Shorter combination TB preventive regimens may be effective alternative to six-month isoniazid preventive therapy

Shorter TB preventive regimens combining isoniazid with a rifamycin-type drug are just as effective as a six-month course of isoniazid in preventing TB in people with HIV, according to preliminary results from a large randomised study conducted in South Africa, presented on Monday at the World Lung Health conference in Paris.

The majority of TB cases occur as the result of the activation of TB from a latent state as a result of immune deficiency. Isoniazid preventive therapy (IPT) is recommended for all people with HIV who are diagnosed with latent tuberculosis on a tuberculin sensitivity test. A six or nine-month course of isoniazid (INH) can cure latent TB infection.

However countries with large HIV and TB burdens have been slow to implement isoniazid preventive therapy, in part because it is a big undertaking, but also because of concerns about poor adherence to isoniazid and the risk that people taking isoniazid could develop – and transmit – resistance to the drug if they acquire TB despite preventive treatment.

For these reasons, and also because of concerns that isoniazid preventive therapy has modest efficacy coupled with a risk of liver toxicity, studies are underway to identify alternative regimens which are shorter, more effective and less toxic.

Neil Martinson of the Perinatal HIV Research Unit presented results of a large randomised study comparing four regimens in people with HIV:

• Rifapentine 900mg plus isoniazid 900mg once a week for 12 weeks, administered as directly observed therapy
• Rifampicin 600mg plus isoniazid 900mg twice a week for 12 weeks, administered as directly observed therapy
• Continuous treatment with isoniazid 300mg throughout the study, self-administered
• Isoniazid 300mg once daily for 6 months, self-administered

The study recruited 1150 HIV-positive participants (83% women) through HIV support groups in the Soweto area. Participants were eligible to join the study if they had a tuberculin skin test reaction of 15mm or greater (an indication of latent tuberculosis), no evidence of liver damage, no HIV-related symptoms and no evidence of active TB infection on either chest X-ray or sputum smear and culture.

The average CD4 count lay between 500 and 600 cells/mm³ in each study arm, reflecting the overwhelmingly female study population diagnosed with HIV during antenatal care.

Median follow-up of study participants was four years.

Preliminary analysis shows no significant difference in the incidence of TB between the four study arms (see table below), but a significantly higher rate of grade 3 and 4 toxicities in the continuous isoniazid arm. There was a higher rate of discontinuation in this arm during the study – by the end of the follow-up period approximately 35% of those assigned to continuous isoniazid had discontinued treatment.

All differences between the study arms were non-significant.

Dr Richard Chaisson of Johns Hopkins University School of Medicine, United States, commented that Kaplan-Meier analysis showed that during years one and two of the study continuous isoniazid was clearly better than the other treatment arms at preventing TB, but the effectiveness of the four regimens equalised during years three and four due to the increasing number of discontinuations in the continuous treatment arm.

Adherence to the 12-week regimens was excellent, Dr Martinson noted: 95% of patients took more than 80% of their doses, while around 80% of those who received a six-month course of isoniazid took at least 80% of their doses.

Serious grade 3 and 4 adverse events, largely liver enzyme elevations, were significantly more frequent in the continuous isoniazid arm, but no cases of clinical hepatitis were seen in the study, Dr Martinson reported.

Although the regimens were equally successful in preventing TB, there were differences in the incidence of drug resistance in those who did develop TB. Two cases of multidrug-resistant TB were identified, one in a participant who had received continuous isoniazid and one in a patient who had received rifapentine. Another case, of rifampicin resistance, was identified in a patient who had received rifapentine.

In short, the findings are unlikely to change guidelines for prevention of TB in people with HIV, Dr Martinson, concluded, but “the shorter regimens may be looked at for patients whose ability to adhere to INH-6 is suspect.”