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Side Effect and CD4 Differences in Four ACTG 5202 Arms at 96 Weeks
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17th Conference on Retroviruses and Opportunistic Infections, February 16-19, 2010, San Francisco
Mark Mascolini
Virologic response rates proved similar with atazanavir/ritonavir and efavirenz in 96-week results of AIDS Clinical Trials Group (ACTG) study 5202, as were responses to tenofovir/emtricitabine (TDF/FTC) versus abacavir/lamivudine (ABC/3TC) in people who began treatment with a viral load under 100,000 copies (the lower viral load arm group) [1]. But this four-way randomized study in previously untreated people discerned side effect and CD4-gain differences between atazanavir/ritonavir and efavirenz and between TDF/FTC and ABC/3TC.
Earlier the ACTG 5202 team reported a significantly higher failure rate in ABC/3TC arms than TDF/FTC arms among people starting treatment with a viral load above 100,000 copies [2]. In that earlier report, time to first adverse event was significantly shorter with ABC/3TC than with TDF/FTC in this group with a high pretreatment viral load (P < 0.001).
ACTG 5202 had three primary endpoints-virologic response (time from randomization to virologic failure), safety (time from treatment dispensation to first grade 3 or 4 symptom, sign, or lab abnormality more than one grade above baseline), and tolerability (time from treatment dispensation to discontinuation). Study participants had to be negative for hepatitis B surface antigen and could not have an active alcohol or substance abuse problem or "relevant cardiac conduction system disease." ACTG investigators randomized them to efavirenz or atazanavir/ritonavir and to TDF/FTC plus ABC/3TC placebo or ABC/3TC plus TDF/FTC placebo.
ACTG researchers enrolled 1857 antiretroviral-naive people from 2005 through 2007 and followed them through September 2009. Most study participants (83%) were men. Median age stood at 38 when the study began, median CD4 count at 230, and median viral load at 50,000 copies. Only 17% of enrollees had an AIDS diagnosis, and only 7% had hepatitis C virus infection.
In people who began treatment with a viral load under 100,000 copies, time to virologic failure did not differ between the atazanavir/ritonavir and efavirenz groups or between the TDF/FTC and ABC/3TC groups. (Technically, ACTG investigators could not conclude that the different regimens were virologically "equivalent" because there were not enough virologic failures to support that conclusion.) Among people taking TDF/FTC, median CD4 gains were greater with atazanavir than efavirenz at week 48 (175 versus 163, P = 0.04) and week 96 (252 versus 221, P = 0.002), but there was no significant CD4 difference between atazanavir and efavirenz among people taking ABC/3TC.
In people who started therapy with fewer than 100,000 HIV RNA copies, those starting ABC/3TC with efavirenz had a shorter time to a safety endpoint than those starting TDF/FTC with efavirenz. People on ABC/3TC with either efavirenz or atazanavir had a shorter time to treatment modification than those on TDF/FTC, primarily because of hypersensitivity reactions to abacavir. (The trial began before HLA-B*5701 screening for hypersensitivity became common.)
Cardiovascular, kidney, and bone fracture rates were low and similar in the ABC/3TC group and the TDF/FTC group. But people taking ABC/3TC with either efavirenz or atazanavir had greater jumps in total cholesterol and low- and high-density lipoprotein (LDL and HDL) cholesterol than people taking TDF/FTC. Those taking ABC/3TC with atazanavir had greater triglyceride gains than those taking TDF/FTC with atazanavir.
Compared with people taking efavirenz, those taking atazanavir/ritonavir with ABC/3TC had a longer time to a safety endpoint and to third drug change. People taking atazanavir/ritonavir with either nucleoside pair had smaller rises in total cholesterol, LDL cholesterol, and HDL cholesterol than people taking efavirenz. The atazanavir group had a modestly greater decline in creatinine clearance when taking TDF/FTC versus ABC/3TC. Overall resistance rates in people with virologic failure were lower with atazanavir/ritonavir than with efavirenz regardless of nucleoside combination.
References
1. Daar E, Tierney C, Fischl M, et al. ACTG 5202: Final results of ABC/3TC or TDF/FTC with either EFV or ATV/r in treatment-naive HIV-infected patients. 17th Conference on Retroviruses and Opportunistic Infections. February 16-19, 2010. San Francisco. Abstract 59LB.
2. Sax PE, Tierney C, Collier AC, et al. Abacavir-lamivudine versus tenofovir-emtricitabine for initial HIV-1 therapy. N Engl J Med. 2009;361:2230-2240.
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