Abstract
Background
Three months of weekly rifapentine plus isoniazid (3HP) therapy for latent tuberculosis infection (LTBI) is recommended worldwide. The development of symptoms and systemic drug reactions (SDRs) on 3HP have not been fully characterized. We aimed to determine the patterns of symptom development and identify SDRs and associated factors in patients taking 3HP.
Methods
We analyzed symptoms data in participants receiving 3HP in the Tuberculosis Trials Consortium's iAdhere study (Study 33). We examined the patterns of symptom reporting across participants from baseline and 4 monthly visits. Bivariate analyses and multivariable regression models were used to identify factors associated with SDRs. Risk ratios (RRs) and 95% confidence intervals (CIs) were calculated.
Results
Among 1002 participants receiving 3HP, 768 (77%) reported at least 1 symptom; 97% of these symptoms were grade 1 (79%) or grade 2 (18%). Most symptoms developed in the first month and resolved. A total of 111 (11%) participants had symptoms that met criteria for SDRs; however, 53 (48%) of these participants completed therapy. Factors associated with SDRs and discontinuation included female sex (RR: 2.05; 95% CI: 1.19–3.54), age ≥45 years (RR: 1.99; 95% CI: 1.19–3.31), and use of concomitant medications (RR: 2.26; 95% CI: 1.15–4.42).
Conclusions
Although most patients receiving 3HP reported symptoms, most were mild, occurred early, and resolved without stopping treatment. Among patients experiencing SDRs, nearly half were able to complete therapy. Patient and provider education should focus on differentiating severe reactions where 3HP should be stopped from minor symptoms that will resolve.
Clinical Trials Registration. NCT01582711.
Keywords: latent tuberculosis treatment, 3HP
We found that patients commonly reported symptoms while receiving 3-month daily rifapentine plus isoniazid for latent tuberculosis infection, which were typically mild and resolved on their own. Systemic drug reactions occurred but did not always lead to discontinuation of treatment.
Treatment of latent tuberculosis (TB) infection (LTBI) is a critical component in the strategy to eliminate TB in the United States, and globally features in the World Health Organization's (WHO’s) END TB strategy [1–3]. There is growing recognition that LTBI treatment for persons at high risk of TB disease should be an essential part of TB-control strategies [4, 5]. The US Centers for Disease Control and Prevention (CDC) and WHO guidelines have added 3 months of once-weekly isoniazid and rifapentine (3HP) to their treatment recommendations for LTBI [6–8]. 3HP has been previously shown to have greater treatment completion rates; to be safe, effective, and tolerable; and to be less hepatotoxic than 9 months of daily isoniazid (9H) [9].
Despite the advantages of rifamycins for LTBI, some patients experience symptoms that have been described as flu-like syndromes or hypersensitivity reactions. While these symptoms are less frequent than more common adverse symptoms (eg, pruritis, rash, nausea, vomiting), concerns about this syndrome have been the source of hesitation, for clinician or patients, in utilizing rifamycins for LTBI. These symptoms were first identified with high-dose, intermittent rifampin use for active TB disease treatment. The mechanism is poorly understood, and the clinical symptoms vary (eg, fevers, chills, headache, dizziness, bone pain, malaise, cutaneous reactions, gastrointestinal symptoms) [10–17]. Similar symptoms were identified with intermittent rifapentine and isoniazid use for LTBI. The symptoms do not appear to be mediated by a traditional allergic-type reaction; thus, the term systemic drug reaction (SDR) was created to provide a more standardized approach to understanding the type and frequency of these reactions [18].
The PREVENT TB clinical trial (TBTC Study 26) compared the effectiveness of 3HP therapy with 9H therapy. This was the first large study of 3HP and to observe the varying patterns of drug-related adverse events. The PREVENT TB researchers created a definition for SDR after the first cases were encountered based on symptoms severe enough to cause treatment discontinuation [18]. Systemic drug reactions were broadly categorized into events of high concern (eg, hypotension, hives, angioedema, acute bronchospasm [category I]) or a more-common “flu-like” syndrome (category II). Although 3HP was as safe and effective as 9H, with a higher overall completion rate, discontinuations due to SDRs were more common in the 3HP arm compared with 9H (3.5% vs 0.4%) [18]. While SDRs were still relatively uncommon, understanding whether they can be predicted or prevented, and their impact on treatment completion, is critical to informing the use of 3HP in routine clinical settings.
Determining whether SDRs can be prevented requires a deeper understanding of the timing, frequency, and severity with which they occur. The iAdhere clinical trial (TBTC Study 33) was designed to compare 3HP treatment completion when given by direct-observed therapy (DOT) versus self-administered therapy (SAT). A secondary objective was to prospectively collect data on the symptoms seen in PREVENT TB to better understand SDRs [19]. Using a standardized approach to evaluate symptoms at baseline, monthly treatment visits, and during unscheduled adverse event visits, iAdhere collected data to enable comprehensive analysis of symptoms of varying severity. By describing symptoms and SDRs among all participants at any visit regardless of severity or whether treatment was discontinued, we present a more complete picture of the changes in symptoms over time and evaluate factors linking SDRs and treatment discontinuation.
METHODS
Study Population and Setting
iAdhere was an open-label, randomized clinical trial, conducted September 2012—April 2014, in the United States, Spain, Hong Kong, and South Africa among adults diagnosed with LTBI (clinicaltrials.gov identifier: NCT01582711). The primary objective was to compare 3HP treatment completion using 3 different strategies—DOT, SAT, and SAT—with text message reminders. The trial methodology and results have been previously published [19].
Data Source and Study Variables
Participants in iAdhere had 44 symptoms assessed and graded in-person using a structured checklist according to the US National Cancer Institute Common Toxicity Criteria, version 2.0, at every scheduled and unscheduled visit [20]. Scheduled visits were at baseline (assessing symptoms in the 28 days before treatment initiation); 4, 8, and 12 weeks (and possibly at 16 weeks, if participants did not complete 3HP within 12 weeks) after treatment initiation; and 28 days after the final treatment dose. Symptoms were self-reported as occurring since the prior study visit. For protocol-defined adverse events, the site principal investigators provided an assessment of how likely the symptom was attributable to the study drug; attribution information was not collected for symptoms that were not protocol-defined adverse events.
Systemic Drug Reactions
Category I SDRs were defined as any reported hypotension, hives (≥grade 2), angioedema (≥grade 3), wheezing/acute bronchospasm (≥grade 3), or conjunctivitis/red eyes (≥grade 2). Category II SDRs were defined as at least 4 of these symptoms concurrently: weakness, fatigue, nausea, vomiting, headache, fever, aches (muscle, bone, or joint), excessive sweating or night sweats, dizziness, shortness of breath, flushing, or chills. At least 1 of these symptoms must have been grade 2 or higher (Supplementary Table 1). Symptom grades were confirmed by the site principal investigator. Participants who reported symptoms meeting either category I or category II criteria were classified as having an SDR. For this analysis, all patients’ symptoms reported at any scheduled and unscheduled visits were considered, regardless of attribution.
Other Definitions
“Symptom development” was considered either the occurrence of a symptom not reported at baseline or a symptom reported at baseline that resolved and then recurred at a later visit. Concomitant medications refer to any medicine other than the study treatment taken by a participant up to 2 weeks prior to study initiation. History of alcohol abuse was determined using CAGE (Cut down, Annoyed, Guilty, Eye-opener) screening [21]. Liver disease was self-reported (ie, history of hepatitis B, hepatitis C, unknown hepatitis type, hepatitis due to alcohol use, or cirrhosis).
Data Analysis
We evaluated the incidence and factors associated with SDRs, as well as the development of individual symptoms while receiving 3HP treatment, regardless of SDR. We performed a descriptive analysis of sociodemographic factors and assessed SDRs among all 1002 enrolled participants. The outcome of interest for bivariate and multivariable analyses was meeting the criteria for a category I or II SDR and discontinuing 3HP treatment. Wald chi-square tests and bivariate log-binomial regression were conducted to assess the relationship between baseline demographic characteristics and SDRs with discontinuation. The reference group included all other participants who did not report SDRs, as well as those who reported SDRs but completed treatment. Multivariable log-binomial regression models were used to identify associated factors and to estimate risk ratios (RRs) and 95% confidence intervals (CIs). When additional statistical methods were required to accommodate small cell sizes, Fisher's exact test was utilized to obtain P values; RRs and CIs were estimated from the odds ratio [22].
We calculated frequencies of symptoms and categorized them into subgroups of newly developed or recurring symptoms. We identified the 3 most common patterns for symptoms that developed in at least 5% of the study population.
Ethical Considerations
This study was approved by the ethics committees of the CDC, all study sites, and Emory University. All participants gave written informed consent.
RESULTS
A total of 1002 participants were enrolled; the median age of 36 years (interquartile range [IQR]: 27–49 years) and 48% were female (Table 1). Fifty-two percent of participants reported White race (31% of whom reported non-Hispanic ethnicity), 25% Black or African-American race, and 20% Asian race. Most participants were enrolled in the United States (77%). Among participants with known human immunodeficiency virus (HIV) status (n = 787), nearly all were HIV-negative (n = 776; 99%).
Table 1.
Demographic Characteristics of Participants at Baseline
| Characteristic | Overall (N = 1002) | No Reported SDR (n = 891) | Reported SDR and Completed Treatment (n = 53) | Reported SDR and Discontinued Treatment (n = 58) |
|---|---|---|---|---|
| Age (years) | ||||
| 18–24 | 181 (18.1) | 168 (18.9) | 6 (11.3) | 7 (12.1) |
| 25–34 | 266 (26.5) | 250 (28.1) | 6 (11.3) | 10 (17.2) |
| 35–44 | 222 (22.2) | 203 (22.8) | 10 (18.9) | 9 (15.5) |
| 45–54 | 192 (19.2) | 150 (16.8) | 20 (37.7) | 22 (37.9)* |
| 55–64 | 111 (11.1) | 93 (10.4) | 9 (17.0) | 9 (15.5) |
| ≥65 | 30 (3.0) | 27 (3.0) | 2 (3.8) | 1 (1.7) |
| Female sex | 482 (48.1) | 408 (45.8) | 34 (64.2) | 40 (69.0)* |
| Race | ||||
| White | 518 (51.7) | 440 (49.4) | 40 (75.5) | 38 (65.5) |
| Black or African-American | 250 (24.9) | 230 (25.8) | 9 (17.0) | 11 (19.0) |
| Asian | 200 (20.0) | 188 (21.1) | 4 (7.5) | 8 (13.8) |
| Othera | 34 (3.4) | 33 (3.7) | 0 | 1 (1.7) |
| Ethnicityb | ||||
| Hispanic or Latino | 393 (39.2) | 348 (39.1) | 24 (45.3) | 21 (36.2) |
| Not Hispanic or Latino | 607 (60.6) | 541 (60.7) | 29 (54.7) | 37 (63.8) |
| Enrollment country | ||||
| United States | 774 (77.2) | 678 (76.1) | 45 (85.9) | 51 (87.9) |
| Spain | 100 (10.0) | 90 (10.1) | 4 (7.5) | 6 (10.3) |
| South Africa | 83 (8.3) | 82 (9.2) | 1 (1.9) | 0 |
| Hong Kong | 45 (4.5) | 41 (4.6) | 3 (5.7) | 1 (1.7) |
| Born outside country of enrollment | 603 (60.2) | 540 (60.6) | 27 (50.9) | 36 (62.1) |
| Homeless within last year | 51 (5.1) | 42 (4.7) | 7 (13.2) | 2 (3.4) |
| Occupationc | ||||
| Healthcare worker | 136 (13.6) | 123 (13.8) | 2 (3.8) | 11 (19.0) |
| Employed, other | 472 (47.1) | 417 (46.8) | 30 (56.6) | 25 (43.1) |
| Unemployed, seeking work | 168 (16.8) | 150 (16.8) | 10 (18.9) | 8 (13.8) |
| Unemployed, not seeking work | 221 (22.1) | 196 (22.0) | 11 (20.8) | 14 (24.1) |
| Current smoker | 250 (25.0) | 217 (24.4) | 18 (34.0) | 15 (25.9) |
| Drug use within last year | 53 (5.3) | 45 (5.1) | 6 (11.3) | 2 (3.4) |
| Diabetes or high blood sugard | 84 (8.4) | 65 (7.3) | 8 (15.1) | 11 (19.0)* |
| Any concomitant medications 2 weeks prior to study starte | 566 (56.5) | 473 (53.1) | 46 (86.8) | 47 (81.0)* |
| History of alcohol abusef | 70 (7.0) | 63 (7.1) | 5 (9.4) | 2 (3.4) |
| History of liver diseaseg | 42 (4.2) | 30 (3.4) | 6 (11.3) | 6 (10.3)** |
| HIV infection | ||||
| Yes | 11 (1.1) | 9 (1.0) | 2 (3.8) | 0 |
| No | 776 (77.4) | 691 (77.6) | 44 (83.0) | 41 (70.7) |
| Declined testing | 215 (21.5) | … | … | … |
Data are presented as no. (%). *Significant in bivariate analysis at P < .01. **Significant in bivariate analysis at P < .05. Abbreviations: HIV, human immunodeficiency virus; SDR, systemic drug reaction.
Twenty-two participants did not report race and are included here.
Information on ethnicity not available for 2 participants.
Five participants did not report a primary occupation.
Diabetes status unknown for 2 participants.
Information on concomitant medications not available for 6 participants.
CAGE (Cut down, Annoyed, Guilty, Eye-opener) score ≥2, as defined in the Methods section.
Self-reported presence of either: hepatitis B virus infection, hepatitis C virus infection, hepatitis of unknown type, hepatitis due to alcohol use, or cirrhosis.
Frequency, Timing, and Severity of Symptoms on 3HP
Enrolled participants commonly reported a variety of symptoms, including before initiating 3HP (Table 2). Among all participants, 768 (77%) reported 1 or more symptom at any time during study treatment. The most common newly reported symptoms were headache (29%), fatigue (23%), nausea (21%), dizziness (14%), and rhinorrhea (14%) (Table 2). Most of these symptoms were reported during a routine study visit (81%) rather than an unscheduled visit (19%). Among the 4842 symptoms graded at scheduled visits, the majority were mild (grade 1: n = 4071 [84%]) or moderate (grade 2: n = 669 [14%]). The most common pattern was a symptom occurring within the first month of treatment and fully resolving before the week 8 visit (Figure 1, Supplementary Table 2). At unscheduled visits, 1079 symptoms were reported (grade 1: n = 600 [56%]; grade 2: n = 358 [33%]).
Table 2.
Reported Signs and Symptoms (Any Grade) at Study Visits After Treatment Start in All Participants
| Sign/Symptom | Reported Prior to Treatment Start | Newly Reported at Any Scheduled Study Visit |
|---|---|---|
| Headache | 175 (17.5) | 243/827 (29.4) |
| Fatigue | 68 (6.8) | 215/934 (23.0) |
| Nausea | 47 (4.7) | 201/955 (21.0) |
| Dizziness | 55 (5.5) | 136/947 (14.4) |
| Rhinorrhea | 85 (8.5) | 128/917 (14.0) |
| Muscular pain | 94 (9.4) | 121/908 (13.3) |
| Cough | 118 (11.8) | 112/984 (11.4) |
| Weakness | 36 (3.6) | 124/966 (12.8) |
| Abdominal pain | 49 (4.9) | 113/953 (11.9) |
| Numbness in extremities | 67 (6.7) | 104/935 (11.1) |
| Sneezing | 72 (7.2) | 99/930 (10.6) |
| Joint pain | 177 (17.7) | 87/825 (10.5) |
| Dry mouth | 37 (3.7) | 93/965 (9.6) |
| Insomnia | 91 (9.1) | 83/911 (9.1) |
| Localized itching | 64 (6.4) | 86/938 (9.2) |
| Loss of appetite (anorexia) | 24 (2.4) | 84/978 (8.6) |
| Vomiting | 5 (0.5) | 69/997 (6.9) |
| Subjective fever | 14 (1.4) | 71/988 (7.2) |
| Chills | 15 (1.5) | 68/987 (6.9) |
| Localized rash | 71 (7.1) | 60/931 (6.4) |
| Diarrhea | 22 (2.2) | 62/980 (6.3) |
| Mood changes | 55 (5.5) | 61/947 (6.4) |
| Bone pain | 43 (4.3) | 47/959 (4.9) |
| Chest pain | 39 (3.9) | 43/963 (4.5) |
| Night sweats | 31 (3.1) | 43/971 (4.4) |
| Generalized itching | 15 (1.5) | 39/987 (4.0) |
Data are presented as no. (%) and represent all symptoms newly reported in at least 4% of the study population.
Figure 1.
Reported grade of commonly reported symptoms at each study visit (includes newly reported and persistent symptoms).
Among participants who experienced a symptom while taking 3HP (n = 768), 622 (81%) completed treatment without having to discontinue treatment, while 146 (19%) participants did not complete treatment for any reason. Commonly reported symptoms in participants who did not complete treatment included headache (43%), fatigue (40%), nausea (40%), and weakness (31%). The most common pattern of symptom development among these 146 participants was development in the first month followed by discontinuation of treatment. Weakness, dizziness, anorexia, fever, chills, and mood changes were symptoms for whom the most or second most common pattern appeared in the first month and then led to discontinuation (Supplementary Table 2).
Systemic Drug Reactions
A total of 111 (11%) participants reported symptoms meeting an SDR definition during treatment. Of these, 16 (1.6% of all participants) met category I criteria and 95 (9.5%) met category II criteria (5 participants in category I also met criteria for category II). Participants who met category I SDR criteria had hypotension (n = 2), hives (n = 8), angioedema (n = 1), wheezing/acute bronchospasm (n = 1), or conjunctivitis/red eyes (n = 4). The most common symptoms that met criteria for category II SDRs were fatigue (n = 75; 79%), headache (n = 66; 69%), nausea (n = 61; 62%), and aches (n = 60; 63%). The symptoms meeting criteria for SDRs were captured at unscheduled visits for 64 participants (58%) and at scheduled visits for 47 participants (42%).
Systemic drug reactions occurred most frequently within the first month on therapy; 68 (61%) of the 111 participants who experienced SDRs reported those symptoms at an unscheduled visit before week 4 (n = 42) or at the week 4 visit (n = 26). Of the remaining SDRs, 14 (13%) were reported at an unscheduled visit between weeks 4 and 8, 14 (13%) at week 8, and 15 (14%) after week 8.
Nearly half (n = 53; 48%) of participants who met criteria for SDRs still completed treatment. Treatment completion and time to treatment completion were similar among participants with category I SDRs (7/11, 64%; median: 79 days; range: 77–95 days), category II SDRs (44/95, 46%; median: 79 days; range: 71–107 days), or both category I and category II SDRs (2/5, 40%; 78 and 78 days). Treatment completion did differ, however, among participants who reported SDR symptoms at scheduled visits (35/47; 74% completed treatment) as compared with participants who reported SDR symptoms at an unscheduled visit (18/64; 28% completed treatment). Five of the 111 (4.5%) participants were hospitalized when SDR criteria were met, although it is not known whether the SDR-related symptoms were the cause for these hospitalizations. These included 4 participants with category II SDRs and 1 participant meeting both category I and II SDRs.
Risk factors associated with SDRs and discontinuation in bivariate analysis were female sex, age 45–54 years, diabetes, use of concomitant medications, and a history of liver disease (Table 3). In multivariable regression, female sex, age older than 45 years, and use of concomitant medications remained statistically significantly associated (Table 3). A self-reported history of liver disease was significant in the final multivariable model but became nonsignificant when accounting for small cell sizes.
Table 3.
Analysis for Factors Associated With Systemic Drug Reactions and Discontinuation
| Variable | RR (95% CI) | |
|---|---|---|
| Bivariate | Multivariable | |
| Sex | ||
| Male | Ref | Ref |
| Female | 2.40 (1.40, 4.12)a | 2.05 (1.19, 3.54) |
| Age (years) | ||
| 18–24 | 1.03 (.40, 2.65) | Ref |
| 25–34 | Ref | |
| 35–44 | 1.08 (.45, 2.61) | |
| 45–54 | 3.05 (1.48, 6.29)a | 1.99 (1.19, 3.31) |
| 55–64 | 2.16 (.90, 5.16) | |
| ≥65 | .89 (.12, 5.51)b | |
| History of Liver Disease | ||
| No | Ref | |
| Yes | 2.62 (1.15, 5.35)a,b | |
| Diabetes or high blood sugar | ||
| No | Ref | |
| Yes | 2.55 (1.36, 4.53)a,b | |
| Concomitant medications | ||
| No | Ref | Ref |
| Yes | 3.25 (1.70, 6.18)a | 2.26 (1.15, 4.42) |
N = 58. Abbreviations: CI, confidence interval; Ref, reference; RR, risk ratio.
Significant at P < .05.
RR and CI obtained from odds ratio [22].
The use of concomitant medications was more common among participants with an SDR (84%; 93/111) than those without an SDR (53%; 473/891). Among those with an SDR, the median number of reported concomitant medications was 2 medications (IQR: 1–3). The most reported concomitant medications were cardiovascular medications (n = 42; 38%), vitamins/supplements (n = 34; 31%), nonsteroidal anti-inflammatory drugs (NSAIDs) (n = 27; 24%), psychiatric drugs (n = 24; 22%), and antihistamines (n = 19; 27%) (Supplementary Table 3).
DISCUSSION
With 3HP now recommended globally—and other rifapentine-based LTBI regimens under investigation (eg, 1HP [one month daily rifapentine and isoniazid], 6wP [six weeks daily rifapentine]) [23, 24]—understanding symptom development and SDRs is crucial for ensuring treatment completion. The iAdhere study evaluated patterns of symptom occurrence in patients receiving 3HP to identify SDR frequency and associated factors. We found that, although most patients reported symptoms on treatment, most were mild, occurred in the first month, and spontaneously resolved. Among those with symptoms, more than 80% completed the 3-month treatment course. Serious adverse events were rare (0.5% of participants). Among the 11% who experienced a study-defined SDR, nearly half still completed treatment. The risk factors for discontinuing treatment and reporting SDRs were female sex, age 45 years or older, use of concomitant medications, and potentially having a history of liver disease; these risk factors are similar to those found previously [18]. Although symptoms were commonly reported while receiving 3HP treatment, a study-defined SDR was not predictive of progressive symptoms, toxicity, or treatment discontinuation. The benefit of short-course regimens makes 3HP an important option to expand TB-preventive therapy. Future research to further understand adverse reactions and improve the definition of an SDR is needed to prevent clinically important events.
iAdhere used a standardized approach to prospectively collect symptoms to assess patterns of adverse events and determine if they were predictable or preventable. We found many symptoms were common prior to initiating 3HP (eg, headache, fatigue, joint pain) (Table 2). Among symptoms reported on treatment, 97% were grade 1 or 2 (Supplementary Table 4), most commonly developing in the first month, followed by resolution despite continued treatment. These data support the safety of 3HP for most patients. Counseling patients regarding common symptoms and providing reassurance that they will likely be transient may assist patients in completing their preventive therapy. In this trial, 81% of participants who experienced at least 1 symptom still completed therapy. These findings are similar to those found in a large 3HP postmarketing study in routine clinical settings where the treatment completion rate was 79% among patients with at least 1 symptom [25].
Systemic drug reactions occurred in 11% of our study population. We used a modified definition of SDR, compared with the PREVENT TB trial, to include prospectively collected, graded symptoms. Applying our modified SDR definition to all time points where symptoms were collected identified milder presentations. In PREVENT TB, an SDR was only assessed when participants reported adverse events and stopped therapy, limiting the ability to understand the full spectrum and patterns of symptoms used to define an SDR [18]. Although 11% of participants in our study met SDR criteria, compared to 3.8% in PREVENT TB, this difference was likely because of the limited SDR assessment in PREVENT TB. When proportions of SDRs and discontinuation are compared, the findings are more similar (this study, 5.8%, vs PREVENT TB, 3.8%). A similar overall proportion of patients experiencing SDRs (10.2% of participants) was seen in a 3HP trial in adult patients with silicosis in China, where symptoms were also self-reported monthly [26].
Most SDR symptoms began within the first month of treatment, similar to other studies [18, 25, 26]. With the first routine follow-up visit scheduled at 1 month after treatment initiation in this trial, there were few opportunities to intervene early to prevent the occurrence of symptoms or treatment discontinuation. Nonetheless, participants experiencing SDR symptoms often completed treatment, suggesting that the current SDR definition is not predictive of severe or progressive drug reactions.
We also identified several subgroups with a higher risk of SDRs and discontinuation. These included female sex, age 45 years and older, use of concomitant medications, and potentially, a history of liver disease. Individuals who fall into these groups may benefit from targeted education, at baseline and on treatment, to ensure they understand and can identify the patterns and severity of reactions with 3HP. This education may reduce the progression of drug-related adverse events, while optimizing treatment completion in individuals with less severe symptoms. Informing all patients that they may experience mild and tolerable symptoms during the first month that are likely to improve with continued treatment may decrease overall discontinuation rates [27–29].
Four months of rifampin (4R) is another recommended option for a shortened LTBI treatment; unfortunately, this study was not designed to directly compare 3HP with 4R. Differences in methods collecting adverse event data between studies preclude direct comparison of tolerability and toxicity. Nonetheless, a retrospective analysis shows that both 3HP and 4R are both well tolerated and effective, with different advantages and disadvantages (eg, lower pill burden vs need for daily dosing) and similar treatment completion rates [30]. Both 3HP and 4R can be offered to patients and selection of regimen can be based on patient and provider preference. Further, each regimen could be considered as an alternative when there are shortages or recalls of any medications.
Our study is subject to a few limitations. Participants self-reported symptoms that occurred between their current and previous visits; thus, the exact onset timing of symptoms, and whether they occurred concurrently, was not always known. This could have resulted in participants being incorrectly classified as having an SDR (in particular, category II), when the symptoms did not occur concurrently. Additionally, we were not able to identify why treatment was discontinued for participants who reported SDRs. It is possible that some may have discontinued for reasons other than an SDR. Third, our method to estimate the RR from the odds ratio when cell sizes were small may have also contributed to narrow confidence limits. The goal of this study was to provide a comprehensive categorization of symptoms, SDRs, and discontinuation of treatment. Thus, even if our estimation of discontinuation specifically due to an SDR was an overestimation, it is likely a more accurate reflection of the full spectrum of outcomes that patients will experience while being treated with 3HP. Finally, most patients in this study were White (52%) and not born in a country with a high TB prevalence; this may limit generalizability to the target population for TB elimination in the United States, which is predominantly non-White and born outside the United States.
The iAdhere study data confirm that 3HP is a safe and well-tolerated regimen that may be implemented in a wide variety of settings [31]. Future studies are warranted to understand how to prevent or manage symptoms, including those indicative of SDRs, in patients taking 3HP, to maximizing LTBI treatment completion. Further efforts are also needed to develop additional, shortened LTBI treatment regimens that are even better tolerated in the future.
Supplementary Data
Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.
Supplementary Material
Contributor Information
Claire Sadowski, Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA; Clinical Research Branch, Division of Tuberculosis Elimination, National Center for HIV, Viral Hepatitis, STD, and TB Prevention (NCHHSTP), US Centers for Disease Control and Prevention, Atlanta, Georgia, USA; Oak Ridge Institute for Science and Education, Oak Ridge, Tennessee, USA.
Robert Belknap, Denver Metro Tuberculosis Program, Denver Public Health, Denver, Colorado, USA.
David P Holland, Department of Medicine, Division of Infectious Diseases, Emory University, Atlanta, Georgia, USA.
Ruth N Moro, CDC Foundation, Research Collaboration, Atlanta, Georgia, USA; Division of Healthcare Quality Promotion, National Center for Emerging and Zoonotic Infectious Diseases (NCEZID), US Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
Michael P Chen, Immunization Services Division, National Center for Immunization and Respiratory Diseases (NCIRD), US Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
Alicia Wright, Division of Infectious Diseases, Vanderbilt University Medical Centers, Nashville, Tennessee, USA.
Joan Pau Millet, Epidemiology Service, Public Health Agency of Barcelona, Barcelona, Spain; CIBER de Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain; Foundation of Tuberculosis Research Unit of Barcelona, Barcelona, Spain.
Joan A Caylà, Foundation of Tuberculosis Research Unit of Barcelona, Barcelona, Spain.
Nigel A Scott, Clinical Research Branch, Division of Tuberculosis Elimination, National Center for HIV, Viral Hepatitis, STD, and TB Prevention (NCHHSTP), US Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
Andrey Borisov, Clinical Research Branch, Division of Tuberculosis Elimination, National Center for HIV, Viral Hepatitis, STD, and TB Prevention (NCHHSTP), US Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
Neel R Gandhi, Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA.
Notes
Author contributions. C. S., R. B., A. B., and N. R. G. conceived of the study, design, and analytic plan. R. B., D. P. H., R. N. M., M. P. C., A. W., J. P. M., J. A. C., N. A. S., and A. B. were engaged in the design, conduct, and data collection in the original clinical trial. Primary analysis and drafting of the initial manuscript draft was carried out by C. S., A. B., and N. R. G. All authors contributed to review and revision of the manuscript and approved the final version. The corresponding author had access to all the data in the study and had final responsibility for the decision to submit for publication.
Disclaimer. The findings and conclusions in this report are those of the authors and do not necessarily represent the official positions of the Centers for Disease Control and Prevention or the authors’ affiliated institutions.
Financial support. TBTC Study 33 (iAdhere) and this analysis were funded by the US Centers for Disease Control and Prevention (CDC). Pharmaceutical support was provided by Sanofi. Funding for the current analysis was also provided in part by the National Institutes of Health (grant number K24AI114444; Principal Investigator, N. R. G.). This work was supported in part by an appointment of the corresponding author (C. S.) to the Research Participation Program at the CDC, administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and CDC.
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