Short TB regimens fall flat

Two short treatment regimens for tuberculosis (TB) failed to match the standard 6 months of therapy in efficacy, researchers reported.

Both experimental regimens substituted a fourth-generation fluoroquinolone antibiotic for one of the drugs used in standard treatment, according to separate reports in the Oct. 23 issue of the New England Journal of Medicine (NEJM).

The reports come as the World Health Organization (WHO) released data showing that the incidence of TB is falling globally, although -- owing to better information gathering -- the actual numbers are about half a million cases higher than previously thought.

The U.N. agency said its data confirm that incidence of the disease is declining at about 1.5% a year and the mortality rate has dropped 45% since 1990.

But because of more accurate data collection, the WHO said it now estimated that about 9 million people developed TB in 2013 and 1.5 million people died from the disease.

The agency estimated that 37 million lives were saved between 2000 and 2013 through effective diagnosis and treatment.

"However, given that most deaths from TB are preventable, the death toll from the disease is still unacceptably high," the WHO said in its Global Tuberculosis Report 2014.

Gatifloxacin

One way of improving therapy would be to shorten or simplify the 6-month treatment period, authors of the two NEJM reports said.

In one study -- a noninferiority, randomized, open-label, controlled trial -- researchers led by Piero Olliaro, MD, PhD, of the WHO in Geneva. tested a 4-month regimen among patients with smear-positive, rifampin-sensitive, newly diagnosed pulmonary TB in five sub-Saharan African countries.

The control group got a standard 6-month regimen of isoniazid (Nydrazid), rifampin (Rifadin), pyrazinamide, and ethambutol (Myambutol) during the 2-month intensive phase of treatment, followed by isoniazid and rifampin during the 4-month continuation phase.

In the experimental arm, they substituted gatifloxacin (Zymaxid) for ethambutol during the intensive phase and continued it, along with rifampin and isoniazid, during a shorter 2-month continuation phase.

The primary endpoint was an unfavorable outcome -- defined as treatment failure, recurrence, death, or dropout during treatment -- measured 24 months after the end of therapy. The noninferiority margin was 6.0 percentage points.

Two years after the end of therapy, the risk of an unfavorable outcome among the 694 patients in the experimental group was 21%, compared with 17.2% among the 662 in the control group.

The difference was 3.5 percentage points, but the upper boundary of the one-sided 97.5% confidence interval was 7.7, so the trial did not show noninferiority of the experimental regimen, the researchers concluded.

The standard regimen, compared with the 4-month regimen, had a higher dropout rate during treatment (5.0% versus 2.7%) and more treatment failures (2.4% versus 1.7%) but fewer recurrences (7.1% versus 14.6%), the investigators found.

The two regimens had equivalent safety profiles and, in particular, there was no evidence of an increased risk of prolonged QT interval or dysglycemia with the 4-month regimen, they reported.

Rifapentine and Moxifloxacin

The second study tested three regimens in 827 patients from South Africa, Zimbabwe, Botswana, and Zambia with newly diagnosed, smear-positive, drug-sensitive TB.

As in the first trial, the control regimen included 2 months of daily ethambutol, isoniazid, rifampicin, and pyrazinamide, followed by 4 months of daily isoniazid and rifampicin.

Researchers led by Amina Jindani, MD, FRCP, of the University of London, compared that with two other regimens:

• A 4-month regimen in which the isoniazid was replaced by daily moxifloxacin (Avelox) for 2 months followed by moxifloxacin and 900 mg of rifapentine (Priftin) twice a week for 2 months.
• A 6-month regimen in which isoniazid was replaced by daily moxifloxacin for 2 months followed by a weekly dose of both moxifloxacin and 1,200 mg of rifapentine for 4 months.

The primary endpoint was a composite of treatment failure and relapse, with a noninferiority margin set at 6.0 percentage points.

In a per-protocol analysis, Jindani and colleagues reported, 4.9% of patients in the control group had an unfavorable response, compared with 3.2% in the 6-month experimental arm and 18.2% in the 4-month arm.

For the latter two, the differences from the control group were, respectively, -1.8 percentage points (90% CI minus 6.1-2.4) and 13.6 percentage points (90% CI 8.1-19.1).

In a modified intention to treat analysis, the pattern was similar: unfavorable outcomes for 14.4% in the control group, 13.7% in the 6-month group, and 26.9% in the 4-month group.

For the 6-month experimental arm, the difference from control was 0.4 (90% CI minus 4.7-5.6), so within the noninferiority margin. In contrast, the difference from control for the 4-month arm was 13.1 percentage points (90% CI 6.8-19.4), which exceeded the noninferiority margin.

The 6-month experimental arm, while it's the same length as standard therapy, might be valuable, the investigators argued, because it is simpler to take since it involves fewer pills.

It "could facilitate the strategy of directly observed treatment" and might be useful as first-line therapy in places where there is a high level of resistance to isoniazid or a low rate of HIV co-infection, they said.

Resistant TB and Co-Infection

In its report, the WHO said it was officially notified of 6.1 million TB cases in 2013, about two-thirds of the estimated total. Of those, 5.7 million were newly diagnosed and another 0.4 million were already on treatment.

Treatment success was 86% among all new TB cases, the agency said.

On the other hand, 3.5% of new infections and 20.5% of previously treated cases were estimated to have had multidrug-resistant (MDR) TB -- an estimated 480,000 people having developed MDR-TB in 2013.

Of those, an estimated 9.0% of patients had what is called extensively drug-resistant TB (XDR-TB).

As in the two trials, drug-susceptible TB is treated with the four first-line drugs -- isoniazid, rifampin, pyrazinamide, and ethambutol -- for 6 months.

But MDR-TB is characterized by resistance to at least isoniazid and rifampin and is treated for at least 18 to 24 months with up to six other drugs, while extensively drug-resistant TB is defined by resistance to isoniazid and rifampin, as well as any fluoroquinolone and at least one of three injectable second-line drugs, such as amikacin (Amikin), kanamycin (Kantrex), or capreomycin (Capastat).

The numbers might be an underestimate of resistant TB, the WHO said, because not all of the 6.1 million newly reported patients had been tested for drug resistance.

If they had been, the WHO estimated testing would have found an extra 300,000 cases of MDR-TB, with more than half of them in three countries: India, China, and the Russian Federation.

HIV co-infection has been a serious issue for decades; in 2013 an estimated 1.1 million (13%) of the 9 million people who developed TB in 2013 were HIV-positive.

Most of those -- 80% of cases and deaths -- were in WHO's African Region.

The number of TB deaths among HIV-positive people has been falling, from 540,000 in 2004 to 360,000 in 2013, the agency said.

In a statement, the agency said TB research and development, as well as prevention diagnosis and treatment, are suffering for lack of money.

"In addition to the serious underfunding for research, $8 billion (U.S.) a year is required for TB and MDR-TB prevention, diagnosis, and treatment," according to Katherine Floyd, PhD, the WHO's coordinator for TB monitoring and evaluation. "Domestic and international financing needs to step up to prevent millions of unnecessary deaths."

The study by Olliaro's group was supported by the Special Program for Research and Training in Tropical Diseases, the U.S. Agency for International Development, the government of Japan, the Global Alliance for TB Drug Development, and the Li Ka Shing Foundation Global Health Programme at the University of Oxford. Lupin Pharmaceuticals, India, supplied the study drugs.

Olliaro disclosed no relevant relationships with industry.

The study by Jindani's group was supported by the European and Developing Countries Clinical Trials Partnership, and the Wellcome Trust.

Jindani disclosed no relevant relationships with industry.

The WHO report was sponsored by the U.N. agency.