Dataset Information

HIV Drug Resistance Mutations in Non-B Subtypes After Prolonged Virological Failure on NNRTI-Based First-Line Regimens in Sub-Saharan Africa.

ABSTRACT: OBJECTIVE:To determine drug resistance mutation (DRM) patterns in a large cohort of patients failing nonnucleoside reverse transcriptase inhibitor (NNRTI)-based first-line antiretroviral therapy regimens in programs without routine viral load (VL) monitoring and to examine intersubtype differences in DRMs. DESIGN:Sequences from 787 adults/adolescents who failed an NNRTI-based first-line regimen in 13 clinics in Uganda, Kenya, Zimbabwe, and Malawi were analyzed. Multivariable logistic regression was used to determine the association between specific DRMs and Stanford intermediate-/high-level resistance and factors including REGA subtype, first-line antiretroviral therapy drugs, CD4, and VL at failure. RESULTS:The median first-line treatment duration was 4 years (interquartile range 30-43 months); 42% of participants had VL ?100,000 copies/mL and 63% participants had CD4 <100 cells/mm. Viral subtype distribution was A1 (40%; Uganda and Kenya), C (31%; Zimbabwe and Malawi), and D (25%; Uganda and Kenya), and recombinant/unclassified (5%). In general, DRMs were more common in subtype-C than in subtype-A and/or subtype-D (nucleoside reverse transcriptase inhibitor mutations K65R and Q151M; NNRTI mutations E138A, V106M, Y181C, K101E, and H221Y). The presence of tenofovir resistance was similar between subtypes [P (adjusted) = 0.32], but resistance to zidovudine, abacavir, etravirine, or rilpivirine was more common in subtype-C than in subtype-D/subtype-A [P (adjusted) < 0.02]. CONCLUSIONS:Non-B subtypes differ in DRMs at first-line failure, which impacts on residual nucleoside reverse transcriptase inhibitor and NNRTI susceptibility. In particular, higher rates of etravirine and rilpivirine resistance in subtype-C may limit their potential utility in salvage regimens.

SUBMITTER: Kityo C

PROVIDER: S-EPMC5427983 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

HIV Drug Resistance Mutations in Non-B Subtypes After Prolonged Virological Failure on NNRTI-Based First-Line Regimens in Sub-Saharan Africa.

Kityo Cissy C Thompson Jennifer J Nankya Immaculate I Hoppe Anne A Ndashimye Emmanuel E Warambwa Colin C Mambule Ivan I van Oosterhout Joep J JJ Wools-Kaloustian Kara K Bertagnolio Silvia S Easterbrook Philippa J PJ Mugyenyi Peter P Walker A Sarah AS Paton Nicholas I NI

Journal of acquired immune deficiency syndromes (1999) 20170601 2

<h4>Objective</h4>To determine drug resistance mutation (DRM) patterns in a large cohort of patients failing nonnucleoside reverse transcriptase inhibitor (NNRTI)-based first-line antiretroviral therapy regimens in programs without routine viral load (VL) monitoring and to examine intersubtype differences in DRMs.<h4>Design</h4>Sequences from 787 adults/adolescents who failed an NNRTI-based first-line regimen in 13 clinics in Uganda, Kenya, Zimbabwe, and Malawi were analyzed. Multivariable logis ...[more]

PMID: 28129253

Similar Datasets

Project description:ObjectiveThis study described the demographics, treatment information and identified characteristics associated with virological failure and being lost to follow-up (LTFU) for patients with HIV on first-line and second-line antiretroviral therapy (ART) regimens in a large South African cohort.DesignA quantitative retrospective cohort study using secondary data analysis.SettingSeven Johannesburg inner city facilities.ParticipantsUnique records of 123 002 people with HIV receiving ART at any point in the period 1 April 2004 to 29 February 2020 were included.MeasuresDemographic characteristics, ART status, CD4 count information and retention status were collected and analysed as covariates of outcomes (viral load (VL) and LTFU).ResultsOf the total study patients, 95% (n=1 17 260) were on a first-line regimen and 5% (n=5742) were on a second-line regimen. Almost two-thirds were female (64%, n=79 226). Most patients (60%, n=72 430) were initiated on an efavirenz-based, tenofovir disoproxil fumarate-based and emtricitabine-based regimen (fixed-dose combination). 91% (n=76 737) achieved viral suppression at least once since initiating on ART and 60% (n=57 981) remained in care as at the end of February 2020. Patients from the community health centre and primary healthcare clinics were not only more likely to be virally suppressed but also more likely to be LTFU. Patients on second-line regimens were less likely to reach viral suppression (adjusted OR (aOR)=0.26, CI=0.23 to 0.28) and more likely to be LTFU (aOR=1.21, CI=1.09 to 1.35). Being older (≥25 years) and having a recent CD4 cell count≥100 cells/µL were predictors of viral suppression and retention in patients on ART.ConclusionPatients on first-line regimens had higher VL suppression rates and were more likely to remain in care than those on a second-line regimen. Being younger and having low CD4 cell counts were associated with poor outcomes, suggesting priority groups for ART adherence support.

Project description:There are limited data of immunologic and virologic failure in Asian HIV-infected children using non-nucleoside reverse transcriptase inhibitor (NNRTI)-based highly active antiretroviral therapy (HAART). We examined the incidence rate of immunologic failure (IF) and virologic failure (VF) and the accuracy of using IF to predict VF in Thai HIV-infected children using first-line NNRTI-based HAART.Antiretroviral (ART)-naïve HIV-infected children from 2 prospective cohorts treated with NNRTI-based HAART during 2001-2008 were included. CD4 counts were performed every 12 weeks and plasma HIV-RNA measured every 24 weeks. Immune recovery was defined as CD4%?25%. IF was defined as persistent decline of ?5% in CD4% in children with CD4%<15% at baseline or decrease in CD4 count ?30% from baseline. VF was defined as HIV-RNA>1,000 copies/ml after at least 24 weeks of HAART. Clinical and laboratory parameter changes were assessed using a paired t-test, and a time to event approach was used to assess predictors of VF. Sensitivity and specificity of IF were calculated against VF.107 ART-naive HIV-infected children were included, 52% female, % CDC clinical classification N:A:B:C 4:44:30:22%. Baseline data were median (IQR) age 6.2 (4.2-8.9) years, CD4% 7 (3-15), HIV-RNA 5.0 (4.9-5.5) log10copies/ml. Nevirapine (NVP) and efavirenz (EFV)-based HAART were started in 70% and 30%, respectively.At 96 weeks, none had progressed to a CDC clinical classification of AIDS and one had died from pneumonia. Overall, significant improvement of weight for age z-score (p = 0.014), height for age z-score, hemoglobin, and CD4 were seen (all p < 0.001). The median (IQR) CD4% at 96 weeks was 25 (18-30)%. Eighty-nine percent of children had immune recovery (CD4%?25%) and 75% of children had HIV-RNA <1.7log10copies/ml.Thirty five (32.7%) children experienced VF within 96 weeks. Of these, 24 (68.6%) and 31 (88.6%) children had VF in the first 24 and 48 weeks respectively.Only 1 (0.9%) child experienced IF within 96 weeks and the sensitivity (95%CI) of IF to VF was 4 (0.1-20.4)% and specificity was 100 (93.9-100)%.Immunologic failure, as defined here, had low sensitivity compared to VF and should not be recommended to detect treatment failure. Plasma HIV-RNA should be performed twice, at weeks 24 and 48, to detect early treatment failure.Clinicaltrials.gov identification number NCT00476606.

Project description:BackgroundMany individuals failing first-line antiretroviral therapy (ART) in sub-Saharan Africa never initiate second-line ART or do so after significant delay. For people on ART with a viral load more than 1000 copies/ml, the WHO recommends a second viral load measurement 3 months after the first viral load and enhanced adherence support. Switch to a second-line regimen is contingent upon a persistently elevated viral load more than 1000 copies/ml. Delayed second-line switch places patients at increased risk for opportunistic infections and mortality.MethodsTo assess the potential benefits of a simplified second-line ART switch strategy, we use an individual-based model of HIV transmission, progression and the effect of ART which incorporates consideration of adherence and drug resistance, to compare predicted outcomes of two policies, defining first-line regimen failure for patients on efavirenz-based ART as either two consecutive viral load values more than 1000 copies/ml, with the second after an enhanced adherence intervention (implemented as per current WHO guidelines) or a single viral load value more than 1000 copies/ml. We simulated a range of setting-scenarios reflecting the breadth of the sub-Saharan African HIV epidemic, taking into account potential delays in defining failure and switch to second-line ART.FindingsThe use of a single viral load more than 1000 copies/ml to define ART failure would lead to a higher proportion of persons with nonnucleoside reverse-transcriptase inhibitor resistance switched to second-line ART [65 vs. 48%; difference 17% (90% range 14-20%)], resulting in a median 18% reduction in the rate of AIDS-related death over setting scenarios (90% range 6-30%; from a median of 3.1 to 2.5 per 100 person-years) over 3 years. The simplified strategy also is predicted to reduce the rate of AIDS conditions by a median of 31% (90% range 8-49%) among people on first-line ART with a viral load more than 1000 copies/ml in the past 6 months. For a country of 10 million adults (and a median of 880 000 people with HIV), we estimate that this approach would lead to a median of 1322 (90% range 67-3513) AIDS deaths averted per year over 3 years. For South Africa this would represent around 10 215 deaths averted annually.InterpretationAs a step towards reducing unnecessary mortality associated with delayed second-line ART switch, defining failure of first-line efavirenz-based regimens as a single viral load more than 1000 copies/ml should be considered.

Project description:First-line antiretroviral therapy (ART) failure often results from the development of resistance-associated mutations (RAMs). Three patterns, including thymidine analogue mutations (TAMs), 69 Insertion (69Ins) and the Q151M complex, are associated with resistance to multiple-nucleoside reverse transcriptase inhibitors (NRTIs) and may compromise treatment options for second-line ART.We investigated patterns and factors associated with multi-NRTI RAMs at first-line failure in patients from The TREAT Asia Studies to Evaluate Resistance - Monitoring study (TASER-M), and evaluated their impact on virological responses at 12 months after switching to second-line ART. RAMs were compared with the IAS-USA 2013 mutations list. We defined multi-NRTI RAMs as the presence of either Q151M; 69Ins; ? 2 TAMs; or M184V+? 1 TAM. Virological suppression was defined as viral load (VL) <400 copies/ml at 12 months from switch to second-line. Logistic regression was used to analyze (1) factors associated with multi-NRTI RAMs at first-line failure and (2) factors associated with virological suppression after 12 months on second-line.A total of 105 patients from 10 sites in Thailand, Hong Kong, Indonesia, Malaysia and Philippines were included. There were 97/105 (92%) patients harbouring ? 1 RAMs at first-line failure, 39/105 with multi-NRTI RAMs: six with Q151M; 24 with ? 2 TAMs; and 32 with M184V+? 1 TAM. Factors associated with multi-NRTI RAMs were CD4 ? 200 cells/µL at genotyping (OR=4.43, 95% CI [1.59-12.37], p=0.004) and ART duration >2 years (OR=6.25, 95% CI [2.39-16.36], p<0.001). Among 87/105 patients with available VL at 12 months after switch to second-line ART, virological suppression was achieved in 85%. The median genotypic susceptibility score (GSS) for the second-line regimen was 2.00. Patients with ART adherence ? 95% were more likely to be virologically suppressed (OR=9.33, 95% CI (2.43-35.81), p=0.001). Measures of patient resistance to second-line ART, including the GSS, were not significantly associated with virological outcome.Multi-NRTI RAMs at first-line failure were associated with low CD4 level and longer duration of ART. With many patients switching to highly susceptible regimens, good adherence was still crucial in achieving virological response. This emphasizes the importance of continued adherence counselling well into second-line therapy.

Project description:BackgroundIncreased second-line antiretroviral therapy (ART) failure rate narrows future options for HIV/AIDS treatment. It has critical implications in resource-limited settings; including sub-Saharan Africa (SSA) where the burden of HIV-infection is immense. Hence, pooled estimate for second-line HIV treatment failure is relevant to suggest valid recommendations that optimize ART outcomes in SSA.MethodsWe retrieved literature systematically from PUBMED/MEDLINE, EMBASE, CINAHL, Google Scholar, and AJOL. The retrieved studies were screened and assessed for eligibility. We also assessed the eligible studies for their methodological quality using the Joanna Briggs Institute's appraisal checklist. The pooled estimates for second-line HIV treatment failure and its associated factors were determined using STATA, version 15.0 and MEDCALC, version 18.11.3, respectively. We assessed publication bias using Comprehensive Meta-analysis software, version 3. Detailed study protocol for this review/meta-analysis is registered and found on PROSPERO (ID: CRD42018118959).ResultsA total of 33 studies with the overall 18,550 participants and 19,988.45 person-years (PYs) of follow-up were included in the review. The pooled second-line HIV treatment failure rate was 15.0 per 100 PYs (95% CI: 13.0-18.0). It was slightly higher at 12-18 months of follow-up (19.0/100 PYs; 95% CI: 15.0-22.0), in children (19.0/100 PYs; 95% CI: 14.0-23.0) and in southern SSA (18.0/100 PYs; 95% CI: 14.0-23.0). Baseline values (high viral load (OR: 5.67; 95% CI: 13.40-9.45); advanced clinical stage (OR: 3.27; 95% CI: 2.07-5.19); and low CD4 counts (OR: 2.80; 95% CI: 1.83-4.29)) and suboptimal adherence to therapy (OR: 1.92; 95% CI: 1.28-2.86) were the factors associated with increased failure rates.ConclusionSecond-line HIV treatment failure has become highly prevalent in SSA with alarming rates during the 12-18 month period of treatment start; in children; and southern SSA. Therefore, the second-line HIV treatment approach in SSA should critically consider excellent adherence to therapy, aggressive viral load suppression, and rapid immune recovery.

Dataset Information

HIV Drug Resistance Mutations in Non-B Subtypes After Prolonged Virological Failure on NNRTI-Based First-Line Regimens in Sub-Saharan Africa.

Publications

HIV Drug Resistance Mutations in Non-B Subtypes After Prolonged Virological Failure on NNRTI-Based First-Line Regimens in Sub-Saharan Africa.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets