In resource-limited settings, people living with HIV have a high risk of death in the first six months after starting antiretroviral therapy (ART) and many of these deaths are due to tuberculosis. A5274 evaluated whether providing a four-drug TB treatment when ART is started would reduce death and the development of active TB (given that active TB can be difficult to diagnose, especially in people living with HIV who are very immunosuppressed). Researchers previously reported 24-week results from A5274, a phase 4 strategy trial that enrolled people living with HIV starting ART with low CD4 counts (<50 cells/mm3) in 10 high TB-burden countries. The study randomized participants to standard four-drug TB therapy or isoniazid preventive therapy (IPT) and reported that the four-drug TB therapy did not reduce death at 24 weeks compared to IPT.
This publication reports on data among 850 participants through 96 weeks and evaluated whether adherence affected the development of active TB and death. By 96 weeks, 85 deaths occurred (standard n=41; IPT n=44), with most (93%) occurring by week 48 and three TB-related deaths after week 48 (all in the standard arm). There was no difference in deaths (10.1% vs 10.5%; p=0.86) or time-to-death (p=0.77) between the standard and IPT groups. 63 cases of TB were diagnosed; 88% developed TB by week 24 and only 2 participants were diagnosed with TB after week 48 (1 in each group). The standard group had a higher risk of TB (6.1% vs 2.7%, p=0.02) and a shorter time to TB (p=0.02) than the IPT group. Self-reported adherence to TB medication lowered the probability of death by > 23% (p=<0.001) in the standard group and > 20% (p=0.035) in the IPT group. Adherence lowered the probability of developing active TB by > 17% in the IPT group.
Based on these data, researchers concluded that standard four-drug therapy offered no longer term survival advantage over IPT. They also demonstrated that being adherent to IPT substantially decreased the development of active TB and death. Shorter preventive TB treatments that improve adherence and completion are likely to be associated with a greater decrease in developing active TB and death. These findings also highlight the need to prioritize the use of and adherence to TB preventive treatment in people living with HIV who are starting ART in high-burden resource-limited settings.
Amita Gupta, Xin Sun, Sonya Krishnan, Mitch Matoga, Samuel Pierre, Katherine McIntire, Lucy Koech, Sharlaa Faesen, Cissy Kityo, Sufia S Dadabhai, Kogieleum Naidoo, Wadzanai P Samaneka, Javier R Lama, Valdilea G Veloso, Vidya Mave, Umesh Lalloo, Deborah Langat, Evelyn Hogg, Gregory P Bisson, Johnstone Kumwenda, Mina C Hosseinipour, ACTG A5274/REMEMBER Study Team. Isoniazid Adherence Reduces Mortality and Incident Tuberculosis at 96 Weeks Among Adults Initiating Antiretroviral Therapy With Advanced Human Immunodeficiency Virus in Multiple High-Burden Settings. Open Forum Infect Dis. 2022 Jul 3;9(7): ofac325. doi: 10.1093/ofid/ofac325. eCollection 2022 Jul.