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Treatment completion for latent tuberculosis infection: a retrospective cohort study comparing 9months of isoniazid, 4months of rifampin and 3months of isoniazid and rifapentine

Treatment completion for latent tuberculosis infection: a retrospective cohort study comparing... Background: 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. Methods: 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. Results: 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. Conclusions: 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. Keywords: Latent Tuberculosis Infection, Rifampin, Isoniazid, Rifapentine, Treatment adherence * Correspondence: ahearst@uw.edu Equal contributors Deceased Division of General Internal Medicine, Department of Medicine, University of Washington School of Medicine, Box 3547654245 Roosevelt Way NE, Seattle, WA 98105, USA Full list of author information is available at the end of the article © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. McClintock et al. BMC Infectious Diseases (2017) 17:146 Page 2 of 8 Background Daily rifampin for four months has long been seen as Treating latent TB infection (LTBI) in high-risk individ- an alternative regimen [7] for people who cannot toler- uals is one of the eight Millennium Development goals ate isoniazid for nine months, or who were exposed to of the United Nations [1]. In the United States alone, INH-resistant TB. Prior studies have demonstrated 9,421 cases of active TB were reported in 2014 [2], and higher completion rates with shorter rifampin-based reg- it is estimated that more than 13 million people have la- imens compared to isoniazid [11, 20, 21]. Additionally, tent TB infection [3, 4]. Aggressive treatment of LTBI in a recent review of LTBI treatment, rifampin was again provides significant cost-savings and quality-adjusted life introduced as a potential regimen with increased com- years saved because it dramatically reduces the risk of pletion rates compared to nine months of isoniazid, progression to active TB [5]. Most of the cases in the though no direct comparisons were made between United States occur in foreign born individuals [6]. In rifampin and isoniazid-rifapentine [22]. With the intro- fact, TB in foreign born individuals is on the rise in the duction of isoniazid plus rifapentine and rifampin only US [6]. Primary care and Public Health clinics are often regimens, isoniazid only therapy use appears to have de- the first contact newly arrived patients have with the clined making a study of completion rates among these health care system for screening for TB infection. regimens particularly useful. With the availability of novel treatment regimens for LTBI, medical providers now face the challenge of Objective choosing which regimen is best suited for an individual To date, there have been no studies directly comparing patient. Historically, the regimen of choice for LTBI was completion rates of isoniazid only, rifampin only, and nine-months of daily isoniazid [7]. Nine months of iso- isoniazid and rifapentine regimens. Data on “actual use” niazid reduces the rate of progression to active TB by up in the outpatient setting would be helpful to health care to 39-86%, but only if the patient is fully adherent [7, 8]. providers to guide choice of therapy for individual pa- In most actual use studies, isoniazid completion rates tients. The aim of this study is to compare the rates of are only 31-59% [9–11] making it a less effective treat- completion of the three LTBI therapies across heteroge- ment choice in non-research settings [7]. Additionally, neous populations in various outpatient settings, includ- use is limited by the concerns for side effects such as ing primary care clinics, subspecialty clinics, and a hepatotoxicity and neuropathy [7]. public health TB clinic. In 2011, the CDC recommended a three-month directly observed, weekly dosed therapy of isoniazid and rifapen- Methods tine as an “equal alternative” to the nine month isoniazid We conducted a retrospective cohort study of all patients regimen [12] in healthy individuals with LTBI. Based on who initiated treatment for LTBI with nine months of iso- three randomized controlled trials [13–15], isoniazid and niazid, rifampin only, or isoniazid and rifapentine dis- rifapentine with directly observed therapy (DOT) is con- pensed at a hospital affiliated pharmacy or TB clinic sidered to be non- inferior to standard self-administered during 2009 or between July 1, 2013 and June 30, 2014. isoniazid for nine months in preventing progression to ac- Five hospital-affiliated clinics in Seattle, Washington par- tive TB, and more likely to be completed than isoniazid ticipated in this study: four outpatient clinics affiliated [12, 15]. Additionally, there is an alternative LTBI regimen with an urban academic tertiary care medical center, and of 3 months of daily rifampin and isoniazid. This regimen one county TB clinic. The outpatient clinics include a hos- is used in parts of Europe and also carries the benefits of pital employee health clinic, a primary care clinic focused short duration and low cost. [16] However, the regimen is on care of immigrants and refugees, a primary care clinic not currently on the list of CDC recommended regimens, focused on the care of homeless individuals, and a sub- and is not commonly used in the US at this time, and so specialty infectious diseases clinic. Given that this was a was not included in this study. retrospective chart review and patient identifiers were There has been significant excitement about three removed before entry into the secure database, subject months of isoniazid and rifapentine as an expedited consent to participate was waived by the Institutional Re- treatment option, but many features of this treatment view Board (IRB) per standard practices at our institution. make it less than ideal for certain patients and clinical The IRB at the University of Washington Human Subjects settings. While the isoniazid and rifapentine regimen of- Division approved this study (#43613). fers the promise of higher completion rates, likely due to Patients were identified for inclusion in the study if less cumbersome dosing and shorter duration, this ther- they were 18 years old or older. For patients treated in apy is also significantly more expensive likely driven by the hospital-affiliated outpatient clinics, pharmacy re- the recommended use of DOT [17–19], which may be cords were used to identify patients who were given a inconvenient for some patients, and requires a large re- prescription for isoniazid without ethambutol or rifam- source commitment for the clinics that administer it. pin, rifampin alone, or isoniazid with rifapentine. For McClintock et al. BMC Infectious Diseases (2017) 17:146 Page 3 of 8 isoniazid monotherapy patients, records were queried as it would have been in a monthly monitoring scenario. for those who initiated treatment in 2009, well before Patients on isoniazid and rifapentine were seen weekly for the nation-wide isoniazid shortage and 9 months of iso- DOT by either a nurse or an outreach worker. A small niazid was standard of care. Records were queried again number of the patients on isoniazid and rifapentine re- for those who initiated treatment between July 1, 2013 ceived weekly phone calls or met virtually with an out- and June 30, 2014 for all three regimens. Medical re- reach worker via webcam, rather than in-person contact. cords for the TB clinic were held separately and LTBI The public health TB clinic used a standard set of ques- cases treated with the regimens of interest were identi- tions to check for specific side effects, whereas in all other fied in a TB Control Program database. Diagnosis of clinics, patients were asked a targeted review of systems at LTBI was made by either tuberculin skin test (TST) or the provider’s discretion to assess for side effects to the interferon gamma release assay (IGRA) in combination regimens. Interpreters were used for non-English- with chest x-ray. Screening for active and latent TB was speaking patients. standard practice for patients in the international clinic, The primary outcome was treatment completion. This homeless clinic and employee health due to the high risk outcome was determined based on pharmacy records of of exposure in those populations. The infectious diseases prescription fulfillment. Patients were considered to have clinic treated patients planning to undergo treatment of completed therapy if they filled prescriptions consecu- another disease process with immunosuppressive therap- tively to correspond to 270 doses of isoniazid within ies. Patients from the Public Health Clinic, were 12 months [7], 120 doses of rifampin in a 6 month screened as contacts of active cases being treated by period [7] or 12 doses of isoniazid and rifapentine in a Public Health. The sample size we had was determined 4 month period [12]. by the number of patients seen in our clinics during our We calculated counts, proportions, and means for study period and so we did not calculate power. The demographic, treatment, and health characteristics for 95% confidence intervals we present in Table 2 provide all participants combined and by treatment type. We the best range of plausible estimates. Only one person estimated counts and row proportions for treatment, was excluded from our chart review because it was de- clinic, and monitoring type. We hypothesized these three termined upon further chart review that the participant factors would be associated with completion of treat- had already completed therapy for LTBI prior to our ment. We used Poisson regression models with a log study time frame. Patients with HIV were not included link and robust error variance to estimate unadjusted in this study, as this medical center has a separate HIV and adjusted relative risks (RR) along with 95% confi- clinic which sees HIV patients, and because of the po- dence intervals (CI) and p-values in lieu of logistic re- tential drug-drug interactions between antiretroviral gression since our outcome was common. We identified therapy and rifamycin-based regimens. potential confounders a priori based on their relation- Patients were evaluated for LTBI treatment and ship between the hypothesized factor and completion of monitored for adverse effects during follow up visits. treatment. Confounders evaluated were specific to each When evaluating forsideeffects,specificsideeffects exposure of interest and included demographic (e.g. age, such as liver function test (LFT) abnormalities, lab type of insurance) and treatment characteristics (e.g. abnormalities, and other known or common medica- clinic, treatment regimen, monitoring type) and were tion side effects were marked as present or absent, modeled as categorized in Table 1. Potential confounders whereas patient side effects were classified as “other” that altered estimates, generally by more than 10%, were if the patient reported a subjective side effect which retained in the adjusted models. Specifically, when deter- was not a known side effect of the medication regi- mining the association between completion of therapy mens (for example, a report of dizziness after taking and treatment regimen, we adjusted for frequency of medications was classified as “other.”) Choice of treat- monitoring and when examining the association between ment regimen, frequency of follow-up visits, and fre- completion of therapy and type of monitoring, we ad- quency of laboratory monitoring were selected by the justed for type of monitoring. Because type of monitor- treating physician at his or her discretion based on ing and treatment regimen may be related, we patients’ other comorbidities, medications, length of conducted sensitivity analyses for these associations with therapy and cost. Patients on the nine-month isonia- and without adjustment for type of monitoring and zid and four-month rifampin daily regimens were typ- treatment regimen, respectively. Additionally, we con- ically seen monthly in the public health clinics, and ducted further sensitivity analyses post-hoc after noting monthly or less often in the outpatient clinics. Pa- differences across treatment regimen in homelessness tients monitored less than monthly were monitored and alcohol use. All analyses were conducted using Stata this way because of poor attendance in clinic. When 13.1 [23]. The University of Washington Human Sub- present in clinic, regular monitoring was completed jects Division reviewed and approved this research. McClintock et al. BMC Infectious Diseases (2017) 17:146 Page 4 of 8 Table 1 Characteristics among all participants and stratified on treatment All Participants (N = 393) Isoniazid + Rifapentine, Rifampin only, 2013 Isoniazid only, 2009 p-value 2013 only (N = 87) only (N = 82) and 2013 (N = 224) b b b b n (%) n (%) n (%) n (%) Gender 0.93 Female 175 (44.5) 38 (43.7) 38 (46.3) 99 (44.2) Age (years) 43.6 (15.0) 43.2 (15.4) 43.4 (13.1) 43.8 (15.5) 0.94 Insurance 0.19 Private 59 (18.0) 10 (15.2) 13 (22.0) 36 (17.8) Government sponsored 76 (23.2) 16 (24.2) 17 (28.8) 43 (21.3) Charity care 163 (49.9) 34 (51.5) 29 (49.2) 100 (49.5) Other 29 (8.9) 6 (9.1) 0 (0.0) 23 (11.4) Race/Ethnicity <0.001 Caucasian 30 (7.9) 8 (9.9) 3 (3.7) 19 (8.8) African or African American 94 (24.9) 18 (22.2) 20 (24.4) 56 (26.1) Asian 161 (42.6) 19 (23.5) 40 (48.8) 102 (47.4) Mexican or Other Hispanic 49 (13.0) 11 (13.6) 10 (12.2) 28 (13.0) Pacific Islander 32 (8.5) 21 (25.9) 6 (7.3) 5 (2.3) Other 12 (3.2) 4 (4.9) 3 (3.7) 5 (2.3) Foreign Born 341 (90.7) 65 (79.3) 79 (98.8) 197 (92.1) <0.001 English Speaking 203 (52.5) 60 (70.6) 38 (46.3) 105 (47.7) 0.001 Homeless/marginally house 45 (12.3) 24 (31.2) 2 (2.5) 19 (9.1) <0.001 Number of other medical problems 0.01 0 178 (45.3) 38 (43.7) 51 (62.2) 89 (39.7) 1-2 119 (30.3) 29 (33.3) 19 (23.2) 71 (31.7) 3+ 96 (24.4) 20 (23.0) 12 (14.6) 64 (28.6) Number of medications <0.001 0-1 139 (35.4) 0 (0.0) 56 (68.3) 83 (37.1) 2-3 138 (35.1) 57 (65.5) 12 (14.6) 69 (30.8) 3+ 116 (29.5) 30 (34.5) 14 (17.1) 72 (32.1) Any tobacco use at start of therapy 49 (12.5) 19 (21.8) 11 (13.4) 19 (8.5) 0.01 Any alcohol at start of therapy 52 (13.2) 21 (24.1) 10 (12.2) 21 (9.4) 0.002 Clinic <0.001 Infectious Diseases 17 (4.3) 8 (9.2) 0 (0.0) 9 (4.0) Public Health 263 (66.9) 69 (79.3) 67 (81.7) 127 (56.7) International Clinic 68 (17.3) 0 (0.0) 15 (18.3) 53 (23.7) Homeless Clinic 18 (4.6) 5 (5.8) 0 (0.0) 9 (4.0) Employee Health 27 (6.9) 5 (5.8) 0 (0.0) 22 (9.8) Type of Monitoring <0.001 Weekly DOT/Phone calls 87 (22.2) 84 (96.6) 1 (1.2) 2 (0.9) Monthly visit 139 (35.5) 2 (2.3) 66 (80.5) 71 (31.8) Less often 166 (42.4) 1 (1.2) 15 (18.3) 150 (67.3) 205/224 were treated in 2009 and 19/224 were treated in 2013. In 2009, 7/9 patients were treated in the Infectious Diseases Clinic, 123/127 at the Public Health clinic, 48/53 in International Clinic, 10/13 in the Homeless Clinic, and 17/22 in Employee Health All estimates are percents except for age which is a mean (standard deviation) c d e Less than 5% of data missing; 16.8% of data are missing; 7.1% of data are missing Results rifapentine, 82 received four months of rifampin and 224 A total of 393 participants were included in the study: received nine months of isoniazid (Table 1). There were 87 patients received three months of isoniazid and more men represented in this study than women (55.5% McClintock et al. BMC Infectious Diseases (2017) 17:146 Page 5 of 8 compared to 44.5%). The average age of study partici- clinic or infectious diseases clinic appeared to be less pants was 43.6 years. Foreign-born and non-English likely to complete treatment than patients in the public speaking participants were less likely to receive isoniazid health TB clinic, although the differences were not sta- and rifapentine. Treatment regimens differed by clinic tistically significant with adjusted RR of 0.65 (95% CI and type of monitoring. 0.38, 1.09) and RR of 0.74 (95% CI 0.48, 1.12), respect- Patients treated with four months of rifampin were as ively (Table 2). likely to complete therapy as those on three months of In unadjusted analyses, patients with monthly or less isoniazid and rifapentine. Patients on nine months of frequent monitoring were less likely to complete therapy isoniazid were less likely to complete treatment than pa- than those with weekly DOT with RR of 0.86 (95% CI tients on four months of rifampin or three months of 0.75, 0.98) and RR of 0.60 (95% CI 0.51, 0.72). However, isoniazid and rifapentine with adjusted relative risk of these associations were no longer apparent after adjust- 0.66 (95% CI 0.56, 0.79) and 0.59 (95% CI 0.36, 0.93), re- ing for clinic location and treatment type with RR of spectively (Table 2). These associations remained statisti- 1.12 (95% CI 0.721, 1.76) and RR of 1.21 (95% CI 0.48, cally significant and in the direction anticipated after 1.12), respectively (Table 2). In sensitivity analyses that adjusting for clinic location and type of monitoring. In examined this association between frequency of moni- our sensitivity analyses, this association between treat- toring and treatment completion without adjusting for ment regimen and completion was similar with and treatment regimen, there is a significant association with without adjustment for type of monitoring. RR of monthly monitoring of 0.82 (95% CI 0.72, 0.94) Patients treated in the employee or refugee clinics and less frequent monitoring of 0.73 (95% CI 0.61, 0.89) were less likely than patients in the public health TB compared to weekly DOT. This difference in association clinic to complete therapy with adjusted RR of 0.37 (95% with and without adjustment for treatment regimen is CI 0.20, 0.69) and 0.64 (95% CI 0.47, 0.85) respectively likely related to the strong association between treat- (all p-values ≤0.01). Patients treated in the homeless ment regimen and monitoring type. Table 2 Factors associated with completion of therapy Not Completed Completed Unadjusted Adjusted n percent n percent RR 95% CI p-value RR 95% CI p-value a,b Type of Therapy Isoniziad + Rifpaentine 13 14.9 74 85.1 Reference Reference Rifampin only 12 14.6 70 85.4 1.00 0.88, 1.14 0.96 0.88 0.55, 1.38 0.57 Isoniazid only 107 48.2 115 51.8 0.61 0.52, 0.71 <0.001 0.58 0.36, 0.93 0.02 Isoniazid only (vs rifampin only) 0.61 0.52, 0.71 <0.001 0.66 0.56, 0.79 <0.001 b,c Clinic Public Health 59 22.5 203 77.5 Reference Reference Employee Health 20 74.1 7 25.9 0.33 0.18, 0.64 <0.001 0.37 0.20, 0.69 <0.01 International 37 54.4 31 45.6 0.59 0.45, 0.77 <0.001 0.64 0.47, 0.85 <0.01 Homeless 9 52.9 8 47.1 0.61 0.37, 1.01 0.06 0.65 0.38, 1.09 0.10 Infectious Diseases 7 41.2 10 58.8 0.76 0.51, 1.14 0.18 0.74 0.48, 1.12 0.16 a,c Type of monitoring Weekly DOT/phone calls 13 15.1 73 84.9 Reference Reference Monthly clinic visits 38 27.3 101 72.7 0.86 0.75, 0.98 0.03 1.12 0.71, 1.76 0.62 Less often 81 48.8 85 51.2 0.60 0.51, 0.72 <0.001 1.21 0.75, 1.96 0.43 Side effects 37 28.2 94 71.8 1.13 0.98, 1.30 0.09 1.03 0.90, 1.18 0.66 a,d Number of other medical problems 0 47 26.6 130 73.5 Reference Reference 1-2 42 35.3 77 64.7 0.88 0.75, 1.03 0.12 1.00 0.84, 1.19 1.00 3+ 43 45.3 52 54.7 0.75 0.61, 0.91 0.01 1.08 0.88, 1.33 0.47 Abbreviations: RR Relative Risk, 95% CI 95% Confidence Interval Adjusted for clinic type Adjusted for type of monitoring Adjusted for treatment Adjusted for insurance McClintock et al. BMC Infectious Diseases (2017) 17:146 Page 6 of 8 We evaluated race/ethnicity, foreign born status and prevention of activation of TB [19, 24]. With this retro- English-speaking for all adjusted associations presented spective cohort study, we confirmed prior findings that in Table 2. None of these variables altered our associa- three months of isoniazid and rifapentine is associated tions or inference (p-values, confidence intervals) in any with higher completion rates relative to nine months of material way (e.g. there was <10% change in our esti- isoniazid. Additionally, these findings were true across a mates and no change in our p-values being above or variety of patient populations and outpatient practice below 0.05). We did not adjust for these factors in our settings, reinforcing that three months of isoniazid and analysis since they did not confound our associations. rifapentine is an excellent treatment option for patients Additionally, we compared our reported results for all who are not likely to adhere to nine months of isoniazid. adjusted associations in Table 2 with models that also ad- New and exciting treatments may not always be the justed for homelessness and alcohol use. We observed no best choice [25]. Rifamycin-based regimens are known material difference in the associations (all were in the to have low toxicity [8], however, all rifamycin based reg- same direction and statistical significance did not change). imens share similar side effect profiles, including discol- There was no difference in reporting of any side effects oration of bodily fluids (a use-limiting effect for some in those who completed versus those who did not patients), and interactions with many common medica- complete therapy with RR of 1.03 (95% CI 0.90, 1.18) tions, including anticoagulants, HIV medications, and (Table 2). We hypothesized a priori that those patients contraception. with three or more medical problems would complete The results of this study have important practical im- therapy less often. However, after adjusting for the clinic plications for providers, patients, and health care sys- type and insurance, there was no significant difference tems. The two regimens likely have similar side effect in completion rates between patients with more medical profiles [15, 26], but four months of rifampin does not problems compared to patients with fewer medical prob- require DOT and is less expensive than three months of lems with RR of 1.08 (95% CI 0.88, 1.33) (Table 2). isoniazid and rifapentine. Both four months of rifampin [8] and three months of isoniazid plus rifapentine [15] Key Findings are also highly effective against latent TB, with similar This retrospective cohort study demonstrated compar- efficacy compared to placebo or isoniazid monotherapy, able completion rates between the novel three months respectively. While rifampin-only regimens are currently of isoniazid and rifapentine and the less often used four considered an alternative regimen, our findings suggest months of rifampin. Both regimens had superior rates of that rifampin-only regimens should be considered not completion compared to nine months of isoniazid. Cur- just as an alternative to nine months of isoniazid, but as rently, four months of rifampin is considered a second- a comparable first-line regimen to three months of iso- ary alternative, rather than a comparable choice with niazid and rifapentine and perhaps even superior to nine nine months of isoniazid or 12 weeks of rifapentine with months of isoniazid given much better completion rates. isoniazid, which are the current standard. Given the Our data show that the type of treatment offered was lower cost to patients and health care settings of four a strong predictor of treatment completion whereas months of rifampin compared to three months of isonia- monitoring type was not. This is contrary to our a priori zid and rifapentine, we suggest that providers consider hypothesis in which we anticipated DOT regimens four months of rifampin as an alternative first-line op- would besuperiordueto thenatureofDOT.Nosig- tion for LTBI treatment among the appropriate popula- nificant difference was found in completion rates be- tions. Use of rifampin would offer significant cost tween DOT and the rifampin-based self-administered savings to patients and health care systems in the United regimen. In other words, non-adherence to the rec- States and abroad. Additionally, improved rates of treat- ommended follow-up was not associated with treat- ment completion would help reduce incidence of active ment non-completion. Our data represent real-life cases in the United States and around the world. scenarios that are often missing from research set- tings, which can make research findings challenging Discussion to apply to the imperfect clinical setting. These find- With the publication in 2011 of non-inferiority of three ings suggest that self-administered four months of ri- months of isoniazid and rifapentine [15] to nine months fampin may be able achieve high compliance rates of isoniazid, many have brought this treatment into the similar to the rates of three months of isoniazid and armamentarium against LTBI. Subsequent statistical rifapentine, without the costs of DOT to both pa- modeling exercises suggest that three months of isonia- tients and health care systems. These findings under- zid and rifapentine is more effective and saves money score the utility of four months of rifampin for compared to nine months of isoniazid because of higher providers who do not have the resources available for rates of treatment completion and subsequent DOT in the outpatient setting. McClintock et al. BMC Infectious Diseases (2017) 17:146 Page 7 of 8 We also found significantly higher completion rates at difference. We did not set up our analysis to compare the public health TB clinic compared to primary care INH in 2009 to INH in 2013 because that was not the clinics. The comparative success of the TB clinic may be primary outcome of interest. Rather, the goal was to the result of having staff that have been trained to focus compare completion rates for INH, rifampin and INH on engagement of patients in LTBI treatment, whereas plus rifapentine regimens in an “actual use” scenario (ra- primary care visits often attempt to address multiple is- ther than research settings, where monitoring and com- sues in a 15-min visit without dedicated staff to address pliance tend to be more rigorous than a “true” patient LTBI treatment. Alternatively, the relative success of the might actually adhere to). Sixth, our study was limited to public health TB clinic may be due in part to patient adults and excluded individuals with HIV co-infection. motivation to complete therapy because personal experi- Lastly, since our sample size was determined by the ence through close contact to active TB cases. number of patients in our clinics we may have had insuf- While a homeless incentive program was used in this ficient power to detect associations. Population-based study, we did not see a higher rate of completion in the studies and randomized clinical trials are needed to clar- homeless clinic compared to other sites. This is in line ify factors associated with non-completion of these regi- with recent findings that incentive programs may have mens, and to assess side effects and adverse events. short term effects on clinic attendance, but do not seem to reliably increase the number of people completing Conclusions treatment for LTBI [27]. In conclusion, this outpatient-based comparison of four Our study has limitations. First, given that our study months of rifampin, three months of isoniazid and rifa- was retrospective and not randomized, the design limits pentine, and nine months of isoniazid demonstrates the strength of the conclusions regarding the true comparable completion rates between four months of ri- equivalence of the regimens. Provider discretion should fampin and three months of isoniazid and rifapentine still guide the choices between rifampin only regimens while taking into consideration the monitoring fre- versus INH-rifapentine, which may still be of greater quency. Given the similar side effect profile but signifi- utility in patient populations with historically low adher- cant cost savings with four months of rifampin, we ence, such as homeless patients and those actively using suggest that four months of rifampin be considered ex- alcohol or other substances. Second, all participating changeable with three months of isoniazid and rifapen- clinics are located in one US city. Though we include a tine and nine months of isoniazid for treatment of latent representative mix of foreign-born and homeless persons tuberculosis infection. (see Table 1), our findings may not be generalizable to Abbreviations all populations in all settings. Further research is needed DOT: Directly observed therapy; LTBI: Latent Tuberculosis infection; to clarify completion rates in other actual use settings TB: Mycobacterium tuberculosis such as other clinic settings, different cities, rural areas, Acknowledgements and other states and countries. Third, there were more Contributors: Thank you to John Lynch MD MPH for participation in early patients from the TB clinic than the other clinic sites, formulation of this project and guiding our data plan, Andrew Brookens MD for involvement in early meetings and thoughtful contributions to the data which may have limited our ability to detect differences capture tool, David Roesel MD for participation in early meetings, Monica in the smaller samples of the non TB clinic patients. Pecha MPH and the public health TB clinic staff for their kind assistance with Fourth, each clinic has unique patient populations and data sets and charts at Tuberculosis Control Program, Public Health - Seattle & King County. characteristics that limit the interpretation of compari- Funders: We gratefully acknowledge funding support from the Division of sons among different clinics. These regimens have differ- General Internal Medicine and data support from the Institute of ent roles in how they are employed in LTBI treatment Translational Health Sciences, both at the University of Washington Prior presentations: Findings were presented at “World TB Day Symposium” programs depending on provider and patient preferences at Harborview Medical Center in Seattle, WA. March 24, 2016. and needs. Fifth, treatment regimens also varied over time based on standard of care. Rifampin alone was used Funding This study had no direct funding source. We gratefully acknowledge support much less frequently in our medical center in 2009, as from the Division of General Internal Medicine at the University of Washington INH was the standard of care. Similarly, once our med- for providing data support, and from the Institute of Translational Health ical center made the switch to isonaizid plus rifapentine Sciences at the University of Washington, for use of data storage and database building support. and rifampin only regimens, the number of people being treated with INH alone was quite small, and a simultan- Availability of data and materials eous comparison of the three regimens using only 2013 The datasets generated and analyzed during the current study are available from the corresponding author upon reasonable request. data would have been underpowered to detect a differ- ence. To adequately compare the three regimens, we Authors’ contributions pooled data from two different time points in order to AM and ME are co-first authors. Both contributed to the study design, data have large enough sample sizes to detect a true collection and preparation of the manuscript. CM aided in study design and McClintock et al. BMC Infectious Diseases (2017) 17:146 Page 8 of 8 all statistical analyses, as well as writing portions of the methods section. CP 14. Schechter M, Zajdenverg R, Falco G, et al. Weekly rifapentine/isoniazid or obtained pharmacy data for determining patient medication history. MN, SD daily rifampin/pyrazinamide for latent tuberculosis in household contacts. and DP all contributed to early study design and manuscript editing. AM is Am J Respir Crit Care Med. 2006;173:922–6. the senior author and was involved in all aspects of study design, data entry 15. Sterling TR, Villarino ME, Borisov AS, et al. Three months of rifapentine and and manuscript preparation and editing. DP remains listed as an author isoniazid for latent tuberculosis infection. N Engl J Med. 2011;365:2155–66. given his significant contributions to this manuscript. He has passed away in 16. Getahun H, Matteelli A, Abubakar I, et al. Management of latent the time since the manuscript was written and prepared and then published. Mycobacterium tuberculosis infection: WHO guidelines for low tuberculosis All authors read and approved the final manuscript. burden countries. Eur Respir J. 2015;46:1563–76. 17. Shepardson D, Marks SM, Chesson H, et al. Cost-effectiveness of a 12-dose regimen for treating latent tuberculous infection in the United States. Int J Competing interests Tuberc Lung Dis. 2013;17:1531–7. The authors declare that they do not have any competing interests. 18. Shepardson D, MacKenzie WR. Update on cost-effectiveness of a 12-dose regimen for latent tuberculous infection at new rifapentine prices. Int J Consent for publication Tuberc Lung Dis. 2014;18:751. Not applicable. 19. Holland DP, Sanders GD, Hamilton CD, Stout JE. Costs and cost- effectiveness of four treatment regimens for latent tuberculosis infection. Am J Respir Crit Care Med. 2009;179:1055–60. Ethics approval and consent to participate 20. Lardizabal A, Passannante M, Kojakali F, Hayden C, Reichman LB. The institutional review board at the University of Washington Human Enhancement of treatment completion for latent tuberculosis infection with Subjects Division approved this study (#43613). 4 months of rifampin. Chest. 2006;130:1712–7. 21. Fresard I, Bridevaux PO, Rochat T, Janssens JP. Adverse effects and adherence Author details to treatment of rifampicin 4 months vs isoniazid 6 months for latent Division of General Internal Medicine, Department of Medicine, University of tuberculosis: a retrospective analysis. Swiss Med Wkly. 2011;141:w13240. Washington School of Medicine, Box 3547654245 Roosevelt Way NE, Seattle, 22. Getahun H, Matteelli A, Chaisson RE, Raviglione M. Latent Mycobacterium WA 98105, USA. Division of Allergy & Infectious Diseases, Department of tuberculosis infection. N Engl J Med. 2015;372:2127–35. Medicine, University of Washington School of Medicine, Seattle, USA. 3 4 23. StataCorp. Stata. 13th ed. College Station, TX: Stata Corp L; 2013. Pharmacy Department, Harborview Medical Center, Seattle, USA. Division of 24. Center for Disease Control. TB Notes Newsletter No. 3. 2012. Accessed 5 Pulmonary & Critical Care Medicine, Department of Medicine, University of Nov 5 2012. Washington School of Medicine, Seattle, USA. Tuberculosis Control Program, 25. Menzies D, Al Jahdali H, Al OB. Recent developments in treatment of latent Public Health - Seattle & King County, Seattle, USA. tuberculosis infection. Indian J Med Res. 2011;133:257–66. 26. Menzies D, Long R, Trajman A, et al. Adverse events with 4 months of Received: 7 July 2016 Accepted: 7 February 2017 rifampin therapy or 9 months of isoniazid therapy for latent tuberculosis infection: a randomized trial. Ann Intern Med. 2008;149:689–97. 27. Lutge EE, Wiysonge CS, Knight SE, Sinclair D, Volmink J. Incentives and References enablers to improve adherence in tuberculosis. Cochrane Database Syst 1. Millennium Development Goals (MDGs). May 2015. At http://www.who.int/ Rev. 2015;9:CD007952. mediacentre/factsheets/fs290/en/. Accessed 6 June 2015. 2. Tuberculosis, Data and Statistics. April 23, 2014. (Accessed 6 June 2015, 2015, at http://www.cdc.gov/tb/statistics/default.htm.) 3. Miramontes R, Hill AN, Yelk Woodruff RS, et al. Tuberculosis Infection in the United States: Prevalence Estimates from the National Health and Nutrition Examination Survey, 2011-2012. PLoS One. 2015;10, e0140881. 4. Bennett DE, Courval JM, Onorato I, et al. Prevalence of tuberculosis infection in the United States population: the national health and nutrition examination survey, 1999-2000. Am J Respir Crit Care Med. 2008;177:348–55. 5. Porco TC, Lewis B, Marseille E, Grinsdale J, Flood JM, Royce SE. Cost- effectiveness of tuberculosis evaluation and treatment of newly-arrived immigrants. BMC Public Health. 2006;6:157. 6. Colleen Scott D, Hannah L, Kirking M, Carla Jeffries J, Price SF, Pratt R. Tuberculosis Trends - United States, 2014. Morbidity and Mortality Weekly Report (MMWR). 2014;64:265–369. 7. Centers for Disease C. Targeted tuberculin testing and treatment of latent tuberculosis infection. MMWR Morb Mortal Wkly Rep. 2000;49:2. 8. Stagg HR, Zenner D, Harris RJ, Munoz L, Lipman MC, Abubakar I. Treatment of latent tuberculosis infection: a network meta-analysis. Ann Intern Med. 2014;161:419–28. 9. Goswami ND, Gadkowski LB, Piedrahita C, et al. Predictors of latent tuberculosis treatment initiation and completion at a U.S. public health clinic: a prospective Submit your next manuscript to BioMed Central cohort study. BMC Public Health. 2012;12:468. 10. Hess K, Goad J, Wu J, Johnson K. Isoniazid completion rates for latent and we will help you at every step: tuberculosis infection among college students managed by a community • We accept pre-submission inquiries pharmacist. J Am Coll Health. 2009;57:553–5. 11. Rivest P, Street MC, Allard R. Completion rates of treatment for latent � Our selector tool helps you to find the most relevant journal tuberculosis infection in Quebec, Canada from 2006 to 2010. Can J Public � We provide round the clock customer support Health. 2013;104:e235–9. � Convenient online submission 12. Centers for Disease C. Recommendations for Use of an Isoniazid–Rifapentine Regimen with Direct Observation to Treat Latent Mycobacterium tuberculosis � Thorough peer review Infection. MMWR Morb Mortal Wkly Rep 2011;60:1650-3. � Inclusion in PubMed and all major indexing services 13. Benator D, Bhattacharya M, Bozeman L, et al. Rifapentine and isoniazid once � Maximum visibility for your research a week versus rifampicin and isoniazid twice a week for treatment of drug- susceptible pulmonary tuberculosis in HIV-negative patients: a randomised Submit your manuscript at clinical trial. Lancet. 2002;360:528–34. www.biomedcentral.com/submit http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png BMC Infectious Diseases Springer Journals

Treatment completion for latent tuberculosis infection: a retrospective cohort study comparing 9months of isoniazid, 4months of rifampin and 3months of isoniazid and rifapentine

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Springer Journals
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Copyright © 2017 by The Author(s).
Subject
Medicine & Public Health; Infectious Diseases; Parasitology; Medical Microbiology; Tropical Medicine; Internal Medicine
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1471-2334
DOI
10.1186/s12879-017-2245-8
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28196479
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Abstract

Background: 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. Methods: 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. Results: 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. Conclusions: 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. Keywords: Latent Tuberculosis Infection, Rifampin, Isoniazid, Rifapentine, Treatment adherence * Correspondence: ahearst@uw.edu Equal contributors Deceased Division of General Internal Medicine, Department of Medicine, University of Washington School of Medicine, Box 3547654245 Roosevelt Way NE, Seattle, WA 98105, USA Full list of author information is available at the end of the article © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. McClintock et al. BMC Infectious Diseases (2017) 17:146 Page 2 of 8 Background Daily rifampin for four months has long been seen as Treating latent TB infection (LTBI) in high-risk individ- an alternative regimen [7] for people who cannot toler- uals is one of the eight Millennium Development goals ate isoniazid for nine months, or who were exposed to of the United Nations [1]. In the United States alone, INH-resistant TB. Prior studies have demonstrated 9,421 cases of active TB were reported in 2014 [2], and higher completion rates with shorter rifampin-based reg- it is estimated that more than 13 million people have la- imens compared to isoniazid [11, 20, 21]. Additionally, tent TB infection [3, 4]. Aggressive treatment of LTBI in a recent review of LTBI treatment, rifampin was again provides significant cost-savings and quality-adjusted life introduced as a potential regimen with increased com- years saved because it dramatically reduces the risk of pletion rates compared to nine months of isoniazid, progression to active TB [5]. Most of the cases in the though no direct comparisons were made between United States occur in foreign born individuals [6]. In rifampin and isoniazid-rifapentine [22]. With the intro- fact, TB in foreign born individuals is on the rise in the duction of isoniazid plus rifapentine and rifampin only US [6]. Primary care and Public Health clinics are often regimens, isoniazid only therapy use appears to have de- the first contact newly arrived patients have with the clined making a study of completion rates among these health care system for screening for TB infection. regimens particularly useful. With the availability of novel treatment regimens for LTBI, medical providers now face the challenge of Objective choosing which regimen is best suited for an individual To date, there have been no studies directly comparing patient. Historically, the regimen of choice for LTBI was completion rates of isoniazid only, rifampin only, and nine-months of daily isoniazid [7]. Nine months of iso- isoniazid and rifapentine regimens. Data on “actual use” niazid reduces the rate of progression to active TB by up in the outpatient setting would be helpful to health care to 39-86%, but only if the patient is fully adherent [7, 8]. providers to guide choice of therapy for individual pa- In most actual use studies, isoniazid completion rates tients. The aim of this study is to compare the rates of are only 31-59% [9–11] making it a less effective treat- completion of the three LTBI therapies across heteroge- ment choice in non-research settings [7]. Additionally, neous populations in various outpatient settings, includ- use is limited by the concerns for side effects such as ing primary care clinics, subspecialty clinics, and a hepatotoxicity and neuropathy [7]. public health TB clinic. In 2011, the CDC recommended a three-month directly observed, weekly dosed therapy of isoniazid and rifapen- Methods tine as an “equal alternative” to the nine month isoniazid We conducted a retrospective cohort study of all patients regimen [12] in healthy individuals with LTBI. Based on who initiated treatment for LTBI with nine months of iso- three randomized controlled trials [13–15], isoniazid and niazid, rifampin only, or isoniazid and rifapentine dis- rifapentine with directly observed therapy (DOT) is con- pensed at a hospital affiliated pharmacy or TB clinic sidered to be non- inferior to standard self-administered during 2009 or between July 1, 2013 and June 30, 2014. isoniazid for nine months in preventing progression to ac- Five hospital-affiliated clinics in Seattle, Washington par- tive TB, and more likely to be completed than isoniazid ticipated in this study: four outpatient clinics affiliated [12, 15]. Additionally, there is an alternative LTBI regimen with an urban academic tertiary care medical center, and of 3 months of daily rifampin and isoniazid. This regimen one county TB clinic. The outpatient clinics include a hos- is used in parts of Europe and also carries the benefits of pital employee health clinic, a primary care clinic focused short duration and low cost. [16] However, the regimen is on care of immigrants and refugees, a primary care clinic not currently on the list of CDC recommended regimens, focused on the care of homeless individuals, and a sub- and is not commonly used in the US at this time, and so specialty infectious diseases clinic. Given that this was a was not included in this study. retrospective chart review and patient identifiers were There has been significant excitement about three removed before entry into the secure database, subject months of isoniazid and rifapentine as an expedited consent to participate was waived by the Institutional Re- treatment option, but many features of this treatment view Board (IRB) per standard practices at our institution. make it less than ideal for certain patients and clinical The IRB at the University of Washington Human Subjects settings. While the isoniazid and rifapentine regimen of- Division approved this study (#43613). fers the promise of higher completion rates, likely due to Patients were identified for inclusion in the study if less cumbersome dosing and shorter duration, this ther- they were 18 years old or older. For patients treated in apy is also significantly more expensive likely driven by the hospital-affiliated outpatient clinics, pharmacy re- the recommended use of DOT [17–19], which may be cords were used to identify patients who were given a inconvenient for some patients, and requires a large re- prescription for isoniazid without ethambutol or rifam- source commitment for the clinics that administer it. pin, rifampin alone, or isoniazid with rifapentine. For McClintock et al. BMC Infectious Diseases (2017) 17:146 Page 3 of 8 isoniazid monotherapy patients, records were queried as it would have been in a monthly monitoring scenario. for those who initiated treatment in 2009, well before Patients on isoniazid and rifapentine were seen weekly for the nation-wide isoniazid shortage and 9 months of iso- DOT by either a nurse or an outreach worker. A small niazid was standard of care. Records were queried again number of the patients on isoniazid and rifapentine re- for those who initiated treatment between July 1, 2013 ceived weekly phone calls or met virtually with an out- and June 30, 2014 for all three regimens. Medical re- reach worker via webcam, rather than in-person contact. cords for the TB clinic were held separately and LTBI The public health TB clinic used a standard set of ques- cases treated with the regimens of interest were identi- tions to check for specific side effects, whereas in all other fied in a TB Control Program database. Diagnosis of clinics, patients were asked a targeted review of systems at LTBI was made by either tuberculin skin test (TST) or the provider’s discretion to assess for side effects to the interferon gamma release assay (IGRA) in combination regimens. Interpreters were used for non-English- with chest x-ray. Screening for active and latent TB was speaking patients. standard practice for patients in the international clinic, The primary outcome was treatment completion. This homeless clinic and employee health due to the high risk outcome was determined based on pharmacy records of of exposure in those populations. The infectious diseases prescription fulfillment. Patients were considered to have clinic treated patients planning to undergo treatment of completed therapy if they filled prescriptions consecu- another disease process with immunosuppressive therap- tively to correspond to 270 doses of isoniazid within ies. Patients from the Public Health Clinic, were 12 months [7], 120 doses of rifampin in a 6 month screened as contacts of active cases being treated by period [7] or 12 doses of isoniazid and rifapentine in a Public Health. The sample size we had was determined 4 month period [12]. by the number of patients seen in our clinics during our We calculated counts, proportions, and means for study period and so we did not calculate power. The demographic, treatment, and health characteristics for 95% confidence intervals we present in Table 2 provide all participants combined and by treatment type. We the best range of plausible estimates. Only one person estimated counts and row proportions for treatment, was excluded from our chart review because it was de- clinic, and monitoring type. We hypothesized these three termined upon further chart review that the participant factors would be associated with completion of treat- had already completed therapy for LTBI prior to our ment. We used Poisson regression models with a log study time frame. Patients with HIV were not included link and robust error variance to estimate unadjusted in this study, as this medical center has a separate HIV and adjusted relative risks (RR) along with 95% confi- clinic which sees HIV patients, and because of the po- dence intervals (CI) and p-values in lieu of logistic re- tential drug-drug interactions between antiretroviral gression since our outcome was common. We identified therapy and rifamycin-based regimens. potential confounders a priori based on their relation- Patients were evaluated for LTBI treatment and ship between the hypothesized factor and completion of monitored for adverse effects during follow up visits. treatment. Confounders evaluated were specific to each When evaluating forsideeffects,specificsideeffects exposure of interest and included demographic (e.g. age, such as liver function test (LFT) abnormalities, lab type of insurance) and treatment characteristics (e.g. abnormalities, and other known or common medica- clinic, treatment regimen, monitoring type) and were tion side effects were marked as present or absent, modeled as categorized in Table 1. Potential confounders whereas patient side effects were classified as “other” that altered estimates, generally by more than 10%, were if the patient reported a subjective side effect which retained in the adjusted models. Specifically, when deter- was not a known side effect of the medication regi- mining the association between completion of therapy mens (for example, a report of dizziness after taking and treatment regimen, we adjusted for frequency of medications was classified as “other.”) Choice of treat- monitoring and when examining the association between ment regimen, frequency of follow-up visits, and fre- completion of therapy and type of monitoring, we ad- quency of laboratory monitoring were selected by the justed for type of monitoring. Because type of monitor- treating physician at his or her discretion based on ing and treatment regimen may be related, we patients’ other comorbidities, medications, length of conducted sensitivity analyses for these associations with therapy and cost. Patients on the nine-month isonia- and without adjustment for type of monitoring and zid and four-month rifampin daily regimens were typ- treatment regimen, respectively. Additionally, we con- ically seen monthly in the public health clinics, and ducted further sensitivity analyses post-hoc after noting monthly or less often in the outpatient clinics. Pa- differences across treatment regimen in homelessness tients monitored less than monthly were monitored and alcohol use. All analyses were conducted using Stata this way because of poor attendance in clinic. When 13.1 [23]. The University of Washington Human Sub- present in clinic, regular monitoring was completed jects Division reviewed and approved this research. McClintock et al. BMC Infectious Diseases (2017) 17:146 Page 4 of 8 Table 1 Characteristics among all participants and stratified on treatment All Participants (N = 393) Isoniazid + Rifapentine, Rifampin only, 2013 Isoniazid only, 2009 p-value 2013 only (N = 87) only (N = 82) and 2013 (N = 224) b b b b n (%) n (%) n (%) n (%) Gender 0.93 Female 175 (44.5) 38 (43.7) 38 (46.3) 99 (44.2) Age (years) 43.6 (15.0) 43.2 (15.4) 43.4 (13.1) 43.8 (15.5) 0.94 Insurance 0.19 Private 59 (18.0) 10 (15.2) 13 (22.0) 36 (17.8) Government sponsored 76 (23.2) 16 (24.2) 17 (28.8) 43 (21.3) Charity care 163 (49.9) 34 (51.5) 29 (49.2) 100 (49.5) Other 29 (8.9) 6 (9.1) 0 (0.0) 23 (11.4) Race/Ethnicity <0.001 Caucasian 30 (7.9) 8 (9.9) 3 (3.7) 19 (8.8) African or African American 94 (24.9) 18 (22.2) 20 (24.4) 56 (26.1) Asian 161 (42.6) 19 (23.5) 40 (48.8) 102 (47.4) Mexican or Other Hispanic 49 (13.0) 11 (13.6) 10 (12.2) 28 (13.0) Pacific Islander 32 (8.5) 21 (25.9) 6 (7.3) 5 (2.3) Other 12 (3.2) 4 (4.9) 3 (3.7) 5 (2.3) Foreign Born 341 (90.7) 65 (79.3) 79 (98.8) 197 (92.1) <0.001 English Speaking 203 (52.5) 60 (70.6) 38 (46.3) 105 (47.7) 0.001 Homeless/marginally house 45 (12.3) 24 (31.2) 2 (2.5) 19 (9.1) <0.001 Number of other medical problems 0.01 0 178 (45.3) 38 (43.7) 51 (62.2) 89 (39.7) 1-2 119 (30.3) 29 (33.3) 19 (23.2) 71 (31.7) 3+ 96 (24.4) 20 (23.0) 12 (14.6) 64 (28.6) Number of medications <0.001 0-1 139 (35.4) 0 (0.0) 56 (68.3) 83 (37.1) 2-3 138 (35.1) 57 (65.5) 12 (14.6) 69 (30.8) 3+ 116 (29.5) 30 (34.5) 14 (17.1) 72 (32.1) Any tobacco use at start of therapy 49 (12.5) 19 (21.8) 11 (13.4) 19 (8.5) 0.01 Any alcohol at start of therapy 52 (13.2) 21 (24.1) 10 (12.2) 21 (9.4) 0.002 Clinic <0.001 Infectious Diseases 17 (4.3) 8 (9.2) 0 (0.0) 9 (4.0) Public Health 263 (66.9) 69 (79.3) 67 (81.7) 127 (56.7) International Clinic 68 (17.3) 0 (0.0) 15 (18.3) 53 (23.7) Homeless Clinic 18 (4.6) 5 (5.8) 0 (0.0) 9 (4.0) Employee Health 27 (6.9) 5 (5.8) 0 (0.0) 22 (9.8) Type of Monitoring <0.001 Weekly DOT/Phone calls 87 (22.2) 84 (96.6) 1 (1.2) 2 (0.9) Monthly visit 139 (35.5) 2 (2.3) 66 (80.5) 71 (31.8) Less often 166 (42.4) 1 (1.2) 15 (18.3) 150 (67.3) 205/224 were treated in 2009 and 19/224 were treated in 2013. In 2009, 7/9 patients were treated in the Infectious Diseases Clinic, 123/127 at the Public Health clinic, 48/53 in International Clinic, 10/13 in the Homeless Clinic, and 17/22 in Employee Health All estimates are percents except for age which is a mean (standard deviation) c d e Less than 5% of data missing; 16.8% of data are missing; 7.1% of data are missing Results rifapentine, 82 received four months of rifampin and 224 A total of 393 participants were included in the study: received nine months of isoniazid (Table 1). There were 87 patients received three months of isoniazid and more men represented in this study than women (55.5% McClintock et al. BMC Infectious Diseases (2017) 17:146 Page 5 of 8 compared to 44.5%). The average age of study partici- clinic or infectious diseases clinic appeared to be less pants was 43.6 years. Foreign-born and non-English likely to complete treatment than patients in the public speaking participants were less likely to receive isoniazid health TB clinic, although the differences were not sta- and rifapentine. Treatment regimens differed by clinic tistically significant with adjusted RR of 0.65 (95% CI and type of monitoring. 0.38, 1.09) and RR of 0.74 (95% CI 0.48, 1.12), respect- Patients treated with four months of rifampin were as ively (Table 2). likely to complete therapy as those on three months of In unadjusted analyses, patients with monthly or less isoniazid and rifapentine. Patients on nine months of frequent monitoring were less likely to complete therapy isoniazid were less likely to complete treatment than pa- than those with weekly DOT with RR of 0.86 (95% CI tients on four months of rifampin or three months of 0.75, 0.98) and RR of 0.60 (95% CI 0.51, 0.72). However, isoniazid and rifapentine with adjusted relative risk of these associations were no longer apparent after adjust- 0.66 (95% CI 0.56, 0.79) and 0.59 (95% CI 0.36, 0.93), re- ing for clinic location and treatment type with RR of spectively (Table 2). These associations remained statisti- 1.12 (95% CI 0.721, 1.76) and RR of 1.21 (95% CI 0.48, cally significant and in the direction anticipated after 1.12), respectively (Table 2). In sensitivity analyses that adjusting for clinic location and type of monitoring. In examined this association between frequency of moni- our sensitivity analyses, this association between treat- toring and treatment completion without adjusting for ment regimen and completion was similar with and treatment regimen, there is a significant association with without adjustment for type of monitoring. RR of monthly monitoring of 0.82 (95% CI 0.72, 0.94) Patients treated in the employee or refugee clinics and less frequent monitoring of 0.73 (95% CI 0.61, 0.89) were less likely than patients in the public health TB compared to weekly DOT. This difference in association clinic to complete therapy with adjusted RR of 0.37 (95% with and without adjustment for treatment regimen is CI 0.20, 0.69) and 0.64 (95% CI 0.47, 0.85) respectively likely related to the strong association between treat- (all p-values ≤0.01). Patients treated in the homeless ment regimen and monitoring type. Table 2 Factors associated with completion of therapy Not Completed Completed Unadjusted Adjusted n percent n percent RR 95% CI p-value RR 95% CI p-value a,b Type of Therapy Isoniziad + Rifpaentine 13 14.9 74 85.1 Reference Reference Rifampin only 12 14.6 70 85.4 1.00 0.88, 1.14 0.96 0.88 0.55, 1.38 0.57 Isoniazid only 107 48.2 115 51.8 0.61 0.52, 0.71 <0.001 0.58 0.36, 0.93 0.02 Isoniazid only (vs rifampin only) 0.61 0.52, 0.71 <0.001 0.66 0.56, 0.79 <0.001 b,c Clinic Public Health 59 22.5 203 77.5 Reference Reference Employee Health 20 74.1 7 25.9 0.33 0.18, 0.64 <0.001 0.37 0.20, 0.69 <0.01 International 37 54.4 31 45.6 0.59 0.45, 0.77 <0.001 0.64 0.47, 0.85 <0.01 Homeless 9 52.9 8 47.1 0.61 0.37, 1.01 0.06 0.65 0.38, 1.09 0.10 Infectious Diseases 7 41.2 10 58.8 0.76 0.51, 1.14 0.18 0.74 0.48, 1.12 0.16 a,c Type of monitoring Weekly DOT/phone calls 13 15.1 73 84.9 Reference Reference Monthly clinic visits 38 27.3 101 72.7 0.86 0.75, 0.98 0.03 1.12 0.71, 1.76 0.62 Less often 81 48.8 85 51.2 0.60 0.51, 0.72 <0.001 1.21 0.75, 1.96 0.43 Side effects 37 28.2 94 71.8 1.13 0.98, 1.30 0.09 1.03 0.90, 1.18 0.66 a,d Number of other medical problems 0 47 26.6 130 73.5 Reference Reference 1-2 42 35.3 77 64.7 0.88 0.75, 1.03 0.12 1.00 0.84, 1.19 1.00 3+ 43 45.3 52 54.7 0.75 0.61, 0.91 0.01 1.08 0.88, 1.33 0.47 Abbreviations: RR Relative Risk, 95% CI 95% Confidence Interval Adjusted for clinic type Adjusted for type of monitoring Adjusted for treatment Adjusted for insurance McClintock et al. BMC Infectious Diseases (2017) 17:146 Page 6 of 8 We evaluated race/ethnicity, foreign born status and prevention of activation of TB [19, 24]. With this retro- English-speaking for all adjusted associations presented spective cohort study, we confirmed prior findings that in Table 2. None of these variables altered our associa- three months of isoniazid and rifapentine is associated tions or inference (p-values, confidence intervals) in any with higher completion rates relative to nine months of material way (e.g. there was <10% change in our esti- isoniazid. Additionally, these findings were true across a mates and no change in our p-values being above or variety of patient populations and outpatient practice below 0.05). We did not adjust for these factors in our settings, reinforcing that three months of isoniazid and analysis since they did not confound our associations. rifapentine is an excellent treatment option for patients Additionally, we compared our reported results for all who are not likely to adhere to nine months of isoniazid. adjusted associations in Table 2 with models that also ad- New and exciting treatments may not always be the justed for homelessness and alcohol use. We observed no best choice [25]. Rifamycin-based regimens are known material difference in the associations (all were in the to have low toxicity [8], however, all rifamycin based reg- same direction and statistical significance did not change). imens share similar side effect profiles, including discol- There was no difference in reporting of any side effects oration of bodily fluids (a use-limiting effect for some in those who completed versus those who did not patients), and interactions with many common medica- complete therapy with RR of 1.03 (95% CI 0.90, 1.18) tions, including anticoagulants, HIV medications, and (Table 2). We hypothesized a priori that those patients contraception. with three or more medical problems would complete The results of this study have important practical im- therapy less often. However, after adjusting for the clinic plications for providers, patients, and health care sys- type and insurance, there was no significant difference tems. The two regimens likely have similar side effect in completion rates between patients with more medical profiles [15, 26], but four months of rifampin does not problems compared to patients with fewer medical prob- require DOT and is less expensive than three months of lems with RR of 1.08 (95% CI 0.88, 1.33) (Table 2). isoniazid and rifapentine. Both four months of rifampin [8] and three months of isoniazid plus rifapentine [15] Key Findings are also highly effective against latent TB, with similar This retrospective cohort study demonstrated compar- efficacy compared to placebo or isoniazid monotherapy, able completion rates between the novel three months respectively. While rifampin-only regimens are currently of isoniazid and rifapentine and the less often used four considered an alternative regimen, our findings suggest months of rifampin. Both regimens had superior rates of that rifampin-only regimens should be considered not completion compared to nine months of isoniazid. Cur- just as an alternative to nine months of isoniazid, but as rently, four months of rifampin is considered a second- a comparable first-line regimen to three months of iso- ary alternative, rather than a comparable choice with niazid and rifapentine and perhaps even superior to nine nine months of isoniazid or 12 weeks of rifapentine with months of isoniazid given much better completion rates. isoniazid, which are the current standard. Given the Our data show that the type of treatment offered was lower cost to patients and health care settings of four a strong predictor of treatment completion whereas months of rifampin compared to three months of isonia- monitoring type was not. This is contrary to our a priori zid and rifapentine, we suggest that providers consider hypothesis in which we anticipated DOT regimens four months of rifampin as an alternative first-line op- would besuperiordueto thenatureofDOT.Nosig- tion for LTBI treatment among the appropriate popula- nificant difference was found in completion rates be- tions. Use of rifampin would offer significant cost tween DOT and the rifampin-based self-administered savings to patients and health care systems in the United regimen. In other words, non-adherence to the rec- States and abroad. Additionally, improved rates of treat- ommended follow-up was not associated with treat- ment completion would help reduce incidence of active ment non-completion. Our data represent real-life cases in the United States and around the world. scenarios that are often missing from research set- tings, which can make research findings challenging Discussion to apply to the imperfect clinical setting. These find- With the publication in 2011 of non-inferiority of three ings suggest that self-administered four months of ri- months of isoniazid and rifapentine [15] to nine months fampin may be able achieve high compliance rates of isoniazid, many have brought this treatment into the similar to the rates of three months of isoniazid and armamentarium against LTBI. Subsequent statistical rifapentine, without the costs of DOT to both pa- modeling exercises suggest that three months of isonia- tients and health care systems. These findings under- zid and rifapentine is more effective and saves money score the utility of four months of rifampin for compared to nine months of isoniazid because of higher providers who do not have the resources available for rates of treatment completion and subsequent DOT in the outpatient setting. McClintock et al. BMC Infectious Diseases (2017) 17:146 Page 7 of 8 We also found significantly higher completion rates at difference. We did not set up our analysis to compare the public health TB clinic compared to primary care INH in 2009 to INH in 2013 because that was not the clinics. The comparative success of the TB clinic may be primary outcome of interest. Rather, the goal was to the result of having staff that have been trained to focus compare completion rates for INH, rifampin and INH on engagement of patients in LTBI treatment, whereas plus rifapentine regimens in an “actual use” scenario (ra- primary care visits often attempt to address multiple is- ther than research settings, where monitoring and com- sues in a 15-min visit without dedicated staff to address pliance tend to be more rigorous than a “true” patient LTBI treatment. Alternatively, the relative success of the might actually adhere to). Sixth, our study was limited to public health TB clinic may be due in part to patient adults and excluded individuals with HIV co-infection. motivation to complete therapy because personal experi- Lastly, since our sample size was determined by the ence through close contact to active TB cases. number of patients in our clinics we may have had insuf- While a homeless incentive program was used in this ficient power to detect associations. Population-based study, we did not see a higher rate of completion in the studies and randomized clinical trials are needed to clar- homeless clinic compared to other sites. This is in line ify factors associated with non-completion of these regi- with recent findings that incentive programs may have mens, and to assess side effects and adverse events. short term effects on clinic attendance, but do not seem to reliably increase the number of people completing Conclusions treatment for LTBI [27]. In conclusion, this outpatient-based comparison of four Our study has limitations. First, given that our study months of rifampin, three months of isoniazid and rifa- was retrospective and not randomized, the design limits pentine, and nine months of isoniazid demonstrates the strength of the conclusions regarding the true comparable completion rates between four months of ri- equivalence of the regimens. Provider discretion should fampin and three months of isoniazid and rifapentine still guide the choices between rifampin only regimens while taking into consideration the monitoring fre- versus INH-rifapentine, which may still be of greater quency. Given the similar side effect profile but signifi- utility in patient populations with historically low adher- cant cost savings with four months of rifampin, we ence, such as homeless patients and those actively using suggest that four months of rifampin be considered ex- alcohol or other substances. Second, all participating changeable with three months of isoniazid and rifapen- clinics are located in one US city. Though we include a tine and nine months of isoniazid for treatment of latent representative mix of foreign-born and homeless persons tuberculosis infection. (see Table 1), our findings may not be generalizable to Abbreviations all populations in all settings. Further research is needed DOT: Directly observed therapy; LTBI: Latent Tuberculosis infection; to clarify completion rates in other actual use settings TB: Mycobacterium tuberculosis such as other clinic settings, different cities, rural areas, Acknowledgements and other states and countries. Third, there were more Contributors: Thank you to John Lynch MD MPH for participation in early patients from the TB clinic than the other clinic sites, formulation of this project and guiding our data plan, Andrew Brookens MD for involvement in early meetings and thoughtful contributions to the data which may have limited our ability to detect differences capture tool, David Roesel MD for participation in early meetings, Monica in the smaller samples of the non TB clinic patients. Pecha MPH and the public health TB clinic staff for their kind assistance with Fourth, each clinic has unique patient populations and data sets and charts at Tuberculosis Control Program, Public Health - Seattle & King County. characteristics that limit the interpretation of compari- Funders: We gratefully acknowledge funding support from the Division of sons among different clinics. These regimens have differ- General Internal Medicine and data support from the Institute of ent roles in how they are employed in LTBI treatment Translational Health Sciences, both at the University of Washington Prior presentations: Findings were presented at “World TB Day Symposium” programs depending on provider and patient preferences at Harborview Medical Center in Seattle, WA. March 24, 2016. and needs. Fifth, treatment regimens also varied over time based on standard of care. Rifampin alone was used Funding This study had no direct funding source. We gratefully acknowledge support much less frequently in our medical center in 2009, as from the Division of General Internal Medicine at the University of Washington INH was the standard of care. Similarly, once our med- for providing data support, and from the Institute of Translational Health ical center made the switch to isonaizid plus rifapentine Sciences at the University of Washington, for use of data storage and database building support. and rifampin only regimens, the number of people being treated with INH alone was quite small, and a simultan- Availability of data and materials eous comparison of the three regimens using only 2013 The datasets generated and analyzed during the current study are available from the corresponding author upon reasonable request. data would have been underpowered to detect a differ- ence. To adequately compare the three regimens, we Authors’ contributions pooled data from two different time points in order to AM and ME are co-first authors. Both contributed to the study design, data have large enough sample sizes to detect a true collection and preparation of the manuscript. CM aided in study design and McClintock et al. BMC Infectious Diseases (2017) 17:146 Page 8 of 8 all statistical analyses, as well as writing portions of the methods section. CP 14. Schechter M, Zajdenverg R, Falco G, et al. Weekly rifapentine/isoniazid or obtained pharmacy data for determining patient medication history. MN, SD daily rifampin/pyrazinamide for latent tuberculosis in household contacts. and DP all contributed to early study design and manuscript editing. AM is Am J Respir Crit Care Med. 2006;173:922–6. the senior author and was involved in all aspects of study design, data entry 15. Sterling TR, Villarino ME, Borisov AS, et al. Three months of rifapentine and and manuscript preparation and editing. DP remains listed as an author isoniazid for latent tuberculosis infection. N Engl J Med. 2011;365:2155–66. given his significant contributions to this manuscript. He has passed away in 16. Getahun H, Matteelli A, Abubakar I, et al. Management of latent the time since the manuscript was written and prepared and then published. Mycobacterium tuberculosis infection: WHO guidelines for low tuberculosis All authors read and approved the final manuscript. burden countries. Eur Respir J. 2015;46:1563–76. 17. Shepardson D, Marks SM, Chesson H, et al. Cost-effectiveness of a 12-dose regimen for treating latent tuberculous infection in the United States. Int J Competing interests Tuberc Lung Dis. 2013;17:1531–7. The authors declare that they do not have any competing interests. 18. Shepardson D, MacKenzie WR. Update on cost-effectiveness of a 12-dose regimen for latent tuberculous infection at new rifapentine prices. Int J Consent for publication Tuberc Lung Dis. 2014;18:751. Not applicable. 19. Holland DP, Sanders GD, Hamilton CD, Stout JE. Costs and cost- effectiveness of four treatment regimens for latent tuberculosis infection. Am J Respir Crit Care Med. 2009;179:1055–60. Ethics approval and consent to participate 20. Lardizabal A, Passannante M, Kojakali F, Hayden C, Reichman LB. The institutional review board at the University of Washington Human Enhancement of treatment completion for latent tuberculosis infection with Subjects Division approved this study (#43613). 4 months of rifampin. Chest. 2006;130:1712–7. 21. Fresard I, Bridevaux PO, Rochat T, Janssens JP. Adverse effects and adherence Author details to treatment of rifampicin 4 months vs isoniazid 6 months for latent Division of General Internal Medicine, Department of Medicine, University of tuberculosis: a retrospective analysis. Swiss Med Wkly. 2011;141:w13240. Washington School of Medicine, Box 3547654245 Roosevelt Way NE, Seattle, 22. Getahun H, Matteelli A, Chaisson RE, Raviglione M. Latent Mycobacterium WA 98105, USA. Division of Allergy & Infectious Diseases, Department of tuberculosis infection. N Engl J Med. 2015;372:2127–35. Medicine, University of Washington School of Medicine, Seattle, USA. 3 4 23. StataCorp. Stata. 13th ed. 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Published: Feb 14, 2017

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