Showing posts with label History of HCV. Show all posts
Showing posts with label History of HCV. Show all posts

Saturday, May 5, 2018

Hepatitis C Timeline - First recorded references to hepatitis epidemics, to the 1989 discovery of the hepatitis C virus, ending with the FDA approved treatments used today.


Page updated August 2018

HCV Flashback: Ancient History

2000 B.C.
First recorded references to hepatitis epidemics.

1947
F.O. MacCallum, using human volunteers, differentiates hepatitis A, which is spread by contaminated food and water, from hepatitis B, which is spread by blood.

1963
Baruch Blumberg and Harvey Alter discover Aa, the Australian antigen (later called HBsAg)..

1967-1968
Blumberg, Kazuo Okochi, Alfred Prince, Alberto Vierrucci, and colleagues report that Aa is involved in the development of hepatitis B.

1969
Irving Millman and Blumberg devise a concept and through the Fox Chase Cancer Center receive a patent for using Aa to prepare a hepatitis B vaccine.

1970
D. S. Dane discovers whole hepatitis B virus particles in blood samples examined with the electron microscope.

1972
Laws are passed in the United States requiring testing of donor blood for HBsAg antigen.

1973-1974
Stephen Feinstone and colleagues and Maurice Hilleman and colleagues discover and describe hepatitis A virus

1974
Post-transfusion non-A, non-B hepatitis was first described as hepatitis C

Hepatitis C  A New Virus
Consequently, chronicity of post-transfusion non-A, non-B hepatitis was discovered as a blandly symptomatic disease with elevation of the liver enzyme alanine aminotransferase (ALT) and chronic hepatitis seen on liver biopsy.

The infectious nature of the entity was confirmed when the disease could be conveyed from humans to chimpanzees. The etiologic agent, the hepatitis C virus (HCV), was recognized as a genetic sequence in 1989 by Choo through random polymerase chain reaction (PCR) assays in plasma of chimpanzees chronically infected with non-A, non-B hepatitis, that led to the development of a first-generation HCV antibody test that identified HCV as the basis of majority cases of formerly "diagnosed" non-A, non-B hepatitis.

In 1974, it was first recognized that not all cases of viral hepatitis were hepatitis A or hepatitis B. It proved difficult to identify the infectious agent responsible for these cases of non-A, non-B hepatitis. However, it has recently become clear that many cases of post-transfusion non-A, non-B hepatitis are the result of infection with a new virus, hepatitis C
Continue reading...

1975
Wolf Szmuness and Hilleman and colleagues begin tests of the hepatitis B vaccine.

1977
Mario Rizzetto and John Gerin discover hepatitis D.

1980-1981
Subunit hepatitis B virus vaccine derived from blood serum is developed by Hilleman and colleagues, proved effective and licensed for general use.

1981.
The Lancet, Volume 317, Issue 8227, Pages 982 - 984, 2 May 1981

NON-A, NON-B HEPATITIS IN WEST LONDON
Original Text
L.J. Farrow a, J.S. Stewart a, H. Stern b, R.E. Clifford c, H.G. Smith c, A.J. Zuckerman

Abstract
Acute and convalescent sera from 368 patients drawn from a 3-year survey of viral hepatitis in West London were tested by radioimmunoassay for evidence of recent infection with hepatitis A or B and, if neither was found, antibody to Epstein-Barr (EB) virus and cytomegalovirus. In 215 patients (58%) there was evidence of hepatitis A, in 98 (27%) hepatitis B, and in 5 both A and B. 2 patients with evidence of recent EB virus infection were excluded, leaving 48 (13%) attributed to non-A, non-B hepatitis. This illness was milder than hepatitis B as judged by duration of jaundice and peak serum bilirubin alanine-aminotransferase levels. The ratio of men to women was 1.4 to 1, but there was an excess of women in their twenties, most of whom were single. Only one had received blood, and none was a drug addict.

1983
Mikhail Balayan describes the hepatitis E virus.

1983-1986
Subunit hepatitis B virus vaccine derived from yeast is developed by William Rutter and colleagues and approved for use.

1984
"In the United States, non-A non-B hepatitis afflicts about 120,000 people a year, 90,000 of whom get the disease through blood transfusion. An estimated 1,000 Americans die each year from non-A non-B hepatitis"

"Dr. Prince said he did not believe the virus his group had found was a retrovirus. He proposes that it be called the ''hepatitis C virus.''The hepatitis in question is now called non-A non-B, signifying that it represents liver disease caused by a virus or viruses other than the two known viruses hepatitis A and hepatitis B. Hole in Screening Process"

NEW REPORT CITES A HEPATITIS CAUSE
By HAROLD M. SCHMECK JR. Published:

November 18, 1984
Scientists of the New York Blood Center have reported the discovery of a new virus they believe may be the major cause of hepatitis transmitted through blood transfusion. The report was the second in two weeks to claim discovery of the probable cause of most cases of post-transfusion hepatitis, a liver disease that affects 90,000 Americans each year. Whether or not the two reports represent the same virus is unknown. If either or both of the research teams that issued reports have found a major cause of this form of the disease, called non-A non-B hepatitis, it may be possible to develop screening tests to eliminate the viruses from blood used for transfusion.....
Continue Reading

1986
Treatment of chronic non-A, non-B hepatitis with recombinant human alpha interferon.
A preliminary report.Volume 315:1575-1578 December 18, 1986 Number 25

Abstract
We treated 10 patients who had chronic non-A,non-B hepatitis with recombinant human alpha interferon in varying doses (0.5 to 5 million units) daily, every other day, or three times weekly for up to 12 months. In 8 of the 10 patients, elevated serum aminotransferase levels decreased rapidly during therapy and eventually fell into the normal or nearly normal range. In two of these patients, the interferon therapy was stopped after four months, and in both cases, a prompt return of aminotransferase activities to pretreatment values occurred. Prolonged treatment was associated with a sustained improvement
continue reading....

1989
Daniel Bradley provides Chiron with non A-non B hepatitis serum from chimpanzees; Michael Houghton and colleagues discover a single virus, publish the genetic sequence of the viral agent, and change the name to hepatitis C.

1990
Blood screening for hepatitis C begins.
January 1990

Hepatitis C test shows promise, pitfalls
An experimental blood test that detects antibodies to hepatitis C in donated blood identities many, but not all, tainted units, two studies indicate. The data suggest that the test, now under consideration by the Food and Drug Administration for routine use in blood banks, will reduce the number of transfusion-associated cases of hepatitis C. But the test's inability to flag all infectious units hints at the presence of an undiscovered causative agent underlying some hepatitis cases, and highlights the difficulties of eliminating the potentially fatal river disease.

1991
FDA Approves Hepatitis C Treatment; Alpha Interferon to Be Used Against Infectious Liver

FDA approves first alfa interferon (Schering’s Intron A) to treat hepatitis C.
By LAWRENCE M. FISHER, Special to The New York Times
Published: February 26, 1991
SAN FRANCISCO, Feb. 25— The Schering-Plough Corporation received Food and Drug Administration approval today to use alpha interferon, one of the earliest drugs produced by biotechnology, for the treatment of hepatitis C. Alpha interferon is the first treatment approved for this sometimes fatal viral infection, which causes chronic liver inflammation and can lead to cirrhosis and liver cancer. which is marked by sustained inflammation of the liver - making them candidates for the drug.

1992
FDA approves first interferon (Schering-Intron A) to treat hepatitis B.

1993
"The committee also suggested that public service announcements be developed to notify people who received blood donations prior to May 20, 1990, to get a test for hepatitis C"

Blood and Hepatitis C; FDA Advises Tracing Recipients When Transfusion Is Tainted

The Washington Post -
Washington, D.C. Author: Sally Squires Date: Dec 7, 1993
The FDA requires the tracing, or look backs, of blood in cases where the blood donor, sometime after the donation, is found to be HIV-positive. Blood is not accepted from anyone who says he has HIV or hepatitis, and it is tested at the time of the donation and discarded if tests reveal the donor has either of the diseases. Sometimes, though, the donor may have contracted one of the diseases but not yet developed the immune system antibodies to fight the viruses, so the blood will pass through the testing undetected. It is blood from those donors that would be traced.The FDA's Blood Products Advisory Committee also recommended unanimously that blood banks begin retrieving and discarding stored plasma and blood products from donors who had recently tested positive for hepatitis C. This would occur even though at the time the blood was drawn the donors tested negative for hepatitis C. The committee also suggested that public service announcements be developed to notify people who received blood donations prior to May 20, 1990, to get a test for hepatitis C.

1996
FDA approves alfa interferon (Roche, now Genentech- Roferon A ) to treat hepatitis C.

1997
FDA approves consensus interferon (Amgennow InterMune-Infergen) to treat hepatitis C.

1998
FDA approves Rebetron (Schering’s Intron A plus ribavirin)for the treatment of hepatitis C.

2001
Peg-Intron
Approved Peg-Intron (Schering’s pegylated interferon alpha-2b) was the first pegylated interferon FDA approved to treat hepatitis C.

2002
Pegasys Approved
Pegasys (Genentech’s pegylated interferon alpha-2a) was approved to treat hepatitis C

2003
Intron A (interferon) plus Rebetol (ribavirin- available in oral solution) approved for treating pediatric patients with chronic hepatitis C.

Of Interest
Halted - First protease inhibitor
In 2003 the first protease inhibitor to enter clinical trials was Boehringer Ingelheim's ciluprevir (BILN 2061) but clinical development was halted in 2006 because of cardiotoxicity in animals. 


Halted - First nucleoside polymerase
In 2004 the first nucleoside polymerase to enter clinical trials was Idenix Pharmaceuticals and Swiss partner Novartis drug Valopicitabine which was discontinued in 2007 because of modest antiviral efficacy along with significant gastrointestinal side effects. 

2005
HCV Replicated in Test Tube

2006
Mouse Model Scientists made dramatic in roads into understanding the various mechanisms of action of the hepatitis C virus and replicated various HCV genotypes in a test tube.

2007
Drugs in Development In 2007, many new drugs were advanced into development. The leading compound is VX-950 (telaprevir) an HCV protease inhibitor that is being developed by Vertex

Drug Telaprevir in Patients with Genotype 1 Hepatitis C May Cut Treatment Time.

2007
Hepatitis B found in South Korean 500 year old mummy's liver

2008
Diabetes Doubles Liver Cancer Risk For Patients With Advanced Hepatitis C

2009
Direct antiviral medications telaprevir and boceprevir(HCV protease inhibitors) finish enrollment in their clinical trials and expect to complete their trials and file formarketing approval late in 2010.

2010
Roche's 18-minute Elecsys Antibody anti-HCV test would scan for total antibodies in human serum or plasma.The test may be used in the diagnosis of HCV infections in those with symptoms of hepatitis or at risk of hepatitis C which is primarily transmitted through contaminated blood and blood products

2011
In May the first direct-acting antivirals (DAAs) boceprevir and telaprevir received FDA approval.

On May 23, the FDA approved protease inhibitor Incivek-telaprevir for the treatment of HCV genotype 1 patients and on May 13, Vicrelis/boceprevir with the same indication was also approved.

Geographic distribution of genotypes

The geographic distribution of genotypes is a starting point for a rich and harrowing look at how viruses move across the world. For example, one of the ways that hepatitis was spread through Egypt was through a campaign against schistosomiasis along the Nile delta in the 1960s.

(Here is one interesting PDF on that.) It was a well-intentioned and needed public health measure but the needles weren’t sterilized and so as people were treated for the parasite, village by village, the virus made its way around. Egypt currently has the highest rates of HCV in the world. Anti-malaria campaigns in Cameroon had a similar impact.

Also fascinating is the fact that the spread of the virus can be traced across slave trade routes from Africa to Europe. And, as Oliver Pybus, an evolutionary biologist at Oxford University, points out, that fact brings up another central mystery about HCV, which is that the virus has been around for thousands of years, but the most common modes of transmission that we know of are connected to relatively modern inventions (blood transfusions and needles to inject drugs). “What is clear is that this endemic transmission was occurring across the whole of Sub-Saharan Africa and Asia and it doesn’t seem right that it would be maintained by very culturally-defined and location-specific routes of transmission,” Pybus once told me. In other words, as he explained, practices like scarification and tattooing could account for some, but not all, of the spread of HCV in that time and place. Making his insights even more fascinating is the fact that Pybus has managed to use genome sequencing and computer programs to trace the phylogenetic tree of HCV that extends over thousands of years. (Pybus was the CDC’s point person on tracking the origin of swine flu a few years back because of the software and methods he’s invented.)
Continue reading....

How Did HCV Infect Humans?
Then there is the question of how HCV got into humans in the first place. Columbia University virologist Ian Lipkin recently shed some fascinating light on this question when he found a genetic homolog of HCV in dogs. Here’s a tiny bit from me on that and a lot more about it from Carl Zimmer.
Continue reading....

2012
Treatment of chronic hepatitis C genotype 1 with triple therapy comprising telaprevir or boceprevir
INCIVEK® (telaprevir) - Updates label after reports of a ‘small number of fatal skin reactions’
Vertex discloses Hep C drug deaths

2012 - New Antiviral Agents for Hepatitis C
This article describes the direct acting antivirals and host-targeted agents that have recently been approved or have been tested in HCV-infected patients and discusses their two current paths of clinical development: with or without interferon-α.

Bristol-Myers Squibb - BMS-986094 (formerly INX-189) - Discontinued
BMS halts the development of BMS-986094 due to patient death The original patient subsequently died and eight others suffered from heart and kidney toxicity, the company said in a statement released last night. Two of the patients remain hospitalized.
Continue Reading...

2013
The Centers for Disease Control and Prevention (CDC) and US Preventive Services Task Force (USPSTF) recommend that all baby boomers, people born from 1945 through 1965 be tested once for hepatitis C

Why Screen All Baby Boomers?
Although the authors of the recommendations regarding screening for HCV infection note that the prevalence of HCV infection in the United States appeared to peak in 2001, there is another clear trend in the epidemiology of HCV infection that merits close attention. Persons born between 1945 and 1965 comprise approximately 27% of the total population of the United States, but they account for a disproportionate share of cases of HCV infection. The prevalence of HCV infection in this age group is 3.25%, and approximately three quarters of active HCV infection cases are encountered among persons born between 1945 and 1965.
Moreover, and more important, persons who are currently in the fifth through seventh decades of life at this time are at the highest risk for complications from HCV infection. They account for 73% of mortality due to HCV infection, and this group is also at the highest risk for hepatocellular carcinoma and cirrhosis. Therefore, the number of patients needed to treat with anti-HCV therapy in order to prevent additional cases of mortality is lower in this specific older cohort of adults compared with younger adults.

Therefore, it is not only the epidemiologic data that drive the new HCV screening recommendations from the USPSTF, but also an expectation that treatment of heretofore undiagnosed HCV infection can put a substantial dent in the broad clinical impact of HCV. The new recommendations call for 1-time screening for all adults born between 1945 and 1965 (B recommendation: high certainty that the net benefit is moderate, or moderate certainty that the net benefit is moderate to substantial). The anti-HCV antibody is test the best screening tool for these adults.

Bats a possible source for HCV-like viruses?
Hepatitis C: Closing in on its viral origins
Just like the bat viruses, these too exhibited a large degree of genetic variability, hinting at an enduring history of infection. Future studies could see rodents emerge as the confirmed source of the virus

None of the rodent sequences was more related to HCV than the horse hepaciviruses, but one of the co-authors of this study, Prof Peter Simmonds from the University of Edinburgh, thinks that the large degree of variability observed in these rodent viruses might prove significant...
Continue reading....

New Drug Approved November/December 2013

Sovaldi 
Sofosbuvir FDA Approved In U.S. and Canada
Gilead's Sovaldi (Sofosbuvir) Is Now FDA Approved
– Sovaldi Approved for Use in Genotypes 1, 2, 3 or 4 –
– High Cure Rates (SVR12) and Shortened, 12-Week Course of Therapy for Many Patients –
– First Ever Oral Treatment Regimen for Genotypes 2 or 3 –
– First Regimen for Patients Awaiting Liver Transplantation to Prevent HCV Recurrence –

Sovaldi is approved in HCV genotypes 1 and 4, treatment-naïve adults in combination with PEG-IFN and ribavirin and the first approved interferon-free treatment regimen for people with HCV genotypes 2 and 3. Overall cure rates are at 80%, response rates and treatment duration varies, depending on genotype, viral and host factors.
Download PDF

OLYSIO
Simeprevir FDA Approved
OLYSIO™ (simeprevir) Receives FDA Approval for Combination Treatment of Chronic Hepatitis C
Johnson & Johnson's protease inhibitor OLYSIO (Simeprevir) is approved for the treatment of HCV genotype 1, in combination with peginterferon alfa and ribavirin in adults with compensated liver disease, including cirrhosis, who are treatment-naïve or who have failed previous interferon therapy (pegylated or non‑pegylated) with ribavirin.

Simeprevir was approved in Japan this past September 2013, and in Canada on November 20th.

2014
May 4 2014
Yellow Blood: Hepatitis C and the Modernist Settlement in Japan.
In 1964, HCV infection via direct blood-to-blood contact with contaminated blood was happening wherever medicine could afford transfusion technology and wherever blood products and hypodermic syringes were in use as therapies or therapy delivery systems. Although the hepatitis C virus probably originated in West Africa in the late 15th century, its global sweep and pandemic status in the world today are both intimately linked with progression of the modernist settlement: the dualistic epistemological structure of modernity in which science and technology are divided from and purified of culture and politics. 

June 20 2014
Boehringer Ingelheim exits hepatitis C field, pulls regulatory filings for faldaprevir
Boehringer Ingelheim on Friday announced that following a strategic review the company has decided against moving forward in the field of hepatitis C. As such, the drugmaker indicated that it will withdraw all regulatory filings for faldaprevir, which had been granted accelerated assessment by the European Medicines Agency, and will discontinue further development of the protease inhibitor.

August 13 2014
PegLambda Discontinued by BMS
We have decided to discontinue the Lambda HCV development program and will no longer be seeking regulatory review of Lambda, globally. We would like to take this opportunity to reinforce that our late-stage HCV DAA development program remains unaffected.

August 14 2014
Vertex to stop selling hepatitis C drug Incivek
Vertex’s decision to stop selling Incivek in the United States as of Oct. 16 was conveyed in a Monday letter to health care providers written by Charles Johnson, the company’s vice president of global medical affairs.

Oct 7 2014
Bristol-Myers withdraws FDA NDA for asunaprevir
Bristol-Myers Squibb (BMY) has decided that it will not pursue U.S. Food and Drug Administration (FDA) approval of the dual regimen of daclatasvir and asunaprevir for the treatment of HCV genotype 1b patients in the United States and has therefore withdrawn its new drug application (NDA) for asunaprevir, an NS3/4A protease inhibitor.

Oct 10 2014
Harvoni FDA APPROVED

U.S. Food and Drug Administration Approves Gilead’s Harvoni® (Ledipasvir/Sofosbuvir), Once-Daily Single Tablet Regimen for the Treatment of Genotype 1 Chronic Hepatitis C
Harvoni is the first combination pill approved to treat chronic HCV genotype 1 infection. It is also the first approved regimen that does not require administration with interferon or ribavirin, two FDA-approved drugs also used to treat HCV infection.

Both drugs in Harvoni interfere with the enzymes needed by HCV to multiply. Sofosbuvir is a previously approved HCV drug marketed under the brand name Sovaldi. Harvoni also contains a new drug called ledipasvir.
Continue reading...

Oct 20 2014
New Report BMS-986094 (halted in 2012)
HCV nucleotide analogue polymerase inhibitor associated with cardiac dysfunction
Fourteen of 34 patients with hepatitis C virus infection who were treated with the novel nucleotide analogue polymerase inhibitor BMS-986094 had some evidence of cardiac dysfunction, according to a new report.

Oct 26 2014
3 die after being administered SOVRIAD™ (simeprevir sodium) Hepatitis C drug
The health ministry said Friday three people have died after taking the hepatitis C drug Sovriad, and it has ordered the distributor to revise the drug packaging to say usage should stop when indicated by a patient blood test. 

Nov 6 2014
FDA approves Medivir's Olysio (simeprevir) in combination with Gilead Sciences' Sovaldi (sofosbuvir)
-Expanded indication includes both treatment-naïve and treatment-experienced adult patients with or without cirrhosis-

Medivir AB (Nasdaq Stockholm:MVIR) announces that the U.S. Food and Drug Administration (FDA) has approved Olysio® (simeprevir) in combination with sofosbuvir as an all-oral, interferon- and ribavirin-free treatment option for genotype 1 chronic hepatitis C infection in adult patients as part of a combination antiviral treatment regimen

Nov 18 2014
European Commission Grants Marketing Authorization for Gilead's Harvoni (Ledipasvir/Sofosbuvir), the First Single Tablet Regimen to Treat the Majority of Chronic Hepatitis C Patients With Genotype 1 and 4

December 19 2014
FDA approves VIEKIRA Pak
FDA Approves AbbVie Combo Hepatitis C Treatment
On December 19, 2014, FDA approved VIEKIRA Pak (ombitasvir, paritaprevir, ritonavir fixed dose combination tablets copackaged with dasabuvir tablets) for use with or without ribavirin for the treatment of patients with genotype 1 chronic hepatitis C virus (HCV) infection including those with compensated cirrhosis.

Medscape - Free registration is required to view slides
Slideshow 25-year span of HCV
The glorious accomplishments in this field are nicely summarized as "the arc of a medical triumph" by Chung and Baumert, highlighting the short, 25-year span from the discovery of hepatitis C virus (HCV) to treatment that now achieves cure in more than 95% of patients with a single oral pill taken once daily for 8-12 weeks.

2015
April 16 2015
FDA approved changes to the Olysio (simeprevir) package insert to include two new Warnings and Precautions 


Mar 21 2015
FDA Update - Important safety information: Harvoni , and Sovaldi‏
Serious and Life-Threatening Cases of Symptomatic Bradycardia as well as One Case of Fatal Cardiac Arrest Reported with Coadministration of amiodarone with either Harvoni® (ledipasvir and sofosbuvir fixed-dose combination) or with Sovaldi® (sofosbuvir) in combination with another direct acting antiviral.

Mar 19 2015
Boceprevir Expected to be Discontinued by December 2015
Merck expects to discontinue the manufacturing and distribution of its inhibitor boceprevir for the treatment of hepatitis C virus by December, according to a company spokesperson.

July 24 2015
FDA APPROVED TWO DRUGS FOR THE TREATMENT OF HCV
Technivie and Daklinza
At the end of July the FDA approved two new drugs for hepatitis C, one for genotype 3 called Daklinza "Daclatasvir" in combination with sofosbuvir and the other is Technivie (ombitasvir, paritaprevir, ritonavir) for genotype 4. To view package insert, dosage, warnings, drug interactions and side effects for the newly approved drugs, click here.

The Food and Drug Administration (FDA) announced that Rebetol(ribavirin; Merck) capsules and PegIntron (peginterferon alfa-2b; Merck) for Injection are being discontinued. The decision is business-related and not due to safety or efficacy issues with the drugs.


Nov 30, 2015 - Imported Generic hepatitis C Drugs - Buyers Club
Real life Dallas Buyers Club operation helps hepatitis C patients with free drugs
Which is why two months ago, as Fairfax Media revealed,  a campaigning group of sufferers and doctors launched a Dallas Buyers Club operation to source and test generic versions of Gilead's drugs – Sovaldi and Harvoni – from manufacturers in China, India and Bangladesh for about $20 a pill.
Since the FixHepC Buyers Club was started by father-and-son team Dr John and Dr James Freeman, tens of thousands of people in more than 100 countries have made several million visits to the fixhepc.com website.

2016
Jan 28 2016​
FDA Approved ZEPATIER
Merck Receives FDA Approval of ZEPATIER™ (elbasvir and grazoprevir) for the Treatment of Chronic Hepatitis C Virus Genotype 1 or 4 Infection in Adults Following Priority Review
ZEPATIER Achieves High Cure Rates (SVR12) in Broad Range of Patients with Chronic Hepatitis C Infection, Including Those with Compensated Cirrhosis, Renal Impairment of Any Degree and HIV-1/HCV Co-infection​
The list price for Zepatier will be $54,600 for a 12-week regimen, which Merck said it expects "to be in the range of net prices" for comparable treatments.​
Prescribing Information for ZEPATIER (elbasvir and grazoprevir)
Patient Information for ZEPATIER 

April 2016
Watch
25 Years From Discovery To Cure: The Hepatitis C Story |
Nezam Afdhal | TEDxOxford
The discovery of the hepatitis C virus in 1989 and 25 years of has led to new treatments that can now cure almost all patients with hepatitis C and have the ability to reach almost 200 million people globally. Dr. Afdhal discusses how discovery of the virus lead to understanding the global epidemiology and modes of spread of hepatitis C and the recognition that it was the commonest cause of cirrhosis, liver cancer and need for liver transplantation. The development of model systems to look at viral replication led to treatments initially with injectable interferon with low cure rates and poor patient tolerability to new all oral direct acting anti-viral agents which can cure patients with a simple, safe and effective 8 – 12 week treatment. Finally Dr. Afdhal discusses how these treatments have changed the discussion in the US on the cost of new medications and the ongoing plans to bring these expensive treatments to developing countries with high hepatitis C burden.

Stigma
Medical practices, not lifestyle choices, are actually behind the generation’s high HCV rates, so now will you go get tested?

HCV epidemic in North America peaked between 1940 and 1965 with medical procedures likely source of most infections
Most baby boomers infected in hospital and by reused medical syringes, not injecting drug use or risky sex..

June 2016
June 9, 2016
The story of hepatitis C from discovery to cure is very much like the plot of a good mystery novel. It begins with a puzzling who-done-it, followed by a lengthy hunt for the suspect, and, finally, rigorous efforts to subdue the perpetrator. Many of these efforts were spearheaded by the NIDDK, and, although the narrative is not quite finished, the battle against hepatitis C is evolving into one of the biggest modern success stories in scientific research.

June 27
Regulus Therapeutics (RGLS) Announces Clinical Hold on RG-101
Regulus Therapeutics Inc. (Nasdaq: RGLS), a biopharmaceutical company leading the discovery and development of innovative medicines targeting microRNAs, today announced it received verbal notice from the U.S. Food and Drug Administration (FDA) that its Investigational New Drug (IND) for RG-101 for the treatment of chronic hepatitis C virus (HCV) infection has been placed on clinical hold. Regulus anticipates it will receive a formal clinical hold letter from the FDA within 30 days and plans to work diligently with the agency to seek the release of the clinical hold​

January 31, 2017
Regulus Announces Continuation of RG-101 Clinical Hold - FDA requests longer-term follow-up data from ongoing studies

June 28 2016
FDA Approved: Epclusa® (Sofosbuvir/Velpatasvir
At the end of June the FDA Approved Gilead's Epclusa® (Sofosbuvir/Velpatasvir) to treat Genotype 1-6, for prescribing information click here, in addition on July 8th the European Commission granted marketing authorization for Epclusa, followed yesterday by approval in Canada.

HCV Guidelines
A great source for learning all about treatment can be found in the HCV Guidelines, this ever changing document is updated when new HCV drugs are approved, and new real world data is established. Last week it was updated to include Epclusan ®.
Stay current with all guideline updates, click here.

July 2016
July 25, 2016
VIEKIRA XR
VIEKIRA XR is a once-daily, extended-release co-formulation of the active ingredients in VIEKIRA PAK (ombitasvir, paritaprevir, and ritonavir tablets; dasabuvir tablets) and is for the treatment of patients with chronic genotype 1 (GT1) hepatitis C virus (HCV) infection, including those with compensated cirrhosis (Child-Pugh A). VIEKIRA XR is not for people with decompensated cirrhosis.

VIEKIRA XR differs from VIEKIRA Pak in that all of the HCV antiviral drugs are now combined in one fixed dose combination tablet for once daily dosing. The daily mg dose of dasabuvir is higher, and dasabuvir is administered once daily as part of the fixed dose combination.

The Controversy - Drug Cost

Epclusa Cost
Bloomberg reported Epclusa will cost $74,760 for a 12-week course of treatment, less than Gilead’s Sovaldi Harvoni, at $84,000 or $94,500 before any discounts, read the article here.

Canada; New Health Canada approved drug costs more than $700 a pill. The list price in Canada is set at $60,000 for a 12-week course

September 2016
Inventor of Hepatitis C Cure (Sovaldi) Wins Lasker Award
Michael Sofia, has netted a prestigious Lasker Award for revolutionizing hepatitis C care. Lasker Awards, which recognize scientists’ major contributions to medical science or those who have performed public service on behalf of the field, are often considered a pit stop on the way to a Nobel Prize.

Oct 2016
FDA MedWatch/Direct-Acting Antivirals for Hepatitis C: Drug Safety Communication - Risk of Hepatitis B Reactivating
The FDA is warning about the risk of hepatitis B virus (HBV) becoming an active infection again in any patient who has a current or previous infection with HBV and is treated with certain direct-acting antiviral (DAA) medicines for hepatitis C virus. In a few cases, HBV reactivation in patients treated with DAA medicines resulted in serious liver problems or death. HBV reactivation usually occurred within 4-8 weeks.

Oct 27, 2016 - Generic imported DAAs - Buyers Club
Buyers’ Clubs: Generic versions of HCV drugs resulted in very high cure rates
Keith Alcorn
Use of generic versions of direct-acting antivirals resulted in very high cure rates for people who obtained the products through three buyers’ clubs, indicating that the generics products are effective, according to three presentations at the International Congress on Drug Therapy in HIV Infection in Glasgow this week.
People who purchased the drugs were cured of hepatitis C at a cost of around $700-$900, Dr Andrew Hill of St Stephen’s AIDS Trust, London, reported in three poster presentations at the conference.
Continue reading ....

Nov 12, 2016
MK3 (MK-3682/grazoprevir/ruzasvir1)
AASLD 2016 Merck's HCV Triple-Combination High Rates of SVR In Genotypes 1, 2 or 3 Infection

Nov 2016
Liver Cancer After Treatment For Hepatitis C
This collection of research articles is updated as information is made available, accessed from online journals, media articles, and conferences with some articles overlapping.

Dec 8, 2016
Gilead Submits New Drug Application to U.S. Food and Drug Administration for the Investigational Single Tablet Regimen Sofosbuvir/Velpatasvir/Voxilaprevir
Gilead Sciences, Inc. announced that it has submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for an investigational, once-daily single tablet regimen containing sofosbuvir 400 mg, velpatasvir 100 mg, and voxilaprevir 100 mg (SOF/VEL/VOX) for the treatment of direct-acting antiviral (DAA)-experienced chronic hepatitis C virus (HCV)-infected patients. The data submitted in the NDA support the use of the regimen for 12 weeks in DAA-experienced patients with genotype 1 to 6 HCV infection without cirrhosis or with compensated cirrhosis.

2017
Jan 2017
Regulus Announces Continuation of RG-101 Clinical Hold - FDA requests longer-term follow-up data from ongoing studies

Feb 2017
Thousands of British Columbians living with hepatitis C will have better access to treatment as a result of successful negotiations brokered by the pan-Canadian Pharmaceutical Alliance (pCPA).
“This agreement changes the landscape for hepatitis C patients living in B.C.,” said Health Minister Terry Lake. “Not only are there four new treatment options for what is now a curable virus, but the savings that were negotiated will allow us to cover treatment options for all hepatitis C patients – rather than just those in more advanced stages of the disease.”

TECHNIVIE (fixed-dose combination of ombitasvir, paritaprevir, and ritonavir) label was updated to expand the indication
On February 27, 2017 the TECHNIVIE  (fixed-dose combination of ombitasvir, paritaprevir, and ritonavir) label was updated to  expand the indication to patients with genotype 4 chronic hepatitis C virus infection (HCV) with compensated cirrhosis. Below is a summary of the major changes to the label based on the results of the AGATE-1 trial in HCV genotype 4 infected adults with compensated cirrhosis who are either treatment-naïve or pegylated interferon/ribavirin treatment experienced. Other minor revisions were made to the table including updates to section 8.1 Pregnancy and 8.2 Lactation.

Feb 2, 2017
U.S. FDA Grants Priority Review to AbbVie’s Investigational HCV Regimen of Glecaprevir/Pibrentasvir (G/P)

Of Interest
March 8, 2017
Full Text Article - Newer medications can cure HCV infections

February 21, 2017
Novel emerging treatments for hepatitis C infection: a fast-moving pipeline
This update reviews some upcoming therapies for the treatment of chronic hepatitis C.

With hep C franchises languishing, Merck’s MK-3682 goes from blockbuster to bomb
by John Carroll
A little less than three years after acquiring the hepatitis C drug MK-3682 (uprifosbuvir) in its $3.85 billion buyout of Idenix, Merck’s prospects in the field have cooled dramatically, and its once great hopes for the drug have been reduced to nearly nothing.
Continue reading...

Controversy
Liver Specialist Refutes Study Claiming Hepatitis C Drug Dangers
The ISMP report cited 524 cases of liver failure and 1,058 cases of severe liver damage in patients taking one of nine DAAs.

2017 - Of Interest
Current therapy for chronic hepatitis C: The role of direct-acting antivirals.
Antiviral Res. 2017 Jun;142:83-122. doi: 10.1016/j.antiviral.2017.02.014. Epub 2017 Feb 24.
Highlights
• HCV genotype-specific drugs evolve to pan-genotypic drugs.
• Drug potency increases from moderate (∼60%) to high (>90%) levels of sustained virologic response.
• Treatment durations are shortened from a 48-week to 12-week or 8-week period.
• HCV therapies based upon multiple pills per day are simplified to a single pill per day.
• HCV therapies are administered orally regardless of prior treatment history and cirrhotic status.

FDA Update
April 7, 2017
FDA Approves HCV Sovaldi and Harvoni For Children Ages 12 to 17

Updates
November 15, 2017
Sep 21, 2017
June 2017
Controversy
Rebuttal over Cochrane Review of DAAs
View each rebuttal and all ongoing media coverage. In June the HCV community was blindsided when an article with a somewhat "clickbait" headline was released by The Guardian. The Guardian reported on a systematic review published by the Cochrane Collaboration that suggested achieving SVR (cure) for patients using hepatitis C direct-acting antivirals (DAAs) doesn't correlate with any long term benefits...

July 18, 2017
FDA APPROVED VOSEVI 
Gilead's VoseviTM (Sofosbuvir/Velpatasvir/Voxilaprevir) FDA Approved for Re-Treatment of Adults with HCV
- Vosevi is the First Once-daily Single-Tablet HCV Regimen Approved as Salvage Therapy for Certain Patients and Completes Gilead's Portfolio of Sofosbuvir-based HCV Direct-acting Antiviral (DAA) Treatments -
FOSTER CITY, Calif.--(BUSINESS WIRE)--Jul. 18, 2017-- Gilead Sciences, Inc. (NASDAQ: GILD) today announced that the U.S. Food and Drug Administration (FDA) has approved VoseviTM (sofosbuvir 400 mg/velpatasvir 100 mg/voxilaprevir 100 mg) tablets, a single-tablet regimen for the re-treatment of chronic hepatitis C virus (HCV) infection in adults with genotype 1, 2, 3, 4, 5 or 6 previously treated with an NS5A inhibitor-containing regimen, or with genotype 1a or 3 previously treated with a sofosbuvir-containing regimen without an NS5A inhibitor. The approval is based on data from the Phase 3 POLARIS-1 and POLARIS-4 studies, which evaluated 12 weeks of Vosevi in direct-acting antiviral-experienced chronic HCV-infected patients without cirrhosis or with compensated cirrhosis.

Aug 1, 2017
Epclusa
FDA Approves Expanded Labeling for Epclusa® for Hepatitis C in Patients Co-Infected with HIV

August 3, 2017
FDA APPROVED MAVYRET 
AbbVie Receives U.S. FDA Approval of MAVYRET™ (glecaprevir/pibrentasvir)
The U.S. Food and Drug Administration today approved Mavyret (glecaprevir and pibrentasvir) to treat adults with chronic hepatitis C virus (HCV) genotypes 1-6 without cirrhosis (liver disease) or with mild cirrhosis, including patients with moderate to severe kidney disease and those who are on dialysis. Mavyret is also approved for adult patients with HCV genotype 1 infection who have been previously treated with a regimen either containing an NS5A inhibitor or an NS3/4A protease inhibitor but not both.

Monthly WAC price for HCV Drugs Including Mavyret
Tweeted by Henry E. Chang



Aug 4, 2017
Of Interest
The changing HCV treatment cascade
The shift in the HCV treatment paradigm is now heavily patient-centric and dependent on genotype, presence of cirrhosis, HIV coinfection, potential drug interactions, previous treatment failure, and renal impairment. In its simplest form, the backbone of HCV treatment requires a combination DAA with or without the addition of ribavirin and duration varies on the presence of cirrhosis.

September 11, 2017
J&J unit ends hepatitis C drug development in crowded market
Janssen Sciences Ireland UC (Janssen), today announced a strategic decision to discontinue further development of the investigational hepatitis C treatment regimen JNJ-4178, a combination of three direct acting antivirals - AL-335, odalasvir and simeprevir. The ongoing phase II studies with JNJ-4178 will be completed as planned, but there will be no additional development thereafter. This decision was made in light of the increasing availability of a number of highly effective therapies addressing the medical need in hepatitis C.

Sept 28, 2017
Is HCV Drug Development Nearing Its End?
Two new FDA approvals fill medical gaps, but access to treatment remains a challenge

Sept 29,2017
Merck Discontinues MK-3682B and MK-3682C Development Programs
Merck to discontinue the development of the investigational combination regimens MK-3682B (grazoprevir/ruzasvir/ uprifosbuvir) and MK-3682C (ruzasvir/uprifosbuvir) for the treatment of chronic hepatitis C virus (HCV) infection.

October 2017 - Generic imported DAAs
High sustained virological response rates using imported generic direct acting antiviral treatment for hepatitis C
High prices of direct acting antivirals (DAAs) for hepatitis C virus (HCV) can lead to restrictions on access to treatment in high- and middle-income countries. An increasing number of people in these regions are treating their HCV infection with generic drugs produced in India, China, Bangladesh or Egypt. This analysis assessed the efficacy of generic imported DAAs

November 16, 2017
HCV Timeline
To get insight into what the recent approvals and pricing structure of new DAA therapies means to treatment of HCV, read the following editorial at Healio, from Michael S. Saag, MD,  here.”

Click on HCV Timeline To Enlarge Image, Or View Image, here.....



December 8, 2017
Liver cancer incidence after HCV therapy linked to risk factors, not treatment
Li DK, et al. Hepatol. 2017;doi:10.1002/hep.29707.
Direct-acting antiviral treatment for hepatitis C did not correlate with an increased risk for hepatocellular carcinoma in a large cohort study of both treated and untreated patients with or without cirrhosis. Those with incident HCC after DAA treatment had higher risk factors at baseline. “There was no increased risk for HCC as a result of having received DAA therapy whatsoever,” Raymond T. Chung, PhD, director of Hepatology and Liver Center at Massachusetts General Hospital, told Healio Gastroenterology and Liver Disease. “The risk was related to their preexisting likelihood of developing HCC. The fact that HCC developed post-DAA, we think, is more likely to be an accident of timing than the idea that it's related to receipt of DAA — these persons were at risk for HCC whether they received DAAs or not.”
Continue reading........

December 30, 2017
The Long Road To Safe and Effective HCV Drugs: A Tribute To The People Who Helped Us Get There
Although before we look ahead to 2018, I thought we might look back. Why? So that we may never forget just how far we've come, and the people who helped us get there.

January 5, 2018
The paradox of HBV evolution as revealed from a 16th century mummy

May 11, 2018
Stone Age hepatitis B virus decoded
Study recovers oldest viral genomes, and shows the hepatitis B virus has been circulating in Europe for at least 7,000 years

Hepatitis B Detected in 4,500-Year-Old Remains
CAMBRIDGE, ENGLAND—Science Magazine reports that a team of scientists led by Eske Willerslev of the University of Cambridge has detected the virus that causes hepatitis B (HBV) in the 4,500-year-old remains of a man who lived in what is now Osterhofen, Germany. In all, the team sequenced the genomes of 304 people who lived in Eurasia between 3500 and 500 B.C., and found the virus in 12 of them. In addition, geneticist Johannes Krause of the Max Planck Institute for the Science of Human History and his colleagues found traces of HBV in the teeth of three skeletons, also unearthed in Germany, dating from 5000 to 3200 B.C. Krause said the liver-destroying disease “seems to have been pretty common in the past.” The oldest-known hepatitis B virus strain before these studies were conducted had been found in a sixteenth-century mummy in Italy. For more on ancient evidence of disease, go to “Heart Attack of the Mummies.”

May 25, 2018
Hepatitis C Virus Infection Treatments to Be Discontinued:Technivie, Viekira XR and Simeprevir 
With an estimated 257 million individuals worldwide living with hepatitis B virus (HBV), the disease constitutes a global health public issue, according to the World Health Organization.

Previously, little has been known about the origins and global spread of HBV-D and HBV-A, the most prevalent genotypes of the virus. A recent study published in eLife sought to establish the HBV dissemination patterns across different geographic regions for both genotypes.

“The epidemiological history of HBV-D and HBV-A remains unclear due to a lack of relevant studies,” lead author Evangelia-Georgia Kostaki, PhD candidate in molecular epidemiology at the National and Kapodistrian University of Athens, said in a statement. “In order to uncover more of this detail, we wanted to establish how HBV was disseminated across different geographic regions.”

To accomplish this goal, the researchers used 916 HBV-D and 493 HBV-A full-genome sequences to reconstruct the genotypes’ evolutionary development and diversification, and analyze their levels of regional clustering.

Using this method, the researchers determined that the origin of HBV-D was in North Africa and the Middle East, although they were not able to locate the exact origin accurately. The researchers also found low levels of regional clustering for the Middle East and Southern Europe.

“We found low levels of HBV-D transmission occurred locally in North Africa and the Middle East, suggesting a high amount of movement among populations infected with HBV in these areas,” senior author Dimitrios Paraskevis, PhD, assistant professor of epidemiology and preventive medicine at the National and Kapodistrian University of Athens, said in the press release.

These findings are reflective of the history of human migration patterns in these areas, resulting in the spread of HBV-D, Dr Paraskevis noted.

For HBV-A, the analysis suggests the origin is close to Africa and Europe, and likely in the Middle East and Central Asia. Following HBV-A’s initial spread in Central Asia, the virus followed 2 distinct pathways: 1 to eastern and southern Africa and another to sub-Saharan and western Africa. The researchers indicated that the slave trade likely contributed to regional shifts in transmission towards Brazil, Haiti, and the Indian subcontinent

“We observed considerable differences in the global dissemination patterns of HBV-D and HBV-A and different levels of monophyletic clustering in relation of the regions of prevalence of each genotype,” the researchers concluded.

References
Kostaki EG, Karamitros T, Stefanou G, et al. Unravelling the history of hepatitis B virus genotypes A and D infection using a full-genome phylogenetic and phylogeographic approach. eLife. 2018. Doi: 10.7554/eLife.36709

Scientists shed new light on hepatitis B virus origins [news release]. eLife’s website. https://elifesciences.org/for-the-press/2bc7c0e1/scientists-shed-new-light-on-hepatitis-b-virus-origins. Accessed August 8, 2018.

Reducing the cost of new hepatitis C drugs
Link to research and news articles addressing the high cost of hepatitis C drugs; insurance restrictions - private insurers/Medicaid - and availability of generic versions/India, Egypt and other lower-income countries or through online "buyers clubs"

Page updated August 2018

Monday, September 28, 2015

Historical Path of Discovery of Viral Hepatitis

Historical Path of Discovery of Viral Hepatitis

Posted on September 27, 2015 by David T. Wong, Martin C. Mihm, MD, James L. Boyer, MD, and Dhanpat Jain, MD

This article presents an overview of the historical timeline of the gradual discovery of various hepatitis viruses and the pivotal roles of epidemiological observations, human experimentations, and laboratory research in their discovery and containment.

Full Text Article

Abstract
Viral hepatitis is an ongoing global infectious public health problem and a major cause of chronic liver diseases, including liver cancer. Previously described as “epidemic jaundice,” viral hepatitis has been known to exist since ancient civilizations. The contagious nature of the illness was suspected even in the eighth century CE. Records from major military campaigns in different continents from the 18th to 20th centuries, including the American Civil War and the First and Second World Wars, reported that “campaign jaundice” caused significant morbidity of the troops and impacted war strategies. Epidemiological observations from late 19th century and research, including human experimentation in the 20th century, led to the gradual identification of a distinct “infectious hepatitis” agent transmitted by oral-fecal transmission, known later as hepatitis A virus (HAV), and a “serum hepatitis” agent transmitted by inoculation or transfusion of serum, blood or plasma, or sexual contact. Experiments that involved feeding and injecting infected feces, urine, and serum into volunteered military personnel, prisoners, and mentally retarded children raised issues of informed consent and mental competency of the retarded children. Only until the 1960s was one of the causative agents of “serum hepatitis,” the hepatitis B virus (HBV), discovered. Further research led to the discovery of additional hepatitis viruses (HCV, HDV, HEV, and HGV). Breakthroughs in the containment of the hepatitis epidemic included development of hepatitis vaccines and recent therapeutic successes for hepatitis C. This paper presents an overview of the historical timeline of the gradual discovery of the causative agents of viral hepatitis.
Continue reading

Of Interest - Hepatitis Timeline 
The Origin Of Hepatitis:HCV and HBV
Hepatitis C Timeline - First recorded references to hepatitis epidemics, to the 1989 discovery of the hepatitis C virus, ending with the FDA approved treatments used today.


Wednesday, April 30, 2014

Watch: The discovery of HCV and why drugs like Gilead’s Sovaldi are the center of an economic debate

http://www.biocenturytv.com/player/3500911830001/3502323830001

Profiles in Innovation: 
The Discovery of HCV 

Topic Description

Thirty years ago patients who received a blood transfusion had a 30% chance of contracting hepatitis infection, in this video Dr. Harvey Alter, whose research led to the discovery of hepatitis C will discuss his work and the history of HCV.

We also examine how Chiron’s secret six-year effort led to the tests that virtually eliminated the virus from the blood supply, why drugs like Gilead’s Sovaldi are the center of an economic debate on the treatment of HCV, and envision a world in which HCV has been eradicated.

And we talk with Dr. Steven Pearson , who led a health technology assessment of Sovaldi.

Click here to view video

Saturday, April 27, 2013

Hepatitis C: Closing in on its viral origins

Hepatitis C: Closing in on its viral origins

26 April 2013 Last updated at 21:17 ET

Artwork of HCV

The virus behind Hepatitis C has been the target of virologists, epidemiologists and geneticists for years, in a bid to find out the animal host from which it likely came. But Prof Jonathan Ball, a virologist at the University of Nottingham, UK, says early indications that bats are the culprit may yet be proven wrong.

The omnipresent bat represents around one fifth of mammal species, yet remains strangely enigmatic.

Known to be the source of a range of human viral infections such as Sars and ebola, a recent study published in PNAS suggests that bats are a large natural reservoir to groups of viruses similar to the hepatitis C virus (HCV).

HCV is a life-threatening infection affecting more than 150 million people worldwide and its origin has eluded scientists for years.

To define if bats were a possible source for HCV-like viruses, Phenix-Lan Quan from Columbia University in New York and her colleagues analysed the blood from hundreds of bats living in South America, Africa and Asia.

To expose any infectious payload that the bats carried, the team used a method called high-throughput sequencing, which surveys all of the genetic material - nucleic acids - present in their blood.

In amongst the bat DNA, in approximately 5% of the animals tested, they discovered novel genetic sequences that were similar to nucleic acid present in viruses belonging to two groups - or genera - called pegiviruses and hepaciviruses. HCV is a member of the hepacivirus genus.

“Start Quote
My prediction is that we will find a range of bat and/or rodent species to be infected with viruses that represent the immediate source of human infections in those parts of Africa and South Asia where HCV seems to have originated”
Quote Prof Peter Simmonds University of Edinburgh

To determine the evolutionary history and relatedness of these viruses, they performed computer analyses to build what is called a phylogenetic tree.

Unlike a family tree, which is built using archive records of significant events like births, deaths and marriages, phylogenetic trees use the historic record written into the sequence of information stored in nucleic acids.

During replication, virus genetic material changes, or mutates, and these mutations accumulate over time allowing the virus to evolve.

Determining the number of genetic differences that exist between viruses gives an idea of how related they are - the fewer the changes, the more closely related - and phylogenetic trees represent this genetic relationship.

Viruses located on connecting branches are most related and the shorter the branches, the more related they are.

In the pegivirus and hepacivirus tree constructed by Dr Quan, the branches leading to clusters of bat virus sequences were numerous and long, indicating that bats have long been infected by a great variety of strains; more so than humans.

The branching pattern of the phylogenetic tree can also provide a clue to the origins of HCV.

If bats are the source of this virus, then the HCV sequences should nestle amongst the branches of the bat hepaciviruses - and at first sight they do.

But before we designate the much-maligned bat as public enemy number one, is there sufficient evidence to suggest that these vital pollinators and insect predators are the direct source of deadly HCV?

Equine enigma

Scientists have used phylogenetic trees to identify the source of many viral infections.

Beccari's freetail batA 2005 paper in Science showed that Sars passed from bats to civet cats then on to humans, and a 2010 Royal Society journal article reported that HIV arose following transmission from African primates.
Initial studies suggested that the bat was responsible, but other suspects have now entered the line-up

The evidence supporting these particular animal-human transmissions - or zoonoses - is strong.

For example, in trees of virus sequences derived from extensive sampling of wild primate and monkey species, HIV is embedded firmly on the branch of the tree containing chimpanzee viruses. Genetically, HIV is most closely related to its chimpanzee counterparts and they are the most likely source.

In the hepacivirus tree, research in Emerging Infections Diseases has shown that HCV is more related to viruses found in horses and dogs than it is to those present in bats, but the branch leading to HCV is very long - it contains lots of genetic change and therefore long evolutionary timeframe.

A virus could have made the jump into humans millennia ago, but this unlikely.

The key to it all is in the virus sampling.

Just as an identity parade is only useful if the guilty party is present, phylogenetic analysis can only identify the cause of a virus outbreak if the most probable source is included.

Although Dr Quan's analysis includes far more viral sequences than has been possible before, the hepacivirus and pegivirus line-up still contained very few suspects.

"Our findings shed new light on the deep evolutionary history of those viruses that ultimately resulted in HCV," Dr Quan explained.

"We show that all known hepaciviruses and pegiviruses - including primates, horses and dogs - fall within the phylogenetic diversity of the bat-derived viruses, suggesting a longer evolutionary history of these viruses in bats than in primates, horses or dogs."

Whilst Dr Quan believes that bats harbour the greatest array of these important viruses, she stops short of arguing that her data prove that bats are the source of HCV.

"With our current data, we cannot conclude whether or not bats are the 'ultimate' reservoir of hepaciviruses and pegiviruses, nor whether HCV came from bats," she said. "To be truly able to answer this question, you would need to study a far larger sample of potential reservoir hosts."

Of mice and men

And to prove this point, a related study published in the journal mBio by a team led by Prof Amit Kapoor, also from Columbia University in New York, reported that numerous species of rodents also harbour hepacivirus and pegiviruses.

Rat and her youngJust like the bat viruses, these too exhibited a large degree of genetic variability, hinting at an enduring history of infection.
Future studies could see rodents emerge as the confirmed source of the virus

None of the rodent sequences was more related to HCV than the horse hepaciviruses, but one of the co-authors of this study, Prof Peter Simmonds from the University of Edinburgh, thinks that the large degree of variability observed in these rodent viruses might prove significant.

"It seems as though different bat and rodent species carry a remarkably diverse range of HCV-like viruses," he said.

"None of these are very close genetically to HCV, but with such limited sampling, it certainly remains possible that other variants exist in other species that match HCV more closely."

Although leaving open the possibility that other animals might be the source of HCV, he added: "My prediction is that we will find a range of bat and/or rodent species to be infected with viruses that represent the immediate source of human infections in those parts of Africa and South Asia where HCV seems to have originated. It's difficult to know what those species are, when and how such species jumps occurred."

So, despite recent growth spurts, the hepacivirus and pegivirus phylogeny is still more of a sapling than a fully grown tree.

Extensive virus sampling from global mammalian species will add further branches and bring us closer to understanding the origin of HCV.

Bats and rodents have been around for more than 50 million years, so it's no surprise they've picked up one or two viruses in their travels.

Some of these, driven by habitat encroachment and human activity, have undeniably passed into humans.

But whether HCV arose from bats or rodents remains to be seen.

Related Internet links
Jonathan Ball at University of Nottingham

The BBC is not responsible for the content of external Internet sites

Related Stories

Updated: May 4 2014
To include this link: Yellow Blood: Hepatitis C and the Modernist Settlement in Japan.
In 1964, HCV infection via direct blood-to-blood contact with contaminated blood was happening wherever medicine could afford transfusion technology and wherever blood products and hypodermic syringes were in use as therapies or therapy delivery systems. Although the hepatitis C virus probably originated in West Africa in the late 15th century, its global sweep and pandemic status in the world today are both intimately linked with progression of the modernist settlement: the dualistic epistemological structure of modernity in which science and technology are divided from and purified of culture and politics.

Wednesday, November 9, 2011

Protons, Electrons, and Hepatitis C


Well, technically that title should be PROTON, ELECTRON, and Hepatitis C, the first two words being the names of two recent studies of PSI-7977, a potential new drug for treating hepatitis C virus (HCV).

The Latest Findings
There’s a lot to talk about with PSI-7977—mainly in light of study results presented a few days ago at the 62nd Annual Meeting of the Association for the Study of Liver Diseases (AASLD) in San Francisco. So let’s get the elephant in the room out of the way before we go any further: I do not know what POSITRON and ELECTRON stand for. Nor do I know what FISSION, PROTON, and ATOMIC stand for—but more on that later. All I can tell you is that at some point in the history of drug development, pharmaceutical companies and/or clinical trial cooperative groups decided that acronyms were necessary or advantageous for some reason, paving the way for many a BLT, BOLERO and COMFORT for years to come.

PSI-7977 is kind of exciting. In the PROTON study, this drug, a nucleotide analog, was combined with the then-standard of care, pegylated interferon plus ribavirin. (Since PROTON was done, telaprevir and boceprevir were approved, changing the standard of care.) In PROTON, 96% of patients had a sustained virologic response (SVR), which is the measure of cure for HCV. Now, to balance this, is a wonderful moment of parsing the data: 96% is impressive, no doubt, but it has to be mentioned that the total number of patients in that study was 25, with 24 patients being actually evaluable. It was an early-phase study, so that small number of patients is not unusual, but most reports about the latest PSI-7977 results are highlighting that initial 96%, and it’s hard to find the actual N of the study. Here is a PDF of the full report of the PROTON study.

After PROTON delivered its encouraging results, Pharmasset, the maker of PSI-7977, launched ELECTRON, a phase II study in which a number of patients were given the experimental drug plus ribavirin. And that is the key: 10 of the enrollees received NO pegylated interferon. And guess what: the combination worked. All 10 of those HCV patients had an SVR.

Now, a couple of things to explain. First, these were patients with genotype 2 or 3 HCV. The reason why these genotypes were selected is because they tend to be highly responsive to interferon. Wait – so, why were those the people who were not given interferon? Well, the logic was that if PSI-7977 plus ribavirin didn’t work, those patients could be more easily rescued with a course of pegylated interferon + ribavirin than HCV patients with, say, genotype 1, the most difficult to treat variety of the disease. As it turned out, that rescue therapy wasn’t needed, but still, the logic is interesting when it comes to understanding drug trials.

Another important point is why eliminating interferon from treatment could be useful. There are two reasons. First, some patients respond to interferon and others do not. As it turns out, variations in the IL28B gene are behind that likelihood (or lack thereof), a discovery that has its own fascinating story. (Here’s a link to an article I wrote about it for Science last year.) David Goldstein, of Duke University, was instrumental in this finding, as was David Thomas, director of the Division of Infectious Diseases at Johns Hopkins School of Medicine, a man whose work with HCV, along with hepatitis B and other illnesses, extends from the genetic aspects to the public health injustices surrounding screening and care.

The second point about interferon is that it’s not for everyone, even those who do respond physically. The drug causes harsh side effects, including mood disorders, to the point where some patients, such as those who are clinically depressed at the time of their diagnosis, may not be candidates for treatment, even if they have the IL28B variant that indicates they’d likely respond to the drug. In short, many researchers and drug developers have been working on finding a way to treat HCV without pegylated interferon. The ELECTRON study is the first (as far as I know) to do it.

In the ELECTRON study, alongside those 10 patients given PSI-7977 + ribavirin were three other groups of patients, each of which was given a different schedule of PSI-7977 + ribavirin + pegylated interferon. All of the patients responded well. The outcomes among the patients not given pegylated interferon were the same as for those given that drug. The difference was that patients in the three-drug groups experienced at least one side effect more often (any of the following: headache, fatigue, depression, insomnia, anxiety, irritability, muscle soreness, upper respiratory tract infections), as well as a greater occurrence of moderate-to-severe drops in neutrophils, a type of white blood cell.
Several new treatment arms have been added to the ELECTRON study, including one in which patients will be given PSI-7977 alone. All of the patients are still genotype 2/3 only.

Another word about the genotype selection. Telaprevir (Incivek) and bocepevir (Victrelis) were both approved for genotype 1 HCV. These drugs are highly effective, and while they won’t cure all patients, they will cure many. So it may be that the drug maker behind PSI-7977 is focusing on a different genotype for marketing purposes. That being said, the phase III clinical trial program will include three studies, one of which will focus on genotype-1 patients. The other two soon-to-be-launched studies (the aforementioned FISSION and POSITRON) will evaluate PSI-7977 + ribavirin in more than 700 patients with genotype 2/3 HCV, according to a recent statement from Pharmasset. And we mustn’t forget the other ongoing study, ATOMIC, a phase IIb study in which 300 patients with chronic HCV genotype 1 are being given the three-drug combo for either 12 or 24 weeks, and 25 patients with genotype 4, 5, 6 or an indeterminate genotype will receive the same medications for 24 weeks.

Other New Drugs for Hepatitis C

If HCV were a party, this would be the point at which the room starts getting a touch crowded; not so much that you have to leave, but definitely to the point where there are no seats left. For although PSI-7977 has got the makers of telaprevir a little concerned about its future earnings, several other compounds, many of which may also work without pegylated interferon, are currently being studied.

These include:
• Second-generation protease inhibitors (telaprevir and boceprevir are protease inhibitors) such as TMC435, danoprevir, GS 9256, BMS 791325, ACH-1625, MK-7009, and BI 201335
• Inhibitors of nonstructural protein 5A, which is involved with viral replication. BMS 790052 is one such compound currently being evaluated
• R7128, another nucleoside polymerase inhibitor (same class as PSI-7977)
• Nonnucleoside polymerase inhibitors (which, for the technically minded among you, seem to exert their effect by “allosteric inhibition of the NS5B HCV polymerase,” according to Ira Jacobson, commenting in Gastroenterology & Hepatology, in October 2010.)
• Cyclophilin antagonists, drugs that target the host cell rather than the virus. Cyclophilin is a protein that the virus uses in the replication of RNA. One of the reasons why this approach could gain traction is because it eliminates concern about the virus becoming resistant to treatment, a feature that warrants having as many treatment options as possible, meaning that it’s probably good that this party is getting crowded.
• Alternatives to pegylated interferon are also being investigated. For example, albumin interferon alfa-2b and pegylated interferon lambda are two candidates. Loteron is an interferon alpha product that could work, and consensus interferon, which is nonpegylated, was already approved for patients who don’t respond to pegylated interferon plus ribavirin.

HCV and the History of the Human Race


On another, related note, we all come across certain topics where we feel like the trajectory of the story somehow encapsulates all there is to understand about human life, or some other big picture for which this smaller story serves as a microcosm.

For me, HCV is one of those stories. This current chapter is not only illuminating so much about the best of modern drug development, but also reveals many of the problems still not being adequately addressed, like screening and prevention (HCV is primarily transferred through dirty drug needles), and the fact that many HCV patients are still not treated until late in the disease, one of the reasons why being a passing of the buck going on at the level of insurance. There is also the question (warning: idealist alert) of whether we will ever come to the day when people won’t feel the need to inject recreational drugs, dirty needle or not, and eliminating, or at least severely shrinking, HCV as a concern once and for all.

But then there is a whole trace of human history—steps and missteps—in the story of HCV. The geographic distribution of genotypes is a starting point for a rich and harrowing look at how viruses move across the world. For example, one of the ways that hepatitis was spread through Egypt was through a campaign against schistosomiasis along the Nile delta in the 1960s.

(Here is one interesting PDF on that.) It was a well-intentioned and needed public health measure but the needles weren’t sterilized and so as people were treated for the parasite, village by village, the virus made its way around. Egypt currently has the highest rates of HCV in the world. Anti-malaria campaigns in Cameroon had a similar impact.

Also fascinating is the fact that the spread of the virus can be traced across slave trade routes from Africa to Europe. And, as Oliver Pybus, an evolutionary biologist at Oxford University, points out, that fact brings up another central mystery about HCV, which is that the virus has been around for thousands of years, but the most common modes of transmission that we know of are connected to relatively modern inventions (blood transfusions and needles to inject drugs). “What is clear is that this endemic transmission was occurring across the whole of Sub-Saharan Africa and Asia and it doesn’t seem right that it would be maintained by very culturally-defined and location-specific routes of transmission,” Pybus once told me. In other words, as he explained, practices like scarification and tattooing could account for some, but not all, of the spread of HCV in that time and place. Making his insights even more fascinating is the fact that Pybus has managed to use genome sequencing and computer programs to trace the phylogenetic tree of HCV that extends over thousands of years. (Pybus was the CDC’s point person on tracking the origin of swine flu a few years back because of the software and methods he’s invented.)

Then there is the question of how HCV got into humans in the first place. Columbia University virologist Ian Lipkin recently shed some fascinating light on this question when he found a genetic homolog of HCV in dogs. Here’s a tiny bit from me on that (scroll to bottom), and a lot more about it from Carl Zimmer.

You see?

There is a whole trace of history inside the story of HCV. With all of the issues that tend to get our dander up when it comes to drug development (and those exist with HCV, too), here is one that piques our fascination and curiosity.

There is one more looming question. When it comes to the increasing number of HCV medications: why now? We know that pharmaceutical companies are businesses, so obviously there is money to be made in creating new drugs for HCV. Has there been some recent dawning realization about this? Are drug makers for some reason now guaranteed a solid return on the investment, whereas they weren’t some years back? Or is it more due to the science and advances in HCV research that have led to so many new targets to investigate?

Clearly, there is at least one more chapter waiting to be written in this compelling story, and I’m sure many more beyond that.
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