Alternatives to isoniazid monotherapy for preventing active tuberculosis in HIV-negative persons

Tuberculosis (TB) is a disease that is caused by a bacterial infection that affects an estimated two billion people (about a third of the world's population). However, most people have dormant (latent) infections and only a small percentage of people infected with TB will develop an active disease. Preventing latent TB infection (LTBI) developing into active TB, through the use of drugs, is an important part of global TB control. Treatment with the drug isoniazid for six months is recommended, but the treatment period is long, it can cause liver damage, and only about half of the people who start this drug treatment complete it.

The authors of this review evaluated alternatives to isoniazid monotherapy in HIV-negative people with LTBI. They identified 10 randomized controlled trials that included 10,717 adults and children, who were mostly HIV-negative, with a follow-up period ranging from two to five years.

Rifampicin for three to four months may give quite similar results to isoniazid for six months in preventing TB, and may cause fewer side effects. As the treatment period with rifampicin is shorter, it may result in more people completing treatment. Two other drug combination treatments (rifampicin plus isoniazid, and rifampicin plus pyrazinamide) did not differ in preventing TB compared with isoniazid alone, but they resulted in more adverse events. A third combination of rifapentine plus isoniazid supervised weekly for three months was as effective in preventing TB as self-administered isoniazid for nine months, increased treatment completion, and caused less liver toxicity, though treatment-limiting adverse events were more frequent with the weekly rifapentine and isoniazid combination.

Authors' conclusions: 

Trials to date of shortened prophylactic regimens using rifampicin alone have not demonstrated higher rates of active TB when compared to longer regimens with INH. Treatment completion is probably higher and adverse events may be fewer with shorter rifampicin regimens. Shortened regimens of rifampicin with INH may offer no advantage over longer INH regimens. Rifampicin combined with pyrazinamide is associated with more adverse events. A weekly regimen of rifapentine plus INH has higher completion rates, and less liver toxicity, though treatment discontinuation due to adverse events is probably more likely than with INH.

Read the full abstract...

Preventing active tuberculosis (TB) from developing in people with latent tuberculosis infection (LTBI) is important for global TB control. Isoniazid (INH) for six to nine months has 60% to 90% protective efficacy, but the treatment period is long, liver toxicity is a problem, and completion rates outside trials are only around 50%. Rifampicin or rifamycin-combination treatments are shorter and may result in higher completion rates.


To compare the effects of rifampicin monotherapy or rifamycin-combination therapy versus INH monotherapy for preventing active TB in HIV-negative people at risk of developing active TB.

Search strategy: 

We searched the Cochrane Infectious Disease Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; EMBASE; LILACS; clinical trials registries; regional databases; conference proceedings; and references, without language restrictions to December 2012; and contacted experts for relevant published, unpublished and ongoing trials.

Selection criteria: 

Randomized controlled trials (RCTs) of HIV-negative adults and children at risk of active TB treated with rifampicin, or rifamycin-combination therapy with or without INH (any dose or duration), compared with INH for six to nine months.

Data collection and analysis: 

At least two authors independently screened and selected trials, assessed risk of bias, and extracted data. We sought clarifications from trial authors. We pooled relative risks (RRs) with their 95% confidence intervals (CIs), using a random-effects model if heterogeneity was significant. We assessed overall evidence quality using the GRADE approach.

Main results: 

Ten trials are included, enrolling 10,717 adults and children, mostly HIV-negative (2% HIV-positive), with a follow-up period ranging from two to five years.

Rifampicin (three/four months) vs. INH (six months)

Five trials published between 1992 to 2012 compared these regimens, and one small 1992 trial in adults with silicosis did not detect a difference in the occurrence of TB over five years of follow up (one trial, 312 participants; very low quality evidence). However, more people in these trials completed the shorter course (RR 1.19, 95% CI 1.01 to 1.30; five trials, 1768 participants; moderate quality evidence). Treatment-limiting adverse events were not significantly different (four trials, 1674 participants; very low quality evidence), but rifampicin caused less hepatotoxicity (RR 0.12, 95% CI 0.05 to 0.30; four trials, 1674 participants; moderate quality evidence).

Rifampicin plus INH (three months) vs. INH (six months)

The 1992 silicosis trial did not detect a difference between people receiving rifampicin plus INH compared to INH alone for occurrence of active TB (one trial, 328 participants; very low quality evidence). Adherence was similar in this and a 1998 trial in people without silicosis (two trials, 524 participants; high quality evidence). No difference was detected for treatment-limiting adverse events (two trials, 536 participants; low quality evidence), or hepatotoxicity (two trials, 536 participants; low quality evidence).

Rifampicin plus pyrazinamide (two months) vs. INH (six months)

Three small trials published in 1994, 2003, and 2005 compared these two regimens, and two reported a low occurrence of active TB, with no statistically significant differences between treatment regimens (two trials, 176 participants; very low quality evidence) though, apart from one child from the 1994 trial, these data on active TB were from the 2003 trial in adults with silicosis. Adherence with both regimens was low with no statistically significant differences (four trials, 700 participants; very low quality evidence). However, people receiving rifampicin plus pyrazinamide had more treatment-limiting adverse events (RR 3.61, 95% CI 1.82 to 7.19; two trials, 368 participants; high quality evidence), and hepatotoxicity (RR 4.59, 95% 2.14 to 9.85; three trials, 540 participants; moderate quality evidence).

Weekly, directly-observed rifapentine plus INH (three months) vs. daily, self-administered INH (nine months)

A large trial conducted from 2001 to 2008 among close contacts of TB in the USA, Canada, Brazil and Spain found directly observed weekly treatment to be non-inferior to nine months self-administered INH for the incidence of active TB (0.2% vs 0.4%, RR 0.44, 95% CI 0.18 to 1.07, one trial, 7731 participants; moderate quality evidence). The directly-observed, shorter regimen had higher treatment completion (82% vs 69%, RR 1.19, 95% CI 1.16 to 1.22, moderate quality evidence), and less hepatotoxicity (0.4% versus 2.4%; RR 0.16, 95% CI 0.10 to 0.27; high quality evidence), though treatment-limiting adverse events were more frequent (4.9% versus 3.7%; RR 1.32, 95% CI 1.07 to 1.64 moderate quality evidence)