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Aim To describe the trajectory of clinical signs in children who developed human immunodeficiency virus encephalopathy (HIVE) after starting early antiretroviral therapy (ART). Method This was a retrospective case-cohort description of HIVE among Cape Town participants from the Children with HIV Early AntiRetroviral treatment (CHER) trial. Criteria for HIVE diagnosis were at least two of: (1) acquired central motor deficit, (2) impaired brain growth, and (3) failure to attain or loss of developmental milestones in the absence of an alternative aetiology. Results Of 133 surviving participants who initiated ART at a median age of 9 weeks and who were followed until a median age of 6 years, 20 (12%) developed HIVE at a median age 31 months (interquartile range 19-37). In these, the first neurological deterioration was noticed at a median age of 19 months, when 16 were on ART and nine had undetectable HIV viral load for a median of 12 months. Signs of upper motor neurons were present in 18, of whom 12 resolved and four had persistent spastic diplegia; 19 had motor delay, of whom 14 resolved; 12 had language delay, of whom 11 resolved; and 16 had impaired brain growth, of whom only five recovered. For the 16 participants already on ART at HIVE diagnosis, regimens were not altered in response to diagnosis. Interpretation HIVE may occur despite early ART initiation and virological suppression and then resolve on unchanged ART, most likely as intrathecal inflammation subsides. What this paper adds Despite suppressive antiretroviral therapy, children can develop human immunodeficiency virus encephalopathy, The most common manifestations are motor deficits and impaired brain growth. Most experience improvement, with many resolving without additional intervention.

Background We explored the effects of predominant breastfeeding on infection-related hospitalization (uncommon outcome), over the first year of life, using the Mother Infant Health cohort study (MIHS), and the effect of early antiretroviral treatment (ART) on viral suppression (< 400 copies/mL) (common outcome), in children aged 7 to 12 weeks, using a subset of the Children with HIV Early AntiRetroviral Treatment (CHER) clinical trial data. We assessed the sensitivity of findings to different models to account for dependency of uncommon and common binary outcome. Methods We fitted generalized linear mixed model with (1) random intercept and (2) random slope, generalized estimating equations (GEE) with 3) an exchangeable correlation structure; 4) autoregressive correlation structure of order 1 (AR1) and 5) unstructured correlation structure and 6) logistic regression model. Results Eighty four and 119 children from MIHS were non-predominantly and predominantly breastfed, respectively. There were 34 infection-related hospitalizations overall. Most infants were hospitalized once, except for four with two hospitalizations. We analysed 88 HIV-infected children from the CHER trial. On average, a child achieved viral suppression twice, range of one to four. The effect of predominant breastfeeding on infection-related hospitalization was similar across all models, except for the GEE with AR1 that had a high estimate (wider confidence intervals). The effect of early ART exposure on viral suppression varied across models. Conclusions The sensitivity of estimates to the method of analysis was driven by frequency of the outcome.

Increased aortic stiffness is an important predictor of cardiovascular disease (CVD). It remains controversial whether HIV infected persons have increased aortic stiffness at the time of HIV diagnosis. An explorative, case-control study was performed using carotid-femoral pulse wave velocity (PWV) in a newly diagnosed, antiretroviral treatment (ART)-naïve cohort with modest baseline cardiovascular risk. We recruited 85 newly diagnosed adults without known CVD from health care facilities in South Africa (43 female; mean age 33). Median CD4 count was 285, IQR 156-393 cells/µL. Twenty two HIV uninfected controls were recruited from the same facilities (8 female; mean age 33). PWV was measured using the Vicorder module (Skidmore Medical, United Kingdom) using a corrective factor of 0.8. The HIV infected group's mean PWV measured 11% higher than controls (5.88 vs 5.28 m/s; P = .02). Median aortic distensibility in HIV infected persons was 18% lower than controls (0.37 vs 0.45 mm Hg-1; P = .009). Multivariate analysis revealed that the difference in PWV between groups remained significant when corrected for age, sex, mean blood pressure and kidney function (mean difference 0.52 m/s; P = .01). Mean blood pressure, estimated glomerular filtration rate, HIV infection per se, age and male sex were important associations with increased PWV. Our study provides evidence for increased aortic stiffness in ART naïve adults already demonstrable at the time of HIV diagnosis. The cohort's young age and recent HIV diagnosis makes atherosclerosis a less likely explanation for the difference. Alternative, potentially reversible, explanations that require further research include vasomotor tone abnormalities and endothelial dysfunction.

We describe 4 Children with HIV Early Antiretroviral Therapy trial participants with late-onset HIV encephalopathy despite long-standing viral suppression in blood and undetectable HIV DNA and RNA polymerase chain reaction in cerebrospinal fluid. Extensive investigations revealed no alternative etiology. Reassuringly, all 4 experienced slow spontaneous recovery despite no change in antiretroviral therapy. Virally suppressed HIV-infected children remain at risk for fluctuating neurologic signs and symptoms.

Background: Most adult cardiovascular disease begins in childhood. Given the burgeoning obesity pandemic in children worldwide, there is a need for precise and scalable surveillance methods to detect subclinical cardiovascular disease in children and adolescents. Early detection allows early intervention and intensified primary prevention strategies in affected individuals. Carotid-femoral pulse wave velocity (PWV) directly measures arterial wall stiffness, an early feature of atherosclerosis. Calculation of PWV in growing children requires an accurate estimation of the true distance travelled by the aorto-femoral pressure wave, using surface anatomy landmarks. However, a variety of methods are used to estimate this distance, and these have not previously been investigated in growing children and adolescents. We sought to investigate this by comparing true arterial path length measured on computerized tomography (CT) scans, with a variety of estimations based on surface anatomy landmarks. Methods: Arterial path lengths were measured using multi-planar reformation (MPR) imaging software. These measurements were then compared with the surface anatomy measurements obtained using the same MPR imaging software. The fidelity of a variety of arterial path length estimation methods was tested. Results: The surface anatomy distance between the suprasternal notch and the angle of the mandible (PWV recording site in the neck), should be adjusted using the formula y=4.791+(1.0534*x). This value subtracted from the unadjusted distance from the suprasternal notch to the umbilicus, through the mid-inguinal crease to the femoral PWV recording site, provides the simplest reliable approximation of true intraluminal distance travelled. Conclusions: There is high correlation between the surface anatomy distances and the arterial path lengths they represent; however, these are not equal. Most surface anatomy measurements require adjustment using the formulae that we have provided, to accurately estimate the true distance travelled by the pulse wave.

Stavudine remains a useful replacement option for treatment for HIV+ children. WHO reduced the adult dose to 30 mg twice daily, which maintains efficacy and lowers mitochondrial toxicity., Stavudine remains a useful replacement option for treatment for HIV+ children. WHO reduced the adult dose to 30 mg twice daily, which maintains efficacy and lowers mitochondrial toxicity. We explored intracellular stavudine triphosphate levels in children receiving a reduced dose of 0.5 to 0.75 mg/kg of body weight twice daily to investigate whether a similar dose optimization can safely be made. A population pharmacokinetic model was developed to describe the pharmacokinetics of intracellular stavudine triphosphate in 23 HIV+ children and 24 HIV+ adults who received stavudine at 0.5 mg/kg and 20 mg twice daily for 7 days, respectively. Simulations were employed to optimize the pediatric dosing regimen to match exposures in adults receiving the current WHO-recommended dose of 30 mg twice daily. A biphasic disposition model with first-order appearance and disappearance described the pharmacokinetics of stavudine triphosphate. The use of allometric scaling with fat-free mass characterized well the pharmacokinetics in both adults and children, and no other significant effect could be detected. Simulations of 30 mg twice daily in adults predicted median (interquartile range [IQR]) stavudine triphosphate minimum drug concentration (Cmin) and maximum drug concentration (Cmax) values of 13 (10 to 19) and 45 (38 to 53) fmol/106 cells, respectively. Targeting this exposure, simulations in HIV+ children were used to identify a suitable weight-band dosing approach (0.5 to 0.75 mg/kg), which was predicted to achieve median (IQR) Cmin and Cmax values of 13 (9 to 18) and 49 (40 to 58) fmol/106 cells, respectively. Weight-band dosing using a stavudine dose of 0.5 to 0.75 mg/kg is proposed, and it shows comparable exposures to adults receiving the current WHO-recommended dose of 30 mg twice daily. Our pharmacokinetic results suggest that the decreased stavudine dose in children >2 years would have a reduced toxic effect while retaining antiretroviral efficacy.

BackgroundFollowing widespread use of stavudine, a thymidine analogue, in antiretroviral therapy (ART) over the past three decades, up to a third of children developed lipoatrophy (LA) and/or lipohypertrophy (LH). Following phasing-out of stavudine, incidence of newly-diagnosed LA and LH declined dramatically. However, the natural history of existing cases should be explored, particularly with prolonged protease inhibitor exposure.MethodsThe Collaborative HIV Paediatric Study (CHIPS) is a multicentre cohort study of most HIV-infected children in the United Kingdom and Ireland. Those on ART with a LA/LH assessment recorded in 2003-2011 were included. Assessments were completed annually by consultant physicians. Using the 0-3 grading system, LA or LH was defined as grade 2 or 3. Resolution was defined as return to grade 1 or 0 in all body regions.ResultsOf 1345 children followed for median (IQR) 5.5 (2.9, 8.2) years after ART initiation, 30 developed LA and 27 developed LH, all at least 2 years after ART initiation. Median age at LA diagnosis was 11 (10, 13) years and at LH diagnosis was 13 (11, 15) years. Children with LA were more likely white (pConclusionsPrevalence of LA and LH were low, with some resolution noted, especially for LA. More long-term data are needed.

Owing to significant dose-related toxicity, the adult stavudine dose was reduced in 2007. The paediatric dose, however, has not been reduced. Although the intended paediatric dose is 1 mg/kg twice daily (b.i.d.), the current weight-band dosing approach results in a mean actual dose of 1.23±0.47 mg/kg. Both efficacy and mitochondrial toxicity depend on the concentration of the intracellular metabolite stavudine triphosphate (d4T-TP). We simulated the effect of reducing the paediatric dose to 0.5 mg/kg. A physiologically-based pharmacokinetic model consisting of 13 tissue compartments plus a full ADAM model was used to describe the elimination of stavudine. The volume of distribution at steady-state and apparent oral clearance were simulated and the resulting AUC profile was compared with literature data in adult and paediatric populations. A biochemical reaction model was utilised to simulate intracellular d4T-TP levels for both the standard and proposed reduced paediatric doses. Simulated and observed exposure after oral dosing showed adequate agreement. Mean steady-state d4T-TP for 1.23 mg/kg b.i.d. was 27.9 (90% CI 27.0-28.9) fmol/10(6) cells, 25% higher than that achieved by the 40 mg adult dose. The 0.5 mg/kg dose resulted in d4T-TP of 13.2 (12.7-13.7) fmol/10(6) cells, slightly higher than the adult dose of 20 mg b.i.d. [11.5 (11.2-11.9) fmol/10(6) cells], which has excellent antiviral efficacy and substantially less toxicity. Current paediatric dosing may result in even higher d4T-TP than the original 40 mg adult dose. Halving the paediatric dose would significantly reduce the risk of mitochondrial toxicity without compromising antiviral efficacy.

PURPOSE OF REVIEW: Perinatally HIV-infected adolescents may be at increased risk of non-infectious co-morbidities later in life. This review summarizes recent advances in the understanding of non-communicable diseases (NCD) among HIV-infected adolescents in high-income and lower-middle-income countries, and identifies key questions that remain unanswered. We review atherosclerotic vascular disease (AVD), chronic bone disease (CBD), chronic kidney disease (CKD), and chronic lung disease (CLD). RECENT FINDINGS: Persistent immune activation and inflammation underlie the pathogenesis of AVD, highlighting the importance of treatment adherence and maintenance of viral suppression, and the need to evaluate interventions to decrease risk. Tenofovir disoproxil fumarate (TDF) and trials of vitamin D supplementation have been the focus of recent studies of CBD with limited studies to date evaluating tenofovir alafenamide as an alternative to TDF for decreasing risk for bone and renal adverse effects among HIV-infected adolescents. Recent studies of CKD have focused primarily on estimating prevalence in different settings while studies of CLD are limited. SUMMARY: As perinatally HIV-infected children age into adolescence and adulthood with effective long-term ART, it is necessary to continue to evaluate their risks for non-infectious co-morbidities and complications, understand mechanisms underlying their risks, and identify and evaluate interventions specifically in this population.

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

Background Stavudine, a nucleoside reverse transcriptase inhibitor, is used commonly to treat HIV-infected children in the developing world. The paediatric liquid formulation presents major logistical difficulties in rural and resource-limited areas, and prescribers are frequently forced to employ off-label ‘opened capsule’ dosing methods using the adult capsule. The South African Department of Health (DoH) has advised that caregivers should be instructed to disperse the contents of an adult capsule in 5 ml water and then withdraw the required dose using a syringe. The bioavailability of stavudine using the opened capsule dosing method has not previously been validated. Methods This was a randomized crossover pharmacokinetic study with each subject serving as his/her own control. A total of 28 healthy HIV-negative adult volunteers were randomized on a 1:1 basis to receive one of the two generic preparations typically available in state hospitals. They were then further randomized to receive either intact or opened 30 mg capsules. After 1 week, those who initially received intact capsules, were given opened capsules and vice versa. The capsule dispersion technique used was identical to that prescribed by the DoH. Serial blood samples were collected and plasma stavudine concentrations were assayed by liquid chromatography tandem mass spectrometry. Stavudine pharmacokinetics were analysed using non-compartmental methods and formulations were compared using ANOVA. Results Plasma drug exposure after stavudine administration as a solution using an opened capsule dosing method was found to be bioequivalent to intact capsule administration. This was true for both generics tested. Conclusions The opened capsule dosing technique is bio-equivalent to intact capsule dosing for stavudine in HIV-seronegative adults.

The UNAIDS global report 2011 estimated that three million children in Sub-Saharan Africa are HIV-infected 1. In South Africa alone, almost half a million children under 15 years of age are HIV-infected, and, despite reductions in vertical transmission, new infections continue to occur 2. South Africa has the largest antiretroviral treatment (ART) program in the world, with an estimated 157,000 infants and children currently on ART (personal communication, Corry van der Walt and Jaco Stokes, South African National Department of Health, 15 October 2013), with many more being added as the antiretroviral program rolls out. These children face a lifetime of ART exposure, extending into several decades. In addition, the rapid changes related to growth may make them more sensitive than adults to drug-induced changes in metabolism. Dyslipidemia is a common late adverse effect of ART in HIV-infected children in the developed world 3. Dyslipidemia and insulin resistance significantly increase the long-term risk of atherosclerotic vascular disease and may have major public health implications for HIV-infected children in Africa, who must already deal simultaneously with the complexities of social stigma, chronic illness and medication adherence. The public health importance of atherosclerotic vascular disease in this extremely vulnerable population will only increase as ART coverage expands. Despite this importance, very little is known about the prevalence and risk factors for dyslipidemia and insulin resistance in pre-pubertal African children on ART. Previous studies of ART-related dyslipidemia in children have focused mostly on children living outside of Africa, who make up less than 8% of the global burden of pediatric HIV infections 1. We investigated the prevalence and predictors of blood lipid abnormalities and insulin resistance in pre-pubertal South African children on ART. Specifically, we examined the correlation of lipid and insulin abnormalities with subcutaneous fat maldistribution (measured by Dual-energy X-ray Absorptiometry [DEXA] and formal grading of visually obvious lipoatrophy), and with ART exposures.

Since 2000, much of the effort of diving surveys offshore of Dounreay to locate the presence of radioactive particles in the seabed sediments has been directed to a programme of repopulation studies, in which selected areas of the seabed have been surveyed a number of times and cleared of identified particles on each occasion. This work has led to an understanding of the distribution of particles within the seabed off Dounreay. The two-population model originally proposed by Atkinson (2001 UKAEA Document reference 000052) and further refined into three populations by Clayton and Atkinson (2002 UKAEA Document PSG Issue Note (02)33) has been substantially confirmed by the extended data set now available. It is apparent that the upper layers of the seabed sediments, containing a population of particles, are essentially mobile. These sediments migrate over the seabed driven by tidal wave and surge induced seabed currents, recontaminating areas which have been previously cleared of particles. The number of particles present in this layer at any given location has not been effectively reduced by the removal of particles over the years, nor has the distribution of activity within this population varied significantly. The highest concentration of particles, and the most active, reside close to and to the northeast of the effluent diffuser outfall. Particle numbers and their activity decrease with distance from the diffuser, and the rate of decrease is significantly greater to the southwest compared to the northeast. By contrast, there is evidence that the population of particles retained in the deeper sediments has changed significantly as a result of the repopulation surveys. Close to the diffuser, the population of particles identified at depth during initial surveys is high and contains significantly more highly active particles than are found in the surface sediments. It is also evident that once the deeper sediments are cleared of particles, the level of repopulation of these sediments over time is substantially reduced. There is little mixing of the more deeply buried sediments. Following a period of stormy weather over the winter of 2004-05, repopulation surveys were initiated in March 2005 to see if the effect of these storm events could be detected in the distribution of particles in the sediments. Little evidence for this was found, and was limited to the recovery of a single particle of high activity in the surface sediments of Repop 12 located over 2 km to the northeast of the effluent diffuser. The justification for continuation of the programme of repopulation surveys is questioned, particularly on health and safety grounds. The programme of surveys may eventually exhaust the mobile particle population such that repopulation rates decrease significantly although there is no evidence as to when this may occur. It is suggested that little further benefit will be obtained from the continued retrieval of additional and similar information.

ObjectiveLongitudinal studies objectively evaluating changes in regional fat distribution of HIV-infected children assessed by whole body dual energy X-ray absorptiometry (DEXA) are scarce, whilst this long-term effect of HIV and antiretroviral therapy (cART) is an important issue in infected children in need for lifelong treatment.MethodsWe assessed regional fat distribution over time, measured with sequential DEXA-scans in HIV-infected children on cART in cohorts from South Africa (SA) and the Netherlands (NL), and in healthy controls (SA). Limb and trunk fat Z-scores were calculated with the lambda-mu-sigma (LMS) method. Multivariable linear regression models with mixed effects were used to investigate the effect of cART compounds on body fat distribution over time.ResultsIn total, 218 children underwent 445 DEXA assessments with a median follow-up of 3.5 years. Fat mass in all limbs was decreased in HIV-infected children compared to controls (arm fat Z-score: coefficient -0.4813; P = 0.006, leg fat Z-score: coefficient -0.4345; P = 0.013). In the HIV-infected group, stavudine treatment was associated with lower subcutaneous fat mass (arm fat Z-score: coefficient -0.5838; P = 0.001), with an additional cumulative exposure effect (arm fat Z-score: coefficient -0.0867; P = 0.003).ConclusionsOur study shows that subcutaneous fat loss is still prevalent in HIV-infected children on cART, and is strongly associated with cumulative stavudine exposure. These results underline the need for early detection of subcutaneous fat loss and alternative treatment options for HIV-infected children globally.

Background The natural history and manifestation of HIV-related neurologic disease have been ameliorated by combination antiretroviral therapy (ART). We describe the characteristics of white matter signal abnormalities (WMSA) on magnetic resonance imaging in children with HIV-related neurologic disease. Methods We reviewed magnetic resonance imaging scans of children with suspected HIV-related neurologic disease despite early ART and correlated with clinical, neurodevelopmental data, virologic markers and time on ART. These children were also on the Children with HIV Early Antiretroviral (CHER) trial. Results Magnetic resonance imaging scans were performed at a mean age 31.9 months (range 8-54) on 44 children: 10 on deferred and 34 on early treatment arms, commencing ART at mean age of 18.5 and 8 weeks, respectively. Multiple high signal intensity lesions on T2/fluid attenuated inversion recovery were documented in 22 patients (50%), predominantly in frontal (91%) and parietal (82%) white matter. No differences in neurodevelopmental scores comparing children with and without WMSA were found. Neither lesion load nor distribution showed significant correlation with neurodevelopmental scores or neurologic examination. Normal head growth was more common in the WMSA group (P = 0.01). There was a trend for association of WMSA and longer time on ART (P = 0.13) and nadir CD4% (P = 0.08). Conclusions Half of children referred with HIV-related brain disease had WMSA on T2/fluid attenuated inversion recovery. Our findings of the association with normal head growth and duration of ART require further study. We suspect that WMSA can occur early and that initiating ART by 8 weeks of life may be too late to prevent HIV from entering the central nervous system.

We report a case of rapidly progressive miliary tuberculosis in a 21-month-old HIV-infected girl exposed to tuberculosis, despite early access to highly active antiretroviral therapy and proven adherence to isoniazid chemoprophylaxis. Post mortem revealed multidrug-resistant tuberculosis. This case report illustrates three important points: a) the consequences of inadequate programmatic management of children exposed to an adult case of sputum smear-positive multidrug-resistant tuberculosis, b) multiple exposures to source cases over time and c) the diffculty in diagnosing childhood tuberculosis in the setting of close supervision. Drug susceptibility testing of the adult source case should become standard of care for all children who have been in close contact with a case of sputum smear-positive tuberculosis, and the choice of chemoprophylactic agents should be based on the sensitivities of the source case organism. Regular inquiry for new exposure to source cases should also be made. New tests are urge...

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.

Objective : To describe the degree of HIV disease progression in infants initiating antiretroviral therapy (ART) by three months of age in a programmatic setting in South Africa. Design : This was a programmatic cohort study. Methods : Electronic and manual data extraction from databases and antiretroviral registers in 20 public clinics in Cape Town and electronic data extraction from a large ART service at Chris Hani Baragwanath Hospital in Soweto were performed. Records of all infants initiated on ART by three months of age between June 2007 and September 2010 were extracted. Demographics, immunological and clinical stage at ART initiation were analyzed descriptively by chi-square, two-sample t -test and Kaplan–Meier methods. Results : A total of 403 records were identified: 88 in Cape Town and 315 in Soweto. Median age at ART initiation was 8.4 [interquartile range (IQR): 7.2–9.7] weeks. At ART initiation, 250 infants (62%) had advanced HIV disease (CD4%

BACKGROUND The prevalence of potentially stigmatizing lipoatrophy in children receiving antiretroviral therapy in Southern Africa is high, affecting around a third of children. Early diagnosis of lipoatrophy is essential for effective intervention to arrest progression. METHODS Prepubertal children receiving antiretroviral therapy were recruited from a hospital-based family HIV clinic in Cape Town and followed up prospectively. Lipoatrophy was identified and graded by consensus between 2 HIV pediatricians. A dietician performed anthropometric measurements of trunk and limb fat. Anthropometric measurements in children with and without lipoatrophy were compared using multivariable linear regression adjusting for age and gender. The most discerning anthropometric indicators of lipoatrophy underwent receiver operating characteristic curve analysis. The precision of anthropometric measurements performed by an inexperienced healthcare worker was compared with that of a research dietician. RESULTS Of 100 recruits, 36 had lipoatrophy at baseline and a further 9 developed lipoatrophy by 15-month follow-up. Annual incidence of lipoatrophy was 12% (confidence interval [CI]: 5-20%) per person-year of follow-up. A biceps skin-fold thickness

Background Despite changes in WHO guidelines, stavudine is still used extensively for treatment of pediatric HIV in the developing world. Lipoatrophy in sub-Saharan African children can be stigmatizing and have far-reaching consequences. The severity and extent of lipoatrophy in pre-pubertal children living in sub-Saharan Africa is unknown. Methods In this cross-sectional study, children who were 3-12 years old, on antiretroviral therapy and pre-pubertal were recruited from a Family HIV Clinic in South Africa. Lipoatrophy was identified and graded by consensus between two HIV pediatricians using a standardized grading scale. A professional dietician performed formal dietary assessment and anthropometric measurements of trunk and limb fat. Previous antiretroviral exposures were recorded. In a Dual-Energy X-ray Absorbtiometry (DXA) substudy body composition was determined in 42 participants. Results Among 100 recruits, the prevalence of visually obvious lipoatrophy was 36% (95% CI: 27%–45%). Anthropometry and DXA measurements corroborated the clinical diagnosis of lipoatrophy: Both confirmed significant, substantial extremity fat loss in children with visually obvious lipoatrophy, when adjusted for age and sex. Adjusted odds ratio for developing lipoatrophy was 1.9 (95% CI: 1.3 - 2.9) for each additional year of accumulated exposure to standard dose stavudine. Cumulative time on standard dose stavudine was significantly associated with reductions in biceps and triceps skin-fold thickness (p=0.008). Conclusions The prevalence of visually obvious lipoatrophy in pre-pubertal South African children on antiretroviral therapy is high. The amount of stavudine that children are exposed to needs review. Resources are needed to enable low-and-middle-income countries to provide suitable pediatric-formulated alternatives to stavudine-based pediatric regimens. The standard stavudine dose for children may need to be reduced. Diagnosis of lipoatrophy at an early stage is important to allow timeous antiretroviral switching to arrest progression and avoid stigmatization. Diagnosis using visual grading requires training and experience, and DXA and comprehensive anthropometry are not commonly available. A simple objective screening tool is needed to identify early lipoatrophy in resource-limited settings where specialized skills and equipment are not available.

We report a case of rapidly progressive miliary tuberculosis in a 21-month old HIV-infected girl exposed to tuberculosis, despite early access to highly active antiretroviral therapy and proven adherence to isoniazid chemoprophylaxis. Post mortem revealed multidrug-resistant tuberculosis. This case report illustrates the consequences of inadequate programmatic management of children exposed to an adult case of sputum smear-positive multidrug-resistant tuberculosis. Drug susceptibility testing of the adult source case should become standard of care for all children who have been in close contact with a case of sputum smear-positive tuberculosis, and the choice of chemoprophylactic agents should be based on the sensitivities of the source case organism.

Lipodystrophy Syndrome (LD) is common in HIV-infected children, particularly in those taking Didanosine, Stavudine, or Zidovudine. Lipoatrophy in particular causes major stigmatization and interferes with adherence. In addition, LD may have significant long-term health consequences, particularly cardiovascular. Since the stigmatizing fat distribution changes of LD are largely permanent, the focus of management remains on early detection and arresting progression. Practical guidelines for surveillance and avoidance of LD in routine clinical practice are presented. Diagnosis of LD is described and therapeutic options are reviewed. The most important therapeutic intervention is to switch the most likely offending antiretroviral to a non-LD-inducing agent as soon as LD is recognised. Typically, where lipoatrophy or lipohypertrophy is diagnosed, the thymidine nucleoside reverse transcriptase inhibitor (NRTI) is switched to a non-thymidine agent such as Abacavir (or Tenofovir in adults). Where dyslipidaemia is predominant, a dietician review is helpful, and the clinician may consider switching to a protease inhibitor (PI)-sparing regimen or to Atazanavir.

Tuberculosis immune reconstitution inflammatory syndrome (IRIS) may present as new or worsening cavitation. We present an HIV-infected infant in whom TB infection and subsequent cavitation of the Ghon focus appeared to coincide with immune reconstitution due to highly active antiretroviral therapy (HAART). TB-IRIS in response to infection that occurs after starting HAART has not previously been described.

INTRODUCTION: If a caregiver does not have access to a refrigerator, the South African National Department of Health advises that stavudine adult capsule formulations be employed using the off-label 'opened capsule' dosing method. The accuracy of this dosing method has not previously been validated. AIM: To assess the accuracy of the off-label opened capsule method for stavudine dosing in infants and children. In addition, we assessed the relative ease of dispersion of generic and original capsule preparations in water to determine which preparations, if any, are suitable for the off-label opened capsule dosing method. METHOD: We evaluated 10 Zerit (Bristol-Myers Squibb), 5 Stavudine (Aspen), and 5 Stavir (Cipla) capsules. Each capsule was dispersed in 30 ml water, creating 20 separate solutions. Timed dispersion of each generic was compared with that of the original (Zerit). Each solution was then centrifuged to remove sediment, and the concentration of active drug (mg/ml) was analysed by high-performance liquid chromatography. RESULTS: The ease of dispersion of the contents of Aspen Stavudine capsules was equivalent to that of Zerit, and resulted in a mean recovery of active drug from solution of over 97%, confirming the accuracy of this dosing method. The contents of Stavir capsules, however, were extremely difficult to disperse in water despite prolonged agitation; consequently, the recovery of active drug from the solution was reduced. CONCLUSION: The accuracy of the off-label opened capsule dosing method for stavudine is acceptable. There is no need to instruct caregivers to include sediment in the aliquot given to the infant. However, studies that confirm adequate bioavailability and efficacy are needed. In addition, it is important to avoid supplying generic capsules the contents of which do not disperse easily in water, as this may lead to a significant reduction in the amount of active drug that a child receives.

Current recommendations advise that stavudine be phased out of use. The logistics and cost of switching are significant, and the World Health Organization has forecast that 1.55 million people will still be on stavudine-based antiretroviral therapy by the end of 2012. Stavudine is co-formulated in many countries, is very cheap and effective, and is well tolerated in initial therapy. However, the 40 mg BD dose was associated with considerable long-term toxicity. Several studies suggest that half the original recommended dose has excellent antiviral efficacy with significantly reduced metabolic side-effects. Despite generic tenofovir now being cheaper than zidovudine, tenofovir consumes the majority of adult antiretroviral programme medication budgets in programmes in Africa, where it is used in first-line therapy. Abacavir is far more expensive than zidovudine or tenofovir, and is a major cost driver in paediatric programmes with access to abacavir-based first-line treatment. Low-dose stavudine may offer the only cheaper (and possibly as effective and safe) alternative to programmes grappling with limited financial resources.

Upper respiratory tract infection (URTI) occurs commonly in both children and adults and is a major cause of mild morbidity. It has a high cost to society, being responsible for absenteeism from school and work and unnecessary medical care, and is occasionally associated with serious sequelae. URTIs are usually caused by several families of virus; these are the rhinovirus, coronavirus, parainfluenza, respiratory syncytial virus (RSV), adenovirus, human metapneumovirus, influenza, enterovirus and the recently discovered bocavirus. This review will mainly focus on the rhinovirus, where significant advances have been made in understanding the epidemiology, natural history and relationship with other pathogens. South African Family Practice Vol. 50 (2) 2008: pp. 6-12

The debate around relooking at stavudine dosing, both in terms of the adult low-dose stavudine study and more broadly, is welcome. The study being proposed to evaluate low-dose stavudine v. tenofovir is a fairly standard placebo-controlled non-inferiority study. The study design is not controversial; however, the choice of study drug has attracted critical attention.