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HBV reactivation can occur while undergoing direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV). The role of hepatitis B surface antibody (HBsAb) has not been systematically explored. Therefore, the purpose of this systematic review was to explore the role of the presence of HBsAb on the risk of HBV reactivation related to DAA therapy. We reviewed MEDLINE, CINAHL, EMBASE and Cochrane Central for studies on DAA therapy and data on HBsAb in patients with resolved hepatitis B (hepatitis B surface antigen-negative and hepatitis B core antibody-positive). We identified twenty-nine reports: thirteen case reports with HBV reactivation (10 HBsAb-negative and 3 HBsAb-positive patients) and sixteen cohort studies totalling 2528 patients with resolved HBV infection (1429 HBsAb negative, 1099 HBsAb positive). Reactivation was found in 12 (0.8%) HBsAb-negative and 7 (0.6%) HBsAb-positive individuals of cohort studies. All but two HBV reactivation occurred in patients with HBsAb titre <30 iU/L. The presence of HBsAb showed a trend towards delayed reactivation (median 12 weeks vs 9.5 weeks; P = .07). Importantly, with the exception of a patient with escape variant and an HIV-infected individual, no HBsAb-positive individual demonstrated clinical reactivation. HBsAb presence seems to protect from clinical HBV reactivation related to DAA therapy. The most pronounced prevention for reactivation may require titres greater than 30 iU/L., (© 2020 John Wiley & Sons Ltd.)

Background and Aims: The aims were to review the diagnosis, testing and presentation of acute hepatitis C (HCV) in patients initially diagnosed to have drug-induced liver injury (DILI) enrolled in the US DILI Network., Methods: All patients with suspected DILI underwent testing for competing causes of liver injury and returned for 6-month follow-up. Causality was adjudicated by consensus expert opinion., Results: Between 2004 and 2016, 1518 patients were enrolled and adjudicated and underwent 6 months of follow-up. Initial locally acquired anti-HCV results were available in 1457 (96%), but HCV RNA in only 795 (52%). Stored sera were available for repeat testing, so that results were available on all 1518 patients (1457 for anti-HCV and 1482 for HCV RNA). A total of 104 subjects (6.9%) had evidence of HCV infection-10 positive for HCV RNA alone, 16 for anti-HCV alone and 78 for both. All 104 HCV-positive cases were reviewed, and 23 cases were adjudicated as acute HCV. All presented with acute hepatocellular injury with median ALT 1448 U/L, alkaline phosphatase 232 U/L and total bilirubin 10.8 mg/dL. Twenty-two (96%) patients were jaundiced. While all 23 cases initially had been suspected of having DILI, 19 were adjudicated as acute HCV and not DILI at the 6-month follow-up; while 4 were still considered DILI., Conclusions: Twenty-three of 1518 (1.5%) cases of suspected DILI were due to acute HCV infection. We recommend that initial and follow-up HCV RNA testing should be performed to exclude HCV in patients with acute hepatocellular injury and suspected DILI.

Cure of hepatitis C virus has become feasible in almost all patients. However, vigilance is needed in 3 scenarios: previous exposure to hepatitis B virus (HBV), history of organ transplantation, and history of cured hepatocellular carcinoma (HCC). The current data suggest that HBV reactivation occurs in about 10% of hepatitis B surface antigen (HBsAg)-positive patients and approximately 1% of hepatitis B core antibody-positive but HBsAg-negative patients. The risk of organ rejection is also around 1%, but can be fatal if not acted on immediately. Finally, the risk of early HCC recurrence may be increased but should not delay initiation of antiviral therapy in the setting of cured HCC; however, increased surveillance may be warranted.

While hepatitis B virus (HBV) screening relies on hepatitis B surface antigen to confirm HBV infection since the early days of hepatitis B disease management, hepatitis C virus (HCV) infection screening is based on anti-HCV testing which does not discriminate active from past infection. Thus to confirm infection HCV RNA testing has been required; recently a HCV core antigen assay became widely commercially available which could serve to confirm infection. That assay is less sensitive than current HCV RNA assays, but as more than 50% of anti-HCV positive persons will be HCV core antigen positive, HCV core antigen testing can be a cost effective and reflex test to confirm HCV infection in anti-HCV positive individuals and will be easier as it can be applied on the same platform. For treatment monitoring, more data need to be generated, but the early data available at present suggest that HCV core antigen may be an alternative to HCV RNA monitoring. With direct antivirals, HCV core antigen could even be superior to HCV RNA testing, as direct antivirals might already prevent virus formation when HCV core antigen is still produced and thereby correlates better with eventual viral clearance.

Background & Aims: The CCR5Δ32 mutation has been suspected to adversely affect outcomes of HCV infection, although reports have remained controversial. Here, we investigated the relative genetic contributions of the CCR5Δ32 deletion and the IL28B rs12979860 polymorphisms to spontaneous clearance of hepatitis C in a single-source outbreak., Methods: We retrieved 396 Caucasian women (119 women with spontaneous HCV clearance) who had been infected with HCV genotype 1-contaminated anti-D immunoglobulin in 1978, and determined their IL28B and CCR5 alleles., Results: IL28B CC, CT, and TT genotypes were found in 35.4%, 50%, and 14.6% of patients and corresponded to spontaneous clearance rates of 50%, 21.2%, and 12.1% (Chi(2)=38.7, p=5.0×10(-10)), respectively. CCR5 WT/WT, WT/Δ32, and Δ32/Δ32 genotypes were observed in 76%, 22.7%, and 1.3% of patients and corresponded to clearance rates of 33.2%, 21.2%, and 0% (Chi(2)=6.9, p=0.009), respectively. In a stepwise forward-conditional multivariate regression model both CCR5 (OR 2.1, p=0.01 for WT/WT) and IL28B genetic variants (OR 4.3, p=4.6×10(-10) for the C/C genotype) were identified as independent predictors of spontaneous HCV clearance. Importantly, favorable response rates were associated with the IL28B CC genotype only in CCR5 wild-type homozygous women, while HCV clearance in CCR5Δ32 carriers remained poor even in patients with the rs12979860 CC genotype., Conclusions: Both IL28B rs1297860 and CCR5Δ32 allelic variants are independent genetic determinants of spontaneous HCV clearance. The variable relative distribution between IL28B rs1297860 and CCR5Δ32 allelic variants in different populations may have masked the role of the CCR5Δ32 mutation in some studies., (Copyright © 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Hepatitis C virus (HCV) and hepatitis B virus (HBV) infections are common in haemodialysis units. Moreover, some studies reported seronegative cases of viral hepatitis. We and others have previously shown an HCV RNA decline during haemodialysis; however, limited data on HBV viraemia during haemodialysis are available., Methods: A total of 142 haemodialysis patients participated in this study, 11 were anti-HCV positive and 7 were HBsAg positive. HCV RNA and HBV DNA were determined in all patients irrespective of hepatitis serology. HBV DNA, HCV RNA, HBsAg and HCV core antigen (HCVcoreAg) were quantified repeatedly in anti-HCV- and HBsAg-positive patients before and after haemodialysis., Results: No case of seronegative viral hepatitis could be identified. HCV RNA was detected in 9 of the 11 anti-HCV-positive patients, while HBV DNA tested positive in all 7 HBsAg-positive patients. A decrease of HCVcoreAg was observed during four dialysis sessions in 8/9 patients (-24.4 ± 22.7%, P < 0.001) parallelled by HCV RNA decline in most individuals (-10.1 ± 48.6%, P = 0.22). In contrast, HBV DNA and HBsAg declined only in 1/7 patients during all four independent measurements. The remaining six patients showed heterogeneous patterns of HBV DNA and HBsAg before and after haemodialysis without a significant change in mean HBV DNA and HBsAg levels (+14 ± 60.6% and -0.2 ± 25.3%, P > 0.05, respectively). HCVcoreAg correlated strongly with HCV RNA (r = 0.937; P < 0.001, n = 72), while there was no correlation between HBV DNA and HBsAg (r = -0.234; P = 0.131, n = 43)., Conclusions: Seronegative viral hepatitis is rare in German maintenance haemodialysis patients. HCV RNA and HCVcoreAg decline during haemodialysis indicating a potential beneficial effect of haemodialysis during antiviral therapy of hepatitis C, which does not apply to HBV infection.

Unlabelled: Two functional variants in the inosine triphosphatase (ITPA) gene causing inosine triphosphatase (ITPase) deficiency protect against ribavirin (RBV)-induced hemolytic anemia and the need for RBV dose reduction in patients with genotype 1 hepatitis C virus (HCV). No data are available for genotype 2/3 HCV. We evaluated the association between the casual ITPA variants and on-treatment anemia in a well-characterized cohort of genotype 2/3 patients treated with variable-duration pegylated interferon alfa-2b (PEG-IFN-α2b) and RBV. Two hundred thirty-eight Caucasian patients were included in this retrospective study [185 (78%) with genotype 2 and 53 (22%) with genotype 3]. Patients were treated with PEG-IFN-α2b plus weight-based RBV (1000/1200 mg) for 12 (n = 109) or 24 weeks (n = 129). The ITPA polymorphisms rs1127354 and rs7270101 were genotyped, and an ITPase deficiency variable was defined that combined both ITPA variants according to their effect on ITPase activity. The primary endpoint was hemoglobin (Hb) reduction in week 4. We also considered Hb reduction over the course of therapy, the need for RBV dose modification, and the rate of sustained virological response (SVR). The ITPA variants were strongly and independently associated with protection from week 4 anemia (P = 10(-6) for rs1127354 and P = 10(-7) for rs7270101). Combining the variants into the ITPase deficiency variable increased the strength of association (P = 10(-11) ). ITPase deficiency protected against anemia throughout treatment. ITPase deficiency was associated with a delayed time to an Hb level < 10 g/dL (hazard ratio = 0.25, 95% confidence interval = 0.08-0.84, P = 0.025) but not with the rate of RBV dose modification (required per protocol at Hb < 9.5 g/dL). There was no association between the ITPA variants and SVR., Conclusion: Two ITPA variants were strongly associated with protection against treatment-related anemia in patients with genotype 2/3 HCV, but they did not decrease the need for RBV dose reduction or increase the rate of SVR., (Copyright © 2010 American Association for the Study of Liver Diseases.)

Background & Aims: A single nucleotide polymorphism (SNP) upstream of the IL28B gene has been associated with response of patients with chronic hepatitis C to therapy with pegylated interferon and ribavirin and also with spontaneous clearance of acute hepatitis C in a heterogeneous population. We analyzed the association between IL28B and the clinical presentation of acute hepatitis C virus (HCV) infection in a homogeneous population., Methods: We analyzed the SNP rs12979860 in 190 women from the German anti-D cohort (infected with HCV genotype 1b via contaminated rhesus prophylaxis) and its association with spontaneous clearance. Clinical data were available in 136 women with acute infection who were also evaluated for IL28B genotype. Based on results of a TaqMan polymerase chain reaction assay, the rs12979860 SNP genotypes studied were C/C, C/T, or T/T., Results: Spontaneous clearance was more common in patients with the C/C genotype (43/67; 64%) compared with C/T (22/90; 24%) or T/T (2/33; 6%) (P < .001). Jaundice during acute infection was more common among patients with C/C genotype (32.7%) than non-C/C patients (with C/T or T/T) (16.1%; P = .032). In C/C patients, jaundice during acute infection was not associated with an increased chance of spontaneous clearance (56.3%) compared with those without jaundice (60.6%). In contrast, in non-C/C patients, jaundice was associated with a higher likelihood of spontaneous clearance (42.9%) compared with those without jaundice (13.7%)., Conclusions: The SNP rs12979860 upstream of IL28B is associated with spontaneous clearance of HCV. Women with the C/T or T/T genotype who did not develop jaundice had a lower chance of spontaneous clearance of HCV infection., (Copyright © 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Polymorphisms in the region of the interleukin (IL)-28B gene on chromosome 19 have been associated with peginterferon-alfa-induced clearance of genotype 1 hepatitis C virus (HCV); there are no data for patients with genotype 2 or 3 HCV. We evaluated the effects of IL-28B polymorphisms on response to treatment with peginterferon and ribavirin in a well-characterized cohort of genotype 2/3 patients., Methods: DNA was analyzed from 268 patients (Caucasian: genotype 2, 213; genotype 3, 55). Patients were randomly assigned to groups that received standard duration (24 wk; n = 68) or variable durations of therapy. Patients who received variable durations (VD) and had a rapid virologic response (RVR) were treated for 12 weeks (VD12; n = 122); those without an RVR were treated for 24 weeks (VD24; n = 78). IL-28B genotypes (rs12979860) were analyzed for association with treatment response., Results: The frequencies of the IL-28B genotypes were as follows: CC, 37%; CT, 48%; and TT, 15%; 82% of patients with the CC genotype achieved a sustained virologic response (SVR), compared with 75% with the CT and 58% with the TT genotypes (P = .0046). Differences between IL-28B genotypes were greatest among patients who failed to attain RVR (VD24 SVR rates: CC, 87%; CT, 67%; and TT, 29%; P = .0002). Among patients with RVRs (61%), the IL-28B genotype was not associated with SVR (>70% for all IL-28B genotypes). In a multivariable logistic regression model, IL-28B genotype predicted SVR (odds ratio, 1.76; 95% confidence interval, 1.16-2.7)., Conclusions: An IL-28B polymorphism was associated with an SVR in patients infected with genotype 2/3 HCV who did not achieve a RVR. Analysis of IL-28B genotype might be used to guide treatment for these patients., (Copyright © 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: We recently identified a polymorphism upstream of interleukin (IL)-28B to be associated with a 2-fold difference in sustained virologic response (SVR) rates to pegylated interferon-alfa and ribavirin therapy in a large cohort of treatment-naive, adherent patients with chronic hepatitis C virus genotype 1 (HCV-1) infection. We sought to confirm the polymorphism's clinical relevance by intention-to-treat analysis evaluating on-treatment virologic response and SVR., Methods: HCV-1 patients were genotyped as CC, CT, or TT at the polymorphic site, rs12979860. Viral kinetics and rates of rapid virologic response (RVR, week 4), complete early virologic response (week 12), and SVR were compared by IL-28B type in 3 self-reported ethnic groups: Caucasians (n = 1171), African Americans (n = 300), and Hispanics (n = 116)., Results: In Caucasians, the CC IL-28B type was associated with improved early viral kinetics and greater likelihood of RVR (28% vs 5% and 5%; P < .0001), complete early virologic response (87% vs 38% and 28%; P < .0001), and SVR (69% vs 33% and 27%; P < .0001) compared with CT and TT. A similar association occurred within African Americans and Hispanics. In a multivariable regression model, CC IL-28B type was the strongest pretreatment predictor of SVR (odds ratio, 5.2; 95% confidence interval, 4.1-6.7). RVR was a strong predictor of SVR regardless of IL-28B type. In non-RVR patients, the CC IL-28B type was associated with a higher rate of SVR (Caucasians, 66% vs 31% and 24%; P < .0001)., Conclusions: In treatment-naive HCV-1 patients treated with pegylated interferon and ribavirin, a polymorphism upstream of IL-28B is associated with increased on-treatment and sustained virologic response and effectively predicts treatment outcome., (Copyright 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.)

There is growing evidence that hepatitis C virus (HCV)-infection may affect the brain. About half of the HCV-infected patients complain of chronic fatigue irrespective of their stage of liver disease or virus replication rate. Even after successful antiviral therapy fatigue persists in about one third of the patients. Many patients, in addition, report of deficits in attention, concentration and memory, some also of depression. Psychometric testing revealed deficits in attention and verbal learning ability as characteristic for HCV-afflicted patients with normal liver function. Magnetic resonance spectroscopic studies showed alterations of the cerebral choline, N-acetyl-aspartate, and creatine content in the basal ganglia, white matter and frontal cortex, respectively. Recently, pathologic cerebral serotonin and dopamine transporter binding and regional alterations of the cerebral glucose utilisation compatible with alterations of the dopaminergic attentional system were observed. Several studies detected HCV in brain samples or cerebro-spinal fluid. Interestingly, viral sequences in the brain often differed from those in the liver, but were closely related to those found in lymphoid tissue. Therefore, the Trojan horse hypothesis emerged: HCV-infected mononuclear blood cells enter the brain, enabling the virus to reside within the brain (probably in microglia) and to infect brain cells, especially astrocytes.

Hepatitis C infection is a common problem in dialysis units. The prevalence ranges from 3% to more than 50%. Several reports have described a variable reduction of HCV-RNA during hemodialysis treatment sessions. But so far nothing is known about the HCV antigenemia or the kinetics of the reduction of HCV-RNA and HCV antigenemia during these sessions. HCV-RNA was monitored using the VERSANT HCV bDNA assay 3.0 (Bayer Healthcare Diagnostics, Leverkusen, Germany) or the HCV-Monitor TaqMan (Roche Diagnostics). HCV antigenemia was tested by using Ortho-trac-C assay (Ortho Clinical Diagnostics, Neckargemünd, Germany). Kinetics of HCV-RNA were available in 15 dialysis sessions measured by bDNA assay and in 5 dialysis sessions measured by rt-PCR. Quantitative HCV-antigenemia was available in fourteen dialysis sessions. Not only HCV-RNA but as expected also the HCV-antigenemia fell during the dialysis session. However, while the average reduction of HCV-antigen appears steady and linear, the level of HCV-RNA seems to be stable during the first 3 hr of dialysis, and decreases rapidly during the last 2 hr. The results seem to be independent of the HCV-RNA detection method. The different kinetics of HCV RNA and HCV antigen load suggest that there are different mechanisms responsible for the reduction of the HCV antigen and HCV-RNA, respectively. Reduction of viral load during dialysis session indicates a potential benefit of dialysis in case of HCV associated antiviral therapy.

Hepatitis virus coinfections [HBV plus HCV coinfection (HBV/HCV) or HBV plus HDV coinfection (HBV/HDV)] may progress more rapidly to cirrhosis than hepatitis B or C monoinfections in immunocompetent patients. Only limited information is available on the outcome of coinfected patients after liver transplantation. We studied survival rates of 204 patients with viral hepatitis transplanted at our center between 1972 and 1997. HBV/HDV and HBV/HCV coinfections were present in 23 and nine individuals, respectively, while 97 patients had monoinfection by HCV and 75 had HBV monoinfection. Survival of coinfected patients was significantly longer than that of monoinfected patients (14.4 +/- 0.9 vs. 8.5 +/- 0.6 yr; p = 0.0003). The same was true for graft survival (p = 0.0002). In Cox's regression, viral coinfection (p = 0.0001), absence of hepatocellular carcinoma (HCC) (p = 0.00001) and no retransplantation (p = 0.02) were independently associated with patient survival. After exclusion of patients with HCC (n = 62), survival of coinfected patients was still significantly longer than that of monoinfected individuals (p = 0.002). The improved outcome was similar for both HBV/HDV and HBV/HCV coinfections. In contrast to immunocompetent patients, individuals with multiple hepatitis virus infections had an improved outcome after liver transplantation. Thus, viral coinfections may be associated with ameliorated courses of diseases under certain conditions.

Background/aims: The significance of hepatitis A virus (HAV) super-infection in patients with chronic hepatitis C had been a matter of debate. While some studies suggested an incidence of fulminant hepatitis A of up to 35%, this could not be confirmed by others., Methods: We identified 17 anti-HCV-positive patients with acute hepatitis A from a cohort of 3170 anti-HCV-positive patients recruited at a single center over a period of 12 years., Results: Importantly, none of the anti-HCV-positive patients had a fulminant course of hepatitis A. HCV-RNA was detected by PCR in 84% of the anti-HCV-positive/anti-HAV-IgM-negative patients but only in 65% of anti-HCV-positive patients with acute hepatitis A (p=0.03), indicating suppression of HCV replication during hepatitis A. Previous HAV infection had no effect on HCV replication. After recovery from hepatitis A, an increased HCV replication could be demonstrated for 6 out of 9 patients with serial quantitative HCV-RNA values available while 2 patients remained HCV-RNA negative after clearance of HAV throughout follow-up of at least 2 years., Conclusions: HAV super-infection is associated with decreased HCV-RNA replication which may lead to recovery from HCV in some individuals. Fulminant hepatitis A is not frequent in patients with chronic hepatitis C recruited at a tertiary referral center.

While HCV was initially believed to uniformly cause liver inflammation with the consequence of liver cirrhosis in most of the infected patients, prospective studies have shown a much lower than expected rate of cirrhosis in patients infected for more than 20 years. However, a new problem associated with hepatitis C virus infection is emerging. This is the development of sometimes disabling fatigue. While many other viruses of the flaviviridae cause encephalitis, the most closely related virus to HCV in humans, the GB Virus C seems not to be associated with fatigue. Thus the mechanism for the development of fatigue in HCV infection seems specific for HCV. Delineating the mechanism will be a first step to develop treatment option for this currently untreatable impairment.

A new quantitative marker of HCV viremia based on the detection of the core antigen of the virus has recently become commercially available in Europe. The usefulness of this test was examined for the management of patients treated with pegylated interferon/ribavirin. One hundred twenty-eight pegylated interferon/ribavirin treated patients were studied. Serum samples were available at baseline, week 4 and week 12 time-points, respectively. Core antigen was quantified using the trak-C assay (Ortho Clinical Diagnostics, Raritan, NJ). For all genotypes at week 4, the positive and negative predictive values of HCV core antigen were 81.4 and 92.9%, respectively, while at week 12 they were 67.9 and 100%, respectively. These predictive values varied substantially according to viral genotype. Among patients with a negative core antigen level (<1.5 pg/ml) at week 12, only 33% of those who were positive at week 4 achieved a sustained virological response whereas 85% of those who were already negative did (P < 0.001). The core antigen assay may be used at week 4 and week 12 to distinguish patients who will achieve a sustained virological response from those who will relapse/breakthrough. This assay is a new reliable alternative for early prediction of virological non-response in patients treated with pegylated interferon/ribavirin., (Copyright 2004 Wiley-Liss, Inc.)

Early treatment of acute hepatitis C infection with interferon alfa-2b (IFN-alpha-2b) prevents chronicity in almost all patients. So far, no data are available on the long-term outcome after interferon (IFN) therapy of acute hepatitis C. The aim of this study was to assess the clinical, virological, and immunological long-term outcome of 31 successfully treated patients with acute hepatitis C infection who were followed for a median of 135 weeks (52-224 weeks) after end of therapy. None of the individuals had clinical evidence of liver disease. Alanine aminotransferase (ALT) levels were normal in all but 1 patient. Serum hepatitis C virus (HCV) RNA was negative throughout follow-up, even when investigated with the highly sensitive transcription-mediated amplification (TMA) assay (cutoff 5-10 IU/mL). In addition, no HCV RNA was detected in peripheral blood mononuclear cells (PBMC) of 15 cases tested. The patients' overall quality-of-life scores as determined by the SF-36 questionnaire did not differ from the German reference control cohort. Ex vivo interferon gamma (IFN-gamma) ELISPOT analysis detected HCV-specific CD4(+) T-helper cell reactivity in only 35% of cases, whereas HCV-specific CD8(+) T-cell responses were found in 4 of 5 HLA-A2-positive individuals. Anti-HCV antibody levels decreased significantly during and after therapy in all individuals. In conclusion, early treatment of symptomatic acute hepatitis C with IFN-alpha-2b leads to a long-term virological, biochemical, and clinical response. Waning of anti-HCV humoral immunity and presence of HCV-specific CD8(+) (but not CD4(+)) T cells highlights the complexity of T-cell and B-cell memory to HCV, which might be significantly altered by IFN treatment.

Treating acute hepatitis C with interferon alpha prevents chronicity in nearly all cases when therapy is initiated within 3 months after infection. However, 15-50% of untreated patients may clear the hepatitis C virus (HCV) spontaneously. Therefore, factors are needed to identify patients prior to therapy who have a higher or lower risk for developing a chronic course to avoid unnecessary treatment. The role of the HCV genotype for spontaneous recovery from acute hepatitis C has been discussed controversially. In the year 2002, all 1,176 new incoming prisoners in a Northern German prison for young men (age 16-24) were screened for anti-HCV antibodies and 92 tested positive. Ninety eight percent of these reported i.v.-drug abuse for a median of 32 months prior to imprisonment. HCV-RNA negative individuals (21%) were serotyped and HCV-RNA positive patients were genotyped. The prevalence of HCV genotype 3 was significantly higher among individuals who had cleared HCV spontaneously as compared to chronically infected patients (86% vs. 38%; P = 0.002). Ninety three percent of individuals exposed to HCV genotype 1 but only 63% of individuals exposed to genotype 3 experienced a chronic course of the infection (P = 0.006). Thus, acute infection in young Caucasian men with HCV genotype 3 leads more often to spontaneous clearance than infection with HCV genotype-1. Considering also the high chance of successful treatment of chronic HCV genotype 3 infection with pegylated-interferon in combination with ribavirin, we suggest not to treat acute hepatitis C genotype 3 infection early but rather to wait at least 3 months after the onset of symptoms when chronicity becomes likely., (Copyright 2004 Wiley-Liss, Inc.)

Autoimmunity and high rates of autoantibodies have been implicated in the pathogenesis of porphyria cutanea tarda. These abnormalities could be in part virus-induced, since porphyria cutanea tarda in most geographical regions is highly associated with hepatitis C virus infection. We analyzed the link of autoantibodies, autoimmune hepatitis and systemic lupus erythematosus in 111 patients with porphyria cutanea tarda and sex- and age-matched controls (mean age 58+/-13 years) in Germany, a region with a low prevalence of hepatitis C virus infection. Patients with porphyria cutanea tarda displayed lower rates of anti-nuclear antibodies (16/111, 14% vs 28/111, 25%, p<0,05) and of antibodies against smooth muscle (25/111, 23% vs 48/111, 43%, p<0,01), than controls. The percentage of patients with porphyria cutanea tarda with positive anti-HCV was low but significantly higher than in our controls (9/111, 8% vs 0/111, 0%, respectively), (p<0,05). Two patients with porphyria cutanea tarda (2/111, 2%) fulfilled the criteria for systemic lupus erythematosus and not one of 65 patients was found to have clinical autoimmune hepatitis. In the first controlled study of a large cohort of patients with porphyria cutanea tarda no increased prevalence of selected autoantibodies and autoimmune hepatitis was found. However, a higher prevalence of HCV infection and systemic lupus erythematosus in patients with porphyria cutanea tarda was confirmed.

Summary: Chronic fatigue, mood alterations and cognitive impairment are frequent accessory symptoms of HCV infection. Fatigue and mood alterations have also been observed in autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC), but not in hepatitis B virus (HBV)‐infection, thus indicating an autoimmune response as possible cause of HCV infection‐associated encephalopathy. Data, however, are sparse. This study aimed to prove that HCV patients feature similar to those with autoimmune liver disease but contrary to HBV patients regarding neuropsychiatric symptoms. A total of 132 noncirrhotic patients (HCV: 46, HBV: 22, AIH: 27, PBC: 29, AIH/PBC: 8) completed questionnaires addressing the domains mentioned above. Eighty‐eight underwent a comprehensive neuropsychological assessment. Patient groups were compared among each other and to 33 healthy controls. Fatigue, anxiety and depression scores were significantly increased, and the SF‐36 mental score significantly decreased in all patient groups compared to controls. Fatigue was significantly more pronounced in HCV than in HBV patients. HCV patients scored significantly worse than HBV patients but not AIH and PBC patients in the SF‐36. HCV, AIH and PBC but not HBV patients did significantly worse than controls in word learning. Recognition of words was impaired in HCV, AIH and PBC patients and recognition of figures in HCV patients, exclusively (P ≤ 0.002). HCV patients did also worse than controls and HBV patients concerning alertness and working memory (P ≤ 0.001). The neuropsychiatric profiles of HCV patients are similar to those of AIH and PBC patients but differ from those of HBV patients, suggesting an autoimmune response as a possible cause for these differences. [ABSTRACT FROM AUTHOR]

Evaluation of: Rocco A, Compare D, Coccoli P et al. Vitamin B12 supplementation improves rates of sustained viral response in patients chronically infected with hepatitis C virus. Gut doi:10.1136/gutjnl-2012-302344 (Epub ahead of print) (2012). Vitamin B12 was first mentioned to have a role in HCV treatment approximately a decade ago, but it has not been well translated into clinical medicine. Recently, however, a randomized trial has reported significantly better response at all time-points during therapy with pegylated interferon plus ribavirin, if such therapy was combined with vitamin B12. This correlates with reports on vitamin B12 being able to inhibit HCV in vitro and a report that vitamin B12 levels were related to treatment response. If further validated, vitamin B12 is another vitamin reported to be beneficial for HCV therapy. Vitamin D had repeatedly been reported to be associated with response to HCV therapy. It will be interesting to see whether vitamins such as B12 and D will remain relevant in the light of direct antivirals. [ABSTRACT FROM AUTHOR]

Background & Aims: IL28B polymorphisms have been associated with both treatment induced and spontaneous clearance of hepatitis C virus (HCV). We previously found that LDL cholesterol levels were higher in chronic hepatitis C (CHC) patients with the CC genotype at the rs12979860 polymorphism, located proximal to the IL28 gene. Here we analyzed the association of steatosis with IL28B genotype in treatment naïve patients with CHC. Methods: Two independent cohorts of 145 genotype 1 infected patients from an antifibrotic study and 180 genotype 1 patients from Duke were analyzed for the presence and severity of steatosis in relation to the rs12979860 polymorphism at the IL28B locus. TaqMan assay based genotyping classified three groups CC, CT, and TT. Results: CC genotype was associated with a lower prevalence of steatosis. In the antifibrotic study, steatosis was found in 47.6% (50/105) of IL28B non-CC vs. 22.5% (9/40; p =0.008) in CC patients. Similarly, steatosis was found in 67.4% (89/132) of non-CC patients compared to only 39.6% (19/48; p =0.001) of CC patients in the Duke cohort. Conclusions: IL28B CC genotype is associated with less pronounced disturbances of lipid metabolism, as reflected both in serum lipoprotein levels and hepatic steatosis, in HCV infection. [ABSTRACT FROM AUTHOR]

Introduction: Polymorphisms near the IL28B gene (e.g. rs12979860) encoding interferon l3 have recently been associated with both spontaneous clearance and treatment response to pegIFN/RBV in chronic hepatitis C (CHC) patients. The molecular consequences of this genetic variation are unknown. To gain further insight into IL28B function we assessed the association of rs12979860 with expression of protein quantitative traits (pQTL analysis) generated using open-platform proteomics in serum from patients. Methods: 41 patients with genotype 1 chronic hepatitis C infection from the Duke Liver Clinic were genotyped for rs12979860. Proteomic profiles were generated by LC-MS/MS analysis following immunodepletion of serum with MARS14 columns and trypsin-digestion. Next, a latent factor model was used to classify peptides into metaproteins based on coexpression and using only those peptides with protein identifications. Metaproteins were then analyzed for association with IL28B genotype using one-way analysis of variance. Results: There were a total of 4,186 peptides in the data set with positive identifications. These were matched with 253 proteins of which 110 had two or more associated, identified peptides. The IL28B treatment response genotype (rs12979860_CC) was significantly associated with lower serum levels of corticosteroid binding globulin (CBG; p = 9.2x10-6), a major transport protein for glucocorticoids and progestins. Moreover, the CBG metaprotein was associated with treatment response (p = 0.0148), but this association was attenuated when both IL28B genotype and CBG were included in the model, suggesting that the CBG association may be independent of treatment response. Conclusions: In this cohort of chronic hepatitis C patients, IL28B polymorphism was associated with serum levels of corticosteroid binding globulin, a major transporter of cortisol, however, CBG does not appear to mediate the association of IL28B with treatment response. Further investigation of this pathway is warranted to determine if it plays a role in other comorbidities of HCV-infection. [ABSTRACT FROM AUTHOR]

In hepatitis C, both susceptibility to infection and the course of disease may depend on differences in the immune response. As the major histocompatibility complex (MHC) plays a crucial role in antigen presentation, we investigated a possible relationship between susceptibility to hepatitis C virus (HCV) infection and human leucocyte antigen (HLA) alleles. Therefore, phenotype frequencies of HLA were compared in 186 anti-HCV positive patients with end-stage renal disease (ESRD) to 328 anti-HCV negative patients with ESRD. HLA class I alleles were determined serologically and HLA class II alleles (DRB1, DQA1, DQB1) by the polymerase chain reaction sequence-specific oligonucleotide (PCR-SSO) technique. Additionally, in anti-HCV positive patients we looked for a relationship between the activity of hepatitis C (indicated by elevation of transaminases or the presence of viremia) and HLA determinants. For the three criteria (antibody status, elevation of transaminases and viremia) a significant association to HLA alleles was not found in patients with ESRD. This suggests that neither susceptibility to HCV infection nor the biochemical activity of hepatitis and HCV-RNA positivity seem to be strongly related to HLA status in Caucasian patients with end-stage renal disease. [ABSTRACT FROM AUTHOR]

In this article, the author focuses on a study by researcher K. Hara and colleagues regarding the relapse of hepatitis C virus (HCV) infection. He informs that HCV infections become undetectable via achievement of a sustained viral response (SVR) after antiviral treatment. He also mentions that persistence of replicative HCV reservoirs can lead to reinfection of the liver.

Background & Aims: Interferon-alfa (IFN)-related cytopenias are common and may be dose-limiting. We performed a genome wide association study on a well-characterized genotype 1 HCV cohort to identify genetic determinants of peginterferon-α (pegIFN)-related thrombocytopenia, neutropenia, and leukopenia. Methods: 1604/3070 patients in the IDEAL study consented to genetic testing. Trial inclusion criteria included a platelet (Pl) count ⩾80×109/L and an absolute neutrophil count (ANC) ⩾1500/mm3. Samples were genotyped using the Illumina Human610-quad BeadChip. The primary analyses focused on the genetic determinants of quantitative change in cell counts (Pl, ANC, lymphocytes, monocytes, eosinophils, and basophils) at week 4 in patients >80% adherent to therapy (n=1294). Results: 6 SNPs on chromosome 20 were positively associated with Pl reduction (top SNP rs965469, p =10−10). These tag SNPs are in high linkage disequilibrium with 2 functional variants in the ITPA gene, rs1127354 and rs7270101, that cause ITPase deficiency and protect against ribavirin (RBV)-induced hemolytic anemia (HA). rs1127354 and rs7270101 showed strong independent associations with Pl reduction (p =10−12, p =10−7) and entirely explained the genome-wide significant associations. We believe this is an example of an indirect genetic association due to a reactive thrombocytosis to RBV-induced anemia: Hb decline was inversely correlated with Pl reduction (r=−0.28, p =10−17) and Hb change largely attenuated the association between the ITPA variants and Pl reduction in regression models. No common genetic variants were associated with pegIFN-induced neutropenia or leucopenia. Conclusions: Two ITPA variants were associated with thrombocytopenia; this was largely explained by a thrombocytotic response to RBV-induced HA attenuating IFN-related thrombocytopenia. No genetic determinants of pegIFN-induced neutropenia were identified. [ABSTRACT FROM AUTHOR]