HIV-1 drug resistance among individuals who seroconverted in the ASPIRE dapivirine ring trial

J Int AIDS Soc. 2021 Nov;24(11):e25833. doi: 10.1002/jia2.25833.


Introduction: A potential concern with the use of dapivirine (DPV) for HIV prevention is the selection of a drug-resistant virus that could spread and reduce the effectiveness of non-nucleoside reverse transcriptase (NNRTI)-based first-line antiretroviral therapy. We evaluated HIV-1 seroconversions in MTN-020/ASPIRE for selection of drug resistance and evaluated the genetic basis for observed reductions in susceptibility to DPV.

Methods: MTN-020/ASPIRE was a placebo-controlled, Phase III safety and effectiveness study of DPV ring for HIV-1 prevention conducted at 15 sites in South Africa, Zimbabwe, Malawi and Uganda between 2012 and 2015. Plasma from individuals who seroconverted in ASPIRE was analysed for HIV-1 drug resistance using both population Sanger sequencing and next-generation sequencing (NGS) with unique molecular identifiers to report mutations at ≥1% frequency. DPV susceptibility of plasma-derived recombinant HIV-1 containing bulk-cloned full-length reverse transcriptase sequences from MTN-020/ASPIRE seroconversions was determined in TZM-bl cells. Statistical significance was calculated using the Fisher's exact test.

Results: Plasma from all 168 HIV seroconversions were successfully tested by Sanger sequencing; 57 of 71 DPV arm and 82 of 97 placebo (PLB) arm participants had NGS results at 1% sensitivity. Overall, 18/168 (11%) had NNRTI mutations including K101E, K103N/S, V106M, V108I, E138A/G, V179D/I/T and H221Y. Five samples from both arms had low-frequency NNRTI mutations that were not detected by Sanger sequencing. The frequency of NNRTI mutations from the DPV arm (11%) was not different from the PLB arm (10%; p = 0.80). The E138A mutation was detected in both the DPV (3 of 71 [4.2%]) and PLB arm (5 of 97 [5.2%]) and conferred modest reductions in DPV susceptibility in some reverse transcriptase backgrounds but not others.

Conclusions: HIV-1 drug resistance including NNRTI resistance did not differ between the DPV and placebo arms of the MTN-020/ASPIRE study, indicating that drug resistance was not preferentially acquired or selected by the DPV ring and that the preventive benefit of DPV ring outweighs resistance risk.

Keywords: HIV-1 drug resistance; HIV-1 prevention; dapivirine; next-generation sequencing; non-nucleoside reverse transcriptase inhibitors (NNRTI); pre-exposure prophylaxis (PrEP).

Publication types

  • Clinical Trial, Phase III
  • Controlled Clinical Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Anti-HIV Agents* / pharmacology
  • Anti-HIV Agents* / therapeutic use
  • Drug Resistance, Viral / genetics
  • HIV Infections* / drug therapy
  • HIV Reverse Transcriptase / genetics
  • HIV Reverse Transcriptase / pharmacology
  • HIV Reverse Transcriptase / therapeutic use
  • HIV Seropositivity* / drug therapy
  • HIV-1* / genetics
  • Humans
  • Mutation
  • Pyrimidines
  • Reverse Transcriptase Inhibitors / therapeutic use


  • Anti-HIV Agents
  • Pyrimidines
  • Reverse Transcriptase Inhibitors
  • HIV Reverse Transcriptase
  • Dapivirine