- Category: Tuberculosis (TB)
- Published on Tuesday, 28 February 2017 00:00
- Written by Keith Alcorn
A 6-month course of isoniazid preventive treatment (IPT) for at the beginning of the Temprano trial in Ivory Coast reduced the risk of death by 37% over a mean follow-up period of 4.5 years, Anani Badje reported at the Conference on Retroviruses and Opportunistic Infections this month in Seattle.
Isoniazid is a drug used in the treatment of tuberculosis (TB) that can also prevent the development of active TB in people with latent TB. People exposed to a person with active TB may acquire an infection that is kept in check by the immune system. However, this latent infection may develop into active TB if immunity is depleted, whether through malnutrition, aging, or HIV infection.
Several large trials have shown that IPT reduces the risk of active TB and death in people with HIV not taking antiretroviral therapy (ART), but the largest of these studies suggested a need for continuous IPT in people not on ART. A randomized study of people taking ART in South Africa showed that a year of IPT reduced the risk of TB by 37% during the 1-year study period, but provided no information about long-term protection.
The World Health Organization (WHO) recommended a 36-month course of IPT for people living with HIV in 2011.
Subsequently, the ANRS 12136 Temprano study showed that a 6-month course of IPT reduced the risk of any severe HIV-related illness or death by 35%, independent of antiretroviral treatment.
The Temprano study assessed 2 interventions:
- Immediate ART compared to starting treatment according to WHO guidelines between 2008 and 2012;
- Isoniazid for the prevention of tuberculosis compared to placebo.
Participants were randomized to each intervention arm, so the study was able to provide independent comparisons of the effects of ART and IPT on survival and morbidity.
The study followed participants for 30 months, after which everyone was offered immediate ART. Participants were then followed for a further 30 months to monitor survival.
Badje, from INSERM, Bordeaux, presented the results of long-term follow-up of Temprano participants.
The study randomized 2056 people, 42% of whom had CD4 cell counts above 500 cells/mm3, to receive isoniazid or placebo for 6 months. Approximately 35% in each arm showed evidence of previous exposure to TB on the Quantiferon Gold assay, and 3% had a previous history of TB. A total of 10.7% in the no-IPT group and 9.4% in the IPT group were lost to follow-up during the trial and its follow-up period.
The 6-year probability of death was 6.9% in the no-IPT group and 4.1% in the IPT group. IPT reduced the risk of death by 37% (hazard ratio 0.63). Kapalan-Meier analysis, which plots the cumulative probability of death over time, showed that the difference in the risk of death appeared to increase over time.
Why should isoniazid have such a prolonged effect on the risk of death in this study compared to previous trials? Unfortunately, the Temprano study investigators were unable to collect data on causes of death in the follow-up period because participants reverted to standard medical care, and medical history information was inconsistent. The lack of information on causes of death makes it impossible to judge whether the risk of TB continued to be lower in the IPT group throughout the follow-up period, as it was during the clinical trial phase.
It is possible that IPT may have a greater effect in people with higher CD4 cell counts; in the Temprano study the mean CD4 cell count at month 60 of follow-up was 655 cells/mm3. Furthermore, IPT might provide a form of bridging protection prior to the improvement of TB-specific immunity on ART (90% of people in the IPT arm of the study eventually started HIV treatment). IPT might also have a more durable effect in settings with a lower rate of TB transmission. For example, a study in Brazil found that IPT reduced the risk of TB over 7 years of follow-up.
Badje said that the study findings provide strong evidence of the merits of IPT for countries that are still reluctant to recommend it for people living with HIV. Fears that IPT will lead to isoniazid resistance if people with undiagnosed active TB are treated have proved unfounded, he told a CROI press conference. A strong and clear policy for implementation of IPT is needed in order to overcome reluctance among health care providers, he said.
AD Badje, R Moh, D Gabillard, et al. Six-month IPT reduces mortality independently of ART in African adults with high CD4.Conference on Retroviruses and Opportunistic Infections. Seattle, February 13-16, 2017.Abstract 78.