June 9, 2013

Provided by NATAP

Clinical Infectious Diseases Advance Access published May 14, 2013

Oscar Cruz Pereira and Jordan J. Feld
Toronto Western Hospital, University Health Network, Sandra Rotman Centre for Global Health, University of Toronto, Ontario, Canada

"Multiple studies have shown that fibrosis, and even cirrhosis, may regress after SVR. Perhaps an assessment of fibrosis after SVR would allow for better risk stratification....larger studies similar to this effort will be useful to identify high-risk patients who require ongoing HCC screening"

"Although this study focused on the risk of HCC, Hultcrantz et al also found that SVR reduced liver-related complications, liver-related mortality, and all-cause mortality. Combining these data with those from the study by van der Meer et al, as well as other published series, there is now solid evidence that SVR changes the natural history of the disease. SVR can no longer be considered a surrogate endpoint as it truly does indicate a very good long-term prognosis. However, as Hultcrantz and colleagues point out, SVR indicates viral eradication but is not a cure of liver disease. At least for now, even if they achieve SVR, patients with cirrhosis need to keep on screening"

"Hultcrantz and colleagues found that patients who were treated but did not achieve SVR had better outcomes than patients who received no treatment, again raising the question of whether unsuccessful treatment is better than no treatment. Although the rate of HCC was much higher in the untreated population than in those who were treated but did not achieve SVR, it is important to note that this was not a randomized study. Treatment was offered at the discretion of the treating physicians. It is likely that untreated patients had more advanced disease or other comorbidities that influenced both their risk of HCC and the decision to withhold therapy. Notably, they were older and a higher percentage was male and had diabetes, all risk factors for HCC development. Multiple studies have addressed the question of long-term suppressive therapy with discouraging results. Although the HALT-C trial did show a lower incidence of HCC in patients randomized to long-term low-dose peginterferon, the difference only emerged after 5-7 years of follow-up [11]. Given the rapid improvements in HCV therapy, long-term suppressive therapy with interferon to prevent HCC is not a realistic strategy."

Liver cancer is the second most common cause of cancer death worldwide, and the sixth most common in developed countries [1]. Depending on the prevalence of hepatitis C in a region, it can account for 13%-66% of cases of hepatocellular carcinoma (HCC) [2]. HCC occurs almost exclusively in patients with cirrhosis [3]; however, other factors such as the etiology of cirrhosis also play a role. For instance, the risk of HCC in patients with cirrhosis and chronic hepatitis B is 3%-8% per year, but in autoimmune hepatitis the risk is only 1.1% per year or lower [3, 4]. Thus, one would expect that curing hepatitis C might modify the risk of developing HCC.

In this issue of Clinical Infectious Diseases, Hultcrantz and colleagues report on the long-term follow-up of 351 Swedish patients with hepatitis C virus (HCV)-related Child-Pugh class A cirrhosis. All but 48 patients received interferon-based therapy, of whom 110 successfully achieved sustained virologic response (SVR) and were compared to the 193 who did not clear the virus. The authors were able to prospectively collect data during an 8-year study period, even for the 7% who were lost to clinical follow-up. This was thanks to the national registries in Sweden that capture >95% of all cases of cancer and record the cause of >99.5% of all deaths. The incidence of HCC was significantly reduced in patients who achieved SVR (1.0 per 100 person-years [PY]) compared to those who failed treatment (2.3 per 100 PY) or those who were never treated (4.0 per 100 PY). In addition, they found that patients who achieved SVR had fewer liver-related complications, liver-related deaths, and overall deaths (0.9, 0.7, and 1.9 per 100 PY, respectively) than non-SVR (3.2, 3.0, and 4.1 per 100 PY, respectively) or untreated patients (4.9, 4.5, and 5.1 per 100 PY, respectively). They were unable to identify any clear risk factors for the development of HCC or other complications after SVR. Notably, the incidence of HCC was similar in the first 3 years and the subsequent 3 years after viral clearance.

These important data add to the accumulating evidence regarding the significance of SVR. Recently, van der Meer and colleagues reported the results of an international, multicenter, long-term follow-up study of 530 patients with chronic hepatitis C and advanced fibrosis treated with interferon-based regimens [5]. During a median follow-up of 8.4 years, patients who achieved SVR had a lower incidence of HCC (0.55 vs 1.01 per 100 PY), liver failure (0.31 vs 3.62 per 100 PY), liver-related mortality (0.23 vs 3.20 per 100 PY) and, most importantly, all-cause mortality (1.01 vs 2.93 per 100 PY) than patients who did not achieve SVR [5]. The van der Meer study also included patients with only bridging fibrosis. Both studies found that patients who achieved SVR had better outcomes, but they both clearly documented that some patients were still at risk of developing HCC, with an incidence of approximately 0.5%-1% per year.

This raises a challenging issue for clinicians. These findings suggest that we may still need to screen for HCC in patients with cirrhosis even after achieving SVR. However, the reported rates are below the threshold of 1.5% per year for screening to be cost effective [6]. The current American Association for the Study of Liver Diseases (AASLD) guidelines recommend screening all patients with cirrhosis [3] based on a randomized controlled trial showing that surveillance reduced mortality by 37% in Chinese patients with cirrhosis due to hepatitis B [7], and a cost-benefit analysis showing that ultrasound was cost-effective in a mixed population of patients with cirrhosis [8]. Notably, however, although the HALT-C (Hepatitis C Antiviral Long-term Treatment Against Cirrhosis) trial showed that patients with bridging fibrosis had a 0.82% per year risk of developing HCC [9], the AASLD guidelines do not recommend screening such patients because the incidence is below the threshold of 1.5% per year [3]. Thus, although SVR did not eliminate the increased risk of HCC, it may have reduced it to a level at which routine screening of every individual may not be cost effective.

Multiple studies have shown that fibrosis, and even cirrhosis, may regress after SVR. Perhaps an assessment of fibrosis after SVR would allow for better risk stratification. Unfortunately, in the Hultcrantz et al study, fibrosis was not assessed after achieving SVR. However, in a recent long-term follow-up study from the clinical center at the National Institutes of Health, investigators estimated liver fibrosis using transient elastography (TE) in 69 patients who had achieved SVR between 1986 and 2003 [10] and were followed for a mean of 7.5 years. Of those with cirrhosis on biopsy prior to treatment, 14% had TE scores of <7.0 kPa (no significant fibrosis) in their most recent follow-up visit, suggesting that they had significant regression of fibrosis. Notably, a small number of patients (2%) appeared to have progressive disease, with mild fibrosis before treatment and high TE scores (>13.8 kPa) at last follow-up [10]. Although these patients likely had another cause for disease progression, this highlights that fibrosis improvement is not universal. Interestingly, although the distribution of fibrosis scores did not appreciably change after SVR, almost all patients had improvement in parameters of liver synthetic function and portal hypertension, such as bilirubin level and platelet count [10]. The event rate was too low (1 HCC) to determine if fibrosis regression by TE or other parameters would be helpful for risk stratification, but larger studies similar to this effort will be useful to identify high-risk patients who require ongoing HCC screening. This will likely require a collaborative effort from multiple centers to accumulate enough patients who develop HCC after SVR to identify factors and allow for risk stratification. In addition to the degree of regression of fibrosis, factors to look at may include degree of steatosis, comorbidities, and patient demographics as well as time since SVR, even though this did not appear helpful in the Hultcrantz study.

Hultcrantz and colleagues found that patients who were treated but did not achieve SVR had better outcomes than patients who received no treatment, again raising the question of whether unsuccessful treatment is better than no treatment. Although the rate of HCC was much higher in the untreated population than in those who were treated but did not achieve SVR, it is important to note that this was not a randomized study. Treatment was offered at the discretion of the treating physicians. It is likely that untreated patients had more advanced disease or other comorbidities that influenced both their risk of HCC and the decision to withhold therapy. Notably, they were older and a higher percentage was male and had diabetes, all risk factors for HCC development. Multiple studies have addressed the question of long-term suppressive therapy with discouraging results. Although the HALT-C trial did show a lower incidence of HCC in patients randomized to long-term low-dose peginterferon, the difference only emerged after 5-7 years of follow-up [11]. Given the rapid improvements in HCV therapy, long-term suppressive therapy with interferon to prevent HCC is not a realistic strategy.

Although this study focused on the risk of HCC, Hultcrantz et al also found that SVR reduced liver-related complications, liver-related mortality, and all-cause mortality. Combining these data with those from the study by van der Meer et al, as well as other published series, there is now solid evidence that SVR changes the natural history of the disease. SVR can no longer be considered a surrogate endpoint as it truly does indicate a very good long-term prognosis. However, as Hultcrantz and colleagues point out, SVR indicates viral eradication but is not a cure of liver disease. At least for now, even if they achieve SVR, patients with cirrhosis need to keep on screening.

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