rugs that interfere with H.I.V. have had a major effect in reducing death and disability from AIDS. Now drug companies are beginning to test the first similar drugs for the hepatitis C virus, which can cause fatal liver disease and has infected far more people than H.I.V.

"If they work, they could have the same impact on H.C.V. that the H.I.V. drugs do," said Dr. Frank Chisari, a professor of virology at the Scripps Research Institute in San Diego.

Hepatitis C is now treated by the combination of alpha interferon, an immune system protein, and a pill called ribavirin. The newest versions of the combination can virtually eliminate the virus in about half of the patients.

But that leaves the other half at the mercy of the virus. Moreover, the treatment has severe side effects that include anemia, birth defects, flu like symptoms, depression and even an urge to commit suicide.

"There's a huge need for better drugs, less toxic drugs," said Dr. Michael G. Katze, a professor of microbiology at the University of Washington.

Neither interferon nor ribavirin was specifically designed to attack hepatitis C. Each appears to give a general boost to the immune system to help it attack the virus, though scientists do not fully understand how they work.

But the new hepatitis C drugs entering clinical trials are designed to interfere with enzymes that the hepatitis C virus needs to replicate, like protease and polymerase. Similarly, the AIDS drugs interfere with two enzymes used by H.I.V. to replicate, protease and reverse transcriptase. Some of the AIDS drugs can also be used for hepatitis B but not for hepatitis C, which operates differently.

It will take years to know if the new drugs will work. But scientists are encouraged by a proof of principle reported by Boehringer Ingelheim, a German drug company, at the American Association for the Study of Liver Diseases conference in Boston in November. The company said its experimental protease inhibitor reduced viral levels by a range of a hundredfold to more than a thousandfold in a small number of patients who took the drug for only two days.

"Sort of a hush went over the audience," Dr. Charles M. Rice, director of the Center for the Study of Hepatitis C at Rockefeller University in Manhattan, recalled.

Others are now entering the race. ViroPharma, a biotech company in Exton, Pa., announced in January that it had begun a clinical trial of a polymerase inhibitor in partnership with the Wyeth drug company. So did Idenix Pharmaceuticals, a biotech company based in Cambridge, Mass. Japan Tobacco reports having a polymerase inhibitor in Phase 2, the middle stage of clinical trials.

Vertex Pharmaceuticals, also of Cambridge, has said it will start a trial later this year of a hepatitis C protease inhibitor and Rigel Pharmaceuticals of South San Francisco, Calif., plans to start a polymerase inhibitor trial this year. Isis Pharmaceuticals of Carlsbad, Calif., is in Phase 2 trials with a drug that tries to interfere with a different part of hepatitis C.

Hepatitis C has infected about four million Americans and 170 million people worldwide, about four times as many as H.I.V.

Hepatitis C is spread mostly by needles or blood transfusions, rarely sexually. The rate of new infections in this country has dropped sharply to about 25,000 a year since a test to screen donated blood for the virus was approved in 1990. But there are still many people infected before the test was used that have yet to develop symptoms. The Centers for Disease Control and Prevention estimates that the number of deaths from hepatitis C, now 8,000 to 10,000 annually in the United States, could triple by 2010.

But while there are now well over a dozen drugs that directly interfere with H.I.V. enzymes, there are none that work that way for hepatitis C.

Scientists say one reason for the discrepancy is that the hepatitis C virus was identified in 1988, four years after H.I.V. Still, numerous drugs for AIDS were approved within 15 years of its discovery. In contrast, 15 years after the hepatitis C discoveries, the first drugs are only entering clinical trials.

Another reason, some scientists say, is that there has been much more federal financing for H.I.V., which has been considered more of a crisis than hepatitis C and has patients who have fought hard for money for research and treatments. Also, many people with the hepatitis C virus never get sick or do so only 10 or 20 years later.

Yet another factor, some say, is that the Chiron Corporation, the biotech company in Emeryville, Calif., that first identified the hepatitis C virus, has demanded too much money for licenses to its patents, discouraging companies from entering the field.

"Chiron has been a little bit like a dog with a bone," said Dr. Donald G. Payan, executive vice president and chief scientific officer of Rigel. "I think they really slowed the field down. A lot of people just didn't want to get into it."

Gilead Sciences, which has developed successful antiviral drugs for H.I.V. and hepatitis B, dropped work on hepatitis C after being sued by Chiron. Vertex, which says it does not violate the patents, is in the midst of a lawsuit.

Robert P. Blackburn, chief patent counsel for Chiron, said the company's patents were available for drug discovery to all comers for a modest upfront fee and royalties if a drug made it to market. He said Chiron took a significant risk in embarking on research to discover the virus and deserved to share in the proceeds from drugs developed by others.

"Clearly companies like Vertex would not be working on an H.C.V. drug today but for our inventions," Mr. Blackburn said.

Still, most scientists agree, the biggest obstacle to the development of drugs for hepatitis C has been the inability to grow the virus in the test tube, a fact that makes it hard to study the virus or to test potential drugs. In addition, there are no animals that get hepatitis C except chimpanzees, which are expensive to use in testing.

Scientists have started to circumvent those problems. In 1999, Dr. Ralf Bartenschlager, then at the University of Mainz and now at Heidelberg University in Germany, developed an artificial viral system known as a replicon. Dr. Rice of Rockefeller University, who was then at Washington University in St. Louis, improved on it.

The replicon consists of some of the RNA from hepatitis C, including that for the protease and polymerase enzymes. This RNA is put into liver tumor cells that can be grown in culture.

The replicon does not produce complete new viruses. But it does reproduce itself using the protease and polymerase enzymes. So drug companies can use the replicon to test if their protease or polymerase inhibitors seem to interfere with replication of the replicon.

"That's definitely a breakthrough that every group has used," said Dr. Marc Collett, vice president for discovery research at ViroPharma.

As with H.I.V., hepatitis C virus mutates rapidly and is likely to develop resistance to drugs, so combinations of drugs will probably be needed. "No one really knows what it's going to take for the antiviral effect to outrun the resistance effect," said Dr. Nathaniel Brown, vice president for hepatitis clinical research at Idenix Pharmaceuticals.

But, he and others said, hepatitis C may be easier to treat in some ways than AIDS. That is because H.I.V. turns its RNA into DNA, which is incorporated into the chromosomes of cells it infects, making it hard to totally eliminate the virus. But hepatitis C virus does not do that, and the experience with interferon has shown that if the virus can be eliminated, patients can be cured.

Dr. Amy Weiner, director of hepatitis C research at Chiron, is optimistic. "It does appear with the data we have to date that it is possible to cure people with H.C.V., which has never been shown with H.I.V.," she said.

Adherence to HCV Therapy the (80/80/80) Rule

Adherence in HCV Therapy 10/24/02 www.NATAP.org

Adherence to combination therapy enhances sustained response in genotype-1-infected patients with chronic hepatitis C

In the current issue of Gastroenterology John McHutchison and colleagues reported an analysis of a group of studies, and the primary aim of this analysis was to evaluate the effect of adherence on sustained response rates to combination therapy (interferon -2b or peginterferon -2b plus ribavirin) in patients with chronic hepatitis C. In short, the results showed that >80% adherence resulted in 25% better response rates for genotype 1, the hardest to treat patient group. For genotype 2 patients they did not see a significant improvement associated with better adherence. The message is that adherence in HCV therapy improves response rates just as in HIV. Below in this article there is a discussion of methods to improve adherence that may be useful in treating HCV. But unlike in HIV there are few programs in place to address these needs.

The main reasons for not achieving the adherence goals (80/80/80) were adverse events to therapy in >75% of the patients. In the remaining patients, failure to attend scheduled appointments, withdrawal of consent, and nonadherence in the absence of apparent side effects were the other reasons for not achieving adherence targets in this study.

A preliminary data analysis presented at hepatitis science conferences from Pegasys plus ribavirin studies also show appreciable improvements in response with >80% adherence. In genotype 1 patients who achieved a viral response by week 12, 65% who were >80% adherent achieved a sustained response vs a 46% sustained response for patients who were <80% adherent. The preliminary findings suggest patients in this study who had a viral response by week 12 and dose reduced still had a good sustained response rate. Further study is needed to confirm the effects of dose reduction, and if dose reduction during the first 12 weeks is more harmful than after 12 weeks. Here is link to full report of this study: http://www.natap.org/2001/aasld2/day6h.htm

In all, 1010 patients treated with interferon a-2b (Schering-Plough) and ribavirin and 511 patients treated with peginterferon a-2b (PEG-Intron; Schering) plus ribavirin were considered in this analysis. These subgroups of patients evaluated in the aforementioned studies had been randomized to receive either interferon a-2b 3 times a week (for 24 or 48 weeks) in combination with daily ribavirin or, alternatively, peginterferon a-2b at a dose of 1.5 µg/kg per week subcutaneously as a single injection with ribavirin 800 mg daily for 48 weeks. These patient subgroups were selected because they were those that received the most effective regimens in these respective trials. Data from a separate monotherapy trial of 304 patients treated with peginterferon a-2b, 1.5 µg/kg per week, and 303 patients who received interferon a-2b 3 times a week for 48 weeks were also analyzed to evaluate the effect of adherence on response in this trial.

For this analysis, the amount of each drug administered to a patient was obtained from drug dispensing/return records and patient dosing diaries. Patients receiving combination therapy were divided into 2 groups for analysis: (1) the 80/80/80 subgroup, comprising patients who were 80% adherent (i.e., received 80% of their total interferon dose and 80% of the ribavirin dose) and were treated for 80% of the expected duration of therapy; and (2) the <80/<80/80 subgroup, comprising patients who underwent dose reduction (<80% of 1 or both drugs for 80% expected duration). Patients who withdrew from the study prematurely were excluded from the analysis. The goal of 80% of the planned drug dosage for 80% of the assigned duration represents an adherence criterion that had been adopted previously in the assessment of the efficacy of other pharmaceutical agents, including HIV drug therapy, antihypertensive drug therapy, and orally administered cancer drug therapies.

In this analysis the observation of improved response was apparent only for genotype 1 infected patients, those most difficult to treat. The results tabulated in table format below show an increase in response by 25% for genotype 1, but there was no statistically significant improvement in response for genotype 2.

Most patients in these clinical trials were able to be adherent because of these patients' motivation and their management in controlled trials at tertiary referral centers, however, these findings may not be representative or applicable to the larger universe of patients managed in clinical practice. Thus patients treated in community practices or in centers with limited expertise in the management of chronic hepatitis C may have lower response rates than those observed in this study. Nevertheless, it seems reasonable that the concept of adherence to therapy should also apply to patients treated outside the realm of clinical trials. Further prospective studies are needed to address this issue.

Of the 1010 patients evaluated who received interferon -2b plus ribavirin, 218 were excluded from further analysis because the duration of therapy was <80% of the assigned treatment regimen. Most of the remaining patients who were treated for longer than 80% of the planned duration, 631 of 792 (80%), also received >80% of both their interferon -2b and ribavirin doses. Similarly, for the 511 patients receiving peginterferon -2b 1.5 µg/kg per week plus ribavirin, 88 were excluded from the analysis, and of the remaining 423, 305 (72%) were adherent and received >80% of both medications as defined previously. Of the 304 patients who received peginterferon -2b 1.5 µg/kg per week alone, 45 (15%) were excluded because they failed to achieve at least 80% of the assigned duration of therapy. Likewise, 56 (18%) individuals were excluded from the 303 patients who received interferon -2b alone. Most of the remaining patients in these monotherapy trials were adherent to therapy, with 236 of 259 (91%) and 242 of 247 (98%) receiving >80% of peginterferon -2b 1.5 µg/kg per week and interferon -2b alone, respectively.

ADHERENCE TECHNIQUES

In HIV infection and other diseases, adherence to therapy is related to the number of medications taken per day, dietary restrictions required for these medications, side effects and complications of the medications, dosing frequency, pill size, and the drug combinations used. In addition, low literacy level, beliefs regarding therapy (whether erroneous or otherwise), lack of support, inconvenient appointments, and lack of transportation have all been associated with a lack of adherence to therapy in HIV-infected patients. In HIV infection, the most common reasons for lack of adherence or skipping doses are simply forgetting, being "too busy," side effects, and feeling ill, all of which would seem to apply to patients with chronic hepatitis C undergoing therapy. Demographic variables, such as gender, age, race, socioeconomic status, and history of prior substance abuse, generally do not predict poor adherence to HIV therapy.

Such variables associated with nonadherence notwithstanding, physicians are able to accurately predict adherence in only about 50% of patients. Thus methods to monitor and improve adherence may help improve the likelihood of successful outcome during and after treatment of any disease process. Although no gold standard exists for monitoring adherence in clinical trials or in practice, theoretically, directly observed therapy (as previously used for tuberculosis) may be impracticable in hepatitis C treatment regimens, but it could be made available to a limited number of patients considered to be at high risk for nonadherence. Although currently impractical in hepatitis C treatment regimens, directly observed therapy could be facilitated by once-weekly peginterferon dosing regimens. Patient self-reporting, as in our studies, is less accurate than other potential methods but is a common and convenient way of aiding adherence. A medication diary is also an important behavioral tool that may help reinforce adherence. Electronic monitoring devices, such as medication event monitoring systems, may also increase adherence, and future studies of hepatitis C therapy involving these microprocessor recorders could provide a better assessment of the effect of adherence. In HIV therapy, encouraging telephone calls and feedback about viral loads have proven to improve adherence, but evidence to support their approach in hepatitis C therapy is lacking. Still, these approaches merit consideration. A number of other factors may impair treatment adherence in hepatitis C, including language barriers, negative staff attitudes toward injecting drug users, and social circumstances, such as lack of family support. Strategies to improve adherence include encouraging "reasonable" adherence instead of demanding full adherence, involving family members or significant others in the treatment process, and anticipating presumptively and responding to adverse social situations that could reduce adherence. Although patients themselves are the primary determinants of adherence, the importance of the role of health care providers should not be overlooked.

It may be possible to use a similar adherence-efficacy model in future clinical trials to gauge the impact of patient adherence on therapeutic outcome, and potentially to determine ideal drug dosages for those most compliant to therapy.

The findings of this study indicate that adherence with prescribed medication regimens does improve sustained response rates in patients with chronic hepatitis C infection. Further research must now be conducted in prospective trials to determine factors associated with adherence or lack thereof and strategies for improving adherence, in an attempt to enhance sustained response rates. Theoretically, patient education about side effects, necessary lifestyle changes during therapy, treatment of depression, support groups, telephone and frequent clinic follow-up visits, printed materials, pill boxes, reminders, and self-monitoring devices, as well as simplification of treatment regimens, all have the potential to improve adherence. Certainly, the introduction of peginterferon, by reducing the number and frequency of injections, has also simplified the treatment regimen, which may facilitate adherence to therapy.

Although more work in improving adherence is necessary, our results suggest that adherence will enhance the likelihood of achieving a virologic response during the first 3-6 months of therapy, and that maintaining adherence in patients who have responded to treatment by week 12-24 will lead to an increase in sustained virologic response rates.

RESULTS

These patients (80/80/80) were patients who took 80% interferon -2b plus 80% ribavirin for more than 80% of the expected duration of therapy. Patients who did not complete 80% of the duration of the study and who took less than 80% of interferon and ribavirin did not respond nearly as well.

10-24-02.gif The overall SVR for study patients was 54%, and 42% for patients with genotype 1. As you can see adherence increased response from 54% to 63% and 42% to 51%.

Adherence did not appear to enhance virologic response in patients with HCV-2 or -3 infection treated for either 24 or 48 weeks. 82% to 90% was not statistically significant but improvement in genotype 1 was significant.

Whereas most patients who reduced their dose within the first 12 weeks of therapy maintained a reduced dose during the remainder of therapy, few if any patients who were not adherent during the first 12 weeks became adherent thereafter. A trend was observed between early dose reductions and impaired sustained response rates; this trend was less apparent for those who required dose reductions late in the course of therapy. But the results of this analysis were not statistically significant. We attempted to analyze the effect of dose reduction of each drug on the sustained response rate; however, >80% of the patients who received >80% of either interferon -2b or peginterferon -2b also received >80% of the doses of ribavirin. Thus we were unable to distinguish which drug was more important in terms of the impact of adherence on sustained response.

Anadys Reports Completion of Phase IA Study of ANA245
Monday March 3, 8:07 am ET

Anadys' First Clinically Tested Compound for Treatment of HCV

     Anadys Pharmaceuticals, Inc., San Diego
     Sarah Neugebauer, 858/530-3627
     Manager, Corporate Communications
     sneugebauer@anadyspharma.com
         or
     Noonan Russo Presence, San Diego
     Tom Baker, 858/587-5673
     tom.baker@nrp-euro.com

Source: Anadys Pharmaceuticals, Inc

Generic Ribavirin on the Way

by Liz Highleyman

The high cost of prescription medications is one of the biggest and fastest growing challenges facing people with chronic hepatitis C and B in the U.S. today. Drug patents, which give pharmaceutical developers the exclusive right to sell their products, have been blamed for contributing to these exorbitant drug prices.

Generic drugs cheaper versions of patented brand-name medications could go a long way toward relieving this sticker shock. Generic drugs have the same active ingredients and clinical effects as brand-name drugs, and they are subject to the same standards for purity and quality as brand-name drugs. Like brand-name medications, generics are subject to rigorous review by the Food and Drug Administration (FDA). But generic drugs typically cost less than half as much as their brand-name equivalents. In fact, last July the Congressional Budget Office estimated that more extensive use of generics could reduce pharmaceutical costs by $60 billion over the next 10 years.

Advocates for people with HCV have long desired a generic version of ribavirin, which, along with interferon, is part of the standard of care treatment for chronic hepatitis C.

On February 7, 2003, that hope came closer to reality when Three Rivers Pharmaceuticals announced that it had reached a settlement with Schering-Plough Corporation in its ribavirin patent lawsuit. Under the terms of the settlement, Schering will provide a non-exclusive license allowing Three Rivers to manufacture and sell generic ribavirin in the U.S. In return, Three Rivers will pay Schering a "reasonable" royalty based on generic sales.

"We are very pleased with the terms of the settlement," said Three Rivers president Donald Kerrish. "It places Three Rivers one step closer to providing an affordable version of ribavirin to persons afflicted with hepatitis C."

Schering’s Rebetol brand of ribavirin costs about $10 per capsule. The Three Rivers version to be sold under the name Ribasphere is expected to cost under $5. "Rebetol is $10 a capsule for a drug that we believe costs 10 cents to make," said Brian Klein of the Hepatitis C Action and Advocacy Coalition. Brand-name manufacturers claim such high prices are necessary in order to provide a sufficient profit to encourage innovation and to pay for the costs of drug development. Critics, however, point out that most large pharmaceutical companies spend more on marketing and advertising than they do on drug research and development.

Don’t look for generic ribavirin in stores just yet. Three Rivers is still awaiting FDA approval for Ribasphere a process that has dragged on for two years. Advocates say the delay is especially troublesome since a larger company, Roche, quickly got FDA approval for its new brand-name ribavirin, Copegus. (Much to the relief of patients and their advocates, Roche priced Copegus 43% lower than Rebetol when it went on the market in January.)

The Three Rivers lawsuit stems from disagreements over patents. Schering’s original patent on ribavirin expired in June 2002. Under the 1984 Hatch-Waxman law which was intended to expand the availability of generic drugs generic manufacturers can apply for approval before the brand-name patent ends. When this happens, the patent-holder gets an automatic 30-month patent extension to negotiate with the generic maker.

But critics contend that pharmaceutical companies have been able to "game the system" by filing additional patent applications for minor changes in things such as manufacturing processes, inactive ingredients, packaging, and labeling information. For each new patent application, the company gets another automatic 30-month extension allowing some companies to prolong patent protection for years. Some brand-name manufacturers have even paid off generic makers to stop them from introducing competing products. The Federal Trade Commission discovered a pattern of repeated delays in bringing generic drugs to market. Although courts have often ended up rejecting frivolous secondary patent applications, the delays due to the automatic extensions cost consumers millions of dollars.

One way a company can get a patent extension is to update a drug’s labeling information, for example by adding new data from recent clinical trials. The Three Rivers lawsuit concerned the wording of Schering’s detailed package information about how ribavirin should be used, its side effects, and clinical trial data specifically recently added information related to pegylated interferon. In all, Schering has some eight patents on Rebetol, many added in the past few years.

A similar move in 2001 by Bristol-Myers Squibb which argued that the FDA could not legally approve a generic version of its diabetes medication, Glucophage, because of a recent label change related to use of the drug in children so annoyed lawmakers that they began working on legislation to close the loophole. Said Senator Charles Schumer (D-NY), "Drug companies are not spending all their time

Copyright March 2003 Hepatitis C Support Project All Rights Reserved. Permission to reprint is granted and encouraged with credit to the Hepatitis C Support Project

Rate of natural disease progression in patients with chronic hepatitis C

SourceURL:http://www.gastrohep.com/news/news.asp?id=1865

Researchers from France and the United States find that an interval of 4 to

5 years is needed between liver biopsies to measure change in patients with
mild liver disease.

The interval at which liver biopsy should be repeated in untreated patients
with chronic hepatitis C is not defined.

In this study, researchers examined fibrosis change by METAVIR scoring in
patients who had 2 or more liver biopsies.

The team's findings are published in the March issue of the Journal of
Hepatology.

The research team studied 180 patients with histologically proven chronic
hepatitis C.

They found that the mean interval between biopsies was 3.67 years. This
interval was 3.08 years in the 16 patients who had had 3 biopsies.

The team performed univariate and multivariate analyses to determine
factors associated with liver fibrosis progression.

The mean interval between biopsies was 3.67 years.


They found that the median rate of fibrosis progression per year was 0.04
to first biopsy, 0 between first and second biopsy, and 0.17 between second
and third biopsy.Multivariate analysis determined that age at first biopsy >40 years (OR=5),
and alcohol consumption of 1 to 50 g per day (OR=4), and more than 50 g per
day (OR=8) were the only factors associated with severe fibrosis.

The team found that the number of patients who increased in fibrosis stage
was significantly higher after 4 years.

Dr Jean-Pierre Zarski's team concluded, "An interval of at least 4 to 5
years is needed between liver biopsies to measure change in patients withmild liver disease."

J Hepatology 2003; 38(3): 307-1421 February 2003

Hepatocytes Experimentally Converted to Pancreatic Cells by Gene Transfer

Reuters Health Information 2003. © 2003 Reuters Ltd.

LONDON (Reuters Health) Feb 19 - British researchers have transdifferentiated hepatocytes into pancreas cells in vivo and in vitro, an achievement they say could pave the way for new treatments for type 1 diabetes.

During experiments carried out at the University of Bath, cultured human hepatocytes took on pancreatic characteristics, including insulin production, after introduction of Pdx1, a transcription factor essential for pancreatic development.

Also, as reported in the journal Current Biology, the researchers generated transgenic Xenopus tadpoles carrying a modified version of the Xenopus homologue of Pdx1, Xlhbox8.

"In the transgenic tadpoles, part or all of the liver is converted to pancreas, containing both exocrine and endocrine cells, while liver differentiation products are lost from the regions converted to pancreas," Professor Jonathan Slack and colleagues report.

"The results from these experiments have been very encouraging," said Professor Slack in statement. "This is the first step in the development of what could ultimately provide a cure for people suffering from diabetes--but there is a lot more work to do."

Other people have tried to carry out this type of experiment but they didn't use the right type of gene to make it work," he added.

Although expression of the transgene is transient, once the ectopic pancreas is established, it persists, the researchers note.

Current Biology 2003;13:105-115

Hepatitis C Infection Causes Cognitive Impairment in a Cohort of Patients with Mild Liver Disease

Patients with chronic hepatitis C virus (HCV) infection frequently report fatigue, lassitude, depression, and a perceived inability to function effectively. Several studies have shown that patients exhibit low quality-of-life scores that are independent of disease severity.

The investigators of this study considered whether HCV infection has a direct effect on the central nervous system, resulting in cognitive and cerebral metabolite abnormalities.

Twenty-seven viremic patients with biopsy-proven mild hepatitis due to HCV and 16 patients with cleared HCV were tested with a computer-based cognitive assessment battery and also completed depression, fatigue, and quality-of-life questionnaires.

The HCV-infected patients were impaired on more cognitive tasks than the HCV-cleared group (mean [SD]: HCV-infected, 2.15 [1.56]; HCV-cleared, 1.06 [1.24]; P = .02). A factor analysis showed impairments in power of concentration and speed of working memory, independent of a history of intravenous drug usage (IVDU), depression, fatigue, or symptom severity.

A subgroup of 17 HCV-infected patients also underwent cerebral proton magnetic resonance spectroscopy (¹H MRS). The choline/creatine ratio was elevated in the basal ganglia and white matter in this group. Patients who were impaired on 2 or more tasks in the battery had a higher mean choline/creatine ratio compared with the unimpaired patients.

In conclusion, these preliminary results demonstrate cognitive impairment that is unaccounted for by depression, fatigue, or a history of IVDU in patients with histologically mild HCV infection. The findings on MRS suggest that a biological cause underlies this abnormality.

02/10/03

Reference
DM Forton and others. Hepatitis C and cognitive impairment in a cohort of patients with mild liver disease. Hepatology 2002; 35: 433-439.

Interdisciplinary Care Works For Hepatitis Patients At Psychiatric Risk A DGReview of :"Adherence and mental side effects during hepatitis C treatment with interferon alfa and ribavirin in psychiatric risk groups."
Hepatology
02/06/2003
By Anne MacLennan

Pre-existing psychiatric disorders or methadone substitution should no longer be seen as contraindicating chronic hepatitis C treatment with interferon-alpha (IFN-alpha), suggest researchers in Germany.

The supposed increased risk for IFN-alpha-induced mental side effects and dropouts in these patients does not exist when they receive interdisciplinary care and antidepressant treatment, the investigators have found.

This prospective study by Dr M Schaefer and colleagues from Humboldt University, Berlin, and Ludwig Maximilians University, Munich, sought to compare adherence to, as well as efficacy and mental side effects of, IFN-alpha treatment in patients with, versus without, various psychiatric disorders.

All 81 study patients had chronic hepatitis C (positive hepatitis C virus[HCV] RNA and elevated alanine aminotransferase[ALT] level). Sixteen of the patients had psychiatric disorders, 21 were on methadone substitution and 21 were former drug addicts. Twenty-three patients with no psychiatric or drug addiction history served as controls.

They were all treated with a combination of IFN-alpha-2a three MU three times weekly and ribavirin (1,000-1,200 mg/d).

There were no significant differences in sustained virologic response (overall, 37%) or in IFN-alpha-related development of depressions between the subgroups. However, significantly more patients in the psychiatric group received antidepressants before and during treatment with IFN-alpha.

As for patients who dropped out of the study, most were former drug addicts (43%; P =.04) as compared with 14% in the methadone group, 13% in the control group and 18% in the psychiatric group.

None of the patients in the psychiatric group had to stop treatment because of psychiatric deterioration.

Hepatology
"Adherence and mental side effects during hepatitis C treatment with interferon alfa and ribavirin in psychiatric risk groups."

PEG-Intron + Ribavirin Produces a Biphasic Decline in HCV Levels and Higher Doses Accelerate Viral Clearance

PEG-Intron (pegylated interferon alfa-2b) plus ribavirin achieves a higher sustained response rate in patients with genotype 1 chronic hepatitis C virus (HCV) than standard combination therapy.
 

This study evaluated HCV kinetics throughout therapy with 2 doses of PEG-Intron and ribavirin in 55 patients. Twenty-eight patients were randomized to receive a high once-weekly dose of PEG-Intron (3 µg/kg for 1 week, 1.5 µg/kg for 3 weeks, and 1.0 µg/kg for 44 weeks), and 27 patients were randomized to receive a low dose (0.5 µg/kg) for 48 weeks. Both groups also received 800 mg ribavirin daily.

Mean baseline HCV RNA load, measured by reverse-transcription polymerase chain reaction, was similar in both groups (5.32 ± 0.86 log vs. 5.15 ± 1.04 log). The 3-µg/kg dose of PEG-Intron inhibited HCV RNA more significantly than the 0.5-µg/kg dose during the first 48 hours (2.08 ± 0.93 log vs. 1.09 ± 0.80 log; P < .001) and both increased at 72 hours (0.54 ± 0.73 log vs. 0.03 ± 0.36 log; P = not significant [NS]), but the high dose showed a greater reduction at the end of the week (1.07 ± 0.99 log vs. 0.72 ± 0.73 log).

Both doses showed a progressive, slower viral decrease throughout therapy; however, HCV RNA became undetectable faster and in more patients with the high dose (22% vs. 7% at week 4, 56% vs. 44% at week 12, 69% vs. 63% at week 24, and 71% vs. 61.5% at the end of therapy).

In conclusion, PEG-Intron/ribavirin produces an initial rapid decline in HCV RNA levels, followed by a slower, progressive decrease, similar to the biphasic kinetic profile of standard combination therapy. Higher doses of PEG-Intron also accelerate viral clearance.

02/10/03