[Show abstract][Hide abstract] ABSTRACT: Introduction: In 2014 the Joint United Nations Programme on HIV/AIDS defined the ambitious 90 90 90 targets for 2020, in which 90% of people living with HIV must be diagnosed, 90% of those diagnosed should be on sustained therapy and 90% of those on therapy should have an undetectable viral load. Children are considered to be a key focus population for these targets. This review will highlight key components of the epidemiology, prevention and treatment of tuberculosis (TB) in HIV-infected children in the era of increasing access to antiretroviral therapy (ART) and their relation to the 90 90 90 targets. Discussion: The majority of HIV-infected children live in countries with a high burden of TB. In settings with a high burden of both diseases such as in sub-Saharan Africa, up to 57% of children diagnosed with and treated for TB are HIV-infected. TB results in substantial morbidity and mortality in HIV-infected children, so preventing TB and optimizing its treatment in HIV-infected children will be important to ensuring good long-term outcomes. Prevention of TB can be achieved by increasing access to ART to both children and adults, and appropriate provision of isoniazid preventative therapy. Co-treatment of HIV and TB is complicated by drug-drug interactions particularly due to the use of rifampicin; these may compromise virologic outcomes if appropriate corrective actions are not taken. There remain substantial operational challenges, and improved integration of paediatric TB and HIV services, including with antenatal and routine under-five care, is an important priority. Conclusions: TB may be an important barrier to achievement of the 90 90 90 targets, but specific attention to TB care in HIV-infected children may provide important opportunities to enhance the care of both TB and HIV in children.
Full-text · Article · Dec 2015 · Journal of the International AIDS Society
[Show abstract][Hide abstract] ABSTRACT: Introduction: There is new emphasis on identifying and treating HIV in the first days of life and also an appreciation that low birth weight (LBW) and preterm delivery (PTD) frequently accompany HIV-related pregnancy. Even in the absence of HIV, PTD and LBW contribute substantially to neonatal and infant mortality. HIV-exposed and -infected infants with these characteristics have received little attention thus far. As HIV programs expand to meet the 90-90-90 target for ending the HIV pandemic, attention should focus on newborn infants, including those delivered preterm or of LBW. Discussion: In high prevalence settings, infant diagnosis of HIV is usually undertaken after the neonatal period. However, as in utero infection may be diagnosed at birth, earlier initiation of therapy may limit viral replication and prevent early damage. Globally, there is growing awareness that preterm and LBW infants constitute a substantial proportion of births each year. Preterm infants are at high risk for vertical transmission. Feeding difficulties, apnoea of prematurity and vulnerability to sepsis occur commonly. Feeding intolerance, a frequent occurrence, may compromise oral administration of medications. Although there is growing experience with post-exposure prophylaxis for HIV-exposed term newborn infants, there is less experience with preterm and LBW infants. For treatment, there are even fewer options for preterm infants. Only zidovudine has adequate dosing recommendations for treating term and preterm infants and has an intravenous formulation, essential if feeding intolerance occurs. Nevirapine dosing for prevention, but not treatment, is well established for both term and preterm infants. HIV diagnosis at birth is likely to be extremely stressful for new parents, more so if caring for preterm or LBW infants. Programs need to adapt to support the medical and emotional needs of young infants and their parents, where interventions may be lifesaving. Conclusions: New focus is required for the newborn baby, including those born preterm, with LBW or small for gestational age to consolidate gains already made in early diagnosis and treatment of young children.
No preview · Article · Dec 2015 · Journal of the International AIDS Society
[Show abstract][Hide abstract] ABSTRACT: The epidemiology of paediatric bloodstream infection (BSI) in Sub-Saharan Africa is poorly documented with limited data on hospital-acquired sepsis, impact of HIV infection, BSI trends and antimicrobial resistance.
We retrospectively reviewed paediatric BSI (0–14 years) at Tygerberg Children’s Hospital between 1 January 2008 and 31 December 2013 (excluding neonatal wards). Laboratory and hospital data were used to determine BSI rates, blood culture contamination, pathogen profile, patient demographics, antimicrobial resistance and factors associated with mortality. Fluconazole resistant Candida species, methicillin-resistant Staphylococcus aureus (MRSA), multi-drug resistant Acinetobacter baumannii and extended-spectrum beta-lactamase (ESBL) producing Enterobacteriaceae were classified as antimicrobial resistant pathogens.
Of 17001 blood cultures over 6 years, 935 cultures isolated 979 pathogens (5.5% yield; 95% CI 5.3-5.7%). Contamination rates were high (6.6%, 95% CI 6.4-6.8%), increasing over time (p = 0.003). Discrete BSI episodes were identified (n = 864) with median patient age of 7.5 months, male predominance (57%) and 13% HIV prevalence. BSI rates declined significantly over time (4.6–3.1, overall rate 3.5 per 1000 patient days; 95% CI 3.3–3.7; Chi square for trend p = 0.02). Gram negative pathogens predominated (60% vs 33% Gram positives and 7% fungal); Klebsiella pneumoniae (154; 17%), Staphylococcus aureus (131; 14%) and Escherichia coli (97; 11%) were most prevalent. Crude BSI mortality was 20% (176/864); HIV infection, fungal, Gram negative and hospital-acquired sepsis were significantly associated with mortality on multivariate analysis. Hospital-acquired BSI was common (404/864; 47%). Overall antimicrobial resistance rates were high (70% in hospital vs 25% in community-acquired infections; p < 0.0001); hospital-acquired infection, infancy, HIV-infection and Gram negative sepsis were associated with resistance. S. pneumoniae BSI declined significantly over time (58/465 [12.5%] to 33/399 [8.3%]; p =0.04).
Although BSI rates declined over time, children with BSI had high mortality and pathogens exhibited substantial antimicrobial resistance in both community and hospital-acquired infections. Blood culture sampling technique and local options for empiric antimicrobial therapy require re-evaluation.
[Show abstract][Hide abstract] ABSTRACT: Background:
Ongoing CD4 monitoring in patients on antiretroviral therapy (ART) with viral suppression has been questioned. We evaluated the probability of CD4 decline in children with viral suppression and CD4 recovery after 1 year on ART.
We included children from 8 South African cohorts with routine HIV-RNA monitoring if: (1) they were "responders" (HIV-RNA <400 copies/ml and no severe immunosuppression after >1 year on ART [time 0]) and (2) >1 HIV-RNA and CD4 measurement within 15 months of time 0. We determined the probability of CD4 decline to WHO-defined severe immunosuppression for 3 years after time 0 if viral suppression was maintained. Follow-up was censored at the first of: day before first HIV-RNA measurement >400 copies/ml; day before a >15 month gap in testing; date of death, loss to follow-up, transfer out or database closure.
Among 5984 children (median age at time 0: 5.8 years [IQR:3.1-9.0]), 270 experienced a single CD4 decline to severe immunosuppression within 3 years of time 0 with probability of 6.6% (95%CI:5.8-7.4). A subsequent CD4 measurement within 15 months of the first low measurement was available for 63% of children with CD4 decline and 86% showed CD4 recovery. The probability of CD4 decline was lowest (2.8%) in children >2 years with no/mild immunosuppression and on ART for <18 months at time 0. This group comprised 40% of children.
This finding suggests that it may be safe to stop routine CD4 monitoring in children aged ≥2 years and rely on virologic monitoring alone.
[Show abstract][Hide abstract] ABSTRACT: There are limited published data on the outcomes of infants starting antiretroviral therapy (ART) in routine care in Southern Africa. This study aimed to examine the baseline characteristics and outcomes of infants initiating ART.
We analyzed prospectively collected cohort data from routine ART initiation in infants from 11 cohorts contributing to the International Epidemiologic Database to Evaluate AIDS in Southern Africa. We included ART-naive HIV-infected infants aged <12 months initiating ≥3 antiretroviral drugs between 2004 and 2012. Kaplan-Meier estimates were calculated for mortality, loss to follow-up (LTFU), transfer out, and virological suppression. We used Cox proportional hazard models stratified by cohort to determine baseline characteristics associated with outcomes mortality and virological suppression.
The median (interquartile range) age at ART initiation of 4945 infants was 5.9 months (3.7-8.7) with follow-up of 11.2 months (2.8-20.0). At ART initiation, 77% had WHO clinical stage 3 or 4 disease and 87% were severely immunosuppressed. Three-year mortality probability was 16% and LTFU 29%. Severe immunosuppression, WHO stage 3 or 4, anemia, being severely underweight, and initiation of treatment before 2010 were associated with higher mortality. At 12 months after ART initiation, 17% of infants were severely immunosuppressed and the probability of attaining virological suppression was 56%.
Most infants initiating ART in Southern Africa had severe disease with high probability of LTFU and mortality on ART. Although the majority of infants remaining in care showed immune recovery and virological suppression, these responses were suboptimal.
No preview · Article · Aug 2015 · JAIDS Journal of Acquired Immune Deficiency Syndromes
[Show abstract][Hide abstract] ABSTRACT: Combination antiretroviral therapy (ART) suppresses viral replication in HIV-infected children. The growth of virologically suppressed children on ART has not been well documented. We aimed to develop dynamic reference curves for weight-for-age z scores (WAZ) and height-for-age z scores (HAZ).
A total of 4,876 children were followed for 7,407 person-years. Analyses were stratified by baseline z-scores and age, which were the most important predictors of growth response. The youngest children showed the most pronounced increase in weight and height initially but catch-up growth stagnated after 1-2 years. Three years after starting ART, WAZ ranged from -2.2 (95% Prediction interval -5.6 to 0.8) in children with baseline age "5 years and z-score "-3 to 0.0 (-2.7 to 2.4) in children with baseline age "2 years and WAZ "-1. For HAZ the corresponding range was -2.3 (-4.9 to 0.3) in children with baseline age"5 years and z-score "-3 to 0.3 (-3.1 to 3.4) in children with baseline age 2-5 years and HAZ "-1.
We have developed an online tool to calculate reference trajectories in fully suppressed children. The web application could help to define 'optimal' growth response and identify children with treatment failure.
No preview · Article · Jul 2015 · The Pediatric Infectious Disease Journal
[Show abstract][Hide abstract] ABSTRACT: Background:
The risk of Kaposi sarcoma (KS) among HIV-infected persons on antiretroviral therapy (ART) is not well defined in resource-limited settings. We studied KS incidence rates and associated risk factors in children and adults on ART in Southern Africa.
We included patient data of 6 ART programs in Botswana, South Africa, Zambia, and Zimbabwe. We estimated KS incidence rates in patients on ART measuring time from 30 days after ART initiation to KS diagnosis, last follow-up visit, or death. We assessed risk factors (age, sex, calendar year, WHO stage, tuberculosis, and CD4 counts) using Cox models.
We analyzed data from 173,245 patients (61% female, 8% children aged <16 years) who started ART between 2004 and 2010. Five hundred and sixty-four incident cases were diagnosed during 343,927 person-years (pys). The overall KS incidence rate was 164/100,000 pys [95% confidence interval (CI): 151 to 178]. The incidence rate was highest 30-90 days after ART initiation (413/100,000 pys; 95% CI: 342 to 497) and declined thereafter [86/100,000 pys (95% CI: 71 to 105), >2 years after ART initiation]. Male sex [adjusted hazard ratio (HR): 1.34; 95% CI: 1.12 to 1.61], low current CD4 counts (≥500 versus <50 cells/μL, adjusted HR: 0.36; 95% CI: 0.23 to 0.55), and age (5-9 years versus 30-39 years, adjusted HR: 0.20; 95% CI: 0.05 to 0.79) were relevant risk factors for developing KS.
Despite ART, KS risk in HIV-infected persons in Southern Africa remains high. Early HIV testing and maintaining high CD4 counts is needed to further reduce KS-related morbidity and mortality.
No preview · Article · Dec 2014 · JAIDS Journal of Acquired Immune Deficiency Syndromes
[Show abstract][Hide abstract] ABSTRACT: Background. Although subSaharan Africa faces the world's largest paediatric HIV epidemic, only 1 in 4 children has access to combination antiretroviral therapy (ART). A decentralised approach to HIV care is advocated, but programmes in resource-limited settings encounter many challenges to community-initiated paediatric ART implementation. Methods. A retrospective cohort analysis of 613 children receiving ART between 2004 and 2009 was performed in seven physician-run primary healthcare (PHC) clinics in Cape Town. Baseline characteristics, serial CD4(+), viral load (VL) levels and status at study closure were collected. Results. Two subgroups were identified: children who were initiated on ART in a PHC clinic (n=343) and children who were down-referred from tertiary hospitals (n=270). The numbers of children initiated on ART in PHC increased sevenfold over the study period. Down-referred children were severely ill at ART initiation, with higher VLs, lower CD4(+) counts and higher rates of tuberculosis co-infection (25.3% v. 16.9%; p=0.01). Median time to virological suppression was 29 weeks in PHC-ART initiates and 44 weeks in children down-referred (p<0.0001). Children down-referred to PHC either maintained or gained virological suppression. Longitudinal cohort analysis demonstrated sustained VL suppression >80%, high rates of immune reconstitution and low mortality. Conclusions. Increasing numbers of children are initiated on ART in PHC settings and achieve comparable immunological, virological and survival outcomes, suggesting successful decentralisation of paediatric HIV care. Down-referral of children with adherence-related virological failure may assist with attainment of virological suppression and sparing use of second-line medications.
Full-text · Article · Dec 2014 · Southern African Journal of HIV Medicine
[Show abstract][Hide abstract] ABSTRACT: Purpose of review:
Early initiation of combination antiretroviral therapy (ART) in infants below 12 weeks of age reduces morbidity and mortality. A recent report of transient HIV remission in a child beginning ART from the second day of life has focused attention on very early therapy in the first days of life.
In the randomized children with HIV, early antiretroviral limited ART beginning at a median of 7.4 weeks of age lowered mortality and disease progression significantly compared with deferred ART beginning at a median of 21 weeks on study. In high-burden settings, infants initiating ART appear sicker than in children with HIV early antiretroviral and start at a later age. Many could be diagnosed on the first day of life. There are still programmatic obstacles to early diagnosis and initiation of ART in high-burden settings. There is growing but insufficient information on ART dosages in newborn infants.
There is now increased focus on initiating ART as postexposure prophylaxis in newborn infants at high risk of vertical transmission in the hope of limiting morbidity and dissemination of the virus.
No preview · Article · Nov 2014 · Current Opinion in HIV and AIDS
[Show abstract][Hide abstract] ABSTRACT: SETTING: Drug resistance threatens tuberculosis (TB) control, particularly among human immunodeficiency virus (HIV) infected persons. OBJECTIVE: To describe practices in the prevention and management of drug-resistant TB under antiretroviral therapy (ART) programs in lower-income countries. DESIGN: We used online questionnaires to collect program-level data on 47 ART programs in Southern Africa (n=14), East Africa (n=8), West Africa (n=7), Central Africa (n=5), Latin America (n=7) and the Asia-Pacific (n=6 programs) in 2012. Patient-level data were collected on 1002 adult TB patients seen at 40 of the participating ART programs. RESULTS: Phenotypic drug susceptibility testing (DST) was available in 36 (77%) ART programs, but was only used for 22% of all TB patients. Molecular DST was available in 33 (70%) programs and was used in 23% of all TB patients. Twenty ART programs (43%) provided directly observed therapy (DOT) during the entire course of treatment, 16 (34%) during the intensive phase only, and 11(23%) did not follow DOT. Fourteen (30%) ART programs reported no access to second-line anti-tuberculosis regimens; 18 (38%) reported TB drug shortages. CONCLUSIONS: Capacity to diagnose and treat drug-resistant TB was limited across ART programs in lower-income countries. DOT was not always implemented and drug supplies were regularly interrupted, which may contribute to the global emergence of drug resistance.
Full-text · Article · Nov 2014 · The International Journal of Tuberculosis and Lung Disease
[Show abstract][Hide abstract] ABSTRACT: Objectives:
Many paediatric antiretroviral therapy (ART) programmes in Southern Africa rely on CD4⁺ to monitor ART. We assessed the benefit of replacing CD4⁺ by viral load monitoring.
A mathematical modelling study.
A simulation model of HIV progression over 5 years in children on ART, parameterized by data from seven South African cohorts. We simulated treatment programmes with 6-monthly CD4⁺ or 6- or 12-monthly viral load monitoring. We compared mortality, second-line ART use, immunological failure and time spent on failing ART. In further analyses, we varied the rate of virological failure, and assumed that the rate is higher with CD4⁺ than with viral load monitoring.
About 7% of children were predicted to die within 5 years, independent of the monitoring strategy. Compared with CD4⁺ monitoring, 12-monthly viral load monitoring reduced the 5-year risk of immunological failure from 1.6 to 1.0% and the mean time spent on failing ART from 6.6 to 3.6 months; 1% of children with CD4⁺ compared with 12% with viral load monitoring switched to second-line ART. Differences became larger when assuming higher rates of virological failure. When assuming higher virological failure rates with CD4⁺ than with viral load monitoring, up to 4.2% of children with CD4⁺ compared with 1.5% with viral load monitoring experienced immunological failure; the mean time spent on failing ART was 27.3 months with CD4⁺ monitoring and 6.0 months with viral load monitoring. Conclusion: Viral load monitoring did not affect 5-year mortality, but reduced time on failing ART, improved immunological response and increased switching to second-line ART.
No preview · Article · Oct 2014 · AIDS (London, England)