Four-month Regimens Research Articles

Efficacy and safety of an innovative short-course regimen containing clofazimine for treatment of drug-susceptible tuberculosis: a clinical trial

ABSTRACT In preclinical studies, a new antituberculosis drug regimen markedly reduced the time required to achieve relapse-free cure. This study aimed to preliminarily evaluate the efficacy and safety of this four-month regimen, consisting of clofazimine, prothionamide, pyrazinamide and ethambutol, with a standard six-month regimen in patients with drug-susceptible tuberculosis. An open-label pilot randomized clinical trial was conducted among the patients with newly diagnosed bacteriologically-confirmed pulmonary tuberculosis. The primary efficacy end-point was sputum culture negative conversion. Totally, 93 patients were included in the modified intention-to-treat population. The rates of sputum culture conversion were 65.2% (30/46) and 87.2% (41/47) for short-course and standard regimen group, respectively. There was no difference on two-month culture conversion rates, time to culture conversion, nor early bactericidal activity (P > 0.05). However, patients on short-course regimen were observed with lower rates of radiological improvement or recovery and sustained treatment success, which was mainly attributed to higher percent of patients permanently changed assigned regimen (32.1% vs. 12.3%, P = 0.012). The main cause for it was drug-induced hepatitis (16/17). Although lowering the dose of prothionamide was approved, the alternative option of changing assigned regimen was chosen in this study. While in per-protocol population, sputum culture conversion rates were 87.0% (20/23) and 94.4% (34/36) for the respective groups. Overall, the short-course regimen appeared to have inferior efficacy and higher incidence of hepatitis but desired efficacy in per-protocol population. It provides the first proof-of-concept in humans of the capacity of the short-course approach to identify drug regimens that can shorten the treatment time for tuberculosis.

Precision-Enhancing Risk Stratification Tools for Selecting Optimal Treatment Durations in Tuberculosis Clinical Trials.

Rationale: No evidence-based tools exist to enhance precision in the selection of patient-specific optimal treatment durations to study in tuberculosis clinical trials.Objectives: To develop risk stratification tools that assign patients with tuberculosis into risk groups of unfavorable outcome and inform selection of optimal treatment duration for each patient strata to study in clinical trials.Methods: Publicly available data from four phase 3 trials, each evaluating treatment duration shortening from 6 to 4 months, were used to develop parametric time-to-event models that describe unfavorable outcomes. Regimen, baseline, and on-treatment characteristics were evaluated as predictors of outcomes. Exact regression coefficients of predictors were used to assign risk groups and predict optimal treatment durations.Measurements and Main Results: The parametric model had an area under the receiver operating characteristic curve of 0.72. A six-item risk score (HIV status, smear grade, sex, cavitary disease status, body mass index, and Month 2 culture status) successfully grouped participants into low (1,060/3,791; 28%), moderate (1,740/3,791; 46%), and high (991/3,791; 26%) risk, requiring treatment durations of 4, 6, and greater than 6 months, respectively, to reach a target cure rate of 93% when receiving standard-dose rifamycin-containing regimens. With current one-duration-fits-all approaches, high-risk groups have a 3.7-fold (95% confidence interval, 2.7–5.1) and 2.4-fold (1.9–2.9) higher hazard risk of unfavorable outcomes compared with low- and moderate-risk groups, respectively. Four-month regimens were noninferior to the standard 6-month regimen in the low-risk group.Conclusions: Our model discrimination was modest but consistent with current models of unfavorable outcomes. Our results showed that stratified medicine approaches are feasible and may achieve high cure rates in all patients with tuberculosis. An interactive risk stratification tool is provided to facilitate decision-making in the regimen development pathway.

THC and CBD blood and brain concentrations following daily administration to adolescent primates

BackgroundCannabis availability with high concentrations of Δ-9-tetrahydrocannabinol (THC) and a range of THC to cannabidiol (CBD) ratios has increased in parallel with a rise in daily cannabis consumption by adolescents. Unanswered questions in adolescents include: 1) whether THC blood concentrations and THC metabolites remain stable or change with prolonged daily dosing, 2) whether CBD modulates THC pharmacokinetic properties and alters THC accumulation in brain, 3) whether blood THC levels reflect brain concentrations. MethodsIn adolescent squirrel monkeys (Saimiri boliviensis), we determined whether a four-month regimen of daily THC (1 mg/kg) or CBD (3 mg/kg) + THC (1 mg/kg) administration (IM) affects THC, THC metabolites, and CBD concentrations in blood or brain. ResultsBlood THC concentrations, THC metabolites and CBD remained stable during chronic treatment. 24 h after the final THC or CBD + THC injection, blood THC and CBD concentrations remained relatively high (THC: 6.0–11 ng/mL; CBD: 9.7−19 ng/mL). THC concentrations in cerebellum and occipital cortex were approximately twice those in blood 24 h after the last dose and did not significantly differ in subjects given THC or CBD + THC. ConclusionsIn adolescent monkeys, blood levels of THC, its metabolites or CBD remain stable after daily dosing for four months. Our model suggests that any pharmacological interactions between CBD and THC are unlikely to result from CBD modulation of THC pharmacokinetics. Finally, detection of relatively high brain THC concentrations 24 h after the final dose of THC suggests that the prolonged actions of THC may contribute to persistent cognitive and psychomotor disruption after THC- or cannabis-induced euphoria wane.

High-dose rifapentine with or without moxifloxacin for shortening treatment of pulmonary tuberculosis: Study protocol for TBTC study 31/ACTG A5349 phase 3 clinical trial

IntroductionPhase 2 clinical trials of tuberculosis treatment have shown that once-daily regimens in which rifampin is replaced by high dose rifapentine have potent antimicrobial activity that may be sufficient to shorten overall treatment duration. Herein we describe the design of an ongoing phase 3 clinical trial testing the hypothesis that once-daily regimens containing high dose rifapentine in combination with other anti-tuberculosis drugs administered for four months can achieve cure rates not worse than the conventional six-month treatment regimen. Methods/DesignS31/A5349 is a multicenter randomized controlled phase 3 non-inferiority trial that compares two four-month regimens with the standard six-month regimen for treating drug-susceptible pulmonary tuberculosis in HIV-negative and HIV-positive patients. Both of the four-month regimens contain high-dose rifapentine instead of rifampin, with ethambutol replaced by moxifloxacin in one regimen. All drugs are administered seven days per week, and under direct observation at least five days per week. The primary outcome is tuberculosis disease-free survival at twelve months after study treatment assignment. A total of 2500 participants will be randomized; this gives 90% power to show non-inferiority with a 6.6% margin of non-inferiority. DiscussionThis phase 3 trial formally tests the hypothesis that augmentation of rifamycin exposures can shorten tuberculosis treatment to four months. Trial design and standardized implementation optimize the likelihood of obtaining valid results. Results of this trial may have important implications for clinical management of tuberculosis at both individual and programmatic levels.Trial registration:NCT02410772. Registered 8 April 2015,https://www.clinicaltrials.gov/ct2/show/NCT02410772?term=02410772&rank=1

Shortened treatment regimens versus the standard regimen for drug-sensitive pulmonary tuberculosis.

Shortened treatment regimens versus the standard regimen for drug-sensitive pulmonary tuberculosis.

A patient-level pooled analysis of treatment-shortening regimens for drug-susceptible pulmonary tuberculosis

Tuberculosis kills more people than any other infectious disease. Three pivotal trials testing 4-month regimens failed to meet non-inferiority margins; however, approximately four-fifths of participants were cured. Through a pooled analysis of patient-level data with external validation, we identify populations eligible for 4-month treatment, define phenotypes that are hard to treat and evaluate the impact of adherence and dosing strategy on outcomes. In 3,405 participants included in analyses, baseline smear grade of 3+ relative to <2+, HIV seropositivity and adherence of ≤90% were significant risk factors for unfavorable outcome. Four-month regimens were non-inferior in participants with minimal disease defined by <2+ sputum smear grade or non-cavitary disease. A hard-to-treat phenotype, defined by high smear grades and cavitation, may require durations >6 months to cure all. Regimen duration can be selected in order to improve outcomes, providing a stratified medicine approach as an alternative to the ‘one-size-fits-all’ treatment currently used worldwide.

Shortened treatment regimens versus the standard regimen for drug-sensitive pulmonary tuberculosis

Shortened treatment regimens versus the standard regimen for drug-sensitive pulmonary tuberculosis

Cost and cost-effectiveness of tuberculosis treatment shortening: a model-based analysis.

BackgroundDespite improvements in treatment success rates for tuberculosis (TB), current six-month regimen duration remains a challenge for many National TB Programmes, health systems, and patients. There is increasing investment in the development of shortened regimens with a number of candidates in phase 3 trials.MethodsWe developed an individual-based decision analytic model to assess the cost-effectiveness of a hypothetical four-month regimen for first-line treatment of TB, assuming non-inferiority to current regimens of six-month duration. The model was populated using extensive, empirically-collected data to estimate the economic impact on both health systems and patients of regimen shortening for first-line TB treatment in South Africa, Brazil, Bangladesh, and Tanzania. We explicitly considered ‘real world’ constraints such as sub-optimal guideline adherence.ResultsFrom a societal perspective, a shortened regimen, priced at USD1 per day, could be a cost-saving option in South Africa, Brazil, and Tanzania, but would not be cost-effective in Bangladesh when compared to one gross domestic product (GDP) per capita. Incorporating ‘real world’ constraints reduces cost-effectiveness. Patient-incurred costs could be reduced in all settings. From a health service perspective, increased drug costs need to be balanced against decreased delivery costs. The new regimen would remain a cost-effective option, when compared to each countries’ GDP per capita, even if new drugs cost up to USD7.5 and USD53.8 per day in South Africa and Brazil; this threshold was above USD1 in Tanzania and under USD1 in Bangladesh.ConclusionReducing the duration of first-line TB treatment has the potential for substantial economic gains from a patient perspective. The potential economic gains for health services may also be important, but will be context-specific and dependent on the appropriate pricing of any new regimen.Electronic supplementary materialThe online version of this article (doi:10.1186/s12879-016-2064-3) contains supplementary material, which is available to authorized users.

The Impact and Cost-Effectiveness of a Four-Month Regimen for First-Line Treatment of Active Tuberculosis in South Africa.

BackgroundA 4-month first-line treatment regimen for tuberculosis disease (TB) is expected to have a direct impact on patient outcomes and societal costs, as well as an indirect impact on Mycobacterium tuberculosis transmission. We aimed to estimate this combined impact in a high TB-burden country: South Africa.MethodAn individual based M. tb transmission model was fitted to the TB burden of South Africa using a standard TB natural history framework. We measured the impact on TB burden from 2015–2035 of introduction of a non-inferior 4-month regimen replacing the standard 6-month regimen as first-line therapy. Impact was measured with respect to three separate baselines (Guidelines, Policy and Current), reflecting differences in adherence to TB and HIV treatment guidelines. Further scenario analyses considered the variation in treatment-related parameters and resistance levels. Impact was measured in terms of differences in TB burden and Disability Adjusted Life Years (DALYs) averted. We also examined the highest cost at which the new regimen would be cost-effective for several willingness-to-pay thresholds.ResultsIt was estimated that a 4-month regimen would avert less than 1% of the predicted 6 million person years with TB disease in South Africa between 2015 and 2035. A similarly small impact was seen on deaths and DALYs averted. Despite this small impact, with the health systems and patient cost savings from regimen shortening, the 4-month regimen could be cost-effective at $436 [NA, 5983] (mean [range]) per month at a willingness-to-pay threshold of one GDP per capita ($6,618).ConclusionThe introduction of a non-inferior 4-month first-line TB regimen into South Africa would have little impact on the TB burden. However, under several scenarios, it is likely that the averted societal costs would make such a regimen cost-effective in South Africa.

Shortened first-line TB treatment in Brazil: potential cost savings for patients and health services.

BackgroundShortened treatment regimens for tuberculosis are under development to improve treatment outcomes and reduce costs. We estimated potential savings from a societal perspective in Brazil following the introduction of a hypothetical four-month regimen for tuberculosis treatment.MethodsData were gathered in ten randomly selected health facilities in Rio de Janeiro. Health service costs were estimated using an ingredient approach. Patient costs were estimated from a questionnaire administered to 126 patients. Costs per visits and per case treated were analysed according to the type of therapy: self-administered treatment (SAT), community- and facility-directly observed treatment (community-DOT, facility-DOT).ResultsDuring the last 2 months of treatment, the largest savings could be expected for community-DOT; on average USD 17,351-18,203 and USD 43,660-45,856 (bottom-up and top-down estimates) per clinic. Savings to patients could also be expected as the median (interquartile range) patient-related costs during the two last months were USD 108 (13–291), USD 93 (36–239) and USD 11 (7–126), respectively for SAT, facility-DOT and community-DOT.ConclusionIntroducing a four-month regimen may result in significant cost savings for both the health service and patients, especially the poorest. In particular, a community-DOT strategy, including treatment at home, could maximise health services savings while limiting patient costs. Our cost estimates are likely to be conservative because a 4-month regimen could hypothetically increase the proportion of patients cured by reducing the number of patients defaulting and we did not include the possible cost benefits from the subsequent prevention of costs due to downstream transmission averted and rapid clinical improvement with less side effects in the last two months.Electronic supplementary materialThe online version of this article (doi:10.1186/s12913-016-1269-x) contains supplementary material, which is available to authorized users.

Month 2 Culture Status and Treatment Duration as Predictors of Recurrence in Pulmonary Tuberculosis: Model Validation and Update

BackgroundNew regimens capable of shortening tuberculosis treatment without increasing the risk of recurrence are urgently needed. A 2013 meta-regression analysis, using data from trials published from 1973 to 1997 involving 7793 patients, identified 2-month sputum culture status and treatment duration as independent predictors of recurrence. The resulting model predicted that if a new 4-month regimen reduced the proportion of patients positive at month 2 to 1%, it would reduce to 10% the risk of a relapse rate >10% in a trial with 680 subjects per arm. The 1% target was far lower than anticipated.MethodsData from the 8 arms of 3 recent unsuccessful phase 3 treatment-shortening trials of fluoroquinolone-substituted regimens (REMox, OFLOTUB, and RIFAQUIN) were used to assess and refine the accuracy of the 2013 meta-regression model. The updated model was then tested using data from a treatment shortening trial reported in 2009 by Johnson et al.FindingsThe proportions of patients with recurrence as predicted by the 2013 model were highly correlated with observed proportions as reported in the literature (R2 = 0.86). Using the previously proposed threshold of 10% recurrences as the maximum likely considered acceptable by tuberculosis control programs, the original model correctly identified all 4 six-month regimens as satisfactory, and 3 of 4 four-month regimens as unsatisfactory (sensitivity = 100%, specificity = 75%, PPV = 80%, and NPV = 100%). A revision of the regression model based on the full dataset of 66 regimens and 11181 patients resulted in only minimal changes to its predictions. A test of the revised model using data from the treatment shortening trial of Johnson et al found the reported relapse rates in both arms to be consistent with predictions.InterpretationMeta-regression modeling of recurrence based on month 2 culture status and regimen duration can inform the design of future phase 3 tuberculosis clinical trials.

Population-level impact of shorter-course regimens for tuberculosis: a model-based analysis.

Despite current control efforts, global tuberculosis (TB) incidence is decreasing slowly. New regimens that can shorten treatment hold promise for improving treatment completion and success, but their impact on population-level transmission remains unclear. Earlier models projected that a four-month regimen could reduce TB incidence by 10% but assumed that an entire course of therapy must be completed to derive any benefit. We constructed a dynamic transmission model of TB disease calibrated to global estimates of incidence, prevalence, mortality, and treatment success. To account for the efficacy of partial treatment, we used data from clinical trials of early short-course regimens to estimate relapse rates among TB patients who completed one-third, one-half, two-thirds, and all of their first-line treatment regimens. We projected population-level incidence and mortality over 10 years, comparing standard six-month therapy to hypothetical shorter-course regimens with equivalent treatment success but fewer defaults. The impact of hypothetical four-month regimens on TB incidence after 10 years was smaller than estimated in previous modeling analyses (1.9% [95% uncertainty range 0.6–3.1%] vs. 10%). Impact on TB mortality was larger (3.5% at 10 years) but still modest. Transmission impact was most sensitive to the proportion of patients completing therapy: four-month therapy led to greater incidence reductions in settings where 25% of patients leave care (“default”) over six months. Our findings remained robust under one-way variation of model parameters. These findings suggest that novel regimens that shorten treatment duration may have only a modest effect on TB transmission except in settings of very low treatment completion.

The Comparison of Six-month and Four-month Regimens of Chemotherapy in the Treatment of Smear Positive Pulmonary Tuberculosis

The Comparison of Six-month and Four-month Regimens of Chemotherapy in the Treatment of Smear Positive Pulmonary Tuberculosis

Traitement de la tuberculose pleurale par un régime court de 4 mois : résultats préliminaires

The aim of this prospective study was to evaluate the results of a four-month regimen (2HRZ/2HR) in the treatment of isolated tuberculous pleurisy with effusion. It included 68 patients presenting with histologically confirmed tuberculous pleurisy treated with 2HRZ/2HR, physiotherapy and aspiration of the pleura. Patients were seen every 2 months during treatment, and then 1, 3, 4, 6, 12, and 24 months after the end of treatment. Preliminary results show a favourable response in 58 patients (85%) and minimal pleural thickening in 10 patients. There were no failures, no relapses nor any extrapleural dissemination after a follow-up period of on average 20 months. These encouraging results need to be evaluated in a long-term study.

Clinical trial of six-month and four-month regimens of chemotherapy in the treatment of pulmonary tuberculosis: The results up to 30 months

In a study in Singapore, Chinese, Malay and Indian patients with pulmonary tuberculosis received 2 months of daily treatment with streptomycin, isoniazid, rifampicin, and pyrazinamide followed by daily isoniazid, and rifampicin either with pyrazinamide (SHRZ/HRZ) or without it (SHRZ/HR), allocated at random. Both regimens were given for either 6 or 4 months by random allocation. All 330 patients with drug-sensitive tubercle bacilli pretreatment had a favourable bacteriological response during chemotherapy. After chemotherapy none of 78 SHRZ/HRZ patients and only 2 of 80 SHRZ/HR patients treated for 6 months relapsed bacteriologically, but 9 (11 %) of 79 SHRZ/HRZ and 6 (8 %) of 77 SHRZ/HR patients treated for 4 months relapsed. Of 33 patients with bacilli resistant to isoniazid, streptomycin, or both drugs pretreatment, only 1 had an unfavourable response during chemotherapy; none of 9 patients treated for 6 months and 2 of 22 treated for 4 months relapsed bacteriologically after stopping chemotherapy.

Clinical trial of six-month and four-month regimens of chemotherapy in the treatment of pulmonary tuberculosis.

In a study in Singapore, Chinese, Malay, and Indian patients with pulmonary tuberculosis received 2 months of daily treatment with streptomycin, isoniazid, rifampin, and pyrazinamide followed either by daily treatment with isoniazid, rifampin, and pyrazinamide (SHRZ/HRZ regimen) or by daily administration of isoniazid and rifampin (SHRZ/HR regimen) allocated at random. Both regimens were given for either 6 or 4 months by random allocation. All 330 patients with drug-sensitive tubercle bacilli before treatment had a favorable bacteriologic response during chemotherapy. During the first 6 months after the end of chemotherapy, there was only a single bacteriologic relapse among 84 SHRZ/HRZ and 80 SHRZ/HR patients treated for 6 months, but 8 (10 per cent) of 80 SHRZ/HRZ and 4 (5 per cent) of 74 SHRZ/HR patients treated for 4 months relapsed. Of a total of 33 patients with bacilli resistant to isoniazid, streptomycin, or both drugs before treatment, only one had an unfavorable response during chemotherapy, and none of 31 patients relapsed during the first 6 months after stopping chemotherapy. The incidence of adverse reactions was low; 11 (3 per cent) of 397 patients had hepatitis, but not all episodes were attributable to drug toxicity, and one patient had thrombocytopenic purpura.