COLUMBUS, Ohio – People who are HIV positive and living in high tuberculosis-transmission regions of the world are much more likely to finish a TB-prevention regimen lasting just three months – half as long as the standard treatment, a large clinical trial in Africa has found.
An added benefit: The protocol involves a total of 12 weekly doses of tuberculosis preventive therapy rather than daily pills for six months.
The study’s preliminary data suggest that the shorter course of treatment was as safe and effective at preventing active TB as the six-month regimen, long considered the standard of care for immunocompromised people in Africa and other high TB-transmission regions.
More than 4,000 people participated in the trial in South Africa, Ethiopia and Mozambique. All were HIV-positive and taking antiretroviral therapy. They were randomized to take a daily dose of isoniazid (INH) for six months or a combination of high doses of INH and rifapentine weekly for three months. Except for when they visited a clinic to pick up their antibiotics, all participants self-administered the medications.
Just 50.5% of participants completed the six-month daily treatment, compared to 90.4% who finished the shorter combined-drug strategy.
“The major objective was determining whether we can replace 180 doses of INH alone over six months with 12 total doses of INH and rifapentine together over three months,” said study co-author Getnet Yimer, director of the Eastern Africa Regional Office of The Ohio State University’s Global One Health initiative (GOHi).
“There was evidence before our study from developed countries that this could work where the incidence of TB is very low, but we didn’t know if it would work in an area where the incidence of TB is very high – 100 or more people per 100,000. We showed the shorter course really works – treatment completion was significantly higher, and effectiveness was just as high.”
The trial was the first TB-prevention study to be conducted with such a large sample in three countries using a method matching how typical clinics would operate, said co-author Shu-Hua Wang, professor of internal medicine specializing in infectious diseases at Ohio State and principal investigator of Ohio State’s participation in the study.
“The goal is to get the medicine out there and have people take it, and not have so many logistical barriers for them,” Wang said.
The results were published Aug. 23 in Annals of Internal Medicine.
An estimated 10 million people worldwide become ill with TB disease each year, and in 2019, 1.4 million people died of TB – including 208,000 people with HIV, according to the World Health Organization (WHO). The 30 countries with the highest TB burden stretch across Southeast Asia, Africa and the Western Pacific.
Yimer, an adjunct associate professor of internal medicine at Ohio State and a longtime physician scientist specializing in TB research across Africa, was selected to lead the two sites in Addis Ababa, Ethiopia, that treated 875 participants for the trial. He partnered with Wang, who is also director of research and implementation for Ohio State’s GOHi.
The 4,014 participants were enrolled in the trial between November 2016 and November 2017, with 404 taking the daily six-month regimen and 3,610 taking the three-month treatment. Half of the participants on the short-course combined regimen received it once, and others took it for two years in a row. The findings suggested that the second round of treatment was no more beneficial at preventing TB than the single course.
About 25% of the world’s population has latent, or symptom-free, TB infection, and people living with HIV are 18 times more likely to develop active TB disease than people without HIV, according to WHO. In countries with a high TB burden, people with compromised immune systems – whether a latent infection is detected or not – are typically given antibiotics to prevent active disease, Yimer said.
“We cannot eliminate tuberculosis without treating individuals who have latent TB infection, who could go on to develop active TB disease,” said Wang, who also directs the Columbus Public Health Ben Franklin TB Program. Columbus was a site for additional testing of the short-course regimen in 2017.
INH and rifampin are the two primary drugs used to treat TB in patients whose infections are not drug-resistant, and a six-month course of a daily 300 milligram dose of INH alone has been a common latent-infection preventive treatment for years in developing and developed countries. In this study, the researchers combined 900 milligrams of INH with another antibiotic from the rifamycin family – 900 milligrams of rifapentine – because it has a longer half-life.
After study leader Gavin Churchyard, founder and CEO of the Aurum Institute in South Africa, presented the initial findings at the Conference on Retroviruses and Opportunistic Infections in March 2020, many countries were quick to adopt the new regimen.
“The number of TB drugs in the pipeline is very limited, so the thinking now is to modify existing drugs and manage them differently for latent and active infection,” Yimer said. “When the preliminary result was out and since there was existing supporting evidence, too, the response was immediate: Most countries accepted the idea and changed guidelines immediately.”
WHO has endorsed the three-month combined TB-prevention protocol for people with HIV, and the regimen has been the preferred latent TB infection treatment in the United States recommended by the Centers for Disease Control and Prevention (CDC) since 2011; people with HIV were added to the recommendation in 2018 after the CDC analyzed the findings of 15 studies.
Yimer said that the 24 nurses, physicians, pharmacists, lab technicians and data managers trained to conduct this international study are now much better equipped to host more human clinical trials in Ethiopia. Long-term capacity building is a core mission of Ohio State’s Global One Health initiative.
This study was funded by the U.S. Agency for International Development through the CHALLENGE TB grant to the KNCV Tuberculosis Foundation.
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