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News Review

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HEPATITIS JOURNAL REVIEW:
A Bi-Monthly Publication of the Hepatitis Support Project

March 29, 2006
Volume 3, Issue 5


Liz Highleyman

To download pdf version click here


In This Issue: Hepatitis C


Potential New HCV Vaccine Strategies

Genotype 1 HCV Lab Cell Culture Developed

Thalidomide for HCV-Related Liver Inflammation

Most Young IDUs Have Contraindications to HCV Treatment


Potential New HCV Vaccine StrategiesDeveloping an effective vaccine remains one of the biggest challenges in the field of hepatitis C research; two recent studies offer potential novel approaches. In the February 2006 Journal of Virology, Stefania Capone and colleagues reported on a new adenovirus type 6-based HCV vaccine vector that induced “potent and broad” cellular immune responses in macaque monkeys. Recombinant vaccines utilizing adenovirus type 5 have shown activity in past studies, but its usefulness is limited because many individuals have preexisting immunity to this virus. The new vaccine, known as MRKAd6-Nsmut, stimulated immune responses against HCV nonstructural proteins in both mice and macaques. In related news, Antonella Folgori and colleagues from Rome described in the February 5, 2006 issue of Nature Medicine a genetically engineered vaccine that protected chimpanzees from HCV infection. The vaccinated animals experienced increased CD8 T-cell activity against various strains of HCV, leading to suppression of acute viremia. The authors concluded that “it is possible to elicit effective immunity against heterologous HCV strains by stimulating only the cellular arm of the immune system” - an approach that may also hold promise for other pathogens such as HIV and malaria that can evade humoral (antibody-based) immune responses.

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Genotype 1 HCV Lab Cell Culture Developed
The study of HCV natural history and treatment has been hampered by the fact that the virus is difficult to grow in the laboratory. Researchers have developed various “replicon” models and cell cultures of genotype 2a HCV, but growing genotype 1 in vitro has proven more challenging. In the February 2006 Journal of Virology, Heather Nelson and Hengli Tang from Florida State University shed light on why this has been so difficult. The authors found that HCV quickly stops replicating in dense cell cultures because it runs out of nucleotides, the building blocks of genetic material (in contrast, the nucleotide supply remains adequate in patients’ livers). They suggested this discovery might lead to better treatments using “nucleotide starvation” therapies to inhibit viral replication - as is done with HIV - although this approach also adversely affects the replication of healthy cells. Nelson and Tang further found they could prolong in vitro HCV replication by adding to cell cultures the nucleosides uridine and cytidine, which are converted into nucleotides. They added that their modified GS4 reporter cell line - in which the cells emit green fluorescent light when the virus is replicating - enables the rapid identification of drug-resistant mutant HCV strains and the screening of potential antiviral agents.

In related news, MinKyung Yi and colleagues from the University of Texas reported in the February 14, 2006 issue of Proceedings of the National Academy of Sciences that they were able to cultivate in the laboratory for the first time infectious genotype 1 HCV, which is the most common type in the United States and responds poorly to interferon-based therapy. The researchers identified five mutations that enhanced the virus’ ability to replicate within cultured human liver cells. The mutated genotype 1a “Hutchinson strain” (H77-S) is sufficiently infectious to allow identification of the receptor molecules HCV uses to enter host cells and testing of experimental antiviral drug candidates. “The ability of this genotype 1a virus to infect cultured cells will substantially benefit antiviral and vaccine discovery programs,” the authors concluded.

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Thalidomide for HCV-Related Liver Inflammation
Thalidomide is infamous for causing birth defects in children whose mothers took the drug during pregnancy in the late 1950s and early 1960s. But it also has immune-modulating properties and has been studied as a treatment for leprosy, HIV, cancer, and hepatitis C. As reported in the February 2006 American Journal of Gastroenterology, Laura Milazzo and colleagues from Milan studied the safety and efficacy of a 24-week course of 200 mg daily thalidomide in eight chronic hepatitis C patients who did not respond or relapsed after treatment with interferon-alpha plus ribavirin. The researchers observed a mean 39 percent decrease in ALT (6 of 8 patients experienced reduced ALT levels) and a mean 61 percent decrease in GGT. They found that thalidomide exhibited anti-inflammatory activity, inhibited production of tumor necrosis factor-alpha, and stimulated production of certain Th1 immune system cytokines (chemical messengers) - including natural interferon-gamma - with minimal side effects. Although the four patients who received post-treatment liver biopsies did not show reduced fibrosis, the authors suggested that thalidomide’s anti-inflammatory effect may slow immune-mediated liver damage (previous studies showed the drug accelerated recovery from cirrhosis in rats). They concluded that thalidomide represents “a promising new approach for the treatment of HCV infection,” and recommended that it be studied in combination with interferon-alpha and ribavirin.

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Most Young IDUs Have Contraindications to HCV Treatment
Shared use of injection drug equipment is the most common route of hepatitis C transmission, and among some groups of injection drug users (IDUs), the HCV infection rate exceeds 90 percent. However, IDUs have traditionally been considered poor candidates for therapy, and thus have often been excluded from clinical trials and denied treatment. In the March 1, 2006 issue of Clinical Infectious Diseases, Holly Hagan and colleagues examined the extent of this exclusion. In a study of 404 young (aged 18-35) HCV positive IDUs in Baltimore, New York, and Seattle, almost all - 96 percent - had factors that are commonly deemed contraindications for HCV treatment, including recent drug injection, alcohol use, or moderate-to-severe depression. “Restrictive eligibility criteria may deny treatment to a large proportion of patients who could benefit from it,” the authors concluded. In an accompanying editorial, Brian Edlin and Michael Carden discussed the importance of offering hepatitis C treatment to all patients who could benefit. It is especially important not to exclude younger patients, who typically have not yet developed severe liver damage and tend to respond best to interferon-based therapy. Further, prompt treatment could produce a public health benefit by reducing the presence of HCV in the population.

According to Hagan, “Even [IDUs] who are actively using drugs show low rates of reinfection and similar treatment completion rates.” Indeed, several past studies have shown that IDUs can adhere to and benefit from anti-HCV therapy, even if they have psychiatric conditions or continue to use drugs or alcohol. For example, in the February 2006 European Journal of Gastroenterology and Hepatology, Geert Robaeys and colleagues reported on a retrospective cohort study of 406 previously untreated chronic hepatitis patients in Belgium and the Netherlands, 24 percent of whom were IDUs. The researchers found that rates of treatment non-compliance did not differ significantly between IDUs and non-IDUs (8.2% vs 6.8%, respectively). There was only a marginally significant difference in sustained virological response (SVR) rates, favoring the IDUs over the non-IDUs (46.6% vs 34.6%, respectively), though this disappeared after adjusting for HCV genotype. Further, no significant differences in adherence or SVR were seen when comparing active and recovering IDUs, or those who were and were not participating in methadone maintenance programs. The authors concluded, based on their data, that “it is no longer justifiable to withhold treatment [from] chronic hepatitis C patients who use intravenous drugs.” Indeed, as Edlin and Carden note, treatment of IDUs “is the battleground on which efforts to control HCV infection in the developed world will be won or lost.”

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