The AIDS Clinical Trials Group (ACTG) has been conducting a study (A5095) for the last several years, comparing three PI-sparing regimens for the initial treatment of HIV infection. The three regimens are:
Arm A: Sustiva (efavirenz) + Combivir (AZT + 3TC)
Arm B: Trizivir (AZT + 3TC + Ziagen)
Arm C: Sustiva + Trizivir
The Division of AIDS (DAIDS) sent a letter to healthcare providers in March concerning the findings of a planned safety review conducted by an independent data safety monitoring board (DSMB). The letter conveyed the following information. "The triple nucleoside regimen, [Trizivir], is demonstrably inferior to the other two regimens, based on rates and time to virologic failure and meets the stopping criteria specified in the protocol. Data on CD4 T-cell counts were not available, but the DSMB felt that those data could not reverse this outcome. The DSMB recommended that the [Trizivir] arm be discontinued, the study volunteers enrolled in this arm be unblinded, and the data be released with this arm compared to the pooled data from the other two arms." There were no toxicity or side effects of concern noted by the DSMB. The DSMB recommended that the study arms with the Sustiva-containing drug combinations continue unchanged.
A total of 1,147 HIV-positive people who had never taken antiretroviral therapy enrolled in A5095. The study population is fairly diverse, with 81 percent men and 19 percent women, 60 percent people of color, and 11 percent with a history of injection drug use participating in the study. The study had a significant percentage of people with HIV viral loads above 100,000 copies/mL at initiation of treatment. Based on earlier studies of Trizivir, there was concern about the potency of this combination in people with high viral loads, so the DSMB monitoring plan incorporated in this study closely monitored the results. What is most surprising is that in people with viral load below 100,000 copies at entry, Trizivir did not perform as well as the Sustiva-containing arms; and even when viral suppression was obtained, there was a higher rate viral rebound in the Trizivir arm.
The definition of viral failure used in this study was two consecutive viral load measurements above 200 copies/mL 16 weeks or more after initiation of treatment. This was a "blinded" study, so everyone took the same number of pills, which included the active drug plus placebos for all the drugs not in their assigned arm. One advantage of Trizivir is that it is only one pill, taken twice a day, and should in theory minimize missed doses. But, in this trial, everyone had to take the same number of pills so this potential "advantage" of Trizivir might have gone unrecognized in this study. Nonetheless, this finding raises the question of whether Trizivir alone should be recommended for the treatment of HIV. The Adult HIV Treatment Guidelines, published by the Public Health Service, are due to be updated soon, and it will be very interesting to see the Guidelines panel's recommendations.
The A5095 study team has revised the protocol as a result of the DSMB review. The people in Arm B who still have HIV viral loads below 50 copies/mL will have their treatment regimen intensified, comparing the addition of Sustiva versus Tenofovir, in a randomized fashion.
Disclaimer: Jeffrey Schouten has been on the A5095 team since its inception, initially as a community representative, and currently as an ACTG investigator.
Dr. Jeffrey T. Schouten is a former general surgeon who has been living with HIV for over 16 years. He is chair of STEP's Publications Advisory Committee and a primary care provider at Harborview's HIV Clinic in Seattle, Washington.