New Optimism on Controlling HIV Infection

Today there is more optimism among leading experts about the prospects for controlling HIV infection than at any previous time in the AIDS epidemic. This change (illustrated by a recent conference, "Can HIV Be Eradicated from an Infected Individual," June 12-13 in Washington, D.C., organized by the University of Amsterdam and the journal ANTIVIRAL THERAPY -- and by a major page-one article in the June 14 WALL STREET JOURNAL) does not reflect any single breakthrough, but rather a number of clinical research findings, which together are strengthening an approach to treatment strategy which began coming into public view a few months ago. It is important to understand the limitations as well as the promise of this new approach.

In late January of this year, at the Third Conference on Retroviruses and Opportunistic Infections, early data from at least two small trials suggested that, under ideal conditions, certain drug combinations could reduce all evidence of viral replication to undetectable levels in most patients. And the proportion of patients achieving this success seemed to increase over time -- the opposite of previous experience with anti-HIV drug treatments, which quickly reached a peak of viral suppression and then steadily lost effectiveness.

Today there is more data, and from different kinds of patients, suggesting that:

(1) Under ideal conditions -- meaning that treatment is started early, using certain antiviral drug combinations, in patients who are previously untreated (at least with all of the drugs in that combination), and with patients who can and do comply with the treatment regimen by using the drugs as directed -- HIV replication in many patients can indeed be reduced to levels which are completely undetectable by any test known, for prolonged periods of time. No one knows how long this essentially complete shut-off of viral replication will last, because the trials are only running now; but in most of the patients who can achieve this suppression and who can continue using their treatments as directed, there seems to be no evidence yet that this antiviral success is coming to an end. Some people have been on treatment in the studies for well over a year.

(2) If viral replication can be reduced to undetectable levels, patients do not progress to more serious disease, in the time frame seen so far. Again, no one knows how long this will last, since there is no long-time experience yet with patients whose viral load has been greatly suppressed by drugs.

Also, there are anecdotal reports of substantial improvements in ongoing AIDS-related symptoms in some of the patients. (There is no scientific data yet on this finding, as trials designed to address this question have not yet been run).

The viral load in these patients is lower than that in long-term nonprogressors, who remain disease-free for many years, possibly indefinitely in some cases. But the number of persons who are naturally long-term nonprogressors (without treatment) is low, probably about five percent or less. By contrast, it appears that currently available drug treatments -- when used under ideal conditions -- can suppress all evidence of viral replication and disease progression in most patients, for an unknown period of time.

(3) The major problem in treating HIV has been that the virus develops resistance to all known drugs, causing treatments to lose effectiveness. It has long been known that the time required for resistant virus to develop varies greatly, depending on the drug. For example, with nevirapine (an experimental treatment recently recommended for approval by an FDA advisory committee), high-level resistance occurs very quickly if the drug is used alone. But AZT resistance develops more slowly, and some patients can use that drug for years without it happening (although there is increasing concern about people being infected with virus which has already become resistant to AZT -- and also concern that some AZT-resistant viruses may be more harmful than most non-resistant viruses, even aside from the problem of loss of effectiveness of AZT).

But now there are trials of antiviral drug combinations active enough to reduce viral replication to undetectable levels in many patients. And it is being learned that when viral replication is reduced to a low enough level, the development of drug resistance is greatly slowed, or possibly even stopped. The example of nevirapine shows how large this difference can be, since resistance develops rapidly if used as a single drug or a single addition to ongoing therapy. But in the right combinations, for patients previously untreated with any of those drugs, nevirapine appears to be useful for a long time.

(4) Like almost all treatments for infectious diseases, this approach works best when treatment is started early -- and when patients do not already have resistance to any of the drugs in the combination they are starting (either from previous use of a drug in a dose which was not effective in shutting off viral replication, or by infection with virus which was already resistant). But there is no known reason why the same approach could not also work in advanced patients who have had many previous treatments, provided that some way could be found to reduce viral load to a low enough level. The problem is that it will be more difficult to find drug combinations which can do this for persons with more advanced HIV disease. This is why it is important to develop new and more powerful drugs, and better information about how to use them in combination, and about what treatments work best for different kinds of patients.

The emerging view of experts today is that what counts is getting the viral load very low and keeping it very low, regardless of how this is achieved -- whether naturally in persons fortunate enough to be long-term nonprogressors, or by whatever antiviral combination works for the particular patient. The more advanced the illness, the higher the viral load is to start with, the more drug-resistant viruses the patient already has, and the more problems there are with continuing the drugs and using them as directed, the more difficult it will be to get the viral load low enough. To maximize potential benefit, the emerging treatment philosophy is "hit hard and hit early."

How low a viral load is low enough? No one knows for sure at this time. A viral load which is and remains below the limit of detection of the Hoffmann-La Roche Amplicor HIV-1 Monitor(TM) test -- the only viral load test currently approved by the FDA -- would seem to be a reasonable goal for now; for more information, see "HIV Viral Load Markers in Clinical Practice," published in NATURE MEDICINE, June 1996 (reviewed in AIDS TREATMENT NEWS #248, June 7, 1996). [As we reported in our last issue, two free tests to establish a baseline are being offered to everyone with HIV in the U.S., but only for a 60-day period beginning June 17, 1996; for more information, call 1-888-TEST-PCR.]

Is Viral Eradication Possible?

If viral replication can be essentially completely suppressed for a long time, is it possible that the virus remaining in the body would eventually die, meaning that HIV was eliminated and the person could stop taking the drugs and would be cured? This is conceivable, but at this time there is no evidence that this is possible. Eventually some people whose virus is now being completely suppressed by antiviral drugs will try going off the drugs, and then we should find out quickly whether or not the virus comes back. (Two patients who had undetectable viral load for two months and four months did interrupt therapy, and the virus returned; this was reported by Dr. Luc Perrin, of Geneva University Hospital, at the recent HIV Eradication conference mentioned above.)

Although there is no evidence today that it is possible to eradicate HIV in an infected person, what is new is that the question is now open. Until recently, all drug regimens had been observed to fail with time; therefore, there was no possibility that any amount of those treatments could eliminate the virus. Today, with better treatments, we do not know. But even if it turns out that HIV cannot be eradicated just by suppressing it completely enough for long enough, the new results would still suggest that for many patients viral activity can be stopped for a long time, and drug efficacy maintained, with combinations of currently available drugs.

Comment: Practical Concerns

Most of the drugs being used in the new trials which appear to have largely shut off HIV replication in many patients are already widely available (in the U.S. and some other countries), by prescription or through expanded-access programs. The researchers running the trials have been unwilling to recommend particular combinations, since what counts is getting the viral load low enough, and the best drugs to use for this purpose will vary depending on the patient. Most of these regimens combine a protease inhibitor with at least two other antivirals. We will report results of particular drug combinations with particular patients as more information becomes available.

One of the practical difficulties in implementing the "hit hard and hit early" strategy, as the new results suggest, is that it means that people in early illness, who have no symptoms, are expected to begin long-term (possibly life-long) therapy with combinations of at least three drugs. All these drugs can have side effects -- and all are expensive, and often inconvenient to use (as most must be taken twice a day or more, some on an empty stomach, others with food, etc.) How many people will be able and willing to begin and stay on such multiple-drug treatment, when they feel completely healthy, and may understandably be inclined to leave well enough alone? How many will be able to pay for expensive treatment (especially when their insurers see that they appear entirely well)? The new results seem to suggest that everyone who is HIV-positive should be on aggressive treatment with multiple antiviral drugs. But how realistic is this?

It seems to us that the widespread use of very early, very aggressive treatment will in practice usually wait until more evidence becomes available. Much more will be known by later this year. And it is possible that persons with a naturally low viral load might need less aggressive treatment to achieve the suppression required. It is also possible that after a period of suppression, maintenance therapy might not need to be as aggressive as the initial therapy. But this is only speculation until more is known.

Meanwhile, physicians and patients should re-think the unfortunately common practice of beginning HIV treatment with AZT alone, or with other regimens not strong enough to suppress the virus sufficiently. This approach is likely to lead to resistant viruses, which might make future treatment more difficult than if the inadequate treatment had never been started at all.