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.