TB prevention trial fails

Preventive tuberculosis therapy had no lasting effect on TB incidence among South African gold miners -- a group hard-hit by the disease, researchers reported.

In a cluster-randomized trial, the therapy -- 9 months of isoniazid (Nydrazid) -- also did not cut prevalence of TB among the miners, according to Gavin Churchyard, MBBCh, PhD, of the Aurum Institute in Johannesburg, South Africa, and colleagues.

On the other hand, while miners were actually taking the drug, they were less likely to develop TB, Churchyard and colleagues reported in the Jan. 23 issue of the New England Journal of Medicine. But that so-called direct effect vanished when the treatment period ended, they reported.

An important implication of the finding might be that preventive therapy with isoniazid is even less likely to work in places like the U.S. where TB prevalence is low, commented Eric Rubin, MD, PhD, of Harvard School of Public Health.

"Even in this high-risk, counseled population, the uptake of isoniazid preventive therapy was unimpressive," Rubin noted in an accompanying editorial.

"Such an outcome is probably even more common in low-burden situations," Rubin argued, noting that it's "not uncommon" in the U.S. for patients to start isoniazid but fail to complete the 9-month regimen.

The findings are disappointing, the researchers said, because previous smaller studies had shown that preventive therapy could interrupt the transmission of the disease in a lasting fashion.

Gold miners in South Africa, they noted, are in desperate need of interventions to reduce the burden of TB: they live and work in close quarters, they are exposed to silica dust, and there is a high prevalence of HIV among them.

In 2008, Churchyard and colleagues wrote, TB case notifications reached 3,000 per 100,000 miners, despite HIV testing linked to free antiretroviral therapy and preventive isoniazid for those with HIV.

To test the effect of wider preventive treatment, they designated 15 clusters of miners -- 40,981 miners in eight intervention clusters and 37,763 miners in seven control clusters.

Miners in the intervention clusters were offered TB screening and, if they had active disease, were referred for treatment. Those without active disease were offered 9 months of isoniazid preventive therapy.

The main outcome of the study was cluster-level TB incidence during the year after the end of the 9-month intervention. A secondary outcome was TB prevalence at the end of the study.

In the intervention clusters, 27,126 miners, or 66.2%, agreed to be screened and some 23,659 of those (87.2%) started taking isoniazid. The drug was dispensed for at least 6 months to 35% to 79% of miners, depending on the cluster, the investigators reported.

But the intervention had little effect. Specifically:

• The post-intervention incidence of TB was 3.02 cases per 100 person-years in the intervention clusters and 2.95 per 100 person-years in the control clusters (adjusted rate ratio [RR] 0.96, 95% CI 0.76-1.21).
• The prevalence of TB was 2.35% in the intervention clusters and 2.14% in the control clusters (adjusted prevalence ratio 0.98, 95% CI 0.65-1.48).
• During the intervention, the incidence of TB was significantly reduced -- 1.10 cases per 100 person-years among miners receiving isoniazid and 2.91 cases per 100 person-years among controls (adjusted RR 0.42, 95% CI 0.20-0.88, P=0.03), but the effect waned rapidly.

One possible reason for the lack of effect, they said, was the "suboptimal" proportion of miners who were taking isoniazid all at the same time, an effect of slow enrollment.

The investigators cautioned that the study's power was limited by the relatively small number of clusters, but noted that results were consistent across various outcomes. In addition, routine TB prevention efforts varied among the three mining companies involved, and there was no information on the prevalence of HIV.

The study was supported by the Consortium to Respond Effectively to the AIDS TB Epidemic, which in turn has financial support from the Bill and Melinda Gates Foundation, the South African Mine Health and Safety Council, the Foundation for Innovative New Diagnostics, the National Institutes of Health, the National Institute of Allergy and Infectious Diseases, the U.K. Department of Health, and the U.K. Medical Research Council. Sanofi-Aventis donated isoniazid.

The journal said no potential conflicts were reported.

Editorialist Rubin said he had no relevant conflicts.