O VIRUS ESQUECIDO HEPATITE D

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Review Article JOURNAL OF CLINICAL AND EXPERIMENTAL HEPATOLOGY
The Forgotten Virus, Hepatitis D: A Review
of Epidemiology, Diagnosis, and Current
Treatment Strategies
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Adam Khattak *, Tahne Vongsavath *, Lubaba Haque *, Amrit Narwan *, Robert G. Gish *,y
*Department of Internal Medicine, Kirk Kerkorian School of Medicine at University of Nevada, Las Vegas, NV, USA and yHepatitis B Foundation,
Doylestown, PA, USA
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Hepatitis D virus (HDV) is an RNA subvirus that infects patients with co-existing hepatitis B virus (HBV) in-
fections. HDV burden is estimated to be approximately 15–20 million people worldwide. Despite HDV
severity, screening for HDV remains inadequate. HDV screening would benefit from a revamped approach
that automatically reflexes testing when individuals are diagnosed with HBV if HBsAg-positive, to total
anti-HDV, and then to quantitative HDV-RNA polymerase chain reaction (PCR) rather than only testing those
at high risk sequentially. There are no current treatments in the United States that are Food and Drug Admin-
istration (FDA)-approved for the treatment of HDV; however, bulevirtide (BLV) is approved in the European
Union conditionally and is under review with the United States FDA. Current treatment strategies in many
countries are centered on the use of pegylated-interferon-alfa-2a (PEG-IFNa-2a). There are other therapies
in development globally that have shown promise, including BLV, pegylated-interferon-lambda (PEG-IFN-
lambda), and lonafarnib (LNF). LNF has shown substantial response in the LOWR trials. BLV is a well-
tolerated drug, but it is not finite therapy and has shown significant on-treatment responses in the MYR clin-
ical trials, and the FDA cited concerns with the manufacturing and patient preparation of the drug that have
delayed approval. The PDUFA date for BLV in the United States is mid-2024. Current studies with both BLV
and LNF are limited in providing sustained virological response (SVR); future trials will need to demonstrate
more substantial SVR with possible triple combination trials as options. ( J CLIN EXP HEPATOL 2024;14:101395)
-
Hepatitis D virus (HDV) is an RNA subvirus that
infects those patients with co-existing hepatitis
B virus (HBV) infections. There are 2 modalities
s: hepatitis D virus, hepatitis B virus, bulevirtide, lonafarnib, inter-
2.1.2024; Accepted: 5.3.2024; Available online 9 March 2024
for correspondence: Robert G. Gish, Robert G. Gish Consultants,
22 La Jolla Mesa Drive, San Diego, CA, 92037, USA. Tel.: +1 866
7.
gish@robertgish.com
tions: AASLD: American Association for the Study of Liver Dis-
LT: alanine aminotransferase; APASL: Asian Pacific Association
tudy of the Liver; BID: twice daily; BLV: bulevirtide; CBC: com-
od count; EASL: European Association for the Study of the Liver;
ectronic medical record; EU: European Union; FDA: Food and
dministration; GI: gastrointestinal; HBcrAg: hepatitis B core-
ntigen; HBsAg: hepatitis B virus surface antigen; HBV: hepatitis
HCC: hepatocellular carcinoma; HCV: hepatitis C virus; HDV:
D virus; HDVAg: hepatitis D virus antigen; HGPS: Hutchin-
ord Progeria Syndrome; HIV: human immunodeficiency virus;
erferon; IgG: immunoglobin G; IgM: immunoglobin M; INR: in-
nal normalized ratio; LNF: lonafarnib; LT: liver transplantation;
4-me+thylbenzhydrylamine; NA: not available; NTCP: sodium
olate cotransporting polypeptide; PCP: primary care physicians;
lymerase chain reaction; PEG-IFN: pegylated interferon; POC:
-concept; QD: once daily; RTV: ritonavir; SVR: sustained virolog-
onse; TID: 3 times daily; TSH: thyroid-stimulating hormone
oi.org/10.1016/j.jceh.2024.101395
Indian National Association for Study of the Liver. Published by Else
JOURNAL OF CLINICAL AN
ite this article as: Khattak et al., The Forgotten Virus, Hepatitis D: A R
-end Journal, https://doi.org/10.1016/j.jceh.2024.101395
of HDV transmission: coinfection and superinfection. Co-
infection is when a person is simultaneously infected with
both HDV andHBV, while superinfection is when a patient
with chronic HBV later acquires HDV; each of these can
present as an acute or chronic infection. Coinfection typi-
cally results in more favorable outcomes in comparison to
superinfection, with most patients being able to clear the
viruses if they do not develop acute liver failure. Both
HBV/HDV coinfection and superinfection can cause rapid
progression towards hepatitis-related complications, such
as fulminant hepatitis, cirrhosis, liver cancer, liver trans-
plantation, and death. Outcomes are less favorable for su-
perinfection of HDV with a rate of progression to chronic
HDV of 40–90%, compared to about 2% in coinfection.1
Chronic HDV occurs when patients with HDV are
unable to clear the viral infection and eventually prog-
ress to longstanding liver issues including hepatocellu-
lar carcinoma (HCC) and cirrhosis.2 Anti-HDV
immunoglobulin M (IgM) at high titers is indicative
of either acute infection or highly active chronic HDV,
and falling levels may be indicative of resolution of
HDV.3 HDV IgM test results are not used in the clinic
today.
vier B.V. All rights reserved.
D EXPERIMENTAL HEPATOLOGY | - 2024 | Vol. 14 | No. 5 | 101395
eview of Epidemiology, Diagnosis, and Current Treatment Strategies, The
mailto:rgish@robertgish.com
https://doi.org/10.1016/j.jceh.2024.101395
http://crossmark.crossref.org/dialog/?doi=10.1016/j.jceh.2024.101395&domain=pdf
Table 1 HDV GenotypesWith Associated Number of Subtypes
and Countries of Prevalence.9
Genotype Number of
subtypes1
Countries of prevalence
1 5 Mongolia, Pakistan, Central Asia,
Nigeria, Ethiopia, Iran
2 2 Japan, Russia
3 3 Bolivia, Venezuela, Brazil
4 2 China, Japan
5 2 Nigeria, Guinea-Bissau
6 3 Cameroon, Nigeria, Central African
Republic
7 2 Cameroon
8 2 Republic of the Congo, Democratic
Republic of the Congo
HDV, hepatitis D virus.
1Subtypes are still not completely certain and remain under debate.
THE FORGOTTEN VIRUS KHATTAK ET AL
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BACKGROUND
HDV infection currently affects approximately 15–20
million people worldwide. This represents �5% of people
infected with HBV.4 In previous years, estimates of global
disease burden significantly varied. For example, estimates
were noted to be approximately 48–60 million in 2018 and
62–72 million in 2019, but these numbers most likely
reflect testing at tertiary care centers. In 2020, this number
was drastically different: 12 million, thought to be a more
accurate estimate.5 The HDV landscape has evolved with
the presence of new tests and new treatment options, in-
crease in HBV vaccination rates, and, on a less positive
note, lack of consistent screening strategies and access to
tests. Hepatology societies have recommended different
ways of approaching HDV screening. To complicate things
further, screening for HDV is extremely inconsistent and at
times, largely ignored, in different countries and centers,
and by some providers.
HDV uses the hepatitis B virus surface antigen (HBsAg)
as its envelope protein. As a result, it can only infect those
individuals and liver cells with HBV infections. It enters he-
patocytes within the HBsAg envelope protein and pro-
duces the HDV antigen (HDVAg), which helps promote
viral RNA replication and assembly of HDV virion particles
for export within the HBsAg.6 The large antigen is involved
in viral release and has a negative effect on replication. It is
well-known that HDV/HBV infection results in a higher
rate of HCC compared to HBV or hepatitis C virus
(HCV) infection alone. The specific molecular mechanism
behind this oncogenesis is largely unknown. However, it
has been hypothesized that HDV can alter many cellular
signaling pathways involved in inflammation, apoptosis,
oxidative stress, and proliferation, whichhttp://refhub.elsevier.com/S0973-6883(24)00052-5/sref33
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	The Forgotten Virus, Hepatitis D: A Review of Epidemiology, Diagnosis, and Current Treatment Strategies
	Background
	Virology
	HDV Diagnosis and Screening
	HDV Transmission
	HDV Diagnosis
	HDV Screening
	Purpose of This Review
	HDV Disease Progression and Prevention
	Progression to Cirrhosisand Hepatocellular Carcinoma/Liver Failure
	Liver Transplant
	Prevention/Vaccination
	Current Treatment Strategies for HDV
	Pretreatment Evaluation
	Who to Treat
	Current Therapies
	Available Therapy: PEG-IFN-2a
	Dosing and Administration
	Monitoring While Receiving Treatment
	Efficacy
	Available Therapy: Nucleoside/Nucleotide Analogs
	Experimental Therapies
	REP 2139 – Replicor NAPS Compounds
	Mechanism of Action
	Current Studies
	Future Directions
	PEG-IFN-Lambda
	Mechanism of Action
	Comparison to PEG-IFNa-2a
	VIR-2218 and VIR-3434
	Emergent Treatments for HDV
	Bulevirtide
	Mechanism of Action
	MYR Clinical Trials
	European Union Studies
	Ongoing Trials
	Safety and Adverse Reactions
	Manufacturing and FDA Approval
	Lonafarnib
	Mechanism of Action
	Monotherapy vs Combination Therapy Trials
	Ongoing Trials
	Adverse Reactions
	Summary
	Future Directions for Treatment in HDV
	Credit authorship contribution statement
	Conflicts of interest
	Acknowledgments
	Funding
	Referencescan thereby result
in oncogenesis by modifying cellular expression.7 Interest-
ingly, there have been recent studies suggesting that HDV
could be transmitted via other viruses, such as the West
Nile, dengue, or even hepatitis C viruses. These data have
not been supported clinically. Given the prevalence of
HCV, the transmission of HDV via HCV envelope proteins
were of interest; however, these studies were largely incon-
clusive.8
Detection of HDV with routine serologies is currently
limited to the detection of total anti-HDV antibodies,
which includes immunoglobin G (IgG) and IgM, and
HDV-RNA polymerase chain reaction (PCR) quantifica-
tion. Total HDV antibody is the key test to screen for
HDV exposure and subsequent linkage to HDV-RNA
quantification, if positive, to prove active HDV infection.
HDV remains endemic in many parts of the world but is
particularly found in those with lower average socioeco-
nomic regions. These include Central Asia, certain islands
in Oceania, West Sub-Saharan Africa, Eastern Europe, up-
per Amazonia, and the Orinoco River Valley, as well as
Pakistan.9,10 Interestingly, the true prevalence of HDV in
2 © 2024 Indian National Associa
Please cite this article as: Khattak et al., The Forgotten Virus, Hepatitis D: A R
End-to-end Journal, https://doi.org/10.1016/j.jceh.2024.101395
the United States or India is not clearly known due to
lack of access to testing and diagnosis.2 Distribution of
HDV may also be dependent on the 8 different genotypes
that have been published (shown in Table 1). Appropriate
characterization of these genotypes is paramount as each
one is associated with a different level of pathology, clinical
presentation, and treatment response.9,11
Currently, HDV genotype 1 is the most common glob-
ally. This is likely due to prolonged transmission world-
wide. Genotypes 2 and 4 are mainly located in Asia,
genotype 3 is located in South America, and genotypes
5–8 are mostly found in parts of Africa.11 Table 1 summa-
rizes these genotypes with their associated subtypes and
common country of detection. Approximately 81–89% of
the genotypes’ nucleotide sequences are homogenous,
with up to a 35% disparity amongst them.12
Virology
HDV is a circular, single-stranded RNA genome that is the
smallest known pathogenic virus, being about 35–41 nm in
diameter and composed of 3 elements: the RNA genome,
HDVAg, and the HBsAg envelope protein. HDV (wrapped
in HBsAg) enters hepatocytes through the sodium tauro-
cholate cotransporting polypeptide (NTCP), where HDV-
RNA is replicated through a rolling circle mechanism. A
unique feature about this virion is that it has a self-
cleaving ribozyme, which does not necessitate the assis-
tance of cellular host enzymes to cleave itself into both
genomic and antigenomic strands.10
To replicate, HDV's genome is copied by host DNA-
dependent RNA polymerases to produce the viral RNA as
if it were cellular DNA. This results in 2 species of HDVAg,
which include a smaller 24-kDA and a larger 27-kDa
HDVAg, abbreviated as ‘small HDVAg’ and ‘L-HDVAg’,
tion for Study of the Liver. Published by Elsevier B.V. All rights reserved.
eview of Epidemiology, Diagnosis, and Current Treatment Strategies, The
JOURNAL OF CLINICAL AND EXPERIMENTAL HEPATOLOGY
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respectively. Small HDVAg promotes genome replication
while L-HDVAg promotes virion packaging while simulta-
neously inhibiting replication. Post-translational, site-spe-
cific farnesylation is a required step for HDV-RNA to
interact with HBsAg in virion assembly after prenylation.4
HDV DIAGNOSIS AND SCREENING
HDV Transmission
HDV is mainly spread through exposure to infected blood
and body fluids similar to HBV although pregnancy-
related transmission is rarer. Therefore, it may be spread
via needle sharing, shared use of razors or toothbrushes,
and unprotected sexual encounters. Intravenous drug
users, human immunodeficiency virus (HIV)-infected indi-
viduals, men who have sex with men, and those from
endemic areas are all at high risk for acquiring HDV coin-
fection or superinfection. Rarely, it can transmit from in-
fected mother to fetus in utero or birth due to low levels
of HBV. HDV can be either transmitted with HBV simulta-
neously, called coinfection, or it can infect those with
chronic HBV, called superinfection. Approximately 2% of
coinfections and over 90% of superinfections become
chronic conditions. Superinfection and coinfection can
lead to more severe hepatitis with a rapid progression to
liver failure, or fulminant hepatitis, and HCC. Coinfection
less commonly results in acute liver failure but also has a
high chance of HDV spontaneous clearance.13
HDV Diagnosis
Diagnosis is made through serologic testing. Due to its
dependence on HBV, HBsAg positivity is necessary for
the consideration of HDV infection. The presence of IgM
antibody to hepatitis B core antigen (IgM anti-HBc) con-
firms the diagnosis of acute HBV and HDV coinfection
differentiating it from HDV superinfection, which would
be negative for IgM anti-HBc. Patients with acute coinfec-
tion and superinfection will also have high titers of HDV-
RNA detected by reverse transcription polymerase chain re-
action (RT-PCR). In HDV coinfection, elevated HDV-RNA
titers will be transient at presentation, whereas HDV super-
infection will have HDV-RNA titers that continue to rise
over time as chronic infection evolves. If HDV-RNA RT-
PCR is unavailable, total/IgM anti-HDV can be used
instead to document HDV exposure and subsequent sero-
conversion. Patients with HDV superinfection may have a
persistent and climbing total/IgM anti-HDV, whereas
HDV coinfected patients will only have a transient increase
in antibody as HDV is commonly cleared in this setting.14
HDVAg has a fleeting presence in the bloodstream dur-
ing acute infection and is therefore not a reliable marker of
active HDV infection and is not used clinically. Further-
more, HDVAg cannot be detected in chronic HDV infec-
tion since it is complexed with anti-HDV antibodies. In
JOURNAL OF CLINICAL AND EXPERIMENTAL HEPATOLOGY | - 2024 | Vol.
Please cite this article as: Khattak et al., The Forgotten Virus, Hepatitis D: A R
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this situation, immunoblot assays can become useful,
but this is much more time- and labor-intensive and is
reserved for research purposes.15
The IgM antibody test was developed as a test for
acute HDV infection but has little clinical role today.
Both IgM and IgG can be detected with serologic testing,
although commercial anti-HDV IgM assays are not
currently clinically available for use globally or in the
United States.16 Anti-HDV IgM usually appears between
the first and third weeks after infection and remains pos-
itive in the chronic phase with fluctuating levels depend-
ing on disease activity.11 Anti-HDV IgM is usually only
detected for 2 months after an acute infection; however,
it may be present for up to 9 months in superinfection.17
Increased levels of IgM are also thought to be associated
with more active HDV-related disease in patients with
chronic HDV, specifically the level of viral replication
and liver inflammation. There may also be a relation to
response to interferon (IFN) treatment.3 Hepatitis B
core-related antigen (HBcrAg) and HBV RNA are 2
HBV-derived biomarkers that are currently under study
as potential serologic markers for HDV activity.3
The European Association for the Study of the Liver
(EASL) Clinical Practice Guidelines published in August
2023 recommend using anti-HDV IgM as a surrogate
marker for chronic HDV detection. Of note, it should
not be used to detect viral replication activity.18 It usually
disappears in patients who have persistent remission after
IFN therapy and following liver transplant. Anti-HDV IgG
is detectable during both active and resolved infection, so it
is a useful marker for detecting prior infection. Total anti-
HDV antibody levels are useful clinically as this is a core
test result that is returned when a providerorders delta
screening tests. Its level correlates with ongoing HDV repli-
cation, although commercial labs do not report a titer or
level.13 HDV-RNA PCR quantification is the most useful
test to confirm the number of active copies of the virus
in the blood or serum and is often a way to determine if tar-
geted treatment is working.11
Aside from serologic markers, markers from liver tissue
are also available for detecting HDV. Both HDVAg and
HDV-RNAcanbedetected for histopathologic examination.
HDVAg is detected primarily by direct immunofluorescence
or immunohistochemistry and was initially the “gold stan-
dard” of diagnosing current HDV infection extending for
several years. However, this was refuted when it was discov-
ered that levels of HDV replication do decrease with time.19
Thus, those with negative HDVAg tissue marker results
need to be concurrently tested for serologic HDV-RNA or
anti-HDV antibodies. HDV-RNA can be detected in the tis-
sue as well, but this practice is not recommended for clinical
purposes given its time-consuming nature.20
Table 2 summarizes common HDV serologic tests and
their interpretations.
14 | No. 5 | 101395 3
eview of Epidemiology, Diagnosis, and Current Treatment Strategies, The
Table 2 Common HDV Serologic Tests and Interpretations in Different Clinical Scenarios.1,2
Serologic marker HBV/HDV
coinfection
HBV/HDV
superinfection
Chronic HDV
infection
HBsAg + + +
Anti-HBc IgM + – –
HDVAg + (early, short-lived,
often missed)
+ (early, short-lived,
often missed)
Undetectable
HDV-RNA + (early, transient) + (rapidly increasing
titers)
+
Anti-HDV, IgM + (transient) + (rapidly increasing titers,
persistent)
+ (usually low)
HBsAg, hepatitis B virus surface antigen; HBV, hepatitis B virus; HDV, hepatitis D virus; HDVAg, hepatitis D virus antigen; IgM, immunoglobin M.
1Table adapted from Negro F, Lok ASF. Epidemiology, clinical manifestations, and diagnosis of hepatitis D virus infection. UptoDate website. Updated
May 1, 2023. Accessed October 22, 2023. https://www.uptodate.com/contents/epidemiology-clinical-manifestations-and-diagnosis-of-hepatitis-d-
virus-infection.21
2Total anti-HDV antibody not included in this table due to its low clinical value when only tested for once. Anti-HDV IgM testing currently not available in
the United States.
THE FORGOTTEN VIRUS KHATTAK ET AL
-
-
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HDV Screening
When a provider orders a screening HDV test, it is primar-
ily made up of testing for total anti-HDV antibodies. If the
antibody screening test is positive, this is then followed up
with HDV-RNA quantification by PCR for confirmation.
Despite the severity of HDV coinfection or superinfec-
tion, screening remains inadequate. Screening is lacking
not only in resource-poor countries, but in resource-rich
countries like the United States. In a recent retrospective
study that evaluated screening efforts of patients with
chronic HBV for HDVwithin a tertiary center in the United
States, only 1444 of 11,190 patients with chronic HBV were
screened for the delta virus.22 Part of the reason is because
different hepatology societies have recommended different
approaches to HDV screening. Both the EASL and the
Asian Pacific Association for the Study of the Liver
(APASL), for example, recommend routine HDV screening
amongst all carriers of HBsAg. However, the 2018 guide-
lines from the American Association for the Study of Liver
Diseases (AASLD) only recommends screening in those
with HBV-DNAwith
several adverse events. This review aims to educate
PCPs, gastroenterologists, and hepatologists not only
about HDV and its currently available treatment, but
experimental and emerging treatments that are in pro-
cess. One of these newer agents for HDV, bulevirtide
(BLV), has been evaluated by the FDA, and a complete
response letter was submitted to change manufacturing
locations and simplify the preparation and injection
process. Lonafarnib (LNF) is a promising oral agent
that has completed a phase 3 clinical trial. Lambda inter-
feron development was recently halted due to adverse
events in the phase 3 HDV study. We hope that this re-
view provides useful information on these therapies so
that both PCPs and specialists feel comfortable knowing
what to anticipate from prescribing them in the future.
HDV DISEASE PROGRESSION AND
PREVENTION
Progression to Cirrhosis and Hepatocellular
Carcinoma/Liver Failure
Approximately 70–90% of individuals with HDV superin-
fection progress to chronic HDV and more severe pathol-
ogy. Recent meta-analysis has shown that HDV will
progress to cirrhosis in 5 years and HCC in 10 years.9 A
study by European Concerted Action on Viral Hepatitis
showed that the risk for HCC in HDV/HBV is 13% in com-
parison to 2–4% for HBV monoinfection.5
JOURNAL OF CLINICAL AND EXPERIMENTAL HEPATOLOGY | - 2024 | Vol.
Please cite this article as: Khattak et al., The Forgotten Virus, Hepatitis D: A R
End-to-end Journal, https://doi.org/10.1016/j.jceh.2024.101395
Given the propensity of progression to cirrhosis and
liver failure in patients living with HDV, it is the deadliest
hepatitis virus with the highest mortality rate at 20%.5
Liver Transplant
Given the scarcity of efficacious HDV treatments currently
available, liver transplantation (LT) remains the “gold stan-
dard” treatment for patients suffering from associated end-
stage liver disease. LT in HDV-related cirrhosis was first
used as a treatment option in Italy in 1987. Initial reports
in the early 1990s showed high rates, up to 80%, of HDV
recurrence after LT in studies from Italy andBelgium.How-
ever, HBV recurrence was confirmed to have a role bymulti-
center surveys performed in 1993. Thereafter, the
implementation of prophylaxis treatment after LT with
long-term immunoglobulins against HBsAg (HBIG) com-
bined with nucleoside analogs has seen a dramatic decrease
in recurrence: as low as 0–10% at 1–2 years after LT. In a Tu-
rin study, the majority of HDV-infected patients receiving
an LT from 2000 to 2019 were doing so for HDV-related
liver failure, rather than HCC.24 Patients who have had
LT have demonstrated good outcomes: a study in Brazil
had an 88% 5-year survival rate following LT.25
Prevention/Vaccination
The estimates of HDV prevalence are vastly underesti-
mated partly due to not having a standard for screening
globally. Current preventive strategies are targeted at
HBV immunization, administration of injections safely,
reduction of risky behaviors, and appropriately timed anti-
viral prophylaxis in pregnant women.
CURRENT TREATMENT STRATEGIES FOR
HDV
Pretreatment Evaluation
Patients under consideration for treatment should be pre-
evaluated with HDV-RNA and transaminase levels ob-
tained as well as biopsy for cirrhosis or non-invasive
fibrosis testing, as well as evaluation of HBV.26 Pre-
evaluation of HBV include HIV screening, HCC screening
if indicated, other etiology of liver disease, as well as base-
line blood work including liver enzymes (aspartate trans-
aminase, ALT, alkaline phosphatase, and gamma-
glutamyltransferase) and liver function tests (formerly
referred to as “LFTs”), and bilirubin, albumin, and coagu-
lation laboratory tests (INR).27
Who to Treat
Individuals with chronic HDV with detectable HDV-RNA
and with or without advanced fibrosis or cirrhosis are
14 | No. 5 | 101395 5
eview of Epidemiology, Diagnosis, and Current Treatment Strategies, The
Ta
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THE FORGOTTEN VIRUS KHATTAK ET AL
6 © 2024 Indian National Associa
Please cite this article as: Khattak et al., The Forgotten Virus, Hepatitis D: A R
End-to-end Journal, https://doi.org/10.1016/j.jceh.2024.101395
-
-
-
eligible for treatment. Using elevated ALT and/or chronic
hepatitis by biopsy is being replaced by a treat-all
approach.
Current Therapies
Table 3 briefly summarizes current treatment options,
some of which are explored further in this article.
AVAILABLE THERAPY: PEG-IFN-2A
Dosing and Administration
Though not officially indicated for HDV treatment, PEG-
IFN-2a is the only available option in most countries.
Treatment typically includes 180 mcg subcutaneously
administered on a weekly basis for 48 weeks.
Monitoring While Receiving Treatment
Patients undergoing treatment should be assessed for
biochemical response as well as virological response during
and after completion of treatment.33 Continual moni-
toring for toxicity related to treatment should also be
done. Pregnancy testing should be done at each interval
when applicable to the patient. Table 4 summarizes recom-
mendations on how to monitor patients receiving PEG-
IFN-2a treatment.
Efficacy
Early studies found that treatment with PEG-IFNa-2a as
monotherapy or in combination with adefovir cleared
HDV-RNA from serum 24 weeks after the end of therapy
in 28% of patients.28 In 2019, clearance of HDN-RNA
was seen in 39% of patients treated with PEG-IFN-2a com-
bined with tenofovir and in 31% of patients treated with
PEG-IFN-2a alone.34
AVAILABLE THERAPY: NUCLEOSIDE/
NUCLEOTIDE ANALOGS
Nucleoside/nucleotide analogs are generally recommen-
ded in combination with PEG-IFN-2a rather than as
monotherapy in patients with chronic HDV to completely
suppress HBV replication. They should only be used in
the management of concomitant HBV. Monotherapy
had no effect on HDV replication in general, although
there may be a hint of activity in patients with concomi-
tant HIV/HBV/HDV tri-infection. In studies where pa-
tients were treated with combination PEG-IFNa-2a and
nucleoside/nucleotide analog vs monotherapy with a
PEG-IFNa-2a control group, overall virological response
was observed withoutany differences in the 2 arms, sug-
gesting that there was no added significant benefit in use
of nucleoside/nucleotide analogs plus PEG-IFNa-2a when
compared to PEG-IFNa-2a alone as the standard of
care.34
tion for Study of the Liver. Published by Elsevier B.V. All rights reserved.
eview of Epidemiology, Diagnosis, and Current Treatment Strategies, The
Table 4 PEG-IFN-2a Recommendations for Monitoring.
Timing* CBC Hepatic Panel Creatinine Glucose INR HDV-RNA HBV-DNA Serum HBsAg TSH
Baseline * * * * * * * * *
Week 4 * * *
Week 12 * * * Optional Optional
Week 24 * * * * * * * *
Week 48 * * * * * * * *
Week 12 after treatment * * * Optional Optional
Week 24 after treatment * * * * * * *
Week 48 after treatment * * * * * * * *
CBC, complete blood count; HBsAg, hepatitis B virus surface antigen; HBV, hepatitis B virus; HDV, hepatitis D virus; HDVAg, hepatitis D virus antigen;
INR, international normalized ratio; TSH, thyroid-stimulating hormone.
*Recommend ordering.
JOURNAL OF CLINICAL AND EXPERIMENTAL HEPATOLOGY
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EXPERIMENTAL THERAPIES
REP 2139 – Replicor NAPS Compounds
Mechanism of Action
REP 2139 works by blocking the release of subviral parti-
cles from covalently closed circular DNA and integrated
HBV-DNA.30
Current Studies
A number of phase 2 studies have been completed
including 12 patients with chronic HDV infection. Patients
were given 500mg REP 2139 intravenously once weekly for
15 weeks, then treated with combination therapy of
250 mg REP 2139 intravenously and 180 mcg PEG-IFNa-
2a subcutaneously once weekly for 15 weeks or monother-
apy with 180 mcg PEG-IFNa-2a intravenously for 33
weeks. Most responses came during the treatment period
when PEG-IFNa-2a was used. Of the 12 patients, 8 had
suppressed HDV levels, 7 were HDV-RNA-negative, and 5
seroconverted from HBsAg to anti-HBs antibody. Howev-
er, flares were reported.30
Future Directions
While it does show utility, REP 2139 is also related to eleva-
tion in liver enzymes, and further studies are needed to
evaluate flares in use of REP 2139 and other replication in-
hibitor compounds. Studies using another replicator com-
pound known as REP 102 were also associated with
hepatitis flares. Flares have been reported in REP 2139,
but there have been no related incidences of liver failure
or elevated bilirubin. There are many more REP studies
including subcutaneous formulations, such as REP 2139-
Mg, which prevents injection-site reactions and avoids
intravenous administration. Compassionate access in Eu-
rope has allowed patients to be treated with it, and it has
been generally well tolerated and safe in patients with
compensated and decompensated cirrhosis. Further, up-
coming phase 2 trials in the use for HBV and HDV infec-
JOURNAL OF CLINICAL AND EXPERIMENTAL HEPATOLOGY | - 2024 | Vol.
Please cite this article as: Khattak et al., The Forgotten Virus, Hepatitis D: A R
End-to-end Journal, https://doi.org/10.1016/j.jceh.2024.101395
tion will likely transition to this subcutaneous
formulation. Phase III studies would be the path to
approval. While NAPS do show utility, there is no current
clear development path forward that is in the public
domain and further evaluation of the overall safety profile
of virion secretion inhibitors such as REP 2139 are needed.
PEG-IFN-Lambda
Mechanism of Action
PEG-IFN-lambda works by using downstream signaling
pathways leading to induction of antiviral activity; however,
it expresses preferentially at type III receptors in hepatocytes,
inducing lesser adverse events than its alpha counterpart.29
Comparison to PEG-IFNa-2a
In the LIMT-1 Phase 2 Study, 36% of patients treated with
PEG-IFN-lambda for 48 weeks achieved undetectable
HDV-RNA 24 weeks after completing therapy, compared
to 29% of patients who received PEG-IFN-2a and achieved
this. This study was subject to discontinuation due to
cholestatic liver injury. Further, while tolerable to a major-
ity, it was associated with increased levels of jaundice and/
or ALT flares, with grade 3 and 4 adverse events, especially
in the Pakistani population.
Use of PEG-IFN-lambda in patients with chronic HDV
showed utility in viral logarithmic reductions. However,
the phase 3 study by Eiger BioPharmaceuticals, Inc., was
discontinued due to recommendations of the Data Safety
Monitoring Board. Four participants reported hepatobili-
ary adverse events leading to liver decompensation.
VIR-2218 and VIR-3434
VIR-2218, is an investigational product using short inter-
fering, or silencing, RNA (siRNA) to target the HBV genome
at the regionofHBx, an enhancer protein that is required for
replication of the virus. VIR-3434 is an Fc-engineeredmono-
clonal antibody that targets the antigen loop of HBsAg that
is present on virions of both HBV and HDV. A phase 2 trial
14 | No. 5 | 101395 7
eview of Epidemiology, Diagnosis, and Current Treatment Strategies, The
THE FORGOTTEN VIRUS KHATTAK ET AL
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was performed, called theMARCH trial, which evaluated the
safety and efficacy of VIR-2218 with VIR-3434 in patients
with chronic HBV infection. The results showed that the
mean HBsAg had a 2.7–3.1 logarithmic reduction with
90% of the patients having mean HBsAgwhile the pa-
tients in the 5 mg combination group showed a sustained
response in 4 of 15 patients. This was the first trial to
demonstrate the curative potential of BLV combination
therapy.
MYR-204 was a multicenter phase 2b trial that also eval-
uated the safety and efficacy of BLV asmonotherapy and in
combination with PEG-IFN.41 Once again, there were
higher rates of HDV-RNA decline in the combination ther-
apy groups compared to the monotherapy groups. The
virological response was as high as 34% in the 10 mg com-
bination group and as low as 4% in the BLV monotherapy
group. This trial showed an improved response in the
higher dose (10 mg) combination group at 34%, compared
to the lower dose (2 mg) combination group at 24%. Given
the MYR-203 trial as context, this could be an argument
that the ideal dose of BLV is 5 mg in combination therapy.
MYR-301 was a phase 3 multicenter study evaluating
treatment with BLV as delayed therapy in comparison to
daily dosing with 2 mg or 10 mg.42 This trial, like the
MYR-202 trial, did not show a dose-dependent response.
Although the treatment lengths were longer, the virolog-
ical responses were minimal, with the highest at 8% in
the 10 mg BLV monotherapy group.
European Union Studies
Following the European Union approval of use of BLV in
July of 2020, 5 studies were released studying its efficacy
in France, Italy, Austria, and Germany. The studies’ find-
ings are summarized in Table 6.
The study performed in France began in 2019 and eval-
uated the use of BLV and PEG-IFN as monotherapy
compared to combination therapy.43 The BLV monother-
apy group demonstrated a 39% virological response, while
the combination group showed a much better response at
85%. This study demonstrated real-world results that
showed better virological response in combination therapy
compared to monotherapy, consistent with the MYR clin-
ical trials. Importantly, virological response was sustained
in 20% of the patients.
BuleDelta is an observational study in France that also
evaluated the use of BLV monotherapy and combination
therapy with PEG-IFN.44 After 24 weeks of therapy, results
are consistently showing an improved virological response
in the combination therapy group at 44%, compared to 8%
tion for Study of the Liver. Published by Elsevier B.V. All rights reserved.
eview of Epidemiology, Diagnosis, and Current Treatment Strategies, The
Table 5 Bulevirtide MYR Clinical Trials.31
MYR-20138 MYR-20239 MYR-20340 MYR-20441 MYR-30142
Patients, n 24 118 90 175 150
Treatment BLV + PEG-IFN dosing and safety BLV + tenofovir
dosing optimization
BLV + PEG-IFN, monotherapy
vs combination
BLV + PEG-IFN, monotherapy
vs combination
BLV + PEG-IFN
� tenofovir, monotherapy
vs combination
Length, weeks 24 24 48 96 240
Cirrhosis, % NA 50 17 34 47
ALT mean, IU/mL NA 116 119 114 111
HDV-RNA mean, IU/mL NA 5.3 5.6 5.3 5.0
Results Combination therapy,
undetectable HDV-RNA: 5/7 patients
BLV virological response
at 24 weeks:
2 mg/day, 50%;
5 mg/day, 44%;
10 mg/day, 73%
Combination therapy, undetectable
HDV-RNA at 72 weeks:
5 mg, 8/15 patients;
10 mg, 4/15 patients
Undetectable HDV-RNA at
24 weeks: PEG-IFN
monotherapy, 13%;
2 mg combination therapy, 24%;
10 mg combination therapy, 34%;
BLV 10 mg monotherapy, 4%
Undetectable HDV-RNA at
48 weeks: BLV 10 mg
monotherapy
control, 0%;
BLV 2 mg monotherapy,
6%; BLV 10 mg
monotherapy, 8%
SVR NA None 5 mg group,
4/15 patients;
10 mg group, none
NA NA
ALT, alanine aminotransferase; BLV, bulevirtide; HDV, hepatitis D virus; NA, not available; PEG-IFN, pegylated interferon; SVR, sustained virological response (HDV-RNA clearance 24 weeks after
treatment completed), virological response, $2 logarithmic decline HDV-RNA or undetectable HDV-RNA.
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THE FORGOTTEN VIRUS KHATTAK ET AL
10 © 2024 Indian National Associa
Please cite this article as: Khattak et al., The Forgotten Virus, Hepatitis D: A R
End-to-end Journal, https://doi.org/10.1016/j.jceh.2024.101395
-
-
-
in the monotherapy group. The results are preliminary as
the study is ongoing. About half of the reported severe
adverse events are represented by bile acid elevations.
The Italy study is from a single center that evaluated the
use of BLV monotherapy.45 Remarkably, virological
response was identified in 83% of patients. However, the
study is limited due to only having 18 patients.
The Austrian study evaluated BLV in combination with
PEG-IFN.46 This study is also limited by its study popula-
tion of only 15 patients. Twenty-seven percent of the pa-
tients were able to achieve virological response with
undetectable HDV-RNA; however, there was no significant
change in HBsAg levels. Two patients had their treatment
discontinued after 6 months; 1 achieved SVR for at least 20
weeks thereafter.
Finally, the German study evaluated 8 patients treated
with BLV in combination with tenofovir.47 The dose of
BLV was 2 mg/day for 16 weeks. The study showed a 0.5
logarithmic drop in HDV-RNA levels. There were no signif-
icant side effects, apart from the usual asymptomatic rise
in bile acids.
Ongoing Trials
Although current studies in the United States are inactive,
there are an ample number of investigator clinical trials
that are currently underway. A United States phase 1 trial
studying the pharmacokinetics of BLV in patients with
normal and impaired liver function anticipates finishing
in February of 2025.48
Safety and Adverse Reactions
BLV is generally a well-tolerated drug, with support from
the MYR trials and European Union studies that have
extensively studied the drug.31 There was no adverse event
serious enough to lead to drug discontinuation. A dose-
dependent reversible elevation in bile acids was well-recog-
nized across studies; however, they typically did not result
in symptoms and there were no signals of cardiac toxicity.
Mild and short-lasting dose-dependent injection-site reac-
tions were also notable in the MYR trials. Recently there
were two reported cases of hypersensitivity reactions;how-
ever, in both cases, patients were able to continue the treat-
ment.49 Other minor adverse events include nausea,
headache, and cytopenia without pruritus.
Manufacturing and FDA Approval
BLV is a daily injectable drug that is manufactured by a
process called solid phase peptide synthesis on a 4-
methylbenzhydrylamine resin to obtain the crude pep-
tide mixture that is then washed and prepared in a series
of steps.50 Gilead acquired the drug in December 2020
for a total cost of $1.4 billion in the acquisition of the
company MYR GmbH. The US FDA declined to have
BLV's approval in October of 2022, the second time it
was declined within an 8-month period.51 The FDA cited
tion for Study of the Liver. Published by Elsevier B.V. All rights reserved.
eview of Epidemiology, Diagnosis, and Current Treatment Strategies, The
Table 7 Summary of 5 Phase 2 Lonafarnib Clinical Studies.
POC study32 LOWR-HDV-152 LOWR-HDV-253 LOWR-HDV-354 LOWR-HDV-455
Publication year 2015 2018 2017 NA 2021
Authors Koh et al. Yurdaydin et al. Yurdaydin et al. Koh et al. Yurdaydin et al.
Patients, n 14 15 58 21 55
Study 8 patients:
LNF 100 mg BID;
6 patients:
LNF 200 mg BID
5 groups:
LNF 200 mg BID for 12
weeks,
LNF 300 mg BID for 12
weeks,
LNF 100mg TID for 5 weeks,
LNF 100 mg BID + PEG-IFN
180 mg Q1W
for 8 weeks, and LNF
100 mg BID + RTV
100 mg QD for 8 weeks
Phase 2 dose-optimization
study. 3 groups:
LNF $75 mg BID + RTV for
12 weeks,
LNF 25/50 mg BID + RTV for
24 weeks, and combination
LNF 25/50 mg
BID + RTV + PEG-IFN for 24
weeks
Phase 2
6 groups;
LNF 50 mg +
RTV 100 mg,
LNF 75 mg +
RTV 100 mg,
LNF 100 mg +
RTV 100 mg for 24 weeks;
placebo for 12 weeks,
followed by:
LNF 50 mg +
RTV 100 mg,
LNF 75 mg +
RTV 100 mg, and LNF
100 mg +
RTV 100 mg
Phase 2 dose-finding study.
3 groups:
LNF $75 mg BID + RTV for
12 weeks, LNF 25/50 mg
BID + RTV for 24 weeks, and
combination LNF 25/50 mg
BID + RTV + PEG-IFN for 24
weeks
Results 0.73 and 1.54
logarithmic declines in
average
serum HDV-RNA values,
respectively
RTV and PEG-IFN addition
resulted in better
antiviral response and fewer
adverse events
than LNF alone
60–78% normalized ALT
levels at 24 weeks; triple
therapy with best response:
60% PCR-negative at
24 weeks, 40% PCR-
negative 24 weeks after
treatment; double therapy at
25/50 mg BID
dose: 1 patient PCR-
negative at 24 weeks
6 patients:
HDV-RNA 2 logarithmic decline: 24/26 patients;
undetectable HDV-RNA levels/below lower limit of
quantification: 20/26 patients
interferon; PEG-IFNa-2a, pegylated-interferon-alfa-2a; RTV, ritonavir.
tion for Study of the Liver. Published by Elsevier B.V. All rights reserved.
eview of Epidemiology, Diagnosis, and CurrentTreatment Strategies, The
JOURNAL OF CLINICAL AND EXPERIMENTAL HEPATOLOGY
tolerated as BLV. Notably, there was 1 reported death in the
LNF trial with PEG-IFN, and 5 patients in the LOWR-
HDV-1 study who discontinued treatment because of
poor tolerability to its adverse events. These adverse events
should be watched closely as the drug is studied further.
Overall, BLV is a proven and well-tolerated drug that re-
quires maintenance dosing. In comparison to LNF, it is
finite treatment with a defined on- and off-treatment
SVR rate and will hopefully move forward to clinical
approval. However, there are still concerns regarding its
manufacturing and delivery of BLV that still need to be ad-
dressed and finalized with the FDA. LNF has also shown
incredible results, as a combination therapy; however, its
tolerability is a question that may limit its use in the
real-world setting in some patients.
-
-
-
FUTURE DIRECTIONS FOR TREATMENT IN
HDV
There are many clinical trials underway for the treatment
of HDV that include siRNAs, BLV, LNF, PEG-IFN, and
REP 2139. The future directions for the treatment of
HDV are certainly promising. As previous trials have
shown, these treatments are showing efficacy with virolog-
ical and biochemical response to the drugs. The key, how-
ever, is ensuring that SVR is optimized as that has been the
most difficult part to sustain in these previous trials. Life-
long treatment with these novel therapeutics could be
considered if further studies do not show good SVR.
The Solstice's trials exploration of VIR-2218, a siRNA,
and VIR-3434 in the treatment of HDV is a promising
exploration with great results in vivo and in vitro, but its
adaptation to humans is yet to be seen. The first poster pre-
sentation for its results in preclinical models was shown on
November 10th, 2023. The title of the poster was “VIR-
2218 and VIR-3434 therapy is efficacious in preclinical
models of hepatitis delta virus infection.”
Combination therapies have shown the most promise
and seem tobe the future ofHDV treatment. Treatment stra-
tegies that combine HBV treatment with the novel HDV
therapies and use reduction ofHBsAg as a primary endpoint
are important to consider. Although Eiger discontinued
further development of LNF for the treatment of HDV,
investigator trials could recommence in the future. Due to
its well-tolerated safety profile, we look forward to BLV's
future promises and anticipate it will be combined with
HBV treatment drugs for optimization of better targets as
the HDV novel therapies limit the therapeutic targets.59
CREDIT AUTHORSHIP CONTRIBUTION
STATEMENT
Conceptualization, A.K. and R.G.; methodology, A.K. and
R.G.; writing—original draft preparation, A.K., T.V., L.H.,
A.N.; writing—review and editing, A.K. and R.G.; visualiza-
JOURNAL OF CLINICAL AND EXPERIMENTAL HEPATOLOGY | - 2024 | Vol.
Please cite this article as: Khattak et al., The Forgotten Virus, Hepatitis D: A R
End-to-end Journal, https://doi.org/10.1016/j.jceh.2024.101395
tion, A.K. and R.G.; supervision, R.G. All authors have read
and agreed to the published version of the manuscript.
CONFLICTS OF INTEREST
The authors have none to declare.
ACKNOWLEDGMENTS
We thank Kelly Schrank, MA, ELS, of Bookworm Editing
Services LLC for her editorial services in preparing the
manuscript for publication.
FUNDING
This research received no external funding.
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