Emergence of Resistance in HIV-1 Integrase with Dolutegravir Treatment in a Pediatric Population from the IMPAACT P1093 Study

Cindy Vavro, Theodore Ruel, Andrew Wiznia, Nicole Montañez, Keith Nangle, Joseph Horton, Ann M Buchanan, Eugene L Stewart, Paul Palumbo, Cindy Vavro, Theodore Ruel, Andrew Wiznia, Nicole Montañez, Keith Nangle, Joseph Horton, Ann M Buchanan, Eugene L Stewart, Paul Palumbo

Abstract

P1093 is a multicenter, open-label, phase I/II study of pharmacokinetics, safety, and tolerability of dolutegravir plus an optimized background regimen in pediatric participants aged 4 weeks to <18 years with HIV-1. Most participants were highly treatment experienced. We report the mechanisms of emergent integrase strand transfer inhibitor (INSTI) resistance among adolescents and children receiving dolutegravir. Plasma was collected at screening and near protocol-defined virologic failure (PDVF) for population-level and, for some samples, clonal-level integrase genotyping, phenotyping, and replication capacity. HIV-1 RNA was assessed in all available plasma samples. Phylogenetic analysis of clonal integrase sequences and homology modeling of HIV-1 intasome complexes containing resistance-associated substitutions were performed. Treatment-emergent INSTI resistance was detected in 8 participants who met PDVF criteria. The rare INSTI resistance-associated substitution G118R or R263K developed in 6 participants. The on-study secondary integrase substitution E157Q or L74I was observed in 2 participants. G118R reduced dolutegravir susceptibility and integrase replication capacity more than R263K and demonstrated greater reduction in susceptibility and integrase replication capacity when present with specific secondary integrase substitutions, including L74M, T66I, and E138E/K. Continuing evolution after R263K acquisition led to reduced dolutegravir susceptibility and integrase replication capacity. Structural examination revealed potential mechanisms for G118R- and R263K-mediated INSTI resistance. G118R and R263K INSTI resistance substitutions, which are distinct to second-generation INSTIs, were detected in adolescents and children with prior virologic failure who received dolutegravir. This study provides additional molecular and structural characterization of integrase to aid in the understanding of INSTI resistance mechanisms in antiretroviral-experienced populations. (This study has been registered at ClinicalTrials.gov under identifier NCT01302847.).

Keywords: HIV-1; dolutegravir; integrase strand transfer inhibitor; pediatric HIV.

Figures

FIG 1
FIG 1
HIV-1 RNA and CD4+ cell count over time in participants with PDVF and treatment-emergent resistance-associated substitutions in integrase. Red boxes denote HIV-1 RNA at the week each participant met PDVF criteria. Solid and dashed lines indicate HIV-1 RNA levels of 400 and 50 copies/mL, respectively.
FIG 2
FIG 2
Phylogenetic analysis of clonal and population integrase amino acid sequences from participants 1 through 6. Bootstrap confidence levels are indicated for each sequence cluster. For population sequences, the naming convention is as follows: participant number, time point in the study, HIV-1 subtype. For clonal sequences, the naming convention is as follows: participant number, time point in the study, C clone identification number (number of clones with identical sequences).
FIG 3
FIG 3
Catalytic site of wild-type or mutant HIV-1 integrase in the intasome complex. HIV-1 integrase is shown in cartoon and colored cyan. Selected catalytic site amino acid residues are displayed as sticks and colored cyan unless otherwise designated. Both the vDNA and tDNA substrates are shown in cartoon and colored orange. The terminal viral 3′ adenosine and target 3′ thymidine are displayed in cartoon and colored magenta and orange, respectively. The catalytic magnesium (Mg2+) is displayed in ball-and-stick format and colored green. Hydrogen bonds are depicted as yellow dashed lines. (A) View of the wild-type HIV-1 catalytic site illustrating the vDNA/tDNA interface and the mechanism of the integration process facilitated by D64, D116, and the Mg2+. (B) Identical view of the G118R HIV-1 catalytic site illustrating the hydrogen bonding complex formed among the terminal tDNA, R118 (in pink), and E92 (in pink) with the addition of the G118R resistance mutant. (C) Identical view of the L74M/V75A HIV-1 catalytic site illustrating the location of M74 (in pink) and A75 (in pink) relative to the nearby catalytic site residues L63, C65, and F121. (D) Identical view of the L74M/V75A/G118R HIV-1 catalytic site illustrating the location of M74 (in pink) and A75 (in pink) relative to R118 (in pink) and E92 (in pink). tDNA, host target DNA; vDNA, viral DNA.

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