TB Prevention in a Month? Yes, Really!

This week’s post is about a topic I only recently learned about, despite evidence being available for a few years. Let me set the scene: I had a patient with HIV on ART and a positive IGRA (Quantiferon), but no signs or symptoms of active TB. My initial plan was to offer at least 6-9 months of daily isoniazid plus vitamin B6 (6H to 9H), given its proven safety and the fact that it doesn’t require adjusting ART dosing.

However, in discussion with my attending and our ID pharmacist, they mentioned 1 month of daily rifapentine plus isoniazid (1HP). I had no idea that such a short therapy existed for latent TB infection. That night, I dove into the literature and even brought it up at our fellow journal club. To my surprise, very few colleagues — attendings or co-fellows — had heard of this regimen. Given how underrecognized it seems in general ID practice, I thought it would be a great topic to share.

I decided to discuss WHO recommendations regarding tuberculosis preventive therapy (TPT) options and how they can be applied in clinical practice. The 2020 WHO recommendations incorporate evidence published in 2018–2019 regarding rifamycin-containing regimens.

Before diving into regimens, it’s important to note that these are global recommendations, including high TB-incidence countries where LTBI testing may not be feasible due to logistic, economic, social, or infrastructural barriers. WHO acknowledges these challenges and recommends LTBI testing whenever feasible to identify those at highest risk for progression. However, testing is not required in people living with HIV or in household contacts under 5 years old. In HIV-negative household contacts ≥5 years or other risk groups, LTBI testing is recommended, but lack of testing should not prevent offering treatment if someone is judged high-risk. In high-prevalence countries, this often means preventative therapy is offered broadly, regardless of testing.

TB Preventive Therapy: Two Main Categories

1. Isoniazid Monotherapy
Isoniazid has been widely studied and remains commonly used due to proven efficacy and safety, even in pregnancy. Typically referred to as 6H, it can be offered for up to 12 months. The use of 9 months (9H) comes from re-analyses of U.S. Public Health Service trials in the 1950s–1960s, which showed that benefit increases up to 9–10 months and stabilizes thereafter (PMID: 10524579). Systematic reviews show that 6H is not significantly less effective than 12H (RR 0.58; 95% CI 0.3–1.12) (PMID: 25111745). A recent systematic review of RCTs (PMID: 28761946) also showed a significantly greater reduction in TB incidence among participants given the 6-month regimen than in those given a placebo (OR 0.65; 95% CI 0.50–0.83). No controlled clinical trials directly compared 9H vs 6H. In people living with HIV, the TEMPRANO trial (PMID: 26193126) demonstrated that 6H reduced severe HIV morbidity and mortality, even in those without confirmed LTBI. WHO guidelines note that 9H is equivalent to 6H in well-resourced countries, but 6H is generally preferred for feasibility, patient acceptability, and resource considerations.

2. Rifamycin-Containing Regimens
To shorten therapy, rifamycins have been explored as alternatives.

• 3HR (3 months of daily rifampin + isoniazid): Meta-analysis in 2005 (PMID: 15714411) showed that this short-course regimen is equivalent to standard isoniazid therapy in efficacy, severe side effects, and mortality.

• 4R (4 months of daily rifampin): The Menzies et al., 2018 RCT (PMID: 30067931) compared 4R vs. 9H in over 1,000 adults. 4R was non-inferior in preventing active TB, with higher completion rates and fewer hepatotoxic events, supporting a shorter, safer option.

• 3HP (3 months of weekly rifapentine + isoniazid): Evidence comes from multiple RCTs in adults with and without HIV, including studies in South Africa, Peru, and other countries with TB incidence <100/100,000 population (PMID: 21732833, 27243774, 22150035). No significant difference in TB incidence was found compared with 6H or 9H (RR 0.73; 95% CI 0.23–2.30). Hepatotoxicity was significantly lower in people living with HIV (PLHIV) (RR 0.26; 95% CI 0.12–0.55) and in HIV-negative adults (RR 0.16; 95% CI 0.10–0.27). Completion rates were higher across all subgroups. One RCT compared 3HP with continuous isoniazid in adult PLHIV; while intention-to-treat TB incidence was similar, per-protocol analysis favored continuous isoniazid. 3HP was typically given under direct observation. In 112 pregnant women, spontaneous abortion and birth defect rates were similar to the general population. Pharmacologically, 3HP can be co-administered safely with efavirenz-based ART. Recent studies with dolutegravir showed good tolerance, viral load suppression, and no significant drug-drug interactions, so per WHO there is no need to change dolutegravir dose in while using this therapy.

• 1HP (1 month of daily rifapentine + isoniazid): The centerpiece of this post. The BRIEF-TB trial (PMID: 30865794) enrolled individuals ≥13 years old who were not pregnant or breastfeeding. Non-inferiority was demonstrated: the incidence rate difference for TB (including death from any cause) between 1HP and 9H was −0.02 per 100 person-years (95% CI −0.35 to 0.30). Treatment completion was similar (RR 1.04; 95% CI 0.99–1.10), and Grade 3–5 adverse events were slightly lower in 1HP (RR 0.86; 95% CI 0.58–1.27). Subgroup analyses confirmed effectiveness in confirmed LTBI, males and females, and those on or off ART. WHO considers 1HP conditionally recommended, and as per their report: “recommended that this regimen may also be used in people without HIV infection” citing its short duration, good safety profile, and feasibility, though noting uncertainty in resource requirements and potential equity concerns (more expensive therefore not avaialable for all populations). A study in non HIV patients should be coming soon but seems like results are promising!

Why This Matters

I’m genuinely optimistic about treatment to prevent tuberculosis!. Shorter, safer regimens like 1HP not only improve adherence and reduce toxicity, but also make TB prevention more accessible to patients who might otherwise never complete therapy. Embracing these options means we can make TB prevention simpler and arguably more effective as adherence rates increases. It’s exciting to see how far we’ve come, and even more encouraging to imagine how much further we can go. I imagine it extremely useful in patients before anti-TNF treatment or preparing for a transplant, also those patients who are incarcerated for a short period of time!

Musical Coda