Case 3: Discussion
HIV RNA Assays
Patients initiating antiretroviral therapy or starting a new regimen should undergo close virologic monitoring to evaluate the response to therapy. In the United States, multiple nucleic acid-based tests are available for the measurement of HIV-1 RNA levels. The HIV RNA assays are typically categorized into one of the following methods: polymerase chain reaction (PCR), reverse transcription polymerase chain reaction (RT-PCR), or nucleic acid sequence based amplication (NASBA). The HIV RNA assays used for monitoring response to therapy typically have a HIV RNA detection threshold of 20 to 75 copies/ml. "Real time" assays have provided several advantages in HIV monitoring, including more rapid turnaround for results and an Given that significant interassay variability can occur, the same assay should ideally be used when following virologic trends and responses to antiretroviral therapy in an individual patient.
HIV RNA Monitoring
The January 2011 United States DHHS antiretroviral therapy guidelines provides the following recommendations for HIV RNA monitoring in patients on antiretroviral therapy. Patients should have a baseline plasma HIV RNA level before initiating or modifying antiretroviral therapy. After starting a new regimen, the HIV RNA level should be checked in 2 to 8 weeks (preferably in 2 to 4 weeks). Patients who adhere to a recommended potent antiretroviral regimen should have a substantial decrease in HIV RNA level within 4 weeks (at least a 1.0 log decrease compared with baseline). Factors that can potentially impact the initial HIV RNA response include preexisting antiretroviral resistance, baseline HIV RNA levels, medication adherence, regimen potency, medication absorption, and drug interactions. After the initial post-treatment HIV RNA level, the patient should have repeat HIV RNA testing every 4 to 8 weeks until the HIV RNA level becomes undetectable (less than 20 to 75 copies/ml). After starting a potent antiretroviral regimen, most patients have a rapid decline in HIV RNA levels and attain an undetectable HIV RNA level within 12 to 24 weeks (Figure 1), but in some instances, particularly with very high baseline HIV RNA level, the time to achieve an undetectable HIV RNA level may exceed 24 weeks. With a delayed response, it is important to continue close monitoring to ensure that HIV RNA levels continue to decline. Once the HIV RNA becomes undetectable, monitoring frequency can decrease to every 3 to 4 months. For adherent patients who have undetectable HIV RNA levels for at least 2 years and are clinically and immunologically stable, it is reasonable to monitor HIV RNA levels every 6 months. Patients who switch a regimen due to medication toxicity (or for a simplified regimen) and who had an undetectable HIV RNA prior to the change should have a follow-up HIV RNA checked within 2 to 8 weeks after making the regimen change to ensure virologic control was maintained with the regimen change. Monitoring HIV RNA levels can indicate a need to perform resistance testing in the following three circumstances: (1) the HIV RNA remains detectable 24 weeks after starting therapy and is no longer not declining (Figure 2), (2) the HIV RNA level initially decreases, but then increases compared with the previous value (Figure 3), and (3) the patient has a significant and persistent increase in HIV RNA levels after a period of sustained optimal HIV RNA suppression (Figure 4). In each of these three circumstances, resistance testing is ideally performed, unless the HIV RNA levels are too low to reliably perform the resistance test.
CD4 Cell Count Monitoring
In the first 6 months after starting antiretroviral therapy, HIV RNA responses are much more important to follow than CD4 responses. The early post change CD4 count responses vary widely and can provide misleading information for the patient. Frequent and intense CD4 count monitoring after starting a new regimen or changing a regimen is not recommended. Further, CD4 count changes as an indicator of antiretroviral failure typically lags far behind changes in HIV RNA levels. With most patients starting on antiretroviral therapy, the CD4 cell count should increase by 50 to 100 cells/mm3 per year until reaching a plateau[3,4]. The CD4 cell count monitoring is the same regardless of the regimen used. In general, patients on antiretroviral therapy should have monitoring of their CD4 cell count every 3 to 4 months to assess immunologic response to antiretroviral therapy. Some patients who maintain an undetectable HIV RNA value and who have a CD4 cell count well above the threshold for risk of developing an opportunistic infection, the frequency of CD4 cell count monitoring can be prolonged to every 6 to 12 months. Although relatively infrequent, some patients have an excellent virologic response, but have minimal CD4 cell count increases, or in some instances, actually have a decline in CD4 cell count. These responses characterized by good HIV RNA responses and poor CD4 cell count responses are often referred to as "discordant responses". The reason for a discordant response is usually not clear, but the poor CD4 cell count response does not indicate a treatment failure. The topic of discordant CD4 and HIV RNA responses is discussed in detail in Case 5 in the Antiretroviral Rx section.
Laboratory Monitoring for Antiretroviral Toxicity
Patients on antiretroviral therapy can develop drug toxicity and monitoring of certain laboratory values is recommended to minimize the risk of toxicity; the DHHS 2011 antiretroviral therapy guidelines provides specific recommendations for laboratory monitoring for patients taking antiretroviral therapy (Figure 5). Routine monitoring of serum lactate is not recommended, regardless of the regimen the patient is taking. Patients should have a baseline fasting lipid panel that includes total cholesterol, low density lipoprotein (LDL), high densitity lipoprotein (HDL), and triglycerides, and these studies should be repeated every 6 months if abnormal or every 12 months if normal. A fasting glucose is recommended prior to starting therapy, and if the level should be repeated every 6 to 12 months depending on whether the prior value was normal. Routine glucose tolerance testing is not recommended. All of the currently marketed non-nucleoside reverse transcriptase inhibitors and protease inhibitors have been associated with increases in serumaminotransferase levels. Thu, the DHHS guideliens recommend monitoring alanine aminotransferase (ALT), aspartate aminotransferase (ALT), and total bilirubin levels every 3 to 6 months. Among the antiretroviral medications, nevirapine (Viramune) poses the greatest risk of developing clinical hepatitis. If a patient starts a regimen that includes nevirapine, hepatic aminotransferase values should be checked at baseline and at 2 and 4 weeks after starting nevirapine. Routine monitoring of renal function is recommended every 3 to 6 months and patients receving tenofovir (Viread) should have a urinalysis checked every 6 months.
1 Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. January 10, 2011; 1–166.AIDSinfo
2 Perelson AS, Essunger P, Cao Y, et al. Decay characteristics of HIV-1 infected compartments during combination therapy. Nature. 1997;387:188-91. PubMed Abstract
3 Yamashita TE, Phair JP, Munoz A, et al. Immunologic and virologic response to highly active antiretroviral therapy in the Multicenter AIDS Cohort Study. AIDS. 2001;15:735-46. PubMed Abstract
4 Le Moing V, Thiebaut R, Chene G, et al. Predictors of long-term increase in CD4(+) cell counts in human immunodeficiency virus-infected patients receiving a protease inhibitor-containing antiretroviral regimen. J Infect Dis. 2002;185:471-80. PubMed Abstract
5 Landay AL, Spritzler J, Kessler H, et al. Immune reconstitution is comparable in antiretroviral-naive subjects after 1 year of successful therapy with a nucleoside reverse-transcriptase inhibitor- or protease inhibitor-containing antiretroviral regimen. J Infect Dis. 2003;188:1444-54. PubMed Abstract
6 Spritzler J, Mildvan D, Russo A, et al. Can immune markers predict subsequent discordance between immunologic and virologic responses to antiretroviral therapy? Adult AIDS Clinical Trials Group. Clin Infect Dis. 2003;37:551-8. PubMed Abstract
7 Yeni PG, Hammer SM, Carpenter CC, et al. Antiretroviral treatment for adult HIV infection in 2002: updated recommendations of the International AIDS Society-USA Panel. JAMA. 2002; 288: 222-35. PubMed Abstract
Copyright © 2004-2013 University of Washington