Liver stiffness measurement as a noninvasive method for the diagnosis of liver cirrhosis in patients with chronic hepatitis D virus infection.

BACKGROUND: Noninvasive tests (NITs) have been proposed as an alternative to liver biopsy for diagnosing liver cirrhosis. The evidence of NIT performance in patients with chronic hepatitis D (CHD) is limited. AIMS: To evaluate the diagnostic performance of liver stiffness measurement (LSM) and other NITs in CHD patients. METHODS: We evaluated the diagnostic performance of LSM by transient elastography for the detection of liver cirrhosis in a retrospective, multicentre cohort of 144 CHD patients with paired (±6 months) LSM and liver biopsies. RESULTS: Cirrhosis was diagnosed histologically in 22 patients (15.3%). Mean LSM was significantly higher in patients with cirrhosis compared to those without fibrosis (23.4 vs 10.2 kPa, p < 0.0001) or with intermediate fibrosis (23.4 vs 13.5 kPa, p < 0.0001). In the detection of liver cirrhosis, LSM was superior to other NITs (AUROCs: 0.89 [LSM], 0.87 [D4FS], 0.74 [APRI], 0.73 [FIB-4], and 0.69 [AAR]). The optimal cut-off for identifying patients with liver cirrhosis was ≥15.2 kPa (Se 91%, Sp 84%, PPV 50%, NPV 98%). The ideal cut-off for diagnosing non-advanced liver fibrosis (Metavir ≤2) was <10.2 kPa (Se 55%, Sp 86%, PPV 90%, NPV 45%), correctly identifying 90% of patients. Data were validated in an independent cohort of 132 CHD patients. CONCLUSIONS: LSM is a useful tool for identifying patients at risk for liver cirrhosis and is superior to other NITs. The cut-offs of <10.2 and < 15.2 kPa reliably diagnose non-advanced liver fibrosis and exclude cirrhosis in the majority of patients. However, LSM cannot completely replace liver biopsy in CHD patients.

Diagnosis of HDV: From virology to non-invasive markers of fibrosis.

Hepatitis D viral infection in humans is a disease that requires the establishment of hepatitis B, relying on hepatitis B surface Ag and host cellular machinery to replicate and propagate the infection. Since its discovery in 1977, substantial progress has been made to better understand the hepatitis D viral life cycle, pathogenesis and modes of transmission along with expanding on clinical knowledge related to prevention, diagnosis, monitoring and treatment. The availability of serologic diagnostic assays for hepatitis D infection has evolved over time with current widespread availability, improved detection and standardized reporting. With human migration, the epidemiology of hepatitis D infection has changed over time. Thus, the ability to use diagnostic assays remains essential to monitor the global impact of hepatitis D infection. Separately, while liver biopsy remains the gold standard for the staging of this rapidly progressive and severe form of chronic viral hepatitis, there is an unmet need for clinical monitoring of chronic hepatitis D infection for management of progressive disease. Thus, exploration of the utility of non-invasive fibrosis markers in hepatitis D is ongoing. In this review, we discuss the virology, the evolution of diagnostics and the development of non-invasive markers for the detection and monitoring of fibrosis in patients with hepatitis D infection.

What does quantitative HBsAg level mean in chronic hepatitis D infection?

OBJECTIVE: In hepatitis delta virus (HDV) infection, which is an important etiological cause of chronic liver disease, the relationship between serum quantitative HBsAg level and fibrosis and histological activity was investigated. METHODS: Between 2014 and 2020, 98 patients with chronic HDV infection (53 noncirrhotic, 45 cirrhotic) participated in this prospectively designed study. Quantitative HBsAg levels of the patients were measured and their relationship with the stage of chronic liver disease was compared with histological activity index (HAI), fibrosis score and HDV RNA, model for end-stage liver disease score and other biochemical parameters. RESULTS: All patients were infected with genotype 1 (100%). HBeAg was positive in 8 (8.1%) of the patients. A correlation was found between quantitative HBsAg level and HDV RNA level in patients with both cirrhotic (r = 0.568; P < 0.001) and noncirrhotic (r = 0.644; P < 0.001) HDV infection. Alanine transaminase (P = 0.001; r = 0.495) and aspartate transaminase (P = 0.001; r = 0.511) levels correlated with quantitative HBsAg levels, more prominently in noncirrhotic patients. There was a correlation between quantitative HBsAg level and histological activity index (HAI) in patients with noncirrhotic HDV infection (P < 0.001; r = 0.664). In receiver operating characteristic analysis, both quantitative HBsAg (for cutoff: 1000; sensitivity 76%; specificity 17%; P = 0.335) and HDV RNA (for cutoff: 100000; sensitivity 2%; specificity 98%; P = 0.096) were not predictive markers for cirrhosis. CONCLUSION: Quantitative HBsAg level can be evaluated as an indicator of viral replication and histological activity in patients with chronic delta hepatitis without cirrhosis. We think that quantitative HBsAg level will be useful in the management of chronic HDV infection, especially in noncirrhotic patients.

Epidemiology, Natural History, and Treatment of Hepatitis Delta Virus Infection in HIV/Hepatitis B Virus Coinfection.

PURPOSE OF REVIEW: Limited data exist on the prevalence, determinants, and outcomes of hepatitis delta virus (HDV) infection among HIV/hepatitis B virus (HBV)-coinfected persons. This review provides current evidence on the epidemiology, natural history, and treatment of HDV infection in patients with HIV/HBV coinfection and highlights future research needs. RECENT FINDINGS: Cross-sectional studies in Europe, Africa, South America, and Asia show that the prevalence of HDV among HIV/HBV-coinfected patients ranges from 1.2 to 25%. No studies have evaluated the prevalence of HDV infection among HIV/HBV-coinfected patients in the USA. HDV infection increases the risk of hepatic decompensation and hepatocellular carcinoma among HIV/HBV-coinfected patients. HDV treatment remains limited to pegylated interferon-alpha, which results in sustained virologic response in fewer than 25%. Data on the epidemiology, natural history, and treatment of HDV among HIV/HBV-coinfected persons remain limited. More research is needed to address these knowledge gaps in order to better manage HDV coinfection in HIV/HBV-coinfected patients.

Innate immune recognition and modulation in hepatitis D virus infection.

Hepatitis D virus (HDV) is a global health threat with more than 15 million humans affected. Current treatment options are largely unsatisfactory leaving chronically infected humans at high risk to develop liver cirrhosis and hepatocellular carcinoma. HDV is the only human satellite virus known. It encodes only two proteins, and requires Hepatitis B virus (HBV) envelope protein expression for productive virion release and spread of the infection. How HDV could evolve and why HBV was selected as a helper virus remains unknown. Since the discovery of Na+-taurocholate co-transporting polypeptide as the essential uptake receptor for HBV and HDV, we are beginning to understand the interactions of HDV and the immune system. While HBV is mostly regarded a stealth virus, that escapes innate immune recognition, HBV-HDV coinfection is characterized by a strong innate immune response. Cytoplasmic RNA sensor melanoma differentiation antigen 5 has been reported to recognize HDV RNA replication and activate innate immunity. Innate immunity, however, seems not to impair HDV replication while it inhibits HBV. In this review, we describe what is known up-to-date about the interplay between HBV as a helper and HDV's immune evasion strategy and identify where additional research is required.

Long-term clinical outcomes in patients with chronic hepatitis delta: the role of persistent viraemia.

BACKGROUND: Chronic hepatitis delta is a severe liver disease with rapid progression to cirrhosis. The impact of hepatitis delta virus (HDV)-RNA on disease progression and interferon treatment in a real-world cohort has been barely explored. AIM: To assess the development of clinical events in a cohort of chronic hepatitis delta patients according to the presence or absence of HDV-RNA METHODS: Multicentre study at four academic hospitals in Spain included anti-HDV-positive patients with compensated liver disease with a follow-up ≥12 months. RESULTS: Among 2888 HBsAg-positive subjects, 151 (5.2%) tested positive for anti-HDV, and 118 were included (58% men; median age, 49 years; 73% detectable HDV-RNA and 30% cirrhosis, most often in subjects with HDV-RNA). After a median follow-up of 8 years, subjects with initially detectable HDV-RNA were more prone to developing cirrhosis (31% vs 0%, P = .002) and/or liver decompensation (28% vs 3%, P = .019). Mortality rate was 0.44 per 1000 person-months. The probability of a clinical event was 6%, 25%, and 80% according to initial baseline-event-anticipation score. HDV-RNA became undetectable in 21 (24%) subjects either due to interferon or spontaneously (48% vs 52%, P = .29). Liver decompensation was reduced in interferon-treated patients (13% vs 38%, P = .026). CONCLUSIONS: Subjects with persistently positive HDV-RNA had a worse prognosis in terms of clinical events. Baseline-event-anticipation score is useful in predicting the risk of developing liver decompensation and hepatocellular carcinoma. Interferon was beneficial in reducing liver decompensation, even in the absence of virological response.

Treating chronic hepatitis delta: The need for surrogate markers of treatment efficacy.

Chronic hepatitis delta represents the most severe form of chronic viral hepatitis. The current treatment of hepatitis delta virus (HDV) infection consists of the use of interferons and is largely unsatisfactory. Several new compounds are currently in development for the treatment of HDV infection. However, surrogate markers that can be used to develop clinical endpoints in HDV infection are not well defined. In the current manuscript, we aimed to evaluate the existing data on treatment of HDV infection and to suggest treatment goals (possible "trial endpoints") that could be used across different clinical trials.

Molecular Signature and Mechanisms of Hepatitis D Virus-Associated Hepatocellular Carcinoma.

There is limited data on the molecular mechanisms whereby hepatitis D virus (HDV) promotes liver cancer. Therefore, serum and liver specimens obtained at the time of liver transplantation from well-characterized patients with HDV-HCC (n = 5) and with non-HCC HDV cirrhosis (n = 7) were studied using an integrated genomic approach. Transcriptomic profiling was performed using laser capture-microdissected (LCM) malignant and nonmalignant hepatocytes, tumorous and nontumorous liver tissue from patients with HDV-HCC, and liver tissue from patients with non-HCC HDV cirrhosis. HDV-HCC was also compared with hepatitis B virus (HBV) HBV-HCC alone, and hepatitis C virus (HCV) HCV-HCC. HDV malignant hepatocytes were characterized by an enrichment of upregulated transcripts associated with pathways involved in cell-cycle/DNA replication, damage, and repair (Sonic Hedgehog, GADD45, DNA-damage-induced 14-3-3σ, cyclins and cell-cycle regulation, cell cycle: G2-M DNA-damage checkpoint regulation, and hereditary breast cancer). Moreover, a large network of genes identified functionally relate to DNA repair, cell cycle, mitotic apparatus, and cell division, including 4 cancer testis antigen genes, attesting to the critical role of genetic instability in this tumor. Besides being overexpressed, these genes were also strongly coregulated. Gene coregulation was high not only when compared with nonmalignant hepatocytes, but also to malignant hepatocytes from HBV-HCC alone or HCV-HCC. Activation and coregulation of genes critically associated with DNA replication, damage, and repair point to genetic instability as an important mechanism of HDV hepatocarcinogenesis. This specific HDV-HCC trait emerged also from the comparison of the molecular pathways identified for each hepatitis virus-associated HCC. Despite the dependence of HDV on HBV, these findings suggest that HDV and HBV promote carcinogenesis by distinct molecular mechanisms.Implications: This study identifies a molecular signature of HDV-associated hepatocellular carcinoma and suggests the potential for new biomarkers for early diagnostics. Mol Cancer Res; 16(9); 1406-19. ©2018 AACR.

Hepatitis D virus replication is sensed by MDA5 and induces IFN-ß/λ responses in hepatocytes.

BACKGROUND & AIMS: Hepatitis B virus (HBV) and D virus (HDV) co-infections cause the most severe form of viral hepatitis. HDV induces an innate immune response, but it is unknown how the host cell senses HDV and if this defense affects HDV replication. We aim to characterize interferon (IFN) activation by HDV, identify the responsible sensor and evaluate the effect of IFN on HDV replication. METHODS: HDV and HBV susceptible hepatoma cell lines and primary human hepatocytes (PHH) were used for infection studies. Viral markers and cellular gene expression were analyzed at different time points after infection. Pattern recognition receptors (PRRs) required for HDV-mediated IFN activation and the impact on HDV replication were studied using stable knock-down or overexpression of the PRRs. RESULTS: Microarray analysis revealed that HDV but not HBV infection activated a broad range of interferon stimulated genes (ISGs) in HepG2NTCP cells. HDV strongly activated IFN-ß and IFN-λ in cell lines and PHH. HDV induced IFN levels remained unaltered upon RIG-I (DDX58) or TLR3 knock-down, but were almost completely abolished upon MDA5 (IFIH1) depletion. Conversely, overexpression of MDA5 but not RIG-I and TLR3 in HuH7.5NTCP cells partially restored ISG induction. During long-term infection, IFN levels gradually diminished in both HepG2NTCP and HepaRGNTCP cell lines. MDA5 depletion had little effect on HDV replication despite dampening HDV-induced IFN response. Moreover, treatment with type I or type III IFNs did not abolish HDV replication. CONCLUSION: Active replication of HDV induces an IFN-ß/λ response, which is predominantly mediated by MDA5. This IFN response and exogenous IFN treatment have only a moderate effect on HDV replication in vitro indicating the adaption of HDV replication to an IFN-activated state. LAY SUMMARY: In contrast to hepatitis B virus, infection with hepatitis D virus induces a strong IFN-ß/λ response in innate immune competent cell lines. MDA5 is the key sensor for the recognition of hepatitis D virus replicative intermediates. An IFN-activated state did not prevent hepatitis D virus replication in vitro, indicating that hepatitis D virus is resistant to self-induced innate immune responses and therapeutic IFN treatment.

Quantification of serum markers of hepatitis B (HBV) and Delta virus (HDV) infections in patients with chronic HDV infection.

The interplay between hepatitis B (HBV) and delta (HDV) viruses is complex and not always characterized during chronic HDV infection. We assessed the clinical usefulness of new quantitative assays for HBV and HDV serum markers in a retrospective cross-sectional study. Sera obtained from 122 HDV genotype 1 and HBV genotype D coinfected, anti-HIV-negative patients (71 males; median age 49.8 [21.7-66.9] years), recruited consecutively in two geographical areas (Italy 69 patients, Romania 53 patients) with different HBV and HDV epidemiology, were tested for HBsAg, HBV-DNA, HBcrAg, total anti-HBc, HDV-RNA, IgM and total anti-HDV using quantitative assays. Cirrhosis, which showed comparable prevalence in the two cohorts, was diagnosed in 97 of 122 (79.5%) patients. At multivariate analysis, cirrhosis was associated with lower total anti-HBc/IgM anti-HDV ratio (OR 0.990, 95% CI 0.981-0.999, P = .038), whereas disease activity was associated with higher total anti-HDV (OR 10.105, 95% CI 1.671-61.107, P = .012) and HDV-RNA levels (OR 2.366, 95% CI 1.456-3.844, P = .001). HDV-RNA serum levels showed a positive correlation with HBV-DNA (ρ = 0.276, P = .005), HBsAg (ρ = 0.404, P < .001) and HBcrAg (ρ = 0.332, P < .001). The combined quantitative profiling of HBV and HDV serum markers identifies specific patterns associated with activity and stage of chronic hepatitis D (CHD). HDV pathogenicity depends on the underlying active HBV infection in spite of the inhibition of its replication. HDV-RNA, IgM anti-HDV, total anti-HDV, total anti-HBc, HBsAg and HBcrAg serum levels qualify for prospective studies to predict progressive CHD and identify candidates to antiviral therapy.

Non-invasive fibrosis score for hepatitis delta.

BACKGROUND & AIMS: Identifying advanced fibrosis in chronic hepatitis delta patients and thus in need of urgent treatment is crucial. To avoid liver biopsy, non-invasive fibrosis scores may be helpful but have not been evaluated for chronic hepatitis delta yet. METHODS: We evaluated eight non-invasive fibrosis scores in 100 HDV RNA-positive patients with available central histological reading. New cut-off values were calculated by using Receiver Operating Characteristics and Youden indexes. Predictors for the presence of ISHAK F3-6 were revealed by t-tests or Mann-Whitney tests. RESULTS: None of the tested scores had an area under the curve (AUROC) > 0.8 and performed according to our predefined requirements of a sensitivity of >80% and a positive predictive value (PPV) >90% - even after adaption. However, the ELF score was able to identify advanced fibrosis with a high sensitivity (93%) and PPV (81%), but relies on expensive extracellular matrix markers with bad availability in many endemic regions of HDV. Thus, we developed a novel non-invasive approach and identified low cholinesterase (P=.002), low albumin (P=.041), higher gamma glutamyl transferase, as well as older age (P<.001) as predictors of fibrosis resulting in the Delta Fibrosis Score (DFS). The DFS performed with a sensitivity of 85% and PPV of 93% with an AUROC of 0.87. CONCLUSIONS: Existing non-invasive fibrosis scores are either impracticable or do not perform well in chronic hepatitis delta patients. However, the new Delta Fibrosis Score is the first non-invasive fibrosis score specifically developed for chronic hepatitis delta and requires only standard parameters.

Chronic Hepatitis B, C, and D.

Chronic hepatitis B, C, and D virus infections contribute significantly to the morbidity and mortality of immunocompromised individuals. To contextualize discussion of these infections in immunocompromised patients, this paper provides an overview of aspects of infection in normal hosts. It then describes differences in disease, diagnostic testing, and therapeutic management observed in immunocompromised patients.

Influence of delta virus infection on the virologic status in Egyptian patients with chronic hepatitis B virus genotype D.

Hepatitis delta virus (HDV) usually have an unfavorable clinical outcome in chronic hepatitis B virus (HBV) patients. In Egypt, data about epidemiology, the spectrum of disease, and impact of HDV on HBV infection are rare. To assess the prevalence, clinical and virological characteristics of HDV infection among Egyptian patients with chronic HBV. Adult patients with Hepatitis B surface antigen (HBsAg)-positive were evaluated for the presence of HDV using anti HDV-IgG and HDV RNA by RT-PCR. Routine laboratory investigations, genotypes and subtypes for both HBV and HDV, abdominal sonography, and transient elastography (TE) were done. Liver biopsy was performed only in whenever indicated. One hundred and twenty-one treatment-naïve chronic HBV patients were included. Wild HBV genotype-D2 was found in 98.2% and 81.9% were HBeAg negative. Prevalence of HDV was 8.3% by anti-HDV IgG and 9.9% by RT-PCR. Wild HDV genotype-IIb was reported in 83.3%. HDV infection was more common in males, 90.9% of delta patients were HBeAg negative. Compared to the mono-infected HBV, concomitant HBV/HDV infection was not associated with more derangment in ALT nor advanced stage of fibrosis. 66.7% of HDV patients had significantly lower HBV-DNA level compared to the non-delta patients (P < 0.001). HDV is not uncommon in Egypt. HBV genotype-D was associated with HDV genotype-IIb. Delta infection was associated with negative HBeAg status, reduction of HBV replication, but neither influenced the clinical course nor increased significant liver damage risk.

Comprehensive analysis of mutations in the hepatitis delta virus genome based on full-length sequencing in a nationwide cohort study and evolutionary pattern during disease progression.

Delta hepatitis, caused by co-infection or super-infection of hepatitis D virus (HDV) in hepatitis B virus (HBV) -infected patients, is the most severe form of chronic hepatitis, often progressing to liver cirrhosis and liver failure. Although 15 million individuals are affected worldwide, molecular data on the HDV genome and its proteins, small and large delta antigen (S-/L-HDAg), are limited. We therefore conducted a nationwide study in HBV-HDV-infected patients from Iran and successfully amplified 38 HDV full genomes and 44 L-HDAg sequences from 34 individuals. Phylogenetic analyses of full-length HDV and L-HDAg isolates revealed that all strains clustered with genotype 1 and showed high genotypic distances to HDV genotypes 2 to 8, with a maximal distance to genotype 3. Longitudinal analyses in individual patients indicated a reverse evolutionary trend, especially in L-HDAg amino acid composition, over time. Besides multiple sequence variations in the hypervariable region of HDV, nucleotide substitutions preferentially occurred in the stabilizing P4 domain of the HDV ribozyme. A high rate of single amino acid changes was detected in structural parts of L-HDAg, whereas its post-translational modification sites were highly conserved. Interestingly, several non-synonymous mutations were positively selected that affected immunogenic epitopes of L-HDAg towards CD8 T-cell- and B-cell-driven immune responses. Hence, our comprehensive molecular analysis comprising a nationwide cohort revealed phylogenetic relationships and provided insight into viral evolution within individual hosts. Moreover, preferential areas of frequent mutations in the HDV ribozyme and antigen protein were determined in this study.

Mouse models of hepatitis B and delta virus infection.

Liver disease associated to persistent infection with the hepatitis B virus (HBV) continues to be a major health problem of global impact. Therapeutic regimens currently available can efficiently suppress HBV replication; however, the unique replication strategies employed by HBV permit the virus to persist within the infected hepatocytes. As a consequence, relapse of viral activity is commonly observed after cessation of treatment with polymerase inhibitors. Among the HBV chronically infected patients, more than 15million patients are estimated to be co-infected with the hepatitis delta virus (HDV), a defective satellite virus that needs the HBV envelope for propagation. No specific drugs are currently available against HDV, while nucleos(t)ide analogs are not effective against HDV replication. Since chronic HBV/HDV co-infection leads to the most severe form of chronic viral hepatitis in men, a better understanding of the molecular mechanisms of HDV-mediated pathogenesis and the development of improved therapeutic approaches is urgently needed. The obvious limitations imposed by the use of great apes and the paucity of robust experimental models of HBV infection have hindered progresses in understanding the complex network of virus-host interactions that are established in the course of HBV and HDV infections. This review focuses on summarizing recent advances obtained with well-established and more innovative experimental mouse models, giving emphasis on the strength of infection systems based on the reconstitution of the murine liver with human hepatocytes, as tools for elucidating the whole life cycle of HBV and HDV, as well as for studies on interactions with the infected human hepatocytes and for preclinical drug evaluation.

An update on hepatitis B, D, and E viruses.

Although newer and more effective treatments are now available for hepatitis C virus (HCV) infection, non-HCV viral hepatitis remains an important cause of liver disease, especially among HIV-infected individuals. Hepatitis B virus (HBV) is the leading cause of cirrhosis worldwide, and approximately one-quarter of patients with cirrhosis develop decompensated liver disease within 5 years. Initial treatment for chronic HBV infection includes peginterferon alfa, entecavir, and tenofovir. Approximately 15 million of the estimated 350 million individuals with chronic HBV infection have evidence of exposure to hepatitis D (delta) virus (HDV), which requires hepatitis B surface antigen for transmission and packaging. HBV/HDV coinfection is associated with more severe acute hepatitis and higher mortality than acute HBV monoinfection. Chronic coinfection is associated with a higher risk of cirrhosis and decompensated liver disease. The mainstay of treatment for HDV infection is peginterferon alfa for at least 48 weeks. Cases of hepatitis E virus (HEV) infection in HIV-infected persons have been reported. HEV infection can become chronic in immunosuppressed patients, and chronic infection is associated with rapid development of cirrhosis. There are no established guidelines for treating HEV infection in HIV-infected persons. This article summarizes a presentation by Jennifer Price, MD, at the IAS-USA continuing education program held in San Francisco, California, in June 2013.

[Chronic viral hepatitis in St.Petersburg].

Morbidity data on chronic viral hepatitis including cirrhotic stages of disease and lethality indexes in St. Petersburg are provided. The necessity of isolation in ICD- 10 and statistical accounting of chronic viral hepatitis diagnosis with outcome into cirrhosis (cirrhotic stage) is shown. During use of viral etiology liver cirrhosis diagnosis the disease is registered in the structure of liver diseases which does not allow to have data on unfavorable outcomes of chronic viral hepatitis and for complete morbidity accounting.

A case of quadruple viral infections and elevated aminotransferase activities.

A 40-year-old man with human immunodeficiency virus (HIV), hepatitis C virus (HCV), and hepatitis B virus (HBV) infection was referred for evaluation of abnormal liver enzyme activities. The patient was maintained on antiretroviral therapy for HIV as well as medication to suppress HBV and had previously undergone treatment for HCV with durable sustained virologic response. The patient was clinically well without any symptoms or evidence of liver decompensation. Laboratory findings were notable for aminotransferase activities in the 200 to 225 U/L range that had been persistent for several months. An extensive workup for the etiology of the aminotransferase elevation ensued. Imaging studies showed no evidence of biliary obstruction. Serology revealed negative autoantibodies, negative serum HCV-RNA, and low level HBV-DNA by polymerase chain reaction. Further testing revealed positive hepatitis delta virus (HDV) antibody and positive HDV RNA in the serum. A percutaneous liver biopsy was performed to further elucidate the cause of the elevated aminotransferase activities. Based on histology, serology, and clinical presentation, a diagnosis of chronic HDV infection was made. HDV infection should be considered in patients with known chronic viral hepatitis B with low viral load, who present with worsening liver function or elevation in aminotransferase activities.