AIDSWEEKLY Plus; Monday, August 6, 2001
Prepared by Staff Medical Writers

NewsRx - HIV patients who receive triple-drug therapy to suppress viral levels below the limit of detection frequently experience intermittently detectable HIV RNA in blood plasma, but this does not predict subsequent virologic failure, researchers say.

Diane V. Havlir, MD, of the University of California, San Diego, and the San Diego Veterans Affairs Healthcare System, and colleagues conducted a retrospective analysis of participants in two studies to determine if HIV infected patients with intermittent viremia (the presence of virus particles in the blood) have a higher risk of virologic failure. The patients were enrolled in the AIDS Clinical Trials Group (ACTG) 343 trial of induction-maintenance therapy (August 1997 to November 1998), and the Merck 035 trial (ongoing since March 1995).

The authors analyzed data on 241 ACTG 343 patients, of whom 101 received triple-drug therapy throughout the study, and a small group of 13 patients from Merck 035 having virologic suppression after six months of treatment with the anti-AIDS drugs indinavir, zidovudine, and lamivudine. They measured the association of intermittent viremia (plasma HIV RNA greater than 50 copies/mL with a subsequent measure of less than 50 copies/mL), with virologic failure (two consecutive plasma HIV RNA measures greater than 200 copies/mL) in both study groups. Havlir's group also looked for evidence of drug resistance in seven patients from the small study group with long-term follow-up.

"Intermittent viremia occurred in 96 (40%) of the 241 ACTG 343 patients of whom 32 (13%) had two consecutive HIV RNA values greater than 50 copies/mL during the median [middle] 84 weeks of observation (median duration of observation after first intermittent viremia episode was 46 weeks)," the authors report JAMA 2001 Jul 11;286(2):171-9.

"Of the 101 individuals receiving triple-drug therapy throughout, 29% had intermittent viremia; the proportion of episodes occurring during the maintenance period was 64% for the entire cohort, and 68% for the group not receiving triple-drug therapy throughout vs. 55% for those who did," they write.

Patients whose plasma HIV RNA levels remained consistently below the level of detection and those whose plasma HIV RNA levels were transiently detectable had similar rates of virologic failure. "Intermittent viremia did not predict virologic failure: 10 (10.4%) of 96 patients with and 20 (13.8%) of 145 patients without intermittent viremia had virologic failure," report Havlir and colleagues.

By applying a more sensitive assay, the researchers demonstrated that patients sustaining levels of HIV RNA less than 50 copies/mL have varying levels of ongoing viral replication. "Median viral load in 10 ACTG 343 patients assessed between 24 and 60 weeks of therapy using an ultra-sensitive 2.5-copies/mL detection level assay was 23 copies/mL in those with intermittent viremia vs. less than 2.5 copies/mL in those without," they write. "Intermittent viremia occurred in six of 13 patients from the small study group assessed after 76 to 260 weeks of therapy (using the 2.5-copies/mL detection level assay) and was associated with a higher steady state of viral replication, but not virologic failure over 4.5 years of observation."

Havlir and coauthors also note that "viral DNA sequences from seven patients did not show evolution of drug resistance."

"In summary, in patients who achieved virologic suppression with indinavir-zidovudine-lamivudine, intermittent viremia was a frequent occurrence and was associated with higher steady-state levels of viral replication (Merck 035) but was not associated with virologic failure for up to 4.5 years (ACTG 343 and Merck 035).

"Clinical management options are increased by this knowledge. A higher HIV RNA level that would trigger a therapy change may preserve the number of drugs available for future therapeutic regimens," they conclude.

Supported by grants to the AIDS Clinical Trials Group from the U.S. National Institute of Allergy and Infectious Diseases, the U.S. National Institutes of Health, and the University of California, San Diego, Center for AIDS Research and the Research Center for AIDS and HIV Infection of the San Diego Veterans Affairs Healthcare System. Dr. Havlir received grants or funding from Merck and GlaxoSmithKline.

In an accompanying article, Deborah Persaud, MD, a Children's Center infectious disease researcher at Johns Hopkins University, and colleagues report they used a novel method for amplification of an HIV-1 gene in patients receiving highly active antiretroviral therapy (HAART), who had prolonged suppression of viral replication and low levels of plasma HIV-1 RNA at the time of the study (JAMA 2001 Jul 11;286(2):196-207). Monika Hermankova, BA, is the first author on this paper.

Genotypic analysis did not show evidence of new resistance mutations in plasma virus clearly attributable to the current therapy. But if resistant virus was selected by prior non-suppressive therapy, production of this resistant virus persisted, whether or not those drugs were continued.

Hermankova and coworkers conducted a study from November 1999 to February 2001 to determine genetic resistance profiles of low-level plasma HIV-1 in 18 infected patients (seven children and 11 adults). The patients had suppression of viral replication while receiving combination therapy that included a protease inhibitor. Two patients with less optimal suppression of viral replication were included to assess virus predominating when plasma HIV-1 RNA levels are low, but detectable (less than 1,000 copies/mL).

"We were able to amplify and characterize the virus present in the plasma at extremely low levels (less than 50 copies/mL) in patients treated with prolonged HAART," they write. "This virus lacked new resistance mutations clearly attributable to selection under HAART."

They also report that "in heavily pre-treated patients, virus with drug resistance mutations possibly attributable to the prior therapy was found in the plasma but was not indicative of impending drug failure. However, the persistence of this 'archival' drug-resistant virus, even in the absence of continued treatment with the relevant drug, argues against the idea of recycling drugs that were part of prior non-suppressive regimens if loss of suppression should occur during long-term HAART."

Hermankova and team conclude: "Developing approaches for eliminating the source of this residual viremia is clearly a prerequisite to virus eradication."

This work was supported by a Child Health Research Center award, an Elizabeth Glaser Pediatric AIDS Foundation Award, a Doris Duke Foundation award to coauthor Deborah Persaud, MD, and grants from the U.S. National Institutes of Health (NIH). Ms. Hermankova received funding from the NIH.

In an accompanying editorial, Steven G. Deeks, MD, of the University of California, San Francisco, and San Francisco General Hospital writes that based on data from these two studies, it may be argued that "complete" viral suppression may not be a prerequisite for durable treatment benefit.

Calling the findings of Havlir and colleagues, and Hermankova and colleagues "intriguing", Deeks also points to two limitations in the studies. "A relationship between low-level viremia and subsequent virologic failure may become apparent with long-term observation," he writes. "It is possible that low-level viremia with regimens that do not contain a protease inhibitor may be associated with rapid rates of virologic failure," he continues.

"These limitations notwithstanding, the data from Hermankova et al. and Havlir et al. deserve careful consideration by clinicians and by those drafting treatment guidelines," he writes. "It must now be accepted that current therapeutic regimens may not be able to completely suppress viral replication, even when used under optimal conditions. Fortunately, complete viral suppression does not appear to be a prerequisite for durable virologic and presumably, clinical benefit.

"Thus, categorizing the response to therapy as a dichotomy (undetectable or detectable, completely suppressed or incompletely suppressed, success or failure) may be misleading. Combination therapy is often only partially effective. The question now is how much viral suppression is required to achieve durable virologic, immunologic, and clinical benefit," he concludes (JAMA 2001 Jul 11;286(2):224-6).

Dr. Deeks has received research grants from Abbott Laboratories, Gilead Sciences, and Triangle Pharmaceuticals, and has served as an ad hoc consultant and/or speaker for Agouron, Bristol-Myers Squibb, Glaxo-Wellcome, Hoffmann La Roche, and Merck.

This article was prepared by AIDS Weekly editors from staff and other reports.

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