Epidemiology, presentation, and therapeutic approaches for hepatitis D Infections

Abstract

Introduction:

Chronic Hepatitis D virus (HDV) infection remains an important global public health problem, with a changing epidemiological landscape over the past decade along with widespread implementation of hepatitis B vaccination and human migration. The landscape of HDV treatments has been changing, with therapies that have been under development for the last decade now in late stage clinical trials. The anticipated availability of these new therapies will hopefully replace the current therapies which are minimally effective.

Areas covered:

This narrative review discusses the clinical course, screening and diagnosis, transmission risk factors, epidemiology, current and investigational therapies, and liver transplantation in HDV. Literature review was performed using PubMed and ClinicalTrials.gov and includes relevant articles from 1977 to 2022.

Expert opinion:

HDV infection is an important global public health issue with a true prevalence that still unknown. The distribution of HDV infection has changed globally with the availability of HBV vaccination and patterns of human migration. As HDV infection is associated accelerated disease courses and poor outcomes, the global community needs to agree upon a uniform HDV screening strategy to understand true of global prevalence such that new therapies can target appropriate individuals as they become available in the future.

1. Introduction

Hepatitis delta (HDV) was first reported in humans in Italy in 1977 by Mario Rizzetto and colleagues in a cohort of Italian patients with hepatitis B (HBV) who presented with severe hepatitis. A new antigen, called the delta antigen, was detected by direct immunofluorescence in the liver cell nuclei of patients with HBV surface antigen (HBsAg) positive chronic liver disease[1]. The HDAg was further found to require HBV surface proteins for hepatocyte entry, with the HDAg encoded by small 1.7 kb single strand of ribonucleic acid (RNA). In fact, HDV has the smallest genome of any animal virus[2]. HDV is circular in shape with the ability to fold into a rod-like secondary structure, and replicates via a rolling-circle mechanism, akin to the plant-based viroids proposed in the 1980s[3]. It is considered a “defective” virus because it requires HBsAg for viral entry[4], assembly[5] and propagation [1, 5].

HDV leverages its HBsAg envelope to gain access to the uninfected hepatocyte by binding to the sodium/bile cotransporter NTCP (sodium-taurocholate co-transporting polypeptide). The virus sheds its envelope and is transported to the nucleus where it undergoes replication. Outside the nucleus, large delta antigen undergoes a process called prenylation to allow for interaction with the HBsAg. This is an important step for virion assembly and facilitates trafficking and release of viral particles out of the hepatocyte. These steps in the HDV lifecycle are viable targets for available and investigational therapies against the virus.

2. Clinical Course

HDV infection occurs in one of two patterns, HBV/HDV co-infection and HDV superinfection. HBV/HDV co-infection is where infection with both viruses occur simultaneously. This pattern can result in extensive hepatic necrosis and can manifest with severe or fulminant hepatitis with a high case fatality rate. Recovery from HBV/HDV co-infection in adults often results in clearance of both viruses, with an estimated 5% progressing to chronic HDV infection. The other pattern of transmission is HDV superinfection, where patients with chronic HBV become infected with HDV. HDV superinfection often results in persistent HDV infection, which leads to accelerated progression to cirrhosis [6–8], an increased risk of HCC [7, 9, 10], and an increased risk for liver transplantation[11] compared to patients with only chronic HBV infection. In fact, 50–70% of patients with chronic HBV/HDV coinfection develop cirrhosis within 5–10 years after diagnosis, corresponding with a 2–3-fold increase when compared to patients with HBV mono-infection [6]. The associated risks of chronic hepatitis D are summarized in Table 1. HDV infections in children are rare [12], with a positive linear relationship between the number of years following the initial infection and cirrhosis [13]. In Europe, HBV/HDV coinfected patients account for about 25% of HBsAg- positive liver transplants [14].

Table 1.

Associated Risks of Chronic Hepatitis D Infection

Clinical outcome	Approximate relative risk increase *
Cirrhosis [6–8]	2- to 3-fold
Hepatocellular carcinoma [7, 9, 10]	3- to 6-fold
Liver transplantation [11]	2-fold

^*Compared with hepatitis B mono-infection.

3. Screening and Diagnosis of HDV Infection

Screening for HDV with serological markers can be performed using commercially available enzyme-linked immunoassays for HDV antibodies or radioimmunoassay (anti-HDV IgG, IgM, and total antibody) (Table 2). IgM anti-HDV is detectable within 2–3 weeks of symptom onset and disappears about 2 months after an acute infection, especially in HBV/HDV co-infection. In superinfection, HDV IgM remains detectable during disease flares in patients with chronic HDV infections. HDV IgG and HDV total antibodies persist after the resolution of acute infection and can be detected in patients with chronic infection[15]. A rapid point of care test for the detection of antibodies against ant-HDV in serum or plasma was recently developed, with this test able to detect all genotypes [16]. Another quantitative microarray antibody capture assay for anti-HDV IgG has been developed for screening [17]. A positive serological test result suggests previous or ongoing exposure to HDAg, though IgM antibodies may be absent in some patients from Africa [18]. The serologic and RNA patterns of both HBV coinfection and superinfection are shown in Figure 1.

Table 2.

Diagnostic tests for hepatitis D

Diagnostic test	Detection	Significance	Comments
Liver HDAg	Detects HDV antigen on liver histology via immunohistochemical staining	Indicates active infection	Lack of availability. Poor sensitivity
Serum HDAg	Detects HDV antigen in the serum	Indicates active infection, disappears at 2 weeks	Rarely performed. May be undetectable in chronic HDV
Anti-HDV IgM	Detects the presence of IgM antibodies against HDV in the serum	Indicates active infection, usually found in acute but can be found in chronic HDV	Often negative in chronic HDV but can be positive during periods of increased HDV replication
Anti-HDV IgG	Detects the presence of IgG antibodies	Indicates previous infection or chronic HDV	Appears late in acute HDV but persistent in chronic HDV
HDV RNA PCR (Qualitative)	Detects HDV RNA in the serum	Indicates active infection, can be found in acute or chronic HDV	LLOD depends on the assay. Useful for diagnosis
HDV RNA PCR (Quantitative)	Quantifies HDV RNA in the serum	Indicates active infection, found in acute or chronic HDV	LLOQ depends on the assay. Useful for treatment monitoring
HDV genotyping	Determines HDV genotype	Distinguish specific HDV genotype (1–8) with possible prognostic significance	Performed for research purposes only

HDAg, hepatitis D antigen; HDV, hepatitis d virus; RNA, ribonucleic acid; PCR, polymerase chain reaction; LLOD, lower limits of detection; LLOQ, lower limits of quantification.

Figure 1.

Serological and RNA pattern of HBV/HDV coinfection and superinfection. (A) Coinfection is characterized by early HDV viremia and HDV antigen present in both the serum and the liver, with seroconversion to Anti-HDV IgM and then IgG. IgM typically appears within 2–3 weeks of symptom onset and disappears after acute infection, with Anti-HDV IgG persisting. (B) Superinfection is characterized by exposure to HDV in an individual with chronic HBV infection. After exposure to HDV, HD Ag and HDV RNA is detectible in the serum and liver, with serum HD Ag detected for only about 2 weeks. As the infection becomes chronic, both IgM and IgG are present.

A positive HDV antibody result should be followed by a HDV RNA test to confirm ongoing viremia. This confirmatory RNA test can either be qualitative or quantitative. Hybridization assays for HDV RNA have been replaced by polymerase chain reaction assays (PCR) because of improved sensitivity as well as improved lower limit of detection (LLOD), with LLOD as low as 10 genomes/mL. Historically, the use of confirmatory HDV RNA qualitative and quantitative PCR is limited by availability, standardization, sensitivity, and even ability to detect certain genotypes and sub-genotypes [19–22]. In 2017, a World Health Organization international RNA standard was established, allowing for reporting of results in international units [23]. New confirmatory tests have been developed in the last few years, including a quantitative PCR test on the Cobas 6800 high throughput system with the ability to detect a lower limit of 10 IU/ml and all 8 genotypes [24], as well as a commercial kit able to quantify RNA viral load in all 8 genotypes through reverse-transcription-quantitative PCR [25].

HDV infection can also be identified on liver biopsy, as HDAg is expressed in the nuclei of liver cells. Intrahepatic HDAg and can be detected by immunohistochemistry, though liver biopsy is an infrequent diagnostic method. Detection of serum HDAg is limited as it is only detectable in the first 2 weeks of acute infection in an immunocompetent host, however, can remain detectable in immunocompromised patients[20, 26].

While both screening and confirmatory testing have become more widely available, guidance for whom and when to test is not globally uniform. The European Association for the Study of the Liver (EASL) Guidelines and the Asian Pacific Associated for the Study of the Liver (APASL) clinical practice guidelines recommend systematic screening for co-infections including HDV, HCV, and/or HIV[27, 28]. In contrast, the American Association for the Study of Liver Disease (AASLD) recommends screening patients for HDV only if they have HBV DNA <2,000 IU/mL but elevated ALT, or at risk for HDV, which they define has having HIV and/or HCV infection, use of intravenous drugs, men who have sex with men, people with multiple sexual partners or any history of sexually transmitted infections, or are immigrants from areas with high HIV endemicity[29].

In Europe, where EASL recommends universal anti-HDV testing of all HBsAg-positive individuals, many cases remain undiagnosed. A recently published study on the implementation of anti-HDV reflex testing among 2,236 HBsAg-positive individuals led to a 5-fold increase in diagnosis of HDV infection. Prior to the implementation of reflex testing, only 7.6% of HBsAg-positive individuals were tested for anti-HDV[30]. This study showed that the implementation of reflex HDV testing in HBsAg increases the diagnosis of patients with HBsAg.

In the U.S., despite current professional guidance, screening for hepatitis D, is rarely performed. In fact, in a 2015 Veterans Affairs retrospective cohort study including 25,603 patients with HBsAg+ in the United States, only 8.5% of patients were tested for HDV with 3.4% of these patients testing positive. Only 8.2% of HDV-positive patients underwent confirmatory PCR testing. Receiving an HDV test was associated with testing for HBV, HIV and HCV. Patients with a high-risk profile (high-ALT, low HBV DNA) were more likely to be tested, 80% of patients with this high-risk profile were not tested. Patients with alcohol use and HCV were less likely to be tested for HDV. Predictors of positive HDV results including substance use and cirrhosis. Interestingly, the majority (59%) of HDV-positive patients were also HCV co-infected [10]. This study demonstrates low rates of HDV testing in the United States, even among patients with high-risk profiles.

4. HDV Genotypes

Eight HDV genotypes (GT) have been identified, with up to 40% of variability in the full-length RNA sequence between genotypes. Additionally, multiple sub-genotypes have been characterized by over 90% similarity over the entire genome sequence. Genotypes have been shown to influence clinical outcomes. A study from Taiwan that included 194 patients with HDV superinfection found that GT-1 was associated with a lower remission rate (15.2% vs 40.2%; P = .007) and more adverse outcomes (cirrhosis, hepatocellular carcinoma, or mortality) (52.2% vs 25.0%; P= .005) than those infected with GT-2 HDV [31]. This result was expanded upon in a large French study that included 1,112 HDV-infected patients, where patients with GT-1 and GT-5 were more likely to develop cirrhosis, GT-5 appearing to be more fibrogenic than GT-1 in African-born patients, however less fibrogenic than GT-1 in non-African patients [32].

Separately, GT-3 which is frequently isolated in South America, is associated with severe hepatitis, with the majority of cases of fulminant hepatitis in the Amazon basin due to HBV/HDV co-infection or superinfection with GT-3 [33–35].

Genotypes also differ in their replication efficacies. Data from a 2021 study on HDV replication found that HDV genotypes differ in replication efficacy, with some replicating with more efficiency with certain HBV genotypes. For example, GT-1 and 8 can be assembled with any HBV genotype, however GT-1 has a strong preference for the envelopes of HBV-D, B, and E. GT-2 and 4 showed a strong preference to HBV B and E. Interestingly, the most efficient combinations of HBV/HDV do not always occur naturally. This finding argues against the co-evolution of HBV and HDV in the human population [36]. In-vitro findings have shown that GT-1 is more efficient at packaging than GT-2 [37]. A recent study demonstrated that DPD, a crucial protein for viral assembly and packaging, has a motif, PXXP, that is involved in protein-protein interactions and/or in transduction of cell signaling are individualized in all HDV genotypes[38]. Together, these studies may provide some explanation as to why certain genotypes are associated with more severe clinical disease.

5. HDV Transmission and risk factors

Like HBV, HDV is spread by parenteral exposure[39], with risk factors for HDV infection including intravenous drug use, high risk sexual activity, and coming from an endemic country [40, 41]. Unlike HBV, vertical transmission is rare. In a study that followed 54 children born to 22 women with known HBV-HDV co-infection, there was no evidence of vertical transmission [42]. Patients infected with HCV and HIV also have been found to have a high rate of HDV co-infection due to shared risk factors such as blood transfusions, tattooing, intravenous drug use, and high-risk sexual practices. In a 2021 single center retrospective cohort study characterizing 652 patients with HBsAg+, 90% were tested for HDV with 19% testing positive for anti-HDV. Of these, 80.5% had confirmed chronic HDV infections, with a total prevalence of HDV viremia of 14%. Of the patients positive for anti-HDV, 65.5% were from an endemic country. Patients with anti-HDV positivity were more likely to be from a HDV endemic country, use IV drugs, and exhibit the typical pattern of low HBV-DNA (<2,000 IU/ml) and high alanine aminotransferase (>40U/L). This study shows a surprisingly high prevalence of HDV in patients with HbsAg positivity in the US, with the results supporting the AASLD guidance on whom to screen [29, 40].

6. Epidemiology

Global estimates of HDV vary widely, with recent estimates ranging between 12 and 74 million infections globally [43–45]. The variability in recent estimates is likely secondary to variability in definitions of seroprevalence as well as using specific data sets to extrapolate larger prevalence estimates [46]. Given the lack of universal screening of HBsAg-positive individuals for anti-HDV, the true prevalence of HDV infection is likely underestimated. When HDV was first isolated in Italy in the 1970s, the initial prevalence rates were high as >20% in Southern Europe with an estimated 5% of HBsAg carriers worldwide infected with HDV in the late 1980s [47, 48]. With the implementation of HBV vaccination as well as with patterns of migration, the epidemiology and geographic distribution of HDV has changed over the last few decades. For example, in Italy, anti-HDV in HBsAg carriers with liver diseases declined from 24.6% in 1983 to just 8% in 1997 [49, 50]. While the success of HBV vaccination has changed the dynamic of HDV worldwide, access to vaccination has not been universal and HDV is still endemic in many countries with a variable distribution. Given these changes, epidemiologic data from the last 10 years will be the primary focus of this review.

The distribution of genotypes is likewise changing with patterns of migration (Figure 2). In a 2017 prospective study, the genotypes of 2,152 viral isolates from patients with active HDV infections were characterized. This study confirmed the presence of 8 genotypes and multiple sub-genotypes as well as explored geographic distribution [51]. While GT-1 is distributed worldwide, other genotypes are more localized, with GT-2 found in parts of Asia, GT-3 in Latin America with predominance in the Amazon basin, GT-4 primarily found in Taiwan and Japan, GT-5 in Western Africa, and GT-6 through 8 in Middle Africa[43]. In more recent years, GT-2 has been found in Egypt and Iran. GT-5, 6, and 7 have been found in parts of Europe, reflecting patterns of immigration [44].

Figure 2.

Geographic distribution of HDV genotypes

6.1. United States and Europe

In the US and Europe, vaccination campaigns against HBV started in the early 1990s, resulting in protection from both HBV and HDV. Given the timing of the vaccination campaigns, the decline in HDV infection is most marked in younger cohorts who received the vaccine. Thus, HDV infections are most frequently seen in older populations or in immigrants that have not received HBV vaccines.

In a 2019 study using the 2011–2016 National Health and Nutrition Examination Survey (NHANES) that included data from 16,143 adult participants, the estimated overall prevalence of HBsAg was 0.36%, with a prevalence of 3.4% in non-Hispanic Asians. Among the adult HBsAg+ population, 42% had HDV antibodies, with anti-HDV prevalence of 46% in HBsAg foreign born adults versus 33% in US born adults [52]. This suggested a much higher prevalence of HDV than previously thought. In contrast, a NHANES study using data from 1999–2012 that included 52,209 individuals with HbsAg and HB core antibody found an overall prevalence of HDV of just 0.02% [53].

As mentioned previously, the demographics of the HDV infected population in Europe are changing. In a 2014 Italian cohort of 513 HBsAg carriers, 11.9% were positive for anti-HDV. The age distribution of anti-HDV positive patients reflected the mass vaccination campaign beginning in 1991, with only 3.3% of anti-HDV patients younger than 30, with 80.3% aged 50 years or older [54]. Furthermore, the majority of patients (52.4%) had cirrhosis, suggesting the that the majority of HDV infections were not recently acquired. In the Netherlands, the confirmed prevalence of HDV viremia in 925 patients with chronic hepatitis B from 2017–2019 in a tertiary care center was 2%. Of these patients, 94% were non-Dutch. Of 17 samples that were successfully genotyped, 14 samples were genotype 1, with genotype 5 found in 3 patients of African origin [55]. This again confirms the patterns of infection in countries with high rates of HBV vaccination, where the majority of HDV infections are seen in immigrants from endemic countries. In HBsAg positive patients in Austria, 0.8% are also anti-HDV positive, with only 40% of these seropositive patients receiving confirmatory testing for active viremia [56].

While HDV infections have decreased in the last decades throughout most of Europe, HDV remains endemic in Romania, Moldova, and parts of Russia. Despite the universal anti-HBV vaccination of newborns beginning in 1995 in Romania, HDV remains endemic. A multicenter study in Romania comprising 2,761 HBsAg+ patients found IgG anti-HDV+ in of 23.1% of patients, with confirmed viremia in 16.4% of patients. HDV infection was most prevalent in patients >50 years of age. While some risk factors for HDV infection were similar to those seen in wealthier countries including use of syringes, other risk factors included lack of anti-HBV vaccination, history of blood transfusions, any previous surgery, frequent hospitalization or endoscopies, tattoos, body piercing, use of glass syringes, and higher number of female sexual partners [57]. In Moldova, a 2019 study found that of 133 patients with HCC, 18.5% of these patients were infected with HDV. Of the patients with HBsAg+, 47.2% patients were infected with HDV [58]. While Russia implemented universal newborn HBV vaccination in 1998, areas of Russia including the Yakutia region, still have high prevalence of both HBV and HDV [59].

Individuals who use intravenous drugs remain high risk for HBV and HDV infection. However, the prevalence of HDV has declined in this population as well, likely from successful HBV vaccinations. For example, in Spain, the prevalence of anti-HDV among active HBsAg-positive IVDUs declined from 30% in the 1990s to 4.2% in 2018 [60]. Interestingly, in the first period, most patients were native of Spain, whereas the two patients who tested positive for HDV in the later period were immigrants from HDV endemic countries. This study confirms the trend that the majority of HDV infections are found in migrants from HDV endemic countries.

6.2. Asia

The burden of HDV varies widely by region in Asia. In Uzbekistan, the seroprevalence of HDV is 83% in patients with HBsAg-positivity and cirrhosis[61]. Interestingly, in neighboring Afghanistan, anti-HDV was detected in just 2.1% of 234 HBsAg+ samples [62]. In Pakistan, HDV infection was found in 14.7% of HbsAg positive patients [63]. In India, the rate of HDV was estimated between 5–10% in a 2006 nationwide survey of HBsAg-positive patients, with seropositivity varying by region[64]. For example, there were no cases of HDV infection found in 262 HBsAg-positive patients in Northern India in 2012–2014 [65], whereas 5.7% patients with HBsAg were found to be HDV positive in Chennai in 2014 [66].

In Mongolia, an astounding 50–60% of the HBsAg-positive population is HDV seropositive [17]. In China, with an overall HBsAg prevalence of 6.9%, country wide data on HDV infection is lacking. [67] A 2020 study including 225 hospitalized HBsAg positive patients in Shanghai found HDV-RNA in 4.9% of patients, with GT-2 the predominant genotype [68]. In Guangdong, China, 6.5% of patients with chronic HBV infections were found to have HDV IgM anti-HDV. Anti-HDV positivity was more common in patients over the age of 50 years (11.7% vs. 5.1%) [69]. In Vietnam, the rate of HDV co-infection in 205 patients with chronic HBV was 16%, with GT-1 genotype predominance [70].

6.3. Africa

In Africa, as of 2016, only 11 countries offer the HBV vaccine at birth, with the majority of countries starting HBV vaccination programs in the 2000s [71]. A 2017 metanalysis on the prevalence of HDV in sub-Saharan Africa determined the pooled seroprevalence of HDV in both the general and liver disease populations at 25.6% and 37.4% in Central Africa and 7.2%, and 9.5% in Western Africa, respectively [72]. This study suggests localized clusters of hepatitis D endemicity.

6.4. Central and South America

In Central and Latin America, the prevalence of HBsAg is generally less than 1%, with data generally lacking on HDV [73]. However, HBV and HDV remains endemic in the Western Amazon Basin, including parts of Brazil, Venezuela, Colombia, Peru, and Ecuador. In a 2019 Systematic review and metanalysis of HDV prevalence in South America, the overall pooled-prevalence has decreased dramatically since the 1980s, when HDV seroprevalence was 40.3%, to 7.0% in the 2010s [74]. In Peru, where a pilot HBV vaccination program was launched in the HBV- and HDV hyperendemic province of Abancay 1991, HDV prevalence has dropped dramatically, with 5.3% of HBsAg positive patients testing positive for anti-HDV from 9% in 1990 [75].

In a 2017 nationwide study of seroprevalence in Brazil, anti-HDV total antibody ELISA assays were performed in 1240 HBsAg positive samples, with 3.2% of individuals positive, with prevalence varying by region, with prevalence as high as 24.5% in Acre, a state in the northern, Amazon region [76]. In Brazil, HDV incidence has decreased 21.6% overall from 2009 to 2018, with this decrease most notable in the under 20-year-old age group (43.4% decrease), likely due to increasing hepatitis B vaccination rates and decreasing hepatitis B infections [74, 77, 78].

A study in the Amazon basin found that of a sample of patients who use drugs with chronic HBV infections, 19.5% had evidence of exposure to HDV. Of 9 samples analyzed for genotypes, 8 were genotype 3 with one sample genotype 1 [79].

7. Introduction to therapies against HDV

Since HDV hijacks the infected hepatocyte’s replicative machinery independent of HBsAg, targeting HDV with antivirals designed for HBV has proven futile[14]. This lack of native replicatory machinery makes antiviral therapies a challenging endeavor.

Currently, there is no treatment for acute HDV infection. Supportive care is offered unless a patient is in acute liver failure, meeting the criteria for liver transplantation[80]. Despite research on HDV for more than three decades, there is no effective therapy for chronic HDV infection. Professional society guidelines including EASL[81] and APASL[28] recommend pegylated interferon (PegIFN) for treatment of chronic HDV infection. However, IFNs are not approved by the US Food and Drug Administration (FDA)[82, 83] for treatment of HDV and the use of IFNs is considered “empirical” at best[5].

CHD’s serious nature coupled with lack of available effective therapies has led the FDA to offer expedited evaluation and priority approval for promising HDV therapies[82]. New therapies under investigation target various aspects of HDV life cycle including interactions of HDV with HBsAg or the multiple processes within the infected hepatocyte[84, 85] (Figure 3).

Figure 3.

Lifecycle of HDV and therapeutic targets

The advent of new therapies under investigation has highlighted the variation in therapeutic endpoints. Even patients with undetectable serum HDV RNA are capable of viral relapse due to limited sensitivity of HDV RNA diagnostic assays. An FDA guidance [82] has urged for a combined endpoint of liver chemistry improvement (ALT normalization) with undetectable serum HDV RNA less than the lower limit of quantification (LLOQ) or 2 ≥ log₁₀ decline in HDV RNA. There is no single therapeutic endpoint that is indubitably linked to clinical benefit. Clinical trials assessing HDV therapies have been using composite endpoints with variability. This topic has been discussed extensively in a special article by Da [83].

8. Interferon and Pegylated interferon for HDV

Drs. Alick Isaacs and Jean Lindenmann discovered interferon’s (IFN) antiviral effect in 1957.[86] They incubated heat-inactivated influenza virus in fragments of chick chorio-allantoic membrane, which released a factor that “interfered” with the virus’s ability to agglutinate red blood cells[86, 87]. IFN’s were later defined as a family of proteins with antiviral, antiproliferative, and immunoproliferative effects. They were postulated to function by the interaction of cell surface receptors inducing a cascade of intracellular proteins[88].

Two types of IFNα (IFNα 2a and IFNα 2b) have been explored for CHD treatment[89]. It was not until 1986 when IFNα 2 was explored as a treatment option for CHD in a study of 11 patients in Italy[90]. The relapse rate after treatment discontinuation was high (four of six patients), a problem that plagues IFN therapy in CHD patients to this day. A meta-analysis of six randomized controlled trials (RCTs) by Abbas et al[91] demonstrated a failure of sustained viral response (SVR) at six months in 82.6% of patients compared with 94.8% in controls (P = 0.02). A recent meta-analysis [92] of 13 studies (4 out of which were RCTs) demonstrated a pooled viral response of 29% at end of 24-week post-treatment with pegylated IFN.

One of the earliest landmark studies by Farci et al[93] evaluated IFNα 2a’s effectiveness in treatment of CHD comparing high dose (9 million thrice weekly), low dose (3 million thrice weekly) vs no treatment for 48 weeks. The high dose group resulted in complete virologic response (normal serum alanine aminotransferase (ALT) and undetectable HDV RNA) in 50% of patients. Unlike the low dose or no treatment groups, the high dose group also demonstrated histologic improvement. Biochemical response persisted for 4 years; however, relapse was noted. Farci et al published a 12-year follow-up in 2004 that showed the high dose group had significantly improved long-term survival in addition to continued normalization in ALT in half of patients who had a biochemical response at end of treatment in the high dose group after 48 weeks. More impressive was the improvement in hepatic function and liver histology in the high dose group with a strong suggestion of reversal in patients with Child Pugh A cirrhosis[94].

Pegylated IFN (PegIFNα) was introduced by conjugating standard IFN with polyethylene glycol to extend plasma half-life and to prolong immunomodulatory action[85]. PegIFNα, like IFNα, has also been studied in two varieties: PegIFNα 2a and PegIFNα 2b. Both are known to have equivalent efficacy[89]. PegIFNα is preferred over non-pegylated IFNα due to simplicity in dosing[95]. The AASLD guidelines recommend PegIFNα 2a for HDV co-infection at 180 μg weekly for 48 weeks[95]. Various derivations of PegIFNα 2a have been explored by duration and strength in the literature. Heller et al[96] performed a dose escalation study of 13 patients with HDV who were treated with PegIFNα 2a starting at 180 μg weekly with titration up to a maximal dose of 270 μg weekly. Four patients were able to tolerate treatment up to five years and three out of four of these patients achieved a complete virological response (combination of HDV virological response with HBsAg seroconversion). A long-term follow-up by Hercun et al[97] encouragingly demonstrated 58% of patients with a durable undetectable HDV and 33% who cleared HBsAg.

EASL concurs with the AASLD with an at least 48 week PegIFNα dosing irrespective of on-treatment response pattern provided drug is being tolerated[81]. APASL guidelines however favor a prolonged treatment approach with at least 12–18 months of treatment and monitoring for 6 months post treatment and beyond[28].

9. Nucleos(t)ide-based Combination Therapies

Nucleos(t)ide analogues (NAs) like lamivudine, adefovir, telbivudine, entecavir and tenofovir disoproxil fumarate (TDF) are used principally in treatment of chronic hepatitis B (CHB). They inhibit HBV DNA polymerase activity and suppress HBV replication[98]. Since NAs do not have an effect on HBsAg, they do not theoretically impact HDV infection[85]. There were 2 major trials that combined PEG-IFN with NAs to assess their combined or individual effect on HDV.

The Hep-Net-International Delta Hepatitis Intervention Trial (HIDIT) study randomized 90 patients in three categories: PEG-IFNα 2a (180 μg once weekly) plus adefovir (ADV): 10 mg daily), PEG-IFNα 2a (180 μg once weekly) plus placebo, and ADV (10 mg daily) alone. The primary endpoint of ALT normalization and HDV RNA clearance at week 48 was achieved in only two patients each in the PEG-IFNα 2a + ADV and PEG-IFNα 2a + placebo groups with none in the ADV-only group. HDV RNA was negative in 23% of patients in first group, 24% in the second group and none in the third group at 48 weeks. Sustained response was measured for 24 additional weeks in 28% of patients in the first and second groups with none in the ADV-only group[99]. A retrospective-prospective long-term follow-up showed a higher number of patients receiving ADV alone required retreatment with PEG-IFNα 2a (48% vs 19%, P = 0.02). It also confirmed HDV RNA relapses in 9/16 patients with longer term follow-up, challenging the concept of sustained viral response in assessment of therapies against HDV[100]. A retrospective 10-year follow-up study of the HIDIT-I trial further assessed late relapse in patients receiving PEG-IFNα where late relapse was defined as RNA positivity at least once after follow-up 24-week response. Late relapse was shown to occur as late as nine years after stopping treatment for one patient [101]. An unrelated retrospective study of 31 patients with a median follow-up of 36 months after PEG-IFN treatment reported a 33.3% relapse rate [102].

The HIDIT-II trial sought to extend PEG-IFNα 2a therapy further by up to 96 weeks and assess whether the addition of TDF to PEG-IFN would improve HDV RNA suppression. The double-blinded trial randomized 120 patients to receive either PEG-IFNα 2a plus TDF versus PEG-IFNα 2a plus placebo. Notably 40% of the patients with cirrhosis were included, a population typically excluded from studies involving Peg-IFN due to concerns of inducing flares and causing acute-on-chronic liver failure in patients with advanced cirrhosis[80, 103]. While extending PEG-IFNα 2a therapy led to HDV RNA suppression rates of ~40% and improved histological fibrosis scores, post-treatment HDV RNA relapses occurred in about 1/3^rd of patients. There was no benefit of adding TDF in combination with PEG-IFNα 2a[104, 105].

10. Entry inhibitors

Bulevirtide

Bulevirtide (BLV), trade name Hepcludex and formerly known as Myrcludex B (MyrB), is a lipopeptide that blocks the binding of HBsAg-enveloped particles to the sodium/bile cotransporter NTCP (sodium-taurocholate co-transporting polypeptide), preventing the entry of HDV into uninfected hepatocytes[106]. A pilot phase Ib/IIa trial (MYR201) studied 24 patients with HDV/HBV co-infection equally randomized to receive BLV or PEG-IFNα 2a or both[107]. There was no change in the primary endpoint, HBsAg, after 12 or 24 weeks of treatment in all three treatment arms. ALT normalized in 75% of patients and HDV RNA decreased in all patients receiving BLV monotherapy. The Myr-IFN cohort demonstrated a significant reduction in HBV RNA, suggesting a synergistic effect of the combination[108]. A recent review by Ferenci et al [109] shows a synergistic on-treatment effect of BLV and PEG-IFN compared to either as monotherapies.

Given encouraging results of MYR201, BLV was studied with addition of TDF in the phase II MYR202 trial. TDF was used as a comparator because of concerns of intolerable adverse effects due to PegIFNα and high relapse after treatment. 120 patients with CHD were randomized in four treatment arms: three arms with escalating doses (2, 5, and 10 mg/day) of BLV combined with TDF with the fourth arm studying TDF-only group[110]. The primary endpoint, HDV RNA negation or decrease by 2 ≥ log₁₀ from baseline by 24 weeks, was achieved in 53.6% (2 mg+TDF), 50.0% (5 mg+TDF), 76.7% (10 mg+TDF), and 3.6% (TDF only)[111]. This trial suggested a dose-dependent effect of BLV; however, relapse was noted in all treatment arms after treatment cessation.

BLV was then evaluated with both TDF and PEG-IFNα 2a in the phase II MYR203 trial[112]. In this multicenter, open-label trial, 90 patients were randomized in six arms: PEG-IFNα 2a 180 μg only, BLV 2 mg + PEG-IFNα 2a, BLV 5 mg + PEG-IFNα 2a, BLV 2 mg only, BLV 10 mg + PEG-IFNα 2a, and BLV 10 mg + TDF all for 48 weeks. A combined response 24 weeks off-therapy defined as negative HDV RNA and ALT normalization was shown at 46.7% for BLV 2 mg + PEG-IFNα 2a cohort and 6.7% for BLV 10 mg + PEG-IFNα 2a cohort[113]. The main adverse effects attributable to BLV were related to elevated bile acids; therefore, careful monitoring of serum bile acids is recommended.

MYR204 is a phase IIb trial that is currently ongoing to evaluate the safety and effectiveness of BLV+PEG-IFNα 2a combination therapy compared to BLV monotherapy[114]. Interim results have thus far shown that BLV+PEG-IFNα 2a combination therapy netted higher rates of HDV viral decline however ALT normalization was higher in BLV monotherapy[115]. These results are intriguing, but they only capture 24 weeks of therapy with final trial results pending. More recently, the phase III MYR301 trial[116] has been ongoing to investigate the efficacy and safety of delayed BLV 10 mg/day compared to BLV 2 mg or 10 mg/day treatment. Interim combined results of MYR202, MYR203, and MYR301 were presented at the 2022 International Liver Congress. The combined study comprised of 281 patients with CHD without cirrhosis or with compensated cirrhosis. The viral response rate (undetectable HDV RNA or decrease by 2 ≥ log₁₀ from baseline) was lower in the BLV 2 mg/day group compared to 10 mg/day (53.3% versus 71.6%), however ALT normalization was reversed with 51.1% versus 42.1% respectively[117].

BLV has been used in real world settings as evidenced by a 2022 study of eight outpatients at a single institution treated with BLV 2 mg/day for 48 weeks. Median ALT decreased from 82 to 34 IU/L and median HDV RNA decreased from 13.38 million to 3,134 copies/mL[106]. BLV has also been studied in patients with compensated cirrhosis and clinically significant portal hypertension. A 48-week course of BLV 2 mg/day monotherapy demonstrated a combined response (undetectable HDV RNA or decrease by 2 ≥ log₁₀ from baseline and ALT normalization) in 67% of patients[118]. A compassionate use program in Austria studied 23 patients (17 of whom had progressed to cirrhosis) with BLV 2 to 10 mg per day for 24 weeks. Seven patients achieved HDV-RNA undetectability [119]. Another compassionate use program studied two patients with HDV-related cirrhosis treated continuously with BLV monotherapy for up to three years with excellent virological and clinical responses[120]. During the most recent 2022 AASLD Meeting, data was presented on a large French multicenter early access program on 146 patients (63% with cirrhosis). Of the patients who received BLV 2 mg once daily, 63.6% (7 out of 11 patients) achieved a HDV RNA decrease by 2 ≥ log₁₀ and undetectable HDV RNA in 45.4% [121].

BLV received a conditional marketing authorization in 2020 in the European Union for treatment of CHD in adult patients with compensated liver disease[122]. It also has been granted Orphan Drug and Breakthrough Therapy designations by the FDA in 2018[123]. A prospective, multicenter, randomized phase IV study is currently ongoing to evaluate 400 patients with HBV/HDV co-infection under treatment with BLV[122, 124].

10.1. Ezetimibe

Ezetimibe, used classically as a cholesterol-lowering drug, has been shown to have NTCP inhibition properties in in vitro studies[125]. This was the premise of a proof-of-concept phase II trial to evaluate the efficacy and safety of ezetimibe 10 mg daily in both IFN-experienced and IFN-ineligible patients. The primary endpoint of HDV RNA 1 ≥ log₁₀ from baseline at week 12 was achieved in 41% of patients. The rest of the patients did not experience a log reduction or rather, an increase[126]. Two phase II clinical trials, one with a higher dose of ezetimibe[127] and another with combination of ezetimibe with Peg-IFN[128] are listed as active. There are no other studies actively studying the use of ezetimibe in CHD.

11. Inhibitors of Viral Assembly/Prenylation Inhibitors

In the host hepatocyte, HDV virion assembly depends on prenyl lipid modification, or prenylation, of its nucleocapsid-like protein large delta antigen[129]. This prenylation is undertaken by the host enzyme, farnesyltransferase, which is an essential step in HDV assembly[80]. An in vivo pre-clinical mouse-based study in 2003 showed the efficacy of prenylation inhibitors as a novel antiviral therapy against HDV[129]. Lonafarnib (LNF) is an oral farnesyltransferase inhibitor that was originally developed in 1998 for anti-cancer therapies[130].

The first proof-of-concept double-blind placebo-controlled phase II trial exploring LNF in CHD randomized 14 patients in two groups[131]. Patients received oral LNF (100 mg or 200 mg) or placebo twice daily for 28 days with 6-month follow-up. At day 28, mean log₁₀ HDV RNA declined from baseline by −0.73 log₁₀ IU/mL and −1.54 log₁₀ IU/mL in the lower and higher dose groups respectively. No virologic resistance was observed[132]. Main side effects were gastrointestinal symptoms such as diarrhea, nausea, abdominal bloating, and weight loss that have been previously described in other disease states (such as myelodysplastic syndrome and Hutchinson-Gilford progeria syndrome) in the literature as well[133, 134]. None of the expected adverse effects led to discontinuation of the drug.

The initial success of lonfarnib [131] was explored in quick succession in other trials designed to assess LNF in varying dosing and combinations with other anti-HDV therapies. LOWR-1[135] was a phase II trial that explored higher dosing LNF (up to 300 mg twice daily) as monotherapy and also lower dosing LNF (100 mg twice daily) in combination with either PEG-IFNα or ritonavir (RTV). RTV is a potent cytochrome P450 3A4 (CYP3A4) inhibitor [136]. Since CYP3A4 is a significant mediator in LNF’s metabolism, the addition of RTV was postulated maintain higher serum levels of LNF at lower doses to abate the GI side effects while enhancing viral response. The log₁₀ reduction in serum HDV RNA was −2.0 log₁₀ IU/mL in the higher dosed LNF monotherapy group (300 mg twice daily). However, this was also balanced by a high proportion of gastrointestinal adverse effects experienced in the higher dosed LNF groups. The addition of RTV to a lower LNF dosing (100 mg twice daily) surprisingly yielded better antiviral responses (−3.2 log₁₀ IU/mL reduction) at week 8 than higher dosed LNF monotherapy. This can be attributed to decreased diarrhea as an adverse effect possibly leading to better effective absorption of LNF[137].

LOWR-2[138] was a phase II trial designed to identify the optimal combination regimens of LNF+RTV with and without PEG-IFNα. The most robust antiviral efficacy was observed in combination LNF 25 or 50 mg with RTV and PEG-IFNα with increased efficacy at 24 weeks with mean log₁₀ HDV RNA declines of −2.69 log₁₀ IU/mL and −3.81 log₁₀ IU/mL[139]. LOWR-3[140] was a dose-escalation phase II trial that focused on RTV boosted LNF therapy with a median log₁₀ HDV RNA decline from baseline at −1.60 log₁₀ IU/mL (LNF 50 mg), −1.33 log₁₀ IU/mL (LNF 75 mg), and −0.83 log₁₀ IU/mL (LNF 100 mg) after 12 weeks. The all-oral combination of RTV boosted LNF was shown to be safe and tolerable after six months of therapy[141]. The last major phase II trial was LOWR-4[142] that was also a dose-escalation study to assess whether step-wise increases in LNF dose can accommodate for higher doses in patients with CHD. 13 out of 15 patients completed 24 weeks of therapy, while 10 out of 15 patients were dose-escalated to LNF 100 mg twice daily boosted with RTV. Mean HDV RNA declined from baseline was −1.58 log₁₀ IU/mL[143].

The Delta Liver Improvement and Virologic Response in HDV study (D-LIVR) study[144] is the first phase III trial to investigate lonafarnib in patients with CHD. It is an international, multicenter, partially double-blind, and randomized study with an estimated enrollment of 400 patients that has completed recruitment and is awaiting results. The all-oral arm will have LNF boosted by RTV and the combination arm will have LNF boosted by RTV combined with PEG-IFNα.[123] The study will utilize FDA’s recommended combined endpoint of ≥2 log₁₀ decline in HDV RNA and ALT normalization[82].

LNF has been granted Orphan Drug, Fast Track, and Breakthrough Therapy Designations for HDV by the FDA[145]. It is already approved by the FDA to reduce mortality in Hutchinson-Guilford Progeria Syndrome and for treatment of processing-deficient Progeroid Laminopathies.

12. Immunomodulators

IFNλ, a novel type III interferon discovered in 2003[146], has been shown to have a targeting advantage and specificity, limiting the adverse effect profile compared to IFNα.[147] IFNλ binds to a receptor that is preferentially expressed in hepatocytes and the gut over other organ systems[148]. IFNλ has been shown to be similarly effective against HBV and HCV with an improved adverse effect profile in randomized controlled trials[149, 150].

It was postulated that PEG-IFNλ 1a would reduce adverse effects due to its specificity while exerting antiviral effects against HDV. This was the main driver behind the phase II LIMT study[151] (Lambda Interferon Monotherapy Study in HDV). LIMT was an open-label randomized study conducted in Pakistan, New Zealand, and Israel with 33 patients who were randomized to either PEG-IFNλ 1a 180 μg or 120 μg weekly subcutaneous injections for 48 weeks with a 24-week off-treatment response. The mean log₁₀ HDV RNA decline was −2.3 IU/mL in both high and low dose groups. The durable viral response was 36% in the high dose group, comparable to historical rates of IFNα. The rate of adverse effects was noted to be lower in PEG-IFNλ 1a compared to α.[152] A phase III LIMT-2 study is currently recruiting patients to evaluate the safety and efficacy of PEG-IFNλ 1a. It is estimated to enroll 150 patients in a 2:1 allocation with PEG-IFNλ 1a 180 μg for 48 weeks with 24 weeks follow-up or no treatment for 12 weeks followed by PEG-IFNλ 1a treatment for 48 weeks with 24 weeks follow-up[153].

In order to combine the encouraging therapeutic effects of LNF and PEG-IFNλ 1a, the Lambda InterFeron combo Therapy (LIFT) study[154], was devised. This open-label phase II trial treated 26 patients with LNF 50 mg twice daily, RTV 100 mg twice daily, and PEG-IFNλ 1a 180 μg weekly for 24 weeks. The primary endpoint of ≥ 2 log₁₀ decline in HDV RNA was met in 78% of patients, but with sustained virologic response of undetectable HDV RNA at both 12 and 24 weeks post triple therapy in only 12% of patients. No patients lost HBsAg at week 24. It was encouraging that there were no mortality or serious adverse events during the study. Minor to moderate adverse effects included predominantly diarrhea, nausea, and decreased appetite. Drug discontinuation before 24 weeks due to intolerance only took place in four patients.[155] The results of this trial overall support the viability of combination therapy, but further research needs to be undertaken to improve off-therapy response rate.

13. Inhibitors of Viral Release/HBsAg secretion inhibitors

Nucleic acid polymers (NAPs) are amphipathic oligonucleotides that possess broad spectrum antiviral activity in enveloped viruses[156]. In a seminal 2013 study, NAPs were shown to enter HBV-infected duck hepatocytes and prevent intracellular accumulation of duck HBsAg in vitro[157]. This study was followed by successful demonstration of NAP activity in vivo against HBV infection in ducks[158]. NAPs were then studied in two phase I and II trials (REP 101[159] and REP 102[160]) using NAPs called REP 2055 and REP 2139-Ca (novel calcium chelate formulation) in eight and 12 patients respectively against HBV in Bangladesh. Both trials demonstrated up to 2–7 log₁₀ reductions in HBsAg and 3–9 log₁₀ reductions in HBV DNA[161].

The impressive therapeutic performance demonstrated by NAPs in CHB was the impetus for the first phase II trial in 12 patients with HBV-HDV co-infection in the Republic of Moldova (REP 301[162]). The NAP REP 2139-Ca 500 mg IV was administered once weekly for 15 weeks followed by combined REP 2139-Ca 250 mg with PegIFNα 2a 180 μg subcutaneously once weekly for 15 weeks followed by PegIFNα 2a for 33 weeks. The HDV RNA reduction was log₁₀ −4.87 IU/mL by end of 24-week follow-up. This was maintained at log₁₀ −4.51 IU/mL at 1 year follow-up. At end of treatment, nine (75%) of patients converted to HDV RNA negative and five patients (42%) were HBsAg negative. 83% of patients experienced thrombocytopenia and 67% experienced neutropenia. Elevations of ALT (42%) and aspartate aminotransferase or AST (33%) were also noted[163].

The encouraging anti-viral effect in REP 301 with lingering safety concerns led to REP 301-LTF[164] study that extended follow-up to 3.5 years. One patient from REP 301 was removed from the REP 301-LTF study due to PegIFNα-induced liver injury which recovered after stopping of the drug, however this was followed by rebound HDV infection. Overall, REP 301-LTF evaluated 11 out of 12 patients from REP 301 and did not show any abnormal liver enzyme elevations throughout the follow-up period. Extended follow-up confirmed seroconversion as evidenced by HBsAg response in four out of 11 patients and maintenance of >2 log₁₀ reduction from baseline in nine out of 11 patients.[165]

14. RNA interference molecules

JNJ-73763989 (JNJ-3989, also formerly known as ARO-HBV) is an RNA interference molecule containing two short-interfering RNA (siRNA) triggers that target translation of HBV RNA. This effectively suppresses HBV replication. 190 patients with HBV/HDV co-infection are currently being recruited for the multicenter, randomized, double-blind, placebo-controlled phase II REEF-D trial[166]. Patients in the experimental arm will receive JNJ-3989 subcutaneous injection every 4 weeks along with a NA for 144 weeks while patients in the placebo comparator will receive a matching placebo with NA for 52 weeks followed by JNJ-3989 for 96 weeks.

VIR-2218 is an investigational N-acetylgalactosamine-conjugated RNA interference therapeutic that targets the region of HBV genome that is common to all viral transcripts and consequently silences all HBV viral RNAs. This is unlike NA therapy, which only inhibits a single viral target.[167] VIR-2218 was studied in a randomized, placebo-controlled phase I/II trial[168] with 82 patients with a maximum reduction of HBsAg until week 16 up to-1.5 log₁₀ IU/mL with no patients experiencing HBsAg loss. The promise of RNA interference therapy has spurred the phase II SOLSTICE trial[169] for 70 patients with CHD. This trial is currently in the recruitment phase. Patients will be administered VIR-2218 with VIR-3434 as monotherapy or in combination. VIR-3434 is an investigational subcutaneous monoclonal antibody that blocks entry of HBV and HDV into hepatocytes and removes virions from blood. SOLSTICE intends to measure changes in the Model for End Stage Liver Disease (MELD) and Child-Pugh-Turcotte (CPT) scores, hinting that patients with cirrhosis or advanced fibrosis will be included, lending relevance to its future findings.

15. Ropeg-IFNα 2b and immune checkpoint inhibitors

Ropeg-IFNα 2b (P1101) is a novel mono-pegylated IFN that is primarily a single homogeneous isomer that has been postulated to have lower adverse effects compared to standard PegIFN which contains 8–14 isomers[170, 171]. It also has a longer effective half-life with less frequent biweekly injections as a viable option[171]. It exerts its antiviral effect by directly inhibiting viral replication and modulation of immune response[171]. Ropeg-IFNα 2b has been studied in phase I and II trials for treatment of CHB[172] and chronic hepatitis C[171, 173]. Ropeg-IFNα 2b was granted EMA marketing authorization for polycythemia vera in 2019.

Immune checkpoint blockade is used in treatment of malignancies such as advanced melanoma, non-small cell lung cancer, and non-Hodgkin’s lymphoma by alleviating T-cell dysfunction[174]. In patients with CHB, inhibitory receptors such as the programmed death receptor (PD-1) are highly expressed in the liver[175]. Immune checkpoint inhibitors such as nivolumab (anti-PD-1) can reverse this process by blocking PD-1. The phase I/II CheckMate040 trial[176] is an open-label, dose escalation trial that assessed the safety and efficacy of nivolumab in patients with advanced HCC with or without HBV or HCV. The data was encouraging with a 15–20% objective responsive rates and substantial tumor reductions in setting of nivolumab[177]. The phase I A20–101 clinical trial[178] in Taiwan has begun recruitment of 20 patients with either CHB or CHD to assess safety and tolerability of sequential administration of P1101, nivolumab and entecavir.

The expert panel of the EASL position paper [179]on systemic treatment of HCC could not make a formal recommendation for the use of immune checkpoint inhibitors in patients co-infected with HBV and HDV. An individualized approach was suggested for patients provided there was no contraindication to concomitant treatment agents against HBV. A recent case report [180] of a patient with advanced HCC, HBV/HDV co-infection, and compensated cirrhosis received an immune checkpoint inhibitor combination of atezolizumab and bevacizumab with no safety concerns after six months of treatment. The patient had partial remission and even a slight decrease in HDV viral load from 290 copies/mL to 170 copies/mL at months 3 and 6.

16. Liver transplantation in HDV

Liver Transplantation (LT) is currently the only effective treatment option in terminal HDV disease[80, 181]. Nevertheless, patients with HBV/HDV infection have a high risk of recurrence of HBsAg recurrence than patients without HBV DNA (96% vs 29% at 2 years)[182]. This might be why the European Liver and Intestine Transplantation Association (ELITA) considers patients with HBV/HDV infection a “special population” (alongside patients with HCC and patients with high risk of poor adherence to antiviral therapy) meriting lifelong combination therapy of Hepatitis B Immunoglobulins (HBIg) and NAs[183]. A recent review by Ferenci et al acknowledged that data on HDV recurrence post LT is limited, however a review of small case series suggested that the recommendation of lifelong HBIg administration should be questioned especially accounting for cost and absence of controlled studies [184]. A retrospective German study[185] evaluated 36 patients who underwent LT for HBV/HDV associated end stage liver disease. 17 patients discontinued HBIg for various reasons and their graft function, liver biopsies, and overall survival was compared to patients receiving HBIg and NA combined therapy. After a median follow-up, recurrence was not significantly different in the standard vs discontinuation groups (21.1% vs 29.4%, P = 0.56). Adjusted survival was also not different after a median follow-up of 227 and 204 months respectively.

17. Expert opinion

HDV infection is an important global public health issue. The distribution of HDV infection has changed globally with the availability of HBV vaccination and patterns of human migration; industrialized nations are now describing lower rates of infection and HDV genotypes that were once geographically isolated are now appearing where they were not previously seen. As HDV infection is associated with an accelerated disease course and poor outcomes, the global community needs to agree upon a uniform HDV screening strategy so that we can improve our understanding of global prevalence and whom we will need to target new therapies when they become available. By expert opinion, all individuals who demonstrate a positive HBsAg test should undergo screening for HDV.

Historically, interferon-based therapy has been the backbone of therapy for all chronic viral hepatitis infections. As therapeutic research in HBV and HCV has progressed faster than HDV, we have seen less reliance on interferon today; Nucleos(t)ide analogues for HBV and direct antiviral therapy for HCV have largely replaced peginterferon α therapies. Although peginterferon α has never received US FDA approval for the treatment of HDV, it continues to be the backbone of HDV therapy today and is still recommended by professional liver societies. It is also the only therapy accessible in the US (albeit off label) for those infected with HDV. The main question related to peginterferon α monotherapy in HDV is whom to treat given the poor success rates. By expert opinion, individuals with HDV in the US who demonstrate advancement of liver disease could be given a course of peginterferon α monotherapy for 48 weeks provided they have not reached advanced levels of cirrhosis.

The experimental therapy pipeline in HDV is robust with various viral and host targets in various phases of investigation. In an endeavor that has been two decades in the making, some of these therapies will be arriving on the scene very shortly. Bulevirtide is in the midst of a phase III clinical trial which will likely provide substantial information regarding the proper use cases for this HDV therapeutic drug. It has also received approval for use in Europe by the EMA and is pending review by the US FDA, thus we have “real world” results for interpretation. Separately, Lonafarnib is being studied in the world’s first phase III clinical trial for HDV and preliminary results are expected within the next year. Notably, one of the arms of this multi-national clinical trial is in combination with peginterferon α which may suggest a continued use for interferon similar to the early days of HCV DAAs coming onto the scene. Thus, early HDV targeted therapies may continue to use peginterferon α for enhanced success.

Separately, exploration of novel combination therapies in HDV have begun. The early response rates of combining peginterferon λ with lonafarnib and ritonavir have substantive promise. Alternatively, Ropeg-IFNα 2b and nivolumab are being evaluated in a bid to minimize adverse effects of peginterferon α and borrowing from oncology literature to effectively attack the HDV life cycle. The precarious balance of efficacy and adverse effects suggests no single therapy will be sufficient to combat HDV that hijacks HBV machinery and accelerates progression to cirrhosis and hepatocellular carcinoma more than other chronic viral hepatitis infections. One early opportunity would be to test the combination of bulevirtide with lonafarnib with and without an interferon backbone given that these are the furthest along in the development pipeline.

It is amazing to see how far the field of HDV therapeutics has come since the turn of the century. Only about 5–10 years ago, clinicians were limited or had no options for their patients and had to hope that their patient could be enrolled in an HDV clinical trial. Now, we are on the horizon of several new therapies becoming available and accessible to patients who were previously faced with no good therapeutic options.

Article Highlights.

• New and improved hepatitis D screening and diagnostic tests have been developed, including those that can detect all genotypes.

• The epidemiology of hepatitis D infection is changing with the variability of hepatitis B vaccination implementation and patterns of human migration.

• There are no FDA-approved therapies against chronic hepatitis D infection, which accelerates cirrhosis and can lead to hepatocellular carcinoma. The traditional therapeutic approach towards chronic HDV infection of interferons was adopted from other chronic hepatitis viral infections. Interferons have significant adverse effects and a known late relapse off-therapy.

• Bulevirtide, an entry inhibitor, has been granted conditional marketing authorization by European Medicines Agency approval but has yet to be authorized for use in the United States.

• Several new investigational agents ranging from lonafarnib to immune checkpoint inhibitors are being studied against HDV, raising hopes for the availability of more effective therapies in the near future.