Transplantation in the Patient with Hepatitis C

Liver disease is one of the leading causes of death in long-term survivors after renal transplantation (1, 2). Hepatitis C virus infection is currently the main cause of chronic liver disease in this group (1, 2). Hepatitis C Virus Infection Hepatitis C Virus Hepatitis C virus (HCV) is a member of the Flaviviridae family, which also includes the classical Flavivirus (yellow fever and dengue virus) and Pestivirus (3). HCV is a small, single-stranded RNA virus, 30 to 36 nm in diameter, with a lipoid envelope. The genome consists of one large open-reading frame of 9379 to 9481 nucleotides. At the 5′ end, there is a terminal region of 329 to 341 nucleotides with 92% homology among different HCV types. This region probably has a function in the translation of the viral genome. Its highly conserved character renders it suitable for diagnostic purposes, i.e., detection of viral nucleic acid with PCR. It has also become a target for the development of nucleic acid-based antiviral agents, such as antisense oligonucleotides and ribozymes (4). Hypervariable domains have been described at the amino terminus of the E2 envelope region. Sequential mutations in this region probably have a role in viral escape from the host immune response (4). There are at least six main genotypes, corresponding to the main branches in the phylogenetic tree, and several subtypes. The types have been numbered 1 to 6 and the subtypes a, b, and c (5). Distinction of HCV genotypes is important, because outcome of HCV disease and response to antiviral therapy with interferon correlates with the HCV type. Genotype I, particularly Ib, has been associated with more severe chronic liver disease and a poor response to interferon therapy. Epidemiology HCV infection is relatively common. Approximately 3% of the world's population is chronically infected with HCV, but there are marked geographical differences (6). HCV infection occurs among people of all ages, but the prevalence is highest among men 20 to 39 yr old (6). HCV accounts for approximately 20% of cases of acute and 70% of chronic hepatitis. Chronic hepatitis C is a major cause of cirrhosis and hepatocellular carcinoma. HCV infection persists in about 80% of cases (7). Moreover, HCV-related end-stage liver disease is the most frequent indication for liver transplantation. The main route of transmission of HCV is parenteral: either intravenous drug abuse or blood products that in the past had not been screened for anti-HCV (7). Other modes of transmission include organ transplantation, tattoos, and needle-stick accidents among healthcare workers (7). Sexual transmission is exceptional in heterosexual relationships, but in homosexuals the risk is high. Finally, there are several reports of nosocomial transmission of HCV, particularly in endoscopy and cardiac surgery units (7). Hemodialysis patients have also been identified as a high-risk group for HCV infection (8). Diagnostic Tests Three categories of assays may be used in the diagnosis of HCV infection: (1) serologic tests, detecting antibodies specifically directed against HCV antigens; (2) assays detecting and quantifying HCV antigens; and (3) assays detecting or quantifying HCV genomes and analyzing their sequence (9). Only serologic- and molecular biology-based assays are used routinely for screening and diagnosis. Serologic assays include screening tests based on enzyme immunoassays (EIA), supplemental immunoblots, and serologic assays detecting genotype-specific antibodies (9). Molecular assays include qualitative tests detecting HCV-RNA, quantitative assays measuring the HCV viral load as an index of HCV replication, and tests analyzing the nucleotide sequence of the HCV genome (9). The diagnosis of HCV infection is made by detecting either anti-HCV or HCV-RNA. Anti-HCV is recommended for routine testing in patients with suspected HCV infection, and PCR for confirmation of the presence of active infection. Transaminases are not specific, but may raise suspicion of HCV infection. Nevertheless, 25% of individuals infected with HCV have normal alanine aminotransferase (ALT) (7, 9). Natural History Infection with HCV causes not only acute and chronic liver disease, but also extrahepatic manifestations, mainly related to chronic stimulation of the immune system and to virus-induced autoimmunity (10). The spectrum of liver disease is broad, and progression rates are extremely variable. The acute clinical phase of HCV infection has been documented mainly in transfusion-associated cases in which the mean incubation period is 6 to 8 wk (range, 2 to 26 wk). In a minority of cases, acute hepatitis C is symptomatic. As a rule, the clinical course is mild, but approximately 75% of patients develop chronic infection (10). The major problem is chronic persistent or active hepatitis. Pooled data from follow-up studies on patients with non-A, non-B hepatitis who were subsequently diagnosed as having HCV infection showed that 20 to 30% developed cirrhosis (10). Prospective studies indicate that 60 to 90% with ALT abnormalities do progress, while a carrier state develops in 10 to 40% of patients with normal ALT. HCV infection is also associated with hepatocellular carcinoma, but the incidence is probably low, although precise figures are not available. The risk of progression toward cirrhosis is increased in the presence of other risk factors, i.e., coinfection with hepatitis B virus, HIV, or hepatotoxic agents such as alcohol. Extrahepatic Manifestations Chronic HCV infection is associated with the presence of specific cytotoxic T lymphocyte responses and neutralizing anti-envelope antibodies (11). The presence of an active immune response with high levels of anti-HCV antibodies and viral antigens predisposes to extrahepatic manifestations (11). The disease most frequently associated with HCV infection is mixed cryoglobulinemia. HCV infection is the most common cause of mixed cryoglobulinemia (12). The serum cryoglobulins represent HCV/anti-HCV immune complexes associated with rheumatoid factor and complement (12). Although detectable cryoglobulins are common in chronic hepatitis C, it is usually asymptomatic. The clinical syndrome of mixed cryoglobulinemia includes arthralgia, Raynaud's disease, and purpura. Glomerulonephritis (GN) and neuropathy are rare, but may be severe and fatal. Different types of GN have been described in association with HCV infection, particularly membranoproliferative GN, with or without cryoglobulins (13). HCV infection may play a role in some patients with low-grade non-Hodgkin's lymphoma (12). Other associated conditions include porphyria cutanea tarda, Sjögren's syndrome, autoimmune-thyroid disease, lichen ruber planus, panarteritis nodosa, and arthralgia; however, whether the association is causal remains unclear (12). Treatment Until recently, interferon-α was the only therapy available for the treatment of patients with chronic hepatitis C. After 48 wk of treatment, an initial response is seen in about half the patients, but a sustained biochemical and virologic response with histologic improvement occurs in only 15 to 20% of treated patients (14). The introduction of ribavirin, a synthetic guanosine nucleoside analogue with in vitro antiviral activity against a range of RNA and DNA viruses, has changed HCV therapy. Several studies have demonstrated that the efficacy of combined interferon and ribavirin therapy doubles the response rate (15, 16). We predict that combination therapy will become the standard initial therapy for HCV patients, including naïve, non-responders, and relapsing patients. HCV in Dialysis Patients Prevalence HCV infection is relatively common in dialysis patients (17). The prevalence in dialysis patients depends on the geographical area, but it is always higher than in the general population. In Mediterranean countries (Spain, Italy, Greece, and France), it is usually higher than 20% in dialysis patients (2). In Northern countries (England, Scandinavia, and Holland), the prevalence is much lower, usually less than 5% (2). In the United States, the prevalence is between 10 and 20% (2). Epidemiologic Factors Factors that may influence the risk of HCV infection in dialysis patients include the following: (1) the number of blood units transfused; (2) the length of dialysis therapy; and (3) the type of renal replacement therapy (2). Blood transfusions have been the main source of HCV infection for many years, but after the introduction of a screening test for blood donors (enzyme-linked immunosorbent assay [ELISA]-HCV), the risk of posttransfusion HCV is less than one case per 100,000 blood units. Duration of renal replacement therapy is clearly related to the risk of developing HCV infection: The prevalence is >80% in patients with more than 20 yr on dialysis (17). Today, the most important factor is the type of replacement therapy. Patients on hemodialysis have a prevalence of HCV infection that is 2 or 3 times greater than in patients on peritoneal dialysis or home hemodialysis (2). Nosocomial transmission of HCV in the dialysis units is probably the main route of HCV infection (18). It is clearly related to the prevalence of HCV infection in the respective dialysis units and reaches 3 to 5% per year in units with a prevalence of >20% (19). Dedicated machines and an adequate nursing staff are mandatory in units with a high prevalence. In Western European countries, the complete isolation of HCV-positive patients in such units has helped to lower the rate of new cases (nosocomial infection) to virtually zero (20). In our opinion, such policies are advised in units with a prevalence of >10%. Diagnosis The diagnostic methods used to detect HCV infection in dialysis patients are similar to those used in the general population (21). Transminases are not specific, but may help raise suspicion. Liver enzymes are usually lower in dialysis patients; therefore, even an increase of ALT within the normal range of values raises suspicion of HCV infection (2, 21). The third-generation EIA test is suitable for screening, with a sensitivity and specificity similar to that in the general population, i.e., 95% (22). Recombinant immunoblot assay and more precise PCR (HCV-RNA) are confirmatory (21). There is some controversy concerning the prevalence of a negative EIA test in the presence of a positive PCR test (23). In studies with third-generation EIA, the percentage is <1%. The diagnosis is made based on a positive EIA test, and PCR confirms active HCV infection. Genotyping and viral load (quantitative PCR) are research procedures suitable for evaluating the efficacy of the Liver The long-term outcome of dialysis patients has but rates will mean more frequent cases of HCV liver In dialysis patients, different types of chronic including liver are but the main problem is HCV disease is a major problem after renal transplantation (1, 21). HCV replication, liver After renal transplantation, the viral load to 10 ALT and the percentage of HCV patients with normal ALT treatment of HCV infection in the dialysis period to negative is transplantation, because after renal transplantation interferon is because of the risk of acute of HCV Infection in Dialysis Patients on the for The of HCV infection in dialysis patients on the has not been and from HCV infection after renal transplantation are and of HCV infection be and for In the of HCV infection, liver tests, liver and virologic tests are Transaminases and are but are not suitable for the of the of and and an endoscopy are recommended Liver the standard for the of liver other test this In the the risk of in dialysis patients the of liver but this risk is with the which on We that liver is mandatory in the tests include the EIA test, immunoblot assay test, PCR viral and After the diagnosis with an EIA test, a positive PCR (HCV-RNA) is to the presence of active infection. PCR may be negative in patients with viral load or in the of HCV infection. one that has become PCR are recommended because of frequent in viral The of viral load and genotypes is to research purposes, although the is in the of interferon therapy. Several reports on interferon therapy in dialysis patients that the rate of response of interferon is higher than in the general population. The rate of development of a negative RNA test is approximately and in most cases the response is sustained The of liver disease after renal transplantation is in patients who had interferon treatment renal transplantation than in patients without treatment It is not the response to interferon is in dialysis patients, but (1) Duration and of HCV infection are probably lower in dialysis patients. (2) in dialysis patients that a higher the is There are only reports on the of ribavirin in dialysis patients. In severe on ribavirin at least has been for for renal transplantation on dialysis with HCV infection is in The indication for interferon treatment is based on liver Patients with chronic hepatitis interferon In patients with severe chronic a liver be on the Patients with normal liver are on the without having antiviral therapy. Patients with liver cirrhosis are for liver and transplantation. The of interferon is 3 units for 1 to 2 by 3 units 3 a to complete a of of therapy. the PCR remains positive after 3 of interferon is therapy in combination with interferon is only in relapsing patients and of hepatitis C virus (HCV) infection in dialysis patients on the for renal in the with Hepatitis C Liver and Diagnostic Tests HCV-positive the infection on dialysis but include transfusions and organ transplantation (2, The prevalence of anti-HCV antibodies by between 10 and (2, on of the of dialysis therapy peritoneal on number of blood presence of B and of intravenous drug abuse (2, 20 and of the patients have chronic liver disease, as serum for more than 6 of anti-HCV antibodies transplantation an increased risk of liver disease after transplantation (21). patients to have detectable This state persists in all patients. In patients with transplantation, viral increased to after transplantation, increased virus do not between patients with or without liver disease (21). assays of HCV antibodies in renal patients are more and specific than but are less than assays the course of infection and liver disease after renal transplantation to virus is of ALT was between patients infected with different genotypes In the Mediterranean area, the most frequent is which is related to severe of liver Nevertheless, the clinical course of chronic liver disease after transplantation in the Mediterranean to be similar to that in other of the in patients with hepatitis the initial course of liver disease after transplantation is In the however, patients with HCV infection frequently develop liver function tests and liver with patients (2, Nevertheless, in 20 to ALT levels normal detectable this not indicate that liver disease is The poor between ALT of HCV-RNA, and liver is a carrier as normal ALT positive HCV-RNA, and normal liver be in approximately of HCV-positive patients The risk of developing chronic liver disease after renal transplantation is mainly related to the and of liver disease, the the presence of B the after transplantation, and the type and of Patients who and are more to have liver disease (21). there is between ALT and of liver disease liver is for a for a and for therapy. the in liver to in patients with chronic of ALT documented severe liver disease, chronic active hepatitis or in to 20% of HCV-positive The prevalence was less were in all HCV-positive patients, of ALT levels and on liver in HCV-positive were in persistent chronic hepatitis in chronic active hepatitis in cirrhosis in and other in that chronic hepatitis is common and cirrhosis The is that liver were after transplantation. It probably to 20 to 30 yr for cirrhosis to develop progression of liver disease in a of patients In of our 15 patients with chronic liver disease who had liver disease Three patients had developed cirrhosis within to In patients with active chronic the index within 36 to patients had more therapy than patients with liver disease cases of hepatocellular have only been from but not from other of the This may be to differences in the of disease than 20 yr are for hepatocellular to of the risk of carcinoma, and be frequently in patients with cirrhosis Patients with hepatitis B and hepatitis C coinfection have more liver disease than patients with HCV infection only to hepatitis B are in HCV patients. Hepatitis hepatitis is a but of liver disease in hepatitis B patients it has also been described in or renal with hepatitis C infection It is by with only of aminotransferase levels and of liver function in and histologic of a with of liver function develops in an HCV-positive liver be Only a HCV-positive patients with have been after renal transplantation. We cases, of which had liver and after transplantation. with a liver and the is on dialysis a combined and liver all had but not had interferon therapy that interferon therapy and of to of liver combination interferon ribavirin with of and of the of has also been the diagnosis of has been by liver as as 10 yr after transplantation. The of is not a of HCV high of the role of is some patients had of liver Treatment The of treatment in HCV-positive patients after transplantation is to the development of cirrhosis and extrahepatic such as In patients, interferon and ribavirin is currently the a high rate of viral and improvement of liver In patients, studies with interferon-α showed poor efficacy virologic response was not and risk of renal that was some in of this treatment be recommended The only indication for interferon therapy after renal transplantation is hepatitis of antiviral in HCV-positive renal patients with ribavirin in patients is In one renal patients to for 6 The efficacy was only patients and only had of liver was the There is with the combination of interferon and on one may be in patients with normal renal function It the efficacy of interferon and ribavirin, and were with renal and there is therapy in renal patients, the is to HCV-positive patients on dialysis transplantation, as HCV infection may be associated with several type membranoproliferative GN with or without cryoglobulinemia less GN (13). may in patients without severe liver may or renal has also been after liver transplantation. and of cases of renal associated with hepatitis C infection after renal transplantation antibodies renal transplantation are a risk factor for the of with poor that HCV may cause with cryoglobulinemia has been in renal patients with anti-HCV antibodies who and positive cryoglobulins serum levels of immune and and antibodies with a In one in which all patients with HCV had the the of was higher in than in serum without cryoglobulinemia has also been described in HCV patients after renal transplantation In one the of patients who developed was higher in HCV-positive of than in of We 15 patients with in HCV-positive for the presence of and to chronic Patients with without or rheumatoid The clinical course was similar to The prevalence of was higher in HCV-positive of than in patients of HCV infection may also be associated with in the and with antibodies This was after transplantation and was fatal. This association may have important clinical The of and in HCV-positive of immune complexes that may in patients. between GN and has also been There is specific therapy for HCV-related GN after renal transplantation in patients and liver function tests but interferon acute or renal in It also and GN in HCV-positive renal on ribavirin in this indication is not available. liver were treated for an syndrome It may be in renal patients as and In it was that patients with non-B hepatitis had marked increase of extrahepatic (2). This has been in HCV-positive patients who had more frequent and of the and blood and are by in HCV-positive patients, of be to the and for is The incidence of acute in HCV-positive patients is a but not a higher of acute in HCV-positive patients with patients In our this rate is lower in HCV-positive 40% in patients; a higher of patients at high risk This may be by of T in HCV-positive patients, in association with T responses to The combination of a incidence of acute and a high prevalence of may be by the state in HCV infection. of HCV Infection on and after HCV infection after renal transplantation and remains on long-term and showed lower The differences may be by factors, differences in and and to HCV infection. In a by HCV-positive were with i.e., and rates were lower in HCV-positive patients and HCV, and were of in renal patients. of were to liver disease in HCV-positive patients. In patients with liver in those with cirrhosis was not different at but lower at 10 yr to patients with and in the at the HCV infection not but after follow-up was lower rates in and studies are probably by liver disease and The rate increased it was at 10 yr and 20% at 20 a high after renal transplantation with patients role for is by the that therapy with or antibodies was associated with more frequent of liver disease Although studies different are not figures incidence of acute and that be on liver The lower in HCV-positive patients may lower and the presence of GN in the Although long-term rates are lower in HCV-positive with transplantation remains the for HCV-positive patients with end-stage renal disease, even be lower on the because of the high on dialysis from The data of the clearly that HCV infection be by organ transplantation of infection was for from and of infected patients developed chronic liver After this several organ recommended all but this has because there are also studies to the The data of the the however, other studies showed that transmission of HCV by and liver disease were Other data that of donors are the rate of transmission was but the of liver disease was not different from that HCV-positive be for After yr of the prevalence of liver disease was higher among patients who had HCV-positive but was not In patients with a HCV-positive was lower with of from donors (21). The of data on the rate of transmission has not been but the virus load in the organ and the of the HCV be of the renal who from HCV-positive donors have a higher risk of liver disease, including hepatitis and also hepatitis. to the is that HCV-positive not be In in this is a of from HCV-positive donors will to the problem of organ As a some have that from HCV-positive donors be HCV-positive In the of from HCV-positive donors for HCV-positive The this The of our showed in the prevalence of liver disease or in the rates in who from donors to of from donors are in with studies and indicate that transplantation of from donors HCV-positive is relatively at least for a period of yr In our of but patients from donors and positive for after transplantation. HCV-positive be only The problem remains that with a new is in this although follow-up showed clinical donors and for HCV be to the risk of and this that dialysis patients on the be for and at with this of from HCV-positive donors showed differences in liver disease or in figures with HCV-positive having of i.e., ALT 80% and and the of policies concerning HCV-positive donors in the United HCV-positive are to organ be the transmission rate and the rate of HCV-positive are the figures be and that the is (21). In from HCV-positive donors are HCV-positive with this that liver disease and and are not different in patients with HCV-positive who from donors This is and of for transplantation. In in the past 10 yr and HCV-positive were in the United and This a percentage of to that be our were a about the risk of with different HCV genotypes be to the and to HCV genotypes in donors and to donors and be with transplantation of from HCV-positive donors HCV-positive HCV infection is a problem in the with end-stage renal Nosocomial transmission of HCV in the dialysis is a risk factor for HCV infection. Dedicated machines and a nursing staff are mandatory in units with a high prevalence of HCV infection. HCV-positive patients be for to infection. of patients on the includes to interferon treatment chronic hepatitis is After transplantation, liver disease is more frequent in HCV-positive patients than in patients. In the this to liver The patients have a higher risk of developing and and rates are lower than in is higher mainly as a of liver disease and Nevertheless, transplantation is the for the HCV-positive with end-stage renal of HCV-positive be to HCV-positive in is in the Finally, several after transplantation the of HCV infection. of and follow-up for detection of infection, and of liver disease are mandatory to HCV in renal patients a