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Single Genome Analysis for the Detection of Linked Multiclass Drug Resistance Mutations in HIV-1-Infected Children After Failure of Protease Inhibitor-Based First-Line Therapy.

ABSTRACT: The WHO recommends protease inhibitor (PI)-based antiretroviral therapy (ART) for vertically infected children after failed nevirapine (NVP) prophylaxis. Emergence of PI resistance on the backdrop of preexisting non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance could compromise long-term treatment options in such children. We characterized multiclass drug resistance using single genome sequencing (SGS) in children with viremia while receiving PI-based ART. We applied SGS of HIV-1 protease (PR) and reverse transcriptase to longitudinal samples from a cohort of the Children with HIV Early Antiretroviral Therapy trial with viral loads >1000 copies per milliliter after 40 weeks of early ART. Bulk sequencing revealed NVP-selected resistance in 50% of these children, whereas SGS revealed NVP-selected resistance in 70%. Two children had baseline NRTI and PI mutations, suggesting previous maternal ART. Linked multiclass drug resistance after PI-based ART was detected by SGS in 2 of 10 children. In one child, the majority species contained M184V in reverse transcriptase linked to L10F, M46I/L, I54V, and V82A in PR and a triple-class drug-resistant variant with these mutations linked to the NNRTI mutation V108I. In the second child, the majority species contained M184V and V82A linked within viral genomes. We conclude that when PI-based ART is initiated soon after birth after single dose-NVP prophylaxis, PI and NRTI resistance can occur in the majority species as expected and also be selected on the same genomes as preexisting NNRTI-resistant mutations. These observations highlight a future therapeutic challenge for vertically infected children where antiretroviral drug classes are limited.

SUBMITTER: Lange CM

PROVIDER: S-EPMC4679142 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Single Genome Analysis for the Detection of Linked Multiclass Drug Resistance Mutations in HIV-1-Infected Children After Failure of Protease Inhibitor-Based First-Line Therapy.

Lange Camille Marie CM Hué Stéphane S Violari Avy A Cotton Mark M Gibb Diana D Babiker Abdel A Otwombe Kennedy K Panchia Ravindre R Dobbels Els E Jean-Philippe Patrick P McIntyre James A JA Pillay Deenan D Gupta Ravindra Kumar RK

Journal of acquired immune deficiency syndromes (1999) 20150601 2

The WHO recommends protease inhibitor (PI)-based antiretroviral therapy (ART) for vertically infected children after failed nevirapine (NVP) prophylaxis. Emergence of PI resistance on the backdrop of preexisting non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance could compromise long-term treatment options in such children. We characterized multiclass drug resistance using single genome sequencing (SGS) in children with viremia while receiving PI-based ART. We applied SGS of HIV-1 ...[more]

PMID: 25923117

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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:Due to the limited availability of viral load testing for treatment outcome monitoring in resource limited settings, identifying predictive factors of antiretroviral treatment failure will help in selecting clients who will benefit most from the targeted use of viral load monitoring. Little is known about the predictors of treatment failure in the study area. This study was conducted to determine factors that predict first-line antiretroviral therapy failure among HIV-infected adult clients at Woldia Hospital, Northeast Ethiopia. For this study, antiretroviral therapy treatment failure was defined as the fulfillment of clinical and/or immunological criteria set by WHO.Case-control study was carried out from November to December 2014. Cases were adult clients who were on failing first line regimen and on active follow up while controls were those adult clients on a non-failing first-line regimen for 36 months and above and on active follow up. Data was entered in to Epi Info version 7 and was exported to SPSS version 20 for analysis. Binary logistic regression model was used to identify predictors of ART failure.A total of 59 cases and 245 controls were included in the analysis. Sixty three percent of the participants were females and the median age at ART enrollment was 33 years (IQR; 28, 40). The median baseline CD4count was not significantly different among cases and controls (105 (IQR = 60-174)vs.131 (IQR = 72.5-189.0); p = 0.301). The median peak CD4 count in the failure group (230 (IQR = 123-387)) was significantly low compared to the non-failure group (463 (IQR = 348.5-577)) [p < 0.001]. High peak CD4count (AOR = 0.993; 95% CI 0.990, 0.996) and longer duration on ART (AOR = 0.923; 95% CI 0.893, 0.954) were protective of treatment failure. In addition stavudine based regimen (AOR = 3.47; 95% CI 1.343, 10.555), low baseline BMI (AOR = 2.75; 95% CI 1.012, 7.457), unemployment (AOR = 4.93; 95% CI 1.493, 16.305) and formal educational level (AOR = 5.15; 95% CI 1.534, 17.276) were independently significant predictors of treatment failure.In this setting low peak CD4count, shorter duration on first line ART, d4T based regimen, low baseline BMI, unemployment and formal educational level were significantly associated with increased treatment failure. Retaining patients on their initial first line regimen with appropriate follow up and improving their socioeconomic status through various livelihood initiatives should be strengthened.

Project description:Background:Assessment of virological outcomes among HIV-infected patients receiving protease (PR) inhibitor-based second-line regimen are uncommon in Cambodia. The objective of this study is to assess the virological effectiveness of this regimen as well as impact of adherence boosting for patients experiencing virological failure. Methods:The 2PICAM study (Clinicaltrial: NCT01801618) is a cross-sectional study of HIV-infected adults on PR inhibitor-based second-line regimen since at least 6?months, conducted in 13 representative sites, comprising more than 90% of the target population. Adults with HIV RNA above 250?copies/mL (threshold of the assay) at inclusion received boosted adherence counseling during 3?months followed by HIV RNA control. For confirmed virological failure, genotype resistance test was performed and expert committee used results for therapeutic decision. Results:Among the 1,317 adults enrolled, the median duration of second-line regimen was 5?years. At inclusion, 1,182 (89.7%) patients achieved virological success (<250?copies/mL) and 135 (10.3%) experienced a virological failure (>250?copies/mL). In multivariable analysis, factors associated with virological success were: CD4 cell count between 201 and 350/mm3 (OR: 4.66, 95% CI: 2.57-8.47, p?<?0.0001) and >350/mm3 (OR: 6.67, 95% CI: 4.02-11.06, p?<?0.0001), duration of PI-based regimen >2?years (OR: 1.64, 95% CI: 1.03-2.62, p?=?0.037), ATV-containing regimen (0R: 1.65, 95% CI: 1.04-2.63, p?=?0.034) and high level of adherence (OR: 2.41, 95% CI: 1.07-5.41, p?=?0.033). After adherence counseling, 63 (46.7%) patients were rescued while 72 (53.3%) were not. For the 54 patients with genotype resistance tests available, high or intermediate levels of resistance to lopinavir, atazanavir, and darunavir were reported for 13 (24%), 12 (22.2%), and 2 (3.7%) patients, respectively. Change to an alternative PR inhibitor-based regimen was recommended for 17 patients and to third-line regimen, including integrase inhibitors for 12. Conclusion:This study reports high rate of virological suppression of second-line regimen and importance of adherence boosting prior to deciding any change of ART regimen. Genotype resistance tests appear necessary to guide decisions. Such information was of great importance for National HIV Program to adapt guidelines and program needs for third-line regimen.

Project description:BackgroundWhile dolutegravir has been added by WHO as a preferred second-line option for the treatment of HIV infection, boosted protease inhibitor (bPI)-based regimens are still needed as alternative second-line options. Identifying optimal bPI-based second-line combinations is essential, given associated high costs and funding constraints in low- and middle-income countries. We assessed the cost-effectiveness of three alternative bPI-based second-line regimens in Burkina Faso, Cameroon and Senegal.MethodsWe used data collected over 2010-2015 in the 2LADY trial/post-trial cohort. Patients with first-line antiretroviral therapy (ART) failure were randomly assigned to tenofovir/emtricitabine + lopinavir/ritonavir (TDF/FTC LPV/r; arm A), abacavir + didanosine + lopinavir/ritonavir (arm B), or tenofovir/emtricitabine + darunavir/ritonavir (arm C). Costs (US dollars, 2016), quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios were computed for each country over 24 months of follow-up and extrapolated to 5 years using a simulated patient-level Markov model. We assessed uncertainty using cost-effectiveness acceptability curves, scenarios and prices threshold analysis.ResultsIn each country, over 24 months, arm A was significantly less costly than arms B and C (incremental costs ranging from US$410-$US721 and US$468-US$546 for B and C vs A, respectively) and offered similar health benefits (incremental QALY: - 0.138 to 0.023 and - 0.179 to 0.028, respectively). Over 5 years, arm A remained the least costly, health benefits not being significantly different between arms. Compared with arms B and C, in each study country, Arm A had a ≥ 95% probability of being cost-effective for a large range of cost-effectiveness thresholds, irrespective of the scenario considered.ConclusionsUsing TDF/FTC LPV/r as a bPI-based second-line regimen provided the best economic value in the three study countries.Trial registrationClinicalTrials.gov Identifier: NCT00928187.

Project description:ObjectivesRates of first-line treatment failure and switches to second-line therapy are key indicators for national HIV programmes. We assessed immunological treatment failure defined by WHO criteria in the Tanzanian national HIV programme.MethodsWe included adults initiating first-line therapy in 2004-2011 with a pre-treatment CD4 count, and ?6-months of follow-up. We assessed subhazard ratios (SHR) for immunological treatment failure, and subsequent switch to second-line therapy, using competing risks methods to account for deaths.ResultsOf 121 308 adults, 7% experienced immunological treatment failure, and 2% died without observed immunological treatment failure, over a median 1.7 years. The 6-year cumulative probability of immunological treatment failure was 19.0% (95% CI 18.5, 19.7) and of death, 5.1% (4.8, 5.4). Immunological treatment failure predictors included earlier year of treatment initiation (P < 0.001), initiation in lower level facilities (SHR = 2.23 [2.03, 2.45] for dispensaries vs. hospitals), being male (1.27 [1.19, 1.33]) and initiation at low or high CD4 counts (for example, 1.78 [1.65, 1.92] and 5.33 [4.65, 6.10] for <50 and ?500 vs. 200-349 cells/mm(3) , respectively). Of 7382 participants in the time-to-switch analysis, 6% switched and 5% died before switching. Four years after immunological treatment failure, the cumulative probability of switching was 7.3% (6.6, 8.0) and of death, 6.8% (6.0, 7.6). Those who immunologically failed in dispensaries, health centres and government facilities were least likely to switch.ConclusionsImmunological treatment failure rates and unmet need for second-line therapy are high in Tanzania; virological monitoring, at least for persons with immunological treatment failure, is required to minimise unnecessary switches to second-line therapy. Lower level government health facilities need more support to reduce treatment failure rates and improve second-line therapy uptake to sustain the benefits of increased coverage.

Dataset Information

Single Genome Analysis for the Detection of Linked Multiclass Drug Resistance Mutations in HIV-1-Infected Children After Failure of Protease Inhibitor-Based First-Line Therapy.

Publications

Single Genome Analysis for the Detection of Linked Multiclass Drug Resistance Mutations in HIV-1-Infected Children After Failure of Protease Inhibitor-Based First-Line Therapy.

Similar Datasets

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