TB treatment guidelines need to change, systematic reviews show

International guidelines for treating tuberculosis need to be updated to recommend six months of rifampicin treatment in first-line therapy for all countries, and to improve the ways in which relapsers and isoniazid-resistant patients are treated, according to two systematic reviews published this week in the open access journal PLoS Medicine.

Public health programmes in many countries follow guidelines developed by the World Health Organization guidelines for treatment of tuberculosis (TB). However, these guidelines have not been revised since 2003 and are due to be updated in 2009.

Dr Dick Menzies, director of the Respiratory Division of McGill University, Montreal, and colleagues from the United States and the International Union Against Tuberculosis and Lung Disease carried out two systematic reviews of the scientific literature to assess the evidence on several controversies in TB treatment:

• How long should patients receive rifampicin in first-line treatment? The current recommendation is for two months of rifampicin, isoniazid, ethambutol and pyrazinamide, followed by 4-6 months of continuation treatment with two antibiotics. Although many countries use rifampicin in the continuation phase, the practice is far from universal. Are rates of failure, relapse and drug resistance higher with a shorter duration of rifampicin treatment?
• How should patients who fail to respond to first-line treatment be treated, especially those without resistance or with resistance only to isoniazid? The current recommendation is that these patients should receive an 8-month course of isoniazid, rifampicin and ethambutol, with pyrazinamide and streptomycin added for the first three and two months respectively.

The studies were partially funded by the World Health Organization in order to inform the development of new TB treatment guidelines.

Rifampicin in first-line treatment

In the first study, the researchers identified and analysed 57 randomised, controlled clinical trials including more than 20,000 participants treated for TB conducted since 1965.

They found that regimens using the drug rifampicin for only the first two months had significantly higher rates of failure, relapse, and acquired drug resistance compared with regimens that used rifampicin for at least six months.

Based on the pooled risk differences from the trial analyses, the reviewers estimate that treatment of 100 patients with a two-month rifampicin-containing introductory regimen, followed by isoniazid/ethambutol for six months (still standard practice in at least 24 countries, according to WHO), would result in 13 more treatment failures or relapses per 100 patients treated when compared to six months of rifampicin-containing treatment.

Patients who had drug resistance at baseline were at particularly high risk of poor treatment outcomes if they received only two months of rifampicin treatment.

The investigators note that because most studies pre-dated the AIDS epidemic it is not possible to provide definitive information about the duration of rifampicin treatment in HIV/TB- coinfected people.

They say that more research is needed in the form of adequately powered clinical trials to determine optimum dosing schedules, management of isoniazid monoresistance and the optimal duration of treatment to prevent relapse.

Some countries have implemented three-times-a-week dosing of rifampicin during the introductory phase of treatment in order to improve the ability of health systems to provide directly observed therapy. The reviewers found that this intermittent dosing schedule was associated with an increased risk of acquired drug resistance, but not of relapse or treatment failure.

Relapsers, non-responders and isoniazid-resistant patients

The second study analysed trials of TB treatment in previously treated individuals who had relapsed after treatment or failed to respond to treatment, or those with isoniazid-resistant infection. (It is important to note that this does not include the more-difficult-to-treat patients with multidrug resistant TB).

The authors note that 10-20% of patients receiving TB treatment in low and middle-income countries require re-treatment, and say that the re-treatment regimen plays a key role in any DOTS strategy.

The researchers found no randomised trials comparing the currently recommended WHO retreatment regimen against other approaches. In non-comparative (cohort) studies, failure rates were generally low if participants were infected with strains that were sensitive to all antibiotics in the regimen.

However, in studies in which participants were infected with a strain of Mycobacterium tuberculosis resistant to one or more drugs, failure rates ranged from 9% to 45%.

The researchers also analysed the combined results of 33 trials that investigated the effect of various regimens on almost 2,000 patients (some receiving their first treatment for TB, others being retreated) with resistance to isoniazid alone.

This meta-analysis found lower relapse, failure and acquired drug resistance rates to be associated with longer duration of rifampicin treatment, daily therapy early in treatment, inclusion of the drug streptomycin, and regimens that included a greater number of drugs to which the patient's TB infection was sensitive.

Nevertheless, the authors say that “the current body of evidence for treatment of previously treated patients is a dog’s breakfast…The current re-treatment regimen was not tested and refined in a sequence of randomized trials. Instead, this regimen was the product of expert opinion.”

The most immediate needs identified by the review, they say, are increased access to drug sensitivity testing, and a redesigned re-treatment regimen that is based on the assumption that in the future all patients will have received a six-month course of rifampicin.

Studies of re-treatment regimens need to be given greater priority, they point out, because cases of monoresistance in TB patients remain around five times more common than multidrug resistance (MDR), and because of the extreme weakness of the evidence base regarding retreatment of isoniazid-resistant TB patients. “An effective regimen for the group that requires re-treatment could reduce generation of MDR,” they conclude.

Taken together, these findings will inform upcoming revisions of the WHO TB treatment guidelines, and identify an important need for clinical trials to evaluate dosing schedules, detection and management of isoniazid resistance, and the optimal duration of treatment to prevent relapse, as well as more effective approaches to retreatment of tuberculosis. International, multicentre trials recruiting large numbers of patients will be needed.