RESUMEN
BACKGROUND: Limited data are available regarding the susceptibility of the reverse transcriptase V106 polymorphism to doravirine. METHODS: Doravirine susceptibility was measured in site-directed mutants (SDMs) containing V106I, V106A, V106M, and Y188L mutations in subtype B (NL4-3, HXB2) and CRF02_AG background and in recombinant viruses with RT harboring V106I alone derived from 50 people with HIV. RESULTS: HIV-1 B subtype was detected in 1523 of 2705 cases. Prevalence of V106I was 3.2% in B and 2.5% in non-B subtypes, and was higher in subtype F (8.1%) and D (14.3%). Fold-changes (FC) in susceptibility for SDMs were below doravirine biological cutoff (3.0) for V106I, but not for V106A, V106M, and Y188L. Clinically derived viruses tested included 22 B (median FC, 1.2; interquartile range [IQR], 0.9-1.6) and 28 non-B subtypes (median FC, 1.8; IQR, 0.9-3.0). Nine (18%) viruses showed FC values equal or higher than the doravirine biological FC cutoff. CONCLUSIONS: The prevalence of the HIV-1 RT V106I polymorphism in MeditRes HIV consortium remains low, but significantly more prevalent in subtypes D and F. V106I minimally decreased the susceptibility to doravirine in SDMs and most clinical isolates. Reduced susceptibility seems to occur at increased frequency in subtype F1; however, the clinical impact remains to be investigated. CLINICAL TRIALS REGISTRATION: NCT04894357.
Asunto(s)
Fármacos Anti-VIH , Farmacorresistencia Viral , Infecciones por VIH , Transcriptasa Inversa del VIH , VIH-1 , Piridonas , Triazoles , Humanos , VIH-1/genética , VIH-1/efectos de los fármacos , VIH-1/clasificación , VIH-1/enzimología , Transcriptasa Inversa del VIH/genética , Infecciones por VIH/virología , Infecciones por VIH/epidemiología , Piridonas/farmacología , Farmacorresistencia Viral/genética , Fármacos Anti-VIH/farmacología , Triazoles/farmacología , Polimorfismo Genético , Prevalencia , Masculino , Femenino , Inhibidores de la Transcriptasa Inversa/farmacología , Adulto , Genotipo , Fenotipo , Persona de Mediana EdadRESUMEN
BACKGROUND: Transmitted drug resistance (TDR) is still a critical aspect for the management of individuals living with HIV-1. Thus, its evaluation is crucial to optimize HIV care. METHODS: Overall, 2386 HIV-1 protease/reverse transcriptase and 1831 integrase sequences from drug-naïve individuals diagnosed in north and central Italy between 2015 and 2021 were analysed. TDR was evaluated over time. Phylogeny was generated by maximum likelihood. Factors associated with TDR were evaluated by logistic regression. RESULTS: Individuals were mainly male (79.1%) and Italian (56.2%), with a median (IQR) age of 38 (30-48). Non-B infected individuals accounted for 44.6% (Nâ=â1065) of the overall population and increased over time (2015-2021, from 42.1% to 51.0%, Pâ=â0.002). TDR prevalence to any class was 8.0% (B subtype 9.5% versus non-B subtypes 6.1%, Pâ=â0.002) and remained almost constant over time. Overall, 300 transmission clusters (TCs) involving 1155 (48.4%) individuals were identified, with a similar proportion in B and non-infected individuals (49.7% versus 46.8%, Pâ=â0.148). A similar prevalence of TDR among individuals in TCs and those out of TCs was found (8.2% versus 7.8%, Pâ=â0.707).By multivariable analysis, subtypes A, F, and CFR02_AG were negatively associated with TDR. No other factors, including being part of TCs, were significantly associated with TDR. CONCLUSIONS: Between 2015 and 2021, TDR prevalence in Italy was 8% and remained almost stable over time. Resistant strains were found circulating regardless of being in TCs, but less likely in non-B subtypes. These results highlight the importance of a continuous surveillance of newly diagnosed individuals for evidence of TDR to inform clinical practice.