Campbell TB, Smeaton LM, Kumarasamy N, et al. Efficacy and safety of three antiretroviral regimens for initial treatment of HIV-1: a randomized clinical trial in diverse multinational settings. PLoS Med. 2012 Aug;9(8):e1001290. Epub 2012 Aug 14.
To investigate the efficacy and safety of antiretroviral regimens with once-daily compared to twice-daily dosing.
Nine countries on four continents (Brazil, Haiti, India, Malawi, Peru, South Africa, Thailand, USA and Zimbabwe).
Randomized controlled trial.
Antiretroviral-naïve HIV-1-infected patients. 47% were women, 50% Black or African-American.
Time from randomization to (1) death; (2) HIV-1 disease progression defined as new or recurrent WHO stage 4 diagnosis, Chagas' disease, or chronic microsporidiosis or cyclosporidiosis occurring at least 12 weeks following randomization and not part of immune reconstitution inflammatory syndrome; or (3) virologic failure (two successive measurements of plasma HIV-1 RNA ≥1,000 copies/ml, with the first measurement at ≥14 wk after randomization). The primary safety endpoint was the earliest of the following times: date of onset of grade ≥3 (at least one grade higher than entry) sign/symptom, date of specimen collection of a grade ≥3 (at least one grade higher than entry) laboratory abnormality, or date of last dose of randomized study treatment before any modification to that treatment (change in drug dosage, addition of another antiretroviral drug, or discontinuation of any component of the randomized antiretroviral regimen). Secondary endpoints were plasma HIV-1 RNA below lower quantitation limit (<400 copies/ml) and time to loss of virologic response (TLOVR) where all antiretroviral substitutions are counted as endpoints.
Participants were assigned with equal probability to open-label antiretroviral therapy with efavirenz (EFV) plus lamivudine (3TC)-zidovudine (ZDV) fixed dose combination, atazanavir (ATV) plus didanosine-EC (ddI) plus emtricitabine (FTC) or EFV plus tenofovir disoproxil fumarate (TDF)-FTC fixed dose combination. Analysis was by intention to treat and compared EFV+3TC-ZDV to EFV+TDF-FTC and EFV+3TC-ZDV to ATV+ddI+FTC but not EFV+TDF-FTC to ATV+ddI+FTC.
An independent monitoring board recommended stopping study follow-up prior to accumulation of 472 treatment failures. Comparing EFV+FTC-TDF to EFV+3TC-ZDV, during a median 184 wk of follow-up there were 95 treatment failures (18%) among 526 participants versus 98 failures among 519 participants (19%; HR 0.95, 95% CI 0.72-1.27; p = 0.74). Safety endpoints occurred in 243 (46%) participants in the EFV+FTC-TDF arm versus 313 (60%) in the EFV+3TC-ZDV arm (HR 0.64, CI 0.54-0.76; p<0.001). There was a significant interaction between sex and regimen safety (HR 0.50, CI 0.39-0.64 for women; HR 0.79, CI 0.62-1.00 for men). ATV+DDI+FTC was clearly inferior to EFV+3TC-ZDV at a median follow-up of 81 weeks (108 failures [21%] among 526 participants in ATV+DDI+FTC arm and 76 [15%] among 519 participants in the EFV+3TC-ZDV arm [HR 1.51, CI 1.12-2.04; p = 0.007]).
The PEARLS trial demonstrates the high and equivalent efficacy of fixed-dose TDF-FTC compared to fixed-dose ZDV-3TC, both when combined with EFV. However, it also demonstrates lower levels of toxicity associated with the TDF-FTC backbone. Finally, it shows that the ATV+ddI+3TC regimen was clearly inferior in terms of efficacy compared to the EFV+ZDV-3TC regimen.
A major strength of PEARLS is its inclusion of a very diverse study population that includes about 50% women. Sites enrolled participants through a centralized system that randomly allocated them to the different arms. Participants were not blinded, but physicians assessing outcomes were. Incomplete outcome data were reported, and there was no evidence of either selective outcome reporting or other threats to study validity. Thus, the overall risk of bias in this study was low.
PEARLS is the second randomized clinical trial to compare EFV+FTC-TDF and EFV+3TC-ZDV in an initial antiretroviral regimen. In contrast to PEARLS, GS-01-934 found that EFV+FTC-TDF was superior to EFV+3TC-ZDV.(1) This was based on the FDA's TLOVR primary endpoint, which assigns equal weight to changes in the randomized 3 drug assignments regardless of the reason for change, including drug substitutions for toxicity management. Thus, regimens that may require more frequent substitutions for toxicity, such as EFV+ZDV-3TC, may appear to be less effective when in fact they perform just as well in terms of virologic suppression and clinical progression.
The efficacy and safety of EFV+TDF-FTC, especially given its co-formulation in a single-dose format that is taken once daily, make it an attractive option for first-line antiretroviral therapy.
- Gallant JE, DeJesus E, Arribas JR, Pozniak AL, Gazzard B, et al. Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV. N Engl J Med 2006; 354: 251-60.