Response to pegylated interferon alfa‐2a and ribavirin in chronic hepatitis C genotype 4

The safety and efficacy of pegylated interferon (PEG‐IFN) alfa‐2a and ribavirin were studied among patients treated for genotype 4 chronic hepatitis C. Ninety‐five patients with chronic hepatitis C genotype 4 were treated with PEG‐IFN alfa‐2a (180 µg/week) plus ribavirin (≥11 mg/kg/day) for 48 weeks. The primary end point was sustained virological response, defined as non‐detectable levels of HCV RNA at the end of follow up (week 72). The proportion with sustained virological response was 58/95 = 61.1% (95% CI = 50.5–70.9%). Side effects were generally mild, well managed by dose reductions (in 62% of patients); in only two patients were side effects sufficiently severe to require treatment interruption. Ninety percent of patients adhered to treatment up to week 12, and their sustained virological response rate was higher compared to non‐adherent (65% vs. 22%, respectively, P = 0.012). None of the patients who failed to achieve 1 log reduction of viral load by week 8 (n = 15), or 2 log reduction by week 12 (n = 17), had a sustained virological response. In conclusion, sustained virological response in genotype 4 Egyptian patients treated with PEG‐IFN alfa‐2a and ribavirin was estimated around 60%, intermediate between sustained virological response observed in genotype 1 and genotype 2–3 patients in Western countries. The early virological response (week 4 or week 8) should be investigated as a criterion to decide whether the patient may benefit from a shorter duration of therapy. J. Med. Virol. 81:1576–1583, 2009. © 2009 Wiley‐Liss, Inc.     

Secondary structure of the amino‐terminal region of HCV NS3 and virological response to pegylated interferon plus ribavirin therapy for chronic hepatitis C

The aim of the study was to identify a predictive marker for the virological response in hepatitis C virus 1b (HCV‐1b)‐infected patients treated with pegylated interferon plus ribavirin therapy. A total of 139 patients with chronic hepatitis C who received therapy for 48 weeks were enrolled. The secondary structure of the 120 residues of the amino‐terminal HCV‐1b non‐structural region 3 (NS3) deduced from the amino acid sequence was classified into two major groups: A and B. The association between HCV NS3 protein polymorphism and virological response was analyzed in patients infected with group A (n = 28) and B (n = 40) isolates who had good adherence to both pegylated interferon and ribavirin administration (>95% of the scheduled dosage) for 48 weeks. A sustained virological response (SVR) representing successful HCV eradication occurred in 33 (49%) in the 68 patients. Of the 28 patients infected with the group A isolate, 18 (64%) were SVR, whereas of the 40 patients infected with the group B isolate only 15 (38%) were SVR. The proportion of virological responses differed significantly between the two groups (P < 0.05). These results suggest that polymorphism in the secondary structure of the HCV‐1b NS3 amino‐terminal region influences the virological response to pegylated interferon plus ribavirin therapy, and that virus grouping based on this polymorphism can contribute to prediction of the outcome of this therapy. J. Med. Virol. 82:1364–1370, 2010. © 2010 Wiley‐Liss, Inc.     

Hepatitis C virus serologic and virologic tests and clinical diagnosis of HCV-related liver disease

The use of serological and virological tests has become essential in the management of hepatitis C virus (HCV) infection in order to diagnose infection, guide treatment decisions and assess the virological response to antiviral therapy. Virological tools include serological assays for anti-HCV antibody detection and serological determination of the HCV genotype, and molecular assays that detect and quantify HCV RNA and determine the HCV genotype. Anti-HCV antibody testing and HCV RNA testing are used to diagnose acute and chronic hepatitis C. Only patients with detectable HCV RNA should be considered for pegylated interferon alfa and ribavirin therapy and the HCV genotype should be systematically determined before treatment, as it determines the indication, the duration of treatment, the dose of ribavirin and the virological monitoring procedure. HCV RNA monitoring during therapy is used to tailor treatment duration in HCV genotype 1 infection, and molecular assays are used to assess the end-of-treatment and, most importantly the sustained virological response, i.e. the endpoint of therapy.     

Use of epoetin beta during combination therapy of infection with hepatitis c virus with ribavirin improves a sustained viral response

The aim of the study was to evaluate the effects of epoetin‐beta on anemia and sustained viral response in patients with chronic hepatitis C receiving treatment with pegylated interferon and ribavirin. Forty‐two Caucasian patients with chronic hepatitis C infection, treated with pegylated interferon α‐2a or α‐2b plus ribavirin, who experienced at least a 2 log decline in HCV‐RNA in the first month of therapy and a ≥2.5 g/dl hemoglobin drop from baseline, were recruited. They were divided into two groups: 22 patients received epoetin‐beta 30,000 U administered s.c. q.w. (group A) and 20 patients received a reduced ribavirin dose of 600 mg daily (group B). The end‐of‐treatment response was 95.4% (21/22) in group A and 80% (16/20) (P = 0.2) in group B. Sustained viral response in group A was 81.8% (18/22), statistically higher than in group B (45%, 9/20) (P = 0.03). Mean corpuscular volume of erythrocytes was statistically lower in group A than in group B 4 weeks after starting epoetin‐beta or reduced ribavirin dose (P < 0.001), end‐of‐treatment (P < 0.001) and after 6 months follow‐up (P < 0.001). A negative correlation between the levels of ferritin serum was found in group A at the baseline and mean corpuscular volume value after 1 month of combination antiviral therapy (r = ?0.45; P = 0.35), 4 weeks after starting epoetin‐beta (r = ?0.43; P = 0.04) and after 6 months follow‐up (r = ?0.45; P = 0.03). Administration of epoetin‐beta increases sustained viral response rates among patients developing anemia, because the standard dose of ribavirin is maintained, thereby reducing the side‐effects of antiviral treatment. J. Med. Virol. 82:49–56, 2010. © 2009 Wiley‐Liss, Inc.     

Randomized trial of low‐dose peginterferon α‐2b plus low and escalating doses of ribavirin in older patients with chronic hepatitis C with high viral load genotype 1

Elderly patients with chronic hepatitis C cannot tolerate standard combination therapy of peginterferon and ribavirin, which remains the backbone of therapy in many countries, including Japan. The efficacy and safety of low‐dose peginterferon α‐2b in combination with low and escalating doses of ribavirin in older patients with high viral load genotype 1 were investigated in this randomized controlled trial. Thirty‐two patients (age ≥60 years) were randomized into standard (group 1) or low (group 2) doses of peginterferon α‐2b in combination with low and escalating doses of ribavirin. Patients were evaluated for safety and efficacy of treatment. There was a higher virological response rate in group 1 than in group 2. However, the response in men was higher than in women in the early treatment phase and 24 weeks after treatment (P = 0.008). There was no significant difference between the two groups in the virological response rate in men and women. Completion of therapy was higher in group 2 than in group 1 (31% vs. 13%, P = 0.200). Dose modification of ribavirin was less frequent in group 2 than in group 1 (69% vs. 88%, P = 0.200). These data suggest that combination therapy with low‐dose peginterferon plus low and escalating doses of ribavirin may be safer in older patients than that with standard dose peginterferon, without impairing the treatment response. J. Med. Virol. 87:2082–2089, 2015. © 2015 Wiley Periodicals, Inc.

     

Pharmacokinetics, pharmacodynamics, and hepatitis C viral kinetics during antiviral therapy: the null responder

Our aim was to study the effect of ribavirin on viral kinetics and to study the early patterns of response to antiviral therapy of hepatitis C and their correlation with interferon pharmacokinetics and pharmacodynamics. We conducted a randomized, controlled trial of peginterferon alfa‐2a with or without ribavirin in interferon naïve patients with HCV genotype 1. HCV RNA levels were measured at frequent intervals during treatment together with serum levels of peginterferon alfa‐2a and 2′5′oligoadenylate synthetase (OAS). Of 29 patients treated, 14 had a complete response at day 29 while 15 had a null response (less than 1 log decline in HCV RNA). There were no significant differences between complete and null responders with regard to gender, age, race, body mass index, HCV subtype, baseline HCV RNA levels, serum aminotransferase activities, stage of fibrosis, peak OAS, or interferon levels. Mean serum IFN levels at day 29 and OAS levels at day 3 were no different between complete and null responders (15,525 vs. 30,768 pg/ml and 2,044 vs. 2,323 pM/hr, respectively, P = n.s.). Addition of ribavirin to pegylated IFN did not significantly affect day 29 IFN levels or Day 3 OAS levels. In conclusion, null responders to either peginterferon alone or in combination with ribavirin have little or no decrease in serum HCV RNA early in therapy and rarely go on to achieve sustained virologic response and have no apparent host differences than complete responders, suggesting that interferon resistance in these patients may be virally rather than host‐determined. J. Med. Virol. 78:446–451, 2006. © 2006 Wiley‐Liss, Inc.     

Influence of the HCV subtype on the virological response to pegylated interferon and ribavirin therapy

The hepatitis C virus genotype is considered to be the most important baseline predictor of a sustained virological response in patients with chronic hepatitis C treated with pegylated interferon and ribavirin. The influence of the subtype on the sustained virological response was investigated in patients infected with genotypes 1, 4, 5, or 6. This study was done on 597 patients with chronic hepatitis C who were given pegylated interferon and ribavirin for 48 weeks. The overall rate of sustained virological response in the 597 patients was 37.8%. Univariate analysis indicated that the sustained virological response of patients infected with subtype 1b (39%) tended to be higher than that of patients infected with subtype 1a (30.6%; P = 0.06) and it was similar to those patients infected with subtypes 4a (51.3%; P = 0.12) or 4d (51.7%; P = 0.16). Multivariate analysis indicated that five factors were independently associated with sustained virological response: the age (OR 0.97; 95% CI = 0.95–0.99), absence of cirrhosis (OR: 2.92; 95% CI = 1.7–5.0; P < 0.01), absence of HIV co‐infection (OR: 2.08; 95% CI = 1.2–3.5; P < 0.01), low baseline plasma HCV RNA concentration (OR: 1.74; 95% CI = 1.2–2.6; P < 0.01), and the subtype 1b (OR: 1.61; 95% CI = 1.0–2.5; P = 0.04) or subtypes 4a and 4d (OR: 2.03; 95% CI = 1.1–3.8; P = 0.03). In conclusion, among difficult‐to‐treat genotypes, the subtype 1a is associated with a lower response to anti‐HCV therapy than subtypes 1b, 4a, and 4d. J. Med. Virol. 81:2029–2035, 2009. © 2009 Wiley‐Liss, Inc.     

Do steatosis and steatohepatitis impact on sustained virological response (SVR) rates in patients receiving pegylated interferon and ribavirin for chronic hepatitis C infection?

The impact of steatosis on treatment response in chronic hepatitis C infection is controversial. The aim of this study was to determine whether steatosis ± steatohepatitis on pre‐treatment liver biopsy influenced sustained virological response (HCV RNA negative 6 months after completing therapy) in patients with chronic hepatitis C infection treated with pegylated interferon‐α and ribavirin. One hundred and seventy‐nine patients, median age 46 years (interquartile range 40–52), treated between 2001 and 2005. Histological evidence of steatosis was present in 93 patients (52%) and steatohepatitis in 33 patients (18%), 31 patients (17.3%) were cirrhotic. There were 106 (59%) responders, who were similar to non‐responders in respect to gender, age, and pre‐treatment ALT. On univariate analysis, infection with genotype 2 or 3 was associated with sustained virological response (odds ratio 6.5 (95% CI, 3.3–12.5); P < 0.0001), whereas cirrhosis and patient weight were associated with a reduced response (odds ratios 0.23 (95% CI, 0.11–0.48); P < 0.0001, and 0.97 (95% CI, 0.95–0.99); P < 0.01, respectively); steatohepatitis but not steatosis impacted on the likelihood of achieving sustained virological response (odds ratio 0.37 (95% CI, 0.17–0.77); P = 0.009, and P = 0.18, respectively). Multivariate analysis revealed that infection with genotype 1 or 4 (odds ratio 0.09 (95% CI, 0.03–0.32); P < 0.001) and pre‐treatment weight (odds ratio 0.94 (95% CI, 0.90–0.98); P = 0.002) were the only variables associated independently with sustained virological response. In chronic hepatitis C infection, although steatosis was associated with steatohepatitis, neither was shown to affect sustained virological response, which was influenced by genotype, patient weight and the presence of cirrhosis. J. Med. Virol. 82:958–964, 2010. © 2010 Wiley‐Liss, Inc.     

Impact of IL28B gene polymorphisms rs8099917 and rs12980275 on response to pegylated interferon-α/ribavirin therapy in chronic hepatitis C genotype 4 patients

Host genetic factors may predict the outcome and treatment response in hepatitis C virus (HCV) infection. One of these factors is the single nucleotide polymorphisms of the interleukin 28B (IL28B) gene. We sought to evaluate the outcome of pegylated interferon and ribavirin therapy in association with IL-28B rs8099917 and rs12980275 in patients infected with HCV genotype 4. A total of 180 patients with chronic hepatitis C were selected from Egyptians who have received combined therapy with pegylated interferon and ribavirin for 6 months and their response was evaluated after follow-up at 0, 6, 12, 24 and 48 weeks from the beginning of the therapy. Blood samples were collected from responders and non-responders. Genomic DNA was extracted from whole blood and genotyping was carried out by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). Our results showed that TT genotype of rs8099917 was associated with higher sustained viral response (SVR) rates and G allele represented a risk factor for failure of response (OR = 3.7, CI = 1.8:7.64) while rs12980275 was not significantly associated with SVR in genotype 4 Egyptian patients. The determination of IL-28B SNPs may be useful in enhancing correct prediction of SVR achievement in treating this group of genotype 4 patients.     

Add‐on therapy of pitavastatin and eicosapentaenoic acid improves outcome of peginterferon plus ribavirin treatment for chronic hepatitis C

Despite the use of pegylated‐interferon (peg‐IFN) plus ribavirin combination therapy, many patients infected with hepatitis C virus (HCV)‐1b remain HCV‐positive. To determine whether addition of pitavastatin and eicosapentaenoic acid (EPA) is beneficial, the “add‐on” therapy option (add‐on group) was compared retrospectively with unmodified peg‐IFN/ribavirin therapy (standard group). Association of host‐ or virus‐related factors with sustained virological response was assessed. In HCV replicon cells, the effects of pitavastatin and/or EPA on HCV replication and expression of innate‐immunity‐ and lipid‐metabolism‐associated genes were investigated. In patients infected with HCV‐1b, sustained virological response rates were significantly higher in the add‐on than standard group. In both groups, sustained virological response rates were significantly higher in patients with genotype TT of IL‐28B (rs8099917) than in those with non‐TT genotype. Among the patients with non‐TT genotype, sustained virological response rates were markedly higher in the add‐on than standard group. By multivariate analysis, genome variation of IL28B but not add‐on therapy remained as a predictive factor of sustained virological response. In replicon cells, pitavastatin and EPA suppressed HCV replication. Activation of innate immunity was obvious in pitavastatin‐treated cells and EPA suppressed the expression of sterol regulatory element binding protein‐1c and low‐density lipoprotein receptor. Addition of pitavastatin and EPA to peg‐IFN/ribavirin treatment improved sustained virological response in patients infected with HCV‐1b. Genotype variation of IL‐28B is a strong predictive factor in add‐on therapy. J. Med. Virol. 85:250–260, 2013. © 2012 Wiley Periodicals, Inc.     

Early anemia and rapid virological response improve the predictive efficiency of IL28B-genotype for treatment outcome to antiviral combination therapy in patients infected with chronic HCV genotype 1

IL28B genotypes and virological response within 4 weeks are predictors of sustained virological response in patients infected with chronic hepatitis C virus (HCV) genotype 1 treated with antiviral dual combination therapy. The predictive value of “early” anemia (within 4 weeks) alone or in combination with the two other predictors has not been studied yet. A total of 305 pegylated interferon‐α and ribavirin‐treated patients with HCV genotype 1 were included in this study. Hemoglobin values at week 0, 4, 8, and 12 as well as the predictive efficiency of early anemia (hemoglobin value below the gender‐specific lower limit: female < 11.5; male < 13.5 g/dl) during therapy were assessed with IL28B genotypes and rapid virological response. Forty‐eight percent of treated patients developed early anemia. In both females and males (64%), a decrease of hemoglobin concentration of 3 g/dl (female: 14.7 ± 1.1 to 11.4 ± 1.3; male: 15.2 ± 1.2 to 12.2 ± 1.5) significantly correlated with sustained virological response. 64% of IL28B‐CC patients showed a sustained virological response. Seventy‐eight percent of patients with rapid virological response definitively eliminated the virus. Early anemia (81:48:41%) and rapid virological response (83:91:92%) increased the predictive efficiency of IL28B rs12979860 genotype distribution (CC:CT:TT). IL28B‐CC and early anemia as well as IL28B‐CC and rapid virological response had an Odds ratio of 42.4 or 75 to achieve a sustained virological response compared to TT without early anemia or rapid virological response. This finding may help to early identify responders to standard PEG‐IFN‐α and ribavirin treatment even within those with unfavorable IL28B genotype. J. Med. Virol. 84: 1208–1216, 2012. © 2012 Wiley Periodicals, Inc.     

Association of IL28B genotype and viral response of hepatitis C virus genotype 2 to interferon plus ribavirin combination therapy

The impacts of IL28B genotype to treatment response of hepatitis C virus (HCV) genotype 2 are still not clear. A total of 381 consecutive Japanese patients infected with HCV genotype 2, who could complete combination therapy with interferon (IFN) plus ribavirin for 24 weeks, were evaluated to investigate pretreatment predictors. Patients, who could not achieve sustained virological response at the first course of 24‐week IFN plus ribavirin, were recruited into the study protocol of total 48‐week IFN plus ribavirin. In 24‐week regimen, rates of sustained virological response and rapid virological response were 82% and 50%, respectively. There were no significant differences in rates of sustained virological response and rapid virological response, according to IL28B genotype. Multivariate analysis identified younger age, higher level of albumin, absence of past history of IFN, and lower level of viremia as significant determinants of sustained virological response. As significant or marginal significant determinants of non‐sustained virological response regardless of rapid virological response, multivariate analysis identified IL28B rs8099917 genotype TG + GG and lower level of albumin. In 48‐week regimen to 10 patients of non‐sustained virological response at the first course of 24‐week regimen, sustained virological response rates were 70%. All of six patients, with IL28B TT and relapse at the first course of 24‐week regimen, could achieve sustained virological response, but two patients with IL28B TG could not achieve sustained virological response. In conclusion, the present results suggest that IL28B genotype might partly affect viral response of HCV genotype 2 to combination therapy. J. Med. Virol. 84:1593–1599, 2012. © 2012 Wiley Periodicals, Inc.     

Association of NKG2A with treatment for chronic hepatitis C virus infection

Natural killer (NK) cells are critical to the immune response to viral infections. Their functions are controlled by receptors for major histocompatibility complex (MHC) class I, including NKG2A and killer‐cell immunoglobulin‐like receptors (KIR). In order to evaluate the role of MHC class I receptors in the immune response to hepatitis C virus infection we have studied patients with chronic HCV infection by multi‐parameter flow cytometry directly ex vivo. This has permitted evaluation of combinatorial expression of activating and inhibitory receptors on single NK cells. Individuals with chronic HCV infection had fewer CD56^dim NK cells than healthy controls (4·9 ± 3·4% versus 9·0 ± 5·9%, P < 0·05). Expression levels of the inhibitory receptor NKG2A was up‐regulated on NK cells from individuals with chronic hepatitis C virus (HCV) (NKG2A mean fluorescence intensity 5692 ± 2032 versus 4525 ± 1646, P < 0·05). Twelve individuals were treated with pegylated interferon and ribavirin. This resulted in a down‐regulation of NKG2A expression on CD56^dim NK cells. Individuals with a sustained virological response (SVR) had greater numbers of NKG2A‐positive, KIR‐negative NK cells than those without SVR (27·6 ± 9·6% NK cells versus 17·6 ± 5·7, P < 0·02). Our data show that NKG2A expression is dysregulated in chronic HCV infection and that NKG2A‐positive NK cells are associated with a beneficial response to pegylated interferon and ribavirin therapy.     

Peginterferon-α-2a (40kD) and Ribavirin in Patients with Chronic Hepatitis C

Background and aims: Addition of a 40kD polyethylene glycol moiety to interferon-α-2a [peginterferon-α-2a (40kD)] improves pharmacokinetic properties over those of standard interferon. We conducted a phase II study to assess the safety and initial efficacy of peginterferon-α-2a (40kD) plus ribavirin combination therapy in patients with chronic hepatitis C (CHC). Methods: Twenty patients received open-label 180μg peginterferon-α-2a (40kD) subcutaneously once weekly and oral ribavirin 1000 or 1200mg daily for patients weighing <75 or ≥75kg, respectively, for a period of 24 weeks. Patients with hepatitis C virus (HCV) genotype 1 and a virological response at week 24 received study drugs for an additional 24 weeks. Results: A sustained virological response, defined as undetectable HCV RNA 24 (i.e. <100 copies/ml) weeks after completing the therapy, was achieved in 50% of patients in an intent-to-treat analysis (6/16 genotype 1 and 4/4 genotype non-1). Adverse events were similar to those reported with unmodified interferon plus ribavirin combination therapy. Anaemia led to ribavirin dose reduction in five patients. Neutropenia led to dose reduction in three patients treated with peginterferon-α-2a (40kD). Conclusions: The addition of ribavirin to a once-weekly peginterferon-α-2a (40kD) regimen should be investigated in larger clinical trials.     

Predictors of sustained virological response in Greek and Egyptian patients with hepatitis C genotype 4: Does ethnicity matter?

Hepatitis C virus genotype 4 (HCV‐4) is spreading beyond Africa and the Middle East but data regarding treatment with pegylated interferon alpha and ribavirin of European populations infected with HCV‐4 remains limited. Interestingly, European (vs. Egyptian) origin has been associated with lower sustained virological response rates. Hence the aim of this study was to investigate the treatment outcomes of Greek (vs. Egyptian), treatment‐naïve patients infected with HCV‐4 (subtype a) and to identify factors influencing response rates. One hundred seventy‐seven consecutive patients (mean age: 44.6 ± 10.2, males: 143/177; 80.8%, Egyptians: 76/177; 42.9%) treated over a 7‐year period at the Hepatology clinics of three tertiary care hospitals in Greece were retrospectively evaluated. Overall, sustained virological response was achieved in 75/177 (42.4%) of the cohort without a significant difference between the two ethnic groups [Greek: 44/101 (43.6%); Egyptian 31/76 (40.8%), P = 0.7598]. In multivariate analysis, it was found that ethnicity was not associated with an impaired response but age ≥45 years [odds ratio (OR): 0.4225, 95% confidence interval (CI): 0.2135–0.8133; P = 0.0134], diabetes (OR: 0.2346, 95% CI: 0.0816–0.0674; P = 0.0071), advanced liver fibrosis (OR: 0.3964, 95% CI: 0.1933–0.8133; P = 0.0116), and treatment suspension (OR: 0.1738, 95% CI: 0.0482–0.6262; P = 0.0075) showed an independent negative association with response to antiviral treatment. In contrast to previous European data suggesting Egyptian ethnicity to be a positive predictor for a sustained virological response, there was no influence of Greek versus Egyptian ethnicity on treatment outcomes. Higher age, advanced liver fibrosis, and diabetes have been shown to reduce significantly response rates in patients infected with HCV‐4. J. Med. Virol. 84: 1217–1223, 2012. © 2012 Wiley Periodicals, Inc.     

Durability of a sustained virological response in chronic hepatitis C patients treated with pegylated interferon alfa and ribavirin

Background/Aims

The reappearance rates of hepatitis C virus (HCV) RNA after a sustained virological response (SVR) have been reported to be 1-2%. We investigated the reappearance rate of HCV RNA after SVR in chronic hepatitis C (CHC) patients treated with pegylated interferon (PEG-IFN) and ribavirin.

Methods

In total, 292 CHC patients who achieved an SVR after PEG-IFN and ribavirin treatment were included. They were treated with subcutaneous injections of either PEG-IFN-α 2a or 2b plus ribavirin orally. Liver function tests and qualitative HCV RNA assays were performed every 6 months during the follow-up period after an SVR.

Results

Among the 292 patients, 224 (genotype 1, 92; genotype non-1, 132) were followed up for more than 6 months after SVR. These 224 patients were aged 48.1±11.5 years (mean±SD), and 129 of them were male. The median follow-up duration was 18 months (range 6-60 months). The reappearance rate of HCV RNA during follow-up was 0%. Two patients who achieved an SVR developed hepatocellular carcinoma during the follow-up period.

Conclusions

An SVR was maintained in all CHC patients treated with PEG-IFN plus ribavirin during a median follow-up of 18 months. However, a screening test for hepatocellular carcinoma is needed for patients with an SVR.     

Management of viral hepatitis in liver transplant recipients

Recurrence of viral hepatitis after liver transplantation (LT) can progress to graft failure and lead to a decrease in long-term survival. Recently, there have been remarkable improvement in the treatment of chronic hepatitis B (CHB) using potent antiviral agents. Combination of hepatitis B immunoglobulin and potent antiviral therapy has brought marked advances in the management of CHB for liver transplant recipients. Post-transplant antiviral therapy for hepatitis C virus infection is generally reserved for patients showing progressive disease. Acheiving a sustained virological response in patients with LT greatly ameliorates graft and overall survival, however this only occurs in 30% of transplant recipient using pegylated interferon and ribavirin (RBV). Direct acting antivirals such as protease inhibitors, polymerase or other non-structural proteins inhibitors are anticipated to establish the new standard of care for transplant recipients. In liver transplant recipients, hepatitis E virus infection is an uncommon disease. However, it can lead to chronic hepatitis and cirrhosis and may require retransplantation. Recently, 3-month course of RBV monotherapy has been reported as an effective treatment. This review focuses on the recent management and therapeutic approaches of viral hepatitis in liver transplant recipient.     

Oxidative stress and antioxidant defense in patients with chronic hepatitis C patients before and after pegylated interferon alfa-2b plus ribavirin therapy

Background  

Oxidative stress could play a role in pathogenesis of hepatitis C virus (HCV) infection. The aim of our study is to determine oxidant/antioxidant status of patients with chronic hepatitis C (CHC), and the effect of pegylated interferon alfa-2b plus ribavirin combination therapy on oxidative stress.     

Involvement of dendritic cell frequency and function in virological relapse in pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C patients

A combination of pegylated interferon alpha (PEG-IFNalpha) and ribavirin has been used widely. Enhancement of immune response against hepatitis C virus (HCV) is known to be involved in the efficacy of the combination therapy. The aim of the study was to elucidate whether the frequency or function of immunocompetent blood cells is related to the outcome of the therapy. Twenty-five chronic hepatitis C patients with high viral load of HCV genotype 1 who underwent 48 weeks of PEG-IFNalpha2b and ribavirin therapy were examined. During the treatment, frequencies of dendritic cell subsets, helper T cell subsets, and NK cells were phenotypically determined. In some patients, the ability of dendritic cells to stimulate allogeneic CD4(+)T cells was examined at the end and after the therapy. Among the 25 patients, 11 showed a sustained virological response, 11 a transient response, and 3 no response. In comparison with sustained virological responders, non-sustained virological responders showed impaired dendritic cell function at the end and after the treatment. The transient responders showed a decline of plasmacytoid dendritic cell frequency from Weeks 1-12 and impaired dendritic cell function as well. Even in patients who attained negative serum HCV RNA at Week 12, the transient responders showed a significant decrease of plasmacytoid dendritic cell frequency and impaired dendritic cell function. In conclusion, in PEG-IFNalpha and ribavirin combination therapy for chronic hepatitis C patients, the early-phase plasmacytoid dendritic cell frequency and/or end-of-treatment dendritic cell function are related to the virological outcome of the therapy.     

Modifications of haematological series in patients co-infected with human immunodeficiency virus and hepatitis C virus during treatment with interferon and ribavirin: differences between pegylated and standard interferon

Therapy with interferon and ribavirin for hepatitis C virus (HCV) infection induces a decrease in several haematological population counts. It is unclear whether haematological toxicity is more severe in patients co-infected with HCV and human immunodeficiency virus (HIV). This study analysed the evolution of haematological population counts during and after interferon and ribavirin therapy for chronic HCV infection. Eleven patients co-infected with HIV and HCV and treated with pegylated interferon plus ribavirin, and ten treated with standard interferon plus ribavirin, were analysed. With reference to baseline values, neutrophil counts decreased by an average of 45% (range 18-67%), total lymphocytes by 50% (16-63%), CD4 lymphocytes by 54% (16-61%), haemoglobin by 9% (5-16%) and platelets by 31% (16-45%). The nadir of the decrease was reached in the first weeks of therapy and was maintained while patients were receiving treatment. The reduction in all series was higher with pegylated interferon. Patients recovered their baseline counts after finishing the treatment. No cases of haemorrhage or outstanding infection were detected during follow-up.