Frequent Cross-Resistance to Dapivirine in HIV-1 Subtype C-Infected Individuals after First-Line Antiretroviral Therapy Failure in South Africa
| Autor: | P. Richard Harrigan, Chanson J. Brumme, Kristen A. Hamanishi, Urvi M. Parikh, Raquel V. Viana, Carole L. Wallis, Kerri J. Penrose, John W. Mellors, Kelley C. Gordon |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Efavirenz Nevirapine Anti-HIV Agents 030106 microbiology Dapivirine HIV Infections Drug resistance Biology Antiviral Agents Inhibitory Concentration 50 South Africa 03 medical and health sciences chemistry.chemical_compound Drug Resistance Multiple Viral medicine Humans Pharmacology (medical) Treatment Failure IC50 Cross-resistance Pharmacology virus diseases Virology HIV Reverse Transcriptase Reverse transcriptase Pyrimidines Infectious Diseases Viral replication chemistry Mutation Vagina HIV-1 Female medicine.drug |
| Zdroj: | Antimicrobial Agents and Chemotherapy. 61 |
| ISSN: | 1098-6596 0066-4804 |
| DOI: | 10.1128/aac.01805-16 |
| Popis: | 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. Plasma samples were obtained from individuals with >10,000 copies of HIV RNA/ml 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 50% inhibitory concentration (IC 50 ) from 12 recombinant subtype C HIV-1 LAI plasma-derived viruses from treatment-naive individuals in South Africa. A total of 25/100 (25%) samples showed >500-FCs to DPV compared to treatment-naive samples with IC 50 s exceeding the maximum DPV concentration tested (132 ng/ml). A total of 66/100 (66%) samples displayed 3- to 306-FCs, with a median IC 50 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 a ≤500-fold resistance. A total of 91% of samples with NNRTI-resistant HIV-1 from individuals on failing first-line ART in South Africa exhibited ≥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. |
| Databáze: | OpenAIRE |
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