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April 2009 HCV Advocate

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In This Issue:

Albuferon Top-Line Results
Alan Franciscus, Editor-in-Chief

Does HCV Cause Diabetes?
Alan Franciscus, Editor-in-Chief

SVR – 5 Years Later
Alan Franciscus, Editor-in-Chief

HealthWise: Hepatitis C and Cannabis
Lucinda Porter, RN

HCV Increases Risk for ITP
Alan Franciscus, Editor-in-Chief

Sexual Transmission of HCV: An Emerging New Consensus?
Liz Highleyman

HCV SnapShots
Alan Franciscus, Editor-in-Chief

HCV Advocate Eblast
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Albuferon Top-Line Results
Alan Franciscus, Editor-in-Chief

Human Genome Sciences (HGS) issued a press release in March that their drug, albuferon (plus ribavirin), was not inferior to Pegasys (plus ribavirin).   One of the criteria for FDA marketing approval is that an experimental drug must be shown to be as effective as the current standard of care.

In the press release issued on March 9, 2009, HGS listed the top-line results of their Phase III clinical trial comparing HGS’s long acting interferon albuferon to  Roche’s long acting interferon Pegasys.  In the study both drugs were used to treat chronic HCV genotype 1 patients. 

The study, called ACHIEVE 1, compared the effectiveness of albuferon (injected every two weeks) to Pegasys (injected once weekly).  Effectiveness was defined as achieving a sustained virological response (SVR-HCV undetectable 24 weeks post treatment).  The safety and tolerability of two drugs were also compared. 

In the albuferon group 48.2% of patients achieved an SVR compared to 51.0% in the Pegasys group.   

Since albuferon stays in the body longer than pegylated interferon there was a concern that the adverse events or serious side effects might be worse in the patients treated with albuferon.  However, it was found that albuferon had a similar rate of adverse events compared to Pegasys – 1.8% in the albuferon group compared to 1.1% in those who received Pegasys.   Another concern was the rate of discontinuation due to adverse events (side effects).  In this respect, albuferon did not fare as well – 10.4% in the albuferon group discontinued compared to 4.1% in the Pegasys group. 

The company expects to file for FDA approval towards the end of 2009.  When and if the drug is approved, it will be interesting to see if it is widely prescribed.  The big question is whether medical providers would be willing to prescribe a new drug that has a similar treatment outcome to the current standard of care – pegylated interferon plus ribavirin  – but has been found to be less tolerable.  Certainly less frequently dosing is very appealing, but does convenience outweigh tolerability?  That is the question that will only be answered if albuferon is approved.

Source:  Company Press Release

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Does HCV Cause Diabetes?
Alan Franciscus, Editor-in-Chief

It has been proven that hepatitis C causes insulin resistance, a pre-cursor to type II diabetes or diabetes mellitus (DM).  However, it has not been proven that HCV causes diabetes. One way to prove that HCV causes diabetes is by studying what happens after successful treatment of HCV – the hepatitis C virus is eliminated – and observing whether or not the incidence of diabetes is lower than in the patients who did not eliminate the hepatitis C virus.  This is exactly what researchers in Japan wanted to answer by conducting one of the largest clinical trials to date on diabetes and HCV. 

Researchers Arase and colleagues conducted a retrospective1 (looking back over time) study of 5,890 patients who were diagnosed with chronic hepatitis C in the Department of Hepatology, Toranomon Hospital, Tokyo, Japan.  Of the original 5,890 patients evaluated for diabetes, 2,842 patients did not have diabetes pre-treatment (but could have had pre-diabetes) before and for 3 months after completion of HCV treatment.  Two thousand-four hundred and seventeen patients received standard interferon monotherapy and 425 received standard interferon plus ribavirin therapy.  The primary aim of the study was to compare the incidence of diabetes in the patients who achieved an SVR to that in those who did not achieve an SVR.  The researchers also looked for other factors associated with the onset of diabetes using the 2003 criteria of the American Diabetes Association.  The average period that the patients were observed was 6.4 years. 

The sustained virological response rates (SVR-HCV RNA or viral load undetectable 24 weeks post-treatment) in the interferon monotherapy group was 36.7%, and 68% in the group that was treated with interferon plus ribavirin. 

One hundred and forty-three patients (102 men and 41 women) developed diabetes during the observation period (mean period = 6.4 years).  Using a statistical method (Kaplan-Meier) to determine the cumulative development rate of diabetes, the incidence of diabetes was found to be 3.6% at 5 years, 8.0% at 10 years and 17.0% at 15 years. 

When the results were compared between the two groups, the group that did not achieve an SVR had a higher onset of diabetes compared to the group that achieved an SVR.  Furthermore, it was found that when an SVR was achieved that there was a two-thirds reduction in the onset of diabetes.  The factors that were found to be associated with the onset of diabetes after therapy was completed were advanced fibrosis, non-SVR, pre-diabetes, and an age greater than or equal to 50 years old.

These results are important because if diabetes can be prevented with successful treatment of hepatitis C the future disease burden of diabetes and hepatitis C can be significantly lowered. 

1 The original study was a prospective clinical study using the older diagnostic criteria of diabetes, but during the trial period the American Diabetes Association changed the diagnostic criteria.

Arase, Y. et al. Sustained Virological Response Reduces Incidence of Onset of Type 2 Diabetes in Chronic Hepatitis C.  Hepatology Volume 49, Issue 3.

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SVR – 5 Years Later
Alan Franciscus, Editor-in-Chief

Does the health of the liver improve after someone achieves a sustained virological response? That’s what researchers Sarah L. George and colleagues set out to answer with a long-term study of patients who achieved an SVR.  

A total of 150 patients who had achieved a sustained virological response (SVR = HCV RNA (viral load) undetectable 24 weeks post-treatment) and who were originally biopsied and scored with fibrosis stage 2 or higher (Ishak system – with 0 being no fibrosis and 6 being cirrhosis) were enrolled in the study between June 1997 and April 2002.  The average age at time of study enrollment was 49 years old; 49% were female, 98% were Caucasian and the genotype distribution was similar to the genotype distribution generally seen in the United States.  Almost all of the patients (87%) were treated with standard interferon (3 shots a week) plus ribavirin daily.  Ninety-eight patients (65%) were treated for one year and the other 35% were treated for 6 months.  Out of the original 150 patients enrolled, 128 patients (85%) were followed through their fourth year and 108 patients (72%) were followed for five or more years after achieving an SVR. 

Pretreatment and long-term follow-up biopsies were performed in 49 patients and blindly scored – that is the person evaluating the biopsy did not have patient information or knowledge of the previous biopsy score.

Of the patients biopsied, 40 patients (82%) had a decrease in fibrosis score, and 45 (92%) had a decrease in the combined inflammation score.  Ten patients (20%) who had follow-up biopsy had near or nearly normal livers. 

Two patients with pre-treatment cirrhosis developed hepatocellular carcinoma (HCC-liver cancer) and one patient died.  However, all of the other patients with pre-treatment cirrhosis or advanced fibrosis had improved fibrosis scores on their long-term follow-up biopsy.

This was the longest and largest study of its kind and the results are very encouraging.  But, the bad news is that one of those patients with pre-treatment cirrhosis died even after achieving an SVR.  These results confirm previous findings that have had similar outcomes.  The two important messages from this study are: 

  • The vast majority of people who achieve an SVR have improved inflammation and fibrosis scores.  But larger and longer studies are needed to confirm these findings.   
  • People with pre-treatment cirrhosis should be closely monitored even when an SVR is achieved because there is a risk that a small minority of patients will continue to have severe disease progression leading to death.  

George, S. et al. Clinical, virologic, histologic, and biochemical outcomes after successful HCV therapy: A 5-year follow-up of 150 patients. Hepatology. Volume 49 Issue 3


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Healthwise: Hepatitis C and Cannabis
Lucinda Porter, RN

Throughout the year, HCV Advocate readers can expect reliable, professional writing from my colleagues.  I, on the other hand, lose control in April.  What good is April Fool’s Day without a little humor?  After eleven years, I figure you are just as likely as I am to be bored with Healthwise, so I’m spicing it up this month.  As always, the opinions expressed here are my own and not those of anyone associated with HCSP. 

One question asked by hepatitis C (HCV) patients is, “Is it safe to smoke marijuana?”  Actually, the older patients ask about pot and the younger patients ask about weed.  This is my least favorite question because I know that medical marijuana use has helped many with various health problems.  Some of the data has been contradictory.  And then there is the problem of marijuana’s legal status. 

I don’t like the question because I don’t know the answer.  There is not a lot of research on this subject.  In the January 2008 issue of Clinical Gastroenterology & Hepatology, J.H.  Ishida and colleagues at the University of California San Francisco reported that daily marijuana use was strongly associated with moderate to severe fibrosis in patients with chronic HCV. 

Researchers interviewed 204 HCV patients who averaged about two daily drinks of alcohol.  Their alcohol history spanned close to 30 years.  The group was mostly men (69%), half Caucasian, earning $15,000 or less annually, with the median age of about 47 years.

Marijuana use was as follows: 14% used it daily; 45% used it occasionally; 41% never used it.  Researchers found a significant association between daily marijuana use and moderate to severe liver fibrosis.  

One thing to keep in mind is that although this data showed an association between daily marijuana use and fibrosis levels, correlation does not mean causation.  So I wondered, perhaps the daily users had fatty liver disease (steatosis) which caused the fibrosis.  Surely they didn’t get much exercise while they were stoned.  Yes, this is a stereotype, but it is a reasonable assumption. 

Delving deeper, I could not find any evidence that patients were asked, “Do you exercise or do you lie around all day smoking reefer?”  However, I did read that the daily cannabis users with more advanced tissue damage had significantly lower body mass index (BMI).  Lower BMI would make them less likely to have steatosis.  So much for the munchies causing them to gain weight.  And so much for my theory. 

Although the pot-smoking liver -damaged group had significantly lower BMI, they still could have had steatosis.  In 2005, a French study reported the relationship between daily marijuana use and fatty liver.  Since there are no overweight people in France, is it possible that the San Francisco weed users had steatosis?

Another French study, also in 2005, fine-tuned the research.  Taking into account a number of independent factors, including steatosis, the investigators concluded that daily pot smoking is significantly associated with fibrosis progression in HCV patients.  The researchers recommended that HCV patients should refrain from regular marijuana use.  My question for the French researchers is this, “Did you tell them they should also refrain from foie gras?”  Surely goose liver is as bad for the liver as marijuana is.  I searched for foie gras and hepatitis C studies.  I found nothing.  

Looking at the bigger picture, I turned to Liz Highleyman’s article, Moderate Cannabis Use Associated with Improved Treatment Response in Hepatitis C Patients on Methadone (hivandhepatitis.com9/15/06).  Medical marijuana may improve HCV treatment response, according to a study published in the October 2006 European Journal of Gastroenterology and Hepatology, by Diana Sylvestre, MD and colleagues at of the University of California at San Francisco.  The theory behind the research is simple.  If the side effects of HCV treatment are relieved, then patients are more likely to tolerate and stay on treatment.  Adherence to treatment is likely to yield a better response to treatment.

Although it was a good study, a lot of questions remain unanswered.  One problem with the research is marijuana was not provided.  Cannabis use was not endorsed or condemned – it was simply noted.  The lack of regulation and scientific measurement left some variables.  A randomized, double-blind study would provide more information.  However, I bet everyone randomized to the non-pot-smoking group might guess they were getting placebo.  The research team would figure it out when patients showed up to their appointments wearing sunglasses and listening to Bob Marley.   

Joking aside, there may be an increased risk of fibrosis for cannabis-using HCV patients, especially those who are coinfected with HIV.  There is not much data but it consistently shows a risk for increased fibrosis.  The Sylvestre study throws a kink in our body of knowledge because it suggests that cannabis use may increase treatment adherence.  Getting rid of HCV is a great way to prevent liver damage. 

Just because I don’t know the answer to the question, “Is marijuana safe for those with HCV?” does not mean I don’t have a personal opinion.  The absence of facts doesn’t prevent me from having an opinion. 

For me, every day I wake up and do the best I can to stay healthy.  I stay away from all substances that aren’t medically supervised.  I don’t drink alcohol, smoke weed or eat foie gras.  If I was to try treatment again, I would seek the most support I could in order to stay on treatment.  I would watch Mork and Mindy reruns and find other ways to laugh. 

My answer changes if I am asked, “What would I do if I were in your shoes?”  If you were nearing or on an organ transplant list, I’d advise against using marijuana.  The same holds for those with cirrhosis, addiction issues, or certain medical conditions.  Otherwise, I don’t know.  Look at the research.  Talk to your doctor.

If you use marijuana, try to use a medical grade.  Educate yourself on safer ways to use cannabis so you don’t inhale all the contaminants.  Warning: if you used marijuana decades ago, it is much more potent now.  Don’t drive under the influence.  Be informed about federal and state laws regarding marijuana.  Stay away from foie gras and pinot noir. 

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HCV Increases Risk for ITP
Alan Franciscus, Editor-in-Chief

A recent journal article points to a higher prevalence of immune thrombocytopenic purpura (ITP) among people with hepatitis C – the same study did not find an association between HCV infection and autoimmune hemolytic anemia (AIHA).

ITP is an autoimmune bleeding disorder caused when the blood doesn’t clot.  Symptoms of ITP are easy bruising of the skin as well as bruising under the skin that can be seen as red or purple dots on the skin.  In severe cases bleeding from the nose, gums and gastrointestinal or urinary systems can occur.  AIHA is a condition when red blood cells are destroyed faster than the body can produce them. 

In the study conducted by Chiao and colleagues, 120,691 U.S. veterans with hepatitis C were compared to 454,905 well-matched U.S. veterans without hepatitis C. 

The researchers found 296 cases of ITP and concluded that HCV infection and HCV treatment were associated with an increased risk for ITP.  Ninety cases of AIHA were also identified, but the only association was found to be HCV treatment.

Based on the results the authors concluded: “Individuals infected with HCV are at an increased risk for ITP, whereas the development of AIHA seems to be associated with HCV treatment.”  Furthermore, “It may be beneficial to test individuals newly diagnosed as having ITP for HCV infection.”  

Arch Intern Med. 2009;169:357-363

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Sexual Transmission of HCV: An Emerging New Consensus?
Liz Highleyman

Traditionally, sexual activity has been regarded as an uncommon route of hepatitis C virus (HCV) transmission. According to the Centers for Disease Control and Prevention (CDC), sex with an HCV-infected person is “an inefficient means of transmission,” and the National Institutes of Health (NIH) states that “changes in sexual practices are not recommended” for monogamous people with chronic hepatitis C.

This information – which appears in most basic hepatitis C educational materials and most doctors give their patients – is based on observational studies of stable, presumably monogamous, HIV negative heterosexual couples with one HCV positive partner.  Such studies have shown HCV sexual transmission rates ranging from 0% (no cases) to about 3%.
But a growing epidemic of apparently sexually transmitted acute HCV infection, primarily among HIV positive men who have sex with men (MSM), has led some experts to revisit this consensus.

An Emerging Epidemic?
Beginning in 2002, clinicians began reporting clusters of acute hepatitis C among HIV positive gay/bisexual men, first in London and Brighton in the U.K., and later in cities in France, Germany, the Netherlands, and Switzerland.  While there were only a few cases in 2000-2004, the numbers increased dramatically around 2005-2006, and the count has now reached the hundreds.

A large proportion of the newly coinfected men in the various cities had HCV genotype 4, which is generally uncommon in Europe.  Genetic studies showed that a majority of the men’s HCV strains were closely related, occurring in a number of well-defined clusters, suggesting transmission within sexual networks, and from network to network due to travel between the cities.

The men in these clusters had several sexual practices in common. Overall – though specific associations vary from study to study – men with acute hepatitis C were more likely to report fisting, unprotected anal sex, multiple sex partners, sex in a group setting (for example, at a sex club or bathhouse), other sexually transmitted diseases (STDs), and use of non-injected recreational drugs.

Now In the U.S.
As late as 2005, researchers from Canada and the U.S. were reporting very few cases of apparently sexually transmitted acute hepatitis C among MSM with no other risk factors, but this began to change around 2006. That year, Annie Luetkemeyer and colleagues published a report of nine cases of acute HCV infection among HIV positive men seen at San Francisco General Hospital (SFGH).

Speaking at a San Francisco community forum on sex and hepatitis C this past January, Brad Hare from the SFGH team reported that 42% of HIV positive men in the hospital’s Positive Health Program are coinfected with HCV, with a majority reporting only sexual risk factors.  Michael Allerton from Kaiser Permanente Northern California said that 10% of the health plan’s HIV positive members also have HCV, and in an informal survey Kaiser doctors estimated that 70% to 100% of their coinfected patients contracted HCV through sex.

At the Conference on Retroviruses and Opportunistic Infection (CROI) in 2007, Daniel Fierer from Mt. Sinai School of Medicine in New York City first reported on a group of HIV positive MSM with acute hepatitis C who showed evidence of unusually rapid liver disease progression.  At this year’s CROI in February, the Mt. Sinai team presented a comparison of the characteristics and risk behaviors of 20 men in their coinfected cohort and 60 similar men in the U.K.

The men in both groups were older than average for STD clinic patients, with a mean age of about 40 years.  The New York men were less likely than the U.K. men to report insertive (33% vs. 73%) or receptive (24% vs. 57%) fisting during the past 12 months.  Majorities in both cities reported both insertive and receptive unprotected anal sex.  While the New York men were about one-third as likely to use non-injection recreational drugs, they reported more sharing of implements for drug smoking (48% vs. 20%) or injection (15% vs. 2%). Unlike European cohorts, 90% of the New York men had HCV genotype 1 and none had genotype 4.

Role of HIV
As noted, most of the recent cases of apparently sexually transmitted acute hepatitis C have been seen in HIV positive gay/bisexual men; in Paris, an HIV positive woman was among the newly coinfected.

This observation suggests that HIV may increase the risk of contracting HCV.  It is already known that HIV positive people are less likely to spontaneously clear HCV without treatment, do not respond as well to interferon-based therapy, and appear to experience more rapid liver disease progression.

Disturbingly, Fierer reported that among 24 newly HCV-infected HIV positive men who underwent liver biopsies an average of four months after their first elevated ALT test, 18 (75%) already had moderate (stage 2) fibrosis, and only two had no evidence of fibrosis.  However, among 10 individuals who completed treatment with pegylated interferon plus ribavirin, eight (80%) achieved sustained virological response – comparable to the success rate for HIV negative people.

HIV causes progressive immune suppression, but across the European and U.S. cohorts, newly coinfected HIV positive men had relatively high CD4 T-cell counts overall, above the current threshold for starting antiretroviral therapy (350) and sometimes as high as 500.

Another possible explanation is that HIV positive men are more likely to be tested for hepatitis C. While on antiretroviral therapy, HIV patients should have their liver enzymes monitored regularly to check for drug toxicity.  If an individual has elevated ALT with no other apparent cause, they are likely to be tested for HCV, and thus may be diagnosed during acute infection, which is often asymptomatic.  In contrast, HIV negative men seldom receive regular HCV screening.  “I think if we start looking for it, we’re going to start finding it,” Allerton predicted at the forum.

However, the few studies that have looked at acute HCV infection among HIV negative men have not seen high rates.  In Brighton, where all sexual health clinic clients have been routinely screened for HCV since 2000, several new HCV infections did turn up in HIV negative men, but their rate was 13 times lower than that of HIV positive men.

Growing Awareness
Awareness of the potential for sexual transmission of HCV has begun to emerge among gay men, particularly within groups – including the leather/BDSM (bondage & discipline/sadism & masochism) community – that engage in practices associated with transmission.  Unfortunately, the awareness of healthcare providers may be lagging: several forum participants related that they were refused HCV testing if they had never injected drugs.

The specific sexual risk factors for sexual HCV transmission remain unclear, since study results are mixed. Unlike most studies, for example, Fierer found that receptive anal or oral sex were associated with acute HCV infection, while fisting was not. But correlation does not necessarily imply causality.  Multiple risk factors tend to occur together, and most gay/bisexual men do not engage in only a single sexual activity.

In its latest hepatitis C information, the CDC acknowledges that “the risk of transmission from sexual contact…increases for those who have multiple sex partners, have a sexually transmitted disease, engage in rough sex, or are infected with HIV.”

Larry Shockey, who hosts fisting parties now strongly encourages the use of gloves for fisting and uses a strong quaternary disinfectant on all play equipment before and after each use. HCV is harder to kill than HIV, and can live longer outside the body. Very small amounts of blood on surfaces and implements (e.g., whips, canes, needles for play piercing) – which may not even be visible – can potentially spread the virus.

Importantly, HIV positive men who have unprotected sex only with other HIV positive men still remain at risk for hepatitis C.

While small amounts of HCV may be present in semen, Hare said that blood is “probably the major route of exposure” to HCV during sex. Anal sex may be an efficient route of transmission because the rectal lining is prone to damage that could allow contact with blood – especially during prolonged sex facilitated by drugs such as crystal meth.

“HCV may have risk factors we don’t understand yet because the studies haven’t been done,” noted Allerton.

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HCV SnapShots
Alan Franciscus, Editor-in-Chief

It’s all about the mega buy-outs & buy-in of HCV drug manufacturers!

Vertex / ViroChem:
In early March 2009, Vertex announced that it will acquire Canadian biotech ViroChem for $100 million in cash and about 10.7 million shares of Vertex common stock.  ViroChem has two HCV non-nucleoside polymerase inhibitors, VCH-222 and VCH-759.  ViroChem’s HCV polymerase inhibitors are in early development and will now be developed by Vertex and combined with Vertex’s HCV development pipeline.  Vertex announced that it expects to begin a combination study of telaprevir with a ViroChem HCV polymerase inhibitor in the second half of 2009.  In addition to the combination study with telaprevir, Vertex announced that it is also planning additional studies of ViroChem’s HCV polymerase inhibitors in combination with pegylated interferon plus ribavirin.
Source:  Company Press Release.

Merck / Schering-Plough:
On March 9, 2009 Merck announced that it had offered to buy Schering-Plough for 41.1 billion dollars.  The deal has been years in the making and is seen as a cost-saving purchase which will allow Merck to increase the numbers of drugs already on the market as well as acquire Schering’s extensive pipeline, which includes boceprevir and Schering’s approved HCV medications – Intron A, PegIntron and Rebetol (brand name for ribavirin).  It is also a move by Merck to diversify their product line with medicines to treat other diseases such as hepatitis C.  The buy-out is contingent upon Merck and Schering-Plough stockholder approval but is expected to be completed by the end of 2009.  Schering’s Board of Directors has approved the buy-out. 
Source:  Company Press Release.

Roche / Genentech:
On March 13, 2009 a deal between Roche and Genentech was finally approved by Genentech’s Board of Directors.   In the $46.8 billion deal, Roche purchased the remaining 44% of Genentech stock.  The take-over will mean that Roche will be the 7th largest U.S. pharmaceutical company in terms of market share with an employee payroll of 17,500 people.  Interestingly Roche (at least the United States portion of Roche Holding AG), will move from Nutley, N.J. to Genentech’s operating site in South San Francisco.  Roche will also assume Genentech’s name.
Source:  Company Press Release.

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