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Background— Premature cardiovascular disease is increasingly recognized in HIV-infected patients, but the mechanisms involved are unclear. The purpose of this study was to determine the impact of HIV infection and antiretroviral therapy (ART) on markers of early vascular disease in children. Methods and Results— We studied 83 HIV-infected children (56 had taken ART, of whom 31 received a regimen containing protease inhibitors [PIs]; 27 were never treated) and a control group of 59 healthy children. Carotid intima-media thickness (IMT) and brachial artery flow-mediated dilatation (FMD) were measured. IMT was significantly greater in HIV-infected children compared with the control subjects ( P P =0.02). FMD was also significantly reduced in the HIV-infected children compared with control subjects ( P =0.02). Pairwise comparisons of different treatment exposure groups revealed that FMD was impaired by a mean of 3.6% (95% CI, 1.8 to 5.3; P P =0.05) compared with non-PI-treated children. HIV-infected children had lipid abnormalities, but they did not account for the observed differences in either FMD or IMT. Conclusions— HIV infection in childhood is associated with adverse structural and functional vascular changes that are most pronounced in children exposed to PI therapy. Longitudinal studies are required to differentiate the relative impact of HIV disease and ART and to assess the potential for prevention.

There have been few major advances in paediatric HIV management over the last 2 years. Decisions about starting antiretroviral therapy can now be based on a recent large meta-analysis of the predictive value of CD4 and HIV RNA viral load (VL) in nearly 4000 untreated children, which is discussed in these updated guidelines. Risk estimates for progression to AIDS and death using surrogate markers can now be broken down by age, allowing more accurate discussion with families. In addition, there is increasing recognition of the problems of long-term adherence, drug resistance and cumulative toxicity in adults and children. The controversy over whether to treat asymptomatic infants continues. For older children more data on the efficacy of ritonavir boosted protease inhibitor (PI) regimens suggests that these may be the PI option of first choice. There is still no adult or paediatric trial evidence on which to base decisions about whether to start with PI- or non-nucleoside reverse transcriptase inhibitor (NNRTI)- based regimens, but the PENPACT 1 trial, which is addressing this question, is ongoing. There are increasing moves to provide simpler antiretroviral therapy (ART) regimens, including once daily dosing, but these lag behind adult regimens because of the paucity of pharmacokinetic data. Resistance assays should now be performed in all HIV-infected infants exposed to ART in pregnancy. Therapeutic drug monitoring may be very important in children because of high between- and within-child variability in drug absorption and metabolism. A trial to evaluate this should start shortly in Europe (PENTA 14 trial). The value of resistance tests for choice of second-line and subsequent choices of ART regimens remain unproven (the PERA trial will report late in 2004), but resistance assays are increasingly being used. The issue of when to switch therapy also remains unanswered and is being addressed within the PENPACT 1 trial. Regular formal assessment of adherence is now the standard of care, and routine monitoring in the clinic for lipodystrophy syndrome (LDS) and other ART toxicities is increasingly important. These guidelines will be updated again in 2006.

ObjectivesTo assess the strength of evidence supporting the routine use of HIV drug resistance testing.DesignA critical review of all studies relating to the clinical utility of HIV resistance testing, with a focus on randomized trials.ResultsTwo cohort studies found no evidence of a difference in virological response in patients who had resistance testing compared with matched controls. We identified nine published randomized trials that were specifically designed to assess the clinical utility of drug resistance testing. In a meta-analysis of these trials, resistance testing increased the proportion of patients who achieved undetectable viral load by an average of 7% (95% confidence interval: 3–11%). However, this may be an over-estimate of the impact of resistance testing in clinical practice because of the idealized design and analytical approaches used in most of the studies.ConclusionsThe available evidence does not clearly demonstrate that HIV drug resistance testing is clinically effective. To optimize their value for health decision-making, future trials of HIV resistance testing should be carefully designed to mimic the circumstances of routine clinical practice.

BACKGROUND: There are few data on the decline of CD4 cells or percentage during unplanned treatment interruptions in HIV-infected children. METHODS: Data were analyzed on children undergoing interruptions of three or four drug antiretroviral therapy (HAART) in the United Kingdom and Irish Collaborative HIV Paediatric Study and from Sophia Children's Hospital, Rotterdam. Children were included if they had taken HAART continuously for 3 months or longer before interruption and stopped for at least 4 weeks. The effects of CD4 at treatment initiation and of age, CD4, HIV RNA and disease stage at interruption on the CD4 decline during interruption were explored with linear mixed models. RESULTS: Seventy-one children (median age, 7.0 years) had experienced 82 unplanned interruptions of median duration 4.1 (interquartile range, 2.3 to 7.6) months. HAART was restarted after 59 (72%) interruptions (17 with the same and 42 with a new regimen). In children restarting HAART, median CD4% increased toward preinterruption levels by 6 months, when 46% had HIV RNA

OBJECTIVE: To assess the feasibility and impact of highly active antiretroviral therapy (HAART) started in vertically HIV-1-infected infants less than 3 months of age. DESIGN: A multicentre, phase I/II, non-randomized, open-label study (PENTA 7). METHODS: Adverse events, plasma HIV-1 RNA, CD4 cell counts, CD4 cell percentage (CD4%) and clinical progression were recorded at baseline and prospectively to 72 weeks in order to assess the toxicity, tolerability and efficacy of a combination of stavudine, didanosine and nelfinavir. Selection of genotypic resistance was also investigated. RESULTS: Twenty infants, of whom only three had Centers for Disease Control and Prevention stage B, initiated HAART at median age 2.5 months (range, 0.9-4.7) with median HIV-1 RNA concentration 5.5 log10 copies/ml (range, 3.2-6.8) and CD4% 33% (range, 11-66). Median follow-up was 96 weeks (range, 60-144). At week 72, 11 infants were still taking the original treatment. Few adverse events were reported related to treatment, all minor and causing treatment interruption in only three infants. No AIDS-defining events occurred; one child died of non-HIV-related causes (prematurity). All but two had CD4% > 25% at 72 weeks; however, 14 infants had virological failure and six acquired resistance mutations. CONCLUSIONS: Early treatment with stavudine, didanosine and nelfinavir was well tolerated and associated with good clinical and immunological outcomes at week 72. However, a high rate of virological failure with emergence of genotypic resistance is of great concern. More palatable drug combinations for infants and closer drug monitoring are required.

OBJECTIVE To produce European Guidelines for the use of antiretroviral therapy (ART) in HIV-infected children. DESIGN Systematic literature review using Medline, the major antiretroviral conference reports, and IDSA recommendations on guideline production. SETTING Pediatric European Network for Treatment of AIDS (PENTA) Steering Committee. OUTCOME MEASURE Guidelines have been produced for the use of antiretroviral therapy in HIV-infected children in Europe. Recommendations on when to start ART and which ART to start, with dosages and a summary of the relevant literature, have been produced. CONCLUSIONS These guidelines are aimed at assisting paediatricians in Europe with ART prescribing, and provide a more cautious approach to starting therapy than current paediatric USA guidelines.

Over one million children world-wide are living with HIV infection and respiratory disease is the commonest cause of morbidity and mortality in these children. The initial presentation of respiratory infection is usually in infancy or early childhood. There is enormous potential to prevent childhood HIV infection that is being realised in industrialised countries but not yet elsewhere. Increasingly, therefore, the burden of HIV disease is in children living in or from non-industrialised countries. This review describes and contrasts the pattern of respiratory infection from both regions. This pattern has changed with the implementation of PCP prophylaxis and the availability of potent antiretroviral therapy for children in resource-rich countries, such as the UK. More data are required from resource-poor regions such as tropical Africa, but it is clear that the major differences reflect greater background risk for respiratory infection and very limited management options rather than specific aetiology.

Background: The World Health Organization (WHO) rehydration management guidelines (Plan C) for children with acute gastroenteritis (AGE) and severe dehydration are widely practiced in resource-poor settings, yet have never been formally evaluated in a clinical trial. A recent audit of outcome of AGE at Kilifi County Hospital, Kenya noted that 10% of children required high dependency care (20% mortality) and a number developed fluid-related complications. The fluid resuscitation trial, FEAST, conducted in African children with severe febrile illness, demonstrated higher mortality with fluid bolus therapy and raised concerns regarding the safety of rapid intravenous rehydration therapy. Those findings warrant a detailed physiological study of children’s responses to rehydration therapy incorporating quantification of myocardial performance and haemodynamic changes. Methods: GASTRO is a multi-centre, unblinded Phase II randomised controlled trial of 120 children aged 2 months to 12 years admitted to hospital with severe dehydration secondary to AGE. Children with severe malnutrition, chronic diarrhoea and congenital/rheumatic heart disease are excluded. Children will be enrolled over 18 months in 3 centres in Kenya and Uganda and followed until 7 days post-discharge. The trial will randomise children 1:1 to standard rapid rehydration using Ringers Lactate (WHO plan ‘C’ – 100mls/kg over 3-6 hours according to age, plus additional 0.9% saline boluses for children presenting in shock) or to a slower rehydration regimen (100mls/kg given over 8 hours and without the addition of fluid boluses). Enrolment started in November 2016 and is on-going. Primary outcome is frequency of adverse events, particularly related to cardiovascular compromise and neurological sequelae. Secondary outcomes focus on clinical, biochemical, and physiological measures related to assessment of severity of dehydration, and response to treatment by intravenous rehydration. Discussion: Results from this pilot will contribute to generating robust definitions of outcomes (in particular for non-mortality endpoints) for a larger Phase III trial.

Objectives Worldwide, school age children and adolescents are vulnerable to conflict and food insecurity and HIV-infected children are increasingly surviving into adolescence. WHO recommends assessing acute malnutrition in this age group using body mass index-for-age Z scores (BMIz). For under-fives, mid upper arm circumference (MUAC) is the mainstay of community diagnosis of acute malnutrition, is simple to perform and predicts survival better than weight-for-height Z scores. MUAC is little-used in older children and adolescents because there is no accepted international reference. This study aimed to construct growth curves for MUAC-for-age Z score (MUACz) for 5-19 year olds that accord with WHO Growth Standards, and evaluate their discriminatory performance for subsequent mortality. Design The HES/NHANES US population datasets (age 5-25 years), which were used to construct the 2007 WHO Growth Reference for BMI in this age group, were merged with an imputed dataset matching the distribution of the WHO 2006 Growth Standards age 2-6 years. To construct standardised growth curves, we used Generalized Additive Models for Location, Scale and Shape with Box-Cox Cole Green transformation and penalized B-spline smoothing. Validation for subsequent mortality in two cohorts was done using Cox proportional hazards models for pre-defined MUACz and BMIz thresholds, with age, gender and HIV status as covariates; and estimation of the area under receiver-operating characteristic curves (AUC). Participants Validation data were from 685 HIV-infected children age 5¬–17 years participating in the ARROW trial in Uganda and Zimbabwe; and 1,741 children age 5–13 years discharged from a rural Kenyan hospital (3.8% HIV-infected). Both cohorts were followed up for survival during one year. Main outcome measures Concordance with WHO 2006 Growth Standards at age 60 months and survival during one year according to MUACz and BMIz. Results The new growth curves transitioned smoothly with WHO Growth Standards at age 5 years. MUACz of -2 to -3 and Conclusions MUACz is at least as effective as BMIz for assessing mortality risks associated with undernutrition among African school-aged children and adolescents. MUAC can provide simplified screening and diagnosis within nutrition and HIV programmes, and in research.

Introduction : With improved survival, adolescents with perinatal HIV (PHIV) are transitioning from paediatric to adult care, but there are few published data on clinical outcomes post-transfer. Using linked data from patients in the national UK/Ireland paediatric cohort (CHIPS) and an adult UK cohort of outpatient clinics (UK CHIC), we describe mortality and changes in immunological status post-transfer. Methods : Participants in CHIPS aged ≥13 years by the end of 2013 were linked to the UK CHIC database. Mixed effects models explored changes in CD4 count before and after transfer, including interactions between time and variables where interaction p 400 copies/mL or one viral load >10,000 copies/mL, and likewise 102 (52%) in the 12 months post-transfer ( p = 0.79). Seven (3%) people died in adult care. In multivariable analysis, CD4 declined as patients approached transition with a greater decline in those with higher nadir CD4 count (mean rates of decline of 3, 13, 15, 30 cells/mm 3 per year for those with nadir CD4 < 100, 100–199, 200–299 and ≥300 cells/mm 3 , respectively). Post-transition, CD4 continued to decline in some groups (e.g. black males, −20 (−34, −5) cells/mm 3 per year post transition, p = 0.007)) while it improved in others. Overall CD4 was higher with later year of birth (14 (7, 21) cells/mm 3 per later year). There was no effect of age at transfer or changing hospital at transfer on CD4. Conclusions : Our findings suggest that CD4 in adolescents with perinatal HIV in the UK was declining in the period before transition to adult care, and there was some reversal in this trend post-transfer in some groups. Across the transition period, CD4 was higher in those with later birth years, suggesting improvements in clinical care and/or transition planning over time. Keywords adolescent; young person; perinatal; HIV; United Kingdom; transition; transfer; adult care; paediatric (Published: 16 May 2017) Judd A et al. Journal of the International AIDS Society 2017, 20(suppl 3) :21577 http://www.jiasociety.org/index.php/jias/article/view/21577 | http://dx.doi.org/10.7448/IAS.20.4.21577

Background The case definition for suspected Ebola virus disease is broad, so many negative children are isolated for testing, risking nosocomial infection. We collected data on children admitted to Ebola holding units in Sierra Leone to refine the case definition and describe outcomes of admitted children. Methods All children aged less than 13 years admitted to 11 Ebola holding units in Sierra Leone between Aug 1, 2014, and March 31, 2015, were eligible for inclusion. Data were collected from paper-based clinical records, district-wide laboratory results, burial records, staff interviews, and follow-up telephone calls. The cohort was split into training and validation datasets. A model was developed with multivariable logistic regression and compared with laboratory results to explore the sensitivity and specificity of the alternative case definition. Findings Of 1054 children admitted, 309 (29%) tested positive for Ebola virus disease and 697 (66%) tested negative (48 [5%] missing). The model had an area under receiver operating characteristic curve of 0·80 (high performance). A case definition of Ebola virus disease contact alone, fever (in children >2 years), or fever and conjunctivitis ( 2 years) improved specificity (97%), with sensitivity of 23%. Children testing negative had a case fatality rate of 8% versus 57% in those with Ebola virus disease (p Interpretation Contact history, fever, conjunctivitis, abdominal pain, and diarrhoea are key characteristics for diagnosis of paediatric Ebola virus disease. The case definitions developed can be used flexibly—for example, for triage into risk categories to reduce risk of nosocomial infection. Funding Save the Children.

Background In sub-Saharan Africa antiretroviral therapy (ART) is being decentralized from tertiary/secondary care facilities to primary care. The Lablite project supports effective decentralization in 3 countries. It began with a cross-sectional survey to describe HIV and ART services. Methods 81 purposively sampled health facilities in Malawi, Uganda and Zimbabwe were surveyed. Results The lowest level primary health centres comprised 16/20, 21/39 and 16/22 facilities included in Malawi, Uganda and Zimbabwe respectively. In Malawi and Uganda most primary health facilities had at least 1 medical assistant/clinical officer, with average 2.5 and 4 nurses/midwives for median catchment populations of 29,275 and 9,000 respectively. Primary health facilities in Zimbabwe were run by nurses/midwives, with average 6 for a median catchment population of 8,616. All primary health facilities provided HIV testing and counselling, 50/53 (94%) cotrimoxazole preventive therapy (CPT), 52/53 (98%) prevention of mother-to-child transmission of HIV (PMTCT) and 30/53 (57%) ART management (1/30 post ART-initiation follow-up only). All secondary and tertiary-level facilities provided HIV and ART services. In total, 58/81 had ART provision. Stock-outs during the 3 months prior to survey occurred across facility levels for HIV test-kits in 55%, 26% and 9% facilities in Malawi, Uganda and Zimbabwe respectively; for CPT in 58%, 32% and 9% and for PMTCT drugs in 26%, 10% and 0% of facilities (excluding facilities where patients were referred out for either drug). Across all countries, in facilities with ART stored on-site, adult ART stock-outs were reported in 3/44 (7%) facilities compared with 10/43 (23%) facility stock-outs of paediatric ART. Laboratory services at primary health facilities were limited: CD4 was used for ART initiation in 4/9, 5/6 and 13/14 in Malawi, Uganda and Zimbabwe respectively, but frequently only in selected patients. Routine viral load monitoring was not used; 6/58 (10%) facilities with ART provision accessed centralised viral loads for selected patients. Conclusions Although coverage of HIV testing, PMTCT and cotrimoxazole prophylaxis was high in all countries, decentralization of ART services was variable and incomplete. Challenges of staffing and stock management were evident. Laboratory testing for toxicity and treatment effectiveness monitoring was not available in most primary level facilities. Electronic supplementary material The online version of this article (doi:10.1186/1472-6963-14-352) contains supplementary material, which is available to authorized users.

Background: Most pediatric lipodystrophy data come from high-income/middle-income countries, but most HIV-infected children live in sub-Saharan Africa, where lipodystrophy studies have predominantly investigated stavudine-based regimens. Methods: Three years after antiretroviral therapy (ART) initiation, body circumferences and skinfold thicknesses were measured (n = 590), and fasted lipid profile assayed (n = 325), in children from 2 ARROW trial centres in Uganda/Zimbabwe. Analyses compared randomization to long-term versus short-term versus no zidovudine from ART initiation [unadjusted; latter 2 groups receiving abacavir+lamivudine+non-nucleoside-reverse-transciptase-inhibitor (nNRTI) long-term], and nonrandomized (confounder-adjusted) receipt of nevirapine versus efavirenz. Results: Body circumferences and skinfold thicknesses were similar regardless of zidovudine exposure (P > 0.1), except for subscapular and supra-iliac skinfolds-for-age which were greater with long-term zidovudine (0.006 < P < 0.047). Circumferences/skinfolds were also similar with efavirenz and nevirapine (adjusted P > 0.09; 0.02 < P < 0.03 for waist/waist-hip-ratio). Total and high-density lipoprotein (HDL)-cholesterol, HDL/triglyceride-ratio (P < 0.0001) and triglycerides (P = 0.01) were lower with long-term zidovudine. Low-density lipoprotein (LDL)-cholesterol was higher with efavirenz than nevirapine (P < 0.001). Most lipids remained within normal ranges (75% cholesterol, 85% LDL and 100% triglycerides) but more on long-term zidovudine (3 NRTI) had abnormal HDL-cholesterol (88% vs. 40% short/no-zidovudine, P < 0.0001). Only 8/579(1.4%) children had clinical fat wasting (5 grade 1; 3 grade 2); 2(0.3%) had grade 1 fat accumulation. Conclusions: Long-term zidovudine-based ART is associated with similar body circumferences and skinfold thicknesses to abacavir-based ART, with low rates of lipid abnormalities and clinical lipodystrophy, providing reassurance where national programs now recommend long-term zidovudine. Efavirenz and nevirapine were also similar; however, the higher LDL observed with efavirenz and lower HDL observed with zidovudine suggests that zidovudine+lamivudine+efavirenz should be investigated in future.

The new 2013 WHO Consolidated Guidelines on the Use of Antiretroviral Therapy (ART) make aspirational recommendations for ART delivery in low and middle income countries. Comprehensive assessments of available evidence were undertaken and the recommendations made are likely to improve individual health outcomes. However feasibility was downplayed, the Guidelines represent high-cost policy options not all of which are compatible with the core public health principles of decentralization; task-shifting; and a commitment to universality. Critically, their impact on equity and the population-level distribution of health outcomes were not fully considered. We analyze the likely distribution of health outcomes resulting from alternative ways of realising the 2013 Guidelines and assess practicality, feasibility and health attainment amongst different sections of the population in the context of financial and human resource constraints. Claim can be made that direct interpretation of the Guidelines follows a "human rights" based approach in seeking to provide individual patients with the best alternatives amongst those available on the basis of current evidence. However, there lies a basic conflict between this and "consequentialist" public health based approaches that provide more equal population-level outcomes. When determining how to respond to the 2013 Guidelines and fairly allocate scarce lifesaving resources, national policymakers must carefully consider the distribution of outcomes and the underpinning social value judgements required to inform policy choice. It is important to consider whose values should determine what is a just distribution of health outcomes. The WHO Guidelines committees are well placed to compile evidence on the costs and effects of health care alternatives. However, their mandate for making distributional social value judgements remains unclear.

Healthcare systems in low- and middle-income countries face considerable population healthcare needs with markedly fewer resources than those in higher income countries. The way in which available resources are allocated across competing priorities has a profound effect on how much health is generated overall, who receives healthcare interventions and who goes without. Judgements about whether interventions and programmes should be regarded as cost-effective and prioritised over others should be based on an assessment of the health benefits that will be lost because the resources required will not be available to implement other effective interventions and programmes that would benefit other patients in the same or different disease areas. Unfortunately, frequently adopted international norms, in particular the cost-effectiveness thresholds recommended by the World Health Organization (WHO), are not founded on this type of assessment. Consequently current judgements about which interventions and programmes are cost-effective are often aspirational and do not reflect the reality of resource constraints. As a consequence their use is likely to reduce overall population health and exacerbate healthcare inequalities. They also fail to identify the real (and greater) value of devoting more resources to these efforts. By obscuring the true implications of current arrangements they do not contribute to greater understanding of and accountability for global and local decisions made on behalf of populations in low and middle as well as in high income countries. We illustrate these points using examples from HIV/AIDS.

Objectives To determine whether antibiotic treatment leads to improvements in growth in prepubertal children in low and middle income countries, to determine the magnitude of improvements in growth, and to identify moderators of this treatment effect. Design Systematic review and meta-analysis. Data sources Medline, Embase, Scopus, the Cochrane central register of controlled trials, and Web of Science. Study selection Randomised controlled trials conducted in low or middle income countries in which an orally administered antibacterial agent was allocated by randomisation or minimisation and growth was measured as an outcome. Participants aged 1 month to 12 years were included. Control was placebo or non-antimicrobial intervention. Results Data were pooled from 10 randomised controlled trials representing 4316 children, across a variety of antibiotics, indications for treatment, treatment regimens, and countries. In random effects models, antibiotic use increased height by 0.04 cm/month (95% confidence interval 0.00 to 0.07) and weight by 23.8 g/month (95% confidence interval 4.3 to 43.3). After adjusting for age, effects on height were larger in younger populations and effects on weight were larger in African studies compared with other regions. Conclusion Antibiotics have a growth promoting effect in prepubertal children in low and middle income countries. This effect was more pronounced for ponderal than for linear growth. The antibiotic growth promoting effect may be mediated by treatment of clinical or subclinical infections or possibly by modulation of the intestinal microbiota. Better definition of the mechanisms underlying this effect will be important to inform optimal and safe approaches to achieving healthy growth in vulnerable populations.

Southall made several points about our recent article.1 2 He suggests that “lethal hyperchloraemia” secondary to use of normal saline in FEAST (for boluses or maintenance) resulted in excess mortality. However, he did not comment on the key finding of the trial—that the increased 48 hour mortality was identical in both normal saline bolus (10.6%) and albumin bolus (10.6%) arms compared with the no bolus control group (7.3%).3 Harm was shown for every age group, in every condition, at each …

There are currently more than 1.3 million children living with HIV in the world today and many more who have been orphaned by the epidemic. This review explores the nature of the widening gap in the experience of HIV infection between high- and low-income countries. The global epidemiology is described, highlighting the burden carried by sub-Saharan Africa and the alarming increase being witnessed in the Asia/Pacific region. Most of these infections are acquired vertically and are now largely preventable in well-resourced settings, and finding and implementing appropriate measures in poorer countries is urgently needed. Finally the ability to diagnose paediatric HIV infection is explored, highlighting the difference in the implications of doing so in settings with limited resources.

Objectives: The outcome of Pneumocystis carinii pneumonia (PCP) in HIV-infected infants is poor, and the role of cytomegalovirus (CMV) co-infection in the course and outcome of PCP is unclear. This study describes the prevalence, clinical characteristics, management and changes in survival over time of vertically HIV-infected infants developing PCP and/or CMV infection.Methods: Data on children with HIV, born in the UK and ireland and reported to the National Study of HIV in Pregnancy and Childhood, with PCP and/or CMV were combined with clinical information collected from reporting paediatricians.Results: By April 1998, 340 vertically HIV-infected children had been reported, of whom 93 had PCP and/or CMV, as their first AIDS indicator disease; 85 (91%) were infants. Among infants with PCP, 79% were born to mothers not diagnosed as HIV infected, and there was an independent and statistically significant association with breast-feeding, being black African, and developing CMV disease. Median survival after PCP and/or CMV was significantly better in those born between 1993 and 1998 compared with those born before 1993 (P = 0.009), and worse than after other AIDS diagnoses (P = 0.01). Infants with dual infection were more likely to be ventilated (P = 0.003) and receive corticosteroids (P = 0.002) than those with PCP alone.Conclusion: Although survival from PCP and CMV has improved over time, these remain serious and potentially fatal infections among infants in whom maternal HIV status is not recognized in pregnancy. Breast-feeding increases the risk of combined PCP and CMV infection, which is associated with severe disease. (C) 2001 Lippincott Williams & Wilkins.

Severe anemia (SA, hemoglobin6 g/dl) is a leading cause of pediatric hospital admission in Africa, with significant in-hospital mortality. The underlying etiology is often infectious, but specific pathogens are rarely identified. Guidelines developed to encourage rational blood use recommend a standard volume of whole blood (20 ml/kg) for transfusion, but this is commonly associated with a frequent need for repeat transfusion and poor outcome. Evidence is lacking on what hemoglobin threshold criteria for intervention and volume are associated with the optimal survival outcomes.We evaluated the safety and efficacy of a higher volume of whole blood (30 ml/kg; Tx30: n = 78) against the standard volume (20 ml/kg; Tx20: n = 82) in Ugandan children (median age 36 months (interquartile range (IQR) 13 to 53)) for 24-hour anemia correction (hemoglobin6 g/dl: primary outcome) and 28-day survival.Median admission hemoglobin was 4.2 g/dl (IQR 3.1 to 4.9). Initial volume received followed the randomization strategy in 155 (97%) patients. By 24-hours, 70 (90%) children in the Tx30 arm had corrected SA compared to 61 (74%) in the Tx20 arm; cause-specific hazard ratio = 1.54 (95% confidence interval 1.09 to 2.18, P = 0.01). From admission to day 28 there was a greater hemoglobin increase from enrollment in Tx30 (global P0.0001). Serious adverse events included one non-fatal allergic reaction and one death in the Tx30 arm. There were six deaths in the Tx20 arm (P = 0.12); three deaths were adjudicated as possibly related to transfusion, but none secondary to volume overload.A higher initial transfusion volume prescribed at hospital admission was safe and resulted in an accelerated hematological recovery in Ugandan children with SA. Future testing in a large, pragmatic clinical trial to establish the effect on short and longer-term survival is warranted.ClinicalTrials.Gov identifier: NCT01461590 registered 26 October 2011.

Summary Background Interim results from the children with HIV early antiretroviral (CHER) trial showed that early antiretroviral therapy (ART) was life-saving for infants infected with HIV. In view of the few treatment options and the potential toxicity associated with lifelong ART, in the CHER trial we compared early time-limited ART with deferred ART. Methods CHER was an open-label randomised controlled trial of HIV-infected asymptomatic infants younger than 12 weeks in two South African trial sites with a percentage of CD4-positive T lymphocytes (CD4%) of 25% or higher. 377 infants were randomly allocated to one of three groups: deferred ART (ART-Def), immediate ART for 40 weeks (ART-40W), or immediate ART for 96 weeks (ART-96W), with subsequent treatment interruption. The randomisation schedule was stratified by clinical site with permuted blocks of random sizes to balance the numbers of infants allocated to each group. Criteria for ART initiation in the ART-Def group and re-initiation after interruption in the other groups were CD4% less than 25% in infancy; otherwise, the criteria were CD4% less than 20% or Centers for Disease Control and Prevention severe stage B or stage C disease. Combination therapy of lopinavir–ritonavir, zidovudine, and lamivudine was the first-line treatment regimen at ART initiation and re-initiation. The primary endpoint was time to failure of first-line ART (immunological, clinical, or virological) or death. Comparisons were done by intention-to-treat analysis, with use of time-to-event methods. This trial is registered with ClinicalTrials.gov, number NCT00102960. Findings 377 infants were enrolled, with a median age of 7·4 weeks, CD4% of 35%, and HIV RNA log 5·7 copies per mL. Median follow-up was 4·8 years; 34 infants (9%) were lost to follow-up. Median time to ART initiation in the ART-Def group was 20 weeks (IQR 16–25). Time to restarting of ART after interruption was 33 weeks (26–45) in ART-40W and 70 weeks (35–109) in ART-96W; at the end of the trial, 19% of patients in ART-40W and 32% of patients in ART-96W remained off ART. Proportions of follow-up time spent on ART were 81% in the ART-Def group, 70% in the ART-40W group, and 69% in the ART-96W group. 48 (38%) of 125 children in the ART-Def group, 32 (25%) of 126 in the ART-40W group, and 26 (21%) of 126 in the ART-96W group reached the primary endpoint. The hazard ratio, relative to ART-Def, was 0·59 (95% CI 0·38–0·93, p=0·02) for ART-40W and 0·47 (0·27–0·76, p=0·002) for ART-96W. Three children in ART-Def, three in ART-40W, and one in ART-96W switched to second-line ART. Interpretation Early time-limited ART had better clinical and immunological outcomes than deferred ART, with no evidence of excess disease progression during subsequent treatment interruption and less overall ART exposure than deferred ART. Longer time on primary ART permits longer subsequent interruption, with marginally better outcomes. Funding US National Institutes of Health.

Using data from the ARROW trial, Joanna Lewis and colleagues investigate the CD4 cell count recovery profiles of children infected with HIV starting antiretroviral therapy in Sub-Saharan Africa. Please see later in the article for the Editors' Summary, Background Long-term immune reconstitution on antiretroviral therapy (ART) has important implications for HIV-infected children, who increasingly survive into adulthood. Children's response to ART differs from adults', and better descriptive and predictive models of reconstitution are needed to guide policy and direct research. We present statistical models characterising, qualitatively and quantitatively, patterns of long-term CD4 recovery. Methods and Findings CD4 counts every 12 wk over a median (interquartile range) of 4.0 (3.7, 4.4) y in 1,206 HIV-infected children, aged 0.4–17.6 y, starting ART in the Antiretroviral Research for Watoto trial (ISRCTN 24791884) were analysed in an exploratory analysis supplementary to the trial's pre-specified outcomes. Most (n = 914; 76%) children's CD4 counts rose quickly on ART to a constant age-corrected level. Using nonlinear mixed-effects models, higher long-term CD4 counts were predicted for children starting ART younger, and with higher CD4 counts (p10 y, ART should ideally be considered even if there is a low risk of immediate disease progression. Further exploration of the immunological mechanisms for these CD4 recovery profiles should help guide management of paediatric HIV infection and optimise children's immunological development. Please see later in the article for the Editors' Summary, Editors' Summary Background Worldwide, about 3.3 million children under 15 years old are infected with HIV, the virus that causes AIDS. More than 90% of these children live in sub-Saharan Africa, where nearly 600 children become infected with HIV every day, usually acquiring the virus from their mother during pregnancy, birth, or breastfeeding. HIV gradually reduces the numbers of CD4 lymphocytes in the immune system, leaving infected individuals susceptible to other infections. HIV infection can be kept in check but not cured with antiretroviral therapy (ART)—cocktails of drugs that have to be taken every day throughout life. ART reduces the amount of virus in the blood (viral load), which allows the immune system to recover (long-term immune reconstitution). Unfortunately, ART is very expensive, but concerted international efforts over the past decade mean that about a third of children who need ART are now receiving it, including half a million children in sub-Saharan Africa. Why Was This Study Done? World Health Organization (WHO) guidelines recommend initiation of ART at age-related CD4 cell count thresholds based on the risk of short-term disease progression. The guidelines recommend that all HIV-positive children under two years old begin ART as soon they receive a diagnosis of HIV infection. For children aged 2–5 years, ART initiation is recommended once the CD4 count drops below 750 cells/µl blood, whereas for older children the threshold for ART initiation is 350 CD4 cells/µl. Because of improved ART coverage, many more HIV-infected children now survive into adulthood than in the past. It is therefore important to know how the timing of ART initiation in childhood affects long-term immune reconstitution. Unfortunately, although several studies have examined the effect of ART on immune reconstitution in adults, the results of these studies cannot be extrapolated to children because of age-related differences in immune reconstitution. In this cohort-based modelling study, the researchers investigate long-term CD4 recovery in a cohort (group) of HIV-infected children initiating ART in Uganda and Zimbabwe, and present statistical models that predict patterns of long-term CD4 status based on age and CD4 count at ART initiation. What Did the Researchers Do and Find? To investigate long-term CD4 reconstitution in children, the researchers used CD4 counts collected during the ARROW trial, a study designed to investigate monitoring strategies during first-line ART in 1,206 HIV-positive children. In three-quarters of the children, CD4 reconstitution following ART initiation was asymptotic—CD4 counts increased rapidly immediately after ART initiation, then slowed before eventually reaching a constant level of about 80% of the CD4 count expected in an uninfected child of the same age. Using a nonlinear mixed-effects statistical model that fitted this pattern of immune reconstitution, the researchers predicted CD4 trajectories for children starting ART at different ages and with different CD4 counts. Higher long-term counts were predicted for children starting ART earlier and with higher CD4 counts. Thus, to achieve a CD4 count greater than 700 cells/µl at age 20 years, CD4 counts of at least 96 cells/µl, 130 cells/µl, and 557 cells/µl are needed for children aged two, five, and 12 years, respectively, when they initiate ART. Qualitatively distinct reconstitution patterns were seen in the remaining children in the study. What Do These Findings Mean? These findings suggest that young HIV-positive, ART-naïve children can achieve high CD4 counts in later life, provided ART is initiated as recommended in the current WHO guidelines. However, the recommended CD4 count thresholds for ART initiation are unlikely to maximize immune reconstitution in treatment-naïve children over ten years old. Rather, these findings suggest that ART initiation should be considered in these older children when their CD4 count is still high—even though they have a low risk of immediate disease progression—in order to achieve higher long-term CD4 levels. The omission of viral load measurements in the researchers' model may limit the accuracy of these findings. Moreover, although the predictions made by the model apply to children who will go on to experience asymptotic recovery, they are less relevant to those with different recovery profiles, who cannot currently be accurately identified. Further exploration of the immunological mechanisms underlying the CD4 recovery profiles described here should improve our understanding of the factors that determine the response of HIV-positive children to ART and provide information to guide the management of HIV infections in children. Additional Information Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001542. Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS NAM/aidsmap provides basic information about HIV/AIDS and summaries of recent research findings on HIV care and treatment Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including information on HIV and AIDS in Africa and on HIV infection in children (in English and Spanish) The UNAIDS World AIDS Day Report 2012 provides up-to-date information about the AIDS epidemic and efforts to halt it; the UNAIDS's 2013 Progress Report on the Global Plan provides information on progress towards eliminating new HIV infections among children by 2015 The World Health Organization provides information about universal access to AIDS treatment (in several languages); its 2010 guidelines for ART in infants and children can be downloaded Information about the ARROW trial is available Personal stories about living with HIV/AIDS, including stories from young people infected with HIV, are available through Avert, through Nam/aidsmap, and through the charity website Healthtalkonline

The introduction of combination antiretroviral therapy has been associated with a dramatic clinical improvement in children with human immunodeficiency virus infection. However, the uptake of antiretroviral therapy has been variable across Europe. The Paediatric European Network for the Treatment of AIDS Steering Committee has performed a systematic literature review of paediatric antiretroviral therapy trials. An analysis of the evidence base for the commencement and maintenance of antiretroviral therapy was produced. Suggestions for when to commence antiretroviral therapy, which drugs to start with and how to monitor and sequence drug regimens are given. Conclusion The aim of these guidelines is to help in obtaining equity of access to a uniformly high standard of care for children with human immunodeficiency virus infection in all European countries.

Aim—To investigate the prevalence, distribution, and clinical details of paediatric hepatitis C virus (HCV) infection in the UK and Ireland. Methods—Active monthly surveillance questionnaire study coordinated through the British Paediatric Surveillance Unit, to all consultant paediatricians in 1997 and 1998. Results—A total of 182 HCV infected children were reported from 54 centres and by paediatricians from eight diVerent specialties. In 40 children HCV was acquired through mother to child transmission (MTC children); 142 were infected by contaminated blood products (n = 134),organ transplantation (n = 2), needles (n = 4), or unknown risk factor (n = 2). Intravenous drug use was the risk factor for 35 mothers of MTC children.Twelve children were coinfected with HIV and four with HBV. Recent serum aspartate aminotransferase or alanine aminotransferase values were at least twofold greater than the upper limit of normal in 24 of 152 children; this occurred in five of 11 HIV coinfected children. Liver histology, available in 53 children, showed normal (7%), mild (74%), moderate (17%), or severe (2%) hepatitis. Twenty eight children had received therapy with interferon alfa. Conclusion—Most current paediatric HCV infection in UK and Ireland has been acquired from contaminated blood products, and most children are asymptomatic. There is a need for multicentre trials to inform clinical practice and development of good practice guidelines in this area. Long term follow up of this cohort of HCV infected children is planned to help determine the natural history over the long term of HCV acquired during infancy and childhood. (Arch Dis Child 2000;82:286‐291)

OBJECTIVE To assess the health service costs and benefits for the woman of an earlier HIV diagnosis as a result of antenatal HIV testing. DESIGN A model of maternal disease progression was developed based on the rate of decline in CD4 cell counts and applied to two matched simulated cohorts of women with identical initial CD4 cell levels and decline rates but whose HIV diagnosis occurred at different times as a result of antenatal HIV testing. UK data on CD4 cell count at HIV diagnosis and annual health service costs of care excluding antiretroviral therapy (ART) incurred at defined states of CD4 cell count were taken from published UK data. Costs of triple ART were added and effectiveness modelled by retarding the rate of CD4 cell count decline. Discounting costs at 6% and life-years at 2% per year, the additional costs per life-year gained by screening were calculated. Uncertainty was explored using sensitivity analysis. RESULTS Costs per life-year gained by antenatal diagnosis of women were pound sterling 51258 ($76887) assuming untested women were diagnosed a median of 20.4 months later than tested women, ART was initiated at a CD4 cell count of 350x10(6) cells/l and ART efficacy retarded decline in CD4 cell counts by 40% for life. Sensitivity analyses showed results were most sensitive to the assumed efficacy of lifetime ART and time assumed to HIV diagnosis for women not tested in pregnancy. CONCLUSION This model provides a way of estimating the additional costs and benefits of future care for the woman resulting from an earlier HIV diagnosis through antenatal testing. These should be included with the paediatric costs averted and life-years gained from interventions to reduce mother-to-child transmission in order to evaluate the cost-effectiveness of antenatal screening in different populations and settings.

Patient adherence to combination therapy is a critical component of successful treatment outcomes. While combination therapy is known to be effective in slowing disease progression, the long-term benefit of these therapies can only be sustained if resistant strains of HIV do not emerge. Among factors that can result in the emergence of resistance, non-adherence is perhaps the most amenable to intervention. To maximize intervention efforts, a program of research on adherence is needed. A prerequisite for progress in adherence research is a focused effort on developing reliable and valid methods for measuring adherence that are feasible for patients living with HIV/AIDS. If new adherence assessment procedures cannot be developed, it would be helpful if a consensus on measurement approaches could be achieved. This consensus might propose strategies for matching measurement approaches with research questions and recommendations for the use of multiple measures where appropriate. It is important that research continue to identify psychological, physiological, socio-cultural and environmental factors that are associated with non-adherence in various populations both in the developed and the developing world. Intervention programs that address these risk factors and promote adherence need to be developed and evaluated in controlled clinical trials. These programs will need to be tailored to different populations and cultural groups, and tested in both developed and developing countries where HIV therapies are being prescribed. The results of this research would significantly contribute to efforts to prevent virus breakthrough and, by doing so, assist persons living with HIV/AIDS in achieving the health benefits that the combination therapies offer.

A family clinic providing specialist paediatric and adult medical, testing, counselling, and terminal care services for families living with HIV was set up at a paediatric tertiary care hospital in London in 1991. During the first five years, until April 1996, 185 children from 149 families attended, including 119 infected children, of whom 32 have died. Only 5% of mothers were born in the UK; the rest were born in 24 different countries, the majority in sub-Saharan Africa. Less than a quarter of children were cared for by both parents, 61% by mothers alone, and 11% by guardians or foster parents. Of the adult attendees, 76% were women, and more than half were untested when they first attended the clinic. Provision of a family planning service within the family clinic was initiated as a result of women presenting with unplanned pregnancies. Shared care with local clinics is increasing, but with the complexity around the management of paediatric HIV infection, particularly with regard to antiretroviral treatments, there is need for continued specialist input. Coordination among specialist and locally based family services is required to provide flexible, accessible, and up to date care for families living with HIV infection in London.

By April 1995, 302 cases of vertically acquired HIV infection had been reported through the British Paediatric Association Surveillance Unit. Over 50% of these children had developed an AIDS indicator disease, including nine malignancies (seven cases of non-Hodgkin’s lymphoma (NHL) and two of Kaposi’s sarcoma). There were two other malignancies that were not AIDS indicator diseases. In children less than 5 years of age the incidence of NHL was approximately 2500 times greater than expected in the UK child population. Three children presented with NHL as their AIDS indicator disease and four developed NHL at a median of 14 (range 10‐19) months after the initial diagnosis of AIDS. Six of the seven children died at a median of 6.5 (range 2‐14) months after the diagnosis of NHL. The seventh child responded to treatment and is alive nearly four years later. Histology was available in five cases, of which four were of B cell and one of T cell origin. Epstein-Barr virus was detected in all three patients with NHL where it was sought; all had B cell lymphomas. Although comparatively rare, malignancies occur in children infected with HIV and may be the presenting illness. Paediatricians now need to consider HIV infection as a predisposing cause of childhood cancer, especially NHL. (Arch Dis Child 1997;76:330‐333)

OBJECTIVES: Young children metabolize nevirapine faster than older children/adults. We evaluated nevirapine pharmacokinetics with or without dose-escalation in Zambian, HIV-infected infants/children and its relationship with safety/efficacy. DESIGN: A retrospective pharmacokinetic substudy of the CHAPAS-1 trial. METHODS: HIV-infected, Zambian children were randomized to initiate antiretroviral therapy (ART) with full-dose twice-daily nevirapine versus 2-week nevirapine dose-escalation. Samples taken 3-4 h postmorning-dose 2 weeks after nevirapine initiation were assayed for nevirapine levels. Viral load was measured on available samples at weeks 4 and 48; adverse events were prospectively reported. RESULTS: Of 162 (77%) children with week-2 samples, 79 (49%) were randomized to nevirapine dose-escalation. At ART initiation, median [interquartile range (IQR)] age, weight and CD4% were 5.2 (1.5-8.7) years, 13.0 (8.1-19.0) kg and 13 (8-18)%, respectively; 81 (50%) were male. With full dose, few children aged less than 2 years (3/23, 13%) or more than 2 years (4/60, 7%) had subtherapeutic nevirapine levels (defined as

Contains fulltext : 125375.pdf (Publisher’s version ) (Open Access) OBJECTIVES: To confirm whether 7 days of phenytoin, an enzyme inducer, would decrease the elimination half-life of single-dose nevirapine and to investigate its effect on the development of nevirapine resistance in pregnant, HIV-infected women. METHODS: In a pharmacokinetic pilot trial (NCT01187719), HIV-infected, antiretroviral (ARV)-naive pregnant women >/=18 years old from Zambia and Tanzania and with CD4 cell counts >350 cells/mm(3) were randomized 1 : 1 to a control (zidovudine pre-delivery, single-dose nevirapine/zidovudine/lamivudine at delivery and zidovudine/lamivudine for 7 days post-delivery) or an intervention (control plus 184 mg of phenytoin once daily for 7 days post-delivery) group. Primary endpoints were the pharmacokinetics of and resistance to nevirapine. RESULTS: Thirty-five and 37 women were allocated to the control and intervention groups, with median (IQR) ages of 27 (23-31) and 27 (23-33) years, respectively. Twenty-three and 23 women had detectable nevirapine levels at delivery and subsequent samples in the control and the intervention groups, respectively. Geometric mean (GM) (95% CI) plasma levels of nevirapine at delivery were 1.02 (0.58-1.78) mg/L and 1.14 (0.70-1.86) mg/L in the control and intervention groups, respectively (P = 0.76). One week after delivery, 0/23 (0%) and 15/22 (68%) control and intervention mothers, respectively, had undetectable levels of nevirapine ( 0.28). CONCLUSIONS: Adding 7 days of an enzyme inducer to single-dose nevirapine to prevent mother-to-child transmission of HIV significantly reduced subtherapeutic nevirapine levels by shortening the half-life of nevirapine. As prolonged subtherapeutic nevirapine dosage leads to the emergence of resistance, single-dose nevirapine could be used with phenytoin as an alternative if other ARVs were unavailable.

Background Bacteremia is common in HIV-infected children in Africa, including after start of antiretroviral therapy (ART), but there are limited data on causative pathogens and their antimicrobial sensitivity patterns in this population. Methods We analyzed data on blood cultures taken from HIV-infected children developing acute febrile illness after enrollment to the Antiretroviral Research for Watoto (ARROW) clinical trial in Uganda and Zimbabwe. Patterns of bacterial pathogens and their antimicrobial susceptibilities were determined and bacteremia rates calculated over time from ART initiation. Results A total of 848 blood cultures were obtained from 461 children, of which 123 (14.5%) from 105 children (median age 3.5 years, 51% girls) were culture positive, including 75 (8.8%) with clearly pathogenic organisms. The event rates for positive cultures with clearly pathogenic organisms after 0-1, 2-3, 4-11 and ≥12 months on ART were 13.3, 11.4, 2.1 and 0.3 per 1000 person-months of follow-up, respectively. The pathogens isolated (n; %) were Streptococcus pneumoniae (36; 28.3%), Staphylococcus aureus (11; 8.7%), Klebsiella pneumoniae (6; 4.7%), Pseudomonas aeruginosa (6; 4.7%), Salmonella spp (6; 4.7%), Escherichia coli (5; 3.9%), Haemophilus influenzae (1; 0.8%) and fungal spp (4; 3.1%). Other bacteria of doubtful pathogenicity (n = 52; 42%) were also isolated. Most isolates tested were highly (80-100%) susceptible to ceftriaxone, cefotaxime and ciprofloxacin; very few (~5%) were susceptible to cotrimoxazole; S. pneumoniae had high susceptibility to amoxicillin/ampicillin (80%). Conclusions Rates of proven bacteremia were >20-fold higher immediately after starting ART compared with 12 months later in African HIV-infected children. S. pneumoniae was most commonly isolated, suggesting need for pneumococcal vaccination and effective prophylactic antibiotics.

OBJECTIVE: Success in diagnosing and treating HIV-infected adults has where HIV care and treatment is available turned HIV into a chronic rather than life-limiting disease. Progress meeting the needs of HIV-infected children perinatally and horizontally infected adolescents pregnant women and older people has lagged behind. We review the special needs and barriers to scaling up care and antiretroviral therapy (ART) coverage in these populations. DESIGN AND METHODS: A literature review combined with personal views and operational experience specifically from countries covered by the Evidence for Action programme. RESULTS: Challenges include logistics of diagnosis and treatment in pregnancy difficulties in early infant diagnosis availability of appropriate paediatric formulations management of adolescents and comorbidities in older people. CONCLUSION: Priorities for development need to focus upon the simplification of HIV care to allow provision for all ages at the primary healthcare level. Specific priorities include focused use of virological testing in infants ongoing development of dispersible and scored fixed-dose ART combinations suitable for use across ages development of adolescent-friendly HIV services catering for perinatally and horizontally infected adolescents to improve adherence and reduce onward transmissions simplification of referral pathways to ensure all pregnant women are tested for HIV and commenced on ART and education of healthcare workers on the specific needs of HIV care in older patients. Each priority will be reviewed and potential solutions discussed.

BACKGROUND: In low-income countries, viral load (VL) monitoring of antiretroviral therapy (ART) is rarely available in the public sector for HIV-infected adults or children. Using clinical failure alone to identify first-line ART failure and trigger regimen switch may result in unnecessary use of costly second-line therapy. Our objective was to identify CD4 threshold values to confirm clinically-determined ART failure when VL is unavailable. METHODS: 3316 HIV-infected Ugandan/Zimbabwean adults were randomised to first-line ART with Clinically-Driven (CDM, CD4s measured but blinded) or routine Laboratory and Clinical Monitoring (LCM, 12-weekly CD4s) in the DART trial. CD4 at switch and ART failure criteria (new/recurrent WHO 4, single/multiple WHO 3 event; LCM: CD4

The prevalence of human immunodeficiency virus (HIV) infection in women who have had live births has increased since 1988, particularly in London (Unlinked Anonymous HIV Surveys Steering Group, 1995). In 1994,1 in every 580 women delivering in London was infected with HIV and in some London maternity units this figure was as high as 1 in every 200 women. As HIV infection can be transmitted from mother to child during pregnancy, labour or breastfeeding (vertical transmission), this rising prevalence has particular relevance to the care of these women during pregnancy, labour and the puerperium.

Purpose of the study: To compare body circumferences, skin-fold thickness (SFT) and lipid levels (LL), as measures of lipodystrophy, among antiretroviral therapy (ART)-naive and experienced children at enrolment into the CHAPAS-3 trial. Methods: HIV-infected children in Uganda and Zambia, either ART-naive or on stavudine (d4T) for ≥2years without clinical lipodystrophy, were randomised to receive d4T, abacavir (ABC) or zidovudine (ZDV) with lamivudine and efavirenz (EFV) or nevirapine. At enrolment, mid-upper arm (MUAC) and calf (CC) circumferences, SFT (biceps, triceps, sub-scapular, supra-iliac) and fasting lipids (total cholesterol (TC), low density lipo-protein (LDL), high density lipoprotein (HDL), triglycerides (TRIG)) were measured. Age/sex adjusted z-scores of MUAC, CC, SFT and the sum of SFT (SSF) used Dutch reference data. ART-naive and ART-experienced children were compared with t-tests using Stata v11.0. Summary of results: Among 444 children, 224 (51%) were male and 331 (74.5%) ART-naive. Mean (sd) CD4% was 19.7% (10.2) versus (vs) 34.2% (7.7) in ART-naive vs ART-experienced children. The ART-naive were younger than the ART-experienced children (median [IQR] age 2.5 [1.5, 4.0] vs 6.0 [5.5, 7.0] years, p

Purpose of the study : Virological outcomes and resistance patterns in children initiating PI-based antiretroviral therapy (ART) immediately following HIV-1 diagnosis are not well described. Challenges include maintaining adherence in asymptomatic patients with very high pre-ART viral loads. The CHER trial compared deferred but continuous ART (arm 1) with early limited ART (arms 2 and 3). Methods : LPV/r+ZDV+3TC was commenced either immediately (in 250 of 252 children randomised in arms 2 and 3) or at clinical/immunological progression (103 of 125 children in arm 1). Interruption of ART occurred after 40 (arm 2) or 96 weeks (arm 3) and re-initiation with LPV/r+ZDV+3TC was based on immunologic/clinical criteria. Viral load was measured on all children with a stored specimen at their last visit, having been on initial or restarted ART following interruption (arms 2 and 3) for at least 24 weeks. Children in arms 1, 2 and 3 not initiating ART due to death (16, 0, 0), LTFU (2, 2, 0) or other reason (4, 0, 0) are excluded. Resistance testing was performed on samples with a VL ≥1000 c/ml together with the matched baseline sample, if available. Reverse transcriptase (NRTI and NNRTI) and protease (PI) inhibitor mutations were analysed using a validated in-house population-based sequencing assay and the IAS 2011 mutation list. Results : 377 infants were enrolled; median age 7.4 (IQR 6.7-8.9) weeks, median baseline viral load was log 10 5.7. By end of study (June 2011), 353/377 children had started LPV/r+ZDV+3TC. Median (IQR) age at ART initiation in arms 1, 2 and 3 was 26.1 (19.9 to 40), 7.4 (6.6-8.7) and 7.5 (6.6-9.0) weeks. Median (IQR) duration on ART was 240 (216-252), 243 (200-260) and 240 (194-257) weeks in arms 1, 2 and 3 respectively. HIV-1 RNA was 1000 c/ml (2/5, 8/14, 12/13 in arms 1, 2 and 3) have had resistance tests to date, 9 (41%) had mutations. There were seven with M184V mutations (1, 4, 2 in arms 1, 2 and 3); two with major PI mutations (V82A/L76V) (1 in each of arms 1 and 2); two with major NNRTI mutations (K103N/M230L) (1 in each of arms 2 and 3). 2 of 10 children tested to date had NNRTI mutations prior to starting PI-based triple therapy. Conclusions : Virological response on ART was excellent in this large cohort of infants initiating LPV/r+ZDV+3TC at a very young age, with no differences between randomised strategies, suggesting that planned interruption after early limited ART does not adversely affect virological outcomes. Overall ~40% of those on ART with VL >1000 c/ml had a resistance mutation; PI mutations were infrequent, despite around 5 years on therapy. Ongoing work will investigate impact of length of time with detectable viral load on risk of developing resistance. (Published: 11 November 2012) Citation: Abstracts of the Eleventh International Congress on Drug Therapy in HIV Infection Violari A et al. Journal of the International AIDS Society 2012, 15 (Suppl 4):18085 http://www.jiasociety.org/index.php/jias/article/view/18085 | http://dx.doi.org/10.7448/IAS.15.6.18085

Mother-to-child transmission is the main mode of acquisition of HIV infection for children, and the estimated rate of vertical transmission ranges from 15 to 20% in Europe, 15 to 25% in the US and 25 to 35% in Africa. Vertical transmission is associated with clinical and immunological progression of disease in the mother, breastfeeding and possibly with vaginal delivery. Recently, the findings of the American/French AIDS Clinical Trial Group (ACTG) trial 076 showed that in women with mildly symptomatic HIV disease and no prior treatment with antiretroviral drugs during the pregnancy, zidovudine (ZDV, 3'-azido-3'-deoxythymidine, AZT) reduced the risk of vertical transmission when administered during pregnancy and delivery and to the infant in the first 6 weeks of life. No significant adverse effects were observed in either the mothers or neonates. Although the results of the American/French trial on the use of zidovudine to prevent vertical transmission are encouraging, many questions remain unanswered. The optimal timing of administration of zidovudine is unknown, as is its effectiveness in women with clinical characteristics that differ from those of the women in the trial. Concern has been expressed about the possibility of long term effects of exposure of zidovudine during pregnancy, both for the mother and the infant (of whom 4 out of 5 are uninfected anyway) and the implications for antenatal screening. Further trials with different zidovudine regimens and other strategies to prevent vertical transmission are being planned in several countries.

Background The outbreak of Ebola virus disease in West Africa has claimed more than 11 200 lives with more than 28 000 cases. Infected children under the age of 5 years have a high mortality rate but little is known about disease progression and possible predictors of outcome. Circumstantial factors such as transfer distances from Ebola holding units to Ebola treatment centres and admission with a caregiver might affect outcome. We aimed to identify clinical, epidemiological, and management risk factors for mortality in children with Ebola virus disease. Methods Children under the age of 12 years admitted to 11 Ebola holding units in the Western Area of Sierra Leone from Aug 1, 2014, to April 1, 2015, were eligible for inclusion. Retrospective data were collected from site admission books, case investigation forms, and clinical records, and cross-referenced with district-wide laboratory results, burial records, child protection records, staff interviews, and telephone calls to guardians. Univariate and multivariate analyses were used to identify features independently associated with mortality. Findings 309 children with Ebola virus disease (aged 2 days to 12 years) were admitted (median age 6 years, IQR 3–10). Outcomes were available for 282 children (91%). 161 children (57%) died with 89 deaths (55%) occurring at Ebola holding units and 72 (45%) at Ebola treatment centres. Marked derangement of white cell count, C-reactive protein, and renal and liver function were seen with extensive hypoglycaemia. Up to 60% of children were admitted without a caregiver. Factors that potentially affected mortality such as age, clinical features, delayed attendance, transfer distance, caregiver accompaniment, and medications received are being examined. Multiple imputation is being performed to account for missing data. Interpretation This is the most comprehensive paediatric cohort of Ebola virus disease to date, and the only cohort to incorporate data from both Ebola holding units and Ebola treatment centres. Data sharing between sites is crucial to identify potentially modifiable risk factors and guide future operational responses. Funding This study was funded by Save the Children and supported by the Medical Research Council and the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London.

Background In the absence of antiretroviral therapy (ART), over 50% of HIV-infected infants progress to AIDS and death by 2 years of age. However, there are challenges to initiate ART in early life, including the possibility of drug resistance in the context of prevention of mother-to-child transmission (PMTCT) programs, a paucity of drug choices , uncertain dosing for some medications and long-term toxicities. Key management decisions include when to start ART, what regimen to start, and whether and when to switch or interrupt therapy. This review aims to summarize the currently available evidence on this topic and inform the ART management in HIV-infected children less than 2 years of age. Objectives To evaluate 1) when to start ART in young children; 2) what ART to start with, comparing first-line non-nucleoside reverse transcriptase inhibitor (NNRTI) and PI-based regimens; and 3) whether and when ART should be stopped or switched from a PI-based regimen to an NNRTI-based regimen. Search methods We searched for published studies in the Cochrane HIV/AIDS Review Group Trials Register, The Cochrane Library, Pubmed, EMBASE and CENTRAL. We screened abstracts from relevant conference proceedings and searched for unpublished and ongoing trials in clinical trial registries (ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform). Selection criteria We identified RCTs that recruited perinatally HIV-infected children under 2 years of age without restriction of setting. We rejected trials that did not include children less than 2 years of age, or did not evaluate either timing of ART initiation, choice of drug regimen or treatment switch/interruption strategy. Data collection and analysis Two reviewers independently applied study selection criteria, assessed study quality and extracted data. Effects were assessed using the hazard ratio (HR) for time-to-event outcomes, relative risk for dichotomous outcomes and weighted mean difference for continuous outcomes. Main results Of 1921 records retrieved, 5 studies were eligible for inclusion in the review, addressing when to start treatment (n=2), what to start (n=2) and whether to switch regimen (n=1). Three ongoing studies that address the question of treatment interruption were also identified.Early infant treatment was associated with a 75% reduction (HR=0.25; 95%CI 0.12-0.51; p=0.0002) in mortality or disease progression in the one trial with sufficient power to address this question. In a smaller trial,median CD4 cell count was not significantly different between early and deferred treatment groups 12 months after ART.Regardless of previous exposure to nevirapine for PMTCT, the hazard for treatment failure was 2.01 (95%CI 1.47, 2.77) times higher in children starting ART with a NVP-based regimen compared to those starting with a LPV/r-based regimen (p 1000 copies/mL) was higher among children who switched to NVP compared to those who remained on LPV/r (HR=10.19, 95% CI 2.36, 43.94, p=0.002). Authors' conclusions Immediate ART reduces morbidity and mortality among infants and may improve neurodevelopmental outcome. However It remains unclear whether all children diagnosed with HIV infection between 1-2 years of age should start ART, as has been recommended by the World Health Organization on practical grounds.The available evidence suggests that a LPV/r-based first-line regimen is more potent than NVP, regardless of PMTCT exposure status. However, this finding provides a dilemma to policy-makers because higher cost, poor palatability, inconvenient formulation and cold chain requirements make LPV/r a more costly and challenging first-line regimen. An alternative approach to long-term LPV/r is switching to NVP (maintaining the NRTI backbone) once virological suppression is achieved. This strategy looked promising in the one trial undertaken, but may be difficult to implement in the absence of VL testing. Ongoing trials are exploring the possibility of starting early ART and interrupting treatment beyond the critical period of rapid disease progression and neurological development. Further evidence is urgently required to better inform policy on first-line treatment recommendations in young children and more robust data addressing non-virological outcomes are also needed.

Background Boosted protease inhibitor (bPI) monotherapy (bPImono) potentially has substantial cost, safety and operational benefits. It has never been evaluated as second-line antiretroviral therapy (ART) in Africa. Methods After 24 weeks of lopinavir/ritonavir- containing second-line therapy, DART participants were randomized to remain on combination therapy (CT), or change to bPI-mono maintenance (SARA trial; ISRCTN53817258). Joint primary end points were CD4+ T-cell changes 24 weeks later and serious adverse events (SAEs); retrospectively assayed viral load (VL) was a secondary end point. Analyses were intention-to-treat. Results A total of 192 participants were randomized to CT ( n=95) or bPImono ( n=97) and followed for median 60 weeks (IQR 45–84). Participants received median 4.0 years (IQR 3.5–4.4) first-line ART. Median CD4+ T-cell count at first-line failure was 86 cells/mm3 (47–136), increasing to 245 cells/mm3 (173–325) after 24-week induction when 77% had VL+ T-cell increase was 42 (CT, n=85) versus 49 cells/mm3 (bPImono, n=88; adjusted difference 13 [95% CI -15, 43], P=0.37; non-inferior compared with predetermined non-inferiority margin [-33]). Virological suppression was greater for CT versus bPImono (trend P=0.009): 77% (70/91) versus 60% (56/94) were 24 weeks after randomization, and 5 (2 CT and 3 bPImono) experienced SAEs ( P=0.51). Conclusions bPImono following a 24-week second-line induction was associated with similar CD4+ T-cell response, but increased low-level viraemia, generally without protease inhibitor resistance. Longer-term trials are needed to provide definitive evidence about effectiveness in Africa.

Item does not contain fulltext OBJECTIVE:: 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.

CITATION: Prendergast, A. J. et al. 2012. Treatment of young children with HIV infection : using evidence to inform policymakers. PLoS Medicine, 9(7): e1001273, doi:10.1371/journal.pmed.1001273.

Item does not contain fulltext BACKGROUND: World Health Organization guidelines recommend zidovudine + lamivudine for 7 days from labor onset in HIV-infected women receiving single-dose nevirapine (sdNVP) to cover prolonged subtherapeutic nevirapine concentrations. Although effective, this is complicated and does not eliminate resistance; alternative strategies could add benefit. METHODS: Antiretroviral-naive HIV-infected pregnant women aged 18-40 years, with CD4 >200 cells per cubic millimeter, able to regularly attend the antenatal clinics in Moshi, Tanzania, were enrolled 1:1 by alternate allocation to receive 200 mg sdNVP alone or in combination with open-label 400-mg single-dose carbamazepine (sdNVP/CBZ) at delivery (ClinicalTrials.gov NCT00294892). The coprimary outcomes were nevirapine plasma concentrations 1 week and nevirapine resistance mutations 6 weeks postpartum. Analyses were based on those still eligible at delivery. RESULTS: Ninety-seven women were assigned to sdNVP and 95 to sdNVP/CBZ during pregnancy, of whom 75 sdNVP and 83 sdNVP/CBZ were still eligible at delivery at study sites. The median (interquartile range) nevirapine plasma concentration was 1.55 (0.88-1.84) mg/L in sdNVP (n = 61) and 1.40 (0.93-1.97) mg/L in sdNVP/CBZ (n = 72) at delivery (P = 0.91), but 1 week later was significantly lower in sdNVP/CBZ [n = 63; 0.09 (0.05-0.20) mg/L] than in sdNVP [n = 52; 0.20 (0.09-0.31) mg/L; rank-sum: P = 0.004] (geometric mean ratio: 0.64, 95% confidence interval: 0.43 to 0.96; P = 0.03). Six weeks postpartum, nevirapine mutations were observed in 11 of 52 (21%) in sdNVP and 6 of 55 (11%) in sdNVP/CBZ (odds ratio = 0.46, 95% confidence interval: 0.16 to 1.34; P = 0.15). CONCLUSIONS: Addition of single-dose carbamazepine to sdNVP at labor onset in HIV-infected, pregnant women did not affect nevirapine plasma concentration at delivery, but significantly reduced it 1 week postpartum, with a trend toward fewer nevirapine resistance mutations.

Diana Gibb and colleagues investigate the effect of in utero tenofovir exposure by analyzing the pregnancy and infant outcomes of HIV-infected women enrolled in the DART trial., Background Few data have described long-term outcomes for infants born to HIV-infected African women taking antiretroviral therapy (ART) in pregnancy. This is particularly true for World Health Organization (WHO)–recommended tenofovir-containing first-line regimens, which are increasingly used and known to cause renal and bone toxicities; concerns have been raised about potential toxicity in babies due to in utero tenofovir exposure. Methods and Findings Pregnancy outcome and maternal/infant ART were collected in Ugandan/Zimbabwean HIV-infected women initiating ART during The Development of AntiRetroviral Therapy in Africa (DART) trial, which compared routine laboratory monitoring (CD4; toxicity) versus clinically driven monitoring. Women were followed 15 January 2003 to 28 September 2009. Infant feeding, clinical status, and biochemistry/haematology results were collected in a separate infant study. Effect of in utero ART exposure on infant growth was analysed using random effects models. 382 pregnancies occurred in 302/1,867 (16%) women (4.4/100 woman-years [95% CI 4.0–4.9]). 226/390 (58%) outcomes were live-births, 27 (7%) stillbirths (≥22 wk), and 137 (35%) terminations/miscarriages (0.4). Of 219 surviving infants, 182 (83%) enrolled in the follow-up study; median (interquartile range [IQR]) age at last visit was 25 (12–38) months. From mothers' ART, 62/9/111 infants had no/20%–89%/≥90% in utero tenofovir exposure; most were also zidovudine/lamivudine exposed. All 172 infants tested were HIV-negative (ten untested). Only 73/182(40%) infants were breast-fed for median 94 (IQR 75–212) days. Overall, 14 infants died at median (IQR) age 9 (3–23) months, giving 5% 12-month mortality; six of 14 were HIV-uninfected; eight untested infants died of respiratory infection (three), sepsis (two), burns (one), measles (one), unknown (one). During follow-up, no bone fractures were reported to have occurred; 12/368 creatinines and seven out of 305 phosphates were grade one (16) or two (three) in 14 children with no effect of in utero tenofovir (p>0.1). There was no evidence that in utero tenofovir affected growth after 2 years (p = 0.38). Attained height- and weight for age were similar to general (HIV-uninfected) Ugandan populations. Study limitations included relatively small size and lack of randomisation to maternal ART regimens. Conclusions Overall 1-year 5% infant mortality was similar to the 2%–4% post-neonatal mortality observed in this region. No increase in congenital, renal, or growth abnormalities was observed with in utero tenofovir exposure. Although some infants died untested, absence of recorded HIV infection with combination ART in pregnancy is encouraging. Detailed safety of tenofovir for pre-exposure prophylaxis will need confirmation from longer term follow-up of larger numbers of exposed children. Trial registration www.controlled-trials.com ISRCTN13968779 Please see later in the article for the Editors' Summary, Editors' Summary Background Currently, about 34 million people (mostly in low- and middle-income countries) are infected with HIV, the virus that causes AIDS. At the beginning of the epidemic, more men than women were infected with HIV but now about half of all people living with HIV/AIDS are women, most of who became infected through unprotected sex with an infected partner. In sub-Saharan Africa alone, 12 million women are HIV-positive. Worldwide, HIV/AIDS is the leading cause of death among women of child-bearing age. Moreover, most of the 400,000 children who become infected with HIV every year acquire the virus from their mother during pregnancy or birth, or through breastfeeding, so-called mother-to-child transmission (MTCT). Combination antiretroviral therapy (ART)—treatment with cocktails of powerful antiretroviral drugs—reduces HIV-related illness and death among women, and ART given to HIV-positive mothers during pregnancy and delivery and to their newborn babies greatly reduces MTCT. Why Was This Study Done? Because of ongoing international efforts to increase ART coverage, more HIV-positive women in Africa have access to ART now than ever before. However, little is known about pregnancy outcomes among HIV-infected African women taking ART throughout pregnancy for their own health or about the long-term outcomes of their offspring. In particular, few studies have examined the effect of taking tenofovir (an antiretroviral drug that is now recommended as part of first-line ART) throughout pregnancy. Tenofovir readily crosses from mother to child during pregnancy and, in animal experiments, high doses of tenofovir given during pregnancy caused bone demineralization (which weakens bones), kidney problems, and impaired growth among offspring. In this study, the researchers analyze data collected on pregnancy and infant outcomes among Ugandan and Zimbabwean HIV-positive women who took ART throughout pregnancy in the Development of AntiRetroviral Therapy in Africa (DART) trial. This trial was designed to test whether ART could be safely and effectively delivered in Africa without access to the expensive laboratory tests that are routinely used to monitor ART toxicity and efficacy in developed countries. What Did the Researchers Do and Find? The pregnancy outcomes of 302 women who became pregnant during the DART trial and information on birth defects among their babies were collected as part of the DART protocol; information on the survival, growth, and development of the infants born to these women was collected in a separate infant study. Most of the women who became pregnant were taking tenofovir-containing ART before and throughout their pregnancies. 58% of the pregnancies resulted in a live birth, 7% resulted in a stillbirth (birth of a dead baby at any time from 22 weeks gestation to the end of pregnancy), and 35% resulted in a termination or miscarriage (before 22 weeks gestation). Of the 226 live births, seven infants died within 2 weeks and seven had birth defects. Similar proportions of the infants exposed and not exposed to tenofovir during pregnancy died soon after birth or had birth defects. Of the 182 surviving infants who were enrolled in the infant study, 14 subsequently died at an average age of 9 months, giving a 1-year mortality of 5%. None of the surviving children who were tested (172 infants) were HIV infected. No bone fractures or major kidney problems occurred during follow-up and prebirth exposure to tenofovir in utero had no effect on growth or weight gain at 2 years (in contrast to a previous US study). What Do These Findings Mean? By showing that prebirth tenofovir exposure does not affect pregnancy outcomes or increase birth defects, growth abnormalities, or kidney problems, these findings support the use of tenofovir-containing ART during pregnancy among HIV-positive African women, and suggest that it could also be used to prevent women of child-bearing age acquiring HIV-infection heterosexually. Notably, the observed 5% 1-year infant mortality is similar to the 2%–4% infant mortality normally seen in the region. The absence of HIV infection among the infants born to the DART participants is also encouraging. However, this is a small study (only 111 infants were exposed to tenofovir throughout pregnancy) and women were not randomly assigned to receive tenofovir-containing ART. Consequently, more studies are needed to confirm that tenofovir exposure during pregnancy does not affect pregnancy outcomes or have any long-term effects on infants. Such studies are essential because the use of tenofovir as a treatment for women who are HIV-positive is likely to increase and tenofovir may also be used in the future to prevent HIV acquisition in HIV-uninfected women. Additional Information Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001217. Information is available from the US National Institute of Allergy and infectious diseases on all aspects of HIV infection and AIDS NAM/aidsmap provides basic information about HIV/AIDS, and summaries of recent research findings on HIV care and treatment (in several languages) Information is available from Avert, an international AIDS nonprofit on many aspects of HIV/AIDS, including detailed information on HIV/AIDS treatment and care, women, HIV and AIDS, children, HIV and AIDS, and on HIV/AIDS and pregnancy (some information in English and Spanish); personal stories of women living with HIV are available More information about the DART trial is available Additional patient stories about living with HIV/AIDS are available through the nonprofit website Healthtalkonline

In order to review the clinical course, laboratory findings, and outcome of children with vertically acquired HIV infection and Pneumocystis carinii pneumonia, questionnaires were sent to paediatricians in the British Isles who had reported P carinii pneumonia and HIV infection through the British Paediatric Surveillance Unit (BPSU). Paediatric reports from the BPSU are linked to reports of pregnancies in HIV positive women and laboratory reports. P carinii pneumonia was the most frequently reported AIDS indicator disease at AIDS diagnosis, occurring in 22/56 (40%) children born in the British Isles; in a further two children P carinii pneumonia occurred after another AIDS indicator disease. The median age at P carinii pneumonia diagnosis was 4.1 (1.4-27.3) months and in 48% it occurred with other AIDS indicator diseases. Despite intensive treatment the three month survival was only 38%. The nine children surviving P carinii pneumonia subsequently developed further AIDS indicator diseases, in particular HIV encephalopathy and four have since died. P carinii pneumonia was present at AIDS diagnosis in 65% of children developing AIDS in the first year of life and caused 82% of infant deaths. Most children were not known to be at risk of HIV until they presented with P carinii pneumonia. Children with HIV infection develop P carinii pneumonia at an early age and have a poor outcome. Increased awareness of the condition is required to initiate early treatment. Prevention may be a compelling incentive for screening in pregnancy, but further study is required to quantify the risks and benefits of initiating early P carinii pneumonia prophylaxis as well as the impact this might have on life expectancy.

The pharmacokinetics of zidovudine in 7 haemophiliac children with symptomatic human immunodeficiency virus disease were assessed after administration of oral dosages of 150 and 180 mg/m2 4 times daily separated by at least 2 weeks. The mean duration of zidovudine treatment was 3 months (range 2 to 5 months). The following mean (± SD) pharmacokinetic parameters were determined with the lower and higher doses, respectively; maximum plasma zidovudine concentration 6.34 ± 3.06 vs 7.09 ± 3.56 µmol/L, terminal half-life 0.84 ± 0.10 vs 0.94 ± 0.25h, and appararent oral clearance 48.8 ± 5.7 vs 54.2 ± 11.3 ml/min/kg. Plasma concentrations of the metabolite 3’-azido-3’-deoxy-5’-β-D-glucopyranosyl thymidine (GZDV) were 2- to 3-fold greater than those of zidovudine, and the terminal portion of the plasma concentration profile of GZDV declined in parallel with that of zidovudine. The pharmacokinetic parameters of zidovudine in these children were very similar to those previously observed in adults. However, there is a suggestion that the apparent oral clearance may be slightly greater in children (present study 49 to 54 ml/min/kg) than in adults (approximately 40 ml/min/kg).

Background As HIV-infected infants have high mortality, the World Health Organization now recommends initiating antiretroviral therapy as early as possible in the first year of life. However, in many settings, laboratory diagnosis of HIV in infants is not readily available. We aimed to develop a clinical algorithm for HIV presumptive diagnosis in infants < 10 weeks old using screening data from the Children with HIV Early Antiretroviral therapy (CHER) study in South Africa. HIV-infected and HIV-uninfected exposed infants < 10 weeks of age were identified through Vertical Transmission Prevention programs. Clinical and laboratory data were systematically recorded, groups were compared using Kruskal-Wallis, analysis of variance (ANOVA), and Fisher's exact tests. Receiver Operating Characteristic (ROC) curves were compiled using combinations of clinical findings. Results 417 HIV-infected and 125 HIV-exposed, uninfected infants, median age 46 days (IQR 38-55), were included. The median CD4 percentage in HIV-infected infants was 34 (IQR 28-41)%. HIV-infected infants had lower weight-for-age, more lymphadenopathy, oral thrush, and hepatomegaly than exposed uninfected infants (Adjusted Odds Ratio 0.51, 8.8, 5.6 and 23.5 respectively; p < 0.001 for all). Sensitivity of individual signs was low (< 20%) but specificity high (98-100%). If any one of oral thrush, hepatomegaly, splenomegaly, lymphadenopathy, diaper dermatitis, weight < 50th centile are present, sensitivity for HIV infection amongst HIV-exposed infants was 86%. These algorithms performed similarly when used to predict severe immune suppression. Conclusions A combination of physical findings is helpful in identifying infants most likely to be HIV-infected. This may inform management algorithms and provide guidance for focused laboratory testing in some settings, and should be further validated in these settings and elsewhere.

Background The aim of this study was to investigate long-term renal function in HIV-infected adults initiating antiretroviral therapy (ART) with a CD4+ T-cell count 3 in Africa. Methods This was an observational analysis within the DART trial randomizing 3,316 adults to routine laboratory and clinical monitoring (LCM) or clinically driven monitoring (CDM). Serum creatinine was measured pre-ART (all ≤360 μmol/l), at weeks 4 and 12, then every 12 weeks for 4-5 years; estimated glomerular filtration rate (eGFR) was determined using the Cockcroft-Gault formula. We analysed eGFR changes, and cumulative incidences of eGFR2 and chronic kidney disease (CKD; 2 or 25% decrease if 2 pre-ART; confirmed >3 months). Results At ART initiation, median CD4+ T-cell count was 86 cells/mm3; 1,492 (45%) participants had mild (60–2), 237 (7%) moderate (30–2) and 7 (0.2%) severe (15–2) decreases in eGFR. First-line ART was zidovudine/lamivudine plus tenofovir (74%), abacavir (9%) or nevirapine (17%). By 4 years, cumulative incidence of eGFR2 was 2.8% ( n=90) and CKD was 5.0% ( n=162). Adjusted eGFR increases to 4 years were 1, 9 and 6 ml/min/1.73 m2 with tenofovir, abacavir and nevirapine, respectively ( P2 for LCM and CDM, respectively ( P=0.005; 2 and 3 ml/min/1.73 m2 to 5 years; P=0.81). Conclusions On all regimens and monitoring strategies, severe eGFR impairment was infrequent; differences in eGFR changes were small, suggesting that first-line ART, including tenofovir, can be given safely without routine renal function monitoring.

Background We examined the prevalence of ritonavir-boosted darunavir (DRV) resistance-associated mutations (RAMs) in HIV-infected children in the UK to determine the drug's potential clinical utility as a first-line or second- line protease inhibitor (PI). Methods The prevalence of DRV RAMs, identified from IAS 2010 and Stanford, and the Stanford susceptibility score, were estimated in PI-naive and PI-experienced children in the Collaborative HIV Paediatric Study and the UK HIV Drug Resistance Database 1998–2008. Associations between type/duration of PI exposure and area under the viraemia curve on PI with the number of RAMs were investigated using multivariate Poisson regression. Results A total of 17/417 (4%) children with a resistance test when PI-naive had one IAS DRV RAM, and 1 had a Stanford mutation; none had multiple DRV RAMs. A total of 177 PI-experienced children had a test after a median 2.7 years (IQR 1.1–5.2) on PIs; 19 (11%) had one IAS DRV RAM, 7 (4%) had two RAMs, 1 (0.6%) had three RAMs and 1 (0.6%) had four RAMs. DRV RAMs were independently associated with increased years on a PI, a larger area under the viraemia curve since starting PIs, and any exposure to PIs other than lopinavir (all P≤0.05). Only 6 (3%) PI-experienced children had intermediate-level DRV/ritonavir resistance; none had high-level resistance. Conclusions DRV resistance was negligible in PI-naive children and those with lopinavir PI exposure alone. However resistance increased with increasing time, and with higher levels of viraemia, on PIs. Once-daily DRV/ritonavir would be valuable as a second PI or an alternative first PI, particularly if coformulated with a booster in an appropriate formulation for children.

Methods We randomly assigned children with severe febrile illness and impaired perfusion to receive boluses of 20 to 40 ml of 5% albumin solution (albumin-bolus group) or 0.9% saline solution (saline-bolus group) per kilogram of body weight or no bolus (control group) at the time of admission to a hospital in Uganda, Kenya, or Tanzania (stratum A); children with severe hypotension were randomly assigned to one of the bolus groups only (stratum B). All children received appropriate antimicrobial treatment, intravenous maintenance fluids, and supportive care, according to guidelines. Children with malnutrition or gastroenteritis were excluded. The primary end point was 48-hour mortality; secondary end points included pulmonary edema, increased intracranial pressure, and mortality or neurologic sequelae at 4 weeks. Results The data and safety monitoring committee recommended halting recruitment after 3141 of the projected 3600 children in stratum A were enrolled. Malaria status (57% overall) and clinical severity were similar across groups. The 48-hour mortality was 10.6% (111 of 1050 children), 10.5% (110 of 1047 children), and 7.3% (76 of 1044 children) in the albumin-bolus, saline-bolus, and control groups, respectively (relative risk for saline bolus vs. control, 1.44; 95% confidence interval [CI], 1.09 to 1.90; P = 0.01; relative risk for albumin bolus vs. saline bolus, 1.01; 95% CI, 0.78 to 1.29; P = 0.96; and relative risk for any bolus vs. control, 1.45; 95% CI, 1.13 to 1.86; P = 0.003). The 4-week mortality was 12.2%, 12.0%, and 8.7% in the three groups, respectively (P = 0.004 for the comparison of bolus with control). Neurologic sequelae occurred in 2.2%, 1.9%, and 2.0% of the children in the respective groups (P = 0.92), and pulmonary edema or increased intracranial pressure occurred in 2.6%, 2.2%, and 1.7% (P = 0.17), respectively. In stratum B, 69% of the children (9 of 13) in the albuminbolus group and 56% (9 of 16) in the saline-bolus group died (P = 0.45). The results were consistent across centers and across subgroups according to the severity of shock and status with respect to malaria, coma, sepsis, acidosis, and severe anemia. Conclusions Fluid boluses significantly increased 48-hour mortality in critically ill children with impaired perfusion in these resource-limited settings in Africa. (Funded by the Medical Research Council, United Kingdom; FEAST Current Controlled Trials number, ISRCTN69856593.)