Therapy In HIV-infected Children Research Articles

Predictors of treatment failure, time to switch and reasons for switching to second line antiretroviral therapy in HIV infected children receiving first line anti-retroviral therapy at a Tertiary Care Hospital in Ethiopia

BackgroundTreatment failure and delay in switching to second line regimen are major concerns in the treatment of HIV infected children in a resource limited setting. The aim of this study was to determine the prevalence and predictors of first line antiretroviral therapy (ART) regimen failure, reasons and time taken to switch to second line antiretroviral (ARV) medications after treatment failure among HIV-infected children.MethodsA retrospective cohort study was conducted February 2003 to May 2018 in HIV-clinic at Tikur Anbessa Specialized Hospital (TASH), Ethiopia. All HIV infected children ≤15 years of age and who were taking first line ART for at least 6 months were included. Data abstraction format was used to collect the data from patients’ chart and registry. Binary and multivariable logistic regression statistics were used.ResultsOut of 318 enrolled HIV-infected children, the prevalence of treatment failure was found to be 22.6% (72/318), among these 37 (51.4%) had only immunologic failure, 6 (8.3%) had only virologic failure and 24 (33.3%) had both clinical and immunological failure. The mean time taken to modify combination antiretroviral therapy (cART) regimen was 12.67 (4.96) weeks after treatment failure was confirmed. WHO Stage 3 and 4 [Adjusted Odds Ratio (AOR), 3.64, 95% CI 1.76–7.56], not having both parents as primary caretakers [AOR, 2.72 95% CI, 1.05–7.06], negative serology of care takers [AOR, 2.69 95% CI, 1.03–7.03], and cART initiation at 11 month or younger were predicting factors of treatment failure. Of the 141 (47.9%) children who had regimen switching or substitution, treatment failure (44.4%) and replacement of stavudine (d4T) (30.8%) were major reasons. Only 6.6% patients had received PMTCT service.ConclusionOne fifth of the patients had experienced treatment failure. Advanced WHO stage at baseline, not being taken care of by mother and father, negative sero-status caretakers, and younger age at initiation of cART were the predictors of treatment failure. PMTCT service uptake was very low. There was a significant time gap between detection of treatment failure and initiation of second line cART. Half of the patients encountered regimen switching or substitution of cART due to treatment failure and replacement of stavudine (d4T).

IMPROVING ANTIRETROVIRAL THERAPY IN CHILDREN WITH HIV INFECTION

The objective — to characterize the effectiveness of different schemes of antiretroviral therapy in children with HIV infection and on the basis of the obtained data to improve of the disease treatment. Patients and Methods: A clinical, immunological and virological examination of 45 children with HIV infection were carried. Patients received antiretroviral therapy — abacavire and lamivudine in combination with lopinavir/ritonavir (24 patients) or nevirapine (21 children). Results: Using both antiretroviral therapy schemes leads to suppression of HIV replication, improvement of clinical and immunological parameters. However, the treatment with lopinavir/ritonavir revealed a significant positive changes of HIV blood viral load, immune status and clinical picture. Testing of clinical and laboratory parameters prior to treatment in the Cox hazard model showed that the independent predictor of prolonging the effectiveness of therapy is the lopinavir/ritonavir use. As a side effect of lopinavir/ritonavir developed dyspeptic symptoms. Conclusion: High efficiency and safety of lopinavir/ritonavir allow us to recommend the inclusion of this drug in the selection schemes of antiretroviral therapy in HIV infected children.

Antiretroviral Therapy in HIV-Infected Children With Tuberculosis: A Systematic Review.

Tuberculosis (TB) is the major cause of mortality in HIV-infected children globally. Current guidelines about the management of antiretroviral therapy in children with TB are based on a limited number of nonrandomized studies involving small numbers of participants. The aim of the study was to systematically retrieve and critically appraise available evidence on the efficacy and safety of different antiretroviral regimens in children with HIV infection who are receiving treatment for active TB. We conducted a systematic review of the literature according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Records were retrieved through March 2016 from Medline, Embase and manual screening of key conference proceedings. Four specific research questions assessing available treatment options were defined. Although 4 independent searches were conducted (1 for each Population, Intervention, Comparator, Outcomes question), results were elaborated and interpreted together because of significant overlap among the retrieved records. Six observational studies were selected for qualitative synthesis while meta-analysis could not be performed. Evidence for optimal treatment options for HIV/TB coinfected children is limited. As the global community strives to reach the fast-track HIV treatment targets and eliminate childhood TB deaths, it must ensure that coinfected children are included in key treatment studies and expand this neglected but crucial area of research.

Efavirenz-based simplification after successful early lopinavir-boosted-ritonavir-based therapy in HIV-infected children in Burkina Faso and C\xf4te d\u2019Ivoire: the MONOD ANRS 12206 non-inferiority randomised trial

BackgroundThe 2016 World Health Organization guidelines recommend all children <3 years start antiretroviral therapy (ART) on protease inhibitor-based regimens. But lopinavir/ritonavir (LPV/r) syrup has many challenges in low-income countries, including limited availability, requires refrigeration, interactions with anti-tuberculous drugs, twice-daily dosing, poor palatability in young children, and higher cost than non-nucleoside reverse transcriptase inhibitor (NNRTI) drugs. Successfully initiating LPV/r-based ART in HIV-infected children aged <2 years raises operational challenges that could be simplified by switching to a protease inhibitor-sparing therapy based on efavirenz (EFV), although, to date, EFV is not recommended in children <3 years.MethodsThe MONOD ANRS 12026 study is a phase 3 non-inferiority open-label randomised clinical trial conducted in Abidjan, Côte d’Ivoire, and Ouagadougou, Burkina Faso (ClinicalTrial.gov registry: NCT01127204). HIV-1-infected children who were tuberculosis-free and treated before the age of 2 years with 12–15 months of suppressive twice-daily LPV/r-based ART (HIV-1 RNA viral load (VL) <500 copies/mL, confirmed) were randomised to two arms: once-daily combination of abacavir (ABC) + lamivudine (3TC) + EFV (referred to as EFV) versus continuation of the twice-daily combination zidovudine (ZDV) or ABC + 3TC + LPV/r (referred to as LPV). The primary endpoint was the difference in the proportion of children with virological suppression by 12 months post-randomisation between arms (14% non-inferiority bound, Chi-squared test).ResultsBetween May 2011 and January 2013, 156 children (median age 13.7 months) were initiated on ART. After 12–15 months on ART, 106 (68%) were randomised to one of the two treatment arms (54 LPV, 52 EFV); 97 (91%) were aged <3 years. At 12 months post-randomisation, 46 children (85.2%) from LPV versus 43 (82.7%) from EFV showed virological suppression (defined as a VL <500 copies/mL; difference, 2.5%; 95% confidence interval (CI), −11.5 to 16.5), whereas seven (13%) in LPV and seven (13.5%) in EFV were classed as having virological failure (secondary outcome, defined as a VL ≥1000 copies/mL; difference, 0.5%; 95% CI, −13.4 to 12.4). No significant differences in adverse events were observed, with two adverse events in LPV (3.7%) versus four (7.7%) in EFV (p = 0.43). On genotyping, 13 out of 14 children with virological failure (six out of seven EFV, seven out of seven LPV) had a drug-resistance mutation: nine (five out of six EFV, four out of seven LPV) had one or more major NNRTI-resistance mutations whereas none had an LPV/r-resistance mutation.ConclusionsAt the VL threshold of 500 copies/mL, we could not conclusively demonstrate the non-inferiority of EFV on viral suppression compared to LPV because of low statistical power. However, non-inferiority was confirmed for a VL threshold of <1000 copies/mL. Resistance analyses highlighted a high frequency of NNRTI-resistance mutations. A switch to an EFV-based regimen as a simplification strategy around the age of 3 years needs to be closely monitored.Trial registrationClinicalTrial.gov registry n°NCT01127204, 19 May 2010.

Antiretroviral therapy in HIV-infected children.

The pediatric highly-active antiretroviral therapy (HAART) has shown enormous progress in recent years but still, a high percentage of children continue to experience treatment failure. The main causes found responsible are the development of drug resistance, inadequate dosing and poor adherence. This review is aimed at exploring the current status of antiretroviral therapy in children with focus on the interaction between disease, drug and patient behavior, all of which are strongly correlated .An overview of HIV viral characteristics and of the available antiretroviral drug classes currently combined to avoid development of resistance has been also discussed.

Early Antiretroviral Therapy in HIV-Infected Children Is Associated with Diffuse White Matter Structural Abnormality and Corpus Callosum Sparing.

Fractional anisotropy in the frontal white matter, corpus callosum, and internal capsule is abnormal in human immunodeficiency virus-positive (HIV+) adults. We describe the distribution and nature of white matter abnormalities in a cohort of children who started antiretroviral therapy within the first year of life and the benefit of early treatment by using DTI measures (fractional anisotropy and mean, axial, and radial diffusion). DTI was performed on children in a neurodevelopmental substudy from the Children with HIV Early Antiretroviral trial. Voxel-based group comparisons were obtained to determine regions where fractional anisotropy and mean diffusion differed between HIV+ and uninfected children. Associations of DTI parameters with the timing of antiretroviral therapy initiation were examined. Thirty-nine HIV+ children (15 boys; mean age, 5.4 years) and 13 controls (5 boys; mean age, 5.7 years) were scanned. Two clusters with lower fractional anisotropy and 7 clusters with increased mean diffusion were identified in the HIV+ group, with symmetric distribution predominantly due to increased radial diffusion, suggestive of decreased myelination. Corticospinal tracts rather than the corpus callosum were predominantly involved. Children on early-interrupted antiretroviral therapy had lower fractional anisotropy compared with those receiving continuous treatment. HIV+ children at 5 years of age have white matter abnormalities measured by fractional anisotropy, despite early antiretroviral therapy, suggesting that early antiretroviral therapy does not fully protect the white matter from either peripartum or in utero infection. In contrast to adults, the corticospinal tracts are predominantly involved rather than the corpus callosum, possibly due to early antiretroviral therapy. Continuous early antiretroviral therapy can limit white matter damage.

Weekends-off efavirenz-based antiretroviral therapy in HIV-infected children, adolescents, and young adults (BREATHER): a randomised, open-label, non-inferiority, phase 2/3 trial

SummaryBackgroundFor HIV-1-infected young people facing lifelong antiretroviral therapy (ART), short cycle therapy with long-acting drugs offers potential for drug-free weekends, less toxicity, and better quality-of-life. We aimed to compare short cycle therapy (5 days on, 2 days off ART) versus continuous therapy (continuous ART).MethodsIn this open-label, non-inferiority trial (BREATHER), eligible participants were aged 8–24 years, were stable on first-line efavirenz with two nucleoside reverse transcriptase inhibitors, and had HIV-1 RNA viral load less than 50 copies per mL for 12 months or longer. Patients were randomly assigned (1:1) to remain on continuous therapy or change to short cycle therapy according to a computer-generated randomisation list, with permuted blocks of varying size, stratified by age and African versus non-African sites; the list was prepared by the trial statistician and randomisation was done via a web service accessed by site clinician or one of the three coordinating trials units. The primary outcome was the proportion of participants with confirmed viral load 50 copies per mL or higher at any time up to the 48 week assessment, estimated with the Kaplan-Meier method. The trial was powered to exclude a non-inferiority margin of 12%. Analyses were intention to treat. The trial was registered with EudraCT, number 2009-012947-40, ISRCTN, number 97755073, and CTA, number 27505/0005/001-0001.FindingsBetween April 1, 2011, and June 28, 2013, 199 participants from 11 countries worldwide were randomly assigned, 99 to the short cycle therapy and 100 to continuous therapy, and were followed up until the last patient reached 48 weeks. 105 (53%) were men, median age was 14 years (IQR 12–18), and median CD4 cell count was 735 cells per μL (IQR 576–968). Six (6%) patients assigned to the short cycle therapy versus seven (7%) assigned to continuous therapy had confirmed viral load 50 copies per mL or higher (difference −1·2%, 90% CI −7·3 to 4·9, non-inferiority shown). 13 grade 3 or 4 events occurred in the short cycle therapy group and 14 in the continuous therapy group (p=0·89). Two ART-related adverse events (one gynaecomastia and one spontaneous abortion) occurred in the short cycle therapy group compared with 14 (p=0·02) in the continuous therapy group (five lipodystrophy, two gynaecomastia, one suicidal ideation, one dizziness, one headache and syncope, one spontaneous abortion, one neutropenia, and two raised transaminases).InterpretationNon-inferiority of maintaining virological suppression in children, adolescents, and young adults was shown for short cycle therapy versus continous therapy at 48 weeks, with similar resistance and a better safety profile. This short cycle therapy strategy is a viable option for adherent HIV-infected young people who are stable on efavirenz-based ART.FundingUK National Institute for Health Research Health Technology Assessment; UK Medical Research Council; European Commission; PENTA Foundation; INSERM SC10-US19, France.

The global burden of oral diseases in pediatric HIV-infected populations: a workshop report.

To achieve a comprehensive understanding about the global burden of oral diseases in HIV-infected children and to identify research needs. A literature search was conducted in PubMed (2009-2014) to address five questions: (i) prevalence of oral diseases in HIV-infected compared with uninfected children, (ii) impact of oral diseases on quality of life, (iii) effect of antiretroviral exposure in utero on craniofacial and dental development, (iv) important co-infections and antiretroviral complications, and (v) value of atraumatic restorative treatment. Studies showed a high prevalence of dental caries in HIV-infected children but the relationship between HIV infection and dental caries remains unclear. Also quality of life needs further investigation supported by better study designs and improvement of the instruments used. Up-to-date evidence suggested long-term harms associated with in utero antiretroviral exposure were minor but would require long-term follow-up through National Registries. The reviews also revealed the wide spectrum of metabolic disease due to antiretroviral therapy and co-infections such as tuberculosis. Finally, atraumatic restorative technique appears to be a simple and safe technique to treat dental caries but outcomes need further evaluation. The impact of antiretroviral therapy in HIV-infected children has raised novel challenging questions in the field of oral health warranting future research.

Adherence and effectiveness of antiretroviral therapy in HIV infected children

Background: Care for HIV infected individuals has dramatically improved by the use of Highly Active Anti Retroviral Therapy (HAART). Nevertheless virological failure occurs and is often associated with development of drug resistance. Adherence is a major factor determining virological suppression. Significant improvement in nutritional status is seen after initiation of ART. Objectives: To study the adherence and effectiveness of antiretroviral therapy in terms of clinical and immunological parameters in HIV infected children. Methods: A prospective clinical study conducted from April 2007 to April 2008 of all the newly diagnosed HIV positive children aged 2-15 years started on ART after approval from the ethical committee. Results: Adherence was > 95% in 35 cases (89.7%) 80-95% was seen in one case (2.6%) and < 80% in 2 cases (5.1%).The mean weight before ART was 15.54±5.63 kg and after ART was 18.88±5.63 kg p value < 0.001 which is statistically significant. The mean height before ART was 102.38±18.49 cm which increased to 109.22±17.65 cm p value < 0.001 which is statistically significant. The mean CD4 count levels increased from 515.23±79.62 to 1199.65±100.31 after ART with p value < 0.001 which was statistically significant. The mean CD4% increased from 12.56±8.06 to 24.45±5.66 p value < 0.001 which was statistically significant. Conclusion: Adherence to HAART was good HAART improved the average weight and height gain and increase in CD4 counts of HIV infected children thus significantly improving the immunological status and WHO staging.

Simple markers for the detection of severe immunosuppression in children with HIV infection in highly resource-scarce settings: experience from the Democratic Republic of Congo

Objectives:The decision to initiate the antiretroviral therapy in HIV-infected children living in poor countries is compromised by lack of resources. The objective of this study is to identify simple clinical and biological markers other than CD4+ count and viral load measurement that could help the decision to introduce antiretroviral treatment and to monitor patients.Methods:A cross sectional study was conducted between January and March 2005 in Kinshasa, Democratic Republic of Congo.Results:Eighty-four children infected with HIV were recruited. In this cohort, the lymphocytes (P = 0.001) and CD4 (P = 0.0001) were significantly lower in children with immunological stage 3 and viral load (P = 0.027) was significantly higher in children at the same immunological stage. Reticulocytes (r = +0.440), white blood cells count (r = +0.560), total lymphocytes (r = +0.675) and albumin (r = +0.381) showed positive significant correlations with CD4. Haemoglobin (r = − 0.372), Haematocrit (r = − 0.248), red blood cells (r = − 0.278) and CD4 (r = − 0.285) showed negative significant correlations with viral load. Neutropaenia (P = 0.02), enlarged nodes (P = 0.005) and oral candidiasis (P = 0.04) were associated with viral load >10 000 copies/ml. Oral candidiasis (P = 0.02) was associated with CD4 level < 15%.Conclusion:Oral candidiasis, enlarged nodes, total lymphocytes count, neutropaenia and albumin predict severe immunodepression. These clinical and biological markers may guide the clinician in making the decision to initiate antiretroviral therapy in highly resource-scarce settings.

Metabolic and renal adverse effects of antiretroviral therapy in HIV-infected children and adolescents.

Worldwide, the benefits of combined antiretroviral (ARV) therapy in morbidity and mortality due to perinatally acquired human immunodeficiency virus infection are beyond question and outweigh the toxicity these drugs have been associated with in HIV-infected children and adolescents to date. In puberty, abnormal body fat distribution is stigmatizating and leads to low adherence to ARV treatment. The other metabolic comorbidities (mitochondrial toxicity, dyslipidemias, insulin resistance and low bone mineral density) and renal toxicity, albeit nonsymptomatic in most children, are increasingly being reported and potentially put this population at risk for early cardiovascular or cerebrovascular atherosclerotic disease, diabetes, pathologic fractures or premature renal failure in the third and fourth decades of life. Evidence from available studies is limited because of methodological limitations and also because of several HIV-unrelated factors influencing, to some degree, the development of these conditions. Current recommendations for the prevention, diagnosis, monitoring and treatment of metabolic and renal adverse effects in HIV-children and adolescents are based on adult studies, observational pediatric studies and experts' consensus. Healthy lifestyle habits (regarding diet, exercise and refraining from toxic substances) and wise use of ARV options are the only preventive tools for the majority of patients. Should abnormal findings arise, switches in one or more ARV drugs have proved useful. Specific therapies are also available for some of these comorbidities, although the experience in the pediatric age is still very scarce. We aim to summarize the epidemiological, clinical and therapeutic aspects of metabolic and renal adverse effects in vertically HIV-infected children and adolescents.

Once-daily antiretroviral therapy in a cohort of HIV-infected children and adolescents.

We evaluated the evolution over time of once-daily antiretroviral therapy in HIV-infected children and its relationship with adherence. An increase on the prevalence of once-daily antiretroviral therapy was observed over time (from 0.9% in 2002 to 44.2% in 2011). There was no difference in adherence regarding once-daily or BID regimens in 2011. Adherence was related to age and pill burden.

Induction with lopinavir-based treatment followed by switch to nevirapine-based regimen versus non-nucleoside reverse transcriptase inhibitors-based treatment for first line antiretroviral therapy in HIV infected children three years and older.

BackgroundThe World Health Organization recommends non-nucleoside reverse transcriptase inhibitors (NNRTIs)-based antiretroviral therapy (ART) for children three years and older. In younger children, starting ART with lopinavir boosted with ritonavir (LPVr) results in lower risk of virological failure, but data in children three years and older are scarce, and long-term ART with LPVr is problematic in resource-poor settings.MethodologyRetrospective cohort of children three years and older who started triple ART including LPVr or a NNRTI between 2007 and 2013 in a rural setting in India. Children who started LPVr were switched to nevirapine-based ART after virological suppression. We analysed two outcomes, virological suppression (HIV-RNA <400 copies/ml) within one year of ART using logistic regression, and time to virological failure (HIV-RNA >1000 copies/ml) after virological suppression using Cox proportional hazard regression. A sensitivity analysis was performed using inverse probability of treatment weighting (IPTW) based of propensity score methods.FindingsOf 325 children having a viral load during the first year of ART, 74/83 (89.2%) in the LPVr group achieved virological suppression versus 185/242 (76.5%) in the NNRTI group. In a multivariable analysis, the use of LPVr-based ART was associated with higher probability of virological suppression (adjusted odds ratio 3.19, 95% confidence interval [CI] 1.11–9.13). After IPTW, the estimated risk difference was 12.2% (95% CI, 2.9–21.5). In a multivariable analysis including 292 children who had virological suppression and available viral loads after one year of ART, children switched from LPVr to nevirapine did not have significant higher risk of virological failure (adjusted hazard ratio 1.18, 95% CI 0.36–3.81).ConclusionsIn a cohort of HIV infected children three years and older in a resource-limited setting, an LPVr induction- nevirapine maintenance strategy resulted in more initial virological suppression and similar incidence of virological failure after initial virological suppression than NNRTI-based regimens.

Optimisation of antiretroviral therapy in HIV-infected children under 3 years of age.

Optimisation of antiretroviral therapy in HIV-infected children under 3 years of age.

Covariate effects and population pharmacokinetics of lamivudine in HIV‐infected children

Lamivudine is used as first line therapy in HIV-infected children. Yet, like many other paediatric drugs, its dose rationale has been based on limited clinical data, without thorough understanding of the effects of growth on drug disposition. Here we use lamivudine to show how a comprehensive population pharmacokinetic model can account for the influence of demographic covariates on exposure (i.e. AUC and Cmax ). Data from three paediatric trials were used to describe the pharmacokinetics across the overall population. Modelling was based on a non-linear mixed effects approach. A stepwise procedure was used for covariate model building. A one compartment model with first order elimination best described the pharmacokinetics of lamivudine in children. The effect of weight on clearance (CL) and volume of distribution (V) was characterized by an exponential function, with exponents of 0.705 and 0.635, respectively. For a child with median body weight (17.6 kg), CL and V were 16.5 (95% CI 15.2, 17.7) l h⁻¹ and 46.0 (95% CI 42.4, 49.5) l, respectively. There were no differences between formulations (tablet and solution). The predicted AUC(0,12 h) after twice daily doses of 4 mg kg⁻¹ ranged from 4.44 mg l⁻¹ h for children <14 kg to 7.25 mg l⁻¹ h for children >30 kg. The use of meta-analysis is critical to identify the correct covariate-parameter relationships, which must be assessed before a model is applied for predictive purposes (e.g. defining dosing recommendations for children). In contrast to prior modelling efforts, we show that the covariate distribution in the target population must be considered.

Isoniazid preventive therapy for HIV infected children: Impact on incidence of tuberculosis?

Isoniazid preventive therapy for HIV infected children: Impact on incidence of tuberculosis?

Cost-Effectiveness of Early Infant HIV Diagnosis of HIV-Exposed Infants and Immediate Antiretroviral Therapy in HIV-Infected Children under 24 Months in Thailand

BackgroundHIV-infected infants have high risk of death in the first two years of life if untreated. WHO guidelines recommend early infant HIV diagnosis (EID) of all HIV-exposed infants and immediate antiretroviral therapy (ART) in HIV-infected children under 24-months. We assessed the cost-effectiveness of this strategy in HIV-exposed non-breastfed children in Thailand.MethodsA decision analytic model of HIV diagnosis and disease progression compared: EID using DNA PCR with immediate ART (Early-Early); or EID with deferred ART based on immune/clinical criteria (Early-Late); vs. clinical/serology based diagnosis and deferred ART (Reference). The model was populated with survival and cost data from a Thai observational cohort and the literature. Incremental cost-effectiveness ratio per life-year gained (LYG) was compared against the Reference strategy. Costs and outcomes were discounted at 3%.ResultsMean discounted life expectancy of HIV-infected children increased from 13.3 years in the Reference strategy to 14.3 in the Early-Late and 17.8 years in Early-Early strategies. The mean discounted lifetime cost was $17,335, $22,583 and $29,108, respectively. The cost-effectiveness ratio of Early-Late and Early-Early strategies was $5,149 and $2,615 per LYG, respectively as compared to the Reference strategy. The Early-Early strategy was most cost-effective at approximately half the domestic product per capita per LYG ($4,420 in Thailand 2011). The results were robust in deterministic and probabilistic sensitivity analyses including varying perinatal transmission rates.ConclusionIn Thailand, EID and immediate ART would lead to major survival benefits and is cost- effective. These findings strongly support the adoption of WHO recommendations as routine care.

Description of the cascade of care and factors associated with attrition before and after initiating antiretroviral therapy of HIV infected children in a cohort study in India

In low- and middle-income countries, the attrition across the continuum of care of HIV infected children is not well known. The aim of this study was to investigate predictors of mortality and loss to follow up (LTFU) in HIV infected children from a cohort study in India and to describe the cascade of care from HIV diagnosis to virological suppression after antiretroviral therapy (ART) initiation. Multivariable analysis was performed using competing risk regression. The cumulative incidence of attrition due to mortality or LTFU after five year of follow-up was 16% from entry into care to ART initiation and 24.9% after ART initiation. Of all children diagnosed with HIV, it was estimated that 91.9% entered into care, 77.2% were retained until ART initiation, 58% stayed in care after ART initiation, and 43.4% achieved virological suppression on ART. Approximately half of the attrition occurred before ART initiation, and the other half after starting ART. Belonging to socially disadvantaged communities and living >90 min from the hospital were associated with a higher risk of attrition. Being >10 years old and having higher 12-month risk of AIDS (calculated using the absolute CD4 lymphocyte count and the age) were associated with an increased risk of mortality. These findings indicate that we should consider placing more emphasis on promoting research and implementing interventions to improve the engagement of HIV infected children in pre-ART care. The results of this study can be used by HIV programmes to design interventions aimed at reducing the attrition across the continuum of care of HIV infected children in India.

Optimization of antiretroviral therapy in HIV-infected children under 3 years of age: a systematic review.

Treatment of young HIV-infected children is challenging because of rapid disease progression, high viral loads and few drug options. This review was undertaken to update evidence on the management of young HIV-infected children and to inform the development of the 2013 WHO guidelines for antiretroviral therapy (ART) in low and middle-income countries. A systematic review and meta-analysis. We identified and critically assessed randomized controlled trials that evaluated treatment strategies in perinatally HIV-infected infants and young children (aged <3 years). Eight studies were included. Antiretroviral therapy (ART) initiation in asymptomatic infants led to 74% reduction in mortality or disease progression [hazard ratio 0.36, 95% confidence interval (CI) 0.18-0.74, P = 0.0002]. Regardless of previous exposure to prevention of mother to child transmission (PMTCT), treatment failure at 24 weeks was more likely in children starting nevirapine-based than in those starting lopinavir/ritonavir (lopinavir/r)-based ART (hazard ratio 1.79, 95% CI 1.33-2.41, P = 0.0001). Infants starting lopinavir/r-based ART and substituting lopinavir/r with nevirapine once virologic suppression was achieved were less likely to experience viral load more than 50 copies/ml (hazard ratio 0.62, 95% CI 0.41-0.92, P = 0.02) but more likely to have confirmed virologic failure (>1000 copies/ml) than those remaining on lopinavir/r (hazard ratio 10.19, 95% CI 2.36-43.94, P = 0.002). Children receiving induction-maintenance ART (four-drug NNRTI-based regimen for 36 weeks followed by three-drug ART) showed better short-term immunologic and virologic responses, but no long-term benefits. The only trial comparing continuous ART from infancy with interrupted ART beyond infancy was terminated early because the duration of treatment interruption was less than 3 months in most infants. ART initiation in asymptomatic infants reduces morbidity and mortality. Lopinavir/r-based first-line ART is superior to nevirapine-based regimens in young children, regardless of PMTCT exposure, but lopinavir/r use is challenging. Substituting lopinavir/r with nevirapine following virologic suppression may be feasible where viral load testing is available. Considering current evidence, induction-maintenance and treatment interruption strategies are not recommended. This review contributed to the evidence base for the 2013 WHO guidelines on antiretroviral therapy, which recommend that all children below 3 years start lopinavir/r-based ART and that lopinavir/r can be substituted with nevirapine once sustained virologic suppression is achieved.

Isoniazid preventive therapy in HIV-infected children on antiretroviral therapy: a pilot study

Tuberculosis (TB) is a common cause of mortality and morbidity in children infected with the human immunodeficiency virus (HIV). Data on isoniazid preventive therapy (IPT) efficacy in HIV-infected children receiving antiretroviral therapy (ART) are inconclusive. To assess the efficacy, tolerability and safety of isoniazid (INH) in HIV-infected children on ART. A pilot randomised controlled study of INH was undertaken in HIV-infected children on ART. The primary outcome measure was TB disease or death. A total of 167 children were randomised to receive INH (n = 85) or placebo (n = 82), and followed for a median of 34 months (interquartile range [IQR] 24-52). The median age was 35 months (IQR 15-65). There was one death in a child on INH and none in the placebo group. Eleven (6.6%) cases of TB occurred, 4 (5%) in the INH and 7 (9%) in the placebo group. Among the TB cases, 5 were culture confirmed-2 in the INH group and 3 in the placebo group, all susceptible to INH. Severe adverse events occurred rarely (n = 6; 2%). IPT is safe and well tolerated in HIV-infected children on concomitant ART. This study supports the need for a larger study to assess efficacy in HIV-infected children living in TB-endemic areas.