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HCV ADVOCATE WEEKLY NEWS REVIEW: A Review of HCV, HBV and HIV/HCV Coinfection Related News and Highlights

Week Ending: January 9^th, 2004

Alan Franciscus
Editor-in-Chief

In This Issue:

Average Hep C Payout Now at €310,000, Report Shows

Doctors Warn of Death Toll from Silent Epidemic of Hepatitis C

CDC Reports on U.S. Incidence of Acute Hepatitis B

Hepsera Reduces Lamivudine-Resistant HBV Levels in Liver Transplant Patients

MELD-Based Allocation Policy Beneficial in Hepatocellular Carcinoma

De Novo Breast Cancer in Patients with Liver Transplantation

Roche Wins U.S. OK for Convenient Hepatitis C Drug

Prevalence of Occult Hepatitis B in Injection Drug Users

Pediatric Fulminant Hepatic Failure in Endemic Areas of Hepatitis B Infection

Emtricitabine (FTC), FDA Approved for HIV, Also Is Active Against Chronic Hepatitis B

Telbivudine (LDT) in Phase III Studies for Chronic Hepatitis B

Entecavir, a Potent Inhibitor of Hepatitis B Virus

Liver Transplantation and Health-Related Quality of Life

Volume Regeneration After Right Liver Donation

January 2nd, 2004


Average Hep C Payout Now at €310,000, Report Shows
Eilish O'Regan
Health Correspondent
© Irish Independent

The average payout to victims of Hepatitis C infection from infected blood or blood products has now risen to €313,180.

The annual report of the Hepatitis C and HIV Tribunal showed the lowest award last year was €650.

The tribunal has been hearing compensation cases in private since 1997 after it was set up in the wake of the tribunal into the contamination of the blood product Anti-D.

Its remit is also now being extended to hear the cases of haemophiliacs who were contaminated with HIV through Factor 8 or Factor 9.

Overall, the tribunal paid out €36m in 2002, but nearly half of this was due to extra compensation which the High Court ruled should be given after 52 claimants appealed their cases. The basis of their case lies in a 1999 High Court decision which revealed for the first time that general damages handed down by the tribunal were capped.

A significant number are just opting for provisional awards, which allows them to take some compensation now and return in the coming years for more if their condition deteriorates.

Hepatitis C can affect the liver and in some cases those with the infection may need a transplant.

One of the benefits of the State compensation scheme is that it reduces the legal costs which would mount up if each person took their claims to court.

However, the report reveals the legal costs are also considerable and lawyers last year received more than €4m for their services.

The legal bill was also topped up by another €1.4m as claimants were entitled to representation when they appealed their awards to the High Court.

For those who do take an appeal, there is the financial gamble that if the case fails they will have to pick up the legal bill. The claimants also received another €7m last year from a reparation fund, which was also agreed as part of the package.

It found that 95 claims were withdrawn, but does not specify if these were bogus claims from people who contracted the virus from other sources.

Meanwhile, it has emerged that a working group, including infectious disease experts, has been established to prepare guidelines for the management of people who die from Hepatitis C. This followed representations by the National Consultative Council on Hepatitis C.

http://www.unison.ie/irish_independent/
& http://www.unison.ie/

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January 5, 2004

Doctors Warn of Death Toll from Silent Epidemic of Hepatitis C
Jeremy Laurance
UK Independent

Hospital specialists criticized the British government on Dec. 31 for not acting to curb the spread of hepatitis C, which officials estimate has infected 200,000 people in the United Kingdom - four times as many as HIV - and infects more than 100 additional people each week. It is the main cause of liver transplants and is predicted to kill more people than AIDS by 2020. However, only a fourth of patients know they are infected, and only 1 percent receive treatment.

The Department of Health published a strategy for dealing with hepatitis C 18 months ago and promised an action plan by the end of 2002. Graham Foster, professor of hepatology at the Royal London Hospital, said, "There is much disappointment at the lack of an action plan. Absolutely nothing is happening."

Last month, the Health Protection Agency announced that 5,901 cases of hepatitis C were diagnosed in 2002, up from fewer than 1,000 in 1994. Foster said over the next 10 to 15 years liver disease and cancer rates would soar if no action is taken. New drug cocktails have increased the proportion of patients who can be cured to 60 percent, but since the virus is symptomless in its early stages, efforts must be made to test and identify people who are infected.

William Irving, professor of virology at Nottingham University, said, "There are a lot of people out there with hepatitis C and there is a window of opportunity to treat them now before they develop liver disease."

The bloodborne virus can be spread through sharing needles, razor blades, toothbrushes and cocaine straws; tattooing; body piercing; and sex. It is 10 times more infectious than HIV via blood-to-blood contact, but less infectious than HIV via sexual contact.

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CDC Reports on U.S. Incidence of Acute Hepatitis B
Source: Immunization Action Coalition http://www.immunize.org/

CDC published "Incidence of Acute Hepatitis B--United States, 1990-2002" in the January 2 issue of MMWR. The article is reprinted below in its entirety, excluding references and a figure.

Hepatitis B virus (HBV) is a bloodborne and sexually transmitted virus that is acquired by percutaneous and mucosal exposure to blood or other body fluids of an infected person. Clinical manifestations of acute hepatitis B can be severe, and serious complications (i.e., cirrhosis and liver cancer) are more likely to develop in chronically infected persons. In the United States, approximately 1.2 million persons have chronic hepatitis B virus (HBV) infection and are sources for HBV transmission to others. However, since the late 1980s, the incidence of acute hepatitis B has declined steadily, especially among vaccinated children. To characterize the epidemiology of acute hepatitis B in the United States, CDC analyzed national notifiable disease surveillance data for 1990-2002. This report summarizes the results of that analysis, which indicated that, during 1990-2002, the incidence of reported acute hepatitis B declined 67%. This decline was greatest among children and adolescents, indicating the effect of routine childhood vaccination. The decline was lowest among adults, who accounted for the majority of cases; incidence increased among adults in some age groups. To reduce HBV transmission further in the United States, hepatitis B vaccination programs are needed that target men who have sex with men (MSM), injection-drug users (IDUs), and other adults at high risk.

CDC analyzed surveillance data for acute hepatitis B cases reported weekly from state health departments and the District of Columbia during 1990-2002. Data included each patient's county of residence, sex, race/ethnicity, and age. Clinical and risk factor data were available for approximately 35% of cases reported since 1990, including death from acute hepatitis B, reported injection-drug use, sex and number of sex partners, and exposure to a household or sex contact during incubation period.

Acute hepatitis B incidence was calculated by using population denominators from the U.S. Census Bureau.

Summary of Incidence
During 1990-2002, the incidence of acute hepatitis B declined 67%, from 8.5 per 100,000 population (21,102 total cases reported) to 2.8 per 100,000 population (8,064 total cases
reported). By region, in 2002, incidence was highest in the South (3.6), followed by the Northeast (3.5), the West (2.3), and the Midwest (1.6). During 1990-2002, decreases in incidence were greatest in the West (78%), followed by the Midwest (72%), the South (59%), and the Northeast (52%); however, incidence in the Northeast has increased 41% since 1999.

The incidence of acute hepatitis B among men has been consistently higher than among women. In 1990, the incidence among men and women was 9.8 and 6.3, respectively; in 2002, the incidence was 3.7 and 2.2, respectively. Overall, incidence among women has declined more than among men; the male-to-female acute hepatitis B rate ratio was 1.5 in 1990, compared with 1.7 in 2002.

By age, the most significant decline (89%) in acute hepatitis B incidence during 1990-2002 occurred among persons aged 0-19 years, from 3.0 in 1990 to 0.3 in 2002. Among persons aged 20-39 and 40 years and older, acute hepatitis B incidence declined 67% and 39%, respectively; however, the majority of this decline occurred during 1990-1998. Since 1999, the incidence of acute hepatitis B has increased 5% among males aged 20-39 years and 20% and 31%, respectively, among males and females aged 40 years and older. Among 6,790 (32%) of the 21,102 cases reported in 1990 and 3,079 (38%) of the 8,064 cases reported in 2002 for which risk factor data were available, the proportion of persons who reported injection-drug use was similar (17% and 15%). However, the proportion of heterosexuals reporting multiple sex partners increased from 14% to 29%, as did the proportion of self-identified MSM, from 7% to 18%. During 1990-2002, the proportion of MSM reporting multiple sex partners was approximately 50%.

Examples of Local Trends
Data from two counties illustrate the changing epidemiology of acute hepatitis B in the United States. In both counties, overall incidence and incidence among children have declined. In Baltimore County (Baltimore, Maryland), acute hepatitis B incidence has been consistently higher than the national average. Since 1990, incidence has declined 26% overall; however, during 2000-2002, incidence increased 15%. In 2002, Baltimore County reported 50 acute hepatitis B cases (29 among men and 21 among women) for an overall incidence of 6.6; incidence for men and women was 8.1 and 5.3, respectively, with a male-to-female rate ratio of 1.5. Of the 38 persons with available risk factor data, 15 (40%) reported injection-drug use, eight (21%) reported having multiple heterosexual sex partners, and three (8%) reported both risk factors; six (16%) persons reported exposure to an HBV-infected household or sex contact, and three (8%) reported being an MSM.

Since 1990 in Mecklenburg County (Charlotte, North Carolina), reported acute hepatitis B incidence has been above the national average; however, during the same period, incidence has declined 82%. In 2002, Mecklenburg County reported 39acute hepatitis B cases (28 among men and 11 among women) for an overall incidence of 5.6; incidence or men and women was 8.2 and 3.1, respectively, with a male-to-female rate ratio of 2.6. Risk factor data were available for all 39 cases; eight (21%) persons reported having multiple heterosexual sex partners, eight (21%) reported being MSM, and three (8%) reported both risk factors. Five (13%) persons reported exposure to an HBV-infected household or sex contact; no persons reported injection-drug use.

Editorial Note:
In 1991, a comprehensive strategy to eliminate HBV transmission was implemented in the United States and has reduced the incidence of acute hepatitis B among children. The strategy included universal infant vaccination, universal screening of pregnant women, and postexposure prophylaxis of infants born to infected mothers to prevent perinatal HBV infection; since 1982, adolescents and adults at high risk have been recommended to receive HBV vaccine. In 1995, the strategy was expanded to include routine vaccination of all adolescents aged 11-12 years and, in 1999, to include all persons aged 0-18 years who had not been vaccinated previously. The incidence of acute hepatitis B has declined steadily during the preceding decade, in part because of successful vaccination and other prevention programs. The observed decline in the incidence of acute hepatitis B among children occurred coincident with an increase in hepatitis B vaccination coverage among children aged 19-35 months, from 16% in 1992 to 90% in 2000.

Since 1999, after more than a decade of decline, hepatitis B incidence among men aged older than 19 years and women aged 40 years and older has increased. The most common risk factors reported among adults with acute hepatitis B continue to be multiple sex partners, MSM, and injection-drug use. Different high-risk behaviors accounted for the majority of transmissions in different locales.

Increases in sexually transmitted diseases (STD), including syphilis and human immunodeficiency virus (HIV) infection among MSM have been attributed to increases in high-risk sexual behavior (e.g., unprotected anal intercourse with more than one
partner and unsafe sex while under the influence of alcohol or recreational drugs). Changes in patterns of sexual behavior also could be responsible for the increasing transmission of HBV among MSM.

In 1982, the Advisory Committee on Immunization Practices recommended hepatitis B vaccination for sexually active homosexual and bisexual men and IDUs and, in 1985, for
heterosexuals with multiple sex partners or a recent STD. Trends in acute hepatitis B infection also reflect poor vaccination coverage among persons who engage in these behaviors. Of 3,432 young MSM in seven U.S. metropolitan areas, only 9% had received HBV vaccine. In a San Diego County, California, survey, only 6% of IDUs had completed the 3-dose HBV vaccine series.

Persons at high risk for HBV infection often seek health care in settings in which vaccination services could be provided. During 1996-1998, approximately half of persons reported with acute hepatitis B had been treated for an STD or incarcerated: 89% of
IDUs, 35% of MSM, and 70% of persons with multiple sex partners. Both STD clinics and correctional facilities are settings in which hepatitis B vaccination services are recommended.

The findings in this report are subject to at least two limitations. First, the quality of surveillance data varies at local and state levels. Second, national viral hepatitis case- reporting is incomplete; only approximately 35% of all reported cases contain risk factor data.

The decline in acute hepatitis B among children indicates that successful hepatitis B vaccination programs are possible. These programs must consider the local epidemiology of hepatitis B and identify ways to reach populations at high risk. Integration of hepatitis B vaccination into health-care programs that target persons at high risk is feasible and cost effective. Hepatitis B vaccination programs have been implemented in STD clinics, juvenile and adult detention facilities, HIV-counseling and -testing centers, and other sites.

No national adult hepatitis B program exists that is similar to those that have proven successful for children and adolescents. Components of a national adult vaccination program must include policies for vaccination, including methods for achieving higher
vaccination rates among adults at greatest risk and appropriate resources to support implementation.

To access a web-text (HTML) version of the complete article, go to:
http://www.cdc.gov/mmwr/preview/
mmwrhtml/mm5251a3.htm
To access a ready-to-copy (PDF) version of this issue of MMWR, go to:
http://www.cdc.gov/mmwr/PDF/wk/
mm5251.pdf
Receive a FREE electronic subscription to MMWR (which includes new ACIP statements) by going to
http://www.cdc.gov/mmwr/
mmwrsubscribe.html


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January 6th, 2004


Hepsera Reduces Lamivudine-Resistant HBV Levels in Liver Transplant Patients

NEW YORK (Reuters Health) - Treatment with adefovir dipivoxil (Hepsera, Gilead Sciences) both prior to and following liver transplantation in patients with lamivudine-resistant chronic hepatitis B (HBV) infection, significantly improves virologic, biochemical and clinical parameters, results of an open-label, compassionate use study indicate.

"Adefovir dipivoxil meets an urgent, unmet medical need and presents a potential life-saving treatment option for pre- and post-liver transplant patients with lamivudine-resistant HBV who are at high risk for morbidity and mortality," the Adefovir Dipivoxil Study 435 International Investigators maintain in their report, published in the December issue of Hepatology.

Treatment with hepatitis B immune globulin and nucleoside analogs such as lamivudine ameliorate HBV recurrence, Dr. Eugene R. Schiff, at the University of Miami in Florida, and colleagues explain. But because emerging lamivudine resistance can lead to rapid disease progression, they examined the role of adefovir, a nucleotide analog of adenosine monophosphate, for patients with lamivudine-resistant HBV.

Included were 128 patients enrolled prior to undergoing liver transplant and 196 post-liver transplantation, who were treated with Hepsera 10 mg/day. Child-Pugh-Turcotte (CPT) scores improved in more than 90% of subjects in both groups. These improvements were accompanied by improvements in ALT, albumin, bilirubin and prothrombin time.

HBV DNA levels declined by 4.1 to 4.3 log-10 copies/mL over 48 weeks of treatment.

The authors report that treatment-related adverse events tended to be mild to moderate in severity, and that "the safety profile was consistent with the advanced stage of liver disease and the attendant comorbidities."

There appeared to be no adefovir resistance mutations after 48 weeks of therapy.

Survival at 1 year was 84% for pre-transplant patients and 93% for post-transplant patients, leading Dr. Schiff and his colleagues to conclude that adefovir dipivoxil provides a clinically meaningful benefit.

In a related editorial, Dr. Fabien Zoulim recommends that adefovir dipivoxil be started soon after lamivudine resistance emerges.

Dr. Zoulim, at INSERM in Lyon, France, also believes that adefovir and lamivudine should be used in combination to prevent the selection of multiple drug-resistant strains.

Source: Hepatology 2003;38:1353-1355,1419-1427.
Reuters Health Information 2004. © 2004 Reuters Ltd.

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January 7th, 2004


MELD-Based Allocation Policy Beneficial in Hepatocellular Carcinoma
Laurie Barclay, MD

The new allocation policy based on the model for end-stage liver disease (MELD) has been beneficial for patients with hepatocellular carcinoma (HCC), according to the results of a review of the United Network for Organ Sharing (UNOS) database published in the January issue of Liver Transplantation.

"The new MELD-based allocation policy has benefited HCC candidates," write Pratima Sharma, MD, from the Mayo Clinic in Scottsdale, Arizona, and colleagues. "Significantly higher proportions of candidates listed with the diagnosis of HCC are receiving a deceased donor liver transplant in the new MELD-based allocation system."

Between July 1999 and July 2002, 2,074 patients with stage T1 or T2 HCC were on the waiting list for a deceased donor liver transplant (DDLT). Based on the listing date, they were divided into two groups: pre- or post-MELD allocation policy, which was implemented on Feb. 27, 2002.

Compared with the pre-MELD group, the transplant rate more than tripled in the post-MELD group (0.439 vs. 1.454 transplant/person-years; P < .001), the time to transplantation decreased from 2.28 years to less than 0.69 years (P < .001), the five-month dropout rate was cut nearly in half (16.5% vs. 8.5%; P < .001), and the five-month waiting list survival increased from 90.3% to 95.7% (P < .001).

Within three months of being listed, more than 87% of HCC patients had received a transplant, suggesting that HCC candidates might have been given priority to the detriment of patients with cirrhosis of other etiologies.

To address these concerns, UNOS and the Organ Procurement and Transplantation Network had a consensus meeting in January 2003 and slightly modified the MELD-based policy. The effects of the new changes have not yet been determined.

"Preliminary indications are that the new allocation system based on MELD has a favorable effect by reducing waiting list mortality while maintaining excellent early post-transplantation survival for all diagnoses," the authors write. "However, the marked advantage given to HCC candidates will need to be addressed further."

Source: Liver Transplant. 2004;10(1):000-000
Reviewed by Gary D. Vogin, MD www.medscape.com/viewarticle/466818

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De Novo Breast Cancer in Patients with Liver Transplantation
Source: www.gastrohep.com

Doctors, in the January issue of Liver Transplantation, find an increased incidence rate of de novo breast cancer in liver recipients.

De novo malignancies are a current problem in patients with organ transplantation.

The incidence is higher as a result of increases of oncogenic viruses in immunosuppressed organ recipients.

Reports have shown increased incidence of de novo tumors such as malignant lymphomas and cutaneous neoplasms, but decreased incidence of breast cancer. 83% of all patients were diagnosed at an early stages Liver Transplantation

A variety of factors affect de novo breast cancer development in organ recipients, including immunosuppression, viruses, and underlying disease.

In this study, doctors from the University of Pittsburgh evaluated the incidence and management of patients with de novo breast cancer. They also evaluated the age-adjusted incidence of de novo breast cancer in published reports.

According to age-adjusted rates presented by the National Cancer Institute's Surveillance, Epidemiology and End Results data, the team found an increased incidence rate of de novo breast cancer in the published series.

The team's incidence rate of de novo breast cancer was determined in a similar way to the Surveillance, Epidemiology and End Results data.

They determined that 83% of all patients were diagnosed at early stages.

They also found that it appeared to take longer for de novo breast cancer to develop in patients treated with tacrolimus than in patients treated with cyclosporine.

Dr Tahir Oruc's team concluded, "Surgical treatment of breast cancer in liver recipients is the same as treatment of breast cancer in patients without transplantation".

"However, the effects of chemotherapy, radiotherapy, and/or tamoxifen remain unclear in transplanted patients and need to be evaluated in larger studies".

Liver Transpl 2004; 10: 1-6

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Roche Wins U.S. OK for Convenient Hepatitis C Drug
Ransdell Pierson, Jed Seltzer; editing by Walter Bagley
Source: Reuters

NEW YORK, Jan 8 (Reuters) - Roche Holding AG <ROG.VX> said on Thursday it won U.S. approval for a pre-filled syringe version of hepatitis C drug Pegasys, which will help it compete against a rival product sold by Schering-Plough Corp. <SGP.N>.

Roche said the new form of Pegasys will be more convenient to patients than the current product, which must be extracted by syringe from vials.

Pegasys, a form of the naturally occurring protein interferon that stimulates the immune system, was approved in the United States in December 2002. The injectable drug is used in combination with a pill containing the anti-viral medicine ribavirin.

Since then, Roche's hepatitis C drugs have overtaken a similar dual therapy sold by Schering-Plough as the top-selling hepatitis C drugs in the United States.

Schering-Plough's third-quarter sales of hepatitis C treatments slumped 43 percent to $398 million.

In an attempt to gain back some market share, Schering-Plough last October won U.S. approval to sell its injectable interferon, called Peg-Intron, in a pre-filled injector "pen" that is more convenient than the product's separate powder and liquid vials.

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January 9th, 2004


Prevalence of Occult Hepatitis B in Injection Drug Users
Source: www.gastrohep.com

There is a high prevalence of occult hepatitis B virus infection in hepatitis C-infected injection drug users, find doctors in the January issue of Hepatology.

Occult hepatitis B is defined by the presence of hepatitis B virus (HBV) DNA in a serum or liver in the absence of hepatitis B surface antigen (HBsAg).

The prevalence and clinical correlates of occult hepatitis B remain undefined.

In this study, doctors from Baltimore, Maryland, determined the prevalence of occult hepatitis B in a high-risk cohort of 188 injection drug users.

All individuals had chronic hepatitis C viral infections confirmed by RNA detection and liver biopsy.

Occult hepatitis B was detected in 45%.

The team performed serologic assays for HBsAg and core antibody (HBcAb).

In addition, serum HBV DNA was detected using the COBAS HBV AMPLICOR monitor assay and a semi-nested PCR assay. The doctors found that although 96% of patients were anti-HBC positive, only 4% were HBsAg positive.

However, occult hepatitis B was detected in 45% of patients using semi-nested PCR.

They found that overall, liver disease was mild, with a median serum alanine aminotransferase (ALT) of 38 IU/L, median activity grade of 3/18, and median fibrosis stage of 1/6.

There was no association detected between the serum AST (aspartate aminotransferase), activity grade, or stage of liver disease and the presence of occult hepatitis B.

The doctors found that serum ALT levels were slightly higher in patients without occult hepatitis B (46 versus 35 IU/L).

They also found that median length of time since first injection drug use was longer in those without occult hepatitis B (24 versus 20 years).

Dr Michael Torbenson's team concluded, "Although further research is needed to assess its clinical significance, there is a high prevalence of occult HBV infection in this cohort of HCV-infected injection drug users".

Hepatology 2004; 39(1): 51-7

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Pediatric Fulminant Hepatic Failure in Endemic Areas of Hepatitis B Infection
Source: www.gatrohep.com

Hepatitis B virus is a significant cause of fulminant hepatic failure in infants, find investigators from Taiwan.

In this study, investigators assessed the role of hepatitis B virus (HBV) infection in pediatric fulminant hepatic failure (FHF) after the launch of universal HBV vaccination.

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

The team analyzed the data from patients with FHF collected from a nationwide collaborative study group.

They included children aged 1 month to 15 years who were diagnosed with FHF between 1985 and 1999.

The investigators determined that HBV infection (hepatitis B surface antigen (HBsAg) and/or immunoglobulin M hepatitis B core antibody (IgM anti-HBc) seropositive) accounted for 46% of all the cases of FHF.

The team calculated that the average annual incidence of FHF during the study period was 0.053 per 100,000 in patients aged 1 to 15 years. Incidence was 1.29 per 100,000 in those patients age < 1 year.

Approximately, 61% of all FHF cases were infants.

Furthermore, the percentage of HBV infection was higher in infants compared with children aged 1 to 15 years (57% versus 27%, respectively).

The team calculated that the incidence rate ratios of patients aged < 1 year to those aged 1 to 15 years was 54.2 for HBV-positive FHF and 15.2 for HBV-negative FHF. 61% of all fulminant hepatic failure cases were infants.

Maternal HBsAg was positive in 97% of the infants with HBV-positive FHF, and hepatitis B e antigen (HBeAg) was negative in 84% of these infants.

The team found that 74% of all HBV-positive FHF patients and 81% of the infantile HBV-positive patients had been vaccinated.

Dr Huey-Ling Chen's team concluded, "Within the first 15 years of universal vaccination, HBV was found to rarely cause FHF in children age > 1 year but remained a significant cause of FHF in infants".

"HBV-positive FHF was prone to develop in infants born to HBeAg-negative, HBsAg-carrier mothers".

"These infants had not received hepatitis B immunoglobulin according to the vaccination program in place".

Hepatology 2004; 39(1): 58-63

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Emtricitabine (FTC), FDA Approved for HIV, Also Is Active Against Chronic Hepatitis B
Mark Nelson
Source: www.hivandhepatitis.com

There are currently three drugs licensed in the US for the treatment of chronic Hepatitis B: Intron A (interferon alfa-2b), Epivir-HBV (lamivudine) and Hepsera (adefovir dipivoxil). Due to the limitations of each of the drugs, there is a need for new therapies for use as monotherapy and/or for combination treatment.

In a report for HIV and Hepatitis.com, Mark Nelson, MD, summarizes new data on new and novel anti-HBV agents presented at the 5th annual HEP DART conference (December 14-18, 2003. Kauai, Hawaii). One promising anti-HBV agent now in Phase III development for the treatment of chronic hepatitis B is emtricitabine, a nucleoside analog similar to 3TC, but which appears to be more potent than 3TC.

Emtricitabine (FTC)
Emtricitabine (Emtriva) has recently been licensed for the treatment of HIV disease. Similar to Epivir (3TC), FTC also has activity against HBV. The development of mutations in the YMDD motif of the HBV DNA polymerase may be slower with FTC than with 3TC.

Study FTC-303 enrolled HIV-infected individuals on a stable lamivudine-containing regime, and individuals were randomized on a 2/1 fashion to switch to FTC or remain on 3TC. 26 hepatitis B surface antigen individuals were identified from this cohort, with 19 switching at baseline to receive FTC and 7 remaining on lamivudine.

At baseline 58% -12 of 19 receiving FTC and 3 of 7 continuing lamivudine- had detectable HBV viraemia. 80% (9 of 12 FTC, 3 of 3 3TC individuals ) entering the study had mutations associated with lamivudine resistance. Individuals with YMDD mutations at baseline who switched to FTC maintained stable HBV DNA levels up to week 48(median +0.08 copies/ml, range -0.63 to +0.81) and maintained the YMDD mutation. The 3 individuals who remained on lamivudine who had the YMDD mutation demonstrated a 1.38 log increase in HBV viral load at week 48.

Of the 3 FTC individuals with wild type virus at baseline, one was below the level of detectability at week 48, one had no response, and one was below the level of detectability at week 36 but rebounded at week 48. The latter 2 individuals with viremia at 48 had developed mutations associated with resistance.

This study suggests that emtricitabine once daily controls HBV replication regardless of genotypic profile in a manner comparable to 3TC twice daily.

Source: HEP DART 2003. December 14-18, 2003. Kauai, Hawaii.

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Telbivudine (LDT) in Phase III Studies for Chronic Hepatitis B
Mark Nelson, MD
Source: www.hivandhepatitis.com

Several L nucleoside analogues are presently being studied for the treatment of HBV. The most advanced are L deoxythymidine (LDT), now known as telbivudine, and valine L deoxycytidine (LDC), both of which are potent inhibitors of HBV replication in vitro and are synergistic in the woodchuck model.

Neither is associated with inhibition of mammalian DNA polymerase gamma with mitochondrial toxicity. Both LDT and LDC target the positive strand of HBV DNA, in contrast to lamivudine, which targets the negative strand. The targeting of the positive strand may be associated with a slower development of resistance mutations.

Clinical results of LDT have been previously reported. In a 52-week study LDT was dosed at 400 or 600mg once daily, either alone or in combination with lamivudine 100mg per day, and this was compared to treatment with lamivudine 100mg per day as sole therapy.

Study entrants were adults with Hb e antigen positive chronic hepatitis B and a baseline ALT > 1.3 times the upper limit of normal. Mean age was 37 years, 86% were Asian and 64% had been infected by the maternal transmission route. 104 individuals were randomised to the study, 19 receiving lamivudine, 44 LDT and 41 LDT with lamivudine. There was no difference obseved between the 400 and 600mg arms, and the results are therefore reported together (see below).

This analysis shows no improvement in antiviral efficacy for dual rather than mono therapy, similar to the recently reported study of adefovir + lamivudine versus lamivudine alone. However, in the adefovir study there was a reduction in the development of lamivudine resistance in the dual therapy arm at 48 weeks, which was not observed in this study.

Genotypic resistance mutations developed in 21% of individuals on 3TC, 5% on LDT and 12% in the combination arm. Resistance mutations that developed were either M204I alone or M204I in combination with L180M. One individual in the 3TC arm had wild type virus.

Source: HEP DART 2003. December 14-18, 2003. Kauai, Hawaii.

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Entecavir, a Potent Inhibitor of Hepatitis B Virus
Mark Nelson
Source: www.hivandhepatitis.com

Entecavir is a guanosine nucleoside analogue which is a potent selective inhibitor of hepatitis B virus, and is currently undergoing phase III development worldwide. In the woodchuck model it is highly active, and importantly has shown reduction in CCC DNA levels and also reduction in development of HCC with prolonged survival.

The results of phase II studies have previously been reported. In the first study, individuals infected with HBV received one of three dose of entecavir -0.01, 0.1 or 0.5 mg qd, or lamivudine 100mg qd for 24 weeks. 177 nucleoside naïve individuals entered this study, 54, 36, 46 and 41 receiving each of these respectively. The viral load reductions were 2.3, 4.7, 4.3 and 3.4 log respectively. The 0.1 and 0.5mg dose groups had significantly higher falls in HBV viral load compared with the 3TC arm and the viral load reduction for 0.5mg was superior to that for 0.1mg of entecavir.

In comparison with lamivudine, entecavir 0.5mg was highly effective in reducing HBV DNA regardless of baseline ALT

The individuals receiving 1 or 0.5mg once daily had superior reductions in HBV DNA after 48 weeks (5.1 and 4.5 log) compared with a 1.4 log reduction for those continuing to receive lamivudine. Among those with abnormal ALT at baseline, Entecavir 1mg and 0.5mg were superior in normalising ALT ,68% and 59% respectively, compared to continued lamivudine 6% (p <0.001). Preliminary data from this trial has also suggested that Entecavir treated individuals had a more durable response off treatment, especially in those with e antigen negative disease.

9 transplant individuals with refractory to lamivudine have also received Entecavir, all 9 of whom had a good initial response in HBV DNA, although one individual developed resistance to Entecavir. All 9 individuals experienced reduction in ALT levels.

The development of lamivudine resistance mutations (L180M and 204V) leads to a 20 fold increase in the IC50 of entecavir at the cellular level compared with > 510 fold for 3TC. As entecavir is readily taken up by cells and phosphorylated rapidly to the active triphosphate, this increase in IC50 does not impact on the ability of entecavir to suppress lamivudine resistant virus.

In over 500 individuals who have received entecavir in phase II studies, resistance monitoring has identified 2 individuals who have developed resistance to entecavir. Both individuals had been heavily pre-treated with lamivudine.

Patient A had lamivudine resistant mutations at L180M, M204V and V173VL at baseline with additional substitutions developing on entecavir treatment at I169T in the B domain, and M250V in the E domain leading to a reduction in entecavir susceptibility. In vitro deletion studies of the mutations showed that it was necessary to have the lamivudine substitutions and the M250V in order to develop entecavir resistance .

Patient B, who had failed famciclovir, ganciclovir, foscarnet and lamivudine therapy, had resistance mutations at S78S/T,L180M, V173V/L, T184T/S and M204V at study entry. Viral rebound occurred after 80 weeks of entacavir therapy with additional substitutions at A38E, T184G and S202I. Single mutations with T184G or S202I in vitro were associated with a 60 fold increase in IC50 to entecavir, but significant phenotypic resistance > 100 fold occurred with the combination of both resistance mutations.

Entecavir is currently in Phase III studies, and Bristol-Myers Squibb is expected to submit an NDA for approval of entecavir to the US Food and Drug Administration (FDA) by the end of 2004.

Source: HEP DART 2003. December 14-18, 2003. Kauai, Hawaii.

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Liver Transplantation and Health-Related Quality of Life
Source: www.gastrohep.com

Education significantly influences health-related quality of life in liver transplant recipients, find doctors in the latest issue of Liver Transplantation.

Orthotopic liver transplantation (OLT) is the treatment of choice for end-stage liver disease of various etiologies.

In this study, doctors from Texas assessed health-related quality of life (HRQOL) in 88 male and 61 female patients before and after liver transplantation.

Patients completed questionnaires both before, and 1 and 2 years after OLT.

In patients with > 12 years education, men scored higher than women. Liver Transplantation

The questionnaire was developed specifically for OLT patients.

The doctors found that male recipients reported a higher degree of overall HRQOL than female recipients, both before and after OLT.

When they controlled for disparity in education between the sexes, the team found that among the less well educated, men and women scored similarly. However, among those with greater than 12 years education men scored higher than women.

In addition, employment findings revealed a higher percentage of men working before transplant and at 1-year post-OLT when compared with women.

However, at 2 years post-OLT, men and women had similar employment rates.

The team determined that male OLT recipients reported a higher level of overall HRQOL, both before and after liver transplantation.

Dr Terianne Cowling's team concluded, "Education appears to significantly affect HRQOL and may account for, at least in part, differences in reported HRQOL between male and female OLT recipients".

Liver Transpl 2004; 10: 88-96

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Volume Regeneration After Right Liver Donation
Source: www.GastroHep.com

When deprived of the middle hepatic vein liver regeneration of segment IV is impaired, find investigators in the January issue of Liver Transplantation.

After right hepatectomy with the middle hepatic vein trunk for a graft, the venous outflow in segment IV is disturbed.

There are limited data regarding the effect of middle hepatic vein deprivation on liver regeneration or functional recovery.

In this study, investigators from Japan reviewed 2 groups of living donors.

Patients in group A underwent right hepatectomy with preservation of the middle hepatic vein, while those in group B were deprived of the middle hepatic vein.

If the donor was less than 50 years old, and the remnant left liver was estimated to be more than 35% of the whole liver, right liver graft harvesting with the middle hepatic vein trunk was considered.

The team assessed the volume regeneration of segments I to III, segment IV, and overall liver using computed tomography 3 months after surgery.

Regeneration rate of segments I to III was significantly higher in group B.

The investigators found that the regeneration rate of segment IV was significantly impaired in group B donors compared with group A (125% versus 45%).

However, the regeneration rate of segments I to III was significantly higher in group B (208% versus 263%).

They did not find any significant difference in the regeneration rate of the whole left liver or functional recovery between groups.

Multivariate analysis revealed that the resection type was a significant predictive factor for the regeneration rate of segments I to III and segment IV.

The investigators determined that when deprived of the middle hepatic vein, liver regeneration of segment IV was impaired but was compensated for by the regeneration of segments I to III.

Dr Shojiro Hata's team concluded, "Extended right hepatectomy can be safely performed with careful preoperative consideration using these criteria".

Liver Transpl 2004; 10: 65-70

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