HDV: Epidemiology, lifecycle, testing, and treatment

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INTRODUCTION

HDV is considered the most severe viral hepatitis with rapid progression toward liver-related death and HCC.¹ It is a circular single-stranded RNA virus with negative polarity and was first described in 1977 in patients either coinfected or super-infected with HBV. Most recent developments in understanding the HDV lifecycle have led to breakthrough potential therapy targets. Although awareness of HDV has increased, there is a lack of standardized screening and assays that have led to widely differing published prevalence.¹

CURRENT EPIDEMIOLOGY

Over the last 20 years, since the implementation of HBV vaccination programs, studies have suggested the overall prevalence of HDV has declined in the developed world.² In high-income countries, HDV is primarily detected in young immigrants from endemic regions. The highest-risk populations in high-income countries are those that use i.v. drugs, although overall the prevalence is also declining.³ In Spain, a high-income country with a robust vaccination program, the prevalence of anti-HDV among HBsAg-positive i.v. drug users declined from 30% in the 1990s to 4.2% in 2018. In this study, new HDV diagnosis was largely identified in foreign immigrants who inject drugs coming from HDV endemic regions.⁴ Patients who are HIV positive, sex workers, and patients on hemodialysis were previously considered high risk but have recently been reported to have declining prevalence.³ Overall, 2 meta-analyses have estimated that between 13.02% and 14.6% of HBV carriers globally are infected with HDV, mainly in or from endemic countries.³ It has been shown that the overall testing rate for HDV is low and it is mainly patients who are seen at liver centers who are tested, which emphasizes the need for screening awareness outside of academic medical centers.³

In low-to-middle-income countries, there has also been a decrease in prevalence following vaccination programs. It is also important to note here that HDV analysis is rarely performed in many low-to-middle-income countries due to limited access to testing.²

LIFECYCLE

HDV is enveloped by the HBV envelope which can attach to heparan sulfate proteoglycans on host cells and then specifically bind to sodium taurocholate cotransporting polypeptide, similar to HBV infection. The subsequent steps of fusion and transport to the nucleus are not well understood and thought to differ between HDV and HBV.¹ The HDV ribonucleoprotein complex, which is composed of circular HDV RNA as well as the large extended and small hepatitis D antigen, is then transported to the nucleus for replication. Transcription is dependent on host polymerases. The large hepatitis D antigen requires prenylation before ribonucleoprotein complex assembly. The ribonucleoprotein complex is then sent to the endoplasmic reticulum for envelopment in the HBV envelope and secretion. HDV, unlike HBV, does activate the innate immune responses eliciting interferon (IFN)-beta and IFN-lambda but not IFN-alpha pathways. It is unclear where HDV RNA is sensed as replication occurs in the nucleus but the innate immune sensors are located in the cytoplasm (Figure 1).¹

FIGURE 1.

Lifecycle of HDV with therapeutic targets. Abbreviations: HDAgs, small hepatitis D antigen; NAP, nucleic acid polymers; NTCP, sodium taurocholate cotransporting polypeptide; RNP, ribonucleoprotein complex.

DIAGNOSIS AND CURRENT GUIDELINES FOR TESTING

Differing regional recommendations for screening may in part be contributing to differences in reported HDV prevalence, presented in Figure 2. The European Association for the Study of the Liver (EASL) and the Asian Pacific Association for the Study of the Liver guidelines recommend that all HBsAg-positive individuals be screened for HDV.³ This is done through screening for anti-HDV antibodies; commercial labs offering this test and other HDV-related tests are listed in Table 1. If this is positive then confirmation with HDV viral load is recommended, very similar to the HIV screening algorithm. This can be done using HDV RNA PCR quantitative or qualitative testing which in some centers can be completed in-house. Qualitative testing is able to detect HDV at lower concentrations while quantitative will determine viral load. Following the implementation of EASL guidelines, a study from a central lab receiving samples from 1 academic hospital and 17 primary care clinics in northern Barcelona, Spain, showed reflex testing increased the detection of HDV in patients who are HBsAg-positive from 7.6% to 93%.^1,5

FIGURE 2.

Diagnosis and current guidelines. Abbreviations: AASLD, American Association for the Study of Liver Diseases; ALT, alanine transaminase; APASL, Asian Pacific Association for the Study of the Liver; AST, aspartate aminotransferase; EASL, European Association for the Study of the Liver; HbsAg+, hepatitis B surface antigen-positive.

TABLE 1.

HDV screening tests and labs

Test	Commercial labs offering tests
Anti-HDV antibodies	Quest, ARUP, Mayo Laboratories, Viracore, and the Centers for Disease Control and Prevention (CDC)
HDV RNA	Can be found in-house in many centers through real-time PCR assay Quantitative: Quest, ARUP, CDC Qualitative: Quest, Viacore, CDC

The American Association for the Study of Liver Diseases guidelines differ slightly. They recommend screening all HBsAg-positive individuals born in regions of high or intermediate HBV endemicity (where the prevalence of HBsAg is >2%), US-born persons who were not vaccinated as infants with parents born in regions of high HBV endemicity, persons who have ever injected drugs, men who have sex with men, and individuals with elevated alanine aminotransferase or aspartate aminotransferase of unknown etiology.³ It is important to continue efforts to understand the true prevalence of HDV in these endemic countries through further screening, ideally through reflex testing of HBsAg-positive individuals.⁶

NONINVASIVE STAGING

While liver biopsy is the gold standard for assessing hepatic fibrosis, it is an invasive, expensive procedure requiring specialized physician training. It is also not a procedure that is typically repeated to determine the staging of the disease after the initial diagnosis. Noninvasive markers of fibrosis, outlined in Figure 3, were developed and validated for HCV and then further validation with HBV virus but further validation in HDV is still needed. These markers include aspartate aminotransferase to alanine transaminase ratio, age-platelet index, aspartate aminotransferase-platelet ratio index, fibrosis-4 index and the Hui score (includes body mass index, bilirubin, albumin, and platelet count).⁷ FIB-4 was the top performer in HCV, HBV, and HDV viral infections. But when studied in patients with HDV it did not significantly outperform the other tests.^8,9 There have been 2 novel scores developed in recent years to assess advanced fibrosis and cirrhosis in patients with chronic hepatitis D: the delta fibrosis score and Delta-4 fibrosis score, further outlined in Table 2. The delta fibrosis score includes cholinesterase levels which is not a widespread test outside of the research setting. The Delta-4 fibrosis score is more applicable to the clinical setting and shows promise but will need to be validated in a large prospective study.¹⁰ It is thought to be more delta-specific due to the typically significantly greater hepatic inflammation in HDV that may affect the liver stiffness measurement.¹⁰

FIGURE 3.

Noninvasive staging. Abbreviations: AAR, aspartate aminotransferase to alanine transaminase ratio; ALT, alanine transaminase; API, age-platelet index; APRI, AST-platelet ratio index; AST, aspartate aminotransferase; FIB-4, fibrosis-4 index.

TABLE 2.

Novel scores for HDV

Score	Components
Delta fibrosis score	DFS=1(if Alb<1.19[× lower limit of normal])+1(if GGT>0.5[× upper limit of normal])+1(if CHE<1.46[× lower limit of normal])+1(if age>42)
Delta-4 fibrosis score	D4FS=[(Liver stiffness measurement via VTCE in kpa)×(GGT IU/L)]/[(Platelet k/μL)× √(ALT IU/L)]

Other noninvasive modalities such as vibration-controlled transient elastography have shown superior performance in HDV when delta fibrosis score and Delta-4 fibrosis score are compared to FIB-4 score. In addition to vibration-controlled elastography, there is sheer wave elastography which is comparable to vibration-controlled transient elastography and slightly better than aspartate aminotransferase-platelet ratio index and fibrosis-4 index.¹¹ However, both modalities require equipment and trained personnel which might not be widely available in many of the endemic regions.

TREATMENT

The current recommendation for treatment is the off-label use of pegylated interferon (PegIFN)-alpha. After treatment, between 19% and 57% of patients will have undetectable HDV RNA. In patients with cirrhosis, there are lower response rates as well as more liver-related adverse outcomes.¹

Other strategies that are currently being studied include bulevirtide (BLV), lonafarnib boosted with ritonavir (LNFr), PegIFN-lambda, and HBsAg targeting drugs (Table 3). Current treatment strategies, type of administration, trial status, and most common side effects are outlined in Table 3.

TABLE 3.

Current agents being used or studied in treatment for HDV

Agent	Administration	Trial status/recommendation	Side effects
Pegylated interferon alpha	Subcutaneous injections	Current recommendation for off-label use	Leukopenia flu-like symptoms
Bulevirtide (BLV)	Subcutaneous injections	Completed phase 3 results	Asymptomatic increase in bile acids
lonafarnib boosted with ritonavir (LNFr)	Oral	Phase 3 trial in process	Gastrointestinal symptoms (nausea, weight loss, and diarrhea)
Pegylated interferon lambda	Subcutaneous injections	Phase 3 trial discontinued	Flu-like symptoms
HBsAg targeting drugs or nucleic acid polymers	Subcutaneous injections	Small phase 2 open-label trial	None identified

BLV is a first-in-class entry inhibitor, meaning it targets the sodium taurocholate cotransporting polypeptide/entry receptor for HBV/HDV. It blocks the viral receptor on the hepatocyte and prevents new infections as well as protects naïve hepatocytes.¹ It has been approved for use in chronic HDV in Europe.¹² One study in a real-world cohort in Germany showed virologic response in 87 of the 114 patients in the study. Twenty-five of these patients achieved HDV RNA negativity.¹³ The results for a phase 3 randomized trial (MYR301), comparing 2 mg BLV and 10 mg BLV to controls showed after 96 weeks there were response rates of 55% and 56% with 2 mg and 10 mg BLV, with similar safety profile to the prior release at 48 weeks where no resistance was observed and no serious adverse events were seen.^14,15 Although phase 2 trials with BLV did not show superiority to current PegIFN-alpha regimens.

Lonafarnib is an oral prenylation inhibitor. It inhibits the prenylation required for the long hepatitis D antigen to encapsulate in the HBV envelope. Lonafarnib has been studied with ritonavir, a protease inhibitor commonly used in HIV, as well as in combination with PegIFN-alpha. Ritonavir is a cytochrome P450 3A4 inhibitor and allows the use of lower doses of lonafarnib as it is metabolized by the same cytochrome. One phase 2 trial showed low-dose lonafarnib combined with PegIFN-alpha had better HDV RNA reduction with lower side effects. A phase 3 double-blind randomized study has recently been conducted comparing LNFr, LNFr and PegIFN-alpha, and PegIFN-alpha versus placebo. Results were presented in a press release showing that a ≥2 log decline in HDV RNA and normalization of alanine transaminase at the end of 48 weeks was achieved in 19.2% of LNFr plus PegIFN, compared to 1.9% of placebo. PegIFN-lambda was thought to have comparable antiviral activity and clearance results with decreased side effects compared to alpha.³ A phase 3 trial was in progress but discontinued early due to safety findings of hepatobiliary events resulting in liver decompensation, as reported in Eiger Biopharmaceuticals’ quarterly report.

Finally, HBsAg targeting drugs or nucleic acid polymers that interfere with the assembly and secretion of HBV are being utilized in clinical trials. These agents inhibit HBsAg release, clear circulating HBsAg, and assist in the control of viral infection. It has been studied in an open-label phase 2 study combined with PegIFN showing 58% with negative HDV RNA by the end of the study. This is approved as a rescue therapy in France for patients who failed all previous therapies.³

CONCLUSIONS

Hepatitis D is the most severe hepatitis virus infection and the exact prevalence in many countries considered endemic is unclear. It is seen in developed countries due to human population migration. Although HDV relies on HBV for entry into the host, the pathogenesis of liver disease is different from HBV. While much has been inferred from other more studied hepatitis viruses, it is important to continue with the investigation of epidemiology, noninvasive staging, and treatment to maximize outcomes for patients infected with HDV. The promise of novel, effective therapies in the not-too-distant future is exciting.

FUNDING INFORMATION

This work was supported by the NIDDK Intramural Research Program.

CONFLICTS OF INTEREST

The authors have no conflicts to report.