Background Assessment of data quality is essential to successful monitoring & evaluation of tuber... more Background Assessment of data quality is essential to successful monitoring & evaluation of tuberculosis (TB) services. South Africa uses the Three Interlinked Electronic Register (TIER.Net) to monitor TB diagnoses and treatment outcomes. We assessed the quality of routine programmatic data as captured in TIER.Net. Methods We reviewed 277 records from routine data collected for adults who had started TB treatment for drug-sensitive (DS-) TB between 10/2018-12/2019 from 15 facilities across three South African districts using three sources and three approaches to link these (i.e., two approaches compared TIER.NET with the TB Treatment Record while the third approach compared all three sources of TB data: the TB treatment record or patient medical file; the TB Identification Register; and the TB module in TIER.Net). We report agreement and completeness of demographic information and key TB-related variables across all three data sources. Results In our first approach we selected 150 p...
Background Tuberculosis remains an important clinical and public health issue in South Africa, wh... more Background Tuberculosis remains an important clinical and public health issue in South Africa, which has one of the highest tuberculosis burdens in the world. We aimed to estimate the burden of bacteriologically confirmed pulmonary tuberculosis among people aged 15 years or older in South Africa. Methods This multistage, cluster-based, cross-sectional survey included eligible residents (age ≥15 years, who had slept in a house for ≥10 nights in the preceding 2 weeks) in 110 clusters nationally (cluster size of 500 people; selected by probability proportional-to-population size sampling). Participants completed face-to-face symptom questionnaires (for cough, weight loss, fever, and night sweats) and manually read digital chest X-ray screening. Screening was recorded as positive if participants had at least one symptom or an abnormal chest X-ray suggestive of tuberculosis, or a combination thereof. Sputum samples from participants who were screen-positive were tested by the Xpert MTB/RIF Ultra assay (first sample) and Mycobacteria Growth Indicator Tube culture (second sample), with optional HIV testing. Participants with a positive Mycobacterium tuberculosis complex culture were considered positive for bacteriologically confirmed pulmonary tuberculosis; when culture was not positive, participants with a positive Xpert MTB/RIF Ultra result with an abnormal chest X-ray suggestive of active tuberculosis and without current or previous tuberculosis were considered positive for bacteriologically confirmed pulmonary tuberculosis.
C oronavirus disease 2019 (COVID-19) represents an unprecedented challenge in modern public healt... more C oronavirus disease 2019 (COVID-19) represents an unprecedented challenge in modern public health practice. Having spread to over 180 countries and having affected millions of individuals, the COVID-19 pandemic requires a coordinated, effective response without sacrifice to quality or availability of other essential medical services [1]. This rapidly-moving pandemic has laid bare the importance of effective surveillance, quarantine, testing and diagnosis, contact tracing and hospital infection prevention and control measures. Certain countries, including Singapore, have effectively contained community spread of the virus through early and broad quarantine, testing and contact tracing measures [2-4]. In countries like Italy and Spain-where responses were slower, narrower in focus and less consistently implemented-COVID-19 transmission has spread widely in the community, and responses have shifted from containment to mitigation [4,5]. In these countries where containment measures have failed, health systems must plan to ration life-saving medical equipment like mechanical ventilators [6-8]. As COVID-19 spreads to more countries daily, governments begin to prepare for community spread and start to impose travel restrictions, quarantines and physical distancing measures in an effort to "flatten the curve" and to minimize health system strain [9,10]. Minimizing nosocomial (hospital-based) infections is integral to an effective COVID-19 response. The World Health Organization (WHO) has published interim COVID-19 infection prevention and control (IPC) guidance, which focuses on administrative controls (including policy, guidance, training and triage practices), environmental controls (including ventilation and waste management) and personal protective equipment (PPE, including rational use thereof) [11]. As more patients become sicker and require hospitalization, public health leaders must look toward existing hospital-based IPC programs to ensure a broad, consistent prevention and control effort. Tuberculosis (TB) IPC programs are uniquely prepared for this challenge and can be leveraged to mobilize already-trained health care workers, to adapt existing TB IPC guidance documents and to implement existing administrative controls, environmental controls and PPE practices.
Over the past 15 years, and despite many difficulties, significant progress has been made to adva... more Over the past 15 years, and despite many difficulties, significant progress has been made to advance child and adolescent tuberculosis (TB) care. Despite increasing availability of safe and effective treatment and prevention options, TB remains a global health priority as a major cause of child and adolescent morbidity and mortality—over one and a half million children and adolescents develop TB each year. A history of the global public health perspective on child and adolescent TB is followed by 12 narratives detailing challenges and progress in 19 TB endemic low and middle-income countries. Overarching challenges include: under-detection and under-reporting of child and adolescent TB; poor implementation and reporting of contact investigation and TB preventive treatment services; the need for health systems strengthening to deliver effective, decentralized services; and lack of integration between TB programs and child health services. The COVID-19 pandemic has had a significant n...
In Africa, incidence and prevalence of drug-resistant tuberculosis have been assumed to be low. H... more In Africa, incidence and prevalence of drug-resistant tuberculosis have been assumed to be low. However, investigation after a 2005 outbreak of extensively drugresistant tuberculosis in KwaZulu-Natal Province, South Africa, found that the incidence rate for multidrug-resistant tuberculosis in KwaZulu-Natal was among the highest globally and would be higher if case-fi nding efforts were intensifi ed. In Africa, resistance to anti-tuberculosis (TB) drugs has been assumed to be low (1). In 2002, the national drug resistance survey showed rates of multidrug-resistant (MDR) TB in South Africa to be 3.0 % among all TB cases, 1.6 % among new cases, and 6.6 % among previously treated cases (2). Surveys in other African countries have yielded MDR TB rates of <3 % among all TB cases, low compared with>20 % reported from former Soviet Union countries; however, MDR TB rates may not be as low as previously estimated (3–7). In response to a 2005 outbreak of extensively drug-resistant (XDR) ...
Purpose: The pharmacokinetics (PK) of anti-tuberculosis drugs, including their bioavailability (B... more Purpose: The pharmacokinetics (PK) of anti-tuberculosis drugs, including their bioavailability (BA), significantly impacts the efficacy and effectiveness of tuberculosis (TB) treatment regimens. Rifampicin, one of the most important drugs in the treatment of drug-sensitive tuberculosis, has been used increasingly in fixed-dose combinations (FDCs). This paper reviews and analyzes available data on BA and PK of rifampicin with a focus on FDCs, from published studies and reports. Methods: Using PubMed as the primary database, Cochrane and other relevant databases, a systematic review of literature was conducted to identify studies on the bioavailability and efficacy of rifampicin in FDCs versus single drug formulations. A number of keywords including "bioavailability", "rifampicin", "fixed dose combinations", and "pharmacokinetics" were used in various combinations. The search covered the period 1980 to 2016. Priority was given to articles on rifampicin bioavailability in fixed dose combinations used in the program setting, and human studies that used the World Health Organization (WHO) approved BA/PK protocol and sample size (≥22 patients). Findings: More than 450 original peer-reviewed articles, reviews and reports, were assessed for this analysis. Eleven papers, which included data from high-TB-burden countries (South Africa, India, and China), raised significant concerns about rifampicin bioavailability within FDCs; the authors of the studies discussed multiple factors associated with low bioavailability, including drug formulation and quality, storage environment, patient factors, and concomitant diseases. Implications: Recent studies and reviews point to the problem of low bioavailability of rifampicin in fixed dose combinations. However, in the field, it remains a hidden or unrecognized factor leading to poor treatment outcomes. It is difficult to study the issue thoroughly unless there is awareness among TB program personnel of its existence, and adequate laboratory and research support is available to national tuberculosis programs (NTPs). In stemming the tide of tuberculosis multi-drug resistance (MDR) and extensive drug resistance (XDR), it is paramount to ensure that rifampicin bioavailability is adequate in FDCs, and to detect and address any deviation from recommended target ranges. There is a need for strategies to minimize the undesirable clinical effects of reduced rifampicin bioavailability in FDCs, and for effective utilization of quality-assured drugs within NTPs programs; these can help NTPs support effective case management in line with the international TB care standards, while taking into consideration the factors affecting drug absorption and therapeutic concentration.
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2021
BACKGROUND Few studies have evaluated tuberculosis control in children and adolescents. We used r... more BACKGROUND Few studies have evaluated tuberculosis control in children and adolescents. We used routine tuberculosis surveillance data to quantify age- and HIV-stratified trends over time and investigate the relationship between tuberculosis, HIV, age and sex. METHODS All children and adolescents (0-19 years) routinely treated for drug-susceptible tuberculosis in South Africa and recorded in a de-duplicated national electronic tuberculosis treatment register (2004-2016) were included. Age- and HIV-stratified tuberculosis case notification rates (CNRs) were calculated in four age bands: 0-4, 5-9, 10-14 and 15-19 years. The association between HIV infection, age and sex in children and adolescents with TB was evaluated using multivariable logistic regression. RESULTS Of 719,400 children and adolescents included, 339,112 (47%) were 0-4-year-olds. The overall tuberculosis CNR for 0-19-year-olds declined by 54% between 2009 and 2016 (incidence rate ratio [IRR]=0.46, 95% confidence interv...
Journal of Tropical Diseases & Public Health, 2019
Background: In recognition of the convergence of high levels of Tuberculosis (TB) and increasing ... more Background: In recognition of the convergence of high levels of Tuberculosis (TB) and increasing Diabetes Mellitus (DM) in South Africa, the country has prioritized integrated clinical service management for acute diseases and chronic conditions at the primary health care level. The shift toward collaborative activities requires changes in all areas of the health system. Objective: To assess the readiness of the primary health care system to provide integrated tuberculosis and diabetes services, this case study assessed leadership/governance, the health workforce, health information systems, access to medicines, and service delivery. Methods: The mixed-method study included interviews with health facility managers, facility checklist of TB and DM supplies and commodities, review of health records, a patient survey, and focus group discussions with health managers in three districts in KwaZulu Natal Province, Eastern Cape Province, and Free State Province. Results: Performance in bi-...
Executive summary South Africa is one of the 22 highest tuberculosis (TB) burdened countries glob... more Executive summary South Africa is one of the 22 highest tuberculosis (TB) burdened countries globally and the occurrence of laboratory-confirmed multi drug resistant TB (MDR–TB) and extensively drug resistant TB (XDR-TB) has long been recognized in South Africa. A drug resistance survey (2012-2014) to quantify and delineate the extent of drug resistance in new and retreatment TB patients nationally and provincially in South Africa, as well as to compare findings with the previous survey (2001-2002) was undertaken based on WHO guidelines. The prevalence of MDR-TB nationally in the latest survey was measured at 2.1% in new cases and 4.6% in retreatment cases with an overall, MDR-TB estimate of 2.8%. Compared to the previous survey, the MDR-TB prevalence has remained relatively stable over the tenyear period. The highest rate observed was in Mpumalanga province with an overall rate of 5.1%. Contrasted to the MDR-TB prevalence nationally, the rate of any rifampicin-resistance prevalence...
Background: Gauteng Province has the second lowest tuberculosis (TB) incidence rate in South Afri... more Background: Gauteng Province has the second lowest tuberculosis (TB) incidence rate in South Africa but the greatest proportion of TB/HIV co-infection, with 68% of TB patients estimated to have HIV. TB treatment outcomes are well documented at the national and provincial level; however, knowledge gaps remain on how outcomes differ across detailed age groups. Methods: Using data from South Africa's National Electronic TB Register (ETR), we assessed all-cause mortality and loss to follow-up (LTFU) among patients initiating treatment for TB between 01/2010 and 12/2015 in the metropolitan municipalities of Ekurhuleni Metropolitan Municipality and the City of Johannesburg in Gauteng Province. We excluded patients who were missing age, had known drug-resistance, or transferred into TB care from sites outside the two metropolitan municipalities. Among patients assigned a treatment outcome, we investigated the association between age group at treatment initiation and mortality or LTFU (treatment interruption of ≥2 months) within 10 months after treatment initiation using Cox proportional hazard models and present hazard ratios and Kaplan-Meier survival curves. Results: We identified 182,890 children (<10 years), young adolescent (10-14), older adolescent (15-19), young adult (20-24), adult (25-49), and older adult (≥50) TB cases without known drug-resistance. ART coverage among HIV co-infected patients was highest for young adolescents (64.3%) and lowest for young adults (54.0%) compared to other age groups (all over 60%). Treatment success exceeded 80% in all age groups (n = 170,017). All-cause mortality increased with age. Compared to adults, young adults had an increased hazard of LTFU (20-24 vs 25-49 years; aHR 1.43 95% CI: 1.33, 1.54) while children, young adolescents, and older adults had lower hazard of LTFU. Patients with HIV on ART had a lower risk of LTFU, but greater risk of death when compared to patients without HIV.
South Africa has the highest tuberculosis (TB) disease incidence rate in the world, and TB is the... more South Africa has the highest tuberculosis (TB) disease incidence rate in the world, and TB is the leading infectious cause of death. Decisions on, and funding for, TB prevention and care policies are decentralised to the provincial governments and therefore, tools to inform policy need to operate at this level. We describe the use of a mathematical model planning tool at provincial level in a high HIV and TB burden country, to estimate the impact on TB burden of achieving the 90-(90)-90 targets of the Stop TB Partnership Global Plan to End TB. "TIME Impact" is a freely available, user-friendly TB modelling tool. In collaboration with provincial TB programme staff, and the South African National TB Programme, models for three (of nine) provinces were calibrated to TB notifications, incidence, and screening data. Reported levels of TB programme activities were used as baseline inputs into the models, which were used to estimate the impact of scale-up of interventions focusing on screening, linkage to care and treatment success. All baseline models predicted a trend of decreasing TB incidence and mortality, consistent with recent data from South Africa. The projected impacts of the interventions differed by province and were greatly influenced by assumed current coverage levels. The absence of provincial TB burden estimates and uncertainty in current activity coverage levels were key data gaps. A user-friendly modelling tool allows TB burden and intervention impact projection at the sub-national level. Key sub-national data gaps should be addressed to improve the quality of sub-national model predictions.
Globally, per-capita, South Africa reports a disproportionately high number of cases of multidrug... more Globally, per-capita, South Africa reports a disproportionately high number of cases of multidrug-resistant (MDR) tuberculosis and extensively drug-resistant (XDR) tuberculosis. We sought to estimate the prevalence of resistance to tuberculosis drugs in newly diagnosed and retreated patients with tuberculosis provincially and nationally, and compared these with the 2001-02 estimates. A cross-sectional survey was done between June 15, 2012-June 14, 2014, using population proportionate randomised cluster sampling in the nine provinces in South Africa. 343 clusters were included, ranging between 31 and 48 per province. A patient was eligible for inclusion in the survey if he or she presented as a presumptive case during the intake period at a drug resistance survey enrolling facility. Consenting participants (≥18 years old) completed a questionnaire and had a sputum sample tested for resistance to first-line and second-line drugs. Analysis was by logistic regression with robust SEs, in...
I consider that the reassuring conclusion of this manuscript should be mitigated and that further... more I consider that the reassuring conclusion of this manuscript should be mitigated and that further validation of the findings should be done using state-of-the-art laboratory methods, which are available in South Africa.
In many countries, regular monitoring of the emergence of resistance to anti-tuberculosis drugs i... more In many countries, regular monitoring of the emergence of resistance to anti-tuberculosis drugs is hampered by the limitations of phenotypic testing for drug susceptibility. We therefore evaluated the use of genetic sequencing for surveillance of drug resistance in tuberculosis. Population-level surveys were done in hospitals and clinics in seven countries (Azerbaijan, Bangladesh, Belarus, Pakistan, Philippines, South Africa, and Ukraine) to evaluate the use of genetic sequencing to estimate the resistance of Mycobacterium tuberculosis isolates to rifampicin, isoniazid, ofloxacin, moxifloxacin, pyrazinamide, kanamycin, amikacin, and capreomycin. For each drug, we assessed the accuracy of genetic sequencing by a comparison of the adjusted prevalence of resistance, measured by genetic sequencing, with the true prevalence of resistance, determined by phenotypic testing. Isolates were taken from 7094 patients with tuberculosis who were enrolled in the study between November, 2009, and M...
Background Pyrazinamide and fl uoroquinolones are essential antituberculosis drugs in new rifampi... more Background Pyrazinamide and fl uoroquinolones are essential antituberculosis drugs in new rifampicin-sparing regimens. However, little information about the extent of resistance to these drugs at the population level is available. Methods In a molecular epidemiology analysis, we used population-based surveys from Azerbaijan, Bangladesh, Belarus, Pakistan, and South Africa to investigate resistance to pyrazinamide and fl uoroquinolones among patients with tuberculosis. Resistance to pyrazinamide was assessed by gene sequencing with the detection of resistance-conferring mutations in the pncA gene, and susceptibility testing to fl uoroquinolones was conducted using the MGIT system. Findings Pyrazinamide resistance was assessed in 4972 patients. Levels of resistance varied substantially in the surveyed settings (3•0-42•1%). In all settings, pyrazinamide resistance was signifi cantly associated with rifampicin resistance. Among 5015 patients who underwent susceptibility testing to fl uoroquinolones, proportions of resistance ranged from 1•0-16•6% for ofl oxacin, to 0•5-12•4% for levofl oxacin, and 0•9-14•6% for moxifl oxacin when tested at 0•5 μg/mL. High levels of ofl oxacin resistance were detected in Pakistan. Resistance to moxifl oxacin and gatifl oxacin when tested at 2 μg/mL was low in all countries. Interpretation Although pyrazinamide resistance was signifi cantly associated with rifampicin resistance, this drug may still be eff ective in 19-63% of patients with rifampicin-resistant tuberculosis. Even though the high level of resistance to ofl oxacin found in Pakistan is worrisome because it might be the expression of extensive and unregulated use of fl uoroquinolones in some parts of Asia, the negligible levels of resistance to fourth-generation fl uoroquinolones documented in all survey sites is an encouraging fi nding. Rational use of this class of antibiotics should therefore be ensured to preserve its eff ectiveness.
Background In South Africa, sputum smear microscopy has been replaced with Xpert MTB/RIF as the i... more Background In South Africa, sputum smear microscopy has been replaced with Xpert MTB/RIF as the initial diagnostic test for tuberculosis. In a pragmatic parallel cluster-randomised trial, we evaluated the eff ect on patient and programme outcomes. Methods We randomly allocated 20 laboratories (clusters) in medium-burden districts of South Africa to either an Xpert (immediate Xpert) or microscopy (Xpert deferred) group (1:1), stratifi ed by province. At two primary care clinics per laboratory, a systematic sample of adults giving sputum for tuberculosis investigation was assessed for eligibility. The primary outcome was mortality at 6 months from enrolment. Masking of participants' group allocation was not possible because of the pragmatic trial design. The trial is registered with the ISRCTN registry (ISRCTN68905568) and the South African Clinical Trial Register (DOH-27-1011-3849). Findings Between June and November, 2012, 4972 people were screened, and 4656 (93•6%) enrolled (median age 36 years; 2891 [62%] female; 2212 [62%] reported being HIV-positive). There was no diff erence between the Xpert and microscopy groups with respect to mortality at 6 months (91/2324 [3•9%] vs 116/2332 [5•0%], respectively; adjusted risk ratio [aRR] 1•10, 95% CI 0•75-1•62]). Interpretation Xpert did not reduce mortality at 6 months compared with sputum microscopy. Improving outcomes in drug-sensitive tuberculosis programmes might require not only better diagnostic tests but also better linkage to care. Funding Bill & Melinda Gates Foundation.
Tuberculosis (TB) remains a global health threat. Despite a slow decline in global TB rates, the ... more Tuberculosis (TB) remains a global health threat. Despite a slow decline in global TB rates, the World Health Organization (WHO) reported 8.6 million new cases of TB in 2012 (13% in people living with HIV), resulting in 1.3 million deaths (23% among HIV-positive persons). [1] South Africa (SA) has one of the world's worst TB epidemics driven by HIV. The WHO has identified 22 high-burden countries (HBCs), which account for 81% of all estimated incident TB cases globally. Among the HBCs, SA has the third highest absolute number of reported incident cases and the fifth highest number of estimated prevalent (undiagnosed active TB) cases. [1] After adjusting for population size, SA has the highest incidence and prevalence of TB among the HBCs. It also has the largest number of HIV-associated TB cases and the second-largest number of diagnosed multidrugresistant (MDR)-TB cases (after India). [1] The National Tuberculosis Programme (NTP), established after SA became a democracy in 1994, faced the challenge of integrating TB services into weak primary healthcare systems and the emergence of the HIV epidemic, which led to TB case rates quadrupling between 1994 and 2012 (Fig. 1). [2] The growing burden of MDR-TB and the emergence of extensively drug-resistant (XDR) TB in 2006 added a further burden to overstretched health services. In order to respond to the dual epidemics of HIV and TB rationally, SA developed an integrated National Strategic Plan (NSP) for HIV, STIs and TB (2012-2016). [3] The targets set in the NSP for TB are to halve TB incidence and mortality by 2016 and to have no new TB infections, deaths or stigma by 2032. In this review we highlight successes and challenges in TB prevention, treatment and care and discuss strategies to achieve the NSP targets.
Background Assessment of data quality is essential to successful monitoring & evaluation of tuber... more Background Assessment of data quality is essential to successful monitoring & evaluation of tuberculosis (TB) services. South Africa uses the Three Interlinked Electronic Register (TIER.Net) to monitor TB diagnoses and treatment outcomes. We assessed the quality of routine programmatic data as captured in TIER.Net. Methods We reviewed 277 records from routine data collected for adults who had started TB treatment for drug-sensitive (DS-) TB between 10/2018-12/2019 from 15 facilities across three South African districts using three sources and three approaches to link these (i.e., two approaches compared TIER.NET with the TB Treatment Record while the third approach compared all three sources of TB data: the TB treatment record or patient medical file; the TB Identification Register; and the TB module in TIER.Net). We report agreement and completeness of demographic information and key TB-related variables across all three data sources. Results In our first approach we selected 150 p...
Background Tuberculosis remains an important clinical and public health issue in South Africa, wh... more Background Tuberculosis remains an important clinical and public health issue in South Africa, which has one of the highest tuberculosis burdens in the world. We aimed to estimate the burden of bacteriologically confirmed pulmonary tuberculosis among people aged 15 years or older in South Africa. Methods This multistage, cluster-based, cross-sectional survey included eligible residents (age ≥15 years, who had slept in a house for ≥10 nights in the preceding 2 weeks) in 110 clusters nationally (cluster size of 500 people; selected by probability proportional-to-population size sampling). Participants completed face-to-face symptom questionnaires (for cough, weight loss, fever, and night sweats) and manually read digital chest X-ray screening. Screening was recorded as positive if participants had at least one symptom or an abnormal chest X-ray suggestive of tuberculosis, or a combination thereof. Sputum samples from participants who were screen-positive were tested by the Xpert MTB/RIF Ultra assay (first sample) and Mycobacteria Growth Indicator Tube culture (second sample), with optional HIV testing. Participants with a positive Mycobacterium tuberculosis complex culture were considered positive for bacteriologically confirmed pulmonary tuberculosis; when culture was not positive, participants with a positive Xpert MTB/RIF Ultra result with an abnormal chest X-ray suggestive of active tuberculosis and without current or previous tuberculosis were considered positive for bacteriologically confirmed pulmonary tuberculosis.
C oronavirus disease 2019 (COVID-19) represents an unprecedented challenge in modern public healt... more C oronavirus disease 2019 (COVID-19) represents an unprecedented challenge in modern public health practice. Having spread to over 180 countries and having affected millions of individuals, the COVID-19 pandemic requires a coordinated, effective response without sacrifice to quality or availability of other essential medical services [1]. This rapidly-moving pandemic has laid bare the importance of effective surveillance, quarantine, testing and diagnosis, contact tracing and hospital infection prevention and control measures. Certain countries, including Singapore, have effectively contained community spread of the virus through early and broad quarantine, testing and contact tracing measures [2-4]. In countries like Italy and Spain-where responses were slower, narrower in focus and less consistently implemented-COVID-19 transmission has spread widely in the community, and responses have shifted from containment to mitigation [4,5]. In these countries where containment measures have failed, health systems must plan to ration life-saving medical equipment like mechanical ventilators [6-8]. As COVID-19 spreads to more countries daily, governments begin to prepare for community spread and start to impose travel restrictions, quarantines and physical distancing measures in an effort to "flatten the curve" and to minimize health system strain [9,10]. Minimizing nosocomial (hospital-based) infections is integral to an effective COVID-19 response. The World Health Organization (WHO) has published interim COVID-19 infection prevention and control (IPC) guidance, which focuses on administrative controls (including policy, guidance, training and triage practices), environmental controls (including ventilation and waste management) and personal protective equipment (PPE, including rational use thereof) [11]. As more patients become sicker and require hospitalization, public health leaders must look toward existing hospital-based IPC programs to ensure a broad, consistent prevention and control effort. Tuberculosis (TB) IPC programs are uniquely prepared for this challenge and can be leveraged to mobilize already-trained health care workers, to adapt existing TB IPC guidance documents and to implement existing administrative controls, environmental controls and PPE practices.
Over the past 15 years, and despite many difficulties, significant progress has been made to adva... more Over the past 15 years, and despite many difficulties, significant progress has been made to advance child and adolescent tuberculosis (TB) care. Despite increasing availability of safe and effective treatment and prevention options, TB remains a global health priority as a major cause of child and adolescent morbidity and mortality—over one and a half million children and adolescents develop TB each year. A history of the global public health perspective on child and adolescent TB is followed by 12 narratives detailing challenges and progress in 19 TB endemic low and middle-income countries. Overarching challenges include: under-detection and under-reporting of child and adolescent TB; poor implementation and reporting of contact investigation and TB preventive treatment services; the need for health systems strengthening to deliver effective, decentralized services; and lack of integration between TB programs and child health services. The COVID-19 pandemic has had a significant n...
In Africa, incidence and prevalence of drug-resistant tuberculosis have been assumed to be low. H... more In Africa, incidence and prevalence of drug-resistant tuberculosis have been assumed to be low. However, investigation after a 2005 outbreak of extensively drugresistant tuberculosis in KwaZulu-Natal Province, South Africa, found that the incidence rate for multidrug-resistant tuberculosis in KwaZulu-Natal was among the highest globally and would be higher if case-fi nding efforts were intensifi ed. In Africa, resistance to anti-tuberculosis (TB) drugs has been assumed to be low (1). In 2002, the national drug resistance survey showed rates of multidrug-resistant (MDR) TB in South Africa to be 3.0 % among all TB cases, 1.6 % among new cases, and 6.6 % among previously treated cases (2). Surveys in other African countries have yielded MDR TB rates of <3 % among all TB cases, low compared with>20 % reported from former Soviet Union countries; however, MDR TB rates may not be as low as previously estimated (3–7). In response to a 2005 outbreak of extensively drug-resistant (XDR) ...
Purpose: The pharmacokinetics (PK) of anti-tuberculosis drugs, including their bioavailability (B... more Purpose: The pharmacokinetics (PK) of anti-tuberculosis drugs, including their bioavailability (BA), significantly impacts the efficacy and effectiveness of tuberculosis (TB) treatment regimens. Rifampicin, one of the most important drugs in the treatment of drug-sensitive tuberculosis, has been used increasingly in fixed-dose combinations (FDCs). This paper reviews and analyzes available data on BA and PK of rifampicin with a focus on FDCs, from published studies and reports. Methods: Using PubMed as the primary database, Cochrane and other relevant databases, a systematic review of literature was conducted to identify studies on the bioavailability and efficacy of rifampicin in FDCs versus single drug formulations. A number of keywords including "bioavailability", "rifampicin", "fixed dose combinations", and "pharmacokinetics" were used in various combinations. The search covered the period 1980 to 2016. Priority was given to articles on rifampicin bioavailability in fixed dose combinations used in the program setting, and human studies that used the World Health Organization (WHO) approved BA/PK protocol and sample size (≥22 patients). Findings: More than 450 original peer-reviewed articles, reviews and reports, were assessed for this analysis. Eleven papers, which included data from high-TB-burden countries (South Africa, India, and China), raised significant concerns about rifampicin bioavailability within FDCs; the authors of the studies discussed multiple factors associated with low bioavailability, including drug formulation and quality, storage environment, patient factors, and concomitant diseases. Implications: Recent studies and reviews point to the problem of low bioavailability of rifampicin in fixed dose combinations. However, in the field, it remains a hidden or unrecognized factor leading to poor treatment outcomes. It is difficult to study the issue thoroughly unless there is awareness among TB program personnel of its existence, and adequate laboratory and research support is available to national tuberculosis programs (NTPs). In stemming the tide of tuberculosis multi-drug resistance (MDR) and extensive drug resistance (XDR), it is paramount to ensure that rifampicin bioavailability is adequate in FDCs, and to detect and address any deviation from recommended target ranges. There is a need for strategies to minimize the undesirable clinical effects of reduced rifampicin bioavailability in FDCs, and for effective utilization of quality-assured drugs within NTPs programs; these can help NTPs support effective case management in line with the international TB care standards, while taking into consideration the factors affecting drug absorption and therapeutic concentration.
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2021
BACKGROUND Few studies have evaluated tuberculosis control in children and adolescents. We used r... more BACKGROUND Few studies have evaluated tuberculosis control in children and adolescents. We used routine tuberculosis surveillance data to quantify age- and HIV-stratified trends over time and investigate the relationship between tuberculosis, HIV, age and sex. METHODS All children and adolescents (0-19 years) routinely treated for drug-susceptible tuberculosis in South Africa and recorded in a de-duplicated national electronic tuberculosis treatment register (2004-2016) were included. Age- and HIV-stratified tuberculosis case notification rates (CNRs) were calculated in four age bands: 0-4, 5-9, 10-14 and 15-19 years. The association between HIV infection, age and sex in children and adolescents with TB was evaluated using multivariable logistic regression. RESULTS Of 719,400 children and adolescents included, 339,112 (47%) were 0-4-year-olds. The overall tuberculosis CNR for 0-19-year-olds declined by 54% between 2009 and 2016 (incidence rate ratio [IRR]=0.46, 95% confidence interv...
Journal of Tropical Diseases & Public Health, 2019
Background: In recognition of the convergence of high levels of Tuberculosis (TB) and increasing ... more Background: In recognition of the convergence of high levels of Tuberculosis (TB) and increasing Diabetes Mellitus (DM) in South Africa, the country has prioritized integrated clinical service management for acute diseases and chronic conditions at the primary health care level. The shift toward collaborative activities requires changes in all areas of the health system. Objective: To assess the readiness of the primary health care system to provide integrated tuberculosis and diabetes services, this case study assessed leadership/governance, the health workforce, health information systems, access to medicines, and service delivery. Methods: The mixed-method study included interviews with health facility managers, facility checklist of TB and DM supplies and commodities, review of health records, a patient survey, and focus group discussions with health managers in three districts in KwaZulu Natal Province, Eastern Cape Province, and Free State Province. Results: Performance in bi-...
Executive summary South Africa is one of the 22 highest tuberculosis (TB) burdened countries glob... more Executive summary South Africa is one of the 22 highest tuberculosis (TB) burdened countries globally and the occurrence of laboratory-confirmed multi drug resistant TB (MDR–TB) and extensively drug resistant TB (XDR-TB) has long been recognized in South Africa. A drug resistance survey (2012-2014) to quantify and delineate the extent of drug resistance in new and retreatment TB patients nationally and provincially in South Africa, as well as to compare findings with the previous survey (2001-2002) was undertaken based on WHO guidelines. The prevalence of MDR-TB nationally in the latest survey was measured at 2.1% in new cases and 4.6% in retreatment cases with an overall, MDR-TB estimate of 2.8%. Compared to the previous survey, the MDR-TB prevalence has remained relatively stable over the tenyear period. The highest rate observed was in Mpumalanga province with an overall rate of 5.1%. Contrasted to the MDR-TB prevalence nationally, the rate of any rifampicin-resistance prevalence...
Background: Gauteng Province has the second lowest tuberculosis (TB) incidence rate in South Afri... more Background: Gauteng Province has the second lowest tuberculosis (TB) incidence rate in South Africa but the greatest proportion of TB/HIV co-infection, with 68% of TB patients estimated to have HIV. TB treatment outcomes are well documented at the national and provincial level; however, knowledge gaps remain on how outcomes differ across detailed age groups. Methods: Using data from South Africa's National Electronic TB Register (ETR), we assessed all-cause mortality and loss to follow-up (LTFU) among patients initiating treatment for TB between 01/2010 and 12/2015 in the metropolitan municipalities of Ekurhuleni Metropolitan Municipality and the City of Johannesburg in Gauteng Province. We excluded patients who were missing age, had known drug-resistance, or transferred into TB care from sites outside the two metropolitan municipalities. Among patients assigned a treatment outcome, we investigated the association between age group at treatment initiation and mortality or LTFU (treatment interruption of ≥2 months) within 10 months after treatment initiation using Cox proportional hazard models and present hazard ratios and Kaplan-Meier survival curves. Results: We identified 182,890 children (<10 years), young adolescent (10-14), older adolescent (15-19), young adult (20-24), adult (25-49), and older adult (≥50) TB cases without known drug-resistance. ART coverage among HIV co-infected patients was highest for young adolescents (64.3%) and lowest for young adults (54.0%) compared to other age groups (all over 60%). Treatment success exceeded 80% in all age groups (n = 170,017). All-cause mortality increased with age. Compared to adults, young adults had an increased hazard of LTFU (20-24 vs 25-49 years; aHR 1.43 95% CI: 1.33, 1.54) while children, young adolescents, and older adults had lower hazard of LTFU. Patients with HIV on ART had a lower risk of LTFU, but greater risk of death when compared to patients without HIV.
South Africa has the highest tuberculosis (TB) disease incidence rate in the world, and TB is the... more South Africa has the highest tuberculosis (TB) disease incidence rate in the world, and TB is the leading infectious cause of death. Decisions on, and funding for, TB prevention and care policies are decentralised to the provincial governments and therefore, tools to inform policy need to operate at this level. We describe the use of a mathematical model planning tool at provincial level in a high HIV and TB burden country, to estimate the impact on TB burden of achieving the 90-(90)-90 targets of the Stop TB Partnership Global Plan to End TB. "TIME Impact" is a freely available, user-friendly TB modelling tool. In collaboration with provincial TB programme staff, and the South African National TB Programme, models for three (of nine) provinces were calibrated to TB notifications, incidence, and screening data. Reported levels of TB programme activities were used as baseline inputs into the models, which were used to estimate the impact of scale-up of interventions focusing on screening, linkage to care and treatment success. All baseline models predicted a trend of decreasing TB incidence and mortality, consistent with recent data from South Africa. The projected impacts of the interventions differed by province and were greatly influenced by assumed current coverage levels. The absence of provincial TB burden estimates and uncertainty in current activity coverage levels were key data gaps. A user-friendly modelling tool allows TB burden and intervention impact projection at the sub-national level. Key sub-national data gaps should be addressed to improve the quality of sub-national model predictions.
Globally, per-capita, South Africa reports a disproportionately high number of cases of multidrug... more Globally, per-capita, South Africa reports a disproportionately high number of cases of multidrug-resistant (MDR) tuberculosis and extensively drug-resistant (XDR) tuberculosis. We sought to estimate the prevalence of resistance to tuberculosis drugs in newly diagnosed and retreated patients with tuberculosis provincially and nationally, and compared these with the 2001-02 estimates. A cross-sectional survey was done between June 15, 2012-June 14, 2014, using population proportionate randomised cluster sampling in the nine provinces in South Africa. 343 clusters were included, ranging between 31 and 48 per province. A patient was eligible for inclusion in the survey if he or she presented as a presumptive case during the intake period at a drug resistance survey enrolling facility. Consenting participants (≥18 years old) completed a questionnaire and had a sputum sample tested for resistance to first-line and second-line drugs. Analysis was by logistic regression with robust SEs, in...
I consider that the reassuring conclusion of this manuscript should be mitigated and that further... more I consider that the reassuring conclusion of this manuscript should be mitigated and that further validation of the findings should be done using state-of-the-art laboratory methods, which are available in South Africa.
In many countries, regular monitoring of the emergence of resistance to anti-tuberculosis drugs i... more In many countries, regular monitoring of the emergence of resistance to anti-tuberculosis drugs is hampered by the limitations of phenotypic testing for drug susceptibility. We therefore evaluated the use of genetic sequencing for surveillance of drug resistance in tuberculosis. Population-level surveys were done in hospitals and clinics in seven countries (Azerbaijan, Bangladesh, Belarus, Pakistan, Philippines, South Africa, and Ukraine) to evaluate the use of genetic sequencing to estimate the resistance of Mycobacterium tuberculosis isolates to rifampicin, isoniazid, ofloxacin, moxifloxacin, pyrazinamide, kanamycin, amikacin, and capreomycin. For each drug, we assessed the accuracy of genetic sequencing by a comparison of the adjusted prevalence of resistance, measured by genetic sequencing, with the true prevalence of resistance, determined by phenotypic testing. Isolates were taken from 7094 patients with tuberculosis who were enrolled in the study between November, 2009, and M...
Background Pyrazinamide and fl uoroquinolones are essential antituberculosis drugs in new rifampi... more Background Pyrazinamide and fl uoroquinolones are essential antituberculosis drugs in new rifampicin-sparing regimens. However, little information about the extent of resistance to these drugs at the population level is available. Methods In a molecular epidemiology analysis, we used population-based surveys from Azerbaijan, Bangladesh, Belarus, Pakistan, and South Africa to investigate resistance to pyrazinamide and fl uoroquinolones among patients with tuberculosis. Resistance to pyrazinamide was assessed by gene sequencing with the detection of resistance-conferring mutations in the pncA gene, and susceptibility testing to fl uoroquinolones was conducted using the MGIT system. Findings Pyrazinamide resistance was assessed in 4972 patients. Levels of resistance varied substantially in the surveyed settings (3•0-42•1%). In all settings, pyrazinamide resistance was signifi cantly associated with rifampicin resistance. Among 5015 patients who underwent susceptibility testing to fl uoroquinolones, proportions of resistance ranged from 1•0-16•6% for ofl oxacin, to 0•5-12•4% for levofl oxacin, and 0•9-14•6% for moxifl oxacin when tested at 0•5 μg/mL. High levels of ofl oxacin resistance were detected in Pakistan. Resistance to moxifl oxacin and gatifl oxacin when tested at 2 μg/mL was low in all countries. Interpretation Although pyrazinamide resistance was signifi cantly associated with rifampicin resistance, this drug may still be eff ective in 19-63% of patients with rifampicin-resistant tuberculosis. Even though the high level of resistance to ofl oxacin found in Pakistan is worrisome because it might be the expression of extensive and unregulated use of fl uoroquinolones in some parts of Asia, the negligible levels of resistance to fourth-generation fl uoroquinolones documented in all survey sites is an encouraging fi nding. Rational use of this class of antibiotics should therefore be ensured to preserve its eff ectiveness.
Background In South Africa, sputum smear microscopy has been replaced with Xpert MTB/RIF as the i... more Background In South Africa, sputum smear microscopy has been replaced with Xpert MTB/RIF as the initial diagnostic test for tuberculosis. In a pragmatic parallel cluster-randomised trial, we evaluated the eff ect on patient and programme outcomes. Methods We randomly allocated 20 laboratories (clusters) in medium-burden districts of South Africa to either an Xpert (immediate Xpert) or microscopy (Xpert deferred) group (1:1), stratifi ed by province. At two primary care clinics per laboratory, a systematic sample of adults giving sputum for tuberculosis investigation was assessed for eligibility. The primary outcome was mortality at 6 months from enrolment. Masking of participants' group allocation was not possible because of the pragmatic trial design. The trial is registered with the ISRCTN registry (ISRCTN68905568) and the South African Clinical Trial Register (DOH-27-1011-3849). Findings Between June and November, 2012, 4972 people were screened, and 4656 (93•6%) enrolled (median age 36 years; 2891 [62%] female; 2212 [62%] reported being HIV-positive). There was no diff erence between the Xpert and microscopy groups with respect to mortality at 6 months (91/2324 [3•9%] vs 116/2332 [5•0%], respectively; adjusted risk ratio [aRR] 1•10, 95% CI 0•75-1•62]). Interpretation Xpert did not reduce mortality at 6 months compared with sputum microscopy. Improving outcomes in drug-sensitive tuberculosis programmes might require not only better diagnostic tests but also better linkage to care. Funding Bill & Melinda Gates Foundation.
Tuberculosis (TB) remains a global health threat. Despite a slow decline in global TB rates, the ... more Tuberculosis (TB) remains a global health threat. Despite a slow decline in global TB rates, the World Health Organization (WHO) reported 8.6 million new cases of TB in 2012 (13% in people living with HIV), resulting in 1.3 million deaths (23% among HIV-positive persons). [1] South Africa (SA) has one of the world's worst TB epidemics driven by HIV. The WHO has identified 22 high-burden countries (HBCs), which account for 81% of all estimated incident TB cases globally. Among the HBCs, SA has the third highest absolute number of reported incident cases and the fifth highest number of estimated prevalent (undiagnosed active TB) cases. [1] After adjusting for population size, SA has the highest incidence and prevalence of TB among the HBCs. It also has the largest number of HIV-associated TB cases and the second-largest number of diagnosed multidrugresistant (MDR)-TB cases (after India). [1] The National Tuberculosis Programme (NTP), established after SA became a democracy in 1994, faced the challenge of integrating TB services into weak primary healthcare systems and the emergence of the HIV epidemic, which led to TB case rates quadrupling between 1994 and 2012 (Fig. 1). [2] The growing burden of MDR-TB and the emergence of extensively drug-resistant (XDR) TB in 2006 added a further burden to overstretched health services. In order to respond to the dual epidemics of HIV and TB rationally, SA developed an integrated National Strategic Plan (NSP) for HIV, STIs and TB (2012-2016). [3] The targets set in the NSP for TB are to halve TB incidence and mortality by 2016 and to have no new TB infections, deaths or stigma by 2032. In this review we highlight successes and challenges in TB prevention, treatment and care and discuss strategies to achieve the NSP targets.
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Papers by Lindiwe Mvusi