| Summary: | <h4>Objective</h4> <p>Long-acting rilpivirine is a candidate for pre-exposure prophylaxis (PrEP) for prevention of HIV-1 infection. However, rilpivirine resistance mutations at reverse transcriptase codon 138 (RT-E138X) occur naturally in a minority of HIV-1-infected persons; in particular those expressing Human Leukocyte Antigen (HLA)-B*18 where RT-E138X arises as an immune escape mutation. We investigate the global prevalence, B*18-linkage and replicative cost of RT-E138X and its regional implications for rilpivirine PrEP.</p> <h4>Methods</h4> <p>We analysed linked RT-E138X/HLA data from 7772 patients from 16 cohorts spanning five continents and five HIV-1 subtypes, alongside unlinked global RT-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.</p> <h4>Results</h4> <p>RT-E138X variants, where the most common were rilpivirine resistance-associated mutations E138A/G/K, were significantly enriched in HLA-B*18-positive individuals globally (p=3.5x10-20) and in all HIV-1 subtypes except A. RT-E138X and B*18 frequencies correlated positively in 16 cohorts with linked HIV/HLA genotypes (Spearman’s R=0.75; p=7.6x10-4) and in unlinked HIV/HLA data from 43 countries (Spearman's R=0.34, p=0.02). Notably, RT-E138X frequencies approached (or exceeded) 10% in key epidemic regions (e.g. Sub-Saharan Africa, Southeastern Europe) where B*18 is more common. This, along with the observation that RT-E138X variants do not confer in vitro replicative costs, supports their persistence and ongoing accumulation in circulation over time.</p> <h4>Conclusions</h4> <p>Results illustrate the potential for a natural immune-driven HIV-1 polymorphism to compromise antiretroviral-based prevention, particularly in key epidemic regions. Regional RT-E138X surveillance should be undertaken before use of rilpivirine PrEP.</p>
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