High-dose rifampicin, moxifloxacin, and SQ109 for treating tuberculosis: a multi-arm, multi-stage randomised controlled trial

BACKGROUND: Tuberculosis is the world's leading infectious disease killer. We aimed to identify shorter, safer drug regimens for the treatment of tuberculosis. METHODS: We did a randomised controlled, open-label trial with a multi-arm, multi-stage design. The trial was done in seven sites in South Africa and Tanzania, including hospitals, health centres, and clinical trial centres. Patients with newly diagnosed, rifampicin-sensitive, previously untreated pulmonary tuberculosis were randomly assigned in a 1:1:1:1:2 ratio to receive (all orally) either 35 mg/kg rifampicin per day with 15–20 mg/kg ethambutol, 20 mg/kg rifampicin per day with 400 mg moxifloxacin, 20 mg/kg rifampicin per day with 300 mg SQ109, 10 mg/kg rifampicin per day with 300 mg SQ109, or a daily standard control regimen (10 mg/kg rifampicin, 5 mg/kg isoniazid, 25 mg/kg pyrazinamide, and 15–20 mg/kg ethambutol). Experimental treatments were given with oral 5 mg/kg isoniazid and 25 mg/kg pyrazinamide per day for 12 weeks, followed by 14 weeks of 5 mg/kg isoniazid and 10 mg/kg rifampicin per day. Because of the orange discoloration of body fluids with higher doses of rifampicin it was not possible to mask patients and clinicians to treatment allocation. The primary endpoint was time to culture conversion in liquid media within 12 weeks. Patients without evidence of rifampicin resistance on phenotypic test who took at least one dose of study treatment and had one positive culture on liquid or solid media before or within the first 2 weeks of treatment were included in the primary analysis (modified intention to treat). Time-to-event data were analysed using a Cox proportional-hazards regression model and adjusted for minimisation variables. The proportional hazard assumption was tested using Schoelfeld residuals, with threshold p<0·05 for non-proportionality. The trial is registered with ClinicalTrials.gov (NCT01785186). FINDINGS: Between May 7, 2013, and March 25, 2014, we enrolled and randomly assigned 365 patients to different treatment arms (63 to rifampicin 35 mg/kg, isoniazid, pyrazinamide, and ethambutol; 59 to rifampicin 10 mg/kg, isoniazid, pyrazinamide, SQ109; 57 to rifampicin 20 mg/kg, isoniazid, pyrazinamide, and SQ109; 63 to rifampicin 10 mg/kg, isoniazid, pyrazinamide, and moxifloxacin; and 123 to the control arm). Recruitment was stopped early in the arms containing SQ109 since prespecified efficacy thresholds were not met at the planned interim analysis. Time to stable culture conversion in liquid media was faster in the 35 mg/kg rifampicin group than in the control group (median 48 days vs 62 days, adjusted hazard ratio 1·78; 95% CI 1·22–2·58, p=0·003), but not in other experimental arms. There was no difference in any of the groups in time to culture conversion on solid media. 11 patients had treatment failure or recurrent disease during post-treatment follow-up: one in the 35 mg/kg rifampicin arm and none in the moxifloxacin arm. 45 (12%) of 365 patients reported grade 3–5 adverse events, with similar proportions in each arm. INTERPRETATION: A dose of 35 mg/kg rifampicin was safe, reduced the time to culture conversion in liquid media, and could be a promising component of future, shorter regimens. Our adaptive trial design was successfully implemented in a multi-centre, high tuberculosis burden setting, and could speed regimen development at reduced cost. FUNDING: The study was funded by the European and Developing Countries Clinical Trials partnership (EDCTP), the German Ministry for Education and Research (BmBF), and the Medical Research Council UK (MRC)

Tuberculosis lymphadenitis, a diagnostic problem in areas of high prevalence of HIV and tuberculosis

No Abstrac

Operational research in Malawi: making a difference with cotrimoxazole preventive therapy in patients with tuberculosis and HIV.

BACKGROUND: In Malawi, high case fatality rates in patients with tuberculosis, who were also co-infected with HIV, and high early death rates in people living with HIV during the initiation of antiretroviral treatment (ART) adversely impacted on treatment outcomes for the national tuberculosis and ART programmes respectively. This article i) discusses the operational research that was conducted in the country on cotrimoxazole preventive therapy, ii) outlines the steps that were taken to translate these findings into national policy and practice, iii) shows how the implementation of cotrimoxazole preventive therapy for both TB patients and HIV-infected patients starting ART was associated with reduced death rates, and iv) highlights lessons that can be learnt for other settings and interventions. DISCUSSION: District and facility-based operational research was undertaken between 1999 and 2005 to assess the effectiveness of cotrimoxazole preventive therapy in reducing death rates in TB patients and subsequently in patients starting ART under routine programme conditions. Studies demonstrated significant reductions in case fatality in HIV-infected TB patients receiving cotrimoxazole and in HIV-infected patients about to start ART. Following the completion of research, the findings were rapidly disseminated nationally at stakeholder meetings convened by the Ministry of Health and internationally through conferences and peer-reviewed scientific publications. The Ministry of Health made policy changes based on the available evidence, following which there was countrywide distribution of the updated policy and guidelines. Policy was rapidly moved to practice with the development of monitoring tools, drug procurement and training packages. National programme performance improved which showed a significant decrease in case fatality rates in TB patients as well as a reduction in early death in people with HIV starting ART. SUMMARY: Key lessons for moving this research endeavour through to policy and practice were the importance of placing operational research within the programme, defining relevant questions, obtaining "buy-in" from national programme staff at the beginning of projects and having key actors or "policy entrepreneurs" to push forward the policy-making process. Ultimately, any change in policy and practice has to benefit patients, and the ultimate judge of success is whether treatment outcomes improve or not

Short-Course, High-Dose Rifampicin Achieves Wolbachia Depletion Predictive of Curative Outcomes in Preclinical Models of Lymphatic Filariasis and Onchocerciasis

Lymphatic filariasis (LF) and onchocerciasis are priority neglected tropical diseases targeted for elimination. The only safe drug treatment with substantial curative activity against the filarial nematodes responsible for LF (Brugia malayi, Wuchereria bancrofti) or onchocerciasis (Onchocerca volvulus) is doxycycline. The target of doxycycline is the essential endosymbiont, Wolbachia. Four to six weeks doxycycline therapy achieves >90% depletion of Wolbachia in worm tissues leading to blockade of embryogenesis, adult sterility and premature death 18–24 months post-treatment. Long treatment length and contraindications in children and pregnancy are obstacles to implementing doxycycline as a public health strategy. Here we determine, via preclinical infection models of Brugia malayi or Onchocerca ochengi that elevated exposures of orally-administered rifampicin can lead to Wolbachia depletions from filariae more rapidly than those achieved by doxycycline. Dose escalation of rifampicin achieves >90% Wolbachia depletion in time periods of 7 days in B. malayi and 14 days in O. ochengi. Using pharmacokinetic-pharmacodynamic modelling and mouse-human bridging analysis, we conclude that clinically relevant dose elevations of rifampicin, which have recently been determined as safe in humans, could be administered as short courses to filariasis target populations with potential to reduce anti-Wolbachia curative therapy times to between one and two weeks

National policy development for cotrimoxazole prophylaxis in Malawi, Uganda and Zambia: the relationship between Context, Evidence and Links

BACKGROUND: Several frameworks have been constructed to analyse the factors which influence and shape the uptake of evidence into policy processes in resource poor settings, yet empirical analyses of health policy making in these settings are relatively rare. National policy making for cotrimoxazole (trimethoprim-sulfamethoxazole) preventive therapy in developing countries offers a pertinent case for the application of a policy analysis lens. The provision of cotrimoxazole as a prophylaxis is an inexpensive and highly efficacious preventative intervention in HIV infected individuals, reducing both morbidity and mortality among adults and children with HIV/AIDS, yet evidence suggests that it has not been quickly or evenly scaled-up in resource poor settings. METHODS: Comparative analysis was conducted in Malawi, Uganda and Zambia, using the case study approach. We applied the 'RAPID' framework developed by the Overseas Development Institute (ODI), and conducted a total of 47 in-depth interviews across the three countries to examine the influence of context (including the influence of donor agencies), evidence (both local and international), and the links between researcher, policy makers and those seeking to influence the policy process. RESULTS: Each area of analysis was found to have an influence on the creation of national policy on cotrimoxazole preventive therapy (CPT) in all three countries. In relation to context, the following were found to be influential: government structures and their focus, donor interest and involvement, healthcare infrastructure and other uses of cotrimoxazole and related drugs in the country. In terms of the nature of the evidence, we found that how policy makers perceived the strength of evidence behind international recommendations was crucial (if evidence was considered weak then the recommendations were rejected). Further, local operational research results seem to have been taken up more quickly, while randomised controlled trials (the gold standard of clinical research) was not necessarily translated into policy so swiftly. Finally the links between different research and policy actors were of critical importance, with overlaps between researcher and policy maker networks crucial to facilitate knowledge transfer. Within these networks, in each country the policy development process relied on a powerful policy entrepreneur who helped get cotrimoxazole preventive therapy onto the policy agenda. CONCLUSIONS: This analysis underscores the importance of considering national level variables in the explanation of the uptake of evidence into national policy settings, and recognising how local policy makers interpret international evidence. Local priorities, the ways in which evidence was interpreted, and the nature of the links between policy makers and researchers could either drive or stall the policy process. Developing the understanding of these processes enables the explanation of the use (or non-use) of evidence in policy making, and potentially may help to shape future strategies to bridge the research-policy gaps and ultimately improve the uptake of evidence in decision making

Pharmacokinetics of rifampicin in adult TB patients and healthy volunteers: a systematic review and meta-analysis

Objectives: The objectives of this study were to explore inter-study heterogeneity in the pharmacokinetics (PK) of orally administered rifampicin, to derive summary estimates of rifampicin PK parameters at standard dosages and to compare these with summary estimates for higher dosages. Methods: A systematic search was performed for studies of rifampicin PK published in the English language up to May 2017. Data describing the Cmax and AUC were extracted. Meta-analysis provided summary estimates for PK parameter estimates at standard rifampicin dosages. Heterogeneity was assessed by estimation of the I2 statistic and visual inspection of forest plots. Summary AUC estimates at standard and higher dosages were compared graphically and contextualized using preclinical pharmacodynamic (PD) data. Results: Substantial heterogeneity in PK parameters was evident and upheld in meta-regression. Treatment duration had a significant impact on the summary estimates for rifampicin PK parameters, with Cmax 8.98 mg/L (SEM 2.19) after a single dose and 5.79 mg/L (SEM 2.14) at steady-state dosing, and AUC 72.56 mg.h/L (SEM 2.60) and 38.73 mg.h/L (SEM 4.33) after single and steady-state dosing, respectively. Rifampicin dosages of at least 25 mg/kg are required to achieve plasma PK/PD targets defined in preclinical studies. Conclusions: Vast inter-study heterogeneity exists in rifampicin PK parameter estimates. This is not explained by the available modifying variables. The recommended dosage of rifampicin should be increased to improve efficacy. This study provides an important point of reference for understanding rifampicin PK at standard dosages as efforts to explore higher dosing strategies continue in this field

HIV-Associated TB in An Giang Province, Vietnam, 2001–2004: Epidemiology and TB Treatment Outcomes

BACKGROUND: Mortality is high in HIV-infected TB patients, but few studies from Southeast Asia have documented the benefits of interventions, such as co-trimoxazole (CTX), in reducing mortality during TB treatment. To help guide policy in Vietnam, we studied the epidemiology of HIV-associated TB in one province and examined factors associated with outcomes, including the impact of CTX use. METHODOLOGY/PRINCIPAL FINDINGS: We retrospectively abstracted data for all HIV-infected persons diagnosed with TB from 2001-2004 in An Giang, a province in southern Vietnam in which TB patients receive HIV counseling and testing. We used standard WHO definitions to classify TB treatment outcomes. We conducted multivariate analysis to identify risk factors for the composite outcome of death, default, or treatment failure during TB treatment. From 2001-2004, 637 HIV-infected TB patients were diagnosed in An Giang. Of these, 501 (79%) were male, 321 (50%) were aged 25-34 years, and the most common self-reported HIV risk factor was sex with a commercial sex worker in 221 (35%). TB was classified as smear-positive in 531 (83%). During TB treatment, 167 (26%) patients died, 9 (1%) defaulted, and 6 (1%) failed treatment. Of 454 patients who took CTX, 116 (26%) had an unsuccessful outcome compared with 33 (70%) of 47 patients who did not take CTX (relative risk, 0.4; 95% confidence interval [CI], 0.3-0.5). Adjusting for male sex, rural residence, TB smear status and disease location, and the occurrence of adverse events during TB treatment in multivariate analysis, the benefit of CTX persisted (adjusted odds ratio for unsuccessful outcome 0.1; CI, 0.1-0.3). CONCLUSIONS/SIGNIFICANCE: In An Giang, Vietnam, HIV-associated TB was associated with poor TB treatment outcomes. Outcomes were significantly better in those taking CTX. This finding suggests that Vietnam should consider applying WHO recommendations to prescribe CTX to all HIV-infected TB patients

Evaluation of high-dose rifampin in patients with new, smear-positive tuberculosis (HIRIF): study protocol for a randomized controlled trial.

BACKGROUND: Evidence has existed for decades that higher doses of rifampin may be more effective, but potentially more toxic, than standard doses used in tuberculosis treatment. Whether increased doses of rifampin could safely shorten treatment remains an open question. METHODS/DESIGN: The HIRIF study is a phase II randomized trial comparing rifampin doses of 20 and 15 mg/kg/day to the standard 10 mg/kg/day for the first 2 months of tuberculosis treatment. All participants receive standard doses of companion drugs and a standard continuation-phase treatment (4 months, 2 drugs). They are followed for 6 months post treatment. Study participants are adults with newly diagnosed, previously untreated, smear positive (≥2+) pulmonary tuberculosis. The primary outcome is rifampin area under the plasma concentration-time curve (AUC0-24) after at least 14 days of study treatment/minimum inhibitory concentration. 180 randomized participants affords 90 % statistical power to detect a difference of at least 14 mcg/mL*hr between the 20 mg/kg group and the 10 mg/kg group, assuming a loss to follow-up of up to 17 %. DISCUSSION: Extant evidence suggests the potential for increased doses of rifampin to shorten tuberculosis treatment duration. Early studies that explored this potential using intermittent, higher dosing were derailed by toxicity. Given the continued large, global burden of tuberculosis with nearly 10 million new cases annually, shortened regimens with existing drugs would offer an important advantage to patients and health systems. TRIAL REGISTRATION: This trial was registered with clinicaltrials.gov (registration number: NCT01408914 ) on 2 August 2011

The Effect of Tuberculosis on Mortality in HIV Positive People: A Meta-Analysis

Tuberculosis is a leading cause of death in people living with HIV (PLWH). We conducted a meta analysis to assess the effect of tuberculosis on mortality in people living with HIV. Meta-analysis of cohort studies assessing the effect of tuberculosis on mortality in PLWH. To identify eligible studies we systematically searched electronic databases (until December 2008), performed manual searches of citations from relevant articles, and reviewed conference proceedings. Multivariate hazard ratios (HR) of mortality in PLWH with and without tuberculosis, estimated in individual cohort studies, were pooled using random effect weighting according to "Der Simonian Laird method" if the p-value of the heterogeneity test was <0.05. Fifteen cohort studies were systematically retrieved. Pooled overall analysis of these 15 studies estimating the effect of tuberculosis on mortality in PLWH showed a Hazard Ratio (HR) of 1.8 (95% confidence interval (CI): 1.4-2.3). Subanalysis of 8 studies in which the cohort was not exposed to highly active antiretroviral therapy (HAART) showed an HR of 2.6 (95% CI: 1.8-3.6). Subanalysis of 6 studies showed that tuberculosis did not show an effect on mortality in PLWH exposed to HAART: HR 1.1 (95% CI: 0.9-1.3). These results provide an indication of the magnitude of benefit to an individual that could have been expected if tuberculosis had been prevented. It emphasizes the need for additional studies assessing the effect of preventing tuberculosis or early diagnosis and treatment of tuberculosis in PLWH on reducing mortality. Furthermore, the results of the subgroup analyses in cohorts largely exposed to HAART provide additional support to WHO's revised guidelines, which include promoting the initiation of HAART for PLWH co-infected with tuberculosis. The causal effect of tuberculosis on mortality in PLWH exposed to HAART needs to be further evaluated once the results of more cohort studies become availabl

Magnetic resonance imaging of anterior cruciate ligament rupture

BACKGROUND: Magnetic resonance (MR) imaging is a useful diagnostic tool for the assessment of knee joint injury. Anterior cruciate ligament repair is a commonly performed orthopaedic procedure. This paper examines the concordance between MR imaging and arthroscopic findings. METHODS: Between February, 1996 and February, 1998, 48 patients who underwent magnetic resonance (MR) imaging of the knee were reported to have complete tears of the anterior cruciate ligament (ACL). Of the 48 patients, 36 were male, and 12 female. The average age was 27 years (range: 15 to 45). Operative reconstruction using a patellar bone-tendon-bone autograft was arranged for each patient, and an arthroscopic examination was performed to confirm the diagnosis immediately prior to reconstructive surgery. RESULTS: In 16 of the 48 patients, reconstructive surgery was cancelled when incomplete lesions were noted during arthroscopy, making reconstructive surgery unnecessary. The remaining 32 patients were found to have complete tears of the ACL, and therefore underwent reconstructive surgery. Using arthroscopy as an independent, reliable reference standard for ACL tear diagnosis, the reliability of MR imaging was evaluated. The true positive rate for complete ACL tear diagnosis with MR imaging was 67%, making the possibility of a false-positive report of "complete ACL tear" inevitable with MR imaging. CONCLUSIONS: Since conservative treatment is sufficient for incomplete ACL tears, the decision to undertake ACL reconstruction should not be based on MR findings alone