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December 2010 HCV Advocate

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In This Issue:

AASLD 2010 Conference – Part 1
Alan Franciscus, Editor-in-Chief

IL28B Gene Highlighted at AASLD
Liz Highleyman

HealthWise: 2010 Liver Meeting Update
Lucinda Porter, RN

HCV Snapshots
Lucinda Porter, RN

HCV Advocate Eblast
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AASLD 2010 Conference – Part 1
—Alan Franciscus, Editor-in-Chief

In late October the American Association for the Study of Liver Diseases (AASLD) held their annual conference—the largest and most important liver conference held in the United States.  This year provided much information on direct-acting antivirals (DAAs) being studied to treat hepatitis C.  In fact there were over 50 presentations and posters released on DAAs.  The posters and presentations included results from early studies of the DAAs in healthy volunteers and in later stage studies in people who are infected with hepatitis C.  Part one of the AASLD report will on focus on those drugs that were actually studied in people with hepatitis C.  In addition to the DAAs listed below there was quite a bit of data released about telaprevir and boceprevir—the new information will be incorporated into our HCSP Fact Sheets.  Boceprevir and telaprevir, which have completed phase III studies, are expected to be approved by the Food and Drug Administration (FDA) in the middle part of 2011.

DAA medications to treat hepatitis C are drugs that work by interfering or blocking the replication process of the hepatitis C virus.   The DAAs that are currently under study include HCV inhibitors such as polymerase, protease, and a new first-in-class HCV NS5A inhibitor.  The studies below represented combination trials of a DAA(s) with the current standard of care (pegylated interferon plus ribavirin) and early studies of the combinations of DAAs with and without interferon/ribavirin. 

Note:  Pegylated interferon plus ribavirin will be listed below as Standard of Care (SOC) since standard doses are given when combined with the study drugs or as the control or comparator group.  However, the treatment period of SOC varies from study to study. 



#81: RG7128 is an HCV polymerase inhibitor that was given to 408 HCV genotype I and 4 treatment naïve patients in doses of 500 or 100 mg twice a day (BID) for either 8 or 12 weeks combined with SOC.  If patients were HCV RNA negative (<15 IU/mL) from week 4 to week 22 all treatment was stopped at week 24.  The patients who did not meet the criteria above were randomized into an RG7128 arm or SOC arm and treated for a total treatment duration of 48 weeks.  Sixty-eight to eighty-seven percent of people were HCV RNA negative at week twelve (cEVR) compared to 49% in the SOC group. 

Comments:  The triple combination looks very encouraging for the following reasons:  (1) the combination was safe and well-tolerated when given for twelve weeks to patients with and without cirrhosis; (2) RG7128 has a high barrier to resistance that will make it a good choice for future treatment and possibly for use with another HCV inhibitor; (3) there is a potential for a shorter treatment duration of 24 weeks compared to the current SOC; and (4) the results are more meaningful since there is a relatively large patient population.


Vaniprevir (MK-7009)

# 82:  Vaniprevir (MK-7009) is an HCV protease inhibitor.  The study included 94 HCV genotype 1 treatment-naïve patients who were administered 1 of 5 regimens—300 mg BID, 600 mg BID, 600 mg QD (once a day), 800QD or placebo combined with SOC for 4 weeks followed by an additional 44 weeks of pegylated interferon.  The sustained virological response or SVR (undetectable HCV RNA 24 weeks after stopping treatment) was 61% to 84% in the groups that received vaniprevir.  No serious side effects were shown—vomiting was noted more in the vaniprevir groups but did not lead to treatment discontinuation. 

Comments:  The increased rates of response when vaniprevir is combined with SOC are encouraging especially the SVR rates in the 800 mg once-a-day dose.  It would certainly make adherence easier compared to taking it three times a day, but hopefully more studies will be conducted that will look at using vaniprevir to reduce treatment duration by response guided therapy and/or in combination with another DAA. 



# 806:  PSI-7977 is an HCV polymerase inhibitor that is dosed once a day (100, 200 and 400 mg) in combination with SOC.  Sixty-three treatment-naïve HCV genotype 1 patients were enrolled in the study.  Eighty-eight to ninety-four percent of the patients who received PSI-7977 plus SOC for 28 days achieved undetectable HCV RNA at week 4 compared to 21% in the group that received SOC but without PSI-7977.  No differences in response were seen between genotypes 1a or 1b (subtypes).  The drug was generally safe and well-tolerated. 

Comments:  Although this is a small study the results are impressive.  It was also noted that PSI-7977 is pan genotypic—that is, it has antiviral activity against all genotypes.  A larger 12-week study is being planned that will hopefully duplicate these results and provide more information about treatment duration, antiviral response and safety.



#LB-5:  Interim 24 week results for a study of TMC435 (75 and 150 mg QD), an HCV protease inhibitor, combined with SOC given for up to 24 weeks to HCV genotype 1 treatment-naïve patients produced significant viral load reductions. In the 130 patients who completed 24 weeks of treatment and in patients who stopped treatment for any reason by week 24—88% to 97% achieved an SVR12 (HCV RNA undetectable 12 weeks after stopping treatment). So far there is a low rate of viral breakthrough and the drugs were generally safe and well-tolerated with few treatment discontinuations and the side effects were similar to the group that received the SOC. 

Comments: The interim results of 88% to 97% are very impressive in the groups that received TMC 435 for 12 or 24 weeks plus SOC and continued SOC for a total treatment duration of 24 weeks.   So far the drug has a good safety profile, low viral rebound and the majority of patients were able to stop treatment at week 24 because they were HCV RNA negative at the time points specified in the study design.

Related news:  In November 2010 top-line interim 24 week results to evaluate TMC435 at either a 100 mg or 150mg dose QD for either 12, 24, or 48 weeks in combination with SOC to treat 462 HCV genotype 1 patients who did not achieve an SVR (relapsers, partial responders and null responders) with a previous course of pegylated interferon plus ribavirin were released.   After the initial period with TMC and SOC, the study participants were continued on SOC for a total treatment duration of 48 weeks.  The percentage of patients who became HCV RNA undetectable ( <25 IU/mL) are listed in the table below:

TMC435 was safe and well-tolerated with a similar safety profile as the study of TMC435 in treatment- naïve patients. 

Comments:  The top-line information release is encouraging for a population of people with hepatitis C who are in the most need for an effective treatment.

TMC435 Genotype 1 Relapser Partial Responder Null Responder
Week 4 81% 62% 38%
Week 12 92% 84% 64%
Week 24 94% 86% 78%



#LB-10: ABT-450 is a protease inhibitor that is being tested in HCV treatment-naïve genotype 1 subjects as a combination therapy that includes ritonavir (boosting agent) and SOC.  For three days the trial participants were given ABT-450 (boosted with ritonavir) at doses ranging from 50 to 200 mg QD  followed by quadruple therapy of ABT-450 (with ritonavir) plus SOC for 12 weeks followed by 36 weeks of SOC alone  At the end of the 4th week, 21 of 23 (91.3%) patients were HCV RNA negative (<25IU/mL) compared to only 1 of 8 (12.5%) of those who received the placebo (plus SOC).  The medications were safe and well-tolerated. 

Comments:  ABT-450 produced very high rates of patients who became HCV RNA negative after 4 weeks of treatment.  The drugs were safe and well-tolerated.   SVR rates will likely be higher and hopefully future studies will be designed to study shortening the total treatment duration. 


GS-9256 Plus GS9190

#LB-1: The combination study of GS-9256 (HCV protease inhibitor) BID plus tegobuvir (GS-9190 polymerase inhibitor) BID with and without ribavirin or SOC to treat HCV genotype 1 treatment-naïve patients was presented at AASLD.  In the group that received the quadruple therapy for 4 weeks followed by 44 weeks of pegylated interferon plus ribavirin 14 out of 14 patients (100%) were HCV RNA negative by day 28.   The quadruple therapy was generally well-tolerated with typical SOC type side effects.  There is an ongoing 4 month study of the quadruple therapy.

Comments:  The quadruple therapy produced the highest response rates at day 28 of therapy compared to the groups that did not include pegylated interferon or the control arm (SOC).  Seventy-one percent of the quadruple group was HCV undetectable (≤ 25 IU/mL) by day 14 so it would be interesting to find out if treatment duration can be shortened from the 48 week duration in this study. 


BMS-790052 Plus BMS-650032

# LB-8:  In an important study the combination of BMS-790052 (NS5A inhibitor) and BMS-650032 (protease inhibitor) was given alone or in combination with SOC to treat HCV genotype 1 null-responders to a prior course of therapy.  The interim 12-week results (total study duration is 24 weeks) produced early potent antiviral activity, but 6 out of the 11 people treated had viral breakthrough.  When the two inhibitors were combined with pegylated interferon and ribavirin 9 out of 10 patients became HCV RNA undetectable by week 12. Final results are expected in 2011. 

Comments:  BMS-790052 (QD) is a new first in-class inhibitor that has been shown to have potent antiviral activity against HCV genotypes 1a and 1 b.  BMS-650032 is an HCV protease inhibitor (BID) that when combined with BMS-790052 plus SOC produced high complete early virologic response rates (cEVR) at 12 weeks. The combination therapy was safe and well-tolerated.  The viral breakthrough of the 6 out of 11 patients who received just the inhibitor combination indicates that pegylated interferon and/or ribavirin may be needed to completely suppress HCV when the two inhibitors are used alone—at least in this study design.  The study design is being expanded to include more arms so stay tuned.  

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IL28B Gene Highlighted at AASLD
—Liz Highleyman

In 2009 researchers first reported that certain variations in the human genetic code near the IL28B gene can help predict which people with hepatitis C virus (HCV) will spontaneously clear acute infection and who will respond well to interferon-based therapy for chronic infection.

Discovery of the IL28B link has spurred a change in thinking about hepatitis C and its treatment. Some experts believe these human gene patterns may prove to be as important as HCV viral genotypes (1, 2, 3, etc.) in predicting outcomes. More than 50 oral and poster presentations at the 61st American Association for the Study of Liver Diseases (AASLD) "Liver Meeting" last month in Boston looked at various aspects of IL28B and its relation to hepatitis C.

As background, the relevant variations—known as single nucleotide polymorphisms (SNPs), or substitution of a single building block at a specific position in the DNA chain—are located on chromosome 19 near the IL28B gene. The IL28B gene encodes instructions for making interferon lambda (a.k.a. interleukin 28). Interferons produced by the body are key to the immune system's response against hepatitis C and B; interferon therapy strengthens this natural response.

Each individual carries two copies of every gene, one from each parent. The IL28B rs12979860 SNP—which has been implicated most often—has two variations, or alleles, known as "C" and "T." Hepatitis C patients with the C/C pattern—that is, two copies of the "C" allele have the best outcomes. People with the T/T pattern (two "T" alleles) have the least favorable response, while those with the C/T pattern (one copy of each variation) fall somewhere in between. 

By now numerous studies have shown that hepatitis C patients with the C/C pattern have much higher rates of sustained virological response (SVR) to pegylated interferon plus ribavirin than those with the T/T pattern. C/C is more common among people of European descent, which helps explain why white patients respond better than black patients to interferon. For more information, see the August 2010 HCV Advocate.


HCV Genotypes 2 and 3

Initial IL28B studies looked at individuals with hard-to-treat HCV genotype 1. Researchers at the Liver Meeting reported associations for people with genotypes 2 and 3. In a study of 267 patients with either genotype 2 or 3, German researchers (abstract 904) found that the rs12979860 protective C/C pattern was significantly associated with both rapid and sustained virological response, but did not see a significant influence for two other SNPs, rs8099917 and rs12980275.

Japanese researchers (abstract 798) who studied nearly 800 hepatitis C patients reported that the rs8099917 protective pattern was a significant predictor of SVR for genotype 2 overall and for genotype 2b (but not for 2a). And a Scandinavian team (abstract 898) looking at 269 Northern European genotype 3 patients found that the protective pattern for either rs12979860 or rs8099917 significantly predicted RVR but not SVR.

Given these conflicting findings, more research is needed in this area.


Interferon Treatment Response

Turning to treatment, R. Roomer from Erasmus University Medical Center and colleagues (abstract LB-13) reported that increasing the dose of interferon alfa-2b (Intron A, the type used in PegIntron) may help overcome poor interferon sensitivity in people with the unfavorable rs12979860 T/T pattern who did not respond to prior combination therapy.

Patients in this small study received continuous infusions of interferon at doses of 6, 9, or 12 million units (MU) per day using a modified insulin pump. Regardless of dose, people with the protective C/C pattern experienced a larger decrease in HCV viral load by week 4 than those with the C/T or T/T patterns (averages of 2.9, 1.7, and 1.3 log, respectively). All C/T and T/T participants who received the highest dose, however, achieved early viral load drops greater than 2 log. Nevertheless, while two of the three C/C patients achieved SVR (using 6 or 9 MU), only four of 20 C/T patients (all receiving 12 MU) and none of the six T/T patients did so.

In a related study, S. Chevaliez from Henri Mondor Hospital in Paris and colleagues (abstract 129) assessed whether IL28B influences response to high-dose pegylated interferon (360 mcg/week) plus ribavirin (1000-1200 or 1200-1600 mg/day) in 83 genotype 1 prior null responders. Only three people in this treatment-resistant population had the rs12979860 C/C pattern. Looking at the other two groups, C/T patients had larger viral load decreases than T/T patients at weeks 2, 4, 12, and 24, and were significantly more likely to achieve undetectable HCV RNA by week 24 (33% vs 12%, respectively). IL28B gene pattern, therefore, could help predict the likelihood of responding to retreatment.


Direct-Acting Antivirals

IL28B genetic variations may also influence response to new direct-acting antiviral agents used in combination with pegylated

interferon and ribavirin, but some of these drugs may be potent enough to overcome poor interferon sensitivity in people with unfavorable gene patterns. Researchers presented data stratified by IL28B status from studies of the HCV polymerase inhibitors PSI-7977 (abstract 815) and ANA598 (abstract 1852).

J. McHutchison from Duke University and colleagues (abstract 810) devised a mathematical model showing how uneven distribution of the protective rs12979860 C/C pattern might bias results in clinical trials of new drugs. They found that the likelihood of IL28B genotypes being unequally represented in different treatment arms was quite high, reaching about 30% for smaller Phase I trials.

"Knowledge of IL28B genotype distribution is important for interpreting early phase clinical trial results, particularly dose-finding studies where dose-related antiviral potency must be weighed against toxicity," they concluded. "Confounding by IL28B genotype imbalance between treatment arms might affect the decision to advance a compound from proof-of-concept to the next stage of clinical development."


Disease Progression

Several teams presented findings linking IL28B gene pattern and disease progression. D. Bitetto from the University of Udine in Italy and colleagues (abstract 230) looked at the same rs12979860 SNP in 548 hepatitis C patients categorized according to liver disease severity. The likelihood of having the unfavorable T/T pattern rose as liver disease worsened from mild fibrosis (9%) to more advanced disease (17%) to hepatocellular carcinoma (24%).

In contrast, A. Thompson and fellow investigators with the IDEAL study (abstract 229), who analyzed more than 1300 genotype 1 patients treated with Pegasys or PegIntron plus ribavirin, saw no association between rs12979860 pattern and advanced fibrosis

But another IDEAL analysis (abstract 1893) found that the protective C/C pattern was associated with higher preteatment alanine aminotransferase (ALT) levels and moderate-to-severe (A2-A3) necroinflammatory activity. The researchers suggested that the commonly reported association between higher ALT and SVR might be explained by IL28B variations.

A smaller Spanish study (abstract 892) looking at 129 genotype 1 patients treated with standard therapy again saw no link between rs12979860 variations and liver fibrosis. Frequencies of the protective C/C pattern were 30% among people with absent to mild (F0-F1) fibrosis, 41% among those with moderate (F2) fibrosis, and 36% among those with advanced (F3-F4) liver disease—not a significant difference.

This study, as well as others presented at the conference (e.g., abstract 1899), showed an association between IL28B gene pattern and glucose metabolism or insulin resistance. Some teams (e.g., abstracts 232, 1879) found an association with low-density lipoprotein (LDL) cholesterol levels. More research is needed to learn about the relationship between IL28B, metabolic abnormalities, and liver disease progression.

Finally, M. Charlton from the Mayo Clinic and colleagues (abstract 1) reported that thers12979860 C/C pattern in either the recipient or the donor liver was associated with delayed HCV recurrence and greater likelihood of sustained response to interferon-based therapy after liver transplantation¾although it did not significantly improve survival. A Spanish study (abstract 1140) likewise saw better post-transplant outcomes among patients who received new livers with the rs12979860 or rs8099917 protective gene patterns. "The data suggest that C/C donor livers might be preferentially allocated to patients with HCV infection," Charlton's team concluded.


Hepatitis B

Turning to hepatitis B, a set of studies suggested that while IL28B may influence outcomes, the link is not as straightforward as it is for hepatitis C. With regard to natural clearance, F. Kurbanov from Johns Hopkins University and colleagues (abstract 1408) found that that people who spontaneously cleared HBV were no more or less likely to carry the rs12979860 "C" allele than those who developed chronic infection.

In a second study, H. Reesink from the University of Amsterdam and colleagues (abstract LB-21) assessed whether the rs12979860 SNP predicts outcomes among chronic hepatitis B patients treated with pegylated interferon plus adefovir (Hepsera). There was a trend toward greater likelihood of SVR among HBeAg negative patients with the C/C pattern (57% vs 36% for C/T and T/T combined), but the difference did not reach statistical significance. In contrast, HBeAg seroconversion among initially HBeAg positive patients was somewhat less likely in the C/C group (22% vs 54%, respectively). Hepatitis B surface antigen (HBsAg) loss rates were similar regardless of IL28B pattern.

However, in a third study, P. Lampertico from Universita degli Studi di Milano and colleagues (abstract 237), looking at 101 HBeAg negative chronic hepatitis B patients (most with HBV genotype D) treated with either conventional or pegylated interferon, found that HBsAg clearance was significantly more likely in people with the T/T pattern than in those with either C/C or C/T (36%, 29%, and 7%, respectively).

Reesink's team concluded that "the heterogeneity of HBV patients, viral genotypes, and definitions of outcome make [hepatitis B] more challenging for evaluation of host genetics" than hepatitis C.


Tailoring HCV Treatment

While IL28B genetic testing could provide useful information about which people with hepatitis C are most likely to respond to interferon, its greatest value may lie in helping to tailor treatment for individual patients.

A. Mangia and colleagues (abstract 897) presented an IL28B gene analysis of about 400 genotype 1 participants in an Italian study of individualized duration of pegylated interferon plus ribavirin. They showed that the rs1279860 C/C pattern was a strong predictor of rapid response, and concluded that, "duration of treatment may be safely reduced" in C/C and C/T patients who achieve RVR.

While RVR remains the best predictor of SVR, they added, only a minority of patients have such good early responses. But among C/C patients, a majority without RVR nevertheless will go on to achieve SVR, so they should not stop treatment prematurely. A Spanish study of HIV/HCV coinfected patients (abstract 131) also found that C/C carriers without RVR still had a good chance of achieving sustained response.

Austrian researchers (abstract 923) also found that people who achieved RVR had a high likelihood of SVR regardless of IL28B pattern. But among slower responders with C/T or T/T, extending treatment to 72 weeks significantly lowered the post-treatment relapse rate.

Taken together, these studies indicate that IL28B genetic variations may be a key factor in ensuring that hepatitis C patients are treated long enough, but no longer than necessary.

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Healthwise: 2010 Liver Meeting Update
—Lucinda K. Porter, RN

The first week of November, I enjoy something even more than eating leftover Halloween candy—the annual Liver Meeting hosted by the American Association for the Study of Liver Diseases (AASLD). The Liver Meeting conjures up images of livers gathering in a convention hall, shooting the breeze about the latest gall bladder medications. Actually, the Liver Meeting is an international assembly of liver specialists who meet to network and exchange the latest research on liver diseases.

Before commenting on the Liver Meeting, I want to remind readers to apply critical thinking when looking at research results. Never make health decisions based on something you read. My mother was famous for taking various dietary supplements because she read something in a magazine. If a study reported that people who didn’t have eyebrows had better memories, my mother might have shaved her brows. It would not have occurred to her that people without eyebrows might have had better memories because they slept more every night and were more prone to rubbing their brows on their pillows. So talk to your medical provider before pulling out your eye brows or trying something because you read it somewhere.

Don’t make conclusions from observational studies. A good example of this is found in the study “Mild Alcohol Consumption is Not Associated with Increased Fibrosis in Patients with Chronic Hepatitis C” by Cheung and colleagues mentioned in this month’s HCV Snapshots. This is an observational study in which participants are grouped by a behavior that they already have; they were not randomly assigned to a no, low, or high drinking group. On the surface it appears that mild alcohol consumption is not harmful to the livers of those with HCV, but perhaps moderate drinkers with HCV have other habits that protect them from liver damage.

Humans tend to look for cause and effect relationships. We want to know if what we are doing is harming or helping us. Research informs us, and gives us data that we can use or discard. We may welcome certain information, particularly if it tells us something that we want to hear. For instance, wouldn’t it be wonderful to read that potato chips are good for us? The person who liked potato chips would be thrilled to learn that a study reported that people who eat potato chips live longer. However, the person who hated potato chips is unlikely to even read the chip research, let alone run out and buy a bag of Ruffles.

With nearly 2000 posters, papers, classes, and press releases, it may be overly simplistic to summarize the entire Liver Meeting, but the word optimism comes to mind. The hope that we will find a cure for everyone with hepatitis C virus  (HCV) is now within reach. The word cure was officially uttered by the president of AASLD, Arun Sanyal, M.D. When asked about the future of HCV in an interview by Michael Smith of MedPage Today, Sanyal said, “We finally believe that cure is possible.”

This optimism stokes my hope, particularly with all the reports that HCV treatments are getting better results. Since the latest HCV-related drugs are abundantly reported on by the press and my colleagues at the HCV Advocate, I am going to highlight two observational studies from the 2010 Liver Meeting that focus on matters other than the latest drug treatments.

The first may particularly interest women, but despite the title, this research also applies to men. This study titled, Menopause Is Associated with Relapse in Chronic Hepatitis C Patients Treated with Pegylated Interferon plus Ribavirin was conducted by French researchers Christiane Stern, Michelle Martinot-Peignoux, Marie-Pierre Ripault,Nathalie Boyer, Ana Carolina Cardoso, Ahmed El Ray, Tarik Asselah,Dominique Valla, and Patrick Marcellin. The purpose of the study was to examine factors associated with relapse after HCV treatment.

There were 249 treatment-naïve participants (no previous HCV treatment) who were treated with peginterferon and ribavirin according to the current standard of care. One third of the study population was genotype 1; the average age was 47 years old; more than a quarter of those enrolled had liver cells with more than 30% fat (marked steatosis); ten-percent were obese with a body mass index of more than 30%. (Apparently there are obese people in France.) Menopause was noted in approximately 59% of the women in the study, so treatment response rates were compared between genders and between those under and over 50 years old.

Approximately one-third of the patients relapsed from HCV treatment. Obesity, genotype 1, marked steatosis, and peginterferon dose reduction were the factors most closely associated with treatment relapse. Menopause was an added factor for women. A closer look at the data showed a relapse rate of 22% for men under age 50; 28% for those over 50. The relapse rate was 14% for women under age 50 and 37% for those over 50.

These findings add fuel to the argument that patients may improve their odds of responding to treatment if they seek treatment earlier while they are younger; this may be particularly true for women.    

The second study I’ll discuss may be particularly relevant to me in the future if I don’t get enough sleep. Reporting on findings from the Hepatitis C Long-Term Treatment against Cirrhosis Trial (Halt-C) Neal D. Freedman, Teresa M. Curto, Karen Lindsay, Elizabeth C. Wright, Rashmi Sinha, and James E. Everhart looked at coffee consumption and response to HCV treatment (peginterferon and ribavirin). This study enrolled 885 participants who did not respond to previous interferon treatment. Participants completed a food survey that included questions about coffee intake from the year prior to retreatment. Coffee intake was classified as none (133 patients), < 1 cup (253 patients), 1 to <3 cups (367 patients), or ≥ 3 cups per day (132 patients).

Among all groups, higher coffee intake was associated with an increased likelihood of response to retreatment. The title of this report is Coffee Is Associated with Virologic Response in Chronic Hepatitis C: Findings from the Hepatitis C Long-Term Treatment against Cirrhosis Trial (Halt-C). Since I want to be in good shape for my next round of HCV treatment, I think I will go drink a cup of java. But since this is an observational study perhaps I better talk to my doctor first.

Note: Those who want to read the latest findings from the Liver Meeting may find abstracts and posters on the HCV Advocate website—www.hcvadvocate.org/news/reports/
, or at the AASLD website at www.aasld.org.
The link to the viral hepatitis section is http://trs.scivee.tv/node/986.

If you are new to reading medical literature, I recommend reading:

HCV Advocacy: A Simple Guide to Reading an Abstract by Alan Franciscus www.hcvadvocate.org/hepatitis/factsheets_pdf

Making Sense of Hepatitis C Research and Medical Literature www.hcvadvocate.org

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HCV Snapshots
—Lucinda K. Porter, RN

Article: Flexible and Individualized Treatment to Achieve Sustained Viral Response for Recurrent Hepatitis C in Liver Transplant Recipients, W.C. Lee, T.J. Wu, H.S. Chou, C.F. Lee, K.M. Chan, S.S. Cheng
Source: Journal of Viral Hepatitis November 2010 Volume 17, Issue 11, pages 770–777

A huge challenge for hepatitis C patients who receive liver transplants is the fact that after the transplant, hepatitis C virus (HCV) usually re-emerges and is a major cause of transplant failure. Researchers have long been interested in improving the prognosis for these patients. This study enrolled 35 patients with HCV after they had received liver transplants. Of these 35 patients, 25 had recurrent HCV.  Every two weeks, they were treated with 180 mcg. of peginterferon and a low daily dose of ribavirin (200–400mg). However, the duration of treatment was tailored to each patient’s tolerance and response to the medication regimen. Anti-rejection medications were gradually decreased. Three patients (12%) died from infections during the study and one patient (4%) was withdrawn from this trial. 18 (72%) of the patients were HCV negative at the end of treatment, dropping to 16 (64%) at the 6-month follow-up point.

The Bottom Line: This small, but important study of typically difficult to treat patients, showed a sustained viral response rate of 64%. This was achieved by using a flexible, individualized treatment regimen. 

Editorial Comment:  When HCV medications were first used, liver transplant patients were usually not treated, primarily for safety reasons. As our experience and understanding of HCV has expanded, so have our options. In this study, not only were transplant patients treated, the majority of them responded to the medications. Look how far we have progressed in such a relatively short period of time.

Article: Pain Management in the Cirrhotic Patient: The Clinical Challenge, N. Chandok and K. D. S. Watt
Source: Mayo Clinic Proceedings May 2010 Vol. 85, No. 5, pages 451-458

Patients with cirrhosis often have difficulty taking pain medications due to the liver’s reduced ability to metabolize drugs.  Cirrhotic patients who take pain medications are at risk for gastrointestinal bleeding, worsening of their liver disease, kidney failure, hepatic encephalopathy (a type of dementia related to end-stage liver disease), and death. This scientific paper reviewed the medical literature, looking at the safety of pain medications. They found that nonsteroidal anti-inflammatory drugs (such as ibuprofen and naprosyn) and opiates (such as morphine, codeine, oxycodone, and hydrocodone) should be avoided. The safest pain medication appears to be acetaminophen (2 to 3 g daily for two weeks). Further, it appears that patients with cirrhosis who drink alcohol regularly can safely take up to 4 g on a short-term basis.

The Bottom Line: The researchers concluded that acetaminophen is likely safe for patients with cirrhosis if taken within prescribed doses. However, they cautioned that these doses may not be safe or suitable for all patients.

Editorial Comment: This literature review is a good start and may be the basis for future, scientific research, such as a randomized, double-blind placebo-controlled study. If the results of a study interest you, discuss this with your medical provider. Never take or stop taking a medication or supplement just because you read about it; talk to your medical provider first.  

Article:  Alcohol Impairs Interferon Signaling and Enhances Full Cycle Hepatitis C Virus JFH-1 Infection of Human Hepatocytes; L. Ye, S. Wang, X. Wang, Y. Zhou, J. Li J, Y. Persidsky, W. Ho
Source: Drug and Alcohol Dependence: An International Journal on Biomedical and Psychosocial Approaches Volume 112, November 2010, Pages 107-116

There has been a fair amount of research examining the impact of alcohol on the liver and general health of individuals with chronic hepatitis C virus (HCV) infection, and this laboratory study adds more to this body of knowledge. A group of scientists at Temple University School of Medicine investigated the relationship of alcohol and HCV, primarily, looking at how alcohol affects the liver cell’s immune response, and whether alcohol affects HCV replication (multiplication of HCV). They found that:

  • Alcohol suppressed naturally occurring interferon in the liver cell, thus interfering with the human body’s natural immunity.
  • Alcohol promoted HCV replication (multiplication).

The Bottom Line: Based on their findings, the researchers theorize that there is a good possibility that alcohol use may contribute to the chronicity of HCV infection, may inhibit interferon’s efficacy and may explain why current HCV treatment does not always have a favorable outcome. 

Editorial Comment: This is an in vitro study, which means that the research was performed in a lab, not using humans. Most studies start in the laboratory before tests are conducted using humans. Since a fair number of studies show that alcohol damages liver cells, it could be difficult to conduct a randomized, double-blind placebo-controlled study testing the relationship between alcohol and HCV. This is because the goal of research is to help patients, and since there is a risk that HCV patients could be harmed by alcohol, it may be too risky for those who were assigned to any arm that required them to drink alcohol. Also, it would be difficult to conceal the placebo.

Article: Mild Alcohol Consumption is Not Associated with Increased Fibrosis in Patients with Chronic Hepatitis C; O. Cheung, R.K. Sterling, J. Salvatori, K. Williams, S. Hubbard, V. A. Luketic, T.R. Stravitz, A.J. Sanyal, M. J. Contos, S. Mills, M.L. Shiffman
Source: Journal of Clinical Gastroenterology published online September 2010

This research is an interesting contrast to the in vitro study mentioned in the previous section. This trial looked at mild-to-moderate alcohol consumption. These researchers chose this study because there is evidence showing that excessive alcohol use increases the risk for HCV-related disease progression and cirrhosis, but little is known about the use of smaller quantities of alcohol by HCV patients.

This study enrolled 857 participants. They were divided into 4 groups based on their average lifetime daily alcohol consumption: those that basically didn’t drink any alcohol, those that averaged <1 daily drink, those that consumed 1 to 3 daily drinks and those that drank >3 drinks per day. Participants were also subdivided into groups based on how long it was presumed that they had HCV: <23 yrs, 23 to 31 yrs., 31 to 38 yrs., or >38 yrs. The designation of mild alcohol use was 1 to 3 drinks daily (< less than 30 grams).

The Bottom Line: The amount of alcohol consumption between those with little or no fibrosis was roughly 2.2 daily drinks compared to those with cirrhosis or advanced fibrosis was 3.2 daily drinks. The researchers felt this was not a significant difference. They did note that there was a significant amount of fibrosis the longer the participants had HCV, independent of mild to moderate alcohol use.

Editorial Comment: This may seem to contradict the previous study, but in fact you can’t compare the two. It may appear that both studies are looking at the affect of alcohol on the HCV patient, but each is radically different. First, one is looking at cells rather than humans. Second, one is looking at the immune response and the virus while the other is examining liver tissue. There is no discussion about HCV symptoms. Neither study is a randomized, double-blind placebo-controlled study. Finally, and most importantly, until there is more research to confirm or contradict this study, the prudent course is to abstain from alcohol use. Studies like this look at a group of people, but don’t take into account the fact that the average woman is unable to metabolize the same amount of alcohol that the average man can. Also, the amount of alcohol one can metabolize varies between individuals. A single study is usually not a compelling reason to make medical decisions.

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