Comparing Daily vs Intermittent Regimen of ATT in HIV With Pulmonary Tuberculosis

HIV positive patients (regardless of ART status) with newly diagnosed pulmonary TB attending the TRC clinics at Chennai, Madurai and Vellore will form the study group. Those who fulfill the clinical inclusion criteria will be evaluated for eligibility to the study after signing a screening consent form. Patients willing to participate in the study will undergo the following investigations namely, sputum examination, chest x-ray, liver and renal function tests. Hematological investigations will include CBC, CD4 and viral load, done periodically at baseline, end of intensive phase of ATT, at the end of TB treatment and once in 6 months during follow-up period of 1 year. Patients getting enrolled in Chennai and its subcentres will also be evaluated for immune reconstitution inflammatory syndrome through additional laboratory investigations. If the patients satisfy the inclusion criteria, a house visit will be done by the social worker to ascertain the facts regarding living condition and domiciliary stability and if continues to remain suitable , will be enrolled into the study after a written, signed and dated informed study consent form. All eligible patients, enrolled into the study, will be randomized to receive one of the three regimens mentioned below. Patients who are ART naïve will be referred to National AIDS Control Organization (NACO) ART centres for assessment and eligibility for procurement of ART according to National guidelines Common opportunistic infections that could occur during study period will be managed according to standard NACO guidelines. Cotrimaxozole DS One tablet once a day will be given to all patients with CD4 < 250 along with multivitamins, unless contraindicated. They will be discharged from the study once their 18th month sputum culture is negative.

Treatment regimens and Dosing:

• Regimen 1. Daily - 2EHRZ7/4HR7 (E 800 mg ,H 300 mg, R 450/600 mg depending on Weight < 60, 600 mg for 60 kg and more, Z 1500 mg daily)

• Regimen 2. Part Daily - 2EHRZ7/4HR3 (E 800 mg ,H 300 mg, R 450/600 mg depending on Weight <60, 600mg for 60 kg and more, Z 1500 mg daily in the intensive phase followed by H-600 mg ,R-450/600 mg in the continuation phase thrice weekly)

• Regimen 3. Intermittent - 2EHRZ3/4HR3 (E 1200mg, H 600 mg, R 450/600 mg depending on Weight < 60, 600 mg for 60 kg and more, Z 1500 mg given thrice weekly)

Statistical design:

Stratification and randomization:

Patients will be stratified based on a) baseline CD4 i) of less than 150 and ii) more than 150 and b) sputum smear grading i) of 0 ,1+ and ii) 2+ , 3+ and randomized to receive one of the three regimens mentioned above, for a period of 6 months, using restricted block scheme. The treatment assignment list will be generated before the start of trial and sequentially numbered sealed opaque envelopes, containing the treatment assigned will be prepared independently in Chennai and Madurai. Assignment of patients to regimens will be done by the study statistician who has no link with the patient.

Sample Size:

Assuming that a daily and a part daily regimen has a 95% resistance- free survival and an intermittent regimen has a 80% resistance free survival during the treatment period, taking into account 20% loss due to death, default and other causes, with a power of 80% and an error of 5%, the sample size was calculated to be 140 per arm (420 cases totally).

Analysis plan Both the efficacy analysis and intent to treat analysis will be undertaken. The primary approach will be intent to treat analysis (ITT) accounting for all patients randomized to study regimen and considering drop outs, deaths and defaulters as unfavourable outcomes. However, Primary MDR -TB will be excluded as an unfavourable response from the ITT analysis despite allocation to study regimen. Efficacy analysis will include only patients who had consumed at least 80 % of the scheduled therapy of ATT. Patients who die within 15 days of starting ATT, and NON-TB deaths during assessment and treatment will not be considered for the efficacy analysis of ATT. Patients who have died during treatment and their cultures grow M.Tb retrospectively will be included as bacteriological failures taking the first event as the outcome. Kaplan Meier survival curves will be constructed and comparison will be done using Log-rank test. To identify the important co-variates in relation to response and toxicity, Cox-regression model will be used. Frailty model will be used to account for individual heterogeneity.