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

The past 2 years have brought major advances in both basic and clinical research on AIDS. The availability of more numerous and more potent drugs to inhibit HIV replication has made it possible to design therapeutic strategies involving combinations of antiretroviral drugs that accomplish prolonged and near-complete suppression of detectable HIV replication in many HIV-infected persons. In addition, more sensitive and reliable measurements of plasma viral load have been demonstrated to be powerful predictors of a person's risk for progression to AIDS and time to death. They have also been demonstrated to reliably assess the antiviral activity of therapeutic agents. It is now critical that these scientific advances be translated into information that practitioners and their patients can use in making decisions about using the new therapies and monitoring tools to achieve the greatest, most durable clinical benefits. Such information will allow physicians to tailor more effective treatments for their patients and to more closely monitor patients' responses to specific antiretroviral regimens. A two-track process was initiated to address this pressing need. 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 delineate, on the basis of its understanding of the biology and pathogenesis of HIV infection and disease, the scientific principles that should be used to guide the most effective use of antiretroviral therapy and viral load testing in clinical practice. The Department of Health and Human Services (HHS) and the Henry J. Kaiser Family Foundation sponsored the Panel on Clinical Practices for the Treatment of HIV Infection. The HHS Panel was charged with developing recommendations, based on the scientific principles, for the clinical use of antiretroviral drugs and laboratory monitoring methods in the treatment of HIV-infected persons. Both documents-the Report of the NIH Panel To Define Principles of Therapy for HIV Infection, developed by the NIH Panel, and the Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents, developed by the HHS Panel-are provided in this supplement. Together, these two documents summarize new data and provide both the scientific basis of and specific guidelines for the treatment of HIV-infected persons. The goal of this supplement is to assist clinicians and patients in making informed decisions about treatment options so that 1) effective antiretroviral therapy is introduced before extensive immune system damage has occurred; 2) viral load monitoring is used as an essential tool in determining an HIV-infected person's risk for disease progression and response to antiretroviral therapy; 3) combinations of antiretroviral drugs are used to suppress HIV replication to below the limits of detection of sensitive viral load assays; and 4) patient adherence to the complicated regimens of combination antiretroviral therapy currently required to achieve durable suppression of HIV replication is encouraged by patient-provider relationships that provide education and support concerning the goals, strategies, and requirements of antiretroviral therapy. The NIH Panel included clinicians, basic and clinical researchers, public health officials, and community representatives. As part of its effort to accumulate the most current data, the Panel held a 2-day public meeting to hear presentations by clinicians and scientists in areas of HIV pathogenesis and treatment, presentations that specifically addressed the following topics: the relationship between virus replication and disease progression; the relative ability of available strategies of antiviral therapy to minimize HIV replication for prolonged periods; the relationship between the emergence of drug resistance and treatment failures; the relative ability of available strategies of antiviral therapy to delay or prevent the emergence of drug-resistant HIV variants; and the relationship between drug-induced changes in virus load and improved clinical outcomes and prolonged survival. Summary of the Principles of Therapy of HIV Infection 1. Ongoing HIV replication leads to immune system damage and progression to AIDS. Infection with HIV is always harmful, and true long-term survival free of clinically significant immune dysfunction is unusual. 2. Plasma HIV RNA levels indicate the magnitude of HIV replication and its associated rate of CD4+ T-cell destruction, whereas CD4+ T-cell counts indicate the extent of HIV-induced immune damage already suffered. Regular, periodic measurement of plasma HIV RNA levels and CD4+ T-cell counts is necessary to determine the risk for disease progression in an HIV-infected person and to determine when to initiate or modify antiretroviral treatment regimens. 3. As rates of disease progression differ among HIV-infected persons, treatment decisions should be individualized by the level of risk indicated by plasma HIV RNA levels and CD4+ T-cell counts. 4. The use of potent combination antiretroviral therapy to suppress HIV replication to below the levels of detection of sensitive plasma HIV RNA assays limits the potential for selection of antiretroviral-resistant HIV variants, the major factor limiting the ability of antiretroviral drugs to inhibit virus replication and delay disease progression. Therefore, maximum achievable suppression of HIV replication should be the goal of therapy. 5. The most effective means to accomplish durable suppression of HIV replication is the simultaneous initiation of combinations of effective anti-HIV drugs that the patient has not previously received and that are not cross-resistant with antiretroviral agents that the patient has previously received. 6. Each of the antiretroviral drugs used in combination therapy regimens should always be used according to optimum schedules and dosages. 7. The available effective antiretroviral drugs are limited in number and mechanism of action, and cross-resistance between specific drugs has been documented. Therefore, any change in antiretroviral therapy increases future therapeutic constraints. 8. Women should receive optimal antiretroviral therapy regardless of pregnancy status. 9. The same principles of antiretroviral therapy apply to HIV-infected children, adolescents, and adults, although the treatment of HIV-infected children involves unique pharmacologic, virologic, and immunologic considerations. 10. Persons identified during acute primary HIV infection should be treated with combination antiretroviral therapy to suppress virus replication to levels below the limit of detection of sensitive plasma HIV RNA assays. 11. Persons with HIV infection, even those whose viral loads are below detectable limits, should be considered infectious. Therefore, they should be counseled to avoid sexual and drug-use behaviors that are associated with either transmission or acquisition of HIV and other infectious pathogens. These topics and other data assessed by the Panel in formulating the scientific principles were derived from three primary sources: recent basic insights into the life cycle of HIV, studies of the extent and consequences of HIV replication in infected persons, and clinical trials of anti-HIV drugs. In certain instances, the Panel based the principles and their associated corollaries on clinical studies conducted in relatively small numbers of patients for fairly short periods of time. After carefully evaluating data from these studies, the Panel concluded that the results of several important contemporary studies have been consistent in their validation of recent models of HIV pathogenesis. The Panel believes that new antiretroviral drugs and treatment strategies, if used correctly, can substantially benefit HIV-infected persons. However, as the understanding of HIV disease has improved and the number of available beneficial therapies has increased, clinical care of HIV-infected patients has become much more complex. Therapeutic success increasingly depends on a thorough understanding of the pathogenesis of HIV disease and on familiarity with when and how to use the more numerous and more effective drugs available to treat HIV infection. The Panel is concerned that even these new potent antiretroviral therapies will be of little clinical utility for treated patients unless they are used correctly and that, if used incorrectly, they may even compromise the potential to obtain long-term benefit from other antiretroviral therapies in the future. The principles and conclusions discussed in this report have been developed and made available now so that practitioners and patients can make treatment decisions based on the most current research results. Undoubtedly, insights into the pathogenesis of HIV disease will continue to accumulate rapidly, providing new targets for the development of additional antiretroviral drugs and even more effective treatment strategies. Thus, the Panel expects that these principles will require modification and elaboration as new information is acquired. Scientific Principles Principle 1. Ongoing HIV replication leads to immune system damage and progression to AIDS. Infection with HIV is always harmful, and true long-term survival free of clinically significant immune dysfunction is unusual. Active replication of HIV is the cause of progressive immune system damage in infected persons [1-10]. In the absence of effective inhibition of HIV replication by antiretroviral therapy, nearly all infected persons will suffer progressive deterioration of immune function resulting in susceptibility to opportunistic infections (OIs), cancer, neurologic diseases, and wasting and ultimately leading to death [11, 12]. For adults who live in developed countries, the average time of progression to AIDS after initial infection is approximately 10 to 11 years in the absence of antiretroviral