Completion Rate and Safety of TuberculosisAndrea T. Cruz, MD, MPH, Jeffrey R. Starke, Infection MD Treatment

BACKGROUND: With Shorter Regimens abstract

The traditional treatment of tuberculosis (TB) infection (9 months of daily isoniazid [9H]) is safe but completion rates of <50% are reported. Shorter regimens (3 months of once-weekly isoniazid and rifapentine [3HP] or 4 months of daily rifampin [4R]) METHODS: are associated with improved adherence in adults. – – ’ This was a retrospective cohort study (2014 2017) of children (0 18 years old) seen at a children s TB clinic in a low-incidence nation. We compared the frequency of completion and adverse events (AEs) in children receiving 3HP, 4R, and 9H; the latter 2 regimens could be administered by families (termed self-administered therapy [SAT]) or as RESULTS: directly observed preventive therapy (DOPT); 3HP was always administered under DOPT. TB infection treatment was started in 667 children: 283 (42.4%) 3HP, 252 (37.8%) 9H, and 132 (19.8%) 4R. Only 52% of children receiving 9H via SAT completed therapy. – Children receiving 3HP were more likely to complete therapy than the 9H (SAT) group – (odds ratio [OR] 27.4, 95% confidence interval [CI]: 11.8 63.7). Multivariate analyses found – – receipt of medication under DOPT (OR: 5.72, 95% CI: 3.47 9.43), increasing age (OR: 1.09, – 95% CI: 1.02 1.17), and the absence of any AE (OR: 1.70, 95% CI: 0.26 0.60) to be associated with completing therapy. AEs were more common in the 9H group (OR: 2.51, 95% CI: 1.48 4.32). Two (0.9%) children receiving 9H developed hepatotoxicity; no child receiving 3HP or CONCLUSIONS: 4R developed hepatotoxicity. Shorter regimens are associated with increased completion rates and fewer AEs than 9H.

Wh’ownat s Kn on This Subject: Treatment of tuberculosis infection is safe and well tolerated. Department of Pediatrics, Baylor College of Medicine, Houston, Texas Completion rates of 9 months of daily isoniazid (9H) Dr Cruz conceptualized and designed the study, performed data collection and analyses, drafted are <50%. Using shorter regimens (3 months of the initial manuscript, and reviewed and revised the manuscript; Dr Starke helped conceptualize once-weekly isoniazid and rifapentine [3HP] and 4 the study and reviewed and revised the manuscript; and all authors approved the final months of daily rifampin) can enhance completion. manuscript as submitted and agree to be accountable for all aspects of the work. What This Study Adds: Children receiving 3HP DOI: https://​doi.​org/​10.​1542/​peds.​2017-​2838 were more likely to complete therapy than those Accepted for publication Nov 8, 2017 receiving daily 9H (odds ratio: 27.4, 95% confidence Address correspondence to Andrea T. Cruz, MD, MPH, Department of Pediatrics, Baylor College of interval: 11.8–63.7); only 52% of those receiving Medicine, 6621 Fannin St, Suite A2210, Houston, TX 77030. E-mail: [email protected] daily 9H completed therapy. Hepatotoxicity was uncommon (0% in 3HP vs 0.9% in 9H). PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2018 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: Dr Starke is on the data safety monitoring board for Otsuka Pharmaceuticals for pediatric pharmacokinetic studies of delamanid; and Dr Cruz has indicated she has no financial relationships relevant to this article to disclose. FUNDING: No external funding. To cite: Cruz AT and Starke JR. Completion Rate and Safety of Tuberculosis Infection Treatment With Shorter Regimens. Pediatrics. 2018;141(2):e20172838

Downloaded from www.aappublications.org/news by guest on September 27, 2021 PEDIATRICS Volume 141, number 2, February 2018:e20172838 Article Therapy for tuberculosis (TB) ability to more accurately identify and (6) children with a positive TST infection is safe, efficacious, and children who would benefit from after having previously negative TST recommended for children who therapy to prevent progression to results. For other children, positive receive test results that are positive disease, coupled with regimens TST results were followed by an γ for an infection (either the tuberculin more palatable to children and IGRA obtained in our clinic and skin test [TST] or an interferon their families, suggests strategies treatment was offered only if the release assay [IGRA]) unless1 specific to improve effectiveness of TB IGRA result was positive for TB. The contraindications exist. In contrast, infection therapy. The goal of this rationale behind why our community effectiveness (how an intervention study was to describe the trends of colleagues used TST versus IGRA was performs in real-world conditions) use, completion rates, and safety not available. has been poor. The long duration of profiles of the 3 most commonly All children were treated by the therapy with the US-recommended used regimens for TB infection in a ≥ authors using 1 of 3 regimens (Table 9 months of daily isoniazid (9H), heterogeneous cohort of children in a 1). 3HP was used in children 2 concerns that families have regarding busy US urban TB clinic. years old and always administered false-positive TSTs in children who Methods as directly observed preventive have received the BCG vaccine, 10,11​ therapy (DOPT). ‍ Children <2 and a culture of TB prevention that years old were not prescribed has made few inroads into high- This retrospective cohort study this regimen given the absence prevalence settings have adversely included 0- to 18-year-old children of data on rifapentine dosing impacted the effectiveness of TB 14 who were offered treatment for in this group. The remaining infection therapy. These factors ’ TB infection from January 2014 regimens, 4R and 9H, were used may be particularly important for to March 2017 at a children s TB in children of all ages and could be immigrant children, a group in which ’ clinic associated with a quaternary administered as DOPT, enhanced the rate of TB infection is far higher 2 care children s hospital. This clinic self-administered therapy ([ESAT] in than for US-born children. Authors is the main referral venue for which medications were delivered of a recent study found that only immigration and refugee programs, monthly to families by health 12% of over 8200 children diagnosed public health departments, and a departments, who called periodically with TB infection before immigrating network of community pediatricians for reminders; daily medication was to the United States successfully in a metropolitan area of almost 7 administered by family members), completed therapy after arrival in the 3 million persons. Using American or self-administered therapy (SAT). United States. ≥ Thoracic Society and Centers for In general, all 3 options were Completion rates of <50% have Disease Control and Prevention presented to patients 2 years old, been reported for both children and guidelines, TB infection was defined but a preference was expressed by adults when TB medications4,5​ are as having positive results12,13​ from providers for 3HP. Isoniazid (INH) administered by families. ‍ either a TST or IGRA. ‍ Children was only administered twice-weekly There are few patient-specific receiving regimens for suspected under DOPT. In DOPT, medications factors associated with completion multidrug-resistant TB infection, were delivered by a health of therapy. Our previous studies families who refused to start children department representative who found that region of origin, language, on therapy, or those still on therapy asked the family about symptoms and the method to test for TB were excluded from this study.8 Eighty before administering the subsequent infection (TST versus IGRA) were children previously published as dose. Completion was calculated for not associated6 with completion of receiving 3HP were included. the first regimen a child received. An therapy. However, provision of exception was if therapy had to be 7 All TSTs were performed before therapy by local health departments changed because of documented drug children were being seen in the TB and using shorter-course therapy resistance from an isolate from a 7 clinic. A positive TST result alone with 4 months of daily rifampin (4R) person close to the child; then, it was (without a confirmatory sequential or 3 months of once-weekly isoniazid that definitive regimen that was used 8 IGRA) defined TB infection in: (1) and rifapentine (3HP) were to evaluate completion. children identified through contact associated with completion rates of tracing of a person with TB disease, The primary outcome was 93% to 99%. (2) immunocompromised children, completion of therapy. Children The last decade has seen publication (3) children about to receive were considered to have completed of more robust data on IGRA use immunosuppressive therapy, (4) therapy (Table 1) if medication was 9 ≥ in children and on shorter10,11​ course children <2 years of age, (5) children given under DOPT, even if they did regimens such as 3HP. ‍ The with TST induration of 20 mm, not return for clinic visits as long as Downloaded from www.aappublications.org/news by guest on September 27, 2021 2 Cruz and Starke TABLE 1 Regimens Used to Treat Children With TB Infection Regimen No. Dose(s), in mg/kg [Maximum Dose] Schedule Optimal Completion Defined As Mode of Duration Administration INH and 283 INH: 25 mg/kg (children 2–11 y) [900 mg]; 15 Weekly 12 wk Receipt of at least 11 doses over DOPT rifapentine mg/kg (children ≥12 y) [900 mg] a 16-wk period (3HP) Rifapentine: 300 mg (10–14 kg); 450 mg (14.1–25 kg); 600 mg (25.1–32 kg); 750 mg (32.1–49.9 kg); 900 mg (≥50 kg) [900 mg] RIF (4R) 132 10–20 mg/kg [600 mg] Daily 4 mo Receipt of at least 4 mo over a DOPT, ESAT, SAT 6-mo period or 52 observed doses if DOPT INH (9H) 178 20–30 mg/kg [900 mg] Twice 9 mo Receipt of 78 doses DOPT weekly INH (9H) 74 10–15 mg/kg [300 mg] Daily 9 mo Receipt of at least 6 mo ESAT, SAT consecutively or 9 mo over a 12-mo period

DOPT provided to the child and administration witnessed by a health department representative. The child’s guardian was asked about possible AEs before each dose of medications. ESAT provided to the family by the health department, but the family was responsible for administering the medication to the child on a daily basis; periodically, the family was called for reminders and queried on adherence and on AEs. For SAT, a prescription was given to the family, who had to then acquire the medication from the pharmacy and administer to the child; there was no system for periodic reminder calls. SAT is an option for families who do not want a health department representative visiting the home, or whose schedule may be sufficiently chaotic that arranging scheduled visits is challenging. For these families, we discuss medication cost before making a joint decision about therapy. In Texas, we can only obtain free medication for our TB infection patients if medication is administered under DOPT or ESAT. In SAT, families do have to purchase medications, and RIF is far more costly to purchase than INH.

medication receipt was documented levels were abstracted. AEs were conditions, or reason for testing for ’ by the health department. For graded using the National Cancer 15 TB infection. children returning for follow-up, Institute s severity grading system. Shift in Diagnosis and Treatment caregivers were questioned about Institutional review board approval medication administration. Families was obtained before study onset. not returning for follow-up were Stata 11 (StataCorp, College Station, called to inquire about adherence TX) was used for analyses. Most children were tested for TB and medication tolerance. Subjects Results infection by using TSTs before receiving medication by SAT who did arrival in our clinic. During the not return for follow-up or could not Demographics study period, use of IGRAs, either be contacted were considered to have inP isolation or obtained after a child not completed therapy. had a positive TST results, increased ( value for trend in odds <.0001) During the study period, 667 children ≥ Our secondary outcome was safety were treated for TB infection. (Fig 1A). IGRA use was higher among and tolerability. Children were seen Two families (0.3% of all families children 5 years old: 246 out of in clinic at the initiation of therapy, seen) refused to initiate therapy; 438 (56.2%) children had IGRAs 4 to 6 weeks after starting therapy, the remainder all agreed to start performed compared with 34 out of 229 (14.8%) children <5 years and every 1 to 3 months thereafter. therapy at the time of the first – We did not routinely obtain liver clinic visit. Children were born in of age (odds ratio [OR]: 7.3, 95% function tests (LFTs) in otherwise 54 countries and families spoke 25 confidence interval [CI]: 4.9 11.1). healthy children. Children receiving different languages; in-person or The most common treatment other potentially hepatotoxic phone translation was used. The regimen was 3HP (283, 42.4%), medications and children with most common reasons for testing followed by 9H (252, 37.8%), and obesity (in whom nonalcoholic for TB infection were as follows: 4R (132, 19.8%). UseP of 3HP increased fatty liver disease could lead to 330 (49.5%) birth in or 59 (8.8%) and 9H decreased significantly over baseline transaminitis) did have travel to high-prevalence countries, the study period ( < .0001) (Fig 1B). LFTs obtained at baseline. Children 211 (33.1%) public health contact Children who received 9H were with abdominal pain, appetite or tracing, and 19 (2.8%) before significantlyP younger than those who weight loss, vomiting, or icterus had immunosuppression or as a prelude received 3HP or 4R (mean 4.5 versus medication(s) withheld pending to organ transplantation (Table 2). 11.2 years, < .0001). Even when LFTs being obtained. Medical records The only variable associated with children <2 years were excluded, the were abstracted for demographic selection of regimens was age; there mean age of 9H recipients remained variables, regimen doses, adherence, were no significant differences in Pyounger than children receiving 3HP and adverse events (AEs). Aspartate the use of regimens based on other or 4R (mean 5.8 versus 11.5 years, and alanine aminotransferase demographic variables, comorbid < .0001). Downloaded from www.aappublications.org/news by guest on September 27, 2021 PEDIATRICS Volume 141, number 2, February 2018 3 0 0 0 9 (9.3) 3 (3.1) 3 (3.1) 1 (1.0) 6 (6.2) 1 (1.0) 6 (6.2) 9 (9.3) 15 (15.5) 4R SAT or ESAT ( n = 97), No. (%) 0 0 0 0 0 0 0 0 0 2 (5.7) 1 (2.9) No. (%) 4R DOPT ( n = 35), 0 0 0 3 (2.3) 3 (2.3) 3 (2.3) 6 (4.5) 1 (0.8) 7 (5.3) No. (%) 63 (47.7) 29 (82.9) 34 (35.1) 4R ( n = 132), 0 0 18 6 (8.1) 15 (11.4) 3 (4.1) 4 (5.4) 1 (1.4) 5 (6.8) 1 (1.4) 3 (4.1) 1 (1.4) 8 (10.8) 17 (12.9) 2 (5.7) 15 (15.5) 9H SAT or ESAT ( n = 74), No. (%) 0 0 0 0 3 (1.7) 4 (2.2) 1 (0.6) 2 (1.1) No. (%) 9H DOPT ( n = 178), 0 1 (0.4) 3 (1.2) No. (%) 68 (27.0) 49 (27.5) 19 (25.7) 13 (9.8) 4 (11.4) 9H ( n = 252), 0 0 0 1 (0.4) 3 (1.2) 5 (1.8) 3 (1.2) 4 (1.4) 8 (3.2) 2 (0.7) 1 (0.4) 2 (0.7) 7 (2.5) 6 (2.4) 7 (2.5) 33 (13.1) 24 (13.4) 9 (12.2) 9 (6.8) No. (%) 12 (4.2) 104 (41.3) 80 (44.9) 24 (32.4) 32 (24.2) 14 (40.0) 18 (18.6) 23 (8.1) 10 (4.0) 4 (2.2) 28 (9.9) 14 (5.6) 6 (3.4) 14 (4.9) 41 (16.3) 30 (16.9) 11 (14.9) 17 (12.9) 4 (11.4) 13 (13.4) 49 (17.3) 25 (9.9) 9 (5.1) 16 (21.6) 14 (10.6) 2 (5.7) 12 (12.4) 46 (16.3) 15 (6.0) 12 (6.7) 3HP ( n = 283), 7 (1.0) 2 (0.3) 2 (0.3) 3 (0.4) 11 (1.6) 15 (2.2) 48 (7.2) 59 (8.8) 19 (2.8) 49 (7.3) 81 (12.1) 88 (13.2) 72 (10.8) 68 (10.2) 148 (22.2) 387 (58.0) 110 (38.9) 203 (80.6) 154 (86.5) 49 (66.2) 74 (56.1) 30 (85.7) 44 (45.4) 158 (23.7)339 (50.8) 68 (24.0) 153 (54.1) 53 (21.0) 120 (47.6) 39 (21.9) 84 (47.2) 14 (18.9) 36 (48.6) 37 (28.0) 66 (50.0) 12 (34.3) 18 (51.4) 25 (25.8) 48 (49.5) 330 (49.5) 138 (48.8) 130 (51.6) 78 (43.8) 52 (70.3) 62 (47.0) 3 (8.6) 59 (60.8) 192 (28.8) 124 (43.8) 24 (9.5) 15 (8.4) 9 (12.2) 44 (33.3) 3 (8.6) 41 (42.3) 328 (49.2)331 (49.6) 130 (45.9) 158 (55.8) 132 (52.4) 115 (45.6) 94 (52.8) 80 (44.9) 38 (51.4) 35 (47.3) 66 (50.0) 58 (43.9) 17 (48.6) 18 (51.4) 49 (50.5) 36 (37.1) 211 (31.6) 87 (30.7) 92 (36.5) 89 (50.0) 3 (4.1) 32 (24.2) 30 (85.7) 2 (2.1) 280 (42.0) 203 (71.7) 27 (10.7) 10 (5.6) 17 (23.0) 50 (37.9) 5 (14.3) 45 (46.4) 142 (21.3) 42 (14.8) 63 (25.0) 41 (22.5) 22 (29.7) 37 (28.0) 6 (17.1) 31 (32.0) 120 (18.0) 69 (24.4) 32 (12.7) 27 (15.2) 5 (6.8) 19 (14.4) 3 (8.6) 16 (16.5) 302 (45.3) 135 (47.7) 102 (40.5) 81 (45.5) 21 (28.4) 65 (49.2) 30 (85.7) 35 (36.1) 130 (19.5) 60 (21.2) 47 (18.7) 26 (14.6) 21 (28.4) 23 (17.4) 1 (2.9) 22 (22.7) 118 (17.7) 35 (12.4) 55 (21.8) 35 (19.7) 20 (27.0) 28 (21.2) 3 (8.6) 25 (25.8) 373 (55.9)291 (43.6) 153 (54.1) 130 (45.9) 151 (59.9) 98 (38.9) 96 (53.9) 80 (44.9) 55 (74.3) 69 (52.3) 6 (17.1) 63 (64.9) 629 (94.3) 269 (95.1) 237 (94.0) 171 (96.1) 66 (89.2) 123 (93.2) 33 (94.3) 90 (92.8) Entire Cohort 8.0 (3.6 – 13.8) 13.1 (9.3 – 16.0) 3.3 (1.8 – 6.9) 3.1 (1.8 – 5.2) 4.4 (1.6 – 8.3)– 13.2) 7.4 (3.6 3.9 (2.6 – 5.9) 9.1 (4.1 – 14.7) ( N = 667), No. (%) a b Variable c d antagonist or other immune-suppression <2 2 – <5 Inflammatory bowel disease 3 (0.4) 5 – <10 Female Foreign birth Renal disease IGRA alone Diabetes Male Contact investigation TST followed by IGRA Other ≥ 10 Asian Foreign travel Before receipt of TNF- α Black Other White Multiracial United States Latin America Asia Unknown Nonrecipient Africa Middle East None Rheumatologic disease  Demographics of the Study Population

LE 2 testing for TB infection birth conditions B Age (y) Median (IQR) A Category Test of infection TST alone Sex Reason for Race/ethnicity Hispanic Child ’ s region of BCG vaccine Recipient Comorbid Three patients receiving dialysis, 3 with nephrotic syndrome, 1 renal tubular acidosis. Includes 6 children in foster care, 4 patients tested so they could volunteer at local hospitals, homeless shelt ers, 2 whose parents were incarcerated, and for symptoms concerning TB; 30 patients, the reason Two each with systemic lupus erythematosus, juvenile idiopathic arthritis, and psoriasis, 1 each with myasthenia gravis, pemphigus, hidradenitis suppurativa, chronic recurrent multifocal osteomyelitis, dermatomyositis. Two Five with epilepsy, 2 with pregnancy, 2 with fatty liver disease, 1 each with hereditary spherocytosis, tropical splenomegaly, refractory hypertension, Five with epilepsy, 2 pregnancy, fatty liver disease, 1 each hereditary spherocytosis, congenital adrenal hyperplasia, portal hypertension, and cutaneous leishmaniasis. for testing was uncertain. Percentages are within-column percentages and may not sum to 100% because of rounding. IQR, interquartile range; TNF, tumor necrosis factor. interquartile range; TNF, Percentages are within-column percentages and may not sum to 100% because of rounding. IQR, a b c d T

Downloaded from www.aappublications.org/news by guest on September 27, 2021 4 Cruz and Starke – Administration of medication by families (OR: 0.40, 95% CI: 0.26 0.60) was associated with failure to complete therapy. As the study period proceeded,P more children were likely to complete therapy for TB infection ( value for trend of odds = .0029), due at least in part to Safetyincreased use of 3HP and DOPT.

Sixty-two (9.3%) children complained of any AE (Table 4). Complaints of any AE were more common in the 9H group compared – with 3HP and 4H groups (OR: 2.51, 95% CI: 1.48 4.32).P There was no difference in hepatotoxicity among the regimens ( = .192). The most AE common was abdominal pain (41 out of 667 children, 6.1%); only 2 out of 667 children treated (0.3%) FIGURE 1 had elevated hepatic transaminases Shift in practice patterns, 2014–2017. A, Shift in use of tests of TB Infection. B, Shift in use of treatment and the remainder had normal regimens. transaminase levels. Only 1 child had a grade 4 AE: a 2-year-old girl Completion Rates with nephrotic syndrome who developed aspartate 1115 U/L and out of 283 children, 96.8%) than alanine aminotransferase 1490 in the 9H group (148 out of 184 – U/L in her eighth month of INH. The highest completion rates were children, 80.4%), (OR: 7.4, 95% CI Therapy was immediately stopped seen with 3HP (96.8%) and the – 3.5 15.8). There was no difference and she recovered. One child, a lowest with 9H under SAT (52.6%) in completion rates under DOPT for 15-year-old with lupus and idiopathic (OR: 27.4, 95% CI: 11.8 63.7) (Table children identified through contact thrombocytopenic purpura, died of a 3). 9H demonstrated completion investigations versus those tested for – hemorrhagic stroke while on 4R; she rates of 89% (in 158 out of 178 TB infection for other reasons (OR: had previous strokes before starting children) when administered under 0.80, 95% CI: 0.38 1.68). 4R, and her stroke was thought to be DOPT, but completion was only because of her underlying diseases. 53% (in 30 out of 57 children) when Failure to complete therapy was – – A 19-month-old child developed administered under SAT (OR: 7.11, associated with the development of ’ hematochezia as a result of a 95% CI: 3.54 14.28). There was any AE (OR: 0.1, 95% CI: 0.06 0.2) Meckel s diverticulum while on 9H; no difference in completion rates and with therapy administered – he was not coagulopathic. between 4R under DOPT and 3HP outside of DOPT (Table 3). A (OR: 1.12, 95% CI: 0.14 9.09). On regression model for completion Nineteen (2.8%, 30.6% of all ≥ univariate analyses, completion was included age, race and/or ethnicity, children with any AE) patients more common in older ( 2 year old) child and/or family region of required a change in regimen – children compared with <2-year-olds residence, BCG status, test used for because of AEs. Seven families (OR: 2.37, 95% CI: 1.30 4.32) and TB infection, mode of administration, refused a second regimen and 12 for children identified via contact regimen used, and the presence of families changed therapy; 7 from – investigations versus children with any AE. Receipt of medication by 9H to 4R, 4 from 3HP to 4R, and 1 other risk factors for TB infection. DOPT (OR: 5.72, 95% CI: 3.47 9.43), from 4R to 9H. The most common ≥ – When subgroup analyses were increasing age (OR: 1.09, 95% CI: reasons for changing therapy were – performed on children 2 years old, 1.02 1.17), and the absence of any AE abdominal pain (8), rash (4), and completion rates were significantly (OR: 1.70, 95% CI: 1.43 2.02) were spitting out medication with the DOT higher in the 3HP group (274 associated with completing therapy. worker (4). In 10 out of 19 (52.6%) Downloaded from www.aappublications.org/news by guest on September 27, 2021 PEDIATRICS Volume 141, number 2, February 2018 5 TABLE 3 Correlates of Completion of Therapy, Univariate Analyses Variable Subcategory All Patients (N = 667), Completed (n = 591), Did Not Complete (n = 76), OR (95% CI) No. (%)a No. (%)b No. (%)b Age (y) 0–<2 81 (12.1) 64 (79.0) 17 (21.0) Ref 2–<5 148 (22.2) 128 (86.5) 20 (13.5) 1.7 (0.8–3.5) 5–<10 158 (23.7) 141 (89.2) 17 (10.8) 2.2 (1.1–4.6) ≥10 280 (42.0) 258 (92.1) 22 (7.9) 3.1 (1.6–6.2) Median (IQR) 8.0 (3.6–13.8) 8.3 (3.7–14.1) 5.1 (2.1–11.3) P = .002 Sex Female 339 (50.8) 309 (91.2) 30 (8.8) Ref Male 328 (49.2) 282 (86.0) 46 (14.0) 0.6 (0.4–1.0) Race and/or ethnicity Hispanic 331 (49.6) 297 (89.7) 34 (10.3) Ref Asian 142 (21.3) 121 (85.2) 21 (14.8) 0.7 (0.4–1.2) Black 120 (18.0) 109 (90.8) 11 (9.2) 1.1 (0.6–2.3) White 72 (10.8) 62 (86.1) 10 (13.9) 0.7 (0.3–1.5) Multiracial 2 (0.3) 2 (100) 0 P = .99 Reason child tested for Foreign birth 330 (49.5) 284 (86.1) 46 (13.9) Ref infection Contact 211 (31.6) 195 (92.4) 16 (7.6) 1.9 (1.1–3.6) investigation Other 126 (18.9) 112 (88.9) 14 (11.1) 1.3 (0.7–2.5) Test of infection used TST alone 387 (58.0) 336 (86.8) 51 (13.2) Ref TST followed by 88 (13.2) 79 (89.8) 9 (10.2) 1.3 (0.6–2.8) IGRA IGRA alone 192 (28.8) 176 (91.7) 16 (8.3) 1.7 (0.9–3.0) How medications SAT 136 (20.4) 96 (70.6) 40 (29.4) Ref administered ESAT 35 (5.2) 29 (82.9) 6 (17.1) 2.0 (0.7–5.2) DOPT 496 (74.4) 466 (94.0) 30 (6.0) 6.5 (3.8–10.9) Regimen and manner of 9H, SAT 57 (8.5) 30 (52.6) 27 (47.4) Ref administration 9H, ESAT 17 (2.5) 13 (76.5) 4 (23.5) 2.9 (0.9–10.1) 9H, DOPT 178 (26.7) 158 (88.8) 20 (11.2) 7.1 (3.5–14.3) 4R, SAT 79 (11.8) 66 (83.5) 13 (16.5) 4.6 (2.1–10.1) 4R, ESAT 18 (2.7) 16 (88.9) 2 (11.1) 7.2 (1.5–34.2) 4R, DOPT 35 (5.2) 34 (97.1) 1 (2.9) 30.6 (3.9–239) 3HP 283 (42.4) 274 (96.8) 9 (3.2) 27.4 (11.8–63.7) IQR, interquartile range; REF, reference for subgroup analyses. a Percentages for each subgroup are within the column; percentages may not sum to 100% because of rounding. b Percentages are within the row.

Discussion instances, children successfully wanted to share the results of our completed the second regimen, – experience with 9H and shorter-

2 children had INH stopped after at Low rates of completion of 9H 3 5 course regimens generated from least 6 months had been given, and have been extensively reported. ‍ ‍ our high-volume referral TB clinic to the remaining families opted to not Unfortunately, this has not greatly demonstrate postmarketing data on restart another regimen. changed practice patterns, with over completion rates and safety. There 85% of pediatric infectious disease were several pertinent findings. First, physicians continuing to recommend completion rates were significantly A 16-year-old who received 3HP 16 9H as first-line therapy. higher for shorter-course regimens developed culture-confirmed Pediatricians in general practice, than 9H, when medications were pulmonary TB 7 months after who treat most children with TB administered by families. Second, completing therapy. There was infection, may feel less comfortable short-course regimens were well concern that she hid her medications moving away from 9H because this tolerated. Third, effectiveness is high in her cheek and spit them out is the regimen with which they have in the short-term. after the health department worker the most experience. We found departed; her isolate was pan that despite extensive education on Successful completion of therapy was susceptible. We are the referral the importance of treatment and not associated with demographic center for all children in an 8-county tolerability of medications, only factors in our study. This means that area with TB disease and we were 50% completed therapy with6 9H choices that clinicians make have not informed by any of the health administered by families. This led the greatest impact on completion departments that any of our other us to be early adopters of shorter of therapy and reduction of TB children developed TB disease after course regimens and advocates of disease in the future. Administration therapy for TB infection. administration under DOPT. We of shorter-course regimens, Downloaded from www.aappublications.org/news by guest on September 27, 2021 6 Cruz and Starke TABLE 4 AE Reported While Children Received Therapy for TB Infection Category Symptom 3HP (n = 281), No. (%) 9H (n = 234), No. (%) 4R (n = 124), No. (%) No events N/A 257 (91.5) 202 (86.3) 118 (95.2) Any AE N/A 24 (8.5) 32 (13.7) 6 (4.8) Constitutional Decreased appetite 5 (1.8) 3 (1.3) 0 Fatigue 0 1 (0.4) 0 Gastrointestinal Abdominal pain 5 (1.8) 14 (6.0) 3 (2.4) Nausea and/or vomiting 5 (1.8) 4 (1.7) 1 (0.8) Hepatotoxicitya 0 2 (0.9) 0 Dermatologic Rash 4 (1.4) 3 (1.3) 1 (0.8) Pruritus 1 (0.4) 0 0 Neurologic Headache 6 (2.1) 1 (0.4) 0 Dizziness 3 (1.1) 0 0 Other Anxiety with the health department 2 (0.7) 3 (1.3) 1 (0.8) worker Myalgias 1 (0.4) 1 (0.4) 0 Unrelated to medicationsb 1 (0.4) 1 (0.4) 0 Symptom severityc Grade 1 24 (8.5) 27 (11.5) 6 (4.8) Grade 2 0 4 (1.7) 0 Grade 4 0 1 (0.4) 0 Not documented N/A 2 (0.7) 18 (7.7) 8 (6.5) Adapted from American Academy of Pediatrics. Tuberculosis. In: Kimberlin DW, Brady MT, Jackson MA, Long SS, eds. Red Book 2015: Report of the Committee on Infectious Diseases. 29th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2015:804–830.1 Percent may sum to >100% because some children reported >1 symptom. For 28 children, the frequency of AEs could not be accurately quantitated; for this reason, the denominators in the column headers differ from those in Table 1. Percentages reflect within-column percentages. N/A, not applicable. a Asparate or alanine aminotransferase >2.5 times the upper limit of normal by age. b 3HP group (1: death from stroke in a child with lupus and idiopathic thrombocytopenic purpura); 9H (hematochezia as a result of Meckel’s diverticulum). c Grading system used by the US Department of Health and Human Services for AEs.15 Grade 1: mild; asymptomatic or mild symptoms only requiring clinical or diagnostic observations, but no intervention. Grade 2: moderate; minimal, local, or noninvasive interventions indicated; some limitation in activities of daily living. Grade 3: severe or medically significant without being life-threatening, requiring hospitalization, limiting activities of daily living. Grade 4: life-threatening. Grade 5: death related to AE.

administration of therapy by local administered by families. Family that use of >1 anti-TB drug could health departments, or both, have the administration of rifampin (RIF) result in hepatotoxicity. This was greatest impact on whether a child was associated with far higher not borne out in 3HP studies, in completes therapy. The role of DOPT completion rates than 9H. The which hepatotoxicity rates were is not solely in terms of medication favorable safety profile, the ability over19 4 times lower for 3HP than for administration, although this is a to retain once-daily dosing, and the ’ 9H ; this is thought to be because critical role that helps overcome relative ease of acquisition of RIF in of a reduction in the total exposure the barrier of a family s ability to the community facilitate uptake of time to hepatically metabolized purchase medications and obtain this regimen. Another alternative medications. We observed no cases is to have more robust capacities refills. The other roles of DOPT are of hepatotoxicity in our patients who to assess for AEs on a regular basis for remotely monitoring adherence received 3HP and a low frequency of and to encourage the child and and assessing toxicity, as has been hepatotoxicity in children receiving family to take medications. Many successfully accomplished with video 9H. Despite actively asking families families that were nonadherent with DOPT programs. In video DOPT, about systemic drug reactions, we clinic visits nonetheless completed medications are left for families who ’ therapy under DOPT because health administer the medication to children did not note many of the systemic departments worked with families in front of a phone-based video drug reactions with 3HP, including schedules and these visits did application for smart phones that influenza-like illnesses and rashes, not interfere with parental work allows for secure transmission of the that have been reported up to 63%20 schedules. Thus, although we were video file to the health department. and 17% of adults, respectively. unable to see many children on the Video DOPT is associated with similar Myalgias were self-limited, predominantly occurred in the recommended schedule, we were still completion rates as to in-person17 apprised immediately if children had DOPT and with lower costs. third to fourth week of therapy, as any AEs. has been described in adults, and Short-course therapy was safe were responsive to nonsteroidal Because DOPT is not available for children. Based on previous anti-inflammatory drugs. When throughout the United States, studies of combination therapy adolescents were given the option of providers should consider moving for TB infection18 with RIF and continuing 3HP or stopping therapy from 9H to 4R if therapy is to be pyrazinamide,​ there was concern and beginning therapy anew with a Downloaded from www.aappublications.org/news by guest on September 27, 2021 PEDIATRICS Volume 141, number 2, February 2018 7 longer regimen, all opted to remain been variation in how providers compared with 9H and were well on 3HP. selected regimens in collaboration tolerated. The effectiveness of these ’ with families. We did not have data regimens is high in the short-term. Short-course therapy was effective, on children s insurance status, and We hope that the coming years will at least in the short-term. Our cannot evaluate the impact that see a shift in TB infection diagnosis to 3HP data mirrors that of the large needing to purchase medication may IGRAs to enable treatment to target prospective trial that enrolled10 have had on adherence. We assumed the children who would receive children 2 to 17 years of age,​ that families not receiving medication the most benefit from therapy, but given the short follow-up through health departments were and that increased data on 3HP period, we cannot comment on the nonadherent if they did not return pharmacokinetics and more child- longer-term effectiveness of 3HP for clinic visits. Although this friendly formulations of 3HP will in our patients. However, the vast may have led to underestimating enable this shorter regimen to be majority of children who develop completion rates, few of our patients used in the most vulnerable pediatric TB disease do so within 2 years, have regular pediatricians who may population: infants and young which increases the likelihood that have been able to continue therapy. children. the treatment was truly effective. Furthermore, we could not evaluate Given the increasing use of IGRAs in for AEs in children who did not Abbreviations our clinic and our recommendation return for follow-up, which may have to community providers to order resulted in underestimating AEs. It IGRAs more frequently as a testing is possible that children could have AE: adverse event tool, we feel that these children moved to other jurisdictions and CI: confidence interval were truly infected, and that their then developed TB disease; thus, the DOPT: directly observed preven- positive test results were not false- effectiveness of therapy could have tive therapy positive reactions caused by non-TB been overestimated; for this reason, ESAT: enhanced self-adminis- γ mycobacteria or previous BCG effectiveness was an exploratory tered therapy vaccination. The improved specificity outcome. The results of our findings IGRA: interferon release assay of IGRAs, particularly in the may not be generalizable to other INH: isoniazid child >2 years of age, enables clinical settings, particularly those LFT: liver function test providers to target resources to in which 3HP or health department OR: odds ratio children who are most likely to assistance with medication RIF: rifampin receive benefit from therapy. administration may not be readily SAT: self-administered therapy available. TB: tuberculosis There were limitations to this Conclusions TST: tuberculin skin test study. There were a small number 3HP: 3 months of once-weekly of missing data elements in this isoniazid and rifapentine retrospective study. Patients We demonstrated that short-course 4R: 4 months of daily rifampin were not randomly assigned to regimens were associated with 9H: 9 months of daily isoniazid interventions, and there may have significantly higher completion rates POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

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Downloaded from www.aappublications.org/news by guest on September 27, 2021 Completion Rate and Safety of Tuberculosis Infection Treatment With Shorter Regimens Andrea T. Cruz and Jeffrey R. Starke Pediatrics 2018;141; DOI: 10.1542/peds.2017-2838 originally published online January 23, 2018;

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