A randomized, controlled, trial of short cycle intermittent compared to continuous antiretroviral therapy for the treatment of HIV infection in Uganda

Abstract

Background: Short cycle treatment interruption could reduce toxicity and drug costs and contribute to further expansion of antiretroviral therapy (ART) programs.

Methods: A 72 week, non-inferiority trial enrolled one hundred forty six HIV positive persons receiving ART (CD4+ cell count > or =125 cells/mm(3) and HIV RNA plasma levels <50 copies/ml) in one of three arms: continuous, 7 days on/7 days off and 5 days on/2 days off treatment. Primary endpoint was ART treatment failure determined by plasma HIV RNA level, CD4+ cell count decrease, death attributed to study participation, or opportunistic infection.

Results: Following enrollment of 32 participants, the 7 days on/7 days off arm was closed because of a failure rate of 31%. Six of 52 (11.5%) participants in the 5 days on/2 days off arm failed. Five had virologic failure and one participant had immunologic failure. Eleven of 51 (21.6%) participants in the continuous treatment arm failed. Nine had virologic failure with 1 death (lactic acidosis) and 1 clinical failure (extra-pulmonary TB). The upper 97.5% confidence boundary for the difference between the percent of non-failures in the 5 days on/2 days off arm (88.5% non-failure) compared to continuous treatment (78.4% non failure) was 4.8% which is well within the preset non-inferiority margin of 15%. No significant difference was found in time to failure in the 2 study arms (p = 0.39).

Conclusions: Short cycle 5 days on/2 days off intermittent ART was at least as effective as continuous therapy.

Trial registration: ClinicalTrials.gov NCT00339456.

Figure 1. Flow diagram for study eligibility and follow-up.

Figure 2. Kaplan-Meier Survival Curve with Time to Failure.

No difference was found in the time to failure in the 2 groups during the 72/73 week study.

Figure 3. A. Change in CD4+ T cells for participants successfully completing 72/73 weeks.

The CD4+ T cell counts in the continuously treated (N = 40) and in the 5 days on/2 days off (N = 46) arms were similar at baseline (255 and 271/mm³, respectively, p = 0.85) and marginally different at week 72/73 (330 and 429/mm³, respectively, p = 0.08). B. The median paired difference in CD4+ T cells between baseline and week 72/73 was greater in the 5 days on/2 days off group (114/mm³) than in the continuously treated group (68/mm³). (p = 0.01). The lines across the box indicates the median values; the boxes contain the 25–75% interquartile range; and the whiskers extend to the highest and lowest values.