• Cissy Kityo, Jennifer Thompson, Immaculate Nankya, Anne Hoppe, Emmanuel Ndashimye, Colin Warambwa, Ivan Mambule, Joep J van Oosterhout, Kara Wools-Kaloustian, Silvia Bertagnolio, Philippa J Easterbrook, Peter Mugyenyi, A Sarah Walker, Nicholas I Paton, and Europe Africa Research Network for Evaluation of Second-line Therapy (EARNEST) Trial Team.
• *Joint Clinical Research Centre (JCRC), Kampala, Uganda; †MRC Clinical Trials Unit at University College London, London, United Kingdom; ‡University of Zimbabwe Clinical Research Centre, Harare, Zimbabwe; §Infectious Diseases Institute, Kampala, Uganda; ‖Malawi-Liverpool-Wellcome Trust Clinical Research Programme, University of Malawi College of Medicine, Blantyre, Malawi; ¶Dignitas International, Zomba, Malawi; #Department of Medicine, Moi University School of Medicine, Eldoret, Kenya; **World Health Organisation, Geneva, Switzerland; and ‡‡Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
• J. Acquir. Immune Defic. Syndr. 2017 Jun 1; 75 (2): e45-e54.

ObjectiveTo determine drug resistance mutation (DRM) patterns in a large cohort of patients failing nonnucleoside reverse transcriptase inhibitor (NNRTI)-based first-line antiretroviral therapy regimens in programs without routine viral load (VL) monitoring and to examine intersubtype differences in DRMs.DesignSequences from 787 adults/adolescents who failed an NNRTI-based first-line regimen in 13 clinics in Uganda, Kenya, Zimbabwe, and Malawi were analyzed. Multivariable logistic regression was used to determine the association between specific DRMs and Stanford intermediate-/high-level resistance and factors including REGA subtype, first-line antiretroviral therapy drugs, CD4, and VL at failure.ResultsThe median first-line treatment duration was 4 years (interquartile range 30-43 months); 42% of participants had VL ≥100,000 copies/mL and 63% participants had CD4 <100 cells/mm. Viral subtype distribution was A1 (40%; Uganda and Kenya), C (31%; Zimbabwe and Malawi), and D (25%; Uganda and Kenya), and recombinant/unclassified (5%). In general, DRMs were more common in subtype-C than in subtype-A and/or subtype-D (nucleoside reverse transcriptase inhibitor mutations K65R and Q151M; NNRTI mutations E138A, V106M, Y181C, K101E, and H221Y). The presence of tenofovir resistance was similar between subtypes [P (adjusted) = 0.32], but resistance to zidovudine, abacavir, etravirine, or rilpivirine was more common in subtype-C than in subtype-D/subtype-A [P (adjusted) < 0.02].ConclusionsNon-B subtypes differ in DRMs at first-line failure, which impacts on residual nucleoside reverse transcriptase inhibitor and NNRTI susceptibility. In particular, higher rates of etravirine and rilpivirine resistance in subtype-C may limit their potential utility in salvage regimens.

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