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Update of Recommendations for Use of Once-Weekly Isoniazid-Rifapentine Regimen to Treat Latent Mycobacterium tuberculosis Infection

Update of Recommendations for Use of Once-Weekly Isoniazid-Rifapentine Regimen to Treat Latent... Morbidity and Mortality Weekly Report Update of Recommendations for Use of Once-Weekly Isoniazid-Rifapentine Regimen to Treat Latent Mycobacterium tuberculosis Infection 1 1 1 1 1 1 Andrey S. Borisov, MD ; Sapna Bamrah Morris, MD ; Gibril J. Njie, MPH ; Carla A. Winston, PhD ; Deron Burton, MD ; Stefan Goldberg, MD ; 1 1 1 1 Rachel Yelk Woodruff, MPH ; Leeanna Allen, MPH ; Philip LoBue, MD ; Andrew Vernon, MD Treatment of latent tuberculosis infection (LTBI) is critical review included English language articles that met the follow- to the control and elimination of tuberculosis disease (TB) in ing criteria: 1) the study design was randomized controlled the United States. In 2011, CDC recommended a short-course trial, quasi-experimental, observational cohort, or other design combination regimen of once-weekly isoniazid and rifapentine with a concurrent comparison group; 2) the target population for 12 weeks (3HP) by directly observed therapy (DOT) for included, but was not restricted to, persons aged ≥12 years, treatment of LTBI, with limitations for use in children aged children aged 2–11 years, or persons with HIV infection; and <12 years and persons with human immunodeficiency virus 3) outcomes reported were prevention of TB disease, treatment (HIV) infection (1). CDC identified the use of 3HP in those completion, adverse events while on 3HP, discontinuation as a populations, as well as self-administration of the 3HP regimen, result of adverse events while on 3HP, or death while on 3HP. as areas to address in updated recommendations. In 2017, a Two reviewers from the CDC Work Group independently CDC Work Group conducted a systematic review and meta- screened citations obtained from the search and retrieved full- analyses of the 3HP regimen using methods adapted from the text articles in the relevant literature to be synthesized. Using a Guide to Community Preventive Services. In total, 19 articles standard data abstraction form, the reviewers abstracted data on representing 15 unique studies were included in the meta- intervention characteristics, outcomes of interest, demograph- analysis, which determined that 3HP is as safe and effective as ics, benefits, harms, considerations for implementation, and other recommended LTBI regimens and achieves substantially evidence gaps. Each study was also assessed for threats to inter- higher treatment completion rates. In July 2017, the Work nal and external validity per Guide to Community Preventive Group presented the meta-analysis findings to a group of TB Services standards (2,3). Any disagreement between reviewers experts, and in December 2017, CDC solicited input from was resolved by consensus of the CDC Work Group members. the Advisory Council for the Elimination of Tuberculosis The CDC Work Group reviewed 292 citations retrieved (ACET) and members of the public for incorporation into from the librarian’s search. Of these, 30 full-text articles were the final recommendations. CDC continues to recommend ordered and screened for inclusion. No eligible studies includ- 3HP for treatment of LTBI in adults and now recommends ing children aged <2 years were identified. In total, 19 articles use of 3HP 1) in persons with LTBI aged 2–17 years; 2) in representing 15 unique studies were included in the meta- persons with LTBI who have HIV infection, including acquired analysis. Findings from the meta-analysis indicated that 3HP immunodeficiency syndrome (AIDS), and are taking antiret- is as safe and effective as other recommended LTBI regimens roviral medications with acceptable drug-drug interactions and achieves significantly higher treatment completion rates. with rifapentine; and 3) by DOT or self-administered therapy Complete results of the systematic review and meta-analysis (SAT) in persons aged ≥2 years. have been published elsewhere (4). Overall, the majority of included studies were of greatest design suitability and good Systematic Review quality of execution, as defined by the Guide to Community Preventive Services (2,3). Issues related to poor reporting of A CDC Work Group including epidemiologists, health appropriate analytic methods and possible selection bias were scientists, physicians from CDC’s Tuberculosis Elimination the most common limitations assigned to the body of evidence. program, and a CDC library specialist, was convened to con- Recently published randomized control trials that were heav- duct the systematic literature review using methods adapted ily weighted in the meta-analyses and drug interaction studies from the Guide to Community Preventive Services (2,3). The (5–9) are summarized as follows: library specialist used a systematic search strategy to identify Study of 3HP in children. A large randomized clinical trial and retrieve intervention studies on the use of 3HP to treat of 3HP administered by DOT, which included children aged LTBI that were published from January 2006 through June 2–17 years, demonstrated that 3HP was as well-tolerated and 2017 and indexed in the MEDLINE, Embase, CINAHL, as effective as 9 months of daily isoniazid (9H) for preventing Cochrane Library, Scopus, and Clinicaltrials.gov databases. To TB (5). The trial also reported that 3HP was safe and had identify missed studies, reference lists from included articles higher treatment completion rates than 9H (5). Data on the were reviewed, and CDC’s TB experts were consulted. This US Department of Health and Human Services/Centers for Disease Control and Prevention MMWR / June 29, 2018 / Vol. 67 / No. 25 723 Morbidity and Mortality Weekly Report safety and pharmacokinetics of rifapentine in children aged rifapentine) and antiretroviral agents, is available in the U.S. <2 years are not available. Department of Health and Human Services Guidelines for Studies of 3HP in persons with HIV infection, including the Use of Antiretroviral Agents in HIV-1-Infected Adults and AIDS. In 2011, CDC recommended the 3HP regimen for Adolescents. These frequently updated guidelines include a treatment of LTBI in persons with HIV infection, including section addressing management of LTBI in persons with HIV AIDS, who are otherwise healthy and who are not taking coinfection and tables with information on drug interactions.* antiretroviral medications (1). Since that time, additional data Use of concomitant LTBI treatment and antiretroviral agents confirm not only the effectiveness of 3HP in persons with HIV should be guided by clinicians experienced in the management infection who are not taking antiretroviral therapy, but also of both conditions. demonstrate the absence of clinically significant drug interac- In 2011, CDC recommended use of the 3HP regimen by tions between once-weekly rifapentine and either efavirenz or DOT (1). Treatment completion rates are highest when the raltegravir in persons with HIV infection who are treated with regimen is administered by DOT (4). However, the burden those antiretroviral medications (4,6–8). and expense of DOT is greater than that for SAT (9). During Study of self-administered therapy. A randomized clinical the expert consultation and again during review by ACET, trial demonstrating noninferior treatment completion and some subject matter experts strongly recommended permit- safety of 3HP-SAT compared with 3HP-DOT in persons aged ting use of SAT, when combined with clinical monitoring, in ≥18 years in the United States provides the primary evidence children aged ≥2 years. Based on this expert opinion, ACET on 3HP administration by SAT (9). The 3HP-SAT regimen formally recommended expansion of the option of parentally has not been studied in randomized controlled trials in persons administered SAT to children. Some experts still prefer DOT aged <18 years. for treating LTBI in children aged 2–5 years, in whom risk for TB progression and severe disease is higher than that in Expert Consultation older children and adults. Health care providers should make joint decisions about SAT with each individual patient (and In July 2017, CDC met with nine non-CDC subject matter parent or legal guardian), considering program resources and experts in TB and LTBI diagnosis, treatment, prevention, sur- the patient’s age, medical history, social circumstances, and veillance, epidemiology, clinical research, pulmonology, pediat- risk factors for progression to severe TB disease. Subject mat- rics, HIV/AIDS, public health programs, and patient advocacy. ter experts stressed the importance of educating providers and CDC presented the systematic review results and proposed patients about 3HP. recommendations to the experts, who provided 1) individual perspectives on the review; 2) experience with implementation Recommendations of the 3HP regimen in various settings and populations; and 3) individual viewpoints on the proposed updates. Subject Based on evidence on effectiveness, safety, and treatment matter experts from programs prescribing 3HP described completion rates from the systematic review, and after consid- benefits of this regimen, including increased acceptance and eration of viewpoints from TB subject matter experts and input completion of treatment. Some experts reported that several from ACET and the public, CDC continues to recommend health departments are currently using 3HP, with high treat- 3HP for treatment of LTBI in adults and now recommends ment completion, in children as young as age 2 years. Some use of 3HP 1) in persons with LTBI aged 2–17 years; 2) in noted that the 2011 recommendation to administer 3HP by persons with LTBI who have HIV infection, including AIDS, DOT limits use of the regimen. In December 2017, CDC and are taking antiretroviral medications with acceptable drug- solicited input from ACET and members of the public for drug interactions with rifapentine; and 3) by DOT or SAT in incorporation into the final recommendations. persons aged ≥2 years. With regard to pediatric use, the 2011 recommendations The health care provider should choose the mode of admin- had included limited use of the 3HP regimen for treatment istration (DOT versus SAT) based on local practice, individual of LTBI in children aged <12 years (1). New data on efficacy patient attributes and preferences, and other considerations, and safety of 3HP in children were determined sufficient to including risk for progression to severe forms of TB disease. recommend the 3HP regimen for treatment of LTBI in chil- Use of concomitant LTBI treatment and antiretroviral agents dren aged ≥2 years (4). should be guided by clinicians experienced in the management Concerning patients with HIV infection, information of both conditions (Box 1). about interactions between specific antimycobacterial * https://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv/367/overview. agents, including rifamycins (e.g., rifampin, rifabutin, and 724 MMWR / June 29, 2018 / Vol. 67 / No. 25 US Department of Health and Human Services/Centers for Disease Control and Prevention Morbidity and Mortality Weekly Report BOX 1. Updated recommendations for once-weekly isoniazid-rifapentine BOX 2. Guidance to health care providers during treatment of latent for 12 weeks (3HP) for the treatment of latent tuberculosis infection tuberculosis infection (LTBI) with a combination regimen of isoniazid and rifapentine in 12 once-weekly doses (3HP) CDC continues to recommend use of the short-course • Evaluate all patients for active tuberculosis disease both combination regimen of once-weekly isoniazid-rifapentine before and during treatment of LTBI. for 12 weeks (3HP) for treatment of latent tuberculosis • Inform the patient or parents or legal guardians about infection (LTBI) in adults. With regard to age limits, HIV possible adverse effects and instruct them to seek infection, and administration of the treatment, CDC now medical attention when symptoms of possible adverse also recommends the following: reaction first appear; particularly drug hypersensitivity • use of 3HP in persons aged 2–17 years; reactions, rash, hypotension, or thrombocytopenia. • use of 3HP in persons with LTBI who are living with • Conduct monthly evaluations to assess treatment human immunodeficiency virus (HIV) infection, adherence and adverse effects, with repeated patient including acquired immunodeficiency syndrome (AIDS) education regarding adverse effects at each visit. and taking antiretroviral medications with acceptable • Order baseline hepatic chemistry blood tests (at least drug-drug interactions with rifapentine*; and aspartate aminotransferase [AST]) for patients with the • use of 3HP by directly observed therapy (DOT) or following specific conditions: human self-administered therapy (SAT) in persons aged immunodeficiency virus infection, liver disorders, ≥2 years; the health care provider should choose the postpartum period (≤3 months after delivery), regular mode of administration (DOT versus SAT) based on alcohol use, injection drug use, or use of medications local practice, individual patient attributes and with known possible interactions. preferences, and other considerations, including risk • Conduct blood tests at subsequent clinical encounters for progression to severe forms of tuberculosis disease. for patients whose baseline testing is abnormal and for * https://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv/367/ others at risk for liver disease. Discontinue 3HP if a overview. serum AST concentration is ≥5 times the upper limit of normal in the absence of symptoms or ≥3 times the Patient monitoring and adverse events. Hepatic enzymes upper limit of normal in the presence of symptoms. and other blood tests should be performed for certain patients • In case of a possible severe adverse reaction, discontinue before initiation of 3HP therapy (Box 2). Approximately 4% 3HP and provide supportive medical care. of all patients using 3HP experience flu-like or other systemic Conservative management and continuation of 3HP drug reactions, with fever, headache, dizziness, nausea, muscle under observation can be considered in the presence of and bone pain, rash, itching, red eyes, or other symptoms mild to moderate adverse events as determined by (4,10). Approximately 5% of persons discontinue 3HP because health care provider. of adverse events, including systemic drug reactions (4,10); these reactions typically occur after the first 3–4 doses, and medications (e.g., methadone or warfarin). Rifapentine can begin approximately 4 hours after ingestion of medication (10). reduce the effectiveness of hormonal contraceptives; therefore, Hypotension and syncope have been reported rarely (two cases women who use hormonal birth control should be advised to per 1,000 persons treated) (4,10). If symptoms suggestive of a add, or switch to, a barrier method. Women should be advised systemic drug reaction occur, patients should stop 3HP while to inform their health care provider if they decide to try to the cause is determined. Symptoms usually resolve without become pregnant or become pregnant during 3HP treatment. treatment within 24 hours. Neutropenia and elevation of liver Because altered dosing might reduce effectiveness or safety, enzymes occur uncommonly (4,10). CDC recommends that patients on 3HP SAT should be encouraged to record medica- health care providers educate patients to report adverse events. tion intake and report deviations from the prescribed regimen. Patient use of symptom checklists might facilitate timely rec- Persons on 3HP regimens should be evaluated monthly (in ognition and reporting. person or by telephone) to assess adherence and adverse effects. Rifapentine is a rifamycin compound; like rifampin, it Additional studies are needed to understand the pharmaco- induces metabolism of many medications. CDC recommends kinetics, safety, and tolerance of 3HP in children aged <2 years; monitoring of patients when 3HP is prescribed with interacting adherence and safety of 3HP-SAT in persons aged <18 years; and safety of 3HP during pregnancy (4). Examples of patient’s medication intake log and symptoms checklists are available at https://www.cdc.gov/tb/publications/pamphlets/12-doseregimen.htm. US Department of Health and Human Services/Centers for Disease Control and Prevention MMWR / June 29, 2018 / Vol. 67 / No. 25 725 Morbidity and Mortality Weekly Report 3. Zaza S, Wright-De Agüero LK, Briss PA, et al.; Task Force on Community Any LTBI treatment–associated adverse effect leading to Preventive Services. Data collection instrument and procedure for systematic hospital admission or death should be reported by health reviews in the Guide to Community Preventive Services. Am J Prev Med care providers to local or state health departments for inclu- 2000;18(Suppl):44–74. https://doi.org/10.1016/S0749-3797(99)00122-1 sion in the National Surveillance for Severe Adverse Events 4. Njie GJ, Morris SB, Woodruff RY, Moro RN, Vernon AA, Borisov AS. Isoniazid-rifapentine for latent tuberculosis infection: a systematic review Associated with Treatment for LTBI (e-mail: ltbidrugevents@ and meta-analysis. Am J Prev Med 2018. Epub June 11, 2018. https:// cdc.gov). Serious drug side effects, product quality problems, doi.org/10.1016/j.amepre.2018.04.030 and therapeutic failures should be reported to the Food and 5. Villarino ME, Scott NA, Weis SE, et al.; International Maternal Pediatric and Adolescents AIDS Clinical Trials Group; Tuberculosis Trials Drug Administration’s MedWatch program (https://www. Consortium. Treatment for preventing tuberculosis in children and fda.gov/Safety/MedWatch/HowToReport/default.htm) or by adolescents: a randomized clinical trial of a 3-month, 12-dose regimen telephoning 1-800-FDA-1088. of a combination of rifapentine and isoniazid. JAMA Pediatr 2015;169:247–55. https://doi.org/10.1001/jamapediatrics.2014.3158 Additional information regarding 3HP is available at 6. Sterling TR, Scott NA, Miro JM, et al.; Tuberculosis Trials Consortium; https://www.cdc.gov/tb/publications/ltbi/ltbiresources. AIDS Clinical Trials Group for the PREVENT TB Trial. Three months htm. Questions also can be directed to CDC’s Division of of weekly rifapentine and isoniazid for treatment of Mycobacterium tuberculosis infection in HIV-coinfected persons. AIDS 2016;30:1607–15. Tuberculosis Elimination by e-mail (cdcinfo@cdc.gov) or by https://doi.org/10.1097/QAD.0000000000001098 telephoning 800-CDC-INFO (800-232-4636). 7. Weiner M, Egelund EF, Engle M, et al. Pharmacokinetic interaction of rifapentine and raltegravir in healthy volunteers. J Antimicrob Conflict of Interest Chemother 2014;69:1079–85. https://doi.org/10.1093/jac/dkt483 8. Podany AT, Bao Y, Swindells S, et al.; AIDS Clinical Trials Group A5279 No conflicts of interest were reported. Study Team. Efavirenz pharmacokinetics and pharmacodynamics in HIV- Division of Tuberculosis Elimination, National Center for HIV/AIDS, Viral infected persons receiving rifapentine and isoniazid for tuberculosis prevention. Hepatitis, STD, and TB Prevention, CDC. Clin Infect Dis 2015;61:1322–7. https://doi.org/10.1093/cid/civ464 9. Belknap R, Holland D, Feng PJ, et al.; TB Trials Consortium iAdhere Corresponding author: Andrey S. Borisov, aborisov@cdc.gov, 404-639-8056. Study Team. Self-administered versus directly observed once-weekly isoniazid and rifapentine treatment of latent tuberculosis infection: a References randomized trial. Ann Intern Med 2017;167:689–97. 1. CDC. Recommendations for use of an isoniazid-rifapentine regimen with 10. Sterling TR, Moro RN, Borisov AS, et al.; Tuberculosis Trials direct observation to treat latent Mycobacterium tuberculosis infection. Consortium. Flu-like and other systemic drug reactions among persons MMWR Morb Mortal Wkly Rep 2011;60:1650–3. receiving weekly rifapentine plus isoniazid or daily isoniazid for treatment 2. Briss PA, Zaza S, Pappaioanou M, et al.; The Task Force on Community of latent tuberculosis infection in the PREVENT Tuberculosis study. Preventive Services. Developing an evidence-based Guide to Community Clin Infect Dis 2015;61:527–35. https://doi.org/10.1093/cid/civ323 Preventive Services—methods. Am J Prev Med 2000;18(Suppl):35–43. https://doi.org/10.1016/S0749-3797(99)00119-1 726 MMWR / June 29, 2018 / Vol. 67 / No. 25 US Department of Health and Human Services/Centers for Disease Control and Prevention http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Morbidity and Mortality Weekly Report Pubmed Central

Update of Recommendations for Use of Once-Weekly Isoniazid-Rifapentine Regimen to Treat Latent Mycobacterium tuberculosis Infection

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Pubmed Central
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0149-2195
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1545-861X
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10.15585/mmwr.mm6725a5
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Abstract

Morbidity and Mortality Weekly Report Update of Recommendations for Use of Once-Weekly Isoniazid-Rifapentine Regimen to Treat Latent Mycobacterium tuberculosis Infection 1 1 1 1 1 1 Andrey S. Borisov, MD ; Sapna Bamrah Morris, MD ; Gibril J. Njie, MPH ; Carla A. Winston, PhD ; Deron Burton, MD ; Stefan Goldberg, MD ; 1 1 1 1 Rachel Yelk Woodruff, MPH ; Leeanna Allen, MPH ; Philip LoBue, MD ; Andrew Vernon, MD Treatment of latent tuberculosis infection (LTBI) is critical review included English language articles that met the follow- to the control and elimination of tuberculosis disease (TB) in ing criteria: 1) the study design was randomized controlled the United States. In 2011, CDC recommended a short-course trial, quasi-experimental, observational cohort, or other design combination regimen of once-weekly isoniazid and rifapentine with a concurrent comparison group; 2) the target population for 12 weeks (3HP) by directly observed therapy (DOT) for included, but was not restricted to, persons aged ≥12 years, treatment of LTBI, with limitations for use in children aged children aged 2–11 years, or persons with HIV infection; and <12 years and persons with human immunodeficiency virus 3) outcomes reported were prevention of TB disease, treatment (HIV) infection (1). CDC identified the use of 3HP in those completion, adverse events while on 3HP, discontinuation as a populations, as well as self-administration of the 3HP regimen, result of adverse events while on 3HP, or death while on 3HP. as areas to address in updated recommendations. In 2017, a Two reviewers from the CDC Work Group independently CDC Work Group conducted a systematic review and meta- screened citations obtained from the search and retrieved full- analyses of the 3HP regimen using methods adapted from the text articles in the relevant literature to be synthesized. Using a Guide to Community Preventive Services. In total, 19 articles standard data abstraction form, the reviewers abstracted data on representing 15 unique studies were included in the meta- intervention characteristics, outcomes of interest, demograph- analysis, which determined that 3HP is as safe and effective as ics, benefits, harms, considerations for implementation, and other recommended LTBI regimens and achieves substantially evidence gaps. Each study was also assessed for threats to inter- higher treatment completion rates. In July 2017, the Work nal and external validity per Guide to Community Preventive Group presented the meta-analysis findings to a group of TB Services standards (2,3). Any disagreement between reviewers experts, and in December 2017, CDC solicited input from was resolved by consensus of the CDC Work Group members. the Advisory Council for the Elimination of Tuberculosis The CDC Work Group reviewed 292 citations retrieved (ACET) and members of the public for incorporation into from the librarian’s search. Of these, 30 full-text articles were the final recommendations. CDC continues to recommend ordered and screened for inclusion. No eligible studies includ- 3HP for treatment of LTBI in adults and now recommends ing children aged <2 years were identified. In total, 19 articles use of 3HP 1) in persons with LTBI aged 2–17 years; 2) in representing 15 unique studies were included in the meta- persons with LTBI who have HIV infection, including acquired analysis. Findings from the meta-analysis indicated that 3HP immunodeficiency syndrome (AIDS), and are taking antiret- is as safe and effective as other recommended LTBI regimens roviral medications with acceptable drug-drug interactions and achieves significantly higher treatment completion rates. with rifapentine; and 3) by DOT or self-administered therapy Complete results of the systematic review and meta-analysis (SAT) in persons aged ≥2 years. have been published elsewhere (4). Overall, the majority of included studies were of greatest design suitability and good Systematic Review quality of execution, as defined by the Guide to Community Preventive Services (2,3). Issues related to poor reporting of A CDC Work Group including epidemiologists, health appropriate analytic methods and possible selection bias were scientists, physicians from CDC’s Tuberculosis Elimination the most common limitations assigned to the body of evidence. program, and a CDC library specialist, was convened to con- Recently published randomized control trials that were heav- duct the systematic literature review using methods adapted ily weighted in the meta-analyses and drug interaction studies from the Guide to Community Preventive Services (2,3). The (5–9) are summarized as follows: library specialist used a systematic search strategy to identify Study of 3HP in children. A large randomized clinical trial and retrieve intervention studies on the use of 3HP to treat of 3HP administered by DOT, which included children aged LTBI that were published from January 2006 through June 2–17 years, demonstrated that 3HP was as well-tolerated and 2017 and indexed in the MEDLINE, Embase, CINAHL, as effective as 9 months of daily isoniazid (9H) for preventing Cochrane Library, Scopus, and Clinicaltrials.gov databases. To TB (5). The trial also reported that 3HP was safe and had identify missed studies, reference lists from included articles higher treatment completion rates than 9H (5). Data on the were reviewed, and CDC’s TB experts were consulted. This US Department of Health and Human Services/Centers for Disease Control and Prevention MMWR / June 29, 2018 / Vol. 67 / No. 25 723 Morbidity and Mortality Weekly Report safety and pharmacokinetics of rifapentine in children aged rifapentine) and antiretroviral agents, is available in the U.S. <2 years are not available. Department of Health and Human Services Guidelines for Studies of 3HP in persons with HIV infection, including the Use of Antiretroviral Agents in HIV-1-Infected Adults and AIDS. In 2011, CDC recommended the 3HP regimen for Adolescents. These frequently updated guidelines include a treatment of LTBI in persons with HIV infection, including section addressing management of LTBI in persons with HIV AIDS, who are otherwise healthy and who are not taking coinfection and tables with information on drug interactions.* antiretroviral medications (1). Since that time, additional data Use of concomitant LTBI treatment and antiretroviral agents confirm not only the effectiveness of 3HP in persons with HIV should be guided by clinicians experienced in the management infection who are not taking antiretroviral therapy, but also of both conditions. demonstrate the absence of clinically significant drug interac- In 2011, CDC recommended use of the 3HP regimen by tions between once-weekly rifapentine and either efavirenz or DOT (1). Treatment completion rates are highest when the raltegravir in persons with HIV infection who are treated with regimen is administered by DOT (4). However, the burden those antiretroviral medications (4,6–8). and expense of DOT is greater than that for SAT (9). During Study of self-administered therapy. A randomized clinical the expert consultation and again during review by ACET, trial demonstrating noninferior treatment completion and some subject matter experts strongly recommended permit- safety of 3HP-SAT compared with 3HP-DOT in persons aged ting use of SAT, when combined with clinical monitoring, in ≥18 years in the United States provides the primary evidence children aged ≥2 years. Based on this expert opinion, ACET on 3HP administration by SAT (9). The 3HP-SAT regimen formally recommended expansion of the option of parentally has not been studied in randomized controlled trials in persons administered SAT to children. Some experts still prefer DOT aged <18 years. for treating LTBI in children aged 2–5 years, in whom risk for TB progression and severe disease is higher than that in Expert Consultation older children and adults. Health care providers should make joint decisions about SAT with each individual patient (and In July 2017, CDC met with nine non-CDC subject matter parent or legal guardian), considering program resources and experts in TB and LTBI diagnosis, treatment, prevention, sur- the patient’s age, medical history, social circumstances, and veillance, epidemiology, clinical research, pulmonology, pediat- risk factors for progression to severe TB disease. Subject mat- rics, HIV/AIDS, public health programs, and patient advocacy. ter experts stressed the importance of educating providers and CDC presented the systematic review results and proposed patients about 3HP. recommendations to the experts, who provided 1) individual perspectives on the review; 2) experience with implementation Recommendations of the 3HP regimen in various settings and populations; and 3) individual viewpoints on the proposed updates. Subject Based on evidence on effectiveness, safety, and treatment matter experts from programs prescribing 3HP described completion rates from the systematic review, and after consid- benefits of this regimen, including increased acceptance and eration of viewpoints from TB subject matter experts and input completion of treatment. Some experts reported that several from ACET and the public, CDC continues to recommend health departments are currently using 3HP, with high treat- 3HP for treatment of LTBI in adults and now recommends ment completion, in children as young as age 2 years. Some use of 3HP 1) in persons with LTBI aged 2–17 years; 2) in noted that the 2011 recommendation to administer 3HP by persons with LTBI who have HIV infection, including AIDS, DOT limits use of the regimen. In December 2017, CDC and are taking antiretroviral medications with acceptable drug- solicited input from ACET and members of the public for drug interactions with rifapentine; and 3) by DOT or SAT in incorporation into the final recommendations. persons aged ≥2 years. With regard to pediatric use, the 2011 recommendations The health care provider should choose the mode of admin- had included limited use of the 3HP regimen for treatment istration (DOT versus SAT) based on local practice, individual of LTBI in children aged <12 years (1). New data on efficacy patient attributes and preferences, and other considerations, and safety of 3HP in children were determined sufficient to including risk for progression to severe forms of TB disease. recommend the 3HP regimen for treatment of LTBI in chil- Use of concomitant LTBI treatment and antiretroviral agents dren aged ≥2 years (4). should be guided by clinicians experienced in the management Concerning patients with HIV infection, information of both conditions (Box 1). about interactions between specific antimycobacterial * https://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv/367/overview. agents, including rifamycins (e.g., rifampin, rifabutin, and 724 MMWR / June 29, 2018 / Vol. 67 / No. 25 US Department of Health and Human Services/Centers for Disease Control and Prevention Morbidity and Mortality Weekly Report BOX 1. Updated recommendations for once-weekly isoniazid-rifapentine BOX 2. Guidance to health care providers during treatment of latent for 12 weeks (3HP) for the treatment of latent tuberculosis infection tuberculosis infection (LTBI) with a combination regimen of isoniazid and rifapentine in 12 once-weekly doses (3HP) CDC continues to recommend use of the short-course • Evaluate all patients for active tuberculosis disease both combination regimen of once-weekly isoniazid-rifapentine before and during treatment of LTBI. for 12 weeks (3HP) for treatment of latent tuberculosis • Inform the patient or parents or legal guardians about infection (LTBI) in adults. With regard to age limits, HIV possible adverse effects and instruct them to seek infection, and administration of the treatment, CDC now medical attention when symptoms of possible adverse also recommends the following: reaction first appear; particularly drug hypersensitivity • use of 3HP in persons aged 2–17 years; reactions, rash, hypotension, or thrombocytopenia. • use of 3HP in persons with LTBI who are living with • Conduct monthly evaluations to assess treatment human immunodeficiency virus (HIV) infection, adherence and adverse effects, with repeated patient including acquired immunodeficiency syndrome (AIDS) education regarding adverse effects at each visit. and taking antiretroviral medications with acceptable • Order baseline hepatic chemistry blood tests (at least drug-drug interactions with rifapentine*; and aspartate aminotransferase [AST]) for patients with the • use of 3HP by directly observed therapy (DOT) or following specific conditions: human self-administered therapy (SAT) in persons aged immunodeficiency virus infection, liver disorders, ≥2 years; the health care provider should choose the postpartum period (≤3 months after delivery), regular mode of administration (DOT versus SAT) based on alcohol use, injection drug use, or use of medications local practice, individual patient attributes and with known possible interactions. preferences, and other considerations, including risk • Conduct blood tests at subsequent clinical encounters for progression to severe forms of tuberculosis disease. for patients whose baseline testing is abnormal and for * https://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv/367/ others at risk for liver disease. Discontinue 3HP if a overview. serum AST concentration is ≥5 times the upper limit of normal in the absence of symptoms or ≥3 times the Patient monitoring and adverse events. Hepatic enzymes upper limit of normal in the presence of symptoms. and other blood tests should be performed for certain patients • In case of a possible severe adverse reaction, discontinue before initiation of 3HP therapy (Box 2). Approximately 4% 3HP and provide supportive medical care. of all patients using 3HP experience flu-like or other systemic Conservative management and continuation of 3HP drug reactions, with fever, headache, dizziness, nausea, muscle under observation can be considered in the presence of and bone pain, rash, itching, red eyes, or other symptoms mild to moderate adverse events as determined by (4,10). Approximately 5% of persons discontinue 3HP because health care provider. of adverse events, including systemic drug reactions (4,10); these reactions typically occur after the first 3–4 doses, and medications (e.g., methadone or warfarin). Rifapentine can begin approximately 4 hours after ingestion of medication (10). reduce the effectiveness of hormonal contraceptives; therefore, Hypotension and syncope have been reported rarely (two cases women who use hormonal birth control should be advised to per 1,000 persons treated) (4,10). If symptoms suggestive of a add, or switch to, a barrier method. Women should be advised systemic drug reaction occur, patients should stop 3HP while to inform their health care provider if they decide to try to the cause is determined. Symptoms usually resolve without become pregnant or become pregnant during 3HP treatment. treatment within 24 hours. Neutropenia and elevation of liver Because altered dosing might reduce effectiveness or safety, enzymes occur uncommonly (4,10). CDC recommends that patients on 3HP SAT should be encouraged to record medica- health care providers educate patients to report adverse events. tion intake and report deviations from the prescribed regimen. Patient use of symptom checklists might facilitate timely rec- Persons on 3HP regimens should be evaluated monthly (in ognition and reporting. person or by telephone) to assess adherence and adverse effects. Rifapentine is a rifamycin compound; like rifampin, it Additional studies are needed to understand the pharmaco- induces metabolism of many medications. CDC recommends kinetics, safety, and tolerance of 3HP in children aged <2 years; monitoring of patients when 3HP is prescribed with interacting adherence and safety of 3HP-SAT in persons aged <18 years; and safety of 3HP during pregnancy (4). Examples of patient’s medication intake log and symptoms checklists are available at https://www.cdc.gov/tb/publications/pamphlets/12-doseregimen.htm. US Department of Health and Human Services/Centers for Disease Control and Prevention MMWR / June 29, 2018 / Vol. 67 / No. 25 725 Morbidity and Mortality Weekly Report 3. Zaza S, Wright-De Agüero LK, Briss PA, et al.; Task Force on Community Any LTBI treatment–associated adverse effect leading to Preventive Services. Data collection instrument and procedure for systematic hospital admission or death should be reported by health reviews in the Guide to Community Preventive Services. Am J Prev Med care providers to local or state health departments for inclu- 2000;18(Suppl):44–74. https://doi.org/10.1016/S0749-3797(99)00122-1 sion in the National Surveillance for Severe Adverse Events 4. Njie GJ, Morris SB, Woodruff RY, Moro RN, Vernon AA, Borisov AS. Isoniazid-rifapentine for latent tuberculosis infection: a systematic review Associated with Treatment for LTBI (e-mail: ltbidrugevents@ and meta-analysis. Am J Prev Med 2018. Epub June 11, 2018. https:// cdc.gov). Serious drug side effects, product quality problems, doi.org/10.1016/j.amepre.2018.04.030 and therapeutic failures should be reported to the Food and 5. Villarino ME, Scott NA, Weis SE, et al.; International Maternal Pediatric and Adolescents AIDS Clinical Trials Group; Tuberculosis Trials Drug Administration’s MedWatch program (https://www. Consortium. Treatment for preventing tuberculosis in children and fda.gov/Safety/MedWatch/HowToReport/default.htm) or by adolescents: a randomized clinical trial of a 3-month, 12-dose regimen telephoning 1-800-FDA-1088. of a combination of rifapentine and isoniazid. JAMA Pediatr 2015;169:247–55. https://doi.org/10.1001/jamapediatrics.2014.3158 Additional information regarding 3HP is available at 6. Sterling TR, Scott NA, Miro JM, et al.; Tuberculosis Trials Consortium; https://www.cdc.gov/tb/publications/ltbi/ltbiresources. AIDS Clinical Trials Group for the PREVENT TB Trial. Three months htm. Questions also can be directed to CDC’s Division of of weekly rifapentine and isoniazid for treatment of Mycobacterium tuberculosis infection in HIV-coinfected persons. AIDS 2016;30:1607–15. Tuberculosis Elimination by e-mail (cdcinfo@cdc.gov) or by https://doi.org/10.1097/QAD.0000000000001098 telephoning 800-CDC-INFO (800-232-4636). 7. Weiner M, Egelund EF, Engle M, et al. Pharmacokinetic interaction of rifapentine and raltegravir in healthy volunteers. J Antimicrob Conflict of Interest Chemother 2014;69:1079–85. https://doi.org/10.1093/jac/dkt483 8. Podany AT, Bao Y, Swindells S, et al.; AIDS Clinical Trials Group A5279 No conflicts of interest were reported. Study Team. Efavirenz pharmacokinetics and pharmacodynamics in HIV- Division of Tuberculosis Elimination, National Center for HIV/AIDS, Viral infected persons receiving rifapentine and isoniazid for tuberculosis prevention. Hepatitis, STD, and TB Prevention, CDC. Clin Infect Dis 2015;61:1322–7. https://doi.org/10.1093/cid/civ464 9. Belknap R, Holland D, Feng PJ, et al.; TB Trials Consortium iAdhere Corresponding author: Andrey S. Borisov, aborisov@cdc.gov, 404-639-8056. Study Team. Self-administered versus directly observed once-weekly isoniazid and rifapentine treatment of latent tuberculosis infection: a References randomized trial. Ann Intern Med 2017;167:689–97. 1. CDC. Recommendations for use of an isoniazid-rifapentine regimen with 10. Sterling TR, Moro RN, Borisov AS, et al.; Tuberculosis Trials direct observation to treat latent Mycobacterium tuberculosis infection. Consortium. Flu-like and other systemic drug reactions among persons MMWR Morb Mortal Wkly Rep 2011;60:1650–3. receiving weekly rifapentine plus isoniazid or daily isoniazid for treatment 2. Briss PA, Zaza S, Pappaioanou M, et al.; The Task Force on Community of latent tuberculosis infection in the PREVENT Tuberculosis study. Preventive Services. Developing an evidence-based Guide to Community Clin Infect Dis 2015;61:527–35. https://doi.org/10.1093/cid/civ323 Preventive Services—methods. Am J Prev Med 2000;18(Suppl):35–43. https://doi.org/10.1016/S0749-3797(99)00119-1 726 MMWR / June 29, 2018 / Vol. 67 / No. 25 US Department of Health and Human Services/Centers for Disease Control and Prevention

Journal

Morbidity and Mortality Weekly ReportPubmed Central

Published: Jun 29, 2018

References