Modest reductions in new cases of TB seen in South African isoniazid trial

Christopher Gadd
Published: 10 June 2005

A study from South Africa has shown that giving isoniazid to HIV-infected adults attending a workplace HIV clinic reduced the incidence of tuberculosis (TB) by over a third. However, the investigators, writing in the 8th June edition of the Journal of the American Medical Association warn that levels of TB diagnoses remained high even after preventive isoniazid treatment and that additional interventions are needed to reduce disease and death most effectively.

Increases in the incidence of TB are a major consequence of the HIV epidemic in developing countries. TB remains a significant concern despite the introduction of directly observed therapy with rifampicin and the introduction of routine chest X-rays to treat and diagnose the disease.

Methods to prevent new TB cases include giving the antibiotic isoniazid to people at risk. Clinical studies have shown that this can reduce the incidence of TB, as recommended by the World Health Organization (WHO) and the Joint United Nations Programme on HIV / AIDS (UNAIDS). However, this recommendation has not been widely implemented, and there are no data on its effectiveness in real-life situations.

To assess the effect of preventive isoniazid in a routine setting, researchers from London, Johannesburg and Baltimore offered the drug to a cohort of HIV-positive South African mine workers at a workplace HIV clinic. The incidence of TB is high in this group of men, at over 4% per year. This is driven by high rates of HIV infection and silicosis, lung damage caused by dust.

The researchers enrolled 1655 HIV-positive men for their study between 1999 and 2001, before antiretroviral treatment was available. The men were invited to attend the HIV clinic in a randomised order, where they were offered a six-month course of isoniazid at a dose of 300mg per day, extended to a year for men with silicosis. Men returned for a check-up every six months, when they were examined and tested for TB.

In total, 679 men started isoniazid therapy and were assessed every six months. Men with active TB were excluded from the study, as isoniazid treatment could lead to the development of resistance.

After a median follow-up of 22 months, the researchers found that there was a significant reduction in the number of new cases of TB after enrolment at the clinic, from 11.9 to 9.0 cases per 100 person-years. After adjusting their results for calendar period, this represented a 32% drop in incidence (p = 0.03).

The incidence of TB was also significantly associated with increasing age, a previous episode of TB, silicosis and more advanced HIV disease.

One hundred and eighty-nine (74%) of the 254 cases of tuberculosis were ‘definite’, as defined by positive smear cultures, with the remainder being ‘possible’ or ‘probable’. Sixty-eight per cent of the cases were in the lungs, with 18% being outside the lungs and 14% both within and outside of the lungs. However, the effect of clinic visits on these distributions is not reported.

The researchers also carried out a multivariate analysis, taking calendar period, age and the grade of silicosis into account in their analysis. This revealed a 38% drop in incidence (p = 0.009) following attending the clinic.

Although this is lower than the rates seen in clinical trials, the investigators point out that this real-life trial may be expected to produce less impressive effects. Notably, in accordance with current guidelines, patients with a history of TB did not receive isoniazid, although their TB incidence rates were included the analysis.

“In this study, a history of TB was a risk factor for a subsequent episode. Individuals with a history of TB had lower median CD4 cell counts at clinic entry than those with no history of TB, putting them at higher risk of TB,” they write. After exclusion of these men, the investigators calculated an overall reduction of 46% (p = 0.004).

The researchers also acknowledge that their results may have been affected by the short follow-up period. “Evidence suggests that the protective efficacy of TB preventive therapy … wanes over time,” they explain. “Thus, our estimate of protective efficacy may have been higher than would be observed over longer follow-up.”

Although this study demonstrates that giving isoniazid to a group of HIV-positive workers can reduce the incidence of TB, additional measures may be needed to reduce TB to acceptable levels in the real-life situation. “Despite our intervention, the TB incidence rate in the postclinic phase remained unacceptably high at nine per 100 person-years,” the investigators write. “Additional strategies are clearly required to further reduce TB incidence in this population.

“Further work is needed to determine how best to use available interventions to minimise TB morbidity in areas where both HIV and TB are highly prevalent.”

Reference

Grant AD et al. Effect of routine isoniazid preventive therapy on tuberculosis incidence among HIV-infected men in South Africa. A novel randomized incremental recruitment study. JAMA 293: 2719-2725, 2005.

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