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Trials and tribulations: ethical dilemmas in HIV therapy Guest editorial Jonathan Weber

Addresses Imperial College School of Medicine, St Mary's Hospital, Jefferiss Research Trust Laboratories, Praed Street, London W2 1 PG, UK; e-mail: j.weber@ic.ac.uk

Current Opinion in Immunology 1997, 9:625-627

http:llbiomednet.comlelecref10952 791500900625

© Current Biology Ltd ISSN 0952-7915

Abbreviations RT reverse transcriptase ZDV zidovudine

The past 12 months have witnessed a revolution in the therapy of HIV infection. Coml~inations of antiretroviral drugs in therapy have substantially altered the natural history of HIV infection and, for some patients at least, it is possible to imagine that HIV might become a treatable chronic infection. The wards of" in-patients with AIDS have thinned out, if not emptied. The large pharmaceutical houses have developed a dozen active drugs against two viral targets, reverse transcriptase (RT) and the viral protease, and more are in the pipeline. Advances in therapy have led in turn to a better understanding of the pathogenesis of HIV disease, in particular the dynamics of HIV replication and CD4 ÷ T cell turnover, which has provided a rationale for earlier intervention. Lay observers might be expected to believe that the HIV epidemic has been resolved. The optimism ignores the rather meagre database of current progress, however, and the short follow-up time which exists for the clinical trials of new therapy. Hope and high expectation have overtaken the rather pedestrian pace of randomised clinical trials. Have we raised patient expectations unreasonably, and unsustainably?

The therapeutic revolution had its origins in 1993, when the Medical Research Council (MRC)/Nationale de Recherches sur le SIDA (ANRS) randomised, double blinded, placebo controlled 'Concorde' trial reported.that monotherapy with zidovudine (ZDV), a RT inhibitor, in patients with asymptomatic HIV infection did not lead to the prolongation of patient survival [1]. ZDV had been widely prescribed for treatment of the early stages of infection, on the basis of small clinical trials suggesting it induced a slower rate of progression to AIDS. The Concorde trial, which combined sample size (circa 2000 subjects) with a long follow-up period (three years) and large numbers of clinical end points (deaths), produced unequivocal evidence of the limited activity of monotherapy. It was a depressing result. Combination trials of antiretroviral drugs followed rapidly; initially,

these were studies comparing monotherapy against a combination of two nucleoside analogue RT inhibitors, including .~DV, dideoxyinosine (ddI), dideoxycytosine (ddC) and 3-thiocytosine (3TC). Studies such as Delta [2], ACTG 215 [3] and CPCRA 001 [4] were all large clinical end point trials, and each of these studies reported in 1996 that two drug combinations lead to a significant survival advantage. This was the first time that an intervention had unequivocally altered the natural history of HIV disease.

In parallel with these clinical trials, which were slowly counting deaths in large cohorts, clinical scientists such as D Ho (Aaron Diamond AIDS Research Center, New York), G Shaw (University of Alabama, Birmingham) and colleagues were studying the treatment effects of the new antiretroviral drugs in small numbers of patients in great detail. The new drugs were the peptidomimetic inhibitors of the HIV-I protease, and the non-nucleoside RT inhibitors. Techniques for the accurate and repro- ducible quantification of HIV-1 viral RNA in plasma by RT-polymerase chain rection (PCR) had recently been developed, and these investigators studied the dynamics of the reduction in viraemia following therapy with these new drugs. In collaboration with mathematical modellers, they showed that HIV replication was a highly dynamic process, with approximately 109 virions being produced every 24 hours, with similar numbers of CD4÷ T cells being produced and destroyed [5,6]. These observations suggested that HIV replication in peripheral blood CD4 ÷ T cells was sufficient to explain their destruction, without the need for more complex theories of pathogenesis. These observations also provided the intellectual rationale to push combination chemotherapy further. If viral replication could be turned off for long periods of time, there would be no biological reason why the immune system should not return to normality. Monotherapy was clearly not a potent enough viral suppressor to affect survival as evidenced by the Concorde trial, and two drugs gave an unequivocal yet modest survival advantage as shown in the Delta trial, but probably still did not suppress viral load for long enough or hard enough to have a sustained action.

Small clinical studies of three drug combinations of RT inhibitors with protease inhibitors rapidly followed these observations (R Gulick et al., abstract ThB391, XI International Conference on AIDS, Vancouver, June 1996). These three drug combinations have led to more profound reductions in viral load than seen in any of the two drug combination studies. It is not uncommon to observe plasma viral load decline by over four orders of magnitude, and the reduction of viraemia has been

696 Guest editorial

sustained in some patients for more than one year of follow up. Few data are available, however, for large clinical cohorts treated with three drug combinations for long periods of time. One such trial [7], of ZDV, ddC and saquinavir in 3 600 patients, shows unequivocal evidence of a highly significant survival advantage in the triple therapy arm, yet 16 deaths occurred even in this triple treated group.

How long will these combination therapies suppress viral replication? Antiretroviral therapy fails because residual viral replication allows the emergence of mutations which confer decreased drug susceptibility on the virus. If a therapy was sufficiently potent, no viral replication would take place, and no resistance would occur. Treatment with ZDV, 3TC and indinavir (a protease inhibitor), a potent antiretroviral combination, however, leads to the 'complete ' suppression of viral load in less than 50% of patients (R Gulick etal., abstract ThB391, XI International Conference on AIDS, Vancouver, June 1996). Even then, the suppression is only to less than detectable quantities of plasma HIV-1 RNA, currently about 20 RNA copies/ml plasma, depending on the sensitivity of the assay. It appears that some viral replication continues in the lymph nodes or other sanctuary sites of viral replication, and that this low level can still lead to resistant mutations being generated. Thus, triple combination therapy will ultimately fail in patients if complete suppression of viral replication is not achieved. Nonetheless, if viral replication could be turned off for long periods of time, there would be no biological reason why the immune system should not return to normality. After all, the clinical results of our still inadequate current therapy procedures are dramatic, and the wards are emptying of AIDS patients as viral load suppression leads to sustained improvements in CD4 ÷ T cell counts and clinical well-being.

As the results of viral load suppression from the small studies are so good, many argue that it is unethical to withhold triple regimes from all patients, who must be treated as early as possible in the course of their infection if maximal benefit is to ensue. The most potent regimes, for example ZDV, 3TC and indinavir, may still lead to the breakthrough of resistant virus, and in the case of these agents, cross-resistance to other agents in the same antiretroviral class is commonly found, severely limiting future therapy options. Other regimes, although less potent, may lead to less cross-resistance, such as commencing therapy with ZDV, ddI and the non-nucleoside RT-inhibitor, nevirapine. It is completely unclear, however, whether a patient would be better off in the long term by taking the most potent therapy early, with a large reduction in viraemia maintained for two years, or whether ultimate survival might be enhanced by taking a sequence of therapies, starting with the less potent regime, if it meant that future options were better maintained. Clearly, the only sensible option now is to do the definitive clinical trial with large enough numbers of patients for long

enough to understand which approach contributes most to the length and quality of life.

Attempts to study alternative strategies for managing therapy and introducing new regimes for viral load suppression are now being jeopardised by clinicians who feel passionately that they already know what the best therapy is, and so do not need to do definitive clinical trials. Owing to our enhanced understanding of viral dynamics, most physicians believe that only by three or four drug regimes will HIV be controlled. Any therapeutic manoeuvre which leads to a less than maximal immediate reduction in viral load is thought to be 'suboptimal' and, therefore, unethical. In the absence of large, robust clinical trials to determine strategies of antiviral therapy, physicians are being forced into a therapeutic straight jacket.

Many questions remain to be determined. When to start therapy? As the groups of Ho [5] and Shaw [6] have shown, the rate of viral production appears to be relatively constant throughout infection; even early HIV infection is probably associated with rapid virion production and turnover. Thus, the model would imply that therapy should be instituted as early as possible in the course of infection, and probably at seroconversion or before. A simple concentration on models of viral dynamics may be misleading, however. Drugs have to be taken for many years, and possibly for life, in otherwise symptom free subjects. Toxicity and tolerability of complex regimes may well become the limiting factor for the success of therapy. It is even possible that none of the existing treatment regimes is currently optimal, and that early HIV positive asymptomatic subjects, with a low viral load and high CD4 ÷ T cell counts, and hence an excellent prognosis, would be best advised to take no therapy, to watch and monitor their viral load, and to wait for better treatment to arrive.

Randomised clinical trials of sufficient size to give highly significant results based on clinical end points have been the foundation for evidence-based medicine over the past 40 years, and should not be overtaken lightly. The history of HIV research shows the potential of small studies to mislead. We do not yet know the optimal therapy of HIV disease, and we should continue to undertake clinical trials until we are certain of the best possible outcomes for our patients.

References 1. Concorde coordinating committee: MRC/ANRS randomised

double-blind controlled trial of immediate and deferred zidovudine in symptom-free HIV infection. Lancet 1994, 343:871-881.

Delta coordinating committee: Delta: a randomised double blind controlled trial comparing combinations of zidovudine plus didanosine or zalcitabine with zidovudine alone in HIV-infected individuals. Lancet 1996, 348:283-291.

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4.

Hammer SM, Katzenstein DA, Hughes MD, Gundacker H, Schooley RT, Haubrich RH, Henry WK, Lederman MM, Phair JP, Niu Met al.: A trial comparing nucleoside monotherapy with combination therapy in HIV-infected adults with CD4 counts between 200 and 500 per cubic millimeter. N Engl J Med 1996, 335:1081-1090.

Saravolatz LD, Winslow DL, Collins G, Hodges JS, PettineUi C, Stein DS, Markowitz N, Reves R, Loveless MO, Crane L eta/.: Zidovudine alone or in combination with didanosine or zalcitebine in HIV-infected patients with the acquired immunodeflciency syndrome or fewer than 200 CD4 cells per cubic millimeter. N Eng/.I Med 1996, 335:1099-1106.

Ho DD, Neumann AU, Perelson AS, Chen W, Leonard JM, Markovitz M: Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature 1995, 373:117-122.

Wei X, Ghosh SK, Taylor ME, Johnson VA, Emini EA, Deutsch P, Lifson JD, Bonhoeffer S, Nowak MA, Hahn BH et al.: Viral dynamics in HIV-1 infection. Nature 1995, 373:117-122.

Collier AC, Coombs RW, Schoenfeld DA, Bassett R, Baruch A, Corey L: Combination therapy with zidovudine, didanoaine and saquinavir. Antivira/Res 1996, 29:99.