Drug-resistant Tuberculosis In South Africa Research Articles

Actor Sensemaking and its Role in Implementation of the Decentralized Drug-Resistant TB Policy in South Africa.

South Africa has a high burden of drug-resistant tuberculosis (DR-TB). A policy to decentralize DR-TB treatment from specialized central hospitals to more accessible district facilities was introduced in 2011, but to date implementation has been suboptimal, with variable pace, coverage and models of care emerging. This study explored multilevel policy implementation of DR-TB decentralization in two provinces of South Africa, Western Cape and KwaZulu-Natal. Applying interpretive policy analysis, this paper describes how actors across health system levels and geographies made sense of the DR-TB policy and how this shaped implementation. In an embedded qualitative case study, districts of the two provinces were compared, through data collected in 94 in-depth interviews, and analysed using Vickers' framework of reality, value and action judgements. Five district cases characterise variation in the pace of implementation and models of DR-TB care that emerged. Individual and collective attitudes for and against the policy were underpinned by different systems of meaning for interpreting policy problems and making decisions. These meaning systems were reflected in actor stances on whether DR-TB care needed to be specialized or generalized, nurse- or doctor-led, and institutionalized or ambulatory. Actors' stances influenced their actions and implementation strategies adopted. Resistance to decentralized DR-TB care related to perceived threats of budget cuts to and loss of authority of central facilities, and was often justified in fears of increased transmission, poor quality of care and inadequate resources at lower levels. New advances in diagnosis and treatment to address the growing burden of DR-TB in South Africa will have little impact unless implementation dynamics are better understood, and attention paid to the mindsets, interests and interpretations of policy by actors tasked with implementation. Deliberative policy implementation processes will enhance the quality of discourse, communication and cross-learning between policy actors, critical for reaching synthesis of meaning systems.

Accessibility of TB diagnostic services at primary healthcare clinics in the eThekwini district, South Africa: a geospatial analysis

BackgroundImproving geographic access can aid in managing tuberculosis (TB) by enabling early diagnosis and treatment initiation. Although geospatial techniques have been used to map the transmission patterns of drug-resistant TB...

Manipulation of solid dosage forms for oral administration to paediatric patients for drug-resistant tuberculosis in South Africa: an observation study

BackgroundChildren represent a particularly vulnerable demographic in the context of drug-resistant (DR) tuberculosis (TB) due to their increased likelihood of close contact with adults diagnosed with the disease. Approximately 25 000–30 000 children develop DR-TB annually. While treatment success rates for DR-TB in children surpass those in adults, children and adolescents encounter distinct challenges throughout the diagnosis and treatment of DR-TB (including MDR-TB, Pre-XDR TB, and XDR-TB).AimTo identify current practices in drug administration to children diagnosed with DR-TB where appropriate dosage forms are not available in South Africa.MethodAn observational study was carried out at the study site to determine how medication prescribed was manipulated and administered by nursing staff to paediatric patients in the wards.ResultsThe observational study identified 8 drugs used in DR-TB at the study site, where some manipulation to the formulation was necessary to enable administration to paediatric patients. Linezolid and para-aminosalicylic acid are the only drugs available and registered in the South Africa in a formulation that is suitable for administration to paediatric patients. Activities carried out by nursing staff to enable the administration of DR-TB medication included cutting capsules and tablets and dissolving the tablet or capsule contents in distilled water to obtain the required suitable dose.DiscussionLack of availability of suitable dosage forms for paediatrics patients results in several challenges, such as additional time required for drug preparation, increased time duration of medication administration, and unpalatability of drugs. These challenges may subsequently affect compliance and therapeutic outcomes of the treatment of paediatric patients, especially as outpatients.ConclusionResearch needs to focus on the development of appropriate dosage forms for the paediatric population and focus on identifying cases of DR-TB in children. This will assist in building evidence to advocate for registration of child-friendly dosage forms thereby ensuring a sustainable supply of medication.

Determining the risk-factors for molecular clustering of drug-resistant tuberculosis in South Africa

BackgroundDrug-resistant tuberculosis (DR-TB) epidemic is driven mainly by the effect of ongoing transmission. In high-burden settings such as South Africa (SA), considerable demographic and geographic heterogeneity in DR-TB transmission exists. Thus, a better understanding of risk-factors for clustering can help to prioritise resources to specifically targeted high-risk groups as well as areas that contribute disproportionately to transmission.MethodsThe study analyzed potential risk-factors for recent transmission in SA, using data collected from a sentinel molecular surveillance of DR-TB, by comparing demographic, clinical and epidemiologic characteristics with clustering and cluster sizes. A genotypic cluster was defined as two or more patients having identical patterns by the two genotyping methods used. Clustering was used as a proxy for recent transmission. Descriptive statistics and multinomial logistic regression were used.ResultThe study identified 277 clusters, with cluster size ranging between 2 and 259 cases. The majority (81.6%) of the clusters were small (2–5 cases) with few large (11–25 cases) and very large (≥ 26 cases) clusters identified mainly in Western Cape (WC), Eastern Cape (EC) and Mpumalanga (MP). In a multivariable model, patients in clusters including 11–25 and ≥ 26 individuals were more likely to be infected by Beijing family, have XDR-TB, living in Nelson Mandela Metro in EC or Umgungunglovo in Kwa-Zulu Natal (KZN) provinces, and having history of imprisonment. Individuals belonging in a small genotypic cluster were more likely to infected with Rifampicin resistant TB (RR-TB) and more likely to reside in Frances Baard in Northern Cape (NC).ConclusionSociodemographic, clinical and bacterial risk-factors influenced rate of Mycobacterium tuberculosis (M. tuberculosis) genotypic clustering. Hence, high-risk groups and hotspot areas for clustering in EC, WC, KZN and MP should be prioritized for targeted intervention to prevent ongoing DR-TB transmission.

Variation in missed doses and reasons for discontinuation of anti-tuberculosis drugs during hospital treatment for drug-resistant tuberculosis in South Africa.

Updated World Health Organization (WHO) treatment guidelines prioritize all-oral drug-resistant tuberculosis (DR-TB) regimens. Several poorly tolerated drugs, such as amikacin and para-aminosalicylic acid (PAS), remain treatment options for DR-TB in WHO-recommended longer regimens as Group C drugs. Incomplete treatment with anti-TB drugs increases the risk of treatment failure, relapse, and death. We determined whether missed doses of individual anti-TB drugs, and reasons for their discontinuation, varied in closely monitored hospital settings prior to the 2020 WHO DR-TB treatment guideline updates. We collected retrospective data on adult patients with microbiologically confirmed DR-TB between 2008 and 2015 who were selected for a study of acquired drug resistance in the Western Cape Province of South Africa. Medical records through mid-2017 were reviewed. Patients received directly observed treatment during hospitalization at specialized DR-TB hospitals. Incomplete treatment with individual anti-TB drugs, defined as the failure to take medication as prescribed, regardless of reason, was determined by comparing percent missed doses, stratified by HIV status and DR-TB regimen. We applied a generalized mixed effects model. Among 242 patients, 131 (54%) were male, 97 (40%) were living with HIV, 175 (72%) received second-line treatment prior to first hospitalization, and 191 (79%) died during the study period. At initial hospitalization, 134 (55%) patients had Mycobacterium tuberculosis with resistance to rifampicin and isoniazid (multidrug-resistant TB [MDR-TB]) without resistance to ofloxacin or amikacin, and 102 (42%) had resistance to ofloxacin and/or amikacin. Most patients (129 [53%]) had multiple hospitalizations and DST changes occurred in 146 (60%) by the end of their last hospital discharge. Incomplete treatment was significantly higher for amikacin (18%), capreomycin (18%), PAS (17%) and kanamycin (16%) than other DR-TB drugs (P<0.001), including ethionamide (8%), moxifloxacin (7%), terizidone (7%), ethambutol (7%), and pyrazinamide (6%). Among the most frequently prescribed drugs, second-line injectables had the highest rates of discontinuation for adverse events (range 0.56-1.02 events per year follow-up), while amikacin, PAS and ethionamide had the highest rates of discontinuation for patient refusal (range 0.51-0.68 events per year follow-up). Missed doses did not differ according to HIV status or anti-TB drug combinations. We found that incomplete treatment for second-line injectables and PAS during hospitalization was higher than for other anti-TB drugs. To maximize treatment success, interventions to improve person-centered care and mitigate adverse events may be necessary in cases when PAS or amikacin (2020 WHO recommended Group C drugs) are needed.

Bedaquiline-based treatment for extensively drug-resistant tuberculosis in South Africa: A cost-effectiveness analysis.

BackgroundThe treatment success rate of conventional anti-tuberculosis (TB) regimens for extensively drug-resistant TB (XDR-TB) is low, resulting in high morbidity and healthcare cost especially in the high TB burden countries. Recent clinical findings reported improved treatment outcomes of XDR-TB with the bedaquiline (BDQ)-based regimens. We aimed to evaluate the cost-effectiveness of BDQ-based treatment for XDR-TB from the perspective of the South Africa national healthcare provider.MethodsA 2-year decision-analytic model was designed to evaluate the clinical and economic outcomes of a hypothetical cohort of adult XDR-TB patients with (1) BDQ-based regimen and (2) injectable-based conventional regimen. The model inputs were retrieved from literature and public data. Base-case analysis and sensitivity analysis were performed. The primary model outputs included TB-related direct medical cost and disability-adjusted life years (DALYs).ResultsIn the base-case analysis, the BDQ group reduced 4.4152 DALYs with an incremental cost of USD1,606 when compared to the conventional group. The incremental cost per DALY averted (ICER) by the BDQ group was 364 USD/DALY averted. No influential factor was identified in the sensitivity analysis. In probabilistic sensitivity analysis, the BDQ group was accepted as cost-effective in 97.82% of the 10,000 simulations at a willingness-to-pay threshold of 5,656 USD/DALY averted (1× gross domestic product per capita in South Africa).ConclusionThe BDQ-based therapy appeared to be cost-effective and showed a high probability to be accepted as the preferred cost-effective option for active XDR-TB treatment.

Pharmacogenetics of Between-Individual Variability in Plasma Clearance of Bedaquiline and Clofazimine in South Africa.

Plasma bedaquiline clearance is reportedly more rapid with African ancestry. Our objective was to determine whether genetic polymorphisms explained between-individual variability in plasma clearance of bedaquiline, its M2 metabolite, and clofazimine in a cohort of patients treated for drug-resistant tuberculosis in South Africa. Plasma clearance was estimated with nonlinear mixed-effects modeling. Associations between pharmacogenetic polymorphisms, genome-wide polymorphisms, and variability in clearance were examined using linear regression models. Of 195 cohort participants, 140 were evaluable for genetic associations. Among 21 polymorphisms selected based on prior genome-wide significant associations with any drug, rs776746 (CYP3A5∗3) was associated with slower clearance of bedaquiline (P = .0017) but not M2 (P = .25). CYP3A5∗3 heterozygosity and homozygosity were associated with 15% and 30% slower bedaquiline clearance, respectively. The lowest P value for clofazimine clearance was with VKORC1 rs9923231 (P = .13). In genome-wide analyses, the lowest P values for clearance of bedaquiline and clofazimine were with RFX4 rs76345012 (P = 6.4 × 10-7) and CNTN5 rs75285763 (P = 2.9 × 10-8), respectively. Among South Africans treated for drug-resistant tuberculosis, CYP3A5∗3 was associated with slower bedaquiline clearance. Different CYP3A5∗3 frequencies among populations may help explain the more rapid bedaquiline clearance reported in Africans. Associations with RFX4 and CNTN5 are likely by chance alone.

Cost-effectiveness of bedaquiline, pretomanid and linezolid for treatment of extensively drug-resistant tuberculosis in South Africa, Georgia and the Philippines

ObjectivesPatients with highly resistant tuberculosis have few treatment options. Bedaquiline, pretomanid and linezolid regimen (BPaL) is a new regimen shown to have favourable outcomes after six months. We present an...

Distribution and Clonality of drug-resistant tuberculosis in South Africa

BackgroundStudies have shown that drug-resistant tuberculosis (DR-TB) in South Africa (SA) is clonal and is caused mostly by transmission. Identifying transmission chains is important in controlling DR-TB. This study reports on the sentinel molecular surveillance data of Rifampicin-Resistant (RR) TB in SA, aiming to describe the RR-TB strain population and the estimated transmission of RR-TB cases.MethodRR-TB isolates collected between 2014 and 2018 from eight provinces were genotyped using combination of spoligotyping and 24-loci mycobacterial interspersed repetitive-units-variable-number tandem repeats (MIRU-VNTR) typing.ResultsOf the 3007 isolates genotyped, 301 clusters were identified. Cluster size ranged between 2 and 270 cases. Most of the clusters (247/301; 82.0%) were small in size (< 5 cases), 12.0% (37/301) were medium sized (5–10 cases), 3.3% (10/301) were large (11–25 cases) and 2.3% (7/301) were very large with 26–270 cases. The Beijing genotype was responsible for majority of RR-TB cases in Western and Eastern Cape, while the East-African-Indian-Somalian (EAI1_SOM) genotype accounted for a third of RR-TB cases in Mpumalanga. The overall proportion of RR-TB cases estimated to be due to transmission was 42%, with the highest transmission-rate in Western Cape (64%) and the lowest in Northern Cape (9%).ConclusionLarge clusters contribute to the burden of RR-TB in specific geographic areas such as Western Cape, Eastern Cape and Mpumalanga, highlighting the need for community-wide interventions. Most of the clusters identified in the study were small, suggesting close contact transmission events, emphasizing the importance of contact investigations and infection control as the primary interventions in SA.

Unprepared and unprotected: Graduating medical students’ knowledge, attitudes, and practices regarding drug-resistant tuberculosis in Cape Town, South Africa

South Africa has a high burden of drug-resistant tuberculosis (DR-TB), which has a particularly high mortality among healthcare workers. Junior clinicians deliver key DR-TB services and require training in DR-TB management and prevention. This study aimed to investigate graduating medical students’ knowledge, attitudes, and practices relating to DR-TB, including management, infection control measures, and occupational health services. This cross-sectional, questionnaire-based study at the University of Cape Town, South Africa, recruited final year medical students and included 87 participants. The mean DR-TB knowledge score was 4.7 points (95% confidence interval [CI]: 4.42–5.06, maximum score 8 points). Students reported challenges in accessing respiratory protection, with half (47.7%) struggling to find an N95 respirator when needed. DR-TB exposure was reportedly common. Three students reported prior TB disease, approximately half (n = 49, 55.9%) reported personal concern of active DR-TB disease during undergraduate studies, and the majority (n = 80, 91.9%) correctly perceived themselves to be at increased risk compared to the general population. Medical students are currently unprepared for their role in managing DR-TB in South Africa and unprotected against occupational illness during their studies. This should be addressed in undergraduate curricula and in establishing comprehensive occupational health policies. Resilient personal protective equipment (PPE) supply chains, infection control training, and comprehensive occupational health support have relevance to both DR-TB and novel pathogens, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Prevalence of Pre-Existing Hearing Loss Among Patients With Drug-Resistant Tuberculosis in South Africa.

Purpose Hearing loss, resulting from aminoglycoside ototoxicity, is common among patients with drug-resistant tuberculosis (DR-TB). Those with pre-existing hearing loss are at particular risk of clinically important hearing loss with aminoglycoside-containing treatment than those with normal hearing at baseline. This study aimed to identify factors associated with pre-existing hearing loss among patients being treated for DR-TB in South Africa. Method Cross-sectional analysis nested within a cluster-randomized trial data across 10 South African TB hospitals. Patients ≥ 13 years old received clinical and audiological evaluations before DR-TB treatment initiation. Results Of 936 patients, average age was 35 years. One hundred forty-two (15%) reported pre-existing auditory symptoms. Of 482 patients tested by audiometry, 290 (60%) had pre-existing hearing loss. The prevalence of pre-existing hearing loss was highest among patients ≥ 50 years (adjusted prevalence ratio [aPrR] for symptoms 5.53, 95% confidence interval (CI) [3.63, 8.42]; aPrR for audiometric hearing loss 1.63, 95% CI [1.31, 2.03] compared to age 13-18 years) and among those with a prior history of second-line TB treatment (aPrR for symptoms 1.73, 95% CI [1.66, 1.80]; PrR for audiometric hearing loss 1.33, 95% CI [1.03, 1.73]). Having HIV with cluster of differentiation 4 cell count < 200 cells/mm3 and malnutrition were risk factors but did not reach statistical significance in adjusted analyses. Conclusion Pre-existing hearing loss is common among patients presenting for DR-TB treatment in South Africa, and those older than the age of 50 years or who had prior second-line TB treatment history were at highest risk.

Aminoglycoside-induced Hearing Loss Among Patients Being Treated for Drug-resistant Tuberculosis in South Africa: A Prediction Model.

Individuals treated for drug-resistant tuberculosis (DR-TB) with aminoglycosides (AGs) in resource-limited settings often experience permanent hearing loss, yet there is no practical method to identify those at higher risk. We sought to develop a clinical prediction model of AG-induced hearing loss among patients initiating DR-TB treatment in South Africa. Using nested, prospective data from a cohort of 379 South African adults being treated for confirmed DR-TB with AG-based regimens we developed the prediction model using multiple logistic regression. Predictors were collected from clinical, audiological, and laboratory evaluations conducted at the initiation of DR-TB treatment. The outcome of AG-induced hearing loss was identified from audiometric and clinical evaluation by a worsened hearing threshold compared with baseline during the 6-month intensive phase. Sixty-three percent of participants (n = 238) developed any level of hearing loss. The model predicting hearing loss at frequencies from 250 to 8000 Hz included weekly AG dose, human immunodeficiency virus status with CD4 count, age, serum albumin, body mass index, and pre-existing hearing loss. This model demonstrated reasonable discrimination (area under the receiver operating characteristic curve [AUC] = 0.71) and calibration (χ2[8] = 6.10, P = .636). Using a cutoff of 80% predicted probability of hearing loss, the positive predictive value of this model was 83% and negative predictive value was 40%. Model discrimination was similar for ultrahigh-frequency hearing loss (frequencies >9000 Hz; AUC = 0.81) but weaker for clinically determined hearing loss (AUC = 0.60). This model may identify patients with DR-TB who are at highest risk of developing AG-induced ototoxicity and may help prioritize patients for AG-sparing regimens in clinical settings where access is limited.

Extensively drug-resistant tuberculosis inSouth Africa: genomic evidence supporting transmission in communities.

Despite evidence that transmission is driving an extensively drug-resistant TB (XDR-TB) epidemic, our understanding of where and between whom transmission occurs is limited. We sought to determine whether there was genomic evidence of transmission between individuals without an epidemiologic connection.We conducted a prospective study of XDR-TB patients in KwaZulu-Natal, South Africa, during the 2011-2014 period. We collected sociodemographic and clinical data, and identified epidemiologic links based on person-to-person or hospital-based connections. We performed whole-genome sequencing (WGS) on the Mycobacterium tuberculosis isolates and determined pairwise single nucleotide polymorphism (SNP) differences.Among 404 participants, 123 (30%) had person-to-person or hospital-based links, leaving 281 (70%) epidemiologically unlinked. The median SNP difference between participants with person-to-person and hospital-based links was 10 (interquartile range (IQR) 8-24) and 16 (IQR 10-23), respectively. The median SNP difference between unlinked participants and their closest genomic link was 5 (IQR 3-9) and half of unlinked participants were within 7 SNPs of at least five participants.The majority of epidemiologically-unlinked XDR-TB patients had low pairwise SNP differences with at least one other participant, consistent with transmission. These data suggest that much of transmission may result from casual contact in community settings between individuals not known to one another.

Prevalence of drug-resistant tuberculosis in South Africa

Prevalence of drug-resistant tuberculosis in South Africa

Transmission of Extensively Drug-Resistant Tuberculosis in South Africa

BackgroundDrug-resistant tuberculosis threatens recent gains in the treatment of tuberculosis and human immunodeficiency virus (HIV) infection worldwide. A widespread epidemic of extensively drug-resistant (XDR) tuberculosis is occurring in South Africa, where cases have increased substantially since 2002. The factors driving this rapid increase have not been fully elucidated, but such knowledge is needed to guide public health interventions.MethodsWe conducted a prospective study involving 404 participants in KwaZulu-Natal Province, South Africa, with a diagnosis of XDR tuberculosis between 2011 and 2014. Interviews and medical-record reviews were used to elicit information on the participants’ history of tuberculosis and HIV infection, hospitalizations, and social networks. Mycobacterium tuberculosis isolates underwent insertion sequence (IS)6110 restriction-fragment–length polymorphism analysis, targeted gene sequencing, and whole-genome sequencing. We used clinical and genotypic case definitions to calculate the proportion of cases of XDR tuberculosis that were due to inadequate treatment of multidrug-resistant (MDR) tuberculosis (i.e., acquired resistance) versus those that were due to transmission (i.e., transmitted resistance). We used social-network analysis to identify community and hospital locations of transmission.ResultsOf the 404 participants, 311 (77%) had HIV infection; the median CD4+ count was 340 cells per cubic millimeter (interquartile range, 117 to 431). A total of 280 participants (69%) had never received treatment for MDR tuberculosis. Genotypic analysis in 386 participants revealed that 323 (84%) belonged to 1 of 31 clusters. Clusters ranged from 2 to 14 participants, except for 1 large cluster of 212 participants (55%) with a LAM4/KZN strain. Person-to-person or hospital-based epidemiologic links were identified in 123 of 404 participants (30%).ConclusionsThe majority of cases of XDR tuberculosis in KwaZulu-Natal, South Africa, an area with a high tuberculosis burden, were probably due to transmission rather than to inadequate treatment of MDR tuberculosis. These data suggest that control of the epidemic of drug-resistant tuberculosis requires an increased focus on interrupting transmission. (Funded by the National Institute of Allergy and Infectious Diseases and others.)

Patients' costs associated with seeking and accessing treatment for drug-resistant tuberculosis in South Africa.

South Africa is one of the world's 22 high tuberculosis (TB) burden countries, with the second highest number of notified rifampicin-resistant TB (R(R)-TB) and multidrug-resistant TB (MDR-TB) cases. To estimate patient costs associated with the diagnosis and treatment of R(R)-TB/MDR-TB in South Africa. Patients diagnosed with R(R)-TB/MDR-TB and accessing care at government health care facilities were surveyed using a structured questionnaire. Direct and indirect costs associated with accessing R(R)-TB/MDR-TB care were estimated at different treatment durations for each patient. A total of 134 patients were surveyed: 84 in the intensive phase and 50 in the continuation phase of treatment, 82 in-patients and 52 out-patients. The mean monthly patient costs associated with the diagnosis and treatment of R(R)-TB/MDR-TB were higher during the intensive phase than the continuation phase (US$235 vs. US$188) and among in-patients than among out-patients (US$269 vs. US$122). Patients in the continuation phase and those accessing care as out-patients reported higher out-of-pocket costs than other patients. Most patients did not access social protection for costs associated with R(R)-TB/MDR-TB illness. Despite free health care, patients bear high costs when accessing diagnosis and treatment services for R(R)-TB/MDR-TB; appropriate social protection mechanisms should be provided to assist them in coping with these costs.

Impact of reduced hospitalisation on the cost of treatment for drug-resistant tuberculosis in South Africa.

The cost of multidrug-resistant tuberculosis (MDR-TB) treatment is a major barrier to treatment scale-up in South Africa. To estimate and compare the cost of treatment for rifampicin-resistant tuberculosis (RR-TB) in South Africa in different models of care in different settings. We estimated the costs of different models of care with varying levels of hospitalisation. These costs were used to calculate the total cost of treating all diagnosed cases of RR-TB in South Africa, and to estimate the budget impact of adopting a fully or partially decentralised model vs. a fully hospitalised model. The fully hospitalised model was 42% more costly than the fully decentralised model (US$13,432 vs. US$7753 per patient). A much shorter hospital stay in the decentralised models of care (44-57 days), compared to 128 days of hospitalisation in the fully hospitalised model, was the key contributor to the reduced cost of treatment. The annual total cost of treating all diagnosed cases ranged from US$110 million in the fully decentralised model to US$190 million in the fully hospitalised model. Following a more decentralised approach for treating RR-TB patients could potentially improve the affordability of RR-TB treatment in South Africa.

How to hinder tuberculosis control: five easy steps

prevalence in China was reduced by shifting to the recommended approach based on directly observed treatment, short course (DOTS) for tuberculosis diagnosis and treatment, but did not consider that economic progress might have also been a driver. Pietersen and coworkers' cohort study, 2 which reported that 73% of patients with extensively drug-resistant tuberculosis in South Africa died within 5 years of treatment initiation, acknowledged the poor treatment outcomes but did not question whether survival is any better than in the pre-treatment era—better than no treatment at all. 3 A review by Dheda and colleagues 4 aptly highlighted that diverting funding to multidrug-resistant tuberculosis control might destabilise national tuberculosis programmes, using the example of South Africa where multidrug-resistant tuberculosis represents less than 3% of tuberculosis cases but consumes over a third of the national tuberculosis budget. Difficult decisions about resource allocation clearly need to be made. These should be made on the basis of evidence and long-term strategic goals. A review of studies done by the British Medical Research Council's tuberculosis units between 1946 and 1986 made the striking assertion that, by the late 1980s, we had all the evidence needed to design successful tuberculosis control programmes. 5 Our historical failure to embed research findings into effective policies has meant we have squandered opportunities and resources. We highlight five steps, commonly taken by policy makers, that might be impeding efforts to control tuberculosis (panel).

The use of bedaquiline in regimens to treat drug-resistant and drug-susceptible tuberculosis: a perspective from tuberculosis-affected communities

In December, 2012, the US Food and Drug Administration (FDA) approved bedaquiline for the treatment of pulmonary drug-resistant tuberculosis. 1 Edney A J&J Sirturo wins FDA approval to treat drug-resistant TB. Bloomberg News. Dec 31, 2012. http://www.bloomberg.com/news/2012-12-31/j-j-sirturo-wins-fda-approval-to-treat-drug-resistant-tb.html Google Scholar WHO has issued normative guidance on bedaquiline, 2 World Health OrganizationThe use of bedaquiline in the treatment of multidrug resistant tuberculosis expert group meeting report. World Health Organization, Geneva2013: 1-31http://www.who.int/tb/challenges/mdr/bedaquiline/en/index.html Google Scholar which is available on the market in the USA and through compassionate use in other countries. As the first new drug from a novel class approved to treat tuberculosis in more than 40 years, bedaquiline's implications for improving treatment of drug-resistant tuberculosis and possible application to create shorter first-line regimens for treatment of drug-susceptible tuberculosis is still unclear. Existing drugs must be taken for months (drug-susceptible tuberculosis) or years (drug-resistant tuberculosis), burdening patients and health systems; even then, cure rates for drug-resistant disease range from 11% to 79% dependent on the extent of resistance. 3 Orenstein EW Basu S Shah NS et al. Treatment outcomes among patients with multidrug-resistant tuberculosis: systematic review and meta-analysis. Lancet Infect Dis. 2009; 9: 153-161 Summary Full Text Full Text PDF PubMed Scopus (464) Google Scholar , 4 Pietersen E Ignatius E Streicher EM et al. Long-term outcomes of patients with extensively drug-resistant tuberculosis in South Africa: a cohort study. Lancet. 2014; 383: 1230-1239 Summary Full Text Full Text PDF PubMed Scopus (184) Google Scholar However, community voices on bedaquiline's use to treat drug-resistant tuberculosis and future development as a potential treatment for drug-susceptible disease have been largely unheard. We provide a community perspective on this issue and list seven questions concerning bedaquiline's safety that researchers should answer before the launch of clinical trials of bedaquiline for drug-susceptible tuberculosis. Informed use of bedaquiline for tuberculosisThe Viewpoint by Laia Ruiz Mingote and colleagues1 raises safety concerns regarding bedaquiline in treatment shortening trials for pan-resistant tuberculosis (tuberculosis that is susceptible to all first-line antituberculosis treatments). A trial with similar issues is STAND TB, by the Global Alliance for TB Drug Development (TBA), which is testing the nitroimidazole PA-824 (pretomanid) in combination with pyrazinamide and moxifloxacin (PaMZ).2 There are little safety data on the use of PA-824 longer than 8 weeks, and both PA-824 and moxifloxacin have significant toxic effects. Full-Text PDF Informed use of bedaquiline for tuberculosisIn their Viewpoint (Jan 31, p 477),1 Laia Ruiz Mingote and colleagues highlight the urgent need for additional safety data on bedaquiline, the first new tuberculosis drug to receive US Food and Drug Administration (FDA) approval in more than 40 years. Because the drug received accelerated approval based solely on phase 2 studies, critical safety data for bedaquiline are incomplete. In view of the scarcity of data, increased mortality in the bedaquiline group of one phase 2 trial, and public health importance of the drug, the FDA's accelerated approval required that a patient registry be set up to assess serious adverse events, including death. Full-Text PDF Informed use of bedaquiline for tuberculosis–Authors' replyWe thank Erica Lessem and colleagues for commenting on our Viewpoint1 regarding the challenges surrounding the bedaquiline patient registry in the USA. For drugs like bedaquiline that receive accelerated approval, patient registries are a critical mechanism for collecting safety data on new drugs. Recent data from the US Centers for Disease Control and Prevention indicate that the tuberculosis epidemic in the USA is marked by increasing racial and ethnic disparities, and concentrated among foreign-born people. Full-Text PDF

Trends in childhood drug-resistant tuberculosis in South Africa: a window into the wider epidemic?

Childhood tuberculosis (TB) is a marker of TB transmission within a community. We present the fourth consecutive survey of children with culture-confirmed TB at a hospital in Cape Town, South Africa, from 2009 to 2011. In comparison to the previous survey, the rate of multidrug-resistant TB (MDR-TB) has stabilised and the human immunodeficiency virus infection rate has declined. We also report on the first systematic surveillance of resistance to second-line drugs. Two concerns following from this are the high rate (22%) of ofloxacin resistance in MDR-TB isolates, and the discordance between isolates with an inhA promoter region mutation, usually implying ethionamide (ETH) resistance, and phenotypic ETH results in these isolates showing ETH susceptibility.