Are long-acting injections the future of TB prevention?
A recent study published in the journal Clinical Infectious Diseases found that there was an association between healthcare workers’ exposure to high levels of carbon dioxide (CO2) and their risk of being exposed to tuberculosis (TB). IMAGE: medicinenet.com/myhealth1st.comInjections given every three months have been used for years as one of a number of contraceptive options for women. More recently, an antiretroviral injection administered every two months have been shown to be highly effective in preventing HIV infection and was recently approved for this use in the United States. In South Africa, the medicines regulator, Sahpra is currently reviewing the product.
Such long-acting products can be particularly valuable for people who, for whatever reason, struggle to take pills every day. No such long-acting formulations have, however, so far been tested in humans to prevent or treat tuberculosis (TB). But while such long-acting TB products are probably years away from clinic shelves, the research push to develop such products is underway. For now, it seems TB prevention rather than treatment is the focus given that prevention involves fewer medicines taken over a shorter time than is the case with treatment.
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Current TB prevention regimens
South Africa is in the process of rolling out a TB prevention regimen called 3HP. 3HP involves taking the drugs isoniazid and rifapentine as pills once a week for 12 weeks (three months).
3HP is gradually replacing the old standard of care of isoniazid pills taken daily for a minimum of six months. In addition to these regimens, the World Health Organization also recommends 1HP, which involves taking the same drugs as 3HP but once a day for a month.
Dr Eric Nuermberger, of the Centre for TB Research at Johns Hopkins University, says these regimens are highly effective when taken to completion but their long duration, especially in the case of isoniazid, causes many people to stop taking it before completing the treatment and this can reduce their effectiveness.
“Another major problem is that the shorter regimens containing rifapentine or rifampin (called rifampicin in South Africa) carry significant risk of drug-drug interactions that can reduce the effectiveness of many other drugs, such as antiretrovirals. So, similarly short or shorter alternative regimens comprised of drugs that don’t cause such interactions would be welcome,” he says.
What are long-acting injectables?
Nuermberger says that long-acting injections are drug formulations that create a drug depot at the site of injection and release the drug into the bloodstream at a much slower rate than when simply 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 time between injections.
“There is no specific definition for what is ‘long-acting’ but antiretroviral formulations in clinical development have yielded results suggesting that they could be effective if dosed anywhere from every month to every six months,” he says.
State of play in TB
Presenting at the recent Conference on Retroviruses and Opportunistic Infections (CROI), Nuermberger said the impressive success of long-acting injections for HIV treatment and prevention should catalyse a similar revolution in the TB space.
There are different considerations between HIV and TB when it comes to long-acting injections. “One big difference for tuberculosis preventive therapy is that it needn’t be an ongoing treatment,” says Nuermberger. “The size (volume) of the injection, which usually goes into a muscle of the arm or buttock, is a major determinant of how acceptable the injection is to the recipient. So, whether enough drug can be squeezed into an acceptable volume for injection can be an important bottleneck in long-acting injection development.”
Long-acting injections for HIV or contraception are administered repeatedly over long periods of time. In the case of TB prevention, he says, “If we can deliver a sufficient dose of drug to treat the infection with a single injection, there would be no need for any further injections. That would perhaps allow for somewhat larger-sized injections that may be tolerable when only given once but would not be well tolerated if they had to be given every one to two months.”
A course of TB preventive therapy given as a single injection could have significant practical implications.
“The ability to prevent the development of active TB with a single injection would essentially eliminate non-adherence and assure treatment completion and, therefore, increase the treatment efficacy,” says Nuermberger. “It would make it much easier to bundle TPT with other health services for at-risk populations, for example, through drug abuse treatment programmes, maternal-child health visits, refugee services, incarcerated individuals, etc. Even mass treatment campaigns could be considered in areas of high endemicity and transmission.”
So far the research is, however, still at a pre-clinical stage.
Nuermberger’s group has a mouse model of TB preventive therapy that has been predictive of the efficacy of the regimens used in humans, including 3HP and 1HP. Their earlier research also suggests that the comparatively new TB drug bedaquiline could be an effective short-course TB prevention regimen that would be useful against both drug-susceptible and MDR-TB infections when taken as a pill.
According to Nuermberger, Janssen Pharmaceuticals have now developed a long-acting injectable formulation of bedaquiline, which has been shown to be effective in the mouse model. “Although it is still early in development, we believe the results support the possibility that a single injection could be sufficient as TB preventive therapy,” he tells Spotlight.
Other research presented at CROI found a long-acting formulation of the drug rifabutin to be 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, drugs best suited for long-acting injections do not dissolve very well in water and have long half-lives in the body.”
Apart from bedaquiline and rifabutin, Nuermberger thinks 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.
While 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, former head of clinical pharmacology at the University of Cape Town Emeritus Professor Gary Maartens says it is an exciting time for TB. However, for long-acting injectables, there is still a long way to go and a lot of hurdles to overcome.
“Long-acting injectables have huge potential,” he says. “But to have them for TB in the short term or medium term, absolutely no way. None of them are anywhere close to being in the market.”
Use as TB treatment
While the initial focus is on prevention, long-acting formulations may also have potential for the treatment of active TB.
Maartens says one big issue with TB is the duration of treatment, which is for at least six months – it is difficult to get everybody to complete therapy. “If we could start therapy for a couple of months and then finish the therapy with an injection once a month or ideally one injection or one implant, that will be perfect. So, it will be lovely to have that but it’s still a long way away,” he says.
Treatment for drug-susceptible TB typically involves a two-month intensive phase where four drugs are used followed by a four-month continuation phase where only two drugs are used. Nuermberger points out that the use of two-drug long-acting formulations during the continuation phase of TB treatment could shorten the overall duration of drug administration by cutting out the last few months of what is now oral treatment. “This could increase treatment completion and success rates, as well as reduce the burden on national treatment programmes,” he says.
With TB, Maartens says, 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 have a product that’s gone into testing and is shown in conjunction with another product that it will do the job. TB trials are difficult,” he says. “They take a long time to set up so you need a very good product first. You need to show in separate studies that product A and product B have the got the right credentials and then you got to put them together. And those 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 after treatment to make sure they stay cured.”
In the context of TB treatment, there is also a potential risk of drug resistance developing should injections be missed or one of the two drugs stays in the body for a shorter period than the other.