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: An Observational Analysis Within the EARNEST Randomized Trial. (28th July 2018)

• Record Type: Journal Article
• Authors: Thompson, Jennifer A; Kityo, Cissy; Dunn, David; Hoppe, Anne; Ndashimye, Emmanuel; Hakim, James; Kambugu, Andrew; van Oosterhout, Joep J; Arribas, Jose; Mugyenyi, Peter; Walker, A Sarah; Paton, Nicholas I
• Is Part Of: Clinical infectious diseases. Volume 68:Number 7(2019)
• Page Start: 1184
• Page End: 1192
• Publication Date: 2018-07-28
• Subjects: HIV-1 -- drug resistance -- protease inhibitor -- second-line antiretroviral therapy -- sub-Saharan Africa; Communicable diseases -- Periodicals; 616.905
• DOI: 10.1093/cid/ciy589
• Languages: English
• ISSNs: 1058-4838

Abstract

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. Abstract : 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).