Potential for immune-driven viral polymorphisms to compromise antiretroviral-based preexposure prophylaxis for prevention of HIV-1 infection.
AIDS
; 31(14): 1935-1943, 2017 09 10.
Article
em En
| MEDLINE
| ID: mdl-28650381
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 (Pâ=â3.5â×â10) 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 Râ=â0.75; Pâ=â7.6â×â10) and in unlinked HIV/HLA data from 43 countries (Spearman's Râ=â0.34, Pâ=â0.02). 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.
Texto completo:
1
Coleções:
01-internacional
Contexto em Saúde:
10_ODS3_salud_sexual_reprodutiva
/
1_ASSA2030
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2_ODS3
Base de dados:
MEDLINE
Assunto principal:
Infecções por HIV
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HIV-1
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Mutação de Sentido Incorreto
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Farmacorresistência Viral
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Antirretrovirais
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Evasão da Resposta Imune
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Profilaxia Pré-Exposição
Tipo de estudo:
Risk_factors_studies
Limite:
Humans
Idioma:
En
Revista:
AIDS
Ano de publicação:
2017
Tipo de documento:
Article