- Gatanaga, Hiroyuki;
- Brumme, Zabrina L;
- Adland, Emily;
- Reyes-Terán, Gustavo;
- Avila-Rios, Santiago;
- Mejía-Villatoro, Carlos R;
- Hayashida, Tsunefusa;
- Chikata, Takayuki;
- Van Tran, Giang;
- Van Nguyen, Kinh;
- Meza, Rita I;
- Palou, Elsa Y;
- Valenzuela-Ponce, Humberto;
- Pascale, Juan M;
- Porras-Cortés, Guillermo;
- Manzanero, Marvin;
- Lee, Guinevere Q;
- Martin, Jeffrey N;
- Carrington, Mary N;
- John, Mina;
- Mallal, Simon;
- Poon, Art FY;
- Goulder, Philip;
- Takiguchi, Masafumi;
- Oka, Shinichi
Objective
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.Methods
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.Results
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.Conclusions
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.