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Limited HIV-1 Subtype C nef 3'PPT Variation in Combination Antiretroviral Therapy Naive and Experienced People Living with HIV in Botswana.

ABSTRACT: Dolutegravir (DTG) is a potent anti-HIV drug that is used to treat HIV globally. There have been reports of mutations in the HIV-1 3'-polypurine tract (3'PPT) of the nef gene, contributing to DTG failure; however, there are limited 'real-world' data on this. In addition, there is a knowledge gap on the variability of 3'PPT residues in patients receiving combination antiretroviral therapy (cART) with and without viral load (VL) suppression. HIV-1 subtype C (HIV-1C) whole-genome sequences from cART naïve and experienced individuals were generated using next-generation sequencing. The nef gene sequences were trimmed from the generated whole-genome sequences using standard bioinformatics tools. In addition, we generated separate integrase and nef gene sequences by Sanger sequencing of plasma samples from individuals with virologic failure (VF) while on a DTG/raltegravir (RAL)-based cART. Analysis of 3'PPT residues was performed, and comparison of proportions computed using Pearson's chi-square test with p-values < 0.05 was considered statistically significant. A total of 6009 HIV-1C full genome sequences were generated and had a median log₁₀ HIV-1 VL (Q1, Q3) copies/mL of 1.60 (1.60, 2.60). A total of 12 matching integrase and nef gene sequences from therapy-experienced participants failing DTG/ RAL-based cART were generated. HIV-1C 3'PPT nef gene sequences from therapy-experienced patients failing DTG cART (n = 12), cART naïve individuals (n = 1263), and individuals on cART with and without virological suppression (n = 4696) all had a highly conserved 3'PPT motif with no statistically significant differences identified. Our study confirms the high conservation of the HIV-1 nef gene 3'PPT motif in 'real-world' patients and showed no differences in the motif according to VL suppression or INSTI-based cART failure. Future studies should explore other HIV-1 regions outside of the pol gene for associations with DTG failure.

SUBMITTER: Seatla KK

PROVIDER: S-EPMC8400509 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:There are limited data on the prevalence of fostemsavir (FTR) resistance-associated polymorphisms in people with HIV in Botswana. We sought to determine the prevalence of FTR resistance-associated polymorphisms in HIV-1 subtype C sequences from antiretroviral therapy (ART)-naïve and ART-experienced individuals in Botswana. Previously reported FTR resistance-associated polymorphisms from literature were surveyed from HIV-1C proviral sequences generated from a large HIV-1 population-based cohort enrolled between 2013 and 2018. Sequences from ART-naïve and ART-experienced individuals were included in the analysis. A total of 6,078 participants with gp120 sequences were included in this study, and 6,030 (99.2%) had known ART status; 1,282 (21.3%) were from ART-naïve individuals, while 4,748 (78.7%) were from individuals on ART at study enrollment. Viral load (VL) data were available for 4,739 (99.8%) ART-experienced individuals, of whom 4,526 (95.5%) were suppressed and 213 (4.5%) had virologic failure (VF) (VL >400). Among those with VF and ART naive, the overall prevalence of FTR resistance was 13.3% (95% CI 11.6%-15.1%) and did not differ between ART-experienced with VF individuals (29/213, 13.6%) and ART-naïve individuals (170/1,282, 13.3%) (P-value = 0.9). The most predominant mutations (prevalence ≥1.0%) were M434I (9.8%), M475I (5.9%), and M426L (1.1%). The overall prevalence of FTR polymorphisms was similar in both ART-naïve and ART-experienced individuals with VF in a setting with no prior FTR exposure. We recommend further studies on the phenotypic impact of these polymorphisms to guide how to monitor for FTR resistance. (This study has been registered at ClinicalTrials.gov under registration no. NCT01965470.) IMPORTANCE Fostemsavir (FTR) is a newly licensed antiretroviral drug that has been shown to have activity against HIV-1. The mechanism of action of FTR is different from all currently available antiretrovirals (ARVs), and as such, it offers hope for HIV-1 suppression in those people with HIV (PWH) who harbor HIV-1 variants with drug resistance mutations to currently used ARVs. Using 6,030 HIV-1 sequences covering the HIV-1 envelope from PWH in Botswana who are antiretroviral therapy (ART) naïve as well as those who are failing ART, we explored the sequences for FTR resistance-associated polymorphisms. We found the prevalence of FTR polymorphisms to be similar in both ART-naïve and ART-experienced individuals with VF in this setting, with no prior FTR exposure. Further studies on the phenotypic impact of these polymorphisms are warranted to guide how to monitor for FTR resistance.

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Project description:Levels of adherence to HIV treatment are lower among adolescents compared with older and younger individuals receiving similar therapies. We purposely sampled the most and least adherent adolescents from a 300-adolescent longitudinal HIV treatment adherence study in Gaborone, Botswana. Multiple objective and subjective measures of adherence were available and study participants were selected based on sustained patterns of either excellent or poor adherence over a one-year period. Focus group discussions (FGD) and in-depth interviews (IDI) were conducted with the adolescents and a subset of their caregivers with the goal of revealing barriers and facilitators of adherence. Focus groups were segregated by adherence classification of the participants. Following coding of transcripts, matrices were developed based on participants' adherence classifications in order to clarify differences in themes generated by individuals with different adherence characteristics. 47 adolescents and 25 adults were included. The non-adherent adolescents were older than the adherent adolescents (median age 18 years (IQR 16-19) vs. 14 years (IQR 12-15 years)), with median time on treatment near 10 years in both groups. Interference with daily activities, concerns about stigma and discrimination, side effects, denial of HIV status, and food insecurity arose as challenges to adherence among both those who were consistently adherent and those who were poorly-adherent to their medications. Low outcome expectancy, treatment fatigue, mental health and substance use problems, and mismatches between desired and received social support were discussed only among poorly adherent adolescents and their caregivers. Challenges raised only among adolescents and caregivers in the non-adherent groups are hypothesis-generating, identifying areas that may have a greater contribution to poor outcomes than challenges faced by both adherent and non-adherent adolescents. The contribution of these factors to poor outcomes should be explored in future studies.

Project description:BackgroundHuman immunodeficiency virus (HIV) functional cure is a novel biomedical strategy characterized by sustained viral suppression without the need for life-long medications. The attitude of people living with HIV (PLHIV) towards functional cure and clinical trials are understudied. We aimed to examine the awareness and levels of anticipation for HIV functional cure among men who have sex with men (MSM) living with HIV, and their willingness to join trials as differentiated by their antiretroviral treatment status.MethodsMSM living with HIV with and those without treatment history were recruited from Hong Kong's HIV specialist clinics. Self-administered questionnaires covering behavioral profile, perceived impact of HIV cure, attitude towards HIV functional cure and related clinical trials were collected. Clinical data were separately transcribed. Determinants of perceptions and attitudes were identified by logistic regression models.ResultsOf 356 MSM living with HIV recruited, less than half (42%) were aware of HIV functional cure, but they had a high level of anticipation for it. Treatment-experienced participants were more likely to be aware of HIV functional cure. Awareness was associated with continued engagement in sexual activities after HIV diagnosis and sexually transmitted infection (STI) diagnosis. Higher anticipation was observed among older MSM living with HIV but it was negatively associated with one's awareness. Over 90% were willing to join functional cure trials, especially those who had previously been diagnosed with STI and had engaged in chemsex in the past year. Advice from healthcare professional was an important factor considered by those willing to join clinical trials. Younger, better educated MSM, and those with lower CD4 counts were more concerned about potential risk of AIDS and potential complications upon trial participation.ConclusionsMSM living with HIV, especially those sexually active, showed positive attitude towards functional cure and willingness to join related clinical trials despite low awareness. To enhance preparedness for HIV functional cure trials, community education, updated information and appropriate medical advice would be needed. Safety is a major concern for potential enrollees in HIV functional cure trials.

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Limited HIV-1 Subtype C nef 3'PPT Variation in Combination Antiretroviral Therapy Naive and Experienced People Living with HIV in Botswana.

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