New dawn in TB prevention therapy

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It is estimated that around 1.7bn people on earth are infected with tuberculosis (TB). Spotlight reports that 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.

The report says 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. The report says 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 report says 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.

In recent months and years, three new options for TB preventative therapy have done well in clinical trials, the report says. 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 report says. 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 US Centres for Disease Control and Prevention and the World Health Organisation. 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 report says 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.

The report says 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 $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.

The report says 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 by researchers at the University of Nebraska Medical Centre, Harvard University, Johns Hopkins Hospital, University of California San Diego, Molepolole Clinical Research Site, GHESKIO, Port-au-Prince, Haiti, Barranco Clinical Research Site, Lima, Peru,University of the Witwatersrand, Social & Scientific Systems, Johns Hopkins University, 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. The report says 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.

Abstract 1
Tuberculosis (TB) is the leading killer of people with HIV infection. Preventive therapy is effective but current regimens are limited by toxicity and low completion rates. We hypothesized that an ultra-short course of isoniazid (H)/ rifapentine (P) would be non-inferior to 9 months H in people with HIV infection.
This multicenter, randomized, open-label, phase 3 trial enrolled HIV-infected individuals >13 y living in high TB-burden areas or who were TB skin test (TST)/Interferon-ϒ release assay (IGRA) positive. Antiretroviral therapy (ART) with efavirenz or nevirapine was permitted. Participants (pts) were stratified by ART status and CD4 count, randomized 1:1 to 1 month of daily H 300 mg plus P 450-600 mg (1HP) or 9 months daily H 300 mg (9H), and followed until 3 y after the last enrollment. The primary objective was to compare incidence rates (IR) of active TB, TB death, or death from an unknown cause. TB diagnoses and deaths were reviewed independently. A non-inferiority margin of 1.25/100 PY was based on an assumed IR of 2.0/100 PY in the 9H arm.
3000 pts were recruited by 45 sites in 10 countries from 5/2012-11/2014 and data are current as of 12/20/2017. 1614 (54%) were women, median age was 35 y (IQR 28-43), 1983 (66%) were Black, 730 (24%) Hispanic, and median BMI was 23.5 (IQR 20.9-27.1). Median CD4 count was 470 cells/mm3 (IQR 346-635) and 50% were on ART at entry. 634 (21%) had positive TST or IGRA. The primary endpoint occurred in 34 pts in the 1HP arm and 35 in the 9H arm, for incidence rates of 0.69/100 PY for 1HP and 0.72/100 PY for 9H (IR difference = -0.025, upper 95% CI: 0.31, Table). Rates were higher for pts not on ART at entry and those with a positive TST/IGRA, with no difference between treatments. For those with baseline CD4 counts <250 cells/mm3, incidence was higher in the 1HP arm, but the difference was not statistically significant (p=0.12). Serious adverse events occurred in 5.6% of 1HP pts and 7.1% of 9H pts (p=0.1). The incidence of targeted safety events was 3.3/100 PY with 1HP and 5.1/100 PY with 9H (P=0.03); treatment completion was higher in the 1HP arm than 9H (97% vs. 90%, P<0.01). There was 1 case of rifampin-resistant TB in each arm and 1 case of H-resistant TB in the 9H arm.
Once daily 1HP was non-inferior to 9H, had fewer adverse events, and was more likely to be completed in HIV-infected adults and adolescents. This ultra-short course TB preventive therapy could be an important tool to control HIV-related TB.

Susan Swindells, Ritesh Ramchandani, Amita Gupta, Constance A Benson, Jorge T Leon-Cruz, Ayotunde Omoz-Oarhe, Marc Antoine Jean Juste, Javier R Lama, Javier A Valencia, Sharlaa Badal-Faesen, Laura E Moran, Courtney V Fletcher, Eric Nuermberger, Richard E Chaisson

Abstract 2
Background: A 9-month regimen of isoniazid can prevent active tuberculosis in persons with latent tuberculosis infection. However, the regimen has been associated with poor adherence rates and with toxic effects.
Methods: In an open-label trial conducted in nine countries, we randomly assigned adults with latent tuberculosis infection to receive treatment with a 4-month regimen of rifampin or a 9-month regimen of isoniazid for the prevention of confirmed active tuberculosis within 28 months after randomization. Noninferiority and potential superiority were assessed. Secondary outcomes included clinically diagnosed active tuberculosis, adverse events of grades 3 to 5, and completion of the treatment regimen. Outcomes were adjudicated by independent review panels.
Results: Among the 3443 patients in the rifampin group, confirmed active tuberculosis developed in 4 and clinically diagnosed active tuberculosis developed in 4 during 7732 person-years of follow-up, as compared with 4 and 5 patients, respectively, among 3416 patients in the isoniazid group during 7652 person-years of follow-up. The rate differences (rifampin minus isoniazid) were less than 0.01 cases per 100 person-years (95% confidence interval [CI], −0.14 to 0.16) for confirmed active tuberculosis and less than 0.01 cases per 100 person-years (95% CI, −0.23 to 0.22) for confirmed or clinically diagnosed tuberculosis. The upper boundaries of the 95% confidence interval for the rate differences of the confirmed cases and for the confirmed or clinically diagnosed cases of tuberculosis were less than the prespecified noninferiority margin of 0.75 percentage points in cumulative incidence; the rifampin regimen was not superior to the isoniazid regimen. The difference in the treatment-completion rates was 15.1 percentage points (95% CI, 12.7 to 17.4). The rate differences for adverse events of grade 3 to 5 occurring within 146 days (120% of the 4-month planned duration of the rifampin regimen) were −1.1 percentage points (95% CI, −1.9 to −0.4) for all events and −1.2 percentage points (95% CI, −1.7 to −0.7) for hepatotoxic events.
Conclusions: The 4-month regimen of rifampin was not inferior to the 9-month regimen of isoniazid for the prevention of active tuberculosis and was associated with a higher rate of treatment completion and better safety. (Funded by the Canadian Institutes of Health Research and the Australian National Health and Medical Research Council

Dick Menzies, Menonli Adjobimey, Rovina Ruslami, Anete Trajman, Oumou Sow, Heejin Kim, Joseph Obeng Baah, Guy B Marks, Richard Long, Vernon Hoeppner, Kevin Elwood, Hamdan Al-Jahdali, Martin Gninafon, Lika Apriani, Raspati C Koesoemadinata, Afranio Kritski, Valeria Rolla, Boubacar Bah, Alioune Camara, Isaac Boakye, Victoria J.Cook, Hazel Goldberg, Chantal Valiquette, Karen Hornby, Marie-Josée Dion, Pei-Zhi Li, Philip C Hill, Kevin Schwartzman, Andrea Benedetti

Spotlight report
CROI 2018 abstract
New England Journal of Medicine abstract

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