Integrase resistance emergence with dolutegravir/lamivudine with prior HIV-1 suppression

• Published in: Journal of antimicrobial chemotherapy Vol. 77; no. 6; pp. 1738 - 1740
• Main Authors: Revollo, Boris, Viñuela, Laura, de la Mora, Lorena, García, Federico, Noguera-Julián, Marc, Parera, Mariona, Paredes, Roger, Llibre, Josep M.
• Format: Journal Article
• Language: English
• Published: England 29.05.2022
• Subjects: Drug Resistance, Viral - genetics; Heterocyclic Compounds, 3-Ring - adverse effects; HIV Infections - drug therapy; HIV Integrase Inhibitors - pharmacology; HIV Integrase Inhibitors - therapeutic use; HIV Seropositivity - drug therapy; HIV-1 - genetics; Humans; Integrases; Lamivudine - therapeutic use; Leukocytes, Mononuclear; Male; Oxazines - therapeutic use; Piperazines; Pyridones - therapeutic use; RNA-Directed DNA Polymerase; Viremia - drug therapy
• ISSN: 0305-7453; 1460-2091; 1460-2091
• DOI: 10.1093/jac/dkac082

Integrase resistance has not been reported with co-formulated dolutegravir/lamivudine in clinical trials or real-life cohorts. We aim to report, to the best of our knowledge, the first case of selection of the key integrase mutation R263K in a subject treated with this regimen started as a switch strategy with undetectable plasma HIV-1 viraemia. Clinical case report. A patient with long-term suppressed HIV-1 viraemia (<50 copies/mL) with no known risk factors for virological failure and never exposed previously to an integrase inhibitor developed virological failure (consecutive plasma HIV-1 RNA 149 and 272 copies/mL) with 322 CD4 cells/mm3 despite good treatment adherence. He was receiving the anticonvulsant clobazam, considered to have a potential weak interaction with dolutegravir, unlikely to require a dose adjustment. Plasma HIV-1 genotypic deep sequencing (Vela System) revealed the emergence of R263K (79.6%) and S230N (99.4%) mutations in the integrase region (intermediate resistance to dolutegravir, score = 30 Stanford HIVDB 9.0). The reverse transcriptase and protease regions could not be amplified due to low viral loads. PBMC DNA deep sequencing performed some months later revealed mutations M184I (14.29%) and M230I (6.25%) in the reverse transcriptase and G163R (9.77%) and S230N (98.8%) in the integrase. R263K was only found at extremely low levels (0.07%). This case illustrates that integrase resistance can emerge in patients treated with co-formulated dolutegravir/lamivudine and raises awareness of the need to carefully consider and monitor drug-drug interactions, even when regarded as having a low potential, in subjects treated with dolutegravir/lamivudine.