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Viral Genetic Diversity and Polymorphisms in a Cohort of HIV-1-Infected Patients Eligible for Initiation of Antiretroviral Therapy in Abuja, Nigeria.

ABSTRACT: Studying the genetic diversity and natural polymorphisms of HIV-1 would benefit our understanding of HIV drug resistance (HIVDR) development and predict treatment outcomes. In this study, we have characterized the HIV-1 genetic diversity and natural polymorphisms at the 5' region of the pol gene encompassing the protease (PR) and reverse transcriptase (RT) from 271 plasma specimens collected in 2008 from HIV-1-infected patients who were eligible for initiating antiretroviral therapy in Abuja (Nigeria). The analysis indicated that the predominant subtype was subtype G (31.0%), followed by CRF02-AG (19.2 %), CRF43-02G (18.5%), and A/CRF36-cpx (11.4%); the remaining (19.9%) were other subtypes and circulating (CRF) and unique (URF) recombinant forms. Recombinant viruses (68.6%) were the major viral strains in the region. Eighty-four subtype G sequences were further mainly classified into two major and two minor clusters; sequences in the two major clusters were closely related to the HIV-1 strains in two of the three major subtype G clusters detected worldwide. Those in the two minor clusters appear to be new subtype G strains circulating only in Abuja. The pretreatment DR prevalence was <3%; however, numerous natural polymorphisms were present. Eleven polymorphic mutations (G16E, K20I, L23P, E35D, M36I, N37D/S/T, R57K, L63P, and V82I) were detected in the PR that were subtype or CRF specific while only three mutations (D123N, I135T, and I135V) were identified in the RT. Overall, this study indicates an evolving HIV-1 epidemic in Abuja with recombinant viruses becoming the dominant strains and the emergence of new subtype G strains; pretreatment HIVDR was low and the occurrence of natural polymorphism in the PR region was subtype or CRF dependent.

SUBMITTER: Diallo K

PROVIDER: S-EPMC4696873 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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Viral Genetic Diversity and Polymorphisms in a Cohort of HIV-1-Infected Patients Eligible for Initiation of Antiretroviral Therapy in Abuja, Nigeria.

Diallo Karidia K Zheng Du-Ping DP Rottinghaus Erin K EK Bassey Orji O Yang Chunfu C

AIDS research and human retroviruses 20150205 5

Studying the genetic diversity and natural polymorphisms of HIV-1 would benefit our understanding of HIV drug resistance (HIVDR) development and predict treatment outcomes. In this study, we have characterized the HIV-1 genetic diversity and natural polymorphisms at the 5' region of the pol gene encompassing the protease (PR) and reverse transcriptase (RT) from 271 plasma specimens collected in 2008 from HIV-1-infected patients who were eligible for initiating antiretroviral therapy in Abuja (Ni ...[more]

PMID: 25582324

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Project description:IntroductionBased on growing evidence mainly from countries outside Sub-Saharan Africa, the World Health Organisation (WHO) now recommends initiation of antiretroviral therapy (ART) in HIV-infected individuals in developing countries when CD4 cell count (CD4+) is ≤ 500 cells/ul. Nigeria accounts for about 14% of the estimated HIV/AIDS burden in Sub-Saharan Africa. We evaluated the factors associated with timing of initiation of ART among treatment-ineligible HIV-infected adults from Nigeria.MethodsWe retrospectively reviewed the hospital records of ART ineligible HIV-infected adults who enrolled into HIV care between January 2008 and December 2012 at two major tertiary hospitals in Bayelsa State, South-South Nigeria. Demographic, clinical and laboratories data were obtained at presentation, at each subsequent visit at 6 monthly intervals and at time of initiation of ART. Cox proportional regression and Kaplan-Meier survival analysis were used to evaluate independent predictors of time to initiation of ART.ResultsAmongst the 280 study participants, 70.6% were females, 62.6% had CD4+ ≥500 cells/ul, 48.4% had WHO HIV Stage 1 disease and 34.3% were lost to follow up. In a cohort of 180 participants followed up for ≥3 months, participants with CD4+ of 351-500 cells/ul and stage 2 disease were more likely to start ART earlier than those with CD4+ > 500 cells/ul (Hazard ratio [HR]-1.7, 95% confidence interval [CI] of 1.0-2.9) and stage 1 disease (HR-2.3 (95% CI-1.3-4.2) respectively. HIV-infected adults with faster CD4+ decay required earlier ART initiation, especially in the first year of follow up.ConclusionART-ineligible HIV-infected adults on follow up in South-South Nigeria are more likely to require earlier initiation of ART if they have stage 2 HIV disease or CD4+ ≤500 cells/ul at presentation. Our findings suggest faster progression of HIV-disease in these groups of individuals and corroborate the growing evidence in support for earlier initiation of ART.

Project description:Abstract Background Single-nucleotide polymorphisms (SNPs) in CYP2B6 have previously been associated with a 10-fold range in trough plasma efavirenz concentrations, but associations between these SNPs and efavirenz (EFV)-mediated viral suppression and tolerability remain unclear. Methods We evaluated three SNPs in CYP2B6 (rs3745274, rs28399499, and rs4803419, Illumina OmniExpress) among HIV-infected Ugandans observed in a cohort study every 3–4 months from 2005–2015. Genotypes from these SNPs were used to group participants into previously described pharmacokinetic strata: extensive (EXT), intermediate (INT), and slow metabolizers (Figure 1). The primary outcomes were viral suppression, defined by an undetectable viral load in the first measurement a minimum of three months after ART initiation, and incident depression in the first two years, defined by a mean score >1.75 on the Hopkins Symptom Checklist. We fitted standard and generalized estimating equations (GEE) logistic regression models for viral suppression and depression, respectively. Models were adjusted for clinical and demographic covariates that reached a significance of P < 0.25 in unadjusted models. Results Among 103 participants with genotyping, there were no differences in pre-ART viral load or depression by metabolism strata (P > 0.5). Minor allele frequencies for rs3745274, rs28399499, and rs4803419 were 33%, 7%, and 4%, respectively. Approximately 79%, 78%, and 94% of participants were suppressed at their first viral load measurement in the extensive, intermediate, and slow metabolizer strata, respectively (Figure 2; P = 0.35). In adjusted models, metabolism strata were not associated with viral suppression (AORINT 0.81, 95% CI 0.26–2.56; AORSLOW 3.92, 95% CI 0.39–39.40) or with depression (AORINT 1.95, 95% CI 0.75–5.09; AORSLOW 0.72, 95% CI 0.17–3.02; Table). Conclusion We did not identify an association between efavirenz-metabolizing polymorphisms and viral suppression or depression in a cohort of HIV-infected individuals initiating ART in southwestern Uganda. Future work should reassess these relationships with larger samples and longer-term outcomes and explore additional polymorphisms that may be associated with efavirenz metabolism in this population. Disclosures P. Hunt, Merck: Consultant, Consulting fee; Gilead: Consultant, Consulting fee; Viiv: Consultant, Consulting fee

Project description:Background: The latent viral reservoir is the major obstacle to achieving HIV remission and necessitates life-long antiretroviral therapy (ART) for HIV-infected individuals. Studies in adults and children have found that initiating ART soon after infection is associated with a reduction in the size of the HIV-1 reservoir. Here we quantified cell-associated HIV-1 DNA in early-treated but currently older HIV-infected children suppressed on ART.Methods: The study participants comprised of a cohort of 146 early-treated children with HIV-1 RNA <50 copies/ml enrolled as part of a clinical trial in Johannesburg, South Africa. A stored buffy coat sample collected after a median 4.3 years on ART and where HIV-1 RNA was <50 copies/ml was tested for cell-associated HIV-1 DNA levels. An in-house, semi-nested real-time quantitative hydrolysis probe PCR assay to detect total HIV-1 subtype C proviral DNA was used. Children were followed prospectively for up to 3 years after this measurement to investigate subsequent HIV-1 RNA rebound/failure while remaining on ART. Age at ART initiation, HIV-1 RNA decline prior to HIV-1 DNA measurement and other factors were investigated.Results: A gradient between age at ART initiation and later HIV-1 DNA levels was observed. When ART was started <2 months of age, the lowest levels of cell-associated HIV-1 DNA (median 1.4 log10copies/106 cells, interquartile range [IQR] 0.95-1.55) were observed compared to ART started at 2-4 months (median 1.68, IQR 1.26-1.97) or 5-14 months of age (median1.98, IQR 1.69-2.25). A low CD4 T-cell count pre-treatment predicted higher levels of HIV-1 DNA on later testing. The probability of HIV-1 RNA rebound >50 copies/ml whilst on ART within 3 years after the DNA measurement was 2.07 (95% CI: 1.352-3.167) times greater if the HIV-1 DNA level was above the median of 55 copies/106 cells.Conclusions: Cell-associated HIV-1 DNA levels measured after more than 4 years on ART were lower the younger the age of the child when ART was initiated. This marker of the size of the viral reservoir also predicted subsequent viral rebound/treatment failure while ART was sustained. The results provide additional evidence of the benefits of prompt diagnosis and early ART initiation in newborns and infants.

Project description:IntroductionAfrican countries are rapidly adopting guidelines to offer antiretroviral therapy (ART) to all HIV-infected individuals, regardless of CD4 count. For this policy of 'treat all' to succeed, millions of new patients must be initiated on ART as efficiently as possible. Studies have documented high losses of treatment-eligible patients from care before they receive their first dose of antiretrovirals (ARVs), due in part to a cumbersome, resource-intensive process for treatment initiation, requiring multiple clinic visits over a several-week period.Methods and analysisThe Simplified Algorithm for Treatment Eligibility (SLATE) study is an individually randomised evaluation of a simplified clinical algorithm for clinicians to reliably determine a patient's eligibility for immediate ART initiation without waiting for laboratory results or additional clinic visits. SLATE will enrol and randomise (1:1) 960 adult, HIV-positive patients who present for HIV testing or care and are not yet on ART in South Africa and Kenya. Patients randomised to the standard arm will receive routine, standard of care ART initiation from clinic staff. Patients randomised to the intervention arm will be administered a symptom report, medical history, brief physical exam and readiness assessment. Patients who have positive (satisfactory) results for all four components of SLATE will be dispensed ARVs immediately, at the same clinic visit. Patients who have any negative results will be referred for further clinical investigation, counselling, tests or other services prior to being dispensed ARVs. After the initial visit, follow-up will be by passive medical record review. The primary outcomes will be ART initiation ≤28 days and retention in care 8 months after study enrolment.Ethics and disseminationEthics approval has been provided by the Boston University Institutional Review Board, the University of the Witwatersrand Human Research Ethics Committee (Medical) and the KEMRI Scientific and Ethics Review Unit. Results will be published in peer-reviewed journals and made widely available through presentations and briefing documents.Trial registrationNCT02891135.

Dataset Information

Viral Genetic Diversity and Polymorphisms in a Cohort of HIV-1-Infected Patients Eligible for Initiation of Antiretroviral Therapy in Abuja, Nigeria.

Publications

Viral Genetic Diversity and Polymorphisms in a Cohort of HIV-1-Infected Patients Eligible for Initiation of Antiretroviral Therapy in Abuja, Nigeria.

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