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January 2008 HCV Advocate

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Happy Anniversary
Lucinda Porter

AASLD 2007 – Part 2: More Drugs in Development
Alan Franciscus, Editor-in-Chief

Disability & Benefits: Public Benefits & Residency Requirements
Jacques Chambers, CLU

Can Mosquitoes Spread HCV?
Alan Franciscus, Editor-in-Chief

Top Eleven News Stories of 2007
Alan Franciscus, Editor-in-Chief

Interferon Maintenance Therapy and Liver Disease Progression
Liz Highleyman

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Happy Anniversary
Lucinda Porter

The first issue of The Advocate appeared in January 1998. It was three doubled-sided pages, with no content on the last page. The front page introduced the Hepatitis C Support Project (HCSP) and sported a drawing of the gastrointestinal tract. The inaugural issue included a personal story from someone living with hepatitis C (HCV) along with a note from Ron Duffy of the now defunct The HCV Global Foundation. (Note: Ron died two years later.)   A liver enzyme article and an excerpted newspaper article titled “Did Shots Cause Hepatitis C?” were in this issue. Rounding out The Advocate – the HCV Global Foundation’s mission Statement, an announcement about the Hepatitis C March on Washington, D.C., a list of San Francisco Bay area support groups (3) clinical trials (2), and a tip to drink plenty of water and use moisturizers if you are on interferon.

The February issue increased by a page and in substance.  By December, The Advocate was ten pages long. My first column appeared in the March issue, although it was not titled HealthWise until August. My intention was to write a few articles every once in awhile. Ten years later, I am still here and I hope I am here in another ten years.

The Advocate started as a paper and snail mail newsletter. Every month, a few people met at Alan’s very small San Francisco apartment in order to assemble and send it out. In ten years, The Advocate has appeared monthly as reliably as any magazine and entirely without advertising. We have come a long way.

Alan Franciscus founded HCSP. After an HCV diagnosis in 1996, he looked for a hepatitis C support group in San Francisco. Finding none, Alan started his own. The rest, as they say, is history.  In 1997, Alan’s first publication was the HCSP Information Packet. It is now titled A Guide to Understanding Hepatitis C. It keeps company with approximately 180 fact sheets and nearly 35 other guides – all relating to HCV. The newsletter and literature are published in a number of languages, including Spanish, French, German, Russian, Vietnamese, Chinese, and Tagalog.  (Note: Not all pieces are published in all these languages.)

Internet presence was a huge milestone for HCSP.  The www.hcvadvocate.org website is “hit” over 400,000 times weekly.  It is a huge, and, I believe, the best HCV website for patients and providers alike. There is something for everyone, whether you are newly diagnosed, a medical professional, or looking for the latest information, support group or physician.

Other highlights in HCSP’s history are:
The Medical Writers’ Circle – a collection of 70 articles written by more than 40 experts in their fields
• A column about work and disability issues
• Information about HCV/HIV co-infection
• Creation of www.hbvadvocate.org along with other information about hepatitis B
• A national HCV program which has trained more than 5,000 people who are reaching people in their communities

When the first HCV Advocate was published, HCV treatment was rough and the results were discouraging. The response rates were around 8 to 9% for genotype 1 and 30% for genotypes 2 or 3. The only treatment was interferon. It was not pegylated and injections were 3 times weekly. Ribavirin was not yet in the picture.

This changed around the Millennium when ribavirin was added. The average genotype 1 patient achieved a response rate close to 30%; genotypes 2 and 3 jumped to over 60%. The biggest gains occurred when interferon was modified to the pegylated form. The response rates for genotype 1 patients jumped to around 50%; genotypes 2 and 3 averaged around 80%.  Now, there are over 50 compounds in development to treat hepatitis C with the hope that in the not too distant future, everyone can be successfully treated. 

HCSP’s staff had first-hand experience with HCV treatment. Nearly everyone tried treatment — some two or even three times. Most, including Alan, responded to treatment and are virus-free.  Although I did not have a sustained response to treatment, my liver biopsy went from moderate tissue damage to none at all.

A lot has happened in ten years, particularly considering that hepatitis C was isolated only 20 years ago. Diagnostic testing is better. Antibody and viral load tests are more accurate. Genotype testing is the norm. Liver biopsy procedures are better. My first one was in 1989 and it felt like it was performed with a post-hole digger. My last one was completely painless.

Another leap is in the area of treatment side effect management. Patients are able to stay on treatment with fewer complaints. Working is the norm.  Some have made monumental achievements, such as mountain climbing or riding across Europe on a Harley with peg-interferon in a cooler. I hold that everyone who has tried treatment has accomplished something monumental.

Over the years, more people than I can list have kept HCSP alive. I cannot resist the temptation to name a few. Rose Christensen has been with the project practically from day one. She has worn many hats during her years with HCSP, including business manager, trainer and board member. David Mazoff is another vital force. HCSP soared into a new dimension when he became the webmaster and managing editor. David’s presence is felt on every piece of literature, whether in print or on the web site. 

Liz Highleyman was The Advocate’s first “real” writer. Although Alan and I wrote articles, Liz was the professional. She taught us a lot. A huge addition to HCSP was when Jacques Chambers joined us. His workplace benefits and disability articles and information pamphlets have helped many patients.

Funding for HCSP and the newsletter came from many sources, including grants, gifts, subscriptions and donations. Thank you! Many physicians and other professionals donated their time and expertise, enabling the Hepatitis C Support Project to publish reliable and timely information.  Again, there are too many to thank by name. On a personal note, I am indebted to my mentor and supervisor at Stanford University Medical Center, Emmet B. Keeffe, M.D. He never once said no when I needed help and information.

Of course, there are the many more who contributed. You know who you are. Thank you, thank you. Together we have made a difference. I look forward to seeing what the next ten years will bring.

Finally, thank you Advocate readers. Your stories and support provide the inspiration that makes this worthwhile. Margaret Mead said, “Never doubt that a small group of thoughtful, committed citizens can change the world. Indeed, it is the only thing that ever has.”

Together, we have made a difference.

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AASLD 2007 Part 2: More Drugs in Development
Alan Franciscus, Editor-in-Chief

In part two of a report from the American Association for the Study of Liver Diseases (AASLD) Conference on drugs in development I will further review information presented at AASLD 2007.  I will also continue to add my thoughts about these new drugs.  However, keep in mind that most of the drugs discussed in this article are in very early development and that it is particularly difficult to evaluate whether these drugs will be viable treatment options until there have been more studies with a larger patient population.  The drugs I will concentrate in this article are nitazoxanide, R7128, Bavituximab, GS-9190, and VCH-759  

Nitazoxanide (brand name Alinia – Romark Laboratories) is a broad spectrum antiviral drug that is approved by the Food and Drug Administration (FDA) for treating diarrhea caused by Giardia and cryptosporidium (protozoan pathogens that infect the GI tract).  In previous studies nitazoxanide was found to be safe and well-tolerated and showed antiviral activity against the hepatitis C virus.  It was also found in the earlier studies that the combination of nitazoxanide and interferon produced a synergetic effect (the sum of the combination creates a greater effect than the use of the agents separately).  At AASLD the results from one study named STEALTH C-1 were presented.  STEALTH C is – STudies to Evaluate Alinia for Treatment of Hepatitis C.  The study was conducted in Egypt among genotype 4 patients. 

There were three treatment groups in the study: 

Group A:  Nitazoxanide in dual therapy with Pegasys
   o  28 treatment naïve and 12 interferon experienced patients – treatment duration 36 weeks (included a 12 week lead-in phase of nitazoxanide only)

Group B:  Nitazoxanide in triple therapy with Pegasys plus ribavirin
   o  28 treatment naïve patients and 12 interferon experienced patients – treatment duration 36 weeks (included a 12 week lead-in phase of nitazoxanide only)

Group C:  Standard of care (control) with Pegasys plus ribavirin
   o  40 treatment naïve patients– treatment duration 48 weeks

The medications:  nitazoxanide (500 mg pill twice a day), Pegasys 180 ug injection weekly, and ribavirin pill 1000/1200 daily (weight based).

All patients received a liver biopsy at baseline, and the weekly injections of Pegasys were given at the clinic.  HCV RNA, lab work and a physical exam were conducted every 4 weeks.  Baseline characteristics of the trial participants were well matched across treatment groups.  Note:  Groups A & B had a 12 week lead-in phase of nitazoxanide treatment that produced a modest, but statistically significant drop in HCV RNA. 

In an intention-to-treat analysis (all patients who received one dose counted) SVR (undetectable HCV RNA (<10 IU/mL) 12 weeks post treatment) results were 68% in the naïve patients in group A (dual therapy), 79% in group B (triple therapy) and 43% in group C (control).  It was also pointed out that in the patients who received nitazoxanide none of the patients relapsed (return of HCV RNA) compared to 15% of patients who relapsed in the control group that did not receive nitazoxanide.  There were no treatment discontinuations due to adverse events in the nitazoxanide treatment groups directly related to the drug.

In the interferon experienced treatment arms of the study, SVR 12 week results were 8% in group A (dual therapy) and 25% in group B (triple therapy).  It was pointed out that the small numbers of interferon experienced patients in the study made it difficult to draw any concrete conclusions about the effectiveness of nitazoxanide containing regimes for retreatment.

Bottom line:  This study is very interesting because it seems (at least in the early stage) that there is a substantial benefit when nitazoxanide is added to pegylated interferon plus ribavirin therapy.  There is also a possibility that adding nitazoxanide could possibly lead to a shorter duration of treatment.  However, a bit of caution is needed.  Most importantly all of the patients were HCV genotype 4 who, typically, as a group, achieve a higher response rate compared to people with genotype 1.  In addition, the data presented was the 12 week SVR results so the results 24 weeks post-treatment (SVR 24) are needed to confirm whether these truly represent SVR.  A larger trial of genotype 4 treatment non-responders (STEALTH C-2) is ongoing and will give a better picture of the effectiveness of adding nitazoxanide to pegylated interferon plus ribavirin in the treatment of non-responders, who are typically a very difficult group to retreat. 

The next step in the development process is a planned clinical trial to be named STEALTH C-3 that will be conducted in HCV genotype 1 treatment naïve patients.  In this study there will be 4 groups (80 patients in each treatment arm).  The study arms will have a 4 week lead-in phase of nitazoxanide only (except in the placebo group) with an additional treatment duration of 48 weeks with various combinations of nitazoxanide, Pegasys, and ribavirin.  In one arm, patients who achieve a rapid virological response (HCV negative after 4 weeks of triple combination) will only be treated for 24 weeks.  This study will test the safety, tolerability, and effectiveness of the combination of drugs as well as look at the effect of shortening treatment duration and will study the effectiveness of combining nitazoxanide plus Pegasys without ribavirin.  This will definitely be one of the most interesting studies to follow in 2008-2009.  

R7128 is an HCV polymerase Inhibitor that is being developed by Pharmasset and Roche.  In this study there were 40 HCV Genotype 1 patients who were previously treated (but non-responders or relapsers) with interferon or interferon plus ribavirin therapy.  There were 5 treatment groups (8 patients in each group) with various doses of R7128 (750 mg QD, 1500 mg QD, 750 mg BID, 1500 mg BID) or placebo.  (Note:  QD=once a day; BID=twice a day.)

The baseline characteristics of the participants were well matched across the treatment arms.  R7128 demonstrated dose-dependent decreases in HCV RNA through the 14 days of monotherapy treatment in all the patients who received R7128 with a mean 2.7 log10 decline of HCV RNA and a maximum decline of 4.2 log10.  It was found that twice a day dosing was superior to once a day dosing. In the participants who were treated with R7128 who had abnormal ALT levels, 78% of the participants’ ALT levels normalized.  R7128 was generally well-tolerated. 

Bottom line:  It is too early to tell if this drug will be a viable drug for treating hepatitis C, but if the twice a day dose proves to be effective it will be an improvement over the three or four times a day dosing of some of the other drugs in development.   

Bavituximab is an anti-phosphotidylserine monoclonal antibody immunotherapeutic that is being investigated to treat hepatitis C.  At AASLD the results from a phase 1b study of 24 patients (15 males, mean age 49) were presented.  In the study, 11 of the patients were treatment non-responders, 8 were treatment relapsers and 5 were treatment-naïve.  The mean baseline HCV RNA was 5,000,000 copies/mL.  Fifteen patients were infected with HCV genotype 1, 8 patients were infected with genotype 3, and 1 patient was infected with genotype 2.  Bavituximab was given by infusions for two weeks at doses of 0.3, 1, 3 or 6 mg/kg.  The patients were observed for a total of  12 weeks.  All of the patients in all the dosing groups achieved a greater than or equal to 0.5 log10 reduction in HCV RNA.  In the 3 mg/kg group 83% of the patients had viral load reductions, and this is the dose that Peregrine will advance into future clinical studies.  The infusions were well-tolerated with no serious adverse events or early discontinuations reported.  There was one grade 3 neck pain and arthralgia (joint pain) in a study participant with a history of joint pain (in the 3 mg/kg group) that was considered dose-related to the study drug. 

Bottom line:  Given the modest antiviral properties of bavituximab it will be interesting to see if there will be a synergistic effect when combined with interferon/ribavirin therapy.  This could mean an improvement in treatment outcome over the current standard of care. 

GS-9190 is an HCV non-nucleoside polymerase inhibitor that is being developed by Gilead Sciences.  The results from a phase I study (part A & part B) were presented at AASLD. 

Part A:  31 HCV genotype 1 treatment naïve patients were treated with escalating doses of GS-9190 (40 mg, 120 mg, 240 mg, 480 mg,  and 240 mg with food) or placebo.  The mean age of the study participants was 44 yo; they were mostly white males and had a median HCV RNA of 6.56 log10.  The HCV RNA reductions seen in a single dose of GS-9190 (across all doses) ranged from 0.7 to 1.2 log10.  GS-9190 was well-tolerated with no serious treatment-limiting adverse events.  

Part B:  Based on the results from Part A, Part B was initiated to study multiple doses of GS-9190 in 23 trial participants over an eight day period.  The study participants received one of the following doses – 40 mg BID, 120 mg BID, 240 mg QD or 240 mg BID.  The baseline mean HCV RNA was 6.65 log10 and the mean age was 44 yo.  The participants were mostly white males.  Data from the 240 mg QD and 240 mg BID groups was available and presented at AASLD.

The reduction in HCV RNA was 1.4 log10 for the 40 mg group and 1.710 for the 120 mg BID group.  GS-9190 given twice daily over the eight day period was generally well-tolerated.  Included in the study design was an electrocardiographic assessment to test for any potential defects in heart rhythm.  In Part B a possible case of QT (arrhythmia) was noted.  Based on this finding, Gilead has initiated a study in healthy subjects to further evaluate the effect of GS-9190 on the heart.  The results from the QT study are expected to be available by the end of 2007. 

Bottom line:  Again too early to tell if this is going to be an effective drug to treat HCV, but if it is found that there is no relationship between GS-9190 and QT, Gilead will continue to study the drug as a possible treatment for hepatitis C.  Results from the QT study in healthy adults are expected to be released by the end of 2007.

VCH-759 is an HCV non-nucleoside polymerase inhibitor.  The results of a phase I study of 32 HCV treatment naïve patients (31 patients with genotype 1, 1 patient with genotype 6) were released at AASLD.  It was noted that the results of the effectiveness of VCH-759 in the person with genotype 6 were not included in the final results.  However, the side effect and safety information from the genotype 6 patient was included in the overall safety information.

The participants were randomized into 4 treatment arms:

• 400 mg TID (three times a day) – 8 patients
• 800 mg BID – 5 patients
• 800 mg TID – 9 patients
• Placebo – 9 patients (included in all treatment arms)

The results showed that all the patients who received VCH-759 achieved more than a 1 log10 decrease in HCV RNA.  The 800 mg TID group had the highest log decrease – 2.5 log10.  The drug was well-tolerated over 10 days.  Studies are underway to determine if there are any mutations associated with viral rebound in some of the subjects who relapsed before the final dose of VCH-759 was given.

Bottom line:  This information is very early data and there can be no conclusions made about the future development of this drug.  However, the results of the genetic sequencing will give a better indication of the drug resistance and whether or not this drug will be advanced into larger studies.    

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Disability & Benefits: Public Benefits & Residency Requirements
Jacques Chambers, CLU

Public benefits, specifically Social Security Retirement and Disability, Supplemental Security Income (SSI), as well as Medicare and Medicaid, are programs to aid the elderly, poor, and disabled. They are available to all eligible citizens of the U.S., including native born and naturalized citizens.

In addition to U.S. citizens, there are certain groups of immigrants who may be eligible for some or all of the benefits. The rules can be very complicated, as are most federal laws, but it is possible to give some general rules about the eligibility of non-citizen residents for these programs. Government benefits are available only to citizens and “qualified immigrants.”

 “Qualified immigrants” includes:
• Naturalized citizens;
• Lawful permanent residents (green card holders);
• Refugees;
• Asylees;
• Persons whose deportation is withheld or cancelled;
• Cuban and Haitian entrants;
• Conditional entrant holders; and,
• Certain spouses and children who are victims of domestic violence.

“Not qualified immigrants” includes all other groups such as:
• Undocumented immigrants;
• Immigrants with Temporary Protected Status (TPS);
• Persons Permanently Residing Under Color of Law (PRUCOL);
• Persons in the U.S. on a temporary non-immigrant visa; and,
• Victims of trafficking.

Although considered Not Qualified, victims of trafficking are actually eligible for the same benefits as refugees.

Social Security offers two programs for disabled persons – Social Security Disability Insurance (SSDI) and Supplemental Security Income (SSI) – and eligibility for both is limited to “qualified immigrants.”

Supplemental Security Income (SSI) is a needs based program. To qualify for this program a person needs to be either at least age 65 or disabled. In addition, the applicant must prove need, few financial resources and low income.

Only “qualified immigrants,” as well as certain U.S. military veterans, in addition to U.S. citizens, of course, can be eligible for this program.

Immigrants who are being sponsored should be aware that the sponsor’s income and resources may be added to the immigrant’s in determining eligibility for SSI, Medicaid and other needs-based programs.

Social Security Disability Income (SSDI) is handled somewhat differently since working individuals contribute to it through F.I.C.A. payroll taxes. However, to be eligible to receive benefits, the person must be living in the United States lawfully. If a person was living and working in the U.S. without a green card or other documentation of work authorization, any SSDI benefits would not be payable until either the residency becomes lawful or the person returns to the country of origin and applies for benefits through the U.S. embassy. Even that eligibility will vary depending on the country of origin.

Medicare, the federal health insurance for persons over age 65 or disabled persons collecting SSDI, is handled the same as SSDI, except that Medicare does not cover persons residing outside the United States.

Medicaid is only available to “qualified immigrants,” although, in most states, undocumented residents are eligible for Emergency Medicaid and Pregnancy Related Medicaid. 

There are other government programs that are available to low-income “qualified immigrants.”  These include food stamps as well as housing assistance from HUD. Different rules apply to state and local housing programs.

Undocumented residents are generally eligible for certain other programs including:
• Prenatal care;
• Children’s Services;
• Children’s Immunizations;
• Women, Infants, & Children (WIC);
• School-based meals;
• Public education; and,
• Help from food pantries, shelters, and many non-profit agencies.

Although the rules, like most federal laws, can be complicated, there is an excellent summary of these rules in the booklet published by the Los Angeles Coalition to End Hunger and Homelessness, called The People’s Guide to Health, Welfare and Other Services. The booklet is online at http://cfpa.net/LosAngeles/ExternalPublications
if you want more information. Although the booklet is California specific, the section on residency and many other sections apply nationwide.

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Can Mosquitoes Spread HCV?
Alan Franciscus, Editor-in-Chief

One of the most frequent questions we receive is about the risk of getting hepatitis C from the bite of a mosquito. The answer is NO! There has never been a documented case of someone getting hepatitis C from a mosquito bite.  But, this is a logical question since the hepatitis C virus is a member of the flavivirus | family that includes many diseases such as West Nile Virus, Dengue and Yellow fever that can be transmitted by mosquitoes.   So if these diseases are transmitted by mosquitoes, why isn’t Hep C transmitted in a similar fashion?  The answer is that these diseases (except Hep C)  are transmitted by the excretion of saliva during the mosquito bite.  For example, the yellow fever virus is transmitted by a virus-carrying mosquito biting another person.  The blood that contains the yellow fever virus is transported from the infected person to the mosquito.  The infected blood is deposited in the mosquito’s intestines where it replicates more viruses.  The additional step is that the yellow fever virustravels to the mosquito’s salivary glands where it continues to multiply.  A mosquito will then bite another person and inject the yellow fever virus infected saliva into the next person.

Hepatitis C is spread by blood-to-blood contact.  Although there have been studies that have found that mosquitoes (collected from households of persons living with HCV and studies that have inoculated mosquitoes with HCV-infected blood) can carry Hep C-infected blood, there is no evidence that it can be passed on to people by being bitten by a mosquito.  The answer lies in the fact that hepatitis C virus is only efficiently transmitted by blood and NOT saliva.

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Top Eleven News Stories of 2007
Alan Franciscus, Editor-in-Chief

It is that time of year again when the staff of the Hepatitis C Support Project/ HCV Advocate compile a list of the most important news stories of the year.  In 2007 we saw some tremendous advances in the development of new drugs to treat hepatitis C.  There was also some disappointing news about the cancellation of some studies on drugs that we were all hoping would become viable treatment options in the near future.  In 2006 there were tremendous strides in our understanding of the HCV lifecycle and we seemed to be on the verge of discovering exactly how the virus replicates and becoming more clued into HCV disease progression.  Unfortunately, 2007 wasn’t as enlightening on these issues as 2006 – still there were some advances in research and the understanding of the hepatitis C virus.  Going forward, 2008 promises to be the year that even more investigational drugs are discovered and advanced through clinical development, and there is a real possibility that science will nail down the lifecycle of the hepatitis C virus and we will finally be able to study it in depth and find out what exactly kills HCV.  As well more drugs will be identified to treat hepatitis C, and improved strategies developed for managing disease progression.

Listed below is a list of news stories that our staff have identified as the most important news stories of 2007.  As in years past, we have identified the number one story, but the ones that follow number one are not necessarily in any particular order.

1.   Telaprevir – Two years in a row, now, telaprevir has been our top newsmaker.  In 2007 phase II studies of the combination of telaprevir, pegylated interferon and ribavirin showed improved sustained virological response rates by about 10% and shortened treatment duration for people infected with HCV genotype 1 (from 48 weeks to 24 weeks).  This is a major advancement.  In 2008, Phase III studies of telaprevir combination therapies will commence.  Another phase II study is eagerly awaited on retreatment of prior genotype 1 non-SVR responders, to see if telaprevir will improve retreatment responses in a population that has few or little treatment options.   

•  Albuferon – this form of time released interferon is advancing through clinical development and may offer a choice of dosing once every 2 weeks compared to weekly injections of the current pegylated interferons.  It may not be a treatment advance in terms of a better treatment response rate, but it might provide less frequent injections.  A phase III study was initiated and enrollment completed in 2007. 

•  The Future of Interferon and Ribavirin – one important piece of information that we have learned in 2007 is that interferon and ribavirin will be included in therapy to treat hepatitis C in the foreseeable future.  We were all hoping that we could eliminate one or both, but the reality is that they are going to be included in the mix for quite some time until we have many more specific HCV antivirals.

•  OraSure – was another top news item in 2007.  There hasn’t been much news out of OraSure about the HCV rapid test, but earlier this year, OraSure stated that they hope to have their clinical trials completed by the end of 2007 and may be able to apply to the FDA for marketing approval in 2008.  A rapid HCV test will hopefully get more of the estimated 70% of people who have HCV and don’t know it tested. 

•  Pegylated Interferon and Ribavirin Therapy – in 2006 and in 2007 we learned a lot about optimizing treatment outcome with pegylated interferon and ribavirin therapy.  There have been two major strides towards improving treatment outcome: prolonging treatment duration and more effective side effect management.  The big lesson we learned was that there are no ‘cookie-cutter’ treatment protocols for people with hepatitis C.  Treatment needs to be individually tailored to a person based on many factors, such as age, viral load, duration of treatment, etc.  Over the years, we have also come to understand treatment-related side effects and, more importantly, how to manage and relieve the side effects so that people can have improved quality of life while on therapy.  Managing side effects is also important so that people can stay on treatment longer, if appropriate, and to help people take all of the prescribed medications as close to 100% of the time as possible.  We have also learned that pegylated interferon and ribavirin will be the backbone of therapy for the foreseeable future; so these strides in current treatment optimization can only help us to improve future treatment outcomes. 

•  Nexavar – a new treatment for liver cancer was recently approved by the Food and Drug Administration (FDA) and is one of a few treatment options for people with liver cancer.  It is currently the only drug approved by the FDA to treat liver cancer.  In clinical trials, Nexavar was found to improve overall survival. Nexavar has already been approved for the treatment of advanced kidney cancer. 

•  R1626 – a promising new HCV polymerase inhibitor that is in early clinical development.  R1626 produced remarkable HCV antiviral activity and does not appear to produce drug resistance – at least in the early studies.  R1626 is creating a lot of excitement, but, due to some of the serious side effects, more clinical studies are being planned with different doses of R1626, pegylated interferon and ribavirin that will hopefully tease out what is the most effective dose that has the least amount of side effects. 

•  Insulin Resistance – information about insulin resistance and its affect on HCV treatment outcome was released in 2007 and showed that just having insulin resistance greatly reduced the chances of achieving an SVR.  More importantly it was also found that lifestyle modification by way of diet, exercise and weight reduction dramatically improved the treatment response in people with insulin resistance.

•  Valopicitabine – In July 2007 the FDA conducted an independent risk-benefit analysis based on the entire development program and based on their findings notified Idenix that they were putting the entire development program on hold, and it appears that Idenix will no longer develop valopicitabine for the treatment of hepatitis C.  Unfortunately, there were also other drugs that didn’t live up to expectations and were taken out of clinical development; but still there are many new drugs under development that have the potential to improve treatment outcome that everyone should be optimistic about.   

•  Psychiatric Populations – one of the most interesting (and sorely needed) studies released in 2007 was a study on people with psychiatric disorders who were treated with interferon- based therapies.  In the study, it was found that in people with psychiatric and substance use  problems there was no association between treatment completion, the baseline use of antidepressants, and a history of substance use.  The researchers found that people with psychiatric or substance use disorders can be considered HCV treatment candidates provided that they are given multidisciplinary support.  As is always the case successful treatment outcome is dramatically influenced by support in almost every area of need.  This was a much needed report on a group of people who have a very high prevalence of hepatitis C.  

•  Harm Reduction Efforts for Injectors – advancements have been made in the United States on various harm reduction efforts such as needle exchange, overdose prevention, and drug injector education and advocacy.  There is a very interesting experiment that is currently being conducted in Vancouver, BC that people in the us should be paying close attention to.  Vancouver, BC is currently running the largest needle exchange program in North America and has opened ‘safe injection sites’ where addicts can inject without fear of reprisal from law enforcement.  Another benefit is that it has reduced the number of accidental overdoses because there are people in the safe sites who can treat a person who accidentally overdoses.  The clear winner so far! – infection rates from HIV and hepatitis C have fallen dramatically.  However, a conservative government has been sworn in and a harder line is being taken at a national level.  Hopefully, we can learn from the successes and problems that the Vancouver experience is teaching us. 

Listed below are some predictions that our staff has made for 2008, based on what has happened in years past. 

Our staff has made the following predictions for 2008: 

•  Hepatitis C will finally get more national and international awareness.  Planning for an expanded World Hepatitis Day is underway.  Stay tuned for more information about events that will take place around the world and how everyone can get involved.

•  Even more drugs will be developed to treat hepatitis C and some of the drugs in current clinical development will advance into larger clinical trials.  The drugs to keep an eye on are telaprevir, boceprevir (SCH 503034), nitazoxanide, and R1626.  

•  We believe that in 2008 science will be able to replicate the hepatitis C virus in a test tube, which will open the door for more drug discovery and information on what kills HCV, as well as on how to prevent or slow down HCV disease progression.

•  In 2008 we believe that there will be more movement towards health care reform on a local and state level as we have seen in Massachusetts and San Francisco.  We all believe that the time is right for major health care reform in this country and that eventually there will be a national focus on health care reform, but it is going to take many years and much advocacy on the part of all Americans to make health care and services for all Americans a reality. 

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Interferon Maintenance Therapy and Liver Disease Progression
Liz Highleyman

Over years or decades, chronic hepatitis C virus (HCV) infection may progress to liver cirrhosis, hepatocellular carcinoma (HCC), end-stage liver disease, and death due to liver failure. Numerous studies have shown that patients who achieve sustained virological response (SVR) to interferon-based therapy experience slower or stable liver disease progression, and, in some cases, even reversal of fibrosis.

Yet the current standard regimen of pegylated interferon alfa plus ribavirin does not lead to sustained response in about half of treated patients, especially “hard to treat” individuals such as those with HCV genotype 1, people of African descent, those coinfected with HIV, and nonresponders to a previous treatment attempt.

In the absence of a virological “cure,” can anything be done to slow, prevent, or reverse liver disease progression? Researchers have explored a variety of experimental anti-fibrotic therapies, including colchicine, the milk thistle extract silymarin, and the licorice root extract glycyrrhizin.

Another proposed strategy is long-term, low-dose interferon maintenance therapy, which was studied in the HALT-C (Hepatitis C Antiviral Long-term Treatment against Cirrhosis) trial.

HALT- C Results
This randomized, controlled study, sponsored by the National Institutes of Health and conducted at 10 U.S. sites, aimed to determine whether interferon monotherapy for several years could prevent progression to cirrhosis, liver decompensation, and HCC, and reduce the need for liver transplantation. The trial enrolled 1,145 chronic hepatitis C patients with advanced fibrosis or cirrhosis (Ishak stages F3-F6; Child-Turcotte-Pugh score ≥ 6), but no decompensated liver disease.

Participants initially received a standard regimen of 180 mcg/week pegylated interferon alfa-2a (Pegasys) plus 1,000-1,200 mg/day weight-based ribavirin for 24 weeks. Those who achieved undetectable HCV RNA continued combination therapy through week 48. The 662 participants who still had detectable virus were randomly assigned to either continue treatment with half-dose (90 mcg/week) pegylated interferon monotherapy for an additional 42 months or to discontinue therapy. Some additional participants were also analyzed (including initial responders who later relapsed), for a total of 1,050 individuals (622 with stage F3-F4; 428 with stage F5-F6).

The researchers looked at a variety of liver-related endpoints: hepatic decompensation (ascites, bleeding varices, bacterial peritonitis, encephalopathy, or a Child-Turcotte-Pugh score ≥ 7), an increase in fibrosis score of ≥ 2 points (for those who did not yet have cirrhosis at baseline), development of HCC, and death. Participants were examined every three months, and liver biopsies were performed at study entry and after 1.5 and 3.5 years.

The latest data from HALT-C were presented by Adrian Di Bisceglie and colleagues in a late-breaker session at 58th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) in Boston last November.

The average serum alanine aminotransferase (ALT) level decreased in the group that continued pegylated interferon, as did mean HCV RNA level and necroinflammatory changes seen on liver biopsy.

Nevertheless, by the end of the study, 34.1% of participants in the maintenance therapy arm and 33.8% in the untreated control arm reached one of the study endpoints, which was not a statistically significant difference. In fact, there were no significant differences in any of the primary outcomes between the maintenance therapy and untreated arms:

•  Liver decompensation: 14.3% vs 13.2%
•  Increased fibrosis 2 points: 28.2% vs 31.9%
•  HCC: 2.8% vs 3.2%
•  Death: 6.6% vs 4.6%.

Rates of serious adverse events were also similar in the treated and untreated groups. In the maintenance arm, 17% discontinued pegylated interferon by 1.5 years, and 30% did so by 3.5 years.

Based on these findings, the researchers concluded that, “Long-term therapy with peginterferon did not reduce the rate of disease progression. These findings do not support maintenance therapy with peginterferon in patients with chronic hepatitis C and advanced hepatic fibrosis who are nonresponders to a course of peginterferon / ribavirin therapy.”

Conflicting Findings?
Another study presented at the same conference, however, produced seemingly conflicting results. Stephan Kaiser and colleagues also conducted a study of low-dose pegylated interferon maintenance therapy, but they used pegylated interferon alfa 2-b (PegIntron), at a dose of 0.5 mcg/kg/week (the usual dose in combination therapy is 1.0 mcg/kg/week).

This study included 182 patients in Germany with chronic hepatitis C and advanced fibrosis or cirrhosis (also Ishak stages F3-F6) who were nonresponders to prior combination antiviral therapy. Whereas everyone in HALT-C started with pegylated interferon plus weight-based ribavirin, the German participants could have previously used conventional or pegylated interferon and/or lower doses of ribavirin. This group was compared with an observational control group of 83 patients who did not receive long-term therapy. Liver histology was evaluated at study entry, at 18 months of treatment, and six months after completion of 36 months of maintenance therapy.

In the maintenance therapy arm, the average fibrosis score decreased from 3.83 at baseline to 2.51 at 18 months and 2.05 post-treatment. In the untreated control arm, by contrast, the average fibrosis score increased from 3.71 at baseline to 4.17 at 18 months and 4.79 at the final assessment.

The average necroinflammatory score fell from 8.61 at baseline to 5.89 at 18 months in the maintenance therapy group, but then increased again to 7.54 after completion of treatment. In the untreated group, necroinflammatory scores remained stable over time (7.89, 7.56, and 7.73, respectively).

Nearly two-thirds of patients in the maintenance therapy group experienced at least a 1 log decline in HCV RNA, and 6% became undetectable, but this was not sustained six months after completion of therapy. The treatment discontinuation rate was 3%, and 13% required pegylated interferon dose reduction. There were 22 serious adverse events, occurring at similar rates in the maintenance therapy and untreated arms.

The German researchers concluded, “Low dose therapy with pegylated interferon alfa-2b in patients with HCV and advanced fibrosis or cirrhosis shows a significant and persistent decrease in fibrosis in comparison to a control group.”

Surrogate Markers vs Clinical Outcomes
What explains the apparent discrepancies between HALT-C and the German trial?

A look at the specific serious adverse events in the latter study show that the trial results are not as dissimilar as they may appear. Twelve of these events (affecting roughly 5% of the total study population) were related to decompensated cirrhosis, including six cases of hydropic decompensation (ascites and/or edema) and six cases of bleeding varices. In addition, five participants (about 2%) developed HCC. As in HALT-C, there was no significant difference in the rates of these complications between the maintenance therapy and untreated arms.

Interim results from HALT-C had also appeared promising, with patients on maintenance therapy experiencing decreases in ALT, HCV RNA, and necroinflammatory score — findings that still held at 42 months. However, an analysis of long-term clinical outcomes indicated that these improvements in surrogate markers, which are often assumed to reflect liver disease progression, did not translate into a lower likelihood of fibrosis progression, hepatic decompensation, liver cancer, or death. ALT, in particular, is a measure of liver inflammation, which may be of little use in predicting fibrosis and its consequences.

The German researchers focused their presentation on surrogate marker data, which looked good, but here too, serious clinical outcomes did not differ in the maintenance therapy and untreated groups. The fibrosis data are more puzzling. While nearly one-third of HALT-C participants experienced an increase of ≥ 2 points (regardless of treatment assignment), the average fibrosis score declined by 1.75 in the maintenance arm of the German trial, while increasing in the untreated arm.

Given these results, long-term pegylated interferon maintenance therapy does not appear to be the answer for preventing or reversing liver disease progression in patients who do not achieve sustained response to standard therapy for hepatitis C.

Researchers continue to study therapies for this purpose (including the ongoing COPILOT trial comparing PegIntron versus colchicine). But the ultimate answer may be targeted antiviral agents – such as HCV polymerase and protease inhibitors – which hopefully will increase the proportion of people who experience initial sustained response, and thus reduce the number with continued detectable HCV who will need anti-fibrotic therapies.

•  A.M. Di Bisceglie, et al. Prolonged Antiviral Therapy With Peginterferon to Prevent Complications of Advanced Liver Disease Associated With Hepatitis C: Results of the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial. 58th Annual Meeting of the AASLD. Boston. November 2-6, 2007. Abstract LB1.
•  S. Kaiser, et al. Long-term Low Dose Treatment with Pegylated Interferon alpha 2b leads to a significant Reduction in Fibrosis and Inflammatory Score in Chronic Hepatitis C Nonresponder Patients with Fibrosis or Cirrhosis. 58th Annual Meeting of the AASLD. Boston. November 2-6, 2007. Abstract 1311.
•  HALT-C trial overview: www.haltctrial.org

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