12 Weeks Isoniazid & Rifapentine (3HP) Benefits, Challenges & Additional Opportunities

Transcription

1 12 Weeks Isoniazid & Rifapentine (3HP) Benefits, Challenges & Additional Opportunities John W. Wilson, MD FIDSA Associate Professor of Medicine Division of Infectious Diseases Mayo Clinic, Rochester MN Tuberculosis Summit, Verona, Wisconsin; April MFMER slide-1

2 Disclosures None 2013 MFMER slide-2

3 Objectives Review the cost considerations for 3HP LTBI treatment. Determine appropriateness of 3HP therapy. Examine national and regional studies of 3HP use MFMER slide-3

4 Treatment Regimens for Latent TB Infection Drug(s) Duration Interval Minimum Doses Isoniazid 9 months Daily 270 Twice weekly 76 6 months Daily 180 Twice weekly 52 Isoniazid & Rifapentine 3 months Once weekly 12 Rifampin 4 months Daily 120 Note: Rifampin (RIF) and Pyrazinamide (PZA) should not be offered to persons with LTBI. RIF and PZA should continue to be administered in multidrug regimens for the treatment of persons with TB disease.

5 3HP considerations The shortened 3HP appears to be an attractive alternative to standard LTBI treatment with 9H from public health and societal perspectives but need to consider: Drug costs The cost of providing DOT Public health TB program feasibility Patient acceptance with swallowing pills and compliance with DOT Perceived risk of progression to TB disease The length of the window of opportunity for intervention e.g. upcoming travel, etc MFMER slide-5

6 Cost considerations of 3HP vs. 9H Cost of a complete course of treatment for latent tuberculous infection with either 9H or 3HP administered by DOT from a health care worker Patients receiving 9H have an initial clinic visit and eight later clinic visits; those receiving 3HP have an initial clinic visit, two later clinic visits and 12 visits by a health care worker for DOT. Patient costs include out-ofpocket expenses and lost productivity; other costs are costs to the health system. Costs are in 2010 US dollars. 3HP = 3 months of weekly isoniazid plus rifapentine; 9H = 9 months of daily, self administered isoniazid; DOT = directly observed treatment. INT J TUBERC LUNG DIS 17(12): MFMER slide-6

7 Cost considerations of 3HP vs. 9H Total (avg.) costs per person treated for LTBI over a 20-year period for individuals treated for LTBI with either 9H or 3HP administered by DOT from a health care worker Costs include those of LTBI treatment and the eventual development of tuberculosis disease in some individuals. Patient costs include out-of-pocket expenses and lost productivity; other costs are costs to the health system. Based on simulated individuals per regimen with a 20-year analytic horizon; costs are reported in 2010 US dollars and have been discounted at an annual rate of 3%. INT J TUBERC LUNG DIS 17(12): MFMER slide-7

8 Important considerations for using 3HP LTBI treatment Must be given via Directly Observed Therapy Local health department needs to incorporate DOT within their available resources Patients need to understand quantity of pills to consume at each weekly DOT session Example: patients > 50 kg: INH 900 mg (3 x 300 mg tabs) RPT 900 mg (6 x 150 mg tabs) = 9 pills (at one time) 2013 MFMER slide-8

9 Patient tolerability in swallowing pills Swallowing pills in single session All together can be rough 1, 2, 3 pills at a time Patients needs to take their time Consider using large cup/glass of water to assist patient in swallowing pills And stay well hydrated 2013 MFMER slide-9

10 Patients need to be educated about requirements with the 3HP program: Pt must be available for weekly scheduled DOT Pt must be available for monthly physical examination Pt will be taking up to 10 tablets weekly Pt must commit to 12 weeks of treatment If these cannot reasonably be assured, another LTBI treatment regimen should be used MFMER slide-10

11 Important points about 3HP 3HP is an LTBI treatment option for otherwise healthy pts 12 yo who have at least one predictive risk factor for developing active TB disease including: A. Recent exposure to contagious TB B. Conversion from negative to positive tuberculin skin test (TST) or Interferon Gamma Release Assay (IGRA) within previous 2 years C. Radiographic findings of inactive, healed pulmonary TB D. HIV/AIDS but not taking antiretroviral medications E. Medical or social circumstances that make adherence and completion of longer regimens unlikely 2013 MFMER slide-11

12 Important points about 3HP 3HP NOT recommended for: A. Children younger than 12 years of age B. Patients with HIV/AIDS who are taking antiretroviral treatment C. Patients with presumed INH or rifampin-resistant LTBI D. Pregnant women or women expecting to become pregnant during treatment Preferred LTBI regimen for children 2-11 yo is INH x 9 mo However, INH-RPT can be considered in this group on a case-bycase basis 3HP not recommended in pts under 2 yo 2013 MFMER slide-12

13 Important points about 3HP Doses should ideally be spaced 7 days apart At a minimum, 72 hours must elapse between doses. The minimum amount of time required for the regimen is 12 weeks and the maximum is 16 weeks INH-RPT cannot be administered in less than 12 weeks Missed doses or altered dosing intervals or amounts could jeopardize efficacy or safety of this regimen 2013 MFMER slide-13

14 Clinical monitoring with 3HP During weekly DOT, assess for adverse effects, and for symptoms of active TB disease e.g.: N/V, abdomen pain, skin rash, weakness, dizziness, F/C, sweats, change in appetite, etc. If (+) adverse sx s - hold 3HP and evaluate for potential causes Monthly physical exam to assess for the presence of jaundice, liver tenderness, and rash 2013 MFMER slide-14

15 Obtain a list of the patient s current medications and consider potential drug interactions with 3HP Some interactions to note: A. INH increases blood levels of phenytoin (Dilantin) and disulfiram (Antabuse) B. RPT decreases blood levels of many drugs including oral contraceptives, Coumadin, sulfoureas, methadone, etc. C. RPT is contraindicated in HIV (+) pts taking: Protease inhibitors (PIs) Most nonnucleoside reverse transcriptase inhibitors (NNRTIs) 2013 MFMER slide-15

16 Determining Appropriateness for 3HP usage Minn. Dept. Health 2-step approach Identifying the higher risk pts MFMER slide-16

17 Determining Appropriateness for 3HP usage MDH 2-step approach Ensuring Patient Understanding / Agreement II MFMER slide-17

18 2013 MFMER slide-18

19 3HP vs. 9 months INH Outcome Treatment completion Permanent drug d/cany reason Permanent drug d/cdue to an adverse event 9H 3HP P-value N=3,745 N=3,986 2,585 (69.0%) 3,362 (82.0%) < ,160 (31.0%) 624 (18.0%) < (3.6%) 188 (4.7%) Death 39 (1.0%) 31 (0.8%) 0.22 N Engl J Med 2011; 365: MFMER slide-19

20 INH-RPT INH Administration Directly-observed therapy Self-administered therapy Frequency Weekly Daily Duration 12 weeks 9 months Effectiveness* 1.9 per 1, per 1,000 Completion rate** 82.1% 69.0% Hepatotoxicity** 0.4% 2.7% *non-inferior ** statistically significant Sterling, N Engl J Med, MFMER slide-20

21 Clin Inf Dis 2016;62(1) MFMER slide-21

22 NYC 3HP findings: 302 pts started on 3HP 40 pts (13%) experienced adverse effect 65 % pts on 3HP completed treatment Less than the 82% from PREVENT TB study (NEJM 2011) however: Reflected diverse NYC practice outside of controlled clinical trial settings Still represents a significant increase in LTBI completion compared with Historical estimates (34%) = double rates Patients receiving other LTBI treatments (46%) Treatment completion in 2 NYC health clinics increased Clin Inf Dis 2016;62(1) MFMER slide-22

23 PREVENT TB Study 26 patient group 2013 MFMER slide-23

24 PREVENT TB subanalysis hepatotoxicity INT J Tuberc Lung Dis 19(9): pts on LTBI treatment with either 3HP or INH x 9 months 77 (1.1%) pts developed hepatotoxicity 0.4% pts on 3HP (15/3545) 1.8% pts on INH x 9 mo (61/3317 3HP hepatoxicity rate was lower compared to INH x 9 mo Associations for hepatoxicity / risks: HCV infection Females, white race, decrease BMI, elevated baseline AST 2013 MFMER slide-24

25 Regional Experiences with 3 HP - Minnesota - New Mexico 2013 MFMER slide-25

26 3 HP in Minnesota: Hennepin Co. TB Clinic 152 patients treated with 3HP 121 (80 %) completed therapy 31 (20%) did not complete therapy Most were drug intolerant & completed treatment with either rifampin or INH 1 pt had significant rise in LFTs 6 refused further treatment 3 moved/lost to follow-up Courtesy of Dr. Dean Tsukayama, HCMC TB Clinic 2013 MFMER slide-26

27 3 HP in Minnesota: Hennepin Co. TB Clinic Impressions: Good completion rates comparable to published studies Initially HCMC was prioritizing 3HP patients for those who had failed previous attempts at LTBI treatment Making subsequent 3HP treatment completion rate that much more impressive Main reason that people do not want the regimen seemed to be too many pills (10) to be taken at one time Courtesy of Dr. Dean Tsukayama, HCMC TB Clinic 2013 MFMER slide-27

28 Assessing 3HP in New Mexico Public Health setting Study objectives Assess the use of 3HP in a programmatic setting Determine 3HP treatment completion rates Evaluate rate of side effects Serious side effects Side effects that resulted in discontinuation of treatment *Courtesy of Dr. Marcos Burgos - TB Control Program, New Mexico Department of Health 2013 MFMER slide-28

29 Enrollment Dates of enrollment: 3/16/2012 to mid-2015 Inclusion criteria Age > 12 year old HIV positive not on HAART Exclusion criteria HIV positive on HAART Pregnant women Major drug interaction to isoniazid and rifamycins *Courtesy of Dr. Marcos Burgos - TB Control Program, New Mexico Department of Health 2013 MFMER slide-29

30 Enrollment 348 persons started on 3HP 275 eligible to complete treatment 73 on treatment 236 (85.5%) completed 39 (14.5%) did not complete 30 (76.9%) because of Adverse events 8 (20.5%) Lost to follow-up 1 (2.6%) Resistance to INH *Courtesy of Dr. Marcos Burgos - TB Control Program, New Mexico Department of Health 2013 MFMER slide-30

31 3HP regimen for LTBI in NM Completion rate: 85.8% (236/275) Non-completion rate: 14.2% (39/275) Reason for non-completion: - adverse effects: 76.9% (30/39) 13% total enrolled pts - lost to follow-up: 20.5% (8/39) - resistance to INH: 2.6% (1/39) *Courtesy of Dr. Marcos Burgos - TB Control Program, New Mexico Department of Health 2013 MFMER slide-31

32 Patient Completion Rates by Risk Factors Risk factors for Treatment Eligible to complete Completed (%) Discontinued With symptoms (%) Contact (85.5) 11 (14.5) Rheumatologic disease (86.8) 7 (13.2) HD/Transplantation 12 9 (75.0) 3 (25.0) Foreign born (86.7) 14 (13.3) HCW (77.3) 5 (22.7) Refugee (86.7) 2 (13.3) Other (92.3) 1 (7.7) * Patients could have more than one risk factor for treatment *Courtesy of Dr. Marcos Burgos - TB Control Program, New Mexico Department of Health 2013 MFMER slide-32

33 Historical NM 9 months of INH vs. 3HP NM Study Cohort 9 mo INH % 3HP NM Study % Completion rate 263/ / P<0.001 *Courtesy of Dr. Marcos Burgos - TB Control Program, New Mexico Department of Health 2013 MFMER slide-33

34 Conclusions from New Mexico Treatment completion significantly higher with 3HP than historical LTBI treatment cohort with daily INH Similar completion rates of 3HP treatment as Prevent TB study 26 The percentage of patients that stopped 3HP due to AE was higher than in the Prevent TB study 26 There were no serious AE Most adverse events occurred within the first 4 doses *Courtesy of Dr. Marcos Burgos - TB Control Program, New Mexico Department of Health 2013 MFMER slide-34

35 Summary 3HP and 4RIF first choices for LTBI treatment if no contraindications Higher treatment completion Lower hepatoxicity May be able to give it SAT in the future Notes see Curry 3/2016 presentation F Curry 3/ HP webinar 2013 MFMER slide-35

36 The End A happy patient after 3HP!! Thank you for your attention 2013 MFMER slide-36