GMHC Treatment Issues, Volume 10, Number 6/7 - June/July 1996
Dave Gilden

Tests for viral load -- the Roche PCR version is newly approved in the U.S. (see page 21) -- may help make some sense of this therapeutic kaleidoscope. Unfortunately, research on the relation of HIV levels to disease has been inadequate. Viral load tests' potential for settling questions of overall therapeutic strategy and for guiding individuals' treatment decisions requires further delineation. Opinion differs in the meantime about the optimal starting point for pharmacological intervention, when to change therapy and which regimens have the best therapeutic indices and duration of effect.

When patients and doctors lack sufficient carefully collected study data, they can only rely on their own and others' clinical experience to guide them. In an effort to further disseminate that experience, we at Treatment Issues surveyed a group of prominent HIV specialists in North America, Europe and Australia. We recapitulate their answers in the pages that follow.

Our respondents have large AIDS practices conducted in diverse care settings -- public clinics, private practice, health maintenance organizations and university hospitals. Many work within the constraints of managed care, payer formularies, Medicaid and ADAP programs. The questions they answered were open-ended and intended to stimulate discussion of diverse treatment strategies.

Our goal was to uncover the range of approaches followed today by experts in the field rather than to systematically reflect the opinions of all physicians who treat HIV and AIDS. We therefore have included answers illustrating both dominant trends and contrarian views. Statements attributed to individuals may be paraphrased and are not necessarily the complete response to any given question. The tables do provide a quick overview of all the responses, but because of the survey's eclectic nature, we urge that readers carefully look at the individual responses rather than just peruse the summaries.

Associating Viral Load and Physical Health

The most striking observation to come from these respondents is the remark by several that they are seeing clinical improvement in patients (i.e., patients noticeably feel better) at the same time as these patients' HIV levels are dramatically reduced by the new treatments. Such observations complement a published report by a group of Australians -- among them was David Cooper, one of our survey participants -- on the partial restoration of 21 volunteers' immune function during an early ritonavir monotherapy trial (see Journal of Infectious Disease, February 1996; 173(2):321-9). Reducing the inflammatory response and cell killing that HIV infection provokes may have a number of immediate benefits in terms of a person's overall functioning.

The great hope that currently available combination regimens are potent enough to lead to at least limited recovery remains entirely speculative. It is notable that the latest word from the Australians describe the qualitative immune improvements they observed as "small and transient and occurr[ing] in a minority of subjects" (see page 27 of this issue).

Our respondents had divergent opinions as to how far viral load has to drop before their patients reach a safe zone. One result is a wide variety of practices concerning initial and subsequent anti-HIV therapy. Several of the less mainstream doctors remain so unconvinced by the present data that they continue to concentrate on aggressively preventing OIs rather than HIV. (This in itself could be a potent antiviral strategy because keeping the immune system relatively quiet reduces the number of activated cells vulnerable to HIV. Lending credibility to this approach is, among others, a recent article on the HIV-simulating effect of tetanus toxoid vaccination. See the New England Journal of Medicine, May 9, 1996, pages 1222-30.)

Responsibility for the confusion over viral load lies at least in part with the developers of viral load tests. The companies have not taken the lead in establishing the worth (as opposed to the accuracy) of their products. University and government researchers instead have been active in establishing guidelines for interpreting viral load tests results. This has turned out to be a slow process, with most of the available data arising from retrospective reviews of trials testing specific drugs. Even though Roche's PCR-based Amplicor test kit has been licensed in the U.S., trials that directly observe the usefulness of viral loads in treatment decisions are only now getting under way. The difficulties of creating ethical designs for such trials and recruiting volunteers for them will surely mount as viral load testing becomes more widely available. (See pages 21-24 of this issue for an examination of the currently available viral tests and what is known of their uses.)

Holding Off on the Protease Inhibitors

With little to guide them, our respondents tend to be conservative about bringing out the heavy guns against HIV. They generally choose two nucleoside analogs as first-line therapy in patients with relatively low viral load and high CD4 counts. Protease inhibitors are added only when patients start to worsen or have exceptionally high viral loads to begin with. Still, the present strategies are a marked change from the recent past, when AZT monotherapy would no doubt have been most frequently mentioned as the preferred first line therapy for HIV, to be applied mainly when CD4 counts were clearly deficient and physical symptoms evident.

Several recent combination drug trials have affected this evolution in treatment strategies. Especially important were ACTG 175 (which tested AZT vs. ddI vs. AZT/ddI and AZT/ddC) and the AZT/3TC trials. AZT/3TC was by far the most commonly mentioned initial regimen. Not only does it have documented substantial and sustained antiviral activity in treatment- naive people, but also its side effect record seems less than that of other possible nucleoside analog pairings.

By comparison, only one doctor mentioned using the non- nucleoside reverse transcriptase inhibitor nevirapine, for which there has been little available data. This drug, currently available in the U.S. through an expanded access program, could be administered with protease inhibitors as an alternative to nucleoside analog regimens or combined with both types of agents to create extra powerful four-drug combinations. (But beware of nevirapine's potential to accelerate liver metabolism of protease inhibitors -- see page 25.)

The reluctance to employ the protease inhibitors stems from fears of increased toxicity, drug interactions and the evolution of drug resistant virus. Patient fatigue could be a big factor, too, in creating difficulties for managing and adjusting multiple drug combinations that must be taken without let-up over long periods of time. It was generally considered best to leave well enough alone when viral loads could be brought and kept down to low levels without the protease inhibitors.

Trials that further explore protease inhibitor use obviously are needed to optimize their use. Such trials would help decide when protease inhibitor therapy can be omitted, when it should be initiated and when it is perhaps no longer needed. And what about using two protease inhibitors concurrently? Another major effort should go to simplifying drug combinations as much as possible. Some two-drug combinations may be as good as combinations of three weaker or more toxic drugs, for example.

The thorniest questions concern the evolution of drug resistant HIV: how do you detect it and what drugs can you switch to when it occurs? The amount of cross-resistance to the various protease inhibitors that HIV mutations can confer requires further exploration, as does the clinical significance of that resistance. Finally, some therapeutic strategies may delay the emergence of drug resistance better than others.

The question of how clinical research should proceed -- who should carry out what studies at this point -- is now the subject of a national working group sponsored by the Keystone Center. This broadly based committee, composed of representatives of the scientific and activist communities, the pharmaceutical industry, health insurers, and the government, will report its conclusions this August to Vice President Al Gore.

Eradicating HIV

Until the threat of resistance and cross-resistance is more fully mapped out, fears will persist of wasting drugs by using them unnecessarily: during the early asymptomatic period of HIV infection, the relatively intact immune system usually keeps viral loads low by itself. From now on all treatment studies will be faced with the fundamental question we need to know -- how much viral suppression is sufficient to keep HIV permanently in check?

There are glimmers of hope that the best combinations of presently available agents are indeed strong enough to suppress HIV over the long-term. Ironically, the best prospects for accomplishing this feat occur during the low HIV levels typical of early disease. The June conference "Can HIV Be Eradicated from an Infected Individual?" (summarized on pages 26-27) was conducted by scientists who foresee using a protease inhibitor plus several other drugs to keep viral loads below currently detectable limits for indefinite lengths of time. The emergence of drug-resistant HIV might be blocked by the virus' inability to develop the large number of needed genetic alterations in the face of such forceful constraints on its replication. After some years, the HIV infection might even peter out as chronically infected cells die off without replacement by newly infected ones.

Our present ability to conquer HIV may turn out to be greatly limited still, but this goal cannot be altogether out of reach. After all, a few people already control their HIV infection without any treatment (and a tiny number seem to eliminate the virus entirely). AZT monotherapy increased the number of success stories somewhat. With the aid of effective therapies, the number of such durable resistors can only increase further. But this is all logical deduction. Reducing viral load below viral load assays' level of detection does not mean that HIV is absent from the body, just that the amount of virus has been reduced beyond a purely artificial threshold set by technology. There is no evidence that people whose viral load is undetectable cannot transmit HIV, for example. The data is also insufficient to say how long it takes for HIV to re-emerge despite continued treatment with potent drug combinations or how often this occurs. Certainly, no one on record has stopped treatment without witnessing a rebound in HIV.

Economic Constraints

These high hopes come at a time when health care delivery faces unprecedented financial pressures, and the new economic constraints can limit physicians' ability to try out the most advanced therapies without waiting for their acceptance by the medical authorities. In our survey, this obstacle arose most commonly in regard to use of viral load testing by U.S. doctors, whose patients could not obtain reimbursement from private and public health plans for what has been an unapproved and costly technique. The failure of state AIDS Drug Assistance Programs (ADAPs) in the U.S. to add newly approved drugs to their formularies in a timely fashion was another frequently mentioned impediment to accessing necessary therapy. More generally, the rise of managed care has restricted treatment options even for those covered by inclusive health plans (see pages 17-20).

Comprehensive care centers for HIV/AIDS were mentioned by several of our respondents as a way to bring together the expertise necessary to keep up with the rapidly evolving, increasingly complex standards of care. Since new standards can be vaguely determined and poorly backed up by experimental data, therapy is best practiced in a collegial setting. As always, open communication needs to exist within teams of specialists advising patients on the different conditions stemming from HIV infection. More urgent than ever is consultation between people in the same field.

But commitment to excellence weakens as economic pressures intensify. The following survey is one small attempt to bridge the gap between health care providers in this uncertain era.

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