Efficacy of a Six-Month versus a 36-Month Regimen for Prevention of Tuberculosis in HIV-Infected Persons in India: A Randomized Clinical Trial

Soumya Swaminathan,Padmapriyadarsini Chandrasekaran,Ponnuraja Chinnaiyan,Mai Tuyet Pho,Narayanan Paranji Ramaiyengar,Pradeep Aravindan Menon,Ranjani Ramachandran,Sheik Iliayas,Thiruvalluvan Elangovan,Narendran Gopalan,Venkatesan Perumal,Ramesh Kumar Santhanakrishnan,Pooranaganga Devi Navaneethapandian,Fraser Wares,Katharina Kranzer

doi:10.1371/journal.pone.0047400

Abstract

BackgroundThe optimal duration of preventive therapy for tuberculosis (TB) among HIV-infected persons in TB-endemic countries is unknown.MethodsAn open-label randomized clinical trial was performed and analyzed for equivalence. Seven hundred and twelve HIV-infected, ART-naïve patients without active TB were randomized to receive either ethambutol 800 mg and isoniazid 300 mg daily for six-months (6EH) or isoniazid 300 mg daily for 36-months (36H). Drugs were dispensed fortnightly and adherence checked by home visits. Patients had chest radiograph, sputum smear and culture performed every six months, in addition to investigations if they developed symptoms. The primary endpoint was incident TB while secondary endpoints were all-cause mortality and adverse events. Survival analysis was performed on the modified intent to treat population (m-ITT) and rates compared.FindingsTuberculosis developed in 22 (6.4%) of 344 subjects in the 6EH arm and 13 (3.8%) of 339 subjects in the 36H arm with incidence rates of 2.4/100py (95%CI- 1.4–3.5) and 1.6/100py (95% CI-0.8–3.0) with an adjusted rate ratio (aIRR) of 1.6 (0.8–3.2). Among TST-positive subjects, the aIRR of 6EH was 1.7 (0.6–4.3) compared to 36H, p = 0.8. All-cause mortality and toxicity were similar in the two arms. Among 15 patients with confirmed TB, 4 isolates were resistant to isoniazid and 2 were multidrug-resistant.InterpretationBoth regimens were similarly effective in preventing TB, when compared to historical incidence rates. However, there was a trend to lower TB incidence with 36H. There was no increase in isoniazid resistance compared to the expected rate in HIV-infected patients.The trial is registered at ClinicalTrials.gov, NCT00351702.

Highlights

Tuberculosis (TB) and Human Immunodeficiency Virus (HIV) are the two leading infectious causes of death globally, with TB being the most common cause of death among HIV-infected persons in the developing world [1,2]
In the pre-antiretroviral therapy (ART) era, several clinical trials demonstrated a reduction in TB incidence in HIV-infected patients with the administration of TB preventive therapy [9,10,11]
A recent metaanalysis found that isoniazid preventive therapy (IPT) reduces the risk of active TB by 33% overall and by 64% among adults with a positive tuberculin skin test (TST) [12]

Summary

Introduction

Tuberculosis (TB) and Human Immunodeficiency Virus (HIV) are the two leading infectious causes of death globally, with TB being the most common cause of death among HIV-infected persons in the developing world [1,2]. Of the approximately 2?4 million people living with HIV in India, the incidence of TB has been reported to be as high as 6?9 cases/100 person-years (PY) [7,8]. The World Health Organization’s (WHO) recommended regimen for TB preventive therapy in adolescents and adults living with HIV is isoniazid (H) 300 mg daily for six months [13]. Challenges faced by programmes in implementing IPT services include the difficulty in excluding active TB disease with certainty prior to initiation of IPT, poor adherence, potential emergence of drug resistance, uncertainty about the optimal length and composition of regimen and the cost-effectiveness of such an approach in high TB prevalence settings [18]. The optimal duration of preventive therapy for tuberculosis (TB) among HIV-infected persons in TB-endemic countries is unknown

Methods

Results

Conclusion