February 19, 2014

Rutgers scientists identify structure of virus that could lead to hepatitis C vaccine


Contact: Robin Lally
Rutgers University

Infection is a major global health problem affecting 160 million people worldwide


This is Joseph Marcotrigiano, associate professor of chemistry and chemical biology, Rutgers University. Credit: Nick Romanenko, Rutgers University

Rutgers University scientists have determined the structure of a hepatitis C surface protein, a finding that could assist in the development of a vaccine to halt the spread of the the deadly disease that has infected 3.2 million Americans.

Joseph Marcotrigiano, associate professor of chemistry and chemical biology, says this new research – published online today in Nature – describes an outer region of hepatitis C that enables the virus to evade the body's natural immune system response, causing persistent, chronic infection.

Hepatitis C is constantly mutating, allowing it to infect a host cell and evade the immune responses, causing chronic infection that can be difficult to treat. By identifying the structure of virus's outer protein, Marcotrigiano, the study's lead author, says scientists will be better able to develop a vaccine that targets the immune system to vulnerable regions of the virus in order to prevent infection.

"Viruses are smart and it is a constant battle to keep them out," says Marcotrigiano who collaborated on the research with colleagues from the Center for Advanced Biotechnology and Medicine at Rutgers and Emory University School of Medicine. "That's why the development of a vaccine is so important. It's always better to prevent infection through an effective vaccine then to treat after a chronic infection has been established."

Hepatitis C virus is a major global health problem with 160 million people infected throughout the world, about four times more individuals than those with HIV. Most of those infected do not show symptoms until the virus – the number one cause of liver transplantation – has caused severe liver damage.

The virus is mainly spread through contact with an infected person's blood, such as sharing of needles. Prior to 1992, when donated blood began being tested, the virus was also spread through blood transfusions and organ donation.

Recently, the Food and Drug Administration approved several new drugs that could cure many patients infected with hepatitis C in as little as 12 weeks. However, at about $1000 per pill, this may not be a cost-effective solution to hepatitis C virus.

Developing a vaccine against hepatitis C would not only prevent people from acquiring the disease, Marcotrigiano says, but would also be the most cost-conscious health intervention.

Michael Houghton, a researcher at the University of Alberta in Canada, has been developing a vaccine that is currently being tested clinically. Houghton, who led a team that discovered the hepatitis C virus in 1989, says the Rutgers finding is important because knowing the structure of the virus will help in the development of a vaccine that enables the immune system to produce more infection-fighting antibodies that can neutralize the virus.


University of Westminster develops groundbreaking method to test hepatitis C cure



Researchers at the University of Westminster have developed a groundbreaking method which can be used to test a new innovative cure for hepatitis C, a liver disease caused by the hepatitis C virus (HCV).

The cure is the first of its kind ever to be tested in humans and comes in the form of a drug based on gene therapy which is under development by the Australian company Benitec Biopharma.

Around 150 million people worldwide are infected with hepatitis C, and more than 350,000 people die every year from hepatitis C related liver diseases. Hepatitis C is one of the leading causes of liver cirrhosis and cancer, and one of the most common and seriously infectious conditions in the world (according to the World Health Organisation (WHO)).

Although treatments are already available for hepatitis C, these are lengthy, have low chances of success, cause significant side-effects, or the virus is already becoming resistant. The new drug, TT-034, developed by Benitec Biopharma, is based on the biological mechanism for which the Nobel Prize in Physiology or Medicine was awarded in 2006. Unlike anything else currently available to patients, this treatment works with a single injection to directly destroy the hepatitis C virus and remove the infection. The drug is currently undergoing clinical trials in the US with results expected in the coming months.

Dr Sterghios A. Moschos, MSB, Director of Westminster Genomic Services at the University of Westminster, developed the comprehensive and innovative method by adapting state-of-the-art genome sequencing technologies to show exactly how the new drug works. The research was conducted in collaboration with the European Bioinformatics Institute and Benitec Biopharma.

Dr Moschos said: “Our entirely new method to test the new drug has had a major impact on building robust confidence in this innovative therapy. For the first time ever we have shown that there are more ways to hit the hepatitis C infection than previously thought possible, and that this treatment works like a combination of multiple drugs. Our approach has helped Benitec Biopharma, to obtain permission to start clinical trials much earlier than we expected. This is unprecedented for gene therapy, particularly for a disease for which treatments already exist.”

For further information you can read the research paper published on Molecular Therapy Nucleic Acids at nature.com.

About the University of Westminster:

The University of Westminster boasts a vibrant learning environment attracting more than 20,000 students from over 150 nations and we continue to invest in our future with new developments, research projects and new ideas.

We offer highly attractive practice-based courses which are independently rated as excellent, many with international recognition. Our distinguished 175-year history has meant we lead the way in many areas of research, particularly politics, media, art and design, architecture and biomedical sciences, and our position in the city of London allows us to continue to build on our close connections with leading figures and organisations in these areas as well as in the worlds of business, information technology, politics and law.

Our commitment to educating graduates for the needs of professional life attracts high quality students from within the UK and around the globe.

Internationalism, employability and sustainability are key elements in the University of Westminster’s vision for the future and we strive to ensure the very highest standards are met and maintained.


Direct Acting Antiviral Combinations

Provided by NATAP

By Jules Levin, NATAP

.......as you can see the SVR rates will be 96-100%. The lowest SVR rates are in the hardest to treat patients: patients who have both cirrhosis and who are prior non-responders. But I expect we can improve SVR rates in studies in these patients too. Some companies are conducting studies by adding another drug to their regimen, see below last parapgraph/link.

Here is a brief simple table, below the table are links to these studies:
These are results for genotype 1 patients with most but not all the regimens in research studies now. This table does not include Simeprevir+Peg/Rbv which was FDA approved in Dec/13. I included the regimens approved by the FDA for mono and connected in December/13 which are: Sofosbuvir (Sovaldi) + Peg/Rbv, approved for mono & coinfected; Sofosbuvir+Rbv approved for both mono & Coinfected. It is widely believed & the data so far supports this, that HCV/HIV connected will respond the same as mono infected to DAA orals, which is why the FDA gave approval for these aforementioned regimens for coinfection. Gilead & Abbvie have studies ongoing now in coinfection, I think when the FDA does provide the expected approvals later this year both Gilead & Abbvie's regimens I think there will be approvals for coinfection too. BMS is in phase 3 now with daclatasvir+sofosbuvir & expected in Western Europe will be expanded access programs, and studies of this regimen just started, here is link to these studies Daclatasvir+Sofosbuvir-new studies, Daclatasvir Phase 3 IFN-free, EMA Compassionate Use, Accelerated EMA Marketing Review Recommendation

There is no data in coinfection with simprevir+sofosbuvir (COSMOS Study), but it can be considered & the ART interactions with the protease simeprevir must be considered. The same can be said for daclatasvir+sofosbuvir, although the interactions with sofosbuvir & ARTs have been reported at a conference & they are not expected to be clinically significant, there are interactions between ARTs & daclatasvir that also were reported at a conference so they too can be adjusted for.

I did not include in this table Achillion data, Presidio data (NS5A), data from Faldaprevir+Peg/Rbv or the 3 drug DAA oral IFN-free Faldaprevir regimen. As you may know recently development of the non-nuke DAA used in the Faldaprevir 3-DAA study was discontinued which included the Presidio NS5A). I did not include Vertex or Idenix data. Vertex is in phase 2 with VX-135 a nucleotide, same class as sofosbuvir. Idenix is in development of several classes of drugs including a NS5A (same class as Ledipasvir, daclatasvir) & nucleotides. Achillion is in development with a protease, a NS5A and a nucleotide.

Merck is in phase 2 lovely quickly into phase 3. BMS is in phase 3. Roche also presented data recently at AASLD in November/13 but their data was disappointing.


Sofosbuvir+Peg/Rbv in HCV/HIV Coinfected (91% SVR) 12 weeks:
Sofosbuvir and Peginterferon Alfa-2a/Ribavirin for Treatment-Naïve Genotype 1-4 HCV-Infected Patients Who Are Coinfected With HIV

Sofosbuvir+Ribavirin in coinfected patients:
AASLD: All-Oral Therapy With Sofosbuvir Plus Ribavirin For the Treatment of HCV Genotype 1, 2, and 3 Infection in Patients Co-infected With HIV (PHOTON-1) - (11/06/13)

This is the most recent data from the COSMOS Study which studied 2 DAAs, sofosbuvir + the protease simeprevir:
SVR results of a once-daily regimen of simeprevir (SMV, TMC435) plus sofosbuvir (SOF, GS-7977) with or without ribavirin in cirrhotic and non-cirrhotic HCV genotype 1 treatment-naïve and prior null responder patients: The COSMOS study - (11/05/13)

Here is the latest study data, slides presented on daclatasvir+sofosbuvir in treatment-naives & in protease failures:
EASL/2012: Potent Viral Suppression With the All-Oral Combination of Daclatasvir (NS5A Inhibitor) and GS-7977 (Nucleotide NS5B Inhibitor), +/- Ribavirin, in Treatment-Naive Patients With Chronic HCV GT1, 2, or 3 (100% SVR gt1, 91% gt2) - (04/19/12)

EASL: Sustained Virologic Response With Daclatasvir Plus Sofosbuvir ± Ribavirin (RBV) in Chronic HCV Genotype (GT) 1-Infected Patients Who Previously Failed Telaprevir (TVR) or Boceprevir (BOC) - (04/27/13)

Here is the very recent journal publication of these studies:
Daclatasvir plus Sofosbuvir for Previously Treated or Untreated Chronic HCV Infection - (01/17/14)

Here is the latest Abbvie data reported by them of their phase 3 data in a press release just recently:
AbbVie Completes Largest Phase III Program of an All-Oral, Interferon-Free Therapy for the Treatment of Hepatitis C Genotype 1 - (01/31/14)


This is the latest presentation of BMS data for their 3 DAA regimen at AASLD November:
Phase 2b Study of the Interferon-Free and Ribavirin-Free Combination of Daclatasvir, Asunaprevir, and BMS-791325 for 12 Weeks in Treatment-Naive Patients With Chronic HCV Genotype 1 Infection - (11/05/13)

This is the most recent Merck data for their 2-drug DAA combination presented at AASLD in November:
AASLD: High Efficacy and Safety of the All-Oral Combination Regimen, MK-5172 / MK-8742 ± RBV for 12 Weeks in HCV Genotype 1 Infected Patients: The C-WORTHY Study - (11/05/13)

Interferon-free Regimen Containing Setrobuvir in Combination with Ritonavir-boosted Danoprevir and Ribavirin with or without Mericitabine in HCV Genotype 1 Treatment-naive Patients: Interim Results from the ANNAPURNA Study - (11/14/13)

As reported by Jurgen Rockstroh, MD, in his NATAP AASLD report [http://www.natap.org/2013/AASLD/AASLD_109.htm], in the NIAID SYNERGY Trial [http://www.natap.org/2013/AASLD/AASLD_30.htm] 60 HCV mono-infected, treatment naïve, GT-1, patients were consecutively enrolled into 3 arms of a phase 2 clinical trial and received: Arm A - sofosbuvir with ledipasvir (400mg/90mg respectively once daily in a fixed dose combination (FDC)) for 12 weeks, Arm B - FDC + GS-9669 (500mg/day), a non nucleoside NS5B inhibitor for 6 weeks, or Arm C - FDC + GS-9451 (80mg/day), an HCV protease inhibitor for 6 weeks (47). 80-95% of study participants were African-American. In this exploratory trial virological responses were very good with 100% SVR12 in the SOF/LDV (12 weeks arm) (n=20), 90% SVR4 in the SOF/LDV/9669 (6 weeks arm) (n=20) and again 100% SVR4 in the SOF/LDV/9451 (6 weeks arm) (n=20). Only one relapse occurred in the SOF/LDV/9669 arm. Tolerability in all arms was good with no treatment related discontinuation or SAEs. Again this 3 DAA combination study underlines that multiple DAA combinations will work and allow to get rid of interferon as well as ribavirin which is accompanied by greatly improved tolerability. Also the combination of 3 DAAs may allow to shorten treatment duration to 6 weeks at least in easier to treat naïve patient populations which may be very important in the more adherence challenged patient groups.