Given that peginterferon-ribavirin treatment is poorly tolerated, there is interest in the identification of predictors of response, particularly in HIV/hepatitis C virus (HCV)-coinfected patients ...that respond less than HCV-monoinfected individuals. A single nucleotide polymorphism (SNP) near the IL28B gene (rs12979860) has been shown to predict treatment response in HCV-monoinfected patients carrying genotype 1. Information is lacking for HIV/HCV-coinfected individuals and/or other HCV genotypes.
From 650 HIV/HCV-coinfected patients, we identified those who had completed a course of peginterferon-ribavirin therapy with a validated outcome and available repository DNA. The rs12979860 SNP was examined in a blinded fashion.
A total of 164 patients were included in the final IL28B genotyping analysis, 90 (55%) of whom achieved sustained virological response (SVR). HCV genotype distribution was as follows: HCV-1 58%, HCV-3 31% and HCV-4 11%. Overall, the SVR rate was higher in patients with CC than in those CT/TT genotypes: 56 of 75 (75%) versus 34 of 89 (38%) (P < 0.0001). The effect of the SNP was seen in HCV genotypes 1 and 4 but not in HCV genotype 3 carriers. In the multivariable analysis (odds ratio; 95% confidence interval; P value), the rs12979860 CC genotype was a strong predictor of SVR (3.7; 1.6-8.5; 0.002), independent of HCV genotype 3 (8.0; 3.1-21.0; <0.001), serum HCV-RNA less than 600,000 IU/ml (11.9; 3.8-37.4; <0.001) and lack of advanced liver fibrosis (3.5; 1.4-8.9; 0.009).
The rs12979860 SNP located near the IL28B gene is associated with HCV treatment response in HIV-infected patients with chronic hepatitis C due to genotypes 1 or 4. Thus, IL28B genotyping should be considered as part of the treatment decision algorithm in this difficult-to-treat population.
Abstract Interleukin 17 (IL17) secreting T (Th17) cells play a protective role against bacterial infections at mucosal surfaces. Recent reports show Th17 cells are depleted in the gut associated ...lymphoid tissue of HIV+ patients, but their role in HIV disease progression is not well understood. Expression of the IL17 receptor (IL17R) and the production of IL17 were compared between two groups of HIV patients with different disease progression (long-term-nonprogressors, LTNP and typical-progressors, TP). IL17R expression was similar in LTNP and TP, whereas Th17 cell number was greater in LTNP than TP (p = 0.015). An inverse correlation between the plasma HIV-RNA and both IL17R expression and Th17 cell number was found (p = 0.001 and p = 0.002, respectively). The increased number of Th17 cells in LTNP could lead to a more preserved immune response against bacterial infections. As a result, lower microbial translocation could explain the reduced immune activation and slower disease progression seen in LTNP.
A single nucleotide polymorphism (SNP) upstream of the IL28B gene (rs12979860) predicts sustained virological response (SVR) to peginterferon-ribavirin therapy in chronic hepatitis C patients. There ...is scarce information regarding the influence of this IL28B SNP on early viral kinetics during therapy, particularly in patients coinfected with HIV, in whom treatment response is lower than in hepatitis C virus (HCV)-monoinfected patients.
We selected 196 HIV/HCV-coinfected individuals who had completed a course of peginterferon-ribavirin therapy, and a validated outcome for SVR. Association of IL28B SNPs with rapid, early and end-of-treatment virological responses rapid virological response (RVR), early virological response (EVR) and end of treatment virological response, respectively was assessed in univariate and multivariate analyses.
Rate of SVR in the study population was 54%. Frequency of the IL28B CC genotype was 44%. The distribution of HCV genotypes was as follows: HCV-1 57%, HCV-2 1%, HCV-3 30% and HCV-4 12%. Compared to CT/TT, the CC genotype was associated with significantly higher rates of all on-treatment viral outcomes, after adjusting for other predictors of viral response as serum HCV-RNA, HCV genotype and liver fibrosis staging. IL28B CC genotype kept its predictive power of SVR in patients who did not achieve RVR or cEVR. The association between IL28B SNP and viral kinetics and treatment outcomes was significant only for HCV genotypes 1 and 4.
IL28B CC genotype is a strong predictor of virological response to therapy in HIV/HCV-coinfected patients. This effect is mediated by an increase in viral clearance during the first 12 weeks of treatment and is mainly seen in patients infected with HCV genotypes 1 and 4.
The mechanism explaining the strong association between IL28B rs12979860 polymorphisms and treatment outcome in chronic hepatitis C remains unclear. We explore whether IL28B protein interferon ...(IFN)-λ3 plasma levels may vary according to IL28B genotype and/or following pegylated IFN-α/ribavirin therapy.
A total of 112 HIV/hepatitis C virus (HCV)-coinfected patients who completed a course of pegylated IFN-α/ribavirin therapy were examined. Sustained virological response (SVR) was achieved by 56% of patients. IL28B rs12979860 alleles were genotyped using the 5' nuclease assay with specific TaqMan probes. A specific enzyme immunoassay was used to measure IFN-λ3 plasma levels before initiating anti-HCV therapy and at week 4 of treatment.
No significant differences between CC and non-CC IL28B carriers were found at baseline, either in the proportion of patients with detectable IFN-λ3 plasma levels or in their median values. In contrast, median IFN-λ3 plasma levels at week 4 of therapy significantly increased with respect to baseline in CC carriers 34.3 (16.7-56.3) versus 15.6 (15.6-30.3) pg/mL, respectively; P < 0.0001, but not in CT/TT carriers. Unexpectedly, increases in IFN-λ3 at week 4 of therapy did not predict SVR.
The exogenous administration of IFN-α may induce IFN-λ3 release in IL28B CC carriers, but not in CT/TT carriers. However, this finding does not account for the link between IL28B polymorphisms and treatment outcome.
The role of rs1127354/rs7270101 alleles at the inosine triphosphatase (ITPA) gene on ribavirin-induced anemia was assessed in 74 human immunodeficiency virus/hepatitis C virus-coinfected patients. ...Anemia developed in 80% of patients with normal compared to 33% of those with reduced ITPA activity. In contrast, ITPA variants did not influence sustained virological response.
The role of rs1127354/rs7270101 alleles at the inosine triphosphatase (ITPA) gene on ribavirin-induced anemia was assessed in 74 patients with hepatitis C virus and human immunodeficiency virus coinfection. Anemia developed in 80% of patients with normal ITPA activity compared with 33% of those with reduced ITPA activity. In contrast, ITPA variants did not influence sustained virological response.
Susceptibility to HIV transmission by sexual intercourse has been associated with cellular anti-HIV responses. We aimed to also evaluate potential systemic humoral responses against HIV in a group of ...HIV-exposed seronegative individuals (HESN) in stable relationship with HIV-infected partners.
We recruited 27 serodiscordant couples. HESN were classified according to HIV exposure into very low/low and moderate/high risk. Plasma from HESN and HIV partners were tested for neutralizing capacity and for the recognition of cell-surface expressed and recombinant forms of HIV envelope glycoproteins (Env). Healthy individuals (healthy control, n=11) were used as controls.
Recognition of cell-surface expressed Env by both immunoglobulin (Ig)G and IgA was higher in plasma samples from HESN than in healthy controls (P=0.0062 and P=0.0144, respectively). IgG binding to Env was significantly increased in HESN after unmasking CD4-induced epitopes (P=0.001), suggesting a wide range of targeted epitopes. Remarkably, ELISA assays using trimeric gp140 or monomeric gp120 failed to detect significant differences in reactivity between groups. Neutralization analysis showed residual activity in only three HESN samples (11%), whereas 70% of HIV-infected partners showed neutralizing activity. Although anti-Env humoral responses were found in 85% of HESN, their magnitude was not associated with the estimated level of exposure or the detection of HIV-specific cellular immune responses.
A high proportion of HESN show detectable plasma IgG or IgA recognizing different exposed and cryptic Env native epitopes unrelated to neutralizing capacity. Therefore, low but persistent HIV exposure induces new virus-specific systemic humoral responses or boosts preexisting natural antibodies.
The critical role of interleukin-28B (IL28B)/interferon-λ3 (IFN-λ3) polymorphisms on the susceptibility to hepatitis C virus infection and the response to peginterferon-ribavirin therapy has ...encouraged exploration of similar effects on other viruses. Given that IFN-λ mediates anti-HIV-1 activity, the protective role of IL28B polymorphisms was examined in 29 seronegative individuals at risk for HIV-infection and in 68 HIV-positive carriers with and without rapid progression of immunodeficiency. No protective role of IL28B polymorphism was found examining both HIV-disease progression and HIV-protection.
Background. A recent genome-wide association study reported a strong association with a single-nucleotide polymorphism (SNP) in the inosine triphosphate (ITPA) gene and hemolytic anemia in patients ...infected with hepatitis C virus (HCV) receiving pegylated interferon and ribavirin. We investigate these polymorphisms in a cohort of human immunodeficiency virus (HIV)/HCV-coinfected patients. Methods. DNA was available for 161 patients with validated outcomes. We analyzed the association between the variants and week 4 hemoglobin reduction. Anemia over the course of therapy, ribavirin (RBV) dose reduction, serum RBV level, and rapid virological response (RVR) and sustained virological response (SVR) were also investigated. Using a candidate gene approach, ITPA variants rsl 127354 and rs7270101 were tested using the ABI TaqMan kit. Multivariable models were used to identify predictors of anemia. Results. A significant minority (33%) of patients were predicted to have reduced ITPase activity. The minor allele of each variant was associated with protection against week 4 anemia. In multivariable models only the genetic variants, creatinine, and zidovudine exposure remained significant. ITPase deficiency was not associated with RBV-dose reduction, RVR, or SVR. Conclusions.This study confirms that polymorphisms in the ITPA gene are associated with protection from RBV-induced anemia in HIV/HCV-coinfected patients but not improved clinical outcomes.
The interaction between interferon-stimulated genes (ISGs) expression, IL28B genotypes and hepatitis C treatment outcomes has been mainly evaluated in the liver tissue from hepatitis C virus ...(HCV)-monoinfected patients but with controversial results. Herein, we examined whether more easily accessible peripheral blood mononuclear cells (PBMCs) could be used for this purpose in HIV-HCV coinfected patients, a population in whom HCV-induced liver disease progression occurs more rapidly and treatment response is lower.
Gene expression profiles were examined using the human whole genome Agilent microarray platform in PBMCs collected from HIV/HCV-coinfected patients who had completed a course of peginterferon/ribavirin therapy with validated outcomes. Patients were split out according to the achievement of sustained virological response (SVR) and IL28B rs12979860 genotypes. The GeneSpringGX software was used to select genes differentially expressed in the different groups.
Nineteen HIV/HCV-coinfected individuals receiving antiretroviral therapy and having undetectable plasma HIV-RNA were examined. Global gene expression profiles showed 42 genes differentially expressed according to treatment outcome and 56 according to IL28B genotype. Common genes were not found and functions differed for genes belonging to either group. Whereas at least 26 out of 37 repressed genes (70.3%) in SVR patients were ISGs, none of the 56 differentially expressed genes in carriers of distinct IL28B variants were ISGs (P < 0.0001).
Baseline expression of ISGs in PBMCs from HCV/HIV-coinfected patients influence the response to peginterferon/ribavirin therapy, regardless of IL28B genotypes. PBMC specimens can reliably be used for evaluating ISGs expression in clinical practice.
Accurate prediction of sustained virological response (SVR) to pegylated interferon-α (Peg-IFN) plus ribavirin in HIV/hepatitis C virus (HCV)-coinfected patients could improve the management of these ...patients. We aimed to develop a model to predict SVR to Peg-IFN/ribavirin in HIV/HCV-coinfected individuals combining HCV genotype and baseline HCV RNA load with interleukin 28B and low-density lipoprotein receptor genetic variations.
Three hundred and twelve treatment-naive HIV/HCV-coinfected patients receiving Peg-IFN/ribavirin were analysed in an on-treatment approach. One hundred and eighty-one of them were included in the development group and 131 in the validation population. The predictive model was obtained from a logistic regression equation including the above-mentioned variables. The areas under the receiver operating characteristic (AUROC) curves (95% CI), sensitivity and specificity, as well as negative and positive predictive values, were calculated.
SVR was achieved by 88 (48.6%) patients from the development group and 68 (51.9%) individuals from the validation group. The AUROC curve values (95% asymptotic CI) were 0.83 (0.77-0.89) for the development group and 0.84 (0.77-0.91) for the validation group. Using two cut-off values, maximum specificity and sensitivity were 89.7% and 96.6%, respectively, with a negative predictive value for SVR of 88.9% and a positive predictive value of 83.6%. Thirteen (7.2%) individuals were misclassified using these cut-off values.
This model represents a reliable and easily applicable tool to individually evaluate the probability of achieving an SVR to Peg-IFN/ribavirin among HIV/HCV-coinfected patients.
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