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A Review for Clinicians

Steven G. Deeks, MD; Mark Smith, MD, MBA; Mark Holodniy, MD; James O. Kahn, MD

JAMA. 1997;277(2):145-153.

Abstract
Objective.
—The clinical care of people infected with human immunodeficiency virus (HIV) has been substantially affected by the introduction of HIV-specific protease inhibitors (Pis). The 4 Pls available are saquinavir mesylate, ritonavir, indinavir sulfate, and nelfinavir mesylate. Comparison studies have not been reported; therefore, an assessment of the available data to aid clinicians and patients in choosing appropriate treatment will be presented.

Data Sources.
—A systematic review of peer-reviewed publications, abstracts from national and international conferences, and product registration information through September 1996.

Study Selection and Data Extraction.
—Criteria used to select studies include their relevance to Pls, having been published in the English language, and pertinence for clinicians. Data quality and validity included the venue of the publication and relevance to clinical care.

Data Synthesis.
—Oral adminstration of ritonavir, indinavir, or nelfinavir generates sustainable drug serum levels to effectively inhibit the protease enzyme; however, saquinavir may not generate sustained levels necessary to inhibit the protease enzyme. Patients treated with ritonavir, indinavir, or nelfinavir experience similar reductions in viral load and increases in CD4⁺ lymphocytes; smaller effects occur among those treated with saquinavir. Two randomized placebo-controlled studies conducted among patients with severe immune system suppression and substantial zidovudine treatment experience demonstrated reduced HIV disease progression and reduced mortality with PI treatment. Genotypic resistance to Pls occurs; the clinical relevance of resistance is unclear. The costs of these agents including required monitoring impose new and substantial costs.

Conclusions.
—The Pls have emerged as critical drugs for people with HIV infection. Optimal use involves combination with reverse transcriptase inhibitors. Resistance develops to each agent, and cross-resistance is likely. These agents must be used at full doses with attention to ensuring patient compliance. The expense of these agents may be offset by forestalling disease progression and death and returning people to productive life. Selecting the initial PI must be individualized, and factors to consider include proven activity, possible toxicities, dosing regimens, drug interactions, and costs.

Author Affiliations
From the University of California, San Francisco, and San Francisco General Hospital (Drs Deeks, Smith, and Kahn); Kaiser Family Foundation, Palo Alto, Calif (Dr Smith); and the Veterans Affairs Palo Alto Health Care System and Stanford University, Palo Alto (Dr Holodniy). Dr. Smith is now with the California Healthcare Foundation.

Footnotes
Dr Deeks has received honoraria from Merck, Hoffmann-La Roche, Glaxo Wellcome, Bristol-Myers Squibb, and Agouron. Dr Kahn has received honoraria from Merck, Glaxo Wellcome, Bristol-Myers Squibb, and Agouron. Clinical trials supported by Merck, Glaxo Wellcome, Bristol-Myers Squibb, Hoffmann-LaRoche, Gilead Sciences, and Agouron provide the University of California support for studies directed by Drs Kahn and Deeks.

Reprints: James Kahn, MD, University of California, San Francisco, 995 Potrero Ave, San Francisco General Hospital, San Francisco, CA 94110 (e-mail: jkahn@sfaids.ucsf.edu).

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