Risk of All-Cause Mortality in HIV Infected Patients Is Associated with Clinical, Immunologic Predictors and the CCR5 Δ32 Deletion

Objective Investigation of the interplay between the CCR5 Δ32/wt genotype and demographic, epidemiological, clinical and immunological factors associated with mortality in the cART era. Design Longitudinal data from 507 HIV-infected patients following the Δ32 allele detection were analyzed. Methods Cumulative 15 years mortality was calculated using Kaplan-Meyer methodology. Hazard ratios were estimated using univariate Cox models. Basing on Akakie information criteria and statistical significance multivariate Cox model was constructed and effect plots presenting adjusted hazard ratio time-dependency were drawn. Analysis of the association of all-cause mortality and CCR5 Δ32/wt genotype prior to the antiretroviral treatment (cART) initiation (n = 507) and on the therapy (n = 422) was also performed. Results A mortality rate of 2.66 (CI 2.57–3.19) per 100 person-years was observed. Univariate analysis factors modifying the risk of death included the CCR5 genotype, gender, history of cART, AIDS diagnosis and also CD4 lymphocyte nadir, zenith, the latest CD4 count and stable levels >500 cells/µl. For multivariate analysis the following predictors were selected: CCR5 genotype (HR for wt/wt 2.53, CI 1.16–5.53, p = 0.02), gender (HR for males 1.91, 95%CI 1.1–3.36, p = 0.023), introduction of combined antiretroviral treatment (HR 4.85, CI 3.0–7.89, if untreated or treated <1 month, p<0.0001) CD4 count of 500 cells/µl for six months or more (HR 4.16, CI 1.95–8.88 if not achieved, p = 0.028), the latest CD4 count (HR 5.44, CI 3.39–8.74 for <100 cells/µl, p<0.0001) and history of AIDS (HR 1.69, CI 1.03–2.79, p = 0.039). Among untreated individuals the Δ32/wt genotype was associated with notably better survival (p = 0.026), while among cART treated individuals the Δ32 mutation did not correlate significantly with higher survival rates (p = 0.23). Conclusions The Δ32 CCR5 allele is associated with a reduction of the risk of all-cause mortality in HIV (+) patients alongside clinical and immunologic predictors such as AIDS, history of cART, lymphocyte CD4 cell count and gender.

[1]  A. Mocroft,et al.  Late presentation of HIV infection: a consensus definition , 2011, HIV medicine.

[2]  A. Rieger,et al.  HIV coreceptor tropism in antiretroviral treatment-naive patients newly diagnosed at a late stage of HIV infection , 2010, AIDS.

[3]  D. Cooper,et al.  Immunodeficiency and the risk of serious clinical endpoints in a well studied cohort of treated HIV-infected patients , 2010, AIDS.

[4]  Coris,et al.  Death rates in HIV-positive antiretroviral-naive patients with CD4 count greater than 350 cells per microL in Europe and North America: a pooled cohort observational study , 2010 .

[5]  R. Kaul,et al.  Effect of Baseline HIV Disease Parameters on CD4+ T Cell Recovery After Antiretroviral Therapy Initiation in Kenyan Women , 2010, PloS one.

[6]  J. Reynolds,et al.  Role of chemokine and cytokine polymorphisms in the progression of HIV-1 disease. , 2010, Biochemical and biophysical research communications.

[7]  C. Katlama,et al.  Is long‐term virological response related to CCR5 Δ32 deletion in HIV‐1‐infected patients started on highly active antiretroviral therapy? , 2010, HIV medicine.

[8]  A. Mocroft,et al.  Risk of all-cause mortality associated with nonfatal AIDS and serious non-AIDS events among adults infected with HIV , 2010, AIDS.

[9]  J. Gatell.  When and why to start antiretroviral therapy? , 2010, The Journal of antimicrobial chemotherapy.

[10]  J. Mulenga,et al.  Donor and Recipient Envs from Heterosexual Human Immunodeficiency Virus Subtype C Transmission Pairs Require High Receptor Levels for Entry , 2010, Journal of Virology.

[11]  Elizabeth T. Cirulli,et al.  Common Genetic Variation and the Control of HIV-1 in Humans , 2009, PLoS genetics.

[12]  R. Coker,et al.  Late diagnosis of HIV in Europe: definitional and public health challenges , 2009, AIDS care.

[13]  J. Goedert,et al.  Host Genetic Influences on Highly Active Antiretroviral Therapy Efficacy and AIDS-Free Survival , 2008, Journal of acquired immune deficiency syndromes.

[14]  C. Katlama,et al.  HIV-Infected Adults With a CD4 Cell Count Greater Than 500 Cells/mm3 on Long-Term Combination Antiretroviral Therapy Reach Same Mortality Rates as the General Population , 2007, Journal of acquired immune deficiency syndromes.

[15]  C. Rouzioux,et al.  Improved virological response to highly active antiretroviral therapy in HIV‐1‐infected patients carrying the CCR5 Δ32 deletion , 2007, HIV medicine.

[16]  J. Goedert,et al.  Effects of CCR5-Δ32 and CCR2-64I alleles on disease progression of perinatally HIV-1-infected children: an international meta-analysis , 2003, AIDS.

[17]  Mardge H. Cohen,et al.  CC chemokine receptor 5 genotype and susceptibility to transmission of human immunodeficiency virus type 1 in women. , 2003, The Journal of infectious diseases.

[18]  J. Goedert,et al.  Effects of CCR5-Δ32 and CCR2-64I alleles on HIV-1 disease progression: the protection varies with duration of infection , 2003, AIDS.

[19]  P. Harrigan,et al.  CCR5Δ32 and promoter polymorphisms are not correlated with initial virological or immunological treatment response , 2001, AIDS.

[20]  H. Ullum,et al.  Effects of CCR5- 32, CCR2-64I, and SDF-1 3A Alleles on HIV-1 Disease Progression: An International Meta-Analysis of Individual-Patient Data , 2001, Annals of Internal Medicine.

[21]  P. Rutgeerts,et al.  Analysis of the CC chemokine receptor 5 (CCR5) delta-32 polymorphism in inflammatory bowel disease , 2001, Human Genetics.

[22]  P. Debré,et al.  CCR5 delta32 deletion and response to highly active antiretroviral therapy in HIV-1-infected patients. , 2000, AIDS.

[23]  M. Carrington,et al.  Effect of chemokine receptor gene polymorphisms on the response to potent antiretroviral therapy , 2000, AIDS.

[24]  M J Dolan,et al.  Race-specific HIV-1 disease-modifying effects associated with CCR5 haplotypes. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[25]  B Wahren,et al.  Treatment history and baseline viral load, but not viral tropism or CCR‐5 genotype, influence prolonged antiviral efficacy of highly active antiretroviral treatment , 1998, AIDS.

[26]  J. Hoxie,et al.  Promiscuous use of CC and CXC chemokine receptors in cell-to-cell fusion mediated by a human immunodeficiency virus type 2 envelope protein , 1997, Journal of virology.

[27]  P. Debré,et al.  Early protective effect of CCR‐5 Δ32 heterozygosity on HIV‐1 disease progression: relationship with viral load , 1997 .

[28]  Nancy Sullivan,et al.  CCR5 Levels and Expression Pattern Correlate with Infectability by Macrophage-tropic HIV-1, In Vitro , 1997, The Journal of experimental medicine.

[29]  A. Iversen,et al.  Heterozygosity for a deletion in the CKR‐5 gene leads to prolonged AIDS‐free survival and slower CD4 T‐cell decline in a cohort of HIV‐seropositive individuals , 1997, AIDS.

[30]  J J Goedert,et al.  Genetic Restriction of HIV-1 Infection and Progression to AIDS by a Deletion Allele of the CKR5 Structural Gene , 1996, Science.

[31]  John W. Ward,et al.  1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. , 1993, MMWR. Recommendations and reports : Morbidity and mortality weekly report. Recommendations and reports.

[32]  H. Akaike.  A new look at the statistical model identification , 1974 .

[33]  M. Kaczmarczyk,et al.  Sequence variants of chemokine receptor genes and susceptibility to HIV-1 infection , 2010, Journal of Applied Genetics.

[34]  M. Leszczyszyn‐Pynka,et al.  [Late AIDS diagnosis in patients hospitalized in Clinic of Infectious Diseases and Hepatology PAM in years 2003-2007]. , 2009, Przeglad epidemiologiczny.

[35]  P. Harrigan,et al.  Short communication. Association of the CCR5delta32 mutation with clinical response and >5-year survival following initiation of first triple antiretroviral regimen. , 2005, Antiviral therapy.

[36]  P. Debré,et al.  Early protective effect of CCR-5 delta 32 heterozygosity on HIV-1 disease progression: relationship with viral load. The SEROCO Study Group. , 1997, AIDS.