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IL28B Genotype Linked to All-Cause Mortality in HIV+ People on cART
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13th European AIDS Conference, October 12-15, 2011, Belgrade
Mark Mascolini
Variations in IL28B, a gene associated with viral load set point before combination antiretroviral therapy (cART), were associated with all-cause mortality in a longitudinal study of 484 HIV-positive people in Poland [1]. Why IL28B genotype appeared to have this impact in people who began combination antiretroviral therapy (cART) remains speculative.
IL28B single-nucleotide variants are associated with levels of interferon-lambda, changes in HCV RNA load, and HIV RNA set point (the level at which viral load settles after the big spike during acute HIV infection). Although interferon-lambda appears to have little effect on expression of the CCR5 coreceptor for HIV, it does induce expression of chemokine receptors on macrophages and dendritic cells and thus stimulates synthesis of HIV-restriction factors [2,3].
Because IL28B studies so far have focused on HCV RNA, researchers in Szczecin, Poland planned this study of single-nucleotide IL28B changes in HIV-positive people before and after they started cART. Specifically, they set out to uncover potential relationships between IL28B rs 1979860 polymorphisms (gene substitutions) and survival in people with HIV. This longitudinal analysis involved 484 people followed for a median of 15.4 months (interquartile range [IQR] 1.2 to 64.5) before they began cART and 406 people followed for a median of 53.9 months (IQR 22.6 to 90.7) after they started therapy.
In the pre-cART group, 41.7% had the IL28B CC genotype, 46.5% the CT genotype, and 11.8% the TT genotype. The 202 people with a CC genotype did not differ from the 282 in the combined CT/TT group in proportion of men (72% and 71%), proportion of injection drug use (47% and 53%), proportion asymptomatic at HIV diagnosis (41% versus 38%), proportion HCV positive (52.5% and 52.5%), median age at HIV diagnosis (29 and 30), median age when starting cART (33 and 33), median pretreatment CD4 count (213 and 223), and median lowest-ever CD4 count (168 and 127, P = 0.1).
During pre-cART and on-cART follow-up, 55 people died of AIDS and 29 died of non-AIDS causes for an overall mortality of 2.3 per 100 person-years. Rates of both AIDS deaths and non-AIDS deaths were higher in people with the IL28B CC genotype. AIDS (malignancy in 22% and bacterial pneumonia in 20%) killed 28 people in the CC group (13.9%) and 27 (9.6%) in the combined CT/TT group. Non-AIDS complications (liver disease in 22%, drug overdose in 21%, endocarditis in 18%) killed 18 in the CC group (8.1%) and 11 (3.9%) in the CT/TT group.
People with a CC or CT genotype had a significantly higher initial viral load than people with a TT genotype (P = 0.032). And the TT group had a higher peak CD4 count than those with a CC or CT genotype, though that difference lacked statistical significance (P = 0.09).
Univariate analysis determined that IL28B genotype (CC versus CT/TT) did not affect the risk of AIDS death or non-AIDS death in antiretroviral-naive people (univariate hazard ratio [HR] 1.04, 95% confidence interval [CI] 0.84 to 1.24, P = 0.68). But in people who had begun cART, survival through 120 months was significantly lower with the CC genotype than with the CT or TT genotype (P = 0.028). In univariate analysis, antiretroviral-treated people with a CC genotype had almost a doubled risk of all-cause death (univariate HR 1.8, 95% CI 1.28 to 2.34, P = 0.029).
After statistical adjustment for age, gender, initial CD4 count, and asymptomatic versus symptomatic disease at HIV diagnosis, the CC genotype independently raised the risk of all-cause mortality almost 75% (adjusted HR 1.74, 95% CI 1.0 to 3.02, P = 0.047). Every 100-cell lower initial CD4 count upped the death risk 80%, but that association stopped just short of statistical significance (adjusted HR 1.8, 95% CI 0.99 to 3.31, P = 0.051).
In the same analysis, female gender cut the death risk by about two thirds (adjusted HR 0.36, 95% CI 0.15 to 0.85, P = 0.02). Being asymptomatic at HIV diagnosis and younger age also tended to lower the risk of all-cause mortality, but not significantly.
The researchers suggested that the impact of IL28B genotype on all-cause mortality may be related to a higher initial viral load and "possibly altered immune reconstitution [reflected in peak CD4 count] associated with differences in interferon-lambda expression."
Because half of this study group injected drugs, it would be valuable to plan another study that focuses solely on people who acquired HIV sexually. Almost two thirds of the non-AIDS deaths in this group could be traced to causes seen predominantly in drug injectors: drug overdose in 21%, liver disease in 21%, endocarditis in 18%, and alcohol overdose in 3%.
References
1. Parczewski M,. Bander D, Leszczyszyn-Pynka M, Urbanska A, Socha L, Boron-Kaczmarska A. IL28B gene polymorphisms and all-cause mortality in HIV infected patients. 13th European AIDS Conference. October 12-15, 2011. Belgrade. Abstract PS2/3.
2. Hou W, Wang X, Ye L, et al. Lambda interferon inhibits human immunodeficiency virus type 1 infection of macrophages. J Virol. 2009;83:3834-3842.
3. Kelly C, Klenerman P, Barnes E. Interferon lambdas: the next cytokine storm. Gut. 2011;60:1284-1293
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