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

Potential for immune-driven viral polymorphisms to compromise antiretroviral-based preexposure prophylaxis for prevention of HIV-1 infection.
Author Information (click to view)

Gatanaga H, Brumme ZL, Adland E, Reyes-Terán G, Avila-Rios S, Mejía-Villatoro CR, Hayashida T, Chikata T, Van Tran G, Van Nguyen K, Meza RI, Palou EY, Valenzuela-Ponce H, Pascale JM, Porras-Cortés G, Manzanero M, Lee GQ, Martin JN, Carrington MN, John M, Mallal S, Poon AFY, Goulder P, Takiguchi M, Oka S, ,


Gatanaga H, Brumme ZL, Adland E, Reyes-Terán G, Avila-Rios S, Mejía-Villatoro CR, Hayashida T, Chikata T, Van Tran G, Van Nguyen K, Meza RI, Palou EY, Valenzuela-Ponce H, Pascale JM, Porras-Cortés G, Manzanero M, Lee GQ, Martin JN, Carrington MN, John M, Mallal S, Poon AFY, Goulder P, Takiguchi M, Oka S, , (click to view)

Gatanaga H, Brumme ZL, Adland E, Reyes-Terán G, Avila-Rios S, Mejía-Villatoro CR, Hayashida T, Chikata T, Van Tran G, Van Nguyen K, Meza RI, Palou EY, Valenzuela-Ponce H, Pascale JM, Porras-Cortés G, Manzanero M, Lee GQ, Martin JN, Carrington MN, John M, Mallal S, Poon AFY, Goulder P, Takiguchi M, Oka S, ,

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AIDS (London, England) 31(14) 1935-1943 doi 10.1097/QAD.0000000000001575

Abstract
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.

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