Daily TB treatment better than intermittent

Cutting back on standard regimens leads to more failures

By the end of 6 months, 98% of patients treated with the daily regimen had negative cultures compared with 92% of the patients treated with a thrice-weekly combination of anti-tuberculosis drugs, a difference that was highly significant (P=0.0002), reported Narendran Gopalan, MBBS, a scientist at the National Institute for Research in Tuberculosis, Chennai, India.

In his oral presentation at the International AIDS Conference, Gopalan also noted that negative cultures reached 98% or better within 2 months of treatment while at 2 months only 87% of the patients treated with the intermittent schedule had achieved negative cultures.

During the oral session reporting several studies that looked at ways of improving treatment of HIV patients who had tuberculosis co-infection, Gopalan also noted that a partial daily schedule did better than the three-times-a-week schedule but was not as efficient as the daily regimen – although the differences did not achieve statistical significance. And, he noted, in the analysis that looked at time to unfavorable responses, the two reduced treatments tracked together while the daily regimen appeared better.

In the study, he and his colleagues enrolled 331 individuals, assigning 111 to a daily regimen that included 2 months of ethambutol, rifampicin, isoniazid and pyrazinamide (EHRZ) followed by 4 months of isoniazid plus rifampicin (HR). Another 111 patients were assigned to receive EHRZ daily for 2 months, followed by HR three times a week. The third group of 109 patients was assigned to receive EHRZ three times a week for 2 months, followed by HR for three times a week for 4 months. They were also treated with antiretroviral therapy to suppress HIV as well as cotrimoxazole and high dose pyridoxine.

“The daily regimen was better than intermittent therapy at the second interim analysis,” Gopalan said. “Sputum culture conversion at the second month was significantly higher with a daily intensive phase. Part daily regimen did not confer any added advantage over intermittent therapy with respect to efficacy, toxicity, or feasibility of administration.”

Overall, adverse reactions were experienced by 24% of patients on the daily regimen; 19% of patients on the part-daily regimen and in 15% of patients on the intermittent regimen. Gopalan said the adverse events were mostly manageable. Four patients in the daily treatment died, but none died with tuberculosis. There were seven deaths among the patients on the part-daily regimen, including one with tuberculosis; four patients in the intermittent groups died, including one person who died with tuberculosis.

He noted that four cases of rifampicin resistance emerged among the patients treated on the intermittent schedule; no cases of resistance were observed among patients on the other two regimens.

In another study, high-dose rifampicin appeared to improve outcomes in a subgroup of patients co-infected with HIV and tuberculosis. Patients with very low CD4-positive cell counts got a benefit from the more intense therapy, said Corinne Merle, MD, lecturer in epidemiology at the London School of Hygiene and Tropical Medicine, and a researcher with the World Health Organization.

In the 12-month RAFA trial, about 90% of 249 patients given a high dose rifampicin and starting treatment with antiretrovirals after 8 weeks survived for a year; 90% were still alive at 18 months. Among 247 patients treated with a standard rifampicin schedule who also initiated antiretrovirals at 8 weeks, 86% were alive at 12 months and 85% survived at least 18 months; among 251 patients treated with standard rifampicin but who started antiretroviral therapy at 2 weeks, 89% survived 12 months and 88% were alive at 18 months (P=0.40).

When the researchers looked at outcomes based on CD4-positive counts at the initiation of treatment, however, Merle said they observed a clear benefit to treatment with the intensified anti-tuberculosis therapy. About 96% of the these 52 patients with CD4-cell counts below 100 cells/mm3 survived one year and 96% were alive at 18 months compared to 72% to 81% of the patients on the standard doses of rifampicin who had low CD4-positive cell counts (P=0.006).

“More aggressive tuberculosis treatment using high-dose rifampicin in addition to antiretroviral therapy could reduce tuberculosis/HIV mortality among co-infected patients with severe immunocompromised states,” Merle suggested. She said there was no evidence that treating patients with the 15 mg/kg daily dose of rifampicin for 2 months increased the risk of hepatotoxicity.