Dataset Information

Virologic Response to First-line Efavirenz- or Nevirapine-based Antiretroviral Therapy in HIV-infected African Children.

ABSTRACT: BACKGROUND:Poorer virologic response to nevirapine- versus efavirenz-based antiretroviral therapy (ART) has been reported in adult systematic reviews and pediatric studies. METHODS:We compared drug discontinuation and viral load (VL) response in ART-naïve Ugandan/Zimbabwean children ?3 years of age initiating ART with clinician-chosen nevirapine versus efavirenz in the ARROW trial. Predictors of suppression <80, <400 and <1000 copies/mL at 36, 48 and 144 weeks were identified using multivariable logistic regression with backwards elimination (P = 0.1). RESULTS:A total of 445 (53%) children received efavirenz and 391 (47%) nevirapine. Children receiving efavirenz were older (median age, 8.6 vs. 7.5 years nevirapine, P < 0.001) and had higher CD4% (12% vs. 10%, P = 0.05), but similar pre-ART VL (P = 0.17). The initial non-nucleoside-reverse-transcriptase-inhibitor (NNRTI) was permanently discontinued for adverse events in 7 of 445 (2%) children initiating efavirenz versus 9 of 391 (2%) initiating nevirapine (P = 0.46); at switch to second line in 17 versus 23, for tuberculosis in 0 versus 26, for pregnancy in 6 versus 0 and for other reasons in 15 versus 5. Early (36-48 weeks) virologic suppression <80 copies/mL was superior with efavirenz, particularly in children with higher pre-ART VL (P = 0.0004); longer-term suppression was superior with nevirapine in older children (P = 0.05). Early suppression was poorer in the youngest and oldest children, regardless of NNRTI (P = 0.02); longer-term suppression was poorer in those with higher pre-ART VL regardless of NNRTI (P = 0.05). Results were broadly similar for <400 and <1000 copies/mL. CONCLUSION:Short-term VL suppression favored efavirenz, but long-term relative performance was age dependent, with better suppression in older children with nevirapine, supporting World Health Organization recommendation that nevirapine remains an alternative NNRTI.

SUBMITTER: Kekitiinwa A

PROVIDER: S-EPMC5533213 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Virologic Response to First-line Efavirenz- or Nevirapine-based Antiretroviral Therapy in HIV-infected African Children.

Kekitiinwa Adeodata A Szubert Alexander J AJ Spyer Moira M Katuramu Richard R Musiime Victor V Mhute Tawanda T Bakeera-Kitaka Sabrina S Senfuma Oscar O Walker Ann Sarah AS Gibb Diana M DM

The Pediatric infectious disease journal 20170601 6

<h4>Background</h4>Poorer virologic response to nevirapine- versus efavirenz-based antiretroviral therapy (ART) has been reported in adult systematic reviews and pediatric studies.<h4>Methods</h4>We compared drug discontinuation and viral load (VL) response in ART-naïve Ugandan/Zimbabwean children ≥3 years of age initiating ART with clinician-chosen nevirapine versus efavirenz in the ARROW trial. Predictors of suppression <80, <400 and <1000 copies/mL at 36, 48 and 144 weeks were identified usin ...[more]

PMID: 28505015

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Project description:WHO recommends starting therapy with a non-nucleoside reverse transcriptase inhibitor (NNRTI) and two nucleoside reverse transcriptase inhibitors (NRTIs), i.e. nevirapine or efavirenz, with lamivudine or emtricitabine, plus zidovudine or tenofovir. Few studies have compared resistance patterns induced by efavirenz and nevirapine in patients infected with the CRF01_AE Southeast Asian HIV-subtype. We compared patterns of NNRTI- and NRTI-associated mutations in Thai adults failing first-line nevirapine- and efavirenz-based combinations, using bayesian statistics to optimize use of data.In a treatment cohort of HIV-infected adults on NNRTI-based regimens, 119 experienced virologic failure (>500 copies/mL), with resistance mutations detected by consensus sequencing. Mutations were analyzed in relation to demographic, clinical, and laboratory variables at time of genotyping. The Geno2Pheno system was used to evaluate second-line drug options. Eighty-nine subjects were on nevirapine and 30 on efavirenz. The NRTI backbone consisted of lamivudine or emtricitabine plus either zidovudine (37), stavudine (65), or tenofovir (19). The K103N mutation was detected in 83% of patients on efavirenz vs. 28% on nevirapine, whereas Y181C was detected in 56% on nevirapine vs. 20% efavirenz. M184V was more common with nevirapine (87%) than efavirenz (63%). Nevirapine favored TAM-2 resistance pathways whereas efavirenz selected both TAM-2 and TAM-1 pathways. Emergence of TAM-2 mutations increased with the duration of virologic replication (OR 1.25-1.87 per month increment). In zidovudine-containing regimens, the overall risk of resistance across all drugs was lower with nevirapine than with efavirenz, whereas in tenofovir-containing regimen the opposite was true.TAM-2 was the major NRTI resistance pathway for CRF01_AE, particularly with nevirapine; it appeared late after virological failure. In patients who failed, there appeared to be more second-line drug options when zidovudine was combined with nevirapine or tenofovir with efavirenz than with alternative combinations.

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:ImportanceAdvantages of using efavirenz as part of treatment for children infected with human immunodeficiency virus (HIV) include once-daily dosing, simplification of co-treatment for tuberculosis, preservation of ritonavir-boosted lopinavir for second-line treatment, and harmonization of adult and pediatric treatment regimens. However, there have been concerns about possible reduced viral efficacy of efavirenz in children exposed to nevirapine for prevention of mother-to-child transmission.ObjectiveTo evaluate whether nevirapine-exposed children achieving initial viral suppression with ritonavir-boosted lopinavir-based therapy can transition to efavirenz-based therapy without risk of viral failure.Design, setting, and participantsRandomized, open-label noninferiority trial conducted at Rahima Moosa Mother and Child Hospital, Johannesburg, South Africa, from June 2010 to December 2013, enrolling 300 HIV-infected children exposed to nevirapine for prevention of mother-to-child transmission who were aged 3 years or older and had plasma HIV RNA of less than 50 copies/mL during ritonavir-boosted lopinavir-based therapy; 298 were randomized and 292 (98%) were followed up to 48 weeks after randomization.InterventionsParticipants were randomly assigned to switch to efavirenz-based therapy (n = 150) or continue ritonavir-boosted lopinavir-based therapy (n = 148).Main outcomes and measuresRisk difference between groups in (1) viral rebound (ie, ≥1 HIV RNA measurement of >50 copies/mL) and (2) viral failure (ie, confirmed HIV RNA >1000 copies/mL) with a noninferiority bound of -0.10. Immunologic and clinical responses were secondary end points.ResultsThe Kaplan-Meier probability of viral rebound by 48 weeks was 0.176 (n = 26) in the efavirenz group and 0.284 (n = 42) in the ritonavir-boosted lopinavir group. Probabilities of viral failure were 0.027 (n = 4) in the efavirenz group and 0.020 (n = 3) in the ritonavir-boosted lopinavir group. The risk difference for viral rebound was 0.107 (1-sided 95% CI, 0.028 to ∞) and for viral failure was -0.007 (1-sided 95% CI, -0.036 to ∞). We rejected the null hypothesis that efavirenz is inferior to ritonavir-boosted lopinavir (P < .001) for both end points. By 48 weeks, CD4 cell percentage was 2.88% (95% CI, 1.26%-4.49%) higher in the efavirenz group than in the ritonavir-boosted lopinavir group.Conclusions and relevanceAmong HIV-infected children exposed to nevirapine for prevention of mother-to-child transmission and with initial viral suppression with ritonavir-boosted lopinavir-based therapy, switching to efavirenz-based therapy compared with continuing ritonavir-boosted lopinavir-based therapy did not result in significantly higher rates of viral rebound or viral failure. This therapeutic approach may offer advantages in children such as these.Trial registrationclinicaltrials.gov Identifier: NCT01146873.

Project description:ImportanceWorldwide, the nonnucleoside reverse transcriptase inhibitors (NNRTIs) efavirenz and nevirapine are commonly used in first-line antiretroviral regimens in both adults and children with human immunodeficiency virus (HIV) infection. Data on the comparative effectiveness of these medications in children are limited.ObjectiveTo investigate whether virological failure is more likely among children who initiated 1 or the other NNRTI-based HIV treatment.Design, setting, and participantsRetrospective cohort study of children (aged 3-16 years) who initiated efavirenz-based (n = 421) or nevirapine-based (n = 383) treatment between April 2002 and January 2011 at a large pediatric HIV care setting in Botswana.Main outcomes and measuresThe primary outcome was time from initiation of therapy to virological failure. Virological failure was defined as lack of plasma HIV RNA suppression to less than 400 copies/mL by 6 months or confirmed HIV RNA of 400 copies/mL or greater after suppression. Cox proportional hazards regression analysis compared time to virological failure by regimen. Multivariable Cox regression controlled for age, sex, baseline immunologic category, baseline clinical category, baseline viral load, nutritional status, NRTIs used, receipt of single-dose nevirapine, and treatment for tuberculosis.ResultsWith a median follow-up time of 69 months (range, 6-112 months; interquartile range, 23-87 months), 57 children (13.5%; 95% CI, 10.4%-17.2%) initiating treatment with efavirenz and 101 children (26.4%; 95% CI, 22.0%-31.1%) initiating treatment with nevirapine had virological failure. There were 11 children (2.6%; 95% CI, 1.3%-4.6%) receiving efavirenz and 20 children (5.2%; 95% CI, 3.2%-7.9%) receiving nevirapine who never achieved virological suppression. The Cox proportional hazard ratio for the combined virological failure end point was 2.0 (95% CI, 1.4-2.7; log rank P < .001, favoring efavirenz). None of the measured covariates affected the estimated hazard ratio in the multivariable analyses.Conclusions and relevanceAmong children aged 3 to 16 years infected with HIV and treated at a clinic in Botswana, the use of efavirenz compared with nevirapine as initial antiretroviral treatment was associated with less virological failure. These findings may warrant additional research evaluating the use of efavirenz and nevirapine for pediatric patients.

Project description:BackgroundThe International Maternal, Pediatric, and Adolescent Clinical Trials P1060 trial demonstrated superior outcomes for HIV-infected children less than 3 years old initiating antiretroviral therapy (ART) with lopinavir/ritonavir compared to nevirapine, but lopinavir/ritonavir is four-fold costlier.Design/methodsWe used the Cost-Effectiveness of Preventing AIDS Complications (CEPAC)-Pediatric model, with published and P1060 data, to project outcomes under three strategies: no ART; first-line nevirapine (with second-line lopinavir/ritonavir); and first-line lopinavir/ritonavir (second-line nevirapine). The base-case examined South African children initiating ART at age 12 months; sensitivity analyses varied all key model parameters. Outcomes included life expectancy, lifetime costs, and incremental cost-effectiveness ratios [ICERs; dollars/year of life saved ($/YLS)]. We considered interventions with ICERs less than 1× per-capita gross domestic product (South Africa: $7500)/YLS as 'very cost-effective,' interventions with ICERs below 3× gross domestic product/YLS as 'cost-effective,' and interventions leading to longer life expectancy and lower lifetime costs as 'cost-saving'.ResultsProjected life expectancy was 2.8 years with no ART. Both ART regimens markedly improved life expectancy and were very cost-effective, compared to no ART. First-line lopinavir/ritonavir led to longer life expectancy (28.8 years) and lower lifetime costs ($41 350/person, from lower second-line costs) than first-line nevirapine (27.6 years, $44 030). First-line lopinavir/ritonavir remained cost-saving or very cost-effective compared to first-line nevirapine unless: liquid lopinavir/ritonavir led to two-fold higher virologic failure rates or 15-fold greater costs than in the base-case, or second-line ART following first-line lopinavir/ritonavir was very ineffective.ConclusionsOn the basis of P1060 data, first-line lopinavir/ritonavir leads to longer life expectancy and is cost-saving or very cost-effective compared to first-line nevirapine. This supports WHO guidelines, but increasing access to pediatric ART is critical regardless of the regimen used.

Project description:BackgroundContemporary data on the immunologic, haematologic and virologic responses and predictors of virologic failure after initiation of free antiretroviral treatment in Cameroon are needed to evaluate the current treatment-monitoring algorithm and to complement efforts to scale-up and improve on the management of HIV infections.MethodsThis was a cross-sectional study conducted between October 2010 and June 2012. A total of 951 participants aged 18-74 years were recruited from selected approved HIV treatment centres of the Northwest and Southwest regions. This comprised 247 males and 704 females. Demographic, self-reported risk behaviours and socioeconomic data were obtained using a structured questionnaire. Full blood and CD4 + T-cell counts were done using standard automated techniques. Determination of viral load (VL) was done using Abbott RealTime HIV-1 m2000™ system. Data was analysed using SPSS version 17. The statistical significance level was P < 0.05.ResultsThe median duration of antiretroviral therapy (ART) was 24 months. The population mean CD4 + T-cell count was 255.3 cells/μL [95% CI, 236.8 - 273.9]. Overall, 45.9%, 43.8% and 10.2% of the participants had CD4 + T-cell counts of < 200 cells/μL, 200-499 cells/μL and > 500 cells/μL respectively. Anaemia was present in 26.2% of the participants with 62.3%, 25.7% and 12% described as mild, moderate and severe anaemia respectively. Virologic failure occurred in 23.2% of the participants with 12.3% having VL > 10,000 RNA copies/mL. Meanwhile 76.8% of patients attained adequate viral suppression with 40.8% having undetectable viral load. The age group 18-29 years (p = 0.024), co-infection with tuberculosis (p = 0.014), anaemia (p = 0.028) and distance from the treatment centre (p = 0.011) independently predicted virologic failure.ConclusionThe majority of the participants achieved adequate viral suppression after ≥ 6 months of ART. Despite these favourable immuno-haematologic and virologic outcomes, the National AIDS Control Program should step-up efforts to improve on antiretroviral drug distribution, as well as proper assessment and management of anaemia, foster early diagnosis and treatment of tuberculosis and enhance treatment adherence counselling especially in younger patients.

Dataset Information

Virologic Response to First-line Efavirenz- or Nevirapine-based Antiretroviral Therapy in HIV-infected African Children.

Publications

Virologic Response to First-line Efavirenz- or Nevirapine-based Antiretroviral Therapy in HIV-infected African Children.

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