Immunologic and virologic failure after first-line NNRTI-based antiretroviral therapy in Thai HIV-infected children

<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Methods</p> <p>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.</p> <p>Results</p> <p>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.</p> <p>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.</p> <p>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.</p> <p>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)%.</p> <p>Conclusion</p> <p>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.</p> <p>Trial Registration</p> <p><b>Clinicaltrials.gov identification number </b><a href="http://www.clinicaltrials.gov/ct2/show/NCT00476606">NCT00476606</a></p

Health-related Quality of Life of Thai children with HIV infection: a comparison of the Thai Quality of Life in Children (ThQLC) with the Pediatric Quality of Life Inventory™ version 4.0 (PedsQL™ 4.0) Generic Core Scales

The purpose of this study was to evaluate the reliability and validity of the Thai Quality of Life in Children (ThQLC) and compare it with the Pediatric Quality of Life Inventory (PedsQL™ 4.0) in a sample of children receiving long-term HIV care in Thailand. The ThQLC and the PedsQL™ 4.0 were administered to 292 children with HIV infection aged 8–16 years. Clinical parameters such as the current viral load, CD4 percent, and clinical staging were obtained by medical record review. Three out of five ThQLC scales and three out of four PedsQL™ 4.0 scales had acceptable internal consistency reliability (i.e., Cronbach’s alpha &gt;0.70). Cronbach’s alpha values of each scale ranged from 0.52 to 0.75 and 0.57 to 0.75 for the ThQLC and the PedsQL™ 4.0, respectively. Corresponding scales (physical functioning, emotional well-being, social functioning, and school functioning) of the ThQLC and the PedsQL™ 4.0 correlated substantially with one another (r = 0.47, 0.67, 0.59 and 0.56, respectively). Both ThQLC and PedsQL™ 4.0 overall scores significantly correlated with the child’s self-rated severity of the illness (r = −0.23 for the ThQLC and −0.28 for the PedsQL™ 4.0) and the caregiver’s rated overall quality of life (r = 0.07 for the ThQLC and 0.13 for the PedsQL™ 4.0). The overall score of the ThQLC correlated with clinical and immunologic categories of the United State-Centers for Disease Control and Prevention (US-CDC) classification system (r = −0.12), while the overall score of the PedsQL™ 4.0 significantly correlated with the number of disability days (r = −0.12) and CD4 percent (r = −0.15). However, the overall score from both instruments were not significantly different by clinical stages of HIV disease. A multitrait-multimethod analysis results demonstrated that the average convergent validity and off-diagonal correlations were 0.58 and 0.45, respectively. Discriminant validity was partially supported with 62% of validity diagonal correlations exceeding correlations between different domains (discriminant validity successes). The Hays-Hayashi MTMM quality index was 0.61. Multivariate regression analysis revealed that the ThQLC physical functioning scale provided unique information in predicting child self-rated severity of the illness and overall quality of life beyond that explained by the PedsQL™ 4.0 in Thai children with HIV infection. We found evidence in support of the reliability and validity of the ThQLC and the PedsQL™ 4.0 for measuring the health-related quality of life of Thai children with HIV infection

The impact of HIV and antiretroviral therapy on TB risk in children: a systematic review and meta-analysis.

BACKGROUND: Children (<15 years) are vulnerable to TB disease following infection, but no systematic review or meta-analysis has quantified the effects of HIV-related immunosuppression or antiretroviral therapy (ART) on their TB incidence. OBJECTIVES: Determine the impact of HIV infection and ART on risk of incident TB disease in children. METHODS: We searched MEDLINE and Embase for studies measuring HIV prevalence in paediatric TB cases ('TB cohorts') and paediatric HIV cohorts reporting TB incidence ('HIV cohorts'). Study quality was assessed using the Newcastle-Ottawa tool. TB cohorts with controls were meta-analysed to determine the incidence rate ratio (IRR) for TB given HIV. HIV cohort data were meta-analysed to estimate the trend in log-IRR versus CD4%, relative incidence by immunological stage and ART-associated protection from TB. RESULTS: 42 TB cohorts and 22 HIV cohorts were included. In the eight TB cohorts with controls, the IRR for TB was 7.9 (95% CI 4.5 to 13.7). HIV-infected children exhibited a reduction in IRR of 0.94 (95% credible interval: 0.83-1.07) per percentage point increase in CD4%. TB incidence was 5.0 (95% CI 4.0 to 6.0) times higher in children with severe compared with non-significant immunosuppression. TB incidence was lower in HIV-infected children on ART (HR: 0.30; 95% CI 0.21 to 0.39). Following initiation of ART, TB incidence declined rapidly over 12 months towards a HR of 0.10 (95% CI 0.04 to 0.25). CONCLUSIONS: HIV is a potent risk factor for paediatric TB, and ART is strongly protective. In HIV-infected children, early diagnosis and ART initiation reduces TB risk. TRIAL REGISTRATION NUMBER: CRD42014014276

Tuberculosis in Pediatric Antiretroviral Therapy Programs in Low- and Middle-Income Countries: Diagnosis and Screening Practices

Background The global burden of childhood tuberculosis (TB) is estimated to be 0.5 million new cases per year. Human immunodeficiency virus (HIV)-infected children are at high risk for TB. Diagnosis of TB in HIV-infected children remains a major challenge. Methods We describe TB diagnosis and screening practices of pediatric antiretroviral treatment (ART) programs in Africa, Asia, the Caribbean, and Central and South America. We used web-based questionnaires to collect data on ART programs and patients seen from March to July 2012. Forty-three ART programs treating children in 23 countries participated in the study. Results Sputum microscopy and chest Radiograph were available at all programs, mycobacterial culture in 40 (93%) sites, gastric aspiration in 27 (63%), induced sputum in 23 (54%), and Xpert MTB/RIF in 16 (37%) sites. Screening practices to exclude active TB before starting ART included contact history in 41 sites (84%), symptom screening in 38 (88%), and chest Radiograph in 34 sites (79%). The use of diagnostic tools was examined among 146 children diagnosed with TB during the study period. Chest Radiograph was used in 125 (86%) children, sputum microscopy in 76 (52%), induced sputum microscopy in 38 (26%), gastric aspirate microscopy in 35 (24%), culture in 25 (17%), and Xpert MTB/RIF in 11 (8%) children. Conclusions Induced sputum and Xpert MTB/RIF were infrequently available to diagnose childhood TB, and screening was largely based on symptom identification. There is an urgent need to improve the capacity of ART programs in low- and middle-income countries to exclude and diagnose TB in HIV-infected childre

Neurocognition and quality of life after reinitiating antiretroviral therapy in children randomized to planned treatment interruption

Objective: Understanding the effects of antiretroviral treatment (ART) interruption on neurocognition and quality of life (QoL) are important for managing unplanned interruptions and planned interruptions in HIV cure research. Design: Children previously randomized to continuous (continuous ART, n=41) vs. planned treatment interruption (PTI, n=47) in the Pediatric European Network for Treatment of AIDS (PENTA) 11 study were enrolled. At study end, PTI children resumed ART. At 1 and 2 years following study end, children were assessed by the coding, symbol search and digit span subtests of Wechsler Intelligence Scale for Children (6-16 years old) or Wechsler Adult Intelligence Scale ( 6517 years old) and by Pediatrics QoL questionnaires for physical and psychological QoL. Transformed scaled scores for neurocognition and mean standardized scores for QoL were compared between arms by t-test and Mann-Whitney U test, respectively. Scores indicating clinical concern were compared (&lt;7 for neurocognition and &lt;70 for QoL tests). Results: Characteristics were similar between arms with a median age of 12.6 years, CD4 + of 830 cells/\u3bcl and HIV RNA of 1.7 log 10 copies/ml. The median cumulative ART exposure was 9.6 in continuous ART vs. 7.7 years in PTI (P=0.02). PTI children had a median of 12 months off ART and had resumed ART for 25.2 months at time of first assessment. Neurocognitive scores were similar between arms for all tests. Physical and psychological QoL scores were no different. About 40% had low neurocognitive and QoL scores indicating clinical concern. Conclusion: No differences in information processing speed, sustained attention, short-term memory and QoL functioning were observed between children previously randomized to continuous ART vs. PTI in the PENTA 11 trial

Pharmacokinetics of nevirapine in HIV-infected children under 3 years on rifampicin-based antituberculosis treatment.

Item does not contain fulltextOBJECTIVE:: There is an urgent need to optimize cotreatment for children with tuberculosis and HIV infection. We described nevirapine pharmacokinetics in Zambian children aged less than 3 years, cotreated with nevirapine, lamivudine and stavudine in fixed-dose combination (using WHO weight bands) and rifampicin-based antituberculosis treatment. DESIGN:: Twenty-two children received antituberculosis and antiretroviral therapy (ART) concurrently for 4 weeks before pharmacokinetic sampling. Plasma nevirapine concentrations were determined in samples taken immediately before, and 1, 2 and 6 h after an observed dose. Nevirapine pharmacokinetics were compared with those in 16 children aged less than 3 years without tuberculosis. RESULTS:: Twenty-two children were treated for HIV/TB coinfection, 10 of whom were girls. One boy was excluded from analysis for nonadherence. The median age was 1.6 years (range: 0.7-3.2). Median weight was 8.0 kg (range: 5.1-10.5). The baseline CD4% was 13.1 (range: 3.9-43.6). Median predose concentration of nevirapine was 2.93 mg/l (range: 1.06-11.4), and peak concentration was 6.33 mg/l (range: 2.61-14.5). The nevirapine AUC up to 12 h was estimated as 52.0 mg.h/l (range: 22.6-159.7) compared with 90.9 mg.h/l (range: 40.4-232.1) in children without tuberculosis (P < 0.001). Predose concentrations of nevirapine were less than 3.0 mg/l in 11 children on tuberculosis treatment versus none of the 16 children without tuberculosis treatment (P = 0.001). AUC was 41% (95% CI: 23-54%) lower in children with tuberculosis than without tuberculosis (P < 0.001) after adjusting for dose per square meter. CONCLUSION:: We found substantial reductions in nevirapine concentrations in young children receiving rifampicin. Further studies are needed to define the pharmacokinetics, safety and efficacy of adjusted doses of nevirapine-based ART in young children with tuberculosis

Defining a Cutoff for Atazanavir in Hair Samples Associated With Virological Failure Among Adolescents Failing Second-Line Antiretroviral Treatment

BackgroundAdequate antiretroviral exposure is crucial to virological suppression. We assessed the relationship between atazanavir hair levels with self-reported adherence, virological outcomes, and the effect of a home-based adherence intervention in HIV-infected adolescents failing second-line antiretroviral treatment in Zimbabwe.MethodsHIV-infected adolescents on atazanavir/ritonavir-based second-line treatment for ≥6 months with viral load (VL) &gt;1000 copies/mL were randomized to either standard care (control) or standard care plus modified directly administered antiretroviral therapy (intervention). Questionnaires were administered; VL and hair samples were collected at baseline and after 90 days in each group. Viral suppression was defined as &lt;1000 copies/mL after follow-up.ResultsFifty adolescents (10-18 years) were enrolled; 23 (46%) were randomized to intervention and 27 (54%) to control. Atazanavir hair concentration &lt;2.35 ng/mg (lower interquartile range for those with virological suppression) defined a cutoff below which most participants experienced virological failure. Male sex (P = 0.03), virological suppression at follow-up (P = 0.013), greater reduction in VL (P = 0.006), and change in average self-reported adherence over the previous month (P = 0.031) were associated with adequate (&gt;2.35 ng/mg) hair concentrations. Participants with virological failure were more likely to have suboptimal atazanavir hair concentrations (RR = 7.2, 95% CI: 1 to 51, P = 0.049). There were no differences in atazanavir hair concentration between the arms after follow-up.ConclusionsA threshold of atazanavir concentrations in hair (2.35 ng/mg), above which virological suppression was likely, was defined for adolescents failing second-line atazanavir/ritonavir-based ART in Zimbabwe. Male sex and better self-reported adherence were associated with adequate atazanavir hair concentrations. Antiretroviral hair concentrations may serve as a useful clinical tool among adolescents