The first animal model for HDV was the chimpanzee, in which key experiments were performed on mechanisms of transmission (28,29). Interestingly, these experiments demonstrated that HDV derived from a human inoculum could be pseudotyped with the woodchuck hepatitis virus envelope proteins to generate infectious HDV-RNA–containing particles. The woodchuck system has also been used to assess candidate antiviral agents (30). A variety of mouse-based models have been used to study HDV and candidate antivirals (31,32). The most recent of these are so-called humanized mice, in which human liver cells are engrafted into the livers of immunodeficient mice. Such mice can support HDV infections and be used to assess novel antiviral strategies (33).
With higher than expected prevalence rates of HDV infection in many countries including the United States, it is recommended that all adult patients with chronic HBV infection be screened for HDV and that special attention be given to patients with higher risk. We believe these adult risk factors (2) include coming from endemic regions (Mediterranean basin, eastern Europe, Middle East, Amazonian basin, Asia, Africa), intravenous drug use or exposure, men who have sex with men, hemodialysis patients, health care workers, or patients with chronic HBV and clinical deterioration have relevance in children and adolescents. The diagnosis of HDV is made serologically through the detection of HDV antigen and anti-HDV antibodies (Table 2) often in combination with HBV serologies (41). Within 2 months of HDV infection, >90% of patients will demonstrate HDV antibody. Total anti-HDV can be detected by commercially available radioimmunoassay or enzyme immunoassay kits. HDV immunoglobulin (Ig) G is produced in all patients with HDV and can persist long after the infection is cleared. Quantitation of HDV RNA via real-time PCR techniques is available commercially in Europe but only on a research basis in the United States at present. Specimens from patients suspected to be infected with HDV can be sent to the Centers for Disease Control and Prevention or other specialized HDV research laboratories for HDV RNA testing. The development of an international standardization for quantitation will enable reporting in international units per milliliter and provide for uniform assessments for diagnostic and treatment monitoring purposes (51). A 1-step real-time PCR assay for the detection and quantitation of HDV RNA of all of the 8 genotypes was recently developed (52). Owing to the variability of the HDV genome sequence, HDV RNA assays may yield false-negative results, if inadequate primers are used. Therefore, HDV IgM should be tested in patients with negative HDV RNA levels if there is a clinical suspicion for HDV infection or high-risk exposures. Furthermore, quantitative assays of HDV in serum do not correlate with disease activity, although serial measurement of HDV may be useful in monitoring response in treatment (53). HDV genotyping is not widely available, although it may be clinically useful because genotype 1 is associated with a higher risk of ESLD and may have implications on therapeutic outcomes (54). The remaining genotypes are more region-specific. Genotype 2 HDV infection, found mainly in Asia, is less commonly associated with fulminant hepatitis in the acute phase or cirrhosis or HCC in the chronic phase. Genotype 3 infections, present in northern South America, are associated with particularly severe disease. Patients with genotype 4, found in Taiwan and Okinawa islands, have similar clinical courses as genotype 2 patients (54,55). Other genotypes have been most commonly of African origin.
Screening of hepatitis C virus (HCV) and human immunodeficiency virus (HIV) is important in patients with HDV because these viruses share common transmission routes. A study in Central Europe showed that approximately one-third of the HDV-infected patients tested positively for HCV (56). In Spain, 5% of HIV infected patients with hepatitis had multiple hepatitis virus infections, of which the most common multiple hepatitis was triple B, C, and D (57).
There are no substantial pediatric series to justify liver biopsy timing. In adults, following HDV confirmation, liver biopsy to grade inflammation and stage liver fibrosis is recommended because the clinical literature has demonstrated that these patients progress to more severe liver disease relatively rapidly (60). Particularly in the setting of an HBV/HDV-co-infected child with persistently elevated ALT or clinical deterioration out of proportion to known disease, we advocate liver biopsy to guide clinical decision making (more aggressive HBV therapy, primary HDV treatment, or LT consideration).
A Baseline-Event Anticipation (BEA) score was developed to assess the risk of developing liver-related complications (decompensation, HCC, liver transplantation, and/or death) in adults with chronic HDV infection (Table 3) (59). The BEA score factors in age, sex, region of origin, bilirubin, platelets, and international normalized ratio, and stratifies patients with high accuracy into 3 risk groups: BEA-A (mild), BEA-B (moderate), and BEA-C (high). Points were allocated according to hazard ratios for the above liver-related morbidity and mortality. Although not yet validated as a tool in the pediatric population, given the aggressive nature of HDV and younger onset of cirrhosis, particularly in HDV superinfection, its utility as a risk-stratifying measure is intriguing. Applying this tool to the 2 pediatric case reports presented from our center, patient 1 would have been correctly classified as moderate risk, and patient 2 met the criteria for high risk. A modified pediatric scale merits further investigation.
The goal of treating HDV infection is a sustained HDV virological response (negative HDV RNA following 6 months of stopping treatment). Ultimately, this may be achieved via the eradication of HBV infection and clearance of HBsAg (60). Oral HBV antivirals alone, however, have not been shown to be effective in clearing HDV infection, which is to be expected given their inability to efficiently achieve clearance of HBsAg (24). First-line treatment for HDV is pegylated IFN-α, although its effects are modest, with only 25% to 30% of patients showing a sustained virological response after 1 to 2 years of therapy as measured by HDV RNA (40). Clearance rates of HDV RNA are even lower with posttreatment relapse (38). IFN-α is naturally produced by monocytes and B lymphocytes, and can be synthetically produced by genetic engineering. Patients with the best response to IFN-α are those with low HBV viral replication, high initial ALT, short duration of the chronic carrier state, and no antibody to HIV (61,62). At our site, HBV/HDV-infected children with clinical decompensation or fibrosis on liver biopsy out of proportion to their HBV disease are considered for treatment.
A meta-analysis of 5 studies using recombinant IFN in the treatment of HDV showed that although serum aminotransferase levels decreased with treatment, the response was not sustained following the discontinuation of treatment, and HDV RNA clearance was not achieved (63). Furthermore, higher doses of IFN yielded better responses: ≥5 MU/day or 9 MU 3 times a week for a longer period of time (12 vs 6 months). Treatment beyond 12 months, however, has not been shown to be superior (64). IFN-induced clearance of HDV RNA is also associated with a reduction in HBsAg levels, although HDV RNA levels tend to decrease first (65). It has been proposed that treatment failure with IFN-α may be secondary to interference of HDV with IFN-α intracellular signaling mechanisms, leading to impaired activation and translocation of STAT 1 and STAT2 (66). A recent study published by Lunemann et al (58) examined the effects of pegylated IFN-α treatment for chronic HDV on the phenotype and function of natural killer (NK) cells. It found that IFN-α treatment leads to a selective loss of terminally differentiated NK cells in addition to a functional impairment of NK cells and impaired STAT4 signaling. It appears, however, that a high frequency of NK cells before treatment and retained high numbers of NK cells during treatment are positively associated with treatment outcomes. In adults, NK cell count and trend may serve as an immunological biomarker for outcomes following IFN-α therapy. This has not been demonstrated in children.
Although there are few published studies on the effectiveness of IFN-α against HDV in children, a retrospective study on IFN-α treatment in Greek children with chronic HDV showed that treatment with IFN-α was safe with few adverse effects but ineffective (67). The patients were treated with IFN-α, 6 MU/m2 body surface area 3 times weekly by intramuscular or subcutaneous injection. Adverse effects included mild fever, arthralgias, malaise, and reversible neutropenia and thrombocytopenia, with no detrimental effects on weight and height development. An observational study in Pakistan showed that in 11 children (mean age 15 ± 2.92 years) and 14 young adults treated with IFN-α for a period of 1 year, 80% were HDV-RNA negative after 1 year with minimal adverse effects from treatment and a decrease in ALT levels (68). A dosing of 6 MU · m−2 · day−1 was applied to the children, and neither growth parameters nor hematological parameters were remarkable during and following treatment.
Pegylated IFN has been increasingly used because of its longer half-life, allowing for once weekly dosing. The HIDIT-1 trial, which studied the treatment of HDV with pegylated IFN-α in Germany, Turkey, and Greece, showed that treatment led to a 28% sustained virological response. The addition of adefovir led to a decrease in HBsAg levels but no change in virological response. Furthermore, treatment with IFN-α and additional HBV-targeted drugs (famciclovir, lamivudine, and adefovir) has not proven to be more efficacious than IFN-α alone (69). Yurdaydin et al (70) classified the response to IFN therapy into 3 groups: complete response (or sustained virological response), with negative RNA levels at 6 months; partial response, with incomplete RNA suppression at 6 months and replication following the discontinuation of treatment; and no response, with a lack of RNA reduction during treatment and follow-up.
The present standard of care for the treatment of chronic HDV is subcutaneous pegylated IFN weekly (1.5 MU/kg for α-2b), although it has not been FDA approved for use in children. Data are lacking for pegylated IFN dosing and efficacy studies in children, but in our experience with HBV and HCV, a dose of 180 μg · 1.73 m2 α-2a per week for ≥48 weeks in patients with HDV RNA replication and evidence of liver disease on biopsy has been found to be safe and can be effective. There are presently no pediatric recommendations to treat HDV in an effort to avoid future liver fibrosis progression. Because the published pediatric case series are unable to justify optimal timing and dosing of HDV therapy, we share our site-specific indications for HDV treatment in children based on our review of the literature: significant fibrosis on liver biopsy with or without ALT elevation despite successful suppression of HBV viral load. Particularly in the setting of unexplained elevated transaminases with evidence of hepatitis B seroconversion (HBeAg−, HBeAb+), HDV treatment should be considered. These recommendations are derived from our institution's treatment experiences in addition to extrapolation from adult literature. We advocate practical and individualized therapy, based on the clinical and virological responses during treatment.
Following a PCR-based assay at 48 weeks, patients with persistent RNA replication, anti-HDV IgM, and elevated ALT are unlikely to benefit from further treatment up to ≥72 weeks compared with patients with decreasing RNA, IgM, and transaminase levels. Anti-HBV nucleotide analogues are indicated in patients with reactivation of HBV following suppression of HDV replication or in patients with detectable HBsAg who cannot be treated with pegylated IFN therapy.
Present HDV treatment options are limited because HDV has no enzymatic proteins such as polymerases or proteases that can be targeted by conventional antiviral strategies. Nucleos(t)ide analogues, including famciclovir, ribavirin, tenofovir, and entecavir, which block the HBV polymerase, have also been studied with mixed results (71–74). As alluded to above, this is not surprising given the inability of these agents to efficiently eradicate HBsAg—which is necessary and sufficient for enabling the continuous spread of HDV infection. Because medical treatment for HDV is limited in efficacy, some patients, including our male patient from Uzbekistan, decompensate from advanced liver disease, requiring LT. The only treatment option in patients with ESLD is LT, which is necessary in patients with acute liver failure with poor prognosis. To reduce the risk of reinfection following LT, long-term administration of hepatitis B immunoglobulin and antivirals can help suppress HBV, in particular HBsAg, and thus HDV infection.
Alternative antiviral agents are being studied for the treatment of HDV infection (75). Prenylation is a site-specific modification of proteins whereby a prenyl lipid—farnesyl or geranylgeranyl—is covalently attached to a cysteine within a characteristic signature motif encoded within the carboxyl terminus of prenylated proteins. Large hepatitis delta antigen (L-HDAg) contains such a motif directing the addition of farnesyl, and farnesylation is necessary for the interaction of L-HDAg with HBsAg and subsequent HDV viral assembly and secretion (76). Farnesylation inhibitors, which inhibit protein farnesyltransferase, are presently being developed to inhibit viral assembly and secretion, with promising in vitro and in vivo study responses thus far (Fig. 5) (2,83). Presently, a phase IIa double-blinded randomized placebo-controlled study is being conducted at the National Institutes of Health to investigate the effectiveness of 28 days of treatment with lonafarnib, an oral farnesyltransferase inhibitor followed by 6 months follow-up of therapy to measure sustained virological response (77).
Viral attachment targets including myristoylated synthetic peptides for the N-terminal region of the pre-S1 domain of HBsAg are also being studied for their impact on HDV infectivity (2). Sodium taurocholate cotransporting polypeptides, a group of bile salt transporters, are important in the binding of myristoylated pre-S1 domain of the HBV large envelope protein to hepatocytes and are blocked by antibodies, cyclosporin A, ezetimibe, and Myrcludex B. Therefore, these agents and others (Table 4) may be useful in preventing HBV and HDV infection and reinfection (78). Inhibiting the release of HBsAg from infected hepatocytes is another target because nucleic acid-based amphipathic polymers are being developed for HBsAg clearance (79). Furthermore, RNA interference–based therapies may be useful in treating HBV/HDV co-infection by targeting conserved HBV sequences leading to repression of viral RNA, proteins, and viral DNA, and maybe HDV viral release (80). Cytokine levels may also be mapped in the future to monitor patients’ responses to new immunotherapy agents. Additional pathway targets such as posttranslational modification of hepatitis delta antigen and virion assembly may also yield effective therapies in the future (81). Pediatric trials studying novel HDV therapies are being considered, even though none presently.
Although HDV is the smallest virus known to infect humans and is dependent on HBV for transmission, it is highly pathogenic, with a rapid onset of disease. The outcome of disease largely depends on whether the HBV and HDV infect simultaneously (co-infection) or whether the newly HDV-infected patient is a chronically infected HBV carrier (superinfection). Up to 70% of patients with chronic hepatitis D develop cirrhosis with mortality ranging from 2% to 20%, values that are 10 times higher than for hepatitis B. Progression to cirrhosis only takes 5 to 10 years, but can occur as early as 2 years after infection, whereas superinfection may lead to fulminant HDV, which carries a mortality rate of 80%. HDV continues to ravage endemic parts of Asia and Europe, and prevalence in the United States, although low, has not decreased in frequency despite universal HBV vaccination as a result of the lack of testing and underrecognition. All children with HBV, particularly those from high-prevalence countries or with risk factors for HDV, should be screened with total HDV Ab. In the setting of clinical deterioration, unexplained or significant ALT elevation, HDV IgM should also be performed. Children with confirmed HDV infection (total HDV Ab+ or HDV IgM+) merit an individualized evaluation, which may include a liver biopsy to guide clinical decision making. Severe or rapidly progressing fibrosis (if serial biopsies are available) warrants consideration for treatment. The present standard-of-care treatment for HDV yields suboptimal results, but insights into the virology of hepatitis D are stimulating the search for novel therapeutic approaches, particularly the development of prenylation inhibitors and viral entry inhibitors.
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