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NRTI-Sparing Second-Line Regimen Holds Its Own in Randomized Trial
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20th Conference on Retroviruses and Opportunistic Infections, March 3-6, 2013, Atlanta
Mark Mascolini
Individually tailored nucleoside reverse transcriptase inhibitor (NRTI)-sparing regimens proved noninferior to traditional NRTI second-line regimens in a 48-week randomized AIDS Clinical Trials Group (ACTG) study with a compound failure endpoint [1]. More people randomized to an NRTI regimen died.
Second-line regimens started after virologic failure typically include two NRTIs. But the availability of antiretrovirals from new classes makes it possible to construct an array of second-line regimens that avoid NRTIs. (And that array is now wider than the options included in this trial.) Excluding NRTIs from second-line or later regimens may simplify those combinations and limit side effects. In addition, using NRTIs for both first and second regimens can raise tricky cross-resistance questions.
The ACTG OPTIONS trial enrolled people taking a failing regimen including NRTIs and a protease inhibitor or a nonnucleoside, or with virus resistant to drugs in those classes. In an open-label design, researchers randomized participants to an individually molded regimen including or excluding NRTIs. Regimen options designed by the ACTG team and selected by site investigators could combine 3 or 4 drugs, including raltegravir, darunavir/ ritonavir, tipranavir/ritonavir, etravirine, maraviroc, or enfuvirtide. The goal was to build a regimen with more than two active drugs by continuous phenotypic sensitivity score or tropism.
The primary endpoint was regimen failure, defined as the first of either confirmed virologic failure or stopping NRTI assignment through week 48. Noninferiority would require the 95% upper confidence bound comparing week-48 cumulative probability of failure between the two arms to lie below 15%. The primary safety endpoint was time to grade 3 or greater signs or symptoms or lab abnormality before stopping NRTIs.
The investigators randomized 179 people to omit NRTIs and 181 to include NRTIs. Median age stood at 46 in both groups, and three quarters of participants were men. Non-Hispanic blacks made up 39% of the omit-NRTI arm and 44% of the include-NRTI arm. Respective proportions of Hispanics were 26% and 21%. Median pretreatment viral load stood at 4.2 log (about 15,000 copies) in both groups, while median CD4 count was 212 in the omit-NRTI arm and 193 in the include-NRTI arm. Just under 20% of participants had taken enfuvirtide or an integrase inhibitor before this trial, with no difference between arms. Median phenotypic sensitivity score stood at 3 in both groups (indicating HIV sensitivity to at least 3 antiretrovirals).
The most popular non-NRTI regimens were raltegravir plus darunavir/ritonavir and etravirine in 56%, raltegravir plus darunavir/ritonavir and maraviroc in 14%, and raltegravir plus darunavir/ritonavir, etravirine, and maraviroc in 9%. More than 80% of study participants took a raltegravir-based regimen. The most frequently prescribed NRTIs were tenofovir/emtricitabine (82%) and tenofovir/emtricitabine plus zidovudine (12%).
Cumulative probability of regimen failure was 30% in the omit-NRTI group and 26% in the include-NRTI group, and the difference (3.2%, 95% confidence interval [CI] -6.1 to 12.5) fell within the noninferiority bound. An omit-NRTI regimen also proved noninferior when the investigators separately considered virologic failure (difference -0.4, 95% CI -9.4 to 8.7) and discontinuation of NRTI assignment (difference 3.6, 95% CI -1.7 to 9.2). The primary safety endpoint did not differ significantly between study arms.
The ACTG team recorded confirmed virologic failure in 25% in both study arms. Proportions of omit-NRTI and include-NRTI participants with week-48 viral loads below 200 and 50 copies were 76% and 77% and 64% and 66%. Median CD4 gains through week 48 stood at 90 in the omit-NRTI group and 106 in the include NRTI group.
During the study period 6 people in the include-NRTI arm and none in the omit-NRTI arm died (P < 0.001). Incidence of death after adding NRTIs was 3.3 per 100 person-years. Deaths were attributed to heart failure in a lymphoma patient, Listeria meningitis in a patient with chronic HCV infection, renal failure in a patient with autoimmune enteropathy, sepsis in a patient with liver failure, progressive multifocal leukoencephalopathy, and intraabdominal bleeding in a patient with HCV and cirrhosis.
While suggesting the results could represent a "game-changer" in HIV medicine, Andrew Zolopa (Stanford University) noted that the between-arm differences would have touched a more traditional upper confidence bound of 12.5%. Karen Tashima (Brown University), who presented the results, said ACTG investigators selected the 15% upper bound to make the study meaningful for clinical practice.
An international randomized trial presented at this conference and reported separately by NATAP found similar 48-week virologic outcomes with lopinavir/ritonavir plus raltegravir and lopinavir/ritonavir plus two or three NRTIs after failure of a nonnucleoside-based combination [2].
References
1. Tashima K, Smeaton L, Andrade A, et al. Omitting NRTI from ARV regimens is not inferior to adding NRTI in treatment-experienced HIV+ subjects failing a protease inhibitor regimen: the ACTG OPTIONS study. 20th Conference on Retroviruses and Opportunistic Infections. March 3-6, 2013. Atlanta. Abstract 153LB.
2. Boyd M, SECOND-LINE Study Team. SECOND-LINE: Ritonavir-boosted lopinavir with 2-3N(t)RTI or raltegravir in HIV+ subjects virologically failing 1st-line NNRTI/2N(t)RTI. 20th Conference on Retroviruses and Opportunistic Infections. March 3-6, 2013. Atlanta. Abstract 180LB.
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