Evaluating pediatric tuberculosis dosing guidelines: A model-based individual data pooled analysis.

BACKGROUND: The current World Health Organization (WHO) pediatric tuberculosis dosing guidelines lead to suboptimal drug exposures. Identifying factors altering the exposure of these drugs in children is essential for dose optimization. Pediatric pharmacokinetic studies are usually small, leading to high variability and uncertainty in pharmacokinetic results between studies. We pooled data from large pharmacokinetic studies to identify key covariates influencing drug exposure to optimize tuberculosis dosing in children. METHODS AND FINDINGS: We used nonlinear mixed-effects modeling to characterize the pharmacokinetics of rifampicin, isoniazid, and pyrazinamide, and investigated the association of human immunodeficiency virus (HIV), antiretroviral therapy (ART), drug formulation, age, and body size with their pharmacokinetics. Data from 387 children from South Africa, Zambia, Malawi, and India were available for analysis; 47% were female and 39% living with HIV (95% on ART). Median (range) age was 2.2 (0.2 to 15.0) years and weight 10.9 (3.2 to 59.3) kg. Body size (allometry) was used to scale clearance and volume of distribution of all 3 drugs. Age affected the bioavailability of rifampicin and isoniazid; at birth, children had 48.9% (95% confidence interval (CI) [36.0%, 61.8%]; p < 0.001) and 64.5% (95% CI [52.1%, 78.9%]; p < 0.001) of adult rifampicin and isoniazid bioavailability, respectively, and reached full adult bioavailability after 2 years of age for both drugs. Age also affected the clearance of all drugs (maturation), children reached 50% adult drug clearing capacity at around 3 months after birth and neared full maturation around 3 years of age. While HIV per se did not affect the pharmacokinetics of first-line tuberculosis drugs, rifampicin clearance was 22% lower (95% CI [13%, 28%]; p < 0.001) and pyrazinamide clearance was 49% higher (95% CI [39%, 57%]; p < 0.001) in children on lopinavir/ritonavir; isoniazid bioavailability was reduced by 39% (95% CI [32%, 45%]; p < 0.001) when simultaneously coadministered with lopinavir/ritonavir and was 37% lower (95% CI [22%, 52%]; p < 0.001) in children on efavirenz. Simulations of 2010 WHO-recommended pediatric tuberculosis doses revealed that, compared to adult values, rifampicin exposures are lower in most children, except those younger than 3 months, who experience relatively higher exposure for all drugs, due to immature clearance. Increasing the rifampicin doses in children older than 3 months by 75 mg for children weighing <25 kg and 150 mg for children weighing >25 kg could improve rifampicin exposures. Our analysis was limited by the differences in availability of covariates among the pooled studies. CONCLUSIONS: Children older than 3 months have lower rifampicin exposures than adults and increasing their dose by 75 or 150 mg could improve therapy. Altered exposures in children with HIV is most likely caused by concomitant ART and not HIV per se. The importance of the drug-drug interactions with lopinavir/ritonavir and efavirenz should be evaluated further and considered in future dosing guidance. TRIAL REGISTRATION: ClinicalTrials.gov registration numbers; NCT02348177, NCT01637558, ISRCTN63579542.

Pediatric coronavirus disease 2019 in Africa.

PURPOSE OF REVIEW: Three years into the coronavirus disease 2019 (COVID-19) pandemic, data on pediatric COVID-19 from African settings is limited. Understanding the impact of the pandemic in this setting with a high burden of communicable and noncommunicable diseases is critical to implementing effective interventions in public health programs. RECENT FINDINGS: More severe COVID-19 has been reported in African settings, with especially infants and children with underlying comorbidities at highest risk for more severe disease. Data on the role of tuberculosis and HIV remain sparse. Compared to better resourced settings more children with multisystem inflammatory disease (MISC) are younger than 5 years and there is higher morbidity in all settings and increased mortality in some settings. Several reports suggest decreasing prevalence and severity of MIS-C disease with subsequent severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variant waves. Whether this decrease continues remains to be determined. Thus far, data on long-COVID in African settings is lacking and urgently needed considering the severity of the disease seen in the African population. SUMMARY: Considering the differences seen in the severity of disease and short-term outcomes, there is an urgent need to establish long-term outcomes in children with COVID-19 and MIS-C in African children, including lung health assessment.

COVID-19 lockdown effect on healthcare utilization and in-hospital mortality in children under 5 years in Cape Town, South Africa: a cross-sectional study.

BACKGROUND: COVID-19 pandemic measures resulted in the de-escalation of non-COVID-19 healthcare provision. METHODS: A retrospective cross-sectional study of routinely collected data was done to investigate the effect of COVID-19 policies on the healthcare utilization and mortality of children younger than 5 years in Eastern Cape Town, South Africa. We compared visits to primary and urgent care facilities, hospitalization, in-hospital deaths, and vaccine uptake from 1 January to 31 December 2020 to similar periods in 2018 and 2019. RESULTS: During April and May 2020, the most restricted period, visits to primary care facilities declined from 126 049 in 2019 to 77 000 (1.8-fold; p < 0.05). This corresponded with a 1.2-fold reduction in the provision of the first dose of measles vaccine at 6 months compared to 2019. Throughout 2020 there was a 4-fold decline in the number of fully immunized children at 1 year of age (p = 0.84). Emergency room visits fell by 35.7% in 2020 (16 368) compared to 2019 (25 446). Hospital admissions decreased significantly (p < 0.01) in 2020 (9810) compared to 2018 (11 698) and 2019 (10 247). The in-hospital mortality rate increased from 2.3% (96/4163) in 2019 to 3.8% (95/2498) (p < 0.01) in Tygerberg Hospital, where 80% (95/119) of deaths were recorded. Twelve of the 119 (10%) deaths occurred in HIV-positive children (p = <0.01). CONCLUSION: Measures instituted during the COVID-19 pandemic disrupted access to healthcare services for children. This resulted in an immediate, and potential future, indirect effect on child morbidity and mortality in Cape Town.

During the COVID-19 pandemic in 2020, lockdown policies restricted movement of people and non-COVID-19 healthcare services were de-escalated. In a large district, Metro East, in Cape Town, South Africa, this resulted in a 1.8-fold decline in primary healthcare clinic visits in children less than 5 years of age. Routine immunizations were negatively impacted with a 1.2-fold decline in the uptake of the first dose of measles vaccine at 6 months of age and a 1.4-fold decline in the number of fully immunized children at 1 year of age. Hospital admissions decreased significantly from 10 247 and 11 698 in 2019 and 2018, respectively, to 9810 admissions in 2020. Although fewer deaths (119) were reported in hospitals in Metro East District, Cape Town, South Africa in 2020, the deaths per number of admissions increased from 2.3% (96/4163) in 2019 to 3.8% (95/2498) in Tygerberg Hospital, where 80% (95/119) of deaths were recorded. Measures instituted during the COVID-19 pandemic in 2020 thus disrupted the access to healthcare services for children. This resulted in an immediate, and potential future, indirect effect on child health and survival in Cape Town.

Optimizing Dosing and Fixed-Dose Combinations of Rifampicin, Isoniazid, and Pyrazinamide in Pediatric Patients With Tuberculosis: A Prospective Population Pharmacokinetic Study.

BACKGROUND: In 2010, the World Health Organization (WHO) revised dosing guidelines for treatment of childhood tuberculosis. Our aim was to investigate first-line antituberculosis drug exposures under these guidelines, explore dose optimization using the current dispersible fixed-dose combination (FDC) tablet of rifampicin/isoniazid/pyrazinamide; 75/50/150 mg, and suggest a new FDC with revised weight bands. METHODS: Children with drug-susceptible tuberculosis in Malawi and South Africa underwent pharmacokinetic sampling while receiving first-line tuberculosis drugs as single formulations according the 2010 WHO recommended doses. Nonlinear mixed-effects modeling and simulation was used to design the optimal FDC and weight-band dosing strategy for achieving the pharmacokinetic targets based on literature-derived adult AUC0-24h for rifampicin (38.7-72.9), isoniazid (11.6-26.3), and pyrazinamide (233-429 mg ∙ h/L). RESULTS: In total, 180 children (42% female; 13.9% living with human immunodeficiency virus [HIV]; median [range] age 1.9 [0.22-12] years; weight 10.7 [3.20-28.8] kg) were administered 1, 2, 3, or 4 FDC tablets (rifampicin/isoniazid/pyrazinamide 75/50/150 mg) daily for 4-8, 8-12, 12-16, and 16-25 kg weight bands, respectively. Rifampicin exposure (for weight and age) was up to 50% lower than in adults. Increasing the tablet number resulted in adequate rifampicin but relatively high isoniazid and pyrazinamide exposures. Administering 1, 2, 3, or 4 optimized FDC tablets (rifampicin/isoniazid/pyrazinamide 120/35/130 mg) to children < 6, 6-13, 13-20. and 20-25 kg, and 0.5 tablet in < 3-month-olds with immature metabolism, improved exposures to all 3 drugs. CONCLUSIONS: Current pediatric FDC doses resulted in low rifampicin exposures. Optimal dosing of all drugs cannot be achieved with the current FDCs. We propose a new FDC formulation and revised weight bands.

Population pharmacokinetics of ethambutol in African children: a pooled analysis.

OBJECTIVES: Ethambutol protects against the development of resistance to co-administered drugs in the intensive phase of first-line anti-TB treatment in children. It is especially relevant in settings with a high prevalence of HIV or isoniazid resistance. We describe the population pharmacokinetics of ethambutol in children with TB to guide dosing in this population. METHODS: We pooled data from 188 intensively sampled children from the DATiC, DNDi and SHINE studies, who received 15-25 mg/kg ethambutol daily according to WHO guidelines. The median (range) age and weight of the cohort were 1.9 (0.3-12.6) years and 9.6 (3.9-34.5) kg, respectively. Children with HIV (HIV+; n = 103) received ART (lopinavir/ritonavir in 92%). RESULTS: Ethambutol pharmacokinetics were best described by a two-compartment model with first-order elimination and absorption transit compartments. Clearance was estimated to reach 50% of its mature value by 2 months after birth and 99% by 3 years. Typical steady-state apparent clearance in a 10 kg child was 15.9 L/h. In HIV+ children on lopinavir/ritonavir, bioavailability was reduced by 32% [median (IQR) steady-state Cmax = 0.882 (0.669-1.28) versus 1.66 (1.21-2.15) mg/L). In young children, bioavailability correlated with age. At birth, bioavailability was 73.1% of that in children 3.16 years or older. CONCLUSIONS: To obtain exposure within the 2-6 mg/L recommended range for Cmax, the current doses must be doubled (or tripled with HIV+ children on lopinavir/ritonavir) for paediatric patients. This raises concerns regarding the potential for ocular toxicity, which would require evaluation.

Abacavir pharmacokinetics in African children living with HIV: A pooled analysis describing the effects of age, malnutrition and common concomitant medications.

AIMS: Abacavir is part of WHO-recommended regimens to treat HIV in children under 15 years of age. In a pooled analysis across four studies, we describe abacavir population pharmacokinetics to investigate the influence of age, concomitant medications, malnutrition and formulation. METHODS: A total of 230 HIV-infected African children were included, with median (range) age of 2.1 (0.1-12.8) years and weight of 9.8 (2.5-30.0) kg. The population pharmacokinetics of abacavir was described using nonlinear mixed-effects modelling. RESULTS: Abacavir pharmacokinetics was best described by a two-compartment model with first-order elimination, and absorption described by transit compartments. Clearance was predicted around 54% of its mature value at birth and 90% at 10 months. The estimated typical clearance at steady state was 10.7 L/h in a child weighing 9.8 kg co-treated with lopinavir/ritonavir, and was 12% higher in children receiving efavirenz. During coadministration of rifampicin-based antituberculosis treatment and super-boosted lopinavir in a 1:1 ratio with ritonavir, abacavir exposure decreased by 29.4%. Malnourished children living with HIV had higher abacavir exposure initially, but this effect waned with nutritional rehabilitation. An additional 18.4% reduction in clearance after the first abacavir dose was described, suggesting induction of clearance with time on lopinavir/ritonavir-based therapy. Finally, absorption of the fixed dose combination tablet was 24% slower than the abacavir liquid formulation. CONCLUSION: In this pooled analysis we found that children on lopinavir/ritonavir or efavirenz had similar abacavir exposures, while concomitant TB treatment and super-boosted lopinavir gave significantly reduced abacavir concentrations.

Paediatric pulmonary actinomycosis: A forgotten disease.

Actinomycosis is a rare, indolent and invasive infection caused by Actinomyces species. Actinomycosis develops when there is disruption of the mucosal barrier, and invasion and systemic spread of the organism, which can lead to endogenous infection affecting numerous organs. It is known to spread in tissue through fascial planes and most often involves the cervicofacial (55%), abdominopelvic (20%) and thoracic (15%) soft tissue. Pulmonary actinomycosis is rare in patients under the age of five years, with the median reported age in the fifth decade. Clinical findings include chest wall mass (49%), cough (40%), pain (back, chest, shoulders) (36%), weight loss (19%), fever (19%), Draining sinuses (15%) and hemoptysis (9%). Chest x-ray findings in pulmonary actinomycosis are mostly nonspecific and can overlap with pulmonary tuberculosis, foreign body aspiration and malignancy. Endobronchial tissue aggregates may show sulphur granules, with yellow to white conglomerate areas of gram positive Actinomyces. Removal or biopsy of these large endobronchial masses must be done with care, because of the risk of bleeding and large airway obstruction. The cytology on bronchoalveolar lavage fluid may show Periodic acid-Schiff (PAS) positive stain, ZN negative and Gram-positive filamentous bacilli which is morphologically suggestive of Actinomycosis. Actinomyces spp is highly susceptible to beta lactam antibiotics, penicillin G, and amoxicillin. A minimum of 3-6 months is needed but up to 20 months of treatment may be needed. Early diagnosis and correct treatment can lead to a good prognosis with a low mortality.

The clinical features and estimated incidence of MIS-C in Cape Town, South Africa.

BACKGROUND: Multisystem inflammatory syndrome is a severe manifestation of SARS-CoV-2 in children. The incidence of MIS-C after infection is poorly understood. There are very few cohorts describing MIS-C in Africa despite MIS-C being more common in Black children worldwide. METHODS: A cohort of children with MIS-C and healthy children was recruited from May 2020 until May 2021 from the two main paediatric hospitals in Cape Town, South Africa. Clinical and demographic data were collected, and serum was tested for SARS-CoV-2 antibodies. The incidence of MIS-C was calculated using an estimation of population exposure from seroprevalence in the healthy group. Summary data, non-parametric comparisons and logistic regression analyses were performed. RESULTS: Sixty eight children with MIS-C were recruited with a median age of 7 years (3.6, 9.9). Ninety seven healthy children were recruited with a 30% seroprevalence. The estimated incidence of MIS-C was 22/100 000 exposures in the city in this time. Black children were over-represented in the MIS-C group (62% vs 37%, p = 0.002). The most common clinical features in MIS-C were fever (100%), tachycardia (98.5%), rash (85.3%), conjunctivitis (77.9%), abdominal pain (60.3%) and hypotension (60.3%). The median haemoglobin, sodium, neutrophil count, white cell count, CRP, ferritin, cardiac (pro-BNP, trop-T) and coagulation markers (D-dimer and fibrinogen) were markedly deranged in MIS-C. Cardiac, pulmonary, central nervous and renal organ systems were involved in 71%, 29.4%, 27.9% and 27.9% respectively. Ninety four percent received intravenous immune globulin, 64.7% received methylprednisolone and 61.7% received both. Forty percent required ICU admission, 38.2% required inotropic support, 38.2% required oxygen therapy, 11.8% required invasive ventilation and 6% required peritoneal dialysis. Older age was an independent predictor for the requirement for ionotropic support (OR = 1.523, CI 1.074, 2.16, p = 0.018). The median hospital stay duration was 7 days with no deaths. CONCLUSION: The lack of reports from Southern Africa does not reflect a lack of cases of MIS-C. MIS-C poses a significant burden to children in the region as long as the pandemic continues. MIS-C disproportionately affects black children. The clinical manifestations and outcomes of MIS-C in this region highlight the need for improved surveillance, reporting and data to inform diagnosis and treatment.

Single Dose Abacavir Pharmacokinetics and Safety in Neonates Exposed to Human Immunodeficiency Virus (HIV).

Abacavir is a potential option for prophylaxis and early treatment of human immunodeficiency virus (HIV), but no data are available in neonates. Ten neonates administered a single abacavir dose of 8 mg/kg before 15 days of life had substantially higher exposures than those reported in infants and children, with no reported adverse events.

Clinical Experience With Severe Acute Respiratory Syndrome Coronavirus 2-Related Illness in Children: Hospital Experience in Cape Town, South Africa.

BACKGROUND: Children seem relatively protected from serious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related disease, but little is known about children living in settings with high tuberculosis and human immunodeficiency virus (HIV) burden. This study reflects clinical data on South African children with SARS-CoV-2. METHODS: We collected clinical data of children aged <13 years with laboratory-confirmed SARS-CoV-2 presenting to Tygerberg Hospital, Cape Town, between 17 April and 24 July 2020. RESULTS: One hundred fifty-nine children (median age, 48.0 months [interquartile range {IQR}, 12.0-106.0 months]) were included. Hospitalized children (n = 62), with a median age of 13.5 months (IQR, 1.8-43.5 months) were younger than children not admitted (n = 97; median age, 81.0 months [IQR, 34.5-120.5 months]; P < .01.). Thirty-three of 159 (20.8%) children had preexisting medical conditions. Fifty-one of 62 (82.3%) hospitalized children were symptomatic; lower respiratory tract infection was diagnosed in 21 of 51 (41.2%) children, and in 11 of 16 (68.8%) children <3 months of age. Respiratory support was required in 25 of 51 (49.0%) children; 13 of these (52.0%) were <3 months of age. One child was HIV infected and 11 of 51 (21.2%) were HIV exposed but uninfected, and 7 of 51 (13.7%) children had a recent or new diagnosis of tuberculosis. CONCLUSIONS: Children <1 year of age hospitalized with SARS-CoV-2 in Cape Town frequently required respiratory support. Access to oxygen may be limited in some low- and middle-income countries, which could potentially drive morbidity and mortality. HIV infection was uncommon but a relationship between HIV exposure, tuberculosis, and SARS-CoV-2 should be explored.

The Critical Need for Pooled Data on Coronavirus Disease 2019 in African Children: An AFREhealth Call for Action Through Multicountry Research Collaboration.

Globally, there are prevailing knowledge gaps in the epidemiology, clinical manifestations, and outcomes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among children and adolescents; and these gaps are especially wide in African countries. The availability of robust age-disaggregated data is a critical first step in improving knowledge on disease burden and manifestations of coronavirus disease 2019 (COVID-19) among children. Furthermore, it is essential to improve understanding of SARS-CoV-2 interactions with comorbidities and coinfections such as human immunodeficiency virus (HIV), tuberculosis, malaria, sickle cell disease, and malnutrition, which are highly prevalent among children in sub-Saharan Africa. The African Forum for Research and Education in Health (AFREhealth) COVID-19 Research Collaboration on Children and Adolescents is conducting studies across Western, Central, Eastern, and Southern Africa to address existing knowledge gaps. This consortium is expected to generate key evidence to inform clinical practice and public health policy-making for COVID-19 while concurrently addressing other major diseases affecting children in African countries.

Abacavir Exposure in Children Cotreated for Tuberculosis with Rifampin and Superboosted Lopinavir-Ritonavir.

In children requiring lopinavir coformulated with ritonavir in a 4:1 ratio (lopinavir-ritonavir-4:1) and rifampin, adding ritonavir to achieve a 4:4 ratio with lopinavir (LPV/r-4:4) overcomes the drug-drug interaction. Possible drug-drug interactions within this regimen may affect abacavir concentrations, but this has never been studied. Children weighing <15 kg needing rifampin and LPV/r-4:4 were enrolled in a pharmacokinetic study and underwent intensive pharmacokinetic sampling on 3 visits: (i) during the intensive and (ii) continuation phases of antituberculosis treatment with LPV/r-4:4 and (iii) 1 month after antituberculosis treatment completion on LPV/r-4:1. Pharmacometric modeling and simulation were used to compare exposures across weight bands with adult target exposures. Eighty-seven children with a median (interquartile range) age and weight of 19 (4 to 64) months and 8.7 (3.9 to 14.9) kg, respectively, were included in the abacavir analysis. Abacavir pharmacokinetics were best described by a two-compartment model with first-order elimination and transit compartment absorption. After allometric scaling adjusted for the effect of body size, maturation could be identified: clearance was predicted to be fully mature at about 2 years of age and to reach half of this mature value at about 2 months of age. Abacavir bioavailability decreased 36% during treatment with rifampin and LPV/r-4:4 but remained within the median adult recommended exposure, except for children in the 3- to 4.9-kg weight band, in which the exposures were higher. The observed predose morning trough concentrations were higher than the evening values. Though abacavir exposure significantly decreased during concomitant administration of rifampin and LPV/r-4:4, it remained within acceptable ranges. (This study is registered in ClinicalTrials.gov under identifier NCT02348177.).

Identification of a novel WAS mutation in a South African patient presenting with atypical Wiskott-Aldrich syndrome: a case report.

BACKGROUND: The X-linked recessive primary immunodeficiency disease (PIDD) Wiskott-Aldrich syndrome (WAS) is identified by an extreme susceptibility to infections, eczema and thrombocytopenia with microplatelets. The syndrome, the result of mutations in the WAS gene which encodes the Wiskott-Aldrich protein (WASp), has wide clinical phenotype variation, ranging from classical WAS to X-linked thrombocytopaenia and X-linked neutropaenia. In many cases, the diagnosis of WAS in first affected males is delayed, because patients may not present with the classic signs and symptoms, which may intersect with other thrombocytopenia causes. CASE PRESENTATION: Here, we describe a three-year-old HIV negative boy presenting with recurrent infections, skin rashes, features of autoimmunity and atopy. However, platelets were initially reported as normal in numbers and morphology as were baseline immune investigations. An older male sibling had died in infancy from suspected immunodeficiency. Uncertainty of diagnosis and suspected severe PIDD prompted urgent further molecular investigation. Whole exome sequencing identified c. 397 G > A as a novel hemizygous missense mutation located in exon 4 of WAS. CONCLUSION: With definitive molecular diagnosis, we could target treatment and offer genetic counselling and prenatal diagnostic testing to the family. The identification of novel variants is important to confirm phenotype variations of a syndrome.

Pediatric Antiretroviral Therapeutic Drug Monitoring: A Five and a Half Year Experience from a South African Tertiary Hospital.

INTRODUCTION: Antiretroviral therapeutic drug monitoring (TDM) is not routinely used in the management of human immunodeficiency virus, but may be useful in pediatric patients who are prone to altered pharmacokinetics. Data on the routine use of antiretroviral TDM in pediatrics are sparse especially data from sub-Saharan Africa. METHODS: We retrospectively reviewed the antiretroviral TDM indications at Tygerberg Children's Hospital, identified pediatric patients who had antiretroviral TDM requests from January 2012 until June 2017 and reviewed their clinical records. RESULTS: Fifty-nine patients were identified who presented with 64 clinical problems for which TDM was requested. TDM was requested for lopinavir, efavirenz and nevirapine in 83% (53/64), 14% (9/64) and 3% (2/64) of clinical problems, respectively. Lopinavir was mostly requested in patients when adherence measures did not correlate with the clinical picture, suspected non-adherence, lopinavir-rifampicin interactions and for neonatal safety monitoring. Efavirenz was requested when toxicity was suspected and nevirapine in patients receiving rifampicin. Lopinavir TDM confirmed non-adherence in 25% (4/16) of cases when adherence measures did not correlate with the clinical picture and in 43% (3/7) of cases when non-adherence was suspected by the clinician. Efavirenz TDM confirmed toxicity in 100% (6/6) of patients. CONCLUSIONS: Lopinavir TDM was mostly requested when adherence measures did not correlate with the clinical picture, when rifampicin was co-administered and for perinatal safety monitoring. Lopinavir TDM excluded pharmacokinetic reasons for failure in patients failing treatment when lopinavir dosing was supervised. Efavirenz TDM was requested for suspected toxicity with a 100% positive predictive value.

Congenital Rubella Syndrome Surveillance in South Africa Using a Sentinel Site Approach: A Cross-sectional Study.

BACKGROUND: Congenital rubella syndrome (CRS) includes disorders associated with intrauterine rubella infection. Incidence of CRS is higher in countries with no rubella-containing vaccines (RCV) in their immunization schedules. In the World Health Organization African region, RCVs are being introduced as part of the 2012-2020 global measles and rubella strategic plan. This study aimed to describe the epidemiology of confirmed CRS in South Africa prior to introduction of RCVs in the immunization schedule. METHODS: This was a descriptive study with 28 sentinel sites reporting laboratory-confirmed CRS cases in all 9 provinces of South Africa. In the retrospective phase (2010 to 2014), CRS cases were retrieved from medical records, and in the prospective phase (2015 to 2017) clinicians at study sites reported CRS cases monthly. RESULTS: There were 42 confirmed CRS cases in the retrospective phase and 53 confirmed CRS cases in the prospective phase. Most frequently reported birth defects were congenital heart disease and cataracts. The median age of mothers of CRS cases was 21 years in the retrospective phase (range: 11 to 38 years) and 22 years in the prospective phase (range: 15 to 38 years). CONCLUSION: Baseline data on laboratory-confirmed CRS will enable planning and monitoring of RCV implementation in the South African Expanded Programme on Immunization program. Ninety-eight percent of mothers of infants with CRS were young women 14-30 years old, indicating a potential immunity gap in this age group for consideration during introduction of RCV.

Pharmacokinetics of adjusted-dose 8-hourly lopinavir/ritonavir in HIV-infected children co-treated with rifampicin.

OBJECTIVES: To evaluate the proportion of children with lopinavir Cmin ≥1 mg/L when receiving a novel 8-hourly lopinavir/ritonavir dosing strategy during rifampicin co-treatment. METHODS: HIV-infected children on lopinavir/ritonavir and rifampicin were enrolled in a prospective pharmacokinetic study. Children were switched from standard-of-care lopinavir/ritonavir-4:1 with additional ritonavir (1:1 ratio) twice daily to 8-hourly lopinavir/ritonavir-4:1 using weight-banded dosing. Rifampicin was dosed at 10-20 mg/kg/day. After 2 weeks, plasma samples were collected ∼2, 4, 6, 8 and 10 h after the morning lopinavir/ritonavir-4:1 dose, ALT was obtained to assess safety and treatment was switched back to standard of care. ClinicalTrials.gov registration number: NCT01637558. RESULTS: We recruited 11 children in two weight bands: 5 (45%) were 10-13.9 kg and received 20-24 mg/kg/dose of lopinavir and 6 (55%) children weighed 6-9.9 kg and received 20-23 mg/kg/dose of lopinavir. The median age was 15 months (IQR = 12.6-28.8 months). The median (IQR) lopinavir Cmin was 3.0 (0.1-5.5) mg/L. Seven (63.6%) of the 11 children had Cmin values ≥1 mg/L. Children with a lopinavir mg/kg dose below the median 21.5 were more likely to have Cmin <1 mg/L (P = 0.02). There was a strong positive correlation between lopinavir and ritonavir concentrations. No associations were found between lopinavir AUC2-10 and age, sex, weight, nutritional status or mg/kg/dose of lopinavir. CONCLUSIONS: These data do not support the use of 8-hourly lopinavir/ritonavir at studied doses. Evaluation of higher doses is needed to optimize treatment outcomes of TB and HIV in young children.

Priorities for Decreasing Morbidity and Mortality in Children With Advanced HIV Disease.

Early mortality and morbidity remain high in children initiating antiretroviral therapy (ART), especially in sub-Saharan Africa. Many children still present with advanced human immunodeficiency virus (HIV) disease. Tuberculosis, pneumonia, and severe bacterial infections are the main causes of hospital admission in HIV-infected children. In contrast to adults with advanced HIV disease, cryptococcal disease is not common in childhood, although there is a peak in infancy and adolescence. Interventions such as TB screening in symptomatic children, and isoniazid and cotrimoxazole prophylaxis should be implemented. There is evidence suggesting that rapid initiation (within 1 week) of ART in children with severe malnutrition or those with advanced HIV disease admitted to hospital is not beneficial and should be delayed until their condition has been stabilized. Research informing the prevention of severe bacterial infections, the management of pediatric immune reconstitution inflammatory syndrome, and other potential strategies to decrease morbidity and mortality in HIV-infected children are urgently needed.

Association of Adolescent- and Caregiver-Reported Antiretroviral Therapy Adherence with HIV Viral Load Among Perinatally-infected South African Adolescents.

Accurate measurement of antiretroviral therapy (ART) adherence remains challenging and there are few data assessing the validity of self-reported adherence among perinatally HIV-infected adolescents. We examined adolescent and caregiver reports of adolescent adherence among perinatally-infected adolescents aged 9-14 years in Cape Town, South Africa, and explored factors that may modify associations between reported adherence and elevated viral load (VL). Among 474 adolescents (median age 12.0 years; median duration of ART use 7.5 years), elevated VL and caregiver- and adolescent-report of missed ART doses were common. Elevated VL was particularly prevalent among older, male adolescents. Low-moderate concordance was observed between caregiver and adolescent report. Among adolescents aged ≥ 12 years, caregiver- and adolescent-reported adherence was associated with elevated VL across most items assessed, but few significant associations were observed among adolescents < 12 years of age. Refined adherence measures and tools to identify adolescents who require adherence interventions are needed in this context.

Trends in paediatric bloodstream infections at a South African referral hospital.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.