A Randomized Trial of Weekly Rifapentine and INH vs. Daily Rifampin and PZA for the Treatment of Latent Tuberculosis Infection in Household Contacts

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1 A Randomized Trial of Weekly Rifapentine and INH vs. Daily Rifampin and PZA for the Treatment of Latent Tuberculosis Infection in Household Contacts M Schechter, R Zajdenverg, G Falco, Grace Barnes, J Coberly, R Moore, C Faulhaber, RE Chaisson Projecto Praca Onze and Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil Johns Hopkins University, Center for Tuberculosis Research, Baltimore, MD NIH ICIDR Grant AI 45432

2 In-vivo Activity of Rifampin 10mg/kg Bacterial Burden Exposure Jayaram et al, AAC 2003; 47:

3 Rifampin vs. Rifapentine Rifapentine CH 3 Rifampin Rifapentine t 1/2 = 2-3 hrs t 1/2 = hrs

4 Background Treatment of latent TB infection (TLTI) is an important element of TB control Short course, rifamycin based regimens have promise for increasing adherence to TLTI Rifapentine is a long acting rifamycin that can be given weekly Rifapentine/INH is effective in mouse models of latent TB

5 Rifapentine for Latent TB: From Bench to Bedside Miyazaki et al., AAC 1999;43:2126

6 Rifapentine for Dormant TB in the Cornell Mouse Model Regimen Spleen CFU Lung CFU Placebo BIW INH 25 daily RIF 10 BIW RPT 10 QW RPT+INH QW Miyazaki et al., AAC 1999;43:2126

7 Objective To compare the safety and efficacy of weekly rifapentine and isoniazid (RPT/INH) to daily rifampin and pyrazinamide (RIF/PZA) in the treatment of latent TB infection in household contacts infectious TB patients

8 Setting Patients Setting: Rio de Janeiro, Brazil Research clinic serving central Rio de Janeiro Public TB clinics served as source of referral Patients: Household contacts of pulmonary TB cases Must sleep at least 2 nights/week in same house First contact of each index case randomized Subsequent contacts assigned to same regimen as first contact

9 Eligibility Criteria Age > 18 years Not pregnant or lactating TST > 5 mm CXR normal and no TB symptoms < 1 month of prior TB treatment AST < 3 times ULN Total Bilirubin <2.5 times ULN Not on antiretroviral therapy

10 Treatment and Outcomes Regimens Rifapentine 900 mg/inh 900 mg once weekly for 12 weeks, directly observed in clinic or Rifampin mg/pza mg daily for 8 weeks, self-administered Endpoints Confirmed or probable TB Toxicity and safety

11 Assumptions and Sample Size Equivalence trial TB rate in Rifapentine/INH arm will be within 3.2% of RIF/PZA Assumptions: Risk of TB in contacts is 8% (Kritski 1996) RIF/PZA will reduce rate to 0.8% (90%) RPT/INH will reduce rate to at least 4% (50%) i.e. 3.2% absolute difference is acceptable Projected sample size with power of 80% 360 patients per arm, 720 total

12 Protocol Modifications During Study April 2001 MMWR report of RIF/PZA hepatotoxicity in HIV- patients Changed dosage of PZA to assure no one receives >20 mg/kg Increased LFTs to q 2 weeks Added warning to consent of higher than expected rates of hepatotoxicity

13 Enrollment of Patients by Month of Study (Starting 1/01) Cumulative Total of Patients, Both Arms J-01 M-01 M-01 J-01 S-01 N-01 J-02 M-02 Month of Study M-02 J-02 S-02 N-02 J-03

14 Interim Data Analysis by NIAID DSMB May 5, 2003 Safety comparison only 10% of RIF/PZA patients with Grade 3/4 hepatotoxicity, no symptoms or hospitalizations DSMB encourages continuation of trial with amendment to change RZ to twice weekly Study team elected to permanently stop enrollment because of impending CDC recommendations to avoid RZ

15 Table 1. Baseline variables Variable RPT/INH RZ ALL N # Index Cases Mean Age (yrs) Sex (M/F) % 37/63 44/56 40/60 Mean TST (mm) % Married %White %Black %Other % Employed % BCG vaccination % Smoker % Alcohol *1 HIV+ subject in RPT/INH arm

16 Table 2. Baseline Laboratory Variables Variable RPT/INH RZ ALL Mean Hct (%) Mean WBC (/ml) Mean AST (IU) Mean Total Bilirubin (IU) Mean Direct Bilirubin (IU) Mean Indirect Bilirubin (IU)

17 Table 3. Adverse Events During Follow Up Variable RPT/INH RZ ALL Death Any Grade 3 / 4 Hepatotoxicity 2 22* 24 Pregnancy (on Tx) *P<0.0001

18 Table 4. AST/ALT During Follow Up Time Week 0 Week 2 Week 4 Week 6 Week 8 RPT/INH Mean / Median RZ Mean / Median AST ALT AST ALT AST ALT AST ALT AST ALT

19 Time of Hepatotoxic Events on RZ 14 Number of Grade 3/4 Events Week of Treatment with RZ

20 Table 5. Comparison of RZ patients who did or did not develop hepatotoxicity Variable RZ Hepatoxicity (N=22) No RZ Hepatotoxicity (N=171) Baseline AST (IU) Baseline Bili (IU) Mean Age (years) % Male Sex Mean Weight (kg) Mean PZA dose (mg/kg) Mean RIF dose (mg/kg)

21 Table 6. Tuberculosis During Follow Up RPT/INH RIF/PZA Number of Patients Person-Years of Follow Up TB Cases 3 (1.5%) 1 (0.5%)* Time of TB (Mos. after enrollment) TB Rate (Cases/ 100 Person-Years) 17, 27, months months *RR 2.8 (95% CI ), P=0.66

22 Conclusions Rifapentine/INH has similar effectiveness in preventing active TB as RIF/PZA No significant difference in rates >50% effective based on hypothesized rates, e.g, <4% Study limited by premature end to enrollment Rifapentine/INH is significantly better tolerated than RIF/PZA in latent TB infection No specific risk factors for RIF/PZA toxicity were identified While additional Phase 3 studies will further define the utility of Rifapentine/INH in treating latent TB infection, this study demonstrates the promise of this simple, short course regimen

23 Clinical Trials of Weekly Rifapentine/INH for Latent Tuberculosis Site Patients Comparator(s) No. Patients Brazil/ICIDR Contacts RIF/PZA 399 (720) South Africa/JHU N. America, Brazil, Spain, Africa/CDC TBTC HIV+/PPD + Contacts, HIV+/PPD + RIF/INH, INH 1150 INH 8000 (6028 to date)

24 Acknowledgements NIH ICIDR Grant AI 45432, AI and TW Solange Cavalcante, MD, MPH Elizabeth Higgs, MD Timothy Sterling, MD Larry Moulton, PhD Jonathan Golub, PhD DMID Data Safety Monitoring Board Aventis Paul Sullivan Giorgio Roscigno

25 Lung CFU counts after 2 Months Treatment with RPT or RIF and Moxi or INH in Murine TB Model D0: 7.06 log 10 CFU in lung Log 10 CFU count in lungs RHZ (5/7) RHZ (2/7) RMZ (2/7) P 10 HZ (2/7) P 15 HZ (2/7) P 20 HZ (2/7) P 15 MZ (2/7) Treatment regimens* P 20 MZ (2/7) R; Rifampin, H; Isoniazid, M; Moxifloxacin, Z; Pyrazinamide *All treatment regimens contained an initial 2 weeks of RHZ (5/7) or RMZ (5/7).

26 Rifapentine for Tuberculosis Rifamycin derivative Half life 15 hours MIC 0.5 ug/ml Approved for use in active TB Once weekly therapy in continuation phase