Disclaimer: CME certification for these activities has expired. All information is pertinent to the timeframe in which it was released.
Therapeutic Challenges and Enhanced Clinical Expectations in the Treatment of HIV
To provide infectious disease specialists and internal medicine physicians with an update on the most current thinking regarding protease inhibitors and their role in anti-HIV therapy.
This activity is designed for infectious disease specialists and internal medicine physicians who treat persons with HIV infection and disease. No prerequisites required.
The Johns Hopkins University School of Medicine takes responsibility for the content, quality, and scientific integrity of this CME activity. At the conclusion of this activity, participants should be able to:
- Outline the limitations of current protease inhibitor options and the associated challenges to optimal management of HIV infection and AIDS.
- Describe the changing demographics and characteristics of HIV-infected patients.
- Discuss current issues surrounding protease inhibitor potency, safety/tolerability, and adherence to anti-HIV therapeutic regimens.
- Evaluate new-generation protease inhibitors and how they may improve on older agents in this class.
- Explain how protease inhibitors may provide improved management options for those living with HIV infection from the perspectives of both the clinician and patient.
The Johns Hopkins University School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to sponsor continuing medical education for physicians.
CREDIT DESIGNATION STATEMENT
The Johns Hopkins University School of Medicine designates this educational activity for a maximum of 2 category 1 credits toward the AMA Physician's Recognition Award. Each physician should claim only those hours of credit that he/she actually spent in the activity.
The estimated time to complete this educational activity: 2 hours.
Release date: November 15, 2003. Expiration date: November 15, 2005.
The opinions and recommendations expressed by faculty and other experts whose input is included in this program are their own. This enduring material is produced for educational purposes only. Use of Johns Hopkins University School of Medicine name implies review of educational format design and approach. Please review the complete prescribing information of specific drugs or combinations of drugs, including indications, contraindications, warnings, and adverse effects, before administering pharmacologic therapy to patients.
This program is supported by an unrestricted educational grant from GlaxoSmithKline.
Full Disclosure Policy Affecting CME Activities:
As a sponsor accredited by the Accreditation Council for Continuing Medical Education (ACCME), it is the policy of Johns Hopkins University School of Medicine to require the disclosure of the existence of any significant financial interest or any other relationship a faculty member or a sponsor has with the manufacturer(s) of any commercial product(s) discussed in an educational presentation. The Program Director and Participating Faculty reported the following:
John G. Bartlett, MD
Professor, Department of Medicine
Chief, Division of Infectious Diseases
Johns Hopkins University School of Medicine
• Dr Bartlett reports serving as a consultant to Abbott Laboratories and
Bristol-Myers Squibb Company.
Constance A. Benson, MD
Chair, NIAID Adult AIDS Clinical Trials Group
Professor of Medicine
Division of Infectious Diseases
Senior Attending Physician
University of Colorado Health Sciences Center
• Dr Benson reports receiving grants/research support from Abbott Laboratories, Bristol-Myers Squibb Company, Epimmune, Inc, and Triangle Pharmaceuticals; serving as a consultant to Abbott Laboratories, Gilead Sciences, GlaxoSmithKline, Merck & Co, Inc, Tibotec/ Virco, and Vertex, Inc; and receiving honoraria from Abbott Laboratories, GlaxoSmithKline, Merck & Co, Inc, and Tibotec/Virco.
Simon A. Mallal, MBBS, FRACP, FRCPA
Professor and Executive Director
Centre for Clinical Immunology and Biomedical Statistics
Department of Clinical Immunology and Biochemical Genetics
Royal Perth Hospital
Perth, Western Australia
• Dr Mallal reports receiving grants/research support from GlaxoSmithKline; serving as a consultant to Bristol-Myers Squibb Company, GlaxoSmithKline, and Merck & Co, Inc; and receiving honoraria from GlaxoSmithKline.
Julio S. G. Montaner, MD, FRCP, FCCP
Chair, AIDS Research Program
University of British Columbia
Director of Clinical Activities
British Columbia Centre for Excellence in HIV/AIDS
St Paul's Hospital
Vancouver, British Columbia, Canada
• Dr Montaner reports receiving grants/research support and honoraria from, and serving as a consultant to Abbott Laboratories, Agouron Pharmaceuticals, Inc, Boehringer Ingelheim, Bristol-Myers Squibb Company, DuPont, Gilead Sciences, GlaxoSmithKline, F. Hoffman LaRoche Ltd, Kucera Pharmaceutical Co, Merck Frosst Canada Ltd, Pharmacia Corporation, Shire BioChem, Inc, and Trimeris, Inc.François Raffi, MD, PhD.
Robert T. Schooley, MD
Tim Gill Professor of Medicine
Head, Division of Infectious Diseases
University of Colorado Health Sciences Center
• Dr Schooley reports receiving grants/research support from Bristol-Myers Squibb Company, GlaxoSmithKline, and Merck & Co, Inc; serving as a consultant to Achillion Pharmaceuticals, Inc, Bristol-Myers Squibb Company, Gilead Sciences, GlaxoSmithKline, Merck & Co, Inc, Roche, Tanox, Inc, Vertex Inc, and ViroLogic; and being a stock shareholder in Achillion Pharmaceuticals, Inc, Tanox, Inc, Vertex Inc, and ViroLogic.
Benjamin Young, MD, PhD
Clinical Instructor of Medicine
Division of Infectious Diseases
University of Colorado Health Sciences Center
Director of Clinical Research in Infectious Diseases
Rose Medical Center
• Dr Young reports receiving grants/research support from Abbott Laboratories, Agouron Pharmaceuticals, Inc, Bristol-Myers Squibb Company, Gilead Sciences, GlaxoSmithKline, and Merck & Co, Inc; serving as a consultant to Abbott Laboratories, Agouron Pharmaceuticals, Inc, Boehringer Ingelheim, Bristol-Myers Squibb Company, Gilead Sciences, GlaxoSmithKline, Merck & Co, Inc, and ViroLogic; and receiving honoraria from Abbott Laboratories, Agouron Pharmaceuticals, Inc, Bristol-Myers Squibb Company, Gilead Sciences, GlaxoSmithKline, Merck & Co, Inc, and ViroLogic.
In accordance with the ACCME Standards for Commercial Support, the audience is advised that one or more articles in this continuing medical education activity may contain reference(s) to unlabeled or unapproved uses of drugs or devices. The following faculty members has disclosed that their articles have referenced the following unlabeled/unapproved uses of drugs or products:
Drs Mallal, Montaner, and Young-tipranavir and TMC-114 for the treatment of HIV.
All other faculty have indicated that they have not referenced unlabeled/unapproved uses of drugs or devices.
Advanced Studies in Medicine provides disclosure information from contributing authors, lead presenters, and participating faculty. Advanced Studies in Medicine does not provide disclosure information from authors of abstracts and poster presentations. The reader shall be advised that these contributors may or may not maintain financial relationships with pharmaceutical companies.
Evolution of the Protease Inhibitor Class
Robert T. Schooley, MD*
It has been nearly 8 years since the US Food and Drug Administration announced the approval of the first protease inhibitor (PI) directed at the treatment of HIV. The initial reductions in HIV-associated morbidity and mortality seen with dual-nucleoside therapy were greatly accelerated with the advent of PIs (Figure).1,2
Since the introduction of PIs, important advances have been made with respect to the convenience, potency, and tolerability of these agents. Potent PIs have been developed with genetic barriers that allow durable suppression of viral replication, long-term immunologic improvement, decreased opportunistic infection frequency and mortality, improved quality of life, and increased years of life. These advances have not occurred without costs and complications.
PI-based antiretroviral therapy has been associated with both short-term and long-term toxicities. Tolerability issues, such as high pill counts, complicated dosing frequencies, food restrictions, and drug interactions, made managing suppression of viral replication nearly a full-time job in the earlier days of highly active antiretroviral therapy. Resistance was found to be overlapping among the PIs. In addition, potency was variable. Some of this could be overcome by boosting with pharmacologic enhancers. Although this improved the pharmacokinetics in many cases, it also increased some of the toxicities seen with long-term treatment.
Over the past 3 years, we have seen the emergence of what may be viewed as the next generation of PIs, developed to address some of the shortcomings of their first-generation predecessors (Table 1). Among the goals of new PI development are improved tolerability (eg, fewer adverse events and drug interactions), improved convenience (eg, fewer pills, no dietary restrictions, and once-daily or twice-daily dosing), improved sequencing options (eg, better definition of resistance pathways and clinical cutoff points), and improved overall quality of life, goals which have arisen in part out of the notion that "therapeutic success or failure is the consequence of many factors, not just drug potency and pharmacokinetics" (Table 2).3 Some of the newer PI agents have nonoverlapping or less cross-resistant resistance profiles. Some can be boosted with ritonavir to allow more flexibility in dosing. Regimens of newer PI drugs allow once-daily and twice-daily dosing. Most notable, perhaps, are the improvements in safety profiles–lipid effects and gas-trointestinal effects–and overall tolerability of PI-based regimens, improvements that reflect a heightened emphasis on the importance of maintaining or improving patient quality of life. Central to achieving this goal is the growing recognition that short-term side effects (eg, diarrhea, nausea, jaundice) play an increasingly important role in determining successful therapeuticoutcome
This issue of Advanced Studies in Medicine focuses on the evolution of the PI class and how individual new PI drugs may improve PI-based therapy. Dr Benjamin Young addresses issues related to potency with the new PIs, providing a historical perspective, a current view, and a glimpse of the future of PI therapy. Dr Simon A. Mallal gives an overview of key challenges regarding safety and tolerability associated with PI therapy and how the newer PIs may help in overcoming some of these challenges. Dr Julio S. G. Montaner discusses issues related to adherence, with special attention to PI regimens, and examines ways to improve this critically important aspect of treatment. Dr Constance A. Benson integrates the principles of potency, safety, tolerability, and adherence with the newer PIs into patient management, through the use of case studies illustrating how these principles may be applied to therapeutic decision making in everyday practice.
The information presented in this issue provides infectious disease specialists and internal medicine physicians who treat patients with HIV the opportunity to learn how the new PIs can enhance expectations of efficacy, safety, and adherence, improving the success of treatment as well as the quality of patients' lives.
The authors gratefully acknowledge Michael Pellegrino, PhD, for editorial contributions and help in assembling the presentations, as well as the assistance of Ms Diane Hoffman and Ms Bridgette Popp, of New World Health CME.
1. Palella F, Chmiel J, Deloria-Knoll M, Moorman A, Holmberg S. Continued low mortality and morbidity, and HAART utilization among HIV-infected patients in the HIV outpatient study (HOPS). HOPS Investigators. In: Program and abstracts of the 8th Conference on Retroviruses and Opportunistic Infections; February 4-8, 2001; Chicago, Ill. Abstract 268B.
2. Centers for Disease Control and Prevention. Update: trends in AIDS incidence, deaths, and prevalence--United States, 1996. MMWR Morb Mortal Wkly Rep. 1997; 46(8):165-173.
3. Becker S, Fisher A, Flexner C, et al. Pharmacokinetic parameters of protease inhibitors and the Cmin/IC50 ratio: call for consensus. J Acquir Immune Defic Syndr. 2001; 27(2):210-211.
*Tim Gill Professor of Medicine; Head, Division of Infectious Diseases, University of Colorado Health Sciences Center, Denver, Colorado.
|Johns Hopkins Advanced Studies in Medicine (ISSN-1558-0334), is published by Galen Publishing, LLC, d/b/a ASiM, PO Box 340, Somerville, NJ 08876. (908) 253-9001. Copyright ©2012 by Galen Publishing. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, without first obtaining permission from the publisher. ASiM is a registered trademark of The Healthcare Media Group, LLC.