Ola Weiland group

Antiviral therapy, immunology and long-term follow-up in chronic viral hepatitis C and B infections

Our overall goal is to improve therapy for chronic viral hepatitis in HBV and HCV mono-infected, HCV/HIV co-infected and liver transplanted patients.

We conduct phase 1-3 clinical trials on new DAA drugs in combination with peg-IFN and ribavirin, and evaluate therapeutic DNA based vaccine therapy for chronic HCV. We further investigate the immunological background for chronic evolution versus spontaneous resolution of viral hepatitis and the long-term clinical outcome. Finally we have developed a database Infcare Hepatitis as an instrument for research on a national basis.

Our research aims to:

  • Evaluate the immunological background for chronicity versus spontaneous resolution of acute and chronic viral hepatitis B and C.
  • Evaluate the potential of new DAA drugs (protease and polymerase inhibitors) for treatment of chronic HCV.
  • Evaluate the usefulness of a therapeutic DNA based HCV vaccine delivered by electroporation for treatment of chronic HCV
  • Evaluates the long-term outcome of chronic HCV and HBV related to antiviral treatment outcome.
  • Evaluate new treatments for liver transplant patients and HIV/HCV co-infected patients

Keywords: Chronic hepatitis C, Chronic hepatitis B, IFN, ribavirin, protease inhibitors, polymerase inhibitors, liver transplantation, HCV/HIV co-infection, therapeutic vaccination.

Members

Ola Weiland, Group Leader, Professor, MD, Chief Liver section Dpt of ID

Member of EASL, AASLD, IDSA, SILK, Svenska Infektionsläkar-och Tropikläkarföreningen.

Published more than 200 articles on chronic viral hepatitis and treatment with antivirals. Has conducted peg-IFN, ribavirin, and DAA studies in chronic hepatitis B and C since more than 20 years.

Phone: +46 8-585 82273

Senior scientists

Karolin Falconer, MD, PhD, lecturer specialist in ID and HIV/HCV co-infections and NK cell immunology.

PhD students

Malin Ackefors, MD, Senior consultant, specialist in ID and post transplant and hematological infections. PhD studies on chronic viral hepatitis in Liver transplant recipients.
Magnus Hedenstierna, MD, ID specialist with studies on long-term consequences of chronic viral hepatitis after SVR in HCV mono- and HIV/HCV co infected patients.

Research nurses

Rebecka Theve, ID specialist nurse
Susanne Cederberg, ID specialist nurse

Projects

1. T - and NK - cell response

Studies on T - and NK - cell response in patients treated with SOC (peg-IFN + ribavirin) in collaboration with professor Matti Sällbergs and Hans-Gustav Ljunggrens groups with PhD students in collaboration. Recently Niklas Björkström, H-G Ljunggren the main tutor, defended his theisis on the importance of NK cells in infection in particular chronic HCV August 2011.

Large patient materials have been collected: among these 100 mono-infected patients with HCV, 50 liver transplant patients, and 30 HCV/HIV co-infected all treated with SOC (peg-IFN + ribavirin). PBMCs and serum have ben collected before, during and after treatment and during long-term follow-up.

2. IL28B SNPs importance for spontaneous clearence versus chronicity

Studies on IL28B SNPs importance for spontaneous clearence versus chronicity in HCV and HCV- HIV co-infected patients with a PhD student JS as responsible. She also investigate the total Swedish HIV cohort with data from the national registers, InfCare HIV and InfCare Hepatitis created by the group.

Furthermore the importance of IL28B snp for the outcome of SOC treatment in liver transplant patients with HCV relapse is studied by the PhD student MA. IL28B snp seem to be of importance both in the recipient and the donor. These studies ar performed on a unique material of treated patients in collaboration the Transplantation and Pathology Clinics at Karolinska and the division of Infectious Diseases, Karolinska University hospital.

We also study the IL28B SNPs importance for HCV viral kinetics during SOC treatment in HCV patients HCV mono-infected, HIV/HCV co-infected, and transplanted utilizing our unique materials. Analyses of IL28B snp are performed at the division of Virologi, Karolinska University hospital. The rs 12979860 SNP genotyping is performed with an allel-specific Taqman-based test for the CC, C/T or TT genotypes.

The histological evaluation in liver transplant patients with HCV relapse is performed on liver biopsies taken 6 and 12 months after liver transplantation as follows.

All protocol liver biopsies were fixed in 4% paraformaldehyde, dehydrated and embedded in paraffin according to standard procedures. 2-3 um thick sections were cut on a microtome and stained with hematoxylin/eosin (HE) and Sirius staining, 8 and 4 section levels respectively.

3. Long-term outcome in patients successfully treated with SOC (peg-IFN + ribavirin)

Studies on the long-term outcome histological, virological and immunological in patients successfully treated with SOC (peg-IFN + ribavirin) for chronic hepatitis C.

A unique patient material has been collected comprising of 50 patients who cleared their HCV infection after SOC treatment mor than 10 years ago. This EC approved study evaluates these 50 patients, and the histological studies are based on liver biopsies taken prior to the original SOC treatment and again in mean 10 years after the infection was cleared. These studies are part of a PhD project for PhD student MH. A preliminary report was given at the AASLD meeting November 2011 in San Francisco which showed tremendous improvement and normalisation of the fibrosis stage.

We also perform virological and immunological studies on the material from these patients. These comprise HCV RNA, antigen and serological determinations as follows: Cobas Amplicor, HCV antibodies EIA and by Western blot using separated HCV antigens, Amplified HCV RNA will be sequenced, the 5´-non coding region is the first target, HCV proteins in the liver will be analyzed by immuno-precipitation western blot and histological. T helper cells are determined in PBMC and liver tissue using ELISpot. Proliferation is determined. gIFN producing cells are quantified. Cytotoxic T lymphocytes (CTLs) are determined in liver tissue and PBMC using ELISpot assays and by tetramer staining by flow cytometry. Specific cells are then analysed by Vantage flow cytometer (BDB) and analyzed by the Cell Quest software (BDB).

4. Construction of a national hepatitis-data base InfCare Hepatitis

This has been developed in collaboration with Health Solutions and is owned by The Infectious Disease Clinic Karolinska. The system is now fully in operation (natinally 6000 patients, a majority from Karolinska, have been included Nov 2011). More than 20 of 29 ID clinics in Sweden are connected and the system is now introduced in all Gast/Hepatological clinics in Sweden. It is expected to cover 100 % of these clinics within 1 year. This InfCare Hepatitis data base is a very strong research instrument.

5. DAA antiviral therapy

DAA antiviral therapy in national and international studies on patients with chronic HCV infection in collaboration with and for major Pharma Industries, Roche, Janssen, BMS, MSD, Gilead and ChronTech Pharma. All studies are preformed with highly qualifies personnel according to GCP. The hospital laboratories are all qualified as is the hospital Pharmacy.

All these Phase I - III studies are headed by the group leader Ola Weiland as principal investigator for Sweden and Scandinavia.

Selected publications

ABT-450, ritonavir, ombitasvir, and dasabuvir achieves 97% and 100% sustained virologic response with or without ribavirin in treatment-experienced patients with HCV genotype 1b infection.
Andreone P, Colombo M, Enejosa J, Koksal I, Ferenci P, Maieron A, et al
Gastroenterology 2014 Aug;147(2):359-365.e1

Sofosbuvir and ribavirin in HCV genotypes 2 and 3.
Zeuzem S, Dusheiko G, Salupere R, Mangia A, Flisiak R, Hyland R, et al
N. Engl. J. Med. 2014 May;370(21):1993-2001

Treatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin.
Feld J, Kowdley K, Coakley E, Sigal S, Nelson D, Crawford D, et al
N. Engl. J. Med. 2014 Apr;370(17):1594-603

Patient-reported outcomes assessment in chronic hepatitis C treated with sofosbuvir and ribavirin: the VALENCE study.
Younossi Z, Stepanova M, Zeuzem S, Dusheiko G, Esteban R, Hezode C, et al
J. Hepatol. 2014 Aug;61(2):228-34

Clinical significance of residual viremia detected by two real-time PCR assays for response-guided therapy of HCV genotype 1 infection.
Vermehren J, Aghemo A, Falconer K, Susser S, Lunghi G, Zeuzem S, et al
J. Hepatol. 2014 May;60(5):913-9

Impact of Il28b-related single nucleotide polymorphisms on liver transient elastography in chronic hepatitis C infection.
Ydreborg M, Westin J, Rembeck K, Lindh M, Norrgren H, Holmberg A, et al
PLoS ONE 2013 ;8(11):e80172

Evolution of fibrosis during HCV recurrence after liver transplantation--influence of IL-28B SNP and response to peg-IFN and ribavirin treatment.
Ackefors M, Nyström J, Wernerson A, Gjertsen H, Sönnerborg A, Weiland O
J. Viral Hepat. 2013 Nov;20(11):770-8

Containing "The Great Houdini" of viruses: combining direct acting antivirals with the host immune response for the treatment of chronic hepatitis C.
Ahlén G, Frelin L, Brenndörfer E, Brass A, Weiland O, Chen M, et al
Drug Resist. Updat. ;16(3-5):60-7

Therapeutic DNA vaccination using in vivo electroporation followed by standard of care therapy in patients with genotype 1 chronic hepatitis C.
Weiland O, Ahlén G, Diepolder H, Jung M, Levander S, Fons M, et al
Mol. Ther. 2013 Sep;21(9):1796-805

A risk for hepatocellular carcinoma persists long-term after sustained virologic response in patients with hepatitis C-associated liver cirrhosis.
Aleman S, Rahbin N, Weiland O, Davidsdottir L, Hedenstierna M, Rose N, et al
Clin. Infect. Dis. 2013 Jul;57(2):230-6

Telaprevir alone or with peginterferon and ribavirin reduces HCV RNA in patients with chronic genotype 2 but not genotype 3 infections.
Foster G, Hézode C, Bronowicki J, Carosi G, Weiland O, Verlinden L, et al
Gastroenterology 2011 Sep;141(3):881-889.e1

Telaprevir for retreatment of HCV infection.
Zeuzem S, Andreone P, Pol S, Lawitz E, Diago M, Roberts S, et al
N. Engl. J. Med. 2011 Jun;364(25):2417-28

Effect of control selection on sustained viral response rates in genotype 2/3 HCV mono-infected versus HIV/HCV co-infected patients.
Nilsson J, Weiland O
Scand. J. Infect. Dis. 2010 Jul;42(6-7):533-9

Telaprevir for retreatment of HCV infection.
Zeuzem S, Andreone P, Pol S, Lawitz E, Diago M, Roberts S, et al
N. Engl. J. Med. 2011 Jun;364(25):2417-28

Effect of control selection on sustained viral response rates in genotype 2/3 HCV mono-infected versus HIV/HCV co-infected patients.
Nilsson J, Weiland O
Scand. J. Infect. Dis. 2010 Jul;42(6-7):533-9

DNA vaccine therapy for chronic hepatitis C virus (HCV) infection: immune control of a moving target.
Sällberg M, Frelin L, Weiland O
Expert Opin Biol Ther 2009 Jul;9(7):805-15

Pegylated interferon and ribavirin combination therapy for chronic hepatitis C virus infection in patients with Child-Pugh Class A liver cirrhosis.
Syed E, Rahbin N, Weiland O, Carlsson T, Oksanen A, Birk M, et al
Scand. J. Gastroenterol. 2008 ;43(11):1378-86

Expansion of functionally skewed CD56-negative NK cells in chronic hepatitis C virus infection: correlation with outcome of pegylated IFN-alpha and ribavirin treatment.
Gonzalez V, Falconer K, Björkström N, Blom K, Weiland O, Ljunggren H, et al
J. Immunol. 2009 Nov;183(10):6612-8

Elevated numbers of Fc gamma RIIIA+ (CD16+) effector CD8 T cells with NK cell-like function in chronic hepatitis C virus infection.
Björkström N, Gonzalez V, Malmberg K, Falconer K, Alaeus A, Nowak G, et al
J. Immunol. 2008 Sep;181(6):4219-28

Elevated numbers of Fc gamma RIIIA+ (CD16+) effector CD8 T cells with NK cell-like function in chronic hepatitis C virus infection.
Björkström N, Gonzalez V, Malmberg K, Falconer K, Alaeus A, Nowak G, et al
J. Immunol. 2008 Sep;181(6):4219-28

Similar hepatitis C virus RNA kinetics in HIV/hepatitis C virus monoinfected genotype 2 or 3 matched controls during hepatitis C virus combination therapy.
Karlström O, Sönnerborg A, Weiland O
AIDS 2008 Apr;22(7):899-901

Lower-than-standard dose peg-IFN alfa-2a for chronic hepatitis C caused by genotype 2 and 3 is sufficient when given in combination with weight-based ribavirin.
Weiland O, Hollander A, Mattsson L, Glaumann H, Lindahl K, Schvarcz R, et al
J. Viral Hepat. 2008 Sep;15(9):641-5

High adherence with a low initial ribavirin dose in combination with pegylated-IFN alpha-2a for treatment of recurrent hepatitis C after liver transplantation.
Hörnfeldt E, Gjertsen H, Weiland O
Scand. J. Infect. Dis. 2008 ;40(3):259-65

Prediction of sustained virological response in chronic hepatitis C patients treated with peginterferon alfa-2a (40KD) and ribavirin.
Foster G, Fried M, Hadziyannis S, Messinger D, Freivogel K, Weiland O
Scand. J. Gastroenterol. 2007 Feb;42(2):247-55

Efficacy of 24 weeks treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C infected with genotype 1 and low pretreatment viremia.
Zeuzem S, Buti M, Ferenci P, Sperl J, Horsmans Y, Cianciara J, et al
J. Hepatol. 2006 Jan;44(1):97-103

Relation between viral fitness and immune escape within the hepatitis C virus protease.
Söderholm J, Ahlén G, Kaul A, Frelin L, Alheim M, Barnfield C, et al
Gut 2006 Feb;55(2):266-74

Evidence for a relation between the viral load and genotype and hepatitis C virus-specific T cell responses.
Hultgren C, Desombere I, Leroux-Roels G, Quiroga J, Carreno V, Nilsson B, et al
J. Hepatol. 2004 Jun;40(6):971-8

Codon optimization and mRNA amplification effectively enhances the immunogenicity of the hepatitis C virus nonstructural 3/4A gene.
Frelin L, Ahlén G, Alheim M, Weiland O, Barnfield C, Liljeström P, et al
Gene Ther. 2004 Mar;11(6):522-33

Translational Medical Research