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Randomized Controlled Trial
. 2014 Jul;69(7):1938-44.
doi: 10.1093/jac/dku052. Epub 2014 Mar 14.

Phenotypic and genotypic analyses to guide selection of reverse transcriptase inhibitors in second-line HIV therapy following extended virological failure in Uganda

R L Goodall  1 , D T Dunn  2 , T Pattery  3 , A van Cauwenberge  3 , P Nkurunziza  4 , P Awio  5 , N Ndembi  6 , P Munderi  4 , C Kityo  5 , C F Gilks  7 , P Kaleebu  4 , D Pillay  8 ; DART Virology Group and Trial Teams
Collaborators, Affiliations
Randomized Controlled Trial

Phenotypic and genotypic analyses to guide selection of reverse transcriptase inhibitors in second-line HIV therapy following extended virological failure in Uganda

R L Goodall et al. J Antimicrob Chemother. 2014 Jul.

Abstract

Objectives: We investigated phenotypic and genotypic resistance after 2 years of first-line therapy with two HIV treatment regimens in the absence of virological monitoring.

Methods: NORA [Nevirapine OR Abacavir study, a sub-study of the Development of AntiRetroviral Therapy in Africa (DART) trial] randomized 600 symptomatic HIV-infected Ugandan adults (CD4 cell count <200 cells/mm(3)) to receive zidovudine/lamivudine plus abacavir (cABC arm) or nevirapine (cNVP arm). All virological tests were performed retrospectively, including resistance tests on week 96 plasma samples with HIV RNA levels ≥1000 copies/mL. Phenotypic resistance was expressed as fold-change in IC(50) (FC) relative to wild-type virus.

Results: HIV-1 RNA viral load ≥1000 copies/mL at week 96 was seen in 58/204 (28.4%) cABC participants and 21/159 (13.2%) cNVP participants. Resistance results were available in 35 cABC and 17 cNVP participants; 31 (89%) cABC and 16 (94%) cNVP isolates had a week 96 FC below the biological cut-off for tenofovir (2.2). In the cNVP arm, 16/17 participants had resistance mutations synonymous with high-level resistance to nevirapine and efavirenz; FC values for etravirine were above the biological cut-off in 9 (53%) isolates. In multivariate regression models, K65R, Y115F and the presence of thymidine analogue-associated mutations were associated with increased susceptibility to etravirine in the cABC arm.

Conclusions: Our data support the use of tenofovir following failure of a first-line zidovudine-containing regimen and shed further light on non-nucleoside reverse transcriptase inhibitor hypersusceptibility.

Keywords: Africa; hypersusceptibility; resistance.

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Figures

Figure 1.
Figure 1.
Phenotypic resistance at baseline and week 96 by antiretroviral drug. The horizontal broken line denotes the drug-specific biological cut-off. FC values >30 are displayed as 30 exactly.
See this image and copyright information in PMC

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