DOCTOR FAX
ISSUE 39 30th January 1998
Sourced Compiled and Edited by Paul Blanchard
Medical Advisor - Dr Graeme Moyle,
Chelsea & Westminster Hospital.
Dr Stefan Mauss
, Munich.
Contents
Ann C. Collier, MD
Introduction
If one views the history and recent events of antiretroviral therapy, the analogy
of a very hilly and winding path comes to mind. The path leads from one place to another, with a final destination that can be imagined
but which cannot be seen beyond the horizon; this describes the tremendous progress that this field continues to make, as
well as the future challenges. However, the path is not a direct, straight approach, but is characterised by highs of excitement
and hope, where it transiently may feel as if we can see far down the road, and lows of disappointment where steep, new challenges
become all too evident.
The past year has had both these aspects. Favorable events include decreasing mortality
and morbidity in persons with AIDS, development of guidelines to assist in use of antiretrovirals in clinical settings, approval
of new antiretroviral agents, and availability of experimental antiretroviral agents via expanded access programs. In contrast,
reports of viral resistance and virological failures with protease inhibitors, potential new complications of antiretroviral
therapies, and dashed hopes about the eradication of HIV have caused disappointment and demonstrated the complexities of understanding
and effectively treating HIV infection.
Clinical Outcome
Clinical benefits of improvements in antiretroviral therapy and management of opportunistic
infections continue to be seen in reports of decreasing mortality and rates of opportunistic infections (1-4). These reports
have originated from several countries and from institutions and clinics in many cities in the United States. Many of these
reports have attributed the clinical improvements to protease inhibitor use, but it is important to be cautious in this interpretation,
since some of the favorable trends predated widespread availability of these agents in many communities. It seems likely
that several factors have contributed to these trends, including widespread use of combinations of antiretroviral therapies,
among them protease inhibitors, use of HIV RNA monitoring, more effective management of opportunistic infections, and possibly
temporal trends in acquisition of HIV years ago. Although current HIV management emphasizes maximal suppression of HIV, even regimens
that result in modest decreases in plasma HIV RNA and which are not currently recommended (such as the addition of lamivudine
to other nucleoside reverse transcriptase inhibitors) improve survival over one year (5). An important issue is whether these
favorable clinical trends will be sustainable--which emphasises the importance of understanding the reasons for success and failure
with newer antiretroviral regimens.
Guidelines
The guidelines for use of antiretroviral therapies that have been developed by organizations
based in the United States have more similarities than differences (6-9). While those outside the field may wonder why
more than one group developed comprehensive therapy guidelines for adults with HIV infection, this is not unique to the field
of antiretroviral therapy. However, the unifying philosophy that all these expert panels expressed was to encourage earlier use
of antiretroviral therapy and to incorporate a goal of maximal suppression of virus (as reflected in plasma HIV RNA) and the use
of potent combinations of antiretrovirals. The aspects which differ among some of the adult recommendations, such as specific plasma
HIV RNA levels for the initiation of therapy in patients with CD4 cell counts greater than 500 per mm3, and the exact drug regimens for first line use are less critical (6,7). The challenge
that faces these (and all) guidelines is to keep them current. If they are out of date, they will not be useful, and persons
with HIV infection will bear the consequences. Clinicians treating patients with HIV infection should be familiar with the latest
versions of these guidelines.
Strategies for Protease Inhibitor Use
There is a dearth of data which answers the question about the best anti-HIV treatment
strategy(ies) for long-term success. (Studies addressing this question are ongoing and being planned.) However, both prospective
clinical studies and reports of the use of protease inhibitors in clinical settings suggest several strategies that are more
likely to result in success as measured by plasma HIV RNA and CD4 cell counts, and one of these is to start multiple new agents
simultaneously. Recent follow-up reports from two clinical studies (Merck's 035 study with indinavir, zidovudine and lamivudine,
and Agouron's 511 study with nelfinavir, zidovudine and lamivudine) emphasised that trends in both HIV RNA and CD4 cells were
better when these agents were started simultaneously than when these therapies were added in a sequential manner (10, 11). Data
from the Merck 035 study showed that the majority of patients able to adhere to their originally assigned triple regimen for 104
weeks had sustained suppression of plasma HIV RNA (~80% below 500 copies/mL and ~65% below 50 copies/mL). Whether these two-year
results will generalise to larger populations remains to be seen.
Several recent reports have described virological outcome associated with use of various
protease inhibitors in clinical settings (12-15). Interestingly, three reports from different institutions each cited almost
identical figures (47-49%) for the proportion of patients taking protease inhibitors (most often with other antiretrovirals)
who had plasma HIV RNA values below the limit of quantification of the assay used, at 16-36 weeks after starting therapy. Many
of these patients had received nucleoside antiretrovirals prior to taking protease inhibitors. Factors associated with failure to
achieve virological suppression included both biological factors (high pre-treatment HIV RNA, low CD4 cells), as well as factors
that may be modifiable (non-adherence). In one of these reports, if at least one new nucleoside reverse transcriptase inhibitor
had been started simultaneously with a protease inhibitor, the rate of virological success rose to 80% (12). These data suggest
a similar clinical message to that mentioned above--if at all possible, when starting a protease inhibitor, add other new agents
at the same time. Unfortunately, there are patients whose prior treatment precludes this approach. In this circumstance, if
a patient is clinically stable, and only "failing" therapy based upon laboratory measures, one approach to consider is to continue
their current regimen until additional new agents are available. The role of phenotypic and genotypic assays to aid clinical
decision making in such circumstances is under study. Finding strategies to increase adherence is also critical.
Metabolic Complications
The epidemiology, aetiology, pathogenesis and best management of the metabolic complications
recently associated with HIV infection need to be investigated. The complications which have been described include new
onset diabetes mellitus and hyperglycaemia, altered lipid metabolism (hyperlipidaemia and hypercholesterolaemia), and body composition
changes (16-19). Whether these are a consequence of HIV infection that has been unmasked by better treatments; a side-effect
of a specific class of antiretroviral agents (e.g. protease inhibitors), specific drugs or regimens; or merely the expression
of concurrent diseases, is not clear. Cases of hyperglycaemia have occurred in patients treated with all four FDA-approved
protease inhibitors, most often within several months of starting a protease inhibitor (16). Current management should include informing
patients taking or considering antiretroviral therapy about the potential for these events and their typical symptoms,
and periodic laboratory and clinical monitoring for these conditions. There is substantial interest in the research community in
these topics, so data to increase our understanding of these events will be forthcoming.
Persistence of HIV
Recent reports have demonstrated that persons who have had sustained plasma HIV RNA
suppression for up to 30 months have HIV present in latently infected cells in the peripheral blood (20,21). These patients were
selected for excellent adherence to their multi-drug antiretroviral regimens. It is now clear that eradication of HIV from a
person is not going to happen with current combination therapies over the time frame of a few years. While disappointing, these
findings emphasise an aspect which was present in all scientific discussions of data about the potential for eradication of HIV--that
this was a hypothesis to be tested--and by no means a proven fact. The creative approaches that these scientists have taken
to increase the sensitivity of HIV cultures in this setting merit recognition. The encouraging news in these reports is the lack
of new mutations associated with drug resistance in the HIV isolates from the later times in these studies. This suggests that
suppression of replication with the combination regimens used was sufficient to prevent the evolution of viral mutants. These
data increase optimism that long-term virologic suppression is possible without the development of viral resistance, if patients
can adhere to a regimen. However, the practical impact of these data are to stress the importance of finding antiretroviral regimens
that will be tolerable, effective, and affordable for long-term use.
References
1. Update: Trends in AIDS Incidence - United States, 1996. MMWR 1997; 46:861-7.
2. Mouton Y, Alfandari S, Valette M, et al. Impact of protease inhibitors on AIDS-defining
events and hospitalizations in 10 French AIDS reference centres. AIDS 1997; 11:F101-5.
3. Moore RD, Keruly JC, Chaisson RE. Effectiveness of combination antiretroviral therapy
in clinical practice. Thirty-seventh Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), Toronto, Ontario,
Canada, September 28-October 1, 1997, Abstract I-176.
4. Palella F, Moorman A, Delaney K, et al. Dramatically declining morbidity and mortality
in ambulatory HIV-infected patients. Thirty-fifty Annual Meeting of the Infectious Diseases Society of America (IDSA), San
Francisco, California, September 14-16, 1997, Abstract 478.
5. Caesar Coordinating Committee. Randomized trial of addition of lamivudine or lamivudine
plus loviride to zidovudine-containing regimens for patients with HIV-1 infection: the Caesar trial. Lancet 1997; 349:1413-21.
6. Carpenter CC, Fischl MA, Hammer SM, et al. Antiretroviral therapy for HIV infection
in 1997: Updated recommendations of the International AIDS Society - USA Panel. JAMA 1997; 277:1962-9.
7. Panel on Clinical Practices for Treatment of HIV Infection. Guidelines for the use
of antiretroviral agents in HIV-infected adults and adolescents. Department of Health and Human Services and the Henry J. Kaiser
Family Foundation. November 5, 1997.
8. Working Group on Antiretroviral Therapy and Medical Management of HIV Infected Children.
Draft guidelines for the use of antiretroviral agents in pediatric HIV infection. National Pediatric and Family HIV Resource
Center and the Health Resources and Services Administration.
9. Draft report of the NIH panel to define principles of therapy of HIV infection. Office
of AIDS Research, NIH, 1997.
10. Gulick R, Mellors J, Havlir D, et al. Indinavir (IDV), zidovudine (ZDV) and lamivudine
(3TC): Concurrent or sequential therapy in ZDV-experienced patients. Thirty-seventh Interscience Conference on Antimicrobial
Agents and Chemotherapy (ICAAC), Toronto, Ontario, Canada, September 28-October 1, 1997, Abstract I-89.
11. Saag M, Knowles M, Chang Y, Chapman S, Clendeninn NJ, for the Viracept Cooperative
Study Group. Thirty-seventh Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), Toronto, Ontario, Canada,
September 28-October 1, 1997, Abstract I-101
12. Deeks S, Loftus R, Cohen P, Chin S, Grant R. Incidence and predictors of virologic
failure of indinavir and/or ritonavir in an urban health clinic. Thirty-seventh Interscience Conference on Antimicrobial Agents
and Chemotherapy (ICAAC), Toronto, Ontario, Canada, September 28-October 1, 1997.
13. Piketty C, Castiel P, Gilquin J, et al. Prospective follow-up of 177 HIV-infected
patients treated with indinavir in combination with nucleoside analogues. Thirty-seventh Interscience Conference on Antimicrobial
Agents and Chemotherapy (ICAAC), Toronto, Ontario, Canada, September 28-October 1, 1997, Abstract I-100.
14. Rhone SA, Hogg RS, Yip B, et al. Antiviral effect of double and tripe drug combinations
among HIV infected adults: lessons from viral load driven antiretroviral therapy. Thirty-seventh Interscience Conference on
Antimicrobial Agents and Chemotherapy (ICAAC), Toronto, Ontario, Canada, September 28-October 1, 1997, Abstract I-103.
15. Clough LA, Haas DW, Raffanti S. Predictors and prevalence of incomplete virologic
response to protease inhibitor-based highly active antiretroviral therapy (HAART) for HIV infection. Thirty-fifty Annual Meeting
of the Infectious Diseases Society of America (IDSA), San Francisco, California, September 14-16, 1997, Abstract 223.
16. FDA Public Health Advisory: Reports of diabetes and hyperglycemia in patients receiving
protease inhibitors for the treatment of human immunodeficiency virus (HIV). June 11, 1997.
17. Dube MP, Johnson DL, Currier JS, Leedom JM. Protease inhibitor-associated hyperglycaemia.
Lancet 1997; 350:713-4.
18. Hengel RL, Watts NB, Lennox JL. Benign symmetric lipomatosis associated with protease
inhibitors. Lancet 1997; 350:1596.
19. Ruane PJ. Atypical accumulations of fatty tissue. Thirty-seventh Interscience Conference
on Antimicrobial Agents and Chemotherapy (ICAAC), Toronto, Ontario, Canada, September 28-October 1, 1997, Abstract I-185.
20. Wong JK, Hezareh M, Gunthard HF, et al. Recovery of replication-competent HIV despite
prolonged suppression of plasma viremia. Science 1997; 278:1291-5.
21. Finzi D, Hermankova M, Pierson T, et al. Identification of a reservoir for HIV-1 in
patients on highly active antiretroviral therapy. Science 1997; 278:1295-1300.
Source: www.healthcg.com
Dr. Collier is Professor of Medicine at the University of Washington in Seattle and
Director of the AIDS Clinical Trials Unit there. She has been on the faculty of the University of Washington since 1985. Her research
activities include a variety of projects relating to the clinical course and treatment of HIV and its associated complications,
and the epidemiology of cytomegalovirus in adult men and women. She has conducted numerous antiretroviral treatment trials,
including combination therapy studies, and served on the AIDS Research Advisory Committee of the National Institute of Allergy
and Infectious Diseases.
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By John G. Bartlett, M.D.
Treatment guidelines from the panel on Clinical Practices for Treatment of HIV Infection
convened by the Department of Health and Human Services (DHHS) and the Henry J. Kaiser family foundation were published in
draft form on June 6, 1997 and published in final form with minor revisions on November 4, 1997 (see ATPs Doctor Fax Issues 26 & 26
). This document is the consensus statement of a 35 member panel that included scientists,
clinicians, consumer groups and diverse federal agencies. Substantial controversy can be expected whenever a diverse group
attempts to address such a multitude of clinical practice issues on a disease with rapidly evolving concepts and extraordinary
complexity, and this process was no exception. Nevertheless, a consensus was achieved on nearly all issues, possibly reflecting
the remarkable statesmanship of Dr. Sharilyn Stanley and Dr. Eileen Daniels who orchestrated the effort. This discussion reviews
those issues considered by this author to be the most controversial and the most likely to be sources of change as the document
is revised.
Goal of Therapy Based on Viral Burden
The current guidelines state that the goal of therapy is to achieve "no detectable
virus" using a viral burden assay with a threshold of 500 copies/ml. Many laboratories now utilise the "third generation" viral
load assays with a threshold of detection at 20-50 copies/ml. Based on the assumption that viral replication results in disease
progression, mutation and resistance, it is intuitively obvious that the goal of therapy should be complete suppression, suggesting,
therefore, that a viral burden of <50 copies/ml is preferred to <500 copies/ml. Long term trials in patients receiving triple
drug therapy indicate that patients with viral burdens of 50-500 copies/ml at intermittent periods are more likely to fail than
those who have persistence of undetectable virus at the 50 copies/ml threshold. Nevertheless, even with the 500 copies/ml threshold,
many clinics are now reporting that 50-60% of patients either do not achieve the goal of undetectable virus, or achieve
this goal and then fail. Many will consider the lower threshold to be unrealistic, although virtually all will agree that it is
a more desirable goal of treatment.
Intensification
The current guidelines state that patients who fail to achieve the goal of undetectable
virus at 12-16 weeks are considered failures and should receive an entirely new regimen. An alternative approach for some
patients is "intensification," which is defined as the addition of one or more other antiretroviral agents. For example, some authorities
would endorse the addition of another agent, such as an NNRTI or another protease inhibitor, for a patient with an initial
baseline viral burden of 100,000 copies/ml who responds to "triple therapy" with a decrease in viral burden to 1,000 copies/ml
at 16 weeks. An advantage to this approach is that it may preserve the utility of drugs incorporated in the original regimen.
The disadvantage is that such sequential addition of antiretroviral agents to combinations that are not completely suppressing
viral load may increase the likelihood of drug resistance. Furthermore, there are no data from clinical trials to justify this
approach, and it is unlikely that such studies will take place in the near future. Thus, this appears to be a theoretically attractive
method in selected cases, but there are no clear guidelines and no therapeutic trials to provide support to this approach.
[A safer approach in terms of likelihood of viral escape and resistance may be to
commence with 4 drug combinations in those with high viral loads at baseline - Ed.]
2 NRTI Regimens
Although not generally recommended in the new guidelines, the use of 2 nucleoside
reverse transcriptase inhibitors (NRTIs) is the standard of care for early stage disease in many other countries. The potential
advantage is the preservation of protease inhibitors for later use when there may be greater need for more potent therapy. The DHHS
guidelines make a strong statement that initial treatment should be "maximally suppressive" and that this can be best achieved
with a triple drug regimen. The preference for more aggressive treatment even in early stage disease is one facet of the guidelines
that received strong and universal support by the panel. It is listed here as a controversy only because of sharp variation
between these guidelines and those of other countries.
There is an additional, related question that remains unanswered. Both the Delta trial
and ACTG 175 showed that a substantial number of patients receiving two nucleosides achieved the goal of undetectable virus
when treatment was initiated with a relatively low viral burden and a CD4 count exceeding 200/mm3. This would appear to support the use of 2 NRTIs, at least in a subset of patients
seen with early stage disease. However, prolonged follow up demonstrated that the desired antiviral effect was not sustained,
with many of these patients subsequently failing treatment. This raises the question of what to do with patients who are already
taking 2 NRTIs and who have achieved the goal of undetectable virus. The current DHHS guidelines provide two options: the first
is to add a PI in order to be using a "preferred treatment" regimen, and the other is to simply follow the patient's viral burden
carefully with appropriate adjustments when virus becomes detectable. The former tactic is favoured by most authorities, but
the latter has the attractive feature of preserving PIs for future use. It is possible that this goal can be more readily achieved
with a triple drug regimen using drugs other than protease inhibitors. The most attractive candidates for the third agent are
new drugs such as abacavir (1592U89), efavirenz (DMP-266), or adefovir. Thus, if therapeutic trials indicate that these drug combinations
compare favourably to the regimens currently in the "preferred status" with respect to efficacy and durability, they
may become the preferred drugs for combination with two NRTIs as initial therapy.
Initial Regimens Containing 2 PIs
The DHHS guidelines call for one protease inhibitor combined with two nucleosides,
but many clinicians endorse the combination of saquinavir plus ritonavir as an initial treatment since this regimen is relatively
well tolerated and requires only twice daily dosing. Viral burden testing shows HIV suppression that is comparable to that achieved
with triple drug regimens. Even though there is limited published experience with ritonavir plus saquinavir as an initial
treatment, the revised guidelines now include this combination along with one or two nucleosides in the preferred category. It
is also anticipated that the more aggressive approach of four drug regimens may become standard practice in the future. Thus, due
to concerns about high rates of failure with regimens in the preferred category, it is expected that the availability of new drugs
will bring even more aggressive treatment. The hope is that this polypharmacy will also bring regimen simplification in terms
of total pills and number of daily doses. This goal may be attained by exploiting drug interactions through the introduction
of agents with optimal bioavailability and pharmacokinetics.
Recommendations for Changing Therapy
This is probably the weakest part of the DHHS guidelines. There are limited trials
that address the issue of "salvage therapy." Those that do seem to indicate relatively poor results in achieving undetectable virus
for sustained periods. There is also a lack of consensus about the concept of "class resistance" among protease inhibitors.
The implication of class resistance would be that there is only one protease inhibitor "card to play," regardless of which drug
is used first. Nelfinavir may be the exception, but this has yet to be proven. The concern about "class resistance" applies to
the NNRTIs. Finally, an assumption is commonly made that after failure with regimens that contain nucleosides, an "entirely new
regimen" containing two new nucleosides is required. However, in some cases failure of two nucleoside regimens may reflect incomplete
suppression rather than resistance. There are also substantial differences between nucleosides with respect to genotypic and
phenotypic resistance profiles. Thus, sequential analysis of isolates in the face of incompletely suppressive regimens show rapid
and high level resistance with 3TC, variable degrees of resistance to ZDV, and relatively minor changes with d4T and ddI. The
therapeutic implications of these differences are unclear. A patient who fails on a regimen containing d4T or ddI is likely to
have strains that are still susceptible.
Rules for Stopping
None of the currently available guidelines address the issue of discontinuing antiretroviral
therapy [This is discussed, however, in the British PACT and BHIVA guidelines - see ATPs Doctor Fax issues 19 & 21
]. Nevertheless, this is obviously important when the drugs are not working in patients
who take 20 pills a day, have substantial side effects and cost $10,000-12,000 per year. My own view is that there should
be consideration of discontinuation of treatment in patients who have viral burden assays and CD4 cell counts that have returned
to baseline. The strength of this recommendation is increased if tolerance is poor, the regimen is complex, and the quality of
life is poor. However, it is unclear whether the rate of disease progression is the same with failed triple therapy as it is in
untreated patients. Discontinuation of treatment in the face of resistance may result in the rapid return of "wild type virus,"
which may be more robust and more virulent. Also compelling are the provocative studies that demonstrate a reduction in vertical
transmission even when there is no demonstrable antiviral affect of ZDV, and the occasional patients who demonstrate a CD4 cell
response despite the failure of viral suppression. These observations collectively suggest that antiviral therapy may be achieving
some clinically important benefit that is not always reflected in the viral load. It is for this reason that many are uncomfortable
about making specific recommendations for stopping treatment.
Conclusions
With the rapid evolution of drugs, new trials and new concepts, antiretroviral therapy
is a moving target. The issues noted above reflect current controversies which are likely to be replaced by new controversies
in the near future. Fortunately, the panel will be convening monthly by conference call to update the guidelines, to address
the controversies, and to make necessary changes as data evolve.
Source: Johns Hopkins AIDS Service
John G. Bartlett is Professor of Medicine, Johns Hopkins University School of Medicine
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The "bioavailability" of HIV-1 protease inhibitors may be increased by inhibition
of the multidrug transporter P-glycoprotein, according to researchers at Vanderbilt University in Nashville, Tennessee. Protease
inhibitor therapy is complicated by limited oral absorption and variable tissue distribution, Dr. Richard B. Kim and colleagues
said in the January issue of the Journal of Clinical Investigation. In an accompanying editorial Lee & Gottesman state "While first
pass metabolism by the cytochrome P450 system may partially account for the poor bioavailability of these drugs, an often overlooked
major determinant of drug pharmacokinetics and bioavailability, the MDR1 multidrug transporter (Pgp), may also be a barrier
to the success of PI treatment."
The researchers "...hypothesised that the limited membrane permeability of HIV-1 protease
inhibitors could be explained if they were substrates of P-glycoprotein and that the tissue expression of this transport
may be a determinant of whether therapeutic drug levels are attained." In the current study, they tested this hypothesis using
indinavir, nelfinavir and saquinavir in an in vitro system and in a mouse model in which the mdr1a gene for P-glycoprotein was disrupted.
"All three compounds were found to be transported by P-glycoprotein in vitro." In the animal model, Dr. Kim's group observed
that following "...oral administration, plasma concentrations were elevated 2-5-fold in mdr1a (-/-) mice and with intravenous
administration, brain concentrations were elevated 7-36-fold."
Based on these findings, they conclude that "...P-glycoprotein limits the oral bioavailability
and penetration of these agents into the brain...creating a potential sanctuary for viral replication." Therefore,
it might be possible to achieve higher concentrations of HIV-1 protease inhibitors "...by targeted pharmacologic inhibition of
P-glycoprotein transport activity."
In the accompanying editorial, Drs. Caroline Lee and Michael Gottesman of the National
Cancer Institute in Bethesda, Maryland, discuss some of the possible implications of these findings. They point out that P-glycoprotein
is also expressed in a percentage of CD4+ T cells, in monocytes and macrophages, which are primary targets for HIV-1
infection. They raise the question of whether the "...expression of Pgp [P-glycoprotein] in these cells [could] explain the resistance
of some patients to PI [protease inhibitors]."
The physicians also raise the question of whether or not P-glycoprotein inhibitors
could alter the bioavailability and biodistribution of other antiretroviral drugs. Also, the addition of a second protease inhibitor
drug to combination regimens could possibly alter the pharmacodynamics of P-glycoprotein, resulting in unanticipated effects.
"Whatever strategy is ultimately pursued, knowledge of the physiological role of the multidrug transporter will allow more
rational approaches to the treatment of AIDS," they conclude. Drugs are already available to suppress the activity of Pgp. They
have been developed over the past 10-20 years because Pgp is also expressed by many cancer tumours. Pgp inhibitors have been used
to boost the effectiveness of chemotherapy in these tumours.
Kim said he would like to study the effectiveness of combining protease inhibitors
with Pgp inhibitors to determine if higher levels of the anti-HIV drugs can be achieved in the bloodstream and in the cerebral
spinal fluid by reducing the barrier function associated with Pgp.
"This work is exciting because the potential of Pgp as a factor in drug absorption
and tissue penetration has not been previously appreciated," Kim said. "We need to find out in humans how active this transporter
is and whether we can inhibit its activity.
Ref: Lee CGL, Gottesman MM. HIV-1 protease inhibitors and the MDR1 multidrug transporter.
Journal of Clinical Investigation 101:287-288 (Jan 15 1998).
Kim RB, Fromm MF, Wandel C, Leake B, Wood AJJ, Roden DM, Wilkinson GR. The drug transporter
P-glycoprotein limits oral absorption and brain entry of hiv-1 protease inhibitors. Journal of Clinical Investigation
101:289-294 (Jan 15 1998).
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Agouron Pharmaceuticals, based in La Jolla, California, have announced that the European
Commission approved for marketing in the European Union Agouron's HIV protease inhibitor nelfinavir mesylate (Viracept) for
treating HIV infection in adults and children in combination with antiretroviral nucleoside analogue(s).
According to an Agouron press release, nelfinavir is the first protease inhibitor
to receive simultaneous approval of paediatric and adult formulations in the European Union. Hoffmann-La Roche, based in Basel,
Switzerland, is marketing and selling nelfinavir in Europe.
The approval was based partially on Study 511, in which nelfinavir in combination
with zidovudine and lamivudine resulted in approximately 80% of the patients having a sustained viral load below the level of detection
of a branch DNA-based assay.
The development, compassionate use, and now the commercial availability of nelfinavir
in Europe have been beset with allegations of misconduct, incompetence and subterfuge leading to soured community relations
with both Agouron and Roche (see ATPs Doctor Fax Issues 10, 13, 14, 15, 22, 27). Due to manufacturing problems, even
though nelfinavir is now approved in the EU (and freely available in the US), there will not be any substantial commercially validated
drug available in the EU at least until May. After scaling up the production process in the Agouron production sites in the
US in the last quarter of 1997 Viracept still needs to go through a 90 days validation process. The application for approval
of the new manufacturing process had not been submitted at the time of writing (24.01.98).
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The results of a major epidemiological study indicate that, as of the end of 1996,
no improvements in detection rates of HIV infection in pregnant women have been made in England since the initiation of a national
policy initiative in 1992.
Although the HIV-positive rates among pregnant women in the UK are low, they increased
six-fold in London between 1988 and 1996, according to one of a collection of reports on antenatal HIV testing in the UK that
appear in the January 24th issue of the British Medical Journal.
Dr. Angus Nicoll of the PHLS Communicable Disease Surveillance Centre in London and
colleagues evaluated HIV infection in pregnant women in the UK between 1988 and 1996. The highest number of cases was in London,
where the rates have increased from 1 in 3,100 women in 1988 to 1 in 520 women in 1996, they report.
Since 1992, the detection of HIV infection in pregnant women before the birth of their
child rose by 51% in Scotland. However, during the same period, detection rates in England rose only 15%. In the London area,
maternal HIV was most prevalent among black Africans, and in Scotland, most cases were associated with injection drug use, the
researchers report.
"We are moving towards...the same sort of recommendations that are already...in the
US," Dr. Nicoll told Reuters Health. On the whole, the UK has been slow to act, he continued. Although it remains up to the woman
whether or not she wishes to know her HIV status, and that has to be respected, it still should be offered and recommended to
women in areas were HIV is prevalent.
The UK currently has "...an equity and professional responsibility problem," Dr. Nicoll
explained. Whether or not a woman is offered an HIV test, even in high-prevalence areas like London, depends on which hospital
she attends and whom she sees at the hospital. He believes that this is "...really not an acceptable situation for the women--and
given the increasing consensus that [HIV testing] should be recommended, it also raises questions of professional responsibility."
In the UK, and particularly in London, "...the majority of the women who are HIV-infected
are black African women...and some of them have some understandable reluctance about knowing their HIV status." And "...midwives
and obstetricians are somewhat wary about raising the issue." However, we now know that when HIV testing is offered, "...it
is taken equally by women of all races. It's a question of offering it," he said.
There's also the belief in the UK, as well as in other industrialised countries, that
"...if you're going to give HIV testing, it has to be done with a large amount of counselling and a lot of preparation." Also,
"...there's a feeling that HIV testing is such a big deal and that it can't be done by anybody and it's got to be done by specialists."
However, Dr. Nicoll points out that some studies, such as the one "...by Simpson et al, shows that in fact you can do
a much slicker, quicker offer [of HIV testing] and that simplifies the whole issue."
In the study Dr Nicoll referred to, also published in the BMJ, Dr. Wendy J. Simpson
of the University of Edinburgh and colleagues investigated "...the uptake and acceptability of different methods of a universal
offer of voluntary HIV testing to pregnant women." They evaluated 3,024 pregnant women seen at an Edinburgh clinic over a 10-month
period.
Overall, in the group that was offered HIV testing, 35% of the women were tested,
compared with 6% of the women in the control group. "Neither the style of leaflet nor the length of discussion had an effect on
uptake," they report. Independent predictors of HIV testing included, being offered testing, the midwife seen, being unmarried,
younger age and previous HIV testing.
Dr. Simpson's group concludes that a "...universal offer of HIV testing is not intrusive
and is acceptable to pregnant women." They therefore recommend that "...all women attending antenatal clinics should be offered
the test and midwives should be required to keep a record of the offer."
The findings of a third study by Dr. E.G. Hermione Lyall of the Imperial College School
of Medicine at St. Mary's in London and colleagues also underscore the importance of HIV testing in pregnant women. Overall,
their findings indicate that pregnant women who are aware of their HIV-positive status will take actions to reduce the odds of
vertical transmission.
Dr. Lyall's group evaluated 57 mother-infant pairs in which the woman was aware of
her HIV-positive status before the birth of her infant or a family member developed HIV-related symptoms. They found that all the
women elected not to breast-feed their infant, and the majority (68.7%) accepted antiretroviral therapy. In addition, 53% of
the women underwent caesarean sections.
In response to these reports and others, the British Medical Association's (BMA) Foundation
for AIDS has announced strong support for "normalising" HIV testing in the general population and among pregnant women
in particular. "There's now compelling evidence in favour of testing," Hilary Curtis, the Foundation's executive director stated
in a press release. "Treatments are available which can benefit an HIV positive woman's own health and reduce the risk of her
baby being infected." HIV testing should be offered "as a matter of course" by doctors and midwives, Curtis continued.
"We'd like to reassure people who may be worried by the widespread myth that merely
being tested for HIV can cause insurance problems. In fact, the industry has now changed it policy, thanks to lobbying from the
Foundation and other groups, and companies do not ask applicants whether they have ever been tested, but only whether they are
HIV positive."
Ref: BMJ 1998;316:253-258 , BMJ 1998;316:262-268 , BMJ 1998;316:268-270
Source: Reuters Health
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Trimeris Inc. announced that it has initiated a Phase II clinical trial for T-20 (pentafuside),
a new class of anti-viral fusion-inhibiting drugs which block HIV infection.
The Phase II study will determine both the optimal dosing for T-20 and the feasibility
of its administration via an infusion device developed by MiniMed Inc., product currently approved for insulin infusion by
diabetics. The clinical protocol for this trial is under normal review by the U.S. Food and Drug Administration.
T20, Trimeris' novel anti-viral compound, is designed to block both virus-to-cell
and cell-to-cell membrane fusion, thereby preventing a critical early step in the spread of viral infection. In August 1997, T-20
completed Phase I/II clinical trials against HIV infection, demonstrating potent anti-HIV activity. Further, no drug-related
adverse effects were seen in any of the 16 patients tested. This study provided the first clinical evidence that inhibition of
membrane fusion results in significant anti-HIV-1 activity.
The current trial will enrol 32 HIV-infected patients who have failed existing triple
combination therapy. Patients will be enrolled at three sites in the United States to assess the safety, plasma pharmacokinetics,
and anti-viral activity of multiple ascending doses of T-20 monotherapy given by continuous subcutaneous infusion to HIV-1
positive adults.
This study will last approximately 21 days in each patient and form the basis of a
pivotal trial in triple-drug-combination resistant patients. The pivotal study should begin by mid-1998.
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Compared with HIV-negative subjects, individuals with HIV infection have significantly
higher indicators of oxidative stress, according to a report in the January issue of the American Journal of Clinical Nutrition.
The Canadian researchers who report this finding suggest "...that a weakened antioxidant defence system may play a significant
role in the increased oxidative stress found in his population."
Increased production of reactive oxygen species may stimulate HIV replication and
immunodeficiency, Dr. Johane P. Allard and colleagues at the University of Toronto explain. In the current study, Dr. Allard's group
evaluated lipid peroxidation indexes and plasma levels of antioxidant micronutrients in 49 HIV-positive patients and 15 matched
HIV-negative controls.
They found "...that lipid peroxidation, measured by breath-alkane output and lipid
peroxide concentration, was significantly higher in HIV-positive patients than in seronegative control subjects." In addition,
the HIV-positive patients also had significantly lower plasma concentrations of selenium and various antioxidant vitamins.
Dr. Allard's group speculates that these increased levels of oxidative stress in HIV-positive
patients "...may have some clinical significance because there is experimental evidence implicating oxidative stress
in the stimulation of HIV replication." But they point out that "...it remains to be determined whether antioxidant supplementation
will have any effect, not only on oxidative stress but also on viral replication and disease progression."
These findings confirm that there may be a link between HIV infection and oxidative
stress, Dr. Donald P. Kotler of St. Luke's Roosevelt Hospital in New York comments in an editorial. However, no published studies
have documented the efficacy of antioxidant therapy in influencing clinical outcomes, he continues. "Thus, the potential for
therapeutic benefit from antioxidant therapies remains questionable."
Ref: Am J Clin Nutr 1998;67:143-147.
Source: Reuters Health
The next Issue of AIDS Treatment Projects Doctor Fax (Issue 40) will report from the
5th Conference on Retroviruses and Opportunistic Infections, Chicago, 1 - 5 February. This important meeting will be attended
by
Paul Blanchard
and
Raffi Babakhanian
as delegates on behalf of AIDS Treatment Project.
Issue 40 will be distributed on 13th February.
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