WHO issues updated TB treatment guidelines; experts say lack of trials in TB/HIV patients `striking`

Treatment regimens for tuberculosis should include an antibiotic of the rifamycin class for the full six months of therapy, according to new World Health Organization TB treatment guidelines.

They also recommend that treatment should be taken daily during the intensive, four-drug period of induction treatment, and that HIV-positive patients should take daily treatment for the entire duration of their tuberculosis (TB) therapy.

Antiretroviral therapy is endorsed in the guidelines for HIV-positive patients with active TB, regardless of their CD4 cell count.

The new guidelines also recommend provider-initiated HIV testing for all TB patients regardless of a country's HIV prevalence, and drug susceptibility testing for all TB patients with HIV at the beginning of a treatment course.

Earlier editions of the guidelines had supported only two months of rifamycin therapy, and thrice-weekly dosing during the intensive, two-month induction phase of TB therapy. The rifamycin class of antibiotics includes rifampicin (the drug most commonly used in TB treatment), rifabutin and rifapentine.

The release of the new guidelines coincided with the publication of a review article that expressed “serious concerns” about earlier guidance for the treatment of the infection in patients with HIV.

A systematic review and meta-analysis published in the May 1^st edition of Clinical Infectious Diseases commissioned by the World Health Organization to assist in the development of the guidelines, showed that the best responses to TB treatment were seen in HIV-positive patients who received rifamycin-based therapy for at least eight months.

Daily, rather than intermittent dosing during the induction period, and the use of concurrent antiretroviral therapy were also associated with better outcomes in people with TB/HIV coinfection.

Duration of rifamycin therapy

Six months of treatment including a rifamycin is now endorsed by WHO for all TB patients.

They recommend that for the intensive, two-month induction phase of treatment, standard therapy should comprise isoniazid, a rifamycin, pyrazinamide and ethambutol.

Treatment for the following four months should comprise isoniazid and rifamycin.

According to the new WHO guidance, patients with HIV should receive a minimum of six months therapy.

The authors of the meta-analysis found that HIV-positive individuals who received only two months of treatment with a rifamycin had an 80% increase in their risk of death compared to patients who were provided with eight months of treatment (adjusted risk ratio [ARR], 1.8; 95% CI, 1.0-3.1, p = 0.03). Only two months of therapy including this class of drug was also associated with a modest increase in the risk of treatment failure (ARR, 1.3; 95% CI, 0.4-4.1).

A moderate increase in the risk of relapse was associated with six months of such therapy compared to eight months (ARR, 2.4; 95% CI, 0.8-7.4).

Frequency of dosing

HIV-positive patients should receive their TB therapy daily for the entire duration of their treatment, according to the new WHO guidance.

Daily treatment is also recommended for all other patients during the two-month induction phase of therapy, and is preferred for non-HIV patients throughout the course of treatment. Three times a week dosing for this patient group should only be considered where every dose is directly observed. Daily dosing is recommended for all patients in HIV-prevalent settings.

The meta-analysis found that intermittent, thrice-weekly dosing during the initial treatment phase was associated with significantly poorer outcomes than daily treatment for patients with HIV.

“Our meta-analysis has demonstrated that rates of failure and relapse are lower if therapy is given daily during the initial intensive phase”, write the authors of the review article.

This also showed that patients who received intermittent doses were more likely to experience treatment failure (ARR = 4; 95% CI, 1.5-10.4, p = 0.02), and relapse (ARR = 4.8; 95% CI, 1.8-12.8, p = 0.002).

Concurrent antiretroviral therapy

HIV-positive patients with TB are now recommended to start antiretroviral therapy as soon as possible, and within eight weeks of the commencement of TB therapy.

Antiretroviral therapy is also endorsed for all HIV-positive patients with active TB, regardless of their CD4 cell count.

The meta-analysis found that taking concurrent antiretroviral therapy was associated with reductions in the risk of treatment failure and relapse. However, these reductions did not meet the test for statistical significance.

Concern over lack of evidence

The authors of the meta-analysis were shocked by “the paucity of well-designed and adequately powered randomized trials of HIV-TB coinfection treatment. Despite the estimated annual incidence of 1.3 million persons with HIV-TB coinfection, very basic treatment questions remained unresolved.”

Just six randomised, controlled trials and 21 cohort studies of sufficient quality to be included in their analysis were identified by the investigators. Moreover, most of these studies were small, the largest including just 553 patients.

“Randomized trials to address the questions raised by this review regarding treatment of active TB in HIV coinfected patients are urgently needed”, comment the authors.

Correction notice

An earlier version of this article referred only to the meta-analysis, and to criticisms of the previous WHO guidelines raised by the authors, and did not discuss the new guidelines. The article has now been updated to reflect the availability of new guidelines.