FUENTES DE INFORMACIÓN

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

100 80 60 40 20 0 >55 20–55 7–20 1.5–7 <1.5 HIV-1 RNA concentration (X10 copies/mL)3

Pre-HAART era 3-y ear pr obabilit y of AIDS (%) <200 201–350 351–500 >750 CD4 count (cells/ųL) 501–750 100 80 60 40 20 0 >55 20–55 7–20 1.5–7 <1.5 HIV-1 RNA concentration (X10 copies/mL)3

Pre-HAART era <200 201–350 351–500 >750 CD4 count (cells/ųL) 501–750

Risk of HIV Progression/Indications for ART | 107 Sec tion 2: Testing and A ssessment

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 3. 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) 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)

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 col- laborative re-analysis. Collaborative Group on AIDS Incubation and

HIV Survival including the CASCADE EU Concerted Action. Lancet.

2000 Apr 1;355(9210):1131-7.

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.

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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.

• Deeks SG, Wrin T, Liegler T, et al.

Virologic and immunologic consequences of discontinuing combination antiretroviral drug therapy in HIV-infected patients with detectable viremia. N Engl J Med. 2001 Feb 15;344(7):472-80.

• 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. Available at hivinsite.ucsf.edu/ InSite?page=kb-00&doc=kb-02-01-04. Accessed December 1, 2013.

• Mellors JW, Rinaldo CR Jr, Gupta P, et al.

Prognosis in HIV-1 infection predicted by the quantity of virus in plasma. Science. 1996;272:1167-70.

• 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. Available at aidsinfo.nih.gov/guidelines. Accessed December 1, 2013.

• Reekie J, Gatell JM, Yust I, et al.; EuroSIDA in EuroCoord. Fatal and nonfatal AIDS and non-AIDS events in HIV-1-positive individuals with high CD4 cell counts according to viral load strata. AIDS. 2011 Nov 28;25(18):2259-68.

• Rodríguez B, Sethi AK, Cheruvu VK, et al. Predictive value of plasma HIV RNA level on rate of CD4 T-cell decline in untreated HIV infection. JAMA. 2006 Sep 27;296(12):1498-506.

• 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.

Early HIV Infection | 109 Sec tion 2: Testing and A ssessment

Early HIV Infection