R. Soffredini

Randomized Study of Peginterferon-α2a Plus Ribavirin vs Peginterferon-α2b Plus Ribavirin in Chronic Hepatitis C

BACKGROUND & AIMS Ribavirin (RBV) combined with either pegylated interferon (PegIFN) alpha2a or PegIFNalpha2b is the standard of care for chronic hepatitis C virus (HCV) infection. Due to the lack of head-to-head studies, the 2 PegIFNs have not been directly compared. The endpoints of our study were safety and antiviral efficacy of the 2 regimens. METHODS Treatment-naïve patients with chronic hepatitis C were randomly (1:1) assigned after stratification for HCV genotype to receive either 1.5 mcg/Kg/week PegIFNalpha2b plus RBV 800-1200 mg/day or 180 mcg/week PegIFNalpha2a plus RBV 800-1200 mg/day for 24 or 48 weeks according to HCV genotype. The study was powered to detect a difference of at least 10% in safety and efficacy of the 2 regimens. RESULTS The 212 patients on PegIFNalpha2a and the 219 patients on PegIFNalpha2b had similar baseline characteristics, including cirrhosis (20% vs 18%, respectively). By intention to treat, the 2 groups showed similar rates of treatment-related serious adverse events (1% vs 1%, respectively) and drop out rates for adverse effects (7% vs 6%, respectively). Overall, sustained virologic response (SVR) rate was higher in PegIFNalpha2a than in PegIFNalpha2b patients (66% vs 54%, respectively, P = .02), being 48% vs 32% in the 222 HCV-1 and -4 patients (P = .04), and 96% vs 82%, respectively, in the 143 HCV-2 patients (P = .01). PegIFNalpha2a independently predicted SVR in the logistic regression analysis (odds ratio, 1.88; 95% confidence interval: 1.20-2.96). CONCLUSIONS Although the 2 regimens showed a similar safety profile, the PegIFNalpha2a-based treatment yielded significantly more SVR than PegIFNalpha2b.

IL28B polymorphisms predict interferon-related hepatitis B surface antigen seroclearance in genotype D hepatitis B e antigen-negative patients with chronic hepatitis B.

Interleukin (IL)28B polymorphisms have been associated with interferon (IFN)‐induced viral clearance in patients with chronic hepatitis C. Whether this is also true for patients with the difficult‐to‐cure hepatitis B e antigen (HBeAg)‐negative chronic hepatitis B (CHB) is unknown. One hundred and one HBeAg‐negative patients (92% genotype D) with compensated CHB (84% males, 46 years; hepatitis B virus [HBV] DNA: 6.0 log cp/mL; alanine aminotransferase [ALT]: 136 IU/L; 42% with cirrhosis) were followed up for a median of 11 years (range, 1‐17) after a median of 23 months (range, 10‐48) of either standard or pegylated (Peg)‐IFN‐alpha therapy. A post‐treatment response was defined as hepatitis B surface antigen (HBsAg) clearance with or without antibody to hepatitis B surface antigen (anti‐HBs) seroconversion. The rs12979860 (C>T) genotype in the IL28B locus was assessed in serum samples by using Custom TaqMan SNP Genotyping Assays (Applied Biosystems, Carlsbad, CA). During a median of 11 years of post‐treatment follow‐up, 21 patients (21%) cleared serum HBsAg, including 15 who developed >10 IU/mL of anti‐HBs titers. Forty‐eight patients (47%) had CC genotype, 42 (42%) had CT, and 11 (11%) had TT, with the allelic frequency being 68% for C allele and 32% for T allele. The rate of serum HBsAg clearance was 29% (n = 14) in CC compared to 13% (n = 7) in non‐CC, genotype carriers (P = 0.039). Baseline HBV DNA levels <6 log cp/mL (odds ratio [OR], 11.9; 95% confidence interval [CI]: 2.8‐50.6; P = 0.001), ALT levels >136 IU/L (OR, 6.5; 95% CI: 1.8‐22.5; P = 0.003), duration of IFN (OR, 1.16; 95% CI: 1.02‐1.31; P = 0.021), and genotype CC (OR, 3.9; 95% CI: 1.1‐13.2; P = 0.025) independently predicted HBsAg clearance. Conclusions: IL28B polymorphism is an additional predictor of off‐therapy IFN‐related HBsAg seroclearance to be used in the pretreatment stratification of HBeAg‐negative patients chronically infected by genotype D of HBV. (HEPATOLOGY 2013)

Genetic variation in the interleukin-28B gene is not associated with fibrosis progression in patients with chronic hepatitis C and known date of infection†

Polymorphisms in the interleukin‐28B (IL28B) region are associated with spontaneous and treatment‐induced viral clearance in hepatitis C virus (HCV) infection. Nevertheless, it is unknown whether genetic variation at the IL28B locus influences the natural history of chronic HCV infection. Thus, we asked whether an association between IL28B polymorphisms and liver fibrosis progression existed. We studied 247 consecutive patients with chronic HCV, an accurate estimate of the date of infection, and a liver biopsy performed before any treatment. No patient had a history of alcohol abuse or coinfection with other viruses. We assessed the role of rs8099917 and rs12979860 polymorphisms and the effect of host and environmental factors on fibrosis progression. Blood transfusion (75%) was the main modality of infection. Median age at infection was 21 years, and median interval between infection and liver biopsy was 25 years. One hundred twenty‐nine patients (52%) were infected by HCV‐1, 74 (30%) by HCV‐2, 34 (14%) by HCV‐3, and 10 (4%) by HCV‐4. Bridging fibrosis/cirrhosis (Ishak ≥4) was detected in 24% of patients. Age at infection had a marked effect on fibrosis progression by both a linear model and Cox proportional‐hazard regression (P < 2E‐16). A 12.1% increase in the hazard of advanced fibrosis was estimated for each additional year at infection, suggesting that this was the major explanatory variable in this cohort. Male gender (P < 0.05), HCV genotype 3 (P < 0.001) and steatosis (P < 0.05) were also associated with faster fibrosis progression. Conversely, the two IL28B polymorphisms had no impact on fibrosis progression. Conclusion: In HCV patients with a known date of infection, IL28B genotype was not associated with fibrosis progression rate or with the risk of developing advanced liver fibrosis. (HEPATOLOGY 2011;)

Interleukin 28B polymorphism predicts pegylated interferon plus ribavirin treatment outcome in chronic hepatitis C genotype 4.

Single nucleotide polymorphisms (SNPs) near the interleukin 28B (IL28B) region are the strongest baseline predictors of a sustained virologic response (SVR) to peg‐interferon (PegIFN) and ribavirin (Rbv) in patients with hepatitis C virus (HCV) genotype 1 infection. Whether this holds true for HCV‐4 patients too is unknown. The aim was to investigate the predictive power of the rs12979860 IL28B SNP for a response to Peg‐IFN and Rbv in HCV‐4 patients. All HCV‐4 patients consecutively treated between September 2004 and June 2010 with PegIFN and Rbv at two liver centers at the Maggiore Hospital Milan (Italy) underwent TaqMan SNP Genotyping assays for testing rs12979860 genotype. Of 112 treated patients (98 males, 75 of Egyptian descent, 26 with cirrhosis) 103 were included in the final analysis; five discontinued treatment for nonvirologic reasons and four did not consent to genetic testing. Twenty‐four (23%) were genotype CC, 65 (63%) CT, and 14 (14%) TT. Overall, 50 (49%) achieved an SVR: 21 (88%) CC patients versus 29 (37%) CT/TT (P < 0.0001). CC patients more often had a rapid virologic response (RVR) than CT/TT patients (12, 50% versus 23, 29%; P = 0.08), while also showing lower relapse rates (0% [0/21] versus 36% [16/45] P = 0.0013). In non‐RVR patients, SVR rates were higher in CC than CT/TT patients (9 [75%] versus 13 [23%] P = 0.001). By logistic regression, the IL28B rs12979860 CC genotype was an independent predictor of SVR with an odds ratio of 8.0 (95% confidence interval 2.00‐32.01; P = 0.003). Conclusion: The IL28B rs12979860 SNP may have an added value in the treatment algorithm of HCV‐4 patients because it is the strongest predictor of an SVR to PegIFN/Rbv therapy. (HEPATOLOGY 2012)

Sustained virological response prevents the development of insulin resistance in patients with chronic hepatitis C

Hepatitis C virus (HCV) infection is associated with insulin resistance (IR), which is a condition known to influence the progression of liver fibrosis and the response to pegylated interferon (PEG‐IFN)/ribavirin (RBV) therapy. We aimed to assess whether a sustained virological response (SVR) after antiviral therapy prevents the development of IR in the long term. Members of the Milan Safety Tolerability study cohort, who received PEG‐IFNα2a/RBV or PEG‐IFNα2b/RBV, underwent a homeostasis model assessment (HOMA) at the baseline and 24 months after treatment completion. For all patients (n = 431), a liver biopsy sample was scored for grading, staging (Ishak), and steatosis. At the baseline, IR (HOMA value > 2) was detected in 48 patients (12%), and it was associated with body weight (P = 0.03), an HCV load < 0.6 × 106 IU/L (P = 0.006), fibrosis staging ≥ 4 (P = 0.01), and moderate to severe steatosis (P = 0.03). IR did not influence the rates of end‐of‐treatment response (75% versus 69%, P = 0.4), SVR (63% versus 60%, P = 0.8), or relapse (19% versus 24%, P = 0.5). After treatment, IR developed in 49 of the 384 nondiabetic patients (14%). Although the mean baseline and posttreatment HOMA values were similar in SVR patients (1.11 ± 0.8 versus 1.18 ± 1.1, P = 0.25), patients experiencing treatment failure showed a significant increase in the mean HOMA value at the follow‐up visit (1.20 ± 0.85 versus 1.49 ± 1.3, P = 0.007), and there was an increased rate of de novo IR in non‐SVR patients versus SVR patients (17% versus 7%, P = 0.007). According to a logistic regression analysis, treatment failure (odds ratio = 2.81, 95% confidence interval = 1.39‐5.67, P = 0.004) and a 10% body mass index increase (odds ratio = 6.42, 95% confidence interval = 1.69‐24.3, P = 0.006) were significantly associated with the development of de novo IR. Conclusion: In nondiabetic patients with chronic HCV, the achievement of SVR with PEG‐IFN and RBV prevents the development of de novo IR. (HEPATOLOGY 2012;56:1681–1687)

Lack of association between type of hepatitis C virus, serum load and severity of liver disease

SUMMARY. Chronic infection with the hepatitis C virus (HCV) may lead to a variety of hepatic lesions from benign inflammation to liver cancer, but the relationships between infection and development of liver disease are poorly understood. To assess whether virus type and load are of pathogenetic importance, 197 Italian carriers with various hepatic lesions were investigated consecutively. Of these, 187 (95%) patients had serum HCV RNA, by reverse transcription‐polymerase chain reaction (RT‐PCR) with a median level of 1003 × 103 genomic equivalents ml‐1 according to the branched‐DNA assay (b‐DNA). One hundred and seven patients (54%) had serotype 1, 22 (11%) had serotype 2, 9 (5%) had serotype 3, 17 (9%) had mixed serotypes and 42 (21%) had no specified serotype. One hundred and thirty four patients were also tested for genotype. The genotype distribution was as follows: 17 (13%) had genotype 1a; 67 (50%) 1b; 29 (22%) 2a; 12 (9%) 3a; 3 (2%) had genotype 1 not classified (NC); 3 (2%) had genotype 2 NC; 2 (1.4%) had genotype 4 and 1 (1%) had mixed genotype la + 3a. No virus type was associated with any particular histological diagnosis and all were equally distributed between progressive and non‐progressive liver disease groups. Serum HCV‐RNA levels were similar in the liver diseases groups. By analogy to hepatitis B, there was no direct correlation between type and level of viraemia and the severity of the underlying liver damage.

Increased detection of antibody to hepatitis C virus in renal transplant patients by third-generation assays

To assess the sensitivity and specificity of third-generation assays for antibody to hepatitis C virus (anti-HCV), sera from 244 renal transplant patients (113 positive for anti-HCV enzyme-linked immunosorbent assay [ELISA]-2) were studied. Hepatitis C virus RNA was detected by a reverse-transcripted nested polymerase chain reaction. Antibody to HCV was detected by ELISA-3 in 108 (96%) ELISA-2-positive samples. Five (4%) ELISA-2-positive sera were negative by both ELISA-3 and polymerase chain reaction. In the anti-HCV-negative group, six (5%) additional cases were ELISA-3-positive; three of these were confirmed by recombinant immunoblot assay-3 (RIBA-3) and polymerase chain reaction. Recombinant immunoblot assay-3 was used to resolve 82 RIBA-2-indeterminate and three RIBA-2-negative sera. Using RIBA-3, 49 (60%) RIBA-2-indeterminate samples were positive, five (6%) ELISA-3-negative samples were negative, and 28 (34%) were remained indeterminate. Recombinant immunoblot assay-2-negative samples were indeterminate with RIBA-3. Hepatitis C virus RNA was detected in all RIBA-3-positive and 58% of the RIBA-3-indeterminate samples. Third-generation assays for anti-HCV are more sensitive and specific than second-generation assays in renal transplant patients.

Serum levels of hepatitis C virus core antigen as a marker of infection and response to therapy

OBJECTIVES:Hepatitis C virus (HCV) core antigen is a recently developed marker of hepatitis C infection. We compared the predictive power of HCV core antigen with reverse transcription polymerase chain reaction (RT-PCR) and branched DNA assay for HCV-RNA as markers of infection and response to interferon therapy.METHODS:Four hundred and forty-four sera from 111 patients (65 men, 52 yr) with chronic hepatitis C, receiving ribavirin together with standard interferon (n = 61) or pegylated interferon (n = 50) were retrospectively investigated.RESULTS:Pretreatment, RT-PCR, branched DNA (median 621,887 IU/ml), and HCV core antigen (median 57 pg/ml) gave positive results in 100%, 99%, and 94% of the sera; the correlation between HCV core antigen and branched DNA was 0.75. The median HCV RNA level among the 7 of 111 (6%) patients that had a negative core Ag result was 15,016 IU/ml. Pretreatment levels of HCV core antigen were significantly lower in the 41 patients with a sustained virological response than in the 39 relapsers and 31 nonresponders (17 pg/ml, 114 pg/ml, 58 pg/ml; p-value 0.005). Independently of treatment schedule, wk 12 more than 2 log10 reduction of viremia or a negative result for HCV core antigen had 100% negative predictive value (NPV) for a response to therapy compared to 94% for negative RT-PCR. The positive predictive value (PPV) of HCV core antigen and branched DNA was only 47% and 48%.CONCLUSIONS:In conclusion, the HCV core antigen is a less sensitive test of HCV viremia than HCV-RNA assays and is competitive with the bDNA assay as an early predictor of a nonresponse.

Long-term titrated recombinant interferon-α2a in chronic hepatitis C: a randomized controlled trial

Summary. The efficacy and tolerability of 12‐month treatment with titrated doses of recombinant interferon‐α2a (IFN‐α2a) in chronic hepatitis C were studied in 67 consecutively recruited patients randomly assigned either to a starting dose of IFN‐α2a 6 MU, subsequently adjusted to the serum alanine aminotransferase (ALT) response (n= 35), or to no therapy (n= 32; controls). End‐of‐treatment ALT levels were normal and hepatitis C virus (HCV) RNA was negative by nested polymerase chain reaction (PCR) in 17 (49%) treated patients compared to none of the controls (P < 0.001). During the 12 months after stopping treatment the number of patients who remained in remission was eight (23%) and one respectively (4%) (P= 0.031). Follow‐up liver biopsy showed reduced hepatic inflammation in 80% of treated patients and in 29% of controls (P < 0.001). The eight sustained responders and 2 7 non‐responders or relapsers received similar mean total doses of IFN (565 MU vs 545 MU) and had a similar incidence of anti‐IFN neutralizing anti‐bodys (13% vs 19%). Absence of cirrhosis was the only independent pretreatment parameter that predicted a sustained response. In conclusion, a mean cumulative dose of IFN 549 MU, titrated over 12 months, was well tolerated, and resulted in the long‐term clearance of HCV RNA and normal ALT levels in 23% of patients.

Transmission of hepatitis G virus in patients with angioedema treated with steam‐heated plasma concentrates of C1 inhibitor

BACKGROUND: Hepatitis G virus (HGV) is a blood‐borne flavivirus that may cause acute and chronic transfusion‐transmitted infections. Patients with complement component 1 (C1) inhibitor (C1‐INH) deficiency may acquire blood‐borne infections through infusion of plasma concentrates. STUDY DESIGN AND METHODS: Serum samples from 84 patients with C1‐INH deficiency (19 who received unmodified C1‐INH concentrates, 23 who received steam‐heated concentrates, and 42 untreated patients) were tested for HGV RNA and hepatitis C virus (HCV) RNA by a nested polymerase chain reaction (PCR). The samples were also tested for antibodies to the E2 envelope protein of HGV (anti‐HGV) and to HCV with enzyme‐linked immunosorbent assays. RESULTS: Nine (11%) patients had serum HGV RNA; that is, 7 (17%) of 42 patients previously treated with C1‐INH concentrates and 2 of 42 previously untreated patients. HGV RNA was as common in the 19 patients treated with unmodified concentrates as in the 23 given steam‐heated concentrates (16 vs. 17%, p = 0.60). Anti‐HGV was more common among the recipients of unmodified concentrates than among those given steam‐heated concentrates (26 vs. 0%, p = 0.014). HCV RNA was more frequently detected in treated patients than in untreated patients (33 vs. 7%, p = 0.005) and in the 19 recipients of unmodified concentrates than in the 23 treated with steam‐heated concentrates (58 vs. 16%, p = 0.003). Only one HGV RNA‐ seropositive patient had elevated serum aminotransferase activity, compared to 11 with HCV RNA. CONCLUSION: HGV was transmitted by both unmodified and steam‐heated concentrates, but it caused persistent viremia in a minority of the cases and was rarely associated with liver disease.