Two Studies Show That Intermittant Increases in Virus Levels During Antiretroviral Therapy Not Indicative of Treatment Failure
Two studies published in today's edition of the Journal of the American Medical Association suggest that temporary increases in the level of HIV RNA detectable in the bloodstream during antiretroviral therapy do not mean that the treatment is failing and do not indicate a need to change drug regimens. The first study, led by Dr. Diane Havlir of the University of California-San Diego, retrospectively examined 241 patients who participated in the AIDS Clinical Trials Group (ACTG) 343 trial from August 1997 to November 1998, 101 of whom were on triple drug combinations throughout the study, and 13 patients in the ongoing Merck 035 study, who showed "virologic suppression" (HIV RNA levels under 50 copies/mL of blood) after six months on a combination of indinavir, zidovudine and lamivudine. Intermittent viremia -- increases in measured HIV RNA levels to above 50 copies/mL followed by a test below 50 copies/mL -- occurred in 96 (40%) of the ACTG patients, of whom 32 (13%) had two consecutive tests above 50 copies/mL. Intermittent viremia did not indicate treatment failure, as only 10 of the 96 patients with intermittent viremia, compared to 20 of the 145 patients without measured increases, had "virologic failure." These findings indicate that "treatment changes may not be necessary to maintain long term virologic suppression with low-level or intermittent viremia," the authors state. As the commonly used lower threshold of viral load detection has decreased from 400 copies/mL to 50 copies/mL, "[c]urrent guidelines thus imply that any detectable or confirmed HIV RNA level above 50 copies/mL should trigger therapy intensification or modification, assuming effective treatment options are available," according to the authors. As a result of the study's findings, those guidelines "warrant reconsideration" because the "[u]nneccesary" switching of medications could "disrup[t]" the patient's routine and lead to side effects from new drugs or the "premature" disposal of "useful" drugs, the authors conclude (Havlir et al., JAMA, 7/11).
Drug Resistance Does Not Mean Drug Failure
The second study, conducted by Monika Hermankova and colleagues at the Johns Hopkins University School of Medicine, aimed to determine the development of genetic resistance in patients on HAART who had prolonged viral suppression. The researchers observed HIV RNA levels in the blood of seven children and 11 adults who had viral suppression while on highly active antiretroviral therapy, including a protease inhibitor. One adult and one child who had higher levels, above 50 copies/mL but below 1000 copies per/mL, were also studied. Seven of the 18 patients who had been on prior nonsuppressive therapy, "with viral loads below 50 copies/mL and during 'blips' to 231 and 64 copies/mL, had only resistance mutations consistent with pre-HAART therapy." The authors conclude that based on their small study, low-level viremia in patients on HAART may be attributable "primarily" to "archival, pre-HAART virus" and does not necessarily indicate the development of "partial resistance" to HAART therapy. The findings indicate that low-level viremia may represent "less of a concern" about "impending" failure of HAART regimens, and "archival" drug resistance may need to be taken into consideration when developing "future treatment strategies" (Hermankova et al., JAMA, 7/11).
Implications for HIV Treatment
Taken together, the two studies may have "significant implications" for HIV treatment, the AP/Minneapolis Star Tribune reports. The new findings "question some of the basic principles upon which therapy is based" and may help patients prolong the amount of time they take certain drugs, Dr. Steven Deeks of the University of California-San Francisco's AIDS Program said in an accompanying editorial (Tanner, AP/Minneapolis Star Trubune, 7/11). "Based on data from the two studies, it may be argued that 'complete' viral suppression may not be a prerequisite for durable treatment benefit," and in fact is "rarely achieved with current therapies," he added. The new findings may allow patients to stay on medicines that they tolerate longer, instead of switching to "more potent" treatments with "harsher" side effects that may "limit" patients' future treatment options, Deeks said (Norton, Reuters Health, 7/10).