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Human Immunodeficiency Virus-1 Sequence Changes and Drug Resistance Mutation Among Virologic Failures of Lopinavir/Ritonavir Monotherapy: AIDS Clinical Trials Group Protocol A5230.

ABSTRACT: 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.

SUBMITTER: Vardhanabhuti S

PROVIDER: S-EPMC5047431 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Human Immunodeficiency Virus-1 Sequence Changes and Drug Resistance Mutation Among Virologic Failures of Lopinavir/Ritonavir Monotherapy: AIDS Clinical Trials Group Protocol A5230.

Vardhanabhuti Saran S Katzenstein David D Bartlett John J Kumarasamy Nagalingeswaran N Wallis Carole L CL

Open forum infectious diseases 20160824 3

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 hammi ...[more]

PMID: 27704010

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Project description:There is scant data on young children receiving protease inhibitor-based therapy in real-life resource-limited settings and on the optimal timing of therapy among children who survive infancy. Our aim was to evaluate outcomes at the Hospital del Niño, Panama, where children have been routinely treated with lopinavir/ritonavir (LPV/r)-based therapy since 2002.Retrospective cohort analysis of all HIV-infected children enrolled in care between January 1, 1991, and June 1, 2011. Kaplan-Meier method and Cox proportional hazards regression were used to evaluate death, virologic suppression and virologic rebound.Of 399 children contributing 1944 person-years of follow-up, 254 (63.7%) were treated with LPV/r and 94 (23.6%) were never treated with antiretrovirals (ARVs). Among infants, improved survival was associated with male gender (hazard rate of death[HRdeath] 0.54, 95% confidence interval [CI]: 0.32-0.92) and treatment with highly active antiretroviral therapy (HRdeath 0.32, 95% CI: 0.12-0.83), whereas residence outside of Panama City was associated with poorer survival (HRdeath 1.72, 95% CI: 1.01-2.94). Among children who survived to 1 year of age without exposure to ARVs, LPV/r-based therapy improved survival (HRdeath 0.07, 95% CI: 0.01-0.33). Virologic suppression was achieved in 42.1%, 70.5% and 85.1% by 12, 24 and 60 months of follow-up among children treated with LPV/r. Virologic suppression was not associated with prior ARV exposure or age at initiation of therapy but was associated with residence outside of Panama City (HR suppression 1.93, 95% CI: 1.19-3.14). Patients with a baseline viral load >100,000 copies/mL were less likely to achieve suppression (HR suppression 0.37, 95% CI: 0.21-0.66). No children who achieved virologic suppression after initiating LPV/r died.LPV/r-based therapy improved survival not only in infants but also in children over 1 year of age. Age at initiation of LPV/r-based therapy or prior ARVs did not impact virologic outcomes.

Dataset Information

Human Immunodeficiency Virus-1 Sequence Changes and Drug Resistance Mutation Among Virologic Failures of Lopinavir/Ritonavir Monotherapy: AIDS Clinical Trials Group Protocol A5230.

Publications

Human Immunodeficiency Virus-1 Sequence Changes and Drug Resistance Mutation Among Virologic Failures of Lopinavir/Ritonavir Monotherapy: AIDS Clinical Trials Group Protocol A5230.

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