Case 3: Discussion

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HIV RNA Assays

Patients initiating antiretroviral therapy or starting a new regimen should undergo close virologic monitoring to evaluate the response to therapy. Currently, three major FDA-approved HIV RNA level assays are available: (a) the HIV-1 reverse transcriptase polymerase chain reaction assay (Amplicor HIV-1 Monitor® Test, version 1.5, Roche Diagnostic), with a lower limit of detection 50 copies/mL); (b) nucleic acid amplification test for HIV RNA (NucliSens® HIV-1 QT, bioMerieux), with a lower limit of detection 80 copies/mL; and (c) signal amplification nucleic acid probe assay (VERSANT® HIV-1 RNA 3.0 assay, Bayer), with a lower limit of detection of 75 copies/mL. Given that significant interassay variability can occur, the same assay should be used when following virologic trends and responses to antiretroviral therapy in an individual patient.

HIV RNA Monitoring

The October 2006 United States DHHS antiretroviral therapy guidelines recommend obtaining a plasma HIV RNA level immediately before starting antiretroviral therapy and 2-8 weeks after initiating therapy [1]. Patients who adhere to a potent antiretroviral regimen should have a substantial decrease in their HIV RNA level (at least a 1.0 log decrease compared with baseline). Factors that affect the initial HIV RNA response include adherence, preexisting resistance, potency of the regimen, absorption of the medications, the patient’s baseline CD4 cell count and viral load, and the presence of opportunistic infections. Most patients should have continued declines in their HIV RNA level and should have an undetectable level by 16 to 24 weeks (Figure 1) [2]. Most experts recommend obtaining an HIV RNA level in the first 2-4 weeks after initiating or changing an antiretroviral regimen, followed by repeat HIV RNA levels every 4 weeks for the first 16-24 weeks until the HIV RNA level becomes undetectable. Once the HIV RNA becomes undetectable on 2 consecutive values, it should then be followed every 12-16 weeks to monitor the ongoing response to antiretroviral therapy. If the HIV RNA has not become undetectable by 16-24 weeks (Figure 2), the patient should be evaluated for resistance. In addition, a patient who has a reversal in the trend of declining HIV RNA level during the first 16-24 weeks (with an increase in HIV RNA compared with the previous value) (Figure 3) should be evaluated for resistance. Similarly, resistance testing should be performed if a patient has a significant and persistent increase in HIV RNA levels after a period of sustained optimal HIV RNA suppression (Figure 4).

CD4 Cell Count Monitoring

In the first 12 weeks after starting antiretroviral therapy, HIV RNA responses are more important to follow than CD4 responses. Typically, the CD4 cell count should increase by at least 50 cells/mm3 at 4 to 8 weeks after starting therapy followed by an increase of 50-100 cells/mm3 per year thereafter until a threshold is reached [3,4]. The CD4 cell count increases are comparable with protease-inhibitor-based regimens and NNRTI-based regimens [5]. In patients who maintain an undetectable HIV RNA value, CD4 cell counts can generally be followed every 12-24 weeks. In some patients, despite an excellent initial virologic response, the early CD4 cell count increase may be minimal. Although uncommon, discordant responses may also occur, with declines in CD4 cell count despite an appropriate virologic response [6]. The reason for a discordant response is usually not clear, but the poor CD4 cell count response does not typically indicate a treatment failure. If, however, the patient was infected with a non-b sub-clade of HIV, a virologic failure could be missed if monitoring involved one of the older HIV RNA assays that often failed to accurately detect a non-b sub-clade. Newer HIV RNA assays usually accurately measure non-b sub-clades and the pre-treatment measurement of HIV RNA levels should have established whether the HIV RNA assay would detect the patient’s HIV. Some medications, such as zidovudine (Retrovir) and trimethoprim-sulfamethoxazole (Bactrim, Septra), have the potential to suppress bone marrow production, and, if possible, any medication that can suppress the bone marrow should be replaced in a patient who has a discordant CD4 cell count response. Medications or infections that suppress the bone marrow, however, should not impact the normal expected increase in CD4 percentage. In the situation where a patient has a discordant CD4 response, it would be reasonable to monitor the CD4 cell counts more frequently.

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 International AIDS Society USA 2002 antiretroviral therapy guidelines provided specific recommendations for laboratory monitoring for patients taking antiretroviral therapy [7]. 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 LDL, HDL, total cholesterol, and triglycerides, and these studies should be repeated 3 to 6 months after starting (or changing) antiretroviral therapy [7]. For patients on antiretroviral therapy who have lipid values within normal limits, the lipid panel should be followed once a year. Among those who require pharmacologic lipid-lowering therapy, the lipid panel should be followed every 3 to 6 months. A fasting glucose is recommended prior to starting therapy, and if the antiretroviral regimen includes a protease inhibitor, a fasting glucose should be repeated every 3-6 months [7]. 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 serum transaminases. Thus it is reasonable to monitor transaminases levels 2-4 times per year at routine visits. 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. These guidelines also recommend that pregnant woman taking the combination of didanosine (Videx EC) and stavudine (Zerit) should have aggressive monitoring of liver function tests and electrolytes, though this combination is not generally recommended. For patients taking either tenofovir-DF (Viread) or indinavir (Crixivan), it is reasonable to monitor BUN and creatinine at routine visits every 3-4 months. For patients taking didanosine, routine monitoring of amylase or lipase levels is not formally recommended, but patients should receive counseling regarding the signs and symptoms of pancreatitis.

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