Cognitive Performance in Asymptomatic Elderly People with Hepatitis C: The Role of Education.

BACKGROUND: Neurotropism of the hepatitis C virus (HCV) can be the source of subtle neuropsychological symptoms in non-cirrhotic patients. Age is a risk factor for cognitive impairment (CI). Thus, asymptomatic elderly people who carry HCV might be at a greater risk of CI. Education can influence test performance. OBJECTIVES: (1) To verify whether elderly people with HCV performed poorer than controls on cognitive tests. (2) To analyze how education affects performance. (3) To verify whether the extent of the effect of education on performance depends on the group (HCV vs. controls) and the type of cognitive test. METHODS: Asymptomatic HCV carriers older than 60 years (n = 41) were matched with 41 corresponding controls. All participants performed the following tests: Mini-Cog, Mini Mental State Examination, clock drawing test (CDT), and verbal fluency. RESULTS: (1) There were no significant differences in cognitive performance between the two groups. (2) Higher education was always associated with better performance. (3) There was a significant group difference in the slopes of the regression lines between years of education and CDT performance. No differences were found for the other three tests. CONCLUSION: Considering the scores on the CDT, the rate of improvement in performance when schooling increases is higher in HCV carriers.

Hepatitis C Virus (HCV) Infection and Neurocognitive Impairment in Subjects with Mild Liver Disease.

Hepatitis C virus (HCV) infection is a leading cause of liver cirrhosis, hepatocellular carcinoma, and liver-related deaths. It is estimated that 40-74% of patients with hepatitis C will experience at least one extrahepatic manifestation within their lifetime. The finding of HCV-RNA sequences in post-mortem brain tissue raises the possibility that HCV infection may affect the central nervous system and be the source of subtle neuropsychological symptoms, even in non-cirrhotic. Our investigation aimed to evaluate whether asymptomatic, HCV-infected subjects showed cognitive dysfunctions. Twenty-eight untreated asymptomatic HCV subjects and 18 healthy controls were tested using three neuropsychological instruments in a random sequence: Symbol Digit Modalities Test (SDMT), Controlled Oral Word Association Test (COWAT), and Continuous Visual Attention Test (CVAT). We performed depression screening, liver fibrosis assessment, blood tests, genotyping, and HCV-RNA viral load. A MANCOVA and univariate ANCOVAS were performed to examine group differences (HCV vs. healthy controls) in four scores of the CVAT (omission errors, commission errors, reaction time-RT, and variability of RT-VRT), and the scores derived from the SDMT, and the COWAT. A discriminant analysis was performed to identify which test variables effectively discriminate HCV-infected subjects from healthy controls. There were no group differences in the scores of the COWAT, SDMT, and in two variables of the CVAT (omission and commission errors). In contrast, the performance of the HCV group was poorer than the controls in RT (p = 0.047) and VRT (p = 0.046). The discriminant analysis further indicated that the RT was the most reliable variable to discriminate the two groups with an accuracy of 71.7%. The higher RT exhibited by the HCV group may reflect deficits in the intrinsic-alertness attention subdomain. As the RT variable was found to be the best discriminator between HCV patients and controls, we suggest that intrinsic-alertness deficits in HCV patients may affect the stability of response times increasing VRT and leading to significant lapses in attention. In conclusion, HCV subjects with mild disease showed deficits in RT and intraindividual VRT as compared to healthy controls.

Before Direct-Acting Antivirals for Hepatitis C Virus: Evaluation of Core Protein R70Q and L/C91M Substitutions in Chronically Infected Brazilian Patients Unresponsive to IFN and/or RBV.

Although chronic hepatitis C has been effectively treated with direct-acting antivirals (DAAs), the use of conventional therapy with peg-interferon (Peg-IFN) or (predominantly) ribavirin (RBV), remains widespread. R70Q/H and L/C91M amino acid substitutions in the hepatitis C virus (HCV) core protein may modulate responses to IFN and/or RBV, and are associated with cirrhosis, hepatocellular carcinoma (HCC), insulin resistance, and liver steatosis. We evaluated the R70Q/H and L/C91M substitutions, clinical and epidemiological profiles, and risk factors of Brazilian patients chronically infected with HCV subgenotypes 1a and 1b (HCV-GT1a and HCV-GT1b) unresponsive to IFN and/or RBV therapy. Sequencing and pyrosequencing analyses and sociodemographic and clinical predictive variables were used to assess the relationship between R70Q/H and L/C91M substitutions. Leukocyte counts, ALT levels, and ALT/AST ratios were significantly reduced in treated individuals, but more of these patients had advanced fibrosis and cirrhosis. L91M was more prevalent (19.7%), occurring only in HCV-GT1b, followed by R70Q/P (11.5%) and R70P (1.4%). R70Q/P exhibited higher mean AST, ALT, and GGT values, whereas L91M showed higher mean GGT values. Pyrosequencing of the L91M position revealed mutant subpopulations in 43.75% of samples.

Different core-specific T cell subsets are expanded in chronic hepatitis C with advanced liver disease.

Chronic hepatitis C (CHC) is frequently related to liver fibrosis, and several studies have suggested that the immunological activity of HCV antigens contributes to hepatic damage. In the present study, among structural and non-structural HCV antigens, elevatedIL-1ß, IL-6, IL-17 levels were secreted by PBMC cultures obtained from CHC patients following stimulation with core antigen. Moreover, the percentage of core-specific IL-6+IL-17+(CD4+ and CD8+) T cells was significantly higher in patients with worsehepatic lesions, determined on the Metavir scale. When compared with healthy subjects, the percentage of circulating Treg cells was elevated in CHC patients, mainly among those with advanced liver fibrosis. Nevertheless, in this last group of patients, the proportion of CD39+ Treg subsets was very low. Finally, the percentage of senescent (CD57+ CD28-) and exhausted (PD-1+CD28+) core-specific T cells in CHC patients was also found to be a result of fibrotic hepatic status. In summary, imbalances between different core-specific T cell subsets are associated with liver fibrosis severity.

Performance of rapid diagnostic tests for detection of Hepatitis B and C markers in HIV infected patients.

There is little information describing the influence of HIV infection upon the performance of rapid diagnostic tests (RDTs) for hepatitis B and C virus diagnosis. This study aims to evaluate the performance of RDTs for HBsAg and anti-HCV detection among HIV-infected individuals. A total of 362 HIV infected individuals were recruited from clinics between January 2013 to November 2014 in the southeast and northeast of Brazil. HBsAg and anti-HCV were detected using commercial EIAs and four RDTs: HBV (Vikia HBsAg® and Wama Imuno-Rapido HBV®) and HCV (Bioeasy Teste Rápido HCV® and Wama Imuno-Rapido HCV®). Reactive HBsAg and anti-HCV serum samples were tested for HBV DNA and HCV RNA. Sensitivity, specificity and kappa statistic were determined. Using EIA, HBsAg and anti-HCV were detected in 14 (3.9%) and 37 (10.2%) serum samples respectively. Using serum only, HBsAg RDTs demonstrated sensitivities and specificities above 92.0% and Kappa values above 89.0%. Anti-HCV RDTs demonstrated sensitivity and specificities above 82.0% and Kappa higher than 89.0%. Using whole blood samples, Vikia HBsAg® and Wama Imuno-Rapido HCV® showed sensitivity and specificity above 99.0% with Kappa of 66.4% and 100%, respectively. HIV viral load was higher among discordant results for anti-HCV RDT. RDTs demonstrated good performance in HIV infected individuals showing the usefulness of assays in this population.

The proportion of different interleukin-17-producing T-cell subsets is associated with liver fibrosis in chronic hepatitis C.

Studies have suggested the pivotal role of T helper type 1 (Th1) -related cytokines on the outcome of hepatitis C virus (HCV) infection. Nevertheless, the role of different interleukin-17 (IL-17) -secreting T cells on chronic hepatitis C (CHC) is less clear. Here, the in vivo IL-1ß, IL-6, and IL-17 levels were positively correlated with both alanine transaminase (ALT) levels and hepatic lesions. When compared with the control group, CHC patients showed a lower proportion of IL-17-secreting (CD4+ and CD8+ ) T cells capable of simultaneously producing IL-21. Moreover, the percentage of IL-10-secreting Th17 cells was also lower in CHC patients. Notably, advanced liver lesions were observed among those patients with lower percentage levels of IL-17-producing T cells positive for IL-21, interferon-γ (IFN-γ) and IL-10. In contrast, the severity of hepatic damage was associated with peripheral single IL-17+ T cells. The percentage of IL-17+ IL-21- IFN-γ+ (CD4+ and CD8+ ) T-cell phenotypes was positively associated with plasma CD14 levels. Finally, elevated levels of circulating CD14 were detected among CHC patients with extensive liver damage. In summary, although preliminary, our results suggest that a balance between different IL-17-producing T cells, associated with peripheral levels of CD14, may be a progress marker for liver disease in chronically HCV-infected patients.

IL28B gene polymorphisms in mono- and HIV-coinfected chronic hepatitis C patients.

INTRODUCTION: Single-nucleotide polymorphisms (SNPs) associated with hepatitis C virus (HCV) clearance were identified near the IL28B gene. Coinfection by the human immunodeficiency virus (HIV) influences the course of HCV contributing to liver damage. Nevertheless, little is known about the relationship between these SNPs and HCV/HIV coinfection. Our aim was to estimate the frequencies of the allelic and genotypic variants of the IL28B polymorphisms rs12979860 (C/T) and rs8099917 (T/G) and their possible association with the establishment of HCV infection. METHODOLOGY: A total of 199 non-infected controls and 230 patients with chronic hepatitis C, including 53 coinfected with HIV, participated in the study. Genotyping consisted of polymerase chain reaction and subsequent analysis of the restriction patterns resulting from exposure to endonucleases. RESULTS: Among the controls with established results, 47.4% (90/190) exhibited the rs12979860 CC genotype, 43.7 CT, and 8.9% TT, whereas 29.1% (66/227), 51.5%, and 19.4% of the patients exhibited the CC, CT, and TT genotypes, respectively. With respect to rs8099917, 66.8% (133/199) of the controls exhibited the TT genotype, 31.2% TG, and 2.0% GG, whereas 56.1% (129/230), 40.9%, and 3.0% of the patients exhibited the TT, TG, and GG genotypes, respectively. CONCLUSION: The frequencies of the rs12979860 C allele and CC genotype and of the rs8099917 T allele and TT genotype were significantly higher among controls compared with patients, thus confirming the suggested protective effect against HCV infection. No significant difference was observed in the genotype and allelic distributions between the mono- and coinfected patients.

Low rates of sustained virologic response with peginterferon plus ribavirin for chronic hepatitis C virus infection in HIV infected patients in Rio de Janeiro, Brazil.

BACKGROUND: The standard treatment for chronic hepatitis C virus (HCV) infection in HIV-infected subjects is the combination of alfapeginterferon (PEG-IFN) plus ribavirin. We designed this study to evaluate the rate of SVR and predictors of SVR in a public health setting in Rio de Janeiro, Brazil. METHODS: Retrospective cohort study of HCV/HIV co-infected patients treated with PEG-IFN plus ribavirin from 2004 to 2011 in 3 outpatient units in Rio de Janeiro. Exposure variables included age, sex, CD4+ cell count, HCV genotype, HCV and HIV viral loads, liver histology (METAVIR fibrosis scoring system) and previous treatment. The main outcome measurement was SVR. RESULTS: 100 patients were included in this analysis. Median age was 47 years and 68% were male. 80%, 4%, 14% and 2% were infected with HCV genotypes 1, 2, 3 and 4, respectively. At baseline, 77% had HCV viral load greater than 800,000 IU/ml, 99% had CD4+ greater than 200 cells/mm(3) and 10% had a diagnosis of cirrhosis. The treatment was withdrawn in 9% of the subjects (5% with adverse effects and 4% dropped out). SVR was observed in 27 (27%) of the 100 patients included. 13 (13%) subjects were classified as null-responders, 33(33%) as non-responders, 9 (9%) as breakthrough and 9(9%) as relapsers. In the multivariate model only being infected with genotype 2 or 3 (p<0.01) and having low levels of gamma glutamyl transferase (GGT) at baseline (p = 0.04), were predictive of SVR. CONCLUSION: SVR in HCV/HIV co-infected subjects in a public health setting is similar to that observed in clinical trials, albeit very low. A delay in therapy initiation should be considered until new therapies as direct acting antiviral drugs (DAA) become widely available and tested in coinfected subjects.