Doctoral Degrees (Paediatrics and Child Health)

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Addressing critical knowledge gaps to improve and shorten multidrug-resistant tuberculosis treatment regimens in children
(Stellenbosch : Stellenbosch University, 2018-12) Garcia-Prats, Anthony Joseph; Hesseling, Anneke Catharina; Schaaf, Hendrik Simon; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Paediatrics and Child Health.
ENGLISH ABSTRACT: Multidrug-resistant (MDR) tuberculosis (TB), defined as TB disease or infection caused by Mycobacterium tuberculosis with resistance to at least both isoniazid and rifampicin, threatens global TB control, with an estimated 490,000 incident cases of MDR-TB globally in 2016. The burden of paediatric MDR-TB has been poorly characterized to date. However, recent modeling studies estimate that there are approximately 26,000- 32,000 incident MDR-TB cases in children (< 15 years of age) worldwide each year. Traditionally, treatment regimens for adults and children were constructed using a minimum of four second-line antituberculosis drugs likely to be effective, including a second-line injectable medication, for up to 6 months, and a total duration of treatment of up to 18-24 months. In 2016, the World Health Organization (WHO) recommended a shortened (9-12 month) treatment regimen, which still includes an injectable drug for four months. In addition, the development and increasing use of the novel TB drugs bedaquiline and delamanid, are radically altering the MDR-TB treatment landscape, although children have lagged behind in accessing these important developments. Treatment outcomes for adults with MDR-TB have been persistently poor, with 54% successfully treated in 2014 both overall globally, and in South Africa. In contrast, treatment outcomes among children with MDR-TB are generally good, with 78-90% successfully treated under routine clinical conditions. However, current paediatric MDR-TB treatment regimens have important limitations. These current regimens remain long (9-18 months or more), which is costly and burdensome. There are also frequent adverse effects, including from the second-line injectable medications (amikacin, kanamycin, capreomycin) that cause permanent sensorineural hearing loss in up to 24% of children treated long-term. Additionally, the injectables are mainly given by painful daily intramuscular injections, resulting in trauma and distress for patients, their caregivers and healthcare providers. Therefore, it is an urgent priority to develop more optimal treatment regimens for children with MDR-TB that retain their efficacy but are shorter, more child-friendly, are better tolerated, safer and which do not require the use of an injectable medication. The purpose of this doctoral research was to address critical knowledge gaps in paediatric MDR-TB treatment, with the aim of informing more effective, safer, and more child-friendly MDR-TB treatment strategies in children. I identified critical knowledge gaps related to the pharmacokinetics, including the effects of formulation, optimal dosing, safety, and tolerability of key second-line and novel antituberculosis drugs in children, and completed complementary studies on ofloxacin, levofloxacin, linezolid, amikacin and bedaquiline designed to address these knowledge gaps. In an observational study of the pharmacokinetics and safety of ofloxacin in children routinely treated for MDR-TB disease or exposure, exposures after a daily 20mg/kg ofloxacin dose were well below target exposures from adults receiving the routine 800 mg dose. Ofloxacin was safe and well tolerated, with few musculoskeletal complaints or serious adverse events. This data adds to the evidence of the safety of fluoroquinolones in children even with long-term use, and identifies the need to revise ofloxacin paediatric doses. Subsequently, in this large observational study, the population pharmacokinetics of levofloxacin among children with MDR-TB disease or exposure was characterized using non-linear mixed effects modeling. One hundred and nine children treated with the routinely available adult 250 mg tablet formulation of levofloxacin at daily doses of 15 mg/kg or 20 mg/kg were included. Levofloxacin’s apparent oral clearance (CL/F) was higher than expected based on previously published data, possibly due to the formulation studied. Simulations using the final model targeting exposures in adults with TB receiving 750 mg of levofloxacin identified weight-banded doses that were much higher than previously in use (18 mg/kg to nearly 40 mg/kg daily). It was concluded that levofloxacin dosing in children should be reassessed, formulation effects explored further, and that safety should be carefully evaluated if higher levofloxacin doses are used. Building on this data, I completed an evaluation of the safety of long-term levofloxacin in children treated for MDR-TB. Among 70 children, median age 2.1 years, treated for a median of 11.6 months, levofloxacin was generally safe and was well tolerated. There were no Grade 4 or serious adverse events, and few musculoskeletal events. There was no QT-interval prolongation and no association of QT interval with levofloxacin concentration. This study supported the safety of long-term fluoroquinolone treatment in children, and provided novel data on the QT prolonging effect of levofloxacin, which is needed, as increasingly levofloxacin is being combined with other QT prolonging medications. The effects of drug formulation in pharmacokinetic studies are critically important. In a lead-in pharmacokinetics study to the TB-CHAMP trial (phase 3 cluster randomized trial comparing levofloxacin vs. placebo for prevention of TB in child contacts of MDR-TB cases), 24 children had pharmacokinetic sampling with a novel dispersible tablet formulation of levofloxacin. The levofloxacin exposures were much higher with this novel formulation compared to those seen in the previously reported study using the adult 250 mg levofloxacin tablet. Combining these two data sets using non-linear mixed effects modeling identified that reduced bioavailability of the adult 250 mg tablet formulation compared to the dispersible levofloxacin tablet was the explanation for the substantial differences in exposures. This study highlighted the importance of formulation considerations to paediatric pharmacokinetic studies and provided practical weight-banded dosing guidelines for use of this formulation now becoming available in the field. Linezolid is a key drug with an increasingly important role in the treatment of MDR-TB strains with additional resistance and in central nervous system TB disease. I performed a structured review of the literature on linezolid to inform its use in children for MDR-TB treatment and identify knowledge gaps for future research. Few children treated with linezolid for MDR-TB were described in the literature. As in adults, linezolid appeared to be effective but was associated with frequent adverse events. There was no data on linezolid pharmacokinetics in children with TB. Practical interim guidance was provided for linezolid use in children. Priority research needs identified included studying linezolid pharmacokinetics in children with TB, characterization of its safety with long-term use, and its optimal dose for TB in MDR-TB regimens going forward. Following on this review, an analysis of linezolid pharmacokinetics and safety from children with MDR-TB was performed with data from 48 children combined from two observational studies using non-linear mixed effects modeling. Seventeen children received long-term linezolid and were monitored longitudinally for safety; 31 children only contributed cross-sectional pharmacokinetic data after a single-dose of linezolid. After accounting for the effects of weight with allometric scaling, no other covariates significantly contributed to the model. Exposures were higher than expected, based on previously reported data. Ten of 17 participants had a linezolid related adverse event, including five Grade 3 or 4 events; anaemia was the most common event. This first data on linezolid pharmacokinetics in children demonstrated higher than expected exposures and frequent, serious linezolid-related adverse events, and will inform the use and future dosing recommendations of this increasingly important antituberculosis medication in children. While drug substitutions for injectable drugs are not yet available for many children, improving the tolerability of the continued use of second-line injectable medications is an important question to address in children. A randomized two-period crossover study was designed to characterize the effect of co-administration of lidocaine on the pain and pharmacokinetics of intramuscular amikacin. Children each received a dose of amikacin with and without additional lidocaine on separate days, and were randomized to the sequence of treatments; pain assessments and pharmacokinetic sampling were performed on each day. Twelve children were enrolled and completed the study. The addition of lidocaine reduced pain immediately after the injection, was safe, and did not affect the pharmacokinetics of amikacin in children, and should be considered as a routine policy in patients with MDR-TB receiving an injectable agent. The novel drug bedaquiline is increasingly used globally and in South Africa for adults with MDR-TB, and ongoing paediatric trials will characterize the pharmacokinetics, safety and optimal dose in children. The paediatric formulation, which is being evaluated in at least one of the ongoing paediatric trials, may not be available for routine care for some time. In order to inform the rational use of the adult bedaquiline formulation in young children, a randomized two-period crossover study in healthy adult volunteers was designed. Adult bedaquiline tablets administered suspended in water were bioequivalent to adult tablets swallowed whole. The suspended tablets were also found to be acceptable and palatable to the majority of participants, an important finding considering that crushing or suspending some tablets, such as the fluoroquinolones, reduces their palatability and acceptability substantially. This data will accelerate access to bedaquiline for young children in research and routine care. In conclusion, this doctoral research has addressed a number of important key knowledge gaps related to more optimal paediatric MDR-TB treatment. This research has raised a number of follow-up questions that have informed subsequent studies that will continue to advance the field towards a goal of effective, safe, shorter MDR-TB treatment for all children.
Complementary surveillance strategies and interventions to inform a tuberculosis care cascade for children
(Stellenbosch : Stellenbosch University, 2021, 2020-12) Du Preez, Karen; Hesseling, Anneke Catharina; Schaaf, Hendrik Simon; Naidoo, Prenavum; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Paediatrics and Child Health.
ENGLISH ABSTRACT: Monitoring and evaluation is an integral component of tuberculosis (TB) control programmes. Children 0-14 years of age contribute substantially to the global TB epidemic, with an estimated 1 million cases and 233,000 deaths in 2017. The limited availability of age-disaggregated TB surveillance data for paediatric and adolescent populations and the lack of specific monitoring and evaluation approaches, hampers TB control efforts in these special populations. Challenges with the sources and the complexity of TB surveillance data in children compound the current limited monitoring and evaluation efforts for paediatric TB. Only 45% of the estimated number of children globally with TB were reported as diagnosed and treated by TB programmes in 2017. More than half of all paediatric TB cases globally were therefore either undiagnosed, or diagnosed but unreported to TB programmes. A TB care cascade framework has been used successfully in HIV and TB control efforts to identify specific gaps and to monitor the impact of targeted programmatic interventions and could also be useful for monitoring and evaluation of paediatric TB. In an effort to address the lack of monitoring and evaluation approaches for paediatric TB, I investigated the role of diagnostic and treatment surveillance strategies to inform two pillars of a paediatric TB care cascade for South Africa. My research quantified the overall paediatric TB reporting gap in South Africa, showing that nearly a third of South African children with TB are undiagnosed, or diagnosed but unreported. Age- and HIV-stratified analyses of a large national routine TB treatment surveillance dataset, spanning a 13-year period (2004-2016), identified young, HIV-infected children (0-4 years) and adolescents (10-19 years) as populations who require additional targeted TB control interventions in South Africa. Diagnostic surveillance conducted at a large tertiary referral hospital and a district-level hospital in Cape Town, South Africa, quantified the substantial burden and spectrum of paediatric TB routinely managed at these levels of care (~400 and ~170 children annually at each hospital, respectively). Surveillance of HIV-infected children and children with TB meningitis (TBM) proved valuable to monitor the impact of TB and HIV prevention strategies and of integrated TB/HIV care. Finally, my research addressed the hospital-reporting gap in a prospective hospital-based study, where an intervention consisting of a simple TB referral service significantly improved recording and reporting as well as linkage to care of children with TB. Including TB data from all hospitals in routine TB surveillance data will substantially reduce the hospital-reporting gap for paediatric TB in South Africa and improve the completeness of routine TB surveillance data. Mandating hospitals to report TB data will also assist with improving the accuracy of reporting on the spectrum of TB disease and HIV data in routine TB surveillance data, increasing the utility of surveillance data for monitoring and evaluation approaches. Together, this research highlights the importance of using multiple sources of data at different levels of health care to strengthen the accuracy and completeness of paediatric TB surveillance. The use of practical monitoring and evaluation approaches, such as a care cascade, can help to improve TB care and services for children and adolescents and will contribute towards achieving the ambitious global targets set for TB control.
Innovative 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.
Pharmacokinetics and safety of first -- and second--line anti-- tuberculosis drugs in children
(Stellenbosch : Stellenbosch University, 2015-12) Thee, Stephanie; Schaaf, Hendrik Simon; Hesseling, Anneke Catharina; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Paediatrics and Child Health
ENGLISH ABSTRACT : The global burden of tuberculosis (TB) in children is high with a high morbidity and mortality, especially amongst young and HIV-‐infected children. The emerging epidemic of multidrug-‐resistant (MDR)-‐TB is a threat to children, while information on the use of second-‐line drugs in children is very limited. By reviewing the literature on the first-‐line anti-‐tuberculosis agents it is shown that isoniazid (INH) and rifampicin (RMP) exhibit a dose-‐dependent activity against Mycobacterium tuberculosis. For effective anti-‐tuberculosis therapy, 2-‐hour serum concentrations of INH 3-‐5µg/ml, RMP 8-‐24µg/ml and pyrazinamide (PZA) >35µg/ml have been proposed. Although not optimal, the major tools at hand to determine desired serum concentrations of an anti-‐tuberculosis drug in children are comparative clinical data from adults and their pharmacokinetic “optimal” target values. In order to achieve serum concentrations in children comparable to those in adults and which are correlated with efficacy, the existing evidence advocates the use of higher mg/kg body weight doses of INH and RMP in younger children compared to adults. For PZA, similar mg/kg body weight doses lead to PZA maximum concentrations (Cmax) similar to those in adults. In 2009, the World Health Organization (WHO) increased their dosing recommendations and now advises giving INH at 10 mg/kg (range: 7-‐15 mg/kg), RMP 15 mg/kg (10-‐20 mg/kg) and PZA 35 mg/kg (30-‐40 mg/kg). Studies of the pharmacokinetics of the first-‐line agents in representative cohorts of children especially in younger ages and with different genetic backgrounds are limited; these needed to better define the doses appropriate for children. I performed a pharmacokinetic study on the first-‐line agents INH, RMP and PZA in 20 children <2 years of age (mean age 1.09 years), following the previous and revised WHO dosing recommendations. Mean (95% confidence interval) Cmaxs [µg/ml], following previous/revised doses, were: INH 3.2 (2.4-‐4.0)/8.1 (6.7-‐9.5)µg/ml, PZA 30.0 (26.2-‐ 33.7)/47.1 (42.6-‐51.6)µg/ml, and RMP 6.4 (4.4-‐8.3)/11.7 (8.7-‐14.7)µg/ml. The mean (95% confidence interval) area under the time-‐concentration curves (AUC) [µg⋅h/ml] were: INH 8.1 (5.8-‐10.4)/20.4 (15.8-‐25.0)µg∙h/ml, PZA 118.0 (101.3-‐134.7)/175.2 (155.5-‐195.0)µg∙h/ml, and RMP 17.8 (12.8-‐22.8)/36.9 (27.6-‐46.3)µg∙h/ml. This study provides the first evidence for the implementation of the revised WHO guidelines for first-‐line anti-‐tuberculosis therapy in children younger than two years of age. Because drug-‐resistant TB is increasing globally, pharmacokinetic studies to guide dosing and safe use of the second-‐line agents in children have become a matter of urgency. In this thesis, priority is given to the thioamides (ethionamide [ETH] and prothionamide [PTH]) and the 3 most frequently used fluoroquinolones, ofloxacin (OFX), levofloxacin (LFX) and moxifloxacin (MFX). By reviewing the literature, I have demonstrated that ETH has shown to be effective in in vitro studies against M. tuberculosis and in combination with other drugs had good outcome in MDR-‐TB and tuberculous meningitis patients, including children. ETH/PTH exhibit dose-‐dependent activity and are bactericidal at higher doses, although dosing is limited mainly by gastro-‐intestinal adverse effects. During long-‐term ETH/PTH therapy hypothyroidism might also occur. An oral daily dose of ETH or PTH of 15-‐20mg/kg with a maximum daily dose of 1,000mg is recommended in children. No child-‐friendly formulations of the thioamides exist. Studies on dosing and toxicity of ETH and PTH in childhood TB are needed. With the first study ever conducted on the pharmacokinetics of ETH in 31 children (mean age 4.25 years), supportive evidence for the current dosing recommendation of ETH 15-‐20mg/kg in children with TB is provided. Mean Cmax was 4.14μg/ml (range 1.48 – 6.99μg/ml) and was reached within two hours (mean tmax 1.29h, range 0.87 – 2.97h). Young children and HIV-‐infected children were at risk for lower ETH serum concentrations, but the mean drug exposure was still within range of the adult Cmax reference target (2.5µg/ml). In a retrospective study on 137 children (median age 2.9 years) receiving anti-‐ tuberculosis therapy including ETH, abnormal thyroid function tests were recorded in 79 (58%) children. The risk for biochemical hypothyroidism was higher for children on regimens including para-‐aminosalicylic acid (PAS) and in HIV-‐infected children. This high frequency of thyroid function abnormalities in children treated with ETH indicates the need for careful thyroid function test monitoring in children on long-‐term ETH treatment, especially in case of HIV co-‐infection and concomitant use of PAS. The literature review on the use of fluoroquinolones in childhood TB revealed that the strong bactericidal and sterilizing activity, favourable pharmacokinetics, and toxicity profile have made the fluoroquinolones the most important component of existing MDR-‐ TB treatment regimens, not only in adults, but also in children. Proposed pharmacodynamic targets for fluoroquinolones against Mycobacterium tuberculosis are AUC0-‐24/MIC >100 or Cmax/MIC 8-‐10. In vitro and murine studies demonstrated the potential of MFX to shorten drug-‐susceptible TB treatment, but in multiple randomized controlled trials in adults, shortened fluoroquinolone-‐containing regimens have found to be inferior compared to standard therapy. Resistance occurs frequently via mutations in the gyrA gene, and emerges rapidly depending on the fluoroquinolone concentration. Fluoroquinolone resistance occurs in 4-‐30% in MDR-‐TB strains depending on the region/country and setting. Emerging data from paediatric studies underlines the importance of fluoroquinolones in the treatment of MDR-‐TB in children. There is a paucity of pharmacokinetic data especially in children <5 years of age and HIV-‐infected children. Fluoroquinolone use has historically been restricted in children due to concerns about drug-‐induced arthropathy. The available data however does not demonstrate any serious arthropathy or other severe toxicity in children. In order to fill the gap in knowledge on fluoroquinolone dosing in children with TB, prospective, intensive-‐sampling pharmacokinetic studies on OFX, LFX, and MFX including assessment of cardiac effects were conducted. In the study on the pharmacokinetics of OFX and LFX, 23 children (median age 3.14 years) were enrolled; 4 were HIV-‐infected (all > 6 years of age) and 6 were underweight-‐ for-‐age (z-‐score <-‐2). The median Cmax [µg/ml], median AUC(0-‐8) [µg⋅h/ml] and mean tmax [h] for OFX were: 9.67 (IQR 7.09-‐10.90), 43.34 (IQR 36.73-‐54.46) and 1.61 (SD 0.72); for LFX: 6.71 (IQR 4.69-‐8.06), 29.89 (IQR 23.81-‐36.39) and 1.44 (SD 0.51), respectively. Children in this study eliminated OFX and LFX more rapidly than adults, and failed to achieve the proposed adult pharmacodynamic target of an AUC0-‐24/MIC >100. Nevertheless, the estimated pharmacodynamic indices favoured LFX over OFX. The mean corrected QT (QTc) was 361,4ms (SD 37,4) for OFX and 369,1ms (SD 21.9) for LFX, respectively and no QTc prolongation occurred. In the study on MFX, 23 children (median age 11.1 years) were included; 6/23 (26.1%) were HIV-‐infected. The median (IQR) Cmax [µg/ml], AUC(0-‐8) [µg⋅h/ml], tmax [h] and half-‐ life for MFX were: 3.08 (2.85-‐3.82), 17.24 (14.47-‐21.99), 2.0 (1.0-‐8.0); and 4.14 (IQR 3.45-‐6.11), respectively. AUC0-‐8 was reduced by 6.85μg∙h/ml (95% CI 11.15-‐2.56) in HIV-‐ infected children. tmax was shorter with crushed versus whole tablets (p=0.047). In conclusion, children 7-‐15 years of age have low serum concentration compared with adults receiving 400mg MFX daily. MFX was well tolerated in children treated for MDR-‐ TB. The mean corrected QT-‐interval was 403ms (SD 30ms) and as for OFX and LFX, no prolongation >450ms occurred. In conclusion, my research identified and addressed critical gaps in the current knowledge in the management of children with both drug-‐susceptible and drug-‐ resistant TB. I provided essential evidence on both the dosing and safety of first-‐ and second-‐line anti-‐tuberculosis agents, informing international treatment guidelines for childhood TB. Nevertheless, more studies in a larger number of children with different genetic backgrounds, HIV co-‐infection nutritional status and with higher drug doses, novel treatment regimens and child-‐friendly formulations are needed to further optimize anti-‐tuberculosis treatment in children.
Prevention and treatment of perinatal and infant tuberculosis in the HIV era
(Stellenbosch : Stellenbosch University, 2016-11-18) Bekker, Adrie; Hesseling, Anneke Catharina; Schaaf, Hendrik Simon; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Paediatrics and Child Health
ENGLISH ABSTRACT : Infants (<12 months) born to women with tuberculosis are at high risk of Mycobacterium tuberculosis (M. tuberculosis) exposure, infection and disease early in life. In settings with high prevalence of human immunodeficiency virus (HIV) and tuberculosis, tuberculosis disproportionately affects women of childbearing age. The aim of this dissertation was to comprehensively investigate prevention and treatment strategies for perinatal and infant tuberculosis in a high HIV-prevalence setting. Research objectives included: 1) defining clinical and epidemiological aspects of maternal-infant tuberculosis at a large referral hospital; 2) identifying barriers and solutions to isoniazid preventive therapy (IPT) delivery in tuberculosis-exposed newborns; and 3) obtaining rigorous pharmacokinetic data to guide the dosing of firstline antituberculosis drugs in newborns and infants for the prevention and treatment of tuberculosis. In the first retrospective study, 70 newborns (42 HIV-exposed) were investigated for tuberculosis at Tygerberg Hospital, a large provincial referral hospital in Cape Town. Newborns were mainly screened for tuberculosis because of maternal tuberculosis. Isoniazid preventive therapy (IPT) was initiated in 36/50 (72%) newborns, because of maternal tuberculosis infectious risk and exposure of infants. Few of the newborns who received IPT were traceable at one-year, and of those traced, less than half completed IPT. To generate more rigorous clinical and epidemiological data on maternal-infant tuberculosis, a prospective cohort study was conducted in pregnant and postpartum women receiving tuberculosis treatment at Tygerberg Hospital. Over a one-year period, 74 pregnant and postpartum women, 53 (72%) HIV-infected, were consecutively enrolled. Nearly half of the women, 35 (47%) were diagnosed with tuberculosis only at delivery or postpartum, and a third of women with tuberculosis reported prior tuberculosis treatment. Tuberculosis-exposed newborns were often premature and of low birth weight (LBW; <2500 grams). All deaths occurred in HIVinfected women (n=5) and all stillbirths (n=4) and newborn deaths (n=6) were from HIV-infected women. Favourable maternal tuberculosis treatment outcomes (cure and tuberculosis treatment completion) were documented only in 41/74 (55%) women, while 33 (45%) had unfavourable treatment outcomes (death, treatment failure and loss to follow-up). These poor observed outcomes highlight the need for earlier diagnosis and treatment of tuberculosis during pregnancy, and close follow-up to ensure maternal tuberculosis treatment completion. Improved care for pregnant women with tuberculosis, with and without HIV infection, will likely reduce morbidity and mortality in mothers and tuberculosis-exposed newborns. Delayed maternal tuberculosis diagnosis led to IPT initiation in a large number of newborns. Forty-four newborns on IPT were followed to 6 months. A hospital-based tuberculosis linkage to care intervention, led to 29/44 (66%) newborns completing IPT without a study team intervention. A further 8 infants completed IPT after studyteam intervention. Appropriate tuberculosis referral and linkage to care from hospital to local tuberculosis clinic substantially improved IPT completion among tuberculosis-exposed newborns. More pharmacokinetic data regarding the appropriate use of antituberculosis drugs are required in neonates and infants, who undergo considerable physiological changes in the first year of life. An intensive isoniazid (INH) pharmacokinetic study was therefore designed and implemented in premature and LBW infants (n=20). Relatively high median INH peak concentrations of 5.63 μg/ml were achieved in LBW infants (at an INH dose of 10 mg/kg), compared to the adult proposed target value of > 3 μg/ml. INH exposures were higher with longer half-lives in smaller infants, and among genotypically determined N-acetyltransferase-2 (NAT2) slow acetylators, suggesting reduced clearance of INH. This first study of isoniazid use in LBW and premature neonates showed that the INH dose in premature and LBW infants should probably not exceed 10 mg/kg/day. The final study evaluated whether the revised higher 2009 World Health Organization (WHO)-recommended paediatric doses for rifampicin (RMP), INH, pyrazinamide (PZA) and ethambutol (EMB) achieved adequate drug concentrations in infants, compared to current adult pharmacokinetic target concentrations. All 39 infants enrolled achieved the minimum proposed adult target peak concentrations of > 3 μg/ml for INH at a mean dose of 12.8 mg/kg (10.3 - 15.4 mg/kg), and the minimum adult target of > 20 μg/ml for PZA at a mean dose of 33.3 mg/kg (28.5 – 38.5 mg/kg). RMP administered at mean dose of 15.4 mg/kg (10.1 - 20.5 mg/kg) resulted in very low RMP peak concentrations for both RMP formulations used during the study. None of the infants achieved the minimum proposed adult RMP target concentration of > 8 μg/ml. Given the findings of this study, higher doses of RMP in infants should be considered especially given emerging data from adult RMP doseescalation studies showing better efficacy at higher doses with limited toxicity for short-term use. For EMB, only 1 of 16 infants achieved the recommended adult target concentration of > 2 μg/ml when given at a mean dose of 20.2 mg/kg (15.4-24.1 mg/kg). EMB dose-dependent ocular toxicity however poses a concern regarding the recommendation of higher EMB doses in infants where vision testing is challenging. This is the largest pharmacokinetic study of first-line antituberculosis drugs performed in infants to date, which has generated valuable pharmacokinetic data to inform the effective and safe dosing of first-line antituberculosis drugs in infants. Pregnant women in settings with a high burden of tuberculosis and HIV and their infants face a considerable burden of tuberculosis disease in HIV-endemic settings. Maternal-infant tuberculosis care can be improved by health systems strengthening interventions. Data generated from pharmacokinetic studies of antituberculosis drugs in tuberculosis-exposed infants will inform much needed dosing guidelines of firstline antituberculosis drugs for newborns and infants, who have a high risk of tuberculosis and are prone to develop severe forms of tuberculosis.
Tuberculosis-associated mortality in South Africa: longitudinal trends and the impact of health system interventions
(Stellenbosch : Stellenbosch University, 2021-03) Osman, Muhammad; Hesseling, Anneke Catharina; Naidoo, Prenavum; Welte, Alex; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Paediatrics and Child Health.
ENGLISH ABSTRACT: Tuberculosis (TB) is estimated to have infected a quarter of the world’s population. In 2019, it was estimated that 10 million people developed TB globally and that the treatment coverage was 71%. In South Africa, approximately 360,000 people developed TB in 2019 with an estimated treatment coverage of 58%. Human immunodeficiency virus (HIV) is one of the most important drivers of TB, especially in sub-Saharan Africa. Of the estimated 38 million people living with HIV globally, 7.5 million (20%) were in South Africa. People living with HIV are more likely to develop TB disease and TB is one of the leading causes of death among people living with HIV. Among the estimated 1.4 million TB deaths in 2019; 59,000 occurred in South Africa. This estimate of mortality includes any death, regardless of the cause, occurring before or during antituberculosis treatment, and does not include TB-related deaths that occurred after the successful completion of treatment. TB reporting in South Africa is based on data captured in TB treatment registers and there are no routine estimates for TB-associated mortality before or after TB treatment. I used the onion model and the TB care cascade frameworks, to evaluate TB-associated mortality during, before and after TB treatment. Through a series of four interlinked studies, I investigated TB-associated mortality during TB treatment for adults and in children. I showed that mortality in South Africa decreased from 11% in 2009 to 8% in 2016 in adults, and from 3.3% in 2007 to 1.9% in 2016 in children and adolescents. I demonstrated that young children, older adolescents, the oldest adults, males, and people living with HIV (especially those with the lowest CD4 counts) were at highest risk of mortality during TB treatment whilst antiretroviral therapy (ART) had a protective effect. I also showed how this differs by HIV status and demonstrated that in people living with HIV, younger adult females have the greatest risk of mortality. I collected data for two studies to evaluate mortality before TB treatment. In the first, I reported a TB prevalence of 8% in people who died suddenly and unexpectedly; more than 90% had undiagnosed TB. I demonstrated multiple missed opportunities for TB screening and testing in these individuals. Sentinel surveillance for TB in this group could be an important indicator of TB control efforts. In the second study, I reported initial loss to follow up (ILTFU) of 20% in TB patients in 2 sub-districts of Cape Town among whom 17% had died. Although hospitals accounted for 25% of TB diagnoses, they contributed to 55% of patients with ILTFU and to 85% of the mortality in this group. This study demonstrates the need for earlier case-finding to reduce mortality and the value of including hospitals in routine TB reporting. Given the exclusion of mortality after TB treatment from the current definition of TB- deaths and the recognition of the burden of post-TB lung health, I conducted a study in Cape Town to assess TB patients who had successfully completed TB treatment. I showed the complexity of tracing these individuals. In the sample of adults located, I reported a high burden of respiratory symptoms and 6% had recurrent TB. The mortality rate following the successful completion of TB treatment was 2.5 deaths per 100 person years with a standardised mortality ratio of 4 compared to the general population. This highlights the need for ongoing care, post TB treatment completion. In this dissertation I documented the key health system changes in the public sector in South Africa and the changes in TB-associated mortality over time. Finally, I attempted to collate the findings of TB-associated mortality during, before and after TB treatment in the context of losses along the TB care cascade. This dissertation provides novel insights into TB-associated mortality in South Africa. I propose additional strategies to improve mortality estimates and to reduce TB-associated mortality in South Africa.

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