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Rapid Screening of HIV Reverse Transcriptase and Integrase Inhibitors
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Emergence of Resistance in HIV-1 Integrase with Dolutegravir Treatment in a Pediatric Population from the IMPAACT

Cindy Vavro1, Theodore Ruel2, Andrew Wiznia3

  • 1ViiV Healthcare, Research Triangle Park, North Carolina, USA.

Antimicrobial Agents and Chemotherapy
|October 25, 2021
PubMed

Insights

Emergent integrase strand transfer inhibitor (INSTI) resistance, specifically G118R or R263K substitutions, was observed in children and adolescents with HIV-1 receiving dolutegravir. These mutations impact drug susceptibility and viral replication capacity.

Area of Science:

  • Virology
  • Pharmacology
  • Pediatric Infectious Diseases

Background:

  • The study investigates integrase strand transfer inhibitor (INSTI) resistance in pediatric HIV-1 patients.
  • Dolutegravir is a key component of optimized background regimens for treatment-experienced children.

Purpose of the Study:

  • To characterize the mechanisms of emergent INSTI resistance in pediatric participants receiving dolutegravir.
  • To analyze the impact of specific resistance substitutions on dolutegravir susceptibility and viral replication capacity.

Main Methods:

  • Multicenter, open-label, phase I/II study (P1093) involving pediatric participants (4 weeks to <18 years) with HIV-1.
  • Population and clonal-level integrase genotyping and phenotyping at screening and virologic failure.
  • Phylogenetic analysis and homology modeling of HIV-1 integrase complexes.

Main Results:

  • Treatment-emergent INSTI resistance was detected in 8 participants meeting protocol-defined virologic failure criteria.
  • The substitutions G118R or R263K were identified in 6 participants, with secondary substitutions also observed.
  • G118R demonstrated a greater reduction in dolutegravir susceptibility and integrase replication capacity compared to R263K, especially with co-occurring mutations.

Conclusions:

  • G118R and R263K are distinct INSTI resistance substitutions detected in pediatric patients with prior virologic failure on dolutegravir.
  • Molecular and structural characterization aids in understanding INSTI resistance mechanisms in antiretroviral-experienced pediatric populations.
  • These findings are crucial for managing HIV-1 treatment in children and adolescents.

Keywords:
HIV-1dolutegravirintegrase strand transfer inhibitorpediatric HIV

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