Delamanid in the treatment of multidrug-resistant tuberculosis.

Otsuka has been engaged in anti-tuberculosis drug development efforts for over 30 years, and is the leading private sector funder of tuberculosis (TB) research and development. Delamanid (DLM), discovered by Otsuka's scientists, has been shown to provide benefit with respect to short-term surrogate markers and long-term treatment outcomes, and it has received regulatory approval for treatment of adult pulmonary multidrug-resistant TB (MDR-TB) as one of only two new anti-tuberculosis drugs in the last 40 years. Lack of drug-drug interactions with major antiretrovirals and efficacy against MDR-TB allow DLM's applicability in a wide range of MDR-TB patients. Current and future efforts are focused on replacing less safe and less efficacious second-line drugs with DLM, its contribution to all-oral and/or shortened treatment regimens, and, ultimately, inclusion in a pan-TB regimen. This manuscript provides a brief review of DLM.

Pain and electrophysiological parameters are improved by combined 830-1064 high-intensity LASER in symptomatic carpal tunnel syndrome versus Transcutaneous Electrical Nerve Stimulation. A randomized controlled study.

AIM: The aim of the study was to compare LASER versus transcutaneous electrical nerve stimulation (TENS) in reducing pain and paraesthesia; and in improving motor and sensory median nerve conduction parameters in mild to moderate carpal tunnel syndrome (CTS). DESIGN: Randomised blinded pilot study. Patients and staff administered treatments and outcome measures were blinded. SETTING: Outpatient; Research and Care Rehabilitation Institute. PARTICIPANTS: Twenty CTS symptomatic patients. INTERVENTIONS: Fifteen sessions of: 1) 100 Hz TENS (30 minutes; rectangular waves; 80 ms width, intensity below muscle contraction); 2) combined 830-1064 nm LASER (radiating dose: 250 J cm-2 delivered to the skin overlying the course of the median nerve at the wrist for 100 s at 25 W (18 W [1064 nm] + 7 W [830 nm]) via a fiber-optic probe with a spot size of ~1 cm2). Outcome measures. Visual analogue scale (VAS) for pain and paresthesia; median nerve distal motor latency and sensory nerve conduction velocity. RESULTS: LASER improved both positive and negative sensory symptoms. TENS induced clinical improvement but this was not statistically significant and was limited to pain reduction. LASER but not TENS favourably modified the neurophysiological parameters. CONCLUSION: High-intensity combined LASER wavelengths of 830 nm and 1064 nm, which produce a better transparency with less scattering and a high energy transfer, are better than TENS in improving both pain and paraesthesia as well as neurophysiological parameters in CTS.

LKB1 tumor suppressor regulates AMP kinase/mTOR-independent cell growth and proliferation via the phosphorylation of Yap.

The liver kinase B1 (LKB1) tumor suppressor inhibits cell growth through its regulation of cellular metabolism and apical-basal polarity. The best understood mechanism whereby LKB1 limits cell growth is through activation of the AMP-activated-protein-kinase/mammalian-target-of-rapamycin (AMPK/mTOR) pathway to control metabolism. As LKB1 is also required for polarized epithelial cells to resist hyperplasia, it is anticipated to function through additional mechanisms. Recently, Yes-associated protein (Yap) has emerged as a transcriptional co-activator that modulates tissue homeostasis in response to cell-cell contact. Thus this study examined a possible connection between Yap and LKB1. Restoration of LKB1 expression in HeLa cells, which lack this tumor suppressor, or short-hairpin RNA knockdown of LKB1 in NTERT immortalized keratinocytes, demonstrated that LKB1 promotes Yap phosphorylation, nuclear exclusion and proteasomal degradation. The ability of phosphorylation-defective Yap mutants to rescue LKB1 phenotypes, such as reduced cell proliferation and cell size, suggest that Yap inhibition contributes to LKB1 tumor suppressor function(s). However, failure of Lats1/2 knockdown to suppress LKB1-mediated Yap regulation suggested that LKB1 signals to Yap via a non-canonical pathway. Additionally, LKB1 inhibited Yap independently of either AMPK or mTOR activation. These findings reveal a novel mechanism whereby LKB1 may restrict cancer cell growth via the inhibition of Yap.

Early bactericidal activity of delamanid (OPC-67683) in smear-positive pulmonary tuberculosis patients.

BACKGROUND: Delamanid (OPC-67683) is a novel mycolic acid biosynthesis inhibitor active against Mycobacterium tuberculosis at a low minimum inhibitory concentration. METHODS: Forty-eight patients with smear-positive tuberculosis (63% male; 54.7 ± 9.9 kg; 30.7 ± 10.8 years) were randomly assigned to receive delamanid 100, 200, 300 or 400 mg daily for 14 days. Colony forming units (cfu) of M. tuberculosis were counted on agar plates from overnight sputum collections to calculate early bactericidal activity (EBA), defined as fall in log(10) cfu/ml sputum/day. RESULTS: The EBA of delamanid was monophasic and not significantly different between dosages; however, more patients receiving 200 mg (70%) and 300 mg (80%) experienced a response of ≥0.9 log(10) cfu/ml sputum decline over 14 days than those receiving 100 mg (45%) and 400 mg (27%). The average EBA of all dosages combined (0.040 ± 0.056 log(10) cfu/ml sputum/day) was significant from day 2 onward. Delamanid exposure was less than dosage-proportional, reaching a plateau at 300 mg, likely due to dose-limited absorption. Moderate but significant correlation was found between C(max) and EBA, indicating exposure dependence. Delamanid was well tolerated without significant toxicity. CONCLUSIONS: Delamanid at all dosages was safe, well tolerated and demonstrated significant exposure-dependent EBA over 14 days, supporting further investigation of its pharmacokinetics and anti-tuberculosis activity.

Bacteriologic monitoring of multidrug-resistant tuberculosis patients in five DOTS-Plus pilot projects.

BACKGROUND: Multidrug-resistant tuberculosis programs in DOTS-Plus pilot sites in five countries. OBJECTIVES: To calculate sputum conversion time and its relationship to treatment outcome, document the frequency of culture reversions and examine concordance of smear and culture to assess the potential consequences of monitoring by smear microscopy alone. DESIGN: Retrospective cohort analysis of 1926 patients receiving individualized, second-line therapy. RESULTS: Among 1385 sputum culture-positive cases at baseline, 1146 (83%) experienced at least one culture conversion during treatment. Conversion, however, was not sustained in all patients: 201 (15%) experienced initial culture conversion and at least one subsequent culture reversion to positive; 1064 (77%) achieved sustained culture conversion. Median time to culture conversion was 3 months. Among 206 patients whose nal conversion occurred 7-18 months after the initiation of therapy, 71% were cured or had completed treatment. CONCLUSIONS: Prolonged treatment for patients with delayed conversion may be beneficial, as 71% of late converters still achieved cure or completed treatment. This has implications for programs with de ned end points for treatment failure. The interval between rst and nal conversion among patients whose initial con- version is not sustained raises concern with respect to the ongoing debate regarding duration of treatment and the definition of cure.

Tuberculosis in asymptomatic HIV-infected adults with abnormal chest radiographs screened for tuberculosis prevention.

BACKGROUND: Isoniazid preventive therapy (IPT) prevents tuberculosis (TB) in people living with HIV (human immunodeficiency virus, PLWH). Symptom screening without chest radiographs (CXRs) was established as the strategy for excluding TB disease among PLWH seeking IPT in Botswana's 2001 pilot project. This strategy was evaluated in 2004-2006 among candidates screened for an IPT clinical trial. METHODS: PLWH referred from clinics and HIV testing centers were screened for TB symptoms. All asymptomatic candidates received CXRs; those with abnormal CXRs were investigated further. RESULTS: Among 2732 asymptomatic candidates screened, 302 (11%) had abnormal CXRs potentially compatible with TB; TB disease was diagnosed in 43 of these 302 (14%), or 43 (1.6%) of the 2732 asymptomatic candidates. While not associated with CD4 lymphocyte counts < 200 cells/mm(3), TB was associated with a positive tuberculin skin test (relative risk 2.1, 95%CI 1.1-4.0). IPT was initiated in 113 (62%) of 182 asymptomatic PLWH with abnormal CXRs; 8/113 (7%) subsequently developed TB, and 7/8 (88%) successfully completed anti-tuberculosis treatment. CONCLUSIONS: The prevalences of abnormal CXRs and TB were respectively 2.6- and 8.9-fold higher among asymptomatic PLWH screened for the trial than in the pilot. A cost-effectiveness analysis is needed to determine whether the benefits of symptom screening alone are offset by the risk of inducing INH resistance by excluding CXRs during screening.

Treatment outcome and follow-up of multidrug-resistant tuberculosis patients, West Coast/Winelands, South Africa, 1992-2002.

SETTING: Brooklyn Chest Hospital, Western Cape, South Africa. OBJECTIVE: To evaluate the treatment outcome and 2- and 5-year follow-up of patients treated for multidrug-resistant tuberculosis (MDR-TB) with individualized regimens. DESIGN: Retrospective cohort study of all MDR-TB patients starting treatment during 1992-2002. Patients were evaluated every 6 months for 2 years after treatment and at 5 years when possible. RESULTS: Over 11 years, 491 (66%) of 747 MDR-TB patients received treatment with two or more second-line drugs; 239 (49%) were cured or completed treatment, 68 (14%) died, 144 (29%) defaulted from treatment, 27 (5%) failed, 10 (2%) transferred out and 3 (<1%) remained on treatment. Only 176 (36%) were tested for human immunodeficiency virus and 15 were positive. The proportion with a successful MDR-TB treatment outcome declined over time, while the proportion who defaulted remained stable. Among 410 patients who had not transferred out or died, 281 (69%) had 2-year data available: 185 (66%) were cured or completed treatment, 32 (11%) were retreated for TB and 64 (23%) died. CONCLUSIONS: Under program conditions in the West Coast/Winelands District, default rates were high and treatment success rates low. Outreach strategies for MDR-TB treatment should only be implemented if adequate resources are committed to the program.

Electronic tuberculosis surveillance systems: a tool for managing today's TB programs.

The World Health Organization (WHO) released the Stop TB Strategy in 2006, along with a revised version of the tuberculosis (TB) recording and reporting forms and register. These publications illustrate the need for an enhanced TB surveillance system that will include such key elements as rapid assessment of the quality of DOTS services; integration and response to the human immunodeficiency virus/acquired immune-deficiency syndrome (HIV/AIDS) epidemic; TB control challenges, such as increased smear-negative and extra-pulmonary TB and multidrug-resistant TB (MDR-TB); increased engagement of all care providers, such as private health care services and the community; and promotion of research to support program improvement. Electronic surveillance systems utilize computer technology to facilitate the capture, transfer and reporting of the WHO-recommended TB data elements. Electronic surveillance offers several potential advantages over the traditional paper-based systems used in many low-resource settings, such as improved data quality and completeness, more feasible links to other health care programs, quality-enhanced data entry and analysis features and increased data security. These advantages must, however, be weighed against the requirements and costs of electronic surveillance, including implementation and support of a quality paper-based surveillance system and the additional costs associated with infrastructure, training and human resources for the implementation and continuing support of an electronic system. Using examples from three different electronic TB surveillance systems that are being implemented in various resource-limited settings, this article demonstrates the feasibility, requirements and value of such systems to support the WHO-recommended enhancement of TB surveillance.

Using program evaluation to improve the performance of a TB-HIV project in Banteay Meanchey, Cambodia.

SETTING: Cambodia has the highest human immunodeficiency virus (HIV) prevalence (1.9%) and tuberculosis (TB) incidence (508/100000) in Asia. Banteay Meanchey, a province with high HIV prevalence of 1.9%, established a pilot project in 2003 to enhance TB-HIV activities. We evaluated this project to improve performance. METHODS: In March 2005, we analyzed 17 months of data on all persons diagnosed with HIV or TB at 11 participating clinics. We determined barriers to HIV testing and TB screening, modified the program to reduce these barriers and assessed whether our interventions improved testing and screening rates. RESULTS: Among 952 patients newly diagnosed with TB disease, 138 (14%) had known HIV infection at the time of TB diagnosis. Of the 814 TB patients with unknown HIV status, 432 (53%) were HIV tested. Of 1228 persons newly diagnosed with HIV infection, 450 (37%) were screened for TB disease. We found and addressed barriers to HIV testing and TB screening. In the 9 months after the interventions, 240/322 (71%) TB patients were HIV tested, an increase of 34% (P < 0.01); 426/751 (57%) HIV-infected patients were screened for TB, an increase of 54% (P < 0.01). CONCLUSION: Evaluations of TB-HIV collaborative activities can lead to increased TB screening and HIV testing rates.

Baseline evaluation of routine HIV testing among tuberculosis patients in Botswana.

In January 2004, the government of Botswana introduced a policy of routine, non-compulsory human immunodeficiency virus (HIV) testing to increase testing and access to antiretroviral treatment (ART) for individuals presenting for medical treatment. Before a systematic implementation of the policy, we conducted a cross-sectional survey of tuberculosis (TB) record data from 46 clinics in 10 districts to assess baseline HIV testing rates among TB patients. Recorded HIV results from the facility TB register and TB treatment card were reviewed. Of the 1242 TB patients entered in the register, 47% had a recorded HIV result and 84% of these were co-infected with HIV. TB treatment cards were available for 862 (69%) registered patients. Among the 411 (47%) with test results recorded on the treatment card, 341 (83%) were HIV-infected; of these, 12% were reported to be receiving ART.

Reported childhood tuberculosis treatment outcomes, Gaborone and Francistown, Botswana, 1998-2002.

SETTING: Botswana. OBJECTIVES: To estimate frequencies of tuberculosis (TB) treatment outcomes, assess the validity of reported treatment outcomes, and identify risk factors for death during TB treatment among children aged <15 years during 1998-2002. DESIGN: We examined TB treatment outcome frequencies using the national Electronic TB Registry (ETR) data. Treatment and medical records were reviewed to calculate predictive values (PV) for outcomes recorded in the ETR. We interviewed parents of children treated for TB and assessed risk factors for death during treatment via case-control study. RESULTS: Of 5483 patients, 3646 (67%) were cured or completed treatment and 577 (10.5%) died during treatment. The PV for ETR was 76% for death and 97% for cured or completed treatment. We interviewed parents of 91 children who died during treatment and 220 children who completed treatment. Human immunodeficiency virus (HIV) status was unknown for 76% of the children and 54% of the parents. Parent-reported adverse effects to anti-tuberculosis medication (adjusted odds ratio [aOR] 4.9, 95% confidence limit [CL] 2.2-9.2), and lower patient age (aOR 2.2, 95%CL 1.2-4.2) were associated with death during treatment. CONCLUSIONS: TB control programs in Botswana should assess for potential adverse effects of anti-tuberculosis medication and expand HIV testing among children with TB and their parents.

The epidemiology of HIV-associated tuberculosis in rural Cambodia.

SETTING: Banteay Meanchey Province, Cambodia. OBJECTIVE: The World Health Organization recommends human immunodeficiency virus (HIV) testing for all tuberculosis (TB) patients and TB screening for all HIV-infected persons in countries with a TB-HIV syndemic. We sought to determine whether evidence supports implementing these recommendations in South-East Asia. DESIGN: We conducted a cross-sectional survey and retrospective cohort study of patients newly diagnosed with HIV or TB from October 2003 to February 2005 to identify risk factors for HIV infection and TB, and for death during TB treatment. RESULTS: HIV infection was diagnosed in 216/574 (38%) TB patients. TB disease was found in 124/450 (24%) HIV-infected persons. No sub-groups of patients had a low risk of HIV infection or TB. Of 180 TB patients with HIV infection and a recorded treatment outcome, 49 (27%) died compared to 17/357 (5%) without HIV infection (relative risk [RR] 5.2, 95% confidence interval [CI] 3.1-8.7). HIV-infected TB patients with smear-negative pulmonary disease died less frequently than those with smear-positive pulmonary disease (RR 0.39, 95%CI 0.16-0.93). CONCLUSIONS: No sub-groups of patients had low risk for HIV infection or TB, and mortality among HIV-infected TB patients was high. These data justify using the WHO global TB-HIV recommendations in South-East Asia. Urgent interventions are needed to reduce the high mortality rate in HIV-infected TB patients.

Reaching the targets for tuberculosis control: the impact of HIV.

In 1991, the 44th World Health Assembly set two key targets for global tuberculosis (TB) control to be reached by 2000: 70% case detection of acid-fast bacilli smear-positive TB patients under the DOTS strategy recommended by WHO and 85% treatment success of those detected. This paper describes how TB control was scaled up to achieve these targets; it also considers the barriers encountered in reaching the targets, with a particular focus on how HIV infection affects TB control. Strong TB control will be facilitated by scaling-up WHO-recommended TB/HIV collaborative activities and by improving coordination between HIV and TB control programmes; in particular, to ensure control of drug-resistant TB. Required activities include more HIV counselling and testing of TB patients, greater use and acceptance of isoniazid as a preventive treatment in HIV-infected individuals, screening for active TB in HIV-care settings, and provision of universal access to antiretroviral treatment for all HIV-infected individuals eligible for such treatment. Integration of TB and HIV services in all facilities (i.e. in HIV-care settings and in TB clinics), especially at the periphery, is needed to effectively treat those infected with both diseases, to prolong their survival and to maximize limited human resources. Global TB targets can be met, particularly if there is renewed attention to TB/HIV collaborative activities combined with tremendous political commitment and will.

Treatment outcome cohort analysis in an integrated DOTS and DOTS-Plus TB program in Latvia.

International guidelines for treatment outcome analysis of tuberculosis cases have been published and are widely used. They do not, however, fully address the incorporation of multidrug-resistant tuberculosis (MDR-TB) cases. Here we present an approach to cohort analysis of treatment outcomes for all registered TB cases, including MDR-TB cases. We analyzed all new pulmonary smear- and/or culture-positive cases registered in Latvia during 2002. Analysis of treatment outcomes at 24 months after initial case registration showed overall treatment success at 84%. This approach to outcome analysis is possible only for settings where MDR-TB treatment is established.

Risk factors associated with default from multidrug-resistant tuberculosis treatment, South Africa, 1999-2001.

SETTING: Multidrug-resistant tuberculosis (MDR-TB) treatment centers in five provinces, South Africa. OBJECTIVES: To estimate the mortality and evaluate risk factors associated with default from MDR-TB treatment. DESIGN: Using registries and a standardized questionnaire, we conducted a case-control study among patients diagnosed and treated for MDR-TB. Cases were defined as patients who began MDR-TB treatment between 1 October 1999 and 30 September 2001 and defaulted from treatment for more than 2 months; controls were defined as patients who began MDR-TB treatment during the same time and were cured, completed or failed. RESULTS: After initial identification and reclassification, 269 cases and 401 controls were confirmed eligible for interview. Further investigation revealed that 74 (27%) cases and 44 (10%) controls had died. Among 96 cases located who consented and were interviewed, 70% had defaulted after receiving at least 6 months of treatment. In a multivariate model, the strongest individual risk factors for default included reporting smoking marijuana or mandrax during treatment, and having an unsatisfactory opinion about the attitude of health care workers. CONCLUSION: Mortality among MDR-TB defaulters was high. Interventions to reduce default from MDR-TB treatment should center on substance abuse treatment, patient education and support and improving provider-patient relationships.

Antituberculosis drug resistance and anonymous HIV surveillance in tuberculosis patients in Botswana, 2002.

Two surveys undertaken in Botswana in the 1990s have recorded low rates of antituberculosis drug resistance, despite a three-fold rise in tuberculosis since 1989. We undertook a third survey to determine both trends since 1995 and HIV prevalence in tuberculosis patients in Botswana. Sputum specimens were obtained from patients nationwide in 2002 who also underwent anonymous, rapid HIV testing by use of Oraquick. Of 2200 sputum smear-positive patients and 219 previously treated patients with suspected recurrent tuberculosis, 1457 (60%) were infected with HIV. Resistance to at least one drug in new patients rose from 16 (3.7%) isolates in 1995 to 123 (10.4%; p<0.0001) in 2002. Interventions for tuberculosis control are urgently needed in Botswana to prevent further emergence of drug resistance.

TST reversion in a BCG-revaccinated population of nursing and medical students, São Paulo, Brazil, 1997-2000.

SETTING: A major university in São Paulo, Brazil, where vaccination against tuberculosis (TB) with bacille Calmette-Guerin (BCG) was routinely offered to first-year medical and nursing students. OBJECTIVES: To estimate the probability of negative tuberculin skin test (TST) results over a 4-year period following BCG revaccination, and to evaluate the effect of factors associated with reversion. DESIGN: Students were enrolled in 1997, initially given a two-step TST, and were retested annually or biannually for the duration of the study. Data on TB exposures and potential risk factors for TST negativity and reversion were collected through annual surveys. A linear mixture survival model was used to estimate the probability of negative TST results over time. RESULTS: Of 159 students, an estimated 20% had a negative TST result despite revaccination, and a further 31% reverted to negative over 4 years of follow-up. No cofactors significantly affected the probability of reversion. CONCLUSION: Overall, in the absence of reported exposure to Mycobacterium tuberculosis, 51% of students revaccinated upon entering nursing or medical school would have a negative TST result by the time they begin their internships. In this recently vaccinated population, reversion was common, suggesting that annual TST screening may remain a useful tool.

Capacity building for international tuberculosis control through operations research training.

SETTING: In resource-poor countries, few tuberculosis (TB) program staff at the national, provincial, and even district levels have the basic analytical and epidemiological skills necessary for collecting and analyzing quality data pertaining to national TB control program (NTP) improvements. This includes setting program priorities, operations planning, and implementing and evaluating program activities. OBJECTIVES: To present a model course for building capacity in basic epidemiology and operations research (OR). DESIGN: A combination of didactic lectures and applied field exercises were used to achieve the main objectives of the 6-day OR course. These were to increase the understanding of quantitative and qualitative research concepts, study design, and analytic methods, and to increase awareness of how these methods apply to the epidemiology and control of TB; and to demonstrate the potential uses of OR in answering practical questions on NTP effectiveness. As a final outcome, course participants develop OR proposals that are funded and later implemented. RESULTS: Since 1997, this OR course has been conducted nine times in five countries; 149 key NTP and laboratory staff have been trained in OR methods, and 44 OR protocols have been completed or are underway. CONCLUSION: This low-cost model course can be adapted to a wide range of public health issues.