Hepatitis D - a forgotten foe ?

Hepatitis Delta: Epidemiology, Diagnosis and Management 40 Years After Discovery

Richard Njouom, PhD/HDR

Head Virology Department

Centre Pasteur of Cameroon

Presentation outline

1. Background

2. The hepatitis D virus (HDV)

3. Natural history of the infection by HDV

4. Epidemiology of HDV infection in the world and in Africa

5. Laboratory diagnosis of HDV infection

6. Hepatitis D treatment/management

7. Conclusion « Take home messages »

Worldwide deaths attributable in 2010 and 2013 to HIV/AIDS, viral hepatitis,

malaria and tuberculosis

GBD 2013 Mortality and Causes of Death Study: Lancet 2014

Viral hepatitis: a high and growing global burden

Chronic viral hepatitis B, C and D are the most concerned

✓ 240 million chronic carriers

of HBV

✓ 185 million chronic carriers

of HCV

✓ 15 to 20 million co-infected

with HBV/VHD

(Wang et al.; 1986 - Ryu et al.; 1993)

The Hepatitis Delta Virus (HDV)

✓ Discovered in 1977 by Rizzetto in Italian HBsAg positive patients.

✓ No well defined taxonomic position (HBV satellite virus, Deltavirus

genus)

✓ Spherical virus about 36 nm in diameter with an envelope anchored

in HBV glycoproteins

✓ Nucleocapsid is composed of 2 protein forms (Protein Delta and

Protein of the envelope of HBV)

✓ Genome: single-stranded circular RNA Negative Polarity

✓ Size: 1700 pb

✓ Possessing a single open reading frame

F. Le Gal et al., Emerging Inf. Diseases 2006 Sept ; 12, (9) : 1447 - 1449

VII

VIII

Genetic Diversity of HDV

✓HDV is characterized by its high genetic diversity

leading to 8 genotypes (HDV-1 to HDV-8) defined

by an intergenotype similarity >85% or >80%,

according to the partial or full-length genome

sequence, respectively.

✓Genotypes can be segregated into two to four

subgenotypes, characterized by an intersubgenotype

similarity >90% (>84% for HDV-1) over the whole

genome sequence.

Live cycle of HDVMutiplication of HDV essentially occurs in the liver

(1) Attachment of the virion to the hepatocyte receptor

(2) Release of RNP in the cytoplasm of the hepatocyte

(3) Displacement of RNP to the hepatocyte nucleus

(4) Transcription of genomic RNA into antigenomic RNA (model for

replication of new circular genome) and 'mRNA (containing the open

reading frame)

(5) Transport of the mRNA to the cytoplasm where it is translated at the

level of the endoplasmic reticulum into proteins of the Ag Delta

(6) Transport of Ag Delta proteins to the nucleus where both forms of Ag

Deltat associate with new genomic RNA transcripts to form new RNPs;

(7) Transport of new RNPs to the cytoplasm where L-AgD facilitates

association with HBV envelope proteins in ER to form new virus

particles;

(8) Budding of new particles at the GA

(9) Transport out of the hepatocyte

Sarah A Hughes, et al. Lancet 2010: Volume 378, Issue 9785, 2011, 73–85

Natural history of HDV infection

HDV infection occurs only in patients infected with HBV in two ways : Coinfection (simultaneous

infections with the two viruses) or Superinfection (in a patient previously infected with HBV)

Spontaneous

Recovery

60 to 80%

5 to 10%

Fulminant hepatitis

2 à 10%

70%

Cirrhosis

Hepatocellular Carcinoma

Chronic Hepatitis

60 to 90% 10 to 30%

Coinfection

(Chronic Hepatitis B) Acute HepatitisSurperinfection

Schematic representation of the clinical course of hepatitis Delta

Botelho-Souza et al. Virology Journal (2017) 14:177

Delta hepatitis: the most severe chronic viral hepatitis

Shirvani-Dastgerdi et al. Curr Opin Virol. PMC 2017 July 13.

✓ Co-infection with HBV and HDV frequently

causes more rapid and exacerbated disease

progression and has been reported to increase

patients’ risk for developing HCC.

✓ The mechanisms underlying this process are

not well understood.HDAg expression alone is not cytopathic and does not

seem to have any oncogenic potential. However, a

high level of liver inflammation has been observed

with intrahepatic expression of L-HDAg and

through activation of NF-κB signaling.

Global prevalence of anti-HDV antibodies✓ Prevalence : 5% to 10%

✓ 240 million HBV carriers, about 15-20 million are carriers of HDV

✓ Heterogeneous distribution of anti-HDV prevalence in the world

(Radjef et al, 2004); (Rizetto et al, 2009)

Heterogeneous distribution of HDV genotypes and subgenotypes in the World

✓ Countries harboring HDV-1 are in light blue.✓ HDV-1a and HDV-1b are restricted to Africa and Madagascar.

✓ HDV-1c to the Oceania islands

✓ HDV-1d is found in the Middle East, eastern and western

Europe, Asia, and North America.

✓ HDV-2 (orange) is found in Asia, including in Taiwan and

Japan for HDV-2a and Siberia for HDV-2b.

✓ HDV-3 (black) is present in the north of South America.

✓ HDV-4a and HDV-4b (light brown) circulate in the Far

East Asia.

✓ HDV-5, HDV-6, HDV-7, and HDV-8 (green, purple, blue,

and brown, respectively) are present in western, sub-

Saharan, and central Africa.

LE GAL ET AL., HEPATOLOGY, Dec 2017

Major endemic regions for hepatitis delta worldwide and predominant

genotype distribution

Soriano V et al. AIDS 2017, 31:875–884

Evolution of the epidemiology of HDV in Europe

✓ 1970-80: High prevalence

✓ 1990: Decrease because HBV vaccination

✓ 2000: a vanishing disease?

✓ 2007: resurgence of HDV

Germany 8-10%

London 8.5%

Italy: 8.6%

France: 3 to 4%

Wedemeyer H, Hepatology 2010; Cross J Med Virol 2008 , Piroth J Hepatol 2010; Boyd J Viral Hepat 2010

Causes:

✓ Immigration from high endemic areas +++

✓ IV Drug addiction

1. Central Africa :

✓ Gen. Pop: 25.64% (12.09–42.00)

✓ HCC: 37.77% (12.13–67.54)

2. West Africa :

✓ Gen. Pop : 7.33% (3.55–12.20)

✓ HCC: 9.57% (2.31–20.43)

3. East and South Africa :

✓ Gen. Pop : 0.05% (0.00–1.78)

Prevalence of anti-HDV antibodies in Africa SA

Alexander J Stockdale, et al. Lancet Glob Health 2017

Prevalence of anti-HDV antibodies in Cameroon: ANRS study 12289

DHS 2011; N = 15,000; 15-59 years

Markers of the diagnosis of HDV infection

Diagnosis of HDV infection is essentially biological

HBV markers : anti-HBc IgM and HBsAg

✓ Indirect diagnosis : ✓ Anti-HDV IgG Ab

✓ Anti-HDV IgM Ab +++

✓Persistence = chronic infection +++

✓NB: may be missing in some African patients

✓ Direct diagnosis:✓ Delta Ag : fugitive++

✓ Delta RNA

✓RT-PCR +++

✓Quantification by real time PCR +++

✓HDV genotypes ?✓ Sequencing

Serologic course of acute resolving (A) and chronic (B) HDV infection.

KAMILI ET AL., HEPATOLOGY, VOL. 66, NO. 6, 2017

Interpretation of the results of the markers of the

diagnosis of HDV infection

Algorithm for the diagnosis of hepatitis Delta

Botelho-Souza et al. Virology Journal (2017) 14:177

Current treatment of Delta chronic hepatitis

Only one treatment : Peg-IFN (180μg / wk)

✓ ≥ 12 months, depending on the qHBsAg

✓ No rule for treatment discontinuation

✓ No definition of the SVR

✓ Predictive factors of response ?

✓ Goal: HBsAg loss

✓ <10% HBsAg loss and <30% undetectable HDV RNA

✓ Frequent relapses upon discontinuation of treatment

Nucleos(t)idic analogues alone

✓ Ineffective on HDV Replication

✓ Associated with Peg-IFN if HBV replication

✓ Useful for ↓ qHBsAg

HIDIT 1: Peg-IFNα2a and Adefovir HIDIT-1 Randomized

Controlled Study, International

Multicentre (Germany, Turkey,

Romania, Greece)

Wedemeyer H, NEJM 2011; Heidrich B, Hepatology 2014

✓ PegIFNα2a-Adefovir: Greater decrease qHBsAg

✓ Late virological relapse> 24 weeks after Peg-IFN discontinuation (56%

of cases)

Delta Hepatitis Treatment with PegIFNα2a:

~ 25% HDV RNA Clearance

New therapeutic targets for HDV

Characteristics of novel drug treatment for chronic hepatitis D.

Results in major hepatitis delta virus therapeutic studies

Soriano V et al. AIDS 2017, 31:875–884

Menashe Elazar et al. ,Best Pract & Res Clin Gastroenterol 2018

Algorithm for HDV infection management

Menashe Elazar et al. ,Best Pract & Res Clin Gastroenterol 2018

Algorithm for HDV infection management based on response to initial treatment

Hepatitis D - a forgotten foe ?

✓ 40 years after its discovery, HDV remains a challenge for clinicians and researchers.

✓ The burden of disease caused by HDV is most probably underestimated since there is a

considerable lack of epidemiologic data from several countries where HBV is highly

prevalent.

✓ Despite considerable progress made in HDV research a significant number of questions

remain to be answered concerning fundamental aspects of its biology, pathogenesis, and

interaction with the host.

✓ The next few years will hopefully bring to light new answers but also new exciting questions,

helping understand this fascinating pathogen, and contributing to reducing morbidity and

mortality among infected individuals.

Manns MP. Lancetgh Vol 5 October 2017

Conclusion : « Take home message »✓ HDV infection is a high and growing global burden

✓ Infects only in the presence of HBV HBsAg

✓ Causes the most severe form of viral hepatitis with rapid progression to HCC

✓ Central African countries are the most affected

✓ Diagnosis of HDV infection is essentially biological by screening of HDV IgG Ab

followed by HDV IgM Ab and HDV RNA (or only RNA for African patients)

✓ Systematically screen any HBsAg positive patient

✓ Difficulty of access to the HDV RNA test (Need for its development)

✓ Only one effective treatment of HDV in 2018: Peg-IFN, disappointing

✓ Several encouraging clinical trials in progress (Inhibitor of entry: Myrcludex B; Inhibitor

of assembly: Lonafarnib; Nucleic Acids Polymers: NAPs)

✓ The best treatment of HDV remains the HBV Vaccination

Thanks

Merci