Hepatitis Delta is an inflammatory liver disease caused by the hepatitis Delta virus (HDV), a defective RNA virus that requires the mandatory helper function of hepatitis B virus (HBV) for its transmission and life cycle. For this reason, HDV is acquired either as a coinfection of the two viruses or as a superinfection of chronic HBV carriers. The clinical outcome is different: coinfection usually runs a self-limited course that terminates with the clearance of both viruses and complete recovery in most cases, due to a transient hepatitis B surface antigenemia, which is required to support HDV replication (Fig. 1). The clinical course and outcome of superinfection varies, but it generally causes severe acute hepatitis with a relatively short incubation period, leading to a progressive chronic hepatitis in over 90% of cases (Fig. 2). More than 350 million people in the world are considered to have chronic HBV infection, and about 5% of them have serological evidence of exposure to HDV, leading to a burden of at least 15-20 million HDV cases worldwide. The improvement in socioeconomic conditions and the introduction of vaccination programs against HBV have resulted in a significant decrease in the incidence of HDV infection over the past two decades, particularly in southern Europe.
However, the prevalence of HDV has risen to levels not seen since the late 1990s due to the immigration of persons from areas where HDV is still endemic, such as eastern Europe, the Middle East, central Africa, and northern South America. The clinical scenario of chronic HDV infection has changed accordingly. The percentage of individuals with active cirrhosis due to chronic hepatitis Delta increased from 20% in the 1980s to almost 70% in the 1990s due to progressive disease in patients who survived the epidemics of the 1970s and 1980s. As a consequence, the current population of HDV carriers now observed in Europe consists of patients with advanced cirrhosis or with an indolent long-lasting disease, together with younger cases, mostly immigrants from countries where HDV is endemic.
The chronic form of hepatitis Delta is most often the result of an acute superinfection in a chronic HBV carrier that provides the biological environment for the maintenance of HDV replication. However, the clinical outcome may have different courses ranging from mildly progressive disease to a severe progressive course that may lead to acute on chronic liver failure and death within a few weeks. The more progressive course of chronic HDV infection seems to be more frequently observed in the Far East as well as in South America. This may be due to different HDV genotypes in these endemic areas. At present, eight genotypes have been described. Genotype 1, which is present worldwide, is characterized by a variable disease course. Genotypes 2 and 4, which are typically present in the Far East, are usually associated with a mild hepatitis, although a subtype of genotype 2 has been associated with a more progressive course. Genotype 3, which is more prevalent in northern South America, is associated with a particularly severe hepatitis. Genotypes 5-8 have recently been described in West and Central Africa. The heterogenicity, geographical distribution, and pathogenicity of these newly identified clades still remains to be established.
The different disease course observed in HDV genotypes 1 and 2 may be related to differences in virion assembly. Indeed, in vitro experiments have indicated that virion assembly efficiency is higher in genotype 1 compared with genotype 2. By the same token, RNA replication of a genotype 2 clone from Taiwan in cell culture was 100-fold less than that of a genotype 1 clone from Italy. Recently, it has been shown that HBV genotypes may also play a role in the progression of chronic HDV infection, with HBV genotype C apparently associated with worse clinical outcome and HBV genotype A associated with lower HDV viral load.
In general, chronic HDV infection leads to cirrhosis in approximately two thirds of cases within a few years of infection. The risk of developing cirrhosis is about 3-fold higher in HDV patients compared with HBV-monoinfected patients. In our experience of 299 patients with a median follow-up of 28 years, cirrhosis occurred at an annual rate of 4%. Once cirrhosis has developed, the disease may remain stable or progress to clinical decompensation and hepatocellular carcinoma (HCC). Although early reports indicated the occurrence of HCC as infrequent in the setting of chronic HDV, a European study on 200 Child-Pugh class A patients with cirrhosis who were followed for 6.6 years reported a 3.2-fold increased risk of developing HCC in HDV-infected patients compared with HBV-monoinfected patients. With regard to the occurrence of liver decompensation, the same study demonstrated a 2.2-fold increased risk of liver decompensation in HDV-positive patients compared with HBV-monoinfected patients. In our experience, clinical decompensation and not HCC was the dominant complication to appear in the setting of chronic HDV infection, with an annual incidence rate of 2.7%. We also found that persistent HDV replication was associated with the development of liver decompensation and was the only predictor of liver-related mortality.
However, at present there has been no conclusive evidence to support a direct correlation between serum levels of HDV RNA and degree of liver disease. In fact, the currently available data suggest that hepatitis Delta is mainly an immunomediated disease, even though specific clinical cases suggests that it may be cytopathic because of unusual histological features observed in fulminant hepatitis induced by HDV genotype 3. Taken together, these data suggest that the optimal therapy against HDV should enhance anti-HDV immunity and reduce viremia, which would result in long-lasting control of the infection.
In conclusion, hepatitis Delta remains a major public health problem characterized by a high pathogenicity and a lack of effective antiviral treatment. Continuous research remains a priority to obtain a better understanding of the pathogenesis of hepatitis Delta and identify treatment strategies to control an ominous disease that affects at least 15 million people worldwide.