Antiretroviral Therapy In HIV-infected Children Research Articles

Factors associated with death and attrition in HIV-infected children under initial antiretroviral therapy in Guangxi Zhuang Autonomous Region, 2004 - 2019

Objective: To investigate death and attrition in HIV-infected children under initial antiretroviral therapy (ART) and associated factors in Guangxi Zhuang autonomous region. Methods: This retrospective cohort study was conducted in HIV-infected children under initial ART in Guangxi from 2004 to 2019, data from ART information system of National comprehensive AIDS prevention and treatment information system. Cox proportional hazards models were used to assess factors associated with the death and attrition. Results: In 943 HIV-infected children, the overall mortality and attrition rates were 1.00/100 person-years and 0.77/100 person-years, respectively. The mortality and attrition rates within the first year of ART were 3.90/100 person-years and 1.67/100 person-years, respectively. The cumulative survival rate during the first, second, fifth and tenth year after ART was 96.14%, 95.80%, 93.68% and 91.54%, respectively. Multivariate Cox proportional hazards models results showed that being female (aHR=2.00, 95%CI: 1.17-3.40), CD4+T lymphocytes (CD4) counts before ART <200 cells/μl (aHR=2.79, 95%CI: 1.54-5.06), weight-for-age Z score before ART <-2 (aHR=2.38, 95%CI: 1.32-4.26), hemoglobin before ART <80 g/L (aHR=2.47, 95%CI: 1.24-4.92), initial ART with LPV/r (aHR=5.05, 95%CI: 1.15-22.12) were significantly associated with death; being female (aHR=2.23, 95%CI: 1.22-4.07) and initial ART with LPV/r (aHR=2.02, 95%CI: 1.07-3.79) were significantly associated with attrition. Conclusions: The effect of ART in HIV-infected children in Guangxi was better, but the mortality and attrition rates were high within the first year of treatment. It is necessary to strengthen the training in medical staff and health education in HIV-infected children and their parents in order to improve the treatment effect.

Late diagnosis of human immunodeficiency virus infection is linked to higher rates of epilepsy in children in the Eastern Cape of South Africa.

BackgroundHuman immunodeficiency virus (HIV)-positive children may present with a wide range of neurological disorders. Among these, epilepsy is of key concern because of its lifelong impact and potential for damage to the central nervous system (CNS). Few studies in developing regions have investigated the prevalence and aetiology of epilepsy in HIV-infected children as a key population.ObjectivesWe describe the prevalence of epilepsy, associated neurological disabilities, immunological status, clinical stage and history of CNS infection at epilepsy diagnosis in a cohort of HIV-infected children receiving antiretroviral therapy (ART) in the Eastern Cape of South Africa.MethodsWe conducted a retrospective study (2004–2014) at two major referral sites for HIV-infected children diagnosed with epilepsy aged 0–16 years. Eligible subjects were extracted from the electronic medicine bridging access to care in excellence (EMBRACE) Paediatric Cohort using the Paediatric ART Data Management Tool (PADMT). Fixed data fields were interrogated for exposures to antiepileptic drugs. Unstructured ‘comments’ fields were searched for the terms: epilepsy, seizures, fits and szs, as well as abbreviated versions of common antiepileptic drug names. Eligible subject folders were then retrieved to validate the digital data.ResultsFrom 2139 children enrolled in the two sites, 53 children were diagnosed with epilepsy (2.48%). In these, the median CD4 count was 591 cells/mm3, and the mean viral load was 4.9 log copies/mL, with undetectable viral loads in only seven children (14.0%). World Health Organization (WHO) clinical HIV stage was available for 46 patients of the sample, with 3, 6, 26 and 11 children graded at stages 1, 2, 3 and 4, respectively. Forty percent children had a history of CNS infection prior to the epilepsy diagnosis, and 55% children were reported to have school problems.ConclusionsIn this descriptive study, the prevalence of epilepsy among children with HIV was 2.48%, mostly diagnosed in advanced HIV-disease stages. Our findings support the usefulness of early detection and initiation of ART in HIV-infected children in order to reduce the risk of epilepsy. In addition, our study demonstrates that novel techniques are effective in accessing cohort-level data that allow interrogation of both structured and unstructured clinical data.

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.

Perturbation of B Cell Gene Expression Persists in HIV-Infected Children Despite Effective Antiretroviral Therapy and Predicts H1N1 Response.

Despite effective antiretroviral therapy (ART), HIV-infected individuals with apparently similar clinical and immunological characteristics can vary in responsiveness to vaccinations. However, molecular mechanisms responsible for such impairment, as well as biomarkers able to predict vaccine responsiveness in HIV-infected children, remain unknown. Following the hypothesis that a B cell qualitative impairment persists in HIV-infected children (HIV) despite effective ART and phenotypic B cell immune reconstitution, the aim of the current study was to investigate B cell gene expression of HIV compared to age-matched healthy controls (HCs) and to determine whether distinct gene expression patterns could predict the ability to respond to influenza vaccine. To do so, we analyzed prevaccination transcriptional levels of a 96-gene panel in equal numbers of sort-purified B cell subsets (SPBS) isolated from peripheral blood mononuclear cells using multiplexed RT-PCR. Immune responses to H1N1 antigen were determined by hemaglutination inhibition and memory B cell ELISpot assays following trivalent-inactivated influenza vaccination (TIV) for all study participants. Although there were no differences in terms of cell frequencies of SPBS between HIV and HC, the groups were distinguishable based upon gene expression analyses. Indeed, a 28-gene signature, characterized by higher expression of genes involved in the inflammatory response and immune activation was observed in activated memory B cells (CD27+CD21−) from HIV when compared to HC despite long-term viral control (>24 months). Further analysis, taking into account H1N1 responses after TIV in HIV participants, revealed that a 25-gene signature in resting memory (RM) B cells (CD27+CD21+) was able to distinguish vaccine responders from non-responders (NR). In fact, prevaccination RM B cells of responders showed a higher expression of gene sets involved in B cell adaptive immune responses (APRIL, BTK, BLIMP1) and BCR signaling (MTOR, FYN, CD86) when compared to NR. Overall, these data suggest that a perturbation at a transcriptional level in the B cell compartment persists despite stable virus control achieved through ART in HIV-infected children. Additionally, the present study demonstrates the potential utility of transcriptional evaluation of RM B cells before vaccination for identifying predictive correlates of vaccine responses in this population.

Universal antiretroviral therapy for HIV-infected children: a review of the benefits and risks to consider during implementation.

Background: The 2016 World Health Organization (WHO) consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection, recommended to start all HIV-infected children on antiretroviral therapy (ART). Here, we explore the possible benefits and risks of implementing universal ART for all HIV-infected children and adolescents and outline some of the key considerations that led to the 2016 revision of WHO guidelines.Methods: We conducted a review of the published data from 2000 to 2016, to ascertain the clinical and programmatic benefits, as well as the risks of implementing universal ART for all children.Results and discussion: Universal ART for all children has the potential to increase treatment coverage, which in 2015 was only 51% globally, as well as providing several biological benefits, by preventing: premature death/loss to follow-up, progressive destruction of the immune system, poor growth and pubertal delay, poor neuro-cognitive outcomes and future burden to the health care system with complications of untreated HIV-infection. However, the strategy could be associated with risks, notably development of HIV drug resistance, antiretroviral drug toxicities and increased costs to an already stretched health system.Conclusion: Overall, our findings suggest that the benefits could outweigh the risks and support universal ART for all HIV-infected children, but recognize that national programmes will need to put measures in place to minimize the risks if they choose to implement the strategy.

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.

Effect of cotrimoxazole prophylaxis on the incidence of malaria in HIV-infected children in 2012, in Abidjan, Côte d'Ivoire: a prospective cohort study.

BackgroundCotrimoxazole prophylaxis has an antimalarial effect which could have an additional protective effect against malaria in HIV-infected children on antiretroviral therapy (ART). We measured the incidence and associated factors of malaria in HIV-infected children on ART and/or cotrimoxazole in Abidjan, Côte d’Ivoire.MethodsAll HIV-infected children <16 years, followed-up in the IeDEA West-African paediatric cohort (pWADA) in Abidjan, were prospectively included from May to August 2012, the rainy season. Children presenting signs suggesting malaria had a thick blood smear and were classified as confirmed or probable malaria. We calculated incidence density rates (IR) per 100 child-years (CY). Risk factors were assessed using a Poisson regression model.ResultsOverall, 1117 children were included, of whom 89 % were ART-treated and 67 % received cotrimoxazole. Overall, there were 51 malaria events occurring in 48 children: 28 confirmed and 23 probable; 94 % were uncomplicated malaria. The overall IR of malaria (confirmed and probable) was 18.3/100 CY (95 % CI: 13.3-23.4), varying from 4.2/100 CY (95 % CI: 1.1-7.3) in children on ART and cotrimoxazole to 57.3/100 CY (95 % CI: 7.1-107.6) for those receiving no treatment at all. In univariate analysis, age <5 years was significantly associated with a 2-fold IR of malaria compared to age >10 years (incidence rate ratio [IRR] = 2.18, 95 % CI: 1.04-4.58). Adjusted for severe immunodeficiency, cotrimoxazole reduced significantly the IR of first malarial episode (adjusted IRR [aIRR] = 0.13, 95 % CI: 0.02-0.69 and aIRR = 0.05, 95 % CI:0.02-0.18 in those off and on ART respectively). Severe immunodeficiency increased significantly the malaria IR (aIRR = 4.03, 95 % CI: 1.55-10.47).When considering the IR of confirmed malaria only, this varied from 2.4/100 CY (95 % CI: 0.0-4.8) in children on ART and cotrimoxazole to 34.4/100 CY (95 % CI: 0.0-73.3) for those receiving no treatment at all. In adjusted analyses, the IR of malaria in children on both cotrimoxazole and ART was significantly reduced (aIRR = 0.05, 95 % CI: 0.01-0.24) compared to those receiving no treatment at all.ConclusionsCotrimoxazole prophylaxis was strongly protective against the incidence of malaria when associated with ART in HIV-infected children. Thus, these drugs should be provided as widely and durably as possible in all HIV-infected children <5 years of age.

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.

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.

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.

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.

Long-term response to combination antiretroviral therapy in HIV-infected children in the Netherlands registered from 1996 to 2012

To describe demographic and treatment characteristics of the Dutch vertically HIV-infected paediatric population from 1996 to 2012, and to investigate the long-term virological and immunological response to combination antiretroviral therapy (cART), with emphasis on the influence of age at cART initiation and initial CD4 cell counts. Descriptive cohort study. From 1996 to 2012, all paediatric HIV clinics in the Netherlands provided data on their HIV-infected population. Descriptive statistics, parametric and non-parametric comparative tests, and random-effects linear regression models were performed to investigate the different aspects of this cohort. A total of 229 vertically HIV-infected children were included. The majority of all mothers (64%) and almost half of the children (43%) originated from sub-Saharan Africa. Ritonavir-boosted lopinavir and efavirenz have replaced indinavir, nelfinavir and nevirapine as preferred first-line cART regimens. Long-term CD4 T-cell reconstitution (with CD4 cell counts corrected for age) was independent of age and CD4 cell count at cART initiation. The decline in HIV viral load after cART introduction occurred faster over the studied time period. The percentage of children with an undetectable viral load rose substantially from 1996 to 2012. Mortality was 0.3 per 100 person-years. A sustained immunological response in the Dutch paediatric HIV-infected population was independent of age as well as CD4 cell count at cART initiation, despite a higher initial HIV viral load in the youngest children. The percentage of children with an undetectable HIV viral load rose substantially over the years and there was a low mortality rate in comparison with reports from other industrialized countries.

Age and CD4 Count at Initiation of Antiretroviral Therapy in HIV-Infected Children: Effects on Long-Term T-Cell Reconstitution

J Lewis, S Walker, H Castro. J Infect Dis. 2012;205(4):548–556 US guidelines for initiating antiretroviral therapy (ART) for children with HIV infection suggest treatment in all patients younger than 12 months of age and for children older than 12 months of age depending upon immunologic (CD4 count) and virologic (plasma viral load) measures. The guidelines, therefore, assume that it is safe to delay therapy in some older children. However, poorer reconstitution of CD4 count has been demonstrated in pediatric patients who start ART at an older age …

Unresolved Antiretroviral Treatment Management Issues in HIV-Infected Children

Antiretroviral therapy in children has expanded dramatically in low-income and middle-income countries. The World Health Organization revised its pediatric HIV guidelines to recommend initiation of antiretroviral therapy in all HIV-infected children younger than 2 years, regardless of CD4 count or clinical stage. The number of children starting life-long antiretroviral therapy should therefore expand dramatically over time. The early initiation of antiretroviral therapy has indisputable benefits for children, but there is a paucity of definitive information on the potential adverse effects. In this review, a comprehensive literature search was conducted to provide an overview of our knowledge about the complications of treating pediatric HIV. Antiretroviral therapy in children, as in adults, is associated with enhanced survival, reduction in opportunistic infections, improved growth and neurocognitive function, and better quality of life. Despite antiretroviral therapy, HIV-infected children may continue to lag behind their uninfected peers in growth and development. In addition, epidemic concurrent conditions, such as tuberculosis, malaria, and malnutrition, can combine with HIV to yield more rapid disease progression and poor treatment outcomes. Additional studies are required to evaluate the long-term effects of antiretroviral therapy in HIV-infected infants, children, and adolescents, particularly in resource-limited countries where concomitant infections and conditions may enhance the risk of adverse effects. There is an urgent need to evaluate drug-drug interactions in children to determine optimal treatment regimens for both HIV and coinfections.

Reliability of absolute lymphocyte count as a marker to assess the need to initiate antiretroviral therapy in HIV-infected children

CD4 counts are a standard laboratory measure of disease progression in HIV-infected children. However, CD4 counting is done by flow cytometry and may not always be possible in every centre treating HIV-infected children in resource-limited countries. Absolute Lymphocyte Count (ALC) can be derived easily by performing a routine white blood cell count. The World Health Organization (WHO) in 2006 had recommended ALC to identify HIV-infected children in need of ART in resource-limited settings, when CD4 cell count is not available. This study aims to assess the reliability of using ALC as a marker for starting antiretroviral therapy (ART) in HIV-infected children in a tertiary hospital setting. Retrospective analysis of 46 HIV-infected children who presented at a pediatric HIV clinic at a tertiary referral centre from 2002-2005. Using WHO 2006 guidelines for cutoff values of ALC and 2008 guidelines for CD4% as a comparative standard, a retrospective analysis was done on ART-naοve HIV-infected children who underwent baseline CD4% and ALC, and sensitivity and specificity of ALC was calculated. Fischer exact two-tailed analysis was used to correlate ALC and CD4 and need for starting ART. Sensitivity of ALC was 27.6% (72.4% were false negatives), specificity was 70.6%, with positive predictive value of 61.5%. On comparison across all clinical stages of disease, only 13/46 children (28.2%) would have been started on ART according to ALC cutoffs versus 29/46 children (63.04%) using CD4 criteria (P value=0.0015). In children with WHO clinical Stage 1 or 2 of disease, only 1/11 (9.1%) children were identified by ALC as requiring ART as opposed to 6/11 (54.5%) children by CD4% (P=0.0635). ALC is an unreliable marker to determine the need for starting ART in HIV-infected children.