Being Alive; August 1996
Jim Stoecker

Overview

The International Conference on AIDS is now being held every two years. This year's gathering in Vancouver was the largest such conference yet held. Over 15,000 people were in attendance for the five-day event. During the conference, there were some 5,000 presentations, as well as satellite symposia and poster presentations.

Almost all participants at the Vancouver conference would characterize it as the most hopeful yet. The big question raised at this conference, and certainly not at any previous conference, was: is eradication of HIV from the body possible?

To set things in perspective, Dr. Katz in his opening remarks laid out a time line of developments. In 1981, we had the first reports of what was then called GRID or Gay-Related Immune Deficiency. By 1982, GRID had become AIDS and researchers were in pursuit of the causative agent of Acquired Immune Deficiency Syndrome. By 1984, both French and American scientists had identified the Human Immunodeficiency Virus or HIV. By 1985 we had the antibody test for HIV, the one still being used today. In 1987, AZT was approved for use as an antiretroviral and prophylaxis for PCP was becoming more widely available. For many years, only AZT was available as treatment; in 1991, ddI became the second FDA-approved antiviral. In 1992, we saw the first combination antiviral therapy approved, AZT and ddC.

The 1993 International Conference on AIDS was possibly the low point in the history of HIV/AIDS. That was the year of the Concorde study which questioned the value of AZT monotherapy. In 1995, the development of viral load tests and the approval of a number of protease inhibitors offered people with HIV/AIDS new hope for treatment. And now in 1996, we are beginning to ask whether the virus can be held in check indefinitely.

Viral Load Testing

Dr. Katz noted that only six months ago, viral load testing was a new concept for most people with HIV. Now, it is becoming a standard part of an individual's care. For some months now, the rule of thumb has been that a viral load of greater than 100,000 indicated that antiviral therapy should be started or, if already used, should be changed. The accepted standard has also been that if the viral load is less than 10,000, antiviral therapy was probably not indicated. A viral load of less than 10,000 represented for many a "comfort zone." After Vancouver, these rules of thumb may no longer be valid.

We are seeing more and more evidence that the viral load level is highly correlated with the progression to AIDS. Viral load predicts AIDS. Researchers looked at data from the MACS (Multicenter AIDS Cohort Study). The stored blood of 1600 men was tested retroactively for a single viral load reading; these men were then followed for from three to six years. Anyone who had less than 500 copies of HIV per milliliter of blood at initial testing did not progress to AIDS during the period of the study.

In addition, the data showed that the percentage of men who progressed to AIDS went up as the initial viral load went up. In other words, the higher your viral load the more likely that you would progress to AIDS during the time period of the study. These data and data from similar studies suggest that there may not, in fact, be a "comfort zone" of viral load level. Maybe the level should be less than 5000 or perhaps less than 500. Maybe undetectable is where you want to be to reach that "comfort zone." What the emerging information is telling us is that the goal of any antiviral therapy should be to keep the viral load level as low as possible for as long as possible.

Protease Inhibitors

To address the issue of how to get the viral load as low as possible for as long as possible, Dr. Gottlieb reviewed the latest information on protease inhibitors. As Dr. Gottlieb noted, the protease inhibitors were the big news out of Vancouver, and most of that news is good.

The Merck (Crixivan), Abbott (Norvir) and Agouron (Nelfinivir) protease inhibitors were the most prominent at the conference. The first two drugs are already approved by the FDA and the Agouron drug is currently finishing up testing. These drugs used in combination with reverse transcriptase inhibitors (AZT, 3TC) have been shown to reduce viral load to less than 100 copies per cubic centimeter using the latest third generation viral load assays.

In one study that combined Crixivan, AZT and 3TC, results showed that even in people who had extensive prior AZT use, viral load was dramatically reduced. And these reductions appear to be long lasting; at one year out, 80% of study participants had viral loads of less than 500.

Another study, prominently reported at the conference, combined ritonivir, AZT and 3TC to treat people who were identified as newly infected with HIV. In this attempt to nip the virus in the bud, so to speak, many did show a reduction of viral load to undetectable levels. It remains to be seen whether these people can later be taken off the combination and remain free of HIV. If this were to happen, we could say that the virus had been eradicated. As of yet, however, no one is declaring a cure.

Such dramatic reductions of viral load force us to take a new look at HIV treatment. To evaluate an antiviral regimen, you should look at the percentage of people on a particular regimen whose viral load has been reduced to less than 100. You then should also look at the length of time that low viral level is maintained.

To receive the benefits that these studies have shown, protease inhibitors must be used in combination with at least two of the nucleoside analogs. From all the data we have so far, this ensures the greatest lowering of viral load; it also decreases the possibility of the virus developing resistance to the drugs. Also, compliance is a critical issue in using protease inhibitors. This means that a person must take the prescribed dosage at the specified time. All the studies have shown that taking too little drug or taking it erratically favors the rapid emergence of virus that is resistant to the drug's effects.

Dr. Gottlieb concluded his remarks by noting that there are a number of questions still to be answered about the use of protease inhibitors in treating HIV disease. Researchers are concerned that the virus that is not detected in the blood may be hiding out in the body in the macrophages and nervous system. Nonetheless, for those that can afford them, these drugs are the best hope yet for controlling HIV. The sad fact is that for most of the world's infected population, these drugs remain out of reach. (See article on the world epidemic.)

Other Antivirals

Dr. Scott Hitt began his remarks about other antivirals by stating that the lessons from all this latest information is that we need to hit the virus early and we need to hit it hard. The word in Vancouver was no more monotherapy, no more deferred therapy.

Protease inhibitors, as Dr. Gottlieb noted, should not be taken alone. Anyone who has been on a combination of reverse transcriptase inhibitors, such as AZT and 3TC, should consult with their physician before adding a protease inhibitor to their regimen. It may be that the antiviral effect of the previous therapy has worn off. In such a case, you would want to look for two other drugs to combine with the protease inhibitor. In this way, you can maximize the effects of the combination therapy. Just adding a protease inhibitor may not be the answer.

Several new drugs are in development; these drugs have new ways to target the virus. One promising class of antivirals would stop the attachment of the virus to the cell. Another class of new antivirals target another enzyme crucial to viral reproduction; these drugs are know as integrase inhibitors.

Dr. Hitt reported that we also have some new reverse transcriptase inhibitors in development. One such drug is called U1952. This appears to be very attractive; it is easy to take, highly effective in the test tube and appears able to reach into the central nervous system. Adefovir is another new antiviral; this drug is termed a nucleotide analog, rather than a nucleoside analog such as AZT, ddI, ddC and the like. The beauty of this drug is that it only needs to be taken once a day. In addition, it appears to attack CMV as well as HIV. The hope is that adefovir might prove useful as prophylaxis for CMV, as well as valuable in fighting HIV.

Nevirapine was recently approved by the FDA for combination therapy; delavirdine may soon follow. (See related article on page 8.) These drugs have been around for some time. They are not useful when taken alone because the virus quickly develops resistance to these drugs. However, they may have a place in combination therapies. One Dutch study that combined nevirapine with two nucleoside analogs showed viral load suppression of the same magnitude as that obtained with a three-drug combination that included a protease inhibitor. The big word of caution about nevirapine and delavirdine is that they may lower the levels of protease inhibitor in the blood. We are still waiting for test results on this issue. Meanwhile, they should be used with caution in combinations with a protease inhibitor. An effective antiviral combination means three drugs that work.

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