PMID- 27704010 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20201001 IS - 2328-8957 (Print) IS - 2328-8957 (Electronic) IS - 2328-8957 (Linking) VI - 3 IP - 3 DP - 2016 Sep TI - Human Immunodeficiency Virus-1 Sequence Changes and Drug Resistance Mutation Among Virologic Failures of Lopinavir/Ritonavir Monotherapy: AIDS Clinical Trials Group Protocol A5230. PG - ofw154 LID - ofw154 AB - Background. The mechanism of virologic failure (VF) of lopinavir/ritonavir (LPV/r) monotherapy is not well understood. We assessed sequence changes in human immunodeficiency virus-1 reverse-transcriptase (RT) and protease (PR) regions. Methods. Human immunodeficiency virus-1 pol sequences from 34 participants who failed second-line LPV/r monotherapy were obtained at study entry (SE) and VF. Sequence changes were evaluated using phylogenetic analysis and hamming distance. Results. Human immunodeficiency virus-1 sequence change was higher over drug resistance mutation (DRM) sites (median genetic distance, 2.2%; Q1 to Q3, 2.1%-2.5%) from SE to VF compared with non-DRM sites (median genetic distance, 1.3%; Q1 to Q3, 1.0%-1.4%; P < .0001). Evolution over DRM sites was mainly driven by changes in the RT (median genetic distance, 2.7%; Q1 to Q3, 2.2%-3.2%) compared with PR (median genetic distance, 1.1%; Q1 to Q3, 0.0%-1.1%; P < .0001). Most RT DRMs present at SE were lost at VF. At VF, 19 (56%) and 26 (76%) were susceptible to efavirenz/nevirapine and etravirine (ETV)/rilpivirine (RPV), respectively, compared with 1 (3%) and 12 (35%) at SE. Participants who retained nonnucleoside reverse-transcriptase inhibitor (NNRTI) DRMs and those without evolution of LPV/r DRMs had significantly shorter time to VF. Conclusions. The selection of LPV/r DRMs in participants with longer time to VF suggests better adherence and more selective pressure. Fading NNRTI mutations and an increase in genotypic susceptibility to ETV and RPV could allow for the reuse of NNRTI. Further studies are warranted to understand mechanisms of PR failure. FAU - Vardhanabhuti, Saran AU - Vardhanabhuti S AD - Harvard T.H. Chan School of Public Health , Boston, Massachusetts. FAU - Katzenstein, David AU - Katzenstein D AD - Division of Infectious Diseases , Stanford University , California. FAU - Bartlett, John AU - Bartlett J AD - Duke University Medical Center , Durham, North Carolina. FAU - Kumarasamy, Nagalingeswaran AU - Kumarasamy N AD - Y.R. Gaitonde Centre for AIDS Research and Education , Chennai , India. FAU - Wallis, Carole L AU - Wallis CL AD - Department of Molecular Pathology , Lancet Laboratories and BARC-SA , Johannesburg , South Africa. LA - eng GR - UM1 AI068634/AI/NIAID NIH HHS/United States GR - U01 AI069432/AI/NIAID NIH HHS/United States GR - U01 AI038858/AI/NIAID NIH HHS/United States GR - U01 AI068636/AI/NIAID NIH HHS/United States GR - U01 AI069518/AI/NIAID NIH HHS/United States GR - UM1 AI106701/AI/NIAID NIH HHS/United States GR - U01 AI068634/AI/NIAID NIH HHS/United States GR - UM1 AI068636/AI/NIAID NIH HHS/United States PT - Journal Article DEP - 20160824 PL - United States TA - Open Forum Infect Dis JT - Open forum infectious diseases JID - 101637045 PMC - PMC5047431 OTO - NOTNLM OT - HIV-1 sequence evolution OT - LPV/r failures OT - drug resistance mutation OT - hamming distance OT - phylogenetic EDAT- 2016/10/06 06:00 MHDA- 2016/10/06 06:01 PMCR- 2016/08/24 CRDT- 2016/10/06 06:00 PHST- 2016/05/12 00:00 [received] PHST- 2016/07/17 00:00 [accepted] PHST- 2016/10/06 06:00 [entrez] PHST- 2016/10/06 06:00 [pubmed] PHST- 2016/10/06 06:01 [medline] PHST- 2016/08/24 00:00 [pmc-release] AID - ofw154 [pii] AID - 10.1093/ofid/ofw154 [doi] PST - epublish SO - Open Forum Infect Dis. 2016 Aug 24;3(3):ofw154. doi: 10.1093/ofid/ofw154. eCollection 2016 Sep.