Frequent Cross-Resistance to Dapivirine in HIV-1 Subtype C-Infected Individuals after First-Line Antiretroviral Therapy Failure in South Africa

Kerri J Penrose; Carole L Wallis; Chanson J Brumme; Kristen A Hamanishi; Kelley C Gordon; Raquel V Viana; P Richard Harrigan; John W Mellors; Urvi M Parikh

doi:10.1128/AAC.01805-16

Frequent Cross-Resistance to Dapivirine in HIV-1 Subtype C-Infected Individuals after First-Line Antiretroviral Therapy Failure in South Africa

Antimicrob Agents Chemother. 2017 Jan 24;61(2):e01805-16. doi: 10.1128/AAC.01805-16. Print 2017 Feb.

Authors

Kerri J Penrose¹, Carole L Wallis², Chanson J Brumme³, Kristen A Hamanishi¹, Kelley C Gordon¹, Raquel V Viana², P Richard Harrigan³, John W Mellors¹, Urvi M Parikh⁴

Affiliations

¹ University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
² BARC-SA and Lancet Laboratories, Johannesburg, South Africa.
³ BC Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada.
⁴ University of Pittsburgh, Pittsburgh, Pennsylvania, USA [email protected].

Abstract

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 (IC₅₀) 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 IC₅₀s exceeding the maximum DPV concentration tested (132 ng/ml). A total of 66/100 (66%) samples displayed 3- to 306-FCs, with a 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 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.

Keywords: HIV-1; NNRTI; antiretroviral therapy; cross-resistance; dapivirine; drug resistance; human immunodeficiency virus; non-nucleoside reverse transcriptase inhibitor.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anti-HIV Agents / pharmacology*
Drug Resistance, Multiple, Viral / drug effects*
Drug Resistance, Multiple, Viral / genetics
Female
HIV Infections / drug therapy*
HIV Infections / virology
HIV Reverse Transcriptase / genetics
HIV-1 / drug effects*
HIV-1 / genetics*
HIV-1 / pathogenicity
Humans
Inhibitory Concentration 50
Mutation
Pyrimidines / blood
Pyrimidines / pharmacology*
South Africa
Treatment Failure
Vagina / virology

Substances

Anti-HIV Agents
Pyrimidines
reverse transcriptase, Human immunodeficiency virus 1
HIV Reverse Transcriptase
Dapivirine