Journal of Hepatology
Volume 52, Issue 5 , Pages 627-629, May 2010

Re-emerging interest in hepatitis delta: New insights into the dynamic interplay between HBV and HDV

Dept. of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Carl-Neuberg Str. 1, 30625 Hannover, Germany

Received 30 January 2010; accepted 1 February 2010. published online 03 March 2010.

Article Outline

 

Delta hepatitis is still a major global health problem affecting 15–20 million individuals world-wide [1], [2]. The implementation of vaccine programs against hepatitis B was initially associated with a decline in hepatitis D virus (HDV) infections in Southern Europe during the 1980s and 1990s [3], [4]. However, several studies published over the last few years have shown that the prevalence of hepatitis delta remains rather high in Europe – in particular in immigrant populations. Between 8% and 12% of HBsAg-positive individuals tested anti-HDV positive in France [5], Germany [6], [7], Italy [8], [9], [10], the United Kingdom [11], and Turkey [4]. A common feature of all these studies was that the majority of HDV-infected individuals were born in highly endemic areas such as Eastern Turkey, Central Asia, or Africa. HDV is also prevalent in South America, in particular in the Amazonian region of Western Brazil [12], and the Western pacific population [13].

Hepatitis D has been considered as the most severe form of viral hepatitis in humans. As compared to mono-infection with the hepatitis B virus (HBV), HBV–HDV coinfection is associated with an accelerated course of fibrosis progression, earlier hepatic decompensation of cirrhosis, and an increased risk for the develop-ment of hepatocellular carcinoma [1], [2]. In a 28-year long-term follow-up study from Italy, earlier findings were confirmed as one quarter of patients with hepatitis D developed hepatocellular carcinoma, and liver failure was the cause of death for nearly 60% of the patients [14], which is in line with a recent preliminary report from Germany [15].

Despite continuous interest in the epidemiology and clinical outcome of hepatitis delta, our knowledge on the pathophysiology of liver disease in HDV infection is still rather limited. Several cross-sectional studies showed that different patterns of viral dominances can be observed in patients with hepatitis delta and that HDV infection is frequently associated with suppressed HBV replication. About 70–90% of HDV-infected patients are HBeAg negative and HDV seems also to suppress hepatitis C virus (HCV) replication in triple infected individuals [16], [17], [18]. However and importantly, very few studies did investigate virological patterns over time and determined virological markers longitudinally for several years. In this context the paper by Maria Buti’s group from Barcelona, published in the current issue of the Journal of Hepatology, is of major interest [19]. In a retrospective-prospective approach, the authors studied samples of HDV-infected patients over a period of 4–8years and determined quantitative levels of HBV DNA, HDV RNA, and HBsAg. Importantly, and in contrast to conclusions drawn from previous cross-sectional approaches, the authors demonstrate a high frequency of fluctuating activity of either one or even both viruses (Fig. 1). Thus, HDV cannot necessarily be considered as the “dominant” virus based on a single determination. The authors conclude that the role of HBV replication for the pathogenesis of liver disease in hepatitis D should not be underestimated.

  • View full-size image.
  • Fig. 1. 

    Schematic representation of HBV DNA and HDV RNA patterns over time observed in the study by Schaper et al. [19]. Three patients showed persistently high viremia for both viruses (upper left panel) while only 5 patients (20%) showed an HDV dominance with suppressed HBV replication throughout follow up (upper right). In eight subjects both viruses fluctuated, either in alternating (lower left) or in parallel (lower right).

Schaper et al. first developed a quantitative real-time PCR assay for HDV RNA. Until recently, few studies quantitated HDV RNA in patients with hepatitis delta [20]. A possible advantage of the assay developed by Schaper et al. is that genomic HDV RNA from an HDV-infected patient was used as a standard instead of a cloned cDNA. Thus, the reverse transcription step was appropriately assessed in this study. Unfortunately, a WHO standard for HDV RNA is still missing which however would be highly desirable as it is difficult to compare quantitative HDV RNA results between different laboratories at present. HDV RNA levels are not associated with grading or staging of liver disease [21]. Nevertheless, HDV RNA quantification may become more important as viral declines during antiviral treatment are associated with long-term virological responses, and thus, treatment duration could be individualized based on HDV RNA kinetics [22], [23], [24]. The genetic variability of HDV has also to be considered when developing new assays for HDV RNA quantification. At least eight different HDV genotypes have been identified [25], [26] and assays have rarely been standardized for all the different variants. However, the HDV genotype was no issue in the study by Schaper et al. as all subjects were infected with HDV genotype 1 which could have been expected for European hepatitis D patients [2].

HDV is considered as the dominant virus in HBV–HDV coinfection or HBV–HCV–HDV triple infection. Analysing quantitative data for HDV RNA, Schaper and colleagues identified HDV as predominant in about half of the patients only. Thus, HDV may not generally suppress HBV. Recently, molecular mechanisms have been proposed to explain how HDV proteins could interfere with HBV replication. Both the small HDV p24 protein as well as the large HDV p27 protein may repress the HBV enhancers pIIE1 and pIIE2 and thereby inhibit HBV replication [27]. However, still up to 30% of hepatitis delta patients are HBeAg positive and also the present data from Barcelona describe several patients with high HBV DNA levels of >105copies/ml despite HDV coinfection [19]. Moreover, any potential suppressive effect of one virus above the other was not fixed as several patients showed fluctuating patterns over time. Notably note, HBV DNA levels did only change if also HDV RNA levels fluctuated. However, both alternating and parallel HBV DNA and HDV RNA profiles were observed, thus making a general dominant direct HBV DNA suppression by HDV unlikely. Overall, these data are also in line with one Italian study that analyzed patients with HBV–HCV coinfection over time including some individuals who were also anti-HDV positive [28]. Nevertheless, both studies included in the end a rather limited number of patients for the various subgroups. It is therefore too early to draw finite conclusions and more studies are needed to define the meaning different virological profiles and dynamics for the long-term outcome of the patients. For example, it will be important to determine if specific fluctuation patterns are associated with an increased risk to develop clinical endpoints, and to define which patients most urgently require antiviral treatment.

Schaper et al. also studied quantitative HBsAg levels over time. HBsAg levels do significantly differ between different phases of HBV infection [29], and are usually high in hepatitis delta despite suppressed HBV DNA [18]. HBsAg levels correlated with HDV RNA levels in various cross-sectional studies [21], [30], [31]. However, longitudinal testing of both parameters in the present study did not reveal parallel fluctuations of HDV RNA and HBsAg in all cases. One has to consider that HBsAg production and HBV DNA replication are disconnected in later phases of infection, which could be due, in part, to integration of HBV into the host genome; potentially providing a separate template for HBsAg production or cytokine dependent modification of viral replication pathways [32]. All these factors could also play a role in HBV–HDV coinfection, and thus, short-term changes in HDV RNA viremia may not necessarily parallel with changes in HBsAg levels.

What are the main clinical consequences of the study by Schaper et al. for the management and treatment of hepatitis delta patients? (i) Most importantly hepatitis delta has to be considered as a highly dynamic disease which is for example in contrast to chronic hepatitis C. Treatment decisions should not be based on single determinations of virological parameters, and patients should be advised to consult their doctors on regular basis, e.g. every 3–6months. (ii) The role of HBV for disease progression in delta hepatitis should not be underestimated. Thus, although nucleoside and nucleotide analogues currently approved for the treatment of HBV infection are not effective against HDV [33], treatment of HBV infection should not be forgotten in hepatitis delta if indicated according to current guidelines [34]. However, HBV resistance should be avoided as treatment-induced HBV polymerase variants may also confer changes in the structure of the HBsAg, as the open reading frames for HBV polymerase and HBsAg overlap. There is some evidence that the lamivudine-induced sW196S HBsAg variant inhibits secretion of HDV particles [35], [36] with yet unknown clinical consequences. (iii) Treatment options for patients with hepatitis delta need to be improved as this complex disease is associated with significant morbidity and mortality. Currently, only interferon alpha is effective against HDV and, as treatment can be complicated in advanced disease, early treatment might be considered. However and most importantly, the study by Schaper et al. can only represent the starting point of investigating the complex nature of virological patterns in hepatitis delta in more detail. Combined efforts by various centers are needed to define distinct clinical courses which may require more aggressive treatment interventions and monitoring strategies. We have just started to understand the complex biology of this very interesting virus – more than 30years after its discovery!

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PII: S0168-8278(10)00037-1

doi:10.1016/j.jhep.2010.02.001

Refers to article:

  • Quantitative longitudinal evaluations of hepatitis delta virus RNA and hepatitis B virus DNA shows a dynamic, complex replicative profile in chronic hepatitis B and D , 08 March 2010

    Melanie Schaper, Francisco Rodriguez-Frias, Rosendo Jardi, David Tabernero, Maria Homs, Gerardo Ruiz, Josep Quer, Rafael Esteban, Maria Buti
    Journal of Hepatology May 2010 (Vol. 52, Issue 5, Pages 658-664)

Journal of Hepatology
Volume 52, Issue 5 , Pages 627-629, May 2010

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