Clinical Guide > Testing and Assessment > CD4 and Viral Load

# CD4 and Viral Load Monitoring

January 2011

### Chapter Contents

      - Background 
      - Patient EducationReferencesTable 1. CD4 and HIV Viral Load Monitoring ScheduleHRSA HAB Core Clinical Performance MeasuresBackground 
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 Monitoring
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 is 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. Clinical status, viral load, pregnancy, comorbidities, and patient adherence to medications 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 this quickly or steadily, even with durable viral load suppression. Patients who are older (age >50 years) 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).
Viral Load Monitoring
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 40-75 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 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*). Although the CD4 cell count is more predictive of clinical disease progression than the HIV RNA level, and is the major factor in determining when to initiate ART for asymptomatic patients, the viral load can play a role (for example, if the viral load is very high).

 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 ScheduleBaselineFollow-Up Before ART InitiationAt ART Initiation or SwitchAfter ART Initiation or SwitchFollow-Up on Effective ART Treatment Failure or Clinical Indications
* Patients on a stable ART regimen with sustained viral suppression for >2-3 years may be monitored every 6-12 months.

** Adherent patients on stable ART with sustained viral suppression and stable clinical and immunologic status for >2-3 years: some experts may monitor every 6 months.

Adapted from U.S. Department of Health and Human Services. *Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents*; Table 3. January 10, 2011.
CD4 CountEvery 3-6 months1-3 monthsEvery 3-6 months*HIV Viral LoadEvery 3-4 months2-8 weeks, then every 4-8 weeks until HIV RNA is undetectableEvery 3-4 months**Patient Education- The CD4 cell count is the best indicator for gauging the strength of the immune system and for determining whether a person is at risk of infection with certain organisms. The higher the CD4 count, the stronger the immune system.
- CD4 counts are variable. Caution patients not to pin emotions and hopes to a single laboratory result. A change of <30% may not be significant.
- The HIV viral load is the best indicator of the level of HIV activity in the patient's body.
- The CD4 count and HIV viral load are used to help determine when to initiate therapy.
- The goal of therapy is to suppress the viral load to below the level of detectability by laboratory tests. An undetectable viral load does not mean HIV has been completely eradicated or that the patient is not infectious to others.
- For most patients on effective ART, the CD4 count will rise as the virus is suppressed. This indicates an improvement in the immune system.
- In stable patients, the CD4 count and HIV viral load usually should be monitored every 3-4 months.
References- Centers for Disease Control and Prevention.  Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents: Recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America . April 10, 2009.
- Hogg RS, Yip B, Chan KJ, et al.  Rates of disease progression by baseline CD4 cell count and viral load after initiating triple-drug therapy . JAMA. 2001 Nov 28;286(20):2568-77.
- Palella FJ, Deloria-Knoll M, Chmiel JS, et al.  Survival benefit of initiating antiretroviral therapy in HIV-infected persons in different CD4+ cell strata . Ann Intern Med. 2003 Apr 15;138(8):620-6.
- Schacker TW, Hughes JP, Shea T, et al.  Biological and virologic characteristics of primary HIV infection . Ann Intern Med. 1998 Apr 15; 128(8):613-20.
- U.S. Department of Health and Human Services.  Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents . January 10, 2011. 
**HRSA HAB Core Clinical Performance MeasuresPercentage of clients with HIV infection who had **two or more CD4 T-cell counts** performed within the measurement year (Group 1)**