1. New Regimens to Prevent Tuberculosis in Adults with HIV Infection Neil A. Martinson, Grace L. Barnes, Lawrence H. Moulton, Reginah Msandiwa, Harry Hausler, Malathi Ram, et al. N Engl J Med 2011;365:11-20. Presented By: Vikash Keshri

2. Introduction: Tuberculosis; most common opportunistic infection, leading cause of death among HIV Infected. Preventive treatment with Isoniazid for 6 to 12 months or a combination of Isoniazid + Rifampin for 3 months reduces the risk of tuberculosis by 32 to 64%. (Whalen CC et al). WHO policy recommend use of Isoniazid for 6 months. Concerns for low completion rates, the potential for re-infection and selection of drug-resistant mycobacterium strains deter public health programs to implement preventive treatment widely.

3. Learning Objective To learn about Randomized Controlled Trial. Kaplan- Meir Method of Survival Analysis.

4. Objective of study: To Evaluate 3 new regimen for latent Tuberculosis in patients with HIV Infection. 12 Weeks course of Rifapentine (900 mg.) given Weekly or Rifampin (600 mg.) given twice weekly both with Isoniazid (900 mg). Continuous Isoniazid (300 mg.) daily for duration of study (≤ 6 Years). Compared to Control regimen of Isoniazid (300 mg.) daily for 6 Months.

5. Methodology Study Design: Open- label, Randomized controlled trial Study Area: Soweto, South Africa, a community with high prevalence of HIV and TB. Study Subjects: HIV infected adults (>18 yrs.), ≥ 5 mm. induration on TST screened. Eligibility Criteria: –Not Pregnant or Lactating. –No active Tuberculosis (Symptoms/CXR or Culture). –Not received TB treatment > 2 months in past. –On Anti retro viral Therapy. –CD4 count < 200 / Cu mm.

6. Methodology Cont… Ethical Clearance: –By IRB, Johns Hopkins Medicine, University of Witwatersrand, FDA and Medicine control council of South Africa. –Written Informed Consent taken Treatment Group and Administration: 3 treatment group and 1 Control group. Treatment for Rifapentine and Rifampin with INH were Observed Isoniazid daily and Isoniazid continuous treatment self administered 25 Mg. Pyridoxine with each ATT dose. Randomization: Block randomization in 2:2:2:1 ratio with computer generated algorithm.

8. Study Procedure: Follow Up: –During treatment Once weekly for Rifapentine +INH group. Twice weekly for Rifampin + INH group. Every 2 Weeks for Isoniazid 6 moths and cont. Isoniazid group. –After treatment completion Monthly for continuous Isoniazid group Every 6 Months for treatment completed or discontinue.

9. Follow Up Symptoms/ Signs of TB Yes No Sputum Smear Mycobacterium culture & Sensitivity Chest X ray AST and ALT level at 1,2 and 6 months then 6 monthly. CD4 Count 6 monthly and 3 monthly for (CD4<350) initially. Patient eligible for ART referred to ART centre but remained in study. Women becoming pregnant switched to 6 months Isoniazid group. All discontinuing patients were followed up.

10. Study End Point  Primary : Tuberculosis free survival. Changed to TB or Death on recommendation of safety monitoring board  Secondary: Adherence to study regimen, adverse events, discontinuation, Drug Resistance. Case Definitions: Confirmed TB: Sign/Symptoms and culture positive from any site. Probable TB: Sign/Symptoms and AFB in Sputum smear or caseous necrosis in tissue biopsy. Possible TB: Sign/Symptoms without microbiological or histological evidence but responding to ATT. Clinical record or Death Certificate obtained. Independent Committee reviewed all End Point.

11. Statistical Analysis: Intention to treat analysis of Primary End Point (Included patient of Confirmed, Probable or Possible TB or Death) As treated analysis for patient who received treatment > 2 months and didn’t had TB for 3 months after randomization. Results:

12. Table 1. Baseline Characteristics of the Study Patients, According to Treatment Group. CharacteristicRifapenti ne with Isoniazid Weekly for 12 Wk (N = 328) Rifampin with Isoniazid Twice Weekly for 12 Wk (N = 329) Isoniazid Daily for ≤6 Yr (N = 164) Isoniazid Daily for 6 Mo (N = 327) All Patients (N = 1148) Female sex no. (%) 277 (84.5) 267 (81.2)139 (84.8)273 (83.5)956 (83.3) Age in Year s Median30.330.530.230.530.4 Inter quartile range 26.3– 35.0 27.0–34.325.4–34.226.3 – 34.926.4–34.7 Black Race No. (%) 325 (99.1) 327 (99.4)163 (99.4)327 (100.0)1142 (99.5) ≥12 Yr of schooling no. (%) 93 (28.4) 102 (31.0)61 (37.2)117 (35.8)373 (32.5)

13. Formal employment no. (%) 40 (12.2)34 (10.3)12 (7.3)39 (11.9)125 (10.9) Imprisoned before enrollment no. (%) 48 (14.6)52 (15.8)21 (12.8)40 (12.2)161 (14.0) Diamete r of indurati on Median14.515.0 I – Q Range12-19 11-1815.0 CD4 count: cells/m m3 Median471498476490484 I-Q Range352–666353–696346–644340–670350–672 Viral load — log10 copies/ml Median 4.3 4.04.2 I- Q Range 3.6–4.8 3.4–4.73.6–4.7 BMIMedian 25.0 24.725.324.9 I- Q Range 21.8–29.2 21.9–28.422.6–29.322.1–29.522.1–29.0

14. Table 2. Rates of Study End Points According to Treatment Group.* End PointRifapentine –Isoniazid Rifampin – Isoniazid Continu ous Isoniazid 6-Mo Isoniazid All Tuberculosis No. of cases24 82278 Person-yr of follow-up1187.51219.7561.01143.94112.1 Incidence rate per 100 person-yr 2.0 1.41.9 Death No. of cases171682566 Person-yr of follow-up1223.61269.8574.21180.04247.6 Incidence rate per 100 person-yr 1.41.31.42.11.6 Death or TB No. of cases 37 351541128 Person-yr of follow-up 1187.5 1219.7561.01143.94112.1 Incidence rate per 100 person-yr 3.1 2.9 2.73.63.1

15. P values are for the comparison with the 6-month regimen of Isoniazid. Tuberculosis Crude incidence- rate ratio (95% CI) 1.05 (0.56– 1.97) 1.02 (0.55– 1.91) 0.74 (0.29– 1.73) Reference 1.0 P value0.870.940.48 Death Crude incidence- rate ratio (95% CI) 0.66 (0.33– 1.26) 0.59 (0.30– 1.16) 0.66 (0.26– 1.50) Reference 1.0 P value0.180.100.31 Death or tuberculosis Crude incidence- rate ratio (95% CI) 0.87 (0.54– 1.39) )0.80 (0.50– 1.29) 0.75(0.38– 1.38) Reference 1.0 P Value0.540.34

19. Discussion: The overall rate of tuberculosis was 1.9 cases per 100 person-years. No significant difference between any of the three new regimens and the control regimen. The expected annual rate of tuberculosis ranges from 5 and 10%. The shorter, Rifampin-based regimens had higher adherence rates than 6-month Isoniazid. Twice weekly regimen of Rifampin + INH is efficacious. No clinically significant safety concern identified with Once- Weekly Rifapentine and Isoniazid

20. Discussion Cont … No additional benefit of continuous Isoniazid as compared with 6 months of Isoniazid as preventive treatment. Post hoc as treated analyses suggest that continuous Isoniazid was effective. Cox Proportional Hazard Analysis Shows 58% less risk of TB or Death among Cont. Isoniazid group ( P value = 0.02) But rate of TB increased markedly after treatment stopped.

21. Other Evidences: Whalen CC, et al. N Engl J Med 1997;337:801- 8. A trial of three regimens to prevent tuberculosis in Ugandan adults infected with the human immunodeficiency virus Randomized Placebo Controlled Trial 6 month Isoniazid confers short term protection. Multidrug regimen of Rifampin +INH for 3 Months is also Effective Pape JW, et al. Lancet 1993;342:268- 72. Effect of Isoniazid prophylaxis on incidence of active tuberculosis and progression of HIV infection Randomized Controlled Trial Incidence of tuberculosis lower in Isoniazid recipients. Mwinga A, et al.. AIDS 1998;12:2447- 57. Twice weekly tuberculosis preventive therapy in HIV infection in Zambia Randomized Double-blind Placebo- Controlled Trial Twice Weekly Isoniazid for 6 months or Rifampicin + Pyrazinamide for 3 months reduced incidence.

22. Other Evidences cont.. Bucher HC, et al. AIDS 1999, 13:501–507 Isoniazid prophylaxis for tuberculosis in HIV infection: a meta-analysis of randomized controlled trials Meta-analysis of Randomized Controlled trials. INH for 6 months effectively reduces the incidence. Statistically Significant. Volmink J, Woldehanna S. Cochrane Database Syst Rev 2010;1: CD000171. Treatment of latent tuberculosis infection in HIV infected persons (Review) 11 trials were included with a total of 8,130 randomized participants. Preventive therapy (any anti-TB drug) versus placebo lower incidence of active tuberculosis (RR 0.64, 95% CI 0.51 to 0.81). Samandari T, et al. Lancet 2011; 377: 1588–98 6-month versus 36-month Isoniazid preventive treatment for tuberculosis in adults with HIV infection in Botswana. Randomized, Double-blind, Placebo- Controlled trial In endemic area 36 months’ isoniazid more effective than 6-month.

23. Conclusions: Short-course, Rifampin-based preventive treatment had similar, not superior, efficacy to 6 months of Isoniazid in tuberculin-positive adults infected with HIV. Use of these regimens in clinical practice could substantially increase the number of patients who receive and complete preventive therapy. More widespread use of preventive therapy, regardless of the regimen chosen, is essential to help control the epidemic of HIV related tuberculosis.

24. Comments: Report of trial confers to CONSORT Statement: (Except Some issue ???) –Blinding not done –Participants flow not properly described. Recruitment time Outcome Measured – TB or Death (cause of Death not evaluated). Role of other covariates or confounders for Death not seen. Ideally Induration > 10 mm. considered +ve (≥ 5 mm in study) Why 83% Women included in the trial.