New dawn in TB prevention therapy

It is estimated that around 1.7 billion people on earth are infected with tuberculosis (TB). In these so-called latent infections, people have TB in their bodies, but they have the bacteria well enough under control so as not to get sick. The risk to these people is that the TB might “activate” and make them ill should their immune system become weak, which could for example happen due to HIV infection.

Without a broadly effective vaccine that could give protection for TB to either prevent TB infection, or prevent infection from activating into TB disease, currently, the best option for TB prevention is to treat such TB infections with medicine.

The benefits of using isoniazid, one of the oldest and most powerful anti-TB medicines, to prevent TB infection from activating have been known for years. Studies published recently have provided very compelling evidence showing that providing people living with HIV with isoniazid substantially reduces their risk of TB and of dying. Yet, uptake of isoniazid preventative therapy around the world has been very slow – with recent scale-up in South Africa being a notable exception.

Isoniazid can prevent TB disease when given daily for anywhere from six to 36 months, with nine months being most common. These days isoniazid is also available in a single tablet along with cotrimoxazole (an important medicine for preventing other kinds of infections in people with advanced HIV) and vitamin B6 (which must be given along with isoniazid to prevent isoniazid’d from damaging nerves).

The long duration of treatment with isoniazid might be one reason why uptake has been poor. Another is that people taking preventative therapy are by definition not ill with TB and might thus lack motivation to take the pills, especially when they come with potential side effects such as liver damage.

New shorter regimens

In recent months and years, three new options for TB preventative therapy have done well in clinical trials. The two common factors in these trials are that (a) the length of treatment is reduced and that (b) they all make use of a class of drugs called the rifamycins.

The most well-studied, and at this stage the most likely new regimen to reach public sector clinics in South Africa, is called 3HP. The 3HP regimen consists of three months during which two medicines are taken just once a week. The two medicines are isoniazid (often abbreviated as H) and rifapentine (abbreviated as P). Like with isoniazid alone, these must also be given with vitamin B6. This regimen is relatively well studied and is already included in the treatment guidelines of the United States Centres for Disease Control and the World Health Organization. Its use is recommended in both people with and without HIV infection, including children age 2 years and older. South Africa’s National Strategic Plan for HIV, TB and STIs 2017 – 2022 specifically mentions 3HP and commits to making this regimen available should further evidence support it.

The 3HP regimen has significant advantages over isoniazid alone. It has much less effect on the liver than the daily isoniazid regimen. Because it is so much shorter—just 12 weeks compared to months or even years of isoniazid—people may prefer it. Indeed, trials have shown that participants complete the 3HP regimen much more often than a longer isoniazid-based regimen.

One concern with the 3HP regimen is that rifapentine may have an interaction with a critical new HIV medicine called dolutegravir. We expect to learn in early 2019 about findings from a study designed to give a definitive answer on whether it is safe to use rifapentine with dolutegravir, and whether dosing changes to dolutegravir will be needed when using the two medicines together.

The other concern with 3HP is that rifapentine is still quite expensive, at USD $45 for the rifapentine portion of the 3HP regimen (this does not include the isoniazid or vitamin B6). The good news, however, is that rifapentine is off patent and more companies are expected to bring rifapentine products to market in the coming years – thus pushing the price down through competition. And even before then, this cost of preventing TB cases is far less than the economic and social costs of allowing the TB infection to progress to active disease and infect others.

A second new option is the so-called 1HP regimen. This regimen requires taking two medicines plus vitamin B6 a day for only one month. This is even shorter than the 3HP regimen, and the daily rather than weekly dosing may be preferred by people with HIV who are taking daily antiretrovirals anyway. The two drugs used in 1HP are the same as in 3HP – rifapentine and isoniazid – accordingly, the same pricing and drug interaction concerns seen with 3HP are also concerns with 1HP. A study reported in March 2018 found that 1HP was non-inferior to nine months of isoniazid in people living with HIV and resulted in fewer adverse events. 1HP is however less well studied than 3HP, and has not yet been studied in people without HIV – something that makes it unlikely that the regimen will beat 3HP to clinics.

A third new option is called 4R and involves four months of daily rifampicin pills. Rifampicin is of the same drug family as rifapentine but has been much more widely used given that, like isoniazid, it forms part of the standard four-drug treatment for active TB. A large study published in August 2018 found that this four-month rifampicin regimen is non-inferior to nine months of isoniazid. Like rifapentine, rifampicin does interact with some HIV medicines and can require dosing adjustments of antiretrovirals. Additionally, there were few people living with HIV in this trial, so it is not yet certain how well 4R works in this population.

One advantage of 4R is that Rifampicin is much less expensive than rifapentine. Another advantage is that this regimen could be good for people who cannot tolerate isoniazid. At four months, 4R is however longer than the rifapentine-based regimens.

In any case, it seems likely the days of isoniazid-only TB prevention are over, with shorter options that may help people start, and finish, therapy to prevent TB. For now, its most likely replacement is 3HP.

 

 

 

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