Doctoral Degrees (Paediatrics and Child Health)
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Browsing Doctoral Degrees (Paediatrics and Child Health) by browse.metadata.advisor "Gie, Robert Peter"
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- ItemAnd 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 SLCO1B1CT (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 TC (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
- ItemDevelopment of a conceptual framework of childhood tuberculosis within which to study the impact of a preventive therapy program for childhood tuberculosis prevention in high burden communities(Stellenbosch : Stellenbosch University, 2015-12) Mandalakas, Anna Maria; Gie, Robert Peter; Hesseling, Anneke; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Paediatrics and Child Health.ENGLISH ABSTRACT: Tuberculosis (TB) control remains a global challenge, with childhood TB representing 15-40% of the disease burden in resource-limited high-burden countries. Following infection with Mycobacterium tuberculosis (M.tb), the 5-year risk of TB is 33% in children under five years of age and 20% for children five to 14 years of age. TB risk is greatest in the year following infection and highest among young, malnourished and immune-compromised children. Preventive therapy (PT) decreases TB morbidity and mortality amongst child contacts. Nevertheless, in 2010, of 7.6 million children infected with M.tuberculosis, over 650,000 developed TB, and 74,000 HIV-uninfected children died of TB. The World Health Organization (WHO) routinely recommends PT in children younger than five years of age and HIV-infected children (regardless of age) who are in close contact with an infectious TB case. Nevertheless, childhood TB has become a public health priority only in the last decade and limited resources have been allocated towards prevention. Major gaps therefore remain between guidelines and implementation of PT in most TB high-burden settings. Childhood TB remains a field with many unanswered questions. How can we accurately identify children with M.tuberculosis infection to support more effective allocation of limited resources through targeted delivery of PT? How may policy be changed to improve PT uptake and adherence? What factors accurately predict which children are at highest risk of acquiring M.tuberculosis infection and progressing to disease? This thesis aimed to address these questions and develop a conceptual framework within which to study the impact of PT as a TB control strategy to reduce the burden of childhood TB in communities with high burden of TB. A stepwise approach supported completion of this thesis. A comprehensive review of the literature and pilot studies were completed to inform subsequent PhD work. A standardized measure of TB contact was developed to serve as a surrogate measure of M.tuberculosis infection in the absence of an accepted gold standard. This standardized measure of TB contact was validated in a well controlled, hospital-based, case-control study that supported comparison of the diagnostic accuracy of tests of M.tuberculosis infection among HIV-infected and HIV-uninfected children in the community. Original data was then generated and compared to the validated measure of TB contact to demonstrate that in a model controlling for multiple confounders new tests of infection correlate better with TB exposure than the traditional Tuberculin skin test. This study further demonstrated that active contact investigation can detect TB in up to 8% of child contacts within three months of exposure. Development of the conceptual framework was complemented by systematic review and metaanalysis of the diagnostic accuracy of tests of M.tuberculosis infection, and decision analysis modeling of the cost-effectiveness of M.tuberculosis testing strategies in child contacts. The conceptual framework was further enriched by a collection of complementary research projects including i) PT operational and qualitative research, ii) epidemiologic studies in South Africa, iii) diagnostic studies in the United States, and iv) invited reviews, commentaries and letters to the editor. The thesis concludes by highlighting remaining gaps in the evidence and future research that could potentially fill these gaps.
- ItemInnovative strategies to improve the diagnosis of intrathoracic tuberculosis in children(Stellenbosch : Stellenbosch University, 2018-12) Walters, Elisabetta; Hesseling, Anneke Catharina; Gie, Robert Peter; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Paediatrics and Child Health.ENGLISH ABSTRACT: Paediatric tuberculosis (TB) contributes approximately 10% of the global TB burden, with over one million estimated new cases and 253,000 TB-related deaths in children during 2016. Paediatric TB is a particular problem in low and middle income countries. However, the majority of paediatric cases were not notified to National TB Programs or the World Health Organization and >96% of deaths were estimated to have occurred in children who were not receiving antituberculosis treatment. Young, HIVinfected and malnourished children progress rapidly from infection with Mycobacterium tuberculosis (M.tb) to TB, and are at exquisite risk of significant morbidity and mortality from complicated and disseminated forms of TB. The challenges around the diagnosis and microbiological confirmation of pulmonary TB (PTB), the most common manifestation of TB disease in children, contribute to poor access to appropriate treatment and to underreporting. The diagnosis of TB in young children typically relies on the evaluation of clinical symptoms and epidemiological factors, and, if available, includes tests of TB infection and chest radiology. All of these tools have considerable limitations and cannot reliably confirm or exclude a diagnosis of PTB. However, the bacteriological confirmation of PTB in children requires the collection of respiratory specimens using procedures that are both relatively invasive and resource-intensive. Furthermore, the current gold standard of diagnosis, mycobacterial culture, has low sensitivity (approximately 30%) and long turnaround time (up to 6 weeks) in children, who typically have paucibacillary TB (low bacillary load). In resource-limited settings, the capacity for respiratory sampling of young children is typically low. These diagnostic challenges prevent adequate reporting and global surveillance of paediatric TB. Diagnostic uncertainty also compromises the clinical management of paediatric PTB, resulting in over- and under-treatment, and has resulted in the systematic exclusion of children from much-needed interventional research, including tuberculosis treatment trials. Diagnostic research in paediatric PTB has also been poorly standardised, making generalizability and comparability of results difficult. In addition, the insensitive reference standard has hindered progress towards the development of new diagnostic tests tailored for children. In an effort to develop and investigate more feasible strategies to improve and promote microbiological testing of children with suspected PTB living in high TB-burden settings, I enrolled a large well-characterized cohort of children presenting to hospital with suspected PTB. Children were thoroughly investigated, using standard approaches and intensive specimen collection for liquid culture and molecular testing by Xpert ® MTB/RIF (Xpert). Chest radiographs were dual read by blinded experts and reported using standard forms. All children were followed regardless of their final diagnosis and the spectrum of TB and non-TB disease was well described. I evaluated a number of novel diagnostic strategies, including the use of stool specimens for diagnosis of PTB using culture and Xpert, using different stool processing methods, and pooling respiratory specimens to improve the diagnostic yield and reduce the cost of laboratory testing. Importantly, I developed a framework for future evaluation of novel diagnostic tools/ biomarkers for the diagnosis of PTB in children. The total cohort included 608 children and was representative of the demographics and spectrum of disease observed in many high TB-burden settings, where young children bear the highest burden of TB disease. The median age of the cohort was 16.2 months, with 11.8% HIV-infected. Infants below 6 months of age constituted almost 15% of the total cohort. More than 20% of children had a non-specific clinical presentation, with similar prevalence of acute respiratory symptoms across all age groups and diagnostic categories. Radiological features not typically associated with PTB were common, and indicate a high burden of respiratory pathology as well as potentially non-typical radiological manifestations of PTB. Two hundred and eighty-one (46.2%) children were diagnosed with PTB and were prescribed antituberculosis treatment: 117 (41.6%) were microbiologically confirmed by Xpert or culture, which represents a high diagnostic yield, considering that approximately 50% of children with PTB had nonsevere pulmonary disease. In addition, 20/327 (6.6%) children initially considered symptomatic controls were initiated on antituberculosis treatment within two months of enrolment, due to poor clinical progress or positive results from baseline and follow-up bacteriological investigations. This emphasizes the importance and utility of careful specimen collection, incorporating different specimen types and different diagnostic tests and of follow-up of all children in whom there is a clinical suspicion of PTB. An unexpectedly high proportion of young infants <6 months of age had severe PTB, including cavities, associated with high bacillary load and smear-positivity. In addition, young infants and HIV-infected children were high-risk groups for disseminated TB. This calls for urgent priority to be given towards the development of tailored diagnostic tests that can rapidly confirm and quantify M.tb disease in the youngest children, and in the early stages of disease, prior to rapid progression to severe TB. Careful consideration should be given to infection control measures when managing and investigating children, including young infants with suspected PTB. I showed that stool as a specimen was useful to confirm M.tb using Xpert in children with severe pulmonary disease, particularly in children with cavities on chest radiograph, detecting 45% of those who were bacteriologically confirmed on respiratory specimens. A novel centrifugation-free processing method for stool specimens (stool processing kit) showed similar results to the more laborious, centrifugation-dependent methods I initially investigated. This new approach could be used with more sensitive molecular assays in future to improve stool-based diagnosis of PTB in children. In contrast, stool culture had limited value in the detection of M.tb, primarily due to very high contamination (>41% of stool cultures) using standard N-acetyl-l-cysteine–sodium hydroxide (NALC-NaOH 1.25%) decontamination protocols. Finally, I showed that pooling up to three respiratory specimens of different types (gastric aspirate, induced sputum and nasopharyngeal aspirate) per child, in children who could not expectorate sputum, had similar diagnostic yield by Xpert and culture as individually testing the same three single respiratory specimens. In paired analyses, pooled specimens had significantly higher overall yield than induced sputum and nasopharyngeal aspirate alone, but had similar diagnostic yield as a single gastric aspirate (86.5% vs. 74.4% respectively, p=0.46). The overall yield of three individual specimens tested individually was 86% of all confirmed cases, similar to the overall yield of pooled specimens. These results support the substantial diagnostic value of a single gastric aspirate using culture and Xpert, and of “front-loading” specimens of different types on one day to improve the feasibility of specimen collection in young children. Through this cohort study, I collected comprehensive follow-up data documenting response to antituberculosis treatment and clinical progress in children not receiving antituberculosis treatment (symptomatic controls), to 6 months. These data will be further analysed to validate recently proposed clinical case definitions for TB diagnostic research in children, including the diagnostic value of clinical and other follow-up measures. Symptomatic controls who initially presented with symptoms suggestive of PTB will be further analysed to better understand the spectrum of non-TB respiratory disease borne by children from high-TB burden settings. I have also established a bio-repository of well-characterised blood and urine specimens for evaluation of promising diagnostic and prognostic biomarkers of TB disease in children. In summary, through this body of research, I have generated novel data on the utility of several feasible diagnostic strategies for the diagnosis of PTB in HIV-infected and uninfected children from high TB-burden settings. I have analysed these data in relation to relevant clinical and laboratory characteristics in order to make specific recommendations on the most appropriate placement of these strategies, considering both target populations and different levels of health care. I was able to do this by carrying out a well-designed study, in a well-described cohort and by comprehensively reporting on all aspects of the study, including non-evaluable results and complex clinical scenarios. These aspects should be considered when future diagnostic studies for paediatric PTB are being designed, implemented and reported. I have created a rigorous framework for the evaluation of future novel diagnostic strategies, and I have identified numerous areas which require further research and intervention.