Q&A: With future study, heartburn drugs may lead to shorter TB treatment

Drugs designed to treat heartburn may also help with tuberculosis by accelerating the treatment process, according to study results published in Proceedings of the National Academy of Sciences.

A common challenge of treating TB is that Mycobacterium tuberculosis becomes tolerant to drugs used in treatment, in a process mediated by mycobacterial drug efflux pumps.

According to a press release from U.K. Research and Innovation, researchers of this study found that verapamil, a calcium channel blocker, prevented these pumps from ejecting rifampin, an antibiotic used in the treatment of TB.

Further testing showed that proton pump inhibitors frequently used to treat heartburn, reflux and gastritis also stopped TB bacteria from ejecting rifampin.

To learn more about TB, current treatment options and findings from this study, Healio spoke with study author Paul H. Edelstein, MD, emeritus professor of pathology and laboratory medicine at the Perelman School of Medicine at the University of Pennsylvania.

Healio: How prevalent is TB and death from TB globally?

Edelstein: In 2021, it is estimated that there were about 10 million new cases of TB worldwide and around 1.5 million deaths. India, Indonesia and the Philippines contributed the largest number of cases. In 2021, India had an estimated 2 million new cases of TB and about 500,000 new deaths.

There are also some countries with smaller populations that have much higher incidence rates. For example, in comparison to India, South Africa had many fewer cases and deaths, but the rate per population is more than twice that of India, around 500 cases per 100,000 population per year driven almost exclusively by the prevalence of HIV/AIDS in that country. Similarly, their death rates are considerably higher than that of India or worldwide.

In contrast, there are relatively few cases of TB reported annually in the U.S. There were around 7,000 to 9,000 cases per year, a rate that is about 1/50th of the rate worldwide and a death rate close to about 1/100th of the death rate worldwide and much lower than found in endemic countries.

In contrast, the U.S. death rates from cancer were at least 1,000 times more than the death rates of TB in the U.S., and the death rates of cancer in India were a little bit less than twice that of the death rate of TB in India. Worldwide, TB is a more common cause of death than HIV/AIDS.

Healio: What does the current treatment regimen for TB look like — such as available drugs, length of treatment, etc — and what are the downsides of current treatments?

Edelstein: Current treatments for drug-susceptible TB usually consists of four drugs: isoniazid or INH, rifampin, ethambutol and pyrazinamide. INH and rifampin are given for 6 months, and the other two are given for just the first 2 months of therapy. They’re generally well tolerated, with hepatitis and gastrointestinal symptoms being the major side effects. These side effects are relatively infrequent, but patients still require close follow-up and clinical monitoring, specifically to make certain that they are taking their drugs because it can be a burden for patients to take all these drugs for an extended period and remember to do so. Depending on the patient, the situation and other things, the drugs might be given every day or as infrequently as three times a week. People tend to get better within weeks or a month after starting their drugs.

In the U.S., monitoring 9,000 people per year with TB is not too difficult from a public health standpoint, but in countries where the disease is much more prevalent, such as in India with 2 million cases per year, monitoring all those cases takes a lot of resources.

Drug therapy for resistant TB — which is rare in the U.S. (around 200 cases per year) compared with India (around 50,000 cases per year) and endemic countries such as South Africa (around 21,000 cases per year) — requires the use of different drug regimens. Luckily, an all-oral regimen that’s relatively nontoxic in comparison to the prior regimens has recently been put in use. However, it still has some major side effects. Because a majority of people experience significant side effects, it requires very close follow-up and good adherence from the patient.

Healio: What was the rationale for studying heartburn drugs in this setting?

Edelstein: We were studying verapamil, a cardiac antihypertensive drug, for reducing the pumping out of drugs by human macrophages and found that use of this drug experimentally reduced the ability of the macrophages to pump out the drug and inhibited the bacterium from growing in the cell through an independent process. In trying to explore some of the specifics on how this pumping out was done, such as what mechanism was used specifically, Alexandra Lake, MD, post-doctoral research fellow in the medical research council laboratory of molecular biology and the department of medicine at the University of Cambridge, decided to look at other compounds. These compounds were inhibitors of a group of enzymes known as p-glycoproteins which help to control absorption of drugs in the body and pump out some drugs and other compounds within cells. She found that a group of compounds that are used to treat acid reflux, proton pump inhibitors, also work quite well at pumping out rifampin and limiting the growth of mycobacteria within cells.

Healio: What were the most significant findings from your study? What are the implications of these findings?

Edelstein: The most significant finding is the discovery of a different mechanism for pumping out rifampin, a major TB drug, from what we had known previously. In addition to using a different kind of efflux pump, there’s also a p-glycoprotein that pumps out this drug, and the pumping out can be more specific to rifampin than other compounds that are used to monitor the pumping out of drugs. This opens the field to the potential use of safe drugs to possibly help shorten TB therapy and to help prevent the emergence of resistance to TB drugs by keeping those drugs in higher concentrations in cells in which TB bacteria are growing. One thing that we know from other studies is that if you can inhibit the pumping out of anti-infective agents from within a bacterium or within a cell, you can limit the emergence of acquired drug resistance. The additional benefit might be to limit the emergence of drug resistance during therapy.

Healio: If future research continues to show benefits of using these drugs in the treatment of TB, what would the potential implications be for patients and their clinicians?

Edelstein: We are far away from using proton pump inhibitors for TB treatment. More laboratory studies are needed, as are animal model studies. Some of the proton pump inhibitors interact with rifampin, so human studies on how to overcome this may be needed. There is no immediate impact of these findings on patient care. We must be patient and wait for further studies to show whether the laboratory based anti-TB activity of these drugs translate to benefit for patients. Years of work need to be done in order to determine whether these compounds have any potential clinical benefit, but if they did have clinical benefit, then probably the best use would be as adjunctive therapy for other TB drugs to help shorten the course of therapy or to help prevent the emergence of resistance to these drugs.

Healio: What are your plans for future studies?

Edelstein: We may study the interaction of proton pump inhibitors with other TB drugs to see if they also can enhance their effectiveness, but we have no human studies planned.

For more information:

Paul H. Edelstein, MD, can be reached at paul.edelstein@pennmedicine.upenn.edu.

References:

Common heartburn drugs could speed up tuberculosis treatment. https://www.ukri.org/news/common-heartburn-drugs-could-speed-up-tuberculosis-treatment/. Published Feb. 7, 2023. Accessed Feb. 7, 2023.

Lake MA, et al. Proc Natl Acad Sci. 2023;doi:10.1073/pnas.2215512120.