rifapentine and Latent-Tuberculosis

3 months of weekly rifapentine plus isoniazid (3HP) and 4 months of daily rifampicin (4R) are recommended for tuberculosis preventive treatment. As these regimens have not been compared directly, we used individual patient data and network meta-analysis methods to compare completion, safety, and efficacy between 3HP and 4R.. We conducted a network meta-analysis of individual patient data by searching PubMed for randomised controlled trials (RCTs) published between Jan 1, 2000, and Mar 1, 2019. Eligible studies compared 3HP or 4R to 6 months or 9 months of isoniazid and reported treatment completion, adverse events, or incidence of tuberculosis disease. Deidentified individual patient data from eligible studies were provided by study investigators and outcomes were harmonised. Methods for network meta-analysis were used to generate indirect adjusted risk ratios (aRRs) and risk differences (aRDs) with their 95% CIs.. We included 17 572 participants from 14 countries in six trials. In the network meta-analysis, treatment completion was higher for people on 3HP than for those on 4R (aRR 1·06 [95% CI 1·02-1·10]; aRD 0·05 [95% CI 0·02-0·07]). For treatment-related adverse events leading to drug discontinuation, risks were higher for 3HP than for 4R for adverse events of any severity (aRR 2·86 [2·12-4·21]; aRD 0·03 [0·02-0·05]) and for grade 3-4 adverse events (aRR 3·46 [2·09-6·17]; aRD 0·02 [0·01-0·03]). Similar increased risks with 3HP were observed with other definitions of adverse events and were consistent across age groups. No difference in the incidence of tuberculosis disease between 3HP and 4R was found.. In the absence of RCTs, our individual patient data network meta-analysis indicates that 3HP provided an increase in treatment completion over 4R, but was associated with a higher risk of adverse events. Although findings should be confirmed, the trade-off between completion and safety must be considered when selecting a regimen for tuberculosis preventive treatment.. None.. For the French and Spanish translations of the abstract see Supplementary Materials section.

Topics: Antitubercular Agents; Drug Therapy, Combination; Humans; Isoniazid; Latent Tuberculosis; Network Meta-Analysis; Rifampin; Tuberculosis

The mainstay therapy for latent tuberculosis infection is a 9-month regimen of daily isoniazid (9H) and a 3-month regimen of 12 once-weekly doses of isoniazid and rifapentine (3HP). We performed this updated meta-analysis to compare hepatotoxicity, efficacy and completion rate between these two regimens.. We searched all literature in the major medical databases using the subject search terms "isoniazid" and "rifapentine", and performed a systemic review and meta-analysis.. A total of 14 studies were eligible for the meta-analysis, which included 5600 (49%) patients who received the 3HP regimen and 5919 (51%) patients who received the 9H regimen. A total of 202 (2%) patients had a drug-induced liver injury (DILI) and 11 317 (98%) did not. The pooled odds ratio (OR) of DILI in the 3HP regimen was 0.18 (95% confidence interval [CI], 0.12-0.26; p < 0.0001), compared with the 9H regimen. This result remained consistent in subgroup analyses of ethnicity and study design. The 3HP regimen was superior to the 9H regimen in the prevention of active tuberculosis (OR, 0.38, 95% CI, 0.18-0.80, p = 0.01). Furthermore, the 3HP regimen was associated with a better completion rate than the 9H regimen (OR: 2.30, 95% CI, 2.10-2.53, p < 0.0001).. The 3HP regimen is superior to the 9H regimen, with less hepatotoxicity, and better efficacy and completion rate in treating latent tuberculosis infection.

Topics: Adult; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Humans; Isoniazid; Latent Tuberculosis; Medication Adherence; Middle Aged; Rifampin; Young Adult

Latent tuberculosis infection (LTBI) represents a major challenge to curing TB disease. Current guidelines for LTBI management include only three older drugs and their combinations-isoniazid and rifamycins (rifampicin and rifapentine). These available control strategies have little impact on latent TB elimination, and new specific therapeutics are urgently needed. In the present mini-review, we highlight some of the alternatives that may potentially be included in LTBI treatment recommendations and a list of early-stage prospective small molecules that act on drug targets specific for

Topics: Drug Therapy, Combination; Humans; Isoniazid; Latent Tuberculosis; Rifampin

Effective yet safe treatment of latent tuberculosis is important for preventing the spread of tuberculosis and the progression to active disease in pediatric patients. As of 2017, the short course combination regimen of weekly isoniazid and rifapentine (3HP) administered by directly observed therapy (DOT) has replaced 9 months of isoniazid as the standard of treatment for latent tuberculosis in pediatric patients. The literature, limited in size, has established the 3HP regimen's superior safety and adherence.. We completed a retrospective chart review (n = 22) of pediatric patients at our institution receiving the 3HP regimen via DOT between 2017 and 2019. Frequencies of selected outcomes were compared to previously published data collected in a literature review.. In this retrospective chart review, pediatric patients ages 2-20 years receiving 3HP with DOT for latent tuberculosis experienced frequent adverse events, more severe adverse events such as anaphylaxis, and higher treatment discontinuation than that which has been previously reported in the literature. Of note, our cohort's race/ethnicity differed from the cohorts described in the literature.. Our data suggests that the short course combination regimen for pediatric latent tuberculosis patients may have a higher adverse event rate than previously established. Although this sample size is small, this study urges further investigation of more diverse cohorts to better establish the 3HP regimen's safety and tolerability.

Topics: Adolescent; Adult; Antitubercular Agents; Child; Child, Preschool; Drug Therapy, Combination; Humans; Isoniazid; Latent Tuberculosis; Retrospective Studies; Rifampin; Young Adult

Topics: Adolescent; Adult; Antitubercular Agents; Child; Developing Countries; Drug Therapy, Combination; HIV Infections; Humans; Isoniazid; Latent Tuberculosis; Rifampin; Young Adult

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibiotics, Antitubercular; Dose-Response Relationship, Drug; Female; Humans; Latent Tuberculosis; Male; Middle Aged; Rifampin; Young Adult

Tuberculosis (TB) remains a common cause of death globally. A regimen of 12 doses of isoniazid (INH) and rifapentine given once weekly (INH/RPT-3) has recently been recommended by the World Health Organization for the treatment of latent TB infection (LTBI). We aimed to determine whether the INH/RPT-3 regimen had similar or lesser rates of adverse events compared to other LTBI regimens, namely INH for 9 months, INH for 6 months, rifampin for 3 to 4 months, and rifampin plus INH for 3 to 4 months.. We searched MEDLINE, Embase, CENTRAL, PubMed, ICTRP, clinicaltrials.gov, and Canadian Agency for Drugs and Technologies in Health's Gray Matters Light for randomized, postmarketing, and comparative nonrandomized studies of patients with confirmed LTBI that reported the frequency of at least 1 adverse event of relevance for a regimen of interest. The search included studies published until March 2017. The frequencies of adverse events were extracted and are presented descriptively.. Data from 23 randomized and 55 nonrandomized studies were included. Although inconsistent event reporting and high heterogeneity limited comparisons, the adverse event profile of INH/RPT-3 appeared generally favorable. Flu-like reactions were reported with an increased frequency and hepatotoxicity with a lower frequency than standard treatment.. While INH/RPT-3 had an overall low frequency of adverse events compared to INH monotherapy, reporting of adverse events for many regimens was limited meaning results should be interpreted cautiously. Future studies of LTBI treatment would benefit from more complete collection and reporting of adverse events and more consistent definitions of hepatotoxicity.

Topics: Antitubercular Agents; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Humans; Incidence; Isoniazid; Latent Tuberculosis; Respiratory Tract Diseases; Rifampin

Latent tuberculosis infection diagnosis and treatment is a strategic priority for eliminating tuberculosis in the U.S. The Centers for Disease Control and Prevention has recommended the short-course regimen of 3-month isoniazid-rifapentine administered by directly observed therapy. However, longer-duration regimens remain the most widely prescribed latent tuberculosis infection treatments. Limitation on adoption of 3-month isoniazid-rifapentine in the U.S. might be because of patients' preference for self-administered therapy, providers' lack of familiarity with 3-month isoniazid-rifapentine, or lack of resources to support directly observed therapy. This review examines the most recent evidence regarding 3-month isoniazid-rifapentine's effectiveness, safety, and treatment completion when directly compared with other latent tuberculosis infection regimens primarily comprising 9-month isoniazid treatment.. Using Community Guide methodology, reviewers identified, evaluated, and summarized available evidence published during January 2006-June 2017. Analysis of the data was completed in 2017.. The analysis included 15 unique studies. Three-month isoniazid-rifapentine was determined to be equal to other latent tuberculosis infection regimens in effectiveness (OR=0.89, 95% CI=0.46, 1.70), and has higher treatment completion (87.5%, 95% CI=83.2%, 91.3%) compared with other latent tuberculosis infection regimens (65.9%, 95% CI=53.5%, 77.3%). Three-month isoniazid-rifapentine was associated with similar risk to other latent tuberculosis infection regimens for adverse events (relative risk=0.59, 95% CI=0.23, 1.52); discontinuing treatment because of adverse events (relative risk=0.48, 95% CI=0.17, 1.34); and death (relative risk=0.79, 95% CI=0.56, 1.11).. The 3-month isoniazid-rifapentine regimen is as safe and effective as other recommended latent tuberculosis infection regimens and achieves significantly higher treatment completion rates.

Topics: Directly Observed Therapy; Humans; Isoniazid; Latent Tuberculosis; Rifampin; Time Factors; United States

First-line therapy for active tuberculosis (TB) has remained unchanged for nearly 40 years. Isoniazid, rifampin, pyrazinamide, and ethambutol for the initial two-month phase followed by isoniazid and rifampin for 4 to 7 months is standard treatment for people at low risk for drug-resistant disease. Directly-observed therapy (DOT) remains the standard of care for pulmonary TB. Virtual treatment monitoring using digital technologies is becoming more common as a way to provide a more patient-centered approach to care. Attempts to shorten treatment duration have been unsuccessful based on recent clinical trials evaluating the role of fluoroquinolones. Treatment-shortening trials using higher doses of rifamycins are currently underway. Recently approved medications for TB treatment are recommended only for drug-resistant disease, but novel agents in varying stages of development are being evaluated. Rifamycin-based regimens for latent TB infection (LTBI) have been successful in preventing progression to TB disease. Once-weekly isoniazid and rifapentine for 12 weeks by DOT was shown to be safe and effective compared with 9 months of isoniazid. The same regimen was shown to have acceptable treatment completion when given self-administered. Newer studies are investigating even shorter LTBI treatment with durations of less than 2 months. Treatment of LTBI in people likely infected with multidrug resistant TB is very limited, but one observational study found that fluoroquinolones appear to be effective. The first randomized trials for treating LTBI in contacts to MDR-TB are currently enrolling.

Topics: Antitubercular Agents; Directly Observed Therapy; Drug Administration Schedule; Drug Monitoring; Drug Therapy, Combination; Humans; Isoniazid; Latent Tuberculosis; Mycobacterium tuberculosis; Randomized Controlled Trials as Topic; Rifampin

Uptake of preventive treatment for tuberculosis (TB) remains poor. A 3-month regimen of rifapentine (RPT) plus isoniazid (INH) (3HP) could facilitate its scale-up. We conducted a systematic review to assess the effects of 3HP compared with daily 6- or 9-month INH monotherapy.. We searched the following databases to identify randomised controlled trials: PubMed, Embase, the Web of Science, Cochrane Central Register of Controlled Trials, three ongoing trial registers and conference abstracts up to 24 January 2017. Where possible, we pooled data using a random-effects model.. Four studies were included. Of those, we included two studies that compared 3HP with daily 6- or 9-month INH (6/9H) among adults with human immunodeficiency virus (HIV) co-infection, one among HIV-negative adults and one among predominantly HIV-negative children and adolescents. Risk of active TB was not significantly different between 3HP and 6/9H (risk ratio [RR] 0.73, 95%CI 0.23-2.29, in adults with HIV; RR 0.44, 95%CI 0.18-1.07, in adults without HIV; RR 0.13, 95%CI 0.01-2.54, in children and adolescents). Risk of hepatotoxicity was significantly lower in the 3HP group among adults with HIV (RR 0.26, 95%CI 0.12-0.55) and those without HIV (RR 0.16, 95%CI 0.10-0.27). 3HP was also associated with a higher completion rate in all subgroups.. HP was shown to have a preventive effect similar to that of INH monotherapy, with fewer adverse events and higher completion rates. 3HP can contribute significantly to the scale-up of preventive treatment.

Topics: Adolescent; Adult; Antibiotics, Antitubercular; Child; Directly Observed Therapy; Drug Administration Schedule; Drug Therapy, Combination; HIV Seronegativity; Humans; Isoniazid; Latent Tuberculosis; Rifampin; Tuberculosis, Pulmonary

We conducted a systematic review and network meta-analysis (NMA) to examine the efficacy and completion rates of treatments for latent tuberculosis infection (LTBI). While a previous review found newer, short-duration regimens to be effective, several included studies did not confirm LTBI, and analyses did not account for variable follow-up or assess completion.. We searched MEDLINE, Embase, CENTRAL, PubMed, and additional sources to identify RCTs in patients with confirmed LTBI that involved a regimen of interest and reported on efficacy or completion. Regimens of interest included isoniazid (INH) with rifapentine once weekly for 12 weeks (INH/RPT-3), 6 and 9 months of daily INH (INH-6; INH-9), 3-4 months daily INH plus rifampicin (INH/RFMP 3-4), and 4 months daily rifampicin alone (RFMP-4). NMAs were performed to compare regimens for both endpoints.. Sixteen RCTs (n = 44,149) and 14 RCTs (n = 44,128) were included in analyses of efficacy and completion. Studies were published between 1968 and 2015, and there was diversity in patient age and comorbidities. All regimens of interest except INH-9 showed significant benefits in preventing active TB compared to placebo. Comparisons between active regimens did not reveal significant differences. While definitions of regimen completion varied across studies, regimens of 3-4 months were associated with a greater likelihood of adequate completion.. Most of the active regimens showed an ability to reduce the risk of active TB relative to no treatment, however important differences between active regimens were not found. Shorter rifamycin-based regimens may offer comparable benefits to longer INH regimens. Regimens of 3-4 months duration are more likely to be completed than longer regimens.

Topics: Antitubercular Agents; Drug Therapy, Combination; Humans; Isoniazid; Latent Tuberculosis; Male; Network Meta-Analysis; Rifampin; Time Factors

One-third of the world's population is infected with Mycobacterium tuberculosis (M.tb.). Latent tuberculosis infection (LTBI) can progress to tuberculosis disease, the leading cause of death by infection. Rifamycin antibiotics, like rifampin and rifapentine, have unique sterilizing activity against M.tb. What are the advantages of each for LTBI or tuberculosis treatment? Areas covered: We review studies assessing the pharmacokinetics (PK), pharmacodynamics (PD), drug interaction risk, safety, and efficacy of rifampin and rifapentine and provide basis for comparing them. Expert commentary: Rifampin has shorter half-life, higher MIC against M.tb, lower protein binding, and better distribution into cavitary contents than rifapentine. Drug interactions for the two drugs maybe similar in magnitude. For LTBI, rifapentine is effective as convenient, once-weekly, 12-week course of treatment. Rifampin is also effective for LTBI, but must be given daily for four months, therefore, drug interactions are more problematic. For drug-sensitive tuberculosis disease, rifampin remains the standard of care. Safety profile of rifampin is better-described; adverse events differ somewhat for the two drugs. The registered once-weekly rifapentine regimen is inadequate, but higher doses of either drugs may shorten the treatment duration required for effective management of TB. Results of clinical trials evaluating high-dose rifamycin regimens are eagerly awaited.

Topics: Animals; Antibiotics, Antitubercular; Dose-Response Relationship, Drug; Half-Life; Humans; Latent Tuberculosis; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Tuberculosis

Testing for and treating latent tuberculosis infection (LTBI) is among the main strategies to achieve TB elimination in the United States. The best approach to testing among non-US born residents, particularly those with comorbid conditions, is uncertain.. To estimate health outcomes, costs, and cost-effectiveness of LTBI testing and treatment among non-US born residents with and without medical comorbidities.. Decision analytic tree and Markov cohort simulation model among non-US born residents with no comorbidities, with diabetes, with HIV infection, or with end-stage renal disease (ESRD) using a health care sector perspective with 3% annual discounting. Strategies compared included no testing, tuberculin skin test (TST), interferon gamma release assay (IGRA), confirm positive (initial TST, IGRA only for TST-positive results; both tests positive indicates LTBI), and confirm negative (initial IGRA, then TST for IGRA-negative; any test positive indicates LTBI). All strategies were coupled to treatment with 3 months of self-administered rifapentine and isoniazid.. Number needed to test and treat to prevent 1 case of TB reactivation, discounted quality-adjusted life-years (QALYs), discounted lifetime medical costs, and incremental cost-effectiveness ratios (ICERs).. Improving health outcomes increased costs, with choice of test dependent on willingness to pay. Strategies ranked by ascending costs and benefits: no testing, confirm positive, TST, IGRA, and confirm negative. The ICERs varied by non-US born patient risk group: patients with no comorbidities, IGRA was likely cost-effective at $83 000/QALY; patients with diabetes, both confirm positive ($53 000/QALY) and IGRA ($120 000/QALY) were likely cost-effective; patients with HIV, confirm negative was clearly preferred ($63 000/QALY); and patients with ESRD, no testing was cost-effective. Increased LTBI prevalence and reduced return for TST reading improved IGRA's relative performance. In 10 000 probabilistic simulations among non-US born patients with no comorbidities, with diabetes, and with HIV, some form of testing was virtually always cost-effective. These simulations highlight the uncertainty of test choice for non-US born patients with no comorbidities and non-US born patients with diabetes, but strategies including IGRA were preferred in over 60% of simulations for all non-US born populations except those with ESRD.. Testing for and treating LTBI among non-US born residents with and without selected comorbidities is likely cost-effective except among those with ESRD in whom competing risks of death limit benefits. Strategies including IGRA fell below a $100 000/QALY willingness-to-pay threshold for non-US born patients with no comorbidities, patients with diabetes, and patients with HIV.

Topics: Antitubercular Agents; Bayes Theorem; Comorbidity; Cost-Benefit Analysis; Decision Trees; Emigrants and Immigrants; Female; Humans; Isoniazid; Latent Tuberculosis; Male; Markov Chains; Quality-Adjusted Life Years; Rifampin; Tuberculin Test; United States

Rifapentine is a rifamycin derivate approved by the US Food and Drug Administration in 1998 for the treatment of active, drug-susceptible tuberculosis (TB). In 2014, rifapentine was approved for the treatment of latent TB infection in patients at high risk of progression to active disease and is currently under evaluation by the European Medicines Agency. Expanding indications of rifapentine largely affect diabetes patients, since about one-third of them harbor latent TB. Clinical consequences of rifapentine use in this population and potentially harmful interactions with hypoglycemic agents are widely underexplored and generally considered similar to the ones of rifampicin. Indeed, rifapentine too may decrease blood levels of many oral antidiabetics and compete with them for protein-binding sites and/or transporters. However, the two drugs differ in protein-binding degree, the magnitude of cytochrome P450 induction and auto-induction, the degree of renal elimination, and so on. Rifapentine seems to be more suitable for use in diabetes patients with renal impairment, owing to the fact that it does not cause renal toxicity, and it is eliminated via kidneys in smaller proportions than rifampicin. On the other hand, there are no data related to rifapentine use in patients >65 years, and hypoalbuminemia associated with diabetic kidney disease may affect a free fraction of rifapentine to a greater extent than that of rifampicin. Until more pharmacokinetic information and information on the safety of rifapentine use in diabetic patients and drug-drug interactions are available, diabetes in TB patients treated with rifapentine should be managed with insulin analogs, and glucose and rifapentine plasma levels should be closely monitored.

Topics: Antibiotics, Antitubercular; Diabetes Mellitus; Drug Interactions; Humans; Hypoglycemic Agents; Latent Tuberculosis; Rifampin; Tuberculosis

Topics: Antitubercular Agents; Drug Administration Schedule; Drug Therapy, Combination; Humans; Isoniazid; Latent Tuberculosis; Mycobacterium tuberculosis; Practice Guidelines as Topic; Rifampin; Risk Factors

Latent tuberculosis infection (LTBI) is characterised by the presence of immune responses to previously acquired Mycobacterium tuberculosis infection without clinical evidence of active tuberculosis (TB). Here we report evidence-based guidelines from the World Health Organization for a public health approach to the management of LTBI in high risk individuals in countries with high or middle upper income and TB incidence of <100 per 100 000 per year. The guidelines strongly recommend systematic testing and treatment of LTBI in people living with HIV, adult and child contacts of pulmonary TB cases, patients initiating anti-tumour necrosis factor treatment, patients receiving dialysis, patients preparing for organ or haematological transplantation, and patients with silicosis. In prisoners, healthcare workers, immigrants from high TB burden countries, homeless persons and illicit drug users, systematic testing and treatment of LTBI is conditionally recommended, according to TB epidemiology and resource availability. Either commercial interferon-gamma release assays or Mantoux tuberculin skin testing could be used to test for LTBI. Chest radiography should be performed before LTBI treatment to rule out active TB disease. Recommended treatment regimens for LTBI include: 6 or 9 month isoniazid; 12 week rifapentine plus isoniazid; 3-4 month isoniazid plus rifampicin; or 3-4 month rifampicin alone.

Topics: Antirheumatic Agents; Antitubercular Agents; Coinfection; Comorbidity; Disease Management; Drug Users; Emigrants and Immigrants; Evidence-Based Medicine; Health Personnel; HIV Infections; Humans; Ill-Housed Persons; Interferon-gamma Release Tests; Isoniazid; Kidney Failure, Chronic; Latent Tuberculosis; Mass Screening; Practice Guidelines as Topic; Prisoners; Public Health; Radiography, Thoracic; Renal Dialysis; Rifampin; Risk Assessment; Silicosis; Substance-Related Disorders; Transplant Recipients; Tuberculin Test; Tumor Necrosis Factor-alpha; World Health Organization

Prophylactic treatment of latent tuberculosis infection (LTBI) is necessary for controlling TB in low-incidence settings. However, treatment is often limited by poor completion rates.. At a community health center serving low-income Hispanics, treatment completion among patients accepting 12 weekly doses of isoniazid (INH) plus rifapentine (RPT) administered as directly observed therapy (DOT) was compared with that among patients accepting nine months of daily self-administered INH during 2012 and 2013 (n=139).. Among patients who agreed to treatment, INH-RPT combination therapy was associated with higher completion rates (OR 3.06; 95% CI, 1.23-7.62; p=.016) when compared to INH only. Overall completion rates were 77.8% (35/45) for INH-RPT combination therapy and 52.1% (49/94) for INH monotherapy.. High completion rates for LTBI treatment can be achieved at a community health center using INH-RPT administered via DOT. Greater success treating with INH-RPT may be attributed to DOT strategy and a shorter treatment regimen.

Topics: Community Health Centers; Directly Observed Therapy; Drug Therapy, Combination; Hispanic or Latino; Humans; Isoniazid; Latent Tuberculosis; Medication Adherence; Poverty; Rifampin; Wisconsin

Effective treatment of latent tuberculosis infection (LTBI) is an important component of TB elimination programs. Promising new regimens that may be more effective are being introduced. Because few regimens can be directly compared, network meta-analyses, which allow indirect comparisons to be made, strengthen conclusions.. To determine the most efficacious regimen for preventing active TB with the lowest likelihood of adverse events to inform LTBI treatment policies.. PubMed, EMBASE, and Web of Science up to 29 January 2014; clinical trial registries; and conference abstracts.. Randomized, controlled trials that evaluated LTBI treatment in humans and recorded at least 1 of 2 prespecified end points (preventing active TB or hepatotoxicity), without language or date restrictions.. Data from eligible studies were independently extracted by 2 investigators according to a standard protocol.. Of the 1516 articles identified, 53 studies met the inclusion criteria. Data on 15 regimens were available; of 105 possible comparisons, 42 (40%) were compared directly. Compared with placebo, isoniazid for 6 months (odds ratio [OR], 0.64 [95% credible interval {CrI}, 0.48 to 0.83]) or 12 months or longer (OR, 0.52 [CrI, 0.41 to 0.66]), rifampicin for 3 to 4 months (OR, 0.41 [CrI, 0.18 to 0.86]), and rifampicin-isoniazid regimens for 3 to 4 months (OR, 0.52 [CrI, 0.34 to 0.79]) were efficacious within the network.. The risk of bias was unclear for many studies across various domains. Evidence was sparse for some comparisons, particularly hepatotoxicity.. Comparison of different LTBI treatment regimens showed that various therapies containing rifamycins for 3 months or more were efficacious at preventing active TB, potentially more so than isoniazid alone. Regimens containing rifamycins may be effective alternatives to isoniazid monotherapy.. None.

Topics: Antitubercular Agents; Chemical and Drug Induced Liver Injury; Drug Administration Schedule; Drug Therapy, Combination; Humans; Isoniazid; Latent Tuberculosis; Pyrazinamide; Rifampin

Latent tuberculosis infection (LTBI) refers to a circumstance in which viable Mycobacterium tuberculosis (MTB) bacilli are present in an individual but symptoms and signs of active disease are lacking, and the bacilli are relatively inactive metabolically. In favorable circumstances, some of these inactive bacilli resume greater metabolic activity and replication, leading to the development of active tuberculosis disease. Treatment of this condition (TLTBI) is designed to prevent (soon, or in the distant future) this progression from asymptomatic infection to symptomatic, potentially lethal, active disease. This narrative review draws upon recent reviews of LTBI and seeks particularly to include recently published or presented data that are not included in those prior reviews. Adverse effects of treatment are considered, as are the special circumstances of human immunodeficiency virus-related LTBI, drug resistance, and use of TLTBI in the context of tumor necrosis factor alpha (TNF-α) inhibition. The review describes the main studies underpinning Centers for Disease Control and Prevention recommendations on use of the new 3-month isoniazid-rifapentine regimen and points to evolving data that may support future modification of those recommendations.

Topics: Antitubercular Agents; Disease Progression; Drug Resistance, Bacterial; Drug Therapy, Combination; HIV Infections; Humans; Isoniazid; Latent Tuberculosis; Mycobacterium tuberculosis; Rifampin; Tumor Necrosis Factor-alpha

Preventing active tuberculosis (TB) from developing in people with latent tuberculosis infection (LTBI) is important for global TB control. Isoniazid (INH) for six to nine months has 60% to 90% protective efficacy, but the treatment period is long, liver toxicity is a problem, and completion rates outside trials are only around 50%. Rifampicin or rifamycin-combination treatments are shorter and may result in higher completion rates.. To compare the effects of rifampicin monotherapy or rifamycin-combination therapy versus INH monotherapy for preventing active TB in HIV-negative people at risk of developing active TB.. We searched the Cochrane Infectious Disease Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; EMBASE; LILACS; clinical trials registries; regional databases; conference proceedings; and references, without language restrictions to December 2012; and contacted experts for relevant published, unpublished and ongoing trials.. Randomized controlled trials (RCTs) of HIV-negative adults and children at risk of active TB treated with rifampicin, or rifamycin-combination therapy with or without INH (any dose or duration), compared with INH for six to nine months.. At least two authors independently screened and selected trials, assessed risk of bias, and extracted data. We sought clarifications from trial authors. We pooled relative risks (RRs) with their 95% confidence intervals (CIs), using a random-effects model if heterogeneity was significant. We assessed overall evidence quality using the GRADE approach.. Ten trials are included, enrolling 10,717 adults and children, mostly HIV-negative (2% HIV-positive), with a follow-up period ranging from two to five years. Rifampicin (three/four months) vs. INH (six months)Five trials published between 1992 to 2012 compared these regimens, and one small 1992 trial in adults with silicosis did not detect a difference in the occurrence of TB over five years of follow up (one trial, 312 participants; very low quality evidence). However, more people in these trials completed the shorter course (RR 1.19, 95% CI 1.01 to 1.30; five trials, 1768 participants; moderate quality evidence). Treatment-limiting adverse events were not significantly different (four trials, 1674 participants; very low quality evidence), but rifampicin caused less hepatotoxicity (RR 0.12, 95% CI 0.05 to 0.30; four trials, 1674 participants; moderate quality evidence). Rifampicin plus INH (three months) vs. INH (six months)The 1992 silicosis trial did not detect a difference between people receiving rifampicin plus INH compared to INH alone for occurrence of active TB (one trial, 328 participants; very low quality evidence). Adherence was similar in this and a 1998 trial in people without silicosis (two trials, 524 participants; high quality evidence). No difference was detected for treatment-limiting adverse events (two trials, 536 participants; low quality evidence), or hepatotoxicity (two trials, 536 participants; low quality evidence). Rifampicin plus pyrazinamide (two months) vs. INH (six months)Three small trials published in 1994, 2003, and 2005 compared these two regimens, and two reported a low occurrence of active TB, with no statistically significant differences between treatment regimens (two trials, 176 participants; very low quality evidence) though, apart from one child from the 1994 trial, these data on active TB were from the 2003 trial in adults with silicosis. Adherence with both regimens was low with no statistically significant differences (four trials, 700 participants; very low quality evidence). However, people receiving rifampicin plus pyrazinamide had more treatment-limiting adverse events (RR 3.61, 95% CI 1.82 to 7.19; two trials, 368 participants; high quality evidence), and hepatotoxicity (RR 4.59, 95% 2.14 to 9.85; three trials, 540 participants; moderate quality evidence). Weekly, directly-observed rifapentine plus INH (three months) vs. daily, self-administered INH (nine months)A large trial conducted from 2001 to 2008 am. Trials to date of shortened prophylactic regimens using rifampicin alone have not demonstrated higher rates of active TB when compared to longer regimens with INH. Treatment completion is probably higher and adverse events may be fewer with shorter rifampicin regimens. Shortened regimens of rifampicin with INH may offer no advantage over longer INH regimens. Rifampicin combined with pyrazinamide is associated with more adverse events. A weekly regimen of rifapentine plus INH has higher completion rates, and less liver toxicity, though treatment discontinuation due to adverse events is probably more likely than with INH.

Topics: Adult; Antibiotics, Antitubercular; Child; Directly Observed Therapy; Drug Administration Schedule; HIV Seronegativity; Humans; Isoniazid; Latent Tuberculosis; Randomized Controlled Trials as Topic; Rifabutin; Rifampin; Tuberculosis, Pulmonary

Treatment of latent tuberculosis (TB) infection is an important component of TB control programs in both high- and low-prevalence countries. Clinical trials of treatment of latent TB conducted over several decades have demonstrated that preventive treatment can reduce the risk of developing active TB up to 90%. Although 9 months of daily, self-administered isoniazid has been the most widely used and recommended regimen for the treatment of latent infection, other regimens such as 3 months of daily isoniazid and rifampin, or 4 months of daily rifampin alone have also been recommended and used. Most recently, a 12-dose regimen of once-weekly isoniazid and rifapentine has been shown to be noninferior to 9 months of daily isoniazid in a large and well conducted clinical trial. Adoption of such a regimen on a large scale could have significant implications for TB elimination efforts.

Topics: Animals; Antitubercular Agents; Drug Administration Schedule; Drug Therapy, Combination; Humans; Isoniazid; Latent Tuberculosis; Rifampin; Time Factors; Tuberculosis

Nine months of daily isoniazid is efficacious in treating latent M. tuberculosis infection, but completion rates are low, limiting treatment effectiveness. In 2011, three important studies were published involving novel regimens for the treatment of latent M. tuberculosis infection. At least 36 months of isoniazid was more effective than 6 months of isoniazid in one study, but not in another-both of which were conducted among tuberculin skin test positive HIV-infected adults living in high tuberculosis incidence settings. Three months of once-weekly isoniazid plus rifapentine or twice-weekly isoniazid plus rifampin (both given under direct observation) resulted in tuberculosis rates similar to those seen with 6 months of isoniazid among HIV-infected persons in high tuberculosis incidence settings. Three months of once-weekly, directly-observed isoniazid plus rifapentine was at least as effective as 9 months of daily isoniazid among predominantly HIV-uninfected persons living in low and medium tuberculosis incidence countries. The 3-month once-weekly isoniazid plus rifapentine regimen demonstrates promise for treatment of latent M. tuberculosis infection in HIV-infected persons.

Topics: AIDS-Related Opportunistic Infections; Anti-HIV Agents; Antitubercular Agents; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Isoniazid; Latent Tuberculosis; Male; Rifampin; Time Factors; Treatment Outcome; Tuberculin Test; Tuberculosis, Multidrug-Resistant

Much remains unknown about latent infection with Mycobacterium tuberculosis. Existing immunodiagnostic tools for this condition have various limitations, most importantly in their ability to predict disease. Randomised controlled trials have established protective efficacy of isoniazid therapy for 6-12 months among non-HIV-infected and HIV-infected subjects. While efficacy may reach 90%, acceptance and adherence to prolonged therapy are less than desired. Rifampicin plus pyrazinamide for 2 months, though efficacious, has been associated with excess hepatotoxicity in non-HIV-infected persons. Isoniazid plus rifampicin for 3 months has proven efficacy, but adverse effects may be more frequent than isoniazid or rifampicin monotherapy. Rifampicin monotherapy for 3-4 months is well tolerated, but efficacy data are currently limited, and concerns remain over possible selection of rifampicin-resistant mutants. For contacts of patients with multidrug-resistant tuberculosis, expert opinions differ on whether to treat with at least two drugs or just a fluoroquinolone, and for how long. With the existing diagnostic and treatment tools, efficacy of preventive therapy does not necessarily translate into field effectiveness. A targeted approach is required to maximise cost-effectiveness. Each geographic region needs to set its own priority after taking into account available scientific data and local circumstances.

Topics: Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Communicable Disease Control; Drug Design; Drug Resistance, Bacterial; Female; HIV Infections; Humans; Isoniazid; Latent Tuberculosis; Male; Mycobacterium tuberculosis; Patient Compliance; Pyrazinamide; Rifampin; Treatment Outcome

Treatment completion is essential for the effectiveness of any latent tuberculosis infection (LTBI) regimen. The Tuberculosis Trials Consortium (TBTC) Study 33 (iAdhere) combined self-report and pill counts - standard of care (SOC) with a medication event monitoring system (MEMS) to determine treatment completion for 12-dose once-weekly isoniazid and rifapentine (3HP). Understanding the performance of SOC relative to MEMS can inform providers and suggest when interventions may be applied to optimize LTBI treatment completion.. iAdhere randomized participants to directly observed therapy (DOT), SAT, or SAT with text reminders in Hong Kong, South Africa, Spain and the United States (U.S.). This post-hoc secondary analysis evaluated treatment completion in both SAT arms, and compared completion based on SOC with MEMS to completion based on SOC only. Treatment completion proportions were compared. Characteristics associated with discordance between SOC and SOC with MEMS were identified.. Overall 80.8% of 665 participants completed treatment per SOC, compared to 74.7% per SOC with MEMS, a difference of 6.1% (95%CI: 4.2%, 7.8%). Among U.S. participants only, this difference was 3.3% (95% CI: 1.8%, 4.9%). Differences in completion was 3.1% (95% CI: -1.1%, 7.3%) in Spain, and 36.8% (95% CI: 24.3%, 49.4%) in South Africa. There was no difference in Hong Kong.. When used for monitoring 3HP, SOC significantly overestimated treatment completion in U.S. and South Africa. However, SOC still provides a reasonable estimate of treatment completion of the 3HP regimen, in U.S., Spain, and Hong Kong.

Topics: Antitubercular Agents; Drug Therapy, Combination; Humans; Isoniazid; Latent Tuberculosis; Self Report; United States

Diabetes mellitus (DM) increases the risk of tuberculosis (TB) and will hamper global TB control due to the dramatic rise in type 2 DM in TB-endemic settings. In this trial, we will examine the efficacy and safety of TB preventive therapy against the development of TB disease in people with DM who have latent TB infection (LTBI), with a 12-week course of rifapentine and isoniazid (3HP).. The 'Prevention of tuberculosis in diabetes mellitus' (PROTID) consortium will randomise 3000 HIV-negative eligible adults with DM and LTBI, as evidenced by a positive tuberculin skin test or interferon gamma release assay, to 12 weeks of 3HP or placebo. Participants will be recruited through screening adult patients attending DM clinics at referral hospitals in Tanzania and Uganda. Patients with previous TB disease or treatment with a rifamycin medication or isoniazid (INH) in the previous 2 years will be excluded. The primary outcome is the occurrence of definite or probable TB disease; secondary outcome measures include adverse events, all-cause mortality and treatment completion. The primary efficacy analysis will be intention-to-treat; per-protocol analyses will also be carried out. We will estimate the ratio of TB incidence rates in intervention and control groups, adjusting for the study site using Poisson regression. Results will be reported as efficacy estimates (1-rate ratio). Cumulative incidence rates allowing for death as a competing risk will also be reported. Approximately 1000 LTBI-negative, HIV-negative participants will be enrolled consecutively into a parallel cohort study to compare the incidence of TB in people with DM who are LTBI negative vs positive. A number of sub-studies will be conducted among others to examine the prevalence of LTBI and active TB, estimate the population impact and cost-effectiveness of LTBI treatment in people living with DM in these African countries and address gaps in the prevention and therapeutic management of combined TB-DM.. PROTID is anticipated to generate key evidence to guide decisions over the use of TB preventive treatment among people with DM as an important target group for better global TB control.. ClinicalTrials.gov NCT04600167 . Registered on 23 October 2020.

Topics: Adult; Antitubercular Agents; Cohort Studies; Diabetes Mellitus, Type 2; HIV Infections; Humans; Isoniazid; Latent Tuberculosis; Randomized Controlled Trials as Topic; Rifampin; Tanzania

The successful scale-up of a latent tuberculosis (TB) infection testing and treatment programme is essential to achieve TB elimination. However, poor adherence compromises its therapeutic effectiveness. Novel rifapentine-based regimens and treatment support based on behavioural science theory may improve treatment adherence and completion.. A pragmatic multicentre, open-label, randomised controlled trial assessing the effect of novel short-course rifapentine-based regimens for TB prevention and additional theory-based treatment support on treatment adherence against standard-of-care. Participants aged between 16 and 65 who are eligible to start TB preventive therapy will be recruited in England. 920 participants will be randomised to one of six arms with allocation ratio of 5:5:6:6:6:6: daily isoniazid +rifampicin for 3 months (3HR), routine treatment support (control); 3HR, additional treatment support; weekly isoniazid +rifapentine for 3 months (3HP), routine treatment support; weekly 3HP, additional treatment support ; daily isoniazid +rifapentine for 1 month (1HP), routine treatment support; daily 1HP, additional treatment support. Additional treatment support comprises reminders using an electronic pillbox, a short animation, and leaflets based on the perceptions and practicalities approach. The primary outcome is adequate treatment adherence, defined as taking ≥90% of allocated doses within the pre-specified treatment period, measured by electronic pillboxes. Secondary outcomes include safety and TB incidence within 12 months. We will conduct process evaluation of the trial interventions and assess intervention acceptability and fidelity and mechanisms for effect and estimate the cost-effectiveness of novel regimens. The protocol was developed with patient and public involvement, which will continue throughout the trial.. Ethics approval has been obtained from The National Health Service Health Research Authority (20/LO/1097). All participants will be required to provide written informed consent. We will share the results in peer-reviewed journals.. EudraCT 2020-004444-29.

Topics: Adolescent; Adult; Aged; Antitubercular Agents; Humans; Isoniazid; Latent Tuberculosis; Middle Aged; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Rifampin; State Medicine; United Kingdom; Young Adult

Pregnancy increases the risk of tuberculosis and its complications. A 3-month regimen of weekly isoniazid and rifapentine (3HP) is safe and effective for tuberculosis prevention in adults and children, including those with HIV, but 3HP has not been evaluated in pregnancy.. IMPAACT 2001 was a phase I/II trial evaluating the pharmacokinetics and safety of 3HP among pregnant women with indications for tuberculosis preventative therapy in Haiti, Kenya, Malawi, Thailand, and Zimbabwe (NCT02651259). Isoniazid and rifapentine were provided at standard doses (900 mg/week). Pharmacokinetic sampling was performed with the first (second/third trimester) and twelfth (third trimester/postpartum) doses. Nonlinear mixed-effects models were used to estimate drug population pharmacokinetics.. Of 50 participants, 20 had HIV and were taking efavirenz-based antiretroviral therapy. Among women without HIV, clearance of rifapentine was 28% lower during pregnancy than postpartum (1.20 vs 1.53 L/hour, P < .001), with area under the concentration-time curve (AUCSS) of 786 and 673 mg × hour/L, respectively. In pregnant women with HIV, clearance was 30% higher than women without HIV (P < .001), resulting in lower AUCss (522 mg × hour/L); clearance did not change significantly between pregnancy and postpartum. Pregnancy did not impact isoniazid pharmacokinetics. There were no drug-related serious adverse events, treatment discontinuations, or tuberculosis cases in women or infants.. 3HP does not require dose adjustment in pregnancy. Rifapentine clearance is higher among women with HIV, but all women achieved exposures of rifapentine and isoniazid associated with successful tuberculosis prevention. The data support proceeding with larger safety-focused studies of 3HP in pregnancy.. ClinicalTrials.gov, NCT02651259.

Topics: Adult; Antitubercular Agents; Child; Drug Therapy, Combination; Female; HIV Infections; Humans; Isoniazid; Latent Tuberculosis; Male; Pregnancy; Pregnant Women; Rifampin; Tuberculosis

Ending the global tuberculosis (TB) epidemic requires a focus on treating individuals with latent TB infection (LTBI) to prevent future cases. Promising trials of shorter regimens have shown them to be effective as preventative TB treatment, however there is a paucity of data on self-administered treatment completion rates. This pilot trial assessed treatment completion, adherence, safety and the feasibility of treating LTBI in the UK using a weekly rifapentine and isoniazid regimen versus daily rifampicin and isoniazid, both self-administered for 12 weeks.. An open label, randomised, multi-site pilot trial was conducted in London, UK, between March 2015 and January 2017. Adults between 16 and 65 years with LTBI at two TB clinics who were eligible for and agreed to preventative therapy were consented and randomised 1:1 to receive either a weekly combination of rifapentine/isoniazid ('intervention') or a daily combination of rifampicin/isoniazid ('standard'), with both regimens taken for twelve weeks; treatment was self-administered in both arms. The primary outcome, completion of treatment, was self-reported, defined as taking more than 90% of prescribed doses and corroborated by pill counts and urine testing. Adverse events were recorded.. Fifty-two patients were successfully enrolled. In the intervention arm 21 of 27 patients completed treatment (77.8, 95% confidence interval [CI] 57.7-91.4), compared with 19 of 25 (76.0%, CI 54.9-90.6) in the standard of care arm. There was a similar adverse effect profile between the two arms.. In this pilot trial, treatment completion was comparable between the weekly rifapentine/isoniazid and the daily rifampicin/isoniazid regimens. Additionally, the adverse event profile was similar between the two arms. We conclude that it is safe and feasible to undertake a fully powered trial to determine whether self-administered weekly treatment is superior/non-inferior compared to current treatment.. The trial was funded by the NIHR, UK and registered with ISRCTN ( 26/02/2013-No.04379941 ).

Topics: Adolescent; Adult; Antitubercular Agents; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Isoniazid; Latent Tuberculosis; London; Male; Middle Aged; Pilot Projects; Rifampin; Self Administration; Treatment Outcome; Young Adult

Using QuantiFERON-TB Gold In-Tube (QFT-GIT) for monitoring tuberculosis (TB) and latent TB infection treatment effect is controversial. The present study aimed to evaluate the dynamic changes of interferon gamma (IFN-γ) levels along with latent TB infection treatment via a randomized controlled study.. A total of 910 participants treated with 8 weeks of once-weekly rifapentine plus isoniazid (group A), 890 treated with 6 weeks of twice-weekly rifapentine plus isoniazid (group B) and 818 untreated controls (group C) were followed for 2 years to track active TB development. QFT-GIT tests were repeated three times for all groups: before treatment (T0), at completion of treatment (T1) and 3 months after completion of treatment (T2).. Similar rates of persistent QFT-GIT reversion were observed in groups A (19.0%, 173/910), B (18.5%, 165/890) and C (20.7%, 169/818) (p 0.512). The dynamic changes of IFN-γ levels were not statistically significant among the three groups. In treated participants, individuals with higher baseline IFN-γ levels showed increased TB occurrence (1.0%, 9/896) compared to those with lower baseline levels (0.2%, 2/904) (p 0.037). A similar but statistically insignificant trend was also observed in untreated controls (1.8% (7/400) vs. 0.5% (2/418), p 0.100). When TB cases were matched with non-TB cases on baseline IFN-γ levels, no significant differences were found with respect to the dynamic changes in IFN-γ levels with time, regardless of whether they received treatment.. QFT-GIT reversion or decreased IFN-γ levels should not be used for monitoring host response to latent TB infection treatment.

Topics: Antitubercular Agents; Biomarkers; China; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Interferon-gamma; Interferon-gamma Release Tests; Isoniazid; Latent Tuberculosis; Male; Rifampin; Treatment Outcome

To investigate treatment outcomes and associated characteristics of persons experiencing homelessness who received 12-weekly doses of directly observed isoniazid and rifapentine (3HP/DOT) treatment for latent TB infection (LTBI).. Among homeless persons treated with 3HP/DOT during July 2011 -June 2015 in 11 U.S. TB programs, we conducted descriptive analyses of observational data, and identified associations between sociodemographic factors and treatment outcomes. Qualitative interviews were conducted to understand programmatic experiences.. Of 393 persons experiencing homelessness (median age: 50 years; range: 13-74 years), 301 (76.6%) completed treatment, 55 (14.0%) were lost to follow-up, 18 (4.6%) stopped because of an adverse event (AE), and 19 (4.8%) stopped after relocations or refusing treatment. Eighty-one (20.6%) had at least one AE. Persons aged ≥65 were more likely to discontinue treatment than persons aged 31-44 years. Programs reported difficulty in following up with persons experiencing homelessness because of relocations, mistrust, and alcohol or drug use.. This study demonstrates the feasibility of administering the 3HP/DOT LTBI regimen to persons experiencing homelessness, a high-risk population.

Topics: Adolescent; Adult; Aged; Antitubercular Agents; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Ill-Housed Persons; Isoniazid; Latent Tuberculosis; Male; Middle Aged; Mycobacterium tuberculosis; Rifampin; United States

Tuberculosis is the leading killer of patients with human immunodeficiency virus (HIV) infection. Preventive therapy is effective, but current regimens are limited by poor implementation and low completion rates.. We conducted a randomized, open-label, phase 3 noninferiority trial comparing the efficacy and safety of a 1-month regimen of daily rifapentine plus isoniazid (1-month group) with 9 months of isoniazid alone (9-month group) in HIV-infected patients who were living in areas of high tuberculosis prevalence or who had evidence of latent tuberculosis infection. The primary end point was the first diagnosis of tuberculosis or death from tuberculosis or an unknown cause. Noninferiority would be shown if the upper limit of the 95% confidence interval for the between-group difference in the number of events per 100 person-years was less than 1.25.. A total of 3000 patients were enrolled and followed for a median of 3.3 years. Of these patients, 54% were women; the median CD4+ count was 470 cells per cubic millimeter, and half the patients were receiving antiretroviral therapy. The primary end point was reported in 32 of 1488 patients (2%) in the 1-month group and in 33 of 1498 (2%) in the 9-month group, for an incidence rate of 0.65 per 100 person-years and 0.67 per 100 person-years, respectively (rate difference in the 1-month group, -0.02 per 100 person-years; upper limit of the 95% confidence interval, 0.30). Serious adverse events occurred in 6% of the patients in the 1-month group and in 7% of those in the 9-month group (P = 0.07). The percentage of treatment completion was significantly higher in the 1-month group than in the 9-month group (97% vs. 90%, P<0.001).. A 1-month regimen of rifapentine plus isoniazid was noninferior to 9 months of isoniazid alone for preventing tuberculosis in HIV-infected patients. The percentage of patients who completed treatment was significantly higher in the 1-month group. (Funded by the National Institute of Allergy and Infectious Diseases; BRIEF TB/A5279 ClinicalTrials.gov number, NCT01404312.).

Topics: Adult; AIDS-Related Opportunistic Infections; Antitubercular Agents; CD4 Lymphocyte Count; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; Humans; Isoniazid; Latent Tuberculosis; Male; Medication Adherence; Rifampin; Tuberculosis

Data are limited regarding the safety of 12-dose once-weekly isoniazid (H, 900 mg) plus rifapentine (P, 900 mg) (3HP) for latent infection treatment during pregnancy.. To assess safety and pregnancy outcomes among pregnant women who were inadvertently exposed to study medications in two latent tuberculosis infection trials (PREVENT TB or iAdhere) evaluating 3HP and 9 months of daily isoniazid (H, 300 mg) (9H).. Data from reproductive-age (15-51 yr) women who received one or more study dose of 3HP or 9H in either trial were analyzed. Drug exposure during pregnancy occurred if the estimated date of conception was on or before the last dose date.. Of 126 pregnancies (125 participants) that occurred during treatment or follow-up, 87 were exposed to study drugs. Among these, fetal loss was reported for 4/31 (13%) and 8/56 (14%), 3HP and 9H, respectively (difference, 13% - 14% = -1%; 95% confidence interval = -17% to +18%) and congenital anomalies in 0/20 and 2/41 (5%) live births, 3HP and 9H, respectively (difference, 0% - 5% = -5%; 95% confidence interval = -18% to +16%). All fetal losses occurred in pregnancies of less than 20 weeks. Of the total 126 pregnancies, fetal loss was reported in 8/54 (15%) and 9/72 (13%), 3HP and 9H, respectively; and congenital anomalies in 1/37 (3%) and 2/56 (4%) live births, 3HP and 9H, respectively. The overall proportion of fetal loss (17/126 [13%]) and anomalies (3/93 [3%]) were similar to those estimated for the United States, 17% and 3%, respectively.. Among reported pregnancies in these two latent tuberculosis infection trials, there was no unexpected fetal loss or congenital anomalies. These data offer some preliminary reassurance to clinicians and patients in circumstances when these drugs and regimens are the best option in pregnancy or in women of child-bearing potential. This work used the identifying trial registration numbers NCT00023452 and NCT01582711, corresponding to the primary clinical trials PREVENT TB and iAdhere (Tuberculosis Trials Consortium Study 26 and 33).

Topics: Adolescent; Adult; Antitubercular Agents; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Infant, Newborn; Isoniazid; Latent Tuberculosis; Middle Aged; Pregnancy; Pregnancy Complications, Infectious; Pregnancy Outcome; Rifampin; Young Adult

Once-weekly isoniazid and rifapentine for 3 months is a treatment option in persons with human immunodeficiency virus and latent tuberculosis infection. This study aimed to examine pharmacokinetic drug-drug interactions between this regimen and dolutegravir, a first-line antiretroviral medication.. This was a single-center, open-label, fixed-sequence, drug-drug interaction study in healthy volunteers. Subjects received oral dolutegravir 50 mg once daily alone (days 1-4) and concomitantly with once-weekly isoniazid 900 mg, rifapentine 900 mg, and pyridoxine 50 mg (days 5-19). Dolutegravir concentrations were measured on days 4, 14, and 19, and rifapentine, 25-desacetyl-rifapentine, and isoniazid concentrations were measured on day 19. Cytokines and antidrug antibodies to isoniazid and rifapentine were examined at select time points.. The study was terminated following the development of flu-like syndrome and elevated aminotransferase levels in 2 of 4 subjects after the third isoniazid-rifapentine dose. Markedly elevated levels of interferon-γ, CXCL10, C-reactive protein, and other cytokines were temporally associated with symptoms. Antidrug antibodies were infrequently detected. Dolutegravir area under the curve (AUC) was decreased by 46% (90% confidence interval, 27-110%; P = .13) on day 14. Rifapentine and 25-desacetyl rifapentine levels on day 19 were comparable to reference data, whereas isoniazid AUCs were approximately 67%-92% higher in the subjects who developed toxicities.. The combined use of dolutegravir with once-weekly isoniazid-rifapentine resulted in unexpected and serious toxicities that were mediated by endogenous cytokine release. Additional investigations are necessary to examine the safety and efficacy of coadministering these medications.. NCT02771249.

Topics: Adolescent; Adult; Aged; Antibiotics, Antitubercular; Cytokines; Drug Administration Schedule; Drug Interactions; Female; Healthy Volunteers; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Isoniazid; Latent Tuberculosis; Male; Middle Aged; Oxazines; Piperazines; Pyridones; Rifampin; Young Adult

Treatment of latent tuberculosis (TB) infection (LTBI) effectively prevents its progression to active TB. However, long treatment duration and drug-related hepatotoxicity limit the effectiveness of the 9-month daily isoniazid (9H). Data on the 3-month weekly rifapentine plus isoniazid (3 HP) in Asian populations are currently unavailable. We prospectively randomised the LTBI contacts aged ≥12 years with positive tuberculin skin test into 9H and 3 HP groups in four hospitals between January 2014 and May 2016 in Taiwan. The primary and secondary outcomes were treatment completion rate and adverse drug reactions (ADRs), respectively. Overall, 263 participants with LTBI were randomised into the 3 HP (n = 132) and 9H groups (n = 131); 14 (10.6%) and 29 (22.1%) participants in the 3 HP and 9H groups, respectively, discontinued therapy (p = 0.011). Discontinuation rates owing to ADRs were 9.1% (3 HP) and 5.3% (9H) (p = 0.241). Clinically relevant hepatotoxicity was more common in the 9H than in the 3 HP group (5.3% vs. 1.5%; p = 0.103), whereas systemic drug reaction was more common in the 3 HP than in the 9H group (3.8% vs. 0%; p = 0.060). Women had a significantly higher rate of Grade II fever than men (13.7% vs. 1.2%; p = 0.003). Compared with the 9H regimen, the 3 HP regimen had a higher completion rate with lower hepatotoxicity and well-tolerated ADR.. number NCT02208427.

Topics: Adolescent; Adult; Aged; Antibiotics, Antitubercular; Antitubercular Agents; Child; Drug Therapy, Combination; Female; Humans; Isoniazid; Latent Tuberculosis; Male; Middle Aged; Mycobacterium tuberculosis; Prospective Studies; Rifampin; Taiwan; Time Factors; Treatment Outcome; Young Adult

Latent tuberculosis infection (LTBI) management is now a critical component of the World Health Organization's End TB Strategy.In this randomised controlled trial (Chinese Clinical Trial Registry identifier ChiCTR-IOR-15007202), two short-course regimens with rifapentine plus isoniazid (a 3-month once-weekly regimen and a 2-month twice-weekly regimen) were initially designed to be evaluated for rural residents aged 50-69 years with LTBI in China.Due to the increasingly rapid growth and unexpected high frequency of adverse effects, the treatments were terminated early (after 8 weeks for the once-weekly regimen and after 6 weeks for the twice-weekly regimen). In the modified intention-to-treat analysis on the completed doses, the cumulative rate of active disease during 2 years of follow-up was 1.21% (14 out of 1155) in the untreated controls, 0.78% (10 out of 1284) in the group that received the 8-week once-weekly regimen and 0.46% (six out of 1299) in the group that received the 6-week twice-weekly regimen. The risk of active disease was decreased, with an adjusted hazard ratio of 0.63 (95% CI 0.27-1.43) and 0.41 (95% CI 0.15-1.09) for the treatments, respectively. No significant difference was found in the occurrence of hepatotoxicity (1.02% (13 out of 1279)

Topics: Aged; Antibiotics, Antitubercular; China; Communicable Disease Control; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Isoniazid; Latent Tuberculosis; Male; Middle Aged; Mycobacterium tuberculosis; Proportional Hazards Models; Rifampin; Risk Factors; Rural Population; Treatment Outcome

Expanding latent tuberculosis treatment is important to decrease active disease globally. Once-weekly isoniazid and rifapentine for 12 doses is effective but limited by requiring direct observation.. To compare treatment completion and safety of once-weekly isoniazid and rifapentine by self-administration versus direct observation.. An open-label, phase 4 randomized clinical trial designed as a noninferiority study with a 15% margin. Seventy-five percent or more of study patients were enrolled from the United States for a prespecified subgroup analysis. (ClinicalTrials.gov: NCT01582711).. Outpatient tuberculosis clinics in the United States, Spain, Hong Kong, and South Africa.. 1002 adults (aged ≥18 years) recommended for treatment of latent tuberculosis infection.. Participants received once-weekly isoniazid and rifapentine by direct observation, self-administration with monthly monitoring, or self-administration with weekly text message reminders and monthly monitoring.. The primary outcome was treatment completion, defined as 11 or more doses within 16 weeks and measured using clinical documentation and pill counts for direct observation, and self-reports, pill counts, and medication event-monitoring devices for self-administration. The main secondary outcome was adverse events.. Median age was 36 years, 48% of participants were women, and 77% were enrolled at the U.S. sites. Treatment completion was 87.2% (95% CI, 83.1% to 90.5%) in the direct-observation group, 74.0% (CI, 68.9% to 78.6%) in the self-administration group, and 76.4% (CI, 71.3% to 80.8%) in the self-administration-with-reminders group. In the United States, treatment completion was 85.4% (CI, 80.4% to 89.4%), 77.9% (CI, 72.7% to 82.6%), and 76.7% (CI, 70.9% to 81.7%), respectively. Self-administered therapy without reminders was noninferior to direct observation in the United States; no other comparisons met noninferiority criteria. A few drug-related adverse events occurred and were similar across groups.. Persons with latent tuberculosis infection enrolled in South Africa would not routinely be treated programmatically.. These results support using self-administered, once-weekly isoniazid and rifapentine to treat latent tuberculosis infection in the United States, and such treatment could be considered in similar settings when direct observation is not feasible.. Centers for Disease Control and Prevention.

Topics: Adult; Antibiotics, Antitubercular; Antitubercular Agents; Directly Observed Therapy; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Isoniazid; Latent Tuberculosis; Male; Medication Adherence; Middle Aged; Reminder Systems; Rifampin; Self Administration; Text Messaging

Currently, treatment of latent tuberculosis infection (LTBI) in Australia consists most commonly of a 9-month course of isoniazid (9H). A 3-month course of weekly isoniazid and rifapentine (3HP) has been shown to be as effective as 9 months of daily isoniazid, and associated with less hepatotoxicity; however, rifapentine is not currently available in Australia. Introduction of this regimen would have apparent advantages for people with LTBI in Victoria by safely shortening duration of LTBI therapy. However, the cost benefit of this new therapeutic approach is uncertain.. Cost-analysis of standard and short-course therapy for LTBI in an Australian context.. Single-centre randomised controlled trial conducted between December 2013-March 2016. Participants underwent 1:1 randomisation to either a 9-month course of daily isoniazid or a 12-week course of weekly isoniazid and rifapentine. The primary outcome measure was total healthcare system costs (in Australian dollars; AUD) per completed course of LTBI therapy. Secondary cost analyses were performed to consider varying assumptions regarding commercial cost of rifapentine.. Overall, 34 of 40 (85%) participants in the 9H group and 36/40 (90%) in the 3HR group completed therapy. One patient in the 3HP group was hospitalised for a febrile illness; no hospitalisations were recorded in the 9H group. The cost per completed course of 9H was 601 AUD, while that of 3HP was significantly lower at 511 AUD (P < 0.01).. This study provides cost analysis evidence to support the use of 3HP for the treatment of LTBI in Australia.

Topics: Adolescent; Adult; Aged; Antibiotics, Antitubercular; Antitubercular Agents; Australia; Cost-Benefit Analysis; Disease Eradication; Drug Administration Schedule; Female; Humans; Isoniazid; Latent Tuberculosis; Male; Middle Aged; New Zealand; Prospective Studies; Rifampin; Self Administration; Young Adult

Three months of a once-weekly combination of rifapentine and isoniazid for treatment of latent tuberculosis infection is safe and effective for persons 12 years or older. Published data for children are limited.. To compare treatment safety and assess noninferiority treatment effectiveness of combination therapy with rifapentine and isoniazid vs 9 months of isoniazid treatment for latent tuberculosis infection in children.. A pediatric cohort nested within a randomized, open-label clinical trial conducted from June 11, 2001, through December 17, 2010, with follow-up through September 5, 2013, in 29 study sites in the United States, Canada, Brazil, Hong Kong (China), and Spain. Participants were children (aged 2-17 years) who were eligible for treatment of latent tuberculosis infection.. Twelve once-weekly doses of the combination drugs, given with supervision by a health care professional, for 3 months vs 270 daily doses of isoniazid, without supervision by a health care professional, for 9 months.. We compared rates of treatment discontinuation because of adverse events (AEs), toxicity grades 1 to 4, and deaths from any cause. The equivalence margin for the comparison of AE-related discontinuation rates was 5%. Tuberculosis disease diagnosed within 33 months of enrollment was the main end point for testing effectiveness. The noninferiority margin was 0.75%.. Of 1058 children enrolled, 905 were eligible for evaluation of effectiveness. Of 471 in the combination-therapy group, 415 (88.1%) completed treatment vs 351 of 434 (80.9%) in the isoniazid-only group (P = .003). The 95% CI for the difference in rates of discontinuation attributed to an AE was -2.6 to 0.1, which was within the equivalence range. In the safety population, 3 of 539 participants (0.6%) who took the combination drugs had a grade 3 AE vs 1 of 493 (0.2%) who received isoniazid only. Neither arm had any hepatotoxicity, grade 4 AEs, or treatment-attributed death. None of the 471 in the combination-therapy group developed tuberculosis vs 3 of 434 (cumulative rate, 0.74%) in the isoniazid-only group, for a difference of -0.74% and an upper bound of the 95% CI of the difference of +0.32%, which met the noninferiority criterion.. Treatment with the combination of rifapentine and isoniazid was as effective as isoniazid-only treatment for the prevention of tuberculosis in children aged 2 to 17 years. The combination-therapy group had a higher treatment completion rate than did the isoniazid-only group and was safe.. clinicaltrials.gov Identifier: NCT00023452.

Topics: Adolescent; Antitubercular Agents; Child; Child, Preschool; Drug Therapy, Combination; Female; Humans; Isoniazid; Latent Tuberculosis; Male; Rifampin; Treatment Outcome

Weekly rifapentine plus isoniazid for 3 months (3HP) is as effective as daily isoniazid for 9 months (9H) for latent tuberculosis infection in high-risk persons, but there have been reports of possible flu-like syndrome.. We identified clinically significant systemic drug reactions (SDR) and evaluated risk factors in patients who did not complete treatment in the PREVENT Tuberculosis study.. Among 7552 persons who received ≥ 1 dose of study drug, 153 had a SDR: 138/3893 (3.5%) with 3HP vs 15/3659 (0.4%) with 9H (P < .001). In the 3HP arm, 87 (63%) had flu-like syndrome and 23 (17%) had cutaneous reactions; 13/3893 (0.3%) had severe reactions (6 were hypotensive) and 6 reported syncope. Symptoms occurred after a median of 3 doses, and 4 hours after the dose; median time to resolution was 24 hours. There were no deaths. In multivariate logistic regression analysis, factors independently associated with SDR included receipt of 3HP (adjusted odds ratio [aOR] 9.4; 95% confidence interval [CI], 5.5, 16.2), white non-Hispanic race/ethnicity (aOR 3.3; 95% CI, 2.3, 4.7), female sex (aOR 2.0; 95% CI, 1.4, 2.9), age ≥ 35 years (aOR 2.0; 95% CI, 1.4, 2.9), and lower body mass index (body mass index [BMI]; P = .009). In a separate multivariate analysis among persons who received 3HP, severe SDR were associated with white non-Hispanic race/ethnicity (aOR 5.4; 95% CI, 1.8, 16.3), and receipt of concomitant non-study medications (aOR 5.9; 95% CI, 1.3, 27.1).. SDR were more common with 3HP, and mostly flu-like. Persons of white race, female sex, older age, and lower BMI were at increased risk. Severe reactions were rare and associated with 3HP, concomitant medication, and white race. The underlying mechanism is unclear.. NCT00023452.

Topics: Adolescent; Adult; Antitubercular Agents; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Isoniazid; Latent Tuberculosis; Male; Middle Aged; Prospective Studies; Respiratory Tract Diseases; Rifampin

Nine months of daily isoniazid (9H) and 3 months of once-weekly rifapentine plus isoniazid (3HP) are recommended treatments for latent tuberculous infection (LTBI). The risk profile for 3HP and the contribution of hepatitis C virus (HCV) infection to hepatotoxicity are unclear.. To evaluate the hepatotoxicity risk associated with 3HP compared to 9H, and factors associated with hepatotoxicity.. Hepatotoxicity was defined as aspartate aminotransferase (AST) >3 times the upper limit of normal (ULN) with symptoms (nausea, vomiting, jaundice, or fatigue), or AST >5 x ULN. We analyzed risk factors among adults who took at least 1 dose of their assigned treatment. A nested case-control study assessed the role of HCV.. Of 6862 participants, 77 (1.1%) developed hepatotoxicity; 52 (0.8%) were symptomatic; 1.8% (61/3317) were on 9H and 0.4% (15/3545) were on 3HP (P < 0.0001). Risk factors for hepatotoxicity were age, female sex, white race, non-Hispanic ethnicity, decreased body mass index, elevated baseline AST, and 9H. In the case-control study, HCV infection was associated with hepatotoxicity when controlling for other factors.. The risk of hepatotoxicity during LTBI treatment with 3HP was lower than the risk with 9H. HCV and elevated baseline AST were risk factors for hepatotoxicity. For persons with these risk factors, 3HP may be preferred.

Topics: Adult; Antitubercular Agents; Aspartate Aminotransferases; Brazil; Canada; Case-Control Studies; Chemical and Drug Induced Liver Injury; Drug Administration Schedule; Drug Therapy, Combination; Female; Hepatitis C; Humans; Isoniazid; Latent Tuberculosis; Male; Middle Aged; Multivariate Analysis; Rifampin; Risk Factors; Spain; United States

A population pharmacokinetic (PPK) study of the correlation of adverse drug reactions (ADRs) with the 3HP regimen (weekly high-dose rifapentine plus isoniazid for 12 doses) for latent tuberculosis infection (LTBI) remains lacking. The purpose of this study is to determine the association of rifapentine or isoniazid concentration and ADRs.. This prospective, multicentre, observational study enrolled LTBI contacts receiving 3HP treatment between January 2017 and August 2020. The concentrations of rifapentine, isoniazid and their metabolites (25-desacetyl-rifapentine and acetyl-isoniazid) in plasma samples collected monthly after 3HP treatment were determined. A PPK model was constructed to predict the maximum concentration (C. A total of 415 LTBI cases were ultimately enrolled; 355 (85.5%) completed the 3HP treatment. Among them, 47 (11.3%) experienced systemic drug reactions and 291 (70.0%) experienced one or more flu-like symptom. The plasma concentration-time profiles of isoniazid, rifapentine and their metabolites were adequately described by the developed models. A higher C. Isoniazid may be responsible for ADRs, especially flu-like symptoms, during 3HP treatment.

Topics: Antitubercular Agents; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Humans; Isoniazid; Latent Tuberculosis; Prospective Studies

Isoniazid pharmacokinetics are not yet well-described during once weekly, high-dose administrations with rifapentine (3HP) for latent tuberculosis infection (LTBI). Fewer data describe 3HP with dolutegravir-based antiretroviral therapy for the treatment of human immunodeficiency virus (HIV). The only prior report of 3HP with dolutegravir reported elevated isoniazid exposures. We measured the plasma isoniazid levels in 30 adults receiving 3HP and dolutegravir for the treatment of LTBI and HIV. The patients were genotyped to determine NAT2 acetylator status, and a population PK model was estimated by nonlinear mixed-effects modeling. The results were compared to previously reported data describing 3HP with dolutegravir, 3HP alone, and isoniazid with neither dolutegravir nor rifapentine. The isoniazid concentrations were adequately described by a one compartment model with a transit compartment absorption process. The isoniazid clearance for slow (8.33 L/h) and intermediate (12 L/h) acetylators were similar to previously reported values. Rapid acetylators (

Topics: Adult; Antitubercular Agents; Arylamine N-Acetyltransferase; Body Weight; Drug Therapy, Combination; HIV; HIV Infections; Humans; Isoniazid; Latent Tuberculosis

We aimed to evaluate safety of 3 months weekly isoniazid-rifapentine (3HP) for tuberculosis (TB) prevention when co-administered with dolutegravir-based antiretroviral therapy (TLD), and compare viral suppression among those initiating TLD + 3HP vs. TLD alone.. We analyzed data from an ongoing Phase 3 randomized trial comparing TB screening strategies among adults with CD4 + ≤350 cells/μl initiating routine antiretroviral therapy (ART) in Kampala, Uganda. TB screen-negative participants without contraindications are referred for self-administered 3HP. HIV viral load is routinely measured at 6 and 12 months. Here, we included TB-negative participants who initiated TLD with or without 3HP. We determined the number who discontinued 3HP due to drug toxicity. In addition, we assessed viral suppression at 6 and 12 months and used log-binomial regression to assess risk of viremia at 6 months for participants who initiated TLD + 3HP vs. TLD alone.. Of 453 participants initiating TLD (287 [63.4%] female, median age 30 years [interquartile range (IQR) 25-37], median pre-ART CD4 + cell count 188 cells/μl [IQR 86-271]), 163 (36.0%) initiated 3HP. Of these, 154 (94.5%) completed 3HP and one (0.6%) had treatment permanently discontinued due to a possible 3HP-related adverse event. At 6 months, for participants who received TLD + 3HP, risk of viremia >50 copies/ml was 1.51 [95% confidence interval (CI) 1.07-2.14] times that of participants who received TLD alone. There was no difference in viral suppression between those who received TLD + 3HP vs. TLD alone at 12 months.. Co-administration of TLD + 3HP was well tolerated. However, those who received TLD + 3HP were less likely to achieve viral suppression within six-months compared to those who received TLD alone.

Topics: Adult; Antitubercular Agents; Drug Therapy, Combination; Female; HIV Infections; Humans; Isoniazid; Latent Tuberculosis; Male; Uganda; Viremia

Three months of weekly rifapentine plus isoniazid (3HP) therapy for latent tuberculosis infection (LTBI) is recommended worldwide. The development of symptoms and systemic drug reactions (SDRs) on 3HP have not been fully characterized. We aimed to determine the patterns of symptom development and identify SDRs and associated factors in patients taking 3HP.. We analyzed symptoms data in participants receiving 3HP in the Tuberculosis Trials Consortium's iAdhere study (Study 33). We examined the patterns of symptom reporting across participants from baseline and 4 monthly visits. Bivariate analyses and multivariable regression models were used to identify factors associated with SDRs. Risk ratios (RRs) and 95% confidence intervals (CIs) were calculated.. Among 1002 participants receiving 3HP, 768 (77%) reported at least 1 symptom; 97% of these symptoms were grade 1 (79%) or grade 2 (18%). Most symptoms developed in the first month and resolved. A total of 111 (11%) participants had symptoms that met criteria for SDRs; however, 53 (48%) of these participants completed therapy. Factors associated with SDRs and discontinuation included female sex (RR: 2.05; 95% CI: 1.19-3.54), age ≥45 years (RR: 1.99; 95% CI: 1.19-3.31), and use of concomitant medications (RR: 2.26; 95% CI: 1.15-4.42).. Although most patients receiving 3HP reported symptoms, most were mild, occurred early, and resolved without stopping treatment. Among patients experiencing SDRs, nearly half were able to complete therapy. Patient and provider education should focus on differentiating severe reactions where 3HP should be stopped from minor symptoms that will resolve. Clinical Trials Registration. NCT01582711.

Topics: Antitubercular Agents; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Isoniazid; Latent Tuberculosis; Middle Aged

Scaling up a shorter preventive regimen such as weekly isoniazid and rifapentine (3HP) for 3 months is a priority for tuberculosis (TB) preventive treatment (TPT). However, there are limited data on 3HP acceptability and completion from high-burden-TB countries.. We scaled up 3HP from 2018 to 2021 in 2 cities in Pakistan. Eligible participants were household contacts of persons diagnosed with TB disease. Participants were prescribed 3HP after ruling out TB disease. Treatment was self-administered. We analyzed the proportion who completed 3HP.. In Karachi, we verbally screened 22 054 household contacts of all ages. Of these, 83% were clinically evaluated and 3% were diagnosed with TB. Of household contacts without TB disease, 59% initiated the 3HP regimen, of which 69% completed treatment. In Peshawar, we verbally screened 6389 household contacts of all ages. We evaluated 95% of household contacts, of whom 2% were diagnosed with TB disease. Among those without TB disease, 65% initiated 3HP, of which 93% completed. Factors associated with higher 3HP completion included residence in Peshawar (risk ratio [RR], 1.35 [95% confidence interval {CI}: 1.32-1.37]), index patient being a male (RR, 1.03 [95% CI: 1.01-1.05]), and index patient with extrapulmonary TB compared to bacteriologically positive pulmonary TB (RR, 1.10 [95% CI: 1.06-1.14]). The age of the index patient was inversely associated with completion.. We observed a high level of acceptance and completion of 3HP in programs implemented in 2 cities in Pakistan, with differences observed across the cities. These findings suggest that 3HP can be effectively scaled up in urban settings to improve the reach and impact of TPT.

Topics: Antitubercular Agents; Drug Therapy, Combination; Humans; Isoniazid; Latent Tuberculosis; Male; Tuberculosis

Administration of tuberculosis preventive therapy (TPT) to individuals with latent tuberculosis infection is an important facet of global tuberculosis control. The use of long-acting injectable (LAI) drug formulations may simplify and shorten regimens for this indication. Rifapentine and rifabutin have antituberculosis activity and physiochemical properties suitable for LAI formulation, but there are limited data available for determining the target exposure profiles required for efficacy in TPT regimens. The objective of this study was to determine exposure-activity profiles of rifapentine and rifabutin to inform development of LAI formulations for TPT. We used a validated paucibacillary mouse model of TPT in combination with dynamic oral dosing of both drugs to simulate and understand exposure-activity relationships to inform posology for future LAI formulations. This work identified several LAI-like exposure profiles of rifapentine and rifabutin that, if achieved by LAI formulations, could be efficacious as TPT regimens and thus can serve as experimentally determined targets for novel LAI formulations of these drugs. We present novel methodology to understand the exposure-response relationship and inform the value proposition for investment in development of LAI formulations that have utility beyond latent tuberculosis infection.

Topics: Animals; Antitubercular Agents; Latent Tuberculosis; Mice; Rifabutin; Rifampin

We present a case of a 53-year-old person living with human immunodeficiency virus and a new diagnosis of latent tuberculosis. The patient had baseline suppressed HIV viral load on fixed dose combination dolutegravir/abacavir/lamivudine when once-weekly rifapentine 900 mg/isoniazid 900 mg/pyridoxine 25 mg was initiated for 12 weeks. An additional 50 mg dolutegravir dose, administered in the evenings, was added to the daily antiretroviral regimen for treatment duration secondary to rifapentine uridine diphosphate glucuronsyl transferase induction. Dolutegravir trough concentrations decreased during concurrent therapy with noted slight HIV viral load rebound. Upon completion of rifapentine use, and a return to dolutegravir 50 mg daily dose, the trough concentrations increased with a return to an undetectable viral load. We provide suggested dolutegravir dosing considerations with concomitant rifapentine use, not currently addressed in recommended guidelines.

Topics: Anti-HIV Agents; Drug Therapy, Combination; HIV Infections; Humans; Isoniazid; Latent Tuberculosis; Middle Aged; Rifampin

The primary objective of this study was to ascertain the acceptance, initiation, implementation and treatment completion rates of tuberculosis (TB) preventive therapy (TPT) using 3HP (INH-Rifapentine) among household contacts of microbiologically confirmed drug sensitive TB cases on anti-tubercular treatment under programmatic real-world settings. The secondary objectives were to estimate the prevalence and predictors of latent TB infection (LTBI) in household contacts of the index TB cases. We also ascertained the safety profile of the 3HP TPT regimen in the household contacts.. This prospective observational study was conducted at 10 TB chest clinics in Delhi, India during 2022-2023. Household contacts aged 14 and older who tested positive for TB infection on a Tuberculin Skin test were initiated on the 3HP regimen. Logistic regression was performed by including statistically significant independent variables in multiple prediction models. p < 0.05 was considered statistically significant. STATA, version 15.1, was used to compute all analyses.. A total of 1067 (84.68%) eligible contacts of microbiologically confirmed, drug sensitive TB cases underwent screening with tuberculin skin test (TST), 614 (95.6%) LTBI positive contacts accepted the initiation of TPT, and 564 (91.8%) of those initiated on TPT completed the treatment. The major reason for refusal of screening was the lack of perception of risk of TB disease due to asymptomatic status. The prevalence of LTBI positivity through TST was 61.5% (95% CI, 58.5%, 64.4%). Adverse events were reported by 195 (31.8%) contacts initiated on 3HP of which 20 participants discontinued TPT. None of the sociodemographic factors showed a significant association with LTBI positivity (except age) or TPT completion rates.. LTBI management with 3HP is feasible among adolescent and adult household contacts in India with high rates of adherence from initiation until treatment completion. The maximum attrition of participants occurred at the time of screening for LTBI using TST.

Topics: Adolescent; Adult; Humans; India; Latent Tuberculosis; Prospective Studies; Tuberculosis

Topics: Antitubercular Agents; Drug Interactions; Drug Therapy, Combination; Humans; Isoniazid; Latent Tuberculosis; Rifampin

Systemic drug reaction (SDR) is a major safety concern with weekly rifapentine plus isoniazid for 12 doses (3HP) for latent tuberculosis infection (LTBI). Identifying SDR predictors and at-risk participants before treatment can improve cost-effectiveness of the LTBI program.. We prospectively recruited 187 cases receiving 3HP (44 SDRs and 143 non-SDRs). A pilot cohort (8 SDRs and 12 non-SDRs) was selected for generating whole-blood transcriptomic data. By incorporating the hierarchical system biology model and therapy-biomarker pathway approach, candidate genes were selected and evaluated using reverse-transcription quantitative polymerase chain reaction (RT-qPCR). Then, interpretable machine learning models presenting as SHapley Additive exPlanations (SHAP) values were applied for SDR risk prediction. Finally, an independent cohort was used to evaluate the performance of these predictive models.. Based on the whole-blood transcriptomic profile of the pilot cohort and the RT-qPCR results of 2 SDR and 3 non-SDR samples in the training cohort, 6 genes were selected. According to SHAP values for model construction and validation, a 3-gene model for SDR risk prediction achieved a sensitivity and specificity of 0.972 and 0.947, respectively, under a universal cutoff value for the joint of the training (28 SDRs and 104 non-SDRs) and testing (8 SDRs and 27 non-SDRs) cohorts. It also worked well across different subgroups.. The prediction model for 3HP-related SDRs serves as a guide for establishing a safe and personalized regimen to foster the implementation of an LTBI program. Additionally, it provides a potential translational value for future studies on drug-related hypersensitivity.

Topics: Antitubercular Agents; Decision Support Techniques; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Humans; Isoniazid; Latent Tuberculosis; Rifampin

A once-weekly oral dose of isoniazid and rifapentine for 3 months (3HP) is recommended by the CDC for treatment of latent tuberculosis infection (LTBI). The aim of this study is to assess 3HP-mediated clearance of M. tuberculosis bacteria in macaques with asymptomatic LTBI. Twelve Indian-origin rhesus macaques were infected with a low dose (~10 CFU) of M. tuberculosis CDC1551 via aerosol. Six animals were treated with 3HP and 6 were left untreated. The animals were imaged via PET/CT at frequent intervals. Upon treatment completion, all animals except 1 were coinfected with SIV to assess reactivation of LTBI to active tuberculosis (ATB). Four of 6 treated macaques showed no evidence of persistent bacilli or extrapulmonary spread until the study end point. PET/CT demonstrated the presence of significantly more granulomas in untreated animals relative to the treated group. The untreated animals harbored persistent bacilli and demonstrated tuberculosis (TB) reactivation following SIV coinfection, while none of the treated animals reactivated to ATB. 3HP treatment effectively reduced persistent infection with M. tuberculosis and prevented reactivation of TB in latently infected macaques.

Topics: Animals; Antitubercular Agents; Isoniazid; Latent Tuberculosis; Lung; Macaca mulatta; Mycobacterium tuberculosis; Positron Emission Tomography Computed Tomography; Rifampin; Tuberculosis

Topics: Animals; Antitubercular Agents; Drug Therapy, Combination; Isoniazid; Latent Tuberculosis; Mice; Rifampin

Short-course preventive therapy with 1-month course of daily administration of isoniazid (300-mg) plus rifapentine (600-mg) (1HP) and 3-month course of weekly administration of isoniazid (900-mg) plus rifapentine (900-mg) (3HP) has higher completion rates than 9-month course of daily isoniazid (9H) for individuals with latent tuberculosis infection (LTBI). We aimed to evaluate the effect, safety and tolerability of 1HP in people living with HIV (PLWH) and LTBI who received coformulated bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF).. PLWH testing positive by interferon-gamma release assay and having received BIC/FTC/TAF for >2 weeks with plasma HIV RNA load (PVL) <200 copies/ml were enrolled. BIC trough plasma concentrations and cytokine profiles were determined before the first dose (day 1/baseline), 24 h after the 14th (day 15) and 28th (day 29) doses of 1HP. PVL were determined on days 15 and 29 of 1HP and every 3 months subsequently after discontinuation of 1HP.. BIC/FTC/TAF in combination with 1HP was well tolerated with a high completion rate. BIC trough plasma concentrations were significantly decreased with concurrent use of 1HP among PLWH with LTBI. While transient viral blips were observed during 1HP without causing subsequent treatment failure, such combination should be applied with caution.

Topics: Adenine; Alanine; Amides; Anti-HIV Agents; Emtricitabine; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Isoniazid; Latent Tuberculosis; Piperazines; Pyridones; Rifampin; Tenofovir

Tuberculosis (TB) remains an important problem among children in the United States and throughout the world. There is no diagnostic reference standard for latent tuberculosis infection (also referred to as tuberculosis infection [TBI]). The tuberculin skin test (TST) has many limitations, including difficulty in administration and interpretation, the need for a return visit by the patient, and false-positive results caused by cross-reaction with Mycobacterium bovis-bacille Calmette-Guerin vaccines and many nontuberculous mycobacteria. Interferon-gamma release assays (IGRAs) are blood tests that use antigens specific for M tuberculosis; as a result, IGRAs yield fewer false-positive results than the TST. Both IGRAs and the TST have reduced sensitivity in immunocompromised children, including children with severe TB disease. Both methods have high positive predictive value when applied to children with risk factors for TBI, especially recent contact with a person who has TB disease. The advantages of using IGRAs and diminished experience with the placement and interpretation of the TST favor expanded use of IGRAs in children in the United States. There are now several effective and safe regimens for the treatment of TBI in children. For improved adherence to therapy, the 3 rifamycin-based regimens are preferred because of their short duration. Daily isoniazid can be used if there is intolerance or drug interactions with rifamycins. A TB specialist should be involved when there are questions regarding testing interpretation, selection of an appropriate treatment regimen, or management of adverse effects.

Topics: Adolescent; Age Factors; Antitubercular Agents; BCG Vaccine; Child; Child, Preschool; Cross Reactions; False Positive Reactions; Humans; Immunocompromised Host; Infant; Interferon-gamma Release Tests; Isoniazid; Latent Tuberculosis; Mycobacterium bovis; Mycobacterium tuberculosis; Nontuberculous Mycobacteria; Rifampin; Sensitivity and Specificity; Tuberculin Test

Topics: Antibiotics, Antitubercular; Antitubercular Agents; Child; Drug Therapy, Combination; Humans; Isoniazid; Latent Tuberculosis; Rifampin

Treatment of latent tuberculosis (LTBI) is important for tuberculosis (TB) prevention, and short course rifamycin-based therapies are preferred. Once-weekly isoniazid-rifapentine by self-administered therapy (3HP-SAT) has never been compared with 4 months of daily rifampin (4R).. Retrospective cohort study of adults ≥18 years of age initiating LTBI treatment with either 3HP-SAT or 4R in a United States (US)-based TB clinic between 11 April 2016 and 31 December 2018. We evaluated treatment completion through pharmacy fills and reviewed charts for reasons of noncompletion, including adverse events (AEs). The χ 2 test and a log-binomial multivariable model were used to compare treatment completion and AEs.. Five hundred sixty individuals (42%) initiated 3HP-SAT and 773 (58%) initiated 4R. Median age was 38, 55% were female, and 89% were born outside of the US. Among those aged 18-49 years, treatment completion with 3HP-SAT was 79% compared to 68% with 4R (adjusted risk ratio [aRR], 1.17 [95% CI, 1.17-1.27]; P < .0001). Among individuals aged ≥50 years, treatment completion with 3HP-SAT was 87% compared to 64% with 4R (aRR, 1.35 [95% CI, 1.19-1.52]; P < .0001). Compared to 4R, there was no difference in risk of AEs in the 18-49 age group (aRR, 0.93 [95% CI, .58-1.48]; P = .75). Reduced risk of AEs was noted among patients aged ≥50 years who received 3HP-SAT (aRR, 0.37 [95% CI, .16-.85]; P = .02).. 3HP-SAT was associated with higher LTBI treatment completion and lower rates of AEs compared to 4R in individuals aged 50 and older. Expanding 3HP-SAT as an option for patients with LTBI may enhance TB prevention strategies in the US.

Topics: Adult; Aged; Antitubercular Agents; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Isoniazid; Latent Tuberculosis; Middle Aged; Retrospective Studies; Rifampin; United States

Weekly rifapentine and isoniazid (3HP) is gaining popularity for latent tuberculosis infection treatment because of its short course and high completion rate. Prior to widespread use, comprehensive 3HP treatment assessment covering an all-age population is essential.. Participants receiving ≥1 3HP dose from September 2014 to December 2019 were stratified into elderly (≥65 years), middle-aged (>35 & <65 years), and younger (≤35 years) age groups. This study investigated the impact of age on treatment outcome, particularly systemic drug reactions (SDRs) and 3HP discontinuation.. Overall, 134 of 579 (23.1%) participants were elderly. The completion rate was 83.1% overall and was highest and lowest in the younger group (94.5%) and elderly (73.9%) group, respectively. However, the 3HP discontinuation rate was not significantly different among the 3 groups in multivariate logistic regression analysis. In total, 362 (62.5%) participants experienced 1 or more adverse drug reactions (ADRs), of which 38 (10.5%) and 98 (27.1%) required temporary and permanent treatment interruption, respectively. The SDR risk was 11.2% in overall and 17.1% in the middle-aged group, 3.04-fold higher than that in the elderly group (P = .025). This finding was consistently observed in different clinical settings. Hypertensive events accompanied with flu-like symptoms occurred in 11.2% of elderly participants, and accounted for 50% of grade ≥3 ADRs.. With proper medical support and programmatic follow-up, the 3HP completion rate is >70% even in elderly participants. In middle-aged and elderly individuals, 3HP should be employed with caution because of risk of SDRs and hypertensive events, respectively. Summary: Under programmatic medical support, widespread use of weekly rifapentine and isoniazid (3HP) for latent tuberculosis treatment is possible for its high completion rate. 3HP should be employed with caution for risk of systemic drug reactions and hypertensive events in middle-aged and elderly individuals, respectively.

Topics: Aged; Antitubercular Agents; Drug Therapy, Combination; Humans; Isoniazid; Latent Tuberculosis; Middle Aged; Rifampin

Successful delivery and completion of tuberculosis preventive treatment are necessary for tuberculosis elimination. Shorter preventive treatment regimens currently have higher medication costs, but patients spend less time in care and are more likely to complete treatment. It is unknown how economic costs of successful delivery differ between longer and shorter regimens in high-tuberculosis-burden settings.. We developed survey instruments to collect costs from program and patient sources, considering costs incurred from when household contacts first entered the health system. We compared the cost per completed course of preventive treatment with either 6 months of daily isoniazid (6H) or 3 months of weekly isoniazid and rifapentine (3HP), delivered by the Indus Health Network tuberculosis program in Karachi, Pakistan, between October 2016 and February 2018.. During this period, 459 individuals initiated 6H and 643 initiated 3HP; 39% and 61% completed treatment, respectively. Considering costs to both the program and care recipients, the cost per completed course was 394 US dollars (USD) for 6H and 333 USD for 3HP. Using a new 2020 price for rifapentine reduced the cost per completed course of 3HP to 290 USD. Under varying assumptions about drug prices and costs incurred by care recipients, the cost per completed course was lower for 3HP in all scenarios, and the largest cost drivers were the salaries of clinical staff.. In a high-burden setting, the cost of successful delivery of 3HP was lower than that of 6H, driven by higher completion.

Topics: Antitubercular Agents; Cost-Benefit Analysis; Drug Therapy, Combination; Humans; Isoniazid; Latent Tuberculosis; Rifampin; Tuberculosis

A 12-dose weekly regimen of rifapentine plus isoniazid (3HP) is recommended for the prevention of active tuberculosis (TB); however, it is unclear whether 3HP should be provided by directly observed therapy (DOT) or self-administered therapy (SAT). In addition, the introduction of patient informed choice between delivery modalities may have a positive impact on factors leading to treatment completion. The authors randomized 252 participants with HIV to a hypothetical scenario of providing preventive therapy by either DOT or an informed choice between DOT and SAT. Out of 104 participants who were randomized to a choice between DOT and SAT, 103 chose therapy by SAT. Participants rated their level of confidence and intention to complete therapy. Compared to those assigned to the DOT scenario, patients assigned to the choice scenario expressed greater confidence and intention to complete preventive therapy. Convenience and travel required to complete 3HP therapy were important factors in deciding between delivery modalities. Those assigned to DOT identified more barriers to completing therapy than those given a choice. Empowering patients to make informed decisions about how they receive TB preventive therapy may improve completion rates.

Topics: Adult; Decision Making; Directly Observed Therapy; Female; HIV Infections; Humans; Isoniazid; Latent Tuberculosis; Male; Middle Aged; Patient Preference; Random Allocation; Rifampin; Self Administration; Self Efficacy; Uganda

To assess the cost effectiveness of once weekly rifapentine and isoniazid for 12 weeks (3HP) to the current standard care for latent tuberculosis (TB) infection (LTBI) in Iqaluit, Nunavut.. A cost-effectiveness analysis using a Markov model reflecting local practices for LTBI treatment.. A remote Canadian arctic community with a high incidence of TB.. Hypothetical patients with LTBI.. The cost effectiveness of 3HP was compared with the existing standard of care in the study region which consists of 9 months of twice weekly isoniazid (9H) given by directly observed therapy.. Effectiveness was measured in quality-adjusted life years (QALYs) with model parameters were derived from historical programmatic data, a local implementation study of 3HP and published literature. Costs from the perspective of the Nunavut healthcare system were measured in 2019 US dollars and were obtained primarily from local, empirically collected data. Secondary health outcomes included estimated TB cases and TB deaths averted using 3HP versus 9H. One way and probabilistic sensitivity analyses were performed.. The 3HP regimen was dominant over 9H: costs were lower (US$628 vs US$924/person) and health outcomes slightly improved (20.14 vs 20.13 QALYs/person). In comparison to 9H, 3HP treatment resulted in fewer TB cases (27.89 vs 30.16/1000 persons) and TB deaths (2.29 vs 2.48/1000 persons). 3HP completion, initiation and risk of fatal adverse events were the primary drivers of cost effectiveness.. In a remote Canadian arctic setting, using 3HP instead of 9H for LTBI treatment may result in cost savings and similar or improved health outcomes.

Topics: Antitubercular Agents; Canada; Cost-Benefit Analysis; Humans; Isoniazid; Latent Tuberculosis; Rifampin

Three months of weekly rifapentine plus isoniazid (3HP) is a short course regimen for latent tuberculosis infection treatment with satisfied safety and efficacy. However, research on its use in children is limited. In this study, we evaluated the completion rate and safety of the 3HP regimen among children in China. Participants aged 1-14 years receiving 3HP for TB prevention at Shanghai Public Health Clinical Center were followed from December 2019 to November 2020 to evaluate the safety and completion rate of the treatment. Thirty-one children were eligible for inclusion, but five were excluded from the analysis (three were treated with a lower than recommended dose, and two were lost to follow-up). Of the 26 children included in the analysis, the treatment completion rate was 100%. Adverse drug reactions (ADRs) were reported in 38.5% (10/26) of the patients. The most common ADRs were gastrointestinal symptoms (19.2%,5/26), and all ADRs were rated as Grade 1. The 3HP regimen has a high completion rate, and it seems well tolerated in our study population. However, further randomized controlled clinical trial with larger sample size are warranted.

Topics: Adolescent; Antitubercular Agents; Child; Child, Preschool; China; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Infant; Isoniazid; Latent Tuberculosis; Male; Medication Adherence; Rifampin

Topics: Animals; Antibiotics, Antitubercular; Antitubercular Agents; Drug Therapy, Combination; Isoniazid; Latent Tuberculosis; Macaca; Models, Animal; Mycobacterium tuberculosis; Rifampin; Treatment Outcome; Tuberculosis

Efficient recruitment of eligible participants, optimizing time and sample size, is a crucial component in conducting a successful clinical trial. Inefficient participant recruitment can impede study progress, consume staff time and resources, and limit quality and generalizability or the power to assess outcomes. Recruitment for disease prevention trials poses additional challenges because patients are asymptomatic. We evaluated candidates for a disease prevention trial to determine reasons for nonparticipation and to identify factors that can be addressed to improve recruitment efficiency.. During 2001-2009, the Tuberculosis Trials Consortium conducted Study 26 (PREVENT TB), a randomized clinical trial at 26 sites in four countries, among persons with latent tuberculosis infection at high risk for tuberculosis disease progression, comparing 3 months of directly observed once-weekly rifapentine plus isoniazid with 9 months of self-administered daily isoniazid. During March 2005-February 2008, non-identifying demographic information, risk factors for experiencing active tuberculosis disease, and reasons for not enrolling were collected from screened patients to facilitate interpretation of trial data, to meet Consolidated Standards of Reporting Trials standards, and to evaluate reasons for nonparticipation.. Of the 7452 candidates screened in Brazil, Canada, Spain, and the United States, 3584 (48%) were not enrolled, because of ineligibility (41%), site decision (10%), or patient choice (49%). Among those who did not enroll by own choice, and for whom responses were recorded on whether they would accept treatment outside of the study (n = 1430), 68% reported that they planned to accept non-study latent tuberculosis infection treatment. Among 1305 patients with one or more reported reasons for nonparticipation, study staff recorded a total of 1886 individual reasons (reason count: median = 1/patient; range = 1-9) for why patients chose not to enroll, including grouped concerns about research (24% of 1886), work or school conflicts (20%), medication or health beliefs (16%), latent tuberculosis infection beliefs (11%), and patient lifestyle and family concerns (10%).. Educational efforts addressing clinical research concerns and beliefs about medication and health, as well as study protocols that accommodate patient-related concerns (e.g. work, school, and lifestyle) might increase willingness to enter clinical trials. Findings from this evaluation can support development of communication and education materials for clinical trial sites at the beginning of a trial to allow study staff to address potential participant concerns during study screening.

Topics: Adolescent; Adult; Antitubercular Agents; Child; Child, Preschool; Clinical Trials, Phase III as Topic; Drug Therapy, Combination; Female; Humans; Isoniazid; Latent Tuberculosis; Male; Patient Selection; Randomized Controlled Trials as Topic; Refusal to Participate; Rifampin; Risk Factors; Young Adult

Topics: Animals; Isoniazid; Latent Tuberculosis; Macaca; Mycobacterium tuberculosis; Rifampin

Treatment data for latent tuberculosis infection (LTBI) among potential living kidney donors are scarce.. This retrospective study was performed to evaluate the prevalence of positive QuantiFERON-TB Gold In-Tube (QFT-GIT) among potential living kidney donors that were screened from 2009 to 2017. We investigated if there was any difference in the time to donation between QFT-GIT-positive and QFT-GIT-negative donors. We assessed the regimens used to treat LTBI and whether the recipients of QFT-GIT-positive donors developed active tuberculosis (TB).. Forty out of 427 (9%) potential living kidney donors had a positive QFT-GIT. QFT-GIT-positive donors were as likely as negative donors to undergo donation (30 [75%] vs 315 [81%], P = .33). The time from QFT-GIT testing to donation was longer among QFT-GIT-positive donors (median 221 days [range: 4-1139] vs 86 days [range: 3-1887], P = .001). Twelve-week rifapentine (RPT)/Isoniazid (INH) was the most common treatment used and was not associated with significant adverse reactions. There was a trend toward longer time to donation among QFT-GIT-positive donors who were treated for LTBI compared with QFT-GIT-positive donors who were not (252 days [range: 88-1139] vs 95 days [range: 4-802], P = .05). Twenty-nine recipients of QFT-GIT-positive living kidney donors were evaluated. Eleven of these recipients received kidneys from donors that were not treated for LTBI. Two of these recipients were treated with INH post-transplantation.. The time from QFT-GIT testing to donation was longer among QFT-GIT-positive donors. The short-course regimens appear to be excellent options for LTBI treatment among living kidney donors and avoid delaying organ donation further.

Topics: Adult; Antibiotics, Antitubercular; Drug Administration Schedule; Humans; Interferon-gamma Release Tests; Kidney; Kidney Transplantation; Latent Tuberculosis; Living Donors; Male; Middle Aged; Mycobacterium tuberculosis; Prevalence; Retrospective Studies; Rifampin

The objective of this study was to evaluate a novel collaborative care model using community pharmacies as additional access points for latent tuberculosis infection (LTBI) treatment for patients using combination weekly therapy with isoniazid and rifapentine (3HP) plus directly observed therapy for 12 weeks.. This prospective pilot study included adult patients diagnosed with LTBI. Patients were eligible for study participation if they spoke English or Spanish and were followed by the New Mexico Department of Health (NM DOH). Patients were excluded if they were pregnant, receiving concomitant HIV antiretroviral therapy, or had contraindications to 3HP due to allergy or drug interactions. Community pharmacy sites included chain, independent, and hospital outpatient pharmacies in Albuquerque and Santa Fe, New Mexico.. A total of 40 patients initiated treatment with 3HP and were included. Most were female (55%) and had a mean age of 46 years (standard deviation, 12.6 y). A total of 75.0% of patients completed LTBI treatment with 3HP in a community pharmacy site. Individuals of Hispanic ethnicity were more likely to complete treatment (76.7% vs 40.0%, P = .04). Most patients (60%; n = 24) reported experiencing an adverse drug event (ADE) with 3HP therapy. Patients who completed treatment were less likely to experience an ADE than patients who discontinued treatment (50.0% vs 90.0%, P = .03). Pharmacists performed 398 LTBI treatment visits (40 initial visits, 358 follow-up visits), saving the NM DOH approximately 143 hours in patient contact time.. High completion rates and safe administration of LTBI treatment can be achieved in the community pharmacy setting.

Topics: Adult; Antibiotics, Antitubercular; Drug Therapy, Combination; Feasibility Studies; Female; Humans; Isoniazid; Latent Tuberculosis; Male; Middle Aged; New Mexico; Pharmacies; Pilot Projects; Prospective Studies; Public Health; Rifampin

China is one of the countries with a high burden of tuberculosis (TB) and latent tuberculosis infection (LTBI). It was recently estimated that China had the highest LTBI burden in the world, with approximately 350 million persons living with the infection. The prevalence of LTBI in China is overestimated by tuberculin skin test (TST) as compared to interferon-gamma release assay (IGRA). A population-based study found that IGRA positivity rates ranged between 13.5% and 19.8%. The annual TB infection rate in the rural population was 1.5% based on persistent positive IGRA results in converters. The development of active TB from LTBI in the general rural population was 0.87 per 100 person-years in the first 2 years among individuals who newly converted to IGRA-positive. TB control in students has been paid more attention by the government, which also improved LTBI management among students in close contact with active TB patients. A 3-month regimen of twice-weekly rifapentine plus isoniazid (3H

Topics: Antitubercular Agents; China; Humans; Incidence; Interferon-gamma Release Tests; Isoniazid; Latent Tuberculosis; Prevalence; Rifampin; Rural Population; Tuberculin Test; Tumor Necrosis Factor-alpha

To estimate the cost of a screening program for identifying latent tuberculosis (TB) infections in migrants to Oman.. A Markov model was used to estimate the cost of screening using an interferon-gamma release assay (IGRA) applied to all migrants from high TB endemic countries, followed by preventive TB treatment.. The model compared seven different scenarios, with a comparison of the direct cost and the quality-adjusted life-years (QALYs) saved.. IGRA testing followed by 3 months of preventive treatment with rifapentine/isoniazid (3HP) was the most cost-effective intervention.

Topics: Cost-Benefit Analysis; Female; Humans; Interferon-gamma Release Tests; Isoniazid; Latent Tuberculosis; Markov Chains; Mass Screening; Oman; Quality-Adjusted Life Years; Rifampin; Transients and Migrants; Tuberculosis

We analyzed data from 2012 to 2016 for patients who were hospitalized or who died after ≥1 dose of isoniazid-rifapentine for treatment of latent Mycobacterium tuberculosis infection. No patients died; 15 were hospitalized. Nine patients experienced hypotension, and 5 had elevated serum aminotransferases, reinforcing the need for vigilant monitoring during treatment.

Topics: Antitubercular Agents; Drug Administration Schedule; Drug Therapy, Combination; Humans; Isoniazid; Latent Tuberculosis; Mycobacterium tuberculosis; Rifampin; United States

The detection and treatment of latent tuberculosis infection (LTBI) is a key step in eliminating tuberculosis (TB), but information on safety and on treatment interruption in elderly LTBI patients remains limited.. This multicenter prospective observational study included individuals with LTBI who underwent preventive therapy. Incidents of systemic adverse reactions (SARs) and treatment interruption rates in an elderly group (≥60 years old) and a young group (<60 years old) were analyzed.. A total of 406 LTBI patients, comprising 167 elderly and 239 young patients, were included in the analyses. The incidence of SARs was similar in the elderly group (18%) and the young group (15.1%). Being middle-aged (35-59 years), body mass index <23 kg/m. The occurrence of SARs was similar in the elderly (≥60 years old) and young (<60 years old) LTBI patients receiving preventive therapy. Extremely old (≥80 years old) LTBI patients had a higher treatment interruption rate, especially when they had SARs.

Topics: Adult; Aged; Aged, 80 and over; Antitubercular Agents; Drug Therapy, Combination; Female; Humans; Incidence; Isoniazid; Kidney Failure, Chronic; Latent Tuberculosis; Male; Middle Aged; Prospective Studies; Rifampin; Taiwan

Topics: Humans; Isoniazid; Latent Tuberculosis; Rifampin

Topics: Antitubercular Agents; Drug Therapy, Combination; Humans; Isoniazid; Latent Tuberculosis; Rifampin; United States

Preventive therapy is essential for reducing tuberculosis (TB) burden among people living with HIV (PLWH) in high-burden settings. Short-course preventive therapy regimens, such as three-month weekly rifapentine and isoniazid (3HP) and one-month daily rifapentine and isoniazid (1HP), may help facilitate uptake of preventive therapy for latently infected patients, but the comparative cost-effectiveness of these regimens under different conditions is uncertain.. We used a Markov state-transition model to estimate the incremental costs and effectiveness of 1HP versus 3HP in a simulated cohort of patients attending an HIV clinic in Uganda, as an example of a low-income, high-burden setting in which TB preventive therapy might be prescribed to PLWH. Our primary outcome was the incremental cost-effectiveness ratio, expressed as 2019 US dollars per disability-adjusted life year (DALY) averted. We estimated cost-effectiveness under different conditions of treatment completion and efficacy of 1HP versus 3HP, latent TB prevalence and rifapentine price.. Assuming equivalent clinical outcomes using 1HP and 3HP and a rifapentine price of $0.21 per 150 mg, 1HP would cost an additional $4.66 per patient treated. Assuming equivalent efficacy but 20% higher completion with 1HP versus 3HP, 1HP would cost $1,221 per DALY averted relative to 3HP. This could be reduced to $18 per DALY averted if 1HP had 5% greater efficacy than 3HP and the price of rifapentine were 50% lower. At a rifapentine price of $0.06 per 150 mg, 1HP would become cost-neutral relative to 3HP.. 1HP has the potential to be cost-effective under many realistic circumstances. Cost-effectiveness depends on rifapentine price, relative completion and efficacy, prevalence of latent TB and local willingness-to-pay.

Topics: Anti-HIV Agents; Antitubercular Agents; Cost-Benefit Analysis; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; Humans; Isoniazid; Latent Tuberculosis; Male; Quality-Adjusted Life Years; Rifampin; Tuberculosis; Uganda

Weekly rifapentine and isoniazid therapy (3HP) is the most frequent treatment for latent tuberculosis infection (LTBI). However, the association between major adverse drug reactions (ADRs) and drug metabolic enzyme single-nucleotide polymorphisms (SNPs) remains unclear. In this study, 377 participants who received the 3HP regimen were recruited and examined for genotyping of CYP5A6, CYP2B6, CYP2C19, CYP2E1, and NAT2 SNPs. In our study, 184 participants (48.4%) developed ADRs. Moreover, CYP2C19 rs4986893 (TT vs. CC+CT, odds ratio [OR] [95% CI]: 2.231 [1.015-4.906]), CYP2E1 rs2070676 (CC vs. CG+GG, OR [95% CI]: 1.563 [1.022-2.389]), and CYP2E1 rs2515641 (CC vs. CT+TT, OR [95% CI]: 1.903 [1.250-2.898]) were associated with ADR development. In conclusion, CYP2C19 and CYP2E1 SNPs may provide useful information regarding ADRs in LTBI patients receiving the 3HP regimen.

Topics: Adult; Antitubercular Agents; Arylamine N-Acetyltransferase; Cytochrome P-450 Enzyme System; Drug Administration Schedule; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Isoniazid; Latent Tuberculosis; Male; Odds Ratio; Polymorphism, Single Nucleotide; Rifampin

The consequences of once-weekly rifapentine plus isoniazid for 3 months (3HP) against latent tuberculosis infections in hemodialysis patients have not been studied before. This is the first study to evaluate the safety and tolerability of 3HP in this population and revealed a completion rate of 65.4%. The therapy was not associated with hepatotoxicity, but with high rates of adverse events (69.2%).

Topics: Adult; Aged; Aged, 80 and over; Antitubercular Agents; Drug Administration Schedule; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Isoniazid; Kidney Failure, Chronic; Latent Tuberculosis; Male; Middle Aged; Renal Dialysis; Rifampin; Safety

Latent tuberculosis infection (LTBI) is a critical driver of the global burden of active TB, and therefore LTBI treatment is key for TB elimination. Treatment regimens for LTBI include self-administered daily isoniazid for 6 (6H) or 9 (9H) months, self-administered daily rifampicin plus isoniazid for 3 months (3RH), self-administered daily rifampicin for 4 months (4R) and weekly rifapentine plus isoniazid for 3 months self-administered (3HP-SAT) or administered by a healthcare worker as directly observed therapy (3HP-DOT). Data on the relative cost-effectiveness of these regimens are needed to assist policymakers and clinicians in selecting an LTBI regimen.. To evaluate the cost-effectiveness of all regimens for treating LTBI.. We developed a Markov model to investigate the cost-effectiveness of 3HP-DOT, 3HP-SAT, 4R, 3RH, 9H and 6H for LTBI treatment in a cohort of 10000 adults with LTBI. Cost-effectiveness was evaluated from a health system perspective over a 20 year time horizon.. Compared with no preventive treatment, 3HP-DOT, 3HP-SAT, 4R, 3RH, 9H and 6H prevented 496, 470, 442, 418, 370 and 276 additional cases of active TB per 10000 patients, respectively. All regimens reduced costs and increased QALYs compared with no preventive treatment. 3HP was more cost-effective under DOT than under SAT at a cost of US$27948 per QALY gained.. Three months of weekly rifapentine plus isoniazid is more cost-effective than other regimens. Greater recognition of the benefits of short-course regimens can contribute to the scale-up of prevention and achieving the 'End TB' targets.

Topics: Adolescent; Adult; Aged; Antitubercular Agents; Cost-Benefit Analysis; Decision Support Techniques; Drug Therapy, Combination; Female; Health Care Costs; Humans; Isoniazid; Latent Tuberculosis; Male; Middle Aged; Rifampin; Young Adult

Topics: Adolescent; Adult; Antitubercular Agents; Drug Therapy, Combination; Female; Humans; Isoniazid; Latent Tuberculosis; Male; Middle Aged; Retrospective Studies; Rifampin; Risk; Treatment Outcome; Young Adult

Topics: Aged; Antitubercular Agents; Humans; Isoniazid; Latent Tuberculosis; Rifampin

In the province of Manitoba, Canada, given that latent tuberculosis infection (LTBI) treatment is provided at no cost to the patient, treatment completion rates should be optimal. The objective of this study was to estimate LTBI treatment completion using prescription drug administrative data and identify patient characteristics associated with completion.. Prescription drug data (1999-2014) were used to identify individuals dispensed isoniazid (INH) or rifampin (RIF) monotherapy. Treatment completion was defined as being dispensed INH for ≥ 180 days (INH180) or ≥ 270 days (INH270) or RIF for ≥ 120 days (RIF120). Logistic regression models tested socio-demographic and comorbidity characteristics associated with treatment completion.. The study cohort comprised 4985 (90.4%) persons dispensed INH and 529 (9.6%) RIF. Overall treatment completion was 60.2% and improved from 43.1% in 1999-2003 to 67.3% in 2009-2014. INH180 showed the highest completion (63.8%) versus INH270 (40.4%) and RIF120 (27.0%). INH180 completion was higher among those aged 0-18 years (68.5%) compared with those aged 19+ (61.0%). Sex, geography, First Nations status, income quintile, and comorbidities were not associated with completion.. Benchmark 80% treatment completion rates were not achieved in Manitoba. Factors associated with non-completion were older age, INH270, and RIF120. Access to shorter LTBI treatments, such as rifapentine/INH, may improve treatment completion.

Topics: Adolescent; Adult; Age Factors; Aged; Antitubercular Agents; Child; Child, Preschool; Databases, Factual; Female; Humans; Infant; Infant, Newborn; Isoniazid; Latent Tuberculosis; Male; Manitoba; Middle Aged; Prescription Drugs; Rifampin; Treatment Adherence and Compliance; Young Adult

Topics: Aged; Antitubercular Agents; Arthritis, Rheumatoid; Drug Administration Schedule; Drug Therapy, Combination; Feasibility Studies; Female; Humans; Isoniazid; Latent Tuberculosis; Male; Middle Aged; Rifampin

Treatment of latent tuberculosis infection (LTBI) is critical to the control and elimination of tuberculosis disease (TB) in the United States. In 2011, CDC recommended a short-course combination regimen of once-weekly isoniazid and rifapentine for 12 weeks (3HP) by directly observed therapy (DOT) for treatment of LTBI, with limitations for use in children aged <12 years and persons with human immunodeficiency virus (HIV) infection (1). CDC identified the use of 3HP in those populations, as well as self-administration of the 3HP regimen, as areas to address in updated recommendations. In 2017, a CDC Work Group conducted a systematic review and meta-analyses of the 3HP regimen using methods adapted from the Guide to Community Preventive Services. In total, 19 articles representing 15 unique studies were included in the meta-analysis, which determined that 3HP is as safe and effective as other recommended LTBI regimens and achieves substantially higher treatment completion rates. In July 2017, the Work Group presented the meta-analysis findings to a group of TB experts, and in December 2017, CDC solicited input from the Advisory Council for the Elimination of Tuberculosis (ACET) and members of the public for incorporation into the final recommendations. CDC continues to recommend 3HP for treatment of LTBI in adults and now recommends use of 3HP 1) in persons with LTBI aged 2-17 years; 2) in persons with LTBI who have HIV infection, including acquired immunodeficiency syndrome (AIDS), and are taking antiretroviral medications with acceptable drug-drug interactions with rifapentine; and 3) by DOT or self-administered therapy (SAT) in persons aged ≥2 years.

Topics: Adolescent; Antibiotics, Antitubercular; Centers for Disease Control and Prevention, U.S.; Child; Child, Preschool; Drug Administration Schedule; Drug Therapy, Combination; Humans; Isoniazid; Latent Tuberculosis; Mycobacterium tuberculosis; Rifampin; United States

Anti-tuberculosis formulations necessitate uninterrupted treatment to cure tuberculosis (TB), but are characterised by suboptimal adherence, which jeopardises therapeutic efficacy. Long-acting injectable (LAI) formulations or implants could address these associated issues.. niazid, rifapentine, bedaquiline and delamanid-in adults for treatment for latent tuberculous infection (LTBI).. PBPK models were developed and qualified against available clinical data by integrating drug physicochemical properties and in vitro and population pharmacokinetic data into a mechanistic description of drug distribution. Combinations of optimal dose and release rates were simulated such that plasma concentrations were maintained over the epidemiological cut-off or minimum inhibitory concentration for the dosing interval.. The PBPK model identified 1500 mg of delamanid and 250 mg of rifapentine as sufficient doses for monthly intramuscular administration, if a formulation or device can deliver the required release kinetics of 0.001-0.0025 h-1 and 0.0015-0.0025 h-1, respectively. Bedaquiline and isoniazid would require weekly to biweekly intramuscular dosing.. We identified the theoretical doses and release rates of LAI anti-tuberculosis formulations. Such a strategy could ease the problem of suboptimal adherence provided the associated technological complexities for LTBI treatment are addressed.

Topics: Adolescent; Adult; Antitubercular Agents; Diarylquinolines; Drug Administration Schedule; Drug Liberation; Drug Therapy, Combination; Female; Humans; Injections, Intramuscular; Isoniazid; Latent Tuberculosis; Male; Middle Aged; Nitroimidazoles; Oxazoles; Proof of Concept Study; Rifampin; Treatment Outcome; Young Adult

Successful treatment of latent tuberculosis infection (LTBI) is essential to reduce tuberculosis (TB) incidence rates in low-burden countries. This study measures treatment completion and determinants of non-completion of LTBI treatment in Norway in 2016.. This prospective cohort study included all individuals notified with LTBI treatment to the Norwegian Surveillance System for Infectious Diseases (MSIS) in 2016. We obtained data from MSIS and from a standardized form that was sent to health care providers at the time of patient notification to MSIS. We determined completion rates. Pearson's chi squared test was used to study associations between pairs of categorical variables and separate crude and multivariable logistic regression models were used to identify factors associated with treatment completion and adverse drug effects.. We obtained information on treatment completion from 719 of the 726 individuals notified for LTBI treatment in 2016. Overall, 91% completed treatment. Treatment completion was highest in the foreign-born group [foreign-born, n = 562 (92%) vs Norwegian-born, n = 115 (85%), p = 0.007]. Treatment completion did not differ significantly between prescribed regimens (p = 0.124). Adverse events were the most common reason for incomplete treatment. We found no significant differences in adverse events when comparing weekly rifapentine (3RPH) with three months daily isoniazid and rifampicin (3RH). However, there were significantly fewer adverse events with 3RPH compared to other regimens (p = 0.037). Age over 35 years was significantly associated with adverse events irrespective of regimen (p = 0.024), whereas immunosuppression was not significantly associated with adverse events after adjusting for other variables (p = 0.306). Treatment under direct observation had a significant effect on treatment completion for foreign-born (multivariate Wald p-value = 0.017), but not for Norwegian-born (multivariate Wald p-value = 0.408) individuals.. We report a very high treatment completion rate, especially among individuals from countries with high TB incidence. The follow-up from tuberculosis-coordinators and the frequent use of directly observed treatment probably contributes to this. Few severe adverse events were reported, even with increased age and in individuals that are more susceptible. While these results are promising, issues of cost-effectiveness and targeting treatment to individuals at highest risk of TB are important components of public health impact.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antitubercular Agents; Child; Child, Preschool; Female; Humans; Incidence; Isoniazid; Latent Tuberculosis; Male; Medication Adherence; Middle Aged; Norway; Prospective Studies; Rifampin; Young Adult

Since January 2013, the New York City (NYC) Health Department Tuberculosis (TB) Program has offered persons diagnosed with latent TB infection (LTBI) the 3-month, once-weekly isoniazid and rifapentine (3HP) treatment regimen. Patients on this treatment are monitored in-person under directly observed therapy (DOT). To address patient and provider barriers to in-person DOT, we piloted the use of a videoconferencing software app to remotely conduct synchronous DOT (video directly observed therapy; VDOT) for patients on 3HP.. The objective of our study was to evaluate the implementation of VDOT for patients on 3HP and to assess whether treatment completion for these patients increased when they were monitored using VDOT compared with that using the standard in-person DOT.. Between February and October 2015, patients diagnosed with LTBI at any of the four NYC Health Department TB clinics who met eligibility criteria for treatment with 3HP under VDOT (V3HP) were followed until 16 weeks after treatment initiation, with treatment completion defined as ingestion of 11 doses within 16 weeks. Treatment completion of patients on V3HP was compared with that of patients on 3HP under clinic-based, in-person DOT who were part of a prior study in 2013. Furthermore, outcomes of video sessions with V3HP patients were collected and analyzed.. During the study period, 70% (50/71) of eligible patients were placed on V3HP. Treatment completion among V3HP patients was 88% (44/50) compared with 64.9% (196/302) among 3HP patients on clinic DOT (P<.001). A total of 360 video sessions were conducted for V3HP patients with a median of 8 (range: 1-11) sessions per patient and a median time of 4 (range: 1-59) minutes per session. Adherence issues (eg, >15 minutes late) during video sessions occurred 104 times. No major side effects were reported by V3HP patients.. The NYC TB program observed higher treatment completion with VDOT than that previously seen with clinic DOT among patients on 3HP. Expanding the use of VDOT may improve treatment completion and corresponding outcomes for patients with LTBI.

Topics: Adult; Ambulatory Care Facilities; Antitubercular Agents; Data Collection; Directly Observed Therapy; Female; Humans; Isoniazid; Latent Tuberculosis; Male; Middle Aged; Rifampin; Telemedicine; Videoconferencing; Young Adult

Topics: Aged; Antitubercular Agents; Humans; Isoniazid; Latent Tuberculosis; Rifampin

Tuberculosis (TB) is caused by the bacterium Mycobacterium tuberculosis and is spread from person to person through the air. TB can be spread in congregate settings, such as school environments, to varying degrees, based on factors including duration of contact and air ventilation (1); therefore, evaluating potential contacts and exposures can be challenging. In February 2015, a student at a Kansas high school received a diagnosis of active pulmonary TB disease. Screening of 385 (91%) school contacts, four (100%) household contacts, and 19 (90%) social contacts resulted in the identification of 50 persons with latent TB infection. Johnson County Department of Health and Environment (JCDHE) Public Health Emergency Preparedness personnel used their experience with points of distribution logistics to optimize testing clinic layouts and implement the incident command structure. Open communication with students, school staff members, the public, and the media about the investigation from the outset was imperative to reduce rumors and unease that can accompany a large communicable disease investigation. The large number of persons needing treatment for latent TB overwhelmed JCDHE's two TB nurses. As a result, JCDHE developed a policy and procedure to allow persons who met eligibility requirements to complete 12 weekly doses of isoniazid and rifapentine treatment using video directly observed therapy (VDOT) rather than traditional in-person directly observed therapy (DOT). This procedure facilitated treatment compliance and completion; among the eligible 15 persons who chose the 12-week VDOT option, 14 (93%) completed treatment. State and local health departments might consider use of VDOT to monitor treatment of persons with latent TB infection.

Topics: Antitubercular Agents; Contact Tracing; Directly Observed Therapy; Humans; Isoniazid; Kansas; Latent Tuberculosis; Mycobacterium tuberculosis; Patient Compliance; Rifampin; Schools; Telemedicine; Treatment Outcome; Videoconferencing

Randomized controlled trials have demonstrated that the newest latent tuberculosis (LTBI) regimen, 12 weekly doses of directly observed isoniazid and rifapentine (3HP), is as efficacious as 9 months of isoniazid, with a greater completion rate (82% vs 69%); however, 3HP has not been assessed in routine healthcare settings.. Observational cohort of LTBI patients receiving 3HP through 16 US programs was used to assess treatment completion, adverse drug reactions, and factors associated with treatment discontinuation.. Of 3288 patients eligible to complete 3HP, 2867 (87.2%) completed treatment. Children aged 2-17 years had the highest completion rate (94.5% [155/164]). Patients reporting homelessness had a completion rate of 81.2% (147/181). In univariable analyses, discontinuation was lowest among children (relative risk [RR], 0.44 [95% confidence interval {CI}, .23-.85]; P = .014), and highest in persons aged ≥65 years (RR, 1.72 [95% CI, 1.25-2.35]; P < .001). In multivariable analyses, discontinuation was lowest among contacts of patients with tuberculosis (TB) disease (adjusted RR [ARR], 0.68 [95% CI, .52-.89]; P = .005) and students (ARR, 0.45 [95% CI, .21-.98]; P = .044), and highest with incarceration (ARR, 1.43 [95% CI, 1.08-1.89]; P = .013) and homelessness (ARR, 1.72 [95% CI, 1.25-2.39]; P = .001). Adverse drug reactions were reported by 1174 (35.7%) patients, of whom 891 (76.0%) completed treatment.. Completion of 3HP in routine healthcare settings was greater overall than rates reported from clinical trials, and greater than historically observed using other regimens among reportedly nonadherent populations. Widespread use of 3HP for LTBI treatment could accelerate elimination of TB disease in the United States.

Topics: Adolescent; Adult; Aged; Antibiotics, Antitubercular; Antitubercular Agents; Child; Child, Preschool; Drug Administration Schedule; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Ill-Housed Persons; Isoniazid; Latent Tuberculosis; Male; Middle Aged; Mycobacterium tuberculosis; Rifampin; Students; United States; Young Adult

There are 8.6 million cases of active tuberculosis (TB) worldwide, and an estimated one-third of the world population has latent tuberculosis infection (LTBI). In the United States, up to 80% of active cases may be caused by untreated reactivated latent infection. A case of TB can spread rapidly impacting the readiness of a unit. To prevent the development of TB, it is critical that active duty service members with LTBI complete treatment. The use of isoniazid (INH) and rifapentine (RPT) as a directly observed therapy (DOT) treatment option was recommended by the Centers for Disease Control and Prevention in late 2011. Since then, there have been limited studies on the use of this treatment regimen in a civilian clinic setting and to our knowledge no studies within a military setting.. This study compares the completion rate of LTBI treatment in 2 military public health clinics, using a retrospective chart review of 179 subjects who attempted treatment with INH/RPT DOT and 186 with the non-INH/RPT non-DOT regimen.. When compared to other LTBI regimens completed or attempted in this period, completion rates were higher in INH/RPT DOT regimens. The INH/RPT DOT treatment regimen allowed enough flexibility with completion between 11 and 16 weeks for active duty service members to increase completion to 94.6%, compared to 73% in the non-INH/RPT regimen.. This project demonstrated the feasibility of INH/RPT DOT treatment within the military population resulting in a higher completion rate than the non-INH/RPT non-DOT regimen. The use of the INH/RPT DOT regimen should be considered for use in all military or similar populations.

Topics: Adolescent; Adult; Ambulatory Care Facilities; Antitubercular Agents; Directly Observed Therapy; Female; Humans; Isoniazid; Latent Tuberculosis; Male; Middle Aged; Military Personnel; Retrospective Studies; Rifampin; United States

The risk of infection with Mycobacterium tuberculosis among healthcare workers (HCWs) is estimated to be higher than the general population. However, HCW acceptance and compliance with available latent tuberculosis infection (LTBI) treatment regimens has been problematic. Recently, regimens have become available that might improve HCW acceptance and compliance with LTBI treatment.. A retrospective single-center review of Employee Health and Wellness Services records of all HCWs diagnosed with LTBI was conducted. HCWs diagnosed with LTBI were offered 9-month isoniazid (INH), 4-month rifampin (RIF), weekly rifapentine/isoniazid (RPT/INH) for 12 weeks, or no treatment. Acceptance, completion rates, and side effects were reported for each regimen. Comparisons of regimens were assessed using Fisher exact test.. Between 2005 and 2014, 363 of 927 (39%) HCWs diagnosed with LTBI accepted treatment. Of 363, 202 chose INH, 106 RIF, and 55 RPT/INH. Completion rates for each regimen were 58%, 80%, and 87%, respectively. HCWs were significantly more likely to have completed treatment with RIF (P < .0001) or RPT/INH (P < .0001) than INH. Rates of discontinuation owing to side effects were 35% for INH, 21% for RIF, and 10% for RPT/INH. Discontinuation of therapy due to side effects was significantly more frequent in the INH than the RPT/INH group (P = .0042).. Completion of RIF and RPT/INH for LTBI in an HCW population is more likely than INH. Rates of discontinuation due to side effects were lower among those taking RPT/INH. Shorter LTBI treatment regimens should be more widely considered for HCWs in the United States.

Topics: Adult; Antitubercular Agents; Disease Management; Drug Therapy, Combination; Female; Health Personnel; Humans; Isoniazid; Latent Tuberculosis; Male; Middle Aged; Retrospective Studies; Rifampin

The primary role of any tuberculosis (TB) control program is to ensure the prompt identification and effective treatment of active disease. The host immune system often succeeds in containing the initial (or primary) infection with Mycobacterium tuberculosis (Mtb), but may fail to eliminate the pathogen. The persistence of viable organisms explains the potential for the development of active disease years or even decades after infection. This is known as latent tuberculosis infection (LTBI) although, rather than a distinct entity, this probably represents part of a dynamic spectrum. Individuals with LTBI are asymptomatic and it is therefore clinically undetectable. The World Health Organization (WHO) estimates that one-third of the global population has been infected with Mtb, with highest prevalence of LTBI in countries/regions with the highest prevalence of active disease. In 2013, 88% of 1322 notifications in Australia were in the overseas-born population (incidence 19.5 per 100,000 v. 1.0 per 100,000), with this proportion rising over the course of the last decade. Combined with epidemiological evidence of low local transmission, this strongly implies that the vast majority resulted from reactivation of latent infection acquired prior to immigration. Contrasting trends in TB incidence in other developed countries probably reflect differences in policy regarding LTBI.. The diagnosis and treatment of LTBI represents an important opportunity for intervention by jurisdictional TB control programs.

Topics: Antitubercular Agents; Australia; Chemoprevention; Communicable Disease Control; Disease Notification; Drug Combinations; Emigration and Immigration; Humans; Interferon-gamma Release Tests; Isoniazid; Latent Tuberculosis; Mycobacterium tuberculosis; Prevalence; Rifampin; Transients and Migrants; Tuberculin Test; Tuberculosis, Pulmonary

Renal transplant candidates (RTC) with latent tuberculosis infection (LTBI) are at significant risk for tuberculosis reactivation. Twelve-week rifapentine (RPT)/isoniazid (INH) is effective for LTBI but clinical experience in RTC is scarce.. We conducted a retrospective study of RTC with LTBI treated with either 12-week RPT/INH or 9-month INH from March 1, 2012, through February 28, 2014. We evaluated both groups for differences in rates of treatment completion, monthly follow-up visit compliance, transaminase elevations, and adverse reactions leading to discontinuation of LTBI treatment. The utility of weekly reminders was also evaluated in the 12-week regimen. Direct observed therapy was not performed in our study.. Of 153 patients, 43 (28%) and 110 (72%) were started on 12-week RPT/INH and 9-month INH, respectively. The treatment completion and monthly follow-up visit compliance rates were higher in the 12-week RPT/INH group (40 [93%] vs 52 [47%], P < 0.001) and (11/40 [28%] vs 13/104 [13%], P = 0.03), respectively. Transaminase elevations were not observed in the RPT/INH group, but occurred in 6 (5%) of the INH group. There were no differences in adverse reactions leading to discontinuation of LTBI treatment.. Twelve-week RPT/INH appears to be an excellent choice for LTBI in RTC. It has a higher treatment completion rate and causes less transaminase elevations, and weekly reminders may be an alternative when direct observed therapy is not feasible.

Topics: Adult; Aged; Antitubercular Agents; Biomarkers; Chemical and Drug Induced Liver Injury; Choice Behavior; Drug Therapy, Combination; Female; Humans; Isoniazid; Kidney Diseases; Kidney Transplantation; Latent Tuberculosis; Male; Medication Adherence; Middle Aged; Reminder Systems; Retrospective Studies; Rifampin; Time Factors; Transaminases; Treatment Outcome; Treatment Refusal; Up-Regulation; Waiting Lists

Topics: Adult; Aged; Antitubercular Agents; Blood Pressure; Cohort Studies; Drug Therapy, Combination; Humans; Hypertension; Isoniazid; Kidney Transplantation; Latent Tuberculosis; Middle Aged; Rifampin; Time Factors; Transplant Recipients

The U.S. Centers for Disease Control and Prevention (CDC) recommended a new regimen for treatment of latent tuberculosis (three months of weekly isoniazid and rifapentine) in late 2011. While completion rates of this regimen were reported to be higher than nine months of isoniazid, little is known about the completion rates of three months of isoniazid and rifapentine compared to nine months of isoniazid or four months of rifampin in actual use scenarios.. We conducted a retrospective cohort study comparing treatment completion for latent tuberculosis (TB) infection in patients treated with nine months of isoniazid, three months of isoniazid and rifapentine or four months of rifampin in outpatient clinics and a public health TB clinic in Seattle, Washington. The primary outcome of treatment completion was defined as 270 doses of isoniazid within 12 months, 120 doses of rifampin within six months and 12 doses of isoniazid and rifapentine within four months.. Three hundred ninety-three patients were included in the study. Patients were equally likely to complete three months of weekly isoniazid and rifapentine or four months of rifampin (85% completion rate of both regimens), as compared to 52% in the nine months of isoniazid group (p < 0.001). These associations remained statistically significant even after adjusting for clinic location and type of monitoring. Monitoring type (weekly versus monthly versus less often than monthly) had less impact on treatment completion than the type of treatment offered.. Patients were equally as likely to complete the three months of isoniazid and rifapentine as four months of rifampin. Four months of rifampin is similar in efficacy compared to placebo as isoniazid and rifapentine but does not require directly observed therapy (DOT), and is less expensive compared to combination therapy with isoniazid and rifapentine, and thus can be the optimal treatment regimen to achieve the maximal efficacy in a community setting.

Topics: Adult; Antitubercular Agents; Centers for Disease Control and Prevention, U.S.; Directly Observed Therapy; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Isoniazid; Latent Tuberculosis; Male; Patient Compliance; Retrospective Studies; Rifampin; United States; Washington

The treatment of latent tuberculous infection (TBI) is a productive and meaningful approach to tuberculosis (TB) control, and an important component of the World Health Organization's (WHO's) new End TB Strategy, especially in high-risk contacts. Unfortunately, although recognized and recommended by the WHO, it continues to be underutilized, and has even been ignored for decades in some high-risk groups, as though it were a taboo. Historical approaches to treating TBI in contacts of drug-susceptible and drug-resistant TB are presented and discussed as compelling experiences. In the United States, the Centers for Disease Control and Prevention have recently shown that a directly observed or even self-administered 12-month regimen to treat TBI with once-weekly isoniazid (INH) and rifapentine is as effective as 9 months of daily INH. Treating TBI in drug-susceptible cases and their contacts should not still be considered taboo-such a short, effective regimen is more akin to the Holy Grail. While not yet confirmed in a clinical trial, treating contacts of drug-resistant TB with the same drugs that are effective in the source case would be expected intuitively and practically to prevent TB in contacts and should be introduced now instead of waiting until clinical trials are completed.

Topics: Antitubercular Agents; Contact Tracing; Drug Therapy, Combination; Global Health; Humans; Isoniazid; Latent Tuberculosis; Rifampin; Taboo; Time Factors; Tuberculosis; World Health Organization

Isoniazid daily for 9 months is the recommended regimen for latent tuberculosis infection (LTBI) in solid organ transplant (SOT) candidates, but its use is controversial, due to reports of hepatotoxicity and low treatment completion rates. A 12-week course of once weekly directly observed therapy (DOT) with isoniazid plus rifapentine (3HP) is a new LTBI treatment regimen. Tolerability and safety data of 3HP LTBI treatment in SOT candidates are limited.. Twelve consecutive SOT candidates who underwent DOT with 3HP for LTBI at Westchester Medical Center, Valhalla, New York, USA, between January 2013 and August 2016 were prospectively evaluated for tolerability and safety of 3HP. The diagnosis of LTBI was made in a person with a positive interferon-gamma release test, without a history of previously treated active or latent tuberculosis infection, and without signs, symptoms, or radiographic evidence of active tuberculosis. Patients were followed up 1 month after treatment completion and at routine follow-up visits with their transplant providers.. Eleven patients were men, and the median age was 60 years (range 44-72). Eight patients were liver, and four kidney transplant candidates. The median Model for End-Stage Liver Disease (MELD score) was 17 (range 10-31). All patients completed treatment. Only a single patient developed transaminitis greater than twice the baseline value. Three patients underwent liver transplantation. None of them developed tuberculosis at 9, 22, or 40 months following transplantation.. Directly observed 3HP LTBI treatment was not associated with hepatotoxicity, even in patients with higher MELD scores. Further studies are needed to confirm the safety and efficacy of this LTBI treatment regimen in the SOT population.

Topics: Adult; Aged; Antibiotics, Antitubercular; Directly Observed Therapy; Drug Therapy, Combination; Female; Humans; Isoniazid; Latent Tuberculosis; Male; Middle Aged; New York; Rifampin

Completion of treatment for tuberculosis infection (TBI) with 9 months of self-administered daily isoniazid (9H) has historically been low (<50%) among New York City (NYC) Health Department tuberculosis clinic patients. Treatment of TBI with 3 months of once-weekly isoniazid and rifapentine (3HP) administered under directly observed therapy (DOT) might increase treatment acceptance and completion.. The study population included patients diagnosed with TBI at 2 NYC Health Department tuberculosis clinics from January 2013 through November 2013. Treatment acceptance and completion with 3HP were compared with historical estimates. Treatment outcomes, side effects, and reasons for refusing 3HP were described.. Among 631 patients eligible for TBI treatment, 503 (80%) were offered 3HP; 302 (60%) accepted, 92 (18%) chose other treatment, and 109 (22%) refused treatment. The most common reason for refusing 3HP was the clinic-based DOT requirement. Forty (13%) patients treated with 3HP experienced side effects--9 were restarted on 3HP, 18 switched treatment regimens, and 13 discontinued. Although treatment acceptance did not differ from historical estimates (78% vs 79%, P = .75), treatment completion increased significantly (65% vs 34%, P < .01).. Implementation of 3HP in 2 NYC Health Department tuberculosis clinics increased TBI treatment completion by 31 percentage points compared with historical estimates. More flexible DOT options may improve acceptance of 3HP. Wider use of 3HP may substantially improve TBI treatment completion in NYC and advance progress toward tuberculosis elimination.

Topics: Adult; Ambulatory Care Facilities; Antitubercular Agents; Directly Observed Therapy; Female; Humans; Isoniazid; Latent Tuberculosis; Male; Middle Aged; New York City; Patient Compliance; Public Health; Rifampin; Young Adult

Treatment of latent tuberculosis infection (LTBI) is essential for eradicating tuberculosis (TB). Moreover, the patient adherence is crucial in determining the effectiveness of TB control. Isoniazid given by DOTS daily for 9 months (9H) is the standard treatment for LTBI in Taiwan. However, the completion rate is low due to the long treatment period and its side effects. The combined regimen using a high dose of rifapentine/isoniazid once weekly for 12 weeks (3HP) has been used as an alternative treatment option for LTBI in the United States. This may result in a higher completion rate. In this pilot study, patient adherence and cost of these 2 treatment regimens were investigated. Thus, we aimed to assess the treatment completion rate and costs of 3HP and compare to those with 9H.Data from 691 cases of LTBI treatments including 590 cases using the conventional regimen and 101 cases with rifapentine/Isoniazid were collected. The cost was the sum of the cost of treatment with Isoniazid for 9 months or with rifapentin/Isoniazid for 3 months of all contacts. The effectiveness was the cost of cases of tuberculosis avoided.In this study, the treatment completion rate for patients prescribed with the 3 months rifapentine/isoniazid regimen (97.03%) was higher than those given the conventional 9-month isoniazid regimen (87.29%) (P <0.001). The cost of 3HP and 9H was US$261.24 and US$717.3, respectively. The cost-effectiveness ratio with isoniazid for 9 months was US$ 15392/avoided 1 case of tuberculosis and US$ 5225/avoided 1 case of tuberculosis with 3HP. In addition, when compared with the conventional regimen, there were fewer patients discontinued with rifapentine/isoniazid regimen due to undesirable side effects.This was the first study to compare the 2 treatment regimens in Taiwan, and it showed that a short-term high-dosage rifapentine/isoniazid treatment regimen reduced costs and resulted in higher treatment completion than the standard LTBI isoniazid treatment.

Topics: Adolescent; Adult; Aged; Antitubercular Agents; Cost-Benefit Analysis; Directly Observed Therapy; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Isoniazid; Latent Tuberculosis; Male; Medication Adherence; Middle Aged; Pilot Projects; Rifampin; Taiwan; Time Factors; Tuberculosis, Pulmonary; Young Adult

Topics: Antitubercular Agents; Female; Humans; Isoniazid; Latent Tuberculosis; Male; Rifampin

Short-course directly observed isoniazid plus rifapentine (INH/RPT) combination could have potential advantages over a standard 9-month INH regimen for the treatment of latent tuberculosis infection in solid-organ transplant (SOT) candidates.. We prospectively assessed the safety and tolerability of 12 weeks of INH/RPT given directly observed therapy in 17 consecutive SOT candidates with latent tuberculosis infection.. The median age was 57 years and 82% were men. Of the 17 patients, 13 (76%) successfully completed therapy and 4 (24%) eventually underwent SOT. Treatment was prematurely discontinued in four patients. One of these patients underwent a kidney transplant. The overall dose compliance was 83% (169/204 scheduled doses), and 12 (71%) of 17 patients received 100% of scheduled doses. No patient developed transaminase elevations greater than twice baseline or greater than four times the upper limit of normal or clinical hepatotoxicity. No cases of TB developed during 20.4 months after transplant among INH/RPT-treated recipients.. For carefully selected SOT candidates, combination INH/RPT weekly given as directly observed therapy seems to be reasonably well tolerated and is associated with a relatively high completion rate. Future larger prospective studies to confirm the safety and high completion rates reported here and to identify the most appropriate SOT candidates for this regimen are warranted.

Topics: Adult; Aged; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Directly Observed Therapy; Female; Humans; Isoniazid; Latent Tuberculosis; Male; Middle Aged; Organ Transplantation; Prospective Studies; Rifampin

Topics: Antitubercular Agents; Drug Costs; Humans; Isoniazid; Latent Tuberculosis; Rifampin

A large randomized controlled trial recently showed that for treating latent tuberculous infection (LTBI) in persons at high risk of progression to tuberculosis (TB) disease, a 12-dose regimen of weekly rifapentine plus isoniazid (3HP) administered as directly observed treatment (DOT) can be as effective as 9 months of daily self-administered isoniazid (9H).. To assess the cost-effectiveness of 3HP compared to 9H.. A computational model was designed to simulate individuals with LTBI treated with 9H or 3HP. Costs and health outcomes were estimated to determine the incremental costs per active TB case prevented and per quality-adjusted life year (QALY) gained by 3HP compared to 9H.. Over a 20-year period, treatment of LTBI with 3HP rather than 9H resulted in 5.2 fewer cases of TB and 25 fewer lost QALYs per 1000 individuals treated. From the health system and societal perspectives, 3HP would cost respectively US$21,525 and $4294 more per TB case prevented, and respectively $4565 and $911 more per QALY gained.. 3HP may be a cost-effective alternative to 9H, particularly if the cost of rifapentine decreases, the effectiveness of 3HP can be maintained without DOT, and 3HP treatment is limited to those with a high risk of progression to TB disease.

Topics: Antitubercular Agents; Computer Simulation; Cost-Benefit Analysis; Directly Observed Therapy; Drug Administration Schedule; Drug Costs; Drug Therapy, Combination; Hospital Costs; Humans; Isoniazid; Latent Tuberculosis; Models, Economic; Quality-Adjusted Life Years; Rifampin; Time Factors; Treatment Outcome; United States

Mycobacterium tuberculosis 18b, a streptomycin (STR)-dependent mutant that enters a viable but nonreplicating state in the absence of STR, has been developed as a simple model for drug testing against dormant bacilli. Here, we further evaluated the STR-starved 18b (SS18b) model both in vitro and in vivo by comparing the behavior of 22 approved and experimental tuberculosis drugs. Using the resazurin reduction microplate assay (REMA), rifampin (RIF), rifapentine (RPT), TMC207, clofazimine (CFM), and linezolid (LIN) were found to be active against SS18b in vitro, and their bactericidal activity was confirmed by determining the number of CFU. A latent 18b infection was established in mice, and some of the above-mentioned drugs were used for treatment, either alone or in combination with RIF. RIF, RPT, TMC207, CFM, and pyrazinamide (PZA) were all active in vivo, while cell wall inhibitors were not. A comparative kinetic study of rifamycin efficacy was then undertaken, and the results indicated that RPT clears latent 18b infection in mice faster than RIF. Intrigued by the opposing responses of live and dormant 18b cells to cell wall inhibitors, we conducted a systematic analysis of 14 such inhibitors using REMA. This uncovered an SS18b signature (CWPRED) that accurately predicted the activities of cell wall inhibitors and performed well in a blind study. CWPRED will be useful for establishing the mode of action of compounds with unknown targets, while the SS18b system should facilitate the discovery of drugs for treating latent tuberculosis.

Topics: Acetamides; Amino Acid Sequence; Animals; Antitubercular Agents; Clofazimine; Diarylquinolines; Disease Models, Animal; Drug Discovery; Drugs, Investigational; Female; Genetic Engineering; Latent Tuberculosis; Linezolid; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Molecular Sequence Data; Mycobacterium tuberculosis; Oxazines; Oxazolidinones; Quinolines; Rifampin; Streptomycin; Structure-Activity Relationship; Xanthenes

Multidrug-resistant and extensively drug-resistant tuberculosis (MDR/XDR-TB) is an emerging global health threat. Proper management of close contacts of infectious patients is increasingly important. However, no evidence-based recommendations for treating latent TB infection (LTBI) after MDR/XDR-TB exposure (DR-LTBI) exist. An ultrashort regimen for LTBI caused by drug-susceptible strains (DS-LTBI) is also desirable. TMC207 has bactericidal and sterilizing activity in animal models of TB and improves the activity of current MDR-TB therapy in patients.. The objective of this study was to determine whether TMC207 might enable short-course treatment of DR-LTBI and ultrashort treatment of DS-LTBI.. Using an established experimental model of LTBI chemotherapy in which mice are aerosol-immunized with a recombinant bacillus Calmette-Guérin vaccine before low-dose aerosol infection with Mycobacterium tuberculosis, the efficacy of TMC207 alone and in combination with rifapentine was compared with currently recommended control regimens as well as once-weekly rifapentine + isoniazid and daily rifapentine ± isoniazid.. Outcomes included monthly lung colony-forming unit counts and relapse rates.. Lung colony-forming unit counts were stable at about 3.75 log(10) for up to 7.5 months postinfection in untreated mice. Rifamycin-containing regimens were superior to isoniazid monotherapy. TMC207 exhibited sterilizing activity at least as strong as that of rifampin alone and similar to that of rifampin + isoniazid, but daily rifapentine +/- isoniazid was superior to TMC207. Addition of TMC207 to rifapentine did not improve the sterilizing activity of rifapentine in this model.. TMC207 has substantial sterilizing activity and may enable treatment of DR-LTBI in 3-4 months.

Topics: Animals; Antibiotics, Antitubercular; Antitubercular Agents; Diarylquinolines; Disease Models, Animal; Drug Administration Schedule; Drug Therapy, Combination; Extensively Drug-Resistant Tuberculosis; Female; Latent Tuberculosis; Lung; Mice; Mice, Inbred BALB C; Mycobacterium tuberculosis; Quinolines; Rifampin; Stem Cells; Treatment Outcome

Rifapentine-based regimens for treating latent tuberculosis infection (LTBI) are being considered for future clinical trials, but even if they prove effective, high drug costs may limit their economic viability.. To inform clinical trial design by estimating the potential costs and effectiveness of rifapentine-based regimens for treatment of latent tuberculosis infection (LTBI).. We used a Markov model to estimate cost and societal benefits for three regimens for treating LTBI: Isoniazid/rifapentine daily for one month, isoniazid/rifapentine weekly for three months (self-administered and directly-observed), and isoniazid daily for nine months; a strategy of "no treatment" used for comparison. Costs, quality-adjusted life-years gained, and instances of active tuberculosis averted were calculated for all arms.. Both daily isoniazid/rifapentine for one month and weekly isoniazid/rifapentine for three months were less expensive and more effective than other strategies under a wide variety of clinically plausibly parameter estimates. Daily isoniazid/rifapentine for one month was the least expensive and most effective regimen.. Daily isoniazid/rifapentine for one month and weekly isoniazid/rifapentine for three months should be studied in a large-scale clinical trial for efficacy. Because both regimens performed well even if their efficacy is somewhat reduced, study designers should consider relaxing non-inferiority boundaries.

Topics: Antitubercular Agents; Cost-Benefit Analysis; Drug Administration Schedule; Humans; Isoniazid; Latent Tuberculosis; Models, Biological; Patient Compliance; Rifampin; Self Administration; United States

Preventing tuberculosis (TB) by treating latent Mycobacterium tuberculosis infection (LTBI) is a cornerstone of the U.S. strategy for TB elimination. Three randomized controlled trials have shown that a new combination regimen of isoniazid (INH) and rifapentine (RPT) administered weekly for 12 weeks as directly observed therapy (DOT) is as effective for preventing TB as other regimens and is more likely to be completed than the U.S. standard regimen of 9 months of INH daily without DOT. This report provides CDC recommendations for using the INH-RPT regimen. The new regimen is recommended as an equal alternative to the 9-month INH regimen for otherwise healthy patients aged≥12 years who have LTBI and factors that are predictive of TB developing (e.g., recent exposure to contagious TB). The new regimen also can be considered for other categories of patients when it offers practical advantages. Although the INH-RPT regimen was well tolerated in treatment trials, monitoring for adverse effects is recommended. Severe adverse effects should be reported to the Food and Drug Administration (FDA) and CDC.

Topics: Adult; Antitubercular Agents; Child; Child, Preschool; Contraindications; Directly Observed Therapy; Drug Administration Schedule; Drug Therapy, Combination; Evidence-Based Medicine; Humans; Isoniazid; Latent Tuberculosis; Randomized Controlled Trials as Topic; Rifampin