The Bay Area Reporter - April 10, 1998
Jeff Gustavson, ACT UP\Golden Gate Writers Pool

Interestingly, however, many such persons appear to have derived clinical benefit, despite having "failed." Many have sustained increases in T-helper (CD4) counts (those cells that HIV directly infects) for up to a year or more past the point of viral breakthrough. Additionally, they also have largely not continued to progress in their illness, despite the presence of viral replication. One other puzzling thing is that there are a number of people for whom viral burden has not returned to baseline (pre-treatment) levels, so it could be argued that such people are gaining some level of suppression by continuing to take their regimen.

Nevertheless, there is understandably a level of anxiety among those who have failed.

For, as the internationally renowned Michael Saag, M.D., from the University of Alabama at Birmingham, recently stressed at Summit Medical Center in Oakland, it is important to distinguish between what is actually known and that of which we are only guessing. And choosing a course of action after failing two or three potent PI-containing regimens clearly falls in the realm of opinion. There are theories, but not clear scientific knowledge, about the best course of action for those who have failed a regimen - or two, or more - containing any of the four different protease inhibitors (PIs) currently approved by the Food and Drug Administration: Fortovase (saquinavir), Viracept (nelfinavir), Crixivan (indinavir), and Norvir (ritonavir). With every passing day, the importance of that hard data grows.

Calling all 'failures'

Realizing the need to address this issue, the AIDS Clinical Trials Group (ACTG), a publicly funded clinical trials network run under the auspices of the National Institutes of Health (NIH), is rapidly moving forward in development of a Phase II trial (ACTG 398). This study will be a randomized, partially placebo-controlled trial of Amprenavir (a protease inhibitor currently in development, formerly GW141) as part of dual protease inhibitor regimens for those who have failed up to three PIs, either sequentially or in combination.

This is in contrast to the preponderance of studies currently being conducted using antiretrovirals that often require participants to be either treatment naive as a whole, or naive to the given class of drugs being tested.

All participants will get Amprenavir in combination with Abacavir (a nucleoside reverse transcriptase inhibitor, formerly GW 1592), Efavirenz (a non-nucleoside reverse transcriptase inhibitor, formerly DMP 266, also known as Sustiva) and Adefovir Dipivoxil (a nucleotide reverse transcriptase inhibitor, also known as bis-pom PMEA).

The only thing that will be placebo-controlled is a second protease inhibitor, and study participants have an equal chance of receiving a PI they have not seen before (they will be randomized to nelfinavir, indinavir, or soft gel saquinavir) or a placebo, giving the study four arms. While it is true that expanded access programs are open for Efavirenz, Adefovir, and Abacavir, there are many who have been holding out for a protease with which to combine them, or for clearer validated direction as to their treatment options.

Participants will have access to a PI not yet available, and also the altruistic opportunity to help researchers decide what course of action is best for others in this situation.

Start date not set

ACTG 398 is expected to begin enrolling locally sometime in late June or early July at the clinical trials unit of UCSF at San Francisco General Hospital. This column will announce its start date and enrollment procedures when they are finalized.

The study has three primary objectives:

To compare the proportion of subjects achieving a plasma HIV-1 RNA concentration below 200 copies/ml across the study arms at 24 weeks;

To compare the time to quantifiable viral load across the study arms;

To compare safety and tolerance across the study arms.

The study's secondary objectives, however, are perhaps more interesting. They include determining the influence of baseline (what you had at the start of the trial) genotypic (the sequence of virus) and phenotypic (how the virus acts in vitro - a test tube) PI and Reverse Transcriptase inhibitor resistance on subsequent plasma viral load and CD4 cell count responses.

This is especially important, because many people are having these very expensive genotype tests done without their having been validated. At the same time there is a clear lack of consensus on how to interpret their results.

Part of the problem is that commercially available assays report only on the presence of a mutation and give a readout that implies there is a single identical virus throughout your bloodstream, when in fact there exists a "swarm" of quasispecies. In other words, some virus copies will have one mutation, but lack another.

Additionally, sequencing RNA does not address the integrated proviral DNA, a pool of potential virus that has received a lot of attention lately, causing many to doubt the possibility of eradication. Researchers hope that addressing this question in the trial will add insight into making sense of both genotype and phenotype tests.
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