The Bay Area Reporter - October 27, 1998
Jeff Gustavson ACT UP\Golden Gate Writers Pool

The AIDS Clinical Trials Group (ACTG), a research network funded by the National Institutes of Health has two trials - called ACTG 398 and ACTG 400 - now open for enrollment. ACTG 398 is a trial discussed in greater detail in a prior writer's pool article [See "Finally, a clinical trial for the rest of us," April 21, 1998.] In brief, it's a trial for people for whom protease inhibitors (PIs) have failed either serially or in combination up to three agents. All participants will be receiving abacavir/ziagen/GW1592, amprenavir/GW141, efavirenz/Sustiva/DMP-266 (a non-nucleoside reverse transcriptase inhibitor or NNRTI), and adefovir/Preveon (a nucleotide analog). Additionally, based on treatment history, participants will be randomized to receive either a), indinavir/Crixivan, b ), nelfinavir/Viracept, c), the soft-gel (good) version of saquinavir/Fortovase or d), placebo.

One concern expressed by the community about this trial is about possible side effects from Gilead Sciences' adefovir. Adefovir is associated with a risk of developing Proximal Renal Tubule Dysfunction (PRTD). Dr. John Mellors, from the University of Pittsburgh, the vice-chair of this protocol and the chair of ACTG 400, describes PRTD as "a largely reversible toxicity that we will be monitoring very closely via monthly blood draws looking at L-carnitine levels [low levels are associated with risk of developing PRTD]. We have opted to use the lower dose [60 mg.] in this trial, and have options for discontinuing its use, and still staying in the trial."

This trial will limit to one-third the number of participants with NNRTI experience (nevirapine/Viramune or delavardine/Rescriptor) and to 50 percent people with multiple PI exposure.

ACTG 400 is a single protease inhibitor failure trial for people on nelfinavir who are failing their first protease inhibitor. This study will look at people with sensitivity to two nucleoside analogs and are non-nucleoside reverse transcriptase inhibitor naive. Participants will be randomized to get two nucleoside analogs and efavirenz/Sustiva and a protease inhibitor, either alone or in combination. Participants will receive either Ritonavir and Saquinavir, indinavir alone, amprenavir alone, or indinavir and amprenavir.

People interested in enrolling in either of these trials should call the outreach coordinator at the local ACTG site UCSF/San Francisco General Hospital at (415) 476-9296, extension 360.

Mellors, a recognized leader in the field of HIV-resistance spoke to the Bay Area Reporter about failing the much-hyped PIs. "Protease inhibitors work by competitively binding in the substrate binding site where the gag gene-encoded protein product normally would bind," he explained. "Mutations, both in the binding site as well as those distant from it, can alter the configuration and therefore lead to protease inhibitor resistance."

For patients who had shown virologic failure, Mellors said, "We would try based on treatment history to construct a regimen that would ideally suppress to less than 50 copies of RNA [undetectable on the ultra-sensitive test] per milliliter."

Mellors commented on apparently discordant responses of viral breakthrough and rising CD4 counts, which usually have an inverse relationship, by saying, "This phenomenon of virologic failure and immunologic success is not all that surprising. Tipping the balance of viral burden towards control, even if relatively modestly, should benefit persons with HIV. As little as three-tenths of a log or 50 percent reduction has been associated with clinical and immunologic benefit [longer life, less opportunistic infections]. Clearly, some suppression is better than none."

Many clinicians as well as people with HIV have been utterly perplexed by resistance testing. Mellors clarified: "The utility of any resistance test will vary from individual to individual. These tests are most useful for identifying which drug of a current regimen is failing. They are least helpful in identifying resistance from the past. The data are incomplete - there's evidence that resistance [as gauged by phenotypic and genotypic tests] may fade quickly off therapy. These tests are most useful in ruling out which drugs not to use, and somewhat less useful in positively predicting a successful regimen."

ADDing up

Dr. Tom Merigan, from Stanford University, is also conducting a trial for people for whom PIs have failed, called the ADD. "When we do genetic sequencing of a person's virus and see pan protease and pan reverse transcriptase inhibitor resistance, we are interested in looking at those persons in our trial," he said. "These are typically persons who have been on at least two proteases.

"Our trial will be using ddI, adefovir, efavirenz, and [the much ballyhooed] Hydroxyurea (HU). Since HU increases the intracellular levels of adefovir and the effectiveness of ddI, we are trying to get those drugs going to protect people from NNRTI resistance. This study will be for a minimum of 24 weeks, with extension for those who are receiving benefit. We have one of our patients who is 16 weeks out and undetectable.

"We know the patterns of resistance and that certain mutations can live together," Merigan continued. "I expect we're going to be in this for the long haul and will have more failure as time goes on. The questions that need to be asked are if a second protease inhibitor can be used more effectively, and if the newer classes of treatments will work in people who are failing."

Becoming animated as he spoke, Merigan added, "I wish the hell we had a goodies bag that was fuller. At the same time, we just can't give up. We've got to reach out to the local informed people in the community - that's how we make progress in our understanding of HIV."

People interested in enrolling in this trial should call Jane Norris at (650) 723-2805.

Run out of options

Dr. Steven Deeks, assistant clinical professor of medicine at UCSF, is also conducting a study funded by the University-wide AIDS Research Program and by the Center For AIDS Research at UCSF (CFAR). In collaboration with Drs. Bob Grant, Marc Hellerstein, and Mike McCune (the big guns of HIV research), Deeks will study 16 people intensely, eight of whom will be randomized to stop therapy for a period of 12 weeks, the other half to remain on their failing regimen. This study came out of the viral breakthrough project, a community-initiated focused inquiry into the nature of PI failure.

"This trial is for people who have run out of options," according to Deeks. "Those who have been on at least two protease inhibitors or one PI and one NNRTI and have failed to achieve durable suppression, with viral loads greater than 5,000 by bDNA or 10,000 by PCR." People in this study will have more than $10,000 worth of tests performed on them, some of which are not regularly available. The researchers will look at T cell turnover, thymic scans, plus naive and memory subsets of T cells, and will closely monitor viral load (every two weeks). If there is more than a one log increase, participants will be allowed to restart therapy, which is also the case if they should suffer a significant loss of CD4 cells. As in all research studies, there is a certain level of altruism required to participate.

Deeks stressed the importance of this study. "This has never been done before," he said. "It will provide a prospective framework to answer the question of whether it is wiser to stay on or go off a failing regimen. There are possible benefits to stopping medications - first, this might prevent continuing mutations. Second, there have been anecdotes about wild-type [protease and RTI sensitive] virus returning after going off therapy. This is worth looking at prospectively. I think we will see a reversion of resistance towards wild-type which will offset the half-log increase we may see in those who have stopped therapy."

People interested in enrolling in this trial should call Becky Ho at (415) 476-3669, ext. 1.
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