Department of Paediatrics and Child Health

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Childhood intra-thoracic tuberculosis : addressing the diagnostic dilemma
(Stellenbosch : University of Stellenbosch, 2006-04) Marais, Barend Jacobus; Beyers, Nulda; Gie, R. P.; University of Stellenbosch. Faculty of Health Sciences. Dept. of Paediatrics and Child Health.
ENGLISH ABSTRACT: Children contribute little to disease transmission and the maintenance of the tuberculosis epidemic, but they constitute a significant proportion of the total tuberculosis (TB) caseload and experience considerable morbidity and mortality in endemic areas, despite the availability of cheap and effective treatment. The difficulty of diagnosing childhood tuberculosis is one of the major obstacles that hinder the provision of antituberculosis treatment to children in endemic areas. The diagnosis of childhood tuberculosis is complicated by the lack of a practical gold standard, as bacteriologic specimens are difficult to collect and the yield is low. In non-endemic countries the diagnosis of childhood tuberculosis is based on the triad of: 1) exposure to an adult index case, 2) a positive tuberculin skin test, and 3) suggestive radiographic signs. However, the triad has limited value in endemic areas where exposure to and/or infection with Mycobacterium tuberculosis is common, and chest radiography is rarely available. The objective of this dissertation was to address the diagnostic dilemma faced by health professionals in endemic areas with limited resources, where children currently have poor access to chemoprophylaxis and antituberculosis treatment. We first clarified basic disease concepts, through a critical review of the pre-chemotherapy literature that documented the natural history of childhood tuberculosis. Three central concepts were identified; 1) the importance of accurate case definition, 2) the relevance of risk stratification, and 3) the diverse spectrum of disease, which necessitates accurate disease classification. The importance of accurate case definition is illustrated by the fact that isolated hilar adenopathy, considered the principal radiographic sign of primary tuberculosis, becomes transiently visible in the majority of children following recent primary infection. Our analysis of the natural history of childhood tuberculosis allowed accurate quantification of the risk to progress to disease following primary infection with M.tuberculosis. This demonstrated that the risk depends mainly on the age and/or immune-status of the child, the time since primary infection occurred and the presence or absence of symptoms. After analysing these historic studies, we proceeded to document the burden of childhood tuberculosis in an endemic area. We first conducted a retrospective study to describe current diagnostic practices and demonstrated almost exclusive reliance on chest radiography. We then calculated the burden of childhood tuberculosis in a prospective descriptive study. The corrected tuberculosis incidence rate in children was 407/100 000/year and children with severe forms of disease, such as disseminated (miliary) tuberculosis and/or tuberculous meningitis, were rarely recorded in the TB treatment register used for routine community-based surveillance. An additional obstacle to progress in the field of childhood tuberculosis has been the lack of standard descriptive terminology. Following a careful review of the literature, we proposed a radiological classification of childhood intra-thoracic tuberculosis and explored the different pathologic mechanisms that underlie these diverse disease manifestations. We then conducted a prospective descriptive study to document the disease spectrum in children treated for tuberculosis in an endemic area. The disease patterns observed were consistent with those described in the pre-chemotherapy literature. In addition, we demonstrated that bacteriologic confirmation may be achieved in the majority of children with intra-thoracic tuberculosis, in highly endemic settings. Finally we developed a novel symptom-based approach to diagnose pulmonary tuberculosis in children from endemic areas with limited resources. We followed a step-wise approach by first conducting a community-based survey to document the prevalence of symptoms traditionally associated with tuberculosis in a random selection of children from an endemic area. The survey demonstrated that poorly defined symptoms offer poor diagnostic value. The second step was to evaluate the diagnostic value of well-defined (persistent, non-remitting) symptoms in a small prospective study. Well-defined symptoms demonstrated good diagnostic value, but these promising results required further validation. As a final step, we validated the diagnostic value of a novel symptom-based approach in a large prospective, community-based study. In this study, a simple symptom-based approach diagnosed childhood pulmonary tuberculosis with a remarkable degree of accuracy, particularly in HIV-uninfected children older than 3 years of age. This novel diagnostic approach offers the exciting prospect of extending antituberculosis treatment to children in endemic areas with limited resources, where current treatment access is poor.
The contribution of a community based HIV Counseling and Testing (HCT) initiative in working towards increasing access to HIV counseling and testing in Cape Town, South Africa
(Stellenbosch : Stellenbosch University, 2018-03) Meehan, Sue-Ann; Beyers, Nulda; Burger, Ronelle; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Paediatrics and Child Health.
ENGLISH ABSTRACT: HIV testing services (HTS) play an important role in South Africa’s response to the HIV epidemic and within the UNAIDS ‘90-90-90’ strategy. Reaching the first ‘90’, diagnosing 90% of individuals unaware of their HIV-positive status is vital for reaching the overall target. It is not possible for public health facilities to reach this target alone, as not all populations access health facilities optimally. Community-based testing services, provided outside of public health facilities are necessary for expanding access to HIV testing and must be explored. There is limited understanding of what constitutes access to community-based HTS. This dissertation used a framework to measure access along three dimensions, availability, affordability and acceptability, in order to determine access of a Community-Based HIV Counseling and Testing (CB-HCT) initiative, comprising mobile and stand-alone services. This dissertation includes six research studies, all of which were conducted within communities situated in the Cape Metro district of the Western Cape Province, South Africa between 2008 and 2015. I used a mixed-methods approach, and included quantitative and qualitative studies as well as a cost-analysis. Participants self-initiated an HIV test at either a mobile or a stand-alone service at a CB-HCT initiative or a public health facility. Mobile services consisted of tents and a mobile van set up at busy spots within the community. Stand-alone centers were fixed sites, not attached to a health facility. Consistently across studies (chapters 2, 4, 7), there was a higher proportion of males amongst the users at mobile (40% to 55%) compared to stand-alone and public health facilities (25% to 27%). As HIV test uptake in public health facilities is low for men, this finding infers that mobile HTS can meet the health seeking needs, regarding HIV testing, of men. Consistently across studies (chapters 2,3,4,5), the majority of users walked to HTS, irrespective of which service they accessed, indicating the importance of providing a geographically accessible service that allows individuals to test in close proximity to where they are. Mobile was also able to provide an immediate opportunity to test for those walking past and not considering an HIV test at that time, highlighting the key role that opportunity to test plays in access. Service providers can create opportunities and play a direct role in making HTS available. As most users walked to HTS, they incurred little or no direct costs. HTS were affordable in our setting. Providing services in close proximity to users will increase the affordability of HTS for the user and enable access (chapters 2 and 4). The largest difference pertaining to user acceptability was waiting times, which were significantly shorter at mobile compared to stand-alone and public health facilities (chapters 2, 3, 4, 5), making mobile a viable option for reaching populations who do not want to wait in long queues. Reports of healthcare worker demeanour varied. Users at mobile and stand-alone consistently reported favourable staff attitudes, while users at public health facilities had mixed reports. The cost to implement mobile and stand-alone services is important when considering scale-up of services. Overall, mobile cost less than stand-alone ($77 764 and $96 616 respectively)-(chapter 7). The mean cost per person tested for HIV at mobile was lower than at stand-alone because of the higher numbers of users testing at mobile, making it a viable service to scale-up. However, the mean cost of diagnosing and linking an HIV-infected person to HIV care was higher at mobile compared to stand-alone. HIV testing service is associated with linkage to care, users diagnosed at stand-alone were significantly more likely to link to care compared to those diagnosed at mobile (chapter 6). Evidenced-based linkage to care interventions will be essential prior to scaling up mobile services. This dissertation provides important insight into the availability, affordability and acceptability of mobile and stand-alone HTS (CB-HCT initiative) as well as considerations for scale-up. The operational nature of this dissertation (studies are based on the operations of the CB-HCT initiative) is able to provide evidence-based lessons learnt for program implementation to make services accessible. Considering the user perspective when aiming to increase access to HIVtesting is vitally important as users have differing needs (pertaining to availability, affordability and acceptability). Tailoring HTS in line with these needs is critical if we are to build a more user responsive health system. The practical application of the findings make this a meaningful dissertation.
Disease dynamics in patients with drug-resistant tuberculosis residing in a high incidence community
(Stellenbosch : Stellenbosch University, 2000-12) Van Rie, Annelies; Beyers, Nulda; Van Helden, P.; Stellenbosch University. Faculty of Medicine & Health Sciences. Dept. of Paediatrics & Child Health.
ENGLISH ABSTRACT: Drug-resistant tuberculosis poses a threat to global tuberculosis control by the WHO DOTS strategy. Studies in the United States and Europe have shown (i) that drug-resistant tuberculosis is present in every country; (ii) that, by contrast to previous dogma, drug-resistant bacilli are virulent and can be transmitted, especially in institutional settings and to immunocompromised patients; and (iii) that the majority of cases arise by acquisition of drug resistance due to errors in the management of TB cases. (iv) Furthermore, it has been shown that the extremely high case fatality rates of the 1980s and early 1990s can be reduced by individualized, but costly treatment. However, the majority of drug-resistant TB cases reside in the developing world. Data on disease epidemics in less developed parts of the world are scarce. The aim of this thesis was to study the disease dynamics of drug-resistant TB in a developing country where TB is endemic. All cases of drug-resistant TB during a 5-year period in two communities with poor socioeconomic living conditions were included for this observational study. Three different methods were used: restriction fragment length polymorphism (RFLP), mutation detection analysis by dot-blot hybridisation technique and a Geographic Information System. Results of RFLP analysis and mutation detection analysis showed that community outbreaks of drug-resistant Mycobacterium tuberculosis strains occur, even without the involvement of immunocomprimised patients. Infection with a drug-resistant strain occurred in new patients (primary drug resistance) as well as in patients treated before (exogenous reinfection). Exogenous reinfection was also shown to be an important mechanism of recurrence after previous cure for drug-sensitive TB. Transmission of drug-resistant strains occurred more frequent in areas with lower socioeconomic living conditions. The relative contribution of transmission differed substantially between the group of multi drugresistant (two thirds of cases) and single-drug-resistant (no cases) cases, which probably reflects the prolonged infectiousness of multi drug-resistant cases. To stop the growing epidemic of multi drug-resistant TB, prevention of acquisition as well as transmission of drug-resistant tuberculosis will be required. This will only be possible in areas where a DOTS strategy is well functioning and with a modification of central elements of the standard DOTS mechanism: a "DOTS-plus" strategy. Early and accurate diagnosis of drug resistance is essential for effective management. Diagnosis based on two direct smear tests might have to be replaced by routine drugsusceptibility tests at diagnosis. Because the routine performance of phenotypic drugsusceptibility tests was inferior to the performance of genotypic tests, the development of an affordable commercial kit testing a limited number of mutations conferring resistance could be of great value in the global fight against multidrugresistant TB. Because of the importance of early diagnosis, selective active contact tracing for multidrug-resistant cases, additional to the routine passive contact tracing, could prove to be cost-effective. Individualized treatment regimens are effective in reducing the failure rate, mortality and probably transmission of multidrug-resistant TB. Multidrug-resistant tuberculosis is a problem confronting the efforts for global tuberculosis control. Efficient strategies to turn the tide exist, but international political commitment and financial support will be essential.
Evaluating the impact of an Xpert® MTB/RIF- based TB diagnostic algorithm in a routine operational setting in Cape Town
(Stellenbosch : Stellenbosch University, 2017-03) Naidoo, Prenavum; Beyers, Nulda; Lombard, Carl; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Paediatrics and Child Health.
ENGLISH SUMMARY: Decades of reliance on slow, inaccurate diagnostic tests have contributed to poor case detection and impeded tuberculosis (TB) control efforts globally. The development of an accurate, rapid molecular diagnostic test, Xpert® MTB/RIF (Cepheid, Sunnyvale, CA, USA) (Xpert), offers the prospect of identifying more cases, detecting them rapidly and enabling quicker treatment initiation. Xpert is a nucleic acid amplification test that simultaneously detects genetic sequences for Mycobacterium tuberculosis complex and the presence of mutations conferring resistance to rifampicin. Xpert sensitivity is substantially higher than smear microscopy (88% compared to 53.8% for a single smear) and provides a test result within a day (compared to 8-16 days for liquid culture). Whilst laboratory and demonstration studies suggest that Xpert has the technical capacity to address the limitations of conventional smear and culture tests, very little is known about how this translates into patient and public health benefits in routine operational conditions. The overall aim of this thesis was to undertake rigorous scientific research into the impact of an Xpert® MTB/RIF-based TB diagnostic algorithm in a routine operational setting in Cape Town. This entailed a pragmatic comparison between the existing smear/culture-based TB diagnostic algorithm and the newly introduced Xpert-based algorithm. The magnitude and range of benefits for laboratory confirmed cases of TB and MDR-TB were assessed. Impact analysis was guided by the Impact Assessment Framework which ensured a systematic and comprehensive approach to the evaluation of the new diagnostic algorithm. This framework addresses five aspects of impact: Effectiveness Analysis assesses the impact on the numbers of cases diagnosed and appropriately started on treatment as well as the timeliness of results and of treatment initiation. Equity Analysis assesses whether marginalised groups who may be more affected benefit from the new test – poor people, women and HIV-infected specifically. Health Systems Analysis assesses the human resource, laboratory infrastructure, procurement and quality assurance implications. Scale-up Analysis assesses the economic costs and benefits of scaling up the new technology from both a provider and a patient perspective. Horizon Scanning assesses what other similar technologies are available or likely to become available and how these compare in their projected performance. The stepped-wedge analysis of TB yield (Chapter 2) in five sub-districts between 2010 and 2013 showed that among the 54,393 presumptive cases tested, the proportion with a bacteriological diagnosis of TB was not increased in the Xpert-based algorithm. We found a decline in TB yield over time, possibly attributable to a declining TB prevalence. When the time-effect was taken into consideration, there was no difference TB yield – yield was 19.3% (95% CI 17.7% to 20.9%) in the Xpert-based algorithm compared to 19.1% (95% CI 17.6% to 20.5%) in the smear/culture-based algorithm with a risk difference of 0.3% (95% CI -1.8% to 2.3%, p=0.796). Inconsistent implementation of the Xpert-based algorithm and the frequent use of culture tests in the smear/culture-based algorithm may have contributed to the yield parity. The multidrug-resistant (MDR)-TB yield study (Chapter 3) found that amongst the 10,284 TB cases identified in the five sub-districts, the Xpert-based algorithm was more effective in identifying MDR-TB than the smear/culture-based algorithm. Pre-treatment, there was a higher probability of having drug susceptibility tests undertaken (RR=1.82, p<0.001) and of being diagnosed with MDR-TB (RR=1.42, p<0.001) in the Xpert-based algorithm than in the smear/culture-based algorithm. Overall 8.5% of TB cases were detected with MDR-TB in the Xpert-based algorithm compared to 6% in the smear/culture-based algorithm, translating to approximately 375 additional MDR-TB cases diagnosed in Cape Town annually. The study on TB treatment initiation and treatment success undertaken in five sub-districts in October – December 2011 (Chapter 4) found that a higher proportion of cases initiated TB treatment in the Xpert group (84%, 508/603) than in the smear/culture group (71%, 493/693, p<0.001). The adjusted odds ratio for treatment initiation in the Xpert group was 1.98 (p<0.001). Cases >44 years in age (AOR=0.49, p<0.001) and previously treated cases (AOR=0.64, p=0.020) were less likely to initiate treatment. Laboratory delay was associated with non-initiation (AOR=0.96 per day, p<0.001). The reduction in TB treatment delay from a median of 15 days in the smear/culture group to 7 days in the Xpert group did not translate into improved TB treatment outcomes and treatment success rates were 80% in both groups (AOR=0.95, p=0.764). The MDR-TB treatment commencement study (Chapter 5) undertaken in 10 high TB burden facilities found that the time from test taken to treatment initiation was reduced from 43 days in the smear/culture-based algorithm (n=375) to 17 days in the Xpert-based algorithm (n=120) with a mean reduction of 25 days (p<0.001). Median laboratory turnaround time from test taken to result available in the laboratory was reduced from 24 days to <1 day with a mean reduction of 20 days (P<0.001) between algorithms. The qualitative study on MDR-TB patient pathways (Chapter 6) showed that patients experienced substantial delays before being diagnosed – these delays may not have been reflected using the data from the laboratory and clinics. Avoidable health system delays resulted from providers not testing for TB at initial health contact, non-adherence to testing algorithms, results not being available and failure to promptly recall patients with positive results. Negative perceptions of the public sector (as over-burdened, with long waiting times, negative staff attitudes and lack of privacy) were prevalent and contributed to deferred health-seeking, interruptions to the diagnostic process and to patient’s preferential use of the private sector, contributing to delays in both algorithms. The MDR-TB patient costing study (Chapter 7) assessed direct (out-of-pocket expenses) and indirect costs (lost productivity costs for patient’s time) incurred. The median patient cost from initial health visit to treatment initiation was reduced from $68.1 in the smear/culture-based algorithm to $38.3 (p=0.004) in the Xpert-based algorithm. Median direct costs were low at $6.7 and $4.4 (p=0.321) respectively. The difference in costs was attributable to time costs as the median number of visits to MDR-TB treatment was reduced from 20 in the smear/culture-based algorithm to 7 in the Xpert-based algorithm (p<0.001). Further details are provided below in the section on equity. From a laboratory costing perspective (Chapter 8) we found a 43% increase in overall PTB laboratory costs at the central laboratory, from $440,967 in the smear/culture-based algorithm to $632,262 in the Xpert-based algorithm for 3-month periods. The cost per TB case diagnosed increased by 157% from $48.77 in the smear/culture-based algorithm to $125.32 in the Xpert-based algorithm. The mean total cost per MDR-TB case diagnosed was similar at $190.14 in the smear/culture-based algorithm compared to $183.86 in the Xpert-based algorithm. From an effectiveness perspective, the Xpert-based algorithm did not result in an increase in the number TB cases diagnosed or improve treatment outcomes amongst those initiating treatment. It did however significantly reduce treatment delay and increased the proportion of TB cases initiating treatment. The Xpert-based algorithm resulted in a higher proportion of MDR-TB cases being diagnosed and reduced MDR-TB treatment commencement time. From an equity perspective the Xpert-based algorithm helped reduce health inequities through improving effectiveness as described above. However, these benefits did not shield patients from economic losses. The proportion unemployed increased (from symptom onset to the time of the interview) in both groups: from 39% to 73% in the smear/culture group (p<0.001) and from 53% to 89% in the Xpert group (p<0.001). From symptom onset to the time of the interview there was a 16% decrease in median household income in the smear/culture group and 13% decrease in the Xpert group and “catastrophic” costs were experienced by 38% and 27% (p=0.165) in respective groups who lost >10% of monthly household income. Health system failures at several levels from poor initial planning for Xpert implementation to human resource and IT infrastructure deficits, to poor accountability and inefficient service delivery as well as low community preparedness are likely to have diminished the full potential impact of the Xpert-based algorithm. Urgent attention needs to be paid to these issues to optimise the benefit of Xpert. From a scale-up perspective the increase in laboratory costs in our study are offset to some extent by the cost-saving to MDR-TB patients. As part of broader work we have developed a discrete event simulation model and validated it using the results from the studies presented in this thesis. This model will be used to evaluate more cost-effective diagnostic options and the benefits of a more sensitive test such as Xpert Ultra, which our horizon scanning suggests is the most likely current replacement for Xpert. These studies have limitations. It was difficult to control for bias - for example the non-random allocation of facilities to different study arms was ouside our control. Generalisability to other settings, especially rural settings, is limited as these studies were undertaken within a well-resourced, urban setting, with relatively good health and laboratory infrastructure. It was possible to address temporal trends in some studies (for example the stepped-wedge analysis of TB yield) but not in others (for example the MDR-TB treatment commencement study where decentralization of services may have contributed to the findings). The studies presented in this thesis have several novel aspects: they were undertaken at the level of the Xpert-based diagnostic algorithm and not the individual test, reflecting how tests were used in clinical practice. They reflect the patient, provider and health system factors that influenced outcomes and that are essential to understanding the impact of the new diagnostic algorithm in routine programmatic conditions. In addition, the use of Impact Assessment Framework provided a comprehensive view of the benefits and limitations of Xpert. These studies highlight the effect of the early introduction of new tools into under-prepared and inefficient health systems and provide insights into some of the health system weaknesses that could be addressed to optimise the impact of Xpert. Unless concerted efforts are made to address these weaknesses, the investment in this expensive new technology will not provide the full range of benefits possible.
How can virtual implementation modelling inform the scale-up of new molecular diagnostic tools for tuberculosis?
(Stellenbosch : Stellenbosch University, 2018-03) Dunbar, Rory; Beyers, Nulda; Langey, Ivor; Naidoo, Pren; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Paediatrics and Child Health.
ENGLISH ABSTRACT: The aim of this dissertation was to develop an operational model to explain why the expected increase in the number of tuberculosis (TB) cases detected was not found in our empirical study, Policy Relevant Outcomes from Validating Evidence on ImpacT (PROVE IT), done in 142 health clinics in Cape Town after the roll-out of a new TB diagnostic test, Xpert MTB/RIF (Xpert). I then used the model to model the effect of interventions to improve the detection of TB and rifampicin resistant (RMP-R) TB. Strategies were modelled to reduce laboratory cost for detecting TB as well as the effect of introducing a more sensitive molecular diagnostic test, Xpert MTB/RIF Ultra (Ultra), as a replacement for Xpert on the number of TB and RMP-R TB cases detected. I developed and validated an operational model using a discrete event simulation approach for the detection of TB and RMP-R TB in a smear/culture-based algorithm and an Xpert-based algorithm using data from published articles as well as from the step-wedge analysis of the Xpert-based TB diagnostic algorithm in Cape Town (PROVE IT). The model was adapted to incorporate a more sensitive molecular diagnostic test as a replacement test for Xpert in the Xpert-based algorithm. All comparisons between algorithms were conducted with identical population characteristics and adherence to diagnostic algorithms. The empirical study found no increase in the number of TB cases detected (20.9% smear/culture-based and 17.7% with the Xpert-based algorithm) while the operational model, using identical population characteristics and adherence to diagnostic algorithms (adherence to algorithms as observed from the analysis of routine data in the empirical study), showed that there were more TB cases detected in the Xpertbased algorithm than in the smear/culture-based algorithm (an increase of 13.3%) (Chapter 2). The model indicated that a decrease in background TB prevalence and the extensive use of culture testing for smear-negative HIV-positive TB cases during the smear/culture-based algorithm contributed to not finding an increase in the number of TB cases detected in the empirical study. When adherence to the diagnostic algorithms was modelled to be 100%, the model indicated a 95.4% increase in the number of RMP-R TB cases detected in the Xpertbased algorithm compared to the smear/culture-based algorithm, while the empirical study showed only a 54% increase (Chapter 3). This difference is attributable to the differences in drug susceptibility test (DST) screening strategy between algorithms as well as poor adherence to diagnostic algorithms. In the smear/culture-based algorithm, only high MDR-TB risk cases are screened for RMP-R pre-treatment compared to all presumptive TB cases screened for RMP-R with the Xpert-based algorithm. The empirical study found that the proportion of TB cases with DST undertaken pretreatment increased from 42.7% in the smear/culture-based algorithm to 78.9% in the Xpert-based algorithm. The model indicated that for the Xpert-based algorithm compared to the smearbased algorithm (with 100% adherence to algorithms), the cost per TB case detected would increase by 114% with only a 5.5% increase in the number of TB cases detected (Chapter 3). Even though the model indicated a small increase in the number of TB cases detected, the real benefit of the Xpert-based algorithm is the 95.4% increase in RMP-R TB cases detected with only a 15.8% increase in the cost per RMP-R TB case detected (Chapter 3). The model indicated that the best approach to improve the laboratory cost per TB case detected, would be a combined approach of increasing the TB prevalence among presumptive cases tested by using either a triage test or other pre-screening strategies, and a reduction in the price of Xpert cartridges (Chapter 4). With an increase in TB prevalence among presumptive cases tested to between 25.9% – 30.8% and the price of the Xpert cartridge reduced by 50%, the cost per TB case detected would range from US$50 to US$59, a level that is comparable with the cost per TB case detected in the smear/culture-based algorithm (US$48.77) found in the empirical laboratory costing study. Finally, when modelling the use of the not-yet released Xpert MTB/RIF Ultra as a replacement for Xpert MTB/RIF (Chapter 5), the number of TB cases detected would increase by 3.4% and RMP-R TB cases detected by 3.5%. The number of falsepositive TB cases detected with Ultra would however increase by 166.6%. We could not model the cost per TB case and cost per RMP-R TB case diagnosed with Ultra, as the price is not available yet. Ultra has small benefits over that of Xpert for both the number of TB and RMP-R TB cases detected and therefore the cost of introducing Ultra would be an important consideration in the decision to implement Ultra. The introduction of Ultra poses potential health system and patient related challenges due to the high number of false-positive TB cases detected. Alternative strategies, such as alternative diagnostic algorithms, will have to be considered to find a balance between increased detection of TB cases and unnecessarily starting patients on TB treatment due to false positive results. The strengths of the model used in this dissertation are that the model was developed and validated using detailed routine data and information collected with the empirical study on health and laboratory processes in a large number of clinics. The model made a direct comparison between the algorithms taking into account differences in population characteristics and adherence to algorithms. Generalisability of findings from the model and the use of the model for other settings may be limited as the model was validated against data from a well-resourced, urban setting, with good health and laboratory infrastructure and therefore may not reflect reality in other settings, such rural areas. The findings from the studies presented in this dissertation highlight the important role that an operation model can play in informing decision makers on the optimal use of a new diagnostic test in an operational setting, even after the rollout of the new test. Operational modelling can therefore be an effective tool to be used to assist the health department to optimise the way in which tests are currently used and could serve to inform decision makers about the implementation of new, more sensitive, diagnostic tests.
The impact of the HPTN 071 (PopART) intervention on mortality and AIDS related morbidity amongst HIV positive adults in South Africa
(Stellenbosch : Stellenbosch University, 2018-03) Bock, Peter; Beyers, Nulda; Fidler, Sarah; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Paediatrics and Child Health.
ENGLISH ABSTRACT: In 2015 WHO recommended antiretroviral treatment (ART) for all HIV-positive individuals regardless of CD4 count and set a target for Universal Access to ART, that >80% of HIV-positive individuals should be on ART. The HPTN 071 (PopART) trial, a community randomized trial in 21 communities in South Africa and Zambia, aims to to determine the impact of two community-level combination prevention packages on population-level HIV incidence. HPTN 071 (PopART) has implemented household-based HIV point of care testing (POCT) and provided ART regardless of CD4 count at department of health clinics (DOH) in the trial communities from January 2014. This was ahead of recent changes to WHO and South African ART guidelines, which now provide ART regardless of CD4 count. The primary outcome of HIV incidence was evaluated in a randomly selected research cohort, the Population Cohort (PC), which aims to recruit 44,500 HIV-positive and negative participants aged 18 to 45, approximately 2000 from each of the 21 communities. The aim of this PhD dissertation was to evaluate the outcomes of clinical activities key to effective provision of HIV treatment services in high burden settings. PhD objectives were to evaluate: i) the accuracy of household HIV POCT and the impact of routine initiation of ART at baseline CD4 counts > 500cells/mL on ii) attrition during early ART, iii) TB incidence during early ART, iv) the incidence of renal dysfunction during early ART and iv) adherence to ART. These objectives were addressed through the completion of five studies. Four of the five studies presented were embedded within the HPTN 071 (PopART) trial. The fifth study, evaluating ART adherence, was a systematic review and meta-analysis. The study presented in chapter 3, evaluated the accuracy of household-based HIV POCT between January 2014 and August 2016 across all 21 PopART sites in both South Africa and Zambia, through a series of cross-sectional analyses. This study showed initial low HIV POCT sensitivity in South Africa (45-54%). HIV POCT sensitivity in Zambia, which implemented more extensive quality assurance (QA) and quality control (QC) and used different HIV POCT kits, during the same time period, was significantly better (95.8%). HIV POCT sensitivity in South Africa improved over time to rates comparable to the Zambian sites when implementing rigorous HIV POCT QA/QC. The studies presented in chapters 4 to 6 analysed data on a cohort of adults (≥18years of age) initiating ART regardless CD4 count at three department of health (DOH) clinics in the Western Cape, South Africa; between January 2014 and November 2015. Cohort follow-up was completed at the end of May 2016. The cohort studies evaluated the impact of routine initiation of ART at baseline CD4 counts >500 cells/μL on i) attrition ii) TB incidence and ii) incidence of renal dysfunction during early ART. A total of 2423 adults with a median baseline CD4 count of 328 (IQR 195-468) cells/μL were included in the clinic cohort. Attrition included individuals no longer retained in ART care due to loss to follow up or death (chapter 4). A total of 636 (26.2%) adults in the cohort experienced attrition during the follow-up period. Attrition was higher amongst individuals with baseline CD4 counts >500 cells/μL compared to individuals with baseline CD4 counts 0-500 cells/μL (aHR 1.28, 95%CI 1.07 -1.55). This finding raised concerns about the potential for increased attrition from ART care when providing ART regardless of CD4 count. The overall TB incidence in the cohort was 4.4 cases/100PY (chapter 5). TB incidence was lower amongst individuals with baseline CD4 counts >500 cells/μL compared to those with baseline CD4 counts 0-500 cells/ μL (aHR=0.27; 95% CI 0.12 to 0.62). There were no incident TB cases in the first three months of ART amongst individuals with baseline CD4 counts > 500 cells/ μL. These findings were promising, highly suggestive that routine provision of ART at baseline CD4 counts >500 cells/μL will lead to a significant reduction in TB amongst individuals starting ART. The prevalence of baseline moderate or severe renal dysfunction (Estimated Glomerular Filtration Rate (EGFR) < 60ml/min) in the cohort was low (1.9%) (chapter 6), as was the rate of incident moderate or severe renal dysfunction after initiation of ART (1.9cases/100PY). The study showed no significant association between baseline CD4 count and incident moderate or severe renal dysfunction occurring after initiation of ART. Analysis restricted to individuals with normal baseline renal function, showed no cases of incident moderate or severe renal dysfunction amongst individuals with baseline CD4 counts >500cells/ μL. This is also a promising finding that needs to be confirmed by completion of further studies. The fifth study (chapter 7), was a systematic review and meta-analysis of studies published between 2004 and 2015, which evaluated the association between baseline CD4 count and ART adherence. This systematic review showed lower ART adherence amongst individuals starting ART at higher baseline CD4 counts categories (pooled OR 0.90; 95%CI 0.84-0.96). Baseline CD4 count categories used in the included studies varied. The most commonly used comparison was between individuals initiating ART at CD4 counts > 200 cells/μL and at CD4 counts 0-200 cells/μL. In the two included studies that reported on individuals with baseline CD4 counts > 500 cells/μL, there was no difference in ART adherence between individuals with baseline CD4 counts > 500 cells/μL and those with baseline CD4 counts 0-500 cells/μL. Overall the studies presented for this PhD dissertation demonstrated both benefits and challenges when conducting household-based HIV POCT and routinely initiating ART in HIV-positive individuals at baseline CD4 counts >500cells/μL. The studies presented in chapters 5 and 6 suggest potential reduction in incidence of TB and renal dysfunction with routine provision of ART at baseline CD4 counts >500cell/μL; providing a strong motivation for striving to attain universal access to ART in high burden settings. At the same time, the reported low HIV POCT sensitivity and the need for rigorous QA/QC when implementing household-based HIV POCT was concerning. As were the study findings showing higher attrition and poorer ART adherence when initiating ART at higher CD4 counts. Strategies to improve HIV POCT sensitivity, retention in ART care and ART adherence, in these contexts, should therefore be a priority for programme implementers in high-burden settings.
The influence of age on the cellular immune response in patients with tuberculosis and healthy controls
(Stellenbosch : Stellenbosch University, 2002) Scholvinck, Elisabeth Henriette; Beyers, Nulda; Beyers, A. D.; Levin, M.; Stellenbosch University. Faculty of Medicine & Health Sciences. Department of Paediatrics and Child Health.
ENGLISH ABSTRACT: Children and adults may differ in their immune function. An adequate function of the individual's immune system is crucial to the risk for development of tuberculosis (TB) after infection with Mycobacterium tuberculosis (Mtb). Epidemiological evidence suggests an age-related incidence of TB. Furthermore, the prevailing clinical expression t ' of TB varies between age groups. -The aims of this study were to characterise the cellular immune response at different ages in TB patients and healthy individuals living in a region highly endemic for TB and to relate the findings to the clinical expression of TB in different age groups. A total of 150 persons of different ages were included in this study: 50 TB patients, (identified on the basis of clinical, radiological and microbiological characteristics), 49 healthy Mantoux positive (~15mm) and 51 healthy Mantoux negative (<15mm) subjects. All patients <12yrs were identified as having primary TB and postprimary TB was only diagnosed in patients ~12yrs. Haematologic indices were obtained from all the included subjects and found to be agerelated. With the exception of the absolute lymphocyte counts, all indices were significantly different in TB patients when compared to healthy controls. Whole blood was cultured and stimulated with PHA, PPD and ESAT -6 to measure lymphocyte proliferation and IFN-y, TNF-a, IL-2 and IL-10 production in the supernatants of the cultures. After stimulation with PHA, the production of IFN-y, TNF-a and IL-10 as well as lymphocyte proliferation were all age-related. After stimulation with PPD, age correlated positively with IFN-y production in healthy Mantoux positive subjects< 12yrs. In the age groups <20 yrs, patients produced similar amounts of IFN-y when compared to healthy age-related Mantoux positive controls. TNF-a and IL-2 production were not different between patients and controls. In this whole blood system, measuring any of these cytokines on their own did not differentiate patients from controls at all ages. The ratio of PPD stimulated IFN-y to TNF-a production was significantly less in patients with primary TB and postprimary TB when compared to Mantoux positive controls, irrespective of age. These findings indicate that calculated ratios between several cytokines may be useful markers of disease at all ages. ESA T -6 stimulated IFN -y production did not result in any significant correlation with age, but was significantly less in healthy Mantoux positive subjects ~12 yrs when compared to healthy Mantoux positive subjects <12 yrs and TB patients of all ages. This finding suggests that a positive immune response to ESAT -6 is indicative of recent immunological contact with Mtb. Total IgE was measured in serum. In children <12 yrs these values correlated with age and were highest in healthy Mantoux positive controls, thereby not confirming any inverse correlation between IgE and TB. Age should be recognised as a significant variable in quantitative measurements of cellular immune responses.
Mathematical modelling to project the impact of interventions targeted to previously treated individuals on the trajectory of the tuberculosis epidemic in high tuberculosis prevalence settings
(Stellenbosch : Stellenbosch University, 2018-03) Marx, Florian Michael; Beyers, Nulda; Cohen, Theodore; Stellenbosch University. Faculty of Medicine and Health Sciences. Paediatrics and Child Health.
ENGLISH ABSTRACT: Better strategies are needed to reduce Mycobacterium tuberculosis (M.tb) transmission in tuberculosis (TB) high-incidence settings. Targeting additional control interventions towards groups at highest TB risk may thereby constitute a reasonable approach to make best use of limited resources. One group considered at high TB risk are people with a history of previous TB treatment. In recent years, high rates of recurrent TB after successful TB treatment, frequently due to reinfection with another M.tb strain, have been reported from several highincidence settings. The extent to which previously treated people contribute to the overall TB burden in these settings, and whether control interventions targeted towards this high-risk group could help reduce transmission has not been established. The aim of the research presented in this dissertation was to characterise the risk of TB among people with a history of previous TB treatment, and to project the impact of control interventions targeted at this subgroup on the trajectory of TB epidemics in high-incidence settings. Towards this aim, I conducted a total of five studies, four of which are based on traditional epidemiological analysis (Chapters 2,3, and 5,6), and one used a transmission-dynamic mathematical model (Chapter 4). Two studies were based on routine TB program data from a high-incidence setting in suburban Cape Town. The first aimed at estimating the rate of re-treatment for smear-positive TB dependent on whether individuals had completed their previous TB treatment (Chapter 2). For the second, I used M.tb strain-type DNA fingerprinting data for a subset of patients re-treated for recurrent smear-positive TB to investigate the relationship between the type of recurrence, i.e. endogenous reactivation (relapse) or exogenous reinfection, and the time to recurrent smear-positive TB (Chapter 3). I found, among 2,136 smear-positive TB patients, a high rate of re-treatment for smear-positive TB among those who had been lost to follow-up from treatment (6.86 [5.59-8.41] per 100 PYRS). By the end of the second year 28% had been diagnosed again with smear-positive TB. The rate was 3-5-times higher (aHR: 3.97 [3.00 - 5.26]) than after treatment success (cure: 2.09 [1.81-2.41]). Among those who had successfully completed TB treatment, the rate of smear-positive TB was at least 4-times higher than the estimated rate of new smear-positive TB in this setting. Individuals after successful treatment accounted for the majority (68%) of TB patients re-treated for smear-positive TB (Chapter 2). Exogenous reinfection was the underlying mechanism of disease recurrence in 66 (51%) of 130 individuals re-treated for smear-positive TB after previous treatment success. The proportion did not change after restricting the analysis to individuals with documented HIVnegative test results (27 [51%] reinfections of 53 recurrences). The rate of relapse was highest 4-5 months after treatment completion, whereas the rate of reinfection TB dominated after the first year and remained high for several years (Chapter 3). I then used a calibrated transmission-dynamic mathematical model to project the populationlevel impact of interventions targeted at previously treated people in the same high-incidence setting. The interventions modelled were annual targeted active case finding (TACF) and secondary isoniazid preventive therapy (2°IPT) among people who had successfully completed TB treatment. The model projected that, under current control efforts, local TB incidence will remain in slow decline for at least another decade in this setting, and that interventions targeted at previously treated people would greatly accelerate this decline. Annual TACF combined with 2°IPT was projected to avert 40% (20%-59%) of incident TB cases and 41% (16%-62%) of TB deaths estimated to occur in the local population between 2016 and 2025 (Chapter 4). While the previous 3 studies (Chapters 2-4) had focussed on a particular TB high-incidence setting in suburban Cape Town, I conducted two further studies to explore whether specific characteristics of previously treated TB observed in suburban Cape Town extend to other highincidence settings in Southern Africa. I analysed TB prevalence survey data for more than 64,000 adults in 8 South African and 16 Zambian communities, to estimate TB prevalence stratified by history of previous TB treatment, and to investigate the extent to which previously treated people contributed to the overall prevalent TB burden. The study revealed a high prevalence of bacteriologically-confirmed TB among previously treated people in the 8 South African (overall: 3.81% [95%CI 3.25%–4.47%]) and the 16 Zambian (1.01% [95%CI: 0.65%–1.55%]) communities. Previously treated people accounted for 20.7% and 10.4% of prevalent TB cases in the South African and Zambian communities, respectively, and for more than 20% in 9 of the 24 communities overall (Chapter 5). Finally, I made use of electronic TB register data from the 52 South African health districts to investigate the proportion of previously treated individuals among notified TB patients treated for bacteriologically-confirmed TB in 2011. The study showed that the proportion of previously treated TB varied in the 52 health districts between 7.6% and 40%. The proportion exceeded 20% in 17 of the 52 districts. Higher proportions of previously treated TB correlated with higher TB case notification rates (r=0.75; P<0.001) and lower estimates of HIV prevalence (r=-0.45; P<0.001) in the districts (Chapter 6). In conclusion, this research documents high rates of TB after previous loss to follow-up from treatment and after treatment success in a high-incidence setting. People who previously completed TB treatment constitute the majority of smear-positive TB re-treatment patients, suggesting that efforts to ensure treatment adherence alone are unlikely to be sufficient to reduce the TB burden among previously treated people. Our study is consistent with earlier findings from this setting that reinfection contributes considerably to recurrent TB, even among HIV-uninfected individuals. I document for the first-time distinct temporal dynamics of relapse and reinfection TB. These dynamics suggest that sampling bias/differences in follow-up time is likely to explain the substantial variation in the contribution of reinfection to disease recurrence reported in observational studies. High rates of reinfection TB over a lengthy time after treatment completion suggest that the performance of TB treatment alone is unlikely to explain the high burden of recurrent TB in this setting. I used a transmission-dynamic mathematical model to address the idea of a targeted control strategy at a time when novel strategies are urgently needed to reduce transmission and the TB burden in populations most severely affected by TB. The model suggests considerable public health potential for TB control interventions targeted at previously treated people in this high-incidence setting. I identified several other high-incidence communities (and districts) where previously treated individuals contribute considerably to the prevalent and incident (notified) TB burden, and where interventions in this high-risk group might be relevant. This work represents only a first step towards evaluating the potential of this targeted control approach. Further research will be necessary to determine the feasibility, impact and costeffectiveness of targeting interventions towards previously treated people for reducing transmission and the TB burden in high-incidence settings.

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