Hepatitis C virus (HCV) infection is a global health problem. An estimated 170-200 million people worldwide are infected with this virus. Chronic HCV infection is the leading cause of liver disease-related morbidity and mortality in the Western world. In the United States alone, there are estimated to be nearly 4 million existing cases, of which at least 20% are expected to eventually develop cirrhosis of the liver. Of these cases, about 25% will die from hepatic failure or require orthotopic liver transplantation (OLT). The progression of HCV infection to clinically significant liver disease is slow, usually taking at least a decade to develop cirrhosis and/or hepatocellular carcinoma.
HCV infection is the leading cause of chronic liver disease and the most common indication for OLT. However, HCV viremia persists in more than 95% of patients, and recurrence of HCV infection can be demonstrated as early as 4 weeks after OLT. Recurrent HCV infection is a significant cause of allograft dysfunction and progression to end-stage liver disease and allograft failure after OLT. Unlike the slow course of HCV infection seen in the nontransplanted population, liver graft damage from recurrent HCV occurs at an accelerated rate, leading to cirrhosis within 5 years. This session provided a review of the immunobiology of HCV infection and the efficacy of various treatment modalities pre- and post-OLT.
Geoffrey McCaughan, MD, of the University of Sydney, Australia, began the session with a review of the immunobiology of HCV infection. The HCV is an RNA virus with a lipid envelope that contains specific hypervariable regions within the envelope proteins that are responsible for the formation of new (mutant) strains of the virus. Studies have demonstrated that while up to 85% of those people infected with HCV go on to develop a chronic disease, those patients who clear the HCV from their blood demonstrate anti-HCV T cells in the peripheral blood, which may be representative of immunity to the virus. It is estimated that approximately 10 virions per day are produced in an individual actively infected with HCV. However, no difference in viral concentration (load) is seen in patients with more severe forms of disease, indicating that accumulation of virus does not lead to accelerated disease.
In some patients infected with HCV, the presence of cytotoxic T cells in biopsy specimens has been shown to correlate with a worse histologic picture. In these patients, only 1% to 2% of all CD8 cytotoxic T cells was directed against the HCV. In addition, a number of cytokines have been shown to be elevated in patients with HCV infection. Elevated interferon (IFN) gamma levels have been shown to correlate with the degree of fibrosis in liver biopsies. In addition, elevations in interleukin (IL)-18 and IL-10 have corresponded with progression to the chronic form of HCV infection, chronic active HCV.
There is a large increase in the HCV viral load following OLT in patients transplanted for HCV infection. This increase correlates with the pretransplant HCV viral load; the greater the viral load pretransplant, the greater the increase in viral load posttransplant. Recurrence of HCV infection following OLT is universal, presumably due to unchecked viremia at the time of transplantation followed by immunosuppression. There are 2 types of recurrent HCV infection: fibrosing cholestatic HCV infection and chronic recurrent HCV infection.
Fibrosing cholestatic HCV infection is rarely seen following OLT. However, when it occurs, progression is rapid and retransplantation is invariably required. Fibrosing cholestatic HCV infection is characterized by:
increased levels of virus in the blood compared with chronic recurrent HCV infection
no change in quasispecies (mutant types) compared with chronic recurrent HCV infection. (Chronic recurrent HCV infection following liver transplantation is characterized by the emergence of quasispecies that may be resistant to standard treatment. In fibrosing cholestatic hepatitis, however, the virus is usually of the same species that caused the original disease.)
severe hepatitis with a reduced CD4 response
elevation in IL-10 and reductions in IFN-alpha and IL-2
minimal immune response to the virus compared with chronic recurrent HCV infection
In contrast to fibrosing cholestatic hepatitis, in which there is a rapid recurrence and progression of disease, chronic recurrent HCV infection is characterized by a more insidious onset and clinical presentation, leading to allograft dysfunction and loss over a period of 5-10 years.
Despite improvements in transplantation technology, approximately 10% of patients transplanted for HCV die or undergo retransplantation within 5 years as a result of recurrent HCV infection. The pretransplant viral load appears to be a significant factor in predicting recurrence. Indeed, in patients with a pretransplant viral load of greater than 1 x 10, the 5-year survival is approximately 60% compared with 90% in patients with a pretransplant viral load of less than 200,000. (Figure 1) In addition, the degree of fibrosis appears to be proportional to the viral load at the time of biopsy. Michael Charlton, MD, of the Mayo Clinic & Foundation, Rochester, Minnesota, discussed treatment strategies for HCV infection prior to OLT.
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Patient Survival by Pre-OLT HCV RNA Level
Until recently, IFN monotherapy was the definitive treatment for HCV infection. Four forms of IFN have been approved for the treatment of HCV infection: consensus IFN, a synthetic, non-naturally occurring IFN; and the naturally occurring recombinant IFNs, IFN-alfa-2a (Roferon), IFN-alfa-2b (Intron A), and IFN-alfa-n3 (Alferon-N). Based on clinical trial data, guidelines for the management of chronic HCV infection were developed from a National Institutes of Health Consensus Development Conference in 1997. The recommended treatment of chronic HCV infection was antiviral therapy with recombinant alfa-IFN. However, HCV is inherently resistant to recombinant alfa-IFNs and sustained, long-term, viral-negative responses are uncommon (ie, in the range of 10% to 20%). The HCV circulates in infected individuals as a mixture of related but genetically distinct quasispecies, which have been implicated in responsiveness to IFN. Thus, it appears that containment of HCV quasispecies mutation and aggressive (eg, daily), long-lasting (eg, pegylated IFN) or combination therapies (ribavarin [Rebetrol] plus IFN) are required for effective treatment of HCV infection.
Attempts at treating HCV-associated cirrhosis prior to OLT with IFN monotherapy have been disappointing. Initial response rates of approximately 20% have been shown, but have been sustained in only 8% of cirrhotic Childs classification A patients vs 20% in noncirrhotics. (Figure 2) Not surprisingly, most studies have demonstrated considerably better results in noncirrhotics compared with cirrhotic patients. Idilman and colleagues demonstrated a 50% reduction in serum aspartate aminotransferase levels in noncirrhotics vs a 25% response in cirrhotics. Similarly, a 25% reduction in viral load was seen in noncirrhotics vs a 5% reduction in cirrhotics.
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IFN monotherapy for HCV cirrhosis
Combination therapy with ribavarin/IFN alfa-2b recombinant significantly improves the sustained biochemical, virologic, and histologic response rates compared with IFN monotherapy. McHutchinson and colleagues treated patients with combination therapy for 48 weeks. The response rate was 38% in both cirrhotic and noncirrhotic patients, compared with a 12% response rate with IFN monotherapy. (Figure 3) Additional evidence for the efficacy of combination therapy continues to accumulate. Combination therapy has been associated with a high rate of sustained response and has been shown to be superior to IFN monotherapy in nonresponders (those who failed to respond to IFN-alfa monotherapy) and relapsers (those who relapsed after IFN-alfa monotherapy). Furthermore, ribavarin/IFN-alfa-2b therapy has been associated with long-term elimination of HCV RNA from the serum and liver as well as evidence of histologic improvement in sustained responders to combination therapy.
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IFN monotherapy for HCV cirrhosis
The following predictors of response to therapy have also been identified:
age, duration of disease, baseline gamma glutamyl transpeptidase and ferritin levels
genotype, baseline viral (HCV RNA) concentration or load, no or little portal fibrosis, female gender, age less than 40
genotype, baseline viral (HCV RNA) concentration or load
African-American race
These predictive factors, particularly viral genotyping,
can be used clinically to more accurately determine the appropriate duration of treatment and timing of monitoring HCV RNA concentrations to measure response to therapy.
Although IFN combination therapy has improved the treatment options and outcomes for patients with HCV infection, success remains limited. Further advances in IFN technology are currently under development. Proteins can be modified with polyethylene glycol (PEG), a process called PEGylation, to increase their plasma half-lives, stability, and therapeutic potency. Two PEGylated interferons have been developed: PEG IFN-alfa-2a (Pegasys) and PEG-Intron. Neither of these agents is currently approved for clinical use.
A commercial form of HCV immunoglobulin may be available in the near future. Interest in an anti-HCV immunoglobulin grew after it was shown that only 54% of patients transplanted for both hepatitis B virus (HBV) and HCV infection had HCV recurrence following OLT when treated with hepatitis B immunoglobulin (HBIg), compared with 94% who experienced recurrence without HBIg treatment. The commercial form of hepatitis C immunoglobulin (HCIg, Civacir) uses a 5% virus-inactivated IgG, negative for HCV RNA, and requires 479 donors to produce 1 dose. Data from clinical studies are not available at present. However, studies in monkeys have demonstrated a greater than 1-log reduction in HCV RNA in 2 of 3 monkeys treated with 100 mg/kg of HCIg twice weekly.
A potential prophylactic treatment for HCV infection is rapamycin, which may prove to inhibit fibrosis in the liver following infection with HCV. The mechanism of action is thought to be secondary to the unique ability of rapamycin to inhibit the production of TGF-beta, procollagen, and transglutaminase. Animal studies with rapamycin have demonstrated a significant reduction in hepatic fibrosis in 14 of 22 treated rats and normalization of alanine transaminase levels in 19 of the 22.
With over 15,000 patients awaiting OLT in the United States, the impact of recurrent disease may become an important factor in deciding who should receive an OLT in the face of a limited organ supply. Edward Gane, MD, of Auckland, New Zealand, discussed factors predictive of long-term graft and patient survival and other outcomes of OLT in patients with chronic HCV infection. Currently, the most common indication for OLT in the United States is cirrhosis due to chronic HCV infection (approximately 60% to 80% of those awaiting OLT). Recent data demonstrated that 10% to 15% of those patients transplanted for HCV infection will develop recurrent disease to the extent that they will either die or require retransplantation within 5 years. Given that HCV infection is the most common indication for OLT, these data could lead to policy changes regarding transplantation and retransplantation for HCV infection. While it is known that HCV infection recurs to some extent in all patients, the degree to which it recurs is highly variable. Known predictors of outcome following OLT are highly desirable in order to allow treatment to be targeted pre- and posttransplantation in this group of patients. Predictors of outcome following OLT for HCV infection include:
pre-OLT HCV RNA (measured by quantitative polymerase chain reaction [PCR]) greater than 1 x 10
elevated viral load early in the posttransplant period
genotype -- most 1b, some 1a
HCV plus hepatoma -- HCV infection plus hepatocellular carcinoma is associated with worse outcome due to early tumor recurrence when compared with patients transplanted for HCV alone
African American race -- for unknown reasons, patient and graft survival following OLT for HCV infection are inferior in the African-American population
immunosuppression -- the cumulative dose of corticosteroids and the use of anti-T cell agents as induction therapy or for steroid-resistant rejection have been shown to have a negative impact on HCV infection recurrence
year of transplant -- the incidence of recurrent HCV infection appears to be increasing over time; this may reflect better diagnostic methods or a true increase in the virulence of the virus
possible relation to cytomegalovirus (CMV) infection
chronic HCV infection, which is associated with an increase in quasispecies viruses
The ability to identify subsets of patients who are at highest risk for recurrent HCV infection will enable physicians treating these patients to predict outcomes following OLT, and thus allow for interventions at earlier stages. In particular, this information would provide opportunities for modulation of immunosuppression, identification of high-risk patients for pretransplant therapy, and identification of patients who would best benefit from retransplantation.
Made possible by an unrestricted educational grant from Roche.