Research

The multi-project program is supported by a contract from NIAID, the Weill Cornell CTSC, and the Milstein Foundation. This program is studying the ability of M. tuberculosis to resist elimination by the human immune system during latency and by antimicrobials during drug treatment. Dr. Fitzgerald is the TBRU Clinical Core Director responsible for recruiting and characterizing unique cohorts in Haiti, including families with multiple siblings with TB, people who are resistant to TB infection, and longitudinal cohorts of patients with MDR-TB. Other TBRU projects are led by world-class investigators from Weill-Cornell, GHESKIO, Memorial Sloan Kettering, and the Rockefeller University with multiple cross-disciplinary collaborations.

The World Health Organization estimates that about one third of the world’s population has a latent M. tuberculosis infection (LTBI). Among them, a minority that cannot be identified prospectively will develop reactivation tuberculosis (TB) despite having apparently normal immunity. The ability of M. tuberculosis to remain latent within the human host, and the related failure of the human immune system to sterilize M. tuberculosis in latently infected individuals, are poorly understood.

Antimicrobial therapy for active infection by drug-sensitive Mtb is effective, but current drugs must be given for 6 months to achieve relapse-free cure rates of >95%. Despite substantial efforts to understand these two critical features of M. tuberculosis infection—latency and persistence—fundamental questions remain about the genetic, immunologic, pharmacologic, and microbiologic contributors to both.

Since 2004 the number of adult HIV-related deaths in the world decreased by 30% as antiretroviral therapy (ART) expanded. However, during the same period, HIV-related deaths for adolescents increased by 50%. Adolescents account for 40% of all new HIV infections in Haiti, and 80% of these occur among sexually-active girls, many of whom live in poverty with little protection from high risk behaviors. The HIV incidence rate among girls age 16-19 in slums of Port au Prince is 1% per year, which is comparable to the incidence in high-risk groups such as commercial sex workers.

ART with other medical and behavioral interventions can prolong the life of persons living with HIV and prevent them from transmitting HIV. However, the social factors which lead to HIV infection (poverty, unstable families, and gender inequality) coupled with high-risk taking adolescent behavior creates a “perfect storm” hindering intervention. Clinical interventions have been only partially effective at stemming the effects of the disease because of lower adherence to treatment among adolescents relative to adults, In Haiti and other resource-poor countries, HIV-infected adolescents are three times more likely to be lost to care than adults, with only ~50% of HIV-infected teens remaining in care at one year.

In 2014 Cornell-GHESKIO piloted an innovative model of care, FANMI (My FAMILY), to improve retention among HIV-infected adolescent girls. Adolescent girls attend monthly HIV care in cohorts of 5-8 peers to address social isolation, gender inequality, and unstable families. HIV care takes place in a community center rather than in a medical clinic to strengthen social support and decrease stigma. Each monthly visit integrates clinical care, group counseling, and social activities in a single session by the same provider to simplify care and strengthen the relationships between peers and providers. Data suggest that FANMI dramatically improves retention compared to adolescent girls receiving standard care at GHESKIO.

Dr Jean Pape is the GHESKIO Principal Investigator (PI) and Dr. Fitzgerald the Cornell Co-PI of the Haiti NIH-sponsored CTU conducting studies with the AIDS Clinical Trials Group (ACTG) and International Maternal, Pediatric, and Adolescent AIDS Trials Group (IMPAACT). This program covers 8 NIAID therapeutic trials, including studies to shorten TB treatment with rifapentine-containing regimens, prophylaxis for household contacts of people with MDR-TB, rifapentine-containing prophylaxis for pregnant women with latent TB, and intensive early antiretroviral treatment of infants to achieve remission.

Clinical trials often take 5 years to conduct and involve scores of investigators and are beyond the scope and timeline of an individual trainee’s project. However, we have found that well-defined participation with ~ 10 – 20% effort is extremely beneficial for our trainees. Trainees learn about the rigor of NIH clinical trials, recruitment and retention strategies, good clinical practice, clinical trial design, data collection tools, and advanced laboratory assays. Trainees attend network meetings and meet leaders in the field. The rigor and knowledge gained from participating in the clinical trials is transferred to the conduct of the trainees’ own research, and trainees are prepared to assume leadership roles in future NIH multi-center clinical trials.