The Washington Blade; Friday, February 7, 1997
Lisa Keen

The good news is that taking into account the three protease inhibitors, five nucleoside analogs, and one non-nucleoside analog available on the market right now, that gives people with HIV infection about 45 different three-drug combinations to choose from.

The hard news is that people with HIV infection have about 45 different three-drug combinations to choose from. There is no consensus yet on which combination is best to start with.

But there was some new information on how some of the combinations are doing. Scientists studying these various combinations in small groups of volunteers presented their latest data at the Fourth Annual Conference on Retroviruses and Opportunistic Infections. Unfortunately, many of the studies had been under way for only two to six months -- 18 months at the longest. And, unfortunately, scientists learned at this conference that it will take at least 24 to 36 months for the AIDS virus to be eliminated from the body. And that's assuming these combinations can stop the virus from replicating long enough for it to be completely eliminated from the body.

So what is the latest data on triple-drug combinations? From more than 800 different posters and presentations on various aspects of treating HIV and its opportunistic infections, there were about two dozen presentations on three-drug combinations involving protease inhibitors. Some stats about these presentations:

--they involved about 850 patients trying about seven triple-drug combinations with a protease inhibitor;

--the greatest number of patients on any one combination was 363 people across four studies taking indinavir-AZT-3TC;

--the longest period of time any group of patients had been on a combination (18 months) came with ritonavir-AZT-3TC (and only one patient had been on it that long);

--the greatest viral load drop registered, thus far, came with the combination of ritonavir-AZT-3TC (3.8 logs); and,

--the greatest increase in CD4 counts (suggesting some restoration of the immune system) came with the combination of nelfinavir-d4T-ddi (an average increase of 218).

Looking at how the various combinations appear to be working on these small groups of patients is a helpful guide but the data has to be taken with six caveats and a half-dozen circumspections. For instance:

--these results are coming out of clinical trials in which patients are being carefully monitored and supported to stay compliant with pill-taking regimens that many people with HIV are finding hard to stick to in "real world" settings. And patients who are compliant are doing much better than those who are not;

--some of these results are in patients who were able to begin treatment fairly early after infection. Early in infection, the virus has not had much time to become entrenched in various non-blood "compartments" of the body and not much time to have mutated into various new forms more resistant to drug therapy; and,

--while the consensus of clinicians and researchers at this conference clearly favored early treatment with triple-drug combinations, they still express considerable worry that these combinations -- after two or more years of therapy -- may begin to fail as their predecessor treatments have failed.

The question Canadian AIDS researcher Julio Montaner posed two months ago at another AIDS research gathering still looms: What shall a patient take if the triple-drug therapy should fail? But contrary to some news reports, possible answers did begin appearing on the horizon at last month's conference.

The latest data suggests that one answer might be four-drug combinations. A study at Mercy Hospital in Miami found that patients who had tried the standard dosage of ritonavir with two nucleosides but could not tolerate the side effects of ritonavir did well when put on a reduced level of ritonavir and the addition of saquinavir.

Two other studies -- one at the Chicago Center for Special Immunology and another at the Desert AIDS Project in California -- found that patients with advanced AIDS who had been on a triple-drug combination with one protease inhibitor experienced an additional viral load drop and CD4 cell gain when a second protease inhibitor was added.

Another possible answer appears to be new drugs. One promising report was that Nelfinavir, a new protease inhibitor which is nearing the market, appears to be effective against the AIDS virus even after the virus has developed resistance to the other protease inhibitors (indinavir, saquinavir, and ritonavir).

Although very preliminary, new data emerged to suggest that so-called "second-generation" protease inhibitors might brighten the future and be able to attack a virus that has mutated to resist first-generation protease inhibitors. For instance, eight posters reported positive developments (albeit only in the test tube thus far) with a second-generation protease inhibitor called ABT-378 from Abbott Laboratories. ABT-378 in combination with ritonavir appears to be able to work against the virus after it has become resistant to ritonavir.

And though they didn't get much news play, a number of completely new classes of drugs appear to be making their way down the pike -- new classes of antivirals with names like nucleocapsid inhibitors, sulfated bio-azo dyes, fusin inhibitors, and bisimidazoacridone compounds. What the more cautious observer can say, however, is that none of these possible answers are certain fallbacks yet. And there are more difficult questions than there are promising answers.

The questions that seem to loom for people with HIV right now tend to hover around time:

When will the durability of triple-drug combinations be known? The answer is: When they fail or when they prove to completely eliminate the AIDS virus from all parts of the body.

When might that be? For some people, they are already failing, but scientists believe that may be a product of the patients' compliance with very burdensome pill-taking regimens and, in some cases, side effects. For patients who are still succeeding on the combinations, it will be at least another year, maybe two, maybe more before the answer to the durability-success question is known. When will new therapies be available to replace them if they fail? The answer, it seems, is: Now for some, soon for others, and no one can be sure for everybody.

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