Frequently Asked Questions – All you need to know about TB Infection

About Latent TB and TB Preventative Treatment

Tuberculosis (TB) is a bacterial infection that spreads through the air. It most often affects the lungs but can exist in any organ of the body. When a person with TB coughs, sneezes or spits, TB bacteria are released into the air. Another person only needs to inhale a few of these bacteria to become infected. TB is curable and preventable, but it remains the top infectious killer worldwide, with 10 million people falling ill with TB in 2018.

It is estimated that just under one quarter of the world’s population is latently infected with the TB bacteria–Mycobacterium tuberculosis (Mtb).[1] “Latent TB” or “TB infection” happens when a person becomes infected with the TB bacteria but does not have any symptoms, is not yet ill and cannot transmit the disease. Most infected people are, however, at risk for active TB disease, with persons with compromised immune systems or young children having a much higher risk of moving from infection to disease. If left untreated, latent infection can develop into active TB, the form of TB that makes people sick and is capable of being transmitted from one person to another. 

[1] Houben RM, Dodd PJ. The Global Burden of Latent Tuberculosis Infection: A Re-estimation UsingMathematical Modelling. PLoS Med 2016,13:e1002152. 

Treatment of latent infection is referred to as TB preventive therapy (TPT) and is one of the most powerful ways to prevent TB. TB preventive therapy has two major goals:

  • Prevent people who are already infected with the TB bacterium from falling ill with active TB
  • Protect people who are uninfected but at risk of TB exposure from getting infected in the first place

Preventive therapy is one of the best ways to keep individuals and families safe from becoming sick with TB, which in turn helps communities become—and remain—TB free.

 It is critical to prevent new cases of TB to reach the End TB targets. At the UN High Level Meeting on TB in New York in September, 2018, heads of states committed to providing TPT to at least 30 million people, including 6 million people living with HIV by 2022, 4 million children <5 years and 20 million household contacts. To date, isoniazid preventive therapy (IPT) initiation has been low, with only 65 countries reporting initiating 1.8 million people living with HIV (PLHIV) and 349,487 children < 5 years initiating IPT in 2018.[1] There is clearly a need for rapid scale-up, and the opportunity to implement shorter regimens must be optimized.

[1] World TB Report 2019, https://www.who.int/tb/publications/global_report/en/

Based on World Health Organization (WHO) recommendations, about 18 million people were in need of TPT in low- and middle-income countries, though less than 10% were started on treatment in 2018. If countries plan to treat not only PLHIV and children but also invest in treating TB infection in household contacts, 3HP could prevent up to 6.5 million TB infections by 2025 in children, adolescents and adults in high-TB-burdened settings.

TPT regimens and services are gradually expanding globally; however, access to TPT services among populations at risk remains low. In 2018, about 1.8 million PLHIV (61% in South Africa) and 349,487 children under 5 years (27% of those eligible) received TPT across 65 countries. Coverage of contacts aged 5 years and older remains limited. This highlights the need for urgent action for resource mobilization and rapid scale-up of TPT services in line with the updated and consolidated WHO recommendations for programmatic management of TB preventive treatment published in 2020.

Additional detail

On average, 5–10% of those infected will develop active TB disease over the course of their lives, most of them within the first five years after initial infection.[1] Studies have found that about 75% of people who develop active disease after contact with someone with TB are estimated to occur within one year of TB diagnosis of the index case and 97% within two years.[2] Additional studies further confirmed the probabilities of developing disease within one, two, and five years as 45%, 62%, and 83%, respectively.[3]

In September 2018, Member States endorsed the first ever UN Political Declaration on Tuberculosis, committing to diagnose and treat 40 million people with TB by the end of 2022 and provide 30 million individuals with TPT to protect them from developing TB disease.[4] The TPT targets include 6 million people living with HIV (PLHIV), 4 million children aged under 5 years and 20 million other household contacts of TB patients.

The End TB Strategy provides indicators to monitor progress against the set global target of 90% coverage of TPT among PLHIV and household contacts by 2035.

[1] Comstock GW, Livesay VT, Woolpert SF. The Prognosis of a positive tuberculin reaction in childhood and adolescence. Am J Epidemiol. 1974 Feb 1;99(2):131–8.

[2] Borgdorff MW, Sebek M, Geskus RB, Kremer K, Kalisvaart N, van Soolingen D. The incubation period distribution of tuberculosis estimated with a molecular epidemiological approach. Int J Epidemiol. 2011 Aug 1;40(4):964–70.

[3] Sloot R, Schim van der Loeff MF, Kouw PM, Borgdorff MW. Risk of Tuberculosis after Recent Exposure. A 10-Year Follow-up Study of Contacts in Amsterdam. Am J Respir Crit Care Med. 2014 Sep 29;190(9):1044–52.

[4] United Nations General Assembly. Political declaration of the High-Level Meeting of the General Assembly on the Fight Against Tuberculosis : 2018 Oct 18 [cited 2020 Jan 10]; Available from: http://digitallibrary.un.org/record/1649568

The lifetime risk of moving from TB infection to TB disease in healthy HIV-uninfected individuals is 5-10%, with 5% developing TB disease during the first 2-5 years after infection. That risk is greatly increased in the context of immunosuppression, including HIV. In fact, PLHIV have a 20- to 37-fold greater risk of developing TB.

While antiretroviral therapy (ART) alone reduces the risk of TB by approximately two-thirds, TB remains a common cause of morbidity, and a leading cause of early mortality, among individuals on ART–with TB causing around one-third of all HIV deaths. TPT, even for individuals on ART, has been shown to reduce TB incidence and death.

Infants and children who are infected with TB and who are exposed to an active case of TB are known to have a significantly higher risk of progressing to active TB. Furthermore, TB can develop rapidly in young children who are also at greatest risk for disseminated disease, which is associated with high morbidity and mortality. TPT for contacts < 5 years has been a cornerstone of TB prevention guidelines, pre-dating the HIV era, but is often a low priority and is poorly implemented

Short-course TB Preventive Treatment: 3HP

3HP is a short-course TPT regimen that combines two TB drugs— isoniazid and rifapentine—weekly for three months. The regimen is easier for patients to take and has fewer side effects than the current standard of care—daily isoniazid for 6 to 36 months. In 2018, WHO released consolidated guidelines for the treatment of latent TB infection that recommends the use of 3HP for people living with HIV and contacts of TB patients of any age.

Treatment for latent TB infection has been available since the 1960s, yet very few people who are eligible for TB preventive therapy are receiving it. Current treatment options are long—with people required to take a pill daily for 6 to 36 months. Even among those who start treatment, many fail to complete the full course. 

Evidence shows that short-course TPT is as effective as the current treatment of choice in preventing progression to active disease. People taking shorter drug regimens are up to three times more likely to complete their course of latent TB infection therapy than those on longer regimens—leading to better outcomes and more lives saved.

A systematic review was conducted which compared the effectiveness of a 3HP with isoniazid (INH) monotherapy—the current treatment of choice. The review covered four RCTs[1][2], [3], [4]

No significant difference was found in the incidence of active TB between participants given 3HP and 6 or 9 months of isoniazid. Furthermore, the risk for hepatotoxicity was significantly lower with 3HP in adults with HIV and those without HIV. The weekly regimen was also associated with a higher completion rate in all subgroups (adults with HIV, adults without HIV, children and adolescents). It was further noted that individuals receiving treatment, clinicians providing treatment and programme managers preferred shorter to longer regimens.

A recent study published in Lancet Infectious Diseases found that rifampicin may be the safest treatment option for latent TB infection.[5] 

 

[1] Martinson NA, Barnes GL, Moulton LH, Msandiwa R, Hausler H, Ram M, et al. New regimens to prevent tuberculosis in adults with HIV infection. N Engl J Med 2011,365:11-20.

[2] Sterling TR, Scott NA, Miro JM, Calvet G, La Rosa A, Infante R, et al. Three months of weekly rifapentine and isoniazid for treatment of Mycobacterium tuberculosis infection in HIV-coinfected persons. AIDS 2016,30:1607-15.

[3] Sterling TR, Villarino ME, Borisov AS, Shang N, Gordin F, Bliven-Sizemore E, et al. Three months of rifapentine and isoniazid for latent tuberculosis infection. N Engl J Med 2011,365:2155-2166.

[4] Villarino ME, Scott NA, Weis SE, Weiner M, Conde MB, Jones B, et al. Treatment for preventing tuberculosis in children and adolescents: a randomised clinical trial of a 3-month, 12-dose regimen of a combination of rifapentine and isoniazid. JAMA Pediatr 2015,169:247-255.

[5] Campbell JR, Trajman A, Cook VJ, et al. Adverse events in adults with latent tuberculosis infection receiving daily rifampicin or isoniazid: post-hoc safety analysis of two randomized controlled trials [published online December 19, 2019]. Lancet Infect Dis. doi: 10.1016/S1473-3099(19)30575-4

  • In March 2020, five countries will be the first in the world to roll out 3HP. These countries are: Cambodia, Ethiopia, Kenya, Malawi and South Africa. Procurement of 3HP in these countries will be supported through the IMPAACT4TB project, except for South Africa, where the Department of Health is procuring the product.
  • Additional countries, including Lesotho, Eswatini, Namibia and Vietnam, are also expected to introduce 3HP around the same time, with support from PEPFAR.
  • Over 300,000 patient courses should be delivered in this first part of 2020. By the end of the year, 600,000 courses of the Sanofi product and 800,000 courses of the new fixed-dose combination will come through in our 12 IMPAACT4TB countries, PEPFAR countries and Global Fund grant-supported countries.
  • This is a new, exciting step in the fight to end TB, reducing pill burdens, shortening treatment time and providing more options to prevent TB. These countries will help further demonstrate the effectiveness of 3HP in their highest TB burden areas before it’s expanded to additional populations.
  • Adults and adolescents living with HIV who are unlikely to have active TB should receive TB preventive treatment as part of a comprehensive package of HIV care. Treatment should also be given to those on antiretroviral treatment, to pregnant women and to those who have previously been treated for TB, irrespective of the degree of immunosuppression and even if LTBI testing is unavailable.
  • Infants aged < 12 months living with HIV who are in contact with a person with TB and who are unlikely to have active TB on an appropriate clinical evaluation or according to national guidelines should receive TB preventive treatment.
  • Children aged ≥ 12 months living with HIV who are considered unlikely to have active TB on an appropriate clinical evaluation or according to national guidelines should be offered TB preventive treatment as part of a comprehensive package of HIV prevention and care if they live in a setting with high TB transmission, regardless of contact with TB.
  • All children living with HIV who have successfully completed treatment for TB disease may receive TB preventive treatment.
  • TB contacts
    • Children aged < 5 years who are household contacts of people with bacteriologically confirmed pulmonary TB and who are found not to have active TB on an appropriate clinical evaluation or according to national guidelines should be given TB preventive treatment even if LTBI testing is unavailable.
    • Children aged ≥ 5 years, adolescents and adults who are household contacts of people with bacteriologically confirmed pulmonary TB who are found not to have active TB by an appropriate clinical evaluation or according to national guidelines may be given TB preventive treatment.
  • In selected high-risk household contacts of patients with multidrug-resistant tuberculosis, preventive treatment may be considered based on individualized risk assessment and a sound clinical justification.

Yes. Based on the available data, it is safe and reasonable to start 3HP and TLD simultaneously, thus reducing risk of TB whilst effectively treating HIV. If ART initiation is done in the context of a visit with a healthcare professional, 3HP can be started at the same time, with counseling provided about both.

There is currently no evidence regarding repeated courses of 3HP. In a study in Soweto, South Africa,[1] the incidence of TB in the continuous IPT and 3HP arms were similar during the first year of follow-up, suggesting that a single round of 3HP may be durable for at least one year in high transmission settings.[2] The results of the WHIP3TB trial,[3] which is comparing a single round of 3HP to annual administration in PLHIV may inform programmatic implementation in the future. Results of the WHIP3TB trial should be available in March 2020.

[1] Martinson NA, Barnes GL, Moulton LH, Msandiwa R, Hausler H, Ram M, et al. New regimens to prevent tuberculosis in adults with HIV infection. N Engl J Med 2011,365:11-20.

[2] Martinson NA, Barnes GL, Moulton LH, Msandiwa R, Hausler H, Ram M, et al. New regimens to prevent tuberculosis in adults with HIV infection. N Engl J Med 2011,365:11-20.

[3] Churchyard GJ, Cardenas V, et al. A randomised, pragmatic, open-label trial to evaluate the effect of three months of high dose rifapentine plus isoniazid administered as a single round or given annually in HIV-positive individuals. Trial ongoing.

There is no evidence of a significant association between TB drug resistance and the use of INH or rifamycins for TPT. In a systematic review of 13 published studies since 1951, there was no suggestion of an increased risk of isoniazid-resistant TB after IPT.

Rifapentine is not recommended for pregnant women, but this is due to an absence of data rather than evidence of harm. Rifapentine has not yet been studied in pregnant women. However, a retrospective look at women who became pregnant while taking 3HP in clinical trials showed no reason for alarm. The WHO continues to recommend that pregnant women with HIV have the option of taking IPT.

 

In a study of 3HP in 112 pregnant women, the rates of spontaneous abortion and birth defects were similar to those in the general U.S. population. However, further evidence is required before 3HP can be recommended during pregnancy. Ongoing trials will provide information on the safety and efficacy of 3HP in pregnancy.

 

A clinical trial assessing the safety and pharmacokinetics (PK) of giving 3HP to pregnant and post-partum women with and without HIV (P2001, U.S. NIH) will report results this year—maybe as soon as the CROI conference in early March.

Rifapentine can reduce the effectiveness of hormonal contraceptives (oral, intramuscular or intradermal); therefore, women who use hormonal birth control should be advised to add or switch to a barrier method.

Pricing and Manufacturing

A three-month treatment course of rifapentine Sanofi singles (Priftin®) will cost approximately US $17 (instead of US $45). Three Priftin® packs are required for a 12-week patient course, plus 36 tablets of INH at about $1 plus 12 tablets of pyridoxine at .80c for PLHIV and malnourished children.

The “ex works” price of the fixed dose combination (FDC) from Macleods is $15 for a three-month treatment course of 3HP FDC. Countries may need to add vitamin B6 here for malnourished children and PLHIV.

These prices are available to the public sectors of low-income countries, lower-middle income countries, and upper-middle income countries with a high burden of TB and TB/HIV. Manufacturers, donors and I4TB are committed to maintaining affordable access to rifapentine beyond 2020, taking into consideration the market entry of additional suppliers of rifapentine-based LTBI treatments in new formulations in 2021.

Modelling studies have shown that the 3HP regimen could be cost-effective, reducing the economic burden of TB control efforts. Although 3HP is currently more expensive than IPT in the short term, the shorter duration of treatment with 3HP and the higher rates of treatment completion make it more cost-effective in the long term. Ultimately, the cost of 3HP will be reduced by further lowering the cost of rifapentine, a major objective of the IMPAACT4TB project, through market shaping, catalyzing demand and the introduction of generic manufacturers over four years. In the last year alone, the cost of a patient course for rifapentine moved from US $72 to US $45 to US $15, an 80% reduction.

As part of the IMPAACT4TB project, CHAI launched a request for proposal (RfP) process in November 2018 that invited pharmaceutical manufacturers to submit competitive bids for the development of rifapentine single 300 mg tablets or a rifapentine/isoniazid 300/300 mg fixed dose combination (FDC). The RfP is part of the project’s effort to ensure affordable and reliable supply of the 3HP regimen through accelerated market entry at a target price by new suppliers. In January 2020, Unitaid concluded a commercialization agreement with Macleods pharmaceuticals for the market entry of a quality assured FDC ofrifapentine(RPT)/isoniazid(INH) 300mg/300mg tablets. Macleods has agreed to offer a ceiling price of US $15 ex works (i.e., direct from the factory or place of manufacture) for a pack of 36 FDC tablets equivalent to a 3-month patient course of 3HP therapy. 

Unitaid intends to support the entry of at least one additional generic supplier of the RPT/INH 300mg/300mg FDC, as well as other rifapentine-based formulations (including for paediatric therapy).