Global availability of susceptibility testing for second-line anti-tuberculosis agents.

BACKGROUND: The continued development of new anti-TB agents brings with it a demand for accompanying treatment regimens to prevent the development of resistance. Effectively meeting this demand requires an understanding of the pathogen´s susceptibility to various treatment options, which in turn makes access to antibiotic susceptibility testing (AST) a paramount consideration in the global treatment of TB.METHODS: A 12-question, quantitative and qualitative survey was developed to gauge global capacity and access to AST. The survey was disseminated to members of the Global Laboratory Initiative, Global Drug-resistant TB Initiative, and the TB section of the International Union Against Tuberculosis and Lung Disease to solicit responses from pertinent stakeholders.RESULTS: A total of 323 complete responses representing 84 countries and all WHO Regions were collected. AST capacity for fluoroquinolones and second-line injectables was high in all WHO Regions. AST capacity for the new and repurposed drugs is highest in the European Region, Region of the Americas and the Western Pacific Region, but quite limited in the African and Eastern Mediterranean Regions. The AST turnaround time for second-line drugs was delayed compared to that for first-line drugs as samples needed to be sent farther for analysis. Common barriers to AST for second-line drugs were lack of specimen transportation infrastructure, high costs, and lack of specialised laboratory workers and specialised laboratory facilities.CONCLUSION: Without expanding global access to AST, the growing availability of new treatment options will likely be threatened by accompanying increase in resistance. There is an earnest and pressing need to improve capacity and access to AST alongside treatment options.

WHO guidelines for the programmatic management of drug-resistant tuberculosis: 2011 update.

The production of guidelines for the management of drug-resistant tuberculosis (TB) fits the mandate of the World Health Organization (WHO) to support countries in the reinforcement of patient care. WHO commissioned external reviews to summarise evidence on priority questions regarding case-finding, treatment regimens for multidrug-resistant TB (MDR-TB), monitoring the response to MDR-TB treatment, and models of care. A multidisciplinary expert panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to develop recommendations. The recommendations support the wider use of rapid drug susceptibility testing for isoniazid and rifampicin or rifampicin alone using molecular techniques. Monitoring by sputum culture is important for early detection of failure during treatment. Regimens lasting ≥ 20 months and containing pyrazinamide, a fluoroquinolone, a second-line injectable drug, ethionamide (or prothionamide), and either cycloserine or p-aminosalicylic acid are recommended. The guidelines promote the early use of antiretroviral agents for TB patients with HIV on second-line drug regimens. Systems that primarily employ ambulatory models of care are recommended over others based mainly on hospitalisation. Scientific and medical associations should promote the recommendations among practitioners and public health decision makers involved in MDR-TB care. Controlled trials are needed to improve the quality of existing evidence, particularly on the optimal composition and duration of MDR-TB treatment regimens.

Experiences of introducing new drugs for drug-resistant TB at the ALERT Hospital, Addis Ababa, Ethiopia, 2017-2019.

BACKGROUND: Drug-resistant TB (DR-TB) remains a major public health concern. DR-TB patient data from ALERT (All Africa Leprosy, Tuberculosis and Rehabilitation Training Centre) Hospital, Addis Ababa, Ethiopia, who received bedaquiline (BDQ) and/or delamanid (DLM) containing regimens were analysed. RESULTS: From 2017 to 2019, 51 DR-TB patients were enrolled. Of 33 patients, 31 (93.9%) had culture converted at 6 months. Of those with final outcomes, 77% (n = 10) were cured. Thirty (58.8%) developed adverse events, the most frequent of which were gastrointestinal disorders (70%), haematological disorders (16.7%) and QTc prolongation (16.7%). Twenty patients discontinued the offending drug permanently. CONCLUSION: With close monitoring, introduction of new DR-TB regimens brought good early results, which encouraged wider programmatic implementation in Ethiopia.

CONTEXTE: La TB pharmacorésistante (DR-TB) reste une préoccupation de santé publique majeure. Les données des patients DR-TB de l'hôpital ALERT (All Africa Leprosy, Tuberculosis and Rehabilitation Training Centre, Addis Ababa, Ethiopie) qui ont reçu des protocoles contenant de la bédaquiline et/ou du délamanide ont été analysées. RÉSULTATS: Des 51 patients DR-TB ont été enrôlés de 2017 à 2019, 90 ont eu une conversion de culture à 6 mois, 77% ont été guéris, 30 ont eu des effets secondaires, les plus fréquents étant des troubles gastro-intestinaux (70%), des troubles hématologique (16,7%) et un allongement de QTc (16,7%). Vingt patients ont définitivement arrêté le médicament incriminé. CONCLUSION: Moyennant une surveillance étroite, l'introduction de nouveaux protocoles DR-TB a eu de bons résultats précoces qui encouragent une mise en œuvre programmatique plus large en Ethiopie.

No universal access to drug-resistant tuberculosis care without engaging all health care providers.

Should the engagement of all health care providers in all aspects of programmatic management of drug-resistant tuberculosis (PMDT) become a priority in the national strategic plans for tuberculosis (TB), progress towards universal access to diagnosis, treatment and care of drug-resistant tuberculosis (DR-TB) would accelerate. This would be especially crucial in countries where the private sector is a significant provider of health services. Proven successful interventions to engage all health care providers and partners in the cascade of prevention, diagnosis, treatment and care of DR-TB patients need to be urgently scaled up. Such engagement should not be limited to the diagnosis and treatment of DR-TB, but extended also to all the aspects of PMDT, including approaches ensuring that patient-centred care, social support, pharmacovigilance and surveillance. Integral to the End TB Strategy, PMDT should be embedded in all public-private mix initiatives for TB and vice versa.

Economic evaluation of public-private mix for tuberculosis care and control, India. Part I. Socio-economic profile and costs among tuberculosis patients.

SETTING: Bangalore City, India. OBJECTIVES: To assess the socio-economic profile, health-seeking behaviour and costs related to tuberculosis (TB) diagnosis and treatment among patients treated under the Revised National TB Control Programme (RNTCP). DESIGN: All 1106 new TB patients registered for treatment under the RNTCP in the second quarter of 2005 participated. Interviews at the beginning and at the end of treatment were conducted. A convenience sample of 32 patients treated outside the RNTCP also participated. RESULTS: Among the TB patients, respectively 50% and 39% were from low and middle standard of living (SL) households, and 77% were from households with a per capita income of less than US$1 per day. The first health contact was with a private practitioner in the case of >70% of patients. Mean patient delay was low, at 21 days, but the mean health system delay was 52 days. The average cost incurred by patients before treatment in the RNTCP was US$145, and during treatment it was US$21. Costs as a proportion of annual household income per capita were 53% for people from low SL households and 41% for those from other households. Costs during treatment faced by patients treated outside the RNTCP averaged US$127. CONCLUSION: Patients treated under the RNTCP through a public-private mix approach were predominantly poor. Many of them experienced considerable health expenditures before starting treatment. Additional efforts are required to reduce the delays and the number of health care providers consulted, and to ensure that patients are shifted to subsidised treatment within the RNTCP.

Economic evaluation of public-private mix for tuberculosis care and control, India. Part II. Cost and cost-effectiveness.

SETTING: Bangalore City, India. OBJECTIVES: To assess the cost and cost-effectiveness of public-private mix (PPM) for tuberculosis (TB) care and control when implemented on a large scale. DESIGN: DOTS implementation under the Revised National TB Control Programme (RNTCP) began in 1999, PPM was introduced in mid-2001 and a second phase of intensified PPM began in 2003. Data on the costs and effects of TB treatment from 1999 to 2005 were collected and used to compare the two distinct phases of PPM with a scenario of no PPM. Costs were assessed in 2005 $US for public and private providers, patients and patient attendants. Sources of data included expenditure records, medical records, interviews with staff and patient surveys. Effectiveness was measured as the number of cases successfully treated. RESULTS: When PPM was implemented, total provider costs increased in proportion to the number of successfully treated TB cases. The average cost per patient treated from the provider perspective when PPM was implemented was stable, at US$69, in the intensified phase compared with US$71 pre-PPM. PPM resulted in the shift of an estimated 7200 patients from non-DOTS to DOTS treatment over 5 years. PPM implementation substantially reduced costs to patients, such that the average societal cost per patient successfully treated fell from US$154 to US$132 in the 4 years following the initiation of PPM. CONCLUSION: Implementation of PPM on a large scale in an urban setting can be cost-effective, and considerably reduces the financial burden of TB for patients.

Diagnosis and treatment of tuberculosis in undocumented migrants in low- or intermediate-incidence countries.

SETTING: Countries with low or intermediate tuberculosis (TB) incidence. OBJECTIVES: 1) To gather information on individuals and TB patients who are undocumented migrants and their access to TB diagnostic and treatment services; 2)to discuss interventions to strengthen diagnosis and treatment and 3) to formulate recommendations on how to ensure adequate TB prevention and control. DESIGN: Questionnaires sent to members of the Working Group (WG) on Transborder Migration and TB, managers of national TB programmes and EuroTB correspondents; literature research and development of a paper by a writing committee through consultation. RESULTS: Undocumented migrants represent 5-30% of immigrants and 5-10% of TB cases. Most countries reported full access to diagnosis and treatment, but in practice there were limitations. Most countries also reported that they could and did deport cases who were on TB treatment. A variety of activities to ensure access were reported from different countries. CONCLUSION: The WG recommends that 1) health authorities and/or health staff should ensure easy access to low-threshold facilities where undocumented migrants who are TB suspects can be diagnosed and treated without giving their names and without fear of being reported to the police or migration officials. Health authorities should remind health staff that they have an obligation of confidentiality; 2) each country should ensure that undocumented migrants with TB are not deported until completion of treatment; and 3) authorities and non-governmental sectors should raise awareness among undocumented migrants about TB, emphasising that diagnosis and treatment should be free of charge and wholly independent of migratory status.

Rapid decline in prevalence of pulmonary tuberculosis after DOTS implementation in a rural area of South India.

SETTING: Tiruvallur District in Tamilnadu, South India, where the World Health Organization-recommended DOTS strategy was implemented as a tuberculosis (TB) control measure in 1999. OBJECTIVE: To assess the epidemiological impact of the DOTS strategy on the prevalence of pulmonary tuberculosis (PTB). DESIGN: Surveys of PTB were undertaken on representative population samples aged > or =15 years (n = 83000-90000), before and at 2.5 and 5 years after the implementation of the DOTS strategy. The prevalence of PTB (smear-positive/culture-positive) was estimated. RESULTS: TB prevalence declined by about 50% in 5 years, from 609 to 311 per 100000 population for culture-positive TB and from 326 to 169/100000 for smear-positive TB. The annual rate of decline was 12.6% (95%CI 11.2-14.0) for culture-positive TB and 12.3% (95%CI 8.6-15.8) for smear-positive TB. The decline was similar at all ages and for both sexes. CONCLUSION: With an efficient case detection programme and the DOTS strategy, it is feasible to bring about a substantial reduction in the burden of TB in the community.

Initial default among diagnosed sputum smear-positive pulmonary tuberculosis patients in Andhra Pradesh, India.

BACKGROUND: Under the Indian Revised National TB Control Programme (RNTCP), smear-positive pulmonary tuberculosis (PTB) patients not confirmed as starting treatment are reported as 'initial defaulters'. SETTING: Twenty districts of Andhra Pradesh State, India. OBJECTIVE: To evaluate reasons for treatment non-initiation in smear-positive PTB patients diagnosed and reported as initial defaulters by the NTP. DESIGN: A cross-sectional survey conducted of all reported initial defaulters during the period July-September 2006. RESULTS: Of 1304 reported initial defaulters, 619 (47.5%) had been placed on treatment, having been incorrectly reported due to poor documentation of patients referred for treatment in the same district or whose treatment initiation was delayed until the subsequent quarter. Of the 685 (4.5% of the total diagnosed) who were confirmed initial defaulters, 350 (51%) were untraceable, 152 (22%) had died before treatment initiation, 38 (5.5%) were treated privately, 93 (13.5%) had other reasons (e.g., refusal of treatment, chronic case, etc.) and no data were available for 52 (8%). CONCLUSIONS: Nearly 5% of smear-positive PTB patients diagnosed in the study period were confirmed as not having initiated treatment under the RNCTP. Improvements in address recording may assist efforts to retrieve these patients for treatment. Additional evaluations are needed of improved counselling of TB suspects to prevent initial default, and of reasons for death before treatment initiation.

Health-seeking behaviour of new smear-positive TB patients under a DOTS programme in Tamil Nadu, India, 2003.

BACKGROUND: Although case detection is above 70% in Tamil Nadu after DOTS implementation, an assessment of the timeliness of patient diagnosis and treatment is still needed. OBJECTIVE: To study the health-seeking behaviour of new smear-positive pulmonary tuberculosis (PTB) patients treated at government facilities. METHODS: New smear-positive patients diagnosed and treated between January and March 2003 in government facilities of randomly selected blocks in Tamil Nadu were interviewed using a semi-structured interview schedule. RESULTS: Of 601 patients interviewed, 65% contacted a provider within 28 days. The first contact was governmental for 47% and non-governmental for 53%. Median total, patient and provider delays were respectively 62, 28 and 28 days; provider delay was 9 days with government and 50 with private provider. In multivariate analysis, patient delay was significantly associated with smoking (P < 0.001) and mode of travel (P < 0.01), and provider delay with first consultation with a private provider (P < 0.001) and distance > 5 km from the health facility (P < 0.01). Twenty-five per cent of patients took more than two actions before diagnosis. CONCLUSION: Community awareness of TB needs to be increased. Greater private sector involvement in the Revised National Tuberculosis Control Programme is essential to reduce provider delay. Referral and sputum transportation to the diagnostic facility should be given priority.

The prevalence of tuberculosis in different economic strata: a community survey from South India.

A cross-sectional socio-economic survey to assess the standard of living index (SLI) of a rural population in South India was undertaken along with a tuberculosis (TB) prevalence survey during 2004-2006. Of 32,780 households, the SLI was low, medium and high in 22%, 36% and 42%, and TB prevalence was 343, 169 and 92 per 100,000 population, respectively, a significant decrease in trend (P < 0.001); 57% of the TB patients had a low SLI and the prevalence of TB was higher amongst the landless (P < 0.001), those living below the poverty line (P < 0.01) and in katcha houses (P < 0.001), suggesting that TB disproportionately affects those with a low SLI.

Initial drug susceptibility profile of M. tuberculosis among patients under TB programme in South India.

SETTING: Pulmonary tuberculosis (PTB) patients enrolled for treatment at government health facilities in a sub-district of Thiruvallur district, Tamil Nadu, India. OBJECTIVES: To determine the drug susceptibility profile among PTB patients admitted to treatment according to the Revised National Tuberculosis Control Programme (RNTCP). METHODOLOGY: From May 1999 to December 2003, two additional sputum samples were collected from all patients at the start of anti-tuberculosis treatment under DOTS and were transported to a central laboratory for Mycobacterium tuberculosis culture and drug susceptibility testing (DST). RESULTS: DST results were available for 1603 new sputum smear-positive patients; 85% of patients had organisms fully susceptible to streptomycin (S), isoniazid (H) and rifampicin (R), 10.4% any resistance to H and 1.7% to HR. Of 443 patients with history of previous anti-tuberculosis treatment, 59% had organisms susceptible to S, H and R, 37% had any resistance to H and 11.7% to HR. CONCLUSION: The DST profile showed that the vast majority of patients have drug-susceptible organisms, and that currently recommended regimens under the RNTCP would be effective in the treatment of TB.

Comparison of variants of carbol-fuchsin solution in Ziehl-Neelsen for detection of acid-fast bacilli.

To evaluate Ziehl-Neelsen (ZN) staining using variants of carbol-fuchsin solution, duplicate smears from 416 samples were stained with ZN, one set with 1% basic fuchsin and the other 0.3%. Another set of duplicate smears from 398 samples were stained with ZN, one with 1% basic fuchsin and the other 0.1%. The coded smears were read and discrepancies resolved. All samples underwent mycobacterial culture. The sensitivity of ZN using 0.3% (65%) and 1% basic fuchsin (62%) was comparable, while it was reduced using 0.1% (74%) compared to 1% basic fuchsin (83%). Reducing the concentration of basic fuchsin below 0.3% in ZN staining was found to significantly reduce its sensitivity.

Application of lot sampling of sputum AFB smears for the assessment of microscopy centres.

SETTING: Designated microscopy centres (DMC) and additional microscopy centres (AMC) performing sputum acid-fast bacilli (AFB) microscopy, the District TB Centre (DTC) and a reference laboratory (RL). OBJECTIVES: To ascertain the feasibility of adopting lot sampling of AFB smears and to assess the performance of MCs employing Senior Tuberculosis Laboratory Supervisors (STLS) with no knowledge about the principles of quality assurance of AFB microscopy and RL-based laboratory technicians with training on quality assurance for blinded checking of AFB smears. METHODS: Slides from MCs were transported to the DTC and the RL; 20 smears per month per MC were selected systematically; 1547 slides from DMCs and 726 from AMCs were checked, respectively, by STLSs at the DTC and by RL laboratory technicians. Discrepancies were resolved by referee. RESULTS: The discrepancy between MC laboratory technicians and STLSs at the DTC was 4.7%, compared to 1% at the RL. The STLSs and RL-based laboratory technicians had 70 and 2 errors, respectively. CONCLUSIONS: Lot sampling of AFB smears is feasible under field conditions. Assessment of MCs was more valid with RL-based technicians trained in principles of quality assurance of sputum AFB microscopy than with STLSs with no such training and working in the field.

Storage of heat-fixed unstained sputum AFB smears for panel testing in a tuberculosis unit in South India.

To evaluate the suitability for panel testing of heat-fixed unstained sputum AFB smears stored for up to 10 months, panels of slides were prepared at the national laboratory and stored under ambient conditions. Every month, three slides were utilised for panel testing in each of 12 microscopy centres; 70 smears were checked in a blinded fashion after 10 months. Reading errors occurred in 15/360 slides used in panel testing and in 4/70 slides used in blinded checking. The quality and grading of heat-fixed unstained smears were unaffected for up to 10 months and were found suitable for panel testing.

Improved tuberculosis case detection through public-private partnership and laboratory-based surveillance, Kannur District, Kerala, India, 2001-2002.

BACKGROUND: Efforts to intensify global tuberculosis (TB) control are limited by difficulties in coordinating with private doctors. More than half of Indian TB patients may initially consult a private provider, but many are neither diagnosed accurately nor treated effectively. We established and evaluated a public-private partnership based on surveillance of TB detected in private laboratories and use of standardised directly observed treatment regimens. METHODS: In one district, the governmental TB control programme offered training in microscopy to all large private sector laboratories, and educated private physicians on the importance of microscopy for TB diagnosis. We reviewed records from participating private laboratories and all publicly diagnosed patients. RESULTS: Of 2328 pulmonary TB patients registered from July 2001 to December 2002, 404 (17%) were detected in the private sector. The annual new AFB-positive case notification rate increased by 21%, from 27.8/100,000 in 2000 to 33.5/100,000 in 2002. Surveillance at private laboratories found an additional 260 nonregistered AFB-positive patients. CONCLUSIONS: This public-private partnership substantially increased TB case detection and established a sustainable framework for private sector involvement in TB control. In the setting of a strong public sector programme, the combination of active surveillance of private laboratories along with physician sensitisation is a promising approach to improve TB case detection.

Could repeated prevalence surveys lead to decreasing tuberculosis prevalence in a community?

SETTING: Tiruvallur District, South India, where one baseline tuberculosis (TB) disease prevalence survey followed by three repeat prevalence surveys were conducted every 2.5 years between 1999 and 2008, and where the DOTS strategy was implemented in 1999. OBJECTIVE: To rule out the possibility that the observed decline in TB prevalence was influenced by conducting repeat prevalence surveys, we compared the findings from two surveys: the third repeat survey conducted in 2006-2008 and an independent single survey in a neighbouring area conducted in 2008-2009. DESIGN: An independent survey was conducted to estimate the prevalence of TB in the same district in 2008-2009 using a different set of villages and employing repeat survey methodology. The independent survey findings were compared with those of the third repeat survey. RESULTS: The estimated prevalence rate of culture- and smear-positive TB was respectively 401 per 100,000 and 186 per 100,000 population in the third repeat survey area. The corresponding rates were 340 and 184/100,000 in the independent survey area. The difference in prevalence was not significant (culture P = 0.09; smear P = 0.93). CONCLUSION: The estimated prevalence rates in the two different sample survey areas were comparable, indicating that the repeated prevalence surveys in the study area did not influence the observed decline in TB disease prevalence.

Cost-effectiveness analysis of the russian treatment scheme for tuberculosis versus short-course chemotherapy: results from Tomsk, Siberia.

SETTING: Tomsk Oblast, Siberia. OBJECTIVE: To assess the cost-effectiveness of individualised Russian treatment and short-course chemotherapy (SCC) regimens for new WHO Category I tuberculosis patients. DESIGN: Analysis of costs incurred by the provider, the household and society as a whole for both treatment approaches, and a sensitivity analysis for SCC with hospitalisation for 2 weeks (patients theoretically at low risk of defaulting) and 2 months (patients theoretically at risk of defaulting). Outcomes were measured as cost per case cured and year of life saved, with cure rates based on a locally conducted trial. RESULTS: The cost per cure using the individualised Russian treatment was US $2,295, vs. US $1,901 when using SCC. The costs per year of life saved were respectively US $123 and US $103. The cost per cure was US $1,457 for SCC with 2 months hospitalisation and US $556 for SCC with 2 weeks hospitalisation, with costs per year of life saved of US $79 and US $30, respectively. CONCLUSION: Major financial savings for both the provider and the household, with cure rates similar to those obtained with the Russian treatment scheme, can be achieved in Tomsk when embarking on SCC with 2 weeks and 2 months hospitalisation.

Improving screening and chemoprophylaxis among child contacts in India's RNTCP: a pilot study.

BACKGROUND: While contact screening and chemoprophylaxis is recommended by India's Revised National Tuberculosis Control Programme for asymptomatic children aged <6 years who are household contacts of smear-positive pulmonary tuberculosis (PTB) patients, implementation is suboptimal. OBJECTIVE: To evaluate the effectiveness of an isoniazid preventive therapy (IPT) register and card in improving the adherence of health care workers (HCWs) to programmatic guidelines. METHODOLOGY: This prospective study was conducted in two Tuberculosis Units in South India. Child contacts of smear-positive PTB patients initiated on treatment between November 2009 and January 2010 were screened, and IPT was initiated in asymptomatic children. HCWs were trained in the use of the IPT register and card. The process was evaluated using patient and HCW interviews. RESULTS: Of 87 children identified aged <6 years, 71 (82%) were traced by HCWs; 53 were screened for TB and initiated on IPT, and 39 completed treatment. HCWs expressed satisfaction with the use of the IPT card and register, saying that it helped them to remember to complete required tasks. CONCLUSION: In a programme setting, with HCW training and introduction of specific documentation (IPT card and register), implementation of contact tracing and chemoprophylaxis for child contacts improved from 19% to 61%.