Prevalence and Predictive Value of Intermittent Viremia with Combination HIV Therapy

In HIV-infected patients, antiretroviral therapy (ART) is directed at achieving and maintaining HIV RNA levels below the limit of detection of currently approved assays. A lower nadir of HIV RNA in response to therapy is an independent predictor of long-term virologic suppression. When patients interrupt therapy or when the potency of a regimen is reduced, abrupt elevations in HIV RNA levels are observed. However, transient smaller elevations in HIV RNA levels are also frequently observed in patients who maintain HIV RNA levels of less than 200 copies/mL with potent ART. These transient episodes have been described as intermittent viremia or "blips." The HIV RNA nadir resulting from ART has been established as an important predictor of long-term virologic suppressions, but the effects of intermittent viremia on rates of viral suppression have not been established.

To determine the prevalence and predictive value of intermittent viremia, the researchers conducted a retrospective analysis of subjects in the AIDS Clinical Trials Group (ACTG) 343 and the Merck 035 trial. Of the 241 ACTG 343 patients, 101 received triple-drug therapy throughout the study. The 13 Merck 035 subjects had virologic suppression after six months of indinavir-zidovudine-lamivudine.

Intermittent viremia occurred in 96 (40 percent) of the 241 ATCG 343 patients, of whom 32 (13 percent) had 2 consecutive HIV RNA values >50 copies m/L during the media 84 weeks of observation. (Median duration of observation after first intermittent viremia episode was 46 weeks.) 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 (P=.25).

Intermittent viremia did not predict virologic failure: 10 (10.4 percent) of 96 patients with 20 (13.8 percent) of 145 patients without intermittent viremia had virologic failure (relative risk, 0.76; 95 percent confidence interval [CI], 0.29-1.72). In a Cox proportional hazards model, the risk for virologic failure was not significantly greater in the ACTG 343 patients with intermittent viremia (hazard ratio, 1.28; 95 percent CI, 0.59-2.79) Median viral load in 10 ACTG 343 patients assessed between 24 and 60 weeks of therapy using an ultrasensitive 2.5-copies/mL detection level assay was 23 copies/mL in those with intermittent viremia vs. <2.5 copies/mL in those without (P=15). 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 (P=.03), but not virologic failure over 4.5 years of observation. Viral DNA sequences from 7 patients did not show evolution of drug resistance.

The authors explained that "if blips or low-level intermittent viremia are not associated with greater rates of virologic failure for as long as 4.5 years, then it may not be necessary to switch or intensify therapy until patients exhibit higher levels. Unnecessary regimen switching may result in disruption of a patient's medication routine, toxic effects from new drugs, and premature discarding of useful drugs."

"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," the researchers concluded. "A higher HIV RNA level that would trigger a therapy change may preserve the number of drugs available for future therapeutic regimens."

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