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Disclaimer: CME certification for these activities has expired. All information is pertinent to the timeframe in which it was released.


Advances and Controversies in the Treatment of HIV


GOAL
To provide infectious disease and HIV physicians with up-to-date information on the diagnosis and treatment of patients with HIV/AIDS.

TARGET AUDIENCE
This activity is designed for infectious disease and HIV physicians. No prerequisites required.

LEARNING OBJECTIVES
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:

  • Integrate and adopt new approaches to assess and diagnose patients at various stages of disease progression.
  • Recognize when to start therapy and resistance testing in chronic infection.
  • Identify when to stop therapy for immune reconstitution syndrome.
  • Evaluate when patients with an acute opportunistic infection should receive antiretroviral therapy.
  • Describe the new antiretroviral agents for treatment-experienced patients.

ACCREDITATION STATEMENT
This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Educaiton through the joint sponsorship of The Johns Hopkins University School of Medicine and the HIV Medicine Association. The Johns Hopkins University School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide 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 credits that he/she actually spent in the activity. The estimated time to complete this educational activity:  2 hours.

Release date: February 15, 2005.
Expiration date: February 15, 2007.

DISCLAIMER STATEMENT
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 educational grant from Bristol-Myers Squibb Company.

Full Disclosure Policy Affecting CME Activities:
As a provider 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:

PROGRAM DIRECTOR

John G. Bartlett, MD
Professor, Department of Medicine
Chief, Division of Infectious Diseases
Johns Hopkins University School of Medicine
Baltimore, Maryland
Dr Bartlett reports serving as a consultant to Abbott Laboratories and Bristol-Myers Squibb Company.

PARTICIPATING FACULTY

Roy M. Gulick, MD, MPH
Associate Professor of Medicine
Weill Medical College of Cornell University
Director, Cornell Clinical Trials Unit
New York, New York
Dr Gulick reports receiving grants/research support from Abbott Laboratories, Boehringer-Ingelheim, Merck and Company, Serono, and Tibotec; serving as a consultant to Abbott Laboratories, Boehringer-Ingelheim, GlaxoSmithKline, Panacos, Pfizer Inc, Schering, Tibotec, and Virologic; and receiving honoraria from Bristol-Myers Squibb Company, Gilead, Merck and Company, and Roche.

Martin S. Hirsch, MD
Professor of Medicine, Harvard Medical School
Professor, Department of Immunology
  and Infectious Diseases
Harvard School of Public Health
Director, Clinical AIDS Research
Infectious Disease Unit
Department of Medicine
Massachusetts General Hospital
Boston, Massachusetts
Dr Hirsch reports receiving grants/research support from Takeda and Elixir; and serving as a consultant to Bristol-Myers Squibb Company and GlaxoSmithKline.

Greg Lucas, MD
Assistant Professor
Department of Medicine
Division of Infectious Diseases
Johns Hopkins University School of Medicine
Baltimore, Maryland
Dr Lucas reports serving as a consultant to GlaxoSmithKline and being a shareholder of Abbott Laboratories.

Henry Masur, MD
Chief, Critical Care Medicine Department
Clinical Center
National Institutes of Health
Bethesda, Maryland
Dr Masur reports having no significant financial or advisory relationships with corporate organizations related to this activity.

William G. Powderly, MD, FRCPI
Professor of Medicine and Therapeutics
University College Dublin
Mater Misericordiae University Hospital
Dublin, Ireland
Dr Powderly reports serving as a consultant to Bristol-Myers Squibb Company and Gilead Sciences.

Valerie E. Stone, MD, MPH
Associate Chief, General Medicine Unit
Massachusetts General Hospital
Associate Professor of Medicine
Harvard Medical School
Boston, Massachusetts
Dr Stone reports receiving grants/research support from Bristol-Myers Squibb Company; serving as a consultant to Abbott Laboratories, Gilead, and GlaxoSmithKline; and receiving honoraria from Pfizer Inc.

Notice: The audience is advised that an article in this CME activity contains reference(s) to unlabeled or unapproved uses of drugs or devices.

Dr Gulick—AMD-070; D-D4FC; PA-457; tipranavir; TMC-114; TMC-125; TNX-355; UK-427,857.

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.

Advances And Controversies In The Treatment Of HIV
John G. Bartlett, MD

The options available for the management of human immunodeficiency virus (HIV) infection have improved considerably during the past decade. Clinical trials that were reported between 1993 and 1996 first demonstrated that combination treatment (eg, the combination of zidovudine and didanosine) was associated with better survival than was a single-agent therapy.1 Subsequently, beginning in 1996, a series of randomized, controlled clinical trials demonstrated that combination therapy—using highly active antiretroviral therapy (HAART) regimens incorporating a protease inhibitor or a nonnucleoside reverse transcriptase inhibitor—could significantly reduce HIV viral load, improve CD4 cell count, and increase the likelihood of long-term survival.2,3 Partly as a result of these developments, the number of cases and deaths attributable to acquired immunodeficiency syndrome (AIDS) in the United States peaked in 1993 and has been declining since that time.4 As AIDS mortality has decreased, the number of individuals with AIDS has increased during the past decade. The Centers for Disease Control and Prevention estimates that 380 000 adolescents and adults with AIDS were living in the United States at the end of 2002.4

Despite these improvements in patient outcomes with the introduction of HAART, a number of unresolved issues and limitations of current therapeutic strategies remain. Many of the limitations of currently available treatment options are well known, including drug toxicity, the potential for drug interactions, the large pill burden, and the difficulty many patients have in remaining on long-term treatment. The available regimens also do not eradicate HIV completely. The decay half-life of HIV in latently infected T cells has been estimated to be more than 6 months, which implies that uninterrupted treatment must continue for 70 years to completely eradicate the virus.5 The emergence of drug-resistant HIV strains is a significant problem. Optimal strategies also have not been developed to define when treatment should begin in asymptomatic patients with HIV infection or how to manage antiretroviral therapy and opportunistic infection (OI) prophylaxis in patients with OIs. This monograph is intended to help educate infectious disease experts on how to better care for patients with HIV/AIDS. At a roundtable discussion held in September 2004 in Boston, Massachusetts, clinical and research experts in the management of HIV discussed recent studies and their own clinical experiences regarding several issues in HIV management.

Martin S. Hirsch, MD, Harvard Medical School and the Harvard School of Public Health, reviewed recent studies examining the usefulness of clinical markers of HIV progression (eg, HIV viral load, CD4 cell counts) to predict patients' responses to antiretroviral therapy (ART) and to decide when patients with HIV infection should begin ART. Dr Hirsch also reviewed the results of several recent clinical trials that have examined different combinations of the available antiretroviral agents for the initial treatment of HIV infection and shown that outcome depends on the specific drug combination used. This decision may also be influenced by baseline resistance testing.

Henry Masur, MD, National Institutes of Health, discussed the management of patients with HIV infection and OIs. With the improvements in immune function that have accompanied improved ART regimens in recent years, many patients now are able to discontinue OI prophylaxis regimens that until recently would have required lifelong treatment. However, some patients who receive ART develop paradoxical worsening of OIs or inflammatory reactions as immune function begins to improve. Dr Masur discussed some of the clinical manifestations of these immune reconstitution syndromes and described proposals for management of these patients. He also reviewed guidelines for stopping OI prophylaxis in patients who have responded well to ART.

William G. Powderly, MD, FRCPI, University College, Dublin, reviewed the potential advantages and disadvantages of starting or deferring ART in patients with OIs and described the design of an ongoing, randomized, controlled clinical trial that compares outcomes among patients who begin ART immediately and patients who receive ART after they are discharged from the hospital.

Roy M. Gulick, MD, MPH, Weill Medical College of Cornell University, reviewed new treatment options for HIV infection that are currently being evaluated in clinical trials but have not yet become available for clinical use. New nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, and protease inhibitors have been developed that provide high-potency suppression of HIV replication, with improved activity against viral strains that are resistant to currently available treatments. In addition, new agents that target novel mechanisms of HIV replication are also being developed, including several new drugs that block HIV entry into CD4 cells.

REFERENCES
1. Collier AC, Coombs RW, Fischl MA, et al. Combination therapy with zidovudine and didanosine compared with zidovudine alone in HIV-1 infection. Ann Intern Med. 1993;119:786-793.
2. Hammer SM, Squires KE, Hughes MD, et al. A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. AIDS Clinical Trials Group 320 Study Team. N Engl J Med. 1997;337:725-733.
3. D'Aquila RT, Hughes MD, Johnson VA, et al. Nevirapine, zidovudine, and didanosine compared with zidovudine and didanosine in patients with HIV-1 infection. A randomized, double-blind, placebo-controlled trial. National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group Protocol 241 Investigators. Ann Intern Med. 1996;124:1019-1030.
4. Centers for Disease Control and Prevention. HIV/AIDS surveillanceÐgeneral epidemiology. Available at:
http://www.cdc.gov/hiv/graphics/surveill.htm. Accessed November 10, 2004.
5. Zhang L, Ramratnam B, Tenner-Racz K, et al. Quantifying residual HIV-1 replication in patients receiving combination antiretroviral therapy. N Engl J Med. 1999;340:1605-1613.


*Professor, Department of Medicine, Chief, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Address correspondence to: John G. Bartlett, MD, Professor, Department of Medicine, Chief, Division of Infectious Diseases, Johns Hopkins University School of Medicine, 1830 E Monument Street, Room 437, 600 North Wolfe Street, Baltimore, MD 21287.
E-mail:
jb@jhmi.edu.





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