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Long-acting rilpivirine is a candidate for preexposure prophylaxis (PrEP) for prevention of HIV-1 infection. However, rilpivirine resistance mutations at reverse transcriptase codon 138 (E138X) occur naturally in a minority of HIV-1-infected persons; in particular those expressing human leukocyte antigen (HLA)-B18 where reverse transcriptase-E138X arises as an immune escape mutation. We investigate the global prevalence, B18-linkage and replicative cost of reverse transcriptase-E138X and its regional implications for rilpivirine PrEP.We analyzed linked reverse transcriptase-E138X/HLA data from 7772 antiretroviral-naive patients from 16 cohorts spanning five continents and five HIV-1 subtypes, alongside unlinked global reverse transcriptase-E138X and HLA frequencies from public databases. E138X-containing HIV-1 variants were assessed for in-vitro replication as a surrogate of mutation stability following transmission.Reverse transcriptase-E138X variants, where the most common were rilpivirine resistance-associated mutations E138A/G/K, were significantly enriched in HLA-B18-positive individuals globally (P = 3.5 × 10) and in all HIV-1 subtypes except A. Reverse transcriptase-E138X and B18 frequencies correlated positively in 16 cohorts with linked HIV/HLA genotypes (Spearman's R = 0.75; P = 7.6 × 10) and in unlinked HIV/HLA data from 43 countries (Spearman's R = 0.34, P = 0.02). Notably, reverse transcriptase-E138X frequencies approached (or exceeded) 10% in key epidemic regions (e.g. sub-Saharan Africa, Southeastern Europe) where B18 is more common. This, along with the observation that reverse transcriptase-E138X variants do not confer in-vitro replicative costs, supports their persistence, and ongoing accumulation in circulation over time.Results illustrate the potential for a natural immune-driven HIV-1 polymorphism to compromise antiretroviral-based prevention, particularly in key epidemic regions. Regional reverse transcriptase-E138X surveillance should be undertaken before use of rilpivirine PrEP.

Original publication




Journal article


AIDS (London, England)

Publication Date





1935 - 1943


aAIDS Clinical Center, National Center for Global Health and Medicine, Tokyo bCenter for AIDS Research, Kumamoto University, Kumamoto, Japan cFaculty of Health Sciences, Simon Fraser University, Burnaby dBritish Columbia Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada eDepartment of Paediatrics, University of Oxford, Oxford, UK fCentre for Research in Infectious Diseases, National Institute of Respiratory Diseases, Mexico City, Mexico gInfectious Diseases Clinic, Roosevelt Hospital, Guatemala City, Guatemala hNational Hospital of Tropical Diseases, Dong Da District, Hanoi, Vietnam iHIV National Laboratory, Honduran Ministry of Health jHospital Escuela Universitario, Tegucigalpa, Honduras kGorgas Memorial Institute for Health Studies, Panama City, Panama lHospital Metropolitano Vivian Pellas, Managua, Nicaragua mMinistry of Health, Belmopan, Belize nUniversity of California San Francisco, San Francisco, California oCancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory, Frederick, Maryland pRagon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts, USA qMurdoch University, Perth, Australia rVanderbilt University, Nashville, Tennessee, USA sDepartment of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada.


International HIV Adaptation Collaborative