From Bench to Bedside: Animal Model Leads to Novel, 1-month TB Preventive Therapy

Identification and treatment of individuals with latent tuberculosis (TB) infection to prevent development of active disease is an essential pillar of the World Health Organization’s End TB Strategy (https://www.who.int/tb/strategy/end-tb/en/). The most widely used regimen to treat latent TB infection currently is a nine-month course of isoniazid, but low completion rates and potentially serious hepatotoxicity undermine its effectiveness. The development of shorter, safer regimens has been constrained by the lack of early clinical biomarkers that predict efficacy and the tremendous cost and duration of definitive clinical trials. As a result, regimen development is highly reliant on animal models. Eric Nuermberger, MD, and colleagues in the Johns Hopkins Center for Tuberculosis Research, including Center director Richard Chaisson, MD, and Kelly Dooley, MD, PhD, have formed unique development partnerships that have rapidly advanced pre-clinical discoveries into clinical trials through NIH- and CDC- sponsored clinical trials consortia. The Nuermberger laboratory has refined and validated a mouse model first put forward by his mentor, Jacques Grosset, MD, emeritus professor of medicine. Early iterations of the model successfully predicted the clinically efficacy of a two-month course of daily rifampin plus pyrazinamide, but this proved too toxic in human studies led by Chaisson and other JHU faculty. Subsequently, the mouse model identified a three-month course of weekly isoniazid plus rifapentine which Chaisson and colleagues showed was safe and efficacious in three large clinical trials. Returning to the mouse model, Nuermberger and colleagues sought to develop even shorter courses of preventive treatment and demonstrated that daily dosing of the rifapentine-isoniazid combination reduced the treatment duration needed to cure latent TB infection to one month. This result provided the scientific justification for the definitive BRIEF TB (Brief Rifapentine–Isoniazid Efficacy for TB Prevention) trial conducted by the AIDS Clinical Trials Group under the leadership of Dr. Chaisson, Amita Gupta, MD, and Susan Swindells, MBBS, of the University of Nebraska. The results of BRIEF TB, published this week in the New England Journal of Medicine, confirmed that rifapentine plus isoniazid for 1 month (1HP) was non-inferior to the prevailing standard of 9 months of isoniazid for prevention of TB in vulnerable populations of individuals living with HIV infection, while having higher completion rates and lower risk of liver toxicity. The productive partnership of pre-clinical and translational researchers in the Center for TB Research has again contributed novel and effective treatments for TB to the global fight to end the TB epidemic.

ARTICLE: One Month of Rifapentine plus Isoniazid to Prevent HIV-Related Tuberculosis

AUTHORS: Susan Swindells, Ritesh Ramchandani, Amita Gupta, Constance A. Benson, Jorge Leon-Cruz, M.S., Noluthando Mwelase, Marc A. Jean Juste, Javier R. Lama, Javier Valencia, Ayotunde Omoz-Oarhe, Khuanchai Supparatpinyo, Gaerolwe Masheto, Lerato Mohapi, Rodrigo O. da Silva Escada, Sajeeda Mawlana, Peter Banda, Patrice Severe, James Hakim, Cecilia Kanyama, Deborah Langat, Laura Moran, Janet Andersen, Courtney V. Fletcher, Eric Nuermberger, and Richard E. Chaisson, for the BRIEF TB/A5279 Study Team

JOURNAL: N Engl J Med. 2019 Mar 14;380(11):1001-1011. doi: 10.1056/NEJMoa1806808.

Abstract

BACKGROUND: Tuberculosis is the leading killer of patients with human immunodeficiency virus (HIV) infection. Preventive therapy is effective, but current regimens are limited by poor implementation and low completion rates.

METHODS: We conducted a randomized, open-label, phase 3 noninferiority trial comparing the efficacy and safety of a 1-month regimen of daily rifapentine plus isoniazid (1-month group) with 9 months of isoniazid alone (9-month group) in HIV-infected patients who were living in areas of high tuberculosis prevalence or who had evidence of latent tuberculosis infection. The primary end point was the first diagnosis of tuberculosis or death from tuberculosis or an unknown cause. Noninferiority would be shown if the upper limit of the 95% confidence interval for the between-group difference in the number of events per 100 person-years was less than 1.25.

RESULTS: A total of 3000 patients were enrolled and followed for a median of 3.3 years. Of these patients, 54% were women; the median CD4+ count was 470 cells per cubic millimeter, and half the patients were receiving antiretroviral therapy. The primary end point was reported in 32 of 1488 patients (2%) in the 1-month group and in 33 of 1498 (2%) in the 9-month group, for an incidence rate of 0.65 per 100 person-years and 0.67 per 100 person-years, respectively (rate difference in the 1-month group, -0.02 per 100 person-years; upper limit of the 95% confidence interval, 0.30). Serious adverse events occurred in 6% of the patients in the 1-month group and in 7% of those in the 9-month group (P = 0.07). The percentage of treatment completion was significantly higher in the 1-month group than in the 9-month group (97% vs. 90%, P<0.001).

CONCLUSIONS: A 1-month regimen of rifapentine plus isoniazid was noninferior to 9 months of isoniazid alone for preventing tuberculosis in HIV-infected patients. The percentage of patients who completed treatment was significantly higher in the 1-month group. (Funded by the National Institute of Allergy and Infectious Diseases; BRIEF TB/A5279 ClinicalTrials.gov number, NCT01404312.).

For a link to the full article, click here: https://www.nejm.org/doi/10.1056/NEJMoa1806808?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dwww.ncbi.nlm.nih.gov

Link to abstract online: https://www.ncbi.nlm.nih.gov/pubmed/30865794

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