Safety and efficacy of N-acetylcysteine in hospitalized patients with HIV-associated tuberculosis: An open-label, randomized, phase II trial (RIPENACTB Study)

Abstract

Despite the availability of effective antimicrobials, tuberculosis (TB) is still a serious health threat. Mortality is even higher in people living with HIV who are diagnosed with TB. New therapies are needed to shorten the time required to cure TB and decrease fatality rates in this population. N-acetylcysteine (NAC) is a glutathione precursor and has shown recently in experimental setting to present in vitro and in vivo anti-mycobacterial activity. We test the hypothesis that NAC is safe, well tolerated and secondarily efficacious as adjunctive anti-TB therapy in hospitalized individuals with HIV-associated TB. Patients were enrolled sequentially in a tertiary care center, in the Brazilian Amazon. We performed a randomized, parallel group, single-center, open study trial of two arms, in hospitalized patients over 18 years of age, with microbiologically confirmed pulmonary TB in HIV: one with rifampicin, isoniazid, pyrazinamide and ethambutol at standard doses (Control Group), and a second in which NAC 600 mg bid for eight weeks was added (NAC Group). A total of 21 and 18 patients were enrolled to the Control Group and NAC Group, respectively. Adverse event rates were similar in the two arms. Our findings suggest that in the more critical population of hospitalized patients with HIV-associated TB, the use of NAC was not unsafe, despite the low

Adjunct N-Acetylcysteine Treatment in Hospitalized Patients With HIV-Associated Tuberculosis Dampens the Oxidative Stress in Peripheral Blood: Results From the RIPENACTB Study Trial

“…The present study is a prospective investigation which was nested with the recently published RIPENACTB Study trial ( 16 ). Detailed description of study design, inclusion and exclusion criteria, randomization and study treatments is presented in our previous publication ( 16 ).…”

“…The present study is a prospective investigation which was nested with the recently published RIPENACTB Study trial ( 16 ). Detailed description of study design, inclusion and exclusion criteria, randomization and study treatments is presented in our previous publication ( 16 ). The RIPENACTB Study trial was an open-label, single center, randomized, phase II trial to test whether NAC-containing treatment regimen was as safe as the standard regimen for TB treatment in hospitalized patients with HIV.…”

“…Patients without HIV, with extrapulmonary TB only, who were unable to collect respiratory sample, pregnant and lactating women, exposed to quinolones in the last 7 days, and in use of anti-TB drugs for more than 72 hours or in use of anti-TB drugs as second line drugs were not included in the study. Enrolled patients were subsequently excluded if their baseline culture (Mycobacteria Growth Indicator Tube, MGIT) failed to grow Mtb or grew a strain of Mtb that was resistant to any anti-TB drug ( 16 ).…”

“…In addition, NAC treatment when given to mice infected with Mtb enhances host capacity in controlling Mtb growth in the lungs ( 11 ), which has also been observed in other animal models ( 12 ). Recently, several clinical studies utilizing NAC as adjunct therapy to TB have shown promising data revealing a potential use for this drug as host-directed therapy (HDT) in TB ( 13 – 16 ).…”

“…Recently, we have reported a clinical trial conducted with hospitalized HIV/TB patients in Brazil in which we evaluated the safety of NAC and its efficacy in accelerating mycobacterial clearance in sputum cultures ( 16 ). In the present study, we leveraged existing data and biospecimens from the RIPENACTB trial to assess the impact of NAC adjunctive treatment on host immune response and redox homeostasis in this population of hospitalized patients with HIV-associated TB.…”