Viral hepatitis: Impressive advances but still a long way to eradication of the disease

This supplement of Liver International for the 7th Paris Hepatitis Conference (PHC) includes review articles by outstanding international experts with the most up-to-date information and their applications to the clinical care of patients with hepatitis B and hepatitis C, which were presented at this meeting. Approximately 170 million people are chronically infected with HCV and 350 million people are chronically infected with HBV worldwide. It is estimated that more than one million of patients die from complications related to chronic viral hepatitis, mainly from hepatocellular carcinoma (HCC) that is one of the most frequent cancers in many countries, especially in Africa, Middle East and Asia. In France, despite a relatively low prevalence of chronic hepatitis B or C, it has been shown that the mortality related to chronic viral hepatitis is around 5000 deaths per year 1. In addition, HBV- and HCV-related cirrhosis and HCC are the most common causes of liver transplantation. In other words, the impact of chronic viral hepatitis is a heavy public health burden. Rapid progress, the availability of new drugs and new therapeutic strategies are increasing the complexity and individualizing the management of patients with viral hepatitis. Therefore, it is extremely important to educate and advise clinicians, so that available information can be exploited to optimize the management of these patients. Recent spectacular innovations were made in the management of hepatitis C; thanks to the development of new therapies 2. However, in the majority of countries, current standard of care is still the combination of pegylated interferon with ribavirin. A significant step forward was achieved recently in the treatment of chronic HCV genotype 1 infection with the triple therapy of pegylated interferon and ribavirin with a protease inhibitor (telaprevir or boceprevir). Even if these triple therapies are associated with side effects, mainly related to pegylated interferon and ribavirin, the sustained virological response (SVR) rates in maïve patients with HCV genotype 1 infection were dramatically increased by 30% (from 40 to 70%). The primary goal of treatment is to achieve a SVR that is usually defined as undetectable serum HCV RNA 24 weeks after the end of treatment. Twelve weeks post-treatment follow-up appears to be as relevant as 24 weeks to determine SVR 3. Long-term follow-up demonstrated that SVR is durable and associated with eradication of HCV infection with undetectable HCV RNA in the serum, and in the liver 4, 5. SVR means cure of the viral infection. In addition, viral eradication is associated with regression of fibrosis and possible reversibility of cirrhosis and significant improvement of the clinical outcome with decreased incidence of complications, especially HCC, and improved survival. Strong predictors of response to treatment with the combination of PEG IFN and RBV have been demonstrated. Some are related to the virus and others to the host 6. The relationship between HCV infection and insulin resistance is fascinating. It has been shown that HCV interferes with intracellular metabolic pathways that induce insulin resistance and increase the risk of diabetes and metabolic syndrome 7, 8. Recently, genetic factors have been emphasized with the high predictive value of IL28B polymorphism 9. It is remarkable that IFN-stimulated genes are highly expressed in non-responders; thus, pre-activation of the IFN system in patients appears to limit the effect of IFN therapy 10, 11. Interestingly, new IFN-based triple therapies with second-wave protease inhibitors (simeprevir and faldaprevir), once a day, will soon be available making treatment easier and better tolerated 12-14. However, the tolerability profile of triple therapy is still a concern with the side effects mostly related to IFN and RBV. Interestingly, in HCV genotype 1-infected patients without cirrhosis, simeprevir is being evaluated for a 12-week short treatment duration according to early virological response (Clinicaltrials.gov: NCT01846832). The development of new DAAs with different viral targets, nucleoside/nucleotide analogues and non-nucleoside inhibitors of the RNA-dependent RNA polymerase, and NS5A inhibitors is crucial. Impressive data have been reported with Simeprevir plus sofosbuvir with or without ribavirin in GT1 naive subjects and prior null responders (COSMOS study) 15. Faldaprevir is being evaluated in IFN- free regimen 16. Furthermore, faldaprevir plus deleobuvir plus PPI-668 (NS5A inhibitor) with or without ribavirin in persons with genotype 1a infection was studied 17. Thirty-seven individuals with GT1a (without cirrhosis) were included. At week 4, HCV RNA was undetectable (<25 IU/ml) for 97% of subjects (35/36). SVR4 was available for 13 persons, and all had undetectable HCV RNA. Recently, sofosbuvir (polymerase nucleotide inhibitor) (Sofosbuvir) has demonstrated an important antiviral efficacy, with a favourable safety profile 18-20, Sofosbuvir plus PEG-IFN and RBV for 12 weeks provide SVR of approximately 90% for HCV genotype 1-infected patients. Sofosbuvir plus RBV for 12 weeks provide excellent results for HCV genotype 2. For HCV genotype 3, sofosbuvir plus RBV for 24 weeks may be an option. Indeed, recent studies have demonstrated that antiviral combinations have additive antiviral potency with no cross resistance and a good safety profile. The ABT-333 (potent protease inhibitor) based regimen provides high antiviral potency with a favourable safety profile 21. The high majority of HCV genotype 4-infected patients remain treated with PEG-IFN plus RBV therapy, we urge for trials with DAAs in this specific population 22. These new DAA combination regimens with a finite duration and without IFN, available in a near future, would make the hope that HCV might be the first chronic viral infection eradicated worldwide. Thus, clinicians have turned their attention to an exciting new direction: investigating interferon free therapies that will be effective in all genotypes. This raises an important issue: which patients should be treated in 2014 and how can we increase their chance of a cure? Which patients can be treated later based on future options? Simultaneously, the PHC 2014, as in the past, will address major issues associated with Hepatitis B. There is cumulative evidence that long-term complete suppression of HBV replication by the most potent drugs (entecavir and tenofovir) results in long-term improved outcome with decreased risk of progression to cirrhosis and complications such as liver failure, HCC and improved survival. In addition, a recent study assessing liver histology of patients treated 5 years with tenofovir demonstrated the regression of fibrosis in the large majority of patients 23, 24. Noteworthy, contrarily to the dogma, reversibility of cirrhosis under treatment was observed in 75% of cirrhotic patients probably associated with a decreased risk of HCC and improved survival. Quantifying HBsAg is certainly an important new tool for predicting the severity of disease, allowing distinguishing inactive carriers from patients with HBeAg-negative chronic active hepatitis, therefore helping to tailor follow-up and decision for treatment 25, 26. In addition, quantitative HBsAg decline during therapy is a strong predictor of SVR after PEG IFN therapy and of the chance of HBsAg loss that is the ultimate goal of therapy 27, 28. In patients treated with analogues, the decline of HBsAg levels is also a predictor of HBsAg loss that allows interrupting therapy. Finally, the optimal management of special populations and difficult situations needs to be improved: pregnancy, co-infections with HIV and/or HDV and HCV, cirrhosis, immunosuppression. This up-to-date issue including comprehensive reviews from outstanding international experts covers every aspect of hepatitis C and hepatitis B management. Nowadays, with very efficient and well-tolerated drugs available, the challenge is to define the best therapeutic strategies and to facilitate the access to therapy. Taking into account the complexity of treatments and their cost, there is a need to develop optimal cost-effective strategies to provide the best chance of cure to as many patients as possible worldwide.