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Principles of Therapy of HIV Infection and Guidelines for the Use of Antiretroviral Agents in HIV-Infected Persons |

Report of the NIH Panel To Define Principles of Therapy of HIV Infection*

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Copyright ©2004 by the American College of Physicians

Ann Intern Med. 1998;128(12_Part_2):1057-1078. doi:10.7326/0003-4819-128-12_Part_2-199806151-00002
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Recent research advances have afforded substantially improved understanding of the biology of HIV infection and the pathogenesis of AIDS.With the advent of sensitive tools for monitoring HIV replication in infected persons, the risk for disease progression and death can be assessed accurately and the efficacy of anti-HIV therapies can be determined directly. Furthermore, when used appropriately, combinations of newly available, potent antiviral therapies can effect prolonged suppression of detectable levels of HIV replication and circumvent the inherent tendency of HIV to generate drug-resistant viral variants. However, as antiretroviral therapy for HIV infection has become increasingly effective, it has also become increasingly complex. Familiarity with recent research advances is needed to ensure that newly available therapies are used in ways that most effectively improve the health and prolong the lives of HIV-infected persons. To enable practitioners and HIV-infected persons to best use rapidly accumulating new information about HIV disease pathogenesis and treatment, the Office of AIDS Research of the National Institutes of Health (NIH) sponsored the NIH Panel To Define Principles of Therapy of HIV Infection. This Panel was asked to define essential scientific principles that should be used to guide the most effective use of antiretroviral therapies and viral load testing in clinical practice. On the basis of detailed consideration of the most current data, the Panel delineated 11 principles that address issues of fundamental importance for the treatment of HIV infection. These principles provide the scientific basis for the specific treatment recommendations made by the Panel on Clinical Practices for the Treatment of HIV Infection sponsored by the Department of Health and Human Services and the Henry J. Kaiser Family Foundation. The reports of both of these panels are provided in this supplement. Together, they summarize new data and provide both the scientific basis and specific guidelines for the treatment of HIV-infected persons. This information will be of interest to health care providers, HIV-infected persons, HIV and AIDS educators, public health educators, public health authorities, and all organizations that fund medical care of HIV-infected persons.

The members of the NIH Panel To Define Principles of Therapy of HIV Infection are Charles Carpenter, MD, Brown University and The Miriam Hospital, Providence, RI (chair); Mark Feinberg, MD, PhD, National Institutes of Health, Bethesda, MD (executive secretary); Wade Aubry, MD, Blue Cross/Blue Shield Association, San Francisco, CA; Dawn Averitt, Women's Information Service and Exchange, Atlanta, GA; John Coffin, PhD, Tufts University School of Medicine, Boston, MA; David Cooper, MD, National Center for HIV Epidemiology and Clinical Research, Sydney, Australia; Stephen Follansbee, MD, Davies Medical Center, San Francisco, CA; Peggy Hamburg, MD, New York City Department of Health, New York, NY; Mark Harrington, Treatment Action Group, New York, NY; Julia Hidalgo, ScD, Center for AIDS Services Planning and Development, Baltimore, MD; Harold Jaffe, MD, Centers for Disease Control and Prevention, Atlanta, GA; Dan Landers, MD, Magee Women's Hospital, Pittsburgh, PA; Henry Masur, MD, National Institutes of Health, Bethesda, MD; Philip Pizzo, MD, Children's Hospital and Harvard Medical School, Boston, MA; Douglas Richman, MD, University of California, San Diego, La Jolla, CA; Michael Saag, MD, University of Alabama at Birmingham, Birmingham, AL; Robert Schooley, MD, University of Colorado Health Sciences Center, Denver, CO; Valerie Stone, MD, MPH, Brown University School of Medicine, Providence, RI; Melanie Thompson, MD, AIDS Research Consortium of Atlanta, Atlanta, GA; Didier Trono, MD, The Salk Institute for Biological Studies, La Jolla, CA; Stefano Vella, MD, Instituto Superiore di Sanita, Laboratory of Virology, Rome, Italy; Bruce Walker, MD, Harvard Medical School, Boston, MA; Patrick Yeni, MD, X.Bichat Medical School, Paris, France.


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Figure 1.
Generalized time course of HIV infection and disease.

Three patterns of disease progression: rapid, intermediate, and late progression.

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Figure 2.
AIDS-free survival by baseline plasma HIV RNA levels and CD4+ T-cell counts.[27]P[27]33

Kaplan-Meier curves showing AIDS-free survival by plasma HIV RNA category among groups of persons with different baseline CD4+ T-cell counts who participated in the Multicenter AIDS Cohort Study . The five categories of baseline HIV RNA levels were I] ≤ 500, II) 501-3000, III] 3001-10 000, IV) 10 001-30 000, and V) >30 000 copies/mL of plasma. Within each CD4+ T-cell category, baseline HIV RNA concentration provided significant discrimination of AIDS-free times ( < 0.001) and survival times . In the lowest CD4+ T-cell category (<200 cells/mm ), there were too few participants with HIV RNA concentrations of ≤ 10 000 copies/mL to provide reliable estimates for RNA categories I to III. In the next lowest CD4+ T-cell categories (201-350 and 351-500 cells/mm ), there were too few participants with HIV RNA concentrations of ≤ 500 copies/mL (category I) to provide reliable estimates. Plasma HIV RNA concentrations were measured by using the Quantiplex HIV RNA branched DNA assay (Chiron Diagnostics, Emeryville, California).

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Figure 3.
Association between rates of decline of CD4+ T-cell counts and baseline plasma HIV RNA level.[27]

The relationship between baseline HIV-1 RNA level and the subsequent rate of decline in CD4+ T cells seen in participants of the Multicenter AIDS Cohort Study . The study population was divided into five categories of plasma HIV-1 RNA defined by baseline levels of 1) ≤ 500, 2) 501-3000, 3) 3001-10 000, 4) 10 001-30 000, and 5) >30 000 copies/mL of plasma. The estimated mean slope of decline in CD4+ T cells (number of cells lost per year) and 95% CIs by plasma HIV-1 RNA category are shown. The estimated rates of decline in CD4+ T-cell counts are substantially different for each of the five baseline HIV RNA categories and show a monotonic relationship; that is, the higher the baseline HIV RNA concentration, the greater the rate of decline of the CD4+ T-cell count. Plasma HIV RNA concentrations were measured by using the Quantiplex HIV RNA branched DNA assay (Chiron Diagnostics, Emeryville, California).

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Figure 4.
Probability of AIDS by baseline HIV RNA level and CD4+ T-cell count.[27]

A regression tree containing 14 distinct categories of risk for progression to AIDS defined among participants in the Multicenter AIDS Cohort Study . The risk for progression to AIDS can be assessed for many infected persons through the combined analysis of their baseline HIV RNA levels and CD4+ T-cell counts. The number of study participants in each group is indicated by “N.” Risk for AIDS with 95% CIs appears at the bottom of the figure. Plasma HIV RNA concentrations were measured by using the Quantiplex HIV RNA branched DNA assay (Chiron Diagnostics, Emeryville, California).

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Figure 5.
Rate of decline of plasma HIV RNA level after initiation of potent combination antiretroviral therapy.1010[37, 39]

A representative time course of rate of decline in plasma HIV RNA concentration (in log copies of RNA/mL) following initiation of a potent regimen of combination antiretroviral therapy (e.g., two nucleoside analogue reverse transcriptase inhibitors [i.e., zidovudine and lamivudine] plus a potent, bioavailable protease inhibitor [i.e., indinavir, nelfinavir, or ritonavir]). The first phase of decline is a rapid, approximately 2-log (100-fold) decrease in plasma HIV RNA concentrations. The slope of this first phase of decline in plasma RNA levels is very similar between different persons initiating effective antiretroviral therapies. A second, more gradual phase of decline in plasma HIV RNA levels is seen over subsequent weeks, the slope of which varies between different treated persons. Many effectively treated persons will demonstrate declines in plasma RNA levels to below the limits of assay detection (500 copies RNA/mL) by approximately 8 weeks after initiation of antiretroviral therapy, although some persons may take longer to demonstrate undetectable virus . When plasma HIV RNA levels decrease below detection, the absolute nadir is unknown. However, plasma HIV RNA levels have decreased below the detection limits of even more sensitive assays (sensitivity of 25 RNA copies/mL) in many effectively treated persons.

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