Guidelines for Using Antiretroviral Agents among HIV-Infected Adults and Adolescents: The Panel on Clinical Practices for Treatment of HIV*

Introduction This report was developed by the Panel on Clinical Practices for Treatment of HIV (the Panel), which was convened by the Department of Health and Human Services (DHHS) and the Henry J. Kaiser Family Foundation in 1996. The goal of these recommendations is to provide evidence-based guidance for clinicians and other health-care providers who use antiretroviral agents in treating adults and adolescents infected with human immunodeficiency virus (HIV), including pregnant women. Although the pathogenesis of HIV infection and the general virologic and immunologic principles underlying the use of antiretroviral therapy are similar for all HIV-infected persons, unique therapeutic and management considerations exist for HIV-infected children. Therefore, guidance for antiretroviral therapy for pediatric HIV infection is not contained in this report. A separate report addresses pediatric-specific concerns related to antiretroviral therapy and is available at www.hivatis.org. These guidelines serve as a companion to the therapeutic principles from the National Institutes of Health (NIH) Panel To Define Principles of Therapy of HIV Infection (1). Together, the reports provide pathogenesis-based rationale for therapeutic strategies as well as guidelines for implementing these strategies. Although the guidelines represent the state of knowledge regarding the use of antiretroviral agents, this is an evolving science and the availability of new agents or new clinical data regarding the use of existing agents will change therapeutic options and preferences. Because this report needs to be updated periodically, a subgroup of the Panel on Clinical Practices for Treatment of HIV Infection, the Antiretroviral Working Group, meets monthly to review new data. Recommendations for changes are then submitted to the Panel and incorporated as appropriate. These recommendations are not intended to supersede the judgment of clinicians who are knowledgeable in the care of HIV-infected persons. Furthermore, the Panel recommends that, when possible, the treatment of HIV-infected patients should be directed by a clinician who has extensive experience in the care of these patients. When this is not possible, the patient should have access to such clinical experience through consultations. Each recommendation is accompanied by a rating that includes a letter and a Roman numeral (Table 1) and is similar to the rating schemes used in previous guidelines concerning prophylaxis of opportunistic infections (OIs) issued by the U.S. Public Health Service and the Infectious Diseases Society of America (2). The letter indicates the strength of the recommendation, which is based on the opinion of the Panel, and the Roman numeral reflects the nature of the evidence supporting the recommendation (Table 1). Thus, recommendations made on the basis of data from clinical trials with clinical results are differentiated from those made on the basis of laboratory results (e.g., CD4+ T lymphocyte count or plasma HIV ribonucleic acid [RNA] levels). When clinical trial data are unavailable, recommendations are made on the basis of the opinions of persons experienced in the treatment of HIV infection and familiar with the relevant literature. Table 1. Rating Scheme for Clinical Practice Recommendations Testing for Plasma HIV RNA Levels and CD4+ T Cell Count To Guide Decisions Regarding Therapy Decisions regarding initiation or changes in antiretroviral therapy should be guided by monitoring the laboratory parameters of plasma HIV RNA (viral load) and CD4+ T cell count in addition to the patient's clinical condition. Results of these laboratory tests provide clinicians with key information regarding the virologic and immunologic status of the patient and the risk for disease progression to acquired immunodeficiency syndrome (AIDS) (3, 4). HIV viral load testing has been approved by the Food and Drug Administration (FDA) for determining prognosis and for monitoring the response to therapy only for the reverse transcriptase-polymerase chain reaction (RT-PCR) assay and in vitro nucleic amplification test for HIVRNA (NucliSens HIV-1 QT, manufactured by Organon Teknika). Multiple analyses among >5000 patients who participated in approximately 18 trials with viral load monitoring indicated a statistically significant dose-responsetype association between decreases in plasma viremia and improved clinical outcome on the basis of standard results of new AIDS-defining diagnoses and survival. This relationship was observed throughout a range of patient baseline characteristics, including pretreatment plasma RNA level, CD4+ T cell count, and previous drug experience. Thus, viral load testing is an essential parameter in deciding to initiate or change antiretroviral therapies. Measurement of plasma HIV RNA levels (i.e., viral load) by using quantitative methods should be performed at the time of diagnosis and every 34 months thereafter for the untreated patient (AIII) (Table 2). CD4+ T cell counts should be measured at the time of diagnosis and every 36 months thereafter (AIII). These intervals between tests are recommendations only, and flexibility should be exercised according to the circumstances of each patient. Plasma HIV RNA levels should also be measured immediately before and again at 28 weeks after initiation of antiretroviral therapy (AIII). This second measurement allows the clinician to evaluate initial therapy effectiveness because, for the majority of patients, adherence to a regimen of potent antiretroviral agents should result in a substantial decrease ("1.0 log10) in viral load by 28 weeks. A patient's viral load should continue to decline during the following weeks and, for the majority of patients, should decrease below detectable levels (i.e., defined as <50 RNA copies/mL of plasma) by 1624 weeks. Rates of viral load decline toward undetectable are affected by the baseline CD4+ T cell count, the initial viral load, potency of the regimen, adherence to the regimen, previous exposure to antiretroviral agents, and the presence of any OIs. These differences must be considered when monitoring the effect of therapy. However, the absence of a virologic response of the magnitude discussed previously should prompt the clinician to reassess patient adherence, rule out malabsorption, consider repeat RNA testing to document lack of response, or consider a change in drug regimen. After the patient is receiving therapy, HIV RNA testing should be repeated every 34 months to evaluate the continuing effectiveness of therapy (AII). With optimal therapy, viral levels in plasma at 24 weeks should be undetectable (5). Data from clinical trials demonstrate that lowering plasma HIV RNA to <50 copies/mL is associated with increased duration of viral suppression, compared with reducing HIV RNA to levels of 50500 copies/mL (6). If HIV RNA remains detectable in plasma after 1624 weeks of therapy, the plasma HIV RNA test should be repeated to confirm the result and a change in therapy should be considered (see Changing a Failing Regimen) (BIII). Table 2. Indications for Plasma Human Immunodeficiency Virus (HIV) Ribonucleic Acid (RNA) Testing When deciding on therapy initiation, the CD4+ T lymphocyte count and plasma HIV RNA measurement should be performed twice to ensure accuracy and consistency of measurement (BIII). However, among patients with advanced HIV disease, antiretroviral therapy should be initiated after the first viral load measurement is obtained to prevent a potentially deleterious delay in treatment. The requirement for two measurements of viral load might place a substantial financial burden on patients or payers. Nonetheless, the Panel believes that two measurements of viral load will provide the clinician with the best information for subsequent patient follow-up. Plasma HIV RNA levels should not be measured during or within 4 weeks after successful treatment of any intercurrent infection, resolution of symptomatic illness, or immunization. Because differences exist among commercially available tests, confirmatory plasma HIV RNA levels should be measured by using the same laboratory and the same technique to ensure consistent results. A minimal change in plasma viremia is considered to be a threefold or 0.5-log10 increase or decrease. A substantial decrease in CD4+ T lymphocyte count is a decrease of >30% from baseline for absolute cell numbers and a decrease of >3% from baseline in percentages of cells (7). Discordance between trends in CD4+ T cell numbers and plasma HIV RNA levels was documented among 20% of patients in one cohort studied (8). Such discordance can complicate decisions regarding antiretroviral therapy and might be caused by factors that affect plasma HIV RNA testing. Viral load and trends in viral load are believed to be more informative for decision-making regarding antiretroviral therapy than are CD4+ T cell counts; however, exceptions to this rule do occur (see Changing a Failing Regimen). In certain situations, consultation with a specialist should be considered. Drug-Resistance Testing Testing for HIV resistance to antiretroviral drugs is a useful tool for guiding antiretroviral therapy. When combined with a detailed drug history and efforts in maximizing drug adherence, these assays might maximize the benefits of antiretroviral therapy. Studies of treatment-experienced patients have reported strong associations between the presence of drug resistance, identified by genotyping or phenotyping resistance assays, and failure of the antiretroviral treatment regimen to suppress HIV replication. Genotyping assays detect drug-resistance mutations that are present in the relevant viral genes (i.e., reverse transcriptase and protease). Certain genotyping assays involve sequencing of the entire reverse transcriptase and protease genes, whereas others use probes to detect selected mutations that are known to confer drug resistance. Genotyping ass