Frequent Cross-Resistance to Dapivirine in HIV-1 Subtype C-Infected Individuals on Failing First-Line Antiretroviral Therapy in South Africa [PublishAheadOfPrint]

Background: A vaginal ring containing dapivirine (DPV) has shown moderate protective efficacy against HIV-1 acquisition, but the activity of DPV against efavirenz (EFV)- and nevirapine (NVP)-resistant viruses that could be transmitted is not well-defined. We investigated DPV cross-resistance of subtype C HIV-1 from individuals on failing NVP- or EFV-containing antiretroviral therapy (ART) in South Africa (SA).

Methods: Plasma samples were obtained from individuals with >10,000 copies/mL HIV RNA and with HIV-1 containing at least one non-nucleoside reverse transcriptase (NNRTI) mutation. Susceptibility to NVP, EFV and DPV in TZM-bl cells was determined for recombinant HIV-1_LAI containing bulk-amplified, plasma-derived, full-length reverse transcriptase sequences. Fold-change (FC) values were calculated compared with a composite IC₅₀ value from 12 recombinant subtype C HIV-1_LAI plasma-derived viruses from treatment-naïve individuals in SA.

Results: 25/100 (25%) samples showed >500-FC to DPV compared to treatment-naïve samples with IC₅₀ values exceeding the maximum DPV concentration tested (132 ng/mL). 66/100 (66%) samples displayed 3 to 306-FC with median IC₅₀ of 17.6 ng/mL. Only 9/100 (9%) samples were susceptible to DPV (FC <3). Mutations L100I and K103N were significantly more frequent in samples with >500-fold resistance to DPV compared to samples with ≤500-fold resistance.

Conclusions: 91% of samples with NNRTI-resistant HIV-1 from individuals on failing first-line ART in SA exhibit ≥3-fold cross-resistance to DPV. This level of resistance exceeds expected plasma concentrations, but very high genital tract DPV concentrations from DPV ring use could block viral replication. It is critically important to assess the frequency of transmitted and selected DPV resistance in individuals using the DPV ring.

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