HIV Infection Clinical Trial
Official title:
A Randomized Controlled Clinical Trial Comparing Daily Vs. Intermittent 6 - Month Short Course Chemotherapy in Reducing Failures & Emergence of Acquired Rifampicin Resistance (ARR) in Patients With HIV and Pulmonary Tuberculosis
Acquired Rifampicin Resistance has emerged as an important issue in the treatment of HIV-TB patients. It has not been a major problem in HIV-negative individuals treated for TB treated with standard intermittent regimens. The study would generate data on the efficacy of daily and thrice weekly regimen of ATT in pulmonary TB patients with HIV in the presence of highly active antiretroviral therapy (HAART). Not many trials have compared sputum conversion and adverse drug reaction between daily and intermittent regimens of ATT in HIV positive patients. This study provides a unique opportunity for comparison of daily and intermittent therapy for HIV patients with pulmonary TB looking into multiple dimensions of HIV-TB treatment namely efficacy, drug resistance, toxicity , drug interaction and immune reconstitution inflammatory syndrome. The primary outcome of the study is to compare the efficacy of three anti-TB regimens in a) reducing bacteriological failures and b) decreasing the emergence of Acquired Rifampicin Resistance (ARR). The secondary outcomes include unfavourable responses (clinical failures, deaths, relapses) as whole, treatment emergent adverse drug reactions, pharmacokinetic levels of ATT and incidence of immune reconstitution syndrome.
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.
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