Report suggests short course of rifampicin/isoniazid as effective as standard course of isoniazid for the treatment of latent TB

A 3-month course of isoniazid (INH) plus rifampicin (RIF) is as effective a treatment of latent tuberculosis (TB) as the standard six to twelve month course of INH alone, according to review published in the March 1 issue of the journal Clinical Infectious Diseases. The review (actually an analysis of the combined data from five randomised controlled clinical trials) also concluded that severe side effects and mortality were similar on both regimens.

The analysis could provide evidence to support altering clinical practice in some settings in favour of the shorter INH/RIF regimen. But according to the paper’s authors: “The choice of which regimen to implement in clinical practice will likely depend on anticipated adherence, cost, availability of drugs, and prevalence of drug resistance in the population.”

Latent TB

After exposure to tuberculosis, the TB infection is usually contained — but not eradicated — by the immune system. The infection can persist for years as latent TB.

A percentage of people with latent TB go on to develop active TB later in life. Patients co-infected with HIV are far more likely to progress to active disease, and do so much more rapidly than those without HIV.

But treatment with INH for six or more months can cure latent TB infection (and thus prevent active TB) in the vast majority of patients. However, there are a few drawbacks to INH treatment of latent TB:

• Toxicity: INH’s side effects are usually temporary including nausea, stomach upset and dizziness. However, the medication can also cause more serious problems such as peripheral neuropathy and severe hepatitis. Liver problems are more common in patients over 50 years of age, and those who drink alcohol regularly.
• Adherence problems: Since INH must be taken for more than six months by patients who do not feel ill, it’s not uncommon for patients to fail to take the medication regularly.
• Resistance: Partly because of lapses in adherence, resistance to INH is becoming increasingly common
• Undiagnosed active disease: Failure to diagnose active TB before starting INH treatment is another cause of INH resistance (and treatment failure) because treatment of active TB requires more than one drug.

Alternatives to INH

Researchers have explored a couple of alternatives to the prolonged course of INH. One, the combination of pyrazinamide and RIF, is no longer used because it results in a substantial rate of severe liver injury and death.

Others, including the British Thoracic Society, have suggested the 3-month course of INH/RIF as another alternative but there have been no large randomised controlled studies to support recommending the regimen.

In the absence of a large study, Ena and Valls searched the medical literature for every randomised controlled trial comparing INH/RIF to INH, and pooled the data for a meta-analysis. This analysis included 1926 adults from five studies (three conducted in Spain, one in Hong Kong and one in Uganda).

Three trials included subjects with HIV infection (n = 1390), and two trials included patients without HIV infection or patients who had not been tested for HIV infection (n = 536). INH was used for 6 months in three of the studies, and for over six months in the other two trials.

Results

The mean duration of follow-up varied from 13 to 37 months. A total of 41 patients (4.2%) who received therapy with INH/RIF developed active tuberculosis, compared with 39 patients (4.1%) who received INH. Overall, development of active tuberculosis was equivalent in both regimens (pooled risk difference, 0%; 95% confidence interval [CI]).

48 patients (4.9%) who received INH/RIF had side effects severe enough to discontinue treatment, compared with 46 patients (4.8%) who received standard INH. Three trials (with 1390 patients) provided data on mortality. A total of 67 patients (9.5%) who received therapy with INH/RIF died, compared with 71 patients (10.4%) who received INH.

Conclusion and Caveats

The study author’s conclude that “In addition to an equivalent effectiveness, compared with standard isoniazid therapy, short-course regimens of rifampin plus isoniazid could provide a priori greater adherence, equivalent cost (because of the reduced number of clinical and liver monitoring tests required), and good access to therapy (because of the existence of commercialized coformulations).”

INH/RIF may be an attractive option in regions where there is decreased susceptibility to INH alone. However, there are some populations, such as people taking or needing antiretroviral drugs that interact with RIF, for whom INH may be the best choice.

Also, the study authors presume that treatment adherence would be dramatically better on the shorter regimen – but that is not necessarily the case.

Adherence to treatment was assessed in four of five trials but this meta-analysis wasn’t designed to pool adherence data. According to the study authors, adherence “was reported as being equal or greater among patients receiving short-course treatment with INH/RIF than among patients receiving standard therapy with INH.”

But the differences in adherence between the two regimens were not great — particularly when the INH regimen lasted 6 months. In two studies where INH was administered for six months, the rate of adherence was 73% and 65% vs. 76% and 69% for INH/RIF.

Furthermore, the difference in the rates of adherence varied widely from study to study — which suggests that the adherence support patients receive may be more important than whether treatment lasts three or six months.

Finally, the consequences of poor adherence to INH/RIF could be much worse than poor adherence to INH. Not taking INH as directed could lead to some INH resistance but patients who develop active TB would still have the potent drug RIF as the cornerstone of a TB treatment regimen.

Poor adherence to INH and RIF, on the other hand could lead to resistance to the two most important TB drugs. Multi-drug resistant TB (MDR-TB) is notoriously hard to treat.

The danger is even greater in the developing world, where active TB often goes undiagnosed — particularly in HIV-positive patients. Without directly observed therapy, or comparable programmes to support adherence, widespread use of INH/RIF for latent TB could simply lead to more widespread MDR-TB.