AIDS TREATMENT UPDATE Issue 26 - Feburary 1995
Edward King

* NEW OPTIMISM

Many respondents felt that the last few months of 1994 had seen the return of a mood of optimism in AIDS research. Every one of the clinicians mentioned the encouraging data presented in Glasgow last November showing that the combination of AZT plus 3TC (lamivudine) produced large, sustained drops in viral load and increases in CD4 count (see AIDS Treatment Update issue 24/25). The enthusiasm shown by Dr Margaret Johnson was typical: "We have never seen data with an antiviral drug that gives such a reduction in viral load and a prolonged CD4 effect. Okay, these are surrogate markers and they need to be validated, but certainly that's better data than we've seen with anything else."

Professor Tony Pinching stressed that "although the AZT & 3TC data have grabbed all the publicity, some of the protease data are equally encouraging". Professor Jonathan Weber pointed out that "The protease inhibitor data are very significant because they prove that this concept works, giving you a whole new target for antivirals as well as reverse transcriptase".

Professor Paul Griffiths drew attention to the two studies published in 1994 suggesting that use of acyclovir can prolong survival, presumably because it inhibits a herpes virus co-factor. "In 1995 I am awaiting the results of the trial ACTG 204 which will tell us which dose of acyclovir is best for providing the survival benefit shown in these studies." He also cited research suggesting that Kaposi's sarcoma may be caused by a herpes virus as reinforcing the significance of herpes virus infections in people with HIV (see AIDS Treatment Update issue 24/25).

* TRIAL PLANS

On the basis of the Glasgow trial results, Professor Weber argues that the triple drug combination of AZT, 3TC and a protease inhibitor is an attractive regime to study: "It should be minimally toxic and pretty synergistic". Both he and Professor Ian Weller agreed that a priority for 1995 is to obtain information on the effects of the combination on surrogate markers; Professor Weber argues that "you could do the study in a year and have the results by January 1996".

Professor Pinching hopes that the results of the Delta and ACTG 175 trials testing combinations of AZT, ddI and ddC wil be announced this year. "These will be the first large-scale test of any combinations and will give us something to work with, even if it may not necessarily be our chosen combination."

However, Professor Weller is anxious that "patients and physicians taking part in the Delta study are wanting to give 3TC a try _ does this mean that the trial's power will be diluted?". This may also have implications for new trials. "I am worried that we may have problems running trials with clinical endpoints now that physicians are looking at the AZT/3TC combination as an established therapeutic option when we don't know its true risk/benefit equation. People are saying that big CD4 increases must translate into clinical benefit but we really don't know that".

Mark Harrington of the Treatment Action Group (TAG) noted that new understanding of the structure of HIV's integrase enzyme (see page 8) "opens up a whole new field for rational drug development". Hans-Josef Linkens, director of the European AIDS Treatment Group (EATG), told us that "this year we hope to see greater involvement of people with HIV in planning trial designs".

* VALIDATING MARKERS

Dr Janet Darbyshire succinctly noted the need "to evaluate the clinical benefit of new drugs and evaluate viral load as a surrogate marker". Many other respondents also identified the need to validate viral markers as a priority for 1995. Dr Johnson describes this as "the most important thing to do. We need to know if tests such as quantitative viral load correlate with anything clinical. If so, we can rationalise trial design, establishing the effects of drugs quickly using laboratory tests."

Dr Gazzard spelt out the flipside: "If we can't validate these markers we will need to rethink how we do trials. We can't go on using surrogate markers as ways of developing drugs unless they can be translated into improvements in quality of life or survival".

"So much importance is being attached to measures of viral load that we need to assess them properly and avoid the problems we had with CD4 counts", agrees Professor Pinching. He also argues that immunological markers need more study. "I'd like to see research on a wider range of markers than CD4 count, such as how well CD4 cells function."

* IMMUNE RESPONSES

Dr Gazzard highlighted two priorities for research: "First, trying to sort out whether there are groups of people who are repeatedly exposed but don't become infected and what determines that. We also need to understand why some people who are infected don't progress. These are the bits of research most likely to give us insight into the pathogenesis of HIV and its potential prevention." Mark Harrington pointed out that antibodies that neutralise 75% of HIV strains have been isolated from a long-term non-progressor, "suggesting that effective vaccine strategies and therapeutic vaccination may be feasible".

* OPPORTUNISTIC INFECTIONS

Relatively few respondents mentioned treatments for opportunistic infections (OIs), which have perhaps been overshadowed by the excitement over new antivirals. Professor Weller hopes that 1995 will produce positive results from trials of new anti-CMV drugs.

For the EATG, Hans-Josef Linkens said that "the most important result in 1994 was the use of oral ganciclovir as a primary prophylaxis against CMV retinitis. Also the availability of different methods of delivering the drug as secondary prophylaxis has had important consequences for the comfort and quality of life of people with AIDS." He believes the priority for 1995 is "improved prophylaxis, diagnosis and treatment for the increasingly common 'end-stage' OIs such as wasting syndrome, PML and MAI."

TAG's Mark Harrington also stressed the significance of oral ganciclovir for CMV prophylaxis, as well as studies showing that eye implants that slowly release ganciclovir over time can delay the progression of CMV retinitis. He too stressed the need to "improve standard-of-care in OI prophylaxis and treatment" as a priority for 1995, citing MAI prophylaxis, treatments for wasting and PML and new treatments for drug-resistant fungal and bacterial infections as areas in which he expects progress.

* PREVENTING TRANSMISSION

Dr Diana Gibb told us that the ACTG 076 trial, in which AZT given during pregnancy, birth and the child's first months reduced the risk of infection among children born to HIV-positive women, "was the most significant thing from the point of view of children. It suggests very strongly that transmission is related to viral load." Professor Weller agreed that the result is interesting "but still the question must be 'Do we need to expose mothers, foetuses and babies to such a long course of AZT to achieve that effect, or would a short course around delivery achieve the same effect?'".

* TREATMENT STRATEGIES

Two respondents hoped for a change in attitudes to treatment in 1995. Dr Mike Youle hopes that "people will realise that the way forward is to have treatment rather than to sit around doing nothing. We need to change the pervading view that therapy is bad and that HIV will not progress if you look after yourself, when all the evidence suggests that lifestyle changes are of only minor benefit compared to the benefits that can accrue through therapy".

Dr Johnson too hopes "that people will start to think about using therapy earlier rather than always focussing on late-stage disease. Much of the work we are doing is perhaps far too late".

* Who we asked:

Janet Darbyshire, head of the Medical Research Council's HIV Clinical Trials Centre Brian Gazzard, Consultant and HIV Clinical Director at the Chelsea & Westminster Hospital, London Diana Gibb, Consultant Pædiatrician, Hospital for Sick Children, Great Ormond Street, London Paul Griffiths, Professor of Virology at the Royal Free Hospital, London Mark Harrington of the Treatment Action Group, New York Margaret Johnson, Consultant at the Royal Free Hospital, London Hans-Josef Linkens, Director of the European AIDS Treatment Group Tony Pinching, Professor of Immunology at St Bartholomew's Hospital, London Jonathan Weber, Professor of Immunology at St Mary's Hospital, London Ian Weller, Professor of GU Medicine at University College London Medical School

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