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Clin Infect Dis. 2018 Jun 1;66(12):1846-1857. doi: 10.1093/cid/cix1108.

Effectiveness of Protease Inhibitor/Nucleos(t)ide Reverse Transcriptase Inhibitor-Based Second-line Antiretroviral Therapy for the Treatment of Human Immunodeficiency Virus Type 1 Infection in Sub-Saharan Africa: A Systematic Review and Meta-analysis.

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Malawi-Liverpool-Wellcome Trust Clinical Research Programme, Blantyre.
Institute of Infection and Global Health, University of Liverpool.
Section of Infectious Diseases and Immunity and Wellcome Trust-Imperial College Centre for Global Health Research, Imperial College London, United Kingdom.
Kirby Institute for Infection and Immunity, University of New South Wales, Sydney.
Lyell McEwin Hospital, University of Adelaide, South Australia, Australia.
Department of Biostatistics, University of Liverpool.
London School of Hygiene and Tropical Medicine, United Kingdom.
Institute of Social and Preventative Medicine, University of Bern.
Department of Infectious Diseases, Bern University Hospital, Switzerland.
Department of Infectious Diseases, University Medical Centre Utrecht, The Netherlands.
Unité Mixte de Recherche de l'Institut de Rech (UMI), Institute de Recherche pour le Développement, Institute National de la Santé et de la Recherche Medicale, University of Montpellier, France.
Institute of Human Virology, University of Maryland School of Medicine, Baltimore.
University of Washington School of Medicine, Seattle.
Yong Loo Lin School of Medicine, National University of Singapore.



In sub-Saharan Africa, 25.5 million people are living with human immunodeficiency virus (HIV), representing 70% of the global total. The need for second-line antiretroviral therapy (ART) is projected to increase in the next decade in keeping with the expansion of treatment provision. Outcome data are required to inform policy.


We performed a systematic review and meta-analysis of studies reporting the virological outcomes of protease inhibitor (PI)-based second-line ART in sub-Saharan Africa. The primary outcome was virological suppression (HIV-1 RNA <400 copies/mL) after 48 and 96 weeks of treatment. The secondary outcome was the proportion of patients with PI resistance. Pooled aggregate data were analyzed using a DerSimonian-Laird random effects model.


By intention-to-treat analysis, virological suppression occurred in 69.3% (95% confidence interval [CI], 58.2%-79.3%) of patients at week 48 (4558 participants, 14 studies), and in 61.5% (95% CI, 47.2%-74.9%) at week 96 (2145 participants, 8 studies). Preexisting resistance to nucleos(t)ide reverse transcriptase inhibitors (NRTIs) increased the likelihood of virological suppression. Major protease resistance mutations occurred in a median of 17% (interquartile range, 0-25%) of the virological failure population and increased with duration of second-line ART.


One-third of patients receiving PI-based second-line ART with continued NRTI use in sub-Saharan Africa did not achieve virological suppression, although among viremic patients, protease resistance was infrequent. Significant challenges remain in implementation of viral load monitoring. Optimizing definitions and strategies for management of second-line ART failure is a research priority.

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