Clinical Manual for Management of the HIV-Infected Adult
2006 Edition

Section 1: Testing and Assessment

CD4 Monitoring and Viral Load Testing

Background

CD4 Monitoring

CD4 cells (also called T cells or T-helper cells) are the primary targets of the HIV virus. The CD4 count is the number of CD4 cells per microliter (µL) of blood. It is the standard test for assessing HIV stage and prognosis, and for monitoring progression to AIDS and risk of opportunistic illnesses. It also guides the provider in formulating differential diagnoses in symptomatic patients (see Table 1, below), deciding about initiating antiretroviral treatment (ART), and beginning prophylaxis for opportunistic infections.

Most laboratories report the CD4 count as part of a list of several types of lymphocytes, as both an absolute count and a relative percentage. The important numbers are the absolute number of CD4 cells per microliter and the CD4 cell percentage, which is the proportion of CD4 cells as a subset of all lymphocytes.

The CD4 count typically declines over time as HIV infection progresses. Many other factors may affect CD4 counts more transiently, including illness, vaccination, diurnal variation, laboratory error, and inter-laboratory differences (see "Patient Education" below). Because fluctuations in the absolute CD4 count are likely, definitive conclusions should rarely be drawn from a single CD4 value. When results are inconsistent with previous trends, tests should be repeated, and treatment decisions usually should be based on 2 or more similar values. The CD4 percentage sometimes is used in coordination with the absolute value to assess the significance of changes in the absolute CD4 count. The absolute CD4 count can fluctuate as overall lymphocyte counts vary, but the CD4 percentage often remains stable during insignificant CD4 fluctuations. CD8 cell (or cytotoxic T cell) counts do not appear to predict clinical outcomes.

As untreated HIV infection progresses, the CD4 count declines by approximately 4% per year. In response to successful ART, the CD4 count typically increases by >50 cells/µL within weeks after viral suppression, and then increases by 50-100 cells/µL per year thereafter until a threshold is reached. In some patients, CD4 counts may not increase this quickly or steadily, even with durable viral load suppression.

The CD4 count is one of many factors (including clinical status, viral load status, and medication adherence) that should be assessed before starting or changing ART. The U.S. Department of Health and Human Services has provided recommendations for starting therapy based on symptoms, CD4 count, and viral load (Table 2). (See chapters Antiretroviral Therapy and Adherence.) Prophylaxis against opportunistic infections also 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 chapter Opportunistic Infection Prophylaxis.)

For monitoring purposes, the CD4 count should be repeated approximately every 3-4 months both in stable untreated patients and in patients on stable ART. The CD4 count should be checked more frequently according to the clinical situation (Table 3).

Viral Load Testing

In untreated HIV infection, replication usually produces billions of new viral copies daily. Plasma HIV RNA (viral load) testing quantifies the HIV viral burden in the plasma. In areas of the world with access to viral load monitoring, the viral load is a standard tool used to monitor treatment response in patients taking ART and, in conjunction with the CD4 cell count, to assess HIV progression. In certain settings in which HIV antibody tests may be negative or misleading, such as in acute HIV infection or neonatal infection, the HIV viral load may be used to help diagnose HIV infection. In some situations, the viral load may factor into decisions to initiate or change ART.

Viral load assays include HIV RNA polymerase chain reaction (Amplicor HIV-1 Monitor; Roche Laboratories), the branched chain DNA (Versant HIV-1 RNA assay; Bayer), and nucleic acid sequence-based amplification (NucliSens HIV-1 QT test; bioMerieux). The lowest level of detection differs for each test. Ultrasensitive assays (which are preferred in most circumstances) measure viral loads to 50-80 copies/mL, depending on the specific test, whereas the older assays usually have a cut-off at <400 copies/mL. A viral load below the level of detection ("undetectable") indicates inability of the assay to detect HIV in the plasma, but does NOT indicate absence or clearance of the virus from the body. Suppressing HIV RNA to an undetectable level (<50-75 copies/mL as measured by the ultrasensitive assay) is an important goal of ART. These assays also have different values for the highest levels of detection, ranging 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.

Whereas the absolute CD4 cell count is more predictive of clinical disease progression than is the baseline viral load, studies have shown that patients who have high plasma viral loads have an increased risk of progression to symptomatic disease and AIDS compared with patients who have low or undetectable levels. Patients with acute HIV infection who are undergoing seroconversion, and those with advanced disease, may have viral loads >500,000 copies/mL, whereas asymptomatic persons with chronic infection usually have considerably lower viral loads. Viral loads, like CD4 counts, are affected by laboratory variation, assay fluctuations, and patient variables such as acute illness and recent vaccinations. Variations less than approximately 0.5 log₁₀ copies/mL (3-fold) 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 2 or more similar values. If patients have had recent illnesses or vaccinations, viral load measurement should be deferred for 4 weeks, if possible.

Viral load should be checked at least twice at baseline, before starting an ART regimen. Follow-up viral load measurement should be performed at regular intervals, depending on the patient's clinical situation (Table 3). In the stable patient, viral load should be monitored every 3-4 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 closer intervals.

S: Subjective

A patient presents with HIV infection.

O: Objective

Complete the initial or interim physical examination according to the protocol. (See chapters Initial Physical Examination and Interim History and Physical Examination.)

A: Assessment

See chapters Initial History, Initial Physical Examination, and Initial and Interim Laboratory and Other Tests.

P: Plan

Laborator

• Obtain a CD4 count and perform viral load testing. See chapter Interim Laboratory and Other Tests for other recommended laboratory work.
• Monitor the results and manage patients using the schematic in Table 2 as a guide. See chapter Antiretroviral Therapy for more specific information.

Table 1. Correlation between CD4 Cell Counts and Complications of HIV Infection

CD4 Count* (cells/µL) Infectious Complications Noninfectious Complications# >500 Acute retroviral syndrome Candidal vaginitis Persistent generalized lymphadenopathy (PGL) Guillain-Barré syndrome Myopathy Aseptic meningitis 200-500 Pneumococcal and other bacterial pneumonias Pulmonary tuberculosis Herpes zoster Oropharyngeal candidiasis (thrush) Cryptosporidiosis (self-limited) Kaposi sarcoma (cutaneous) Oral hairy leukoplakia Herpes simplex (oral/genital) Cervical intraepithelial neoplasia Cervical cancer B-cell lymphoma Anemia Mononeuronal multiplex Idiopathic thrombocytopenic purpura Hodgkin lymphoma Lymphocytic interstitial pneumonitis Fatigue <200 Pneumocystis jiroveci pneumonia (PCP) Disseminated histoplasmosis and coccidioidomycosis Miliary/extrapulmonary tuberculosis Progressive multifocal leukoencephalopathy (PML) Wasting Peripheral neuropathy HIV-associated dementia Cardiomyopathy Vacuolar myelopathy Progressive polyradiculopathy Non-Hodgkin lymphoma <100 Disseminated herpes simplex virus Toxoplasmosis Cryptococcosis Cryptosporidiosis, chronic Microsporidiosis Candidal esophagitis Kaposi sarcoma (visceral/pulmonary) <50 Disseminated cytomegalovirus (CMV) Disseminated Mycobacterium avium complex (MAC) Central nervous system (CNS) lymphoma

* Most complications occur with increasing frequency at lower CD4 cell counts. # Some conditions listed as "noninfectious" are probably associated with transmissible microbes. Examples include lymphoma (Epstein-Barr virus) and cervical cancer (human papillomavirus). Adapted from Bartlett JG, Gallant JE. Medical Management of HIV Infection. Baltimore: Johns Hopkins University School of Medicine; 2005-2006. Used with permission.

Table 2. DHHS Guidelines for Initiating Antiretroviral Therapy in Chronically Infected Adults

Clinical Category CD4 Count (cells/µL) Plasma HIV Viral Load (copies/mL) Antiretroviral Therapy Recommendations Repeat CD4 and HIV Viral Load Test Asymptomatic >350 <100,000 Defer therapy Every 3-4 months if not on ART (see below if on ART) Asymptomatic >350 ≥100,000 Most clinicians recommend deferring therapy, some may treat Every 3-4 months until ART is started, then check for viral load response at 2-8 weeks; monitor CD4 and viral load every 3-4 months if satisfactory response Asymptomatic ≥200 but ≤350 Any value Treatment should be offered As above Asymptomatic, AIDS <200 Any value Treat As above AIDS-defining illness or severe symptoms Any value Any value Treat As above

Adapted from U.S. Department of Health and Human Services. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. May 4, 2006.

Table 3. Indications for CD4 Count and Plasma HIV RNA (Viral Load) Testing

Clinical Indication Test and Information Provided Use Syndrome consistent with acute or primary HIV infection HIV viral load: establishes diagnosis when HIV antibody test is negative or indeterminate Diagnosis (should be confirmed by standard HIV antibody test 2-4 months after initial test) Initial evaluation of newly diagnosed HIV infection Baseline CD4 and viral load values; disease staging Decision to start or defer ART* Every 3-4 months in patients not on therapy CD4 cell count and viral load; disease monitoring Decision to start or defer ART* 2-8 weeks after initiation of or change in ART CD4 count and viral load: Initial assessment of drug regimen efficacy Decision to start or defer ART* 3-4 months after starting ART CD4 count and viral load: Assess treatment efficacy; viral load should be undetectable by 16-24 weeks; CD4 cell count likely to continue to increase Decision to start or defer ART* Every 3-4 months in patients on ART CD4 count and viral load: Assess durability of immunologic response (CD4 increase) and virologic suppression (undetectable viral load) Decision to start or defer ART* Clinical event, or significant decline in CD4 cells or increase in viral load CD4 count and viral load: Check for association of clinical events with changing or stable CD4 cell count and/or plasma HIV viral load; confirm changes in CD4 and viral load Decision to initiate, continue, or change therapy*

* Decisions to initiate or change antiretroviral therapy (ART) should be based on 2 or more similar CD4 and viral load values. Adapted from U.S. Department of Health and Human Services. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. May 4, 2006.

Patient Education

• CD4 counts are the best indicator of how healthy the immune system is and whether a person is at risk of getting certain infections.
• CD4 counts are variable. Caution patients not to pin emotions and hopes to a single lab result.
• The HIV viral load is the best indicator of how active HIV is in the patient's body.
• Several ARVs may be used in combination to reduce the amount of virus in the body of someone with HIV. For each of these regimens, it is important to take each dose on time, every time. (See chapters on Antiretroviral Therapy and Adherence if the patient is getting ready to start ART.)
• ART directly affects the activity of HIV in the body and will lower the viral load. With less HIV present, the body is able to produce more CD4 cells and improve the immune system.
• An undetectable viral load does not mean HIV is cured or that the patient is not infectious to others. It means that virus cannot be detected in the blood, although it exists in other parts of the body.
• If the patient's CD4 count increases with successful ART, he or she may be protected from infections and other illnesses related to HIV.

References

• Bartlett JG, Gallant JE. 2005-2006 Medical Management of HIV Infection. Baltimore: Johns Hopkins University Division of Infectious Diseases; 2005. Available online at hopkins-aids.edu/mmhiv/order.html.
• U.S. Public Health Service, Infectious Diseases Society of America. Guidelines for preventing opportunistic infections among HIV-infected persons -- 2002. MMWR Recomm Rep. 2002 Jun 14;51(RR08);1-46. Available online at aidsinfo.nih.gov/Guidelines/. Accessed May 19, 2006.
• U.S. Department of Health and Human Services. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. May 4, 2006. Available online at aidsinfo.nih.gov/Guidelines/GuidelineDetail.aspx?GuidelineID=7. Accessed May 19, 2006.
• 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.