Risk of HIV Progression/Indications for ART

Background

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 is complex and incompletely understood.

CD4 Count

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 helps to determine the urgency and the timing of ART initiation, and the need for prophylaxis against opportunistic infections. It also 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).

Table 1. Correlation Between CD4 Cell Counts and Complications of HIV Infection
CD4 Count* (cells/µL) Infectious Complications Noninfectious Complications#

* Most complications occur with increasing frequency at lower CD4 cell counts.

# Some conditions listed as "noninfectious" are associated with transmissible microbes. Examples include lymphoma (Epstein-Barr virus) and anal and cervical cancers (human papillomavirus).

Adapted from Bartlett JG, Gallant JE, Pham P. 2012 Medical Management of HIV Infection. Baltimore: Johns Hopkins University School of Medicine; 2012. Used with permission.

>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
  • Mononeuropathy 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

Increasing evidence suggests that the risk of complications from HIV infection occurs across a broad spectrum of CD4 counts, and that patients with relatively high 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 been used as 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 also is beneficial for persons with high 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 several randomized controlled studies and cohort studies have found decreased rates of complications and death among persons who initiated ART at CD4 counts of ≥350 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. A randomized controlled trial to evaluate the strategy of starting treatment at CD4 counts >500 cells/µL is under way.

These lines of evidence, along with studies showing a substantial 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. The current U.S. Department of Health and Human Services (HHS) adult and adolescent treatment guidelines recommend starting ART for all HIV-infected persons regardless of CD4 count, both to enhance the health of the infected individual and to prevent transmission of HIV. The strength of this recommendation is greater if the CD4 count is lower or the clinical status is poorer, and according to transmission risk groups (see Tables 2 & 3 and chapter Antiretroviral Therapy ).

HHS Recommendations on Initiation of Antiretroviral Therapy

The HHS guidelines state that, "Antiretroviral therapy (ART) is recommended for all HIV-infected individuals to reduce the risk of disease progression." The strength and evidence for this recommendation vary by pretreatment CD4 cell count, as follows:

Table 2. HHS Recommendations on Initiation of Antiretroviral Therapy CD4 Criteria
CD4 Criteria Strength of Recommendation*

Adapted from Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents . Department of Health and Human Services. Accessed December 1, 2013.

* Rating of recommendation: A = strong; B = moderate; C = optional
Rating of evidence: I = data from randomized controlled trials; II = data from well-designed nonrandomized trials or observational cohort studies; III = expert opinion
CD4 count <350 cells/µL Strongly recommended (AI)
CD4 count 350-500 cells/µL Strongly recommended (AII)
CD4 count >500 cells/µL Moderately recommended (BIII)

Additionally, the guidelines state that, "ART also is recommended for HIV-infected individuals for the prevention of transmission of HIV." The strength and evidence for this recommendation vary by transmission risk, as follows:

Table 3. HHS Recommendations on Initiation of Antiretroviral Therapy: Transmission Risk Group Criteria
Transmission Risk Group Strength of Recommendation*

Adapted from Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents . Department of Health and Human Services. Accessed December 1, 2013.

* Rating of recommendation: A = strong; B = moderate; C = optional
Rating of evidence: I = data from randomized controlled trials; II = data from well-designed nonrandomized trials or observational cohort studies; III = expert opinion

Perinatal transmission Strongly recommended (AI)
Heterosexual transmission Strongly recommended (AI)
Other transmission risk groups Strongly recommended (AIII)

Considerations

Patients starting ART should be willing and able to commit to treatment and understand the benefits and risks of therapy and the importance of adherence (AIII). Patients may choose to postpone therapy, and providers, on a case-by-case basis, may elect to defer therapy on the basis of clinical and/or psychosocial factors.

A number of factors and coexisting conditions signal the need for speedier initiation of therapy, if possible. According to the HHS guidelines, these include the following:

  • Pregnancy
  • History of AIDS-defining illness
  • Acute opportunistic infection
  • Lower CD4 cell count
  • Acute/recent HIV infection
  • HIV-associated nephropathy
  • Hepatitis B coinfection
  • Hepatitis C coinfection
  • Rapidly declining CD4 counts (e.g., >100 cells/µL per year)
  • Higher HIV RNA (e.g., >100,000 copies/mL)

HIV Viral Load

Figure 1. Prognosis According to CD4 Cell Count and Viral Load in the Pre-ART and ART Eras: Kaplan-Meier Estimates of the Probability of AIDS at 3 Years

Prognosis According to CD4 Cell Count and Viral Load in the Pre-ART and ART Eras: Kaplan-Meier Estimates of the Probability of AIDS at 3 Years

Abbreviations: HAART = highly active antiretroviral therapy

Egger M, May M, Chene G, Phillips AN, Ledergerber B, Dabis F, Costagliola D, D'Arminio Monforte A, de Wolf F, Reiss P, Lundgren JD, Justice AC, Staszewski S, Leport C, Hogg RS, Sabin CA, Gill MJ, Salzberger B, Sterne JA; ART Cohort Collaboration. Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies. Lancet. 2002 Jul 13;360(9327):119-29. Reprinted with permission from Elsevier.

Figure 1. Prognosis According to CD4 Cell Count and Viral Load in the Pre-ART and ART Eras: Kaplan-Meier Estimates of the Probability of AIDS at 3 Years

Prognosis According to CD4 Cell Count and Viral Load in the Pre-ART and ART Eras: Kaplan-Meier Estimates of the Probability of AIDS at 3 Years

Abbreviations: HAART = highly active antiretroviral therapy

Egger M, May M, Chene G, Phillips AN, Ledergerber B, Dabis F, Costagliola D, D'Arminio Monforte A, de Wolf F, Reiss P, Lundgren JD, Justice AC, Staszewski S, Leport C, Hogg RS, Sabin CA, Gill MJ, Salzberger B, Sterne JA; ART Cohort Collaboration. Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies. Lancet. 2002 Jul 13;360(9327):119-29. Reprinted with permission from Elsevier.

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; they also may have a higher rate of non-AIDS-related events even with relatively high CD4 counts (e.g., >350 cells/µL). Those with low viral loads 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).

Other Factors Associated with HIV Progression

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.

Viral factors

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 immune factors

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.

Age

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 and may have a higher rate of non-AIDS-related morbidities.

Table 4. Median Survival and Time to AIDS by Age at Seroconversion
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)

Patient Education

  • The CD4 cell count and HIV viral load are the two markers that provide information on the degree of current immunocompromise and the risk of disease progression.
  • The lower the CD4 count, the higher the risk of AIDS-related illness.
  • Current United States guidelines recommend ART for all HIV-infected individuals. In areas where treatment resources are limited, the CD4 count is the major indicator for initiation of ART.
  • A low HIV viral load is associated with slower immune deterioration; a high viral load is associated with quicker immune deterioration.
  • Older individuals may have a poorer response to therapy; earlier initiation of therapy may be considered for older patients.

References

  • Cohen MS, Chen YQ, McCauley M, et al.; HPTN 052 Study Team. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med. 2011 Aug 11;365(6):493-505.
  • Collaboration of Observational HIV Epidemiological Research Europe (COHERE) Study Group. Response to combination antiretroviral therapy: variation by age. AIDS. 2008 Jul 31;22(12):1463-73.
  • Concerted Action on Sero-Conversion 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.
  • Connor RI, Sheridan KE, Ceradini D, et al. Change in coreceptor use coreceptor use correlates with disease progression in HIV-1-infected individuals. J Exp Med. 1997 Feb 17;185(4):621-8.
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  • Egger M, May M, Chêne G, et al. Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies. Lancet. 2002 Jul 13;360(9327):119-29.
  • European AIDS Clinical Society. Clinical Management and Treatment of HIV-Infected Adults in Europe. English Version 5; November 2009.
  • Kirchhoff F, Greenough TC, Brettler DB, et al. Brief report: absence of intact nef sequences in a long-term survivor with nonprogressive HIV-1 infection. N Engl J Med. 1995 Jan 26;332(4):228-32.
  • Kuller L, SMART Study Group. Elevated levels of interleukin-6 and D-dimer are associated with an increased risk of death in patients with HIV. In: Program and Abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; Boston; February 3-6, 2008. Abstract 139.
  • Lederman MM, Rodriquez B, Sieg S. Immunopathogenesis of HIV Infection . In: Coffey S, Volberding PA, eds. HIV InSite Knowledge Base [online textbook]. San Francisco: UCSF Center for HIV Information; January 2006. Accessed December 1, 2013.
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  • Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents . Department of Health and Human Services. Accessed December 1, 2013.
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  • Sterne JA, May M, Costagliola D, et al; When to Start Consortium. Timing of initiation of antiretroviral therapy in AIDS-free HIV-1-infected patients: a collaborative analysis of 18 HIV cohort studies. Lancet. 2009 Apr 18;373(9672):1352-63.

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Abbreviations for Dosing Terminology

BID
twice daily
BIW
twice weekly
IM
intramuscular (injection), intramuscularly
IV
intravenous (injection), intravenously
PO
oral, orally
Q2H, Q4H, etc.
every 2 hours, every 4 hours, etc.
QAM
every morning
QD
once daily
QH
every hour
QHS
every night at bedtime
QID
four times daily
QOD
every other day
QPM
every evening
TID
three times daily
TIW
three times weekly