HCV-associated liver disease after liver transplantation

Associate Professor in Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska, Corresponding Author: smukherj AT unmc.edu

HCV-associated liver disease after liver transplantation

INTRODUCTION

Hepatitis C virus (HCV)-associated liver disease continues to be the most common indication for liver transplantation (LT) in the United States accounting for nearly 50% of all liver transplants. Recurrence is universal in patients viremic at the time of transplantation with histological hepatitis developing in the majority of patients. Although the natural history of recurrent HCV is difficult to predict, it is widely accepted that cirrhosis from recurrent HCV occurs in up to 30% of patients within five years of transplantation. Once cirrhosis is established, the annual risk of hepatic decompensation defined as the development of ascites, hepatic encephalopathy or variceal bleeding, is 42% [1]. These statistics highlight the importance of recurrent HCV after LT, which in turn has stimulated the controversy surrounding retransplantation of recurrent HCV, particularly in the first post-operative year when retransplantation for severe recurrence is not recommended due to poor outcomes [2]. It would seem insightful that eradicating HCV either before LT or treating recurrent HCV shortly after LT would have a major impact on decreasing the incidence of recurrent HCV and its expected complications. Unfortunately, most patients referred for LT evaluation have decompensated disease and are often unable to tolerate pegylated interferon and ribavirin therapy [3]. The treatment of recurrent HCV is complicated further by poor sustained viral response (SVR) rates and reports of progressive fibrosis with hepatic decompensation despite SVR. The most successful approach to the treatment of recurrent HCV remains eradicating HCV before hepatic decompensation in which reported SVR rates with pegylated interferon and ribavirin vary from 50% to 70%. The natural history of recurrent HCV, risk factors associated with severe recurrence and the treatment of recurrent HCV will be discussed in this article.

POST TRANSPLANT COURSE OF HCV INFECTION
HCV infection of the allograft occurs at the time of transplantation, with HCV ribonucleic acid (RNA) detectable in the first postoperative week. HCV RNA is cleared rapidly from serum during the anhepatic phase and levels typically increase rapidly from week two posttransplantation, peaking by the fourth postoperative month [4]. Acute hepatitis typically develops between months one and four posttransplantation, whereas changes consistent with chronic hepatitis usually are seen after months two to three [5]. However, severe recurrent HCV developing as early as the ninth post-operative day has been described [6]. By the fifth postoperative year between 10- 30% of patients have progressed to cirrhosis-once cirrhosis is established, the one year actuarial risk of hepatic decompensation is approximately 40%. A small proportion of patients (5%) may develop an accelerated course of liver injury called fibrosing cholestatic hepatitis C (FCH) which is associated with severe jaundice in the absence of biliary or vascular disease and elevated levels of HCV RNA. This syndrome is characterized histologically by severe hepatocyte ballooning particularly in the perivenular zone, intrahepatic cholestasis, pericellular and/or portal fibrosis and a paucity of inflammation. A diagnosis of FCH portends a poor prognosis due to the development of rapid allograft failure and often a lack of response to antiviral therapy [7]. Possible explanations for FCH development include defects in innate immunity such as reduced counts and impaired cytolytic activity of non killer cells, down regulation of CD16 and upregulation of Fas ligand, a marker of hepatotoxicity [8]. The initial enthusiasm for liver transplantation for HCV has waned as initial reports that five year survival rates were comparable to other liver transplant recipients may not be reproducible for medium- and long-term survival [9, 10].

IMMUNOSUPPRESSION
Immunosuppression impacts the natural history of recurrent HCV at all stages of the transplant process from induction therapy to maintenance treatment and during the treatment of rejection. Despite several advances in our understanding on the impact of various medications on HCV recurrence, the ideal immunosuppressive regimen for these patients has not been established. We will discuss the impact of various immunosuppressive drugs on the post transplant outcome of HCV induced liver disease.
(a) Corticosteroids
High dose corticosteroids were historically used during induction therapy and for the treatment of rejection. However, several studies have reported that repeated administration of high dose corticosteroids in patients with recurrent HCV, regardless of the indication, is associated with poorer outcomes and should be avoided unless absolutely necessary [11]. Until recently, steroids were often discontinued in most LT programs by three months due to their long-term side effects and inherent belief steroids increased HCV liver injury. However, a single-center, retrospective study by Brillanti et al [12] reported slow steroid tapering was associated with less severe recurrent disease at six and twelve months. This was supported by Berenguer et al [13] who compared outcomes between two cohorts of recurrent HCV patients. The first group was transplanted between 2001 and 2004 and the second between 1999 and 2000 before dual immunosuppression (cyclosporine or tacrolimus plus steroids) or slow steroid taper over six months was instituted. Severe disease was considerably lower in the group transplanted between 2001 and 2004 (29% versus 48%; P = 0.02) although definite conclusions could not be made due to the retrospective nature of the study and selective bias. An important prospective study by Vivarelli et al [14] assessed the effect of long-term maintenance steroids (slow taper over two years) versus steroid withdrawal at 90 days. Although histological recurrence was similar in both groups, only 7.6% of patients developed advanced fibrosis in the slow taper group in contrast to 42.1% in the rapid taper group at 1 year post transplantation (P=0.03). Two year advanced fibrosis-free survival was also greater in the slow taper group versus the rapid taper group (93.7% versus 60.7%, P = 0.02). However, there were several unanswered question such as duration of therapy with low dose steroid and whether these medications could be discontinued. Two studies also evaluated the impact of steroid-free protocols on HCV recurrence and fibrosis. Kato et al [15] reported no differences in mean fibrosis stage between the three different immunosuppression groups but noted that patients who developed acute cellular rejection had a 63% chance of developing advanced fibrosis, defined as stage 2 -4 fibrosis. Klintmalm et al [16] also reported similar rates of HCV recurrence (60% at one year) in all groups using similar immunosuppression and confirmed that acute cellular rejection and older donor age were associated with early and more severe recurrence.
(b) Calcineurin inhibitors
Calcineurin inhibitors remain the most commonly used medications for maintenance therapy and their impact on the natural history of recurrent HCV has been extensively studied. This is in part related to in vitro studies which have shown an inhibitory effect of cyclosporine on HCV replication which is enhanced in the presence of interferon [17, 18]. Recent clinical studies in non-transplant patients have reported that the use of a cyclophilin-inhibitor without calcineurin binding properties has both additive and synergistic effects when combined with pegylated interferon and specifically targeted antiviral therapy for hepatitis C [19, 20]. Although no studies of the independent impact of tacrolimus on HCV viremia have been reported, posttransplant HCV levels are similar among patients receiving tacrolimus and patients receiving cyclosporine A. In a prospective randomized controlled study by Levy G et al [21], no difference was seen in the histological recurrence rate of hepatitis C at twelve months posttransplantation between patients receiving cyclosporine versus tacrolimus. A recent meta-analysis of five randomized, controlled trials on 366 patients comparing cyclosporine with tacrolimus reported similar rates of acute rejection, FCH, fibrosis and patient and graft survival at one year regardless of which calcineurin inhibitor was chosen [22]. These findings are interesting as the inhibitory effect of cyclosporine on HCV replication has not translated into improved outcomes in post-transplant patients. It could be argued initial maintenance immunosuppression for recipients with HCV infection should be with tacrolimus but switched to cyclosporine at the initiation of interferon-based therapy. This would take advantage of cyclophilin inhibiting properties of cyclosporine during antiviral therapy and the greater immunosuppressive potency of tacrolimus during maintenance therapy but needs to be affirmation in controlled trials.
(c) Azathioprine and mycophenolate mofetil
There has been a strong interest in MMF, a potent inosine monophosphate inhibitor, as it has antiviral properties against flaviviruses and in theory may decrease HCV recurrence Although numerous studies have evaluated the impact of azathioprine (AZA) and mycophenolate mofetil (MMF) on HCV recurrence, most of these studies were retrospective or single center studies and are unlikely to be repeated in a controlled manner as AZA use currently is virtually obsolete. However, data on the impact of azathioprine and MMF on HCV recurrence has been conflicting For example, smaller and nonrandomized studies have reported worsening HCV RNA viremia upon either azathioprine substitution for MMF or when azathioprine is compared with MMF [23]. However, a randomized, prospective study of 106 patients comparing tacrolimus plus steroids versus. tacrolimus plus steroids plus MMF showed no effect of MMF on patient or graft survival or HCV recurrence [24]. A further randomized, double blind study of AZA versus MMF with cyclosporine and steroids had several interesting findings [25]. The investigators reported that the incidence of rejection and graft loss was reduced in the MMF arm versus AZA at six months post-transplant as was the incidence of recurrent HCV (MMF 18%, AZA 29%, P< 0.05). However, at twelve months follow up, there was no statistically significant difference in the incidence of rejection between the two arms (MMF 31%, AZA 39%, P=0.1). These findings do not support a beneficial effect of either drug on the natural history of recurrent HCV, suggesting overall intensity of immunosuppression may have a more significant impact on HCV recurrence than the independent action of either AZA or MMF.
(d) Rapamycin
Rapamycin has gained widespread use in few transplant programs as a maintenance agent because of its renal-sparing effects. An interesting case series on two patients with recurrent HCV reported spontaneous HCV RNA clearance when immunosuppression was switched to rapamycin in the absence of antiviral therapy [26]. However, in the absence of well-designed, randomized trials, there is little evidence to support its widespread role in recurrent HCV patients and treatment should be determined on a case by case basis.
(e) T-cell depleting therapies
OKT3 administration has consistently been identified as a significant risk factor for rapid onset and the severity of histological recurrence of HCV [27]. The notion of a negative impact of T-cell depletion on posttransplant outcomes in recipients with HCV infection is supported by the potent effect of alemtuzumab (campath) in exacerbating recurrence of HCV [28]. Data concerning the impact of rabbit antithymocyte globulin (ATG), an increasingly popular induction agent are less clear. An early randomized study reported a reduced incidence of recurrent HCV in ATG-treated patients (50%) versus steroid bolus recipients (71%), although this was not a statistically significant difference [29]. Outcomes in patients with HCV infection who received induction ATG have been reported to be similar to controls who did not receive ATG, with an analysis of outcomes from three centers further suggesting that induction with ATG is associated with less severe fibrosis progression [30]. Interpreting these studies is limited by the lack of protocol biopsies and the use of historical controls. While it is possible that the complex effects of ATG results in an environment that favors less severe recurrence of HCV (in contrast to the specific CD3 depletion associated with OKT3), there is a paucity of data which definitively shows that ATG has a positive impact on HCV recurrence when compared to steroid induction.

IMPACT OF DONOR AND RECIPIENT FACTORS
(a) Viral and recipient factors
Although HCV genotype and quasispecies emergence have been reported to affect the severity of recurrent HCV, these factors lack sufficient sensitivity and specificity to be used in determining eligibility of patients for liver transplantation or identifying candidates for preemptive antiviral therapy. The same holds true for recipient variables such as age, gender, HLA type and ethnicity [31, 32].
(b) Donor factors
Donor factors are potentially modifiable and are thus of particular interest as they may influence the natural history of recurrent HCV. An association of advancing donor age, with donor age greater than 65 years associated with more rapid progression of fibrosis and allograft failure as well as with more rapid and severe histological progression of HCV recurrence has been very reproducible [33]. Prolonged cold and warm ischemia times have also been identified as risk factors for more severe post-LT HCV infection, as has early posttransplant preservation injury and excess donor fat content, although the latter is not specific for HCV [34]. A prospective study of 76 patients followed for 36 months reported no difference between the frequency of development of recurrent HCV and fibrosis between patients who received living-donor organs compared to deceased-donor organs [35].
One of the more controversial issues regarding extended-criteria donors revolves around the potential positive impact of HCV-infected donors on short-term outcomes. Initial reluctance with using HCV positive donors was misguided until data confirmed that patient and graft survival comparable to patients who received non-HCV donors [36]. A recent interesting case-control study by Wilson et al [37] using data from United Network for Organ Sharing (UNOS) and local donor data showed that one year patient survival rates of 97% favored recipients of HCV-infected livers compared with one year patient survival rates of 87.5% for recipients of organs meeting UNOS criteria. Demographics, cold and warm ischemic times were similar between both groups. A 26% increase in fibrosis developed in HCV-infected organs at one year post-LT compared with a 69% increase in fibrosis in the UNOS-approved group. The findings of this study have important implications because such organs are underused but over represented in the donor pool.
(c) Cytomegalovirus (CMV)
Posttransplant CMV infection has been strongly associated with increased severity of recurrence, even after adjusting for covariables such as degree of immunosuppression.This link appears to be strengthened if patients are genotype 1a. However, a long term retrospective study of liver transplant recipients with CMV disease did not report any significant differences in graft survival, HCV recurrence, or incidence of rejection compared with a control arm who never developed CMV disease or received CMV prophylaxis [38]. Recurrent HCV occurred in 55.6% of the patients with CMV treated with preemptive therapy and 49.8% of those without CMV infection (P > 0.20). While this recent data suggests that targeted prophylaxis against CMV may not reduce the impact of CMV infection on posttransplant outcomes in HCV-infected liver transplant recipients, a randomized controlled trial directly addressing this question has never been performed.
(d) Human Immunodeficiency Virus (HIV)
HIV co-infection has recently emerged as an important predictor of poor survival among liver transplant recipients with HCV infection. One year patient mortality attributable to HCV in co-infected recipients ranges between 27-54%. Factors associated with increased risk of post-LT mortality among HCV–HIV co-infected recipients include African-American recipient ethnicity, pre-LT Model of End-Stage Liver Disease (MELD) score of > 20, intolerance of Highly Active Anti-Retroviral Therapy (HAART) and higher pre-LT HCV level of viremia.. Reduced response rates to treatment of HCV with interferon and ribavirin further attenuate post-LT outcomes in HIV–HCV co-infected liver transplant recipients [39]. In a single center study from France, investigators compared the survival and severity of recurrent HCV infection after liver transplantation in HIV-HCV-coinfected and HCV-monoinfected patients. Seventy-nine patients receiving a first liver graft for HCV were included of whom 35 had HAART-controlled HIV infection [40]. All patients were monitored for HCV viral load and liver histology during the posttransplantation course. Two and five year survival rates were 73% and 51% and 91% and 81% in coinfected patients and monoinfected patients, respectively (log-rank P = 0.004). Under multivariate Cox analysis, survival was related only to the MELD score Progression to fibrosis was also significantly higher in the coinfected group (P < 0.0001).The investigators concluded that outcomes of LT in HIV-HCV-coinfected patients were satisfactory in terms of survival benefit.
The National Institutes of Health in the United States is currently funding a multicenter trial to prospectively evaluate outcomes of LT for HIV-HCV coinfected patients (http://www.hivtransplant.com/). The study aims to enrol 125 patients at twenty major transplant centers. Until the findings from this study are available, it appears reasonable to recommend LT for these patients provided clinicians adhere to standard guidelines and liaise closely with an HIV specialist.

TREATMENT
(a) Pretransplant anti-viral therapy
A landmark study reported that patients with high preliver transplant HCV RNA titers experienced greater mortality and graft loss rates than recipients with lower titers [41]. This has led investigators to treat patients with advanced or decompensated cirrhosis, a group at high-risk for developing complications from anti-viral therapy, in an attempt to render patients HCV RNA negative prior to transplantation [42-44]. In the pilot study of 11 patients by Crippin et al [42], no patient achieved undetectable HCV RNA. In addition, several patients developed severe infections with two patients dying as a consequence of their anti-viral therapy. The largest study to date consisted of 124 patients with decompensated cirrhosis treated with a low accelerating dose of either interferon alpha-2b or pegylated interferon alpha-2b with ribavirin [45]. Overall SVR was 24% but closer inspection of the data reveal that 45% of patients had compensated cirrhosis, 49% of non genotype one patients had CTP class 3 and only 13% of genotype one patients achieved SVR. Life-threatening complications were also more common in these patients, a complication reproducible in all 4 studies. Due to the high frequency of serious adverse events (33%), among patients with more severe liver disease (Child’s class B or C), the International Liver Transplant Society consensus panel concluded that treatment should be limited to cirrhotic patients with Child-Turcotte-Pugh (CTP) score ≤ 7 or MELD score < 18 and is contraindicated when the CTP score is >11 or MELD score is > 25 [43]. The risks and benefits of antiviral therapy need to be carefully evaluated in these vulnerable patients and should only be undertaken in an environment where these patients can be closely supervised.
(b) Post transplantation early prophylactic treatment
There are two randomized, controlled trials-a prophylaxis trial and a treatment trial-reporting the safety and efficacy of peginterferon alpha-2a in the early postoperative period [47]. In the prophylaxis trial, treatment was initiated within three weeks after LT versus 6-60 months in the treatment trial. Only two patients treated in the prophylaxis trial (8%) and three in the treatment trial (12%) achieved an SVR. A nonrandomized preemptive therapy study reported similar (5%) SVR rates. These studies confirm the findings of previous single center studies that prophylactic therapy is frequently ineffective and not recommended for recurrent HCV [48].
(c) Post transplantation treatment of recurrence
There is a lack of well designed randomized studies evaluating the outcome of interferon-based treatment in LT patients. Most studies report an SVR between 33% and 42% when treating patients with histologic recurrence and 0-33% when used in a pre-emptive protocol for genotype one patients [49]. This was supported by a recent randomized controlled trial from Spain in which patients were randomized to no treatment (group A, n = 27) or peginterferon alpha-2b/ribavirin for 48 weeks (group B, n = 27). All patients with with severe recurrent HCV were also treated (group C, n = 27). Only 13 (48%) patients of group B and 5 (18.5%) of group C achieved sustained virological response, translating to an efficacy of pegylated interferon and ribavirin of approximately one-third less than in the nontransplant setting [50]. These investigators also reported that response to antiviral therapy was influenced by stage of fibrosis. For example, SVR was 48% in patients with fibrosis stages 0-2 compared to 18% in patients with fibrosis stages 3-4. In addition, fibrosis correlated closely with wedged hepatic venous pressures (kappa value of 0.65) and this raises the question whether this investigation should be performed in all patients with recurrent HCV.
The reported incidence of acute cellular rejection on interferon-based antiviral therapy ranges from 0-25% with a mean incidence of 12% [51]. This wide range is in part due to the difficulties encountered in differentiating recurrent HCV from mild or moderate rejection, particularly when they may co-exist [52]. Alloimmune hepatitis can also occur in association with post-LT antiviral therapy in approximately 5% of cases, typically after HCV RNA clearance and associated with an important risk of graft failure [53]. Immunosuppression levels can decrease significantly in patients responding favorably to anti-HCV therapy, predisposing to acute cellular rejection. In a retrospective single center study of 44 patients treated with antiviral therapy, 5 patients developed acute rejection while receiving interferon of whom 4 had undetectable serum HCV RNA [54]. Two patients did not respond to standard treatment for rejection-one patient died and the other was successfully retransplanted. Two of the three patients who were successfully treated developed cirrhosis leading the authors to conclude that interferon may cause rejection and despite achieving SVR, progressive fibrosis and cirrhosis can still develop in selected patients. There also is evidence of progressive liver fibrosis after SVR eradication in patients treated with interferon-based therapies. In some instances this has led to decompensated cirrhosis requiring retransplantation in patients remaining serum HCV RNA negative at a mean follow-up period of eighteen months after LT [55]. Other centers have reported the development of chronic rejection in patients who have achieved SVR after anti-HCV therapy which has required retransplantation [56]
A cost-effectiveness study by Saab et al [57] of treatment with standard interferon and ribavirin reported an incremental cost-effectiveness ratio of $29,100 per life-year saved for men > 55 years. The investigators used a model sensitive to medication costs, rate of cirrhosis development and SVR. Furthermore, the two way sensitivity analysis showed that antiviral therapy remained cost-effective even if drug costs increased provided these increased costs occurred in concert with an improved SVR.
(d) IL28 genotyping and Protease inhibitors
Pre-transplant patients who are –CC- homozygous for the gene coding for interferon lambda 3 (IL28B rs12979860) are more likely to achieve SVR and this appears to hold true for post-transplant patients in a few recent studies. However, the role of protease inhibitors for treating recurrent HCV is contraindicated due to the inhibition of cytochrome CYP 3A5/5 activity, an important cytochrome in calcineurin inhibitor metabolism, leading to toxic levels of these immunosuppressants.

RETRANSPLATATION
Several studies have reported poor outcomes compared with other liver retransplant recipients, particularly for those transplanted for severe early recurrent HCV occurring within 6-12 months of LT [58]. However, the policy for retransplantation continues to vary between transplant programs in part owing to subjective differences in perceived results between transplant physicians, surgeons, and the patient-family unit despite widely published data supporting comparable results with non-HCV retransplants if guidelines are followed [59]. A recent multicenter study by McCashland et al [60] concluded that patients retransplanted for recurrent HCV had similar 1- and 3-year survival rates when compared with patients undergoing retransplantation for other indications although many patients with recurrent HCV were not considered for retransplantation and died from recurrent disease.

CONCLUSION
HCV-associated liver failure continues to be the most common indication for LT, with virological recurrence virtually universal after LT. Although outcomes for recipients with HCV infection are generally comparable to those for other indications for liver transplantation, the impact of HCV recurrence on posttransplant patient and graft survival is substantial. Approximately 30% of HCV-infected recipients will die or lose their allograft or develop cirrhosis secondary to HCV recurrence by the fifth postoperative year. Strategies for minimizing the frequency of severe HCV recurrence are evolving and include avoidance of older donors, early diagnosis and treatment of CMV and minimization of immunosuppression such as T-cell depleting therapies and pulsed corticosteroid treatment of acute cellular rejection. Competing goals of reducing immunosuppression and avoiding treatment of acute cellular rejection complicate the choice of immunosuppressive agents. Treatment with pegylated interferon and ribavirin is advised once histological evidence of recurrence of HCV is confirmed but patients still require education on the side effects and poor efficacy of antiviral therapy [61,62].

List of Abbreviations

• FCH | fibrosing cholestatic hepatitis C
• RNA | ribonucleic acid
• HCV | hepatitis C virus
• LT | liver transplantation
• EVR | early virological response
• SVR | sustained viral response
• MMF | Mycophenolate mofetil
• ATG | antithymocyte globulin
• AZA | azathioprine
• MELD | Model of End-Stage Liver Disease
• CTP | Child-Turcotte-Pugh
• CMV | Cytomegalovirus
• HIV | Human Immunodeficiency Virus
• HAART | Highly Active Anti-Retroviral Therapy
• UNOS | United Network for Organ Sharing

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45. Everson, G.T.; Trotter, J.; Forman, L.; et al. Treatment of advanced hepatitis C with a low accelerating dosage regimen of antiviral therapy. Hepatology, 2005, 42, 255-262.
46.. Wiesner, R.H.; Sorrell, M.; Villamil, F. International Liver Transplantation Society Expert Panel. Liver Transpl., 2003, 9, S1-9.
47. Chalasani, N.; Manzarbeitia, C.; Ferenci, P.; et al. Peginterferon alfa-2a for hepatitis C after liver transplantation: two randomized, controlled trials. Hepatology, 2005, 41, 289-298.
48. Shergill, A.K.; Khalili, M.; Straley, S.; et al. Applicability, tolerability and efficacy of preemptive antiviral therapy in hepatitis C-infected patients undergoing liver transplantation. Am J Transplant., 2005, 5, 118-124.
49. Arjal, R.R.; Burton, J. R., Jr.; Villamil, F., Rosen, H. R.: Review article: the treatment of hepatitis C virus recurrence after liver transplantation. Aliment Pharmacol Ther., 2007, 26, 127-140.
50. Carrión JA.; Navasa M.; García-Retortillo M.; et al. Efficacy of antiviral therapy on hepatitis C recurrence after liver transplantation: a randomized controlled study. Gastroenterology, 2007,132,1746-1756
51. Watt, K.; Veldt, B.; Charlton, M. A practical guide to the management of HCV infection after liver transplantation. Am J Transplant., 2009, 9,1707-1713.
52. Unitt, E.; Gelson, W.; Davies, SE.; et al. Minichromosome maintenance protein-2-positive portal tract lymphocytes distinguish acute cellular rejection from hepatitis C virus recurrence after liver transplantation. Liver Transpl., 2009, 15, 306-312.
53. Stravitz, R.T.; Shiffman, M. L.; Sanyal, A. J.; et al. Effects of interferon treatment on liver histology and allograft rejection in patients with recurrent hepatitis C following liver transplantation. Liver Transpl., 2004, 10, 850-858.
54. Saab S, Kalmaz D, Gajjar NA, Hiatt J, Durazo F, Han S, et al. Outcomes of acute rejection after interferon therapy in liver transplant recipients. Liver Transpl,2004, 10, 859-867.
55. Mukherjee, S. Fatal liver disease despite sustained eradication of recurrent hepatitis C virus requiring liver retransplantation. Transplantation, 2006, 82, 286-288.
56. Stanca CM, Fiel MI, Kontorinis N, Agarwal K, Emre S, Schiano TD. Chronic ductopenic rejection in patients with recurrent hepatitis C virus treated with pegylated interferon alpha-2a and ribavirin. Transplantation, 2007,27,180-186
57. Saab S, Ly D, Han SB, Lin R, ROjter SE, Ghobrial RM, Busuttil RW. Is it cost-effective to treat recurrent hepatitis C in orthotopic liver transplantation patients. Liver Transpl., 2002, 8,449-457.
58. Forman LM. To transplant or not to transplant recurrent hepatitis C and liver failure. Clin Liver Dis., 2003, 7, 615-629.
59. Burton, J.R. Jr,; Rosen, H.R. Liver retransplantation for hepatitis C virus recurrence: a survery of liver transplant programs in the United States. Clin Gastroenterol Hepatol,. 2005, 3, 700-704.
60. McCashland, T.; Watt, K.; Lyden, E.; et al. Retransplantation for hepatitis C: results of a U.S. multicenter retransplant study. Liver Transpl., 2007, 13, 1246-1253.
61. Kornberg A, Kupper B, Tannapfel A, Thrum K, Barthel E, Habrecht O, et al. Transplantation,2008,86,469-473.
62. Rodriguez-Luna H, Vargas HE. Management of hepatitis C virus infection in the setting of liver transplantation. Liver Transpl.,2005,11;479-489.

http://www.news-medical.net/news/20110608/Hepatitis-C-virus-(HCV)-associated-liver-disease-after-liver-transplantation.aspx

Medscape;Coffee Consumption is Associated with Response to Peginterferon/Ribavirin Therapy in Hepatitis C

From Gastroenterology

Coffee Consumption is Associated with Response to Peginterferon and Ribavirin Therapy in Patients with Chronic Hepatitis C

Neal D. Freedman; Teresa M. Curto; Karen L. Lindsay; Elizabeth C. Wright,; Rashmi Sinha; James E. Everhart

Posted: 06/24/2011; Gastroenterology. 2011;140(7):1961-1969. © 2011 AGA Institute

http://www.medscape.com/viewarticle/744495

Abstract and Introduction


Abstract

High-level coffee consumption has been associated with reduced progression of pre-existing liver diseases and lower risk of hepatocellular carcinoma. However, its relationship with therapy for hepatitis C virus infection has not been evaluated.

METHODS: Patients (n = 885) from the lead-in phase of the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis Trial recorded coffee intake before retreatment with peginterferon α-2a (180 μg/wk) and ribavirin (1000–1200 mg/day). We assessed patients for early virologic response (2 log10 reduction in level of hepatitis C virus RNA at week 12; n = 466), and undetectable hepatitis C virus RNA at weeks 20 (n = 320), 48 (end of treatment, n = 284), and 72 (sustained virologic response; n = 157).

RESULTS: Median log10 drop from baseline to week 20 was 2.0 (interquartile range [IQR], 0.6 –3.9) among nondrinkers and 4.0 (IQR, 2.1– 4.7) among patients that drank 3 or more cups/day of coffee (P trend <.0001). After adjustment for age, race/ethnicity, sex, alcohol, cirrhosis, ratio of aspartate aminotransferase to alanine aminotransferase, the IL28B polymorphism rs12979860, dose reduction of peginterferon, and other covariates, odds ratios for drinking 3 or more cups/day vs nondrinking were 2.0 (95% confidence interval [CI]: 1.1–3.6; P trend = .004) for early virologic response, 2.1 (95% CI: 1.1–3.9; P trend = .005) for week 20 virologic response, 2.4 (95% CI: 1.3–4.6; P trend = .001) for end of treatment, and 1.8 (95% CI: 0.8 –3.9; P trend = .034) for sustained virologic response.

CONCLUSIONS: High level consumption of coffee (more than 3 cups per day) is an independent predictor of improved virologic response to peginterferon plus ribavirin in patients with hepatitis C. Introduction Approximately, 70%–80% of individuals exposed to hepatitis C virus (HCV) become chronically infected.[1] Worldwide these individuals are estimated to number between 130 and 170 million.[2] Treatment with peginterferon and ribavirin resolves chronic hepatitis C in about half of patients.[3,4] However, those who fail or are unable to tolerate treatment have few current treatment options. A number of factors affect response to therapy,[5] including African-American race,[6–8] presence of cirrhosis,[8] baseline aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio,[8] baseline serum HCV level,[8] insulin resistance,[9,10] particular single nucleotide polymorphisms, including rs12979860 or rs8099917 near IL28B,[11–15] genotype 1 of HCV,[8,16,17] and patients' ability to tolerate full doses of peginterferon during treatment.[18] Coffee drinking has been associated with several aspects of liver health, including concentrations of the liver enzymes ALT, AST, and γ-glutamyltransferase,[19–24] progression of pre-existing liver disease,[25] and hepatocellular carcinoma.[26,27] It is not known whether coffee affects spontaneous HCV clearance or, among chronically infected individuals, patients' response to HCV therapy.[28]

Therefore, we investigated the association between coffee intake and virologic response to peginterferon plus ribavirin treatment in the lead-in phase of the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C) Trial of patients with baseline fibrosis or cirrhosis who had failed previous interferon therapy.[29]

Materials and Methods

As described previously,[8,18,29,30] the lead-in phase of HALT-C enrolled 1145 HCV-positive patients who had an Ishak fibrosis score ≥3, had failed previous interferon treatment, and had no evidence of hepatic decompensation or hepatocellular carcinoma. During lead-in, patients received 180 μg per week of peginterferon α-2a and 1000 mg/day ribavirin for those weighing ≤75 kg and 1200 mg/day for those weighing >75 kg. Patients with declining neutrophil, platelet, or hemoglobin counts, or other adverse effects, were managed by dose reduction of peginterferon and or ribavirin.[18] The amount of medication taken by each patient during the first 20 weeks was expressed as a proportion of the original prescribed dosage. The study protocol was approved by the institutional review board of each participating institution and written consent was obtained from all patients.

Assessment of Coffee and Tea Consumption

At the beginning of the lead-in-phase, patients completed a previously validated[31,32] Block 98.2 food frequency questionnaire (FFQ; NutritionQuest, Berkeley, CA). Patients reported typical intake of 110 food items during the past year using 9 frequency categories ranging from "never" to "every day" and 4 categories of portion size (ie, 1 cup, 2 cups, 3–4 cups, and 5+ cups). One question assessed coffee intake and did not distinguish decaffeinated from caffeinated coffee. A second question assessed tea intake and did not distinguish black from green tea. Patients failing lead-in therapy entered the randomized phase and completed a second Block FFQ approximately 1 year after beginning the randomized phase.

For analysis, we created categorical variables of coffee (never, >0 to <1, ≥1 to <3, and ≥3 cups/day) and tea intake (never, >0 to ≥1, ≥1 to <2, and ≥2 cups/day). We excluded 259 patients who did not complete an FFQ and 1 patient with extreme caloric intake (>2 interquartile ranges [IQR] from the median), leaving 885 patients for the current analysis. Patients completing the FFQ were similar to those who did not, other than being more typically white (76.2% vs 65.3%; P = .034) and having a lower baseline AST/ALT ratio (median = 0.78 vs 0.82; P = .0056).

Assessment of Outcomes

Serum samples obtained from all subjects enrolled in the HALT-C Trial were tested in real-time at the University of Washington Virology Laboratory with both the quantitative Roche COBAS Amplicor HCV Monitor Test, v. 2.0 assay (lower limit of detection 600 IU/mL) and, if negative, by the Roche COBAS Amplicor HCV Test, v. 2.0 assay (Roche Molecular Systems, Branchburg, NJ) with lower limit of detection 100 IU/mL as described previously.[8,33] HCV genotypes were determined with the INNO-LiPA HCV II kit (Siemens Medical Solutions Diagnostics, Tarrytown, NY). Serum HCV RNA level was assessed at baseline, along with week 12, week 20, and week 48 of treatment. Early virologic response was de- fined as a ≥2-log10 decline in serum HCV RNA level at week 12. Week 20 virologic response was defined as the absence of detectable serum HCV RNA (<100 IU/mL) at week 20. Week 20, as opposed to the traditional week 24, was chosen in order to provide sufficient time to identify nonresponders for randomization into the main HALT-C trial. Patients with undetectable virus at week 20 continued to receive peginterferon plus ribavirin treatment for an additional 28 weeks (48 weeks total), at which point treatment was stopped. Sustained virologic response was defined as the absence of detectable serum HCV RNA at week 72, twenty-four weeks after the end of treatment. For analysis, we set undetectable viral levels at the detection limit (100, ie, 2 log10, IU/mL).

Statistical Analysis

All tests were 2-sided and α < .05 was considered to be statistically significant. Analyses were performed with SAS software (release 9.2, SAS Institute, Cary, NC). We tabulated baseline behavioral and clinical, demographic, and genetic features by categories of coffee intake. The Jonckheere-Terpstra test for trend for continuous variables and the Mantel-Haenszel test for trend for categorical variables were used to assess variation across categories of coffee intake. Variation across categories of race/ethnicity was assessed by the Pearson χ[2] test. Associations between coffee and tea intake with virologic response were determined using logistic regression. Linear trend tests were performed by assigning participants the median intake for their categories and entering that term as a continuous variable in the regression models. We present results from unadjusted crude models, along with models adjusted for continuous baseline age, AST/ALT ratio, log HCV RNA level, hemoglobin, neutrophils, platelets, and categories of sex, race/ethnicity, alcohol use at baseline, cirrhosis, HCV genotype 1, previous use of ribavirin, dose reduction of peginterferon during the first 20 weeks of treatment, and rs12979860 genotype. Additional adjustment for Short Form-36[34] general health, physical function, or vitality quality of life scores, packyears of cigarettes, rs8099917 genotype, dose reduction of ribavirin during the first 20 weeks of treatment, body mass index, the homeostatic model assessment score of insulin resistance (HOMA2), total serum cholesterol, high-density lipoprotein cholesterol, or triglycerides had no appreciable effect on risk estimates for virologic response (data not shown). Additionally, we performed propensity score analysis[35] in order to better balance possible confounders between coffee drinkers and nondrinkers. We created a propensity score for coffee intake using the following covariates: age (continuous), sex, race/ethnicity (white, African American, Hispanic, other), alcohol use (current, former, and never), cirrhosis at baseline, genotype 1, AST/ALT ratio (continuous), log HCV RNA level at baseline (continuous), previous use of ribavirin, hemoglobin (continuous), neutrophils (continuous), platelets (continuous), categories of peginterferon medication dose during first 20 weeks of treatment (≥98%–100%, ≥80%–<98%, ≥60%–<80%, and <60%), and rs12979860 genotype (TT, CT, CC). We then adjusted risk estimates for coffee with virologic response for quintiles of the propensity score using indicator variables. Risk estimates were also calculated across strata of propensity score quintiles.

We investigated possible interactions between coffee intake and number of clinical and behavioral features by examining the association between coffee and virologic response by stratum of each clinical and behavioral feature. We formally tested for effect modification by including an interaction term between each stratifying variable and continuous coffee intake in the model.

We present results from unadjusted crude models, along with models adjusted for continuous baseline age, AST/ALT ratio, log HCV RNA level, hemoglobin, neutrophils, platelets, and categories of sex, race/ethnicity, alcohol use at baseline, cirrhosis, HCV genotype 1, previous use of ribavirin, dose reduction of peginterferon during the first 20 weeks of treatment, and rs12979860 genotype. Additional adjustment for Short Form-36[34] general health, physical function, or vitality quality of life scores, packyears of cigarettes, rs8099917 genotype, dose reduction of ribavirin during the first 20 weeks of treatment, body mass index, the homeostatic model assessment score of insulin resistance (HOMA2), total serum cholesterol, high-density lipoprotein cholesterol, or triglycerides had no appreciable effect on risk estimates for virologic response (data not shown).

Additionally, we performed propensity score analysis[35] in order to better balance possible confounders between coffee drinkers and nondrinkers. We created a propensity score for coffee intake using the following covariates: age (continuous), sex, race/ethnicity (white, African American, Hispanic, other), alcohol use (current, former, and never), cirrhosis at baseline, genotype 1, AST/ALT ratio (continuous), log HCV RNA level at baseline (continuous), previous use of ribavirin, hemoglobin (continuous), neutrophils (continuous), platelets (continuous), categories of peginterferon medication dose during first 20 weeks of treatment (≥98%–100%, ≥80%–<98%, ≥60%–<80%, and <60%), and rs12979860 genotype (TT, CT, CC). We then adjusted risk estimates for coffee with virologic response for quintiles of the propensity score using indicator variables.

Risk estimates were also calculated across strata of propensity score quintiles. We investigated possible interactions between coffee intake and number of clinical and behavioral features by examining the association between coffee and virologic response by stratum of each clinical and behavioral feature. We formally tested for effect modification by including an interaction term between each stratifying variable and continuous coffee intake in the model.

Results

Of the 885 patients who began full-dose peginterferon and ribavirin therapy, 85% drank coffee and 14.9% of patients drank 3 or more cups per day. At baseline, those consuming higher quantities of coffee were more likely to be white; drink alcohol and smoke cigarettes; have the CC genotype of rs12979860 (near IL28B); have higher hemoglobin, neutrophils, platelets, and total cholesterol; less likely to have cirrhosis at baseline; and have lower serum AST/ALT and HOMA2 score of insulin resistance (P < .05 for all; Tabel 1

Click Here For  Table 1).

Although 50.4% of noncoffee drinkers tolerated the full dose of peginterferon α-2a during treatment, 60.6% of 3 or more cups per day coffee drinkers tolerated the full dose (P = .0015). Among determinants of peginterferon dose reduction, 58% were due to low neutrophils and 22.6% were due to low platelets.

During treatment, coffee drinkers were less likely to have a dose reduction due to either low neutrophils (P = .016) or platelets (P = .059). The relationships between coffee and clinical and demographic variables were generally similar in analyses restricted to white patients (n = 674), although we noted one difference. The association for coffee with rs8099917 genotype became statistically significant (P = .001).

More coffee consumption was associated with slightly higher baseline HCV RNA levels (P for trend = .007) (Table 2). Yet with increasing coffee intake, the decline in patients' serum HCV RNA level from baseline was greater and absolute levels of patients' serum HCV RNA at weeks 12 and 20 were lower (Table 2).

Click To Enlarge Table 2

For example, the median log10 HCV RNA at week 20 was 4.6 (IQR, 2.0 –5.8) for nondrinkers and 2.0 (IQR, 2.0–4.3) for those who drank 3 or more cups per day (P trend <.0001). Consistent results were observed for the log decrease in HCV RNA from baseline to week twelve, 1.7 (IQR, 0.7–3.6) in nondrinkers vs 3.7 (IQR, 1.8–4.2) for 3 or more cups per day drinkers; P trend <.0001) and from baseline to week twenty, 2.0 (IQR, 0.6 –3.9) in nondrinkers vs 4.0 (IQR, 2.1–4.7) for 3 or more cups per day drinkers; P trend < .0001).


Coffee drinkers were also more likely to have a virologic response according to the predefined end points

Click To Enlarge Table 3




Among nondrinkers, 45.7% had an early virologic response (≥2 log drop in their serum HCV RNA level at week 12), 26.3% had no detectable serum HCV RNA at week 20, 21.8% had no detectable serum at week 48, and 11.3% had a sustained virologic response. In contrast, the corresponding proportions for 3 or more cups per day coffee drinkers were 72.7%, 52.3%, 49.2%, and 25.8%, respectively. From crude logistic regression models, patients who drank 3 or more cups per day of coffee were about 3 times more likely to have a virologic response at the 4 time points of interest (Table 3).


Ability to tolerate treatment had minimal effect on the relationship of coffee and virologic response. For example, the odds ratio for patients who drank 3 or more cups per day relative to nondrinkers for week 20 response changed slightly from 3.07 (crude: Table 3) to 2.92 (data not in Table) with control for peginterferon dose and the P trend remained highly statistically significant (P trend <.0001). Multivariate adjustment for age, sex, race/ethnicity, alcohol use, cirrhosis at baseline, genotype 1, AST/ALT ratio, log HCV RNA level at baseline, previous use of ribavirin, hemoglobin, neutrophils, platelets, peginterferon medication dose during first 20 weeks of treatment, and rs12979860 genotype, attenuated associations with coffee, although associations remained significant for each virologic response end point (Table 3). Risk estimates using propensity score methods were similar to those from multivariate adjusted models (data not shown).


In contrast to results for coffee, no effect was observed for drinking tea (P trend = .92, .96, .89, and .49 for early, week 20, week 48, and sustained virologic response, respectively).

In stratified analyses, we investigated effect modification (interaction) for week 20 HCV negativity across stratum of HCV genotype, race/ethnicity, cirrhosis at baseline, baseline AST/ALT ratio, hemoglobin, neutrophils, platelets, total cholesterol, HOMA2 score, Short Form-36 general health score, dose reduction of peginterferon, alcohol use, cigarette smoking, or rs12979860 genotype. Results are presented for week 20 virologic response, but were similar for early virologic response (week 12), end of treatment response (week 48), and sustained virologic response (week 72; data not shown). Risk estimates generally appeared similar in each stratum and the P values for interaction were all >.05 (Figure 1). For example, of the 454 patients who tolerated full dose, 43.4% had a week 20 virologic response compared with 28.5% of the 431 patients who took less than full dose. The relative benefit of coffee on virologic response was similar in these two groups (odds ratio = 1.26 for full dose and 1.18 for lower dose) despite the absolute difference in response. The relationships between coffee and virologic responses were also very similar in analyses restricted to white patients. Specifically, there was a statistically significant increase in week 20 virological response per cup increase in coffee consumption among white patients. Associations between coffee intake and virologic response were apparent in patients with both fibrosis and cirrhosis at baseline; although stronger in those with fibrosis. Finally, risk estimates for coffee appeared stronger in patients with the less favorable IL28B rs12979860 TT or CT genotype, although again, differences in risk estimates were not statistically significant. We were unable to determine coffee intake during lead-in therapy. But for patients failing lead-in therapy, coffee intake was assessed on a second occasion, 18 months after baseline, ie, 12 months after these patients had been randomized to low-dose peginterferon or no treatment. Median coffee intake was the same (1 cup per day) at baseline and at the second time point for patients in both randomization groups. The weighted κ for the 2 assessments was .58 overall (P < .0001), .54 in those receiving treatment (P < .0001), and .63 in those receiving no-treatment (P < .0001), indicating good agreement.

Figure 1.


Stratified analysis of the association of baseline coffee intake with week 20 virologic response in the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) Trial. Odds ratios shown are for an increase in coffee consumption of 1 drink per day and are adjusted for age (continuous), sex, race/ethnicity (white, African American, Hispanic, other), alcohol use (current, former, and never), cirrhosis at baseline, genotype 1, aspartate aminotransferase to alanine aminotransferase (AST/ALT) ratio (continuous), log hepatitis C virus (HCV) RNA level at baseline (continuous), previous use of ribavirin, hemoglobin (continuous), neutrophils (continuous), platelets (continuous), categories of peginterferon medication dose during first 20 weeks of treatment (≥98%–100%, ≥80%–<98%, ≥60%–<80%, and <60%), and rs12979860 genotype (TT, CT, CC). Median values were used to define cut-points for the starred characteristics. Black diamond indicates the overall point estimate. Black circles, squares, and triangles represent the point estimate for each indicated subgroup. Horizontal lines represent 95% confidence intervals (CI). The solid vertical line indicates an odds ratio of 1. P values are for the interaction between coffee intake and each stratifying variable and are taken from the Wald test for the cross-product term of each stratifying variable and continuous coffee intake.


Discussion

In patients with advanced HCV-related chronic liver disease in the HALT-C trial receiving peginterferon plus ribavirin treatment, 3 or more cups per day coffee drinkers were 3 times more likely to have a virologic response than nondrinkers. Associations were attenuated but persisted after adjustment for a wide range of behavioral, clinical, and genetic features, suggesting an effect independent of other known risk factors. In contrast to results for coffee, no effect was observed for tea drinking.

Coffee intake has been associated with lower level of liver enzymes, reduced progression of chronic liver disease,[25] and reduced incidence of hepatocellular carcinoma.[26,27] Because few other data on the association of coffee drinking with virologic response are available, the association observed here needs replication in other studies.

A number of risk factors have previously been associated with virologic response in HALT-C and in other studies,[5,8,12,14,15,18,25] including African American race, presence of cirrhosis, AST/ALT ratio, serum HCV RNA level, particular genotypes near the IL28B gene, and ability to tolerate full doses of peginterferon during treatment. Intriguingly, coffee was modestly associated with nearly all of these factors. African Americans in our study tended to drink less coffee than white patients, and coffee drinking was associated with lower AST/ALT ratio, ability to tolerate full doses of peginterferon α-2a during treatment, and particular genotypes of single nucleotide polymorphisms near to the IL28B gene, which have recently been linked to virologic response.[11–15] Yet, the association for coffee persisted after adjustment for these and other potential confounders and was similar across stratums of each of these risk factors, eg, a similar effect for coffee on virologic response was observed for both those receiving a full dose of peginterferon and those having a dose reduction. These results suggest that coffee drinkers had a better response to treatment that was independent of other risk factors, including higher tolerance for peginterferon treatment.

Associations between coffee and features associated with virologic response raise the possibility of reverse causality, ie, sicker patients were less likely to drink coffee and, in this way, less likely to respond to treatment. But in HALT-C, patients drinking coffee reported a worse quality of life on the Short Form-36 quality of life questionnaire than nondrinkers. Quality of life was also not associated with virologic response. As in all observational studies, we cannot exclude unmeasured or residual confounding as an explanation for our results. Observed associations could also simply be due to chance.

Coffee has >1000 compounds, any one of which could be involved in virologic response. One major constituent of coffee is caffeine. Although we could not distinguish caffeinated from decaffeinated coffee in our study, we found no association with consumption of black or green tea. Fewer individuals consumed tea in our study and tea contains less caffeine than coffee. It is unlikely that coffee and its constituents have a direct antiviral effect. If so, HCV RNA levels at baseline would have been expected to be lower with greater coffee consumption. In fact, baseline levels were actually higher with greater consumption (Table 2). More likely coffee would have a facilitating effect on response to peginterferon and ribavirin treatment by a mechanism yet to be understood. It is intriguing that the C allele of rs12979860 near the IL28B gene has been associated with higher baseline viral levels, lower levels of interferon-stimulated gene expression, and better treatment response.[14,36,37] The IL28B genotype effect on virologic response may be through the Janus kinasesignal transducer and activator of transcription pathway.[38] Recently published results potentially link kahweol, a diterpene in coffee, to Janus kinase-signal transducer and activator of transcription pathway,[39] suggesting one of many possible mechanisms for the observed association in our study.

A number of studies have linked high serum total and low-density lipoprotein (LDL) cholesterol with increased virologic response to peginterferon plus ribavirin therapy.[40–42] LDL has also been recently posited to mediate, at least partly, the effect of the rs12979860 C allele.[41,43] Coffee intake was associated with higher serum total cholesterol in our study and has also been linked to higher serum total cholesterol and LDL in past observational and interventional studies.[44] Adjustment for total cholesterol, however, did not affect risk estimates in the current analysis. We lacked assessment of LDL. Alternatively, insulin resistance has been associated with poor virologic response in a number of previous studies.[9,10] Consistent with previous studies of type 2 diabetes,[45,46] coffee intake was inversely associated with insulin resistance in HALT-C. Adjustment for HOMA2 score did not affect risk estimates for coffee with virologic response in the current analysis.

Our study has several advantages, including a large number of patients with histological staging of liver fibrosis, careful assessment of virologic response using a central virology laboratory, and comprehensive assessment of clinical and histologic features. Limitations include a lack of information on caffeine and coffee brewing methods and the assessment of coffee via self-report at a single time point. As such, we do not know patients' coffee intake at the time of initial treatment or whether coffee consumption was maintained during the course of the lead-in phase. However, for patients failing lead-in therapy subsequently randomized to half-dose peginterferon treatment or to no treatment, coffee consumption was similar at baseline and 18 months later (6 months after randomization). Because patients in HALT-C also had previously failed interferon therapy, it is not clear whether our results can be generalized to other patient populations, such as those with less advanced disease, those who are treatment-naïve to prior therapy, or who are being treated with newer antiviral agents.

In summary, we observed an independent association between coffee intake and virologic response to peginterferon plus ribavirin retreatment in the lead-in phase of the HALT-C trial. Future studies are needed to replicate this finding in other populations.

References


Authors and Disclosures

Neal D. Freedman,* Teresa M. Curto,‡ Karen L. Lindsay,§ Elizabeth C. Wright,‖ Rashmi Sinha,* and James E. Everhart¶ for the Halt-C Trial Group

*Nutritional Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Rockville, Maryland; ‡New England Research Institutes, Watertown, Massachusetts; §Division of Gastrointestinal and Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, California; ‖Office of the Director, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland; ¶Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland

Hepatitis News;Listen "New Treatment for HCV" and Online Chat/Webcam to Instruct on Injecting HCV Drugs

Listen; New Treatment for Hepatitis C

New studies show a recently approved drug for Hepatitis C doubles the cure rate of the standard treatment. We discuss the new treatment, and the disease that affects nearly four million Americans and is linked to about 12,000 deaths a year.

Host: Dave Iverson
Guests:
Natalie Bzowej, director of clinical viral hepatitis at the California Pacific Medical Center and principal investigator on the clinical trials that led to the approval of the new Hepatitis C medication

Orlando Chavez, Hepatitis coordinator at the Berkeley Free Clinic



http://www.kqed.org/a/forum/R201106240931


Widow Questions How Vet Caught  HCV in Vietnam War
Dear Sgt. Shaft: I want to know why the military did not send out information to all Vietnam-era veterans asking them to get checked for ...
http://www.washingtontimes.com/news/2011/jun/28/sgt-shaft-widow-questions-how-vet-caught-hepatitis/


Online Chat and Webcam Used to Instruct on Injecting Hepatitis C Drugs
ITSRx is an online specialty pharmacy that dispenses drugs for serious and chronic diseases like cancer, hepatitis C and multiple sclerosis. Many of the medications have to be injected, which means the retailer's customer service agents often have to assuage the concerns of those new to the drugs.


For years the retailer handled those requests via e-mail, phone, mail or fax. But last September it launched both a webcam-based video chat and a text-based live chat program. The video chat service gives customers the option of scheduling one-on-one private consultations via webcam with ITSRx pharmacists. A customer, for example, can show the pharmacist how he is injecting the needle to see if he is doing it correctly. Or he can talk with the pharmacist about drug interactions or side effects.

http://www.internetretailer.com/2011/06/30/customer-service


Over 75 Percent Cured of Hep C with Incivek
A new antiviral drug that recently won federal approval to treat hepatitis C can effectively cure most patients of the infectious disease, which for more than 20 years has been notoriously difficult to treat, according to two studies released today.

Roughly 80 percent of patients with the most common strain of hepatitis C and who had either never undergone treatment before or had suffered a relapse were cured when they took the antiviral Incivek in addition to the standard drugs, according to one study led by researchers at California Pacific Medical Center and published in the New England Journal of Medicine.

That is a marked improvement over the previous treatment, which cured less than half of those patients. Most patients in the study were able to stop treatment after 24 weeks instead of the standard 48 weeks - a significant change, because the drugs can have brutal side effects.

"This is going to change the field of hepatitis C dramatically," said Dr. Natalie Bzowej, a liver disease specialist at California Pacific Medical Center who was a lead researcher in the study. "The treatment may not be easier, but it does have a higher chance of cure. And side effects are a lot more tolerable if you have them for a shorter period of time."

What 'cure' means
Hepatitis C is a viral infection that is transmitted through the blood, similar to HIV. Like HIV, it has long carried a stigma that can prevent people from being screened for the virus or seeking treatment. Patients are considered cured of hepatitis C when the virus is no longer detectable in their blood, but it is possible for traces of the virus to remain, and people may have relapses.

About 4 million Americans are thought to be infected with hepatitis C, although public health officials believe 75 percent of them don't know it. New cases of hepatitis C are decreasing year to year, but Baby Boomers are thought to be a large reservoir of the disease. They were more likely than other generations to have been exposed to the virus, through anything from intravenous drug use in the '70s to blood transfusions in the '80s, when the nation's blood supply was much less protected.

Risk of liver cancer
Hepatitis C typically affects only the liver, and symptoms often don't become apparent until liver damage has started. One in 10 people infected with hepatitis C is able to lose the virus without any medical intervention. The remaining people have chronic hepatitis C, although about 80 percent of them will never suffer serious symptoms.

But in up to 20 percent of chronic patients, hepatitis C causes severe liver damage and can lead to liver cancer. The infection kills about 10,000 people every year in the United States, and it's the leading reason for liver transplants.

"You're talking about a disease that affects millions of people, and now we can more than double the response rate to medication. This is a very big deal," said Dr. Joanna Ready, chief of gastroenterology at Kaiser Santa Clara, who handles all of the hepatitis C cases there.

Incivek and an antiviral called Victrelis were approved by the U.S. Food and Drug Administration last month to treat people with the most common strain of hepatitis C. Both drugs are used in conjunction with the previous standard treatment for hepatitis C.

Difficult therapy
That treatment is a toxic cocktail of weekly intravenous chemotherapy drugs and an older antiviral that patients took for at least 48 weeks - if they could tolerate the side effects, which included flu-like symptoms, anemia and depression. The treatment didn't reach the hepatitis C virus specifically, but boosted the patient's immune system to help it fight off the infection.

But the treatment was effective only about 46 percent of the time, and if people underwent the drug therapy once without success, their chances of a cure if they tried again were slim - only about 5 percent if the earlier treatment didn't work at all...............continue reading........


Smartphones used in life-saving procedures
LONDON, Ont. - Scalpel . . . Check. Sutures and sponges . . . Check. Smartphone . . . Check.

Smartphones may become a must for London surgeons sent to retrieve organs for transplant surgery after a Blackberry Bold was used to secure a liver for a patient dying in London.

The clock was ticking when two London surgeons and a transplant co-ordinator from London Health Sciences Centre (LHSC) were dispatched out of town to remove a liver from a middle-aged man who had sustained brain death from a head trauma.

Days earlier, a 56-year-old man with hepatitis C had been taken to a London hospital with his liver failing, joining a waiting list that for some becomes a death sentence because they die before an organ is found.

On a scale of 1 to 40, with 40 being the most severe liver failure, the man rated a 34.

"This was a person who was very sick with significant liver failure. A not insignificant proportion of people die waiting for a transplant," said Dr. Kris Croome, a surgeon developing expertise transplanting livers, a specialty area for London surgeons who transplant about 70 livers a year.

Croome was joined by a more senior trainee, Dr. Jeff Shum, and a transplant co-ordinator, Michael Bloch.

Back in London, transplant surgeon Roberto Hernandez prepped the hepatitis patient for an operation -- the doctor had to be ready to go when the liver returned because a liver is generally useful only within six to eight hours of being removed.

The retrieval team operated on the brain-dead patient, removed his liver, only to find a 6-cm. lesion that could be cancerous or otherwise make it unsuitable for an organ. They phoned Hernandez, asking if they should return with the liver or cancel the operation and hope another organ became available.

Had a smartphone not been used, Hernandez would have likely had to cancel the transplant. Instead, he directed Croome and Sum to take a series of photos that were e-mailed back to London. Each image prompted further surgical investigation of the lesion and together they allowed Hernandez to give a green light to the operation.

A year later, the hepatitis patient is alive and doing well.

The work of the London team is garnering attention after an account was published in the Journal of Telemedicine and Telecare. And London transplant surgeons are seriously considering making smartphones required equipment for surgery.

"It had worked so well we should put that out there," Croome said.
A smartphone was also used a month ago to help rule out the use of a liver, saving a patient in London from enduring the start of an operation that would have to be cut short.

"The current case illustrates how smartphone technology can be an invaluable tool in performing real time consultations," the London team wrote in the journal.
http://www.sunnewsnetwork.ca/sunnews/sciencetech/archives/2011/07/20110702-091929.html

 
Cirrhosis risk score predicts fibrosis progression in HCV
The latest Journal of Hepatology investigates role of a cirrhosis risk score for the early prediction of fibrosis progression in hepatitis C patients with minimal liver disease.

Fibrosis progression in patients with chronic hepatitis C is highly variable.

A Cirrhosis Risk Score (CRS) based on 7 genetic variants has been recently developed for identifying patients at risk for cirrhosis.

Dr Eric Trépo and colleagues assessed the role of the CRS for the early prediction of fibrosis progression in chronic hepatitis patients with mild liver fibrosis.

In addition, the research team evaluated the potential benefit, for prediction accuracy, of a recently described non-invasive fibrosis staging assay, the Enhanced Liver Fibrosis (ELF) test.

The research team retrospectively analyzed separate cohorts of HCV patients.

Only patients with a fibrosis Ishak or METAVIR score of F0–F1 at baseline were included.
The Cirrhosis Risk Score was associated with fibrosis progression
Journal of Hepatology

The researchers classified patients as progressors if they showed an increase 2 fibrosis stages at the second histological evaluation after a follow-up of 5 years.

The Cirrhosis Risk Score was calculated locally. Genotyping was performed by PCR and oligonucleotide ligation with the resulting signal detected with a Luminex® 200TM and computer analysis.

In Brussels, 48% of patients progressed.

Similarly in Hannover, 52% of patients progressed.

In both sample sets, the Cirrhosis Risk Score was significantly associated with fibrosis progression.

The team noted that the ELF test was only a significant predictor in Hannover.

On further analysis, the researchers found that the Cirrhosis Risk Score remained the only variable associated with fibrosis progression.

Dr Trépo's team concludes, "Although conducted on a limited number of patients, this study in 2 independent centres confirms that the Cirrhosis Risk Score predicts fibrosis progression in initially mild chronic hepatitis C."
http://www.gastrohep.com/news/news.asp?id=108147


Outcomes of adult living donor liver transplantation
This month's issue of Liver Transplantation compares the adult-to-adult living donor liver transplantation cohort study with the national experience.

Dr Kim Olthoff and colleagues from Philadelphia, USA determined whether the findings of the Adult-to-Adult Living Donor Liver Transplantation Cohort Study (A2ALL) reflect the U.S. national experience.

In addition, the team defined risk factors for patient mortality and graft loss in living donor liver transplantation.

A2ALL previously identified risk factors for mortality after living donor liver transplantation, which included early center experience, older recipient age, and longer cold ischemia time.

The team evaluated living donor liver transplantation procedures at 9 A2ALL centers, and 67 non-A2ALL centers from 1998 through 2007 in the Scientific Registry of Transplant Recipients database.

The team identified potential predictors of time from transplantation to death or graft failure.
There was no significant difference in overall mortality between centers
Liver Transplantation

The research team observed no significant difference in overall mortality between A2ALL and non-A2ALL centers.

Higher hazard ratios were associated with donor age, recipient age, serum creatinine levels, hepatocellular carcinoma or hepatitis C virus, intensive care unit stay or hospitalization versus home, earlier center experience, and a cold ischemia time more than 4.5 hours.

Except for center experience, the team found that risk factor effects between A2ALL and non-A2ALL centers were not significantly different.

Variables associated with graft loss were identified and showed similar trends.

Dr Olthoff's team commented, "Mortality and graft loss risk factors were similar in A2ALL and non-A2ALL centers."

"These analyses demonstrate that findings from the A2ALL consortium are relevant to other centers in the U.S. performing living donor liver transplantation."

"Conclusions and recommendations from A2ALL may help to guide clinical decision making."

http://www.gastrohep.com/news/news.asp?id=108149


Pharmaceutical
.
Frequently Asked Questions About Ghostwriting
Few topics are more contentious than ghostwriting - the mysterious practice in which an article lands in a medical journal with the names of various authors who, as it turns out, had little or nothing to do with the substance of the publication. The issue has caused several scandals for several drugmakers and medical journals, causing embarrassment and turmoil... continue reading....


The Op-Ed: Pharma Should Not Be Run By Finance

Control of Pharma Operations by Finance: Sign of a Declining Industry

At the same time, the weekly drumbeat of scandals involving off-label marketing, ghostwritten and fudged studies, Medicaid fraud and slanted promotions take their toll - the cost of defending prosecutions and paying fines, as well as eroded public confidence

By Daniel Hoffman, PhD and president of Pharmaceutical Business Research Associates

It is no secret that pharma is going through a rough decade. Over the past ten years, the industry has lost $1 trillion of capitalization. Some equity analysts even suggest that pharma company shares would trade at higher multiples if they labeled themselves as consumer products companies that just happen to run pharma operations. According to one report, this year alone, pharma will lose control over more than 10 blockbusters with combined annual sales nearing $50 billion. And next year, meds with another $44.6 billion in annual sales will lose patent protection.

As top-selling older products fall off the table, compounds in the pipeline show scant potential for replacing these lost revenues. In fact, industry productivity at pursuing its lifeblood mission - developing new compounds that substantially advance the standards of care - has steadily declined. Over the past decade, an annual average of 30 applications for new molecular entitites have been submitted to the FDA. This is down from 45 submissions during 1996 and reflects a 9 percent to 11 percent annual decline that has occurred for some time.

According to equity analysts, this slow pace has created a qualitative change to the point where “research is no longer a core competency.” While the R&D slowdown offers customers fewer compelling reasons to buy new products, payors around the world are also showing ever-increasing resistance to paying the premium prices demanded by branded drugs.

At the same time, the weekly drumbeat of scandals involving off-label marketing, ghostwritten and fudged studies, Medicaid fraud and slanted promotions take their toll - the cost of defending prosecutions and paying fines, as well as eroded public confidence. More important, they have caused many industry customers to try shutting down communication channels that pharma uses to differentiate its brands. Medical specialty societies have been limiting industry-sponsored CME, while medical schools and teaching clinics restrict access of their physicians to pharma’s sales reps.

So amid this perfect storm, how has the industry responded? For the most part they’ve addressed the matter in three ways: cutting R&D, laying off experienced people and raising prices. In a less-is-more approach to new drug development, many big drugmakers have reduced R&D spending - between 2009 and 2012, Pfizer will have cut spending by 9.2 percent, AstraZeneca by 11 percent, GlaxoSmithKline by 11.6 percent and Sanofi by 8.7 percent.

Then there are layoffs. In an economy beholden to short-term horizons, manufacturers are managing according to the trends of their quarterly earnings and/or net income. In line with that imperative, pharmas continued their bottom line growth by cutting SG&A, principally through staff reductions. Last year, pharma led all commercial sectors in terms of the absolute number of layoffs. Only government and non-profits put more people onto the streets.

While layoffs during hard times are inevitable in a private enterprise economy, an ability to raise prices during the worst recession in 70 years is not. Over the last several years, pharma exercised this cartel prerogative by virtue of patent protection and regulatory entry barriers. In 2010, the industry raised drug prices an average 6.9 percent, following a 6.6% increase the year before.

Yet the sure sign that pharma has not figured a way out of its quandary is not the shrinking volume of new products or the apparent lack of well-defined strategies for a changed environment. That indicator appears in the fact that pharma has defaulted its operational management to finance.

As manufacturing executives, finance people possess neither the scientific and technical acumen of R  & D, the creative touches of marketers or the people skills of sales. Perhaps to make these shortcomings appear less obvious, the finance wizards have worked through their henchmen in human resources to systematically eliminate people with extensive knowledge of the industry and its functional operations.

People over age 50, many with hard-earned wisdom, have been shown the door and replaced by 30-year old, business school graduates. With due allowance for exceptions, many of the latter have been miseducated to believe that they can manage all commercial entities, regardless of the industry, with spreadsheets containing the same formulas and ratios.

In their cognitive framework, concepts such as strategic sense, historical tendencies and the intuition borne of experience don’t even exist because insights from those sources have not been adequately quantified and stated in graphic form. Numbers constitute their only reality. As managers, finance people deal in measurement without substance and data without context.

At a time when business research can point the way to new concepts, product lines and organizational approaches, finance managers disdain such insights. Instead they decree that managers in marketing, managed care and other functions should eschew insight and consider business research a commodity function. Finance thereby empowers its hatchet men and women in the purchasing department to select proposals from larger suppliers that offer volume discounts in preference to discernment.

This mismanagement by finance is evident in the extent to which many pharma departments are handcuffed to so-called preferred, value-preferred and agency-of-record suppliers. In the last of these arrangements, finance and/or its purchasing functionaries deploy their blunderbuss wisdom by selecting the most frequent or costliest engagements that a particular department has outsourced during the previous year.

Then they approach one of the largest suppliers of that service and offer them a monopoly to perform one or more of these common/expensive functions in return for an annual cost guarantee amounting to 10 percent to 15 percent below the previous year’s cost. In this manner, research on customer needs and competitor planning becomes equivalent to buying pork bellies or soybeans.

An example appears in a memo that the “vice-president for customer insight” at a big pharma sent to all of his 120-plus charges earlier this year. With a subtlety capable of hitting the broad side of a barn, this VP admonished his supervisees to only use the Preferred/Value Preferred vendors by congratulating them on their subservience the previous year. Their compliance during 2010, in his words, “secured over $250,000 in Value Preferred vendor rebates! These cash rebates directly impact our bottom line.” He then extended “a special thanks…to [redacted]’s team. In 2010, her team had the greatest percentage of their overall spend go towards Preferred Agencies and Value Preferred Agencies — 89%! Nice work Immunology/Arthritis/(overactive bladder) team.”

Although this approach to managing a research-driven business is unsettling, some may question why it indicates an industry in decline and not just pharma during the current down cycle. Their answer may lie in looking to historical precedent. For the most part it, this supports the claim that clueless industries turn to finance management. A recent example comes from the US auto industry, a sector that effectively extended its down cycle for almost 40 years before crawling into bankruptcy.

Consider the recollections of Bob Lutz, an executive who spent 47 years in various auto industry positions, including the presidency of Chrysler and the vice-chairmanship of General Motors. In an excerpt from his memoir, “Car Guys vs. Bean Counters,” Lutz describes a growing obsolescence that overtook the US auto industry by the 1970s. Detroit’s physical plant was older than those of the Japanese, its legacy costs for health care and an older workforce were higher, and the Big Three remained unable to break their dependence on large gas-guzzlers.

“Faced with this environment,” Lutz writes, “General Motors embarked on a series of initiatives to overcome both the perception and reality of the growing import threat.” The common factor in these various palliatives was the decline of what Lutz calls the ‘product guys’ and the ascendancy of finance people.

The finance-dominated culture that came to rule Detroit actually held little regard for cars or customers. Both were seen as merely the incidental means of obtaining financial processes that provided the purpose and satisfaction of the business. According to Lutz:

(The finance culture created a) generalized consensus that we were, after all, primarily in the business of making money, and cars were merely a transitory form of money: put a certain quantity in at the front end, transform it into vehicles, and sell them for more money at the other end. The company cared about “the other two ends” - minimizing cost and maximizing revenue- but assumed that customer desire for the product was a given.

It remains too early to speculate on whether pharma at some point will also require a government bailout. The fact that industry operations presently remain under the thumb of its own finance management, however, brings to mind some dialogue from an Ernest Hemingway story, where one character asked another how a third character went broke.

“Two ways,” came the answer, “first gradually and then all of a sudden.”
http://www.pharmalot.com/2011/07/the-op-ed-pharma-should-not-be-run-by-finance/


Healthy You

Don’t wait until it’s too late to know more about your liver

Recent studies show that one out of 10 Asian Americans are chronically infected with hepatitis B and may not even know it since there are no symptoms in the early stages of the disease. Experts estimate that there is approximately 1.4 to 2 million individuals who are chronically infected with the disease in the United States today. It can lead to liver failure and cancer.

Researchers Dr. Naoky Chih-Su Tsai, Dr. Howman Lam, and Dr. Philip J. Suh, sponsored by Bristol-Myers Squibb, gathered at the Waikiki Edition Hotel for a “Chronic Hepatitis B Awareness” press conference on June 29. The purpose of the event was to educate the community about chronic hepatitis B disease, how it affects peoples’ livers, how the virus spreads from person to person, and disease prevention.

Dr. Lam, a fellow of the American Academy of Family Physicians, the Hawaii Medical Center, the Hawaii Academy of Physicians and a senior associate at Queen’s Medical Center in Hawaii, said, “there is no symptom of chronic hepatitis B. That’s why it is a very dangerous disease.”

Part of the problem is people can be carriers of the disease and not know that they have it or that they need treatment for it to not pass it on to others. Dr. Suh, an internist and a holder of Pediatrics Board Certification, added, “there is always a misconception that hepatitis B carriers think they are fine and do not need to receive any treatment before it is too late.”

According to recent studies, 15 to 40 percent of people with chronic hepatitis B develop serious liver disease, including liver failure, cirrhosis, and liver cancer. Experts say men are up to three times more likely than women to get liver cancer.

“There are misconceptions that a simple kiss, hug, breathing the same air, or dining together are causes of chronic hepatitis B infection,” said Dr. Chih-Su Tsai, the medical director of the Liver Center and Liver Transplant Program at Hawaii Medical Center East, a professor of medicine at the University of Hawaii, and a UNOS certified transplant hepatologist.

“In fact, most of the cases are infected by their mothers because the disease is transmitted only through blood and other bodily fluids,” Dr. Tsai continued.

Dr. Hong Tang, host of the event, also a fellow of the American College of Physicians (FACP) and a director of Viral Hepatitis US Medical at Bristol-Myers Squibb, emphasized the importance of prevention and encouraged people to make sure they have received proper immunization.

“Everyone should have received immunization when they were first born,” added Dr. Lam. “We only have to get three shots within six months in general. But that can be 99.9 percent prevention from getting chronic hepatitis B infected in our lifetime.

“However, if a baby is infected by his mother, he will have to receive an additional shot to kill the virus first before receiving the vaccination,” Dr. Lam said.

Dr. Tang said the additional shot the baby needs to receive “is called Hepatitis B Immune Globulin (HBIG). But that only works for newborn babies. If you are old enough to be a college student, you should go to see doctor and double check it before you feel sick.”

"However, if you are not infected by your mother, there are also other ways to prevent [getting the disease]. In fact, those preventions can be means of transmission if you do not handle them carefully," Dr. Lam continued listing some of the precautions people should take. “Only use sanitized needles for any drug injection or blood donation, take extra care in handling blood products, and do not share tooth brush and shaver with other people. Remember chronic hepatitis B has no symptom. But it can lead to liver cancer.”

The four doctors, including Dr. Tang, reminded people that most of the patients do not have any symptoms before they are in the last stage of liver cancer. In fact, liver cancer is the No. 1 cause of death in China today, according to Dr. Tsai.

“It’s your liver. Take charge now,” is a new motto the doctors hope people will follow.
http://kealakai.byuh.edu/index.php?option=com_content&task=view&id=3998&Itemid=78


Red Meat Increases Risk of Liver Cancer


Summary
This study examines the relationship between meat consumption and the incidence of liver cancer and chronic liver disease mortality. Nearly 500,000 people were included in this questionnaire-based study, of which 551 had developed chronic liver disease and 338 had developed liver cancer by the end of the study. White meat consumption was inversely related to the incidences of both chronic liver disease and liver cancer, while red meat consumption increased the incidence. Thus it may be said that red meat and saturated fat increased the incidence of liver diseases and cancer.

Introduction
Cancer of the liver is the third most common cause of death among overall cancer-related mortalities. It has been known that certain toxins, excess alcohol, and hepatitis virus cause liver cancers and chronic liver diseases. However, liver disorders have been reported even in the absence of the above factors. Recently, red meat has been associated with the increasing incidence of liver cancer. Excess saturated fatty acids in the diet are a risk factor of liver cancer and red meat is a rich source of these fatty acids. Not many studies have investigated the consequences of dietary factors leading to liver cancer. Although many studies have investigated white meat and liver cancer risks, the data on red and white meat influencing chronic liver disorders, is incomplete.

Methodology
A total of 495,006 participants, aged between 50-71 years, took a survey in the year 1995-1997. The questionnaire focused on dietary habits and cooking styles.

The total incidence of liver cancer was ascertained from state cancer registries and the incidence of chronic liver disease was assessed from the National Death Index Plus records.

Further analysis was done by classifying the participants, based on the meat consumed, content of fat intake and risk of cancer or liver disease.

Results
Males consumed more red meat than the females and it was more common among the white non-Hispanics. Men were also found to more frequently use alcohol and cigarettes and consume less fruits and vegetables.

There were a total of 551 deaths from chronic liver diseases and 338 incidences of liver cancer.

White meat consumption was inversely related to chronic liver disease and liver cancer occurrences. But results were opposite with red meat. The hazard ratio for occurrence of chronic liver disease was 0.52 for white meat, whereas it was 4.0 for red meat.

The risk of red meat inducing liver diseases and cancer were escalated on including fat intake, especially saturated fats. Nitrates and nitrites were found to increase the incidence of both liver diseases and cancer.

Shortcomings/Next steps
This study failed to consider the incidence of hepatitis in the participants. The diet of the participants was assessed once and a food frequency questionnaire was used, which, being reported by the participants, could have errors. Pre-existing liver diseases and cancers were not assessed in the participants. The authors suggest the inclusion of details on hepatitis virus infection in future studies.

Conclusion
It is clearly shown, in this study, that red meat consumption could increase the incidence of chronic liver diseases and liver cancer. Also, saturated fats are associated with increased incidence of both the above, irrespective of whether present in red meat or white meat. There was no association found between liver cancer and compounds formed while grilling meat. Red meat like beef, pork, lamb and veal could increase the risk of liver cancer. In fact, saturated fats, which form a major portion of red meat, could make it a higher risk element. Thus, it could be better to consume more white meat like chicken, turkey, and fish, which have less saturated fat content.

For More Information:
Read more at FYI Living: http://fyiliving.com/research/red-meat-increases-risk-of-liver-cancer/#ixzz1QxYW21l5


New On The Blog; Worth A Look

 Lawyers and Doctors Agree: Hepatitis C is Likely Curable; Telaprevir-Incivek, Boceprevir-Victrelis

Emerging therapies for hepatitis C offer a significant increase in SVR and bring treatment complexity

Educational Webcast and Video Podcast of a selection of presentations of the AASLD/CDC SINGLE TOPIC CONFERENCE - Chronic Viral Hepatitis - Strategies to Improve Effectiveness of Screening and Treatment
To view these presentations you must register, the process is quick. During the registration when in doubt type in "none" to proceed. Once you begin to view/hear the webcast click on "Presentation on the sidebar to view slides and data". This is worth the effort folks.

From HCV Advocate;
July 2011

HCV Advocate Newsletter

In This Issue:
The New HCV Epidemic?
Alan Franciscus, Editor-in-Chief
Quick Facts about the PI's
Alan Franciscus, Editor-in-Chief
HealthWise: Resisting Resistance
Lucinda K. Porter, RN
HCV Snapshots
Lucinda K. Porter, RN and Alan Franciscus, Editor-in-Chief
The Next Wave(s)
Alan Franciscus, Editor-in-Chief