Last data update: May 20, 2024. (Total: 46824 publications since 2009)
Records 1-16 (of 16 Records) |
Query Trace: Moro RN [original query] |
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Assessment for antibodies to rifapentine and isoniazid in persons developing flu-like reactions during treatment of latent tuberculosis infection
Moro RN , Mehaffy C , De P , Phillips E , Borisov AS , Sterling TR , Dobos KM . J Infect Dis 2024 BACKGROUND: Flu-like reactions can occur after exposure to rifampin, rifapentine, or isoniazid. Prior studies have reported the presence of antibodies to rifampin, but associations with underlying pathogenesis are unclear. METHODS: We evaluated PREVENT TB study participants who received weekly isoniazid + rifapentine for 3 months (3HP) or daily isoniazid for 9 months (9H) as treatment for M. tuberculosis infection. Flu-like reaction was defined as a grade ≥2 of any of flu-like symptoms. Controls (3HP or 9H) did not report flu-like reactions. We developed a competitive enzyme-linked immunosorbent assays (ELISA) to detect antibodies against rifapentine, isoniazid, rifampin, and rifapentine metabolite. RESULTS: Among 128 participants, 69 received 3HP (22 with flu-like reactions; 47 controls) and 59 received 9H (12 with flu-like reactions; 47 controls). In participants receiving 3HP, anti-rifapentine IgG was identified in 2/22 (9%) participants with flu-like reactions and 6/47 (13%) controls (P = 0.7), anti-isoniazid IgG in 2/22 (9%) participants with flu-like reactions and 4/47 (9%) controls (P = 0.9), and anti-rifapentine metabolite IgG in 2/47 (4%) controls (P = 0.9). Among participants receiving 9H, IgG and IgM anti-isoniazid antibodies were each present in 4/47 (9%) controls, respectively, but none among participants with flu-like reactions; anti-rifapentine IgG antibodies were not present in any participants with flu-like reactions or controls. CONCLUSIONS: We detected anti-rifapentine, anti-isoniazid, and anti-rifapentine metabolite antibodies, but the proportions of participants with antibodies were low, and did not differ between participants with flu-like reactions and those without such reactions. This suggests that flu-like reactions associated with 3HP and 9H were not antibody-mediated. |
Using a medication event monitoring system to evaluate self-report and pill count for determining treatment completion with self-administered, once-weekly isoniazid and rifapentine
Scott AA , Sadowski C , Vernon A , Arevalo B , Beer K , Borisov A , Cayla JA , Chen M , Feng PJ , Moro RN , Holland DP , Martinson N , Millet JP , Miro JM , Belknap R . Contemp Clin Trials 2023 129 107173 BACKGROUND: 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. METHOD: 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. RESULTS: 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. CONCLUSION: 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. |
Symptoms and systemic drug reactions in persons receiving weekly rifapentine plus isoniazid (3HP) treatment for latent tuberculosis infection
Sadowski C , Belknap R , Holland DP , Moro RN , Chen MP , Wright A , Millet JP , Cayla JA , Scott NA , Borisov A , Gandhi NR . Clin Infect Dis 2023 76 (12) 2090-2097 BACKGROUND: Three months of weekly rifapentine plus isoniazid (3HP) therapy for latent tuberculosis infections (LTBI) is recommended worldwide. The development of symptoms and systemic drug reactions (SDR) on 3HP have not been fully characterized. We aimed to determine the patterns of symptom development and identify SDR and associated factors in patients on 3HP. METHODS: We analyzed symptoms data in participants undergoing 3HP in Tuberculosis Trials Consortium's (TBTC) iAdhere study (Study 33). We examined the patterns of symptom reporting across participants from baseline and four monthly visits. Bivariate analyses and multivariable regression models were used to identify factors associated with SDR. Risk ratios and 95% confidence intervals (CI) were calculated. RESULTS: Among 1,002 participants receiving 3HP, 768 (77%) reported at least one symptom; 97% of these symptoms were grade 1 (79%) or grade 2 (18%). Most symptoms developed in the first month and resolved. 111 (11%) participants had symptoms that met criteria for SDR; however, 53 (48%) of these participants completed therapy. Factors associated with SDR and discontinuation included female sex (RR 2.05, CI: 1.19-3.54), age ≥45 years (RR 1.99, CI: 1.19-3.31), and use of concomitant medications (RR 2.26, CI: 1.15-4.42). CONCLUSIONS: Although most patients receiving 3HP reported symptoms, most were mild, occurred early, and resolved without stopping treatment. Among patients experiencing SDR, 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. |
US Emergency Department Visits for Acute Harms from Over-the-Counter Cough and Cold Medications, 2017-2019
Mital R , Lovegrove MC , Moro RN , Geller AI , Weidle NJ , Lind JN , Budnitz DS . Pharmacoepidemiol Drug Saf 2021 31 (2) 225-234 BACKGROUND AND PURPOSE: Characterization of emergency department (ED) visits for acute harms related to use of over-the-counter cough and cold medications (CCMs) by patient demographics, intent of CCM use, concurrent substance use, and clinical manifestations can help guide prevention of medication harms. METHODS: Public health surveillance data from the National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance project were used to estimate numbers and population rates of ED visits from 2017-2019. RESULTS: Based on 1,396 surveillance cases, there were an estimated 26,735 (95% CI, 21,679-31,791) US ED visits for CCM-related harms annually, accounting for 1.3% (95% CI, 1.2%-1.5%) of all ED visits for medication adverse events. Three fifths (61.4%, 95% CI, 55.6%-67.2%) of these visits were attributed to non-therapeutic CCM use (nonmedical use, self-harm, unsupervised pediatric exposures). Most visits by children aged <4 years (74.0%, 95% CI, 59.7%-88.3%) were for unsupervised CCM exposures. Proportion hospitalized was higher for visits for self-harm (76.5%, 95% CI, 68.9%-84.2%) than for visits for nonmedical use (30.3%, 95% CI, 21.1%-39.6%) and therapeutic use (8.8%, 95% CI, 5.9%-11.8%). Overall, estimated population rates of ED visits for CCM-related harms were higher for patients aged 12-34 years (16.5 per 100,000, 95% CI, 13.0-20.0) compared with patients aged <12 years (5.1 per 100,000, 95% CI, 3.6-6.5) and ≥35 years (4.3 per 100,000, 95% CI, 3.4-5.1). Concurrent use of other medications, illicit drugs, or alcohol was frequent in ED visits for nonmedical use (61.3%) and self-harm (75.9%). CONCLUSIONS: Continued national surveillance of CCM-related harms can assess progress toward safer use. |
Clinical and virologic characteristics of the first 12 patients with coronavirus disease 2019 (COVID-19) in the United States.
Kujawski SA , Wong KK , Collins JP , Epstein L , Killerby ME , Midgley CM , Abedi GR , Ahmed NS , Almendares O , Alvarez FN , Anderson KN , Balter S , Barry V , Bartlett K , Beer K , Ben-Aderet MA , Benowitz I , Biggs HM , Binder AM , Black SR , Bonin B , Bozio CH , Brown CM , Bruce H , Bryant-Genevier J , Budd A , Buell D , Bystritsky R , Cates J , Charles EM , Chatham-Stephens K , Chea N , Chiou H , Christiansen D , Chu V , Cody S , Cohen M , Conners EE , Curns AT , Dasari V , Dawson P , DeSalvo T , Diaz G , Donahue M , Donovan S , Duca LM , Erickson K , Esona MD , Evans S , Falk J , Feldstein LR , Fenstersheib M , Fischer M , Fisher R , Foo C , Fricchione MJ , Friedman O , Fry A , Galang RR , Garcia MM , Gerber SI , Gerrard G , Ghinai I , Gounder P , Grein J , Grigg C , Gunzenhauser JD , Gutkin GI , Haddix M , Hall AJ , Han GS , Harcourt J , Harriman K , Haupt T , Haynes AK , Holshue M , Hoover C , Hunter JC , Jacobs MW , Jarashow C , Joshi K , Kamali T , Kamili S , Kim L , Kim M , King J , Kirking HL , Kita-Yarbro A , Klos R , Kobayashi M , Kocharian A , Komatsu KK , Koppaka R , Layden JE , Li Y , Lindquist S , Lindstrom S , Link-Gelles R , Lively J , Livingston M , Lo K , Lo J , Lu X , Lynch B , Madoff L , Malapati L , Marks G , Marlow M , Mathisen GE , McClung N , McGovern O , McPherson TD , Mehta M , Meier A , Mello L , Moon SS , Morgan M , Moro RN , Murray J , Murthy R , Novosad S , Oliver SE , O’Shea J , Pacilli M , Paden CR , Pallansch MA , Patel M , Patel S , Pedraza I , Pillai SK , Pindyck T , Pray I , Queen K , Quick N , Reese H , Reporter R , Rha B , Rhodes H , Robinson S , Robinson P , Rolfes MA , Routh JA , Rubin R , Rudman SL , Sakthivel SK , Scott S , Shepherd C , Shetty V , Smith EA , Smith S , Stierman B , Stoecker W , Sunenshine R , Sy-Santos R , Tamin A , Tao Y , Terashita D , Thornburg NJ , Tong S , Traub E , Tural A , Uehara A , Uyeki TM , Vahey G , Verani JR , Villarino E , Wallace M , Wang L , Watson JT , Westercamp M , Whitaker B , Wilkerson S , Woodruff RC , Wortham JM , Wu T , Xie A , Yousaf A , Zahn M , Zhang J . Nat Med 2020 26 (6) 861-868 Data on the detailed clinical progression of COVID-19 in conjunction with epidemiological and virological characteristics are limited. In this case series, we describe the first 12 US patients confirmed to have COVID-19 from 20 January to 5 February 2020, including 4 patients described previously(1-3). Respiratory, stool, serum and urine specimens were submitted for SARS-CoV-2 real-time reverse-transcription polymerase chain reaction (rRT-PCR) testing, viral culture and whole genome sequencing. Median age was 53 years (range: 21-68); 8 patients were male. Common symptoms at illness onset were cough (n = 8) and fever (n = 7). Patients had mild to moderately severe illness; seven were hospitalized and demonstrated clinical or laboratory signs of worsening during the second week of illness. No patients required mechanical ventilation and all recovered. All had SARS-CoV-2 RNA detected in respiratory specimens, typically for 2-3 weeks after illness onset. Lowest real-time PCR with reverse transcription cycle threshold values in the upper respiratory tract were often detected in the first week and SARS-CoV-2 was cultured from early respiratory specimens. These data provide insight into the natural history of SARS-CoV-2. Although infectiousness is unclear, highest viral RNA levels were identified in the first week of illness. Clinicians should anticipate that some patients may worsen in the second week of illness. |
Emergency department visits attributed to adverse events involving benzodiazepines, 2016-2017
Moro RN , Geller AI , Weidle NJ , Lind JN , Lovegrove MC , Rose KO , Goring SK , McAninch JK , Dowell D , Budnitz DS . Am J Prev Med 2020 58 (4) 526-535 INTRODUCTION: Characterization of emergency department visits attributed to adverse events involving benzodiazepines can be used to guide preventive interventions. This study describes U.S. emergency department visits attributed to adverse events involving benzodiazepines by intent, patient characteristics, and clinical manifestations. METHODS: Data from the 2016-2017 National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance project were analyzed in 2019 to calculate estimated annual numbers and rates of emergency department visits attributed to adverse events involving benzodiazepines, by intent of benzodiazepine use. RESULTS: Based on 6,148 cases, there were an estimated 212,770 (95% CI=167,163, 258,377) emergency department visits annually attributed to adverse events involving benzodiazepines. More than half were visits involving nonmedical use of benzodiazepines (119,008; 55.9%, 95% CI=50.0%, 61.9%), one third were visits involving self-harm with benzodiazepines (64,721; 30.4%, 95% CI=25.6%, 35.2%), and a smaller proportion of visits involved therapeutic use of benzodiazepines (29,041; 13.6%, 95% CI=11.4%, 15.9%). The estimated population rate of visits was highest for nonmedical use of benzodiazepines by patients aged 15-34 years (7.4 visits per 10,000 people). Among visits involving nonmedical use of benzodiazepines, 54.8% (95% CI=49.8%, 59.8%) were made by patients aged 15-34 years, 82.7% (95% CI=80.1%, 85.4%) involved concurrent use of other substances (illicit drugs, alcohol, prescription opioids, and/or other pharmaceuticals), and 24.2% (95% CI=17.7%, 30.6%) involved cardiorespiratory arrest or unresponsiveness. CONCLUSIONS: These findings support recommendations to assess for and address substance use disorder before initiating or continuing benzodiazepines and reinforce the need for validated self-harm risk assessment tools for clinicians. |
Assessment of ICD-10-CM code assignment validity for case finding of outpatient anticoagulant-related bleeding among Medicare beneficiaries
Shehab N , Ziemba R , Campbell KN , Geller AI , Moro RN , Gage BF , Budnitz DS , Yang TH . Pharmacoepidemiol Drug Saf 2019 28 (7) 951-964 PURPOSE: To assess performance of International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) code assignments for identifying bleeding events resulting in emergency department visits and hospitalizations among outpatient Medicare beneficiaries prescribed anticoagulants. METHODS: Performance of 206 ICD-10-CM code assignments indicative of bleeding, five anticoagulant adverse effect/poisoning codes, and five coagulopathy codes (according to Medicare Parts A and B claims) as assessed among Medicare fee-for-service beneficiaries prescribed anticoagulants between October 1, 2015 and September 30, 2016 (according to Part D claims). Structured medical record review was the gold standard for validating the presence of anticoagulant-related bleeding. Sensitivity was adjusted to correct for partial verification bias due to sampling design. RESULTS: Based on the study sample of 1166 records (583 cases, 583 controls), 57 of 206 codes yielded the optimal performance for anticoagulant-related bleeding (diagnostic odds ratio, 51; positive predictive value (PPV), 75.7% [95% CI, 72.0%-79.1%]; adjusted sensitivity, 70.0% [95% CI, 63.2%-77.7%]). Codes for intracranial bleeding demonstrated the highest PPV (85.0%) and adjusted sensitivity (91.0%). Bleeding codes in the primary position demonstrated high PPV (86.9%), but low adjusted sensitivity (36.0%). The adjusted sensitivity improved to 69.5% when codes in a secondary position were added. Only one adverse effect/poisoning code was used, appearing in 7.8% of cases and controls (PPV, 71.4% and adjusted sensitivity, 6.8%). CONCLUSIONS: Performance of ICD-10-CM code assignments for bleeding among patients prescribed anticoagulants varied by bleed type and code position. Adverse effect/poisoning codes were not commonly used and would have missed over 90% of anticoagulant-related bleeding cases. |
Isoniazid-rifapentine for latent tuberculosis infection: A systematic review and meta-analysis
Njie GJ , Morris SB , Woodruff RY , Moro RN , Vernon AA , Borisov AS . Am J Prev Med 2018 55 (2) 244-252 CONTEXT: 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. EVIDENCE ACQUISITION: 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. EVIDENCE SYNTHESIS: 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). CONCLUSIONS: 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. |
Exposure to latent tuberculosis treatment during pregnancy: The PREVENT TB and the iAdhere Trials
Moro RN , Scott NA , Vernon A , Tepper NK , Goldberg SV , Schwartzman K , Leung CC , Schluger NW , Belknap RW , Chaisson RE , Narita M , Machado ES , Lopez M , Sanchez J , Villarino ME , Sterling TR . Ann Am Thorac Soc 2018 15 (5) 570-580 RATIONALE: Data are limited regarding the safety of 12-dose once-weekly isoniazid (900 mg) plus rifapentine (900 mg) (3HP) for latent tuberculosis infection (LTBI) treatment during pregnancy. OBJECTIVE: To assess safety and pregnancy outcomes among pregnant women who were inadvertently exposed to study medications in two LTBI trials (PREVENT TB or iAdhere) evaluating 3HP and 9 months of daily isoniazid (300 mg) (9H). METHODS: Data from reproductive age (15-51 years) women who received >/=1 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. RESULTS: 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% CI -17% to +18%); and congenital anomalies in 0/20 and 2/41 (5%) live births, 3HP and 9H, respectively (difference 0 - 5% = -5%; 95% CI -18% to +16%). All fetal losses occurred in pregnancies <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. CONCLUSION: Among reported pregnancies in these two LTBI 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. Clinical trial registered with clinicaltrials.gov (NCT00023452 and NCT01582711). |
Self-administered versus directly observed once-weekly isoniazid and rifapentine treatment of latent tuberculosis infection: A randomized trial
Belknap R , Holland D , Feng PJ , Millet JP , Cayla JA , Martinson NA , Wright A , Chen MP , Moro RN , Scott NA , Arevalo B , Miro JM , Villarino ME , Weiner M , Borisov AS . Ann Intern Med 2017 167 (10) 689-697 Background: 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. Objective: To compare treatment completion and safety of once-weekly isoniazid and rifapentine by self-administration versus direct observation. Design: 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). Setting: Outpatient tuberculosis clinics in the United States, Spain, Hong Kong, and South Africa. Participants: 1002 adults (aged ≥18 years) recommended for treatment of latent tuberculosis infection. Intervention: 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. Measurements: 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. Results: 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. Limitation: Persons with latent tuberculosis infection enrolled in South Africa would not routinely be treated programmatically. Conclusion: 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. Primary Funding Source: Centers for Disease Control and Prevention. |
High rate of treatment completion in program settings with 12-dose weekly isoniazid and rifapentine (3HP) for latent Mycobacterium tuberculosis infection
Sandul AL , Nwana N , Holcombe JM , Lobato MN , Marks S , Webb R , Wang SH , Stewart B , Griffin P , Hunt G , Shah N , Marco A , Patil N , Mukasa L , Moro RN , Jereb J , Mase S , Chorba T , Bamrah-Morris S , Ho CS . Clin Infect Dis 2017 65 (7) 1085-1093 Background: RCTs demonstrated the newest LTBI regimen, 12 weekly doses of directly observed isoniazid and rifapentine (3HP), as efficacious as 9 months of isoniazid (9H) with a greater completion rate (82% versus 69%); however, 3HP has not been assessed in routine health care settings. Methods: Observational cohort of LTBI patients receiving 3HP through 16 US programs was used to assess treatment completion, adverse drug reactions (ADRs), and factors associated with treatment discontinuation. Results: Of 3288 patients eligible to complete 3HP, 2867 (87.2%) completed treatment. Children 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% CI, 0.23-0.85]; P = .014), and highest in persons ≥65 years (RR, 1.72 [95% CI, 1.25-2.35] P = .001). In multivariable analyses, discontinuation was lowest among contacts of patients with TB disease (adjusted relative risk [ARR], 0.68 [95% CI, 0.52-0.89]; P = .005), and students (ARR, 0.45 [95% CI, 0.21-0.98]; P = .044); 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). ADRs were reported by 1174 (35.7%) patients, of whom 891 (76.0%) completed treatment. Conclusions: Completion of 3HP in routine health care 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. |
Factors associated with non-completion of follow-up: 33-month latent tuberculous infection treatment trial
Moro RN , Sterling TR , Saukkonen J , Vernon A , Horsburgh CR Jr , Chaisson RE , Hamilton CD , Villarino ME , Goldberg S . Int J Tuberc Lung Dis 2017 21 (3) 286-296 SETTING: A post-hoc exploratory analysis of a randomized, open-label clinical trial that enrolled 8053 participants from the United States, Canada, Brazil, and Spain. OBJECTIVE: To assess factors associated with non-completion of study follow-up (NCF) in a 33-month latent tuberculous infection treatment trial, PREVENT TB. DESIGN: Participants were randomized to receive 3 months of weekly directly observed therapy vs. 9 months of daily self-administered therapy. NCF was defined as failing to be followed for at least 993 days (33 months) from enrollment. Possible factors associated with NCF were analyzed using univariate and multivariate regression via Cox proportional hazard model. RESULTS: Of 7061 adults selected for analysis, 841 (11.9%) did not complete study follow-up. Homelessness, young age, low education, history of incarceration, smoking, missing an early clinic visit, receiving isoniazid only, and male sex were significantly associated with NCF. Similar results were found in the North American region (United States and Canada) only. In Brazil and Spain, the only significant factor was missing an early clinic visit. CONCLUSIONS: Study subjects at higher risk for NCF were identified by characteristics known at enrollment or in early follow-up. Evaluation of follow-up in other trials might help determine whether the identified factors consistently correlate with retention. |
Factors associated with non-completion of latent tuberculosis infection treatment: experience from the PREVENT TB trial in the United States and Canada
Moro RN , Borisov A , Saukkonen J , Khan A , Sterling TR , Villarino ME , Scott NA , Shang N , Kerrigan A , Goldberg SV . Clin Infect Dis 2016 62 (11) 1390-1400 BACKGROUND: Overall rates of non-completion of treatment (NCT) for latent tuberculosis infection (LTBI) in the PREVENT TB trial were 18% for 12 directly observed doses of once-weekly isoniazid (900 mg) and rifapentine (900 mg) (3HP-DOT) and 31% for 9 months of daily self-administered isoniazid (300 mg) (9H-SAT). NCT for LTBI reduces its effectiveness.The study objective was to assess factors associated with NCT for LTBI among adult participants enrolled at US and Canadian sites of the PREVENT TB trial. METHODS: A post-hoc exploratory analysis of the randomized, open-label PREVENT TB trial. Factors were analyzed by univariate and multivariate logistic regression (with enrollment site as a random-effect). RESULTS: From 6,232 participants analyzed, 1,406 (22.6%) did not complete LTBI treatment (317 NCT attributed to an adverse event [NCT-AE], and 1,089 NCT attributed to reasons other than adverse event [NCT-O]). The proportion of NCT-AE was similar with both regimens (3HP-DOT=6.4% versus 9H-SAT=5.9%;P=0.23); NCT-O was higher among participants enrolled in 9H-SAT (9H-SAT=24.5% versus 3HP-DOT=12.7%;P=0.02). Among the NCT-AE group, being non-Hispanic and receiving 3HP-DOT, having cirrhosis and receiving 9H-SAT, alcohol consumption among men, and use of concomitant medication were associated with NCT-AE. Among the NCT-O group, receiving 9H-SAT, missing ≥1 early visit, men receiving 9H-SAT, men with history of incarceration, alcohol abuse, use ever of intravenous drugs, younger age receiving 9H-SAT, and smoking were associated with NCT-O. CONCLUSION: Factors associated with NCT, such as missing a clinic visit early during treatment, might help identify persons for whom tailored interventions could improve completion of LTBI treatment. |
Flu-like and Other Systemic Drug Reactions Among Persons Receiving Weekly Rifapentine Plus Isoniazid or Daily Isoniazid for Treatment of Latent Tuberculosis Infection in the PREVENT Tuberculosis Study
Sterling TR , Moro RN , Borisov AS , Phillips E , Shepherd G , Adkinson NF , Weis S , Ho C , Villarino ME . Clin Infect Dis 2015 61 (4) 527-35 BACKGROUND: Weekly rifapentine plus isoniazid for 3 months (3HP) is as effective as daily isoniazid (9H) for 9 months for latent tuberculosis infection in high-risk persons, but there have been reports of possible flu-like syndrome. METHODS: We identified clinically significant systemic drug reactions (SDR) and evaluated risk factors in patients who did not complete treatment in the PREVENT TB study. RESULTS: Among 7,552 persons who received >1 dose of study drug, 153 had a SDR: 138/3,893(3.5%) with 3HP vs. 15/3,659(0.4%) with 9H(P<0.001). In the 3HP arm, 87(63%) had flu-like syndrome and 23(17%) had cutaneous reactions; 13/3,893(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 (aOR 9.4;95%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 (BMI; P=0.009). 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). CONCLUSIONS: 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. |
Daily rifapentine for treatment of pulmonary tuberculosis. A randomized, dose-ranging trial
Dorman SE , Savic RM , Goldberg S , Stout JE , Schluger N , Muzanyi G , Johnson JL , Nahid P , Hecker EJ , Heilig CM , Bozeman L , Feng PJ , Moro RN , MacKenzie W , Dooley KE , Nuermberger EL , Vernon A , Weiner M . Am J Respir Crit Care Med 2015 191 (3) 333-43 RATIONALE: Rifapentine has potent activity in mouse models of tuberculosis chemotherapy but its optimal dose and exposure in humans are unknown. OBJECTIVES: We conducted a randomized, partially blinded dose-ranging study to determine tolerability, safety, and antimicrobial activity of daily rifapentine for pulmonary tuberculosis treatment. METHODS: Adults with sputum smear-positive pulmonary tuberculosis were assigned rifapentine 10, 15, or 20 mg/kg or rifampin 10 mg/kg daily for 8 weeks (intensive phase), with isoniazid, pyrazinamide, and ethambutol. The primary tolerability end point was treatment discontinuation. The primary efficacy end point was negative sputum cultures at completion of intensive phase. MEASUREMENTS AND MAIN RESULTS: A total of 334 participants were enrolled. At completion of intensive phase, cultures on solid media were negative in 81.3% of participants in the rifampin group versus 92.5% (P = 0.097), 89.4% (P = 0.29), and 94.7% (P = 0.049) in the rifapentine 10, 15, and 20 mg/kg groups. Liquid cultures were negative in 56.3% (rifampin group) versus 74.6% (P = 0.042), 69.7% (P = 0.16), and 82.5% (P = 0.004), respectively. Compared with the rifampin group, the proportion negative at the end of intensive phase was higher among rifapentine recipients who had high rifapentine areas under the concentration-time curve. Percentages of participants discontinuing assigned treatment for reasons other than microbiologic ineligibility were similar across groups (rifampin, 8.2%; rifapentine 10, 15, or 20 mg/kg, 3.4, 2.5, and 7.4%, respectively). CONCLUSIONS: Daily rifapentine was well-tolerated and safe. High rifapentine exposures were associated with high levels of sputum sterilization at completion of intensive phase. Further studies are warranted to determine if regimens that deliver high rifapentine exposures can shorten treatment duration to less than 6 months. Clinical trial registered with www.clinicaltrials.gov (NCT 00694629). |
Treatment for preventing tuberculosis in children and adolescents: a randomized clinical trial of a 3-month, 12-dose regimen of a combination of rifapentine and isoniazid
Villarino ME , Scott NA , Weis SE , Weiner M , Conde MB , Jones B , Nachman S , Oliveira R , Moro RN , Shang N , Goldberg SV , Sterling TR . JAMA Pediatr 2015 169 (3) 247-55 IMPORTANCE: 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. OBJECTIVES: 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. DESIGN, SETTING, AND PARTICIPANTS: 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. INTERVENTIONS: 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. MAIN OUTCOMES AND MEASURES: 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%. RESULTS: 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. CONCLUSIONS AND RELEVANCE: 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. TRIAL REGISTRATION: clinicaltrials.gov IDENTIFIER: NCT00023452. |
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