July 10, 2001

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Intermittent Appearance of Detectable HIV Levels Occurs Frequently Among Patients Who Achieve Viral Suppression While Receiving Combination Therapy

But intermittent appearance does not signal therapy failure

CHICAGO – 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 it does not predict subsequent virologic failure, according to an article in the July 11 issue of The Journal of the American Medical Association (JAMA).

Diane V. Havlir, M.D., of the University of California, San Diego School of Medicine, 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 human immunodeficiency virus (HIV) that causes AIDS is a retrovirus – a virus with its genetic makeup stored in RNA. HIV RNA levels are measured in copies per milliliter (mL). According to background information cited in the article, antiretroviral therapy (ART) is directed at achieving and maintaining HIV RNA levels below the limit of detection of currently approved assays.

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. The authors 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 percent) of the 241 ACTG 343 patients of whom 32 (13 percent) 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.

“Of the 101 individuals receiving triple-drug therapy throughout, 29 percent had intermittent viremia; the proportion of episodes occurring during the maintenance period was 64 percent for the entire cohort, and 68 percent for the group not receiving triple-drug therapy throughout vs. 55 percent 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 percent) of 96 patients with and 20 (13.8 percent) of 145 patients without intermittent viremia had virologic failure,” the authors write.

By applying a more sensitive assay, the authors 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 6 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.”

“Viral DNA sequences from seven patients did not show evolution of drug resistance,” the authors state.

“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),” the authors write.

“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.

(JAMA.2001; 286:171-179; available post-embargo at jama.com)

Editor’s Note: Supported by grants to the AIDS Clinical Trials Group from the National Institute of Allergy and Infectious Diseases, the 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. Financial disclosures of the co-authors are listed at the end of the JAMA article.

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