GMHC Treatment Issues, Vol. 10, No. 2; February 1996
Dave Gilden

Emilio Emini, M.D., head of antiviral research for Merck & Co., set the atmosphere for the rest of the conference by describing these new tools in one of the event's lead-off presentations. Reviewing the public data on protease inhibitors and their combination with one or two nucleoside analogs, Dr. Emini urged a "new paradigm" for AIDS treatment, in which the goal is to administer combinations of drugs that lower viral loads for as long as feasible to below current assays' limit of detection. The idea is to shut down HIV replication as much as possible so as to eliminate or delay the accumulation of mutations leading to drug resistance, the chief nemesis of HIV therapy up to this point. (Considering the source, it is not surprising that Merck's protease inhibitor indinavir had a featured role in this "new paradigm.")

The results presented both before and during the conference concerning such drug combinations are very impressive. Combinations of some of the new protease inhibitors and the older nucleoside analogs caused drops in plasma viral loads of a thousand-fold and more, accompanied by average CD4 cell rebounds of up to two hundred and, in one trial, a sharp decrease in new AIDS-related diseases and death. (For details, see Theo Smart's article starting on page 3.) Yet many questions persist. The data accumulated so far cover only six months of treatment and/or a handful of trial participants. Already it is apparent that there is wide interpersonal variation in response to treatment, especially to the protease inhibitors. Conference reports on the various clinical trials commonly lacked important information on this score, such as baseline viral load and other characteristics of the best responders.

The duration of treatment benefit remains unknown and probably also differs greatly between individuals. When patients should switch treatment and to what remains the subject of much speculation. And the extent to which people can tolerate the many, sometimes interacting, side effects of combination therapy also remains to be seen.

New Agents Galore

There is no question that a new era is dawning for therapy of HIV and AIDS. As this edition of Treatment Issues goes to press, the FDA's Antiviral Advisory Committee is poised to take up consideration of two protease inhibitors, Merck's indinavir (brand name: Crixivan) and Abbott's ritonavir (Norvir), plus human growth hormone ("Serostim," from Serono) for AIDS-associated wasting. Meetings for these three are scheduled for February 28 through March 1. Delavirdine (made by Upjohn) and nevirapine (Boehringer Ingelheim), two reverse transcriptase inhibitors that are not nucleoside analogs like AZT, also are expected to go before the FDA in coming months. The FDA reportedly has urged the manufacturers of indinavir, ritonavir and delavirdine to file as quickly as possible, even if trials are not completed or manufacturing facilities ready. Judging by the examples of saquinavir and 3TC, approved last November, the agency may take only a few weeks to license drugs for market after its advisory committee has recommended approval.

By the end of this year, if not this summer, there should be at least ten anti-HIV therapies on the market, and the FDA is in the process of approving a variety of new medications for opportunistic infections, too. All this activity is creating a considerable amount of confusion about when and how to apply treatment.

At the Third Conference on Retroviruses, many experts' inclination seemed to be, don't hesitate, use everything now. In a review entitled "Antiviral Therapy '96," Australian researcher David Cooper, M.D., told his audience that 1995 saw the "demise of monotherapy and the ascendancy of combination therapy." But he warned that in the absence of hard data, there was a "danger of patients getting anecdotal combinations" based on physicians' informal summaries of their own experience.

Because of the rush to combination therapy and the large number of available or soon-to-be-available drugs, recruitment for future clinical trials may be difficult, and dropouts may be common. Nevertheless, testing of innovative combinations against standard ones needs to take place. One goal would be to find "the most compact, least toxic combinations with the greatest antiviral activity," to use Dr. Cooper's words. Combining different protease inhibitors, an uncharted field so far, would be a particularly fruitful area to investigate. Another area is the use of maintenance therapy: Once HIV replication is tightly suppressed for some months, and nearly all the infected cells harboring the virus are dead, it may be possible to switch to simpler therapies with fewer drugs to provide a barrier against a resurgence of HIV.

Dr. Cooper also proposed looking at disease progression in people with life-threatening opportunistic illnesses for which there are no adequate treatment options. Here, investigators would measure by how much a new anti-HIV therapy increased the time until diseases such as CMV or lymphoma recurred.

Trials monitoring the recurrence of OIs might give some quick answers, or they might have ambiguous results because unhealable damage inflicted during HIV infection prevents the recovery of effective immune function (see below). Certainly these trials would not tell how to best use antiviral therapy earlier in HIV infection. Efforts to evaluate compact and efficient combinations in a more complete fashion could perhaps take the form of large treatment strategy trials involving changing combination therapies as conditions seem to warrant. Such trials could, and preferably should be, conducted by community physicians in a real world setting.

Counting Virions

The use of viral load assays -- PCR and bDNA -- to measure changes in the level of free HIV in blood plasma, and hence a drug's antiviral activity, has been widely proposed as a way to radically shorten trials. The problem has been that no one has established how predictive viral load measurements are of a person's long-term disease course. Even more in question has been the significance of short-term reductions in circulating HIV induced by a specific treatment.

Almost unnoticed among the news about protease inhibitors and combination therapy were the Conference presentations that promised to revolutionize trials of anti-HIV compounds by confirming viral load as a marker for drug effectiveness. The announcements concerning viral load began in mid-January, when representatives of the newly merged corporation Pharmacia & Upjohn first broadcasted the preliminary results from two large trials combining delavirdine with either AZT or ddI (see last month's Treatment Issues, page 9). Researchers found that delavirdine trial participants who registered a 0.5 log (70 percent) reduction in viral load in their eighth week of treatment experienced a 50 percent reduction in AIDS progression (as measured by opportunistic infections or death). In contrast, a CD4 count increase of 25 or 50 at week eight was not predictive of improved clinical outcome over the next year. (See abstract LB8c.)

But a CD4 count gain of 50 sustained for a year was indeed accompanied by less illness and death. The Upjohn researchers argue from their analysis that early viral load changes are nevertheless more useful for evaluating experimental drugs and managing individual patient's therapy. In their cohort, though, those people with reduced viral load tended to keep that reduction for a year's time, leaving open the question of precisely how long a treatment has to show antiviral activity before that activity translates into symptomatic relief for the patient.

A number of other objections could also be raised concerning this confusing trial analysis, which easily leant itself to rationalizing the approval of delavirdine, a drug with modest antiviral effect when combined with AZT and little effect on CD4 counts. "I'd love to see this in the hands of an objective, outside statistician," commented one skeptical conference attendee.

Be that as it may, Upjohn's so far preliminary conclusions about the value of viral load were reproduced in several other conference reports, particularly the virologic analysis of a subset of the participants in the ACTG 175 trial (abstract S24). ACTG 175, it should be recalled, was a 2,500- person, government-sponsored trial spanning three years that compared AZT alone, ddI alone, AZT plus ddI and AZT plus ddC in HIV-positive individuals with and without prior AZT therapy (see Treatment Issues, October, 1995, pages 2-4).

Although CD4 cell count gains sustained for more than a year seemed to best reflect improved outcome during the course of the trial, baseline plasma viral load and treatment-induced reductions at week 8 were more predictive than CD4 count or change in CD4 count in the first eight weeks of trial observation. A ten-fold drop in viral load correlated with a 70 to 87 percent decreased risk of disease progression as measured by various endpoints -- 50 percent drop in CD4 count, AIDS-defining disease and/or death.

The ACTG 175 analysis further found that initial, pretreatment viral load was a good predictor of future health, as did the Upjohn and several other studies. John Mellors, M.D., reported viral load trends seen in a retrospective analysis of 181 gay men with early HIV infection in the years 1984-85 (abstract S22). (The group was part of the Multicenter AIDS Cohort Study, or MACS.) Based on these people's experience, Dr. Mellors observed, "[Plasma viral load] is an earlier and more accurate predictor than CD4 count--Viral load reflects the balance between the immune system and the virus. It is the most important determinant of outcome."

These studies do not establish how well viral load can be used when making treatment decisions for individual patients. They are a further indication, though, that in the future, optimum combination therapies will be formulated for each patient according to how his or her viral load responds. More and more experts are concluding that the advantages gained are worth the added complexity and cost. "I'm a believer in HIV RNA [viral load]," concluded Harvard's Scott Hammer, M.D., when reporting on ACTG 175.

Holes in the Defense

In the great new age of elaborate antiviral combinations that pack a real wallop, there will be plenty of reason to closely monitor how well that wallop is reaching HIV. First of all is the issue of side effects, which may make patients take their drugs erratically or cease altogether. It is worth noting that in Jacques Liebowitch's small but highly successful Paris study of ritonavir/AZT/ddC (abstract 285, see page 2 of this issue), eleven of 32 volunteers dropped out. Mostly it was the nausea and vomiting that drove them out, despite almost 1,000-fold drops in HIV levels and gains in CD4 counts of nearly 300. (The new capsule form of ritonavir may induce fewer of these adverse effects than the older liquid formulation used here.)

Also, ritonavir's particular molecular structure was chosen for its inhibitory effect on the liver, which stabilizes the drug's level in the bloodstream. Ritonavir as a result cannot be taken along with the many drugs that depend on the liver to break them down and prevent any toxic accumulation in the blood. If prescribed ritonavir, patients may sometimes be faced with choosing between their anti-HIV medication and their OI drugs.

The other way these therapies will fail is through the development of mutant HIV whose altered enzymes no longer interact with suppressive compounds like the nucleoside analogs or protease inhibitors. The ritonavir trial for people with CD4 counts less than 100 (abstract LB6a -- see page 3 of this issue) did find a rapid reduction in the rates of death and new opportunistic infection, but the level of HIV went right back up after the second week. At sixteen weeks, average viral loads were approaching their initial values, leading one to wonder how trial participants will fare later on.

These volunteers merely added ritonavir to their existing therapy, leading the presenter John Leonard of Abbott Laboratories to reckon that the trial was "almost sequential monotherapy" since the other therapies had probably outlived their usefulness because of drug resistance. Dr. Leonard remarked that it would be preferable "to start multiple agents simultaneously."

The futility of monotherapy with even a very potent protease inhibitor, at least at less than optimal doses, was underscored further in an analysis of seven participants in an early ritonavir study using 600 to 900 mg per day (the current dosage is 1200 mg per day). An outgrowth of HIV with a single specific mutation known to confer resistance to ritonavir in the test tube led to a rebound in viral load (abstract 201).

Disappointing expectations that mutant virus would be somehow impaired, this ritonavir-resistant HIV had a robust doubling time of two to four days, perhaps partially due to a second, compensatory mutation. Worse yet, the mutant HIV was already present in very small amounts prior to ritonavir treatment. The time to virus load rebound after therapy began was highly associated with the pretreatment virus level. It was only weakly associated with the dose of ritonavir.

This ritonavir study was remarkable in that it confirmed some of the predictions made by various scientists, including John Coffin of Tufts University (abstract L13) and David Ho (abstract S21) in their reports to the conference on HIV dynamics: there is a close link between the detection of certain mutations and the rebound in viral load; mutant HIV is able to establish significant growth rates only slightly below that of nonmutant virus; and the HIV with point mutations contributing to reduced susceptibility to particular drugs exists even before exposure to those drugs. Attaining the goals Dr. Cooper set out for ideal antiviral therapy may require personal modification of proposed treatment plans based on genetic analysis of the resistance mutations present in a patient's pool of HIV. Such complex testing would be in addition to viral load monitoring and the multitude of laboratory tests needed to check for side effects like liver and bone marrow damage.

Holes in the Repertoire

Time will tell if it is possible with our current technology to root out absolutely all the HIV in a person and thus avoid the rise of mutant varieties resistant to treatment. There are three distinct "reservoirs" beyond the scope of present treatment that may preserve some HIV indefinitely. One is the brain and central nervous system, which is poorly penetrated by most drugs. The second is chronically infected macrophages, which store HIV for many months. Finally, there are antibody-coated HIV particles adhering to the surface of the follicular dendritic cells, which trap such virus in lymph node fluid.

The follicular dendritic cells (FDCs) hold HIV for an unknown length of time, creating a library of the past HIV variants in someone's body, including any previous drug-resistant variants. A paper in the journal Nature last fall (SL Heath et al., October 26, 1995, pages 740-4) reported that virus sticking to FDCs easily infect the circulating immune cells with which they come in contact despite being covered with what are normally highly neutralizing antibodies. "Time bombs waiting to explode," is the way one expert observer, Cecil Fox, Ph.D., characterized them. (Dr. Fox specializes in the analysis of HIV-infected lymph and other tissue.)

It could well be that people with established HIV infections will need some kind of antiviral therapy for the rest of their lives given the limitations on what current treatments can reach. Besides their antiviral cover, people with AIDS may continue to need medications to treat or prevent various infections because they are unable to recover their complete immune response even with HIV permanently suppressed. Mark Connors, of the National Institute of Allergy and Infectious Diseases, compared the CD4 cell "repertoire" in ten HIV-positive and seven HIV-negative individuals (abstract 397). The people with HIV had a more uniform CD4 cell population containing cells able to respond to fewer different foreign proteins. In theory, these HIV-induced "holes in the repertoire" will prevent their immune systems from recognizing specific pathogens, making them vulnerable to diseases most people are immune to.

The gaps essentially persisted in patients even though antiviral and IL-2 therapy raised their CD4 cell count from about 200 to 1,000. Presumably they could not rebuild their normal CD4 cell diversity because the damage to the thymus and other lymph organs wrought by HIV infection makes it impossible for fresh CD4 cells to develop and mature. The NIAID study contrasted with a report from Australia of improved CD4 cell response in a few persons with advanced HIV taking ritonavir in one of the original trials (abstracts 232 and 451 -- see page 3 of this issue). Counts of CD8 cells (which play an important role in eliminating virus-infected and cancerous cells) also exhibited a substantial, sustained rise -- the first time this has been observed in trials of anti-HIV agents.

The clinical implications of either the Australian reports or the contrary NIAID study have not been determined and will require prolonged following of many patients' experience. As reported at the Second Retrovirus Conference last year, the Australians did see some resolution in several patients' physical symptoms.

The hope expressed by one of the Australian observers that under the influence of ritonavir, "[advanced] patients' immune profile becomes similar to that of asymptomatic patients" for now seemed more like a prayer than a realistic assessment to many observers. But still, it is encouraging that immune improvements correlated with the depth and length of viral load decrease. Just getting rid of HIV may turn out to be the linchpin of immune therapy.

Who's Footing the Bill?

Roche's protease inhibitor saquinavir (Invirase) entered the market in December with a retail price tag of about $7,500 per year, and Merck and Abbott, though refusing to comment on pricing issues, can be expected to charge a similar amount. It would be one thing if a cure for HIV could be procured for a cost of $15,000 or $20,000. The benefits of combination drug therapy are finite, though. People with HIV will have to come up with the money for all their drugs and for monitoring their own HIV over an indefinite period.

In the U.S., there are a million people, more or less, infected with HIV. Arguably, they all could profit from the new therapeutic advances (although this is not yet proven). Who will pay is going to become a big question, especially when cuts in Medicaid are in the offing and the states' AIDS Drug Assistance Programs (ADAPs) are already in financial crisis (see page 11). Effective treatment requires social commitment as well as technical finesse.

The experience with tuberculosis, which has some parallels to HIV, is not encouraging. TB requires six to nine months of daily treatment, usually with one inexpensive drug if the disease is latent and with four drugs of moderate price in the case of active, symptomatic TB. When TB elimination seemed within our grasp, a concerted effort to finish off the disease was never undertaken. The result has been incomplete courses of treatment, a resurgence in the number of cases and the emergence of drug-resistant TB requiring novel and costly antibiotics. HIV is even more prone to drug resistance, and its treatment is more complicated and prolonged in the first place.

Then there are all the "developing" countries, whose citizens will have almost no access to the new treatment modalities. Scientists may worry about the protected reservoirs of HIV within the body, but political figures will have to worry about the vast reservoirs of HIV within the planet's human population. Unless the virus can be controlled worldwide, it will keep coming back to haunt us, just as TB does.

960201
GM100201

Copyright © 1996 - Treatment Issues. Reproduced with permission. Treatment Issues is published twelve times yearly by GMHC, Inc. All rights reserved. Noncommercial reproduction is encouraged. Subscription lists are kept confidential. GMHC Treatment Issues, The Tisch Building, 119 West 24th Street, New York, NY 10011  fredg@gmhc.org  http://www.gmhc.org

AEGiS is made possible through unrestricted grants from Boehringer Ingelheim, Elton John AIDS Foundation, iMetrikus, Inc., John M. Lloyd Foundation, the National Library of Medicine, and donations from users like you. Always watch for outdated information. This article first appeared in 2003. This material is designed to support, not replace, the relationship that exists between you and your doctor.

AEGiS presents published material, reprinted with permission and neither endorses nor opposes any material. All information contained on this website, including information relating to health conditions, products, and treatments, is for informational purposes only. It is often presented in summary or aggregate form. It is not meant to be a substitute for the advice provided by your own physician or other medical professionals. Always discuss treatment options with a doctor who specializes in treating HIV.

Copyright ©1980, 2003. AEGiS. All materials appearing on AEGiS are protected by copyright as a collective work or compilation under U.S. copyright and other laws and are the property of AEGiS, or the party credited as the provider of the content. .