• 10-year assessment of treatment outcome among Cambodian refugees with sputum smear-positive tuberculosis in Khao-I-Dang, Thailand.

      Sukrakanchana-Trikham, P; Puéchal, X; Rigal, J; Rieder, H L; Médecins sans Frontières Tuberculosis Programme, Khao-I-Dang, Prachinburi, Thailand. (International Union Against Tuberculosis and Lung Disease, 1992-12)
      Tuberculosis control among displaced persons is fraught with difficulties to ensure adherence of patients to treatment for a prolonged period of time. In the Khao-I-Dang camp for Cambodian refugees an approach with daily, directly observed treatment throughout the course of 6 months duration was chosen to address the problem. Of a total 929 patients with sputum smear-positive tuberculosis who were enrolled from 1981 to 1990, 5.0% died, 75.5% completed treatment and were bacteriologically cured with a day-to-day adherence of more than 98%, none failed bacteriologically, 19.2% were transferred to another camp where continuation of treatment was guaranteed, and only 0.4% absconded from treatment. These data suggest that the approach to tuberculosis control in this refugee camp was very effective in cutting the chain of transmission of tuberculosis in a highly mobile population and in reducing substantially unnecessary morbidity and mortality.
    • Coadministration of lopinavir/ritonavir and rifampicin in HIV and tuberculosis co-infected adults in South Africa

      Murphy, R A; Marconi, V C; Gandhi, R T; Kuritzkes, D R; Sunpath, H; Medical Unit, Médecins Sans Frontières/Doctors Without Borders, New York, New York, United States of America (Public Library of Science, 2012-09-28)
      In HIV-infected patients receiving rifampicin-based treatment for tuberculosis (TB), the dosage of lopinavir/ritonavir (LPV/r) is adjusted to prevent sub-therapeutic lopinavir concentrations. In this setting, South African clinicians were advised to administer super-boosted LPV/r (400 mg/400 mg) twice daily, instead of standard dosed LPV/r (400 mg/100 mg) twice daily. We sought to determine--in routine practice--the tolerability and HIV treatment outcomes associated with super-boosted LPV/r compared to unadjusted LPV/r in combination with rifampicin-based TB treatment.
    • Cotrimoxazole prophylaxis in HIV-infected individuals after completing anti-tuberculosis treatment in Thyolo, Malawi.

      Zachariah, R; Spielmann M P; Harries, A D; Gomani, P; Bakali, E; Médecins Sans Frontières-Luxembourg, Thyolo, Thyolo District, Malawi. zachariah@internet.lu (2002-12)
      SETTING: Thyolo, rural southern Malawi. OBJECTIVES: To determine 1) the proportion who continue with cotrimoxazole prophylaxis for the prevention of opportunistic infections, and 2) the reasons for continuing or stopping prophylaxis, in human immunodeficiency virus (HIV) infected individuals with tuberculosis (TB) who complete anti-tuberculosis treatment. DESIGN: A cross-sectional study. METHODS: A questionnaire study of all HIV-infected TB patients who had been registered over a 3-month period to receive anti-tuberculosis treatment and cotrimoxazole prophylaxis and who had completed antituberculosis treatment 3-6 months earlier. RESULTS: Of 82 HIV-infected individuals who were alive at the time of interview, 76 (93%) were continuing with cotrimoxazole and wished to do so indefinitely. The most common reason for continuing the drug was to prevent illness associated with HIV, while the most common reason for stopping was long distances to the health facility. Ninety-six percent of patients received cotrimoxazole free of charge from a health centre. Of those who wished to continue indefinitely, the majority (63%) could not afford to pay for the drug. CONCLUSIONS: In a rural setting, the great majority of HIV-infected individuals continued with cotrimoxazole after completing anti-tuberculosis treatment. Making the drug available and providing it free of charge is essential if it is to remain accessible for longer term prevention.
    • Diagnosis of pulmonary tuberculosis in a pastoralist population in Ethiopia: are three sputum specimens needed?

      Khogali, M; Tayler-Smith, K; Zachariah, R; Gbane, M; Zimble, S; Weyeyso, T; Harries, A D; Medecins sans Frontieres - Medical Department (Operational research Unit/Operations), Operational centre Brussels, MSF, Luxembourg, Luxembourg. Mohammed.Khogali@gmail.com (Blackwell Publishing Ltd, 2013-05-18)
      To assess the number of sputum specimens necessary for a reliable diagnosis of pulmonary tuberculosis (PTB) in a pastoralist population in Ethiopia.
    • Evaluation of Tuberculosis Diagnostics in Children: 1. Proposed clinical case definitions for classification of Intrathoracic Tuberculosis Disease. Consensus from an expert panel

      Graham, S M; Ahmed, T; Amanullah, F; Browning, R; Cardenas, V; Casenghi, M; Cuevas, L E; Gale, M; Gie, R P; Grzemska, M; et al. (Oxford University Press, 2012-03-22)
      There is a critical need for improved diagnosis of tuberculosis in children, particularly in young children with intrathoracic disease as this represents the most common type of tuberculosis in children and the greatest diagnostic challenge. There is also a need for standardized clinical case definitions for the evaluation of diagnostics in prospective clinical research studies that include children in whom tuberculosis is suspected but not confirmed by culture of Mycobacterium tuberculosis. A panel representing a wide range of expertise and child tuberculosis research experience aimed to develop standardized clinical research case definitions for intrathoracic tuberculosis in children to enable harmonized evaluation of new tuberculosis diagnostic technologies in pediatric populations. Draft definitions and statements were proposed and circulated widely for feedback. An expert panel then considered each of the proposed definitions and statements relating to clinical definitions. Formal group consensus rules were established and consensus was reached for each statement. The definitions presented in this article are intended for use in clinical research to evaluate diagnostic assays and not for individual patient diagnosis or treatment decisions. A complementary article addresses methodological issues to consider for research of diagnostics in children with suspected tuberculosis.
    • Field research in humanitarian medical programmes. Treatment of a cohort of tuberculosis patients using the Manyatta regimen in a conflict zone in South Sudan.

      Keus, K; Houston, S; Melaku, Y; Burling, S; Médecins Sans Frontières-Holland, Max Euweplein 40, PO Box 10014, 1001 EA Amsterdam, The Netherlands. (Elsevier, 2008-01-31)
      This is a descriptive report of a pilot project of tuberculosis (TB) treatment in a conflict zone. A TB programme was implemented by Médecins Sans Frontières(MSF)-Holland in a semi-nomadic population in a very insecure and underdeveloped area of Upper Nile province in Southern Sudan. Outcome measures were operational feasibility, default rate, and sputum smear conversion at 4 months. A cohort of TB patients was admitted over a 10-week period (July-September 2001). Adherence strategy, project implementation, and and contingency planning were adapted to local conditions. The treatment regimen (4 HRZE [4-month daily supervised regimen] followed by 3EH or 3TH [3-month unsupervised regimen]: isoniazid (H), rifampicin (R), pyrazinamide (Z), ethambutol (E) and thiacetazone (T)) was a variant on the Manyatta regimen developed for semi-nomads in Kenya. Of 163 patients, 84 (52%) were children aged < 15 years. Lymph node TB comprised 34% and spinal TB 15% of all patients. Among adults, 41% had smear-positive pulmonary disease. Only 1 patient (0.6%) defaulted. All sputum smear-positive patients who completed 4 months of therapy converted to smear-negative, although 2 were subsequently found to have relapsed. TB in complex emergency situations is an underrecognized priority. Using an approach adapted especially to this setting, TB treatment was successfully implemented with minimal risk of promoting drug resistance, in an unstable setting.
    • Low uptake of antiretroviral therapy after admission with human immunodeficiency virus and tuberculosis in KwaZulu-Natal, South Africa.

      Murphy, R A; Sunpath, H; Taha, B; Kappagoda, S; Maphasa, K T M; Kuritzkes, D R; Smeaton, L; Doctors Without Borders USA, New York, USA; McCord Hospital, South Africa; Harvard Medical School, Massachusetts, USA; Division of Infectious Disease and Geographic Medicine, California, USA; Zoe-Life, South Africa; Section of Retroviral Therapeutics, Massachusetts, USA; Centre for Biostatistics in AIDS Research, Massachusetts, USA (2010-07-01)
      A prospective cohort study was conducted among human immunodeficiency virus (HIV) infected in-patients with tuberculosis (TB) or other opportunistic infections (OIs) in South Africa to estimate subsequent antiretroviral therapy (ART) uptake and survival.
    • Multidrug- and isoniazid-resistant tuberculosis in three high HIV burden African regions

      Sanchez-Padilla, E; Ardizzoni, E; Sauvageot, D; Ahoua, L; Martin, A; Varaine, F; Adatu-Engwau, F; Akeche, G; Salaniponi, F; Bonnet, M (International Union Against Tuberculosis and Lung Disease, 2013-08)
      Despite major progress in the surveillance of drug-resistant tuberculosis (TB), data are lacking for many low-resource countries. World Health Organization estimates of multidrug-resistant TB (MDR-TB) rates in Africa are low, and based on very limited data from the African continent.
    • Multidrug-Resistant Tuberculosis in Central Asia.

      Cox, H; Orozco, J D; Male, R; Ruesch-Gerdes, S; Falzon, D; Small, I; Doshetov, D; Kebede, Y; Aziz, M; Médecins Sans Frontières Aral Sea Area Programme, Uzbekistan and Turkmenistan, Tashkent, Uzbekistan. hom@msfh-tashkent.uz (2004-05)
      Multidrug-resistant tuberculosis (MDR-TB) has emerged as a major threat to TB control, particularly in the former Soviet Union. To determine levels of drug resistance within a directly observed treatment strategy (DOTS) program supported by Médecins Sans Frontières in two regions in Uzbekistan and Turkmenistan, Central Asia, we conducted a cross-sectional survey of smear-positive TB patients in selected districts of Karakalpakstan (Uzbekistan) and Dashoguz (Turkmenistan). High levels of MDR-TB were found in both regions. In Karakalpakstan, 14 (13%) of 106 new patients were infected with MDR-TB; 43 (40%) of 107 previously treated patients were similarly infected. The proportions for Dashoguz were 4% (4/105 patients) and 18% (18/98 patients), respectively. Overall, 27% of patients with positive smear results whose infections were treated through the DOTS program in Karakalpakstan and 11% of similar patients in Dashoguz were infected with multidrug-resistant strains of TB on admission. These results show the need for concerted action by the international community to contain transmission and reduce the effects of MDR-TB.
    • New and Repurposed Drugs for Pediatric Multidrug-Resistant Tuberculosis. Practice-based Recommendations

      Harausz, E; Garcia-Prats, A; Seddon, J; Schaaf, H; Hesseling, A; Achar, J; Bernheimer, J; Cruz, A; D'Ambrosio, L; Detjen, A; et al. (American Thoracic Society, 2017-05-15)
      It is estimated that 33,000 children develop multidrug-resistant tuberculosis (MDR-TB) each year. In spite of these numbers, children and adolescents have limited access to the new and repurposed MDR-TB drugs. There is also little clinical guidance for the use of these drugs and for the shorter MDR-TB regimen in the pediatric population. This is despite the fact that these drugs and regimens are associated with improved interim outcomes and acceptable safety profiles in adults. This review fills a gap in the pediatric MDR-TB literature by providing practice-based recommendations for the use of the new (delamanid and bedaquiline) and repurposed (linezolid and clofazimine) MDR-TB drugs and the new shorter MDR-TB regimen in children and adolescents.
    • Passive Versus Active Tuberculosis Case Finding and Isoniazid Preventive Therapy Among Household Contacts in a Rural District of Malawi.

      Zachariah, R; Spielmann M P; Harries, A D; Gomani, P; Graham, S; Bakali, E; Humblet, P; Operational Research (HIV/TB), Medical Department, Médecins sans Frontières-Brussels Operational Centre, Brussels, Belgium. zachariah@internet.lu (International Union Against TB and Lung Disease, 2003-11)
      SETTING: Thyolo district, rural Malawi. OBJECTIVES: To compare passive with active case finding among household contacts of smear-positive pulmonary tuberculosis (TB) patients for 1) TB case detection and 2) the proportion of child contacts aged under 6 years who are placed on isoniazid (INH) preventive therapy. DESIGN: Cross-sectional study. METHODS: Passive and active case finding was conducted among household contacts, and the uptake of INH preventive therapy in children was assessed. RESULTS: There were 189 index TB cases and 985 household contacts. Human immunodeficiency virus (HIV) prevalence among index cases was 69%. Prevalence of TB by passive case finding among 524 household contacts was 0.19% (191/100000), which was significantly lower than with active finding among 461 contacts (1.74%, 1735/100000, P = 0.01). Of 126 children in the passive cohort, 22 (17%) received INH, while in the active cohort 25 (22%) of 113 children received the drug. Transport costs associated with chest X-ray (CXR) screening were the major reason for low INH uptake. CONCLUSIONS: Where the majority of TB patients are HIV-positive, active case finding among household contacts yields nine times more TB cases and is an opportunity for reducing TB morbidity and mortality. The need for a CXR is an obstacle to the uptake of INH prophylaxis.
    • Patients' Costs Associated With Seeking and Accessing Treatment for Drug-Resistant Tuberculosis in South Africa

      Ramma, L; Cox, H; Wilkinson, L; Foster, N; Cunnama, L; Vassall, A; Sinanovic, E (International Union Against TB and Lung Disease, 2015-12)
      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.
    • Screening of patients with diabetes mellitus for tuberculosis in India

      Kumar, A; Gupta, D; Nagaraja, S B; Nair, S A; Satyanarayana, S; Zachariah, R; Harries, A D (Blackwell Publishing Ltd, 2013-05)
      To assess the feasibility, results and challenges of screening patients with diabetes mellitus (DM) for tuberculosis (TB) within the healthcare setting of six DM clinics in tertiary hospitals across India.
    • Screening of patients with tuberculosis for diabetes mellitus in India

      Kumar, A; Jain, D C; Gupta, D; Satyanarayana, S; Zachariah, R; Harries, A D (2013-05)
      To assess feasibility and results of screening patients with tuberculosis (TB) for diabetes mellitus (DM) within the routine healthcare setting across the country at: eight tertiary care hospitals and more than 60 peripheral health institutions in eight tuberculosis units.
    • Short communication: antituberculosis drug-induced hepatotoxicity is unexpectedly low in HIV-infected pulmonary tuberculosis patients in Malawi.

      Tostmann, A; Boeree, M J; Harries, A D; Sauvageot, D; Banda, H T; Zijlstra, E E; Department of Pulmonary Diseases, Radboud University Nijmegen Medical Centre and University Lung Centre Dekkerswald, Nijmegen, The Netherlands. A.Tostmann@ulc.umcn.nl (2007-07)
      The proportion of patients with antituberculosis drug-induced hepatotoxicity (ATDH) was unexpectedly low during a trial on cotrimoxazole prophylaxis in Malawian HIV-positive pulmonary tuberculosis patients. About 2% of the patients developed grade 2 or 3 hepatotoxicity during tuberculosis (TB) treatment, according to WHO definitions. Data on ATDH in sub-Saharan Africa are limited. Although the numbers are not very strong, our trial and other papers suggest that ATDH is uncommon in this region. These findings are encouraging in that hepatotoxicity may cause less problem than expected, especially in the light of combined HIV/TB treatment, where drug toxicity is a major cause of treatment interruption.
    • Towards Early Inclusion of Children in Tuberculosis Drugs Trials: A Consensus Statement

      Nachman, S; Ahmed, A; Amanullah, F; Becerra, M C; Botgros, R; Brigden, G; Browning, R; Gardiner, E; Hafner, R; Hesseling, A; et al. (Elsevier, 2015-06)
      Children younger than 18 years account for a substantial proportion of patients with tuberculosis worldwide. Available treatments for paediatric drug-susceptible and drug-resistant tuberculosis, albeit generally effective, are hampered by high pill burden, long duration of treatment, coexistent toxic effects, and an overall scarcity of suitable child-friendly formulations. Several new drugs and regimens with promising activity against both drug-susceptible and drug-resistant strains have entered clinical development and are either in various phases of clinical investigation or have received marketing authorisation for adults; however, none have data on their use in children. This consensus statement, generated from an international panel of opinion leaders on childhood tuberculosis and incorporating reviews of published literature from January, 2004, to May, 2014, addressed four key questions: what drugs or regimens should be prioritised for clinical trials in children? Which populations of children are high priorities for study? When can phase 1 or 2 studies be initiated in children? What are the relevant elements of clinical trial design? The consensus panel found that children can be included in studies at the early phases of drug development and should be an integral part of the clinical development plan, rather than studied after regulatory approval in adults is obtained.
    • Treatment outcome of patients with smear-negative and smear-positive pulmonary tuberculosis in the National Tuberculosis Control Programme, Malawi.

      Harries, A D; Nyirenda, T E; Banerjee, A; Boeree, M J; Salaniponi, F M L; National Tuberculosis Control Programme, Community Health Science Unit, Lilongwe, Malawi. epicentre@imul.com (Elsevier and the Royal Society of Tropical Medicine and Hygiene, 1999)
      National tuberculosis control programmes (NTPs) in sub-Saharan Africa do not routinely record or report treatment outcome data on smear-negative pulmonary tuberculosis (PTB) patients. Twelve-month treatment outcome on patients with smear-negative PTB registered in all district and mission hospitals in Malawi during the year 1995 was collected, and was compared with 8-month treatment outcome in smear-positive PTB patients registered during the same period. Of 4240 patients with smear-negative PTB, 35% completed treatment, 25% died, 9% defaulted and 7% were transferred to another district with no treatment outcome results available. In 24% of patients treatment cards were lost and treatment outcome was unknown. These results were significantly inferior to those obtained in 4003 patients with smear-positive PTB in whom 72% completed treatment, 20% died, 4% defaulted, 2% were transferred and 1% had positive smears at the end of treatment. These differences between patients with smear-negative and smear-positive PTB were similar when analysed by sex and by most age-groups. Higher mortality rates in patients with smear-negative PTB are probably attributable to advanced HIV-related immunosuppression, and higher default and treatment unknown rates probably reflect the lack of attention paid by TB programme staff to this group of patients. As a result of this country-wide study the Malawi NTP has started to record routinely the treatment outcomes of smear-negative TB patients and has set treatment completion targets of 50% or higher for this group of patients.
    • Tuberculosis recurrence and mortality after successful treatment: impact of drug resistance.

      Cox, H; Kebede, Y; Allamuratova, S; Ismailov, G; Davletmuratova, Z; Byrnes, G; Stone, C; Niemann, S; Rüsch-Gerdes, S; Blok, L; et al. (PLoS, 2006-10)
      BACKGROUND: The DOTS (directly observed treatment short-course) strategy for tuberculosis (TB) control is recommended by the World Health Organization globally. However, there are few studies of long-term TB treatment outcomes from DOTS programs in high-burden settings and particularly settings of high drug resistance. A DOTS program was implemented progressively in Karakalpakstan, Uzbekistan starting in 1998. The total case notification rate in 2003 was 462/100,000, and a drug resistance survey found multidrug-resistant (MDR) Mycobacterium tuberculosis strains among 13% of new and 40% of previously treated patients. A retrospective, observational study was conducted to assess the capacity of standardized short-course chemotherapy to effectively cure patients with TB in this setting. METHODS AND FINDINGS: Using routine data sources, 213 patients who were sputum smear-positive for TB, included in the drug resistance survey and diagnosed consecutively in 2001-2002 from four districts, were followed up to a median of 22 months from diagnosis, to determine mortality and subsequent TB rediagnosis. Valid follow-up data were obtained for 197 (92%) of these patients. Mortality was high, with an average of 15% (95% confidence interval, 11% to 19%) dying per year after diagnosis (6% of 73 pansusceptible cases and 43% of 55 MDR TB cases also died per year). While 73 (74%) of the 99 new cases were "successfully" treated, 25 (34%) of these patients were subsequently rediagnosed with recurrent TB (13 were smear-positive on rediagnosis). Recurrence ranged from ten (23%) of 43 new, pansusceptible cases to six (60%) of ten previously treated MDR TB cases. MDR M. tuberculosis infection and previous TB treatment predicted unsuccessful DOTS treatment, while initial drug resistance contributed substantially to both mortality and disease recurrence after successful DOTS treatment. CONCLUSIONS: These results suggest that specific treatment of drug-resistant TB is needed in similar settings of high drug resistance. High disease recurrence after successful treatment, even for drug-susceptible cases, suggests that at least in this setting, end-of-treatment outcomes may not reflect the longer-term status of patients, with consequent negative impacts for patients and for TB control.
    • WHO Clinical Staging of HIV Infection and Disease, Tuberculosis and Eligibility for Antiretroviral Treatment: Relationship to CD4 Lymphocyte Counts.

      Teck, R; Ascurra, O; Gomani, P; Manzi, M; Pasulani, O; Kusamale, J; Salaniponi, F M L; Humblet, P; Nunn, P; Scano, F; et al. (International Union Against TB and Lung Disease, 2005-03)
      SETTING: Thyolo district, Malawi. OBJECTIVES: To determine in HIV-positive individuals aged over 13 years CD4 lymphocyte counts in patients classified as WHO Clinical Stage III and IV and patients with active and previous tuberculosis (TB). DESIGN: Cross-sectional study. METHODS: CD4 lymphocyte counts were determined in all consecutive HIV-positive individuals presenting to the antiretroviral clinic in WHO Stage III and IV. RESULTS: A CD4 lymphocyte count of < or = 350 cells/microl was found in 413 (90%) of 457 individuals in WHO Stage III and IV, 96% of 77 individuals with active TB, 92% of 65 individuals with a history of pulmonary TB (PTB) in the last year, 91% of 89 individuals with a previous history of PTB beyond 1 year, 81% of 32 individuals with a previous history of extra-pulmonary TB, 93% of 107 individuals with active or past TB with another HIV-related disease and 89% of 158 individuals with active or past TB without another HIV-related disease. CONCLUSIONS: In our setting, nine of 10 HIV-positive individuals presenting in WHO Stage III and IV and with active or previous TB have CD4 counts of < or = 350 cells/microl. It would thus be reasonable, in this or similar settings where CD4 counts are unavailable for clinical management, for all such patients to be considered eligible for antiretroviral therapy.