Association of IL28B genotypes with metabolic profiles and viral clearance rate in chronic hepatitis C patients

Purpose

IL28B genotypes have a strong impact on treatment outcomes of chronic hepatitis C (CHC) and on-treatment viral kinetics. Since metabolic regulation and interferon response are highly integrated, metabolic profiles may play an important role in the link between IL28B genotypes and hepatitis C virus (HCV) infection. Thus, the association of IL28B rs8099917 genotypes with metabolic profiles and the impact of metabolic profiles on hepatitis C viral kinetic parameters were examined.

Methods

A case–control analysis including 278 CHC patients and 280 subjects without chronic HCV infection was performed. The associations of IL28B rs8099917 genotype with pretreatment metabolic profiles and early viral kinetic parameters were evaluated.

Results

Compared to HCV genotype 1 patients, the differences in metabolic profiles were more significant in genotype 2 patients. HCV genotype 2 patients with TT genotype had higher serum total cholesterol and high density lipoprotein (HDL) levels than those with GT genotype, and the differences remained significant when adjusted for age, sex, and body mass index (p = 0.005 for total cholesterol; p = 0.006 for HDL). In addition, patients with higher serum TG, higher fasting blood glucose, and lower HDL had a lower viral clearance rate.

Conclusions

IL28B genotypes may affect lipid profiles of CHC patients, especially in HCV-genotype 2 patients. Patients with higher serum fasting blood glucose, triglyceride, and lower HDL have a lower viral clearance rate during pegylated interferon plus ribavirin therapy.     

IL28B polymorphisms predict the virological response to standard therapy in patients with chronic hepatitis C virus genotype 4 infection

Background

Genome-wide association studies have recently revealed that several single-nucleotide polymorphisms (SNPs) in the interleukin (IL) 28B genes can predict the sustained virological response (SVR) to pegylated interferon-α2a/b plus ribavirin in hepatitis C virus (HCV)-genotype 1 patients. However, data for patients infected with HCV genotype 4 (HCV-G4) are limited.

Aim

We analyzed the association of IL28B SNPs (hematological, biochemical, virological, and pathological factors) with SVR in the HCV-G4 monoinfected cohort of patients.

Patients and methods

One hundred twenty-nine treatment-naïve HCV-G4 patients undergoing treatment were recruited from three tertiary care centers in Saudi Arabia. Five IL28B SNPs (rs12979860, rs12980275, rs8105790, rs8099917, and rs72486680) were identified by polymerase chain reaction and DNA sequencing. SVR was statistically correlated with various clinical, histopathological, virological, and genetic parameters.

Results

SVR was significantly associated with the CC and AA alleles of rs12979860 (p = 0.008) and rs12980275 (p = 0.004), respectively. Moreover, albumin levels (p = 0.002) and platelet count (p = 0.039) showed significant differences in the SVR and No SVR groups. On multivariate analysis, the CC allele of rs12979860 (OR, 2.89; 95 % CI 1.6–6.2, p = 0.006) and albumin levels (OR, 1.2; 95 % CI 1.1–1.4, p = 0.001) independently predicted SVR.

Conclusions

IL28B polymorphism (CC allele of rs12979860) predicts the sustained response to antiviral therapy in HCV-G4.     

Decrease in alpha-fetoprotein levels predicts reduced incidence of hepatocellular carcinoma in patients with hepatitis C virus infection receiving interferon therapy: a single center study

Background

Increasing evidence suggests the efficacy of interferon therapy for hepatitis C in reducing the risk of hepatocellular carcinoma (HCC). The aim of this study was to identify predictive markers for the risk of HCC incidence in chronic hepatitis C patients receiving interferon therapy.

Methods

A total of 382 patients were treated with standard interferon or pegylated interferon in combination with ribavirin for chronic hepatitis C in a single center and evaluated for variables predictive of HCC incidence.

Results

Incidence rates of HCC after interferon therapy were 6.6% at 5?years and 13.4% at 8?years. Non-sustained virological response (non-SVR) to antiviral therapy was an independent predictor for incidence of HCC in the total study population. Among 197 non-SVR patients, independent predictive factors were an average alpha-fetoprotein (AFP) integration value ≥10?ng/mL and male gender. Even in patients whose AFP levels before interferon therapy were ≥10?ng/mL, reduction of average AFP integration value to <10?ng/mL by treatment was strongly associated with a reduced incidence of HCC. This was significant compared to patients with average AFP integration values of ≥10?ng/mL (P?=?0.009).

Conclusions

Achieving sustained virological response (SVR) by interferon therapy reduces the incidence of HCC in hepatitis C patients treated with interferon. Among non-SVR patients, a decrease in the AFP integration value by interferon therapy closely correlates with reduced risk of HCC incidence after treatment.     

Incidence of hepatocellular carcinoma in HCV-infected patients with normal alanine aminotransferase levels categorized by Japanese treatment guidelines

Background

This study was conducted to evaluate Japanese treatment guidelines for patients with chronic hepatitis C virus (HCV) infection and normal alanine aminotransferase (N-ALT) levels from the viewpoint of the incidence of hepatocellular carcinoma (HCC).

Methods

Four groups of patients with chronic HCV infection treated with pegylated interferon (Peg-IFN) plus ribavirin, and classified according to the N-ALT guidelines, were examined for HCC incidence: group A (n = 353), ALT ≤30 IU/L and platelet (PLT) ≥15 × 10⁴/mm³; group B (n = 123), ALT ≤30 IU/L and PLT <15 × 10⁴/mm³; group C (n = 233), 30 < ALT ≤ 40 IU/L and PLT ≥15 × 10⁴/mm³; and group D (n = 100), 30 < ALT ≤ 40 IU/L and PLT <15 × 10⁴/mm³. The mean observation period was 36.2 ± 16.5 months

Results

In groups A and C, the HCC incidence was low even in patients with non-response (NR) (cumulative rates at 3 years, 0.0 and 2.9 %, respectively). In groups B and D, 14.5 and 5.3 % of NR patients had developed HCC at 3 years, but none of the patients with sustained virologic response (SVR) or relapse had developed HCC. In group B, no patients with mild fibrosis developed HCC irrespective of the antiviral effect of the treatment. Among patients with PLT <15 × 10⁴/mm³ (group B plus group D), the HCC incidence was significantly lower in patients with SVR and relapse than in NR patients (p < 0.001, p = 0.021, respectively).

Conclusion

These results suggest that N-ALT patients with PLT <15 × 10⁴/mm³ could be candidates for early antiviral therapy.     

Clinical Outcomes of Hepatitis C Treated with Pegylated Interferon and Ribavirin via Telemedicine Consultation in Northern California

Background

Patients in rural communities are less likely to receive treatment for their hepatitis C (HCV) infection. Telemedicine (TM) consultation can close the gap of access to specialists in remote and under-served areas.

Aim

To determine treatment response and side-effect profiles among HCV patients treated with pegylated interferon and ribavirin via TM consultation in different rural locations in Northern California compared with patients treated in traditional hepatology office visits.

Methods

We performed a retrospective analysis of 80 HCV patients treated at different TM sites (TM, n = 40) and at the University of California Davis Hepatology Clinic (HC, n = 40) between 2006 and 2010, comparing baseline characteristics and clinical outcomes.

Results

At baseline, response to therapy was similar for patients in both groups. Sustained virological response (SVR) was similar in both groups (TM: 55 vs. HC: 43 %; p = 0.36), and a higher proportion of patients treated via telemedicine completed treatment (TM: 78 vs. HC: 53 %; p = 0.03). TM patients had many more visits per week of therapy (TM: 0.61 vs. HC: 0.07; p < 0.001). Neutropenia, GI side effects, fatigue, depression, weight loss, insomnia, and skin rash were similar in both groups. For HC patients incidence of anemia was significantly higher (53 %) than for the TM group (25 %; p = 0.02).

Conclusions

The two groups had equivalent SVR. For the TM group therapy completion was superior and incidence of anemia was lower. This initial study suggests that, as a group, patients with HCV, can be safely and effectively treated via telemedicine.     

Association of two polymorphisms of the IL28B gene with viral factors and treatment response in 1,518 patients infected with hepatitis C virus

Background

Two nucleotide polymorphisms of the interleukin-28B (IL28B) gene, at rs8099917 and rs12979860, influence the response to interferon (IFN)-based therapies in patients infected with hepatitis C virus (HCV) of genotype 1. We aimed to investigate whether these polymorphisms showed complete linkage in Japanese patients.

Methods

A total of 1,518 Japanese patients infected with HCV were genotyped for the two IL28B loci, and the two sets of genotypes were compared.

Results

TT at rs8099917 and CC at rs12979860 were detected in 77.7 and 76.8%, respectively, of the 1,518 patients and TG/GG and CT/TT were detected in 22.3 and 23.2%. These two sets of IL28B genotype stood in strong linkage disequilibrium (r ²?=?0.98). Discordance between the two IL28B polymorphisms occurred in 16 (1.1%) patients, and 13 (0.9%) of them possessed IFN-sensitive TT at rs8099917 and IFN-resistant CT at rs12979860. Three of these 13 patients had HCV of genotype 1b and had received pegylated-interferon and ribavirin, and none of them gained a sustained virological response. At rs8099917, IFN-resistant TG/GG were more frequent in patients infected with HCV of genotype 1 than in those infected with HCV of genotype 2 [258/1,046 (24.7%) vs. 75/441 (17.0%), p?=?0.001]. The response to pegylated-interferon/ribavirin in 279 patients who were infected with HCV-1 and the response to IFN monotherapy in 361 patients who were infected with HCV-1 , was higher in those with TT than in those with TG/GG at rs8099917, as well as being higher in those with CC than in those with CT/TT at rs12979860 (p?Conclusions Linkage disequilibrium between two IL28B polymorphisms at rs8099917 and rs12979860 is strong in Japanese HCV patients, but there are some discrepancies between the two sets of genotypes.     

IL28B minor allele is associated with a younger age of onset of hepatocellular carcinoma in patients with chronic hepatitis C virus infection

Background

IL28B polymorphisms were shown to be associated with a response to peg-interferon-based treatment in chronic hepatitis C (CHC) and spontaneous clearance. However, little is known about how this polymorphism affects the course of CHC, including the development of hepatocellular carcinoma (HCC). We evaluated the influence of IL28B polymorphisms on hepatocarcinogenesis in CHC patients.

Methods

We genotyped the rs8099917 single-nucleotide polymorphism in 351 hepatitis C-associated HCC patients without history of IFN-based treatment, and correlated the age at onset of HCC in patients with each genotype.

Results

Frequencies of TT, TG, and GG genotypes were 74.3 % (261/351), 24.8 % (87/351), and 0.9 % (3/351), respectively. The mean ages at onset of HCC for TT, TG, and GG genotypes were 69.9, 67.5 and 66.8, respectively. In multivariate analysis, IL28B minor allele (TG and GG genotypes) was an independent risk factor for younger age at onset of HCC (P = 0.02) in males (P < 0.001) with higher body mass index (BMI; P = 0.009). The IL28B minor allele was also associated with a lower probability of having aspartate aminotransferase-to-platelet ratio index (APRI) >1.5 (minor vs. major, 46.7 vs. 58.6 %; P = 0.01), lower AST (69.1 vs. 77.7 IU/L, P = 0.02), lower ALT (67.8 vs. 80.9 IU/L, P = 0.002), higher platelet count (12.8 vs. 11.2 × 10⁴/μL, P = 0.002), and higher prothrombin time (79.3 vs. 75.4 %, P = 0.002).

Conclusions

The IL28B minor allele was associated with lower inflammatory activity and less progressed fibrosis of the liver; however, it constituted a risk factor for younger-age onset of HCC in CHC patients.     

Thyroid autoantibodies and dysfunction do not impact the treatment efficacy of peginterferon and ribavirin combination therapy in chronic hepatitis C

Aims

Thyroid disorders, such as the emergence of thyroid autoantibodies (TAs) and thyroid dysfunction (TD), are not uncommon in chronic hepatitis C (CHC) patients. The study aimed to investigate the impact of TAs and dysfunction on the treatment response to pegylated interferon-?? plus ribavirin (PegIFN/RBV) combination therapy in CHC patients. The association between interleukin-28B (IL-28B) genetic variants and occurrence of TAs and dysfunction was also analyzed.

Methods

A total of 449 treatment-naive Taiwanese CHC patients with euthyroid status were consecutively enrolled. They received PegIFN/RBV combination therapy with current recommendation. TAs, TD, and IL-28B genetic variants were measured before treatment. Monitoring of TD was done at 3-month intervals during treatment, at end of treatment, and at end of follow-up (EOF).

Results

The development of TAs was detected in 42 (9.4%) patients before treatment, and the incidence of TD during or at EOF was 20%. Of 287 patients with IL-28B rs8099917 TT genotype, 29 (10.1%) had TAs before treatment, whereas the patients with other genotypes did not have TAs (P?=?0.04). There was no significant difference of TD incidence during treatment or at EOF between the patients with different IL-28B genotypes. There was also no significant difference of sustained virologic response according to the presence of TAs, TD, or different manifestations of TD.

Conclusion

Taiwanese CHC patients with rs8099917 TT genotype had a higher incidence of TAs. The development of TAs and TD did not impact the treatment efficacy of PegIFN/RBV combination therapy.     

The impact of patatin-like phospholipase domain-containing protein 3 polymorphism on hepatocellular carcinoma prognosis

Background

The single nucleotide polymorphism (SNP) rs738409 in patatin-like phospholipase domain-containing protein 3 (PNPLA3) is associated with hepatic fat accumulation and disease progression in patients with non-alcoholic fatty liver disease and alcoholic liver disease (ALD). This study was conducted to determine whether PNPLA3 rs738409 SNPs affect development and prognosis of hepatocellular carcinoma (HCC) in patients with various liver diseases.

Methods

We enrolled 638 consecutive Japanese patients newly diagnosed with HCC between 2001 and 2010: 72 patients with hepatitis B virus (HBV), 462 with hepatitis C virus (HCV), and 104 with non-B non-C (NBNC).

Results

NBNC patients exhibited large tumors of advanced TNM stages at HCC diagnosis, and had significantly poorer prognosis than HBV or HCV patients (P < 0.001 and <0.001, respectively; log-rank test). The G/G genotype of PNPLA3 rs738409 SNP had significantly higher distribution in NBNC patients (P < 0.001) and was significantly associated with higher body mass index (BMI) and an increased aspartate aminotransferase to platelet ratio index. No significant differences were observed in survival with differences in PNPLA3 SNP genotypes among the patients, although ALD patients with the G/G genotype of PNPLA3 SNP and low BMI had significantly poorer survival than those with high BMI (P = 0.028).

Conclusions

The G/G genotype of PNPLA3 rs738409 SNP was more frequently distributed, and associated with BMI and fibrosis among NBNC-HCC patients but not among HBV or HCV patients. These genotypes might affect HCC prognosis in ALD patients, but not in HBV, HCV, or NAFLD patients.     

Using early viral kinetics to predict antiviral outcome in response-guided pegylated interferon plus ribavirin therapy among patients with hepatitis C virus genotype 1

Background

HCV kinetics during treatment demonstrated strong association with the antiviral outcome of patients treated with pegylated interferon (Peg-IFN) plus ribavirin. However, the relationship between HCV kinetics and pre-treatment factors remains unclear.

Methods

Of 547 patients with HCV genotype 1 treated with Peg-IFN alfa-2b plus ribavirin, 401 completed the response-guided therapy and were assessed for per protocol analysis.

Results

The sustained virologic response (SVR) rate was 53 % for all patients, 60 % for those with genotype TT, and 19 % for those with genotype TG/GG according to IL28B (rs8099917) single nucleotide polymorphisms. The SVR rates increased with HCV decrease at week 4; 4 % (2/56) with <1 log₁₀ decrease, 13 % (7/56) with 1–2 log₁₀ decrease, 51 % (44/87) with 2–3 log₁₀ decrease, 64 % (56/87) with 3–4 log₁₀ decrease, 88 % (72/82) with more than 4 log₁₀ decrease but with detectable HCV RNA and 100 % (33/33) with undetectable HCV RNA (p < 0.001). Similarly, SVR rates increased step-by-step in proportion to HCV decrease in both IL28B TT and TG/GG groups, showing almost the same SVR rates for the same conditions. In multivariate analysis, age (p = 0.005) and the magnitude of HCV decrease at week 4 (p < 0.001) but not IL28B were associated with SVR. Advanced liver fibrosis (p = 0.004) and the magnitude of HCV decrease at week 4 (p < 0.001) but not IL28B were associated with non-response.

Conclusions

The magnitude of the HCV decrease at week 4 seems to be the most reliable marker for predicting antiviral outcome after starting Peg-IFN plus ribavirin therapy.     

Long-term interferon therapy after radiofrequency ablation is effective in treating patients with HCV-associated hepatocellular carcinoma

Purpose

This study investigates the usefulness of long-term interferon (IFN) therapy following radiofrequency ablation (RFA) for HCV-associated hepatocellular carcinoma (HCC).

Methods

This is a retrospective observational study. Patients underwent pegylated IFN-α/ribavirin combination therapy for 48 weeks and then were maintained on IFN-α administration on average for 68 weeks (mean total duration 116 weeks). Patients who underwent IFN monotherapy were maintained on IFN administration on average for 78 weeks.

Results

There were biases in the background factors between the IFN and non-IFN groups. Therefore, a covariate adjustment was performed using the propensity score. An analysis of 20-matched patients from each group showed the 5-year cumulative survival rate was higher in the IFN group than in the non-IFN group (100 and 76%, respectively), and the 3-year cumulative recurrence rate was significantly lower in the IFN group than in the non-IFN group (38.0 and 64.2%, respectively). In 14 patients (i.e., IFN responders), the serum alanine aminotransferase (ALT) level remained normalized at 30 IU/mL or lower, regardless of disappearance of serum HCV RNA. In these patients, the cumulative recurrence rate was low, the hazard ratio was 0.158 (95% confidence interval = 0.045–0.561, P = 0.004), and the serum albumin level was retained.

Conclusion

These results show the importance of maintaining the liver function and suggest that long-term IFN administration after RFA inhibits recurrence and contributes to an improved outcome in patients (in particular, IFN responders) who initially develop HCC.     

U.S. Multicenter Pilot Study of Daily Consensus Interferon (CIFN) Plus Ribavirin for ��Difficult-to-Treat�� HCV Genotype 1 Patients

Background

Patients with chronic hepatitis C genotype 1 (HCV-1) and difficult-to-treat characteristics respond poorly to pegylated interferon alfa and ribavirin (RBV), and could benefit from an interferon with increased activity (consensus interferon or CIFN), favorable viral kinetics from daily dosing, and a longer duration of therapy. The purpose of this pilot study was to determine the efficacy and safety of daily CIFN + RBV for initial treatment of patients with HCV-1 infection.

Methods

Patients with difficult-to-treat characteristics (92% male, 33% African American, 78% Veterans Affairs [VA]; 67% high viral load, 59% stage 3?C4 fibrosis, and mean weight of 204 lbs) were enrolled at seven VA and two community medical centers. They were randomized to daily CIFN (15 mcg/day SQ) and RBV (1?C1.2 g/d PO) given for either 52 weeks (group A, n = 33) or 52?C72 weeks (from time of viral response +48 weeks) (group B, n = 31).

Results

Intention to treat analysis for treatment groups A and B demonstrated 33% (11/33) and 32% (10/31) sustained virologic response (SVR), respectively. Only 2/31 patients in group B received more than 52 weeks of treatment. The overall group demonstrated a 31% (20/64) rapid virologic response rate (RVR), 54% (34/64) end of treatment virologic response and a 33% (21/64) SVR. Patients with RVR at 4 weeks, early virologic response from 8?C12 weeks, and late virologic response from 16?C24 weeks demonstrated SVR of 75% (15/20), 31% (4/13), and 22% (2/9), respectively. Overall early non-protocol discontinuation occurred in 26/64 (40%) patients.

Conclusion

Daily CIFN and ribavirin for initial treatment of HCV-1 patients has potential for achieving a relatively high RVR rate, but discontinuations are frequent and successful use of this regimen is highly dependent on adequate patient support to maintain adherence.     

Molecular Evolution of Genetic Susceptibility to Hepatocellular Carcinoma

Background

Hepatocellular carcinoma (HCC) is a leading cancer-related cause of death worldwide. There are widespread global differences in HCC risk. Although the impact of geographic prevalence of specific causes of chronic liver disease on HCC is recognized, the contribution of the underlying genetic architecture to the risk of HCC remains undefined. Our aim was to characterize evolutionary trends in genetic susceptibility to HCC.

Methods

We examined the genetic risk associated with HCC risk alleles identified from genome-wide association studies and correlated these with geographic location and temporal and spatial patterns of human migration.

Results

A moderate increase in differentiation was noted for rs2596542 (F _st = 0.106) and rs17401966 (F _st = 0.116), single nucleotide polymorphisms (SNPs) associated with an increased risk of HCC in patients with chronic HCV and HBV, respectively. Both of these SNPs show a recent increase in allelic frequency with the most recent human migrations into East Asia, Oceania and the Americas. In contrast another SNP associated with an increased risk of HCC, rs9275572, showed a lack of differentiation (F _st = 0.09) with stable allelic expression across populations. The genetic risk score for HCC, based on the allelic frequency and risk odds ratio of five SNPs associated with increased risk of HCC, was greatest in populations from Africa and decreased with subsequent migration into Europe and Asia. However, a major increase was noted with the most recent migrations into Oceania and the Americas.

Conclusions

There are differences in directional differentiation of HCC risk alleles across human populations that can contribute to population-based differences in HCC prevalence.     

Laparoscopic liver resection for treating recurrent hepatocellular carcinoma

Background

It is still unknown whether laparoscopic liver resection is suitable for recurrent hepatocellular carcinoma (HCC) after previous curative hepatic resection.

Method

The perioperative outcomes of 40 patients treated with second surgery for recurrent HCC by partial hepatectomy were studied retrospectively. The second surgery was performed under laparotomy in 20 patients (laparotomy group) and under laparoscopy in 20 patients (laparoscopy group).

Results

Intraoperative blood loss (p < 0.0001) and the incidence of postoperative complications (p = 0.0004) were lower in the laparoscopy group than in the laparotomy group. The incidence rates of surgical site infection and intractable ascites were significantly higher in the laparotomy group than in the laparoscopy group (p = 0.0202, p = 0.0436, respectively). The proportion of patients classified as Clavien grade IIIa was higher in the laparotomy group than in the laparoscopy group (p = 0.0033). The duration of the postoperative hospital stay was significantly shorter in the laparoscopy group than in the laparotomy group (p < 0.0001).

Conclusions

Postoperative morbidity has been decreased by the introduction of laparoscopic liver resection in patients with recurrent HCC after curative hepatic resection. As a result, the duration of the postoperative stay is shorter.     

Pre-S Mutation Is a Significant Risk Factor for Hepatocellular Carcinoma Development: A Long-Term Retrospective Cohort Study

Background

Several cross-sectional studies have shown an association between pre-S mutation and hepatocellular carcinoma (HCC).

Aims

We aim to verify whether pre-S mutation represents a risk for HCC development in a longitudinal way.

Methods

A total of 195 patients with chronic HBV infection [age: 43.7 ± 10.8 years, males: 141 (72.3 %), genotype C: 195 (100 %), hepatitis B e antigen (HBeAg) positive: 109 (55.9 %), cirrhosis: 79 (40.5 %), and pre-S mutation positive: 44 (22.6 %)] were followed up for a median of 7.2 years (range 1.0–7.8 years).

Results

HCC developed in 24 patients during follow-up. The 1-, 3-, and 5-year cumulative incidences of HCC were 0.5, 4.9, and 10.4 %, respectively. Patients with pre-S mutation had significantly higher 5-year cumulative incidences of HCC than those without (26.5 vs. 5.7 %, p < 0.001) and showed higher hazard ratio for HCC [3.04 (95 % CI 1.24–7.42), p = 0.015, adjusted for age, gender, HBeAg, cirrhosis and baseline HBV DNA level]. Notably, in patients aged ≥50 years, the 5-year cumulative incidences of HCC in patients with pre-S mutation were considerably high (58.3 %), compared to those without (16.1 %, p < 0.001).

Conclusions

Patients with pre-S mutations had higher incidence of HCC during follow-up, especially in aged patients. Patients with pre-S mutations, especially older ones, may require careful attention to HCC development.     

Inhibition of hepatocellular carcinoma by PegIFNα-2a in patients with chronic hepatitis C: a nationwide multicenter cooperative study

Background

We investigated whether the administration of maintenance doses of interferon prevented hepatocellular carcinoma (HCC) in patients with chronic hepatitis C.

Methods

Study 1: A multicenter, retrospective, cooperative study was carried out to determine whether long-term administration of low-dose peginterferon alpha-2a (PegIFNα-2a) prevented HCC development in patients with chronic hepatitis C. In total, 594 chronic hepatitis C patients without a history of HCC were enrolled and treated with 90 μg PegIFNα-2a administered weekly or bi-weekly for at least 1 year. Study 2: HCC developed in 16 of 99 additional patients without PegIFNα-2a treatment during 3.8 years of observation. A propensity-matched control study was then carried out to compare the incidence of HCC between the 59 patients who received low-dose PegIFNα-2a (PegIFNα-2a group) and 59 patients who did not receive PegIFNα-2a treatment (control group), matched for sex, age, platelet count, and total bilirubin levels.

Results

Study 1: HCC developed in 49 patients. The risk of HCC was lower in patients with undetectable hepatitis C virus RNA, ≤40 IU/L alanine aminotransferase (ALT), or ≤10 ng/L alpha-fetoprotein (AFP) 24 weeks after the start of therapy. Study 2: The incidence of HCC was significantly lower in the PegIFNα-2a group than in the control group.

Conclusions

Low-dose and long-term maintenance administration of PegIFNα-2a decreased the incidence of HCC in patients with normalized ALT and AFP levels at 24 weeks compared with patients without normal ALT and AFP levels.     

Thrombocytosis and Hepatocellular Carcinoma

Background

Thrombocytopenia has been reported to be both a risk factor for hepatocellular carcinoma (HCC) development as well as a prognostic factor. Many HCCs also occur in presence of normal platelets.

Aim

To examine a cohort of HCC patients with associated thrombocytosis.

Methods

Records were examined of a cohort of 634 biopsy-proven and randomly presenting HCC patients without thrombocytopenia.

Results

In the total cohort, 52 patients were identified with thrombocytosis (platelet levels >400 × 10⁹/L) and compared with 582 patients with normal platelet values. The average tumor sizes were 13.1 versus 8.8 cm (p < 0.0001), and their total average bilirubin levels were 0.9 versus 1.5 (p = 0.02), comparing thrombocytosis patients versus normal platelet count HCC patients. These differences were even more pronounced in patients with HCC sizes >5 cm. Thrombocytosis patients were younger and had less cirrhosis, but similar percent with hepatitis B or C or alcohol consumption.

Conclusion

Thrombocytosis in association with HCC occurs in patients with larger tumor sizes and better liver function.     

The safety and efficacy of peginterferon plus ribavirin in hepatitis C patients concomitant with malignancy other than hepatocellular carcinoma: a multicenter study

Purpose

Cancer patients were generally excluded from the therapeutic guidelines of antiviral therapy. We aimed to evaluate the efficacy and safety of antiviral therapy in patients with hepatitis C virus (HCV) infection concomitant with malignancy other than hepatocellular carcinoma (HCC).

Methods

Twenty-five HCV patients with curative malignancy other than HCC (group A) and 75 sex- and age-matched controls (group B) were recruited into a prospective and case–control analysis. All patients received peginterferon-alpha-2a (PegIFN-alpha-2a) and weight-based ribavirin according to the current treatment recommendations. The primary outcome measurement was sustained virological response (SVR). The safety issue between groups was also compared.

Results

There were 22 (88.0 %) patients of group A and 59 (78.7 %) patients of group B who achieved an SVR (p = 0.39). The SVR rate was comparable between groups both in genotype-1 (HCV-1) (81.8 vs. 72.7 %, p = 0.70) and in genotype-2 (HCV-2) (92.9 vs. 83.3 %, p = 0.66) patients. Multivariate logistic regression analysis demonstrated that the achievement of a RVR (viral clearance during first 4 weeks of treatment) was the strongest predictor of an SVR (odds ratio/95 % confidence intervals [OR/CI]: 6.357/1.50 ? 26.99, p = 0.01), followed by lower baseline viral loads (OR/CI: 0.403/0.174 ? 0.936, p = 0.034) and higher dose of ribavirin exposure (OR/CI: 1.287/1.092 ? 1.517, p = 0.003), whilst previous occurrence of cancer was not associated with SVR. Treatment adherence (76.0 vs. 72.0 %, p = 0.70) and the incidences of grade 3 or more adverse events (28.0 vs. 20.0 %, p = 0.40) were comparable between two groups.

Conclusions

Chronic hepatitis C patients with non-HCC malignancies receiving peginterferon/ribavirin combination therapy carried favorable efficacy and safety outcomes.     

Fibrosis and AST to platelet ratio index predict post-operative prognosis for solitary small hepatitis B-related hepatocellular carcinoma

Purpose

Although advanced liver fibrosis is crucial in the development of hepatocellular carcinoma (HCC) for patients with chronic hepatitis B, whether it is associated with the recurrence of HCC after resection remains obscure. This study was aimed to compare the outcomes for patients with minimal or advanced fibrosis in solitary small hepatitis B virus (HBV)-related HCC.

Methods

This study enrolled 76 patients with small (<5 cm) solitary HBV-related HCC who underwent resection. The outcomes of patients with minimal and advanced fibrosis in non-tumor areas were compared. Serum markers were tested to assess the stage of hepatic fibrosis and to predict prognosis.

Results

Fourteen patients with an Ishak fibrosis score of 0 or 1 were defined as having minimal fibrosis; the remaining 62 patients were defined as having advanced fibrosis. During a follow-up period of 77.0 ± 50.7 months, 41 patients died. The overall survival rate was significantly higher (P = 0.018) and recurrence rate was lower (P = 0.018) for patients in the minimal fibrosis group. Aspartate aminotransferase–platelet ratio index (APRI) exhibited the most reliable discriminative ability for predicting advanced fibrosis. The overall survival rate was significantly higher (P = 0.003) and recurrence rate was lower (P = 0.005) for patients with an APRI of 0.47 or less.

Conclusions

For patients with solitary small HBV-related HCC who underwent resection, minimal fibrosis is associated with a lower incidence of recurrence and with better survival. APRI could serve as a reliable marker for assessing hepatic fibrosis and predicting survival.     

Strategies to treat interferon-induced graft dysfunction after living donor liver transplantation for hepatitis C

Purpose

Interferon-induced graft dysfunction (IGD) is a poorly defined, unrecognized, but potentially serious condition for patients receiving antiviral drugs after liver transplantation for hepatitis C.

Methods

We evaluated the characteristics of 80 patients who received pegylated interferon-based antiviral treatment for hepatitis C after living donor liver transplantation (LDLT).

Results

Eight patients experienced IGD either during (n = 6) or after completing (n = 2) antiviral treatment. Pathological diagnosis included acute cellular rejection (ACR, n = 1), plasma cell hepatitis (PCH, n = 2), PCH plus ACR (n = 3), and chronic rejection (CR, n = 2). One patient with CR initially presented with PCH plus ACR and the other presented with ACR; both had apparent cholestasis. The six patients with ACR or PCH without cholestasis were successfully treated by discontinuing antiviral treatment and increasing immunosuppression, including steroids. By contrast, both of the patients with CR and cholestasis experienced graft loss, despite aggressive treatment. Univariate analysis showed that pegylated interferon-α2a-based treatment (75 vs. 26.4 %, p < 0.01) was the only significant factor for IGD, and was associated with decreased 5-year graft survival (93.4 vs. 71.4 %, p = 0.04).

Conclusions

IGD is a serious condition during or even after antiviral treatment for hepatitis C after LDLT. Early recognition, diagnosis, discontinuation of interferon, and introduction of steroid-based treatment may help to save the graft.