Study Finds Less Intensive Treatments May Not Maintain HIV Suppression

"These findings suggest that patients who have responded well to intensive antiretroviral therapy, as evidenced by prolonged suppression of HIV viral load, should continue with their current treatment regimen," says NIAID Director Anthony S. Fauci, M.D. "Recent research describing persistent HIV reservoirs in individuals receiving highly active antiretroviral therapy (HAART) - even after their viral loads have been driven below the level of detection by current assays - points to the same conclusion." He adds, however, that these data do not eliminate the possibility that this may be a successful strategy for some patients.

Begun in early 1997, ACTG 343 is the first large-scale clinical trial to investigate whether one- or two-drug therapies can hold virus production at bay after HIV levels are driven down by intensive therapy. The multicenter study enrolled more than 500 individuals, each of whom had HIV viral loads greater than 1,000 copies of RNA per milliliter (ml) of blood and at least 200 CD4+ T cells per cubic millimeter (mm3) of blood. During the induction, or initial, phase of the study, all individuals received the protease inhibitor indinavir (IDV) in combination with zidovudine (AZT) and lamivudine (3TC).

After six months, more than 300 individuals whose viral loads had been reduced to 200 or fewer copies of HIV RNA/ml of blood were randomized to receive either the same triple-drug therapy as before, a two-drug combination of AZT and 3TC, or monotherapy with IDV. Researchers led by Diane Havlir, M.D., and Douglas Richman, M.D., of the University of California San Diego AIDS Clinical Trials Unit, measured study participants' viral loads at regular intervals. The primary endpoint of the study was viral load rebound - defined as two consecutive viral load measurements of at least 200 copies/ml.

The investigators found that viral load rebound occurred in a total of 51 study participants: four in the triple-therapy group, 24 in the double-therapy group and 23 in the monotherapy group. The difference between the triple-therapy group and each of the other groups was statistically significant. However, among patients who had not taken AZT before entering the study, the difference between the triple- and double-therapies was not statistically significant.

High viral load at entry to the study and slower rates of viral clearance during the induction phase of the study were identified as risk factors for viral load rebound. The presence of AZT-resistance mutations in HIV RNA was strongly predictive of viral load rebound in individuals in the double-therapy group.

"Interestingly, the magnitude of the increase in CD4+ T-cell count during the triple-drug therapy phase of the study also correlated highly with subsequent viral load rebound. For each increase of 100 in the CD4+ T-cell count, there was a 30 percent increase in the risk of rebound." Dr. Havlir explains that an increase in the number of CD4+ T cells increases the number of target cells available for new HIV infection, which could occur when less intensive therapies are instituted.

The researchers conclude that maintaining HIV suppression with antiretroviral therapy leaves little margin for error. Poor adherence to even one component of a regimen may result in viral load rebound.

"Although the results of this trial are somewhat disappointing," notes Dr. Havlir, "they should not discourage future attempts to simplify therapies for HIV. Data from this trial and from other recently completed trials argue that induction therapy, maintenance therapy, or both must have greater virologic potency than the regimens used in these trials if they are to sustain viral suppression. It is also possible that longer periods of intense induction therapy or different maintenance regimens may still be found to be effective."

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