Universal antiretroviral therapy for HIV-infected children: a review of the benefits and risks to consider during implementation.
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ABSTRACT:
SUBMITTER: Barlow-Mosha L
PROVIDER: S-EPMC5527851 | biostudies-other | 2017 Jun
REPOSITORIES: biostudies-other
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Project description:BACKGROUND:Randomized-trial data on the risks and benefits of antiretroviral therapy (ART) as compared with zidovudine and single-dose nevirapine to prevent transmission of the human immunodeficiency virus (HIV) in HIV-infected pregnant women with high CD4 counts are lacking. METHODS:We randomly assigned HIV-infected women at 14 or more weeks of gestation with CD4 counts of at least 350 cells per cubic millimeter to zidovudine and single-dose nevirapine plus a 1-to-2-week postpartum "tail" of tenofovir and emtricitabine (zidovudine alone); zidovudine, lamivudine, and lopinavir-ritonavir (zidovudine-based ART); or tenofovir, emtricitabine, and lopinavir-ritonavir (tenofovir-based ART). The primary outcomes were HIV transmission at 1 week of age in the infant and maternal and infant safety. RESULTS:The median CD4 count was 530 cells per cubic millimeter among 3490 primarily black African HIV-infected women enrolled at a median of 26 weeks of gestation (interquartile range, 21 to 30). The rate of transmission was significantly lower with ART than with zidovudine alone (0.5% in the combined ART groups vs. 1.8%; difference, -1.3 percentage points; repeated confidence interval, -2.1 to -0.4). However, the rate of maternal grade 2 to 4 adverse events was significantly higher with zidovudine-based ART than with zidovudine alone (21.1% vs. 17.3%, P=0.008), and the rate of grade 2 to 4 abnormal blood chemical values was higher with tenofovir-based ART than with zidovudine alone (2.9% vs. 0.8%, P=0.03). Adverse events did not differ significantly between the ART groups (P>0.99). A birth weight of less than 2500 g was more frequent with zidovudine-based ART than with zidovudine alone (23.0% vs. 12.0%, P<0.001) and was more frequent with tenofovir-based ART than with zidovudine alone (16.9% vs. 8.9%, P=0.004); preterm delivery before 37 weeks was more frequent with zidovudine-based ART than with zidovudine alone (20.5% vs. 13.1%, P<0.001). Tenofovir-based ART was associated with higher rates than zidovudine-based ART of very preterm delivery before 34 weeks (6.0% vs. 2.6%, P=0.04) and early infant death (4.4% vs. 0.6%, P=0.001), but there were no significant differences between tenofovir-based ART and zidovudine alone (P=0.10 and P=0.43). The rate of HIV-free survival was highest among infants whose mothers received zidovudine-based ART. CONCLUSIONS:Antenatal ART resulted in significantly lower rates of early HIV transmission than zidovudine alone but a higher risk of adverse maternal and neonatal outcomes. (Funded by the National Institutes of Health; PROMISE ClinicalTrials.gov numbers, NCT01061151 and NCT01253538 .).
| S-EPMC5214343 | biostudies-literature
Project description:Initiation of antiretroviral therapy (ART) in all HIV-infected adults, regardless of CD4? T-cell count, is a proposed strategy for reducing HIV transmission. We investigated the conditions under which starting ART early could entail more risks than benefits for patients with high CD4? T-cell counts.We used a simulation model to compare ART initiation upon entry to care ('immediate ART') to initiation at CD4? T-cell count ? 350 cells/?l ('WHO 2010 ART') in African adults with CD4? T-cell counts >500 cells/?l. We varied inputs to determine the combination of parameters (population characteristics, conditions of care, treatment outcomes) that would result in higher 15-year mortality with immediate ART.The 15-year mortality was 56.7% for WHO 2010 ART and 51.8% for immediate ART. In one-way sensitivity analysis, lower 15-year mortality was consistently achieved with immediate ART unless the rate of fatal ART toxicity was >1.0/100 person-years, the rate of withdrawal from care was >1.2-fold higher or the rate of ART failure due to poor adherence was >4.3-fold higher on immediate than on WHO 2010 ART. In multi-way sensitivity analysis, immediate ART led to higher mortality when moderate rates of fatal ART toxicity (0.25/100 person-years) were combined with rates of withdrawal from care >1.1-fold higher and rates of treatment failure >2.1-fold higher on immediate than on WHO 2010 ART.In sub-Saharan Africa, ART initiation at entry into care would improve long-term survival of patients with high CD4? T-cell counts, unless it is associated with increased withdrawal from care and decreased adherence. In early ART trials, a focus on retention and adherence will be crucial.
| S-EPMC3893045 | biostudies-literature
Project description:Respiratory disease is a major cause of morbidity and mortality in HIV-infected children. Despite antiretroviral therapy (ART), children suffer chronic symptoms. We investigated symptom prevalence, lung function and exercise capacity among older children established on ART and an age-matched HIV-uninfected group.A cross-sectional study in Zimbabwe of HIV-infected children aged 6-16 years receiving ART for over 6 months and HIV-uninfected children attending primary health clinics from the same area.Standardized questionnaire, spirometry, incremental shuttle walk testing, CD4 cell count, HIV viral load and sputum culture for tuberculosis were performed.A total of 202 HIV-infected and 150 uninfected participants (median age 11.1 years in each group) were recruited. Median age at HIV diagnosis and ART initiation was 5.5 (interquartile range 2.8-7.5) and 6.1 (interquartile range 3.6-8.4) years, respectively. Median CD4 cell count was 726 cells/?l, and 79% had HIV viral load less than 400 copies/ml. Chronic respiratory symptoms were rare in HIV-uninfected children [n?=?1 (0.7%)], but common in HIV-infected participants [51 (25%)], especially cough [30 (15%)] and dyspnoea [30 (15%)]. HIV-infected participants were more commonly previously treated for tuberculosis [76 (38%) vs 1 (0.7%), P?<?0.001], had lower exercise capacity (mean incremental shuttle walk testing distance 771 vs 889?m, respectively, P?<?0.001) and more frequently abnormal spirometry [43 (24.3%) vs 15 (11.5%), P?=?0.003] compared with HIV-uninfected participants. HIV diagnosis at an older age was associated with lung function abnormality (P?=?0.025). No participant tested positive for Mycobacterium tuberculosis.In children, despite ART, HIV is associated with significant respiratory symptoms and functional impairment. Understanding pathogenesis is key, as new treatment strategies are urgently required.
| S-EPMC5106089 | biostudies-other
Project description:BACKGROUND:Recent attention has focused on the question of how quickly antiretroviral therapy (ART) should be started once HIV diagnosis is confirmed. We assessed whether rapid ART initiation improves patient outcomes. METHODS:We searched five databases from inception up to August 2017. Rapid ART initiation was defined as initiation within 14 days of HIV diagnosis. Data were pooled using random effects meta-analysis. RESULTS:Across the randomized trials, ART start on the same day increased viral suppression at 12 months [three trials: relative risk (RR) 1.17, 95% confidence interval (CI) 1.07-1.27], retention in care at 12 months (RR 1.11, 95% CI 0.99-1.26), and the likelihood of starting ART within 90 days (four trials: RR 1.35, 95% CI 1.13-1.62) and 12 months after eligibility was established (three trials: RR 1.17, 95% CI 1.07-1.27). There was a nonsignificant trend toward reduced mortality (three trials: RR 0.53, 95% CI 0.24-1.08), as well as reduced loss to follow-up at 12 months (2 trials: RR 0.66, 95% CI 0.42-1.04). In the observational studies, offering accelerated ART initiation resulted in a greater likelihood of having started ART within 3 months (two studies: RR 1.53, 95% CI 1.11-2.10). There was a trend toward an increased risk of being lost to follow-up at 6 months (three studies: RR 1.85, 95% CI 0.96-3.55). CONCLUSION:Accelerated ART initiation can lead to improved clinical outcomes and is likely to be of particular benefit in those settings where extensive patient preparation prior to starting ART results in long delays. These findings informed a WHO recommendation supporting accelerated ART initiation, including same day ART start.
| S-EPMC5732637 | biostudies-literature
Project description:Balance disorders have been poorly investigated and somewhat neglected in people infected with the human immunodeficiency virus, especially in children, whose have intrinsic and extrinsic risk factors that may compromise the balance. To evaluate the foot plantar pressures and the balance in children with acquired immunodeficiency. We recruited 53 children aged between 6 and 15 years: 33 healthy children, and 20 children with positive serology for the human immunodeficiency virus. A physical examination included anthropometric, reflexes, tactile sensitivity of the foot and orthopedic evaluation. We also collected data of them using Pediatric Equilibrium Scale, baropodometry, and stabilometry. We considered significance level of 0.05 for statistics. Both groups were aged-, sex-matched and similar body mass index and scores of the Pediatric Equilibrium Scale. Three infected children had altered tactile sensitivity, and none had orthopedic or reflex alteration. Infected children had higher mean plantar pressure in the hindfoot than of the control group (p = 0.02). There was higher maximum plantar pressure in the hindfoot of the infected children than of the controls (p = 0.04). Controls had lower maximum plantar pressure in the forefoot than the infected children (p = 0.04). Infected children had larger displacement of the center of pressure (p = 0.006), larger mean velocity of displacement (p = 0.006), and longer duration between successive peaks of displacement than the controls (p = 0.02). Children living with the human immunodeficiency virus discharges great plantar pressures in the hindfoot and to present balance disturbances in the absence of neurological symptomatology.
| S-EPMC6416285 | biostudies-other
Project description:OBJECTIVES:To estimate age at attaining Tanner stages in Ugandan/Zimbabwean HIV-infected children initiating antiretroviral therapy (ART) in older childhood and investigate predictors of delayed puberty, particularly age at ART initiation. DESIGN:Observational analysis within a randomized trial. METHODS:Tanner staging was assessed every 24 weeks from 10 years of age, menarche every 12 weeks and height every 4-6 weeks. Age at attaining different Tanner stages was estimated using normal interval regression, considering predictors using multivariable regression. Growth was estimated using multilevel models with child-specific intercepts and trajectories. RESULTS:Median age at ART initiation was 9.4 years (inter-quartile range 7.8, 11.3) (n?=?582). At the first assessment, the majority (80.2%) were in Tanner stage 1; median follow-up with staging was 2.8 years. There was a strong delaying effect of older age at ART initiation on age at attaining all Tanner stages (P?<?0.05) and menarche (P?=?0.02); in boys the delaying effect generally weakened with older age. There were additional significant delays associated with greater impairments in pre-ART height-for-age Z-score (P?<?0.05) in both sexes and pre-ART BMI-for-age in girls (P?<?0.05). There was no evidence that pre-ART immuno-suppression independently delayed puberty or menarche. However, older children/adolescents had significant growth spurts in intermediate Tanner stages, and were still significantly increasing their height when in Tanner stage 5 (P?<?0.01). CONCLUSION:Delaying ART initiation until older childhood substantially delays pubertal development and menarche, independently of immuno-suppression. This highlights that factors other than CD4, such as pubertal development, need consideration when making decisions about timing of ART initiation in older children.
| S-EPMC4342414 | biostudies-literature
Project description:For HIV-infected children, adherence to antiretroviral therapy (ART) is often assessed by caregiver report but there are few data on their validity. We conducted prospective evaluations with 191 children ages 0-14 years and their caregivers over 6 months in western Kenya to identify questionnaire items that best predicted adherence to ART. Medication Event Monitoring Systems(®) (MEMS, MWV/AARDEX Ltd., Switzerland) electronic dose monitors were used as external criterion for adherence. We employed a novel variable selection tool using the LASSO technique with logistic regression to identify items best correlated with dichotomized MEMS adherence (?90 or <90 % doses taken). Nine of 48 adherence items were identified as the best predictors of adherence, including missed or late doses in the past 7 days, problems giving the child medicines, and caregiver-level factors like not being present at medication taking. These items could be included in adherence assessment tools for pediatric patients.
| S-EPMC4393778 | biostudies-literature
Project description:There have been no paediatric randomised trials describing the effect of planned treatment interruptions (PTIs) of antiretroviral therapy (ART) on adherence, or evaluating acceptability of such a strategy. In PENTA 11, HIV-infected children were randomised to CD4-guided PTIs (n = 53) or continuous therapy (CT, n = 56). Carers, and children if appropriate, completed questionnaires on adherence to ART and acceptability of PTIs. There was no difference in reported adherence on ART between CT and PTI groups; non-adherence (reporting missed doses over the last 3 days or marking <100 % adherence since the last clinical visit on a visual analogue scale) was 18 % (20/111) and 14 % (12/83) on carer questionnaires in the CT and PTI groups respectively (odds ratios, OR (95 % CI) = 1.04 (0.20, 5.41), ?(2) (1) = 0.003, p = 0.96). Carers in Europe/USA reported non-adherence more often (31/121, 26 %) than in Thailand (1/73, 1 %; OR (95 % CI) = 54.65 (3.68, 810.55), ?(2) (1) = 8.45, p = 0.004). The majority of families indicated they were happy to have further PTIs (carer: 23/36, 64 %; children: 8/13, 62 %), however many reported more clinic visits during PTI were a problem (carer: 15/36, 42 %; children: 6/12, 50 %).
| S-EPMC3548111 | biostudies-other
Project description:The objective of this study was to describe lipid profiles and glucose homeostasis in HIV-positive children after initiating or changing antiretroviral therapy and their associations with viral, immune, antiretroviral therapy, and growth factor parameters.Ninety-seven prepubertal HIV-positive children aged 1 month to <13 years were observed for 48 weeks after beginning or changing antiretroviral therapy. Fasting lipid panels, serum glucose, insulin, insulin-like growth factor-1 and binding proteins-1 and -3, plasma viral load, and CD4% were measured. Each child was matched on age, gender, and race/ethnicity to children from the National Health and Nutrition Examination Survey, used to give z scores for each child's lipid values. Multivariate regression was used to evaluate the association of changes in z scores over 48 weeks with suppression of HIV-1 RNA, change in CD4% and growth factors, and antiretroviral therapy, adjusted for entry z score, CD4%, log(10) HIV-1 RNA, Centers for Disease Control and Prevention category, and total fat and cholesterol dietary intake.Lipid, apolipoprotein, and insulin levels all increased significantly by 48 weeks. Multivariate analysis of changes demonstrated that increased HDL and decreased total-HDL cholesterol ratio were associated with CD4% increase and with insulin-like growth factor-1, which increased to normal (versus remained stable or became low) over 48 weeks. Total cholesterol levels increased among children who achieved HIV-1 RNA of <400 copies per mL. Antiretroviral therapy regimens that included both a protease inhibitor and a non-nucleoside reverse transcriptase inhibitor were associated with greater increases in total-HDL cholesterol ratio than regimens that contained a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor but not both.In these HIV-positive children with predominantly mild-to-moderate disease, initiation or change in antiretroviral therapy was associated with significant increases in multiple lipid measures and insulin resistance. Favorable lipid changes were associated with CD4% increases, suggesting a protective effect of immune reconstitution on atherosclerosis, and with increased insulin-like growth factor-1 levels, supporting the theory that reduced growth hormone resistance may be a mechanism by which lipid profiles are improved. Finally, antiretroviral therapy regimens that contain both a non-nucleoside reverse transcriptase inhibitor and a protease inhibitor are associated with worse lipid profiles than regimens that contain 1 but not both of these drug classes.
| S-EPMC2782494 | biostudies-literature
Project description:BackgroundAntiretroviral therapy (ART) has decreased mortality so that increasing numbers of children with HIV are reaching adolescence. However, longstanding HIV infection and/or its treatment in children is associated with noninfectious complications including cardiac disease. We investigated the prevalence, spectrum and risk factors for echocardiographic abnormalities among children established on ART.MethodsHIV-infected children aged 6-16 years, on ART at least 6 months were enrolled into a cross-sectional study from a public-sector paediatric HIV clinic in Harare, Zimbabwe. A standardized examination including transthoracic echocardiography was performed. Local echocardiographic reference ranges were used to define cardiac abnormalities. Logistic regression was used to examine the association between cardiac abnormalities and risk factors.ResultsOf the 201participants recruited, 92 (46%) were girls and median age was 11 (IQR 9-12) years; CD4+ cell count was 727?cells/?l (IQR 473-935) and 154 (78%) had viral load less than 400?copies/ml. Echocardiographic abnormalities were found in 83 (42%); left ventricular (LV) diastolic dysfunction was the most common abnormality 45 (23%) and LV hypertrophy in 22 (11%). LV and left atrial dilatation were found in 9 (5%) and 16 (8%), respectively. Right ventricular dilatation and systolic dysfunction were found in 13 (7%) and 4 (2%), respectively, of whom 60% had concurrent left heart abnormalities. Current use of nevirapine was associated with LVH [aOR 3.14 (1.13-8.72; P?=?0.03)] and hypertension was associated with LV diastolic dysfunction [aOR 3.12 (1.48-6.57; P?<?0.01)].ConclusionHIV-infected children established on ART have a high burden of echocardiographic abnormalities. Right heart disease was predominantly associated with left heart abnormalities and may be part of a global cardiomyopathic process. Further studies are needed to investigate the natural history, aetiology, and pathogenesis of these abnormalities, so that appropriate monitoring and treatment strategies can be developed.
| S-EPMC6250247 | biostudies-literature