Rigorous Clinical Trial Design in Public Health Emergencies Is Essential.

Randomized clinical trials are the most reliable approaches to evaluating the effects of new treatments and vaccines. During the 2014-2015 West African Ebola epidemic, many argued that such trials were neither ethical nor feasible in an environment of limited health infrastructure and severe disease with a high fatality rate. Consensus among the numerous organizations providing help to the affected areas was never achieved, resulting in fragmented collaboration, delayed study initiation, and ultimately failure to provide definitive evidence on the efficacy of treatments and vaccines. Randomized trials were in fact approved by local ethics boards and initiated, demonstrating that randomized trials, even in such difficult circumstances, are feasible. Improved planning and collaboration among research and humanitarian organizations, and affected communities, in the interepidemic periods are needed to ensure that questions regarding the efficacy of vaccines and treatments can be definitively answered during future public health emergencies.

Building clinical trial capacity to develop a new treatment for multidrug-resistant tuberculosis.

PROBLEM: New drugs for infectious diseases often need to be evaluated in low-resource settings. While people working in such settings often provide high-quality care and perform operational research activities, they generally have less experience in conducting clinical trials designed for drug approval by stringent regulatory authorities. APPROACH: We carried out a capacity-building programme during a multi-centre randomized controlled trial of delamanid, a new drug for the treatment of multidrug-resistant tuberculosis. The programme included: (i) site identification and needs assessment; (ii) achieving International Conference on Harmonization - Good Clinical Practice (ICH-GCP) standards; (iii) establishing trial management; and (iv) increasing knowledge of global and local regulatory issues. LOCAL SETTING: Trials were conducted at 17 sites in nine countries (China, Egypt, Estonia, Japan, Latvia, Peru, the Philippines, the Republic of Korea and the United States of America). Eight of the 10 sites in low-resource settings had no experience in conducting the requisite clinical trials. RELEVANT CHANGES: Extensive capacity-building was done in all 10 sites. The programme resulted in improved local capacity in key areas such as trial design, data safety and monitoring, trial conduct and laboratory services. LESSONS LEARNT: Clinical trials designed to generate data for regulatory approval require additional efforts beyond traditional research-capacity strengthening. Such capacity-building approaches provide an opportunity for product development partnerships to improve health systems beyond the direct conduct of the specific trial.

Delamanid for multidrug-resistant pulmonary tuberculosis.

BACKGROUND: Delamanid (OPC-67683), a nitro-dihydro-imidazooxazole derivative, is a new antituberculosis medication that inhibits mycolic acid synthesis and has shown potent in vitro and in vivo activity against drug-resistant strains of Mycobacterium tuberculosis. METHODS: In this randomized, placebo-controlled, multinational clinical trial, we assigned 481 patients (nearly all of whom were negative for the human immunodeficiency virus) with pulmonary multidrug-resistant tuberculosis to receive delamanid, at a dose of 100 mg twice daily (161 patients) or 200 mg twice daily (160 patients), or placebo (160 patients) for 2 months in combination with a background drug regimen developed according to World Health Organization guidelines. Sputum cultures were assessed weekly with the use of both liquid broth and solid medium; sputum-culture conversion was defined as a series of five or more consecutive cultures that were negative for growth of M. tuberculosis. The primary efficacy end point was the proportion of patients with sputum-culture conversion in liquid broth medium at 2 months. RESULTS: Among patients who received a background drug regimen plus 100 mg of delamanid twice daily, 45.4% had sputum-culture conversion in liquid broth at 2 months, as compared with 29.6% of patients who received a background drug regimen plus placebo (P=0.008). Likewise, as compared with the placebo group, the group that received the background drug regimen plus 200 mg of delamanid twice daily had a higher proportion of patients with sputum-culture conversion (41.9%, P=0.04). The findings were similar with assessment of sputum-culture conversion in solid medium. Most adverse events were mild to moderate in severity and were evenly distributed across groups. Although no clinical events due to QT prolongation on electrocardiography were observed, QT prolongation was reported significantly more frequently in the groups that received delamanid. CONCLUSIONS: Delamanid was associated with an increase in sputum-culture conversion at 2 months among patients with multidrug-resistant tuberculosis. This finding suggests that delamanid could enhance treatment options for multidrug-resistant tuberculosis. (Funded by Otsuka Pharmaceutical Development and Commercialization; ClinicalTrials.gov number, NCT00685360.).

Delamanid improves outcomes and reduces mortality in multidrug-resistant tuberculosis.

Multidrug-resistant and extensively drug-resistant tuberculosis (TB) are associated with worse treatment outcomes for patients, including higher mortality, than for drug-sensitive tuberculosis. Delamanid (OPC-67683) is a novel anti-TB medication with demonstrated activity against multidrug-resistant disease. Patients who participated in the previously reported randomised, placebo-controlled trial of delamanid and the subsequent open-label extension trial were eligible to participate in a 24-month observational study designed to capture treatment outcomes. Treatment outcomes, as assessed by clinicians and defined by the World Health Organization, were categorised as favourable and unfavourable. Delamanid treatment groups were combined for analysis, based on their duration of treatment. In total, for 421 (87.5%) out of 481 patients from the original randomised controlled trial, consent was granted for follow-up assessments. Favourable outcomes were observed in 143 (74.5%) out of 192 patients who received delamanid for ≥6 months, compared to 126 (55%) out of 229 patients who received delamanid for ≤2 months. Mortality was reduced to 1.0% among those receiving long-term delamanid versus short-term/no delamanid (8.3%; p<0.001). Treatment benefit was also seen among patients with extensively drug-resistant TB. This analysis suggests that treatment with delamanid for 6 months in combination with an optimised background regimen can improve outcomes and reduce mortality among patients with both multidrug-resistant and extensively drug-resistant TB.

Moving toward tuberculosis elimination: implementation of statewide targeted tuberculin testing in Tennessee.

RATIONALE: From 1993 to 2010, annual U.S. tuberculosis (TB) rates declined by 58%. However, this decline has slowed and disproportionately occurred among U.S.-born (78%) versus foreign-born persons (47%). Addressing the high burden of latent TB infection (LTBI) must be prioritized. OBJECTIVES: Only Tennessee has implemented a statewide program for finding and treating people with LTBI. The program was designed to address high statewide TB rates and growing burden among the foreign-born. We sought to assess the feasibility and yield of Tennessee's program. METHODS: Analyzing data from the 4.8-year period from program inception in March 2002 through December 2006, we quantified patients screened using a TB risk assessment tool, tuberculin skin tests (TST) placed and read, TST results, and patients initiating and completing LTBI treatment. We then estimated the number needed to screen to find and treat one person with LTBI and to prevent one case of TB. MEASUREMENTS AND MAIN RESULTS: Of 168,517 persons screened, 102,709 had a TST placed and read. Among 9,090 (9%) with a positive TST result, 53% initiated treatment, 54% of whom completed treatment. An estimated 195 TB cases were prevented over the 4.8 years analyzed, and program performance measures improved annually. The number of TSTs placed to prevent one TB case ranged from 150 for foreign-born persons to 9,834 for persons without TB risk. CONCLUSIONS: Targeted tuberculin testing and LTBI treatment is feasible and likely to reduce TB rates over time. Yield and cost-effectiveness are maximized by prioritizing foreign-born persons, a large population with high TB risk.

6-month versus 36-month isoniazid preventive treatment for tuberculosis in adults with HIV infection in Botswana: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: In accordance with WHO guidelines, people with HIV infection in Botswana receive daily isoniazid preventive therapy against tuberculosis without obtaining a tuberculin skin test, but duration of prophylaxis is restricted to 6 months. We aimed to assess effectiveness of extended isoniazid therapy. METHODS: In our randomised, double-blind, placebo-controlled trial we enrolled adults infected with HIV aged 18 years or older at government HIV-care clinics in Botswana. Exclusion criteria included current illness such as cough and an abnormal chest radiograph without antecedent tuberculosis or pneumonia. Eligible individuals were randomly allocated (1:1) to receive 6 months' open-label isoniazid followed by 30 months' masked placebo (control group) or 6 months' open-label isoniazid followed by 30 months' masked isoniazid (continued isoniazid group) on the basis of a computer-generated randomisation list with permuted blocks of ten at each clinic. Antiretroviral therapy was provided if participants had CD4-positive lymphocyte counts of fewer than 200 cells per µL. We used Cox regression analysis and the log-rank test to compare incident tuberculosis in the groups. Cox regression models were used to estimate the effect of antiretroviral therapy. The trial is registered at ClinicalTrials.gov, number NCT00164281. FINDINGS: Between Nov 26, 2004, and July 3, 2009, we recorded 34 (3·4%) cases of incident tuberculosis in 989 participants allocated to the control group and 20 (2·0%) in 1006 allocated to the continued isoniazid group (incidence 1·26% per year vs 0·72%; hazard ratio 0·57, 95% CI 0·33-0·99, p=0·047). Tuberculosis incidence in those individuals receiving placebo escalated approximately 200 days after completion of open-label isoniazid. Participants who were tuberculin skin test positive (ie, ≥5 mm induration) at enrolment received a substantial benefit from continued isoniazid treatment (0·26, 0·09-0·80, p=0·02), whereas participants who were tuberculin skin test-negative received no significant benefit (0·75, 0·38-1·46, p=0·40). By study completion, 946 (47%) of 1995 participants had initiated antiretroviral therapy. Tuberculosis incidence was reduced by 50% in those receiving 360 days of antiretroviral therapy compared with participants receiving no antiretroviral therapy (adjusted hazard ratio 0·50, 95% CI 0·26-0·97). Severe adverse events and death were much the same in the control and continued isoniazid groups. INTERPRETATION: In a tuberculosis-endemic setting, 36 months' isoniazid prophylaxis was more effective for prevention of tuberculosis than was 6-month prophylaxis in individuals with HIV infection, and chiefly benefited those who were tuberculin skin test positive. FUNDING: US Centers for Disease Control and Prevention and US Agency for International Development.

Isoniazid-associated hepatitis and antiretroviral drugs during tuberculosis prophylaxis in hiv-infected adults in Botswana.

RATIONALE: Little is known about the incidence of isoniazid-associated hepatitis in HIV-infected Africans who receive both isoniazid preventive therapy (IPT) and antiretroviral therapy (ART). OBJECTIVES: To assess the rate of and risk factors for isoniazid (INH)-associated hepatitis in persons living with HIV (PLWH) during IPT. METHODS: PLWH recruited for a clinical trial received 6 months of open-label, daily, self-administered INH at public health clinics. At screening PLWH were excluded if they had any cough, weight loss, night sweats, or other illness. Alcohol abuse was defined as meeting any CAGE criterion. INH-associated hepatitis (INH-hepatitis) was defined as having either alanine or aspartate aminotransferase greater than 5.0 times the upper limit of normal regardless of symptoms when INH was not excluded as the cause. MEASUREMENTS AND MAIN RESULTS: Of 1,995 PLWH enrolled between 2004 and 2006, 1,762 adhered to at least 4 months of IPT and were analyzed. Nineteen (1.1%) developed hepatitis probably or possibly associated with INH including one death at month 6; 14 of 19 (74%) occurred in months 1-3. Antiretroviral therapy (ART) was received by 480 participants but was not statistically associated with INH-hepatitis (relative risk [RR], 1.56; 95% confidence intervals [CI], 0.62-3.9); those receiving nevirapine had a higher rate (2.0%) than those receiving efavirenz (0.9%; P = 0.34). Although alcohol use did not reach significance (RR, 1.42; 95% CI, 0.57-3.51), meeting at least one CAGE criterion approached statistical significance (RR, 2.37; 95% CI, 0.96-5.84). Neither age greater than 35 years nor the presence of hepatitis B virus core antibody was associated with INH-hepatitis. CONCLUSIONS: The observed rates of INH-hepatitis were similar to published data. Six months of IPT, which is recommended by the World Health Organization, was relatively safe in this, the largest cohort of African PLWH. Clinical trial registered with www.clinicaltrials.gov (NCT 00164281).

Global Impact of Multidrug-Resistant Pulmonary Tuberculosis Among HIV-Infected and Other Immunocompromised Hosts: Epidemiology, Diagnosis, and Strategies for Management.

Multidrug-resistant (MDR) tuberculosis (TB), or TB caused by strains of Mycobacterium tuberculosis resistant to at least isoniazid and rifampicin, represents a major threat to global TB control. Comprising more than 5% of all TB cases annually worldwide, these cases require treatment duration of 2 years on average with expensive and toxic second-line anti-TB drugs. Cure rates are far lower and mortality far higher than for drug-susceptible TB, particularly if patients are coinfected with HIV. Use of rapid diagnostic tools and assessment of risk factors for MDR TB, as well as rapid initiation of MDR TB treatment as recommended by the World Health Organization, including use of appropriate empiric regimens as necessary, is essential to achieving good outcomes from treatment. Rapid initiation of antiretroviral therapy (ART) for those with HIV coinfection, as well as strategic management of overlapping side effects from ART and first and second-line drugs for treating MDR TB to maintain patients on treatment are critical to patient survival and achieving good treatment outcomes. Employing sensible infection control practices in the context of diagnosis and treatment is essential to reducing transmission of MDR TB strains among patient populations and healthcare personnel.

Isoniazid, rifampin, ethambutol, and pyrazinamide pharmacokinetics and treatment outcomes among a predominantly HIV-infected cohort of adults with tuberculosis from Botswana.

BACKGROUND: We explored the association between antituberculosis drug pharmacokinetics and treatment outcomes among patients with pulmonary tuberculosis in Botswana. METHODS: Consenting outpatients with tuberculosis had blood samples collected 1, 2, and 6 h after simultaneous isoniazid, rifampin, ethambutol, and pyrazinamide ingestion. Maximum serum concentrations (C(max)) and areas under the serum concentration time curve were determined. Clinical status was monitored throughout treatment. RESULTS: Of the 225 participants, 36 (16%) experienced poor treatment outcome (treatment failure or death); 155 (69%) were infected with human immunodeficiency virus (HIV). Compared with published standards, low isoniazid C(max) occurred in 84 patients (37%), low rifampin C(max) in 188 (84%), low ethambutol C(max) in 87 (39%), and low pyrazinamide C(max) in 11 (5%). Median rifampin and pyrazinamide levels differed significantly by HIV status and CD4 cell count category. Only pyrazinamide pharmacokinetics were significantly associated with treatment outcome; low pyrazinamide C(max) was associated with a higher risk of documented poor treatment outcome, compared with normal C(max) (50% vs. 16%; P < .01). HIV-infected patients with a CD4 cell count <200 cells/microL had a higher risk of poor treatment outcome (27%) than did HIV-uninfected patients (11%) or HIV-infected patients with a CD4 cell count 200 cells/microL (12%; P = .01). After adjustment for HIV infection and CD4 cell count, patients with low pyrazinamide C(max) were 3 times more likely than patients with normal pyrazinamide C(max) to have poor outcomes (adjusted risk ratio, 3.38; 95% confidence interval, 1.84-6.22). CONCLUSIONS: Lower than expected antituberculosis drug C(max) occurred frequently, and low pyrazinamide C(max) was associated with poor treatment outcome. Exploring the global prevalence and significance of these findings may suggest modifications in treatment regimens that could improve tuberculosis cure rates.

HIV care and treatment factors associated with improved survival during TB treatment in Thailand: an observational study.

BACKGROUND: In Southeast Asia, HIV-infected patients frequently die during TB treatment. Many physicians are reluctant to treat HIV-infected TB patients with anti-retroviral therapy (ART) and have questions about the added value of opportunistic infection prophylaxis to ART, the optimum ART regimen, and the benefit of initiating ART early during TB treatment. METHODS: We conducted a multi-center observational study of HIV-infected patients newly diagnosed with TB in Thailand. Clinical data was collected from the beginning to the end of TB treatment. We conducted multivariable proportional hazards analysis to identify factors associated with death. RESULTS: Of 667 HIV-infected TB patients enrolled, 450 (68%) were smear and/or culture positive. Death during TB treatment occurred in 112 (17%). In proportional hazards analysis, factors strongly associated with reduced risk of death were ART use (Hazard Ratio [HR] 0.16; 95% confidence interval [CI] 0.07-0.36), fluconazole use (HR 0.34; CI 0.18-0.64), and co-trimoxazole use (HR 0.41; CI 0.20-0.83). Among 126 patients that initiated ART after TB diagnosis, the risk of death increased the longer that ART was delayed during TB treatment. Efavirenz- and nevirapine-containing ART regimens were associated with similar rates of adverse events and death. CONCLUSION: Among HIV-infected patients living in Thailand, the single most important determinant of survival during TB treatment was use of ART. Controlled clinical trials are needed to confirm our findings that early ART initiation improves survival and that the choice of non-nucleoside reverse transcriptase inhibitor does not.

Multidrug-resistant TB and HIV in Thailand: overlapping, but not independently associated, risk factors.

The HIV and multi-drug resistant tuberculosis (MDR-TB) epidemics are closely linked. In Thailand as part of a sentinel surveillance system, we collected data prospectively about pulmonary TB cases treated in public clinics. A subset of HIV-infected TB patients identified through this system had additional data collected for a research study. We conducted multivariate analysis to identify factors associated with MDR-TB. Of 10,428 TB patients, 2,376 (23%) were HIV-infected; 145 (1%) had MDR-TB. Of the MDR-TB cases, 52 (37%) were HIV-infected. Independent risk factors for MDR-TB included age 18-29 years old, male sex, and previous TB treatment, but not HIV infection. Among new patients, having an injection drug use history was a risk factor for MDR-TB. Of 539 HIV-infected TB patients in the research study, MDR-TB was diagnosed in 19 (4%); the only significant risk factors were previous TB treatment and previous hepatitis. In Thailand, HIV is common among MDR-TB patients, but is not an independent risk factor for MDR-TB. Populations at high risk for HIV-young adults, men, injection drug users - should be prioritized for drug susceptibility testing.

Multi-drug resistant TB and HIV in Thailand: overlapping, but not independently associated risk factors.

The HIV and multi-drug resistant tuberculosis (MDR-TB) epidemics are closely linked. In Thailand as part of a sentinel surveillance system, we collected data prospectively about pulmonary TB cases treated in public clinics. A subset of HIV-infected TB patients identified through this system had additional data collected for a research study. We conducted multivariate analysis to identify factors associated with MDR-TB. Of 10,428 TB patients, 2,376 (23%) were HIV-infected; 145 (1%) had MDR-TB. Of the MDR-TB cases, 52 (37%) were HIV-infected. Independent risk factors for MDR-TB included age 18-29 years old, male sex, and previous TB treatment, but not HIV infection. Among new patients, having an injection drug use history was a risk factor for MDR-TB. Of 539 HIV-infected TB patients in the research study, MDR-TB was diagnosed in 19 (4%); the only significant risk factors were previous TB treatment and previous hepatitis. In Thailand, HIV is common among MDR-TB patients, but is not an independent risk factor for MDR-TB. Populations at high risk for HIV-young adults, men, injection drug users - should be prioritized for drug susceptibility testing.

Performance of the BACTEC MGIT 960 compared with solid media for detection of Mycobacterium in Bangkok, Thailand.

Controlled trials have demonstrated that liquid media culture (LMC) is superior to solid media culture for diagnosis of Mycobacterium tuberculosis (MTB), but there is limited evidence about its performance in resource-limited settings. We evaluated the performance of LMC in a demonstration project in Bangkok, Thailand. Sputum specimens from persons with suspected or clinically diagnosed tuberculosis were inoculated in parallel on solid (Lowenstein-Jensen [LJ]) and liquid (mycobacterial growth indicator tube [MGIT 960]) media. Biochemical tests identified isolates as MTB or nontuberculosis mycobacteria (NTM). Of 2566 specimens received from October 2004 to September 2006, 1355 (53%) were culture positive by MGIT compared with 1013 (39%) by LJ. Median time to growth for MGIT was significantly less than LJ: 11 versus 27 days. Of 1417 isolates detected by at least 1 media, 1255 (86%) were identified as MTB and 162 (11%) NTM. MGIT improved speed and sensitivity of MTB isolation and drug susceptibility testing, regardless of HIV status.

Childhood TB epidemiology and treatment outcomes in Thailand: a TB active surveillance network, 2004 to 2006.

BACKGROUND: Of the 9.2 million new TB cases occurring each year, about 10% are in children. Because childhood TB is usually non-infectious and non-fatal, national programs do not prioritize childhood TB diagnosis and treatment. We reviewed data from a demonstration project to learn more about the epidemiology of childhood TB in Thailand. METHODS: In four Thai provinces and one national hospital, we contacted healthcare facilities monthly to record data about persons diagnosed with TB, assist with patient care, provide HIV counseling and testing, and obtain sputum for culture and susceptibility testing. We analyzed clinical and treatment outcome data for patients age < 15 years old registered in 2005 and 2006. RESULTS: Only 279 (2%) of 14,487 total cases occurred in children. The median age of children was 8 years (range: 4 months, 14 years). Of 197 children with pulmonary TB, 63 (32%) were bacteriologically-confirmed: 56 (28%) were smear-positive and 7 (4%) were smear-negative, but culture-positive. One was diagnosed with multi-drug resistant TB. HIV infection was documented in 75 (27%). Thirteen (17%) of 75 HIV-infected children died during TB treatment compared with 4 (2%) of 204 not known to be HIV-infected (p < 0.01). CONCLUSION: Childhood TB is infrequently diagnosed in Thailand. Understanding whether this is due to absence of disease or diagnostic effort requires further research. HIV contributes substantially to the childhood TB burden in Thailand and is associated with high mortality.

Risk-based screening for latent tuberculosis infection.

BACKGROUND: National guidelines recommend targeted tuberculin testing and treatment of latent tuberculosis infection (LTBI) among high-risk groups but discourage testing low-risk persons. METHODS: We determined the LTBI prevalence (tuberculin skin test [TST] reaction > or = 10 mm) among adults with and without TB exposure risk factors screened in Tennessee from 1/2/2002 to 4/19/2005. We then quantified LTBI risk among groups at high-risk for TB using multivariate analysis. RESULTS: Of 53,061 adults tested, the LTBI prevalence was 34% among foreign-born persons, compared with 3.2% among nonforeign-born persons (prevalence odds ratio [POR] 15.7, 95% confidence interval [CI] 14.5-16.8). Among nonforeign-born adults, Asian race (POR 11.7, 95% CI 5.9-23.4), and Hispanic ethnicity (POR 11.7, 95% CI 9.0-15.2) were most strongly associated with LTBI. Only 2.4% of low-risk persons had LTBI. CONCLUSIONS: Risk-based screening can effectively distinguish persons who will benefit from LTBI testing and treatment. Targeted testing programs should prioritize foreign-born persons. Testing of low-risk persons is unnecessary.

Time to sputum culture conversion in multidrug-resistant tuberculosis: predictors and relationship to treatment outcome.

BACKGROUND: Conversion of sputum mycobacterial cultures from positive growth to negative growth of Mycobacterium tuberculosis in patients with pulmonary tuberculosis (TB) is considered the most important interim indicator of the efficacy of anti-TB pharmacologic treatment for multidrug-resistant disease. OBJECTIVE: To evaluate and compare time to and predictors of initial sputum culture conversion with predictors of treatment outcome for patients with multidrug-resistant TB. DESIGN: Retrospective cohort study. SETTING: Latvia. PATIENTS: All civilian patients with multidrug-resistant TB treated with the DOTS-Plus strategy between 1 January and 31 December 2000. INTERVENTION: Individualized treatment for confirmed sputum culture-positive pulmonary multidrug-resistant TB. MEASUREMENTS: Time to initial sputum culture conversion and treatment outcome. RESULTS: Among 167 patients who were sputum culture-positive at initiation of second-line therapy, 129 (77%) converted in a median time of 60 days (range, 4 to 462 days) and 38 (23%) did not convert. Independent predictors of a longer sputum culture conversion time, using an accelerated failure time regression model, included previous treatment for multidrug-resistant TB, high initial sputum culture colony count, bilateral cavitations on chest radiography, and the number of drugs the initial isolate was resistant to at treatment initiation. Treatment outcomes were statistically significantly worse for patients who did not convert their sputum culture within 2 months. LIMITATIONS: Twenty-five percent of patients missed 5 or more monthly sputum collections. CONCLUSIONS: Under program conditions in Latvia, most patients with multidrug-resistant TB achieved sputum culture conversion within 12 weeks of starting treatment. Chest radiography and sputum culture drug susceptibility testing can assist physicians in predicting which patients will convert more slowly. Sputum culture conversion is a useful and appropriate interim indicator of treatment outcome in patients with multidrug-resistant TB.