The CD4 cell count and HIV viral load (RNA level) are closely linked to HIV-related illness and mortality, and are the laboratory measures that are followed in clinical practice. They are the primary markers that give prognostic information on disease progression and on response to antiretroviral therapy (ART) (see chapter CD4 and Viral Load Monitoring). However, it is increasingly recognized that a number of other factors are involved in HIV disease progression. These include individual HIV-specific immune responses, immune activation, viral factors, host genetics, and age. The role of these factors and their interplay are complex and incompletely understood.
The CD4 count (and CD4 percentage) marks the degree of immunocompromise. The CD4 count is used to stage the patient's disease progression, determine the risk of opportunistic illnesses, and assess prognosis (see chapter CD4 and Viral Load Monitoring). The CD4 count also guides decision making about the timing of ART initiation, helps in determining the need for prophylaxis against opportunistic infections, and helps in formulating differential diagnoses for symptomatic patients (see Table 1, Figure 1, and chapters CD4 and Viral Load Monitoring and Opportunistic Infection Prophylaxis).
Persons with HIV infection are at increased risk of complications at lower CD4 counts. A CD4 count of <200 cells/µL (or CD4 percentage of <14%) indicates severe immunosuppression, and is an AIDS-defining condition. Persons with CD4 counts below this level are at greater risk of a number of opportunistic illnesses and death, increasingly so at lower CD4 counts (see Table 1).
|CD4 Count* (cells/µL)||Infectious Complications||Noninfectious Complications#|
Increasing evidence suggests that the risk of complications from HIV infection occur across a broad spectrum of CD4 counts, and that patients with relatively high CD4 counts (those with counts of >350 cells/µL and even those with counts of >500 cells/µL) also have increased rates of morbidities compared with HIV-uninfected persons. The complications in persons with higher CD4 counts typically are not the classic AIDS-related opportunistic illnesses but are "non-AIDS" illnesses such as cardiovascular disease, neurocognitive decline, and non-AIDS-associated cancers.
In asymptomatic individuals, CD4 count has typically been the main indicator of need for ART. It is well established that ART is extremely effective at reducing HIV-related illness in persons with lower CD4 counts. In recent years, accumulating data have suggested that ART may be beneficial even for persons with higher pretreatment CD4 counts.
Randomized trials have shown that starting ART for asymptomatic patients with pretreatment CD4 counts of 200-350 cells/µL results in decreased morbidity and mortality compared with starting therapy for persons with CD4 counts of <200 cells/µL. For patients with pretreatment CD4 counts of >350 cells/µL, data from randomized controlled studies showing benefit of ART are not available, but several cohort studies have found decreased rates of complications and death among persons who initiated ART at CD4 counts of 350-500 cells/µL, compared with persons who initiated treatment at lower CD4 counts. Additionally, some (though not all) observational evidence suggests a mortality benefit of ART even among persons with pretreatment CD4 counts of >500 cells/µL. These cohort studies are complemented by a number of investigations that demonstrate ongoing and adverse effects of HIV and associated inflammation on various organ systems.
These lines of evidence, along with the demonstrations of the impact of ART in decreasing HIV transmission, and the availability of ARVs that generally are safe, tolerable, and effective, support the rationale for earlier initiation of treatment. Many experts favor treatment of all HIV-infected individuals, regardless of CD4 count. The current U.S. Department of Health and Human Services (DHHS) adult and adolescent treatment guidelines recommend starting ART for all willing asymptomatic patients whose CD4 counts are <500 cells/µL. Additionally, the guidelines emphasize that half of its panel members favor initiating ART for patients with CD4 counts of >500 cells/µL, whereas the other half consider ART for those patients to be optional (see Table 2 and chapter Antiretroviral Therapy).
|CD4 Count <350 Cells/µL|
|Pregnancy, HIV-Associated Nephropathy, Hepatitis B Coinfection (if treatment for hepatitis B is indicated)|
|CD4 Count <500 Cells/µL|
|CD4 Count >500 Cells/µL|
Whereas the CD4 count is an indicator of immune system function, the HIV viral load (RNA level) gives prognostic information on how quickly the CD4 count is likely to decline and, consequently, the risk of disease progression. Patients with high HIV viral loads generally demonstrate a faster decline in CD4 count and progression to AIDS-related illnesses, whereas those with low viral loads will usually have higher CD4 counts and remain asymptomatic for prolonged periods. A small percentage of persons with HIV infection may have very low or undetectable viral loads for extended periods of time.
By themselves, CD4 count and HIV viral load are useful, albeit rough, prognostic indicators. When considered together, they constitute a finer tool to estimate the risk of progression (see Figure 1).
Although the CD4 count and HIV viral load are the most important predictors of HIV progression, it is increasingly recognized that a number of other factors, and likely others that remain unknown, contribute to disease progression in HIV infection.
Variations in the HIV genome have been associated with an altered rate of disease progression. For example, deletions in the nef gene have been associated with a slow rate of progression. On the other hand, virus that uses the CXCR4 protein as a coreceptor for entry (termed X4 virus or syncytia-inducing virus) has been associated with accelerated progression. As another example, drug-resistance mutations may affect how efficiently the virus replicates (viral fitness). Patients who have virus with decreased fitness have slower immune deterioration than those with wild-type virus.
Host genetic factors have been shown to alter the rate of HIV progression. Various human leukocyte antigen (HLA) alleles have been associated with faster or slower progression rates. Genetic polymorphisms also play a role. For example, CCR5 is a chemokine receptor that can serve as a coreceptor for HIV entry into the CD4 cell. A naturally occurring variant allele for CCR5 has a 32 base pair deletion. Individuals who are heterozygous for this allele have slower progression of HIV disease.
Increased immune activation and elevated markers of inflammation, such as IL-6 and D-dimer, also have been associated with risk of disease progression and death. They also may be involved in the ongoing damage seen in a number of end organs. Although T-cell activation and levels of inflammation decrease with ART, they often do not return to normal.
Several studies have shown a higher risk of morbidity and mortality in older patients. When followed from seroconversion, older patients demonstrate faster disease progression compared with younger patients (see Table 3). Older patients also are found to have a less robust increase in the CD4 count in response to ART. These observations have led to the recommendation to consider age as a factor in determining when to initiate therapy in the European AIDS Clinical Society (EACS) guidelines.
|Age at Seroconversion (years)||Median (95% CI) Survival (years)||Median (95% CI) Time to AIDS (years)|
|Adapted from Concerted Action on SeroConversion to AIDS and Death in Europe. Time from HIV-1 seroconversion to AIDS and death before widespread use of highly-active antiretroviral therapy: a collaborative re-analysis. Collaborative Group on AIDS Incubation and HIV Survival including the CASCADE EU Concerted Action. Lancet. 2000 Apr 1;355(9210):1131-7.|
|15-24||12.5 (12.1-12.9)||11.0 (10.7-11.7)|
|25-34||10.9 (10.6-11.3)||9.8 (9.5-10.1)|
|35-44||9.1 (8.7-9.5)||8.6 (8.2-9.0)|
|45-54||7.9 (7.4-8.5)||7.7 (7.1-8.6)|
|55-64||6.1 (5.5-7.0)||6.3 (5.5-7.2)|
|≥65||4.0 (3.4-4.6)||5.0 (4.0-6.2)|