfinavir (n=102) and efavirenz (n=101) with AZT+3TC in treatment naïve patients, the total cholesterol rose by a similar amount in individuals randomised to nelfinavir (29 mg/dl) and efavirenz (31 mg/dl).

The proportion of patients who achieved the NCEP recommended intervention level of greater than 240 mg/dl was 19% in the nelfinavir group and 16% in efavirenz group. For LDL cholesterol, the mean change in the nelfinavir group was 23 mg/dl but only 12 mg/dl in patients randomised to efavirenz (p = 0.04).

The proportion of patients achieving the NCEP recommended intervention level for LDL cholesterol of >160 mg/dl was 16% in the nelfinavir group and 8% in the efavirenz group, these differences not being significantly different.

For HDL cholesterol, the mean change in the nelfinavir group was 5 mg/dl where HDL rose by 10 mg/ dl in the efavirenz group (p = 0.02). The mean change in triglycerides was smaller in the nelfinavir group (18mg/dl) compared with the efavirenz group (38mg/dl) (p = 0.3) but similar proportions of patients had fasting triglycerides values above 200 mg/dl, 30% and 23% for the nelfinavir and efavirenz groups, respectively.

In a multivariate logistic regression model, baseline LDL cholesterol was the strongest predictor of achieving an LDL in the NCEP recommended intervention range (Abstract H 1914).

Efavirenz improves HDL:LDL ratio

A small study of 17 individuals treated for 16 weeks with efavirenz-based therapy reported more detailed information regarding changes in lipid particle subfractions. Individuals in the study experienced a 22% rise in total cholesterol and a 44% rise in triglycerides levels.

Whilst the LDL cholesterol rose by 17%, the HDL cholesterol rose by 35% leading to an improved HDL:LDL ratio. Sub-fractional analysis indicated that the LDL particles rose only modestly and most of the LDL rise was made up by large LDL, a subfraction of low atherogenic risk. Amongst the HDL fractions the largest rise was seen amongst larger HDL particles, the most cardioprotective subfraction (Abstract H 1917).

A third study also supported the evidence that efavirenz improved lipid profile by substantially increasing the HDL fraction relative to the LDL cholesterol (abstract H 1918).

Atazanavir vs Efavirenz: effects on fasting metabolic profiles

The BMS 034 study provided a randomised comparison of the fasting metabolic profile of individuals commencing AZT +3TC with either the investigational protease inhibitor atazanavir or efavirenz.

Total cholesterol raised by a mean 2% in the atazanavir group and a mean 21% with efavirenz. These changes were made up of LDL cholesterol, which increased by 1% with atazanavir and 18% with efavirenz, and HDL cholesterol which increased by 13% with atazanavir and 24 % with efavirenz over 48 weeks of follow-up (p < 0.0001).

Triglycerides levels actually fell in the atazanavir group by 9% abut rose by 23% in efavirenz treated patients (p < 0.0001). Differences in fasting glucose and insulin were not observed.

Dyslipidaemia

There was limited new information about the management of dyslipidaemia.

Dietary advice and exercise is, of course the first line of therapy, the basic intervention.

A study looking at the impact of dietary advice in people with HIV infection, on therapy and who had either cholesterol > 200 mg/dl or triglycerides values > 200 mg/dl reported data. The study included 161 individuals who are evaluated from baseline to three months with follow-up to six months on 70 individuals.

Patients were evaluated by whether they reported good adherence to the dietary advice or poor adherence to dietary advice. Individuals who adhered to dietary advice saw an 11mg/dl (~5%) median decline in cholesterol at three months relative to a change of just 1mg/dl decline in those who adhered poorly to dietary advice.

Benefits to triglycerides levels were 12 mg/dl (~3%) in individuals in adhered to dietary advice and 1mg/dl in those who did not. Body mass index fell by one unit over three months and two units over six months in individuals who followed dietary advice and fell by _ unit at three and six months in those who did not follow dietary advice, the BMI remaining in the normal range throughout.

These indicate that dietary advice does provide some useful benefits with regard to cholesterol and triglycerides but that changes are modest and many individuals find it difficult to adhere to dietary advice. For example, at three months 58 individuals in the cohort adhered well to dietary advice but 103 individuals had poor adherence to dietary advice (Abstract H 1933).

A previous study with pravastatin plus dietary advice vs. dietary advice alone indicated that individuals who received a pharmaceutical intervention for dyslipidaemia were less likely to adhere to dietary advice (Moyle et al, AIDS 2001).

A clinical cohort analysis of 93 individuals stable on protease inhibitor-based regimens and with triglycerides levels >300 mg/dl and/or cholesterol >280 mg/dl. Patients were given dietary advice and either statins (pravastatin 20 mg qd (n=22), atorvastatin 20 mg qd (n=19)) or fibrates (bezafibrate 400 mg qd (n=27), fenofibrate 200 mg qd (n=25)), in a non-randomised manner.

Over 12 months, statins reduced triglycerides by 39% and cholesterol by 30% and fibrates reduced triglycerides by 40% and cholesterol by 29%, respectively. Reductions in both groups being significant relative to baseline. No differences between choice of fibrate or statin were observed, despite the low dose of pravastatin (normal dose 40 mg daily) and relatively high dose of atorvastatin (recommended starting dose 10 mg in the presence of protease inhibitors) used. Adverse events were uncommon with only six individuals failing to complete 12 months of follow-up.

Morphological changes

Several approaches to the management of morphological change were reported.

Two previously reported randomised studies of substitution of thymidine analogues, or specifically d4T, with abacavir had indicated some modest improvement in fat mass as measured by DEXA scan over six to 12 months (Carr et al JAMA 2002, Moyle et al, World AIDS conference, Barcelona 2002).

Two further cohort studies reported on this management approach at the ICAAC meeting. It is a pity that control populations to gain better understanding of these outcomes were not included in the larger of these studies.

Switch from d4T to Abacavir or Zidovudine: 48-week data

A cohort study of 118 individuals who switched from d4T to (predominantly) abacavir oir zidovudine was followed by DEXA scans. Details of this cohort followed to 24 weeks were reported at the 9th Retrovirus Conference in Seattle earlier this year.

Updated results to week 48 indicated that, relative to baseline, arm fat had increased by 35%, and leg fat by 12%. Abdominal CT scan results indicated a median increase in subcutaneous fat of 4% and a median decrease in visceral fat of 2%. owever, these changes are likely to be within the variances of the test.

Viral load data indicated that 5% of individuals rebounded over 400 copies/ml and 13% of individuals had values above 50 copies/ml at week 48 (Abstract H. 1929). A subgroup of 16 individuals who replaced d4T with abacavir had mitochondrial DNA levels determined from fat, muscle and PBMC at baseline and week 48 using real-time PCR.

Both HIV negative and HIV-positive antiretroviral naive controls were also assessed.

At baseline only seven of the 16 patients entering the cohort demonstrated decreases in mitochondrial respiratory chain complexes one, two or three or decreased citric synthetase (another mitochondrial enzyme). The baseline mitochondrial DNA content in PBMC’s was similar to controls and rose significantly over 48 weeks of treatment. The mitochondrial DNA per fat cell was reported to be markedly reduced at baseline compared to control patients and rose significantly over the course of 48 weeks, but to levels which remained approximately 50% of control values. Muscle mitochondrial DNA was similar to control values at baseline and rose over 48 weeks to values 100% higher than control patients.

Correlation of the data with clinical changes was not reported. The meaning of mitochondrial DNA values that are higher than control values is not known (Abstract H 1930).

A second fat biopsy study found that levels of circulating tumour necrosis factor receptors type I and II were higher in individuals with more extensive and diffuse fat cell apoptosis on fat biopsy samples. As tumour necrosis factor exerts its apoptotic effects by triggering the release of pro-apoptotic mitochondrial factors, these data may provide some linkage with the changes in mitochondrial mass observed in fat cells (abstract H 1915).

Effects on lipoatrophy following d4T switch from d4T to abacavir

A case control study of 30 individuals who switched from d4T-based regimens to abacavir compared with 22 individuals who continued on d4T-based regimens was reported.

No significant differences in changes in cholesterol or triglycerides were observed although lactate levels declined significantly in the group who modified therapy. 43% of cases and 28% of controls reported improvement in their lipoatrophy after six months, although details of how this was assessed were not adequately provided (abstract H 1928).

Treatment of facial lipoatrophy

Plastic surgery offers the best “quick fix” approach for improving facial lipoatrophy. A range of different techniques has been suggested, with the most commonly reported method being the sub-dermal injection of polylactic acid (NewFill™).

Polylactic acid (NewFill)

A randomised study of immediate vs delayed polylactic acid therapy in 30 individuals with facial lipoatrophy was reported. Improvements in appearance were reported by patient’s self-assessment and by independent assessment of photographs. These improvements coincided with declines in anxiety and depression scores as measured by the HADS scale and in increases in facial skin thickness measured by ultrasound (H-1934).

Human growth hormone (Serostim)

A randomised study of 12 lipoatrophic patients with stable weight who received an initial induction period of 4mg/day of recombinant human growth hormone (SerostimÔ) followed by maintenance doses of either 4mg/alternate days, 4mg/ twice-weekly or placebo for a further 12 weeks.

During the initial induction phase, patients gained lean body mass and two to three kilograms of weight, with a decline in truncal fat and improvements in total and LDL cholesterol values.

The self assessed visual analogue scales indicated that patients felt that their physical appearance had improved in a range of body areas including the face. These improvements tended to be maintained over the course of 12 weeks by continued alternate day growth hormone whereas the benefits, in terms of both objective and subject evaluations, were lost in individuals who discontinued growth hormone.

However, at 48 weeks of follow-up, when individuals had been off therapy for a minimum of 24 weeks, it was noted that the patients had tended to maintain the weight that they had gained on growth hormone, but lost lean body mass from their peak 12 weeks values and had increased fat mass relative to baseline values.

Fat gains included increases in both leg and arm fat of approximately 20% (H-1935). These data suggest that further investigation of the benefits of growth hormone in lipoatrophy should be pursued.

References

Unless otherwise noted, all references are to the programme and abstracts of the 42nd ICAAC. September 27 - 30, 2002, San Diego, CA.

Reproduction of articles for personal or educational use is encouraged and does not require permission from the publisher.

Permission to re-print copyrighted articles is almost always granted, but does require written permission from the publisher (email webmaster@HIVandHepatitis.com)

HIV Treatment Bulletin Vol3 No9 November 2002

WORKSHOP REPORT

THE 4TH INTERNATIONAL WORKSHOP ON DRUG REACTIONS AND LIPODYSTROPHY IN HIV INFECTION

San Diego 22-25 September 2002

Leptin, lipodystrophy and insulin resistance

Simon Collins, HIV i-Base

The opening lecture at this year’s lipodystrophy workshop was given by Jeffrey Friedman, who is known for his work identifying genetic causes of obesity, and was titled leptin, lipodystrophy and insulin resistance. [1]

Earlier this year two papers looked at the role of leptin to treat diabetes cases of congenital lipodystrophy and to reverse insulin resistance and hepatic steatosis in patients with severe lipodystrophy who were HIV-negative, so this review in the context of an HIV-focused meeting was welcomed. [2, 3] In the second lecture of the meeting, Phillip Gorden from the research group behind these papers presented a summary of these results. [4]

Leptin and regulation of body weight

Leptin is a natural hormone produced by fat cells that works as an afferent signal in negative feedback loop linking nutrition to other physiologic systems.

This research was based on previous work with an obese mouse that continued to grow to three times normal weight with five times the normal amount of fat, and the discovery of the obi gene that altered the phenotype - making the mouse think it was in state of perceived starvation. As a result it ate more and burnt less in energy.

Friedman explained that circulating leptin is made by fat. If there are inadequate fat stores, leptin levels fall, signalling a response to starvation that includes increasing food intake and reducing energy levels and body temperature etc. When fat levels are high, leptin levels increase, signalling the hypothalamus to respond to obesity by reducing food intake and lipid content in tissue and increasing energy expenditure and insulin action. Leptin acts in the region of the hypothalamus known to regulate feeding and the ob/ob mouse has defective signalling resulting in similar reduced energy and increased food intake. When administered directly to the brain leptin produces higher doses than when given peripherally and a brain-specific knockout of the leptin receptor leads to obesity.

Leptin suppresses the firing rate of some neurons - NPOV and AGRB - and stimulates firing of POMC neurons. When leptin is absent one neuron fires continually and the other stops and vice versa, although the system is more complex than this and involves many other neurons that are less understood. For example, mutations in POMC reducing MC4R explains only 5% of severe obesity in humans and further research is expected to find others.

In addition to effects on metabolism via the hypothalamus, leptin also has a direct effect on T-cells, pancreatic B-cells and skeletal muscle. Immune defects in ob/ob mice include reduced CD4 and CD8 lymphocytes, reduced TH-1 responses, reduced thymus and spleen weight and reduced macrophage function. These same abnormalities are evident in starved mice and leptin corrects these abnormalities in both cases. Less research has been done in leptin deficiency.

Clinical utility of leptin

It was originally thought that leptin could be used to treat obesity in humans, but most overweight humans have normal levels of leptin and these are approximately 50 ng/ml higher than lean individuals – the assumption being that leptin resistance has developed. However, a subset of people have leptin levels less than 10 ng/ml

Some obese subjects have responded in trials, but with only one published study ongoing, research is still assessing whether individuals with lower levels of leptin will respond better and the threshold of response itself isn’t known. However, treating people who have congenital lipodystrophy and leptin levels under 3ng/ml has generated a response. Friedman observed that it is also easier to treat hormone deficiency than hormone resistance.

Congenital leptin deficiency associated with early onset obesity is a rare condition although around 20 cases have been described worldwide and this has been reported to have been reversed by the effect of recombinant leptin therapy in children (NEJM Sadif Farooqi et al 1999).

Leptin and lypodystrophy

Friedman then explained how leptin improves insulin sensitivity and lipid abnormalities indirectly via the CNS but that the exact mechanism for this effect is unknown. As well as improving insulin action it has been shown to improve glucose turnover in normal mice (Kamohara, Nature 1998) and correct insulin resistance and diabetes in lipodystrophic mice (Shimomura, Brown and Goldstein, Nature 1999). As food and diet (‘pair feeding’) had no effect in these studies this suggested leptin is doing something unique to homeostasis that cannot be achieved with diet alone.

The mechanisms of leptin’s effect on insulin sensitivity could be as hormone replacement but leptin deficiency per se is not associated with lipodystrophy and the effect of leptin is not immediate. Something else has to happen and intracellular leptin may reduce the content of peripheral tissues.

In lipodystrophic animals reduction of lipid levels in peripheral tissues were correlated with effects of six different doses of leptin (0-200ng/hr).

An effect on weight was seen at 100ng/ml and higher levels. However correction of hyperglycaemia and hyperinsulinaemia were seen at 50ng/hr without affecting liver triglycerides, which required doses of 200ng/hr. Studies of muscle lipid content and glucose clamps are currently ongoing. The effect of leptin deficiency on liver produces a much enlarged liver in ob/ob mice.

Affymetrix technology used to look for the genes responsible in eight experiments produced 12,000 genes and 96,000 data points ranked to increases in obi liver with stearoyl CoA desaturase (SCD), the rate limiting enzyme in the biosynthesis of monounsaturated fats, at the top of this list.

Leptin and stearoyl CoA desaturase-1 (SCD-1)

Friedman concluded that leptin reduces fat content in peripheral tissues by suppressing SCD-1 having studied the physiologic role of SCD-1 in SCD-1 knockout asebia mice. These mice have reduced weight, reduced adiposity and increased lean mass. They eat less and are resistant to high fat diet induced weight gain. Somehow deficiency of SCD-1 increases energy expenditure and food increases but not sufficiently and lean mass is reduced. Mice lacking SCD-1 also accumulate significantly less triglyceride in liver following EtOH feeding.

The mechanism for this is not known, but the hypothesis proposed is that in the absence of SCD-1 there are reduced triglycerides and reduced VLDL synthesis and that SCD-1 inhibits malonyl CoA (when malonyl reduced PST-1 is inhibited and oxidation is increased).

Alternative possibilities include altered levels of ligands for PPAR-a, PPAR-g or other nuclear hormone receptors, altered phospho-lipid composition changing signal transduction and/or membrane properties and direct or indirect effects of fatty acids on uncoupling proteins.

Limits to treatment based on this approach - and there are no SCD-1 inhibitors near the end of the pipeline - include the risk that increased free radicals could affect cardiovascular effects. Complete deficiency of this enzyme may not be a good thing and we would need to see if partial reduction might be useful.

The biochemical defects of leptin resistance are not known. The concept of insulin resistance for example was developed in the 1950s and yet the chemical molecular basis for this is only just being understood. The biochemical basis cannot be understood until we understand cellular mechanisms of resistance – and this is likely to occur in CNS as no cases of leptin resistance in peripherals has so far been found to lead to any change in phenotype.

The link to lipodystrophy in humans was then explored further in a plenary lecture by Phillip Gorden on the treatment of non-HIV congenital and acquired lipodystrophy with thiazolidinediones and leptin. [4]

Typical physical symptoms include lack of fat, hypertropic muscles and veins, acanthosis nigricans, hirsutism and virilization in women, enlarged liver and ovaries and increased body temperature and sweating.

Three types of clinical phenotypes were given as examples showing acquired lipodistrophy that was complete at age 14, two sisters with congenital lipodystophy and no body fat and an example of dunnigans ‘partial’ lipodystrophy that presented as normal or increased fat in upper body but complete loss of fat in arms and legs.

Genetics of these syndromes have shown the locus for genes for each case at 11q13, 9q34 and 1q21q22 affecting the Seipin, ASPAT2 and Lamin a/c proteins respectively.

Typical laboratory values include insulin resistance and hyperinsulinaemia, diabetes mellitus or impaired glucose tolerance, elevated triglyceride and FFA levels, decreased HDL-cholesterol levels, sometimes elevated LDL cholesterol and elevated androgen levels in women.

The rationale for treating with the PPAR-y agonist troglitazone includes promoting fat cell differentiation in vitro, insulin sensitising and triglyceride lowering in vivo. Arioglu E et al reported statistically significant reductions in HbA5, triglycerides, free fatty acids and liver volume and increases in percentages of fat oxidation and body fat in Ann Int Med, 2000 following six months treatment.

The rationale for leptin was largely outlined through the details in the previous lecture - as some patients with lipodystrophy have low levels of leptin and this was the group of patients studied (leptin levels under 4ng/ml).

Recombinant human methionyl-leptin (sc, BID) (Amgen corp).produces peak effect after 3-4 hours. Average concentrations increased as the dose increased over several months and showed a large variability between patients. Replacement dose was 0.02mg/kg/day for men aged 14 and over, 0.03mg/kg/day from women 14-18 years and 0.04mg/kg/day for women > 18 years. The protocol included a recommendation to adjust other anti-diabetic therapy down if needed, and the wide diversity in background of insulin resistance etc also led to very different results.

Symptoms for patient NIH-1 included an enlarged and distended stomach that was due to increased liver, and triglyceride levels in tens of thousands. In response to treatment and as dose increased to 200ng/ml, triglyceride levels fell, haemoglobin fell over time and liver size reduced by 40%. Benefit has so far continued out to 24 months (triglyceride values settled at 400-900; 200 = ULN) therefore this acquired form of genetic lipodystrophy has profound response.

However, no response to leptin was first found in a congenital case in a person with insulin resistance and diabetes type-1 – although some response may now be starting (after six months). Two sisters responded differently: one is OK. The other stopped treatment at four months – reverted, and then started again – and got a similar response. But the two different response rates in two sisters showed that genotype can produce different responses.

Grouped response showed 60-70% reductions and when contrasted to the troglitazone study showed an enormous difference in the quantitative response to different patients.

In conclusion, leptin was well tolerated, and led to significant decreases in glucose and haemoglobin HbA1c, triglycerides, free fatty acids, liver volume and liver fat as well as reducing resting metabolic rate and food intake. Six patients have been studied out to a year with a few to 18 months. Some neutralising antibodies have been detected but they have not appeared to have an effect on therapy. The dose has not been modified but from animal studies increasing the dose is expected to increase activity.

Future studies also need to determine whether there is an advantage for people who do not have such extreme leptin deficiency, and the protocol has since raised this level to 6ng/ml. No changes in intraabdomial fat have been recognised.

Notes:

** Oral et al reported in the NEJM the benefits from use of recombinant methionyl human leptin (RL) administered sub-cutaneously every 12 hours for four months in nine women with lipodytrophy and serum leptin levels <4ng/ml. Eight women had diabetes mellitus and five had congenital generalised lipodystrophy. The physiologic replacement dose was estimated to be 0.03mg/kg body weight/day for girls under 18 years and 0.04 mg/kg/day for women over 18 years and this was approximately 10% of the doses used in previous obesity trials. Doses were escalated to achieve low, intermediate, and high physiologic replacement levels of leptin during the first, second and third/fourth months respectively.

Four months of therapy decreased average triglyceride levels by 60% (95% confidence interval, 43- 77% ; P<0.001) and liver volume by an average of 28% (95% confidence interval, 20-36%; P=0.002) in all nine patients and led to the discontinuation of or a large reduction in anti-diabetes therapy. Self-reported daily caloric intake and the measured resting metabolic rate also decreased significantly with therapy. Overall, recombinant leptin therapy was well tolerated. [2]

Petersen and colleagues from the same group reported in JCI the results from treating three patients with severe, generalised lipodystrophy associated with diabetes (fasting leptin concentration less than 4 ng/ml) with leptin replacement treatment for three months and six healthy nonsmoking women of similar age, weight, and body mass index as controls. [3]

Chronic leptin treatment improved insulin-stimulated hepatic and peripheral glucose metabolism in severely insulin-resistant lipodystrophic patients and was associated with a marked reduction in hepatic and muscle triglyceride content suggesting that leptin may represent an important new therapy to reverse the severe hepatic and muscle insulin resistance and associated hepatic steatosis in patients with lipodystrophy.

There was a marked reduction in the fasting plasma glucose concentration. The changes in hepatic and peripheral insulin sensitivity were associated with an 86% ± 8% reduction in hepatic triglyceride content (P = 0.008 compared with before leptin treatment) and a 33% ± 3% decrease in muscle triglyceride content (P = 0.006 compared with before leptin treatment). The leptin treatment–induced reduction in muscle triglyceride content was matched by an approximately 30% decrease in muscle total fatty acytl CoA concentrations. Leptin induced reduced food intake, rather than increased energy expenditure, was suggested as the mechanism for reduced triglycerides.

References:

Jeffrey Friedman - Leptin, lipodystrophy and insulin resistance. 4th Intl Workshop on Adverse Drug Reactions and Lipodystrophy in HIV. Sep 22-25 2002. San Diego. Keynote lecture.
Oral EA - Leptin-Replacement Therapy for Lipodystrophy. New England Journal of Medicine February 21, 2002, Volume 346, Issue 8. 570-578.
Petersen KF, Oral EA, Dufour S et al – Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy. Jour Clin Invest May 2002. Vol109 No10 1345-1350.
Phillip Gorden - Treatment of non-HIV lipodystrophy with thiazolidinediones and leptin. 4th Intl Workshop on Adverse Drug Reactions and Lipodystrophy in HIV. Sep 22-25 2002. San Diego. Plenary lecture.

Links:

http://www.intmedpress.com/lipodystrophy/set.cfm

http://www.hivandhepatitis.com/2002conf/adversedrug/main.html

HIV Treatment Bulletin Vol3 No9 November 2002

A range of treatments for facial lipoatrophy

Simon Collins, HIV i-Base

Very few posters or presentations concerned themselves with the clinical management of lipodystrophy and in particular with reconstructive procedure to repair facial atrophy at the 4th International Workshop on Drug Reactions and Lipodystrophy in HIV Infection.

This gap was surprising given that the first presentations on New-Fill were presented at this meeting two years ago and additional treatment and updates were also presented at last year’s meeting. As this area falls outside the regular experience of HIV clinicians, calling on new expertise, a more detailed scientific overview of the risks and benefits of the various corrective procedures would be welcomed in next year’s programme.

The level of interest from patients, and the confusion in this area, was shown at a separate community-organised meeting held on the second evening of the Workshop. Four companies presented different approaches to a capacity audience of around 130 patients, doctors and community advocates. Further details from that meeting including material provided by those companies has been posted to the organisers’ website:

http://www.facialwasting.org

One of the speakers at that meeting also provided the final talk at the Lipodystrophy Workshop and had the difficult task of summarising around 20 treatments, especially as comparative data and results from clinical studies are not available for many of these products.

Dr Jones is a clinical assistant professor at UCLA and an investigator for the SilSkin studies of a new formulation of silicone oil – and his presentation tended, not surprisngly, to show preferences for this treatment. Dr Jones works with Alistair Carruthers (‘the father of Botox’) who has also developed a lipodystrophy scale grade 1-4 to categorise HIV-related atrophy. The overview included slides showing results from each procedure but it was not possible to evaluate single cases with any degree or accuracy or critical comparison.

The four categories of procedure discussed were permanent and non-permanent FDA-approved procedures, and permanent and non-permanent procedures that are non-FDA approved.

Non-permanent FDA-approved procedures included autologous fat transfer – although some surgeons working in this area have claimed that this can produce a lasting result. The procedure is reported as being biocompatible, predictable and safe. It requires the ability to carefully harvest fat and this can present a problem in some patients. It also requires more substantial surgery and related costs. At least one surgeon has suggested that reinjecting fibrous brown fat from a buffalo hump may contribute to more durable results - fat is otherwise usually harvested from the stomach or buttocks – and it can be frozen to be used again later for repeat and corrective administrations.

Collagen injections (products such as Fascian TM) with preserved particulate fascia derived from screened human cadavers are FDA approved as a procedure but non-permanent and its use to correct HIV lipatrophy has reported very short term effects and dissatisfaction with both the duration and cost.

Micronised alloderm (Cymetra TM) is a micronised collagen, reported as being more expensive than other collagen products with permanency of less than six months.

Alloderm is also available in non-micronised sheets that can be implanted through face-lift incision. Cost in this lecture was estimated at greater than $10,000 with limitations of surgical downtime. These grafts may become reabsorbed over time.

Bovine collagen (Collagen TM) is another FDA approved non-permanent treatment that was reported to improve mild lipoatrophy, although this was reported as rapidly reabsorbing over 3-6 months in the 100 patients receiving this treatment in Dr Jones’ practice.

Benefits for HIV-related facial atrophy from regular face-lift surgery were also limited and temporary – particularly if the underlying atrophy continues to progress – and is associated with major surgery and cost.

Permanent implants of ePTFE (Gore-tex, Softform, Ultrasoft) are ‘straw-like hollow implants’ that are threaded under the dermis in a radial distribution. They are FDA approved and have been used to treat HIV-related atrophy (Glougau, ASDS 2000).

Also mentioned in the permanent procedures was a product called SilSkin which is a high grade silicone oil that is reported not to have the problems of migration linked to silicone injections and which is being studied in an FDA approved facial atrophy study although it is not licensed for general use.

The list of non-FDA approved products largely contained products that are available and being used in other countries including in Europe. Non-permanent products include Polylactic acid and hyaluronic acid.

Of these, Polylactic acid (PLA, New-Fill) has received most attention in France and the UK where controlled clinical trials have shown generally very successful results with a high level of patient satisfaction and minimal complications to correct HIV-associated facial lipoatrophy. PLA is non-permanent being rapidly absorbed but then generates new collagen growth that appears to produce lasting results out to two years following three to six courses of initial treatment. Developed in France New-Fill has reportedly been bought by a US-based company and this may lead to controlled studies in the US.

Slides of two complications were shown of minor skin reactions including permanent nodules at the injection side and permanent purple staining of the skin in the area of the injections. In clinical practice a substantial number of patients show only a temporary response despite repeated injections (ref: Stefan Mauss).

Hyaluronic acid gel (Restylane, Perlane) is a polysaccharide component of living tissue that is identical in all species and tissue types and which is bioabsorbable. It is non-permanent and reportedly widely used in Europe. It is manufactured by Q-Med in Sweden and is undergoing FDA studies.

Polymethylmethacrylate (Metacrill, Artecoll) is a permanent injectable filler. Metacrill is used in Brazil and results from this unapproved and unlicensed product were presented by Dr Serra at the liodystrophy workshop in 2001. Artecoll is a formulation of polymethylmethacrylate suspended in bovine collagen and is currently being studied in FDA trials.

The final products listed included even sparser information as permanent treatments. Matrex (acrylate and methylacrylate spheres) and Kopolymer-E (containing polyoxiethylene-4 fatty esther) are both manufactured by Kuhra Vital in Switzerland, but no known regulatory approvals exist for any human indication, and claims of safety and efficacy are unsubstantiated by any clinical trials.

Biopolymere is a silicone product of unknown origin manufactured by Biocell Laboratories in Switzerland reportedly still being used by ‘backroom’ practitioners.

Polyalkylimide (Bio-Alcamid) is a synthetic filling agent (3% polyalkylimide, 97% water) manufactured in Italy (and available in Mexico) that is permanent but which can be removed later if necessary. Pre and post photos were reported as convincing and infections can occur but again no peer-reviewed data has been produced. Information from the Mexican clinic specialising in using this product is available at: http://www.clinicestetica.com

A study presented at the Athens meeting using Polyvinyl gel and polyacramide microspheres (Evolution) covered 35 HIV-positive patients with reported benefits, and only mild facial swelling in two patients.

Conclusion

This presentation clearly showed a wide range of products are currently available and being used in some degree to treat the effects of facial atrophy. However it also raised the significant concerns about lack of safety and efficacy data on many of these products and the vulnerability of patients to less than rigorously studied procedures. An inherent problem for agents used as fillers for cosmetic procedures is that they are usually used for indications not covered by health insurance companies. Because of this, manufacturers are only seeking approval as a medical device which is much easier and less expensive compared to an approval as a medication or medical therapy which would allow for health insurance cover, but needs formal controlled trials.

The list of compounds included in this short presentation was also by no means comprehensive (check out http://www.yestheyrefake.net for a list of injectable fillers used in the US for cosmetic procedures).

In the UK, the results of the Vega study in Paris and a New-Fill study at the Chelsea and Westminster Hospital have led to small numbers of people starting to access this treatment on the NHS. Many more have already accessed New-Fill privately, and the safety profile and results have been widely reported to greatly improve the quality of life for those patients. As with antiretroviral drugs, there will never be sufficient long-term data, but where a procedure has proved both safe and effective it should be available as a reconstructive procedure given that the lipoatrophy is either HIV or medication related.

HIV Treatment Bulletin Vol3 No9 November 2002

ANTIRETROVIRALS

Autopsy evidence confirms that ARVs tackle CNS lesions

Graham McKerrow, HIV i-Base

Neuropathological data from a large autopsy series have confirmed clinical observations concerning the efficacy of HAART in reducing the frequency of HIV-related CNS lesions in AIDS patients.

Researchers in Milan and other Italian centres reviewed 1,597 consecutive autopsies of HIV-positive patients performed between 1984 and 2000. Their objective was to evaluate the prevalence of HIV-related central nervous system (CNS) lesions (HIV-encephalitis and/or HIV-leukoencephalopathy: HIV-E/L) with and without concomitant opportunistic diseases and to correlate it with the changes in antiretroviral treatment that have occurred since the beginning of the epidemic.

They divided the autopsies into four time periods on the basis of the therapeutic regimens available: 1984–1987, no therapy; 1988–1994, monotherapy (AZT, zidovudine); 1995–1996, dual combination therapy with nucleoside reverse transcriptase inhibitors (NRTI); and 1997–2000, triple combination therapy including two NRTI and at least one protease inhibitor or non-NRTI.

They found that the CNS of 1,210 patients (76%) was affected by opportunistic diseases, HIV-related lesions or both. The prevalence of HIV-related lesions in the four periods was respectively 54%, 32%, 18% and 15%; this reduction was statistically significant (P < 0.000001). During the last period, however, differences in HIV-E/L between treated and untreated patients were not statistically significant, although there were fewer than expected cases among the treated patients (six instead of eight) and more than expected among the untreated patients (10 instead of eight).

The researchers write: “It must be emphasised, however, that even though lower than that reported in other studies, the frequency of HIV-related lesions is still relatively high in patients on antiretroviral treatments (15%). “In conclusion, our data – obtained from a large autopsy series – support the efficacy of antiretroviral treatment in reducing the frequency of HIV-related CNS lesions in AIDS patients.”

Ref: Vago, Luca; Bonetto, Sara; Nebuloni, Manuela et al. Pathological findings in the central nervous system of AIDS patients on assumed antiretroviral therapeutic regimens: retrospective study of 1597 autopsies. AIDS 2002 Sep 27;16(14):1925-1928

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd= Retrieve&db=PubMed&list_uids=12351952&dopt=Abstract

HIV Treatment Bulletin Vol3 No9 November 2002

New evidence favours routine measurement of plasma concentrations in salvage therapy to maintain sustained drug levels

Graham McKerrow, HIV i-Base

New evidence from researchers in Italy and the UK supports the practice of routine measurements of plasma concentrations in salvage therapy to help maintain sustained drug concentrations in plasma.

Researchers at the University of Turin and the University of Liverpool studied the pharmacokinetics and pharmacodynamics in the clinical use of lopinavir/ritonavir (LPV, Kaletra) in salvage therapy.

In a letter published in the 18 October issue of the journal AIDS, Dr Marta Boffito and colleagues report a study where LPV was administered to 35 HIV-infected patients after therapeutic failure with other protease inhibitors. The pharmacokinetics (trough concentrations) and baseline viral genotype were determined, together with the immunovirological outcome.

The 22 responders had significantly higher mean lopinavir concentrations and lower baseline numbers of mutations. On multivariate analysis, a lopinavir concentration of 5.7 µg/ml or greater was an independent predictor of viral suppression over a nine month follow-up period.

Although the therapeutic efficacy of LPV has been repeatedly confirmed in patients with previous PI exposure and failure, it is not clear to what extent such a regimen is able to overcome pre-existing resistance to other PIs, and whether this can be predicted by the determination of measurable parameters such as baseline viral genotype or pharmacokinetics.

In PI-experienced patients who had a therapeutic failure under lopinavir-containing regimens, mutations at codons 82, 54 and 10 were seen in combination with four additional mutations in the protease genome. According to the latest available information, the assessment of viral susceptibility to lopinavir based on genotyping seems to be quite a quantitative rather than a qualitative matter, with a greater number of protease mutations being associated with increasing EC50 values. In the clinical use of lopinavir in PI-experienced patients, however, it is not yet known whether variations in individual drug levels may have any substantial influence on the therapeutic outcome.

In order to provide additional information on this, the researchers investigated both the pharmacokinetic and genotyping profile of PI-experienced patients who started LPV after therapeutic failure with PI-containing antiretroviral regimens.

Lopinavir plasma trough concentrations and viral genotypes were determined at baseline, and lopinavir trough concentrations were measured by high-performance liquid chromatography–mass spectrometry/mass spectrometry monthly during follow-up, with at least three lopinavir measurements for each patient. Two groups of patients were defined according to the kinetics of their plasma viral load after the initiation of the LPV-containing regimen.

The researchers defined responders (n = 22) as those who achieved and maintained plasma viral loads below the current detectable limit of 50 copies/ml, whereas those whose viral load did not fall to less than 50 copies/ml or showed an increase in viral load during follow-up (median 10 months, range 9–12) or had a detectable viral load at the last evaluation were considered to be non-responders (n = 13).

Patients had a heavy previous intake of nucleoside reverse transcriptase inhibitors (100%; median 78 months, range 8–180) and non-nucleoside reverse transcriptase inhibitors (89%; median 12 months, range 1–58). The time of the previous intake of PI-based combination therapy was 30 months (range 8–58), including saquinavir hard-gel (91.4%), indinavir (74.3%), nelfinavir (68.6%), saquinavir soft-gel (14.3%), ritonavir (11.4%) and amprenavir (11.4%).

No significant difference was recorded by the researchers between responders and non-responders in terms of the previous intake of antiretroviral agents. The intake of LPV led to significant immunological recovery and the inhibition of HIV replication: the mean viral load and CD4 cell count at baseline were 4.9 ± 0.8 log and 235 ± 155 cells/mm3, with no difference between responders and non-responders (4.8 ± 0.9 versus 5.2 ± 0.5 log, P = 0.142; 241 ± 175 versus 225 ± 118 cells/mm3, P = 0.771). At last follow-up, the viral load had declined to 2.3 ± 1.4 log and the CD4 cell count increased to 359 ± 212 cells/mm3, both changes over the follow-up being significant with respect to the baseline values (P = 0.000). 90M, 10I and 71I were the mutations more frequently detected (49, 51 and 40%, respectively).

The mean lopinavir trough concentration was 5.9 ± 1.8 µg/ml (25th and 75th percentiles 4.9 and 6.2 µg/ml). Not surprisingly, report Boffito and colleagues, the 22 full responders had both higher trough lopinavir concentrations (6.5 ± 1.9 versus 4.9 ± 1.1 µg/ml, P = 0.014) and a baseline lower, but not significantly lower, mean number of mutations in the HIV protease genome compared with the rest of the series (4.2 ± 2.4 versus 5.4 ± 2.9, P = 0.194). However, on multivariate analysis, only a lopinavir trough concentration in plasma of 5.7 µg/ml or greater was confirmed as being an independent predictor of viral suppression at the end of follow-up (odds ratio 17.7, 95% confidence intervals 1.1–39.6, P = 0.015).

The researchers write: “Interestingly, all the seven women investigated here had a full response to LPV compared with 15 out of 28 men. Their lopinavir trough concentration was higher than that of the men (7.5 ± 1.5 versus 5.5 ± 1.7 µg/ml, P = 0.012). Moreover, their body weight was significantly lower compared with that of non-responders (61.9 ± 13.8 versus 70.7 ± 6.8 kg, P = 0.040) as well as compared with that of the men (44.7 ± 2.2 versus 70.2 ± 7.1, P = 0.000).

“It would seem that when the number of protease mutations is below five, HIV suppression below 50 copies/ml is achieved and maintained, even at relatively low lopinavir concentrations, but higher drug levels are required to achieve the same result when protease mutations are more than five.

“The cut-off of lopinavir concentration determined here (5.70 µg/ml, relative operating characteristic curve analysis) was just below the mean drug level measured in the whole group, thus suggesting that such an effective concentration was achieved by the majority of patients with ordinary drug dosing. “These data also suggest that in patients whose response to LPV is suboptimal, an increase in dosage could be a useful option. The combination of LPV, as with most other antiretroviral drugs, is administered at the same standard dosage, independently of body weight. According to the lopinavir trough concentrations measured in our patients, and especially considering that no concentration-related side-effects were seen even with drug levels as high as 12.0 µg/ml, it would seem that the opportunity to administer higher dosages in selected cases deserves attention. As there are so far no data on the maximum lopinavir concentration that is tolerated in clinical practice, further investigations are warranted to explore the therapeutic potential of LPV fully.”

They conclude: “We believe that these data lend support to the current practice of measuring plasma concentrations routinely in a salvage therapy setting, as they stress the importance of maintaining sustained drug concentrations in plasma, a solution that allows us to overcome any pre-existing resistance to PIs.”

Ref: Boffito, Marta; Arnaudo, Isabellaa; Raiteri, Riccardoa et al. Clinical use of lopinavir/ritonavir in a salvage therapy setting: pharmacokinetics and pharmacodynamics (Research Letters) AIDS 16(15): 2081-2083 Oct 2002

Link:

http://www.aidsonline.com/

comment

In general higher trough levels in salvage regimens are desirable, however, to balance efficacy and adverse effects a resistance guided trough level, the “virtual IQ”, may represent the best approach currently available for a rational, individualized salvage strategy.

HIV Treatment Bulletin Vol3 No9 November 2002

New safety information for ddI used with ribavirin

The ddI (didanosine, Videx) label has been revised to include new, precautionary information about co-administration of VIDEX and ribavirin (RBV) in HIV/HCV co-infected patients.

Literature reports [1, 2] and 24 cases submitted to the FDA Adverse Event Reporting System (AERS) were reviewed to examine cases of patients receiving ddI who added treatment with ribavirin. There appeared to be a relationship between the time that ribavirin was initiated and the occurrence of toxicity, on average 4.8 months.

In vitro data demonstrating that RBV increases the levels of the active ddI metabolite, dideoxyadenosine 5’-triphosphate (ddATP), and clinical reports suggesting the potential for didanosine-related toxicities led to the addition of new precautionary language in the ddI label. The following has been added to the “Precautions” section of the label:

“Exposure to didanosine or its active metabolite (dideoxyadenosine 5’-triphosphate) is increased when didanosine is co-administered with ribavirin. Increased exposure may cause or worsen didanosine-related clinical toxicities, including pancreatitis, symptomatic hyperlactatemia/lactic acidosis, and peripheral neuropathy. Co-administration of ribavirin with Videx should be undertaken with caution, and patients should be monitored closely for didanosine-related toxicities. Videx should be suspended if signs or symptoms of pancreatitis, symptomatic hyperlactatemia, or lactic acidosis develop.”

References

Lafeuillade A, Hittinger G, Chadapaud S. Increased mitochondrial toxicity with ribavirin in HIV/HCV coinfection. The Lancet, Vol 357, Jan 27, 2001.
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd= Retrieve&db=PubMed&list_uids=11214134&dopt=Abstract
Salmon-Ceron D, Chauvelot-Moachon L, Abad S, et al. Mitochondrial toxic effects and ribavirin. The Lancet, Vol 357, June 2, 2001.
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd= Retrieve&db=PubMed&list_uids=11407389&dopt=Abstract

This document was provided by the US Food and Drug Administration.

Link:

http://www.aidsinfonyc.org/pwahg/info/riba.html

HIV Treatment Bulletin Vol3 No9 November 2002

US FDA issues new safety information for tenofovir co-administration with ddI

Pharmacokinetic data demonstrate that co-administration of tenofovir (disoproxil fumarate, Viread) and ddI (didanosine, Videx) resulted in significant increases in ddI exposures; this information was included in the tenofovir label at the time it was initially approved. Recently the results of an interaction study of tenofovir and ddI EC were submitted and reviewed. Based on this new study, it was concluded that the magnitude of the interaction between tenofovir and ddI was significant enough to warrant additional precautionary language to be included in both products’ labelling.

ddI Buffered Tablets

Design

This was a Phase I, open-label, multiple-dose, crossover, and drug interaction study. Eighteen otherwise healthy male and female subjects were randomised to receive the following treatments in a random sequence: tenofovir 300 mg once daily for seven days, tenofovir 300 mg plus ddI Tabs 250mg (wt < 60 kg) or 400 mg (wt > 60 kg) once daily for seven days, ddI Tabs 250mg (wt < 60 kg) or 400 mg (wt > 60 kg) once daily for seven days with a seven -day washout between treatments. Tenofovir was administered one hour following ddI Tabs, and both were administered under fasted conditions. Samples for assessment of tenofovir and didanosine pharmacokinetics were collected frequently throughout the study period.

Pharmacokinetic results

The results demonstrated that tenofovir pharmacokinetics were not affected by co-administration of ddI Tabs. However, following co-administration, there were significant increases in ddI exposures.

Effects of tenofovir on ddI pharmacokinetics:

DdI Tabs alone resulted in ddI Area Under the Curve (AUC) of 3560 ng*hr/mL and ddI maximum concentration (Cmax) of 2131 ng/mL.
DdI Tabs + tenofovir resulted in a ddI AUC of 5167 (44% increase) and ddI Cmax of 2761 (28% increase).

DdI EC

Design

This was an open-label, fixed-sequence, drug-drug interaction, and drug-food interaction study conducted in 28 healthy volunteers. On day one, subjects received a single 400-mg dose of ddI EC following an overnight fast. On day two, 15 subjects were dosed with tenofovir 300 mg with a light meal. On day eight, subjects took another 400-mg dose of ddI EC two hours prior to tenofovir. On day nine, subjects received ddI EC and tenofovir simultaneously. Samples for assessment of tenofovir and ddI pharmacokinetics were collected frequently throughout the 15-day study period.

Pharmacokinetic results

The results demonstrated that ddI EC had no effect on the pharmacokinetics of tenofovir. However, either following simultaneous (fed) or staggered (fasted) administration, there were significant increases in ddI exposures.

Effects of tenofovir on ddI pharmacokinetics:

DdI EC alone resulted in ddI AUC of 3160 ng*hr/mL, and ddI Cmax of 1050 ng/mL.
DdI EC + tenofovir (simultaneous) resulted in ddI AUC of 4990 (* 60% increase) and ddI Cmax of 1720 (* 64% increase).
DdI EC (two hours prior to tenofovir) resulted in ddI AUC of 4660 ng*hr/mL (* 48% increase) and ddI Cmax of 1560 (* 48% increase).

Based on the results of these two interaction studies, the ddI and tenofovir labels have been revised as follows:

The pharmacokinetic results of both interaction studies are being added.
The following precautionary language has been added:

Exposure to ddI or its active metabolite (dideoxyadenosine 5'-triphosphate) is increased when ddI is co-administered with tenofovir. Increased exposure may cause or worsen ddI -related clinical toxicities, including pancreatitis, symptomatic hyperlactataemia/lactic acidosis, and peripheral neuropathy. Co-administration of tenofovir with ddI should be undertaken with caution, and patients should be monitored closely for ddI-related toxicities. DdI should be suspended if signs or symptoms of pancreatitis, symptomatic hyperlactataemia, or lactic acidosis develop.

This document was provided by the U.S. Food and Drug Administration.

Link:

http://www.fda.gov/

HIV Treatment Bulletin Vol3 No9 November 2002

European Commission approves new boosted saquinavir regimen (1000 mg saquinavir / 100 mg ritonavir twice daily) for the treatment of HIV-1

Roche have announced that the Committee for Proprietary Medicinal Products (CPMP) has granted approval for both saquinavir hard gel capsules (Invirase™) and saquinavir soft gel capsules (Fortovase™), to be co-administered with a low dose of ritonavir (1000 mg saquinavir/100mg ritonavir twice daily).*

Boosting saquinavir with low doses of ritonavir allows more saquinavir to be absorbed into the blood and keeps saquinavir in the body for longer. The benefit for patients is that by using this approach, highly potent therapeutic levels of saquinavir are achieved in the blood with an excellent safety and tolerability while it is possible to reduce the dosing frequency and the required number of capsules. Previous regimens of both Invirase and Fortovase have been hampered by high pill burden, poor bioavailability and three times a day dosing requirements.

For an historical overview of the controversies surrounding the development of saquinavir from the Treatment Action Group go to:

http://www.aidsinfonyc.org/tag/tx/sqv.html

Ref: Roche media release

http://www.roche-hiv.com/hotnewsdet.cfm?hnid=246

HIV Treatment Bulletin Vol3 No9 November 2002

METABOLIC TOXICITIES AND SIDE EFFECTS

Tamoxifen for male breast enlargement?

HIV-infected patients who use highly active antiretroviral therapy (HAART) can develop changes in body shape, mostly because of fat loss, fat gain and fat redistribution. Usually, fat in the face, arms and legs gradually disappears while fat builds up in the abdomen, making bellies look larger. In women, breast size may also increase. In men, enlarged breasts are uncommon, occurring between 3% and 5% of HAART users.

The cause of male breast enlargement in HAART users is not clear. When doctors review blood test results, in most cases oestrogen and other hormone levels are within their normal ranges. It is possible that some HAART drugs may have a direct stimulative effect on breast tissue, but this has not been proven. There is also the issue that some male patients are taking other drugs in addition to HAART, which could also have an impact on breast enlargement.

Doctors in London recently reported the details of one of their male patients who developed breast enlargement while on HAART. The HIV positive 30-year-old man was taking the following regimen: 3TC (Epivir, lamivudine), d4T (Zerit, stavudine) and efavirenz (Sustiva)

Six months after he began using this combination, doctors prescribed the appetite booster Megace (megestrol acetate, a female hormone). A further six months later he developed a painful lump in his left nipple, which appeared to be growing. Although he then stopped taking Megace, another lump began to grow in his right breast.

Doctors then prescribed the drug tamoxifen (Novaldex, Tamofen) 10 mg/day for the first month, increasing to 20 mg/day in the second month. This medication is used as part of the treatment of breast cancer. This is because breast tumours thrive on oestrogen, and tamoxifen works by blocking the tumour’s access to oestrogen and thus reducing its growth.

After two months of treatment with tamoxifen, the man’s breasts began to shrink and his doctors plan to continue prescribing the drug for an additional month.

This case highlights some of the potential risks of using drugs such as Megace with HAART in males with HIV/AIDS. Tamoxifen has side effects, including an increased risk of bleeding. Anecdotal reports suggest that it is becoming a common option for the treatment of male breast enlargement associated with the use of HAART. Perhaps a study of the safety and effectiveness of tamoxifen in male HAART users would be useful.

References

Piroth L, Grappin M and Petit JM. Incidence of gynecomastia in men infected with HIV and treated with highly active antiretroviral therapy. Scandinavian Journal of Infectious Diseases 2001;33(7):559-560.
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd= Retrieve&db=PubMed&list_uids=11515774
Paech V, Lorenzen T, von Krosigk A, et al. Gynaecomastia in HIV-infected men: association with effects of antiretroviral therapy. AIDS 2002;16(8):1193-1195.
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd= Retrieve&db=PubMed&list_uids=12004284
Manfredi R, Calza L and Chiodo F. Gynecomastia associated with highly active antiretroviral therapy. Annals of Pharmacotherapy 2001;35(4):438-439.
Kegg S and Lau R. Tamoxifen in antiretroviral-associated gynaecomastia. International Journal of STD & AIDS 2002;13:582-583.
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd= Retrieve&db=PubMed&list_uids=12194746

Source: Canadian AIDS Treatment Information Exchange (CATIE). For more information visit CATIE’s Information Network at:

http://www.catie.ca

HIV Treatment Bulletin Vol3 No9 November 2002

Diet can help reduce lipid levels in people with HAART-related dyslipemia

Graham McKerrow, HIV i-Base

A dietary intervention seems to be moderately effective for reducing lipid levels in HIV-infected patients with highly active antiretroviral therapy (HAART)-related dyslipemia and provides the benefit of avoiding the potential toxicity of lipid-lowering drugs, according to researchers in Madrid.

Changes in cholesterol and triglyceride levels after prescribing a lipid-lowering diet were assessed in 230 HIV-infected patients with dyslipemia associated with antiretroviral therapy. The results were reported in a letter published in the 18 October issue of the journal AIDS

Researchers at the Instituto de Salud Carlos III and the Universidad Autónoma de Madrid report that lipid levels decreased significantly in subjects having good diet compliance. The reduction in triglyceride levels was greater than in cholesterol levels. Patients on protease inhibitor-containing regimens experienced a significantly greater decline in lipid levels compared with the rest.

Dyslipemia associated with HAART is a prevalent condition in patients living with HIV. Both hypercholesterolemia and hypertriglyceridemia constitute well-recognised cardiovascular risk factors.

“This fact raises major concerns,” they write, “because HIV infection has become a chronic disease in most infected patients. Episodes of serious premature vascular events (mainly myocardial infarction) have begun to be reported in individuals on HAART.”

Pancreatitis also represents a relevant complication of severe hypertriglyceridemia. Therapeutic interventions in HIV-infected patients with lipid disorders include low-fat diet, exercise, smoking cessation, drug therapy (fibrates and statins), and a modification of antiretroviral therapy.

No specific recommendations exist for the management of dyslipemia in people on HAART and interventions are based on guidelines drawn up for the general population, report the researchers.

“The use of lipid-lowering drugs is of concern given their toxicity, intolerance, and potential interactions with antiretroviral agents,” they write. “Non-pharmacological interventions (diet and exercise) should always be the first line of intervention.

“In HIV-uninfected individuals, dietary advice may achieve an 11 and 22% decline in cholesterol and triglyceride levels, respectively. In HIV-infected individuals, these figures range from 4 to 17% and from 21 to 26%, respectively.”

They assessed prospectively the efficacy of a low-fat diet on cholesterol and triglyceride level reduction in a well-characterised group of 230 HIV-infected patients on HAART with dyslipemia. Subjects with hypercholesterolemia (cholesterol >= 200 mg/dl) or hypertriglyceridemia (triglycerides >= 200 mg/dl) were prescribed a lipid-lowering diet and followed for three months (n = 161) and six months (n = 70). None received drugs for dyslipemia, and antiretroviral regimens remained unchanged during the study period. Fasting lipid levels, lipid variation (percentage), and nutritional status (weight and serum albumin) were recorded longitudinally. Mean values were compared according to diet adherence and type of antiretroviral regimens.

Lipodystrophy body shape changes were present in 66% of individuals. Within the study population, 40% had only hypercholesterolemia, 7% had only hypertriglyceridemia, and 53% had both.

Overall, 58 (36%) and 32 (45%) of patients reported a good compliance with the prescribed diet at three and six months, respectively. The mean values of lipid levels significantly decreased compared with baseline in those subjects. The reduction at three and six months was of 11% (n = 58) and 10% (n = 28) for cholesterol, and of 12% (n = 31) and 23% (n = 20) for triglyceride levels, respectively. In subjects who were non-adherent to diet, cholesterol values decreased in 1% (n = 92) and 2% (n = 35), and triglyceride values decreased in 1% (n = 66) and 9% (n = 21), respectively, at three and six months.

With respect to antiretroviral treatment, the decrease in lipid levels in patients adherent to diet was greater in those under PI-based combinations, being statistically significant for both cholesterol and triglyceride values at six months. In subjects on PI, cholesterol and triglyceride reductions were 13 and 15% at three months (n = 48), and 22 and 49% at six months (n = 17), respectively. In contrast, in patients under PI-sparing regimens, these figures were 8 and 7% at three months (n = 41), and 3 and 8% at six months (n = 31), respectively.

In multivariate analysis, physical exercise was significantly associated with triglyceride level variation, and good adherence to dietary advice was significantly associated with cholesterol level variation at three months. At six months, the variables significantly associated with a decline in lipids were good diet compliance with triglyceride level variation, and good diet compliance along with PI-based treatment with cholesterol level variation.

The researchers conclude: “A dietary intervention seems to be moderately effective for reducing lipid levels in HIV-infected patients with HAART-related dyslipemia. It provides the benefit of avoiding the potential toxicity of lipid-lowering drugs. Good diet compliance was followed by less than half of the subjects.

“In individuals with mild or moderate dyslipemia, a low-fat diet prescription could be sufficient to treat their metabolic abnormality, particularly if no other cardiovascular risk factors are present. Whereas good diet compliance may result in a significant reduction in triglyceride levels, without compromising the nutritional status, the benefit is less apparent on cholesterol levels. Reductions in cholesterol levels are more apparent in subjects under PI-based combinations.”

Ref: Ana Barrios; Francisco Blanco; Teresa García-Benayas et al. Effect of dietary intervention on highly active antiretroviral therapy-related dyslipemia. (Research letters) AIDS 16(15): 2079-2081; Oct 2002

Link:

http://www.aidsonline.com/

HIV Treatment Bulletin Vol3 No9 November 2002

OPPORTUNISTIC EVENTS

HAART enhances regression of cervical intraepithelial neoplasia in HIV-seropositive women

HIV infection is associated with an increased prevalence and severity and with a lower rate of regression of human papillomavirus (HPV)-associated cervical intraepithelial lesions. With increases in life expectancy due to antiretroviral treatment, one may speculate that HIV-positive women would be put at greater risk of developing cervical cancers from persistent cervical intraepithelial neoplasia (CIN). Alternatively, it is possible that immune restoration associated with antiretroviral treatment would enhance regression of CIN, thereby precluding the development of malignant disease.

However, there have been limited and controversial data on the effect of highly active antiretroviral therapy (HAART).

The authors previously reported a regression rate of 35% of squamous intraepithelial lesions in 34 HIV-seropositive women with cervical disease who were receiving HAART for a median duration of five months. The current article discusses the long-term follow-up (17.7 months) of 168 HIV-positive women with CIN, of whom 96 were receiving HAART.

This was a prospective study of cervical disease in HIV- seropositive women attending two outpatient HIV clinics in Paris initiated in May 1993. The study included 168 HIV-infected women with evidence of CIN until regression to a lower grade or to normality (end-point) or until surgical treatment or last visit. Women were examined every six months by Papanicolaou smears, colposcopy, and biopsy if required. The probability of CIN regression was calculated using survival analysis. HAART was entered as a time-dependent covariate according to the date of first prescription of the medication.

The results indicate that there is a positive association of HAART with CIN regression that may be associated with some restoration of specific immune reactivity. Specific results included: regression of CIN in 67 (39.9 percent) women. The probability values for regression at 12 months were significantly higher for high-grade CIN (23 percent) than for low-grade lesions (14.8 percent). The risk of regression of CIN was twice as high in women receiving HAART as compared with women not receiving HAART. There was a trend for a larger increase in CD4 cell counts among those women taking HAART and who showed regression as compared with those who did not regress.

Importantly, however, according to the authors, the positive effect of HAART on the regression of CIN is not sufficient to modify the current recommendations for the gynaecological follow-up of HIV-infected women, including systematic colposcopy and biopsy if indicated.

Ref:

Heard I, Tassie JM, Kazatchkine MD, Orth G. Highly active antiretroviral therapy enhances regression of cervical intraepithelial neoplasia in HIV-seropositive women. AIDS 2002 Sep 6;16(13):1799-802.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12218392

Source:

CDC HIV/STD/TB Prevention News Update

HIV Treatment Bulletin Vol3 No9 November 2002

IMMUNOLOGY

Study shows why some immune systems can control HIV through CD8 cells

Scientists are beginning to change their thinking about why the immune systems of most people infected with HIV cannot control the spread of the virus while the immune systems of a rare group of individuals, called long-term non progressors, can.

For some time, scientists thought that people who could not control HIV had too few CD8+ T cells. However, a new study suggests the difference is not the number but the quality of these cells: both non progressors and others have about the same number of HIV-fighting CD8+ T cells, but the cells of non progressors function better.

“Understanding the mechanisms by which the immune systems of long-term non progressors control HIV is important to our development of effective vaccines,” says Anthony S Fauci, director of the National Institute of Allergy and Infectious Diseases (NIAID). “Studies like this one, which reveal basic knowledge about how the immune system interacts with HIV, form the foundation of our effort to fight this disease.”

Instead of attacking HIV directly, CD8+ cells inhibit virus spread by killing off other immune system cells infected with HIV. ”For some time we have known that even patients who cannot control HIV maintain high numbers of HIV-specific CD8+ T cells,” says senior author Mark Connors MD, of NIAID’s Laboratory of Immunoregulation. However, this study represents the first time scientists have observed a difference in the HIV-specific CD8+ T-cell response of non progressors, he says. This study also suggests a mechanism whereby the CD8+ T cells of non progressors control HIV and those of most individuals do not.

Dr Connors and colleagues closely examined the immune systems of 40 people infected with HIV, including a group of about 15 non progressors - people who have controlled HIV for up to 20 years without antiretroviral therapy. The researchers found no significant difference in the number of HIV-fighting CD8+ cells between non progressors and the others. Instead, the scientists found that the non progressors’ cells were better able to divide and proliferate when called on to go into action; they also produced higher levels of the molecule perforin, which helps them to kill off cells infected with HIV.

“Some of the newer techniques used in this study enabled us to see the functional differences in the CD8+ T cells of the two groups,” says lead author Stephen Migueles MD, also at NIAID’s Laboratory of Immunoregulation. “The CD8+ T cells of people in the study who did not control HIV had retained only a limited ability to divide and produce perforin.”

This finding is especially important to HIV vaccine research efforts, says Dr Connors, because many candidate HIV vaccines attempt to induce a strong CD8+ T-cell response. New knowledge about CD8+ T-cell function opened up by this line of research might lead to preventive vaccines that avoid the development of poorly functioning CD8+ T-cells. In addition, this research might lead to therapeutic vaccines for HIV-infected people that improve the function of their CD8+ T-cells and control HIV infection.

Next, Dr Connors and colleagues plan to analyse an even broader array of differences between the CD8+ T cells of non progressors and others infected with HIV, seeking to understand what causes the poor function of most HIV-infected people’s CD8+ T-cells.

NIAID is a component of the National Institutes of Health (NIH). NIAID supports basic and applied research to prevent, diagnose, and treat infectious and immune-mediated illnesses, including HIV/AIDS and other sexually transmitted diseases, illness from potential agents of bioterrorism, tuberculosis, malaria, autoimmune disorders, asthma and allergies.

Ref:

SA Migueles and others. HIV-specific CD8+ T-cell proliferation is coupled to perforin expression and maintained in nonprogressors. Nature Immunology, advanced online publication.

Source:

NIAID News http://www.niaid.nih.gov/

HIV Treatment Bulletin Vol3 No9 November 2002

PATHOPHYSIOLOGY

Intestinal worm eradication lowers viral load in HIV-positive patients

Eradication of intestinal worms in HIV-infected patients living in Ethiopia leads to a decrease in viral load, according to a report in the 1 September issue of the Journal of AIDS.

“Helminthic infection affects a huge number of people in the world, and plays a very important role in making them more susceptible to HIV and tuberculosis and less able to mount a proper immune response. Thus, eradication of helminths may change the face of the AIDS and tuberculosis epidemics,” said Dr Zvi Bentwich.

Dr Bentwich, from Hebrew University Hadassah Medical School in Rehovot, Israel, and colleagues investigated whether treatment of helminthic infections would affect HIV disease progression in 56 otherwise asymptomatic HIV-infected Ethiopian patients - for whom antiretroviral treatment is unavailable and in whom helminthic infections are common.

Among the 31 patients with helminthic infections at baseline, there was a strong association between the helminthic load (as measured by the amount of eggs excreted in stools) and the HIV plasma viral load, the authors report.

Antihelminthic treatment clearly reduced the proportion of helminth-infected patients and the helminthic load in patients infected at baseline. According to the report, the successful treatment of helminthic infection was associated with a significant decrease in HIV levels, while the group of patients whose helminthic infections were not eradicated experienced a significant increase in mean HIV load.

“The decrease in HIV viral load, even of 0.35 logs only, is expected to have a very significant impact on the spread of the epidemic in the developing countries,” Dr Bentwich commented.

CD4+ T-lymphocyte counts did not change significantly during the course of the six-month study, the results indicate.

“In the absence of antiretroviral therapy in Africa, and the serious problems of compliance to ART even if it was available, eradication of helminths is a very attractive, simple, cheap and feasible measure to curb HIV infection,” Dr. Bentwich concluded.

Ref: Wolday D, Mayaan S, Mariam ZG et al. Treatment of Intestinal Worms Is Associated With Decreased HIV Plasma Viral Load. J Acquir Immune Defic Syndr 2002 Sep 1;31(1):56-62

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd= Retrieve&db=PubMed&list_uids=12352151

Source:

Reuters Health

HIV Treatment Bulletin Vol3 No9 November 2002

PPAR agonists inhibit HIV replication and TNF-alpha production

In HIV-infected patients, stimulation of peroxizome proliferator-activated receptors (PPAR) may not only improve the metabolic alterations associated with highly active antiretroviral therapy (HAART) but may also decrease viral replication and TNF-alpha production, according to a report in the I September issue of the Journal of Acquired Immune Deficiency Syndromes.

Because of speculation that insulin resistance is involved in HIV-related lipodystrophy, PPAR-gamma agonists (e.g., glitazones) and PPAR-alpha agonists (e.g., fenofibrate) are being used to treat the condition, the authors explain. However, other drugs such as metformin that have been tried have increased HIV replication and decreased CD4 cell counts.

Dr. Paul Skolnik from Boston University Medical Center, Massachusetts, and colleagues investigated the effects of PPAR agonists on HIV replication and TNF-alpha production (which increases HIV replication) in acutely infected human peripheral blood mononuclear cells (PBMCs), alveolar macrophages (AMs), and a monoblastoid cell line chronically infected with HIV-1 (U1 cells).

PPAR agonists inhibited HIV-1 replication up to 65%, depending on drug concentrations and the presence or absence of lipopolysaccharide (LPS), in PBMCs and U1 cells, the authors report, without affecting cell viability except at the highest drug concentrations.

PPAR agonists also significantly inhibited TNF-alpha production in the absence and presence of LPS in PBMCs, U1 cells, and AMs at very low concentrations, the report indicates, with AMs showing greater resistance to the effects of PPAR agonists than the other two cell types.

“We hypothesize that alterations in mitogen-activated protein kinase signaling pathways have contemporaneous and interrelated effects on HIV replication, cytokine production, and lipid metabolism,” the investigators write. “Modulation of these pathways using PPAR agonists may improve the metabolic alterations during HAART in conjunction with desirable decreases in HIV replication and TNF-alpha production.

“More detailed studies of the mechanism of action of these agents on lipid metabolism and HIV replication may allow for the discovery of more selective agents or the establishment of more focused treatment protocols to help HIV-infected persons experiencing adverse metabolic effects from HAART,” the researchers conclude.

Ref: J Acquir Defic Synd 2002;31:1-10.

Source:

Reuters Health

HIV Treatment Bulletin Vol3 No9 November 2002

Many HIV-infected CD4 cells are HIV-specific in patients on HAART

Among HIV-infected patients receiving prolonged highly active antiretroviral therapy (HAART), a substantial proportion of replication-competent HIV-infected CD4 T cells are memory cells directed against HIV determinants, French researchers report.

They suggest that this reservoir of cells might be targeted for elimination using recombinant HIV antigens.

Dr. Yassine Taoufik from Universite Paris, Bic tre, and colleagues studied five HIV-positive patients who were highly adherent to an unmodified HAART regimen and had long-term undetectable HIV levels.

Using a limited dilution-based culture assay, the researchers examined CD4 memory cells infected with replication-competent HIV from these patients to determine their antigen specificities.

They looked at the ability of recall antigens, including Tuberculin purified protein derivative, cytomegalovirus, and HIV-1 p24 with and without HIV-1 Nef, to induce virus production by peripheral blood mononuclear cells (PBMC) depleted of CD8 T cells, according to their report in the 6 September issue of AIDS.

Dr. Taoufik’s team found that the number of HIV-specific cells in the pool of infected CD4 T cells was five to 100 times more than the number of cells with specificities for cytomegalovirus or tuberculin.

They conclude that “altogether, our results show that HIV antigens can induce marked HIV replication by latently infected cells from patients on prolonged HAART.”

Dr. Taoufik and colleagues add that this finding “may provide a rationale for the use of recombinant HIV antigens to activate latently infected cells and thereby to reduce this reservoir, as it is likely that infected cells die following virus activation, while HAART inhibits new cell formation. Specific immunotherapy based on recombinant HIV antigens might have fewer adverse effects than cytokine therapy. “

Ref: AIDS 2002;16:1749-1754.

Source:

Reuters Health

HIV Treatment Bulletin Vol3 No9 November 2002

PHARMACOKINETICS

Milk thistle can reduce levels of indinavir in the blood Hosein SR, for CATIE TreatmentUpdate

Background and summary

Some people with HIV/AIDS (PHAs) use vitamins, supplements and herbs to complement their drug-based therapy. One complementary therapy that is popular is the herb milk thistle. Traditionally, this herb has been used for the treatment of liver disorders such as jaundice (yellowing of the skin and whites of the eyes). Recent laboratory research on cells suggests that milk thistle extracts may be useful in helping the liver and kidneys recover from damage caused by certain drugs and alcohol.

A concern with herbal supplements is that they may interact with medications by either raising or lowering levels of medications used to treat HIV/AIDS and other conditions. Interactions can occur because many drugs are processed by enzymes in the liver. Herbs and drugs can speed up or slow down the activity of these enzymes, raising or lowering drug levels.

If an interaction raises drug levels, new or intensified side effects may occur. Similarly, if drug levels are lowered, the effectiveness of treatments will also be reduced. In the case of therapies for HIV/AIDS, this could lead to the development of drug-resistant HIV and reduced treatment options in the future.

This concern is not just a theory. The plant St John’s wort, often used for managing anxiety and mild depression, can interact with many drugs, including two classes used for the treatment of HIV/AIDS:

protease inhibitors (PIs)
non-nucleoside reverse transcriptase inhibitors (non-nukes or NNRTIs)

In laboratory experiments with cells, researchers found that extracts from milk thistle significantly reduced the activity of certain liver enzymes, specifically those used to process PIs and non-nukes. In theory, these extracts could raise levels of PIs and non-nukes in the blood.

To find out if this was the case in people, researchers at the National Institutes of Health in Bethesda, Maryland, conducted a small study. They found that, overall, milk thistle reduced levels of the PI indinavir (Crixivan) in the blood by about 9%. They also found that just before it was time to take the next dose of indinavir, in subjects using indinavir and milk thistle, blood levels of this drug fell 25% lower than they normally should. The implications of these findings are discussed later in this report.

Study details

Researchers enrolled 10 healthy, HIV negative subjects (four females, six males) whose average age was 35 years. At different times over a period of six weeks, subjects received the following regimens:

indinavir 800 mg every eight hours on an empty stomach
indinavir and milk thistle
milk thistle only

The brand of milk thistle used in the study was Thisilyn, made by Nature’s Way. This product contained 80% silymarin - one of the compounds responsible for the herb’s beneficial effect. Subjects received 175 mg three times daily with meals.

A note about drug levels

The highest level a drug reaches in the blood is called the “peak” and the lowest level the “trough.” The level of a drug in the blood usually reaches the trough level when it’s time to take the next scheduled dose. If viral resistance is to develop, it often occurs when drug levels are at their lowest - the trough.

Results: indinavir and milk thistle

Overall, the total amount of indinavir that entered the blood was decreased by only 9% with the use of milk thistle. Perhaps more significant were the changes in trough levels of indinavir. Levels of this drug are at their lowest just before it’s time to take the next dose - eight hours after the last dose was taken. Milk thistle lowered indinavir trough levels by about 25% compared to their levels when indinavir was taken alone. This change was statistically significant, that is, not likely due to chance alone. In one subject, trough levels decreased by about 60%.

Results: side effects

Milk thistle was “generally well tolerated”; subjects using indinavir reported “an odd taste in their mouth” and nausea.

Why these results?

That milk thistle interacted with indinavir to cause a decrease in that drug’s level in the blood of people is surprising because experiments with cells suggested the opposite. The reasons for this difference may be due to the following:

not using identical ingredients in both sets of studies (test-tube and people)
using a concentration of substances in the lab that is much higher than that used in people
experiments based solely on what’s happening in a test tube don’t always reflect the complexity of the organs and systems found in a body

Milk thistle and HIV/AIDS drugs

A decrease of 25% in trough levels may be a concern for some people who are using only one protease inhibitor in their HIV drug combination. However, in North America and perhaps the European Union, more doctors are increasingly prescribing indinavir along with another PI, ritonavir (Norvir). This is because ritonavir increases or boosts the level of indinavir in the blood and maintains this level for prolonged periods. As a result, ritonavir-indinavir need only be taken twice daily. Similarly, ritonavir is used to boost other PIs including the following:

amprenavir (Agenerase)
lopinavir (in Kaletra)
saquinavir (Fortovase or Invirase)

When taken with ritonavir, because it is such a powerful booster, indinavir levels are not likely to be significantly affected by the dose of milk thistle used in this study.

The effect of milk thistle on unboosted protease inhibitors and non-nukes, until studied, is not clear.

References

Venkataramanan R, Ramachandran V, Komoroski BJ, et al. Milk thistle, an herbal supplement, decreases the activity of CYP 3A4 and uridine diphosphoglucuronosyl transferase in human hepatocyte cultures. Drug Metabolism and Disposition 2000;28(11):1270-1273.
Sonnenbichler J, Scalera F, Sonnenbichler I and Weyhenmeyer R. Stimulatory effects of silibinin and silicristin from the milk thistle Silybum marianum on kidney cells. Journal of Pharmacology and Experimental Therapeutics 1999;290(3):1375-1383.
Flora K, Hahn M, et al. Milk thistle (Silybum marianum) for the therapy of liver disease. American Journal of Gastroenterology 1998 February; 93(2):139-143.
Piscitelli SC, Formentini E, Burstein AH, et al. Effect of milk thistle on the pharmacokinetics of indinavir in healthy volunteers. Pharmacotherapy 2002;22(5):551-556.
Anderson PL, Brundage RC, Kakuda TN and Fletcher CV. CD4 response is correlated with peak plasma concentrations of indinavir in adults with undetectable human immunodeficiency virus ribonucleic acid. Clinical Pharmacokinetics 2002;71:280-285.
Anderson PL and Fletcher CV. Clinical Pharmacological considerations for HIV-1 protease inhibitors. Current Infectious Disease Reports 2001;3:381-387 [Medline].

Source:

CATIE TreatmentUpdate 2002 Sept/Oct Volume 14 Issue 7

HIV Treatment Bulletin Vol3 No9 November 2002

OTHER NEWS

The Children’s HIV Association of the UK and Ireland – CHIVA

This Association has been founded as a sub-section of the British HIV Association (BHIVA) for all professionals involved in issues relevant to children infected or affected by HIV. CHIVA was conceived a year ago and was delivered at the Autumn BHIVA conference this October. The aims in brief are:

to promote issues relevant to children infected or affected by HIV, including perinatal mother-to-infant transmission of HIV
to act as a resource for relevant national organisations such as the Department of Health, Commissioning Authorities, Royal Colleges (such as RCPCH, RCOG, RCN), Public Health Laboratory Service and BHIVA itself
to develop and regularly update standards of care for children and families with HIV, recognising and promoting the multidisciplinary support that is required
to encourage service providers to use the standards for audit, clinical governance and to inform local commissioning authorities
to highlight the needs of adolescents with HIV and promote good practice for transitional care to adult services
to help service providers achieve continuing professional development in this field
to promote involvement in multicentre research trials both by active involvement in trial design and regular open meetings to discuss results, implement evidence based changes in practice and identify future research priorities
to represent relevant issues to the BHIVA Executive Committee and ensure that BHIVA Spring and Autumn conferences and business meetings address these issues

There are now approaching 200 members, and following a ballot of the membership for which the BHIVA Secretariat acted as scrutineers the following were elected to the Executive Committee:

Gareth Tudor-Williams, Paediatrician, St. Mary’s Hospital, London – Chair
Andrew Riordan, Paediatrician, Birmingham Heartlands Hospital.
Elizabeth Kawonza, HIV Health Promotion, Terence Higgins Trust
Sheila Donaghy, Paediatric HIV Nurse Specialist, St. George’s Hospital, London
Hermione Lyall, Paediatrician, St. Mary’s Hospital, London

Anyone interested in joining is encouraged to contact the BHIVA Organising Secretariat who are overseeing all administrative affairs for CHIVA. The address is:

1 Mountview Court,
310 Friern Barnet Lane,
London
N20 0LD.

Tel. 020 8446 8898

Fax 020 8446 9194

email: bhiva@bhiva.org

website: http://www.bhiva.org

Registered Charity No 1056354

HIV Treatment Bulletin Vol3 No9 November 2002

Highlights of the Autumn CHIVA meeting

Pat Tookey gave an update of UK epidemiological data. There has been a continuing rise in antenatal seroprevalence as judged by anonymous unlinked Guthrie card testing. About 1:230 women delivering live babies in London are HIV infected. The most dramatic rise has been in Outer London over the last two years. In the rest of the UK and Scotland, approximately 1:5000 women are infected. Antenatal testing rates are improving but do not look likely to meet the Dept of Health targets of 90% uptake by the end of 2002.

Di Gibb used the Collaborative HIV Paediatric Surveillance study (which captures data on 85% of infected children living with HIV in the UK and Ireland) to draw attention to the improvements in survival for infected children over time.

Crude mortality in vertically infected children by calendar year in this analysis (n=687) showed that the estimated number of children in this follow up rose at approximately 50 children each year from100 in 1991 to 500 in 2000, with a slight fall to 490 in 2001.

In the years 1993-1996 approximately 10-20 deaths were recorded each year, dropping to less than five for 1997 and 1998, no deaths in 1999 and 2000 and a small increase to less than five in 2001.

HIV Treatment Bulletin Vol3 No9 November 2002

Multivitamins limit HIV transmission through breastfeeding for some women

Among women who are immunologically or nutritionally compromised, multivitamin supplementation—excluding vitamin A—reduces the risk of HIV transmission through breastfeeding, according to a report in the 27 September issue of AIDS.

HIV-1 transmission through breastfeeding has been associated with poor maternal micronutrient status, the authors explain, but an earlier study showed that multivitamin supplementation had no statistically significant effect on HIV transmission through the intrauterine or intrapartum routes or through breastfeeding up to six weeks postpartum.

Dr. Wafaie Fawzi from Harvard School of Public Health in Boston, Massachusetts and colleagues examined the effects of maternal supplementation with vitamin A or multivitamins excluding A in approximately 1000 HIV-infected pregnant women in Tanzania. Outcomes were transmission through breastfeeding after six weeks of age and child mortality in the first two years of life.

“To our knowledge,” the investigators write, “this is the first randomized study to examine the effect of maternal multi-micronutrient supplements on infant health [in the setting of HIV infection].”

Multivitamin use had no effect on the overall HIV-1 transmission rate, the authors report, but total child mortality was lower among the multivitamin group than among those who did not receive multivitamins.

Vitamin A supplementation was associated with a 33% higher risk of HIV-1 transmission through breastfeeding compared with the no-vitamin-A arm, the report indicates, though vitamin A use had no effect on infant mortality by 24 months.

In women with low total lymphocyte counts, the researchers note, multivitamin use was associated with a 63% lower HIV transmission rate and with a 70% better chance of infant survival to 24 months.

Moreover, multivitamin use was associated with a reduction in mortality among children who were HIV-negative at birth, the results indicate, but not among those who were HIV-positive at birth.

“Vitamins B, C and E provided to HIV-positive women during pregnancy and lactation are likely to reduce the risks of mortality and other adverse effects among children born to these women,” Dr. Fawzi told Reuters Health.

“There are efforts in many developing countries to encourage early weaning by HIV-positive women—at about six months,” Dr. Fawzi explained. “By this age, the benefits of breastfeeding are thought likely to be outweighed by the risks of transmission. So the approach would be to provide multivitamins for the duration of breastfeeding as well as during pregnancy.”

Dr. Fawzi stressed the need to maintain efforts to get antiretroviral therapy to women in developing countries. “Meanwhile, low-cost interventions, such as micronutrients, could be beneficial in alleviating some of the adverse effects of HIV-infection.”

Ref: AIDS 2002;16:1935-1944.

Source:

Reuters Health

HIV Treatment Bulletin Vol3 No9 November 2002

Prison health services will be taken over by the NHS from next year

Graham McKerrow, HIV i-Base

The National Health Service is to take over from the Prison Service responsibility for the much-criticised health care services in British prisons. It is hoped the changes could improve HIV care in prisons.

The Department of Health will fund prison health services from April 2003 and over the next five years primary care trusts will take responsibility for the commissioning and provision of health services in prisons.

In addition to the funding currently used by the prison service to provide health care for prisoners, the Department of Health will, over the next three years, allocate further resources to improve these services, rising to around an extra £46m a year by 2005-06.

The health services run by the Prison Service have long been criticised. Aids activists have been particularly angry that standards of care vary from prison to prison. Many prisoners are moved from jail to jail on a regular basis and people prescribed drugs in one institution have had difficulty getting them in another. There are worries that such random interruptions to treatment could result not only in poorer health but also in the development of drug resistant virus.

Gabrielle Brown, HIV coordinator at Brixton Prison, where HIV services are already bought in from the NHS, told HTB: “NHS specialists are very important and the Prison Service is to be congratulated for buying in GU and HIV services. This move [to make the NHS responsible for health care in all prisons] should expand an area of good practice.”

An employee of the Prison Service, who asked not to be identified, highlighted the need for more prevention work. He said: “I would like to see a public outcry about clean needles because the risks of transmission in prisons are as bad as they ever were because clean needles are not allowed.”

Home Office prisons minister, Hilary Benn, said: “Improving health services for prisoners is important for their rehabilitation and resettlement to reduce their chances of reoffending. We know that health problems such as mental illness can contribute to reoffending, so high quality, professional care, which continues on release, is vital.”

Dr Paddy Keavney, a Nottingham GP and part time prison medical officer, welcomed the Home Office announcement but warned that prison health services needed more money. “The resources available at the moment do not come anywhere near meeting the needs of the clinical workload in our prisons. There are tremendous manpower problems in terms of recruiting and retaining doctors. If the recruitment problems in general practice are bad, then they are absolutely diabolical in prisons,” he said.

Prisoners’ health is particularly poor, and Home Office studies have found that 90% of all prisoners have a mental health problem (including personality disorder), a substance misuse problem, or both. More than 80% of prisoners smoke and 24% have injected drugs. One in five women prisoners asks to see a doctor or nurse each day.

Last year Martin Narey, director general of the Prison Service, told an NHS Confederation conference that, despite an 18 month partnership between the NHS and the prison service aimed at improving services, few prisoners had seen any real differences.

He added that conditions for some prisoners were “worse than the kennels in which I leave my dog when I go on holiday.”

Joe Levenson, a policy officer at the Prison Reform Trust, welcomed the move to give the NHS responsibility for prison health and said that prisoners were entitled to the same level of health care as any other member of the public.

He added: “There is not enough psychiatric expertise within prison medical teams. Prisoners are some of the neediest people in society, and they are not receiving the level of care they need. There has been a suicide in prison once every four days this year.”

However, Brian Caton, general secretary of the Prison Officers’ Association, said that prisoners should not be treated like ordinary patients.

“When a prisoner becomes ill we have made the mistake of thinking the prisoner ceases to be a prisoner and is now a patient,” he said. “When people have relaxed on that issue they have found themselves with either an injured prisoner or an injured member of staff. People forget that prisoners are capable of extreme levels of violence.”

comment

Activists and professionals may grumble about HIV care and prevention in society at large, but prisoners should be so lucky. In taking over responsibility for health care in prisons, the NHS is taking on a huge and complex responsibility. It will have to tackle problems handed over by the Prison Service, as well as others of its own making. Many people in our jails are there because the NHS has already failed them. If they needed mental health care outside, that need multiplies on the inside.

The system often fails people with HIV in prisons repeatedly and in a number of ways. Prevention initiatives in society have made enormous progress over the years with the distribution of condoms and clean works to avoid transmitting HIV, hepatitis and other infections. This work has hardly begun in prisons.

In the few institutions where condoms are available, some make prisoners ask a doctor for them, others have them freely available in very public places where everyone can see them being collected. The result is that very few are distributed. The NHS should start by making a thorough survey of the provision of condoms in prisons throughout the country.

The situation with IV drug works is even worse. The Prison Service still operates under the pretence that there are no drugs in prisons – a ludicrous self-delusion as has often been reported, most recently by Lord Archer in his prison diaries – and therefore no need for prevention information let alone clean works. Indeed, it is still argued, as it used to be in society at large, that prevention initiatives would encourage drug use. People arrive in prisons having used clean works outside but face risks in prisons as bad as they ever were because clean needles are forbidden. Further, by testing prisoners for drug use they are encouraging the use of heroin – which can be swiftly flushed from the body – rather than marijuana, which can be traced in the body for some weeks after use.

So, the Prison Service encourages the use of IV drugs and takes steps to make sure they are administered with dirty works. The NHS will have to change this culture completely.

Then there is treatment. Or not. The standard of care varies widely between institutions, and it is just bad luck for a prisoner who is moved from one with good HIV health care provision, to one with poor provision. Some prisoners receive treatment, some don’t and others have treatment started but interrupted. The NHS will have to end a system that denies treatment to people or treats people in ways that lead to them developing virus that is resistant to treatment.

The NHS must take into prisons its excellent record on confidentiality. It must take the healthcare to prisoners, not the other way round: taking prisoners on a regular basis to sit in chains in a public clinic must be halted.

The prison authorities have clung to policies that spread the virus, deny treatment and develop drug resistant strains of HIV. If there were any justice, the people responsible would be locked up.

The NHS has a tremendous opportunity to revolutionise HIV care in prisons and the Home Office must provide the institutional and political backing for these moves. But they should be wary of placing too much trust in GPs. The HIV experience and knowledge of GPs varies almost as much as current health care in prisons, so we cannot assume that handing matters over to primary health care groups will result in uniform improvements.

When society denies someone their liberty we take on a duty of care, and HIV voluntary organisations have a role to play. We must publicise the issues, pressurise the authorities and support individuals.

HIV Treatment Bulletin Vol3 No9 November 2002

ON THE WEB

New PRN Notebook Online

September 2002, Vol. VII, Num. 3

Includes articles on:

Lymphoma in the setting of HIV disease

David T. Scadden, MD

Lymphomas have long been some of the most devastating and complex opportunistic diseases of HIV infection. Their epidemiologies, both before and after the widespread use of HAART, have not been fully elucidated, and their various treatments, both in the setting of underlying immune suppression and used concurrently with antiretroviral therapy, have not been officially standardized.

As for their etiologies and pathogeneses, there is still much to understand, including the role of Kaposi’s sarcoma-associated herpesvirus (KSHV/HHV-8) and the Epstein-Barr virus (EBV) in the transformation of B-cells into lymphomas in the setting of HIV disease. But this much is clear: lymphomas remain the most lethal complications of HIV disease (Chaisson, 1998).

Yet it is also true that the incidence of HIV-related lymphoma has decreased in recent years. What’s more, the immune recovery associated with antiretroviral treatment has enabled many more patients to better tolerate chemotherapy and to live longer, healthier, and cancer-free lives after receiving what is potentially a grim diagnosis.

Full text at:

http://www.prn.org/prn_nb_cntnt/vol7/num3/scadden_frm.htm

Mitochondrial toxicity in HAART

Hélène C.F. Côté, Ph.D

Damage to cellular mitochondria has snowballed into one of the most feared toxicities of antiretroviral therapy.

Yet its incidence and prevalence among patients being treated with various nucleoside reverse transcriptase inhibitors (NRTIs)—believed to be the most likely culprits—have not been elucidated and the precise role, if any, of drug-induced mitochondrial damage in the development of hallmark NRTI-related side effects remains unclear.

Needless to say, a great deal of research is still needed to better understand the link between antiretroviral treatment and mitochondrial damage and the ways this toxicity can be monitored, managed, and if possible, avoided completely.

Full text at:

http://www.prn.org/prn_nb_cntnt/vol7/num3/cote_frm.htm

Mechanisms of T-cell depletion and repletion in HIV disease

Joseph M. McCune, MD, PhD

More than 20 years since the beginning of the AIDS epidemic, there is still no clear-cut explanation for HIV’s most basic and insidious effect in the human body: the gradual depletion of CD4+ T-lymphocytes in the absence of antiretroviral treatment. At the same time, there is little consensus regarding the mechanism(s) by which CD4+ cell counts improve once therapy is commenced.

On some level, the fact that CD4+ cell counts do improve—both quantitatively and qualitatively—with antiretroviral therapy should be enough to satisfy the hearts and minds of HIV-treating clinicians. But there is much to be gained medicinally with the continued exploration of these fundamental questions. For example, antiretroviral therapy plays a critical role in halting the accelerated destruction of CD4+ cells, perhaps the most widely accepted mechanism of HIV-associated CD4+ cell depletion. But there is also at least one other mechanism to ponder—the impaired production of new CD4+ cells as a result of HIV infection—that may have a significant bearing on the evaluation and potential use of various immune-based therapies in the clinical management of HIV-positive patients.Full text at:

http://www.prn.org/prn_nb_cntnt/vol7/num3/mccune_frm.htm

HAART interruption strategies: how, when & why?

Mark Dybul, MD

Although structured treatment interruptions (STIs) are no longer the most pressing topic among the many researchers who were initially charmed by their multifaceted potential, STIs very much remain in the hearts and minds of clinicians and people living with HIV. And why shouldn’t they? The reasons for wanting to halt therapy, even temporarily, are just as valid today as they once were. Even in this day and age, in which once-daily drug regimens with low pill burdens are plausible, there are countless patients who continue to grapple with adherence issues and treatment ‘burnout’. There is also the issue of long-term side effects, whether it’s preventing, delaying, or reversing their onset.

Immune augmentation still remains a worthwhile goal, although its potential seems limited to those fortunate few diagnosed during the primary stages of infection. Finally, there is the possibility of using STIs to overcome drug-resistant virus in patients running low on fresh treatment options.

It is encouraging to know that numerous researchers, Dr. Mark Dybul being one of them, still see hope in treatment interruption strategies. “It’s important to remember that treatment interruptions have implications on a global scale,” Dr. Dybul said during his opening remarks. “Both in resource-rich and resource-poor areas of the world, toxicities and quality-of-life issues are important factors to consider when discussing long-term treatment. In resource-poor settings, there is also the cost issue to consider. The costs of antiretroviral medication are prohibitive if our goal is to make these therapies more widely available. Reducing the length of time a patient needs to be treated is certainly one way to deal with this issue.”

Full text at:

http://www.prn.org/prn_nb_cntnt/vol7/num3/dybul_frm.htm

HIV/AIDS related Spanish language sites, from thirteen different countries.

http://hivinsite.ucsf.edu/InSite.jsp?page=li-10-01

New treatment information from Visionary Health Concepts

http://www.vhconcepts.com/

Body changes:

The Guide to Lipodystrophy in HIV

A helpful overview of lipodystrophy as it pertains to body changes, including management tools that promote wellness for those suffering from these symptoms. PDF file only:

http://www.vhconcepts.com/pdfs/2002.changes.pdf

LIPOWatch

Receive a monthly one-page fax or e-mail with timely and useful information about the latest research in metabolic abnormalities (eg body changes, insulin resistance).

The LipoWatch fax provides handy management information that not only provides antiviral strategies but also lifestyle support information about vitamins and supplements, exercise and diet, hormone replacement (testosterone and Human Growth Hormone), plastic surgery and other useful information. Latest issue at:

http://www.vhconcepts.com/newsletter/lipo5_email.htm

Fat in the blood

A must-read patient pamphlet for people on anti-HIV medications at risk for dangerous levels of fat (ie cholesterol and/or triglycerides) in the blood. Available in both English and Spanish. PDF file only:

http://www.vhconcepts.com/pdfs/2002.Fat%20in%20the%20Blood.pdf

Current status of ARV treatment interruption and intermittent therapy strategies

Joel E Gallant, MD, MPH from Medscape HIV/AIDS eJournal (TM)

Only a few years ago there was no term for a medically sanctioned interruption of antiretroviral therapy. Patients who interrupted therapy generally did so of their own volition, and this was called “nonadherence.” Doctors occasionally recommended “drug holidays” to allow resolution of drug toxicity, but otherwise it was assumed that once started, antiretroviral therapy was a life-long commitment. Today, the situation is different.

Treatment interruption studies abound, and intermittent therapy strategies are being embraced outside of clinical trials by both clinicians and their patients. The rationale for treatment interruption varies from study to study, and the terminology remains variable and imprecise. This article discusses the data and current thinking on a variety of treatment interruption and intermittent therapy strategies.

Full text at:

http://www.medscape.com/viewarticle/440897

Pathogenesis and epidemiology of metabolic abnormalities

Judith S Currier MD MSc

from HIV/AIDS Annual Update 2002

The metabolic and morphologic abnormalities that complicate the management of HIV infection include dyslipidemia, insulin resistance, peripheral fat wasting, central fat accumulation, lactic acidemia and acidosis, reduced bone mineral density, and avascular necrosis of hip and shoulder. The interrelationship between these clinical problems and the roles of specific antiretroviral agents and HIV infection itself in their pathogenesis have been the focus of intensive clinical investigation for several years.

Concern over the long-term sequelae of these metabolic abnormalities (in particular, cardiovascular risk) has led both clinicians and patients to consider deferring antiretroviral therapy. This review focuses on the epidemiology and pathogenesis of changes in lipids, glucose, and body shape.

In addition, data on the direct effects of antiretroviral agents on these changes are reviewed, and proposed mechanisms promoting specific metabolic complications are highlighted.

Full text at:

http://www.medscape.com/viewarticle/441490

Management of morphologic changes during antiretroviral therapy: insights from etiology

Graeme Moyle MD MBBS, Christine Baldwin BSc Dip Diet

from HIV/AIDS Annual Update 2002

It is now more than two years since the widespread recognition of the metabolic and morphologic changes observed during antiretroviral therapy. The characteristic morphologic changes observed are highly stigmatising to individuals and may lead to consideration of delayed initiation of antiretroviral therapy, modification of established therapy to alternative regimens, or discontinuation of therapy to prevent or attempt to manage the problems.

Debate continues as to the possible linkage of the main components of the syndrome and indeed as to whether several different, overlapping syndromes may exist. The main components, which may be observed individually or in combination in persons on antiretroviral therapy, include:

dyslipidaemia with elevated total cholesterol, low high-density-lipoprotein (HDL) cholesterol, and triglycerides, with increased lipid cycling or turnover
insulin resistance with hyperglycaemia, particularly in individuals with a family history of type two diabetes mellitus
visceral, breast, and/or local fat accumulation
generalised diminution of subcutaneous fat mass, possibly with fat cell loss

Other metabolic and physical changes may also be present in patients receiving long-term antiretroviral therapy, including raised serum lactate, low bone mineral density, avascular necrosis of the hip, hypogonadism, and hypertension. The relationship of these problems to other metabolic and morphologic changes remains to be elucidated.

A clinical case definition has now been developed, based on physician and patient agreement regarding significant and characteristic morphologic changes together with the results of routine blood tests and specialist computed tomography (CT) and dual-energy x-ray absorptiometry (DEXA) investigations. This will potentially enable more homogeneous populations to be studied and comparisons to be made between intervention studies. However, this methodology is not suitable for routine clinical use.

Full text at:

http://www.medscape.com/viewarticle/441842

Entry inhibitors

Joseph J Eron Jr MD

from HIV/AIDS Annual Update 2

Antiretroviral medication development has grown out of an understanding of the HIV life cycle. The more detailed our knowledge about the steps in the viral life cycle, the greater potential there is to develop effective therapies. Steps in the life cycle that are specific for the virus and distinct from ongoing processes in human cells may represent therapeutic targets that have a greater likelihood of success and a lower incidence of toxicity.

Thus, HIV-1 enzymes such as reverse transcriptase (RT), protease, and integrase have been logical targets for inhibition. Success in these areas can be measured by the number of RT and protease inhibitors currently available, although the lack of integrase inhibitors highlights the potential limitations even when a step in the HIV life cycle is fairly well understood.

The interaction of HIV-1 with the cell membrane of CD4+ cells is a process involving several specific interactions between the virus and host and within the viral envelope, and therefore has been an intended target for antiretroviral therapy for many years.

The first interaction between virus and cell is the specific binding of the HIV envelope protein, gp120, to the CD4 molecule, and early attempts to target this interaction held promise in vitro; however, they failed dismally when inhibition of viral replication in the clinical setting was attempted.

In recent years there has been rapid progress towards understanding that the process of HIV-1 attachment and entry into a CD4+ cell can be divided into three basic steps:

HIV-1 attaches to the CD4 molecule on the cell surface via envelope gp120
a conformational change occurs in gp120, allowing it to bind to the chemokine coreceptor (CCR5 or CXCR4)
the HIV envelope fuses with the cell membrane via a structural change in the gp41 envelope protein.

Full text at:

http://www.medscape.com/viewarticle/440909

Diagnosis and management of hepatitis C

David Bernstein MD provides a state-of-the-art guide to the diagnosis and management of this disease entity.

Full text at:

http://www.medscape.com/viewarticle/416562_1

Mitochondrial toxicity

Simon A Mallal FRACP, FRCPA from HIV/AIDS Annual Update 2002

Nucleoside analogue reverse transcriptase inhibitors (NRTI) were the first therapeutic agents to demonstrate clinical efficacy as antiretroviral therapy for HIV infection, and they continue to be used in contemporary highly active antiretroviral therapy (HAART) regimens that may combine three NRTIs, or two drugs from this class with either HIV protease inhibitors (PIs) or nonnucleoside reverse transcriptase inhibitors (NNRTIs).

The use of NRTI therapy appears to be an important determinant of the durability and effectiveness of these HAART regimens, indicating that this drug class will be a component of HIV therapy for the foreseeable future. This knowledge also highlights the need for a comprehensive understanding of NRTI-induced drug toxicities.

As HIV infection becomes a “manageable” disease with greatly reduced morbidity and mortality attributable to immune deficiency, the identification, monitoring, and management of these adverse effects assumes proportionally greater importance in the clinical setting. Full text at:

http://www.medscape.com/viewarticle/441841

HIV-1-associated dementia: a basic science and clinical perspective

Thomas S Diesing MD, Susan Swindells MD, Harris Gelbard MD, Howard E Gendelman MD

from The AIDS Reader ®

HIV-1 associated dementia (HAD) is a metabolic encephalopathy induced by viral infection and fuelled by immune activation of brain mononuclear phagocytes (perivascular and parenchymal macrophages and microglia). These same cells serve as reservoirs for persistent infection and sources for soluble neurotoxins. Neurologic impairments are manifested by cognitive, behavioural, and motor abnormalities that occur years after viral exposure and are associated with depletion of CD4+ T lymphocytes and high viral loads. Improvements in antiretroviral and adjunctive therapies have decreased HAD incidence, but cognitive dysfunction remains a cause of morbidity in many infected persons.

Full text at:

http://www.medscape.com/viewarticle/441085

Clinicians debate antiretroviral tactics and toxicities, resistance testing, and hepatitis virus coinfection

Mark Mascolini - IAPAC Monthly - Vol. 8, No. 7, July 2002

First-time visitors to the University of Chicago’s Gleacher Center, Room 200, may get the vague sense that they’ve seen this place before - perhaps in certain circa-1600 oil paintings. More than anything, Room 200 looks like a 21st century reimagining of a 17th century surgery, those steeply banked semicircles where medicine’s initiates, and the merely curious, gathered to watch the day’s deans dissect cadavers - or less fortunate live specimens - for their edification.

Something very much like that happened on May 16-17, 2002, in Chicago, when the International Association of Physicians in AIDS Care (IAPAC) gathered some of this era’s top HIV thinkers and asked them to anatomise four specimens before an eager crowd. And the specimens were very much alive, and expertly vivisected though not human, mammalian, or even Drosophilian, but rather conceptual.

In anatomy lessons led by Christine Wanke (Tufts University, Boston), Diane Havlir (University of California, San Diego), Daniel Kuritzkes (Brigham and Women’s Hospital, Boston), and Maurizio Bonacini (California Pacific Medical Center, San Francisco), a faculty of eight pared away superficial tissue and probed the tendons of four topics: antiretroviral tactics, their metabolic and morphologic side effects, resistance testing, and the confluence of HIV with hepatitis B and C viruses.

The IAPAC Sessions 2002 differed from classically limned anatomy lessons in another important way: although the audience included a sprinkling of the merely curious, most attendees were anything but acolytes in HIV medicine. They were carefully selected clinicians seeing large quotas of people with HIV, and imbued with a matching commitment to the corpus of complication and contingency that defines the art in this science. Full text at:

http://www.aegis.org/pubs/iapac/2002/ia020703.html

HIV medicine after the Barcelona conference: interview with Howard Grossman MD

AIDS Treatment News Issue #383, September 6, 2002

John S James

Howard A Grossman MD is a leading HIV physician who has practised HIV medicine in New York City since 1987. He is also Assistant Clinical Professor of Medicine at Columbia University and Associate Attending Physician at St. Luke’s Roosevelt Hospital. With his associate and a physician assistant, his clinic works with approximately 850 people living with HIV. AIDS Treatment News interviewed Dr Grossman on 16 August 2002.

Full text at:

http://ww2.aegis.org/pubs/atn/2002/atn38301.html

Once-daily antiretroviral options

STEP Perspective Volume 02, Number 2, Fall 2002

Lara Strick MD

Numerous studies have now shown that very high levels of adherence to medication regimens are necessary for adequate HIV suppression. The ideal antiretroviral (ARV) regimen is simple, effective, and well tolerated. An increasing number of approved once-daily regimens are being used to minimise pill burden and optimise adherence. There is already data showing the efficacy of once-daily dosing of Videx, Epivir, Viread, Viramune, Sustiva, Fortovase/Norvir and Agenerase/Norvir.

Full text:

http://www.thebody.com/step/fall02/once_daily.html

PUBLICATIONS AND SERVICES FROM i-BASE

Introduction to Combination Therapy

This revised August 2002 edition of our guide provides the minimum information required for anyone about to start combination therapy.

As with all i-Base treatment guides is is written in non-technical language in a ‘question and answer’ format.

Guide to Avoiding and Managing Side Effects

This comprehensive 36-page guide, was revised and reprinted in August 2002, and contains individual sections for each of the most common side effects, together with both compimentary and traditional treatments.

This booklet is also available in French and Chinese.

The latest issue of Positive Treatment News (PTN)

The latest issue of Positive Treatment News, our magazine for positive people, looks at adherence (missed any pills recently, need any advice?), the latest information about side effects and treatments, and the benefits and risks of joining a drug trial or study.

There is also a detailed look at weight loss and what can be done about it, the official treatment guidelines, salvage therapy and treatment information provision for the African community.

To order copies, see below.

Changing treatment: an updated guide to second-line and salvage therapy

This is 16-page non-technical guide to resistance testing, intensifying treatment, treatment interruptions, switching drugs to avoid side-effects, experimental drugs and drugs available through expanded access programmes.

HIV i-Base treatment guides are reviewed every six months to keep them up-to-date.

Since the previous edition several new treatments have become available to use in salvage therapy:

The nucleotide tenofovir (Viread) has been approved for use in second-line therapy. This drug can work against virus that has low-level resistance to AZT, 3TC and other nucleosides.
T-20 has started trials in the UK for people resistant to current drugs - with a limited expanded access programme expected to follow later in the year. T-20 will have activity against any resistant virus.

Other changes to this edition are to the sections on phenotypic resistance testing, treatment interruptions and Mega-HAART (and the Optima Study) and changing treatment because of side effects.

The sections on expanded access and experimental treatments have also been updated.

To order copies, see below.

French and Chinese translations of the i-Base booklet on avoiding and managing side effects

This comprehensive 36-page guide is aimed at helping anyone using HIV drugs to get the most out of their treatment, the most out of their relationships with their doctor and other health professionals, to get better medical care to improve their health and, most importantly, to enjoy a better quality of life.

It was written by people who are HIV-positive, who have been on most of the treatments, who have had many of the side effects and who have learnt to negotiate their own healthcare.

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i-Base offers specialised treatment information for individuals, based on the latest research.

We can provide information and advice over the phone, and we can also mail or email copies of the latest research studies relevant to the caller.

For details call the i-Base treatment information free phone line on 0808 800 6013. The line is usually staffed by positive people and is open Mondays, Tuesdays and Wednesday from 12 noon to 4pm.

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HIV Treatment Bulletin Vol3 No9 November 2002