Hepatitis D; Causes, Symptoms, Diagnosis, Treatment - Health

Hepatitis D also is known as delta hepatitis, is a liver infection caused by the hepatitis D virus (HDV). Hepatitis D only occurs in people who are infected with the hepatitis B virus because HDV is an incomplete virus that requires the helper function of HBV to replicate. HDV can be an acute, short-term, infection or a long-term, chronic infection. Hepatitis D is transmitted through percutaneous or mucosal contact with infectious blood and can be acquired either as a coinfection with HBV or as a superinfection in people with HBV infection. There is no vaccine for hepatitis D, but it can be prevented in people who are not already HBV-infected by hepatitis B vaccination.

Hepatitis delta virus (HDV) is a defective virus that requires the hepatitis B virus (HBV) to complete its life cycle in human hepatocytes. HDV virions contain an envelope incorporating HBV surface antigen protein and a ribonucleoprotein containing the viral circular single-stranded RNA genome associated with both forms of hepatitis delta antigen, the only viral encoded protein. Replication is mediated by the host cell DNA-dependent RNA polymerases.

Causes and Transmission of Hepatitis D

Acute infection

Sometimes people can become infected with both hepatitis B and hepatitis D at the same time (co-infection). While most people with co-infection will get rid of both viruses on their own, there is a higher risk (2 to 20%) of developing fulminant (overwhelming) hepatitis (acute liver failure). When someone with hepatitis B virus later becomes infected with hepatitis D virus (superinfection) acute hepatitis D develops.

Chronic infection

Most people with superinfection develop chronic hepatitis D infection with few, if any, symptoms initially, but are capable of spreading the hepatitis D virus to others. Most people with chronic hepatitis D (70 to 80%) develop cirrhosis (scarring of the liver). About one-quarter of people with cirrhosis due to chronic hepatitis D infection will die of liver failure. People with cirrhosis are also at increased risk of developing liver cancer.

The routes of transmission of hepatitis D are similar to those for hepatitis B. Infection is largely restricted to persons at high risk of hepatitis B infection, particularly injecting drug users and persons receiving clotting factor concentrates. HDV is rare in most developed countries and is mostly associated with intravenous drug use. ^[rx]

This can happen in two ways

Co-infection – You can contract HBV and HDV at the same time
Super-infection – You can get sick with hepatitis B first, then later come down with HDV. This is the most common way to get hepatitis D. HDV can be acquired either as a coinfection with HBV, or a superinfection among patients with existing chronic HBV infection. People with HBV-HDV coinfection can have more severe, acute disease and higher risk (2% to 20%) of developing acute liver failure, compared with those infected with HBV alone.

Situations in which a person may come into contact with an infected person’s bodily fluids include

Sharing needles
Having unprotected sex
Having blood-to-blood contact
During childbirth
Using unsterilized medical or drug equipment

People cannot contract the virus from the following activities or types of contact

Coughing or sneezing
Sitting next to someone
Hugging
Shaking or holding hands
Sharing eating utensils

People who are more at risk of getting hepatitis D include those who

Have hepatitis B
Have not received the hepatitis B vaccine
Inject drugs
Have unprotected sex with multiple partners
Live in a part of the world where hepatitis D is more prevalent

Symptoms of Hepatitis D

The signs of HDV can include

Yellow skin and eyes (jaundice)
Jaundice
Fatigue, dark urine
Abdominal pain
Loss of appetite
Nausea – vomiting and joint pain.
Stomach upset
Pain in your belly
Throwing up
Not feeling hungry
Joint pain
Dark urine
Light-colored stool
Bruising, or bleeding depending on the severity of illness

Diagnosis of Hepatitis D

Molecular Test – The advent of molecular techniques has provided highly sensitive tools to diagnose HDV infection. The detection of HDV RNA by polymerase chain reaction (PCR) is presently the most reliable diagnostic method. This molecular test has overcome the limitations of the direct detection of HDAg in serum by enzyme immunoassay or radioimmunoassay due to antigen sequestration in immune complexes with high-titered circulating antibodies. Its role is crucial not only in the early phase of infection, before antibody seroconversion, but also to investigate the molecular events during both acute and chronic hepatitis. PCR has also offered a sensitive tool for monitoring the efficacy of antiviral agents since it can detect 10–100 copies of the viral genome in serum. Because of the genetic heterogeneity of HDV, primers from the most conserved region, the C-terminal half of the HD gene, are most useful in clinical practice.
HDV Antigen Test – can be measured; however, it is only transiently detectable in serum. The detection of HDV antibodies in HBsAg-positive patients is usually the initial step in the diagnosis of HDV; however, these antibodies can be falsely negative. Recently, there has been an emphasis on testing for HDV RNA viral load as more laboratories have gained experience in measuring it. To date, this method has mostly been done in academic centers.
Magnetic Resonance Elastography (MRE) – A noninvasive alternative to a liver biopsy. MRE combines magnetic resonance imaging technology with patterns formed by sound waves bouncing off the liver to create a visual map showing gradients of stiffness throughout the liver. Stiff liver tissue indicates the presence of scarring of the liver (fibrosis) as a result of chronic hepatitis D.
Transient Elastography – Another noninvasive test, transient elastography is a type of ultrasound that transmits vibrations into the liver and measures the speed of their dispersal through liver tissue to estimate its stiffness.
Liver biopsy – Typically done using ultrasound guidance, this test involves inserting a thin needle through the abdominal wall to remove a small sample of liver tissue for laboratory testing. Liver biopsies are used to determine the degree of liver damage present; however, there are risks from the procedure.^[rx] The typical changes seen are lymphocytes within the parenchyma, lymphoid follicles in the portal triad, and changes to the bile ducts.^[rx] There are a number of blood tests available that try to determine the degree of hepatic D fibrosis and alleviate the need for biopsy.^[rx]
Blood tests – A series of blood tests can indicate the extent of fibrosis, infection in your liver.
Transient elastography – A member of the care team performs transient elastography – a painless alternative to liver biopsy to assess liver damage.
The hepatitis D PCR test – is recommended for anyone who has positive hepatitis D antibodies unless they have recently completed hepatitis D treatment. If you have had treatment, antibodies will persist whether you have cleared the hepatitis D virus or not.

Treatment of Hepatitis D

Interferon-α

Thirty years have elapsed since interferon-α (IFN-α) was first used to treat chronic hepatitis D. Despite this long period of time and the progress made in the therapy of chronic hepatitis B and C, IFN-α still remains the only drug currently used for the treatment of HDV infection.
Initial research using standard IFN-α provided evidence that the efficacy of this drug was related to the dose and duration of therapy,^[rx]although a 1-year course of high-dose standard IFN-α induced only a 10% to 20% rate of sustained HDV clearance and a 10% rate of HBsAg clearance.^[rx^,^rx]
Strategies to increase the efficacy of standard IFN-α, such as longer duration of treatment^[rx^,^rx] or even continuous therapy for up to 12 years, were explored,^[rx] but most patients still failed to clear HDV, and the rate of relapse remained high.

Combination Therapy With Standard or Pegylated Interferon-α

The efficacy of standard IFN-α in combination with ribavirin^[rx] or lamivudine was not significantly higher than that of IFN-α monotherapy in chronic hepatitis D. Similar results were obtained when pegylated IFN-α was used in combination with ribavirin^[rx] or adefovir.^[rx]
In the largest randomized trial, HIDIT (Hep-Net International Delta Hepatitis Intervention Trial-1), pegylated IFN-α either alone or in combination with adefovir was compared to adefovir monotherapy.^[rx] Clearance of HDV RNA was observed in 28% of the patients in the 2 pegylated IFN-α treatment arms, but none of those who received adefovir monotherapy, 6 months after completion of treatment.

Monitoring Antiviral Therapy

Patients treated with standard or pegylated IFN-α should be monitored monthly with measurement of complete blood counts and serum alanine aminotransferase (ALT) levels. Serum HDV RNA and HBV DNA should be quantified at baseline and at 3-month intervals during treatment, and then every 6 months during follow-up after the completion of therapy.
Quantification of serum HBsAg levels provides an additional tool for monitoring antiviral therapy.^[rx^–^rx] The side effects, which are typical of IFN-α treatment and are particularly common with high doses and a prolonged course of therapy,^[rx] include flulike symptoms such as fatigue and weight loss. Reasons for dose modification or cessation of therapy most often include thrombocytopenia, neutropenia, anemia, and psychiatric complications.

Myclurdex – an HBV entry inhibitor, may also hinder the establishment of HDV infection by breaking the cycle of hepatocyte infection and possibly re-infection [rx]. REP 9AC is a nucleic acid-based amphipathic polymer (NAP) which inhibits the release of HBsAg from infected hepatocytes. REP 9AC is currently being evaluated in patients with chronic HBV in a proof-of-concept clinical trial. Interim data showed that seven out of eight patients treated with REP 9AC cleared HBsAg or had only residual levels [rx, rx].

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Summary of the studies evaluating molecules in clinical development.

Treatment	Treatment duration	Virological outcome	Development stage and References
Pegylated IFN-lambda 120 or 180 µg qw sc	48 weeks	At week 24 of treatment: 4/10 patients are HDV PCR-negative	Phase 2 [rx]
Myrcludex B 2 mg/Kg QD sc, 24 weeks followed by pegylated IFN-alpha monotherapy, 48 weeks	72 weeks	The decline in HDV RNA at week 24 of treatment: 1.67 log10 decrease in HDV RNA	Phase 2 [rx]
Myrcludex B 2 mg/Kg QD sc + pegylated IFN 24 weeks followed by Pegylated IFN-alpha monotherapy, 24 weeks	48 weeks	The decline in HDV RNA at week 24 of treatment: 2.59 log10 decrease in HDV RNA
Pegylated IFN-alpha monotherapy	48 weeks	Decline in HDV RNA at week 24 of treatment: 2.17 log10
Myrcludex B 2, 5 or 10 mg QD sc	24 weeks	The decline in HDV RNA at week 24 of treatment: 2 mg: 1.75 log10 5 mg: 1.6 log10 10 mg: 2.7 log10	Phase 2b [rx]
Tenofovir 245 mg QD PO	24 weeks	The decline in HDV RNA at week 24 of treatment: 0.18 log10	Phase 2b [rx]
Myrcludex B 2 or 5 mg QD sc + pegylated IFN-alpha sc	48 weeks	The decline in HDV RNA at week 48 of treatment: 2 mg: 3.62 log10 5 mg: 4.48 log10	Phase 2 [rx]
Myrcludex B 2 mg QD sc	48 weeks	The decline in HDV RNA at week 48 of treatment: 2.84 log10
Pegylated IFN-alpha sc	48 weeks	The decline in HDV RNA at week 48 of treatment: 1.14 log10
Lonafarnib 100 or 200 mg bid iv	4 weeks	The decline in HDV RNA at day 28 of treatment: 100 mg: 0.73 log10 200 mg: 1.54 log10	Phase 2A [rx]
Lonafarnib 200 mg bid PO	12 weeks	Variation in HDV RNA at week 12 of treatment: 0.03 log10	Phase 2 [rx]
Lonafarnib 300 mg bid PO	12 weeks	The decrease in HDV RNA at week 12 of treatment: 1.78 log10
Lonafarnib 100 mg tid PO	5 weeks	The decrease in HDV RNA at week 4 of treatment: 1.31 log10
Lonafarnib 100 mg bid PO + pegylated IFN-alpha) qw sc	8 weeks	The decrease in HDV RNA at week 8 of treatment: 2.19 log10
LNF 100 mg PO bid + ritonavir 100 mg QD PO	8 weeks	The decrease in HDV RNA at week 8 of treatment: 2.97 log10
Lonafarnib 50 mg bid PO (increased at 4-week intervals to 75 mg and then 100 mg) + ritonavir 100 mg bid PO	24 weeks	Dose escalation possible in 10 patients At the end of treatment, mean HDV RNA decline was 1.58 ± 1.38 log10 IU/mL	Phase 2 [rx]
Lonafarnib 50, 75 or 100 mg QD + ritonavir 100 mg QD PO	12 or 24 weeks	The decrease in HDV RNA at week 12 of treatment: 50 mg: 1.6 log10 75 mg: 1.3 log10 100 mg: 0.83 log10 Decrease in HDV RNA up to 3.7 log10 at week 24 of treatment	Phase 2 [rx]
Lonafarnib 50 mg bid PO + ritonavir 100 mg bid PO or Lonafarnib 25 mg bid PO + Ritonavir 100 mg bid PO or Lonafarnib 50 mg bid PO + ritonavir 100 mg bid PO + pegylated IFN-alpha qw sc or Lonafarnib 25 mg bid + Ritonavir 100 mg bid + pegylated IFN-alpha qw sc or Lonafarnib 50 mg bid PO + ritonavir 100 mg bid PO + addition of pegylated IFN-alpha qw for weeks 12–24	24 weeks	The decrease in HDV RNA at week 24 of treatment: 21 of 33 patients had a > 2 log10 decrease in HDV RNA	Phase 2 [rx]
REP 2139-Ca 500 mg qw iv 15 weeks followed by REP 2139-Ca qw + pegylated IFN-alpha 15 weeks followed by pegylated IFN-alpha 33 weeks	63 weeks	– At week 30 of treatment: >5log decline in HDV RNA in 11 patients Undetectable HDV RNA in 10 patients – At the end of treatment: HBs seroconversion in 5 patients; Undetectable HDV RNA in 9 patients; −18 months after treatment: 4 patients HBsAg negative 7 patients maintain undetectable HDV RNA	Phase 2 [rx], [rx]

Abbreviations: bid, twice a day; iv, intravenous; po, per os; qw, weekly; qd, daily; sc, subcutaneous, tid, three times per day.

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Pegylated Interferon Lambda

Pegylated-interferon-lambda (PEG-IFN-λ) is a well-characterized, late-stage, first in class, type III interferon that stimulates cell-mediated immune responses that are critical for the development of host protection during viral infections. This drug has now been granted “Orphan Drug Designation” by the FDA, fast-tracking the development process.

Myrcludex B

This drug is an “entry inhibitor” that prevents the virus from entering into hepatocytes (liver cells) and has shown activity against the hepatitis B virus. It may also stop the development of a hepatitis D infection. A recent study showed promise for Myrcludex B when combined with PEG-INF in reducing hepatitis D viral levels. It has been granted PRIME Eligibility by the European Medicines Agency, a status that promotes support in the development of drugs that serve an unmet medical need.

Ezetimibe

Currently used to lower cholesterol in the blood, Ezetimibe is being studied for effectiveness against hepatitis D. Ezetimibe possesses pharmacophore features to stop NTCP, the receptor required for hepatitis B and hepatitis D hepatocyte entry.

Lonafarnib

This drug works by targeting the protein assembly process, preventing the production of new virus particles. In a current clinical trial, Lonafarnib combined with Ritonavir has shown promise in reducing hepatitis D viral levels, and the FDA has granted its fast-track status since this class of drugs has been developed for the treatment of cancers and have been shown to be safe.

Rep 2139

This compound is known as a “Nucleic acid-based Amphipathic Polymer” (NAP) which prevents the release of hepatitis B surface antigen (HBsAg) from infected liver cells and is being evaluated for hepatitis D virus in combination with pegylated interferon (PEG IFN).

GI-18000

GI-18000 Tarmogen is being studied for its effectiveness in causing a T cell immune response against cells infected with Hepatitis D and thereby improving outcomes. The strategy is to identify molecular targets that distinguish diseased cells from normal cells and activate the immune system to selectively target and eliminate only the diseased cells.

ALN-HDV

This approach is being used for both the hepatitis B and hepatitis D virus to “silence” the viral RNA with compounds that interfere with and cause the destruction of the viral genome (e.g. stop the replication of the virus).

Prevention

Prevention and control of HDV infection require the prevention of HBV transmission through hepatitis B immunization, blood safety, injection safety, and harm reduction services. Hepatitis B immunization does not provide protection against HDV for those already HBV infected.

Exclusion of people with hepatitis D from childcare, preschool, school, and work is not necessary.
Hepatitis B vaccination will prevent infection with hepatitis D. Hepatitis B vaccination is recommended for infants and those at a higher risk of acquiring hepatitis B infection and/or at higher risk of severe infection. Vaccination for hepatitis B, when given to newborn infants, is effective in preventing hepatitis D (even if the mother has hepatitis D).
Any open sores, cuts or abrasions should be covered with waterproof dressings
Practice safer sex – use condoms consistently and correctly.
Injecting drug users should never share injecting equipment.
If required to handle blood or body fluids, the use of standard precautions will reduce the risk of spreading the hepatitis D virus.
Infected health care workers must comply with the requirements of their professional boards.

WHO Response

WHO does not have a specific recommendation on hepatitis D, however prevention of HBV transmission by hepatitis B immunization, safe injection practices, blood safety, and harm reduction services with clean needles and syringes, are effective in preventing HDV transmission.

In May 2016, The World Health Assembly adopted the first “Global Health Sector Strategy on Viral Hepatitis, 2016-2021”. The strategy highlights the critical role of Universal Health Coverage and the targets of the strategy are aligned with those of the Sustainable Development Goals. The strategy has a vision of eliminating viral hepatitis as a public health problem and this is encapsulated in the global targets of reducing new viral hepatitis infections by 90% and reducing deaths due to viral hepatitis by 65% by 2030. Actions to be taken by countries and WHO Secretariat to reach these targets are outlined in the strategy.

To support countries in moving towards achieving the global hepatitis goals under the Sustainable Development Agenda 2030 WHO is working in the following areas:

raising awareness, promoting partnerships and mobilizing resources;
formulating evidence-based policy and data for action;
preventing transmission; and
scaling up screening, care and treatment services.

WHO also organizes World Hepatitis Day on 28 July every year to increase awareness and understanding of viral hepatitis.

References

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