SAN DIEGO, Jan. 26, 2011 /PRNewswire/ -- Anadys Pharmaceuticals, Inc. (Nasdaq: ANDS) announced today that dosing has begun in the Phase IIb study of ANA598 in combination with pegylated interferon and ribavirin in hepatitis C patients. ANA598, the Company's direct-acting antiviral, is being tested in both treatment-naive patients and patients who failed a prior course of HCV therapy with interferon and ribavirin. Approximately 275 patients are expected to be enrolled in the study. The primary endpoint of the study is Sustained Virological Response 24 weeks after patients complete treatment, known as SVR24.
The Company expects to receive Week 8 antiviral response data for treatment-naive patients by the end of the second quarter of 2011, Week 12 antiviral response data for treatment-experienced patients in the third quarter of 2011 and Week 24 antiviral response data for both groups in the fourth quarter of 2011.
About Anadys
Anadys Pharmaceuticals, Inc. is a biopharmaceutical company dedicated to improving patient care by developing novel medicines for the treatment of hepatitis C. The Company believes hepatitis C represents a large unmet medical need in which meaningful improvements in treatment outcomes may be attainable with the introduction of new medicines. Anadys is conducting a Phase IIb study of ANA598, the Company's DAA, added to current standard of care for the treatment of hepatitis C. The Company is also preparing to resume clinical development of ANA773, the Company's oral, small-molecule inducer of endogenous interferons that acts via the Toll like receptor 7, or TLR7, pathway in hepatitis C.
Safe Harbor Statement
Statements in this press release that are not strictly historical in nature constitute "forward-looking statements." Such statements include, but are not limited to, references to Anadys' expectations regarding the timing of receipt of data from the study and the ability to achieve the primary endpoint of the study. Such forward-looking statements involve known and unknown risks, uncertainties and other factors, which may cause Anadys' actual results to be materially different from historical results or from any results expressed or implied by such forward-looking statements. For example, the results of preclinical and early clinical studies may not be predictive of future results, and Anadys cannot provide any assurances that ANA598 will not have unforeseen safety issues, will have favorable results in ongoing or future clinical trials or will receive regulatory approval. In addition, Anadys' results may be affected by competition from other biotechnology and pharmaceutical companies, its effectiveness at managing its financial resources, its ability to enter into transactions around its product candidates, its ability to successfully develop and market products, difficulties or delays in its non-clinical studies or clinical trials, difficulties or delays in manufacturing its clinical trials materials, the scope and validity of patent protection for its products, regulatory developments and its ability to obtain additional funding to support its operations. Risk factors that may cause actual results to differ are more fully discussed in Anadys' SEC filings, including Anadys' Form 10-Q for the quarter ended September 30, 2010. All forward-looking statements are qualified in their entirety by this cautionary statement. Anadys is providing this information as of this date and does not undertake any obligation to update any forward-looking statements contained in this document as a result of new information, future events or otherwise.
SOURCE Anadys Pharmaceuticals, Inc.
RELATED LINKS
http://www.anadyspharma.com/
Source
January 26, 2011
HIV+ Liver Cancer Patients Less Likely to Get Transplant
But overall survival in those who received donor organ same as for other patients, study finds
Posted: January 26, 2011
WEDNESDAY, Jan. 26 (HealthDay News) -- HIV-infected patients with liver cancer who are waiting for a liver transplant are more likely to drop off the transplant waiting list than other patients, a new study has found.
But the researchers also found that the overall survival and cancer recurrence-free survival of HIV-infected patients after a liver transplant is the same as other patients.
This finding is especially important because in an era when more HIV patients survive with the use of highly active antiretroviral therapy, end-stage liver disease has now become the main cause of death among HIV patients who are also infected with chronic hepatitis B virus or hepatitis C virus, according to background material in the study. In addition, studies have shown that one-fourth of liver-related mortality in HIV-positive patients is attributable to liver cancer.
In the new study, French researchers analyzed data from 21 HIV-positive and 65 HIV-negative patients with liver cancer who were placed on a liver transplant list between 2003 and 2008. The drop-out rate from the waiting list was 23 percent for the HIV-positive patients and 10 percent for those without HIV, the investigators found.
Among HIV-infected patients, the drop-out factor was related to the patients' alpha-fetoprotein (AFP) levels. Previous research indicates that a greater than 15 microgram per liter (mcg/L) increase per month in a patient's AFP levels while on a liver transplant waiting list is a major predictive risk factor for liver cancer recurrence after a transplant.
Patients with HIV who dropped off the list had much higher AFP levels than those who eventually received a liver transplant -- 98 mcg/L versus 12 mcg/L, respectively. This large degree of difference in AFP levels was not found in HIV-negative patients -- 18 mcg/L for those who dropped off the list versus 13 mcg/L for those who underwent a liver transplant.
"Liver transplantation is the optimum treatment for [liver cancer] and can also be considered for controlled HIV-positive patients with liver cancer," lead author Dr. Rene Adam, from Hospital Paul Brousse, said in a journal news release. "Our study showed that HIV infection impaired the results of liver transplantation on an intent-to-treat basis but exerted no significant impact on overall survival and recurrence-free survival following transplantation."
The researcher also said the study confirmed the importance of AFP levels.
"There is clearly a critical need for more effective neoadjuvant therapy in HIV-positive patients with [liver cancer]; however there are no objective arguments to contraindicate liver transplantation in this group if strict criteria are used for selection and patients are closely monitored until surgery," Adam concluded in the news release.
The study findings were released online in advance of publication in the February print issue of the journal Hepatology.
Source
Also See: Survival following transplant surgery for liver cancer not impacted by HIV-positive status
Posted: January 26, 2011
WEDNESDAY, Jan. 26 (HealthDay News) -- HIV-infected patients with liver cancer who are waiting for a liver transplant are more likely to drop off the transplant waiting list than other patients, a new study has found.
But the researchers also found that the overall survival and cancer recurrence-free survival of HIV-infected patients after a liver transplant is the same as other patients.
This finding is especially important because in an era when more HIV patients survive with the use of highly active antiretroviral therapy, end-stage liver disease has now become the main cause of death among HIV patients who are also infected with chronic hepatitis B virus or hepatitis C virus, according to background material in the study. In addition, studies have shown that one-fourth of liver-related mortality in HIV-positive patients is attributable to liver cancer.
In the new study, French researchers analyzed data from 21 HIV-positive and 65 HIV-negative patients with liver cancer who were placed on a liver transplant list between 2003 and 2008. The drop-out rate from the waiting list was 23 percent for the HIV-positive patients and 10 percent for those without HIV, the investigators found.
Among HIV-infected patients, the drop-out factor was related to the patients' alpha-fetoprotein (AFP) levels. Previous research indicates that a greater than 15 microgram per liter (mcg/L) increase per month in a patient's AFP levels while on a liver transplant waiting list is a major predictive risk factor for liver cancer recurrence after a transplant.
Patients with HIV who dropped off the list had much higher AFP levels than those who eventually received a liver transplant -- 98 mcg/L versus 12 mcg/L, respectively. This large degree of difference in AFP levels was not found in HIV-negative patients -- 18 mcg/L for those who dropped off the list versus 13 mcg/L for those who underwent a liver transplant.
"Liver transplantation is the optimum treatment for [liver cancer] and can also be considered for controlled HIV-positive patients with liver cancer," lead author Dr. Rene Adam, from Hospital Paul Brousse, said in a journal news release. "Our study showed that HIV infection impaired the results of liver transplantation on an intent-to-treat basis but exerted no significant impact on overall survival and recurrence-free survival following transplantation."
The researcher also said the study confirmed the importance of AFP levels.
"There is clearly a critical need for more effective neoadjuvant therapy in HIV-positive patients with [liver cancer]; however there are no objective arguments to contraindicate liver transplantation in this group if strict criteria are used for selection and patients are closely monitored until surgery," Adam concluded in the news release.
The study findings were released online in advance of publication in the February print issue of the journal Hepatology.
Source
Also See: Survival following transplant surgery for liver cancer not impacted by HIV-positive status
Impact of a sustained virological response on the long-term outcome of hepatitis C
Liver International
Special Issue: Proceedings of the 4th Paris Hepatitis Conference. The publication of this supplement was supported by an unrestricted educational grant from F. Hoffmann-Laroche Ltd.
Volume 31, Issue Supplement s1, pages 18–22, January 2011
Alfredo Alberti
Article first published online: 4 JAN 2011
DOI: 10.1111/j.1478-3231.2010.02378.x
© 2011 John Wiley & Sons A/S
Author Information
Department of Histology, Microbiology and Medical Biotechnologies, Venetian Institute of Molecular Medicine, University of Padova, Padova, Italy
* Correspondence: Correspondence Prof. Alfredo Alberti, Department of Histology, Microbiology and Medical Biotechnologies, Venetian Institute of Molecular Medicine, University of Padova, Via Orus 2, 35100 Padova, Italy Tel: +39 049 821 2293 Fax: +39 049 821 1826 e-mail: alfredo.alberti@gmail.com
Keywords:
cirrhosis progression; decompensation; fibrosis; HCC; modelling; natural history; outcomes; remission
Abstract
A sustained virological response (SVR), defined as undetectable hepatitis C virus (HCV)-RNA 24 weeks after withdrawal from therapy (SVR-24w), is the primary endpoint of antiviral therapy in chronic hepatitis C. There is solid evidence that patients who reach this target will remain virus free during long-term follow-up, with a risk of late HCV recurrence of <2% in published series using the most stringent criteria for assessing the virological response during and after antiviral therapy. Long-term observational studies indicate that SVR-24w has a profound impact on the natural course of chronic hepatitis C in relation to biochemical and histological remission of liver disease and improvement in quality of life. The effects of successful antiviral therapy on clinical endpoints such as the development of end-stage liver disease, its severe complications and liver-related mortality have been more difficult to ascertain because of the heterogeneity of the initial staging and rate of progression of chronic hepatitis C. However, most available data suggest that SVR following antiviral therapy reduces the risk of progression to cirrhosis and may prevent the development of severe liver complications and improve survival, at least in successfully treated patients who have already progressed to significant liver fibrosis or early cirrhosis. Outcome modelling suggests that these effects might also include HCV patients treated with milder forms of liver damage.
The primary endpoint of antiviral therapy for chronic hepatitis C is achieving sustained virological response (SVR), defined as undetectable hepatitis C virus (HCV)-RNA in serum 24 weeks after stopping antiviral therapy (SVR-24w). This is the endpoint used in all clinical trials to assess therapeutic interventions as well as by clinicians treating patients. This is because a large body of evidence exists that SVR-24w is an excellent surrogate endpoint to identify a permanent virological cure in most patients, with a clear clinical benefit in many of them. While it has been fairly easy to show that SVR-24w is associated with an extremely low risk of persistent HCV or recurrence during longer follow-up, data on the impact of SVR for more specific clinical endpoints have been limited by the heterogeneity of the initial presentation and rate and speed of chronic hepatitis C disease progression.
It is clear from studies on the natural history of HCV that a minority of patients with chronic infection develop significant life-long clinical complications, and it is also well known that current clinical practice has extended the indication to start antiviral therapy to patients with the mild or moderate hepatitis C, whose risk of progression is often difficult to define. When these patients receive antiviral therapy, data show that SVR improves quality of life and reduces the risk of histological progression. Although there is no direct evidence, outcome modelling suggests that there may be significant effects on clinical complications and survival in a subgroup of patients at risk of more rapid disease progression. On the other hand, solid evidence shows that the risk of developing end-stage liver disease, portal hypertension and hepatocellular carcinoma (HCC) is reduced in patients with more advanced liver disease or cirrhosis who achieve SVR with antiviral therapy.
In this chapter, we briefly discuss the data on the impact of SVR on long-term HCV eradication as well as on biochemical, histological and clinical outcomes in patients with hepatitis C depending on the phase of liver disease when therapy was begun.
Sustained virological response and long-term eradication of hepatitis C virus
There is good evidence that HCV permanently disappears from serum when antiviral therapy is successful. Most experts consider this to be the expression of complete and permanent viral eradication, while data on a persistent occult form of HCV in the liver and/or peripheral blood mononuclear cells (PBMC) are not fully convincing. Because HCV-RNA may be negative in serum during and at the end of antiviral therapy and reactivate after treatment withdrawal in a subgroup of patients with incomplete clearance (relapsers), viral negativity must be confirmed during off-therapy follow-up to confirm a definitive cure of hepatitis C. SVR is the primary goal of antiviral therapy in chronic hepatitis C and is classically defined as the absence, by the most sensitive polymerase chain reaction assay, of HCV-RNA in serum, 24 weeks after therapy has been withdrawn (SVR-24w) (1). This has been the definition since standard interferon (IFN) monotherapy was implemented and remained valid for IFN plus ribavirin combination therapy and more recently for pegylated interferon (PEG-IFN) plus ribavirin combination regimens. The SVR-24w definition of response to therapy will be maintained when new strategies of HCV treatment, including direct antiviral agents, are introduced into clinical practice. Indeed, most published studies as well as extensive clinical experience show that an absence of HCV-RNA in serum 6 months after therapy is the best indicator of HCV clearance, whatever the HCV genotype, patient characteristics, type and duration of treatment. This has been confirmed in several studies evaluating the long-term virological profile in large cohorts of patients treated with different schedules of IFN-based therapies and tested for HCV recurrence several months or years after having achieved SVR-24w.
Recently, Welker and Zeuzem (2) reviewed available data on the rates of late virological relapse in hepatitis C patients treated with IFN (or PEG-IFN) therapy with a sustained response based on the 24 week off-therapy rule. The authors identified 44 studies, including more than 4200 patients who had been followed up to 108 months after the end of therapy. Overall, late virological relapses were rare (3%). There was considerable heterogeneity among the different studies, with some of the smaller series reporting the highest rates of HCV recurrence. On the other hand, the larger series and those with the most stringent criteria to define SVR conclude that negative HCV-RNA in serum 24 weeks after the end of therapy is associated with a durable response and no recurrence of HCV during follow-up in more than 98% of cases.
Some studies have suggested that HCV-RNA may persist in the liver and/or in PBMC in patients who achieve SVR after antiviral therapy and with undetectable HCV-RNA in serum (3, 4). The significance of these findings is uncertain but most available data suggest that they are not clinically significant, at least in the immunocompetent host.
Thus, patients achieving SVR-24w with antiviral therapy can be considered clinically cured of viral infection, with an extremely low risk of late virological recurrence. If this occurs, reinfection rather than a ‘true’ relapse could be suspected and should be evaluated carefully.
Recently, it has been proposed that a 12-week post-treatment follow-up might be as relevant as 24 weeks to determine the sustained virological response in patients with hepatitis C virus receiving PEG-IFN and ribavirin (5).
Biochemical outcomes after sustained virological response
Alanine transaminase (ALT)/aspartate aminotransferase (AST) levels markedly improve in most patients who achieve SVR with antiviral therapy and permanently normalize in many (6, 7). The mean ALT and AST activities after therapy are significantly lower than the pretreatment baseline levels even in HCV carriers who began antiviral therapy with ‘normal’ ALT levels (8). Indeed, eradication of HCV by antiviral therapy in these cases is associated with a significant improvement in liver enzyme levels, which decrease from pretreatment ‘high normal’ to post-treatment ‘low normal’ levels. These findings suggest the presence of ongoing marginal liver disease activity even in HCV carriers with ‘normal’ range ALT levels, in agreement with histological findings of inflammation and fibrosis in around 15–25% of these patients (9).
On the other hand, liver enzymes may not normalize completely in patients with cirrhosis who achieve SVR. The discrepancy between biochemical and virological outcomes does not exclude a clinical benefit and is probably a sign of profound irreversible changes in hepatocyte metabolism from advanced cirrhosis.
As a general rule, other causes of liver damage (coinfections, alcohol, drugs, metabolic abnormalities) should be investigated in patients who achieve SVR with antiviral therapy but still have elevated ALT and/or AST.
Histological outcomes after sustained virological response
Many studies have described the histological outcome following antiviral therapy for chronic hepatitis C and have clearly identified some major differences among non-responders, partial responders, relapsers and sustained responders (10–15). Although the benefit to disease activity and progression with a partial or a transient virological response remains controversial, these studies clearly confirm that SVR is associated with histological improvement in disease activity and associated fibrosis. Liver steatosis is also improved when it is directly linked to HCV as for HCV-3.
The type and degree of histological benefit after SVR is highly dependent on pretreatment activity, the stage of liver disease and the interval between end of therapy and liver biopsy. Improvement in liver inflammation is more evident when a liver biopsy is obtained years rather than months after the end of therapy. The effect of time is even more evident for the regression of liver fibrosis. Available studies indicate that liver inflammation resolves in most, if not all, patients after SVR while improvement in fibrosis (regression) is found in 25–80%, worsening (progression) in only 0–12, and 16–68% remain stable. These results are significantly different from those in patients who do not achieve SVR. Table 1 describes some studies that have evaluated histological outcome after SVR using paired liver biopsies before and at different intervals after antiviral therapy. Available cumulative data on progression to cirrhosis have indicated that the risk after 1–10 years is reduced from 7–10% in non-responders to 0.5–1% in sustained responders, although it should be emphasized that patients who achieve SVR might have a milder and less progressive form of liver disease compared with non-responders.
Reversal of histological cirrhosis has been reported in patients achieving SVR with antiviral therapy. Although in most patients the benefit was limited to regression to METAVIR stage 3, i.e. advanced fibrosis with bridging, a histological sampling error cannot be excluded, other patients have been shown to achieve more marked and permanent histological benefit with regression from signs of cirrhosis to minimal-mild fibrosis.
Recent non-invasive markers of liver fibrosis, such as the FibroTest and FibroScan, have become important new tools for the management of patients with chronic hepatitis C. Results in patients receiving antiviral therapy have confirmed a marked improvement in liver fibrosis indexes following SVR (16, 17). Further validation for the optimized use of these methods during and after antiviral therapy is ongoing in several centres.
Sustained virological response and clinical outcomes
Morbidity and mortality in chronic hepatitis C infection are mainly associated with the complications of cirrhosis and the development of HCC, as well as an increased risk in liver-related deaths. It is therefore essential to assess the impact of SVR on these clinical outcomes. Because of the heterogeneity of the clinical presentation of chronic HCV infection, the slow and unpredictable progression and the lack of longitudinal studies of adequate size and duration, the impact of antiviral therapy and SVR on liver-related complications and mortality has been difficult to determine, especially in patients with milder forms of HCV-related liver disease. Although the endpoint of SVR is clearly associated with reduced histological disease progression in these patients, there is no clear evidence that this will result in reduced morbidity and mortality. At present, many patients with mild chronic hepatitis C are treated with antiviral therapy, especially younger patients or those infected with easy to clear HCV genotypes.
High SVR rates are achieved in these patients and outcome modelling also suggests that successful antiviral therapy could reduce the clinical burden of their disease. On the other hand, there are also convincing results associating a marked improvement in quality of life with SVR after antiviral therapy. This effect is largely independent of the stage of disease when treatment is begun (18). The clinical benefit associated with HCV clearance at any stage of chronic HCV infection is supported by recent results in a large population-based survey by Omland and Krarup (19), showing that overall life-long mortality as well as liver-and HCC-related mortality were significantly lower in HCV patients who showed a clearance of viraemia than in those with chronic viraemia.
Unlike the data for patients with milder forms of chronic hepatitis C, several studies have clearly shown that antiviral therapy with SVR is associated with a marked improvement in clinical outcomes in patients with advanced fibrosis or compensated cirrhosis. Indeed, most studies show that ascites, hepatic encephalopathy, jaundice or gastrointestinal bleeding are extremely rare after SVR has been achieved. Development of hepatocellular carcinoma is also significantly reduced, but patients with cirrhosis who clear HCV during antiviral therapy are still at a risk of developing HCC. Although the risk is certainly much lower than in age/gender/race-matched patients with active disease, continued monitoring is recommended. One of the most recent reports on the impact of combination PEG-IFN and ribavirin therapy on clinical outcome and complications in patients with chronic hepatitis C and advanced fibrosis is that of Cardoso et al. (20). These authors describe long-term outcomes in 307 patients with chronic hepatitis C and advanced fibrosis (127 cases) or cirrhosis (180 cases) treated with PEG-IFN plus ribavirin and followed up for a mean 3–5 years after treatment. SVR-24w was found in 33% of the cases, with no significant differences between patients with advanced fibrosis (37%) and cirrhosis (30%). During follow-up, the incidence of liver-related complications, HCC and liver-related deaths per 100 person – years was 0.63, 1.24 and 0.61, respectively, in patients with SVR and 4.16, 5.85 and 3.66, respectively, in patients without SVR. The difference for each outcome was statistically significant (P<0.001 by log-rank test). Multivariate analysis confirmed that SVR protected against progression to liver complications, HCC and liver-related deaths, with the relative risk in the absence of SVR ranging between 3.06 and 4.73. These results confirm those of several previous studies based on cohorts of patients treated with standard IFN, standard IFN plus ribavirin or PEG-IFN plus ribavirin, showing that antiviral treatment provides a definitive clinical advantage to patients with compensated cirrhosis who tolerate treatment and achieve an SVR.
Another recent study published by Bruno et al. (21) reported the effect of antiviral therapy and SVR on portal hypertension in HCV patients with cirrhosis. The authors reported results in 218 patients with cirrhosis who were untreated or treated with IFN-α-based therapy and followed up for a median 11.4 years. All patients had compensated cirrhosis when therapy began without oesophageal varices. Endoscopic monitoring was performed at 3-year intervals. None of the patients who achieved SVR developed oesophageal varices during follow-up compared with 32% of untreated patients and 39% of treated patients who did not achieve SVR, showing that SVR clinically improved the development of portal hypertension.
In conclusion, SVR improves the clinical outcomes in patients with chronic hepatitis C and advanced fibrosis or compensated cirrhosis. On the other hand, most studies assessing whether a partial response or long-term maintenance therapy with PEG-IFN without viral eradication is beneficial have failed to demonstrate any significant improvement in clinical outcomes (22, 23).
Conflicts of interest
The author has declared no potential conflicts.
References
1 Ghany MG, Strader DB, Thomas DL, Seeff LB. American association for the study of liver diseases diagnosis, management, and treatment of hepatitis C: an update. Hepatology 2009; 49: 1335–74.
2 Welker MW, Zeuzem S. Occult hepatitis C: how convincing are the current data? Hepatology 2009; 49: 665–75.
3 Bartolomé J, López-Alcorocho JM, Castillo I, et al. Ultracentrifugation of serum samples allows detection of hepatitis C virus RNA in patients with occult hepatitis C. J Virol 2007; 81: 7710–5.
4 Radkowski M, Horban A, Gallegos-Orozco JF, et al. Evidence for viral persistence in patients who test positive for anti-hepatitis C virus antibodies and have normal alanine aminotransferase levels. J Infect Dis 2005; 191: 1730–3.
5 Martinot-Peignoux M, Stern C, Maylin S, et al. Twelve weeks posttreatment follow-up is as relevant as 24 weeks to determine the sustained virologic response in patients with hepatitis C virus receiving pegylated interferon and ribavirin. Hepatology 2010; 51: 1122–6.
6 Chavalitdhamrong D, Tanwandee T. Long term out-comes of chronic hepatitis C patients with sustained virological response at 6 months after the end of treatment. World J Gastroenterol 2006; 12: 5532–5.
7 Marcellin P, Boyer N, Gervais A, et al. Long-tem histological improvement and loss of detectable intrahepatic HC RNA in patients with chronic hepatitis C and sustained response to interferon alfa therapy. Ann Int Med 1997; 127: 875–81.
8 Zeuzem S, Diago M, PEGASYS Study NR16071 Investigator Group et al. Peginterferon alfa-2a (40 kilodaltons) and ribavirin in patients with chronic hepatitis C and normal aminotransferase levels. Gastroenterology 2004; 127: 1724–32.
9 Alberti A. Towards more individualised management of hepatitis C virus patients with initially or persistently normal alanineaminotransferase levels. J Hepatol 2005; 42: 266–74.
10 Shiratori Y, Imazeki F, Moriyama M, et al. Histologic improvement of fibrosis in patients with hepatitis C who have sustained response to interferon therapy. Ann Intern Med 2000; 132: 517–24.
11 Poynard T, McHutchison J, Manns M, et al. Impact of pegylated interferon alfa-2b and ribavirin on liver fibrosis in patients with chronic hepatitis C. Gastroenterology 2002; 122: 1303–13.
12 Toccaceli F, laghi V, Capurso L, et al. Long-term liver histology improvement in patients with chronic hepatitis C and sustained response to interferon. J Viral Hepat 2003; 10: 126–33.
13 Veldt BJ, Saracco G, Boyer N, et al. Long term clinical outcome of chronic hepatitis C patients with sustained virological response to interferon monotherapy. Gut 2004; 53: 1504–8.
14 Maylin S, Martinot-Peignoux M, Moucari R, et al. Eradication of hepatitis C virus in patients successfully treated for chronic hepatitis C. Gastroenterology 2008; 135: 821–9.
15 George SL, Bacon BR, Brunt EM, et al. Clinical, virological, histologic, and biochemical outcomes after successful HCV therapy: a 5-year follw-up of 150 patients. Heatology 2009; 49: 729–38.
16 Poynard T, Ngo Y, Munteanu M, et al. Biomarkers of liver injury for hepatitis clinical trials: a meta-analysis of longitudinal studies. Antivir Ther 2010; 15: 617–31.
17 Wang JH, Changchien CS, Hung CH, et al. Liver stiffness decrease after effective antiviral therapy in patients with chronic hepatitis C: longitudinal study using FibroScan. J Gastroenterol Hepatol 2010; 25: 964–9.
18 Arora S, O'Brien C, Zeuzem S, et al. Treatment of chronic hepatitis C patients with persistently normal alanine aminotransferase levels with the combination of peginterferon alpha-2a (40 kDa) plus ribavirin: impact on health-related quality of life. J Gastroenterol Hepatol 2006; 21: 406–12.
19 Omland LH, Krarup H, DANVIR Cohort Study et al. Mortality in patients with chronic and cleared hepatitis C viral infection: a nationwide cohort study. J Hepatol 2010; 53: 36–42.
20 Cardoso AC, Moucari R, Figueiredo-Mendes C, et al. Impact of peginterferon and ribavirin therapy on hepatocellular carcinoma: incidence and survival in hepatitis C patients with advanced fibrosis. J Hepatol 2010; 52: 652–7.
21 Bruno S, Crosignani A, Facciotto C, et al. Sustained virologic response prevents the development of esophageal varices in compensated, Child-Pugh class. A hepatitis C virus-induced cirrhosis a 12-year prospective follow-up study. Hepatology 2010; 51: 2069–76.
22 Shiffman ML. Impact of peginterferon maintenance therapy on the risk of developing hepatocellular carcinoma in patients with chronic hepatitis C virus. Oncology 2010; 78 (Suppl. 1): 11–6.
23 Di Bisceglie AM, Shiffman ML, Everson GT, et al. Prolonged therapy of advanced chronic hepatitis C with low-dose peginterferon. N Engl J Med 2008; 359: 2429–41.
Source
Special Issue: Proceedings of the 4th Paris Hepatitis Conference. The publication of this supplement was supported by an unrestricted educational grant from F. Hoffmann-Laroche Ltd.
Volume 31, Issue Supplement s1, pages 18–22, January 2011
Alfredo Alberti
Article first published online: 4 JAN 2011
DOI: 10.1111/j.1478-3231.2010.02378.x
© 2011 John Wiley & Sons A/S
Author Information
Department of Histology, Microbiology and Medical Biotechnologies, Venetian Institute of Molecular Medicine, University of Padova, Padova, Italy
* Correspondence: Correspondence Prof. Alfredo Alberti, Department of Histology, Microbiology and Medical Biotechnologies, Venetian Institute of Molecular Medicine, University of Padova, Via Orus 2, 35100 Padova, Italy Tel: +39 049 821 2293 Fax: +39 049 821 1826 e-mail: alfredo.alberti@gmail.com
Keywords:
cirrhosis progression; decompensation; fibrosis; HCC; modelling; natural history; outcomes; remission
Abstract
A sustained virological response (SVR), defined as undetectable hepatitis C virus (HCV)-RNA 24 weeks after withdrawal from therapy (SVR-24w), is the primary endpoint of antiviral therapy in chronic hepatitis C. There is solid evidence that patients who reach this target will remain virus free during long-term follow-up, with a risk of late HCV recurrence of <2% in published series using the most stringent criteria for assessing the virological response during and after antiviral therapy. Long-term observational studies indicate that SVR-24w has a profound impact on the natural course of chronic hepatitis C in relation to biochemical and histological remission of liver disease and improvement in quality of life. The effects of successful antiviral therapy on clinical endpoints such as the development of end-stage liver disease, its severe complications and liver-related mortality have been more difficult to ascertain because of the heterogeneity of the initial staging and rate of progression of chronic hepatitis C. However, most available data suggest that SVR following antiviral therapy reduces the risk of progression to cirrhosis and may prevent the development of severe liver complications and improve survival, at least in successfully treated patients who have already progressed to significant liver fibrosis or early cirrhosis. Outcome modelling suggests that these effects might also include HCV patients treated with milder forms of liver damage.
The primary endpoint of antiviral therapy for chronic hepatitis C is achieving sustained virological response (SVR), defined as undetectable hepatitis C virus (HCV)-RNA in serum 24 weeks after stopping antiviral therapy (SVR-24w). This is the endpoint used in all clinical trials to assess therapeutic interventions as well as by clinicians treating patients. This is because a large body of evidence exists that SVR-24w is an excellent surrogate endpoint to identify a permanent virological cure in most patients, with a clear clinical benefit in many of them. While it has been fairly easy to show that SVR-24w is associated with an extremely low risk of persistent HCV or recurrence during longer follow-up, data on the impact of SVR for more specific clinical endpoints have been limited by the heterogeneity of the initial presentation and rate and speed of chronic hepatitis C disease progression.
It is clear from studies on the natural history of HCV that a minority of patients with chronic infection develop significant life-long clinical complications, and it is also well known that current clinical practice has extended the indication to start antiviral therapy to patients with the mild or moderate hepatitis C, whose risk of progression is often difficult to define. When these patients receive antiviral therapy, data show that SVR improves quality of life and reduces the risk of histological progression. Although there is no direct evidence, outcome modelling suggests that there may be significant effects on clinical complications and survival in a subgroup of patients at risk of more rapid disease progression. On the other hand, solid evidence shows that the risk of developing end-stage liver disease, portal hypertension and hepatocellular carcinoma (HCC) is reduced in patients with more advanced liver disease or cirrhosis who achieve SVR with antiviral therapy.
In this chapter, we briefly discuss the data on the impact of SVR on long-term HCV eradication as well as on biochemical, histological and clinical outcomes in patients with hepatitis C depending on the phase of liver disease when therapy was begun.
Sustained virological response and long-term eradication of hepatitis C virus
There is good evidence that HCV permanently disappears from serum when antiviral therapy is successful. Most experts consider this to be the expression of complete and permanent viral eradication, while data on a persistent occult form of HCV in the liver and/or peripheral blood mononuclear cells (PBMC) are not fully convincing. Because HCV-RNA may be negative in serum during and at the end of antiviral therapy and reactivate after treatment withdrawal in a subgroup of patients with incomplete clearance (relapsers), viral negativity must be confirmed during off-therapy follow-up to confirm a definitive cure of hepatitis C. SVR is the primary goal of antiviral therapy in chronic hepatitis C and is classically defined as the absence, by the most sensitive polymerase chain reaction assay, of HCV-RNA in serum, 24 weeks after therapy has been withdrawn (SVR-24w) (1). This has been the definition since standard interferon (IFN) monotherapy was implemented and remained valid for IFN plus ribavirin combination therapy and more recently for pegylated interferon (PEG-IFN) plus ribavirin combination regimens. The SVR-24w definition of response to therapy will be maintained when new strategies of HCV treatment, including direct antiviral agents, are introduced into clinical practice. Indeed, most published studies as well as extensive clinical experience show that an absence of HCV-RNA in serum 6 months after therapy is the best indicator of HCV clearance, whatever the HCV genotype, patient characteristics, type and duration of treatment. This has been confirmed in several studies evaluating the long-term virological profile in large cohorts of patients treated with different schedules of IFN-based therapies and tested for HCV recurrence several months or years after having achieved SVR-24w.
Recently, Welker and Zeuzem (2) reviewed available data on the rates of late virological relapse in hepatitis C patients treated with IFN (or PEG-IFN) therapy with a sustained response based on the 24 week off-therapy rule. The authors identified 44 studies, including more than 4200 patients who had been followed up to 108 months after the end of therapy. Overall, late virological relapses were rare (3%). There was considerable heterogeneity among the different studies, with some of the smaller series reporting the highest rates of HCV recurrence. On the other hand, the larger series and those with the most stringent criteria to define SVR conclude that negative HCV-RNA in serum 24 weeks after the end of therapy is associated with a durable response and no recurrence of HCV during follow-up in more than 98% of cases.
Some studies have suggested that HCV-RNA may persist in the liver and/or in PBMC in patients who achieve SVR after antiviral therapy and with undetectable HCV-RNA in serum (3, 4). The significance of these findings is uncertain but most available data suggest that they are not clinically significant, at least in the immunocompetent host.
Thus, patients achieving SVR-24w with antiviral therapy can be considered clinically cured of viral infection, with an extremely low risk of late virological recurrence. If this occurs, reinfection rather than a ‘true’ relapse could be suspected and should be evaluated carefully.
Recently, it has been proposed that a 12-week post-treatment follow-up might be as relevant as 24 weeks to determine the sustained virological response in patients with hepatitis C virus receiving PEG-IFN and ribavirin (5).
Biochemical outcomes after sustained virological response
Alanine transaminase (ALT)/aspartate aminotransferase (AST) levels markedly improve in most patients who achieve SVR with antiviral therapy and permanently normalize in many (6, 7). The mean ALT and AST activities after therapy are significantly lower than the pretreatment baseline levels even in HCV carriers who began antiviral therapy with ‘normal’ ALT levels (8). Indeed, eradication of HCV by antiviral therapy in these cases is associated with a significant improvement in liver enzyme levels, which decrease from pretreatment ‘high normal’ to post-treatment ‘low normal’ levels. These findings suggest the presence of ongoing marginal liver disease activity even in HCV carriers with ‘normal’ range ALT levels, in agreement with histological findings of inflammation and fibrosis in around 15–25% of these patients (9).
On the other hand, liver enzymes may not normalize completely in patients with cirrhosis who achieve SVR. The discrepancy between biochemical and virological outcomes does not exclude a clinical benefit and is probably a sign of profound irreversible changes in hepatocyte metabolism from advanced cirrhosis.
As a general rule, other causes of liver damage (coinfections, alcohol, drugs, metabolic abnormalities) should be investigated in patients who achieve SVR with antiviral therapy but still have elevated ALT and/or AST.
Histological outcomes after sustained virological response
Many studies have described the histological outcome following antiviral therapy for chronic hepatitis C and have clearly identified some major differences among non-responders, partial responders, relapsers and sustained responders (10–15). Although the benefit to disease activity and progression with a partial or a transient virological response remains controversial, these studies clearly confirm that SVR is associated with histological improvement in disease activity and associated fibrosis. Liver steatosis is also improved when it is directly linked to HCV as for HCV-3.
The type and degree of histological benefit after SVR is highly dependent on pretreatment activity, the stage of liver disease and the interval between end of therapy and liver biopsy. Improvement in liver inflammation is more evident when a liver biopsy is obtained years rather than months after the end of therapy. The effect of time is even more evident for the regression of liver fibrosis. Available studies indicate that liver inflammation resolves in most, if not all, patients after SVR while improvement in fibrosis (regression) is found in 25–80%, worsening (progression) in only 0–12, and 16–68% remain stable. These results are significantly different from those in patients who do not achieve SVR. Table 1 describes some studies that have evaluated histological outcome after SVR using paired liver biopsies before and at different intervals after antiviral therapy. Available cumulative data on progression to cirrhosis have indicated that the risk after 1–10 years is reduced from 7–10% in non-responders to 0.5–1% in sustained responders, although it should be emphasized that patients who achieve SVR might have a milder and less progressive form of liver disease compared with non-responders.
Reversal of histological cirrhosis has been reported in patients achieving SVR with antiviral therapy. Although in most patients the benefit was limited to regression to METAVIR stage 3, i.e. advanced fibrosis with bridging, a histological sampling error cannot be excluded, other patients have been shown to achieve more marked and permanent histological benefit with regression from signs of cirrhosis to minimal-mild fibrosis.
Recent non-invasive markers of liver fibrosis, such as the FibroTest and FibroScan, have become important new tools for the management of patients with chronic hepatitis C. Results in patients receiving antiviral therapy have confirmed a marked improvement in liver fibrosis indexes following SVR (16, 17). Further validation for the optimized use of these methods during and after antiviral therapy is ongoing in several centres.
Sustained virological response and clinical outcomes
Morbidity and mortality in chronic hepatitis C infection are mainly associated with the complications of cirrhosis and the development of HCC, as well as an increased risk in liver-related deaths. It is therefore essential to assess the impact of SVR on these clinical outcomes. Because of the heterogeneity of the clinical presentation of chronic HCV infection, the slow and unpredictable progression and the lack of longitudinal studies of adequate size and duration, the impact of antiviral therapy and SVR on liver-related complications and mortality has been difficult to determine, especially in patients with milder forms of HCV-related liver disease. Although the endpoint of SVR is clearly associated with reduced histological disease progression in these patients, there is no clear evidence that this will result in reduced morbidity and mortality. At present, many patients with mild chronic hepatitis C are treated with antiviral therapy, especially younger patients or those infected with easy to clear HCV genotypes.
High SVR rates are achieved in these patients and outcome modelling also suggests that successful antiviral therapy could reduce the clinical burden of their disease. On the other hand, there are also convincing results associating a marked improvement in quality of life with SVR after antiviral therapy. This effect is largely independent of the stage of disease when treatment is begun (18). The clinical benefit associated with HCV clearance at any stage of chronic HCV infection is supported by recent results in a large population-based survey by Omland and Krarup (19), showing that overall life-long mortality as well as liver-and HCC-related mortality were significantly lower in HCV patients who showed a clearance of viraemia than in those with chronic viraemia.
Unlike the data for patients with milder forms of chronic hepatitis C, several studies have clearly shown that antiviral therapy with SVR is associated with a marked improvement in clinical outcomes in patients with advanced fibrosis or compensated cirrhosis. Indeed, most studies show that ascites, hepatic encephalopathy, jaundice or gastrointestinal bleeding are extremely rare after SVR has been achieved. Development of hepatocellular carcinoma is also significantly reduced, but patients with cirrhosis who clear HCV during antiviral therapy are still at a risk of developing HCC. Although the risk is certainly much lower than in age/gender/race-matched patients with active disease, continued monitoring is recommended. One of the most recent reports on the impact of combination PEG-IFN and ribavirin therapy on clinical outcome and complications in patients with chronic hepatitis C and advanced fibrosis is that of Cardoso et al. (20). These authors describe long-term outcomes in 307 patients with chronic hepatitis C and advanced fibrosis (127 cases) or cirrhosis (180 cases) treated with PEG-IFN plus ribavirin and followed up for a mean 3–5 years after treatment. SVR-24w was found in 33% of the cases, with no significant differences between patients with advanced fibrosis (37%) and cirrhosis (30%). During follow-up, the incidence of liver-related complications, HCC and liver-related deaths per 100 person – years was 0.63, 1.24 and 0.61, respectively, in patients with SVR and 4.16, 5.85 and 3.66, respectively, in patients without SVR. The difference for each outcome was statistically significant (P<0.001 by log-rank test). Multivariate analysis confirmed that SVR protected against progression to liver complications, HCC and liver-related deaths, with the relative risk in the absence of SVR ranging between 3.06 and 4.73. These results confirm those of several previous studies based on cohorts of patients treated with standard IFN, standard IFN plus ribavirin or PEG-IFN plus ribavirin, showing that antiviral treatment provides a definitive clinical advantage to patients with compensated cirrhosis who tolerate treatment and achieve an SVR.
Another recent study published by Bruno et al. (21) reported the effect of antiviral therapy and SVR on portal hypertension in HCV patients with cirrhosis. The authors reported results in 218 patients with cirrhosis who were untreated or treated with IFN-α-based therapy and followed up for a median 11.4 years. All patients had compensated cirrhosis when therapy began without oesophageal varices. Endoscopic monitoring was performed at 3-year intervals. None of the patients who achieved SVR developed oesophageal varices during follow-up compared with 32% of untreated patients and 39% of treated patients who did not achieve SVR, showing that SVR clinically improved the development of portal hypertension.
In conclusion, SVR improves the clinical outcomes in patients with chronic hepatitis C and advanced fibrosis or compensated cirrhosis. On the other hand, most studies assessing whether a partial response or long-term maintenance therapy with PEG-IFN without viral eradication is beneficial have failed to demonstrate any significant improvement in clinical outcomes (22, 23).
Conflicts of interest
The author has declared no potential conflicts.
References
1 Ghany MG, Strader DB, Thomas DL, Seeff LB. American association for the study of liver diseases diagnosis, management, and treatment of hepatitis C: an update. Hepatology 2009; 49: 1335–74.
2 Welker MW, Zeuzem S. Occult hepatitis C: how convincing are the current data? Hepatology 2009; 49: 665–75.
3 Bartolomé J, López-Alcorocho JM, Castillo I, et al. Ultracentrifugation of serum samples allows detection of hepatitis C virus RNA in patients with occult hepatitis C. J Virol 2007; 81: 7710–5.
4 Radkowski M, Horban A, Gallegos-Orozco JF, et al. Evidence for viral persistence in patients who test positive for anti-hepatitis C virus antibodies and have normal alanine aminotransferase levels. J Infect Dis 2005; 191: 1730–3.
5 Martinot-Peignoux M, Stern C, Maylin S, et al. Twelve weeks posttreatment follow-up is as relevant as 24 weeks to determine the sustained virologic response in patients with hepatitis C virus receiving pegylated interferon and ribavirin. Hepatology 2010; 51: 1122–6.
6 Chavalitdhamrong D, Tanwandee T. Long term out-comes of chronic hepatitis C patients with sustained virological response at 6 months after the end of treatment. World J Gastroenterol 2006; 12: 5532–5.
7 Marcellin P, Boyer N, Gervais A, et al. Long-tem histological improvement and loss of detectable intrahepatic HC RNA in patients with chronic hepatitis C and sustained response to interferon alfa therapy. Ann Int Med 1997; 127: 875–81.
8 Zeuzem S, Diago M, PEGASYS Study NR16071 Investigator Group et al. Peginterferon alfa-2a (40 kilodaltons) and ribavirin in patients with chronic hepatitis C and normal aminotransferase levels. Gastroenterology 2004; 127: 1724–32.
9 Alberti A. Towards more individualised management of hepatitis C virus patients with initially or persistently normal alanineaminotransferase levels. J Hepatol 2005; 42: 266–74.
10 Shiratori Y, Imazeki F, Moriyama M, et al. Histologic improvement of fibrosis in patients with hepatitis C who have sustained response to interferon therapy. Ann Intern Med 2000; 132: 517–24.
11 Poynard T, McHutchison J, Manns M, et al. Impact of pegylated interferon alfa-2b and ribavirin on liver fibrosis in patients with chronic hepatitis C. Gastroenterology 2002; 122: 1303–13.
12 Toccaceli F, laghi V, Capurso L, et al. Long-term liver histology improvement in patients with chronic hepatitis C and sustained response to interferon. J Viral Hepat 2003; 10: 126–33.
13 Veldt BJ, Saracco G, Boyer N, et al. Long term clinical outcome of chronic hepatitis C patients with sustained virological response to interferon monotherapy. Gut 2004; 53: 1504–8.
14 Maylin S, Martinot-Peignoux M, Moucari R, et al. Eradication of hepatitis C virus in patients successfully treated for chronic hepatitis C. Gastroenterology 2008; 135: 821–9.
15 George SL, Bacon BR, Brunt EM, et al. Clinical, virological, histologic, and biochemical outcomes after successful HCV therapy: a 5-year follw-up of 150 patients. Heatology 2009; 49: 729–38.
16 Poynard T, Ngo Y, Munteanu M, et al. Biomarkers of liver injury for hepatitis clinical trials: a meta-analysis of longitudinal studies. Antivir Ther 2010; 15: 617–31.
17 Wang JH, Changchien CS, Hung CH, et al. Liver stiffness decrease after effective antiviral therapy in patients with chronic hepatitis C: longitudinal study using FibroScan. J Gastroenterol Hepatol 2010; 25: 964–9.
18 Arora S, O'Brien C, Zeuzem S, et al. Treatment of chronic hepatitis C patients with persistently normal alanine aminotransferase levels with the combination of peginterferon alpha-2a (40 kDa) plus ribavirin: impact on health-related quality of life. J Gastroenterol Hepatol 2006; 21: 406–12.
19 Omland LH, Krarup H, DANVIR Cohort Study et al. Mortality in patients with chronic and cleared hepatitis C viral infection: a nationwide cohort study. J Hepatol 2010; 53: 36–42.
20 Cardoso AC, Moucari R, Figueiredo-Mendes C, et al. Impact of peginterferon and ribavirin therapy on hepatocellular carcinoma: incidence and survival in hepatitis C patients with advanced fibrosis. J Hepatol 2010; 52: 652–7.
21 Bruno S, Crosignani A, Facciotto C, et al. Sustained virologic response prevents the development of esophageal varices in compensated, Child-Pugh class. A hepatitis C virus-induced cirrhosis a 12-year prospective follow-up study. Hepatology 2010; 51: 2069–76.
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Source
How to assess liver fibrosis in chronic hepatitis C: serum markers or transient elastography vs. liver biopsy?
Liver International
Special Issue: Proceedings of the 4th Paris Hepatitis Conference. The publication of this supplement was supported by an unrestricted educational grant from F. Hoffmann-Laroche Ltd.
Volume 31, Issue Supplement s1, pages 13–17, January 2011
Laurent Castera 1, Pierre Bedossa 2
Article first published online: 4 JAN 2011
DOI: 10.1111/j.1478-3231.2010.02380.x
© 2011 John Wiley & Sons A/S
Author Information
1 Department of Hepatology, Hôpital St André & Haut Lévêque, Bordeaux University Hospital, Bordeaux, France
2 Department of Pathology, Beaujon Hospital, Assistance Publique-Hôpitaux de Paris, INSERM, Paris-Diderot University, Paris, France
* Correspondence: Correspondence Laurent Castera, MD, PhD, Service d' Hépatologie, Hǒpital Beaujon, Assistance Publique Hǒpitaux de Paris, 100 Boulevard du Général Leclerc, 92110 Clichy, France Tel: +33 5 57 65 64 39 Fax: +33 5 57 65 64 45 e-mail: laurent.castera@chu-bordeaux.fr
Keywords:
FibroScan; liver biopsy; liver fibrosis; non-invasive; serum biomarkers; transient elastography
Abstract
The assessment of liver fibrosis is a major issue in the management of patients with chronic hepatitis C. Liver biopsy has traditionally been considered the gold standard for the evaluation of tissue damage, including fibrosis. In addition, it detects associated lesions such as steatosis, steatohepatitis or iron overload, which provide useful information for patient management and prognosis. Liver biopsy is, however, an invasive procedure, with a risk of rare but potentially life-threatening complications and it is prone to sampling errors. These limitations have led to the development of non-invasive methods. Currently available tests rely on two different but complementary approaches: (i) a ‘biological’ approach based on the dosage of serum biomarkers of fibrosis; (ii) a ‘physical’ approach based on the measurement of liver stiffness, using transient elastography. Although significant progress has been made in the non-invasive diagnosis of fibrosis, it is increasingly clear that these methods will not completely replace liver biopsy. Instead, non-invasive methods and liver biopsy should be used in an integrated approach for more efficient and convenient management of patients with chronic hepatitis C. The aim of this review is to discuss the advantages and limitations of liver biopsy and non-invasive methods and the perspectives for their use in clinical practice.
Liver fibrosis is a result of excessive extracellular matrix deposition in the liver in response to chronic inflammatory injury triggered by persistent hepatitis C virus in the liver. Hepatic fibrosis is determined by the replication balance between fibrogenesis and fibrosis degradation. When this balance favours fibrogenesis, there is a resulting accumulation of collagen and extracellular matrix, leading eventually to cirrhosis. Liver fibrosis and its end-point cirrhosis are the main causes of morbidity and mortality in patients with hepatitis C virus (HCV) infection (1, 2). Besides the development of antiviral drugs, there are intensive efforts to develop drugs to effectively target the mechanism of fibrogenesis or to eliminate fibrous tissue once it has accumulated in the liver (3). Therefore, the assessment of liver fibrosis is a major issue in the management of patients with chronic HCV infection (4, 5).
Liver biopsy
For many years, liver biopsy has been considered the gold standard for the evaluation of tissue damage including fibrosis. Histological assessment is based on semiquantitative scoring systems (METAVIR, Ishak score) (4, 5). Fibrosis is scored in stages while necroinflammation is evaluated by grade. Staging fibrosis is an assessment of the combination of the amount of fibrosis and architectural disorganization. These semiquantitative histological scores have been used successfully for years in both clinical trials and for individual evaluation.
However, liver biopsy has certain drawbacks. Because liver biopsy only samples a very small part of the whole organ, there is a risk that this part might be irrelevant in the evaluation of lesions that are heterogeneously distributed throughout the entire liver (5). This may be true for tissue fibrosis. There is extensive literature showing that increasing the length of the liver biopsy decreases the risk of sampling error (6, 7). Except for cirrhosis, for which microfragments may be sufficient (8), a 25 mm long biopsy is considered an optimal specimen for accurate evaluation, while 15 mm is considered sufficient in most studies.
Observer variation is another potential limitation of biopsy that is related to the difference between pathologist's interpretation of the biopsy (6, 9, 10). The use of histopathological scoring systems for the evaluation of fibrosis has limited this drawback and several studies have shown that agreement between pathologists is satisfactory, especially when the staging of fibrosis is performed by specialized liver pathologists (9, 10). Thus, although liver biopsy has its limitations, appropriate precautions may reduce the flaws inherent in this method.
Because liver biopsy is invasive, the only serious limitations are the potential adverse effects and complications that have been comprehensively reviewed elsewhere (11). Transient and moderate pain along with anxiety and discomfort are common (12, 13). Severe complications such as haemoperitoneum, biliary peritonitis and pneumothorax are rare (0.3–0.5%). Death is exceedingly rare, but has been reported occasionally for biopsies in advanced liver diseases, haemorrhagical tumours and in patients with major comorbidities. A biopsy via the transjugular route considerably reduces the risk of bleeding in patients with advanced liver disease and coagulation disorders. Biopsy performed by a trained physician, limiting the number of passes and ultrasound guidance can significantly decrease the risk of complications, thus increasing the safety of biopsy. Nevertheless, a liver biopsy should be performed only after carefully balancing the risks of the procedure with the potential benefits in terms of patient management. Despite these limitations, liver biopsy provides invaluable information that none of the non-invasive markers provide. Although the evaluation of fibrosis is a major decision criterion for hepatologists, fibrosis is only one of the many elementary histopathological features present on liver biopsy. In effect, fibrosis is not an autonomous feature, but scar tissue resulting from other pathobiological mechanisms such as inflammatory, degenerative or dystrophical processes. The simultaneous evaluation of necroinflammation (portal tract inflammation, interface hepatitis, lobular inflammation) shows whether fibrosis is the result of a past event that has stabilized or even regressed or is an ongoing process that may continue to worsen. Associated lesions such as steatosis, steatohepatitis, iron overload, etc., which provide useful information for patient management and prognosis, can also frequently be detected with biopsy (14).
Finally, in difficult diseases such as hepatitis C, liver biopsy may also reveal that abnormal liver function tests are related to unexpected liver diseases other than hepatitis C (15). Clearly, all this information may influence patient management. Therefore, limiting the definition of chronic liver disease to the extent of fibrosis is an oversimplification that may be misleading.
Non-invasive methods for the assessment of liver fibrosis
There are two distinct approaches among the currently available non-invasive methods: (i) a physical approach based on the measurement of liver stiffness using transient elastography (TE); (ii) a biological approach based on serum biomarkers of fibrosis (16). Although complementary, these two approaches are based on different rationales and conceptions: TE measures liver stiffness in relation to elasticity, corresponding to a genuine and intrinsic physical property of the liver parenchyma, while serum biomarkers are a combination of several, not strictly liver-specific blood parameters optimized to mimic the stages of fibrosis as assessed by liver biopsy (17).
Numerous biomarkers have been proposed in hepatitis C (18, 19, 20) but the most widely used and validated with TE are the aspartate-to-platelet ratio index (APRI) (a free non-patented index) and the FibroTest (21, 22, 23).
The results of TE and serum biomarkers for the diagnosis of significant fibrosis have been shown to be equivalent in patients with chronic hepatitis C infection (24, 25). Indeed, in the largest study to date (n=1307) (25), comparing TE with several patented and non-patented biomarkers (FibroTest, Fibrometre, Hepascore and APRI) and using liver biopsy as a reference, the AUROCs of TE (0.76) did not differ from those of serum biomarkers (0.72–0.78).
In order to increase the diagnostic accuracy of these tests, the sequential combination of biomarkers (26, 27) or the concomitant combination of TE and biomarkers (24, 28, 29) has been proposed. The latter strategy may be more effective for diagnosing significant fibrosis, leading to a reduction in the use of liver biopsy in more than 70% of cases compared with 50% when using biomarkers (APRI and FibroTest) sequentially (30). Another advantage of combining two unrelated methods such as TE and biomarkers rather than two biomarkers is that TE provides a more direct measurement of liver structure than biomarkers and there is no relationship between the applicability of TE and biomarkers such as the FibroTest (28).
For the diagnosis of cirrhosis, the situation is different because TE appears to be the most accurate method compared with currently available biomarkers and routine blood tests, preventing the need for a liver biopsy in around 90% of cases (25, 31). As a result, a combination of both methods does not seem to increase the diagnostic accuracy (30).
Limitations of non-invasive methods
Serum markers
Although the applicability and interlaboratory reproducibility of different tests have been shown to be satisfactory for use in clinical practice (32, 33), interpretation of each test requires critical analysis to avoid false-positive or false-negative results (34).
Transient elastography
Although the reproducibility of TE has been shown to be excellent for inter- and intra-observer agreement (35, 36), its applicability may not be as good as that of biomarkers. Indeed, in our experience of more than 13 000 exams over a 5-year period, liver stiffness measurements (LSM) could not be interpreted in nearly one in five cases (failure to obtain any measurement in 4% and unreliable results that did not meet the manufacturer's recommendations in 17%) (37). The principal reasons were obesity, particularly increased waist circumference, and limited operator experience.
Finally, because the liver is an organ wrapped in an expandable but non-elastic envelope (Glisson's capsula), additional space-occupying tissue abnormalities independent of fibrosis, such as oedema and inflammation, cholestasis and congestion, may interfere with LSM. The risk of overestimating liver stiffness values has been reported in the case of alanine aminotransferase flares in patients with acute viral hepatitis or chronic hepatitis B (38, 39, 40) as well as in cases of extrahepatic cholestasis (41) or congestive heart failure (42).
How to use liver biopsy and non-invasive methods in clinical practice?
A liver biopsy should be performed in the case of comorbidities such as alcoholism or metabolic syndrome when non-invasive methods cannot be used or in any unclear situation such as discordant results of non-invasive tests. Conversely, liver biopsy should not be performed when the clinical diagnosis is obvious (cirrhosis) or when no benefit can be expected from the biopsy for patient management. Although there is no optimal threshold, the longer the specimen, the more accurate the staging will be (43). A 20–25 mm long biopsy is considered optimal although a robust evaluation is often possible on a 15 mm long biopsy. Ideally, the biopsy should be read by an experienced liver pathologist because it decreases the source of variability in the histological interpretation (44).
In naïve patients without comorbidities who are candidates for antiviral treatment, non-invasive tests can be used for the first-line staging of fibrosis. The use of either TE or several patented biomarkers (FibroTest, Fibrometer and Hepascore) has recently been recommended, based on an independent systematic review by the French Health Authorities (45). However, this strategy should also take into account HCV genotype, local availability of non-invasive methods and any clinically relevant variable. For instance, when there is a strong clinical suspicion of cirrhosis, in most cases the use of TE is enough to confirm the diagnosis without a liver biopsy. Conversely, a liver biopsy may be necessary to differentiate between F1 and F2 in genotype 1-infected patients before making a decision on antiviral treatment. In the same way, a liver biopsy may be useful to differentiate between F3 and F4 when cirrhosis is not clinically obvious and to decide when to start screening for hepatocellular carcinoma. However, with the availability of new antiviral treatments (46, 47), differentiating between F1 and F2 may not be as important for treatment indications.
When deciding on retreatment, a liver biopsy may be indicated to investigate the presence of factors of impaired response such as non-alcoholic steatohepatitis or to obtain a prognosis especially if a liver biopsy has not been performed previously.
Finally, non-invasive methods can be of interest in the follow-up of untreated patients (48). Given the slow rate of the progression of fibrosis in chronic hepatitis C, a non-invasive evaluation can be performed on a yearly basis.
Conclusion and perspectives
There is an urgent need to pursue the development of non-invasive tests in addition to a liver biopsy for the staging of fibrosis. Because of the conditional relationship with biopsy, the development of serum markers will always have obvious limitations. Promising preliminary results suggest that novel alternative imaging techniques such as magnetic resonance elastography, acoustic radiation force impulse imaging or perfusion computed tomography will eventually be refined to reach an acceptable level of accuracy, especially for the evaluation of early and intermediate stages of fibrosis (49–51). These might become less pertinent as antiviral treatments become more efficient, with fewer side effects.
Conflicts of interest
The authors have declared no potential conflicts.
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28 Poynard T, Ingiliz P, Elkrief L, et al. Concordance in a world without a gold standard: a new non-invasive methodology for improving accuracy of fibrosis markers. PLoS ONE 2008; 3: e3857.
29 Boursier J, Vergniol J, Sawadogo A, et al. The combination of a blood test and FibroScan improves the non-invasive diagnosis of liver fibrosis. Liver Int 2009; 29: 1507–15.
30 Castera L, Sebastiani G, Le Bail B, et al. Prospective comparison of two algorithms combining non-invasive methods for staging liver fibrosis in chronic hepatitis C. J Hepatol 2010; 52: 191–8.
31 Castera L, Le Bail B, Roudot-Thoraval F, et al. Early detection in routine clinical practice of cirrhosis and oesophageal varices in chronic hepatitis C: Comparison of transient elastography (FibroScan) with standard laboratory tests and non-invasive scores. J Hepatol 2009; 50: 59–68.
32 Imbert-Bismut F, Messous D, Thibaut V, et al. Intra-laboratory analytical variability of biochemical markers of fibrosis (Fibrotest) and activity (Actitest) and reference ranges in healthy blood donors. Clin Chem Lab Med 2004; 42: 323–33.
33 Cales P, Veillon P, Konate A, et al. Reproducibility of blood tests of liver fibrosis in clinical practice. Clin Biochem 2008; 41: 10–8.
34 Poynard T, Munteanu M, Imbert-Bismut F, et al. Prospective analysis of discordant results between biochemical markers and biopsy in patients with chronic hepatitis C. Clin Chem 2004; 50: 1344–55.
35 Fraquelli M, Rigamonti C, Casazza G, et al. Reproducibility of transient elastography in the evaluation of liver fibrosis in patients with chronic liver disease. Gut 2007; 56: 968–73.
36 Boursier J, Konate A, Gorea G, et al. Reproducibility of liver stiffness measurement by ultrasonographic elastometry. Clin Gastroenterol Hepatol 2008; 6: 1263–9.
37 Castera L, Foucher J, Bernard PH, et al. Pitfalls of liver stiffness measurement: a 5-year prospective study of 13 369 examinations. Hepatology 2010; 51: 828–35.
38 Coco B, Oliveri F, Maina AM, et al. Transient elastography: a new surrogate marker of liver fibrosis influenced by major changes of transaminases. J Viral Hepat 2007; 14: 360–9.
39 Sagir A, Erhardt A, Schmitt M, et al. Transient elastography is unreliable for detection of cirrhosis in patients with acute liver damage. Hepatology 2007; 47: 592–5.
40 Arena U, Vizzutti F, Corti G, et al. Acute viral hepatitis increases liver stiffness values measured by transient elastography. Hepatology 2008; 47: 380–4.
41 Millonig G, Reimann FM, Friedrich S, et al. Extrahepatic cholestasis increases liver stiffness (FibroScan) irrespective of fibrosis. Hepatology 2008; 48: 1718–23.
42 Millonig G, Friedrich S, Adolf S, et al. Liver stiffness is directly influenced by central venous pressure. J Hepatol 2010; 52: 206–10.
43 Scheuer PJ. Liver biopsy size matters in chronic hepatitis: bigger is better. Hepatology 2003; 38: 1356–8.
44 Rousselet MC, Michalak S, Dupre F, et al. Sources of variability in histological scoring of chronic viral hepatitis. Hepatology 2005; 41: 257–64.
45 Non invasive methods for the evaluation of hepatic fibrosis/cirrhosis: an update, 2008. Available at http://www.has-sante.fr/
46 Hezode C, Forestier N, Dusheiko G, et al. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med 2009; 360: 1839–50.
47 Kwo PY, Lawitz EJ, McCone J, et al. Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naive patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre phase 2 trial. Lancet 2010; 376: 705–16.
48 Hézode C, Castéra L, Rosa I, et al. Prospective evaluation of liver stiffness dynamics during and after peginterferon alpha-ribavirin treatment in patients with chronic hepatitis C (abstract). Hepatology 2008; 48 (Suppl.): 849A.
49 Huwart L, Sempoux C, Vicaut E, et al. Magnetic resonance elastography for the noninvasive staging of liver fibrosis. Gastroenterology 2008; 135: 32–40.
50 Friedrich-Rust M, Wunder K, Kriener S, et al. Liver fibrosis in viral hepatitis: noninvasive assessment with acoustic radiation force impulse imaging versus transient elastography. Radiology 2009; 252: 595–604.
51 Ronot M, Asselah T, Paradis V, et al. Liver fibrosis in chronic hepatitis C virus infection: differentiating minimal from intermediate fibrosis with perfusion CT. Radiology 2010; 256: 135–42.
Source
Special Issue: Proceedings of the 4th Paris Hepatitis Conference. The publication of this supplement was supported by an unrestricted educational grant from F. Hoffmann-Laroche Ltd.
Volume 31, Issue Supplement s1, pages 13–17, January 2011
Laurent Castera 1, Pierre Bedossa 2
Article first published online: 4 JAN 2011
DOI: 10.1111/j.1478-3231.2010.02380.x
© 2011 John Wiley & Sons A/S
Author Information
1 Department of Hepatology, Hôpital St André & Haut Lévêque, Bordeaux University Hospital, Bordeaux, France
2 Department of Pathology, Beaujon Hospital, Assistance Publique-Hôpitaux de Paris, INSERM, Paris-Diderot University, Paris, France
* Correspondence: Correspondence Laurent Castera, MD, PhD, Service d' Hépatologie, Hǒpital Beaujon, Assistance Publique Hǒpitaux de Paris, 100 Boulevard du Général Leclerc, 92110 Clichy, France Tel: +33 5 57 65 64 39 Fax: +33 5 57 65 64 45 e-mail: laurent.castera@chu-bordeaux.fr
Keywords:
FibroScan; liver biopsy; liver fibrosis; non-invasive; serum biomarkers; transient elastography
Abstract
The assessment of liver fibrosis is a major issue in the management of patients with chronic hepatitis C. Liver biopsy has traditionally been considered the gold standard for the evaluation of tissue damage, including fibrosis. In addition, it detects associated lesions such as steatosis, steatohepatitis or iron overload, which provide useful information for patient management and prognosis. Liver biopsy is, however, an invasive procedure, with a risk of rare but potentially life-threatening complications and it is prone to sampling errors. These limitations have led to the development of non-invasive methods. Currently available tests rely on two different but complementary approaches: (i) a ‘biological’ approach based on the dosage of serum biomarkers of fibrosis; (ii) a ‘physical’ approach based on the measurement of liver stiffness, using transient elastography. Although significant progress has been made in the non-invasive diagnosis of fibrosis, it is increasingly clear that these methods will not completely replace liver biopsy. Instead, non-invasive methods and liver biopsy should be used in an integrated approach for more efficient and convenient management of patients with chronic hepatitis C. The aim of this review is to discuss the advantages and limitations of liver biopsy and non-invasive methods and the perspectives for their use in clinical practice.
Liver fibrosis is a result of excessive extracellular matrix deposition in the liver in response to chronic inflammatory injury triggered by persistent hepatitis C virus in the liver. Hepatic fibrosis is determined by the replication balance between fibrogenesis and fibrosis degradation. When this balance favours fibrogenesis, there is a resulting accumulation of collagen and extracellular matrix, leading eventually to cirrhosis. Liver fibrosis and its end-point cirrhosis are the main causes of morbidity and mortality in patients with hepatitis C virus (HCV) infection (1, 2). Besides the development of antiviral drugs, there are intensive efforts to develop drugs to effectively target the mechanism of fibrogenesis or to eliminate fibrous tissue once it has accumulated in the liver (3). Therefore, the assessment of liver fibrosis is a major issue in the management of patients with chronic HCV infection (4, 5).
Liver biopsy
For many years, liver biopsy has been considered the gold standard for the evaluation of tissue damage including fibrosis. Histological assessment is based on semiquantitative scoring systems (METAVIR, Ishak score) (4, 5). Fibrosis is scored in stages while necroinflammation is evaluated by grade. Staging fibrosis is an assessment of the combination of the amount of fibrosis and architectural disorganization. These semiquantitative histological scores have been used successfully for years in both clinical trials and for individual evaluation.
However, liver biopsy has certain drawbacks. Because liver biopsy only samples a very small part of the whole organ, there is a risk that this part might be irrelevant in the evaluation of lesions that are heterogeneously distributed throughout the entire liver (5). This may be true for tissue fibrosis. There is extensive literature showing that increasing the length of the liver biopsy decreases the risk of sampling error (6, 7). Except for cirrhosis, for which microfragments may be sufficient (8), a 25 mm long biopsy is considered an optimal specimen for accurate evaluation, while 15 mm is considered sufficient in most studies.
Observer variation is another potential limitation of biopsy that is related to the difference between pathologist's interpretation of the biopsy (6, 9, 10). The use of histopathological scoring systems for the evaluation of fibrosis has limited this drawback and several studies have shown that agreement between pathologists is satisfactory, especially when the staging of fibrosis is performed by specialized liver pathologists (9, 10). Thus, although liver biopsy has its limitations, appropriate precautions may reduce the flaws inherent in this method.
Because liver biopsy is invasive, the only serious limitations are the potential adverse effects and complications that have been comprehensively reviewed elsewhere (11). Transient and moderate pain along with anxiety and discomfort are common (12, 13). Severe complications such as haemoperitoneum, biliary peritonitis and pneumothorax are rare (0.3–0.5%). Death is exceedingly rare, but has been reported occasionally for biopsies in advanced liver diseases, haemorrhagical tumours and in patients with major comorbidities. A biopsy via the transjugular route considerably reduces the risk of bleeding in patients with advanced liver disease and coagulation disorders. Biopsy performed by a trained physician, limiting the number of passes and ultrasound guidance can significantly decrease the risk of complications, thus increasing the safety of biopsy. Nevertheless, a liver biopsy should be performed only after carefully balancing the risks of the procedure with the potential benefits in terms of patient management. Despite these limitations, liver biopsy provides invaluable information that none of the non-invasive markers provide. Although the evaluation of fibrosis is a major decision criterion for hepatologists, fibrosis is only one of the many elementary histopathological features present on liver biopsy. In effect, fibrosis is not an autonomous feature, but scar tissue resulting from other pathobiological mechanisms such as inflammatory, degenerative or dystrophical processes. The simultaneous evaluation of necroinflammation (portal tract inflammation, interface hepatitis, lobular inflammation) shows whether fibrosis is the result of a past event that has stabilized or even regressed or is an ongoing process that may continue to worsen. Associated lesions such as steatosis, steatohepatitis, iron overload, etc., which provide useful information for patient management and prognosis, can also frequently be detected with biopsy (14).
Finally, in difficult diseases such as hepatitis C, liver biopsy may also reveal that abnormal liver function tests are related to unexpected liver diseases other than hepatitis C (15). Clearly, all this information may influence patient management. Therefore, limiting the definition of chronic liver disease to the extent of fibrosis is an oversimplification that may be misleading.
Non-invasive methods for the assessment of liver fibrosis
There are two distinct approaches among the currently available non-invasive methods: (i) a physical approach based on the measurement of liver stiffness using transient elastography (TE); (ii) a biological approach based on serum biomarkers of fibrosis (16). Although complementary, these two approaches are based on different rationales and conceptions: TE measures liver stiffness in relation to elasticity, corresponding to a genuine and intrinsic physical property of the liver parenchyma, while serum biomarkers are a combination of several, not strictly liver-specific blood parameters optimized to mimic the stages of fibrosis as assessed by liver biopsy (17).
Numerous biomarkers have been proposed in hepatitis C (18, 19, 20) but the most widely used and validated with TE are the aspartate-to-platelet ratio index (APRI) (a free non-patented index) and the FibroTest (21, 22, 23).
The results of TE and serum biomarkers for the diagnosis of significant fibrosis have been shown to be equivalent in patients with chronic hepatitis C infection (24, 25). Indeed, in the largest study to date (n=1307) (25), comparing TE with several patented and non-patented biomarkers (FibroTest, Fibrometre, Hepascore and APRI) and using liver biopsy as a reference, the AUROCs of TE (0.76) did not differ from those of serum biomarkers (0.72–0.78).
In order to increase the diagnostic accuracy of these tests, the sequential combination of biomarkers (26, 27) or the concomitant combination of TE and biomarkers (24, 28, 29) has been proposed. The latter strategy may be more effective for diagnosing significant fibrosis, leading to a reduction in the use of liver biopsy in more than 70% of cases compared with 50% when using biomarkers (APRI and FibroTest) sequentially (30). Another advantage of combining two unrelated methods such as TE and biomarkers rather than two biomarkers is that TE provides a more direct measurement of liver structure than biomarkers and there is no relationship between the applicability of TE and biomarkers such as the FibroTest (28).
For the diagnosis of cirrhosis, the situation is different because TE appears to be the most accurate method compared with currently available biomarkers and routine blood tests, preventing the need for a liver biopsy in around 90% of cases (25, 31). As a result, a combination of both methods does not seem to increase the diagnostic accuracy (30).
Limitations of non-invasive methods
Serum markers
Although the applicability and interlaboratory reproducibility of different tests have been shown to be satisfactory for use in clinical practice (32, 33), interpretation of each test requires critical analysis to avoid false-positive or false-negative results (34).
Transient elastography
Although the reproducibility of TE has been shown to be excellent for inter- and intra-observer agreement (35, 36), its applicability may not be as good as that of biomarkers. Indeed, in our experience of more than 13 000 exams over a 5-year period, liver stiffness measurements (LSM) could not be interpreted in nearly one in five cases (failure to obtain any measurement in 4% and unreliable results that did not meet the manufacturer's recommendations in 17%) (37). The principal reasons were obesity, particularly increased waist circumference, and limited operator experience.
Finally, because the liver is an organ wrapped in an expandable but non-elastic envelope (Glisson's capsula), additional space-occupying tissue abnormalities independent of fibrosis, such as oedema and inflammation, cholestasis and congestion, may interfere with LSM. The risk of overestimating liver stiffness values has been reported in the case of alanine aminotransferase flares in patients with acute viral hepatitis or chronic hepatitis B (38, 39, 40) as well as in cases of extrahepatic cholestasis (41) or congestive heart failure (42).
How to use liver biopsy and non-invasive methods in clinical practice?
A liver biopsy should be performed in the case of comorbidities such as alcoholism or metabolic syndrome when non-invasive methods cannot be used or in any unclear situation such as discordant results of non-invasive tests. Conversely, liver biopsy should not be performed when the clinical diagnosis is obvious (cirrhosis) or when no benefit can be expected from the biopsy for patient management. Although there is no optimal threshold, the longer the specimen, the more accurate the staging will be (43). A 20–25 mm long biopsy is considered optimal although a robust evaluation is often possible on a 15 mm long biopsy. Ideally, the biopsy should be read by an experienced liver pathologist because it decreases the source of variability in the histological interpretation (44).
In naïve patients without comorbidities who are candidates for antiviral treatment, non-invasive tests can be used for the first-line staging of fibrosis. The use of either TE or several patented biomarkers (FibroTest, Fibrometer and Hepascore) has recently been recommended, based on an independent systematic review by the French Health Authorities (45). However, this strategy should also take into account HCV genotype, local availability of non-invasive methods and any clinically relevant variable. For instance, when there is a strong clinical suspicion of cirrhosis, in most cases the use of TE is enough to confirm the diagnosis without a liver biopsy. Conversely, a liver biopsy may be necessary to differentiate between F1 and F2 in genotype 1-infected patients before making a decision on antiviral treatment. In the same way, a liver biopsy may be useful to differentiate between F3 and F4 when cirrhosis is not clinically obvious and to decide when to start screening for hepatocellular carcinoma. However, with the availability of new antiviral treatments (46, 47), differentiating between F1 and F2 may not be as important for treatment indications.
When deciding on retreatment, a liver biopsy may be indicated to investigate the presence of factors of impaired response such as non-alcoholic steatohepatitis or to obtain a prognosis especially if a liver biopsy has not been performed previously.
Finally, non-invasive methods can be of interest in the follow-up of untreated patients (48). Given the slow rate of the progression of fibrosis in chronic hepatitis C, a non-invasive evaluation can be performed on a yearly basis.
Conclusion and perspectives
There is an urgent need to pursue the development of non-invasive tests in addition to a liver biopsy for the staging of fibrosis. Because of the conditional relationship with biopsy, the development of serum markers will always have obvious limitations. Promising preliminary results suggest that novel alternative imaging techniques such as magnetic resonance elastography, acoustic radiation force impulse imaging or perfusion computed tomography will eventually be refined to reach an acceptable level of accuracy, especially for the evaluation of early and intermediate stages of fibrosis (49–51). These might become less pertinent as antiviral treatments become more efficient, with fewer side effects.
Conflicts of interest
The authors have declared no potential conflicts.
References
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13 Castera L, Negre I, Samii K, et al. Patient-administered nitrous oxide/oxygen inhalation provides safe and effective analgesia for percutaneous liver biopsy: a randomized placebo-controlled trial. Am J Gastroenterol 2001; 96: 1553–7.
14 Bedossa P, Moucari R, Chelbi E, et al. Evidence for a role of nonalcoholic steatohepatitis in hepatitis C: a prospective study. Hepatology 2007; 46: 380–7.
15 Saadeh S, Cammell G, Carey WD, et al. The role of liver biopsy in chronic hepatitis C. Hepatology 2001; 33: 196–200.
16 Castera L, Pinzani M. Non-invasive assessment of liver fibrosis: are we ready? Lancet 2010; 375: 1419–20.
17 Bedossa P, Carrat F. Liver biopsy: the best, not the gold standard. J Hepatol 2009; 50: 1–3.
18 Pinzani M, Vizzutti F, Arena U, et al. Technology Insight: noninvasive assessment of liver fibrosis by biochemical scores and elastography. Nat Clin Pract Gastroenterol Hepatol 2008; 5: 95–106.
19 Manning DS, Afdhal NH. Diagnosis and quantitation of fibrosis. Gastroenterology 2008; 134: 1670–81.
20 Castera L, Pinzani M. Biopsy and non-invasive methods for the diagnosis of liver fibrosis: does it take two to tango? Gut 2010; 59: 861–6.
21 Friedrich-Rust M, Ong MF, Martens S, et al. Performance of transient elastography for the staging of liver fibrosis: a meta-analysis. Gastroenterology 2008; 134: 960–74.
22 Poynard T, Morra R, Halfon P, et al. Meta-analyses of FibroTest diagnostic value in chronic liver disease. BMC Gastroenterol 2007; 7: 40.
23 Shaheen AA, Myers RP. Diagnostic accuracy of the aspartate aminotransferase-to-platelet ratio index for the prediction of hepatitis C-related fibrosis: a systematic review. Hepatology 2007; 46: 912–21.
24 Castera L, Vergniol J, Foucher J, et al. Prospective comparison of transient elastography, Fibrotest, APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C. Gastroenterology 2005; 128: 343–50.
25 Degos F, Perez P, Roche B, et al. Diagnostic accuracy of FibroScan and comparison to liver fibrosis biomarkers in chronic viral hepatitis: a multicenter prospective study (the FIBROSTIC study). J Hepatol 2010; 53: 1013–21.
26 Sebastiani G, Vario A, Guido M, et al. Stepwise combination algorithms of non-invasive markers to diagnose significant fibrosis in chronic hepatitis C. J Hepatol 2006; 44: 686–93.
27 Sebastiani G, Halfon P, Castera L, et al. SAFE biopsy: a validated method for large-scale staging of liver fibrosis in chronic hepatitis C. Hepatology 2009; 49: 1821–7.
28 Poynard T, Ingiliz P, Elkrief L, et al. Concordance in a world without a gold standard: a new non-invasive methodology for improving accuracy of fibrosis markers. PLoS ONE 2008; 3: e3857.
29 Boursier J, Vergniol J, Sawadogo A, et al. The combination of a blood test and FibroScan improves the non-invasive diagnosis of liver fibrosis. Liver Int 2009; 29: 1507–15.
30 Castera L, Sebastiani G, Le Bail B, et al. Prospective comparison of two algorithms combining non-invasive methods for staging liver fibrosis in chronic hepatitis C. J Hepatol 2010; 52: 191–8.
31 Castera L, Le Bail B, Roudot-Thoraval F, et al. Early detection in routine clinical practice of cirrhosis and oesophageal varices in chronic hepatitis C: Comparison of transient elastography (FibroScan) with standard laboratory tests and non-invasive scores. J Hepatol 2009; 50: 59–68.
32 Imbert-Bismut F, Messous D, Thibaut V, et al. Intra-laboratory analytical variability of biochemical markers of fibrosis (Fibrotest) and activity (Actitest) and reference ranges in healthy blood donors. Clin Chem Lab Med 2004; 42: 323–33.
33 Cales P, Veillon P, Konate A, et al. Reproducibility of blood tests of liver fibrosis in clinical practice. Clin Biochem 2008; 41: 10–8.
34 Poynard T, Munteanu M, Imbert-Bismut F, et al. Prospective analysis of discordant results between biochemical markers and biopsy in patients with chronic hepatitis C. Clin Chem 2004; 50: 1344–55.
35 Fraquelli M, Rigamonti C, Casazza G, et al. Reproducibility of transient elastography in the evaluation of liver fibrosis in patients with chronic liver disease. Gut 2007; 56: 968–73.
36 Boursier J, Konate A, Gorea G, et al. Reproducibility of liver stiffness measurement by ultrasonographic elastometry. Clin Gastroenterol Hepatol 2008; 6: 1263–9.
37 Castera L, Foucher J, Bernard PH, et al. Pitfalls of liver stiffness measurement: a 5-year prospective study of 13 369 examinations. Hepatology 2010; 51: 828–35.
38 Coco B, Oliveri F, Maina AM, et al. Transient elastography: a new surrogate marker of liver fibrosis influenced by major changes of transaminases. J Viral Hepat 2007; 14: 360–9.
39 Sagir A, Erhardt A, Schmitt M, et al. Transient elastography is unreliable for detection of cirrhosis in patients with acute liver damage. Hepatology 2007; 47: 592–5.
40 Arena U, Vizzutti F, Corti G, et al. Acute viral hepatitis increases liver stiffness values measured by transient elastography. Hepatology 2008; 47: 380–4.
41 Millonig G, Reimann FM, Friedrich S, et al. Extrahepatic cholestasis increases liver stiffness (FibroScan) irrespective of fibrosis. Hepatology 2008; 48: 1718–23.
42 Millonig G, Friedrich S, Adolf S, et al. Liver stiffness is directly influenced by central venous pressure. J Hepatol 2010; 52: 206–10.
43 Scheuer PJ. Liver biopsy size matters in chronic hepatitis: bigger is better. Hepatology 2003; 38: 1356–8.
44 Rousselet MC, Michalak S, Dupre F, et al. Sources of variability in histological scoring of chronic viral hepatitis. Hepatology 2005; 41: 257–64.
45 Non invasive methods for the evaluation of hepatic fibrosis/cirrhosis: an update, 2008. Available at http://www.has-sante.fr/
46 Hezode C, Forestier N, Dusheiko G, et al. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med 2009; 360: 1839–50.
47 Kwo PY, Lawitz EJ, McCone J, et al. Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naive patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre phase 2 trial. Lancet 2010; 376: 705–16.
48 Hézode C, Castéra L, Rosa I, et al. Prospective evaluation of liver stiffness dynamics during and after peginterferon alpha-ribavirin treatment in patients with chronic hepatitis C (abstract). Hepatology 2008; 48 (Suppl.): 849A.
49 Huwart L, Sempoux C, Vicaut E, et al. Magnetic resonance elastography for the noninvasive staging of liver fibrosis. Gastroenterology 2008; 135: 32–40.
50 Friedrich-Rust M, Wunder K, Kriener S, et al. Liver fibrosis in viral hepatitis: noninvasive assessment with acoustic radiation force impulse imaging versus transient elastography. Radiology 2009; 252: 595–604.
51 Ronot M, Asselah T, Paradis V, et al. Liver fibrosis in chronic hepatitis C virus infection: differentiating minimal from intermediate fibrosis with perfusion CT. Radiology 2010; 256: 135–42.
Source
Advances in Chronic Hepatitis C Treatment And Liver Transplantation: An Update
ISSUE: JANUARY, 2011
VOLUME: 62:01
The Center for the Study of Hepatitis C (CSHC) at NewYork-Presbyterian/Weill Cornell Medical Center is engaged in diverse HCV investigations. One of us (Dr. Talal) has undertaken research on viral kinetics, presenting the first evaluation of pegIFN pharmacokinetics in patients coinfected with HCV and HIV, finding that, although pharmacokinetic parameters do not differentiate sustained virological responders from nonresponders, certain pharmaco - dynamic measurements do and might therefore serve as useful predictors of treatment outcome.
PDF Download: Advances in Chronic Hepatitis C Treatment And Liver Transplantation: An Update (Acrobat Reader is required)
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VOLUME: 62:01
The Center for the Study of Hepatitis C (CSHC) at NewYork-Presbyterian/Weill Cornell Medical Center is engaged in diverse HCV investigations. One of us (Dr. Talal) has undertaken research on viral kinetics, presenting the first evaluation of pegIFN pharmacokinetics in patients coinfected with HCV and HIV, finding that, although pharmacokinetic parameters do not differentiate sustained virological responders from nonresponders, certain pharmaco - dynamic measurements do and might therefore serve as useful predictors of treatment outcome.
PDF Download: Advances in Chronic Hepatitis C Treatment And Liver Transplantation: An Update (Acrobat Reader is required)
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Adult Stem Cells Treat End-Stage Liver Disease
January 26, 2011
A team of researchers in California and in Egypt report therapeutic benefit treating end-stage liver disease patients with adult stem cells A total of 48 patients were treated with their own adult stem cells–36 patients with chronic, end-stage hepatitis C-induced liver disease, and 12 patients with end-stage autoimmune liver disease. Researchers used the factor G-CSF, commonly used to mobilize bone marrow adult stem cells into the circulation, to obtain the cells from each patient. The CD34+ stem cells were then isolated, amplified to increase numbers of cells, partially differentiated in culture, then re-injected into each patient via their hepatic artery or portal vein. The results were published in Cell Transplantation
According to co-author Dr. Mark A. Zern of University of California-Davis Medical Center:
“This enabled us to transplant as many as one billion of these cells per patient. For all patients there was a statistically significant decrease in peritoneal cavity fluid, or ‘ascites’. There was also clinical and biochemical improvement in a large percentage of patients who received the transplantation. The finding of improvement in ascites in a significant number of patients is impressive and somewhat surprising, suggesting that cell transplantation might be clinically significant beyond the improvement in laboratory parameters.”
The mechanism by which the infusion of CD34+ adult stem cells improves liver function is still unclear. As to whether any partial differentiation into liver cells was needed for the therapeutic results, Dr. Stephen Strom at the University of Pittsburgh and section editor for Cell Transplantation, noted:
“Other research groups are now showing similar results with cells without any hepatic characteristics, including fractionated and unfractionated bone marrow and mesenchymal stem cells. Taken together, these data suggest that the positive effects these researchers find may be the result of paracrine effects from factors secreted by the donor cells.
Published data in 1999 suggested that some bone marrow adult stem cells could form liver hepatocytes. Others reported similar results in 2000 using mice, by observing liver cells of human bone marrow adult stem cell transplant patients, and in experiments showing regeneration of liver in mice. However, some published evidence also indicates that the regenerative capacity of bone marrow adult stem cells is due to paracrine effects, i.e., secreted factors.
No matter what the mechanism, various clinical trials are investigating use of adult stem cells for liver diseases. Published results from earlier trials show therapeutic benefit of adult stem cells for liver repair and regeneration.
In a published 2010 report, a Korean group found some improvement in liver cirrhosis patients using their own adult stem cells.
In 2006 a U.K. group reported improvement in patients with liver insufficiency treated with their own adult stem cells, and the same group reported in 2008 the long-term improvement of chronic liver disease patients, using the patients’ own adult stem cells in a trial similar to the current Egyptian trial.
Also in 2006, a German group reported increased liver regeneration in liver cancer patients using adult stem cells, and a Japanese team found improved liver function in cirrhosis patients after using the patients’ own bone marrow adult stem cells.
Adult stem cells continue to provide ethical and successful results for patients.
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