UCSF Co-led Study Demonstrates Safety and Efficacy of 4-Month Tuberculosis Treatment Regimen

UCSF researchers in collaboration with the Centers for Disease Control’s Tuberculosis Trials Consortium and the AIDS Clinical Trials Group published a landmark study this May in the New England Journal of Medicine that demonstrated a new four-month treatment regimen for tuberculosis (TB) was safe and as efficacious as the standard six-month therapy. 

“The new four-month regimen is going to be a preference for many patients and TB programs as it provides faster cure and eases burden on patients and providers,” said Dr. Payam Nahid, protocol co-chair of the trial, corresponding author of the primary publication, and Director of the UCSF Center for Tuberculosis.

Prior to the COVID-19 pandemic, TB was the leading cause of death by an infectious disease worldwide. According to the World Health Organization (WHO), an estimated 10 million people suffer from active TB every year. Since 1970, doctors have treated the disease with a six-month regimen consisting of four antimicrobial drugs: rifampicin, isoniazid, pyrazinamide, and ethambutol. Researchers have been trying to shorten the duration of therapy to four months to improve treatment completion and lower patient burden since 1976. UCSF researchers and their partners are the first to accomplish this feat in over 40 years.

Study 31/A5349, a randomized controlled trial, compared two four-month rifapentine-based regimens to the standard six-month regimen, one also including moxifloxacin. Rifapentine and moxifloxacin are antibiotics that treat bacterial infections such as TB. Researchers found that the four-month regimen consisting of rifapentine, isoniazid, pyrazinamide, and moxifloxacin had similar efficacy and safety compared to the standard six-month therapy for treating TB.

Last month, the WHO’s Guideline Development Group released a rapid communication endorsing the four-month regimen as a possible alternative to the standard therapy. Prior to results of Study 31/A5349, there had only been a single standardized option for the treatment of drug-sensitive TB. The WHO’s policy guidelines on tuberculosis, updated with their transformational endorsement of the 4-month regimen, will be released later this year.

“Many developing countries where tuberculosis is a major disease lean heavily on WHO guidelines when they develop their own country-specific guidelines,” said Dr. Rada Savic, Associate Director of the UCSF Center for Tuberculosis, Study 31/A5349 trial pharmacologist, and Professor of Bioengineering. As a result, this WHO endorsement has the potential to have a large impact on patient care worldwide.

As the first international tuberculosis phase III trial to comprehensively utilize modern pharmacometrics, a field founded at UCSF in the 1980’s and now a discipline that underlies every modern drug design, Study 31/A5349 was avant-garde because it used principles of data analysis and modelling in the design stage to select dosage and regimen composition, setting a standard for how this methodology should be implemented going forward, added Dr. Savic. She believes this is an exciting and key moment for science, inspiring for many in the field and offering a prospect for future advances in tuberculosis treatment.

Dr. Kelly Holland, a community health center physician in Massachusetts, has had first-hand experience with taking standard TB therapy. Although 2 months is not a huge reduction, shortening the duration of treatment can mean a lot for patients, their families, and the community, he said.

“My son was just 2 years old when I was on treatment,” Dr. Holland said. “Two months in the life of a 2 year old child is a lot of his life. Those were special times when he was early in his development, and I was not able to be as present as I wanted to be because [of the toxicities of the medications].”

As a practicing physician and member of the We Are TB survivor community, Dr. Holland knows that on top of issues such as stigma, isolation, and financial pressures, a major reason so many people stop taking their medications early is because of side effects such as nausea, fatigue, and irritability. Trying to keep patients’ spirits up and engaging them in treatment when they feel awful is an ongoing challenge. For a disease that consumes the lives of not only patients, but also their families and communities, a shorter duration of therapy is not to be underestimated.

Dr. Patrick Phillips, lead biostatistician of the trial and Assistant Professor in the Division of Pulmonary and Critical Care Medicine, said that Dr. Savic has brought TB drug development into the 21st century through the application of modern pharmacometrics.

“Tuberculosis is a severely neglected disease and although less prevalent in the United States, it is a global problem,” Dr. Phillips said. “The trial’s finding is a major milestone in fighting the epidemic.” 

Furthermore, UCSF is responsible for leading this fight at the UCSF Center for Tuberculosis through public funding from the Centers for Disease Control and National Institutes of Health. The Chancellor has also directly encouraged the university to foster collaboration in working toward a common mission to address the world’s health issues.

“This is an example of how UCSF faculty have demonstrated tremendous impact on international global health through collaborative research,” Dr. Payam said. “Landmark findings like this do not come around that often, and I was personally gratified to see the WHO’s rapid communication, expressing that patients would prefer this 4-month regimen over the standard.”

The study authors believe that in the coming months to years, the scaling up of this 4-month regimen will be feasible based on access to both rifapentine and moxifloxacin through a global drug facility system available to low-resource countries. 

The study authors and Dr. Holland noted that while this is an encouraging advancement in tuberculosis therapy, there is still much to be done for this disease that affects and consumes the lives of millions of people every year. Beyond the primary outcomes of the trial, Dr. Nahid said that there are many more learnings that will come from Study 31/A5349 as the authors designed several important sub-studies, including NIH-funded biomarker discovery and PK/PD workstreams into the trial. These robust and high quality data will inform and be a critical resource to the TB therapeutics community for years to come. 

“Tuberculosis is often a disease of poverty, and it does not get the research dollars and attention it deserves,” Dr. Holland said. “This advancement is exciting because it means that [the scientific community] is still trying to do better.”