Journal Article

Evolution of Protease Inhibitor Resistance in Human Immunodeficiency Virus Type 1 Infected Patients Failing Protease Inhibitor Monotherapy as Second-line Therapy in Low-income Countries

Kambugu, Andrew, van Oosterhout, Joep J., Arribas, Jose, Hakim, James, Mugyenyi, Peter, Walker, A. Sarah, Kityo, Cissy, Thompson, Jennifer A., Dunn, David, Hoppe, Anne, Ndashimye, Emmanuel, Paton, Nicholas I.

2019

Overview

Abstract Background Limited viral load (VL) testing in human immunodeficiency virus (HIV) treatment programs in low-income countries often delays detection of treatment failure. The impact of remaining on failing protease inhibitor (PI)–containing regimens is unclear. Methods We retrospectively tested VL in 2164 stored plasma samples from 386 patients randomized to receive lopinavir monotherapy (after initial raltegravir induction) in the Europe–Africa Research Network for Evaluation of Second-line Therapy (EARNEST) trial. Protease genotypic resistance testing was performed when VL >1000 copies/mL. We assessed evolution of PI resistance mutations from virological failure (confirmed VL >1000 copies/mL) until PI monotherapy discontinuation and examined associations using mixed-effects models. Results Median post-failure follow-up (in 118 patients) was 68 (interquartile range, 48–88) weeks. At failure, 20% had intermediate/high-level resistance to lopinavir. At 40–48 weeks post-failure, 68% and 51% had intermediate/high-level resistance to lopinavir and atazanavir; 17% had intermediate-level resistance (none high) to darunavir. Common PI mutations were M46I, I54V, and V82A. On average, 1.7 (95% confidence interval 1.5–2.0) PI mutations developed per year; increasing after the first mutation; decreasing with subsequent mutations (P < .0001). VL changes were modest, mainly driven by nonadherence (P = .006) and PI mutation development (P = .0002); I47A was associated with a larger increase in VL than other mutations (P = .05). Conclusions Most patients develop intermediate/high-level lopinavir resistance within 1 year of ongoing viral replication on monotherapy but retain susceptibility to darunavir. Viral load increased slowly after failure, driven by non-adherence and PI mutation development. Clinical Trials Registration NCT00988039. In patients failing protease inhibitor (lopinavir) monotherapy, intermediate/high level lopinavir resistance increased from 19% at failure to 68% 48 weeks later. Most retained darunavir susceptibility. Viral load increased slowly after failure, driven by nonadherence and protease inhibitor mutation development (particularly I47A).

• Publisher: Oxford University Press
• Subject: Adult / Africa / ARTICLES AND COMMENTARIES / Developing Countries / Drug Resistance, Viral / Female / Genotyping Techniques / HIV Infections - drug therapy / HIV Infections - virology / HIV Protease Inhibitors - pharmacology / HIV Protease Inhibitors - therapeutic use / HIV-1 - drug effects / HIV-1 - genetics / HIV-1 - isolation & purification / Humans / Lopinavir - pharmacology / Lopinavir - therapeutic use / Male / Randomized Controlled Trials as Topic / Treatment Failure