RCT comparing daily vs intermittent therapy of ATT in HIV in reducing failures and emergence of acquired rifampicin resistance

Findings from earlier trials conducted among patients with Human immunodeficiency virus and Pulmonary Tuberculosis infection (HIV and PTB) at Indian Council of Medical Research-National Institute for Research in Tuberculosis (ICMR-NIRT) formerly Tuberculosis Research Center (TRC), acquired rifampicin resistance (ARR) was found to be high among failures in HIV- associated TB (tuberculosis).

 A cross-protocol analysis by the same Principal Investigator (PI) on ARR showed that ARR was only reduced not eliminated by thrice weekly ATT, even with timely antiretroviral therapy (ART) initiation. Hence, in order to maximize TB treatment efficacy and reduce emergence of antimicrobial resistance (ARR), especially in HIV, this trial, was started by the investigator with intellectual guidance from ICMR-NIRT and World Health Organization (WHO), funded by USAID (United States Agency for International Development) through the Model DOTS project and partially by the ICMR intramural grant.

The trial evaluated the efficacy of three different anti-tuberculosis therapy (ATT) regimens of 6 months, with drugs dosed as daily, part daily and intermittent, given along with ART in the trial mode among HIV-PTB coinfected individuals in order to reduce failures and acquisition of Rifampicin resistance. In fact, the TB programme was keenly waiting for this valuable evidence to decide whether to shift to a daily regimen at that time. Systematic and meticulous trial procedures were incorporated for detailed clinical assessment and interventional procedures in advanced Immunodeficiency carried out by the PI and team to collect not only sputum specimens, but pleural, pericardial, Lymph node aspirate and Cerebrospinal fluid from these advanced HIV –TB co-infected participants, to establish TB treatment failure or recurrence apart from ruling out other opportunistic infection.

 The trial also helped to predict and manage immune reconstitution inflammatory syndrome (IRIS) or paradoxical reaction, which was a big hurdle to initiation of ART at that time in the face of Active TB. The findings from this trial, which highlighted the superior outcomes of daily ATT over intermittent therapy, were aligned with ICMR's relentless efforts to improve tuberculosis treatment strategies and reduce the emergence of drug resistance, saving thousands of lives among the dually infected. It provided the vital evidence for a change in the schedule of TB therapy and remains the only global evidence of a daily regimen establishing the superiority over thrice weekly therapy using a  direct comparison in the randomized controlled clinical trial mode.