Mary-Ann Davies

Missed opportunities to prevent mother-to-child-transmission: systematic review and meta-analysis

Objectives:To determine magnitude and reasons of loss to program and poor antiretroviral prophylaxis coverage in prevention of mother-to-child transmission (PMTCT) programs in sub-Saharan Africa. Design:Systematic review and meta-analysis. Methods:We searched PubMed and Embase databases for PMTCT studies in sub-Saharan Africa published between January 2002 and March 2012. Outcomes were the percentage of pregnant women tested for HIV, initiating antiretroviral prophylaxis, having a CD4 cell count measured, and initiating antiretroviral combination therapy (cART) if eligible. In children outcomes were early infant diagnosis for HIV, and cART initiation. We combined data using random-effects meta-analysis and identified predictors of uptake of interventions. Results:Forty-four studies from 15 countries including 75 172 HIV-infected pregnant women were analyzed. HIV-testing uptake at antenatal care services was 94% [95% confidence intervals (CIs) 92–95%] for opt-out and 58% (95% CI 40–75%) for opt-in testing. Coverage with any antiretroviral prophylaxis was 70% (95% CI 64–76%) and 62% (95% CI 50–73%) of pregnant women eligible for cART received treatment. Sixty-four percent (95% CI 48–81%) of HIV exposed infants had early diagnosis performed and 55% (95% CI 36–74%) were tested between 12 and 18 months. Uptake of PMTCT interventions was improved if cART was provided at the antenatal clinic and if the male partner was involved. Conclusion:In sub-Saharan Africa, uptake of PMTCT interventions and early infant diagnosis is unsatisfactory. An integrated family-centered approach seems to improve retention.

Comparison of T-SPOT.TB Assay and Tuberculin Skin Test for the Evaluation of Young Children at High Risk for Tuberculosis in a Community Setting

OBJECTIVE. We wished to compare the sensitivity of an enzyme-linked immunospot assay (T-SPOT.TB; Oxford Immunotec, Oxford, United Kingdom) and the tuberculin skin test for the detection of tuberculosis infection in very young children being evaluated for active tuberculosis in a rural community setting. METHODS. Children with a history of exposure to tuberculosis and children presenting to a local clinic or hospital with symptoms suggesting tuberculosis were admitted to a dedicated case verification ward. T-SPOT.TB testing was performed, and children were evaluated with a clinical examination, a tuberculin skin test, chest radiographs, and cultures of induced sputum and gastric lavage specimens. The diagnosis was determined by using a clinical algorithm. RESULTS. A total of 243 children (median age: 18 months) were recruited, of whom 214 (88%) had interpretable T-SPOT.TB results. Children ≥12 months of age were more likely than younger children to have positive T-SPOT.TB results, whereas tuberculin skin test results were unaffected by age. The sensitivity of the T-SPOT.TB was no better than that of the tuberculin skin test for culture-confirmed tuberculosis (50% and 80%, respectively) and was poorer for the combined group of culture-confirmed and clinically probable tuberculosis (40% and 52%, respectively). For the 50 children clinically categorized as not having tuberculosis, the specificity of both the T-SPOT.TB and the tuberculin skin test was 84%. CONCLUSIONS. For young children presenting in a community setting after exposure to tuberculosis or with symptoms suggesting tuberculosis, T-SPOT.TB cannot be used to exclude active disease. The sensitivity of this assay may be impaired for very young children.

Outcomes of the South African national antiretroviral treatment programme for children : the IeDEA southern Africa collaboration

OBJECTIVES To assess paediatric antiretroviral treatment (ART) outcomes and their associations from a collaborative cohort representing 20% of the South African national treatment programme. DESIGN AND SETTING Multi-cohort study of 7 public sector paediatric ART programmes in Gauteng, Western Cape and KwaZulu-Natal provinces. SUBJECTS ART-naive children (< or = 16 years) who commenced treatment with > or = 3 antiretroviral drugs before March 2008. OUTCOME MEASURES Time to death or loss to follow-up were assessed using the Kaplan-Meier method. Associations between baseline characteristics and mortality were assessed with Cox proportional hazards models stratified by site. Immune status, virological suppression and growth were described in relation to duration of ART. RESULTS The median (interquartile range) age of 6 078 children with 9 368 child-years of follow-up was 43 (15 - 83) months, with 29% being < 18 months. Most were severely ill at ART initiation. More than 75% of children were appropriately monitored at 6-monthly intervals with viral load suppression (< 400 copies/ml) being 80% or above throughout 36 months of treatment. Mortality and retention in care at 3 years were 7.7% (95% confidence interval 7.0 - 8.6%) and 81.4% (80.1 - 82.6%), respectively. Together with young age, all markers of disease severity (low weight-for-age z-score, high viral load, severe immune suppression, stage 3/4 disease and anaemia) were independently associated with mortality. CONCLUSIONS Dramatic clinical benefit for children accessing the national ART programme is demonstrated. Higher mortality in infants and those with advanced disease highlights the need for early diagnosis of HIV infection and commencement of ART.

Early mortality and loss to follow-up in HIV-infected children starting antiretroviral therapy in Southern Africa

Background:Many HIV-infected children in Southern Africa have been started on antiretroviral therapy (ART), but loss to follow up (LTFU) can be substantial. We analyzed mortality in children retained in care and in all children starting ART, taking LTFU into account. Patients and Methods:Children who started ART before the age of 16 years in 10 ART programs in South Africa, Malawi, Mozambique, and Zimbabwe were included. Risk factors for death in the first year of ART were identified in Weibull models. A meta-analytic approach was used to estimate cumulative mortality at 1 year. Results:Eight thousand two hundred twenty-five children (median age 49 months, median CD4 cell percent 11.6%) were included; 391 (4.8%) died and 523 (7.0%) were LTFU in the first year. Mortality at 1 year was 4.5% [95% confidence interval (CI): 2.8% to 7.4%] in children remaining in care, but 8.7% (5.4% to 12.1%) at the program level, after taking mortality in children and LTFU into account. Factors associated with mortality in children remaining in care included age [adjusted hazard ratio (HR) 0.37; 95% CI: 0.25 to 0.54 comparing ≥120 months with <18 months], CD4 cell percent (HR: 0.56; 95% CI: 0.39 to 0.78 comparing ≥20% with <10%), and clinical stage (HR: 0.12; 95% CI: 0.03 to 0.45 comparing World Health Organization stage I with III/IV). Conclusions:In children starting ART and remaining in care in Southern Africa mortality at 1 year is <5% but almost twice as high at the program level, when taking LTFU into account. Age, CD4 percentage, and clinical stage are important predictors of mortality at the individual level.

Adherence to antiretroviral therapy in young children in Cape Town, South Africa, measured by medication return and caregiver self-report: a prospective cohort study

BackgroundAntiretroviral therapy (ART) dramatically improves outcomes for children in Africa; however excellent adherence is required for treatment success. This study describes the utility of different measures of adherence in detecting lapses in infants and young children in Cape Town, South Africa.MethodsIn a prospective cohort of 122 HIV-infected children commenced on ART, adherence was measured monthly during the first year of treatment by medication return (MR) for both syrups and tablets/capsules. A questionnaire was administered to caregivers after 3 months of treatment to assess experience with giving medication and self-reported adherence. Viral and immune response to treatment were assessed at the end of one year and associations with measured adherence determined.ResultsMedication was returned for 115/122 (94%) children with median age (IQR) of 37 (16 – 61) months. Ninety-one (79%) children achieved annual average MR adherence ≥ 90%. This was an important covariate associated with viral suppression after adjustment for disease severity (OR = 5.5 [95%CI: 0.8–35.6], p = 0.075), however was not associated with immunological response to ART. By 3 months on ART, 13 (10%) children had deceased and 11 (10%) were lost to follow-up. Questionnaires were completed by 87/98 (90%) of caregivers of those who remained in care. Sensitivity of poor reported adherence (missing ≥ 1 dose in the previous 3 days) for MR adherence <90% was only 31.8% (95% CI: 10.7% – 53.0%). Caregivers of 33/87 (38.4%) children reported difficulties with giving medication, most commonly poor palatability (21.8%). Independent socio-demographic predictors of MR adherence ≥ 90% were secondary education of caregivers (OR = 4.49; 95%CI: 1.10 – 18.24) and access to water and electricity (OR = 2.65; 95%CI: 0.93 – 7.55). Taking ritonavir was negatively associated with MR adherence ≥ 90% (OR = 0.37; 95%CI: 0.13 – 1.02).ConclusionExcellent adherence to ART is possible in African infants and young children and the relatively simple low technology measure of adherence by MR strongly predicts viral response. Better socio-economic status and more palatable regimens are associated with better adherence.

Immunodeficiency at the start of combination antiretroviral therapy in low-, middle- and high-income countries

Objective:To describe the CD4 cell count at the start of combination antiretroviral therapy (cART) in low-income (LIC), lower middle-income (LMIC), upper middle-income (UMIC), and high-income (HIC) countries. Methods:Patients aged 16 years or older starting cART in a clinic participating in a multicohort collaboration spanning 6 continents (International epidemiological Databases to Evaluate AIDS and ART Cohort Collaboration) were eligible. Multilevel linear regression models were adjusted for age, gender, and calendar year; missing CD4 counts were imputed. Results:In total, 379,865 patients from 9 LIC, 4 LMIC, 4 UMIC, and 6 HIC were included. In LIC, the median CD4 cell count at cART initiation increased by 83% from 80 to 145 cells/&mgr;L between 2002 and 2009. Corresponding increases in LMIC, UMIC, and HIC were from 87 to 155 cells/&mgr;L (76% increase), 88 to 135 cells/&mgr;L (53%), and 209 to 274 cells/&mgr;L (31%). In 2009, compared with LIC, median counts were 13 cells/&mgr;L [95% confidence interval (CI): −56 to +30] lower in LMIC, 22 cells/&mgr;L (−62 to +18) lower in UMIC, and 112 cells/&mgr;L (+75 to +149) higher in HIC. They were 23 cells/&mgr;L (95% CI: +18 to +28 cells/&mgr;L) higher in women than men. Median counts were 88 cells/&mgr;L (95% CI: +35 to +141 cells/&mgr;L) higher in countries with an estimated national cART coverage >80%, compared with countries with <40% coverage. Conclusions:Median CD4 cell counts at the start of cART increased 2000–2009 but remained below 200 cells/&mgr;L in LIC and MIC and below 300 cells/&mgr;L in HIC. Earlier start of cART will require substantial efforts and resources globally.

Virologic failure and second-line antiretroviral therapy in children in South Africa--the IeDEA Southern Africa collaboration.

Background: With expanding pediatric antiretroviral therapy (ART) access, children will begin to experience treatment failure and require second-line therapy. We evaluated the probability and determinants of virologic failure and switching in children in South Africa. Methods: Pooled analysis of routine individual data from children who initiated ART in 7 South African treatment programs with 6-monthly viral load and CD4 monitoring produced Kaplan-Meier estimates of probability of virologic failure (2 consecutive unsuppressed viral loads with the second being >1000 copies/mL, after ≥24 weeks of therapy) and switch to second-line. Cox-proportional hazards models stratified by program were used to determine predictors of these outcomes. Results: The 3-year probability of virologic failure among 5485 children was 19.3% (95% confidence interval: 17.6 to 21.1). Use of nevirapine or ritonavir alone in the initial regimen (compared with efavirenz) and exposure to prevention of mother to child transmission regimens were independently associated with failure [adjusted hazard ratios (95% confidence interval): 1.77 (1.11 to 2.83), 2.39 (1.57 to 3.64) and 1.40 (1.02 to 1.92), respectively]. Among 252 children with ≥1 year follow-up after failure, 38% were switched to second-line. Median (interquartile range) months between failure and switch was 5.7 (2.9-11.0). Conclusions: Triple ART based on nevirapine or ritonavir as a single protease inhibitor seems to be associated with a higher risk of virologic failure. A low proportion of virologically failing children were switched.

Antiretroviral treatment for children

OBJECTIVE To describe the response of children during their first year on highly active antiretroviral therapy (HAART). DESIGN Retrospective, descriptive. SETTING Tertiary, referral hospital. SUBJECTS All HIV-infected children commenced on HAART from 1 August 2002 until 31 December 2004. OUTCOME MEASURES Children were retrospectively restaged using the WHO 4-stage clinical classification and CDC immunological staging system. After commencing HAART, patients were assessed at monthly intervals for the first 6 months and thereafter mostly 3-monthly. Baseline and 6- monthly CD4 counts and viral loads were performed. RESULTS Of 409 children commenced on HAART, 50.6% were < 2 years old, 62.7% had severe clinical disease and 76.6% had severe immune suppression. After 1 year, 65.8% were alive and continued HAART at the hospital, 11.2% had been transferred to another antiretroviral site, 15.4% had died, 4.6% were lost to follow-up and treatment had been discontinued in 2.9%. Kaplan-Meier survival estimate for 407 children at 1 year was 84% (95% confidence interval (CI) 80 - 87%). On multivariate analysis, survival was adversely affected in children with WHO stage 4 v. stage 2 and 3 disease (adjusted hazard ratio (HR): 5.26 (95% CI 2.25 - 12.32), p = 0.000), age < 12 months (adjusted HR: 2.46 (95% CI 1.48 - 4.09), p = 0.001) and CD4 absolute count (per 100 cell increase) (adjusted HR: 0.93 (95% CI 0.88 - 0.98), p = 0.013). In a separate multivariate model including only children with an initial viral load (N = 367), viral load > or = 1 million copies/ml (adjusted HR: 1.84 (95% CI 1.03 - 3.29)) and taking a protease inhibitor (PI)-based regimen (adjusted HR: 2.25 (95% CI 1.10 - 4.61)) were additionally independently associated with poorer survival; however, young age was not a significant predictor of mortality, after adjusting for viral load (p = 0.119). After 1 year of HAART 184/264 (69.7%) of children had a viral load < 400 copies/ml. Comparative analysis showed significant improvements in growth, immunological status and virological control. CONCLUSION HAART can improve the health of many HIV-infected children with advanced disease, including those aged less than 2 years in resource-limited settings.

Initial experience of a public sector antiretroviral treatment programme for HIV-infected children and their infected parents.

OBJECTIVE To describe the initial experience of treating HIV-infected children and their infected parents with antiretroviral therapy. DESIGN Prospective, cohort study. SETTING Tertiary, referral hospital. PATIENTS HIV-infected children and their parents. METHODS This report focuses on the early response of children to highly active antiretroviral therapy (HAART). Children were followed up at 4-weekly intervals. Monitoring included initial and yearly viral load measurements, baseline and 6-monthly CD4 counts and 4-weekly adherence checks. RESULTS Between August 2002 and June 2003, 80 children were enrolled in the programme, representing a follow-up period of 23.9 patient-years. Seventy-five children had severe clinical disease, severe immune suppression, or a combination of the two. The response of children who had received HAART for > or = 6 months (N = 17) was assessed. There was no change in mass z-score (p = 0.11) or length z-score (p = 0.37), but a significant increase in CD4 percentage (p < 0.0001) during the first 6 months of therapy. Six-month viral loads were available for 12 children. There was a significant drop in viral load (p = 0.001) and 9 achieved undetectable levels by 6 months. Most children achieved > or = 85% adherence. By June 2002, 67 children (84%) were relatively well, 1 had B-cell lymphoma, 7 (8.8%) had died, 4 (5%) were lost to follow-up and 1 was withdrawn from the programme. Of 57 children who completed 3 months of HAART, 12 were admitted a total of 17 times for infectious complications. There were no severe drug reactions. Three of 7 mothers on HAART received treatment through the programme. CONCLUSION These initial results suggest that many HIV-infected children in the public sector will benefit from antiretroviral therapy. However, both ambulatory and inpatient facilities are required to manage children on HAART comprehensively.

Causes of hospital admission among people living with HIV worldwide: a systematic review and meta-analysis

BACKGROUND Morbidity associated with HIV infection is poorly characterised, so we aimed to investigate the contribution of different comorbidities to hospital admission and in-hospital mortality in adults and children living with HIV worldwide. METHODS Using a broad search strategy combining terms for hospital admission and HIV infection, we searched MEDLINE via PubMed, Embase, Web of Science, LILACS, AIM, IMEMR and WPIMR from inception to Jan 31, 2015, to identify studies reporting cause of hospital admission in people living with HIV. We focused on data reported after 2007, the period in which access to antiretroviral therapy started to become widespread. We estimated pooled proportions of hospital admissions and deaths per disease category by use of random-effects models. We stratified data by geographical region and age. FINDINGS We obtained data from 106 cohorts, with reported causes of hospital admission for 313 006 adults and 6182 children living with HIV. For adults, AIDS-related illnesses (25 119 patients, 46%, 95% CI 40-53) and bacterial infections (14 034 patients, 31%, 20-42) were the leading causes of hospital admission. These two categories were the most common causes of hospital admission for adults in all geographical regions and the most common causes of mortality. Common region-specific causes of hospital admission included malnutrition and wasting, parasitic infections, and haematological disorders in the Africa region; respiratory disease, psychiatric disorders, renal disorders, cardiovascular disorders, and liver disease in Europe; haematological disorders in North America; and respiratory, neurological, digestive and liver-related conditions, viral infections, and drug toxicity in South and Central America. For children, AIDS-related illnesses (783 patients, 27%, 95% CI 19-34) and bacterial infections (1190 patients, 41%, 26-56) were the leading causes of hospital admission, followed by malnutrition and wasting, haematological disorders, and, in the African region, malaria. Mortality in individuals admitted to hospital was 20% (95% CI 18-23, 12 902 deaths) for adults and 14% (10-19, 643 deaths) for children. INTERPRETATION This review shows the importance of prompt HIV diagnosis and treatment, and the need to reinforce existing recommendations to provide chemoprophylaxis and vaccination against major preventable infectious diseases to people living with HIV to reduce serious AIDS and non-AIDS morbidity. FUNDING None.