Jennifer A Thompson1,2, Cissy Kityo3, David Dunn1, Anne Hoppe1,4, Emmanuel Ndashimye3,5, James Hakim6, Andrew Kambugu7, Joep J van Oosterhout8,9, Jose Arribas10, Peter Mugyenyi3, A Sarah Walker1, Nicholas I Paton1,11. 1. Medical Research Council Clinical Trials Unit at University College London, United Kingdom. 2. Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, United Kingdom. 3. Joint Clinical Research Centre, Kampala, Uganda. 4. Division of Infection and Immunity, University College London, United Kingdom. 5. Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada. 6. University of Zimbabwe Clinical Research Centre, Harare, Zimbabwe. 7. Infectious Diseases Institute, Makerere University, Kampala, Uganda. 8. Department of Medicine, University of Malawi College of Medicine, Blantyre, Malawi. 9. Dignitas International, Zomba, Malawi. 10. IdiPAZ, La Paz Hospital, Madrid, Spain. 11. Yong Loo Lin School of Medicine, National University of Singapore.
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 receivelopinavir 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.
RCT Entities:
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.
Authors: Soo-Yon Rhee; Michael Boehm; Olga Tarasova; Giulia Di Teodoro; Ana B Abecasis; Anders Sönnerborg; Alexander J Bailey; Dmitry Kireev; Maurizio Zazzi; Robert W Shafer Journal: Pathogens Date: 2022-05-05
Authors: Nicaise Ndembi; Ravindra K Gupta; Rawlings Datir; Steven Kemp; Kate El Bouzidi; Petra Mlchocova; Richard Goldstein; Judy Breuer; Greg J Towers; Clare Jolly; Miguel E Quiñones-Mateu; Patrick S Dakum Journal: mBio Date: 2020-11-03 Impact factor: 7.867