Charles W. Flexner
Johns Hopkins University
Novel Approaches to HIV Treatment and Prevention using LA Drug Delivery
Oral antiretroviral regimens are extremely effective at suppressing HIV with minimal toxicity. They also offer the simplicity of once daily single-tablet dosing. However, long-acting regimens with infrequent dosing, for example weekly oral or long-acting parenterally administered agents, may be useful for treatment or prevention in circumstances where daily oral therapies are difficult to administer, and/or when adherence may be inadequate. In such circumstances, alternatives to oral therapy may be life-saving and reduce the transmission of infection to others. Limitations of such an approach to drug delivery include the management of toxicities, given that exposure to these agents is not easily reversed, and prevention of drug resistance when these drugs are discontinued and drug concentrations are slowly reduced over time. Agents with long-acting anti-HIV-1 activity are being tested in both treatment of chronic infection, and in pre-exposure prophylaxis for persons at risk of infection. The combination of long-acting intramuscular cabotegravir and rilpivirine is likely to be the first such regimen to gain regulatory approval. These approaches appear to be especially attractive for patients complaining of pill fatigue, including adolescents, and for those experiencing HIV-associated stigma. Long-acting broadly-neutralizing anti-HIV monoclonal antibodies (bnAb’s) are in clinical trials, but carry possible drawbacks of substantial primary resistance and the promotion of secondary resistance if used as monotherapy. Newer bnAb’s with broader coverage, and combinations of bnAb’s, may solve a number of these problems. Additional formulations in development include inert and bioerodable implants, and transcutaneous drug delivery using microneedle patches. As these formulations are shown to be safe, well-tolerated, and economical, they are likely to gain broader appeal.
Charles W. Flexner, M.D., is Professor of Medicine in the Divisions of Clinical Pharmacology and Infectious Diseases, and Professor of Pharmacology and Molecular Sciences at the Johns Hopkins University School of Medicine. He is also Professor of International Health at the Johns Hopkins University Bloomberg School of Public Health. Dr. Flexner is an expert on the basic and clinical pharmacology of drugs for HIV/AIDS and related infections, including viral hepatitis and tuberculosis. His research teams developed a number of ways to reduce drug doses and toxicity while maintaining desired activity. He led clinical development teams for seven new drugs for HIV. He has published extensively on antiviral and antibiotic drug transport and metabolism, and metabolic drug interactions. He has published nearly 250 peer-reviewed scientific manuscripts, reviews, and book chapters, and has authored two medical textbooks. His current research includes the discovery and development of new molecules and formulations for long-acting parenteral administration for treatment and prevention of HIV infection. He directs the Long Acting/Extended Release Antiretroviral Research Resource Program (LEAP; www.longactinghiv.org), which provides advice and support to an international audience that includes the World Health Organization (WHO) and Unitaid. He is Co-Director of the Johns Hopkins University Baltimore-Washington-India HIV Clinical Trials Unit (BWI CTU). Dr. Flexner is the Chief Scientific Officer of the Institute for Clinical and Translational Research at Johns Hopkins. He also serves as Associate Vice-Chair for Academic Fellowship Programs in the Department of Medicine, and Associate Director of the Graduate Training Programs in Clinical Investigation of the Johns Hopkins University School of Medicine and Bloomberg School of Public Health. He chairs the antiretroviral therapy committee of the AIDS Clinical Trials Group, an international consortium funded by NIH. Dr. Flexner served as President of the American Federation for Medical Research (AFMR) from 1999-2000, and was President of the AFMR Foundation from 2001-2002. He is a member of the editorial board of 12 scientific journals, and served as a consultant for three dozen pharmaceutical and biotechnology companies. He is a Consultant for the Bill and Melinda Gates Foundation and the Clinton Health Access Initiative, and served as a Consultant on FDA Reform for the United States House of Representatives. He currently serves on the WHO Clinical Guidelines Development Group for Treatment and Prevention of HIV in Adults, Adolescents, and Children.