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CD4 and Viral Load Monitoring
Guide for HIV/AIDS Clinical Care, HRSA HIV/AIDS Bureau
The CD4 cell count and HIV viral load (RNA level) are closely linked to HIV-related illness and mortality. They give prognostic information on HIV progression and on response to therapy.
CD4 lymphocyte cells (also called T-cells or T-helper cells) are the primary targets of HIV. The CD4 count and the CD4 percentage mark the degree of immunocompromise. The CD4 count is the number of CD4 cells per microliter (µL) of blood. It is used to stage the patient's disease, determine the risk of opportunistic illnesses, assess prognosis, and guide decisions about when to start antiretroviral therapy (ART) (see chapters Risk of HIV Progression/Indications for ART and Antiretroviral Therapy).
The CD4 percentage is the percentage of the lymphocyte population that is CD4+; it is measured directly by flow cytometry. A CD4 percentage of <14% is considered to correspond to the same degree of immunosuppression as an absolute CD4 count of <200 cells/µL. The absolute CD4 count is calculated from the CD4 cell percentage and the total white blood cell count. The normal values for CD4 count vary considerably among different laboratories. The mean normal value for most laboratories is approximately 500-1,300 cells/µL. This calculated value is subject to more fluctuations than the CD4 cell percentage. Illness, vaccination, diurnal variation, laboratory error, and some medications can result in transient CD4 cell count changes, whereas the CD4 percentage remains more stable. Because CD4 counts may vary, treatment decisions generally should not be made on the basis of a single CD4 value. When results are inconsistent with previous trends, tests should be repeated, and treatment decisions usually should be based on two or more similar values. A change between two test results is considered significant if it is a 30% change in absolute CD4 count or 3 percentage point change in CD4 percentage.
In persons with untreated HIV infection, the CD4 count declines by approximately 50-80 cells/µL per year, on average. The pattern of decline may be slow and steady, or the CD4 count may level off for an extended period of time (as in long-term nonprogressors) and then decrease. Although it takes an average of 10 years for a newly infected person to progress to AIDS, there is great variation among patients. For some patients, disease progression occurs within a couple of years. For others, it takes more than 20 years, and a small number of patients appear to maintain high CD4 counts and undetectable HIV RNA levels without ART (aviremic or "elite" controllers).
Among asymptomatic individuals, the CD4 count typically has been the major factor that guides the decision to initiate therapy, though the trend in recent years has been to treat willing individuals even at very high CD4 levels (current United States guidelines recommend treatment for all HIV-infected individuals). Clinical status, viral load, pregnancy, comorbidities, patient adherence to medications, and risk of HIV transmission are among the other factors that should be taken into consideration (see chapters Risk of HIV Progression/Indications for ART and Antiretroviral Therapy).
Prophylaxis against opportunistic infections is based on CD4 count, and sometimes on CD4 percentage. For example, a CD4 count of <200 cells/µL or a CD4 percentage of <14% is an indication for prophylaxis against Pneumocystis jiroveci pneumonia; a CD4 count of <50 cells/µL is an indication for prophylaxis against Mycobacterium avium complex. (See chapters Opportunistic Infection Prophylaxis and Risk of HIV Progression/Indications for ART.) The CD4 count also guides decision making in determining when to stop prophylaxis against opportunistic infections with patients whose CD4 counts rise in response to ART.
Effective ART typically results in CD4 count increases of >50 cells/µL within weeks after viral suppression, and increases of 50-100 cells/µL per year thereafter. For some patients, CD4 counts may not increase that quickly or steadily, even with durable viral load suppression. Patients who are older (age >50) and those with lower baseline CD4 cell counts are more likely to have blunted CD4 count responses. For monitoring purposes, the CD4 count should be repeated approximately every 3-6 months both in stable untreated patients and in patients on ART (for patients on ART with persistently suppressed HIV RNA and CD4 counts solidly above thresholds for opportunistic infection risk, current guidelines suggest monitoring every 6-12 months). The CD4 count should be checked more frequently if clinically indicated (e.g., switching therapy, ART failure, rapidly declining CD4 count) (see Table 1).
The HIV-1 viral load measurement indicates the number of copies of HIV-1 RNA per milliliter of plasma. Although HIV ultimately resides within cells, the plasma measurement is an accurate reflection of the burden of infection and the magnitude of viral replication. It is used to assess the risk of disease progression and can help guide initiation of therapy. It is critical in monitoring virologic response to ART.
There are several commercially available HIV-1 viral load assays and numerous institution-specific assays. The range of detectable virus differs somewhat with each test, but the lowest level of detection generally is 20-75 copies/mL. A viral load below this "undetectable" level indicates the inability of the assay to detect HIV in the plasma, but does not indicate absence or clearance of the virus from the body. The highest levels of detection of the viral load assays typically are between 500,000 copies/mL and 750,000 copies/mL. Viral loads higher than these levels are reported, for example, as >500,000 copies/mL. Note that commercially available assays may not detect HIV-2, and they do not accurately quantify it.
After initial infection with HIV, the viral load quickly peaks to very high levels, usually >100,000 copies/mL (see chapter Primary HIV Infection). During the period of acute infection, when HIV antibody testing may indicate negative results, the viral load test may be used to detect HIV infection (however, most viral load assays are not diagnostic tests, so the HIV antibody assay should be repeated in 4-6 weeks to confirm the HIV diagnosis). Generally, 3-6 months after primary infection, the viral load declines and then levels off, remaining in a steady state. Among patients who are not taking ARV medications, a small number maintain a low or even undetectable viral load (aviremic or "elite" controllers), but the vast majority of those patients have relatively high HIV RNA levels.
Higher plasma viral loads are associated with more rapid declines in CD4 cells and with increased risk of progression to symptomatic disease and AIDS; they also are associated with higher risk of HIV transmission (see chapter Risk of HIV Progression/Indications for ART). ). In untreated persons, the CD4 cell count is more useful in determining the urgency of ART initiation, but once a patient has started ART, the viral load is used to monitor the response to therapy. A key goal of ART is to achieve a viral load that is below the level of detection (e.g., <40 copies/mL). Because CD4 and clinical responses may lag behind changes in viral load, viral load testing is essential for detecting virologic failure in a timely manner. With an effective ARV regimen, a 10-fold decline (1 logarithm) is expected within the first month, and suppression to undetectable levels should be achieved within 3-6 months after initiation of therapy. Isolated low-level elevations (typically <400 copies/mL) in viral load may occur in patients on ART; these "blips" generally do not predict subsequent virologic failure. (Additionally, some viral load assays appear to produce low-level positive results (<200 copies/mL) more commonly than others; as with blips, these do not appear to increase the risk of virologic failure.) To avoid confusing virologic failure with blips or test variability, current guidelines define virologic failure as repeated HIV RNA levels >200 copies/ mL. If the viral load does not reduce to an undetectable level (or at least <200 copies/mL), or if it rebounds after suppression, virologic failure has occurred, and possible causes should be investigated (e.g., poor ARV adherence, resistance to ARVs, or reduced drug exposure).
The HIV viral load should be checked at least twice at baseline, before the patient starts an ART regimen. Follow-up viral load measurement should be performed at regular intervals, depending on the patient's clinical situation (see Table 1). For stable patients, viral load usually should be monitored every 3-4 months; for highly adherent and stable patients with suppressed viral loads for at least several years, some experts monitor every 6 months. With new therapy or changes in therapy, significant change in viral load or CD4 count, or declining clinical status, the viral load should be measured at more frequent intervals.
Viral loads, like CD4 counts, are affected by laboratory variation, assay fluctuations, and patient variables such as acute illness and recent vaccinations. Variations of <0.5 log10 copies/mL (threefold) usually are not clinically significant. Viral load results that are inconsistent with previous trends should be repeated, and treatment decisions usually should be based on two or more similar values. Recent illnesses or vaccinations can transiently increase viral load. If a patient has had a recent illness or vaccination, the viral load measurement should be deferred for 4 weeks, if possible.
Table 1. CD4 and HIV Viral Load Monitoring Schedule
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