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The Best in the News on HCV, HBV and HIV/HCV Coinfection from July 15th, 2003 to August 13th, 2003

Alan Franciscus
Editor-in-Chief

1. Millions Unaware They Have Hepatitis C
2. Prevention of Hepatitis B Recurrence after Liver Transplantation
3. Nelfinavir Has Least Liver Risk in HIV-Hepatitis Co-Infected Patients
4. Surgery-related Morbidity in Living Donors of Right-lobe Liver Graft
5. FERX Receives Phase Ii SBIR Grant to Develop Targeted Radioactive Particles for Treatment of Liver Tumors
6. Alcohol Ups Hepatitis C Virus Replication
7. The Impact of Hepatitis C Virus Coinfection on HIV Disease Progression Before and After HAART
8. Association of HCV Prevalence, RNA, Genotype, and Drug Use with HIV Infection in a Cohort of New York City Drug Users
9. Effects of Heparin on Liver Fibrosis in Patients with Chronic Hepatitis B
10. Prisons to Reduce Hepatitis Treatment: Fewer Pa. Inmates will be Eligible, Due to Budget Issues. Officials Say The Candidates Will Be Better Targeted.
11. Quebec to Offer Free Injection Kits to Addicts
12. HCV infection raises the risk for type 2 diabetes in predisposed individuals
13. State Prisons Changing Way It Treats Inmates with Hepatitis C
14. Spontaneous Resolution of Chronic Hepatitis C after Withdrawal of Immunosuppression
15. Viral Protein Could Help Liver Therapy
16. 24 Weeks of Therapy with Peginterferon Alfa Plus Ribavirin Is Sufficient for HCV Genotypes 2 and 3
17. FDA Approves New Hemophilia Therapy
18. Canadian Docs Develop Gene Therapy for Hepatitis
19. Specific Markers in the Body May Indicate Fibrosis Risk As Well as Liver Biopsy
20. Is Liver Biopsy Needed in Co-Infected People?
21. Drugs, Words Battle Deadly Hepatitis C
22. Ribavirin ANDAs Await Decision by FDA; Par, Roche Expect Launch In August
23. New Clotting Factor for Hemophiliacs
24. Chicago Hospitals Accused of Transplant Fraud
25. Maxim Announces Completion of Enrollment of Phase 2 Hepatitis C Clinical Trial
26. Maxygen Reports Second Quarter 2003 Financial Results Company Updates 2003
27. ALT Levels May Show Response to HCV Care: Small Viral Kinetics Study
28. Quality of Life and Cognitive Function in Hepatitis C at Different Stages of Liver Disease
29. Cytokines Participate in Pathogenesis of HCV and Help to Predict Efficacy of Interferon
30. Favorable Prognosis of Hepatitis C after Interferon Therapy
31. Hepatitis C Coinfection Hampers Benefits of HAART in HIV Patients
32. Immune System Drug May Reduce Transplant Risk in Fatty Livers
33. Prophylaxis and Treatment of Hepatitis B Recurrence after Liver Transplantation
34. Efficacy of Intron A (interferon alfa-2b) and Epivir-HBV (lamivudine) Combination Therapy for Chronic Hepatitis B in Children
35. Noninvasive Index to Predict Fibrosis and Cirrhosis in Hepatitis C
36. Japanese Delicacy Shown to Raise Hepatitis Risk
37. Outcome of Liver Transplantation for Patients Infected by Hepatitis C
38. Guidelines for the Screening and Follow-up of Infants Born to Anti-HCV Positive Mothers
39. Hepatitis C Drug for Children
40. ICN Pharmaceuticals Resolves Arbitration with Schering-Plough on Indigent Royalty Payments - Company Expects No Material Current or Future Financial Benefit
41. Use of Hepatitis B Core Antibody-positive Liver Donors in Recipients without Evidence of Hepatitis B Infection: A Survey of Current Practice in the US
42. Role of Hepatitis B Immunoglobulin in Infants Born to Hepatitis B “e” Antigen-negative Carrier Mothers in Taiwan
43. Hepatitis C Virus and HIV Coinfection in Spain
44. Progression of Fibrosis in Hepatitis C Is Most Influenced by Age, Date of Infection, Alcohol Consumption, and Genotype
45. Retreatment with Daily High Dose Interferon Alfa plus Ribavirin Produces Significantly Higher SVR Rates Among
46. Artists to Play for Escovedo in Gotham Trilogy
47. NIH Panel Formally Recommends Further Ampligen/SARS Testing
48. Interferon Alfa Combined with Ketoprofen in Treatment-naove HCV Patients Is Significantly More Effective Than Interferon Alfa Monotherapy
49. Hepatitis B Severity May Be Based on a Clotting Protein, Claim Scientists
50. High Rate of Long-term Virological Response After a 1 Year Course of Interferon and Ribavirin in Chronic Hepatitis C Relapsers
51. Husband's Liver Donation a Success
52. Report From The 2nd IAS Conference on Pathogenesis and Treatment
53. Schering-Plough Business Won't Fund Costs
54. Schering-Plough Warns on Cash
55. Liver Function Tests
56. Schering-Plough Warns, Dividend Cut Ahead?
57. Schering-Plough May Borrow to Meet 2nd-Half Cash Needs
58. Doctor Held Over ‘Infecting Patients with Hepatitis C’
59. Retreatment with Interferon and Ribavirin Versus Interferon Alone in Interferon Responder-Relapser HCV Patients
60. Japanese Red Cross to Revise Donor System After Tainted Blood Scare

July 15th, 2003

Millions Unaware They Have Hepatitis C

Millions of people have been unknowingly infected with hepatitis C, some of them from contaminated blood during transfusions, according to health officials.

"We know that many people are infected with hepatitis C and are unaware that they have the disease," said newly appointed US Surgeon General Dr. David Satcher.

"Unfortunately, many of them cannot be readily identified because the disease does not cause symptoms until it is far advanced."

"Many with hepatitis C virus have no reason to believe they are infected," researchers say. "Many of those at high risk are average people -- middle-aged housewives who had a cesarean section delivery, young adults who had transfusions as high-risk babies or middle-aged men who served in Vietnam."

It is believed that millions are infected with hepatitis C by transfusions.

Hepatitis C is a potentially deadly disease that infects the liver, causing extreme fatigue, nausea, loss of appetite and abdominal pain. It can eventually cause cirrhosis of the liver and death.

It is considered a silent epidemic because many people don't develop symptoms for decades. The Centers for Disease Control and Prevention (CDC) in Atlanta estimates that 40 to 70 percent of those exposed to tainted blood become infected with hepatitis C. Symptoms of Hepatitis C are nausea and vomiting, weakness, fever, muscle and joint pain, yellowing of eyes and skin, dark urine and tenderness in upper abdomen.

It is spread most commonly through intravenous drug use, blood transfusions and organ transplants. It can also be spread through sexual contact, although it is a less likely means of transmission.

Satcher said that those who were infected from contaminated blood transfusions could be tracked through hospital and blood bank records.

An estimated 8,000 to 10,000 people die from hepatitis C each year.

Combined lamivudine and HBIg is effective in preventing recurrence of HBV infection in patients who are HBsAg-positive/HBV DNA negative before liver transplantation, find doctors in the August issue of the American Journal of Transplantation (Am J Transpl 2003; 3(8): 999-1002).

Hepatitis B immunoglobulin (HBIg) has been shown to be effective in preventing recurrent hepatitis B virus (HBV) infection after liver transplantation (LT).

In this study, researchers from France determined whether the addition of lamivudine to HBIg would be more effective in the prevention of HBV recurrence after LT.

The team assessed 60 HBsAg-positive/HBV DNA-negative patients who underwent LT between 1990 and 2001.

All 60 patients received intravenous HBIg to maintain serum anti-HB levels above 500 IU/L, indefinitely.

However, 17 patients received combined oral lamivudine (150 mg/day) and HBIg. These patients were compared with the historical cohort of 43 patients.

None of the 17 patients in the combined treatment group had HBV recurrence.

The physicians found that in the historical control group, the recurrence rate was 23%, after a median follow-up of 98 months.

They found that 5 patients died from HBV-related liver disease.

However, the team found that after a median follow-up of 30 months, none of the 17 patients in the combined treatment group had HBV recurrence. HBV DNA was undetectable by PCR in at least 3 serum samples per patient.

The team determined that HBV recurrence was significantly lower in the combined group, when compared with the historical control group.

Dr. Jerome Dumortiera's team concluded, "Our results suggest that combined lamivudine and HBIg can avoid the recurrence of HBV infection in patients who are HBsAg-positive/HBV DNA negative before LT".


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July 16th, 2003

Nelfinavir Has Least Liver Risk in HIV-Hepatitis Co-Infected Patients
by Michael Smith

Antiretroviral medications can be toxic to the liver, which creates a dilemma for physicians whose patients are co-infected with HIV and hepatitis -- which drugs to choose?

Using a large Canadian database, Elizabeth Phillips, MD, of Sunnybrook and Women's College Health Sciences Centre, in Toronto, Ontario, Canada, attempted to tease out some answers. The analysis showed that ritonavir, boosted protease-inhibitor regimens, and high cumulative exposure to stavudine (d4T) are associated with a significantly higher risk of severe liver toxicity.

However, patients on nelfinavir-based regimens -- without other protease inhibitors, didanosine, or stavudine -- appeared to be at lesser risk, Dr. Phillips said.

"Nelfinavir is not an important risk factor for liver toxicity," she said. She presented the findings here at the 2nd International AIDS SocietyConference on HIV Pathogenesis and Treatment.

Dr. Phillips used the HIV Ontario Observational Database to study the histories of 404 patients with both HIV and hepatitis B or C, as well as 1,653 HIV-positive patients without hepatitis. The patients who were not co-infected acted as controls in the retrospective study, she said.

Just over 60% of co-infected patients had ever had severe liver toxicity, compared with 41% of patients without hepatitis, she said. Liver toxicity was defined as grade 3 or 4 elevations in transaminase enzymes.

The biggest risk factor for severe liver toxicity was just the hepatitis co-infection, Dr. Phillips said, while both male gender and age were also significant.

But also significant were the extent of exposure to antiretroviral drugs, number of nucleoside analogues, number of non-nucleoside reverse transcriptase inhibitors, and number of protease inhibitors.

"Nelfinavir overall -- without accounting for drugs given with nelfinavir -- has about a 70% risk of these patients ever having had a grade 3 or 4 toxicity," Dr. Phillips said.

Even that level of risk for nelfinavir, however, "may be the company it keeps," she said: When the effect of other drugs is removed statistically, the risk drops to about 61%.

July 21st, 2003

Surgery-Related Morbidity in Living Donors of Right-lobe Liver Graft

Complications occur in a significant proportion of right-lobe liver graft donors, find investigators in the latest issue of Transplantation (Transplantation 2003; 76(1): 158-63).

Living-donor liver transplantation (LDLT) using the left lateral segment or left-lobe graft is widely accepted. However, right-lobe grafts are commonly used in many LDLT programs.

The risks for the donors of right-lobe grafts are unknown. 75 complications were identified in 69 donors.

In this study, researchers from Japan assessed 200 donors of right-lobe grafts. They focused on the incidence and variety of surgery-related morbidity.

The team evaluated changes in liver function tests to clarify the relation with donor age, steatosis of the liver, and residual liver volume (RLV).

Complications were surveyed for a median period of 28.7 months.

The physicians found that liver enzymes and bilirubin normalized within 1 month in all donors.

However, enzymes in older donors, those with macrovesicular steatosis, or with larger RLV, were significantly higher on day 1.

The team also determined that bilirubin on day 1 was significantly higher in donors with smaller RLV.

In addition, they found that biliary enzyme was not normalized in the majority at 1 month after donation.

Overall, the team identified 75 complications in 69 donors.

Of these, they found that biliary complications were the most common. These consisted of bile leakages (13%) and biliary strictures (2%), in 27 donors.

However, no complications led to mortality or to long-term sequelae.

Dr Takashi Ito's team concluded, "Complications occurred in a significant proportion of right-lobe donors irrespective of donor age, BMI, estimated RLV, and medical history".

"Living-liver donor surgery requires more care in right-lobe transplants".

Delivery of Radionuclides Using FeRx Magnetic Targeted Carriers (MTCs) Could
Result in Localization of Radiation Dose In Tumor Sites, Eliminating Exposure to Healthy Tissue or Organs

FeRx Incorporated, a targeted drug delivery company, today announced that it has been awarded a $640,000 Phase II Small Business Innovation Research (SBIR) grant from the National Cancer Institute of The National Institutes of Health (NIH). The grant, entitled "Targeted Radioactive Particles for Liver Tumor Therapy", supports research to continue the development of an intra-tumoral radiation therapy of liver lesions using FeRx's proprietary MagneTarg(tm) drug delivery system. Receipt of the entire grant award
is contingent upon the achievement of certain research and development milestones.

The ultimate goal of the program is to fund pre-clinical and clinical development of an MTC-radionuclide product.

"This continuing grant award recognizes the need to develop an innovative product that could overcome the dosing limitations of current external and internal radiotherapies," said Jacqueline Johnson, Ph.D., President and CEO of FeRx. "While our initial clinical indication under investigation is the treatment of both primary and metastatic liver cancers, the characteristics of the MagneTarg system could also allow for other solid tumor types to be studied as well."

The NIH SBIR program is a competitive, peer-reviewed grant program that provides research support to small businesses to discover and develop innovative biomedical products for the treatment of serious unmet medical needs. FeRx previously received a $100,000 Phase I SBIR grant award from the National Cancer Institute to prepare and characterize in vitro radiolabeled Magnetic Targeted Carriers(tm) (MTCs) and then investigate in vivo the binding stability, targeting and retention of these radioactive particles. The Principal Investigator on the grant is Gilles Tapolsky, Ph.D., MBA, Senior Director of Research at FeRx.

Results from preclinical studies investigating the use of MTCs in the local delivery of the radionuclide 90Yto the livers of rabbits implanted with VX2 tumors were presented at the SIR meeting in March 2003 by Jeff Geschwind, MD, Associate Professor of Radiology, Oncology, and Surgery at The Johns Hopkins University School of Medicine, and Director of Interventional Radiology at The Johns Hopkins Hospital. In these studies, radioactivity measured in organs on various days post-dosing showed that the majority of the 90Y was localized in the liver. MRI performed 7 days after treatment showed the presence of MTCs in the tumors and microscopic examination of tissue showed that these particles were confined to the liver. Importantly, liver necrosis was greater in treated animals (> 70% necrosis) when compared to controls (50% necrosis), with complete tumor destruction seen at the highest dose administered. The study suggested the feasibility of intra-tumoral radiotherapy using magnetic targeting and provides the foundation for the additional investigations being conducted under the Phase II SBIR grant.

Existing data from clinical studies in humans indicate that MTCs can be efficiently targeted to and distributed within the tumor while remaining at the site of localization without redistribution. Thus, the MagneTarg drug delivery system may achieve the selective targeting needed to deliver radiation therapy to the desired site, while minimizing the radiation dose to the untargeted organs. An additional advantage to using MTCs is that larger doses of radiation could be delivered to the tumor site if radioactivity does not readily escape the magnetic targeting mechanism.

FeRx Incorporated is a privately held drug delivery company pursuing the development and commercialization of its proprietary MagneTargTM system. MagneTarg offers a unique and simple method for localized delivery of a variety of pharmaceutical agents. FeRx believes the proprietary MagneTarg drug delivery system can efficiently deliver an increased concentration of drug to the desired site in the body while reducing the total amount of drug administered and limiting the toxic side effects commonly found in association with chemotherapy and other nonspecific systemic therapies. The MagneTarg System has applications across a range of therapeutic areas and provides a broad technology platform for targeted delivery of small molecules, radionuclides, biologics and genetic vectors.

Current clinical studies conducted by FeRx are designed to demonstrate the intra-arterial delivery of magnetically targeted pharmaceuticals to specific areas of the body while reducing systemic toxicity and increasing the local concentration of drug at the target site. These trials are focused on the delivery of FeRx's lead product, MTC-DOX (doxorubicin), to primary liver tumors (hepatocellular carcinoma -- HCC) and to tumors that have metastasized to the liver.

The Company strategy is to initially focus on the use of MagneTarg drug delivery for the treatment of certain solid tumors for which there are few, if any, effective therapies today. FeRx will use potent anti-cancer drugs whose mechanism of action is well understood, but whose efficacy and use are often limited by the debilitating side effects of systemic circulation. In addition to the tumors treated in our ongoing clinical trials, other solid tumors such as those found in the lung, pancreas, kidney, bladder, head and neck and limb can also be treated with the MagneTarg system. The Company believes that future applications beyond oncology could include targeted drug delivery in infectious disease, transplantation surgery and gene therapy.

July 22nd, 2003

Alcohol Ups Hepatitis C Virus Replication

Alcohol increases the replication of hepatitis C virus (HCV), and it interferes with the effectiveness of interferon used to treat hepatitis C.

That warning comes from an article in the medical journal Hepatology. The authors—Dr. Wen-Zhe Ho from The Children’s Hospital of Philadelphia, Pennsylvania and associates—examined the effects of alcohol on HCV-infected cells in lab dishes.

“As demonstrated in our study, alcohol not only induced HCV replicon expression but also compromised anti-HCV effect of interferon alfa,” Dr. Ho told Reuters Health. “These findings provide practical guidance toward the reduction of risk factors that interfere with interferon-based therapy and promote HCV disease progression.”

Other experiments showed that naltrexone, a drug used to treat opiate addiction, blocked the enhancing effect of alcohol on HCV. This suggests that “there might be an additional benefit for treating HCV-infected alcohol abusers with naltrexone,” Dr. Ho added.

However, Dr. Ho stressed that all this was determined in laboratory research, not patients. Whether it is meaningful in clinical practice “needs to be confirmed by epidemiological investigations, which is what we would like to do in the future.”

SOURCE: Hepatology, July 2003.

July 23rd, 2003

The Impact of Hepatitis C Virus Coinfection on HIV Disease Progression Before and After HAART

As the nature of the HIV epidemic changes, there is increasingly an overlap between the populations at risk for acquiring HIV and hepatitis C virus (HCV) infections because of shared routes of transmission.

Injection drug use is the fastest growing risk for both infections, accounting for 26% of new HIV infections in Canada in 1999.
The results of several studies have suggested that HCV disease progression is enhanced by coinfection with HIV. Whether HCV is a co-factor for HIV disease progression remains unclear. Most studies, conducted in the era before HAART, suggest that HCV has a limited effect on the progression or severity of HIV disease.

The two studies conducted in the post-HAART era have conflicting results. The Swiss Cohort found that HCV coinfection was associated with HIV progression, whereas the Johns Hopkins Cohort found no such association.

To compare the impact of hepatitis C virus (HCV) coinfection on progression of HIV infection in the eras before and after the introduction of highly active antiretroviral therapy (HAART), researchers at the Royal Victoria Hospital, McGill University Health Centre, Montreal, Quebec, Canada conducted a retrospective cohort study.

Results of the study appear in the July 1, 2003 issue of JAIDS.

Abstract
One hundred twenty-five HCV+ patients and 1076 HCV- patients were studied; 83% of HCV+ patients were injection drug users.
HCV+ subjects experienced no clear benefit from HAART. The adjusted hazard ratios (HRs) of opportunistic infection, death, and hospitalization were 0.74, 1.78, and 2.1, respectively, comparing the post-HAART era with the pre-HAART era.

In contrast, HCV- subjects experienced rate reductions for all outcomes. Comparable HRs for opportunistic infection, death, and hospitalization were 0.49, 0.28, and 0.51, respectively.

HCV+ subjects remained at increased risk for death and hospitalization post-HAART even after additional adjustment for antiretroviral use and time-updated CD4 cell and viral load measures.

Deaths and hospitalizations in HCV+ patients were primarily for non-AIDS-defining infections and complications of injection drug use.

The authors conclude “HCV coinfection and comorbidity associated with injection drug use are preventing the realization of substantial health benefits associated with HAART.”

Commentary
In the pre-HAART era, the unadjusted rates were consistently lower for HCV+ subjects compared with HCV- subjects for all outcomes. The rates were 11.0 versus 22.9 per 100 person-years for opportunistic infection, 6.9 versus 14.9 per 100 person-years for death, and 9.7 versus 21.0 per 100 person-years for hospitalization, respectively, and are illustrated in crude survival analyses. After adjustment, rate ratios remained below 1, but confidence bounds included 1.

In the post-HAART era, there was no difference in the rate of opportunistic infection observed between HCV+ and HCV- subjects (unadjusted rate: 12.8 vs. 13.1 per 100 person-years).

A reversal occurred with respect to the other outcomes, however. HCV+ subjects in the post-HAART era experienced greater rates of both death (unadjusted rate: 9.5 vs. 5.3 per 100 person-years) and hospitalization (unadjusted rate: 25.9 vs. 12.6 per 100 person-years). The adjusted risks of death and hospitalization remained significantly higher among HCV+ subjects.
In both the pre- and post-HAART eras, baseline CD4 cell count was an independent protective factor against opportunistic infection, death, and hospitalization (i.e., in the post-HAART era, for each additional 100 cells, the HR of opportunistic infection was 0.50, 95% CI: 0.39-0.65, p = .001). History of prior AIDS-defining illness increased risks of death and hospitalization, and longer duration of HIV infection increased risk of death. Calendar year of cohort entry was strongly associated with primary outcomes. For example, after HAART, the risk of death diminished substantially in each additional year (i.e., HR = 0.046, 95% CI: 0.013-0.165 for 1999 compared with 1996). Adjustment for calendar year did not change risk estimates associated with HCV status, however. The following factors were not associated with primary outcomes: age, gender, birthplace, and baseline CD8+ cell count.

In the pre-HAART era, both HCV+ subjects and HCV- subjects died predominantly from AIDS-related complications. Despite chart review, the exact cause of death could not be determined for a number of subjects who died at home or in a hospice (likely AIDS related). In the post-HAART era, deaths and hospitalizations among HCV+ subjects were primarily attributable to non-AIDS-defining infections (i.e., bacteremia, pneumonia) and complications of injection drug use.

Hepatitis C virus infection is fast becoming one of the greatest challenges facing an increasing number of HIV-infected individuals and their care providers.

Understanding the impact of coinfection on morbidity and mortality in HIV infection is essential to optimizing the management of the epidemic in developed countries.

The impact of HCV infection on the progression of HIV infection in the era prior to widespread use of HAART has been debated. The majority of older studies have shown no association between HCV infection and survival from HIV disease. In contrast, more recent studies have reported that immunologic progression, development of AIDS, and shorter survival after AIDS were associated with HCV coinfection.

Recently, the Swiss HIV Cohort Study reported that HCV infection was independently associated with the combined outcome development of a new AIDS-defining condition or death (HR = 1.7, 95% CI: 1.26-2.30) in individuals beginning HAART. In contrast, the Johns Hopkins Cohort, which included both treated and untreated individuals, detected no increased risk in HCV-coinfected persons of a first opportunistic infection, CD4 cell decline, or death once adjustments were made for use of HAART and failure to suppress HIV replication. The reason for these discrepant findings is unclear but may be related to demographic differences in the populations studied and the inclusion criteria employed, primarily the receipt of HAART. By examining both the pre-HAART and post-HAART eras, this study attempted to assess the impact of HCV on HIV progression directly while accounting for HAART exposure.

In the post-HAART era, we found that HCV status was clearly associated with an increased risk of both death and hospitalization but not of opportunistic infection. The lack of an observed effect of HCV status on the risk of opportunistic infection raises the possibility that HCV status does not influence HIV-related outcomes so much as other health events (i.e., other infections, liver disease).

Undoubtedly, one of the major factors contributing additional increased risk of morbidity and mortality associated with HCV infection is the high prevalence of active injection drug use in this population.

This lifestyle has been shown to be associated with violent and accidental deaths, suicide, and overdose, which were also seen in our cohort.

This is the only study to have examined the morbidity and mortality associated with HCV coinfection in both the pre-HAART and post-HAART eras and regardless of antiretroviral treatment. As stated earlier, the study findings suggest that HCV infection, and comorbidity associated with injection drug use, are preventing the realization of improved health outcomes in this population.

07/23/03
Source
MB Klein. The Impact of Hepatitis C Virus Coinfection on HIV Progression Before and After Highly Active Antiretroviral Therapy. Journal of Acquired Immune Deficiency Syndromes 33(3): 365-372. July 1, 2003.

Association of HCV Prevalence, RNA, Genotype, and Drug Use with HIV Infection in a Cohort of New York City Drug Users
by hivandhepatitis.com

Nearly 4 million persons in the United States and an estimated 170 million worldwide have been infected with hepatitis C virus (HCV). Transmission occurs primarily via injection, and injection drug users (IDUs) are at particularly high risk for HCV infection.

It has been reported that 40-85% of IDUs are HCV seropositive, and injection drug use (IDU) accounts for approximately 60% of HCV transmission in the United States. Although acute HCV infection is usually mild, 70-80% of those infected develop chronic hepatitis, with substantial long-term morbidity and mortality due to HCV-related chronic liver disease.

Among HIV-infected IDUs, rates of HCV co-infection range from 52-93%. As potent antiretroviral therapy for HIV has decreased AIDS-associated morbidity and mortality, chronic HCV has become a significant cause of morbidity and mortality in this population.

End-stage liver disease has become a leading cause of death in HIV-infected persons. HIV co-infection may accelerate progression of HCV infection, with more severe liver fibrosis and a higher frequency of decompensated liver disease and cirrhosis. HIV infection is also associated with a higher level of HCV RNA.

The purpose of the current study, published in JAIDS (July 1, 2003), was to identify prevalence of and factors associated with HCV seropositivity, detectability and level of serum HCV RNA, and HCV genotype in a cohort of current and former opiate-addicted drug users in the Bronx, New York City.

Factors associated with serum HCV antibody, HCV RNA level, and HCV genotype were assessed in 557 current and former drug users. Additional assays included HIV antibody, CD4+ lymphocyte counts, HIV viral loads, and hepatitis B markers.

Seventy-five percent of subjects were anti-HCV positive, of whom 75% had detectable HCV RNA.

On multivariate analysis HCV seropositivity was associated with history of drug injection, HIV seropositivity, and increased age and inversely with drug snorting.

Among anti-HCV-positive persons, detectable HCV RNA was independently associated with HIV seropositivity, male gender, and history of injection and inversely associated with hepatitis B surface antigen positivity.

Among persons with detectable HCV RNA, higher levels were independently associated with higher HIV viral load, increased age, and genotypes 2a and 2b.

Genotype could be determined in 303 (96.8%) of the 313 individuals with detectable HCV RNA. Most common were genotypes 1a and 1b, found in 180 (59.4%) and 59 (19.5%) participants, respectively. Other genotypes included 3 (1.0%) type 2a, 38 (12.5%) type 2b, 15 (5.0%) type 3a, and 8 (2.6%) type 4a.

The distribution of HCV genotypes did not differ significantly by gender, whether persons had ever injected drugs, HIV status, or age. However, blacks were significantly more likely than others to have genotype 1a or 1b. Multivariate analysis confirmed an independent association of genotype with race, but with no other variables.

These findings demonstrate an association of HCV RNA level with HIV viral load, independent of the level of immunosuppression.

However, a substantial degree of the person-to-person variability in the prevalence and level of detectable HCV RNA remains unexplained.

Commentary
This study confirms that there is an alarmingly high prevalence of HCV infection among drug users and that persistent HCV infection is especially common among those co-infected with HIV.

HCV RNA levels showed a trend toward being higher in HIV seropositives, among whom levels were significantly higher in those with higher HIV viral load, independent of CD4+ lymphocyte count. These findings are consistent with increasing evidence that HCV infection is more severe when HIV co-infection is present.

Persons with genotypes 2a or 2b had significantly higher HCV RNA levels than those with other genotypes. While some studies have observed no relationship between genotype and HCV RNA levels, others have reported increased RNA levels in association with HCV genotype 1.

The authors conclude, “In summary, this study of New York City drug users shows that the risk of having acquired HCV infection was independently associated with HIV seropositivity, increased age, and having ever injected drugs and was inversely associated with drug snorting.

False-negative HCV antibody results were not found, even among those with HIV infection.”

“Among persons anti-HCV positive, detectable serum HCV RNA was independently associated with HIV co-infection, male gender, and IDU and was inversely associated with HBsAg positivity. Higher HCV RNA levels were seen with HIV seropositivity and were significantly associated with higher HIV viral loads, genotype 2a or 2b, and increased age.

Despite these findings, the substantial degree of interperson variability in rates of detectable HCV RNA and in HCV RNA levels remains unresolved.”

07/23/03
Source
L Strasfeld and others. The Association of Hepatitis C Prevalence, Activity, and Genotype with HIV Infection in a Cohort of New York City Drug Users. Journal of Acquired Immune Deficiency Syndromes 33(3): 356-364. July 1, 2003.

Effects of Heparin on Liver Fibrosis in Patients with Chronic Hepatitis B
By hivandhepatitis.com

The aim of this study, conducted at the Shandong Provicial Hospital in Shandong Province, China, was to evaluate the effects of heparin on liver fibrosis in patients with chronic hepatitis B.

Fifty-two cases under study were divided into two groups, group A and group B. The two groups were given regular treatment and heparin/low molecular weight heparin (LMWH) treatment respectively. Hepatic functions, serum hyaluronic acid (HA) and type IV collagen levels were measured before and after the treatment, and six cases had liver biopsy done twice.

After treatment, hepatic functions became significantly better in both groups. Serum HA and type IV collagen levels in group B compared with group A decreased significantly after treatment. Collagen proliferation also decreased in group B after treatment.

The authors conclude Heparin/LMWH can inhibit collagen proliferation in liver tissues with hepatitis B.

July 24th, 2003

Prisons to Reduce Hepatitis Treatment: Fewer Pa. Inmates will be Eligible, Due to Budget Issues. Officials Say The Candidates Will Be Better Targeted
by Mark Fazlollah, Inquirer Staff Writer

Faced with looming state budget problems, Pennsylvania prisons this fall will begin reducing by about 75 percent the number of inmates being treated for the potentially deadly hepatitis C virus.

Pennsylvania now has 8,030 state inmates infected with hepatitis C and is treating 550, said Fred Maue, chief of medical services for the Department of Corrections. He said those 550 would get their medicines, which cost $16,000 per patient for a 48-week course of treatment.

But beginning in September, he said, prisons will apply stricter rules for treating infected inmates. He estimated that 130 a year would receive medicines and that that number eventually might be cut to fewer than 100. He said the number of infected inmates is likely to remain constant-about 23 percent of the prison population.

“We were facing medical cutbacks. We were faced with having to live with a limited budget,” he said. “We felt that we needed to prioritize our budget.”

Maue said much of the treatment would be focused on prisoners with a highly curable form of hepatitis C - about 15 percent of those infected.

He stressed that the reduction in treatment was justified because the state was doing better at targeting patients who could benefit from the medicine.

Thomas Shaw-Stiffel, a specialist at Pittsburgh’s Center for Liver Diseases, said that approach might get more bang for the buck.

“It’s to the patients’ benefit to be more focused,” said Shaw-Stiffel, who worked with the University of Rochester’s hospital when it was treating New York inmates with hepatitis C. “On the surface, [the reduction] may look ominous, but it may be beneficial.”

The new guidelines are in line with national prison standards.

More than three million Americans are infected with hepatitis C, with a huge portion rotating through the correctional system. An estimated one million infected inmates leave jails and prisons each year, the U.S. Centers for Disease Control and Prevention says.

Nationally, hepatitis C is the leading reason for liver transplants. It has become one of the leading causes of death among Pennsylvania inmates.

The reduction in treatment comes at a time when the medications are more successful in effectively curing the disease - prompting some criticism that the state is going in the wrong direction.

“It’s disappointing,” said lawyer Angus Love, director of the Pennsylvania Institutional Law Project, when told of the state’s new rules. “It’s not surprising, given the budgetary constraints.”

Despite the reductions in treatment, Pennsylvania will still be providing more care than many states. New Jersey, for example, is treating 33 inmates - a dramatic change from last year, when it was treating one. Officials do not know how many inmates are infected because New Jersey prisons do not conduct widespread testing.

Under Govs. Tom Ridge and Mark Schweiker, Pennsylvania developed one of the nation’s most aggressive treatment programs. In the past, the state’s secretary of corrections had boasted that his department was saving lives of inmates. The secretary, Jeffrey A. Beard, also said that treating the disease in prisons made inmates less likely to spread it after their release.

Maue said his department last year was “over our budget,” spending about $8.8 million for treating hepatitis C.

He estimated that for this year, “top dollar would be $6 million,” with treatment costs even lower next year.

Maue said prisons would require that inmates have at least 18 months remaining on their sentences before consideration for medication. In the past, inmates were required to have a year left on their sentences.

Inmates also will be required to undergo liver biopsies before being considered for treatment.

Quebec to Offer Free Injection Kits to Addicts

Drug addicts in Quebec will be offered free injection kits to try to cut transmission of the hepatitis C virus, the provincial government said on Wednesday.
A Quebec government official said the Canadian province will spend C$600,000 ($430,000) a year to buy about 150,000 kits.

The kits consist of syringes, utensils to heat drugs, filters, sterile water phials and dry wads to be used after injection.
The kits will be available at Quebec’s 680 so-called syringe replacement centers. About 23,000 hard-drug addicts are targeted.

“We want to prevent new contamination. Most young drug users are infected with hepatitis C after six months. We have to target those people,” said Richard Cloutier, a civil servant in charge of the program at the provincial health department.

He said the sharing of utensils, filters or liquids such as saliva and urine contribute to the propagation of the hepatitis C virus, which affects the liver.

A total or one million syringes will be made available each year, but the number is low as some cocaine addicts inject themselves as many as 30 times a day.

“We are far behind places like British Columbia, a province that has three million syringes for the same number of drug users. We are urging community groups to help us out,” Cloutier said.

A prospective study of individuals diagnosed with type 2 diabetes has shown that hepatitis C virus (HCV) infection heightens the risk for the disease in people who are already predisposed to developing it.

In the case-cohort analysis, researchers at Johns Hopkins University in Baltimore, Maryland looked at diabetes onset among more than 1000 men and women between the ages of 44 and 65.

“Among 1084 adults free of diabetes at baseline, 548 developed diabetes over 9 years of follow-up evaluation,” reported Shruti H. Mehta and colleagues in Hepatology.

Using common factors such as body mass index (BMI), investigators categorized study participants relative to their having a high or low risk for acquiring diabetes.
“Among those at high risk for diabetes, persons with HCV infection were more than 11 times as likely as those without HCV infection to develop diabetes (relative hazard, 11.58; 95% CI, 1.39-96.6),” they said.

In contrast, the group with a low risk for diabetes didn’t show elevated diabetes rates in the face of HCV infection, investigators noted (Hepatitis C virus infection and incident type 2 diabetes. Hepatology, 2003;38(1):50-56).

Although larger studies are needed to confirm the results, Mehta’s team concluded that those with risk factors for type 2 diabetes face a heightened risk with HCV infection.

Key points reported in this study include:
1) Over half the more than 1000 individuals enrolled in a case-cohort study acquired type 2 diabetes over a 9-year follow-up period
2) People with a heightened risk for acquiring type 2 diabetes were more likely to develop the disease if they were infected with hepatitis C virus (HCV)
3) HCV infection encourages the development of type 2 diabetes in people with pre-existing risk factors.

This article was prepared by Biotech Week editors from staff and other reports.

July 25th, 2003

Spontaneous Resolution of Chronic Hepatitis C after Withdrawal of Immunosuppression
Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, 32 Fruit Street, Boston, MA 02114, USA.

Approximately 85% of acute cases of hepatitis C infection result in chronic hepatitis.

Spontaneous clearance of hepatitis C virus has been thought to occur exclusively after acute infection and is associated with a robust cellular immune response.

In the June 2003 issue of Gastroenterology, researchers describe a case of a renal (kidney) transplant recipient who acquired post-transplant hepatitis C virus infection with rapid histological progression.

However, the patient subsequently experienced spontaneous viral clearance along with histological remission after removal of immunosuppression.

Immunologic studies showed persistently strong cellular immune responses.
The authors conclude, “This case underscores the importance of restoration of the immune system in the control of hepatitis C virus viremia and disease progression and the need to minimize or obviate immunosuppression in organ transplant recipients.”

July 27th, 2003

Viral Protein Could Help Liver Therapy
by Science News

Researchers experimenting with a protein from hepatitis B virus have developed a new technique for delivering therapeutic genes to the liver while minimizing the accidental introduction of genes to other tissues.

The ideal delivery system for a gene therapy would target only those organs or tissues that need genetic repairs. Live viruses that are altered to carry human genes meet that criterion, but they can trigger dangerous immune responses and cause other problems. Other delivery vectors tend to usher genes to tissues other than the intended ones, a flaw that can lead to side effects.

Shun’ichi Kuroda of Osaka University in Japan and his colleagues suggest a hybrid vehicle: hollow globules of fat covered with a protein isolated from hepatitis B virus. These so-called L particles selectively target liver cells, just as hepatitis B virus does, but are less likely than an intact virus to get out of hand, the researchers say.

Using L particles, the researchers introduced a test gene into clusters of human liver cells growing in laboratory dishes and into mice that had received injections of cancerous human liver cells. In both sets of experiments, the viral protein helped guide the particles to targeted cells, the researchers report in an upcoming Nature Biotechnology.

L particles are big enough to accommodate even relatively large medicinal parcels, which could include some conventional drug molecules in addition to therapeutic genes, the researchers note. Furthermore, they suggest, the particles could be engineered to have different surface proteins that would target organs and tissues other than the liver.

July 28th, 2003

24 Weeks of Therapy with Peginterferon Alfa Plus Ribavirin Is Sufficient for HCV Genotypes 2 and 3

Patients with chronic hepatitis C infected with HCV genotypes 2 and 3 can be successfully treated in more than 80% of cases. This is in sharp contrast to success rates for treatment of patients with genotype 1, which is about 60%.

It has been shown that a 24-week TIW [3 times weekly] treatment period with standard interferon alfa and ribavirin is sufficient for patients with genotypes 2 and 3. However, the recent multicenter studies investigating the effect of the pegylated interferons and ribavirin used a 48-week schedule for all patients irrespective of the HCV genotype.

In this German study, researchers prospectively investigated the efficacy of a 24-week treatment period with PEG-Intron (peginterferon alfa-2b), 1.0-1.5 microgram/kg once weekly and ribavirin (1-1.2 g daily) in 54 patients with HCV-genotype 2 and 3 at two different sites.

29 patients were included in Herne (private practice) and 25 patients were treated in Hannover (Medical School). After the end of follow-up, 46 (85%) patients showed a virological sustained response in the intent to treat analysis. Only four patients demonstrated a virological treatment failure (3 relapses, 1 breakthrough), two patients were non-compliant, and at each center therapy was stopped in one patient due to adverse events.

There was no difference regarding treatment response between the two sites, even though the patients in Herne were treated only with 1.0 microg/kg PEG-IFN alfa-2b, while patients in Hannover received 1.5 microgram/kg PEG-IFN alpha-2b.

The authors conclude, “The response rates of this study do not differ from the results of the 48-week treatment period of the recently published multicentre trials. Thus, we suggest treating all patients with HCV-genotype 2 and 3 for only 24 weeks when PEG-IFN alfa-2b is used in combination with ribavirin.”

Healthcare products maker Baxter International Inc. said on Friday it won U.S. approval for a hemophilia drug that eliminates the risk of infection because it treats the bleeding disorder without using human or animal materials.

Unlike other hemophilia treatments, Baxter’s latest generation medicine, Advate, is genetically engineered without using human or animal plasma proteins, which may carry viruses or blood-borne diseases. It is injected directly into a vein.

Deerfield, Illinois-based Baxter, which also makes vaccines, intravenous drug delivery systems and renal therapy products, is pinning its recovery in the second half of the year on Advate sales. This third-generation treatment will be priced at a premium, the company has said.

Baxter said it expects to begin shipping Advate to distributors in three to six weeks. A spokeswoman for the company said it had not yet determined the exact price of the new product.

Hemophilia, a potentially deadly disorder, is caused by a deficiency of a particular blood protein called Factor VIII, one of a series of proteins essential to the blood clotting process.

Hemophiliacs, who are almost exclusively male, suffer recurrent bleeding, mostly into joints and muscles. They also have a high incidence of AIDS resulting from their treatment.

Baxter, which up until early last year could not make enough of its lucrative hemophilia treatment to meet demand, suddenly saw its fortunes turn, due in part to increased competition and price pressures in the market.

Advate is under regulatory review in Europe and Canada. European approval is expected in the second half of the year.

According to the World Health Organization, more than 400,000 people in the world may have hemophilia A, which affects 15 to 20 out of every 100,000 males born worldwide.

“The hemophilia community has indicated there will be a high demand for this innovative therapy because it removes concerns about unknown viruses and infectious proteins carried in protein additives,” Baxter said in a statement.

Canadian Docs Develop Gene Therapy for Hepatitis
by John C. Martin, hepatitisneighborhood.com

A gene-based therapy may someday become the next promising treatment for hepatitis C (HCV) after it cleared a hurdle in a Canadian study this past spring.
Doctors with the Ontario Cancer Institute, part of the University Health Network in Toronto, successfully treated HCV-infected mice using a form of gene therapy that forces hepatitis-infected cells to commit suicide through a process known as apoptosis (ap-uh-TOE-sis).

‘Genetic Smart Bomb’
Christopher Richardson, Ph.D., and Eric Hsu, Ph.D., of the Ontario Cancer Institute and their colleagues inserted a gene into a harmless virus, then introduced the engineered virus into the livers of mice infected with HCV. Once the gene entered infected cells, it was only then that it was activated, causing apoptosis to occur. In turn, this cellular suicide halted the replication of the virus, a process by which the virus reproduces itself in an infected host.

This modified gene “acts as a ‘genetic smart bomb’ that targets hepatocytes [liver cells] and other cells that are infected with hepatitis C virus,” said Richardson, in an e-mail interview with Priority Healthcare.
The newly discovered therapeutic approach could theoretically reduce the amount of virus in the blood in humans, and potentially eliminate HCV at early stages of infection or prior to liver transplantation, experts contend.

The technique was tested in vitro in a laboratory setting before it was done with mice, Richardson explained.

Success with the mice translated to the amount of virus present, he said. “When the initial virus loads were low to medium, virus clearance was extremely efficient, and there did not appear to be any rebound over 28 days. Higher initial virus loads may require prolonged treatments to completely clear the virus, and further experiments are addressing this issue.”

History of Gene Therapy
Gene therapy is a concept that is not new. Genes, which are carried on chromosomes, are the basic physical and functional units of heredity. They essentially carry instructions for cells about how to make protein, the substances that make up most life functions and are the most common component of cells.

However, when genes are altered so that their corresponding proteins can’t function properly, genetic disorders or disease results. So, medical scientists have developed a technique to replace the faulty gene with one that works correctly. There are several approaches used with this objective in mind:
• A normal gene may be inserted into a nonspecific location within the genome (the entire set of genes within a person) to replace a defective gene. This is the most common technique.
• An abnormal gene could be traded for a normal gene
• The defective gene could be repaired through a process known as selective reverse mutation, which returns the gene to its normal function.
• The regulation (the degree to which a gene can be turned on or off) of a particular gene could be altered.

Delivering a Therapeutic Gene
In most studies using gene therapy, a normally functioning gene is used to replace a disease causing gene by using a carrier molecule called a vector. The vector delivers the normal gene to the patient’s target cells. Currently, the most common vector used is a virus that has been re-engineered so that it does not create disease; it only delivers the therapeutic gene to cells.

Target cells like those of the liver or lung are “infected” with the viral vector. The vector then unloads its genetic material containing the therapeutic human gene into the target cells. The gene, in turns, restores the target cell to a normal state.

Limitations of Gene Therapy
Yet despite what appears to be a valuable treatment for human disease, gene therapy does have its limitations and potential risks. Before gene therapy can be a permanent cure for any condition, the therapeutic DNA introduced into target cells must remain functional for the long-term, and the cells containing the new DNA must also be long-lived and stable. So far, problems with integrating therapeutic DNA into the genome, and the rapidly dividing nature of many cells, is preventing gene therapy from providing any long-term benefits.

Additionally, the risk of stimulating the immune system when a virus even one that causes no harm is introduced into the body is ever present. Not only that, but the immune system becomes enhanced when it spots viruses it has seen before. This also limits gene therapy’s effectiveness.

Viruses themselves also present a range of problems relative to gene therapy, including potential toxicity, immune and inflammatory responses, and gene control and targeting problems. Scientists are also concerned that the initially harmless virus may somehow recover its ability to cause disease.

Finally, more common diseases high blood pressure, Alzheimer’s disease, arthritis, heart disease and diabetes are caused by abnormalities in many combinations of genes. That multi-faceted problem means these diseases are very difficult to treat using gene therapy.

A Hopeful Finding
Meanwhile, the scientists who took part in the hepatitis study using this novel gene therapy approach are hopeful. Still, much research still needs to be accomplished before the therapy can be tested in a human clinical trial, Richardson explained. First, there are plans to attempt the technique in chimpanzees chronically infected with hepatitis C.

“Human trials with this protocol are probably premature at this time,” Richardson said. “Safety issues would have to first be addressed in the chimpanzee studies. However, we were pleasantly surprised as to how effective the approach was in our mouse model.”

Specific Markers in the Body May Indicate Fibrosis Risk As Well as Liver Biopsy
by John C. Martin, hepatitisneighborhood.com

Five specific biomarkers in the body can predict whether patients co-infected with hepatitis C (HCV) infection and HIV will progress to fibrosis as well as liver biopsy. That’s according to a group of Paris doctors who set out to determine ways to predict fibrosis non-invasively. Their findings are published in the March 2003 issue of the journal AIDS.

Biomarkers That Predict Fibrosis
The biomarkersbiochemicals that serve as an indication of disease include proteins known as alpha2-macroglobulin, apolipoprotein A1, and haptoglobin; a pigment called bilirubin that is produced when the liver processes waste products; and an enzyme known as gamma-glutamyl-transpeptidase.

The researchers say the patient’s age and sex also serve as key indictors of fibrosis development. Their study was led by Robert P. Myers, M.D., of the department of hepatology and gastroenterology at Hopital La Pitie-Salpetriere.

These biomarkers, taken together, accurately predict HCV-related lesions that appear on the liver in patients without HIV co-infection, but has never been tested in those who are also infected with the AIDS virus, the clinicians noted.

Liver Biopsy Comparison
To make that determination, Myers and his colleagues compared the diagnostic value of the biomarkers with that of liver biopsy in a group of 130 co-infected patients at their hospital. Indicators of HIV infection, such as numbers of CD4 cells (targeted by HIV during onset of infection), and HIV-RNA (an indicator of HIV infection) were also included.

They found that higher levels of alpha2-macroglobulin and GGT, lower levels of apolipoprotein A2, and male sex were the “most informative” markers of liver fibrosis. These markers were similar to the predictive value of liver biopsy, the researchers noted.

Using this biomarker combination as a diagnostic measurement” could reduce the necessity for liver biopsy by 55 percent, while maintaining an accuracy of 89 percent,” the French doctors noted.

Is Liver Biopsy Needed in Co-Infected People?

In an editorial accompanying the French study, Vincent Soriano, M.D., and his colleagues from Hospital Carlos III in Madrid, Spain, describe the need for routine liver biopsy in patients with chronic HCV without HIV co-infection as controversial. Such routine biopsy may be even less justifiable in co-infected patients, they write.

That’s because 95 percent of people with both HIV and hepatitis C have at least moderate fibrosis, compared to those with only hepatitis C. Plus, these patients face higher risks of biopsy-related complications, Soriano and his co-authors pointed out.
Instead, most patients co-infected with HCV and HIV should be considered candidates for hepatitis C therapy, regardless of the health of their liver.

Drugs, Words Battle Deadly Hepatitis C
by Jason Felch, Denver Post

Mackie Faye Hill carried hepatitis C for 20 years before discovering she was infected with the “silent killer.”

When her doctor told her that she had the disease, the 50-year-old, who holds a doctorate in psychology, began preparing for death. There was no cure, she was told, and without a liver transplant the disease could be terminal.

She wrote a list of all the things she wanted to do before she died and began a book about her life.

Today, Hill, of Denver, laughs at the death plans she made. Thanks to new drug treatments, Hill says, “the virus disappeared, and they never saw it again. I think I’m cured.”

Her doctor agrees. The challenge now, says University of Colorado Hospital’s Dr. Gregory Everson, one of the nation’s top liver specialists, is to spread the word.

Despite being the most common blood-borne disease in the United States - four times more common than AIDS - most people are still confused about hepatitis C, a recent survey by the American Gastroenterological Association shows.

More than 2.7 million Americans are infected with the virus - perhaps as many as 5 million, Everson says - yet only 49 percent of the population is aware of the disease, as compared with the 81 percent familiar with HIV, the June survey found. The Colorado Department of Public Health and Environment estimates that 60,000 people in Colorado carried the virus in 2001.

And despite the new drug treatments available, which some doctors say cure half of those who receive it, fewer than half of people infected are receiving any prescription treatment.

Many have no idea they carry the virus. After 20 years, Hill only learned of her infection in 1993 after donating blood. She had never felt ill, and never heard of the disease. “I thought, what is that? I had heard of A and B, but not C,” Hill said.

With the help of doctors, she discovered she had probably been exposed to the virus when she received a blood transfusion during a difficult pregnancy in 1973.

Between 1973 and 1984, Hill donated her infected blood regularly. “Probably somebody got my blood and is now carrying this virus,” Hill said.

The virus wasn’t identified until 1988, and an accurate test was not developed until the early 1990s.

Everson says those at risk of carrying the virus include people who received a transfusion of blood products before 1992; those who have used intravenous drugs, even once in their lives; those who have snorted cocaine; and those who have been tattooed in unsanitary tattoo parlors.

Myths about the disease are still common. “You can’t get hepatitis C from hugging, eating, kissing, sitting on toilets,” Everson said. Sexual transmission of the disease is “exceedingly rare,” he said.

Symptoms are often subtle, and include chronic fatigue and nausea, which can be indicators of many other problems. Those who think they may have been exposed should see to a doctor about getting tested, Everson said.

But for many in Colorado - particularly the poor and uninsured - identifying hepatitis C is only half the problem.

Without health insurance, the combination drug therapy can cost more than $20,000 per year, Everson and drug companies estimate. Some uninsured patients may be eligible for patient-assistance programs.

The Hispanic community has been particularly hard-hit by the virus. In Colorado, though the majority of those infected are white, 30 percent are Hispanic, though Hispanics make up only about 17 percent of the state’s total population, according to a study by the Colorado Department of Public Health and Environment.

“Over a third of our community doesn’t have health insurance,” said Rosario C. de Baca, a health worker at Denver’s Latin American Research and Service Agency. Because of the cost, “when people have hepatitis C, they sometimes don’t have a choice but to live with it,” Baca said.

“There are thousands of people who can’t afford the treatment,” said Ann Jesse, founding director of Denver-based Hep C Connection, which runs 13 support groups in Colorado and mails newsletters to 7,000 people nationwide.

Jesse visited Congress in May for the introduction of the Hepatitis C Epidemic Control and Prevention Act. If passed, the legislation could help more people get the care they need, Jesse said.

Hill, who received the treatment for free by participating in one of the early trials, thinks more needs to be done to make information and the treatment available to everyone.

“We should encourage our elected officials to get more money for research and education,” she said.

Par expects a final decision on the approvability of generic versions of ribavirin by Aug. 1.

FDA is resolving issues regarding the labeling of generics and the potential for shared exclusivity among the three pending ANDA applicants: Geneva, Teva and Three Rivers. Par will market the Three Rivers product.

“I would hope that by the time we get to late next week at the latest we will have an answer between labeling and the shared exclusivity issue,” Par CEO Scott Tarriff told a July 24 investor conference call.

The Los Angeles federal court ruled July 14 that the generics do not infringe ICN’s patents on Rebetol (ribavirin) (“The Pink Sheet” July21, 2003, p. 12).

Par’s Tarriff declared that the company is ready to launch upon approval, despite the likelihood of an appeal by ICN.

FDA recognizes generics are ready to launch and “they want to have that happen,” Tarriff maintained.

ICN argues that generics should not be approved without language included in the Rebetol label referencing use in conjunction with Schering-Plough’s PEG-Intron; the labeling is still protected by exclusivity.

However, according to the L.A. court, FDA told Three Rivers that it can carve out the pegylated interferon labeling and reference only combination use with the older Intron formulation.

ICN and Hogan & Hartson have submitted citizen petitions to FDA raising concerns about potential generic approvals.

The determination of 180-day exclusivity could also be complicated. Three Rivers expects to receive shared exclusivity, but Tarriff acknowledged the possibility that it would not.

“The possible scenarios could be Geneva by themselves, it could be us having shared exclusivity with Geneva, or it could be all three of us going to market,” Tarriff said.

In any event, it is a “great victory for us,” Tarriff declared. “We won on non-infringement. That means...we are going to market ribavirin. We’re either going to start marketing it now or we’re going to market it in six months, and I think either scenario is wonderful.”

“Obviously, marketing it now is more wonderful,” Tarriff added.

Because the ruling was non-infringement and not invalidity of the patents, Tarriff noted, any additional generic competitors will be relatively slow in coming to market.

“I would think at the end of the exclusivity, the three parties -whichever way it shakes out - will wind up being on the market by themselves for another 12 months after that, give or take.”

Roche, which markets the ribavirin brand Copegus under a separate license with ICN, predicted that generics will come to market soon.

“We know that over the month to come, generic ribavirin will appear,” Pharmaceutical Division President William Burns told a July 23 conference call. “That is now pretty clear from ICN having lost the court case.”

However, Burns noted at an analysts conference later that day, there is another regulatory wrinkle for ribavirin ANDAs.
“There is still an open question whether Copegus can be substituted by a generic,” Burns said. Since Copegus and Rebetol were approved under separate NDAs, “why should generics that come in for Rebetol be substitutable for Copegus?”

“Its an open question,” Burns said. “It may be a nicety, but we have to see how this plays out.”

Burns maintained that the generic impact would be less significant for Roche in any event. He estimated that more than two-thirds of Roche hepatitis C sales are from the interferon ingredient Pegasys, rather than ribavirin.

“The other guy took a lot of their profit and sales through ribavirin,” Burns said.

July 29th, 2003

New Clotting Factor for Hemophiliacs
HealthDayNews

The U.S. Food and Drug Administration has approved a new clotting factor to treat people with hemophilia A. It’s the first such treatment produced without using additives derived from human or animal blood, the agency says, eliminating the risk of viral and bacterial contamination with germs including hepatitis, HIV, and West Nile virus.

People with hemophilia are unable form blood clots, and risk life-threatening bleeding episodes. Advate (Antihemophilic Factor (Recombinant), Plasma/Albumin-Free Method) is approved to prevent and control bleeding or to prepare hemophilia patients for surgery.

Existing clotting factors derived from human or animal plasma are processed to kill any germs before they are administered to hemophiliacs. None of these products has transmitted HIV or hepatitis since 1987, the FDA says.

Advate, rAHF-PFM is manufactured by Baxter Healthcare Corp.

Three Chicago hospitals were accused of fraud by prosecutors on Monday for manipulating diagnoses of transplant patients to get them new livers.

Two of the institutions paid fines to settle the charges.

The University of Chicago Hospitals and Northwestern Memorial Hospital paid fines of $115,000 and $23,587, respectively, without admitting or denying guilt in the “whistle-blower” suits initiated by a transplant specialist.

The University of Illinois Hospital was sued for $3 million.

“By falsely diagnosing patients and placing them in intensive care to make them appear more sick than they were, these three highly regarded medical centers made patients eligible for liver transplants ahead of others who were waiting for organs in the transplant region,” said Patrick Fitzgerald, the U.S. attorney for the Northern District of Illinois.

“Organ donation can be a matter of life and death. There is no room for fraud when it comes to deciding which patient receives an organ,” Illinois Attorney General Lisa Madigan said in the joint statement.

Some patients were hospitalized in intensive care or given a more urgent transplant status to make them eligible for precious livers from organ donors.

The suit against the University of Illinois hospital said the improper diagnoses were used to meet the minimum number of liver transplants to qualify for government health insurance programs.

Donated livers are in short supply, with nearly 20,000 Americans awaiting new ones and roughly 5,000 transplants performed each year. The United Network for Organ Sharing draws up regional lists based on patient need and other factors.

The cases grew out of a 1999 lawsuit filed by transplant specialist Dr. Raymond Pollack, who will share in the fine proceeds.

Maxim Announces Completion of Enrollment of Phase 2 Hepatitis C Clinical Trial

Maxim Pharmaceuticals announced that it has completed enrollment of a Phase 2 trial of its drug candidate Ceplene™ (histamine dihydrochloride) for the treatment of hepatitis C nonresponder patients. The M0406 Phase 2 trial includes 302 hepatitis C patients who failed to respond to prior therapy with the combination of interferon-alpha and ribavirin. The randomized, controlled Phase 2 trial is designed to compare the treatment of nonresponder hepatitis C patients with a triple-drug combination of Ceplene, Peg-Intron® (peginterferon alfa-2b) and Rebetol® (ribavirin, USP) versus treatment with the Peg-Intron and Rebetol combination.

“Enrollment of this trial was one of our key corporate objectives for 2003, and we are pleased to have reached this milestone,” said Larry G. Stambaugh, Maxim’s Chairman and Chief Executive Officer. “Current treatments are ineffective for approximately half of the patients with hepatitis C, and in particular there are a lack of effective treatment options for patients that have failed prior treatment. The M0406 trial is one of the programs that we have underway to advance the potential use of histamine therapy in chronic liver disease, including the development of an oral form of histamine.”

In the M0406 trial, patients will be treated for up to 48 weeks and followed for an additional 24 weeks after completion of treatment. The primary measures of efficacy in the study are sustained complete viral response and sustained biochemical response (normalization of the liver enzyme ALT, a standard measure of liver function) at 72 weeks. The trial is being conducted in North America, Western Europe and Israel.

Overview of Ceplene and Histamine Therapy
Research has shown that oxygen free radicals released by certain immune cells can suppress the immune system and damage normal tissue, a process commonly referred to as oxidative stress. Oxidative stress, implicated in numerous diseases, is most pronounced in the liver and can damage or destroy liver tissue in patients with hepatitis and other chronic liver diseases.

The naturally occurring molecule histamine has been shown in preclinical work to prevent the production and release of oxygen free radicals, thereby reducing oxidative stress. Accordingly, treatment with histamine has the potential to prevent or reverse damage induced by oxidative stress and