Parallel XXXII: HCV: Diagnosis and Outcome

Tue, Nov 04 - 11:15 AM

Epidemiology – General

262. Strong Racial Differences in Lipid Metabolism Genetic Associations with Hepatic Fibrosis in Chronic Hepatitis C Infected Patients.

J. McCarthy; K. Patel; J. G. McHutchison.

Background:

Numerous studies in European and Asian cohorts support a link between host cholesterol metabolism and outcome of Hepatitis C virus (HCV) infection. We therefore sought to determine if putative functional polymorphisms in the genes encoding the low density lipoprotein receptor (LDLR) and its natural ligand apolipoprotein E (APOE) were associated with HCV-related liver fibrosis, and whether differences in these associations could explain the lower rates of hepatic fibrosis seen in Black versus White Americans.

Methods:

Allelic forms of APOE (e2/e3/e4) and LDLR rs688 (T/C), both associated with LDL cholesterol levels in other studies, were genotyped using the 5’ nuclease assay with allele specific TaqMan probes. METAVIR staging of liver biopsies from 278 White and 87 Black chronic HCV-infected treatment-naive patients were tested for association with LDLR and APOE genotypes using multivariable ordinal regression, controlling for age, sex, race, alcohol, HCV genotype and duration of infection.

Results:

Overall Black and White subjects showed significantly different genotype associations with fibrosis stage. Among Blacks, presence of APOE e3 conferred a significant two-fold decreased odds of fibrosis (OR 0.49; 95% CI 0.26-0.94; p=0.03). This effect was greatly enhanced in Black subjects with the LDLR variant (+) allele, where presence of APOE e3 conferred a 25-fold decreased odds of fibrosis (OR 0.04; 95% CI: 0.003-0.42; p=0.007). This combination of LDLR variant and APOE e3 genotype was found in 25% of Blacks, representing a common protective factor. Whites with the APOE e3 allele, on the other hand, showed a significant increased odds of fibrosis, regardless of LDLR genotype (OR 1.83; 95% CI: 1.20- 2.80; p=0.005). The APOE genotype by race interaction was significant at p=0.002.

Conclusion:

This is the first study to examine LDLR/APOE variants related to HCV fibrosis in Blacks. Our results suggest that lower rates of HCV liver fibrosis observed in Blacks could partly be related to genetic factors involved in lipid transport.

Odds ratios (95% CI) for association between APOE and LDLR polymorphisms and Metavir fibrosis score in chronic HCV-infected patients by race

	Blacks	Whites
LDLR alone	0.96 (0.41, 2.28)	0.83 (0.58, 1.20)
APOE e3 alone	0.49 (0.26, 0.94)	1.83 (1.20, 2.80)
APOE e3 in LDLR+	0.04 (0.003, 0.42)	1.71 (1.02, 2.87)
APOE e3 in LDLR-	0.84 (0.37, 1.92)	1.77 (0.68, 4.57)

HCV Treatment - General

263. Sustained Virological Response is Associated with Decrease in Liver Stiffness Using FibroScan in Patients with HCV Related Cirrhosis.

A. F. Cardoso; C. Stern; R. Moucari; N. Giuily; C. G. Figueiredo-Mendes; N. Boyer; M. Ripault; C. Castelnau; T. Asselah; M. Martinot-Peignoux; S. Maylin; P. Bedossa; P. Marcellin.

Background and Aim

Liver stiffness measurement using FibroScan is a non-invasive method proposed for the assessment of hepatic fibrosis in patients with liver diseases. The effect of the response to treatment on liver stiffness has not been well determined. In this study, we evaluated the influence of the response to antiviral therapy on liver stiffness in patients with cirrhosis according to the time after treatment.

Patients and Methods

From September 2006 to April 2008, 136 consecutive CHC patients with bridging fibrosis or cirrhosis were evaluated. They had all received a treatment course with interferon (conventional or pegylated) with or without ribavirin for at least 12 weeks. Liver stiffness measurement using FibroScan was assessed after treatment in patients with or without sustained virological response (SVR). Correlations between results of liver stiffness and genotype, BMI, mean delay between the end of treatment and Fibroscan evaluation, the presence of diabetes, and dyslipidemia were analyzed.

Results

One hundred fourteen of 136 tested patients had reliable FibroScan results. This subgroup was not different from the overall group. The 114 patients had the following characteristics: male gender (72%), mean age (54±9 years), diabetes (26%), mean BMI (26±6 kg/m2), genotype 1 (59%), 2 (6%), 3 (22%), 4 (12%), 5 (1%). Mean follow-up was 45±33 months. SVR was observed in 33% of patients.

Patients with SVR had lower median Fibroscan results (8.4 kPa; range 3.3-45) when compared to non SVR patients (15.7 kPa; range 5.3-75) (p<0.001). In the univariate analyses, the median of liver stiffness was higher in genotype 1 and 4 vs. genotypes 2 and 3 (p=0.02) and in patients with diabetes mellitus (p=0.006). The median of results was 15.4 (5.4-75) when the delay was inferior to 2 years and 10.7 (3.3-75.0) when the delay was more than 2 years between the FibroScan measurement and the end of therapy (p=0.03). BMI and dyslipidemia did not influence the median of the fibroscan results. In the logistic regression, the median of the fibroscan results was independently associated with response to the anti-viral treatment (p=0.001) and presence of diabetes (0.002).

Conclusion

In patients with cirrhosis, stage of fibrosis assessed by transient elastography was lower in patients with SVR than in those without SVR and this difference increased with the time, These results suggest the possibility of progressive reduction of fibrosis in patients with SVR and Fibroscan could be an important tool for the assessment of fibrosis stage during the post-treatment follow-up.

Treatment – General

264. Lower Risk of Hepatocellular Carcinoma and Improved Survival in patients with HCV Related Cirrhosis with Sustained Virological Response.

A. F. Cardoso; R. Moucari; N. Giuily; C. G. Figueiredo-Mendes; N. Boyer; M. Ripault; C. Castelnau; T. Asselah; M. Martinot-Peignoux; S. Maylin; C. Stern; P. Bedossa; P. Marcellin.

Background and Aim

To evaluate the influence of antiviral therapy on the incidence of hepatocellular carcinoma (HCC), liver transplantation (LT) and death in chronic hepatitis C (CHC) patients with bridging fibrosis or cirrhosis.

Patients and Methods

307 consecutive CHC patients with bridging fibrosis or cirrhosis were retrospectively evaluated. They had all received at least one treatment course with interferon (conventional or pegylated) with or without ribavirin for at least 12 weeks. Cumulative incidence of HCC, LT and mortality were compared between patients who developed or not sustained virological response (SVR).

Results

The patients characteristics were: male gender (68%), mean age (55±10 years), mean BMI (26±4 kg/m2), mean serum HCV RNA level (5.7±0.6 log IU/ml), genotype 1 (60%), 2(8%), 3 (16%), 4 (13%). Median follow-up was 3.5 (1-18) years after treatment. SVR was observed in 33% of patients.

Patients with SVR developed less frequently HCC (6% vs. 19%, p=.002). The cumulative incidence of HCC was significantly lower in patients with than in those without SVR (p=0.001). HCC developed 1 to 9 years after therapy in patients without SVR and 1 to 4 years in patients with SVR. By univariate analyses, HCC was associated with male gender, age>50 years, overweight, diabetes, and treatment failure. By logistic regression, HCC was independently associated with: male gender (OR=2.4), age>50 years (OR=3.7) and non SVR status (OR=4.3). The 6 patients who developed HCC despite SVR were all male and significantly older than those who did not develop HCC (64±8 vs. 55±10 years, p=0.04). Ten patients have been transplanted, all were non SVRs (p=0.01). The survival LT free was significantly different between patients with and without SVR (p<0.001). Twenty-three patients died, 20 non responders and 3 SVR (2 liver related) (p=0.03).

Conclusion

In CHC patients with cirrhosis, SVR is associated with a lower rate of HCC, LT and improved survival. However, despite SVR, HCC occurred in 6% of patients up to 4 years after therapy. In those patients, male gender and old age seem to be risk factors of HCC. Therefore, surveillance should be maintained in patients F3/F4 and SVR.

Treatment – General

265. Changes in Health-Related Quality of Life are Associated with Disease Progression and Peginterferon Therapy in Patients with Advanced Hepatitis C in the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C) Trial.

K. K. Snow; H. L. Bonkovsky; R. J. Fontana; J. H. Hoofnagle; H. Kim.

Background/Aims:

Primary analysis of the HALT-C Trial showed long-term peginterferon therapy did not reduce complications in prior non-responders with chronic hepatitis C (CHC) and advanced fibrosis or cirrhosis [Hepatology 2007; 46(4S):290A]. This planned secondary analysis assessed the effects of treatment and disease progression on health-related quality of life (HRQOL).

Methods:

1044 of the 1050 randomized patients were analyzed. 515 received peginterferon alfa-2a (90 µg/week) and 529 received no additional treatment for 3.5 years (controls). 618 patients (59%) had bridging fibrosis (Ishak 3-4) and 426 (41%) had compensated cirrhosis (Ishak 5-6). Patients were followed for clinical outcomes (death, hepatocellular carcinoma, decompensation). Sexual health and SF-36 physical and mental summary scales (0=worst; 100=best) were assessed at baseline, 0.5, 1.5, 2.5, 3.5 and 4.0 years using repeated measures analysis of variance controlling for baseline score.

Results:

Mean age was 50.1 ± 7.2 years; 71% were male. Overall mean baseline physical scores were 44.5 ± 11.3, mental scores were 50.5 ± 9.0, and sexual health scores were 71.1 ± 30.9. SF-36 physical scores significantly declined over time (p for trend=0.001); patients with cirrhosis reported lower scores than those with fibrosis (-1.5 points, p=0.001); and treated patients experienced a greater decline than control patients (-0.8 points, p=0.04). SF-36 mental scores were lower in patients with cirrhosis (-0.8 points, p=0.05) and did not change significantly over time or with treatment. Among men, sexual health scores were not associated with histological stratum, but were significantly worse in the treatment group (-8.7 points, p<0.001) and worsened over time (p for trend=0.04). Among women, sexual health scores were not associated with treatment or stratum, but declined significantly over time (p for trend=0.04). The 179 patients (17%) who experienced a clinical outcome had significantly greater declines in physical (-3.3 points, p<0.001), mental (-1.5 points, p=0.02), and sexual health scores (-8.2 pts, p<0.001) compared to non-progressors, which differed by stratum and time for physical scores and by treatment group and time for sexual heath scores.

Conclusions:

Clinical progression of CHC as well as low-dose peginterferon therapy led to statistically and clinically significant decrements in HRQOL and sexual health. The strong association between changes in HRQOL and development of clinical outcomes suggests the SF-36 may be a valid and useful tool in monitoring disease progression in CHC.

HCV Treatment – Drug Resistance

266. Naturally occurring STAT-C resistance mutations in treatment-naïve HCV infected patients - an international multi-center study.

T. Kuntzen; J. Timm; A. Berical; A. M. Berlin; C. Oniangue-Ndza; B. Lee; D. Heckerman; J. Carlson; H. R. Rosen; F. K. Bihl; A. Cerny; U. Spengler; Z. Liu; Y. Xing; M. A. Madey; J. F. Fleckenstein; V. M. Park; C. A. Riely; G. Lake-Bakaar; E. S. Daar; I. M. Jacobson; E. D. Gomperts; B. R. Edlin; S. M. Donfield; R. T. Chung; A. Talal; T. N. Marion; B. W. Birren; M. R. Henn; T. M. Allen.

Introduction

Resistance mutations to HCV NS3 protease inhibitors in <1% of the viral quasispecies may still allow >1000-fold viral load reductions upon treatment, consistent with their reported reduced replicative fitness in vitro. Recently, however, an R155K protease mutation was reported as the dominant quasispecies in a treatment-naïve individual, raising concerns about possible full drug resistance.

Methods

To broadly investigate the prevalence of dominant STAT-C resistance mutations in the population we analyzed HCV genome sequences from 507 treatment-naïve HCV genotype 1 infected patients from the US, Germany and Switzerland. Phylogenetic sequence analysis and viral load data were used to identify the possible spread of replication competent, drug resistant viral strains in the population and to infer the consequences of these mutations upon viral replication in vivo.

Results

Mutations conferring resistance to the protease inhibitors VX-950, BILN2061, ITMN-191, SCH6 and SCH503034, and to the NS5B polymerase inhibitor AG-021541 were observed mostly as sporadic, unrelated cases, each at frequencies between 0.3% and 2.8% in the population, including two patients with possible multi-drug resistance. Collectively, however, 8.3% of the genotype 1a and 1.4% of the genotype 1b infected patients carried at least one dominant resistance mutation. Viral loads were high in the majority of these patients, suggesting that drug resistant viral strains might achieve replication levels comparable to non-resistant viruses in vivo.

Conclusion:

Naturally occurring dominant STAT-C resistance mutations are common in HCV genotype 1 infected treatment-naïve patients. These data provide the rationale to examine the influence of baseline drug resistance mutations on treatment outcome in future clinical studies to enable individual tailoring of drug combinations when treatment options are limited due to previous non-response to interferon and ribavirin.

Treatment – General

267. Decline in Sexual Desire, Function and Satisfaction in Men During Peginterferon and Ribavirin Therapy for Chronic Hepatitis C.

L. M. Dove; R. C. Rosen; D. Ramcharran; A. S. Wahed; S. H. Belle; R. S. Brown; J. H. Hoofnagle.

Introduction:

The currently recommended therapy for chronic hepatitis C is the combination of peginterferon and ribavirin given for up to 48 weeks. Sexual dysfunction has been reported to be a side effect of interferon therapy, but its frequency and severity have not been defined. The Study of Viral Resistance to Antiviral Therapy of Chronic Hepatitis C (Virahep-C) was a multicenter study of combination therapy in treatment-naïve African American (AA) and Caucasian American (CA) patients infected with hepatitis C virus (HCV) genotype 1. We report the assessment of sexual health in men who participated in Virahep-C.

Methods:

A total of 401 adult AA and CA patients were enrolled at 8 U.S. centers. All were treated with peginterferon alfa-2a (180µg/wk) and oral ribavirin (1000-1200 mg/day). Patients who remained HCV RNA positive after 24 wks stopped therapy at that point; those who became HCV RNA negative continued for 48 wks. All were followed for 24 wks after therapy. Self-administered sexual health questionnaires were obtained at wks 0, 4,12,24, 48, and 72. Five sexual health questions were used to assess sexual desire, function (erection & ejaculation), and satisfaction. SF-36 and CES-D were used to assess quality of life and depression.

Results:

260 men completed the sexual health questionnaire at least once. At baseline 37% described impairment of sexual desire, 26% noted erectile and 21% ejaculatory dysfunction. 44% reported moderate or severe dissatisfaction with their sex life. During therapy, all domains of sexual health worsened; impaired desire to 53%, erectile dysfunction to 39%, ejaculatory dysfunction to 31% and dissatisfaction to 54%. By the end of 48 wks of therapy, 51% of pts reported that their sex life was worse than before therapy. Initial impairment as well as worsening of sexual desire, function and satisfaction was associated with the presence of and increase in depressive symptoms. 24 wks after therapy was stopped, most components of sexual health returned to baseline. Among those treated for 48 wks, the proportion with erectile and ejaculatory dysfunction remained slightly higher than at baseline.

Discussion:

Declines in sexual desire, function and satisfaction are common side-effects of combination antiviral therapy in men. The onset of dysfunction appears within 4 wks with gradual worsening over time. Most components of sexual dysfunction resolve within 24 wks of stopping therapy, but erectile and ejaculatory dysfunction may persist in a small proportion. Education and counseling regarding the potential of sexual side effects of peginterferon and ribavirin therapy is warranted.