Doctoral Degrees (Paediatrics and Child Health)

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And therapeutic outcomes lopinavir-ritonavir and a rifampicin containing anti-tuberculosis pharmacokinetics in children with tuberculosis/hiv co-infection treated with regimen
(Stellenbosch : Stellenbosch University, 2019-10-15) Rabie, Helena; Cotton, Mark F.; Schaaf, Hendrik Simon; Gie, Robert Peter; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Paediatrics and Child Health.
ENGLISH ABSTRACT: Background Despite the scale-up of the prevention of mother to child transmission of HIV, an estimated 240,000 children were infected in 2013. Currently, The Joint United Nations Programme on HIV and AIDS (UNAIDS) estimates that 110,000 to 260,000 children less than 14 years of age are newly infected annually. Tuberculosis remains an important cause of morbidity and mortality in HIV co-infected children. The overlapping epidemiology of tuberculosis and HIV in sub-Saharan Africa is well known. Despite reductions in incident tuberculosis cases brought about by both the general roll out of antiretroviral therapy (ART) and the improvement of personal health of HIVpositive children, HIV-positive children remain at high risk for tuberculosis. Currently the World Health Organization (WHO) recommends rifampicin containing fixed-dose combinations for treatment of tuberculosis. Rifampicin induces its own metabolism and concentrations are affected by SLCO1B1CT (rs4149032) polymorphism. Rifampicin is well known to cause significant drug-drug interactions through activation of the nuclear pregnane X receptor that in turn affects cytochromes P450, glucuronosyltransferases and p-glycoprotein activities. This activation causes significant drug interactions with protease inhibitors and non-nucleoside reverse transcriptase inhibitors. In addition, SLCO1B1 521 TC (rs4149056) and CYP3A5 polymorphisms may affect lopinavir exposures through altering uptake and metabolism. Abacavir, together with the protease inhibitor lopinavir co-formulated with the pharmacokinetic enhancing protease inhibitor, ritonavir, is a preferred first-line medication for young children with HIV. Rifampicin causes up to 90% reduction in lopinavir exposure, but there are no data on its effect on abacavir in children. Understanding these interactions is essential to ensure effective co-treatment that will suppress HIV replication during co-treatment. For co-formulated lopinavir with ritonavir in a 4:1 ratio, achieving a morning trough concentration (Ctrough) of ≥1mg/L is associated with acceptable viral load outcomes. Doubling the dose of co-formulated lopinavir-ritonavir-4:1 does not consistently achieve this target in children, but limited data suggested that adding ritonavir to achieve a 1:1 ratio of lopinavir-ritonavir (LPV/RTV-1:1) is successful. Furthermore, modelling data suggested that an 8-hourly adjusted dose may achieve this lopinavir trough concentration target, but there was no pharmacokinetic data to this effect. We undertook studies to evaluate two strategies to adjust medication in co-treated children and performed pharmacokinetic evaluation and safety evaluations during these studies and assessed virological outcomes in the larger study. We also studied the pharmacokinetic profile of abacavir during rifampicin containing first-line tuberculosis therapy. Methods To study the lopinavir morning Ctrough and the abacavir area under the curve from 0- 12 hours (AUC0-12) during LPV/RTV-1:1 we prospectively enrolled HIV-positive children with tuberculosis requiring co-treatment with rifampicin and oral solution lopinavir-ritonavir-4:1. Children weighing 3 kg to 15 kg and a post-conception age more than 42 weeks were included into a prospective, multicentre, open-label, nonrandomized study. Children received lopinavir-ritonavir-4:1 with additional ritonavir to achieve a 1:1 ratio. Weight-banded doses of anti-tuberculosis and antiretroviral medications were used. Three intensive pharmacokinetic evaluations were done: the first in the intensive phase of tuberculosis treatment, the second in the last month of tuberculosis treatment and the third evaluation two weeks after completing tuberculosis treatment. We compared a model-based morning Ctrough of lopinavir at the second assessment and the third assessment and tested for non-inferiority, using a non-inferiority margin of 10%. We also assessed model-based abacavir AUC0-12 during LPV/RTV-1:1 superboosting and thereafter. Safety, tolerability and virological outcomes were assessed through special investigations, including hepatic enzymes, electrocardiogram, viral load tests and resistant tests as well as questionnaires. In the second study, children were switched from standard of care (super-boosted lopinavir-ritonavir 1:1) to receive 2 weeks of adjusted dose 3 times daily lopinavirritonavir 4:1. After 2 weeks an intensive pharmacokinetic evaluation was performed and the patient switched back to standard of care ART. We determined the number of children with a morning Ctrough of lopinavir ≥1mg/L. Safety was assessed by measuring hepatic enzymes. Results For the first strategy (LPV/RTV-1:1) 96 children with a median age of 18.2 months enrolled into a non-inferiority study of super-boosting lopinavir-ritonavir-4:1 to achieve a 1:1 ratio. Of these 96 children, 80 (83%) completed all three pharmacokinetic evaluations. The model-based lopinavir morning Ctrough on super-boosted lopinavir ritonavir 4:1 with additional ritonavir to achieve a 1:1 ratio whilst receiving rifampicinbased tuberculosis treatment was non-inferior to the model-based morning Ctrough in children on lopinavir-ritonavir-4:1 after the end of tuberculosis therapy and superboosting. The model-predicted percentage of morning Ctrough less than 1.0 mg/L after tuberculosis treatment without super-boosting was 8·8% (95% confidence interval [CI] 0·6–19·8), versus 7·6% (95% CI 0·4–16·2) during super-boosting and tuberculosis treatment. At the non-inferiority margin of 10%, this difference of –1·1% (95% CI –6·9 to 3·2) met the criterion for non-inferiority. This strategy was safe and the viral load outcomes were acceptable: children who failed to suppress HIV did not develop resistance. Caretakers reported poor palatability and tolerability of both lopinavirritonavir-4:1 oral solution and ritonavir oral solution. For the second strategy (8-hourly adjusted dosing) 11 children were enrolled into the study assessing adjusted-dose 8-hourly lopinavir-ritonavir 4:1. Children were divided into two weight bands: 5 (45%) were 10–13.9 kg and received 20–24 mg/kg/dose, and 6 (55%) children weighed 6–9.9 kg and received 20–23 mg/kg/dose of lopinavir. Seven children (63.6%) met the suggested morning Ctrough target. Children with a lopinavir mg/kg dose below the median of 21.5mg/kg/dose were more likely to have a morning Ctrough below 1 mg/L (p=0.02). There was a strong correlation between lopinavir and ritonavir concentrations. To model the AUC0-12 of abacavir we included 85 children at PK1, 74 at children at PK2 and 72 children at PK3 on abacavir and in whom pharmacokinetic information was available. Children were participating in the non-inferiority study of super-boosted lopinavir-ritonavir-4:1 to achieve a 1:1 ratio. Abacavir pharmacokinetics was described by a two-compartment model with first-order elimination and transit compartment absorption. Clearance was predicted to reach half its mature value at around 2 months after birth and to be fully mature by approximately 2 years of age. During coadministration of rifampicin and super-boosting with ritonavir, a 36% decrease in bioavailability (and AUC0-12) was found. Conclusions Super-boosting lopinavir-ritonavir-4:1 with ritonavir to a 1:1 ratio during rifampicin containing tuberculosis treatment is non-inferior to lopinavir-ritonavir-4:1 without rifampicin. It is also safe and effective but it is poorly tolerated and has poor palatability. Adjusted 8-hourly dosing requires further study. During super-boosting of lopinavir-ritonavir while on rifampicin containing tuberculosis treatment, there is a drug interaction causing a 36% reduction in abacavir AUC0-12
Determinants of healthcare-associated infection among hospitalized children
(Stellenbosch : Stellenbosch University, 2017-03) Dramowski, Angela; Cotton, Mark F.; Whitelaw, Andrew; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Paediatrics and Child Health.
ENGLISH SUMMARY: Healthcare-associated infection (HAI) is the most frequent complication of hospitalization resulting in suffering, excess mortality and increased healthcare costs. Although paediatric HAI burden and impact is well-described in high-income countries, it is largely unquantified in Africa. Our research aimed to: (i) comprehensively describe the epidemiology and impact of HAI and HA-bloodstream infections in an African cohort of hospitalized children; (ii) establish appropriate HAI surveillance methods for our setting; (iii) investigate selected local determinants of paediatric HAI (including healthcare worker HAI-related knowledge, attitudes and practices, isolation facility utilization and terminal cleaning practices). In a retrospective analysis of paediatric bloodstream infection trends at Tygerberg Hospital, we reported the highest estimate of HA-bloodstream infections rates among African children to date. HIV-infection, HA-bloodstream infection, fungal and Gram-negative pathogens were important predictors of bloodstream infection-associated mortality. We conducted prospective clinical surveillance in paediatric wards and the intensive care unit at Tygerberg Children’s Hospital. HAI incidence (31/1000 patient days) exceeded published rates in high and low-middle income countries, with highest infection density in the paediatric intensive care unit (94/1000 patient days). Children experiencing HAI events were young (median 8.4 months), more likely to be malnourished, HIV-exposed uninfected or HIV-infected and to have pre-existing co-morbidities. Hospital-acquired pneumonia, bloodstream and urinary tract infections predominated. The increased odds for HAI in HIV-exposed uninfected and HIV-infected children is a novel association. Two-thirds of in-patient mortality was associated with HAI and patients with any HAI event had a 6-fold increase in crude mortality. Patients experiencing HAI had 3-fold higher rates of re-hospitalization within 30 days. Direct costs of HAI were substantial; mean duration of hospitalization, bed availability, antimicrobial consumption and laboratory investigation usage were significantly impacted by HAI. Although prospective clinical HAI surveillance is considered the reference standard, its use in Africa is limited by lack of resources and expertise. We compared the performance of three alternate HAI surveillance methods (point prevalence surveys [PPS], laboratory surveillance and tracking of antimicrobial prescriptions) using the prospectively collected paediatric HAI dataset as the reference standard. Although repeated PPS, laboratory and antimicrobial prescription tracking were demonstrated to be feasible HAI surveillance methods, a combination of laboratory-antimicrobial surveillance achieved best sensitivity (85%) and positive predictive value (97%), and required fewer resources to perform. South African paediatric healthcare facilities should individualise HAI surveillance, selecting a method suited to available resources and practice context. We identified a shortage of isolation facilities and sub-optimal identification of patients requiring isolation as potential contributors to infection transmission. The need for negative-pressure ventilation and airborne isolation facilities on children’s wards in TB-endemic settings was also highlighted. For terminal cleaning of paediatric isolation rooms we investigated three evaluation methods; fluorescent markers emerged as most cost-effective and feasible for our resource-limited setting. Finally, we surveyed two-thirds of our paediatric department’s staff regarding their knowledge, attitudes and practices related to HAI, identifying several knowledge gaps and opportunities for improved infection prevention practice. Owing to the extreme paucity of data, paediatric HAI in Africa remains an underappreciated and underfunded public health problem. We believe that this doctoral research dissertation provides unequivocal justification for greater resource allocation to HAI surveillance and prevention programmes for hospitalized African children.
Lipoatrophy in HIV-infected children on antiretroviral therapy
(Stellenbosch : Stellenbosch University, 2013-03) Innes, Steven Eugene Vere; Cotton, Mark F.; Rosenkranz, Bernd; Rabie, Helena; Zollner, Ekkehard Werner; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Paediatrics and Child Health.
ENGLISH ABSTRACT: Introduction: Lipoatrophy is a common adverse effect of stavudine and this effect is strongly dose-dependent. Stavudine remains the most commonly used paediatric antiretroviral drug in sub-Saharan Africa, yet when the current study began in 2009, the prevalence and severity of lipoatrophy in children on antiretroviral therapy in sub-Saharan Africa had never been studied. The development of lipoatrophy may have serious and far-reaching consequences for patients and their families. The off-label stavudine dosing method, prescribed to children whose caregivers do not have access to a refrigerator, in which the contents of an adult capsule is mixed into tap water, has potential for over-dosing or under-dosing. In addition, children on stavudine continue to be exposed to a disproportionately high dose out of line with the reduced adult dose. Aims: 1. a) To investigate the prevalence and risk factors for lipoatrophy in HIV-infected children in Southern Africa b) To identify a simple anthropometric screening tool to detect early lipoatrophy in children 2. To validate the off-label stavudine dosing method prescribed to children whose caregivers do not have access to a refrigerator, with a view to reducing the recommended dose and thereby the side-effects. Methods: 1. a) We recruited pre-pubertal children on antiretroviral therapy from a family HIV clinic in our facility. Lipoatrophy was identified by two experienced paediatric HIV clinicians using a standardized grading scale. A dietician performed dietary assessment and anthropometric measurements. Previous antiretroviral exposures were recorded. A subset of recruits received Dual-Energy X-ray Absorbtiometry scanning. b) Anthropometric measurements in children with and without lipoatrophy were compared using multivariate linear regression adjusting for age and gender. The most discerning anthropometric variables underwent Receiver Operating Characteristic curve analysis to identify the most appropriate diagnostic cut-off. 2. a) Accuracy of the standard off-label stavudine dosing method was investigated using high-performance liquid chromatography to recover active drug from solutions made up using the prescribed method. This was compared to the stated drug content of the capsules. b) Bioavailability was investigated by performing a randomized crossover pharmacokinetic study wherein healthy HIV-seronegative adult volunteers received one of two generic stavudine capsule formulations, either intact or mixed in water using the prescribed method. Plasma stavudine concentrations were assayed by liquid chromatography tandem mass spectrometry. Results: 1. a) Prevalence of lipoatrophy was 36%, and incidence was 12% per person-year. Adjusted odds ratio for developing lipoatrophy was 1.9 (CI: 1.3–2.9) for each additional year of accumulated exposure to standard-dose stavudine. b) Baseline biceps skin-fold thickness correlated well with maximum lipoatrophy grading score at any site, giving a partial correlation coefficient of 0.33 (p=0.0006), and a receiver operating characteristic area-under-curve value of 0.75 (CI: 0.64 – 0.84). Biceps skin-fold thickness <5mm at baseline had a sensitivity of 89% (CI: 67–100%) and a negative predictive value of 97% (CI: 91–100%) for predicting which children would go on to develop lipoatrophy by 15 month follow-up. Specificity was 60% (CI: 46–75%) and positive predictive value was 32% (CI: 14–50%). 2. a) Recovery of active drug from solution was 97.1%, 97.4% and 93.8% for the proprietary and two generic formulations respectively. b) Pharmacokinetic parameters of the off-label dosing method were well within the target range of intact capsule dosing for both generics. Conclusions: 1. a) The prevalence and incidence of lipoatrophy in pre-pubertal children on antiretroviral therapy in South Africa is high. Cumulative exposure to standard-dose stavudine was the greatest risk factor for lipoatrophy. b) Biceps skin-fold thickness provided reasonable sensitivity and specificity to detect and predict lipoatrophy in pre-pubertal children on antiretroviral therapy. 2. The off-label dosing method for stavudine prescribed to children whose caregivers do not have access to a refrigerator is reasonably accurate and is bioequivalent to intact capsule administration.
Neuro-imaging in paediatric HIV, a MRI/DTI study
(Stellenbosch : Stellenbosch University, 2020-03) Ackermann, Christelle; Cotton, Mark F.; Andronikou, Savvas; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Paediatrics and Child Health.
ENGLISH ABSTRACT: The HIV epidemic has been largely controlled by antiretroviral treatment (ART) which improves neurodevelopmental outcomes. Nevertheless, many HIV-infected (HIV+) children on long-term treatment may have HIV-related brain injury, ongoing cognitive impairment and treatment-related neurological complications. Magnetic resonance imaging (MRI) and in particular diffusion tensor imaging (DTI) are sensitive tools in assessing the integrity of white matter (WM) microstructure in HIV. The pictorial review describes common causes of HIV-related cerebral WM disease as well as the role of neuro-imaging in managing these patients. In the following chapters the characteristics of WM signal abnormalities on MRI and DTI (using DTI derived measures - fractional anisotropy (FA), mean (MD), axial (AD) and radial diffusion (RD)) in children with HIV, recruited as part of the Children with HIV early antiretroviral (CHER) trial and who started ART within the first year of life, are described. In the CHER trial, infants were randomized to early limited or deferred continuous ART. Methods: Structural MRI scans of children at mean age 39.1 months were reviewed and correlated with clinical and neurodevelopmental data, virological markers and time on ART. DTI was acquired in a similar cohort (which included several children in the first study and control subjects) at mean age of 64.7 months. Voxel-based group comparisons were performed to determine regions where FA and MD differed between HIV+ and uninfected children. Associations of DTI parameters with timing of ART initiation and correlations of DTI parameters in abnormal WM with directed neurodevelopmental tests were examined. Results: MRI scans of 44 children were reviewed at mean age of 39.1 months: 10 on deferred and 34 on early CHER treatment arms, commencing ART at mean age of 18.5 and 8 weeks respectively. Multiple high signal intensity lesions on T2 /FLAIR were documented in 22 patients (50%), predominantly in frontal (91%) and parietal (82%) WM. There were no differences in neurodevelopmental scores in children with and without WM signal abnormalities. Neither lesion load nor distribution showed significant correlation with neurodevelopmental scores or neurological examination. There was a trend for association of WM signal abnormalities and longer time on ART (p=0.13) and nadir CD4% (p=0.08). 39 HIV+ children (15 male) and 13 controls (5 male) were imaged (using DTI) at mean age of 64.7 months. 2 Clusters with decreased FA and 7 clusters with increased MD were identified in the HIV+ group with symmetrical distribution predominantly due to increased RD, suggestive of decreased myelination. Children on early interrupted ART had lower FA compared to those receiving continuous treatment. The only neurodevelopmental domain with a trend of difference between the HIV+ children and controls (p=0.08), was personal social quotient which correlated to improved myelination of the forceps minor in the control group. As a combined group there was a negative correlation between visual perception and RD in the right superior longitudinal fasciculus and left inferior longitudinal fasciculus which may be related to these tracts, part of the visual perception pathway, are at a crucial state of development at age 5. Conclusion: Half of children at mean age of 39.1 months, referred with HIV-related brain disease had WM signal abnormalities on T2/FLAIR structural MRI. HIV+ children at 5 years have WM abnormalities measured by FA, despite early ART, confirming that early ART does not fully protect the WM either from peripartum or in utero infection. In contrast to adults, the corticospinal tracts are predominantly involved rather than the corpus callosum. Continuous early ART, however limits the extent of WM damage. Even directed neurodevelopmental tests will underestimate the degree of microstructural WM damage detected by DTI. The visual perception deficit detected in the HIV study population should be further examined as it persists in longitudinal follow up of these patients at age 7.
The neurodevelopmental outcomes of perinatally HIV-infected children on different antiretroviral treatment (ART) strategies
(Stellenbosch : Stellenbosch University, 2019-12) Laughton, Barbara; Cotton, Mark F.; Kruger, Mariana; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Paediatrics and Child Health.
ENGLISH ABSTRACT: At the commencement of this study, it was apparent that antiretroviral therapy (ART) improved neurodevelopmental outcomes of children infected with HIV. Little was known about the long-term outcomes in infants who commenced early ART, or whether there would be consequences of temporary ART interruption. We conducted a prospective, longitudinal, observational study to determine the neurodevelopmental outcomes of children perinatally infected with HIV on different ART strategies from the Children with HIV Early antiRetroviral treatment (CHER) trial. We compared the outcomes of children whose ART was deferred to children who started early ART but with planned interruption of treatment. We also assessed the neurodevelopmental outcomes at 11months of age in a cohort of children perinatally infected with HIV, who started ART within the first few weeks of life. The Griffiths mental development scales (GMDS) were used to assess neurodevelopment at 11, 20, 30, 42 and 60 months, and the Beery-Buktenica developmental tests of visual motor integration were performed at 60 months. HIV-exposed uninfected (HEU) and HIV-unexposed (HU) children from similar neighbourhoods were enrolled for comparison. Mixed model repeated measures were used to compare groups over time. We found that children whose ART was deferred, had worse locomotor and general development in the first year of life compared to those who started treatment early and whilst asymptomatic with planned interruption. However, by five years of age the GMDS scores were similar. Children who started very early ART at a median age of 6 days, had similar GMDS scores at 11 months of age to the early treatment arm on CHER, who had started ART at median of 8 weeks. During the study we noted that children developed HIV encephalopathy, despite being on ART, including some with viral suppression. These children were followed for a median or 6.2 years and most recovered. This suggested a temporary insult, possibly due to inflammation associated with immune reconstitution that then resolved over time. An important finding was the visual perceptual deficit noted in HIV-infected children, compared to uninfected controls at 5 years of age. This study demonstrated that initiation of ART at a young age in an asymptomatic HIV- infected cohort had encouraging neurodevelopmental outcome at 5 years, apart from visual perception which was noted regardless of ART treatment strategy. Planned treatment interruption did not affect neurodevelopmental outcome by 5 years of age, but this was with careful clinical surveillance. Longer-term outcomes in older children would continue to provide further knowledge on ART treatment strategies.
Social and contextual factors affecting HIV-infected women’s feeding practices for their infants in normal practice settings : effects on growth and morbidity
(Stellenbosch : Stellenbosch University, 2016-03) Zunza, Moleen; Cotton, Mark F.; Esser, Monika; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Paediatrics and Child Health.
ENGLISH ABSTRACT: the significant reduction in HIV transmission through breastfeeding by antiretroviral treatment guided the current recommendations favouring breastfeeding which has to be continued until 12 months of age. Infant feeding guidelines for HIV-infected women in low-resourced settings are primarily informed by studies that spend much effort in controlling guideline adherence by investigators and participants. These studies however may not reflect the real world effects of the feeding options on important outcomes because such efforts are less enforced or rear in primary care settings. Reliable studies are lacking for predicting the real world effects of the feeding options on infant growth and morbidity to guide healthcare authorities in decision making. Social and contextual factors affecting HIV-infected women’s infant feeding practices are major barriers to uptake of infant feeding recommendations to levels that would result in a significant impact. Yet less attention is paid to these during guideline development and implementation. Methods: To address this knowledge gap we performed a longitudinal cohort study in primary healthcare settings, over a 12 months period. The objectives were to a) describe HIV-infected women’s infant feeding practices b) compare infant feeding practices of HIV-infected and HIV-uninfected breastfeeding women c) assess growth and infection-related hospitalizations among predominantly breastfed and predominantly formula-fed HIV-exposed uninfected infants. We explored infant feeding experiences of a sub-set of HIV-infected women who were followed-up for at least 6 months post-delivery in the longitudinal cohort. Results: We found that few HIV-infected women chose breastfeeding, and among those who did, many switched to formula feeding early. The proportion of women who continued predominantly breastfeeding was only slightly lower among HIV-infected compared to HIV-uninfected women (p = 0.0005). These differences were seen from about two weeks, and persisted throughout follow-up. By about four months, half of the HIV-infected women had switched to predominant formula feeding. However, the proportion of HIV-uninfected women who switched to formula feeding was also relatively high. The dual infant feeding option employed by the Western Cape PMTCT program while transitioning from formula feeding policy confused HIV-infected women who were worried that their child may contract HIV through breastmilk because of conflicting messages they received from healthcare providers, possibly explaining why some women stopped breastfeeding. Women’s interpretation of information about risks and benefits of infant feeding options, formula feeding stigma and the quality of infant feeding counselling affected women’s infant feeding practices. Mean weight velocity Z-scores (95% CI) of predominantly breastfed infants was -0.70 (-1.31 to -0.09; p = 0.024) lower than that of predominantly formula fed infants in the two to four months age interval. Protection against infections by breastfeeding was minimal and insignificant, odds ratio (OR) 0.95 (95% CI 0.33 to 2.74). In conclusion, it is important that all women, whether HIV-infected or not, be educated that breastfeeding is the feeding of choice in this setting. The potential of breastfeeding to reduce risks of infections to levels similar to those observed under highly controlled settings, involves changing women’s infant feeding practices. Strategies to promote and sustain continued breastfeeding by women, to levels that would result in a significant impact on the growth and protection against infections of their children are urgently needed. The strategies should be guided by social and contextual factors affecting women’s feeding practices

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