Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents
USE OF TESTING FOR PLASMA HIV RNA LEVELS AND CD4+T CELL COUNT IN GUIDING DECISIONS FOR THERAPY
Decisions regarding either initiating or changing antiretroviral therapy should be guided by monitoring the laboratory parameters of both plasma HIV RNA (viral load) and CD4+T cell count and by assessing the clinical condition of the patient. Results of these two laboratory tests provide the physician with important information about the virologic and immunologic status of the patient and the risk of disease progression to acquired immunodeficiency syndrome (AIDS) (see Principle 2 in the first section of this report). HIV viral load testing has been approved by the U.S. Food and Drug Administration (FDA) only for the RT-PCR assay (Roche) and only for determining disease prognosis. However, data presented at an FDA Advisory Committee for the Division of Antiviral Drug Products (July 14 & 15, 1997, Silver Spring, MD) provide further evidence for the utility of viral RNA testing in monitoring therapeutic responses. Multiple analyses of more than 5,000 patients who participated in approximately 18 trials with viral load monitoring demonstrated a reproducible dose-response type association between decreases in plasma viremia and improved clinical outcome based on standard endpoints of new AIDS-defining diagnoses and survival.
This relationship was observed over a range of patient baseline characteristics, including pretreatment plasma RNA level, CD4+T cell count, and prior drug experience. The consensus of the Panel is that viral load testing is the essential parameter in decisions to initiate or change antiretroviral therapies. Measurement of plasma HIV RNA levels (viral load), using quantitative methods, should be performed at the time of diagnosis of HIV infection and every 3 & 4 months thereafter in the untreated patient (AIII) (Table 2). CD4+T cell counts should be measured at the time of diagnosis and generally every 3 & 6 months thereafter (AIII). These intervals between tests are merely recommendations, and flexibility should be exercised according to the circumstances of the individual case. Plasma HIV RNA levels also should be measured immediately prior to and again at 4 & 8 weeks after initiation of antiretroviral therapy (AIII). This second time point allows the clinician to evaluate the initial effectiveness of therapy because in most patients, adherence to a regimen of potent antiretroviral agents should result in a large decrease (~0.5 to 0.75 log10) in viral load by 4 & 8 weeks. The viral load should continue to decline over the following weeks, and in most persons it becomes below detectable levels (currently defined as <500 RNA copies/mL) by 12 & 16 weeks of therapy. The speed of viral load decline and the movement toward undetectable are affected by the baseline CD4+T cell count, the initial viral load, potency of the regimen, adherence, prior exposure to antiretroviral agents, and the presence of any OIs. These individual differences must be considered when monitoring the effect of therapy. However, the absence of a virologic response of the magnitude previously described (i.e., ~0.5 to 0.75 log10 by 4 & 8 weeks and undetectable by 12 & 16 weeks) should prompt the physician to reassess patient adherence, rule out malabsorption, consider repeat RNA testing to document lack of response, and/or consider a change in drug regimen. Once the patient is on therapy, HIV RNA testing should be repeated every 3 & 4 months to evaluate the continuing effectiveness of therapy (AII). With optimal therapy, viral levels in plasma at 6 months should be undetectable (i.e., <500 copies of HIV RNA per mL of plasma) (2). If HIV RNA remains above 500 copies/mL in plasma after 6 months of therapy, the plasma HIV RNA test should be repeated to confirm the result, and a change in therapy should be considered according to the guidelines provided in “Considerations for Changing a Failing Regimen” (BIII). More sensitive viral load assays are in development that can quantify HIV RNA down to approximately 50 copies/mL. Preliminary data from clinical trials strongly suggest that lowering plasma HIV RNA to below 50 copies/mL is associated with a more complete and durable viral suppression, compared with reducing HIV RNA to levels between 50 & 500 copies/mL. However, the clinical significance of these findings is currently unclear.
When deciding whether to initiate therapy, the CD4+T cell count and plasma HIV RNA measurement ideally should be performed on two occasions to ensure accuracy and consistency of measurement (BIII). However, in patients with advanced HIV disease, antiretroviral therapy should generally be initiated after the first viral load measurement is obtained to prevent a potentially deleterious delay in treatment. Although the requirement for two measurements of viral load may place a substantial financial burden on patients or payers, two measurements of viral load should provide the clinician with the best information for subsequent follow up of the patient. 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 (see Principle 2). Because differences exist among commercially available tests, confirmatory plasma HIV RNA levels should be measured by the same laboratory using the same technique to ensure consistent results.
A substantial change in plasma viremia is considered to be a threefold or 0.5 log10 increase or decrease. A substantial decrease in CD4+T cell count is a decrease of >30% from baseline for absolute cell numbers and a decrease of >3% from baseline in percentages of cells (3,4). Discordance between trends in CD4+T cell numbers and plasma HIV RNA levels can occur and was found in 20% of patients in one cohort studied (5). Such discordance can complicate decisions regarding antiretroviral therapy and may be due to several factors that affect plasma HIV RNA testing (see Principle 2). Viral load and trends in viral load are considered to be more informative for guiding decisions regarding antiretroviral therapy than are CD4+T cell counts; exceptions to this rule do occur, however(see Considerations for Changing a Failing Regimen); when changes in viral loads and CD4+T cell counts are discordant, expert consultation should be considered.
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