Speaker
Thomas Lietman, MD
Director
Francis I. Proctor Foundation
University of California, San Francisco
Keywords
Child Mortality; Antibiotics; Large Simple Trial
Key Points
- Trachoma is a disease that affects the human eye, caused by infection with a strain of chlamydia. The scar tissue that is left behind warps the shape of eyelid, irritating the cornea and eventually causing full blindness. Antibiotics have been shown to reduce trachoma infection, with azithromycin being the preferred treatment.
- Dr. Lietman described a series of mass azithromycin trials, including the “Azithromycine pour la Vie des Enfants au Niger: Implementation et Recherche” (AVENIR) trial in Niger and the “Macrolides Oraux pour Réduire les Décès avec un Oeil sur la Résistance” (MORDOR) trial in Niger, Tanzania, and Malawi.
- In one of these trials, the mass distribution of azithromycin for trachoma control was shown to reduce the overall child mortality rate. The research team sought to test these findings in a younger age group (preschool-aged children) and with a larger sample size.
- The MORDOR trial found that biannual azithromycin distribution reduced overall mortality in 1 – 59 month old children, though more so for the younger children. The WHO amended their guidelines to recommend administration of azithromycin in high mortality Sub-Saharan African settings to children 1 – 11 months old.
- The release of the WHO guidelines was followed by the AVENIR trial, which – in addition to re-testing whether mass azithromycin distribution reduced childhood mortality in 1 – 59 month-olds – compared the reduction in mortality when treating only 1 – 11 month-olds as opposed to 1 – 59 month-olds. They also monitored antibiotic resistance.
- The research team found that the 1 – 11 month-olds had significantly better outcomes in the latter treatment arm, in which children 1 – 59 months old received Azithromycin. The herd effect led to an indirect benefit for the younger children when the older children were treated.
- The researchers successfully adapted toward the 1 – 59 month-old treatment group after 12 months, using a tempering algorithm to avoid dramatic swings in allocation probabilities.
- They found that trachoma distributions and the childhood mortality distributions do select for macrolide resistance in a number of different bacteria, with resistance decreasing when the programs are stopped. Since they are only treating 1/6 of a population, there is less antibiotic pressure than with trachoma programs that treat an entire community.
- AVENIR 2 will expand AVENIR to the entire country of Niger.
Discussion Themes
The ethical considerations of the trial were enormous and included consent and post-trial availability. It was very important for the research team A) to have strong, local collaborators and B) not to impose Western academic ways of thinking when partnering with these communities.
The researchers were mindful of the risk that, with adaptive trials, you can lose a treatment arm if you adapt too much early on. Retrospectively, Dr. Lietman noted, they were overly cautious when it came to tempering. Ultimately, everyone was treated by 24 months.
The team is hoping to eventually create a platform to monitor and coordinate treatment efforts between trials.