Received Interferon Therapy Research Articles

GB Virus Type C NS5A Sequence Polymorphisms: Association with Interferon Susceptibility and Inhibition of PKR-Mediated eIF2α Phosphorylation

GB virus type C (GBV-C) causes persistent infection in humans, although the mechanism by which the virus avoids clearance by the host is unknown. To determine if amino acid polymorphisms in the GB virus type C (GBV-C) NS5A and E2 proteins alter response to interferon (IFN) therapy, we studied the sequence of GBVC NS5A and E2 obtained from people receiving IFN therapy. In addition, we expressed recombinant GBVC NS5A protein to determine if it interferes with RNA-activated protein kinase (PKR) function in vitro. GBVC NS5A amplified from a person whose virus was cleared by IFN therapy (IFN sensitive) demonstrated unique amino acid changes occurring in the region that aligns with the hepatitis C virus (HCV) IFN sensitivity-determining region (ISDR) compared with NS5A sequences from individuals who did not clear GBV-C (IFN resistant). There were no differences in the E2 sequences obtained from IFN-sensitive and IFN-resistant isolates. Using a yeast genetic system, IFN-resistant NS5A inhibited PKR-mediated phosphorylation of eukaryotic initiation factor 2alpha (eIF2alpha) in yeast, whereas IFN-sensitive NS5A did not inhibit PKR function. GBV-C NS5A amino acid polymorphisms appear to be involved in response to IFN therapy, and IFN-resistant GBV-C NS5A inhibited PKR-mediated eIF2alpha phosphorylation in a yeast genetic system, suggesting a mechanism by which GBV-C may evade clearance by naturally occurring host antiviral responses.

Susceptibility to Thyroid Disorders in Hepatitis C

Autoimmune thyroid disorders (AITDs) are reported, especially during interferon treatment, in chronic HCV infection, in which non-organ-specific autoantibodies (NOSAs) are common. We wondered whether seropositivity for NOSA is associated with susceptibility to AITDs. We evaluated thyroid function and antithyroglobulin and antithyroperoxidase antibodies in 348 Italian patients with chronic hepatitis C (34% NOSA-positive), 196 patients (33% NOSA-positive) of whom received interferon treatment. At baseline, thyroid disorders were significantly more frequent in liver/kidney microsomal antibody type 1 (LKM1)-positive patients (29% vs 9%, P < .005). Similarly, on interferon therapy de novo autoimmune thyroid markers and/or symptomatic thyroid disorders appeared more often in LKM1-positive patients (50% vs 3%, P < .0001). Both female sex and LKM1 positivity were predictors of AITD, but only the latter remained significant after logistic regression analysis. Cross-reactivity to all 7 linear epitopes encoding homologous amino acid sequences shared by the HCV polyprotein, CYP2D6 (the LKM1 autoantigen), and thyroperoxidase was detected in 86% LKM1-positive HCV patients with clinical thyroid disorders, but in none of the LKM1-positive or negative HCV patients without thyroid disease, and none of an HCV-negative control group comprising subjects with LKM1-positive autoimmune hepatitis or AITD without liver disease ( P < .0001). Patients receiving interferon therapy for hepatitis C seropositive for LKM1 are susceptible to develop AITDs, in association with treatment. Molecular mimicry and epitope spreading are potential pathogenic mechanisms.

Interferon therapy for aged patients with chronic hepatitis C: improved survival in patients exhibiting a biochemical response

In Japan, generally, patients with chronic hepatitis C are aged. The aim of this study was to investigate the effect of interferon (IFN) therapy on the mortality of chronic hepatitis C patients over age 60. Seven-hundred and seven patients with histologically proven chronic hepatitis C were enrolled in this study; 649 received IFN therapy (IFN group) and 58 did not (control group). The standardized mortality ratio (SMR) and Cox proportional hazard regression analysis were used to evaluate the effect of IFN on the survival of the patients. Mean follow-up periods in the IFN and control groups were 5.7 and 6.7 years, respectively. During follow-up, 13 patients in the control group died (7 of liver-related diseases) and 42 in the IFN group died (29 of liver-related diseases). The SMRs of the control and IFN groups were 1.40 (95% confidence interval [CI], 0.76-2.45) and 0.73 (95% CI, 0.52-0.98) for overall death, and 10.70 (95% CI, 4.29-22.05) and 5.05 (95% CI, 3.38-7.26) for liver-related death, respectively. Sustained and transient biochemical responders in the IFN group (SMR, 0.53; 95% CI, 0.01-2.97 and SMR, 3.25; 95% CI, 0.87-8.32, respectively) showed lower liver-related mortality compared with the control group. In patients with sustained virological response, liver-related mortality was also very low (SMR, 0.65; 95% CI, 0.01-3.61). The risk for liver-related death of sustained and transient biochemical responders was also low compared with that of the control group (adjusted risk ratios 0.10 [95% CI, 0.01-0.95] and 0.50 [95% CI, 0.11-2.21], respectively). These results suggest that IFN treatment could reduce liver-related mortality in chronic hepatitis C patients over age 60, notably in patients showing a biochemical response and in those showing a sustained virological response.

PSORIASIS SHOULD NOT BE A CONTRAINDICATION TO INTERFERON THERAPY IN PATIENTS WITH CHRONIC HEPATITIS C

Purpose: The purpose of the study was to determine the safety and efficacy of interferon therapy on psoriasis in hepatitis C patients treated with interferon. Psoriasis, as an autoimmune condition, has been considered a contraindication to interferon therapy in chronic hepatitis C. Methods: A retrospective review of 100 charts of patients with Hepatitis C at an outpatient tertiary liver clinic was performed. 6 patients were identified who had psoriasis and received interferon therapy. A systematic chart review was performed; age, sex, and biopsy results were obtained. The type and duration of therapy was also reviewed including the response to treatment and psoriatic flares during treatment. Results: Of the 6 patients, 4 were male and 2 were females. The majority of patients had advanced liver disease, either bridging fibrosis (2) or cirrhosis (3). Treatment duration ranged from 24 to 96 weeks with either conventional interferon 3/week or pegylated interferon, or both. 3/6 patients had a sustained virologic response (SVR) with therapy. While 2 patients had a worsening of their psoriasis, it had little impact on their treatment since they were able to complete a full course of treatment. One patient who had a SVR has actually had complete resolution of his psoriasis while on treatment that has still not reappeared 6 months after stopping treatment. Conclusions: Interferon therapy for Hepatitis C patients did not have a clinically significant impact on their psoriasis. Patients were able to tolerate the standard duration of therapy and obtain a SVR in 33% of those treated. Patients with psoriasis and Hepatitis C, especially those with advanced his-tologic liver disease, should be considered for interferon therapy in order to prevent progression to cirrhosis and its deadly consequences. Psoriasis should not be considered a contraindication to interferon therapy in patients with hepatitis C.Table 1

Interferon treatment improves survival in chronic hepatitis C patients showing biochemical as well as virological responses by preventing liver-related death.

Interferon therapy for chronic hepatitis C reduces the risk of hepatocellular carcinoma, especially among virological and biochemical responders. However, little is known about the effect of interferon therapy on mortality. We studied the long-term effect of interferon therapy on mortality in patients with chronic hepatitis C. For this retrospective cohort study, 2954 patients with chronic hepatitis C were recruited, of whom 2698 received interferon therapy and 256 did not. The effect of interferon therapy on survival was assessed by standardized mortality ratio (SMR) based on published mortality data for the general Japanese population and by risk ratio calculated by proportional hazard regression. Over 6.0 +/- 2.2 years follow-up, death from liver-related diseases was observed in 69 (68%) of 101 deaths among interferon-treated patients and in 42 (81%) of 52 deaths among untreated patients. Compared with the general population, overall mortality was high among untreated patients (SMR: 2.7; 95% CI: 2.0-3.6) but not among interferon-treated patients (SMR: 0.9; 95% CI: 0.7-1.1). Liver-related mortality was extremely high among untreated patients (SMR: 22.2; 95% CI: 16.0-30.0) and less among interferon-treated patients (SMR: 5.5; 95% CI: 4.3-6.9). The risk of death from all causes was lower for interferon-treated than untreated patients (risk ratio: 0.47; 95% CI: 0.261-0.836; P = 0.01). The risk of death from liver-related diseases was significantly lower for sustained virological responders (risk ratio: 0.04; 95% CI: 0.005-0.301; P = 0.002) compared with untreated patients, but not for nonsustained virological responders. Sustained biochemical responders (risk ratio: 0.03; 95% CI: 0.004-0.230; P < 0.001) and transient biochemical responders (risk ratio: 0.18; 95% CI: 0.063-0.532; P = 0.002) showed a significantly reduced risk of death from liver-related death, whereas biochemical nonresponders did not. Hence interferon treatment improved survival in chronic hepatitis C patients showing a biochemical as well as a virological response by preventing liver-related deaths.

Analysis of approach to therapy for chronic liver disease in an HCV hyperendemic area of Japan.

In 1990, we conducted an epidemiological study of 509 residents in a hepatitis C virus (HCV) hyperendemic area in Japan. The purpose of the present study was to examine the approach to therapy for liver diseases accompanied by HCV and hepatitis B virus (HBV) infections among the surviving residents in the town after 12 years. Fifty-three with HCV or HBV infections among 385 people who resided in the town were clearly analyzed in 2002. The number of persons diagnosed with the liver diseases was as follows: HCV-related asymptomatic healthy carrier (1), past history of HCV infection (15), chronic hepatitis C (22), HCV-related liver cirrhosis (6), HCV-related hepatocellular carcinoma (HCC) (5), and HBV-related asymptomatic healthy carrier (4). HCC was detected in residents who did not have periodic regular hospital checkups. Only 19% of the 53 inhabitants consulted liver medical specialists, and 75% (3/4) who received interferon therapy received treatment from a liver medical specialist. It is necessary to provide continuous medical treatment to HCV carriers, minimizing difference in treatment quality in different medical institution. An efficient HCV medical checkup and a program of subsequence health management are important problems to be solved for improved health care.

Non-organ-specific autoantibodies in children with chronic hepatitis C: clinical significance and impact on interferon treatment.

We evaluated the prevalence and clinical significance of non-organ-specific autoantibodies (NOSAs) in 47 hepatitis C virus (HCV)-positive children with abnormal alanine transaminase levels and analyzed the association between NOSAs and virus level, genotype, human leukocyte antigen status, and interferon (IFN) response. Forty-two hepatitis B virus (HBV)-positive children and 25 age- and sex-matched healthy children served as control subjects. NOSAs were found in 34% of the HCV-positive children, 12% of the HBV-positive controls, and none of the healthy control subjects. Liver-kidney microsomal antibody type 1 (LKM1) was detected in 11% of the HCV-positive children but in none of the controls. The HCV load was significantly higher in NOSA-negative than in NOSA-positive children. HCV genotype distribution and human leukocyte antigen alleles were similar, irrespective of NOSA status. Long-term response to IFN therapy was achieved by 18% of the NOSA-positive and 55% of the NOSA-negative subjects. Two LKM1-positive children developed acute, self-limited hepatocellular necrosis while receiving IFN therapy. NOSAs are frequently present in children with hepatitis C, who are less likely to benefit from IFN therapy.

MARKEDLY ELEVATED ALPHA FETO PROTEIN LEVELS WITHOUT HEPATOCELLULAR CARCINOMA

Although low-grade elevations of AFP are associated with benign liver disease including acute and chronic hepatitis and cirrhosis, AFP values above 400 ng/mL are often used as a surrogate marker for HCC. The case of a 45-year-old Caucasian woman, who while receiving interferon therapy for HCV, was found to have a marked elevation of her serum AFP level, is reported. Her baseline AFP of 7.0 ng/mL increased progressively over three months to a peak value of 734.5 ng/mL. Initial imaging was normal. Three months later, a CT scan detected two focal lesions in the dome of the liver. A post-ethiodol hepatic CT scan revealed persistent uptake at this site but fluoroscopy-guided liver biopsy failed to identify a HCC. Normalization of her AFP level occurred while she continued to receive IFN for HCV. The patient has remained stable over more than three years of follow-up. While others have reported AFP elevations in cirrhotics with HCV without evidence of HCC, to our knowledge there are no reports of an individual receiving IFN treatment for hepatitis C with AFP levels that rose over several months in the absence of a HCC.

Comparison of three commercially available assays for HCV RNA using the international unit standard: implications for management of patients with chronic hepatitis C virus infection in clinical practice

Objectives The present study was performed to evaluate the impact of the international unit standard for measuring HCV RNA in the management of patients with chronic hepatitis C virus (HCV) infection. Methods The three assays used were Amplicor Monitor PCR, the National Genetics Institute PCR assay, and branched chain DNA. HCV RNA was measured at four time points (baseline, 3 months after the start of therapy, at the end of treatment, and 6 months after discontinuation of therapy) in 106 consecutive patients who received interferon and ribavirin for chronic HCV. Results The mean age of the patients was 44 yr. Of the patients, 62% were male, 24% were African American, 38% had bridging fibrosis or cirrhosis, and 75% were HCV genotype 1. Of the 424 samples analyzed, 82–89% of values were within 1 log unit and 85–92% were within 2 log units by the various assays. This variability was not dependent upon HCV genotype. HCV RNA was undetectable in 1.4–6.8% of samples when virus was detected by another assay. The mean HCV RNA in these discordant samples was 1.47–6.33 log IU/ml (30–2,100,000 IU/ml). Conclusions These data demonstrate that approximately 90% of serum values for HCV RNA were within 1 log unit by the international unit standard regardless of which virological assay was used. However, false positive and false negative results as well as variations in the HCV RNA level of more than 1 to 2 log units can occur with any of the assays, and these results may have an impact upon the management of patients receiving interferon therapy. It is therefore unwise in clinical practice to base important treatment decisions upon a single HCV RNA determination.

EFFECT OF CHRONIC HEPATITIS C INFECTION ON LYMPHOCYTE SUBSETS IN RENAL TRANSPLANT PATIENTS

Chronic hepatitis C (HCV) infection is prevalent in renal allograft recipients. Consequently, this group is more likely to develop liver complications and have poorer graft outcome. The interaction between viral and host factors under immunosuppressive therapy is important in highlighting the response to HCV infection after renal transplantation. The aim of this study was to assess changes that occur in the lymphocyte subsets of HCV‐infected kidney recipients, and to determine how these relate to allograft rejection. We investigated 50 patients (33 males and 17 females; mean age 32.0±9.9years; mean time since transplantation: 27.6±26.5months) who were receiving standard immunosuppressive therapy. Data concerning acute or chronic allograft rejection were retrieved from the patients' records. Lymphocyte subsets (CD4, CD8, CD3, CD19, CD16–56), serum albumin levels, and anti‐HCV positivity were evaluated after renal transplantation, and findings in the HCV‐positive and ‐negative groups were compared. Seven of the 50 patients had HCV infection. Anti‐HCV positivity was detected before transplantation in three cases, and these patients received interferon therapy before transplantation. Four patients were found to be HCV positive after transplantation. The anti‐HCV (+) patients had significantly lower serum albumin (P&lt;0.02), lower CD4/CD8 (P&lt;0.02) ratios, and a lower percentage of CD 19 (P&lt;0.001) and a higher percentage of CD8 (P&lt;0.01) cells. Chronic allograft rejection was observed in 71.4% of the HCV‐positive patients (P&lt;0.04), whereas no acute rejection was detected in this group. The findings indicate that HCV infection may alter the immune response in renal transplant recipients, and that the immunogenic potential of the virus may be higher in this patient group because of low serum albumin levels. It appears that this immunomodulatory action and low albumin levels may increase the risk of chronic rejection for HCV‐infected kidney recipients.

Ig M class anticardiolipin antibody and anti‐Ro/SS‐A positivity in urticarial vasculitis associated with hepatitis C virus infection

The association between hepatitis C virus (HCV) infection, cryoglobulinemia and urticarial vasculitis is well documented. However, urticarial vasculitis is extremely rare in HCV infection when not complicated by cryoglobulinemia. Here we describe a patient with urticarial vasculitis who had previously received interferon therapy for HCV infection. This HCV‐infected patient with urticarial vasculitis was found to be negative for cryoglobulinemia but positive for anticardiolipin and anti‐SS‐A/Ro antibodies. The association between HCV infection, urticarial vasculitis, interferon therapy and anticardiolipin antibodies are discussed.

Effect of combination therapy (ribavirin and interferon) in HCV-related glomerulopathy.

Hepatitis C virus (HCV) is a major cause of acute and chronic hepatitis throughout the world. Several extrahepatic manifestations, including glomerulonephritis, have been reported to be associated with this type of infection. Cryoglobulinaemic and non-cryoglobulinaemic membranoproliferative glomerulonephritis (MPGN) and membranous nephropathy (MN) are the commonest lesions associated with HCV. Results of treatment of these patients with interferon therapy have been disappointing, since relapse of the viraemia and subsequent relapse of the renal disease are major problems. Combination of interferon with ribavirin in patients with chronic liver disease has been shown to increase the rate of sustained response. In this work, 20 patients with HCV-associated glomerulopathy were subjected to an in-depth evaluation of their kidney lesions and HCV involvement. Laboratory, histopathological, immunohistochemical, and electron-microscopy techniques were used. The patients received interferon therapy for 12 months; in interferon-resistant subjects, interferon was combined with ribavirin. MPGN was the commonest kidney lesion, being reported in 85% of these cases, followed by MN and mesangioproliferative glomerulonephritis (10 and 5% respectively). Mixed cryoglobulinaemia was encountered in 60% of the cases. Twelve months' anti-viral treatment resulted in aviraemia in 25% of cases, while liver enzymes were normalized in 75%, 24-h proteinuria significantly decreased (from median 4 g to 1.10 g, P=0.001), serum albumin increased (from median 2.50 to 3.55 g/dl, P=0.012), lower viral titres (from median 1.15 to 0.53 mega-Eq/ml, P=0.049), and C3 and C4 concentrations returned to normal. Basal serum creatinine and viral titres were important determinants of response to treatment. This study supports the relationship between HCV and glomerulonephritis, especially MPGN, and the use of a combination of interferon and ribavirin in the treatment of selected cases of HCV-related glomerulopathy.

Clinical significance of the changes of platelet counts and serum thrombopoietin levels in chronic hepatitis C patients treated with different doses of consensus interferon

Thrombocytopenia is commonly seen in patients with cirrhosis. Both splenomegaly and inadequate thrombopoietin (TPO) production by the cirrhotic liver are responsible for thrombocytopenia. In addition, thrombocytopenia is frequently observed in chronic hepatitis patients who received interferon therapy, and may even lead to the discontinuation of treatment. The aim of this study is to evaluate the clinical significance of the changes of platelet counts and serum TPO levels in chronic hepatitis C patients treated with different doses of consensus interferon (CIFN). Data from 75 chronic hepatitis C patients who received subcutaneous injection of either CIFN 9 (25 patients) or 3 μg (26 patients) or placebo (24 patients), three times a week for 24 weeks, were analyzed from a randomized controlled study. All patients received a 24-week observation period after the end of the treatment. The results showed a significantly higher degree of decrease in platelet counts and elevated serum TPO in patients receiving CIFN 9 or 3 μg as compared with placebo at week 12 and week 24 of treatment, respectively. These changes were more obvious in patients receiving CIFN 9 μg than in patients receiving CIFN 3 μg. However, both the decrease of platelet counts and elevated serum TPO levels returned to the baseline values after stopping CIFN therapy. Lower hepatic fibrosis score, lower pretreatment serum HCV RNA level, genotype non-1b infection and patients with sustained response to CIFN were manifested with higher degree of serum TPO elevation in response to the CIFN-induced thrombocytopenia. Multivariate logistic regression analysis showed that an age of less than 45 years and a serum TPO level elevation greater than 50% of baseline level at week 12 of CIFN treatment were significantly independent predictors associated with the sustained response to the CIFN treatment. In conclusion, the changes of platelet counts and serum TPO levels in chronic hepatitis C patients during CIFN therapy were reversible, and the degree of changes were more prominent in higher doses of CIFN treatment. The serum TPO response to CIFN-induced thrombocytopenia may serve as a marker for the degree of liver fibrosis, and also as a parameter for predicting therapeutic response.

Interferon therapy prolonged life expectancy among chronic hepatitis C patients

Background & Aims: The effects of interferon therapy in chronic hepatitis C patients on survival are unclear. Our objective was to analyze survival among a large cohort of chronic hepatitis C patients. Methods: We used a retrospective cohort study design in the setting of 7 university hospitals and 1 regional core hospital in Japan. Our study included 2889 patients with histological-proven chronic hepatitis C: 2430 patients received interferon therapy, and 459 patients were untreated. For intervention, the median dose and duration of interferon administration was 480 million units and 137 days, respectively. For measurements, survival status was confirmed by medical records or direct questionnaires. The effect of interferon therapy on survival was assessed by standardized mortality ratio (SMR) based on published mortality among the Japanese general population and by risk ratio calculated by proportional hazards regression. Results: Thirty of 459 untreated patients, 7 of 817 virologic sustained responders, and 49 of 1613 nonresponders died in 5.4-years follow-up. Fifty-eight (67%) of 86 patient deaths were due to liver diseases (39 to hepatocellular carcinoma). Compared with the general population, overall mortality was high among untreated patients (SMR: 1.9; CI: 1.3–2.8) but not among interferon-treated patients (SMR: 0.9; CI: 0.7–1.1). The risk of death was reduced, compared with untreated patients, among interferon-treated patients (risk ratio for overall death: 0.367; CI: 0.236–0.596; for liver-related death: 0.284; CI: 0.164–0.494) and among sustained responders (risk ratios: 0.148; CI: 0.064–0.343 and 0.050; CI: 0.012–0.216). The risk of liver-unrelated deaths remained unchanged. Conclusions: Interferon therapy improved survival of chronic hepatitis C patients by preventing liver-related deaths.GASTROENTEROLOGY 2002;123:483-491

Spectrum of disease in U.S. veteran patients with hepatitis C

OBJECTIVE: Hepatitis C virus (HCV) infection is more prevalent in U.S. veterans attending Veterans Affairs Medical Centers than in the general population. The purpose of this study was to examine the risk factors, psychiatric and substance abuse conditions, and severity of liver disease in veterans with HCV. METHODS: The medical records and liver biopsies of 206 consecutive patients with HCV attending a multidisciplinary medical/psychiatric chronic hepatitis clinic and who met eligibility criteria for interferon α-2b therapy were reviewed. RESULTS: The mean age was 46.5 ± 6.8 yr and 77% were Vietnam-era veterans. Risk factors included i.v. drug use (64%), blood transfusion (15%), and cocaine use (9%), and were unknown in 12%. The average estimated duration of disease was 24 ± 7.6 yr. A history of alcohol abuse or dependence was identified in 80% of patients. Psychiatric illnesses were present in 60%, the most common being depression and posttraumatic stress disorder. Overall, 89% of patients had documented psychiatric and/or substance abuse diagnoses. Severe fibrosis (stages 3–4) was present in 32% and severe inflammation (grades 2–3) was present in 71% of biopsies. Psychiatric and substance abuse diagnoses did not correlate with severity of liver disease. A total of 145 patients (71%) were prescribed interferon-based treatment. The overall virological sustained response rates were 16% after interferon monotherapy and 28% after interferon/ribavirin therapy. Reasons for not receiving interferon therapy included minimal fibrosis on liver biopsy (37 patients [18%]), worsening medical conditions (nine [4%]), and worsening psychiatric and substance abuse problems (14 [7%]). CONCLUSIONS: Advanced fibrosis is common in this cohort of veteran patients with chronic hepatitis C, and the overwhelming majority of these patients have psychiatric and/or substance abuse diagnoses. Despite these comorbidities, the majority received interferon therapies in the context of a multidisciplinary clinic. These data emphasize the importance of hepatitis C care that includes linkage of medical care and psychiatric services.

Spectrum of disease in U.S. veteran patients with hepatitis C.

Hepatitis C virus (HCV) infection is more prevalent in U.S. veterans attending Veterans Affairs Medical Centers than in the general population. The purpose of this study was to examine the risk factors, psychiatric and substance abuse conditions, and severity of liver disease in veterans with HCV. The medical records and liver biopsies of 206 consecutive patients with HCV attending a multidisciplinary medical/psychiatric chronic hepatitis clinic and who met eligibility criteria for interferon alpha-2b therapy were reviewed. The mean age was 46.5+/-6.8 yr and 77% were Vietnam-era veterans. Risk factors included i.v. drug use (64%), blood transfusion (15%), and cocaine use (9%), and were unknown in 12%. The average estimated duration of disease was 24+/-7.6 yr. A history of alcohol abuse or dependence was identified in 80% of patients. Psychiatric illnesses were present in 60%, the most common being depression and posttraumatic stress disorder. Overall, 89% of patients had documented psychiatric and/or substance abuse diagnoses. Severe fibrosis (stages 3-4) was present in 32% and severe inflammation (grades 2-3) was present in 71% of biopsies. Psychiatric and substance abuse diagnoses did not correlate with severity of liver disease. A total of 145 patients (71%) were prescribed interferon-based treatment. The overall virological sustained response rates were 16% after interferon monotherapy and 28% after interferon/ribavirin therapy. Reasons for not receiving interferon therapy included minimal fibrosis on liver biopsy (37 patients [18%]), worsening medical conditions (nine [4%]), and worsening psychiatric and substance abuse problems (14 [7%]). Advanced fibrosis is common in this cohort of veteran patients with chronic hepatitis C, and the overwhelming majority of these patients have psychiatric and/or substance abuse diagnoses. Despite these comorbidities, the majority received interferon therapies in the context of a multidisciplinary clinic. These data emphasize the importance of hepatitis C care that includes linkage of medical care and psychiatric services.

Relationship between diversity of hepatitis C virus quasispecies and viremia, activity of liver disease and response to interferon therapy

To determine the relationship between diversity of hepatitis C virus quasispecies and viremia, activity of liver disease and response to interferon therapy. HCV quasispecies heterogeneity in 68 patients with chronic hepatitis C were detected by single stranded conformational polymorphism (SSCP) analysis of the HCV E2 hypervaribale region 1 (HVR1); of these, 48 were subsequently treated with interferon-alpha for 6 months. HVR1 was amplified in 61 patients. The average number of SSCP bands was 6.2+/-2.4. Quasispecies heterogeneity significantly correlated with serum HCV RNA levels (P<0.01), but not with serum ALT, AST levels and histological activity index (P>0.05). Of the patients who received interferon therapy, 43 were HVR1 positive. Patients who gained sustained response (n=11) had lower pre-treatement quasispecies heterogeneity (3.3+/-1.2) compared to those who had complete end-of-treatment response (ETR) with relapse (6.3+/-2.2, n=12, P<0.5) or no response (8.0+/-3.3, n=20, P<0.01). At the end of treatment, HVR1 could still be detected in 16 patients. The number of quasispecies heterogeneity in these patients decreased to 3.4+/-1.2, which was significantly lower than that in the patients who didn't receive interferon therapy (6.8+/-2.5, P<0.01). Of these 16 patients, 10 had change in quasispecies patterns. Increased quasispecies heterogeneity can cause high HCV viremia, but it is not related to severity of liver disease. Quasispecies heterogeneity is another marker to predict the response to interferon-alpha in patients with chronic hepatitis C.

Transient biochemical response in interferon therapy decreases the development of hepatocellular carcinoma for five years and improves the long-term survival of chronic hepatitis C patients

The development of hepatocellular carcinoma (HCC) was significantly reduced in both sustained responders (SR) and transient biochemical responders (TR) in chronic hepatitis C (CH-C) patients who received interferon (IFN) therapy. However, the long-term clinical outcome of TR remains unclear. One thousand three hundred and seventy CH-C Japanese patients who received IFN therapy and 54 control cirrhotic patients were enrolled. TR were defined as those patients who showed a normal serum alanine aminotransferase level (≦30 IU/l) at the end of therapy and then relapsed. Mean follow-up period was 5.6 years (6.1 years in 48 cirrhotic patients) in the IFN group and 8.3 years in the 54 control cirrhotic patients. HCC was detected in 114 patients in the IFN group among whom 4 were in the 425 SR, 21 were in the 359 TR and 89 were in the 586 non-responders (NR). The cumulative incidence of HCC was significantly ( P=0.0001) inhibited in both SR and TR compared with NR. Its inhibitory effect in TR was within 5 years. Platelet count did not significantly decrease for 2–4 years after IFN therapy in TR, but it significantly decreased in NR 2 years after IFN therapy. The cumulative survival in both SR and TR was significantly higher than NR (SR vs NR; P=0.0001, TR vs NR; P=0.0305). These results indicate that IFN therapy lowers the rate of the progression of HCC and improves the long-term survival even in CH-C patients who transiently respond to IFN therapy.

Constrained genomic and conformational variability of the hypervariable region 1 of hepatitis C virus in chronically infected patients.

We analysed the genomic and conformational variability of the hypervariable region 1 (HVR1) of the hepatitis C virus (HCV) to evaluate the importance of its biological role. A total of 865 genotype 1b HVR1 subclones were collected from serially sampled sera in 11 patients with chronic hepatitis C, four of whom received interferon therapy. Consequently, 169 distinct sequences were examined for amino acid substitutions as well as hydrophilic or hydrophobic profile at each amino acid position within HVR1. Secondary structure of HVR1 was also predicted by the method of Robson in 90 distinct sequences from eight patients, including three interferon-treated patients. Some positions within the HVR1 were invariable or nearly so as to amino acid substitution. Hydrophilic or hydrophobic residues exclusively predominated at several positions. These constrained amino acid replacement and hydrophilic or hydrophobic profiles were conserved irrespective of interferon therapy, though the frequency of amino acid replacement was greater at almost all amino acid positions within the HVR1 in interferon-treated patients. The quasispecies of HCV showed various secondary structures of HVR1, but many sequences seemed to have common characteristics. beta sheet conformations around both the N-terminus and position 20 (numbered from the NH2 terminus of E2 envelope glycoprotein), and/or coil structures around the C-terminus of HVR1 could be identified. These results suggest that HVR1 amino acid replacements are strongly constrained by a well-ordered structure, in spite of being tolerant to amino acid substitutions, and imply an important biological role of the HVR1 protein in HCV replication.

Analysis of Background Factors Influencing Long-Term Prognosis of Patients with Chronic Hepatitis C Treated with Interferon

Objective: Interferon (IFN) therapy has been used as antiviral therapy for chronic hepatitis C (CH-C); however, complete response to the therapy is observed in only about 30% of patients in Japan. Background factors involved in the responsiveness to IFN therapy, and progression to liver cirrhosis (LC) and hepatocellular carcinoma (HCC) after IFN therapy have not yet been sufficiently investigated. Methods: One hundred twenty-one patients with CH-C who received IFN therapy at Showa University Hospital between 1984 and 1999 were analyzed. Results: At 6 months after the termination of IFN therapy, 53 patients achieved a complete response, 11 patients incomplete response, and 57 patients no response. During a mean follow-up of 52.7 months, 12 patients progressed to LC, and 10 patients developed HCC. Multivariate analysis showed that significant independent factors involved in progression to LC were platelet count and the efficacy of IFN therapy. The significant independent factor involved in the development of HCC was platelet count. The factor involved in the therapeutic effect at 6 months after the termination of IFN administration was the serum hepatitis C virus (HCV) RNA levels before IFN therapy. Conclusion: Patients with high HCV RNA levels and low platelet counts should be considered to be at high risk of progressing to LC and developing of HCC and should be carefully followed after IFN therapy using ultrasonography, CT scan and MRI.