Chronic hepatitis B and C virus infections are a major global public health problem. It is roughly estimated that 400 million and 200 million people are infected with them, respectively. This population is at increased risk of cirrhosis, hepatocellular carcinoma, liver failure and ruptured esophageal variceal bleeding, making it the leading cause of liver-related deaths today and a major indication for liver transplantation in developing countries. However, because of the slow natural course of the disease and the ethical limitations of pilot studies in this area, surrogate endpoints are commonly used in clinical practice to assess the efficacy of related therapeutic measures, and there is a need to demonstrate that the surrogate endpoints truly reflect long-term outcomes.
Definition of antiviral treatment efficacy endpoints
The most important difference between HCV and HBV is that HCV can be cleared, whereas HBV is always detectable in the liver. Therefore, the goal of treatment for the former is durable viral clearance, whereas the goal of treatment for the latter is sustained suppression of viral replication. Viral clearance in patients with hepatitis C refers to sustained virologic response (SVR), a surrogate endpoint that has been shown to reflect durable clearance of serovirus. Both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have recently shortened the post-treatment follow-up period required to define SVR by using SVR12, i.e., undetectable HCV RNA for 12 consecutive weeks of treatment with PegIFN/RBV, which is supported by the results of two studies.
The ideal treatment endpoint for patients with hepatitis B is sustained HBsAg disappearance with or without anti-HBs, but this is actually achieved in only 1% to 7% of cases after a 1-year period of treatment. Thus, for HBeAg-positive patients, durable HBeAg seroconversion is a satisfactory treatment endpoint, whereas for HBeAg-positive patients who do not achieve HBeAg seroconversion and for all HBeAg-negative patients, the desired treatment endpoint is persistent undetectable HBV DNA.
Does the treatment endpoint change the natural history of HBV infection?
Although HBV DNA suppression is the most reliable predictor of response to all anti-HBV therapy, the vast majority of patients who discontinue antiviral therapy with undetectable serum HBV DNA will have re-emerging viremia. Virologic response rates in patients with hepatitis B are also limited by patient resistance, which is as high as 80% for lamivudine and 29% for adefovir. Similarly, the HBV DNA cut-off for patient response to PegIFN has an impact on virologic response rates.
With advances in serum HBV DNA testing methods and therapeutic agents, entecavir (ETV) or tenofovir (TDF) alone can now adequately suppress viral replication in 95% of patients for 5 years (Tables 1 and 2). Treatment endpoints have also evolved from HBeAg and HBsAg seroconversion to undetectable HBV DNA by RT-PCR. studies have shown that quantitative measurement of serum HBsAg at 12 weeks of treatment can accurately predict whether patients will respond to PegIFN and thus determine which patients need to discontinue IFN early and switch to long-term NUC therapy.
Depending on age, ALT levels, and HBV genotype, spontaneous HBeAg seroconversion can occur in 2% to 15% of chronic carriers and usually predicts a reduced risk of patients developing cirrhosis and hepatocellular carcinoma, especially if it occurs before age 30. HBeAg seroconversion has long been used worldwide as the standard endpoint for IFN treatment of HBeAg-positive patients. HBeAg seroconversion is achieved in approximately 1/3 of patients with active hepatitis treated with PegIFN, with a higher incidence of HBeAg seroconversion in patients with baseline HBV DNA levels of 2-5× ULN and HBV genotypes A and B without BCP region and pre-C region variants (Table 1), and patients with seroconversion have a The likelihood of cirrhosis, HCC and liver-related mortality was reduced in seroconverted patients. However, those who fail to maintain HBeAg seroconversion over time may develop HBeAg-negative CHB, which is only seen in patients with sustained HBV DNA levels below 2,000 IU/mL, especially those on third-generation NUC therapy with good compliance and high HBeAg seroconversion rates (Table 2). In addition, such patients experience positive serum HBeAg conversion or develop serum HBeAg-negative CHB after discontinuation of NUC, however, this result still needs further proof.
Therefore, the use of HBeAg seroconversion and HBV DNA <2 000 IU/mL as treatment endpoints, both for treated and untreated patients, is plausible but not ideal.
Spontaneous HBsAg clearance can occur in inactive HBV carriers and in patients with chronic active hepatitis who produce a virologic response. Asian cohort studies have shown that in more than 95% of patients, undetectable HBV DNA is a prerequisite for HBsAg clearance. Less than 2% of inactive carriers clear HBsAg spontaneously; however, HBsAg clearance with IFN therapy is strongly influenced by the patient’s HBeAg status, age, and underlying liver disease, with clearance rates ranging from approximately 0.5% to 2.3%. HBsAg clearance with direct antiviral therapy is also low. Conversely, IFN has shown faster and more significant clearance of HBsAg than direct antivirals. However, some studies have shown that occult HBV infection can occur in seronegative HBsAg patients. A Hong Kong analysis found that most patients developed HCC 1 to more than 10 years after spontaneous clearance of HBsAg, leading to speculation of a potential pathogenic role for latent HBV infection in advanced liver fibrosis and/or long-term exposure to carcinogenic factors. There is now evidence that occult infection is a risk factor for the development of HCC.
Studies of patients with advanced cirrhosis have demonstrated that effective anti-HBV therapy can improve patient survival by preventing liver-related complications.
Chang et al. in Taiwan studied 10 patients with cirrhosis and for the first time documented histological reversal in four of them. Another study conducted a secondary analysis of 96 mostly HBeAg-negative cirrhotic patients on entecavir and a second liver biopsy after 5 years of undetectable HBV DNA by PCR. As a result, 70 (73%) had at least a 2-point reduction in Ishak histology score and 71 (74%) had histological reversal of cirrhosis.
A study of patients with advanced cirrhosis demonstrated that LAM slows the progression of HBV-related liver disease. The rates of liver disease progression in the placebo and treatment groups in the study were 24% and 9%, respectively (p=0.001). However, patients who experienced virologic breakthrough after resistance to LAM had a higher rate of clinical endpoint events at 32 months of treatment than the placebo group (11%, 5%; P<0.031). This study demonstrated that HCC was the only complication in virologically responsive patients (Table 3).
A systematic review has shown that anti-HBV therapy prevents HCC in patients with CHB but not in patients with cirrhosis. A recent Greek cohort study confirmed that patients with cirrhosis who are long-term responders to LAM are still at risk of developing hepatocellular carcinoma. However, the treatment used in the study is no longer recommended by international guidelines for the treatment of patients with CHB. In addition, an Italian multicenter study of patients with compensated cirrhosis found that despite persistently undetectable HBV DNA over 4 years of treatment with ETV alone, patients had an average annual incidence of hepatocellular carcinoma of approximately 2.5%, similar to the incidence of HCC in untreated HBeAg-negative patients in Europe. However, HCC in the above cirrhotic patients occurred during the extended survival period after NUC treatment. In addition, trials have shown that esophageal varices improve in cirrhotic patients successfully treated with LAM (with or without ADV) and are similar to the improvement measured by hepatic venous pressure gradient (HVPG) in treated patients with portal hypertension.
In addition, persistently elevated serum HBV DNA levels independently predicted cirrhosis loss. An Asian trial showed that long-term suppression of HBV DNA with ETV or TDF promoted reversal of clinical decompensation and improved Child-Pugh scores and MELD scores in most patients, and patients treated with LAM had an approximately 3-fold higher 1-year transplant-free survival than untreated patients. Other studies have found that remedial therapy with third-generation NUC is still available for patients who develop loss of compensation after resistance to first- and second-generation NUC. However, approximately 20% of clinically decompensated patients with severe disease have been reported to die within the first 6 months of treatment or to develop HCC within the first 2 years of treatment. 14,717 patients with viral cirrhosis underwent liver transplantation in Europe between 1988 and 2007, 37% of whom required anti-HBV therapy. The highest survival rates were observed in patients with end-stage HDV infection (10-year survival rate of 90%), with overall survival rates of more than 70% in patients with hepatitis B, higher than in patients with hepatitis C, which was about 60%. A study conducted a secondary analysis of 74 HCC patients who were first treated with NUC to achieve sustained suppression of serum HBV DNA and subsequently underwent liver transplantation had a 5-year survival rate of 89%, with only 6% having recurrence of liver cancer, and almost all were patients who underwent transplantation beyond the Milan criteria. Although there is disagreement about the severity of disease between patients included in the study and those in the clinic, the HBV suppression rates achieved with third-generation NUC in the clinic were very similar to those achieved in the registry trial.
Does the treatment endpoint change the natural history of HCV infection?
For patients with non-cirrhotic liver, anti-HCV therapy does not prevent liver-related deaths. First, epidemiologic studies have shown that extrahepatic causes are the leading cause of death in patients with hepatitis C, resulting in three times more deaths than liver-related causes. Second, the majority of patients who die from liver-related complications need to develop cirrhosis, which is also a major risk factor for the development of HCC. However, indirect evidence does exist that HCV has a negative impact on survival in patients who do not develop cirrhosis. Amin et al. from Australia found that liver-related mortality was 16.9 times higher in HCV-infected patients than in the general population of the same sex and age group. In Denmark, Omland et al. analyzed 6,292 patients who developed anti-HCV antibodies, and the liver-related 8-year mortality rate was 2% in 37% of those who had cleared the virus, compared with 5.5% in those who had not. A large U.S. study also found that SVR reduced all-cause mortality. Another study confirmed a clinical benefit of HCV clearance in patients who did not develop cirrhosis.
A secondary goal of anti-HCV therapy is to prevent extrahepatic clinical signs caused by the virus. HCV can cause cryoglobulinemia, involve the nervous system and kidneys, and can increase the risk of developing diabetes and carotid atherosclerosis. Similarly, HCV can lead to the development of non-Hodgkin’s lymphoma in some patients. There is evidence that SVR can ameliorate or prevent the development of many of these diseases.
Patients with cirrhosis due to HCV infection are at risk for liver-related death. Many studies have shown that SVR can improve survival in patients with hepatitis C cirrhosis. Among them, Yoshida et al. from the University of Tokyo, Japan, reported a lower annual incidence of HCC and lower 5-year liver-related mortality in patients with SVR. A study from Tokyo Women’s University, Japan, reported similar results.
Bruno et al. in Milan, Italy, found lower rates of liver-related complications, HCC, and liver-related death in patients with SVR than in those who failed treatment. Velt et al, Erasmus MC University Medical Center, Rotterdam, The Netherlands, confirmed that SVR reduces the risk of all liver-related events, including liver failure. Cardoso et al. in Clichy, France, followed 307 patients with bridging fibrosis or cirrhosis for 3.5 years after the end of treatment and found that patients who achieved SVR had significantly lower rates of liver-related complications, liver-related death and HCC than those who did not.
Two Italian studies have confirmed the effect of SVR on the clinical course of portal hypertension.Bruno et al. followed 218 patients for up to 18 years and found that SVR prevented the progression of esophageal varices.D’Ambrosio et al. followed 127 patients who completed IFN treatment for 108 months and found that despite SVR , the incidence of esophageal varices was reduced in the patients.
The current study demonstrates that SVR prevents hard clinical endpoints in patients with advanced hepatic fibrosis/cirrhotic hepatitis C and improves METAVIR scores and reduces liver-related complications.
Mallet et al. found a reduction in liver-related clinical events in patients who achieved SVR with improved cirrhosis and a clinical benefit in patients with recurrent HCV infection after liver transplantation who achieved SVR]. Recent studies have also shown that patients awaiting liver transplantation who achieve undetectable HCV RNA with IFN therapy are less likely to be reinfected with HCV and are cured of HCV infection even after transplantation in approximately 70% of patients.
Summary
It is now safe to assume that the surrogate endpoints generally used to assess the efficacy of anti-HBV or anti-HCV therapy are very practical indicators of efficacy, but are not always effective in actual medical practice, the main problem being underdiagnosis and inequity in treatment access. In the case of hepatitis C, poor tolerance and acceptability of IFN treatment will remain a major factor limiting clinical efficacy. For HBV infection, the main reasons limiting treatment access are healthcare costs and patient reluctance to take medications for long periods of time. In conclusion, it has been more than 30 years since effective anti-HBV and anti-HCV treatments were first introduced, but efforts are still needed to improve diagnosis rates, ensure equal treatment access and develop effective antiviral treatments that are better tolerated and will benefit the majority of patients.