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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
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.
Learning Objective
• To learn about Randomized Controlled Trial.
• Kaplan- Meir Method of Survival Analysis.
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.
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.
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.
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.
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.
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.
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:
Table 1. Baseline Characteristics of the Study Patients, According to Treatment Group.
Characteristic Rifapentine withIsoniazid Weeklyfor 12 Wk(N = 328)
Rifampin withIsoniazid TwiceWeekly for 12 Wk(N = 329)
Isoniazid Dailyfor ≤6 Yr(N = 164)
Isoniazid Dailyfor 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 Years
Median 30.3 30.5 30.2 30.5 30.4
Inter quartile range
26.3–35.0
27.0–34.3 25.4–34.2 26.3 – 34.9 26.4–34.7
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)
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)
Diameter of induration
Median 14.5 15.0 15.0 15.0 15.0
I – Q Range 12-19 12-19 12-19 11-18 15.0
CD4 count: cells/mm3
Median 471 498 476 490 484
I-Q Range 352–666 353–696 346–644 340–670 350–672
Viral load — log10 copies/ml
Median 4.3 4.0 4.2 4.2 4.2
I- Q Range
3.6–4.8 3.4–4.7 3.6–4.7 3.6–4.7 3.6–4.7
BMI Median 25.0 24.7 25.3 24.9 24.9
I- Q Range
21.8–29.2 21.9–28.4 22.6–29.3 22.1–29.5 22.1–29.0
Table 2. Rates of Study End Points According to Treatment Group.*
End Point Rifapentine–Isoniazid
Rifampin–Isoniazid
Continuous Isoniazid
6-Mo Isoniazid
All
Tuberculosis
No. of cases 24 24 8 22 78
Person-yr of follow-up 1187.5 1219.7 561.0 1143.9 4112.1
Incidence rate per 100 person-yr
2.0 2.0 1.4 1.9 1.9
Death
No. of cases 17 16 8 25 66
Person-yr of follow-up 1223.6 1269.8 574.2 1180.0 4247.6
Incidence rate per 100 person-yr
1.4 1.3 1.4 2.1 1.6
Death or TB
No. of cases 37 35 15 41 128
Person-yr of follow-up 1187.5 1219.7 561.0 1143.9 4112.1
Incidence rate per 100 person-yr
3.1 2.9 2.7 3.6 3.1
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 value 0.87 0.94 0.48
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 value 0.18 0.10 0.31
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 Value 0.54 0.34 0.34
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
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.
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. Lancet1993;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 preventivetherapy in HIV infection in Zambia
Randomized Double-blind Placebo-Controlled Trial
Twice Weekly Isoniazid for 6 months or Rifampicin + Pyrazinamide for3 months reduced incidence.
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. StatisticallySignificant.
Volmink J, Woldehanna S.Cochrane Database Syst Rev 2010;1:CD000171.
Treatment of latent tuberculosis infection in HIV infectedpersons (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 treatmentfor 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.
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.
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.