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News Review

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

April 25, 2006
Volume 3, Issue 7


Liz Highleyman

To download pdf version click here


In This Issue: Hepatitis C

Clinical Outcomes Match Trials

Donor Mismatches Increase HCV Recurrence Risk

Immunosuppressive Therapy Affects Transplant Outcomes


Immune Response to HCV


Clinical Outcomes Match Trials
Because subject populations in clinical trials are often selected based on various restrictive exclusion criteria, it is not uncommon for trial outcomes to look considerably better than treatment under “real world” conditions. But, according to a study published in the February 2006 Canadian Journal of Gastroenterology, outcomes at specialty clinics treating chronic hepatitis C can be comparable to those seen in clinical trials. K. Kaita and colleagues conducted a retrospective analysis of the medical records of 331 patients who received antiviral treatment for hepatitis C at the Viral Hepatitis Investigative Unit in Winnipeg, Canada, between 1998 and 2003. In this population - 65% of whom had genotype 1 HCV - sustained virological response (SVR) rates were 22% for conventional interferon monotherapy, 44% for conventional interferon plus ribavirin, and 54% for pegylated interferon plus ribavirin. These rates were “similar to those described in industry-sponsored registration trials,” the authors concluded, “despite the high selection and support provided to patients enrolled in the latter studies.”

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Donor Mismatches Increase HCV Recurrence Risk
Recent studies have shed further light on liver transplantation in hepatitis C patients. In the March 2006 issue of Gastroenterology, Luca Saverio Belli and colleagues from Italy reported that donor-recipient mismatches can affect post-transplant HCV recurrence. Human tissues contain a wide variety of HLA antibodies, which the immune system uses to distinguish “self” from “non-self.” While transplants of kidneys and some other organs require a close HLA match to prevent rejection, liver transplants can be performed between mismatched donors and recipients. However, the Italian study - which looked at two separate cohorts of 120 and 190 transplant recipients - found that such mismatches were associated with poorer outcomes. Recipients who received livers from donors with fully mismatched DRB1 HLA alleles (genetic variants) were more likely to have HCV recurrence (59% vs 23%) and to experience liver disease progression beyond fibrosis stage 3 (71% vs 39%) after transplantation. “This information is clinically relevant as it may help to better allocate organs and to recognize patients at risk for progression so that specific interventions can be implemented,” the researchers concluded.

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Immunosuppressive Therapy Affects Transplant Outcomes
Three studies reported in the April 2006 Journal of Hepatology suggested that less intensive regimens of immunosuppressive drugs - which are given to prevent organ rejection - can improve post-transplant outcomes. Giuseppe Tisone and colleagues weaned 34 HCV positive transplant recipients off cyclosporine monotherapy an average of 64 months after transplantation; patients received follow-up annual biopsies for three years. About one-quarter of the patients (23%) were able to have their immunosuppressive drugs withdrawn completely and permanently; in contrast, 41% experienced organ rejection within eight months after stopping and 35% experienced rejection during drug tapering. (Rejection was controlled by restarting cyclosporine.) After a mean follow-up of about four years, patients who successfully stopped cyclosporine had stable or improved liver fibrosis, reduced necroinflammation, lower HCV viral load, and improved liver function compared with patients who required continued immune suppression. The researchers also found that patients who did not receive a corticosteroid as part of their initial immunosuppresive regimen were more likely to be able to successfully stop all immune-suppressing drugs. “Reconstitution of immune competence in the host improves the natural history of HCV recurrence in the graft,” they concluded. However, in an accompanying editorial, John Lake suggested that, “one has to question whether it is reasonable to routinely subject patients to these potential risks” of withdrawing immunosuppressive therapy, given that rejection increases the risk of death in HCV patients, and that less than 25% stand to benefit.

While weaning patients off immunosuppressive drugs may be beneficial, rapid tapering of corticosteroids may be detrimental, according to a study by Marina Berenguer and colleagues. The researchers compared recent transplant patients (2001-2004) with a group of historical controls who received transplants in 1999-2000. The more recent group received a two-drug immunosuppressive regimen containing a corticosteroid plus either cyclosporine or tacrolimus, and the steroid was tapered off slowly (over six months or longer). The earlier group was more likely to receive three- or four-drug regimens and took prednisone for longer periods. The recent group was significantly less likely to develop severe liver disease (bridging fibrosis, cirrhosis, or fibrosing cholestatic hepatitis) after transplantation compared with the earlier group (29% vs 48%). “Improving the outcome of recurrent hepatitis C may be achieved by reducing overall immunosuppression and avoiding abrupt variations in immunosuppression,” the authors concluded.

Finally, Laura Llado and colleagues randomly assigned 198 liver transplant recipients to receive immunosuppressive regimens containing cyclosporine plus basiliximab (Simulect), with or without the corticosteroid prednisone. Both the steroid and no-steroid arms had similar liver rejection rates (13% vs 18%; not a significant difference), as well as similar HCV recurrence rates (about 90%) after six months. However, patients in the prednisone arm were more likely to develop high blood pressure (44% vs 25%) and new onset diabetes (29% vs 18%), and the diabetic patients taking prednisone had more bacterial infections (54% vs 14%). Despite the greater rate of complications, six-month survival rates did not differ significantly in the steroid and no-steroid groups (89% vs 94%). The researchers concluded that “[i]mmunosuppression without steroids is safe and reduces infection and metabolic complications.”

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Immune Response to HCV
Much remains to be learned about how the immune system responds to HCV infection, and several recent studies have addressed this issue. In the March issue of Hepatology, C. Neumann-Haefelin and colleagues reported that a specific allele, HLA-B27, is associated with spontaneous HCV clearance. In this study, women with the HLA-B27 allele had specific types of CD8 T-cells that targeted HCV. As reported in the same issue, P.T. Kennedy and colleagues examined HCV-specific T-cell responses in HCV-exposed individuals who did or did not spontaneously clear the virus. They concluded that the “conspicuous deficit” of T-cells specifically targeting HCV in patients who developed chronic infection (i.e., did not spontaneously clear the virus) “confirms the profound collapse of virus-specific T-cell response caused by HCV persistence.” And in the March 2006 Journal of Hepatology, Carla Nisii and colleagues reported on a study looking at peripheral blood CD8 T-cells in 32 patients with chronic hepatitis C. They found that CD8 cells in the livers of chronically infected patients are less responsive than those from uninfected subjects. In addition, these “hypo-responsive” CD8 cells were associated with more severe fibrosis. The authors concluded that “[u]nderstanding the mechanisms underlying this impairment may be helpful in the design of innovative strategies for HCV treatment."

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