Potential for immune-driven viral polymorphisms to compromise antiretroviral-based preexposure prophylaxis for prevention of HIV-1 infection

Journal article

Objective

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.

Methods

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.

Results

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.

Conclusions

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.

Authors: Gatanaga, H; Brumme, Z; Adland, E; Reyes-Terán, G; Avila-Rios, S

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Lippincott, Williams & Wilkins
• Journal: AIDS
• Volume: 31
• Issue: 14
• Pages: 1935-1943
• Publication date: 2017-09-10
• Acceptance date: 2017-06-09
• DOI: 10.1097/qad.0000000000001575
• EISSN: 1473-5571
• ISSN: 0269-9370
• Pmid: 28650381
• Language: English
• Keywords: rilpivirine; escape mutation; HLA-B*18; E138X; replication fitness