Injections given every three months have been used for years as one of many contraceptive options for women. More recently, an antiretroviral injection given every two months has been shown to be very effective in preventing HIV infection and has recently been approved for this use in the United States. In South Africa, the medicines regulator, Sahpra, is currently reviewing the product.
These long-acting products can be especially helpful for people who, for whatever reason, find it difficult to take pills every day. However, none of these long-acting formulations have so far been tested in humans to prevent or treat tuberculosis (TB). But while these long-acting TB products are likely years away from clinic shelves, research to develop such products is ongoing. For now, it seems that TB prevention rather than treatment is the goal since prevention involves fewer drugs taken over a shorter period of time than is the case with treatment.
Current TB prevention regimens
South Africa is rolling out a TB prevention regimen called 3HP. 3HP involves taking the drugs isoniazid and rifapentine in tablet form once a week for 12 weeks (three months).
3HP is gradually replacing the older standard of care of isoniazid pills taken daily for at least six months. In addition to these diets, the World Health Organization also recommends 1HP, which involves taking the same medications as 3HP but once a day for a month.
Dr. Eric Nuermberger of the Center for TB Research at Johns Hopkins University says these regimens are very effective when followed through, but their long duration, particularly with isoniazid , causes many people to stop taking it before completing treatment. may reduce their effectiveness.
“Another major issue is that shorter treatment regimens containing rifapentine or rifampicin (called rifampicin in South Africa) carry a significant risk of drug interactions which can reduce the effectiveness of many other drugs, such as So equally or shorter alternative treatment regimens consisting of drugs that do not cause such interactions would be welcome,” he says.
What are long-acting injectables?
Nuermberger says long-acting injections are drug formulations that create a depot of drug at the injection site and release the drug into the bloodstream at a much slower rate than when just injecting the drug alone. He says long-acting injections could be used to maintain effective drug concentrations in the bloodstream and at the site of infection for a much longer period between injections.
“There is no specific definition of what is ‘long-acting’, but antiretroviral formulations in clinical development have shown results suggesting that they may be effective if given between monthly and every six months,” he said.
State of tuberculosis
In a presentation at the recent Conference on Retroviruses and Opportunistic Infections (CROI), Nuermberger said the impressive success of long-acting injections for the treatment and prevention of HIV should catalyze a similar revolution in the field of tuberculosis.
There are different considerations between HIV and TB when it comes to long-acting injections. “A big difference for TB preventive treatment is that it doesn’t have to be ongoing treatment,” Nuermberger says. “The size (volume) of the injection, which typically goes into a muscle in the arm or buttock, is a major determinant of the acceptability of the injection to the recipient. So whether enough drug can be squeezed into an acceptable volume for injection can be a significant bottleneck in the development of long-acting injections.”
Long-acting injections for HIV or contraception are given repeatedly over long periods of time. In the case of TB prevention, he says, “if we can give a sufficient dose of the drug to treat the infection with a single injection, there would be no need for further injections. -be somewhat larger injections which may be tolerable when given only once, but would not be well tolerated if given every one to two months.”
Preventive treatment for tuberculosis given in a single injection could have important practical implications.
“The ability to prevent the development of active TB with a single injection would essentially eliminate non-adherence and ensure treatment completion and, therefore, increase treatment efficacy,” Nuermberger says. “It would be much easier to bundle TPT with other health services for at-risk populations, for example, through drug treatment programs, mother-child health visits, refugee services, of incarcerated individuals, etc. Even mass treatment campaigns could be envisaged in areas of high endemicity and transmission.”
So far, however, the research is still at a preclinical stage.
Nuermberger’s group has a mouse model of TB preventive therapy that has been predictive of the effectiveness of treatment regimens used in humans, including 3HP and 1HP. Their previous research also suggests that bedaquiline, a relatively new tuberculosis drug, could be an effective short-course treatment for the prevention of tuberculosis that would be useful against both drug-susceptible infections and multidrug-resistant tuberculosis when it is taken in pill form.
According to Nuermberger, Janssen Pharmaceuticals has now developed a long-acting injectable formulation of bedaquiline, which has been shown to be effective in the mouse model. “Although still in early development, we believe the results support the possibility that a single injection may be sufficient as a preventive treatment for tuberculosis,” he told Spotlight.
Other research presented at CROI found that a long-acting formulation of the drug rifabutin was effective in another mouse model. “Not all drugs are suitable for LAI formulations,” says Nuermberger. “In fact, most drugs designed for oral use are not suitable for long-acting injections. In addition to having very potent activity, the drugs best suited for long-acting injections are not do not dissolve very well in water and have long half-lives in the body.”
Besides bedaquiline and rifabutin, Nuermberger believes that rifapentine and delamanid may also be effective as long-acting formulations. He also points out that it may be possible to chemically modify existing drugs to make them more suitable for long-acting formulations and that he is involved in a project to do just that with isoniazid.
Although the current focus is on injections, other types of long-acting formulations such as polymer implants, like those already used for contraception, may also be possible. Such implants for HIV prevention are already being researched.
Long way to go
Speaking to Spotlight, the former head of clinical pharmacology at the University of Cape Town, Emeritus Professor Gary Maartens, said it was an exciting time for TB. However, for long-acting injectables, there is still a long way to go and many hurdles to overcome.
“Long-acting injectables have enormous potential,” he says. “But having them for TB in the short to medium term is absolutely impossible. None of them are close to being on the market.”
Use as a treatment for tuberculosis
While the initial focus is on prevention, long-acting formulations may also have potential for the treatment of active tuberculosis.
Maartens says a big problem with TB is the length of treatment, which is at least six months – it’s hard to get everyone to complete treatment. “If we could start therapy for a few months and then finish therapy with an injection once a month or ideally an injection or an implant, that would be perfect. So it would be nice to have that but it’s still a long way away,” he says.
Treatment of drug-susceptible tuberculosis usually involves a two-month intensive phase in which four drugs are used, followed by a four-month continuation phase in which only two drugs are used. Nuermberger points out that using long-acting two-drug formulations during the continuation phase of TB treatment could shorten the overall duration of drug administration by cutting out the final months of what is now oral treatment. “This could increase treatment completion and success rates, as well as reduce the burden on national treatment programs,” he says.
With TB, says Maartens, what we can learn from other diseases is that it is possible and people like it. “But we can’t talk about it until we’ve tested a product and it’s been shown, in combination with another product, that it will do. TB trials are difficult,” he said. “They take a long time to set up, so first you need a really good product. You have to show in separate studies that product A and product B have the right credentials, and then you have to put them together And these trials take years to set up and years to do because what you want to do is you want to show at the end of treatment that people are cured and you have to wait a year or two afterwards treatment to make sure they stay cured.”
In the treatment of tuberculosis, there is also a potential risk of developing drug resistance if injections are missed or if one of the two drugs remains in the body for a shorter period of time than the other. .