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Editorials and Perspectives: Overview

Treatment of Hepatitis C Virus Infection (HCV) After Renal Transplantation: Implications for HCV-Positive Dialysis Patients Awaiting a Kidney Transplant

Kamar, Nassim1; Ribes, David1; Izopet, Jacques2; Rostaing, Lionel1,3

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doi: 10.1097/01.tp.0000238898.14393.c9
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Abstract

The prevalence of hepatitis C virus (HCV) infection in renal-transplant (RT) patients varies from country to country, and, in a given country, from center to center because HCV prevalence in patients with transplants is almost the same as those on dialysis. However, it has been demonstrated that the survival of HCV-positive patients who undergo successful renal transplantation is significantly better than that of matched HCV-positive patients that remain on dialysis (1, 2), despite the fact that immunosuppressive therapies administrated after organ transplantation are responsible of a significant increase in HCV viremia. It probably reflects the loss of immune control due to immunosuppressive drugs and the establishment of a new equilibrium between virion production and clearance. A significant rise in HCV viremia in renal transplant patients a year after introduction of mycophenolate mofetil therapy was reported (3). Antithymocyte globulins were also incriminated in the elevation of HCV viremia (4). Regarding calcineurin inhibitors, it was recently shown in vitro that cyclosporin A, but not tacrolimus, specifically inhibits the replication of HCV in cultured hepatocytes at clinically relevant concentrations (5, 6). The effect of cyclosporin A against HCV seems to be specific, and independent of its immunosuppressive function (5, 6).

Recent data suggests that the increase viremia observed after kidney transplantation does not affect significantly liver fibrosis progression. Alric et al. found that the progression rate of liver fibrosis was lower in HCV(+) RT patients compared with that observed in HCV(+) immunocompetent patients (7). The study of our cohort suggests that not only HCV infection is not harmful to liver histology in more than 50% of renal-transplant patients with a functioning graft of more than 6 years, but that liver fibrosis might also regress (8). High diversification of the hypervariable region (HVR)-1 of HCV E2 glycoprotein between transplantation and a liver biopsy performed three years after transplantation were independent factors associated with liver-fibrosis regression (8). HVR-1 is involved in the interaction with CD81, a putative cellular receptor of HCV (9). The tetraspanin/CD81 is a widely expressed cell-surface protein. Recently, Bartosch et al. have demonstrated that HVR-1 is a critical determinant that mediates entry in scavenger receptor class B, type-1 (SR-B1) positive cells (10). SR-B1, another HCV receptor candidate, is required to infect CD81-expressing hepatic cells. However, the authors have suggested that additional hepatocyte-specific cofactors are necessary for HCV entry into hepatocytes (11). Thus, CD81, possibly in association with a liver-specific endocytotic protein(s), represents one of the pathways by which HCV can infect hepatocytes (12). The binding of HCV E2 to CD81 also leads to a stimulation of autoreactive T cells, which might contribute to liver damage (13).

In contrast, the survival of HCV-positive RT patients is significantly lower than that of HCV-negative RT patients (14). This might be related to an increased risk of cardiovascular disease (15), posttransplant diabetes mellitus (16), and sepsis (17). HCV-related de novo glomerulopathies are responsible for a decrease in renal allograft survival in HCV(+) patients compared to HCV(−) patients (14). Therefore, this has led us to address the relevance of treating HCV infection after renal transplantation.

Treatment of Hepatitis C Infection following Renal Transplantation

Recent reports indicate that a combined anti-HCV therapy of alpha interferon (α-IFN) plus ribavirin is safe and effective for use in HCV-positive liver-transplant patients (18). However, attempts to treat hepatitis C in patients with a renal transplant have not been promising, and α-IFN has been almost abandoned for these patients (19–21). Initial studies of antiviral therapy in renal-transplant patients prescribed α-IFN monotherapy at doses of 1.5 to 6 million units SC three times a week for 24 or 48 weeks. About half the patients had improved aminotransferase activity during therapy and up to 25% lost HCV RNA, but only a few patients had a sustained virological response to treatment. More worrisome was that acute cellular or humoral rejection appeared to be more frequent among α-IFN-treated patients, and in many series instances of renal failure and graft loss (despite aggressive immunosuppressive therapy) were common (22, 23). These reports led to the recommendation that patients with a renal transplant should not be given interferon alpha (24).

An exception to the prescription of α-IFN for renal-transplant patients is the occurrence of fibrosing cholestatic hepatitis, a rare but severe form of chronic hepatitis C that occurs most commonly in the setting of severe immunosuppression after solid-organ transplantation. This severe, progressive form of liver dysfunction was originally described in liver-transplant recipients with recurrent hepatitis B, but has also been reported with HCV infection after liver and renal transplantation (25). A dramatic report on the use of α-IFN in two renal-transplant patients with fibrosing cholestatic hepatitis suggested that this life-threatening form of HCV-related liver disease can be effectively treated with α-IFN and that the risk of severe rejection in this situation is counterbalanced by the risks caused by the untreated liver disease (26).

Ribavirin monotherapy in HCV-positive patients after renal transplantation showed improvements in serum aminotransferase and proteinuria (27). Its effect upon liver histology is controversial (27–30). The main side effect of ribavirin in renal-transplant patients is a dose-dependent hemolytic anemia, which requires recombinant erythropoietin therapy. Chronic hemolysis may result in iron overload, and hence accelerate liver fibrosis progression (31). Because a beneficial effect of ribavirin monotherapy upon renal function and proteinuria has been also reported in both HCV (+) immunocompetent (32) and liver-transplant patients (33) presenting with an HCV-related glomerulopathy, and despite the small number of patients enrolled in these studies, ribavirin monotherapy might be only given to HCV-positive RT patients that have overt proteinuria in the setting of HCV-related de novo glomerulopathy. The daily dosage of ribavirin for patients with impaired renal function should be adapted to creatinine clearance, and can be predicted by a formula (34, 35).

Several small studies have indicated that the oral antiviral agent amantadine can improve aminotransferase levels in patients with hepatitis C (36, 37). We used amantadine to treat renal-transplant patients and found that it was well-tolerated and had some effect on serum aminotransferase, but not on HCV RNA levels or liver histology (38).

Because immunosuppression regimes are improving and becoming more powerful, a group have recently reported on the use of α-IFN plus ribavirin to treat four HCV positive renal-transplant patients (39). These four patients developed (sub)acute HCV infections in the first months following renal transplantation. The disease was so severe that they treated their patients with α-IFN (3 million IU three times a week) plus ribavirin (1000 to 1200 mg per day). This was scheduled for 48 weeks. Three patients showed clearance of the HCV virus without any change in their renal function. However, hemolysis was the most common side effect, causing ribavirin to be decreased or temporarily stopped.

Thus, there are no clearly effective therapies for hepatitis C that can be used safely for renal-transplant patients. This has led to an increased focus on identifying and treating hepatitis C in patients with end-stage renal disease who are eligible for transplantation.

Treatment of HCV Infection in Patients with End-Stage Renal Disease

The liver enzymes alanine (ALT) and aspartate (AST) aminotransferase, in dialysis patients with chronic liver HCV infection, are often within the normal range (40–42), and so are poor markers of disease. The HCV viral load is consistently lower in HCV-positive dialysis patients than in HCV-positive patients with normal renal function or in HCV-positive liver- or kidney-transplant patients (43). HCV seems to have a lower impact on the liver histology of dialysis patients than on the liver histology of HCV-positive immunocompetent patients with normal renal function (7).

Acute hepatitis C infection is often asymptomatic in dialysis patients (44). When it occurs, HCV seroconversion seems to appear within following three months (40). In the study (40), 21% of patients had spontaneous HCV RNA clearance. Therefore, one has to wait at least three months after diagnosis before implementing antiviral therapy for these patients. We had 14 cases of acute hepatitis C infection in our dialysis centers between 1994 and 1997, and treated seven cases of acute HCV infection in chronic hemodialysis (CHD) patients with α-IFN (3 MU SC three times a week) for 48 weeks. Of the five patients who completed the treatment: all were cleared of the virus, but not the two patients who were treated for less than three months (45). Gürsoy et al. reported on 36 dialysis patients with acute hepatitis C who were treated with α-IFN for three months at either 3 MU SC three times a week or at 6 to 10 MU SC three times a week (46). The virological responses of the two groups at the end of therapy were similar (56.5% and 65.4%), but were significantly higher than that of an untreated control group (5.6%). Sustained virological response was observed in, respectively, 26.1 and 50% of treated patients and in 5.6% of untreated patients. Quasi-species heterogeneity was the only predictive factor for a response to α-IFN therapy.

In immunocompetent patients, the treatment of HCV infection relies on the combination of Pegylated interferon and ribavirin (47). To date, two different pegylated interferon which are two different molecules are available, i.e. the pegylated interferon alfa-2a (Pegasys, Hoffmann-La Roche, Basel, Switzerland) and the pegylated interferon alpha-2b (Peg-Intron, Schering-Plough, Berlin Germany). The pegylation of α-IFN resulted in an increase of its half life. In patients on hemodialysis the Cmax, the area under the curve (AUC) and the half-life of α-IFN following a SC injection of 3 MU are significantly higher than in patients with normal renal function (48). For both pegylated interferon formulations, renal clearance accounts for a relatively smaller proportion of its total clearance than for non-pegylated interferons, i.e. 30% (49, 50). Prospective controlled trials using pegylated interferon in hemodialysis patients are ongoing in order to determine dosing recommendations, and to assess its safety and tolerability.

The response to standard α-IFN therapy in dialysis patients varies from 10 to 100% according to the series; but the average virological response is ∼40% (51, 52). This sustained virological response observed in dialysis patients is higher than the one reported in immunocompetent patients with normal renal function, i.e. 6 to 13% (53), and is independent of HCV genotypes. The absence of clearance of HCV RNA by three months after the beginning of α-IFN therapy is significantly associated with a virological relapse after the end of α-IFN therapy. Therefore, it is reasonable to withdraw α-IFN therapy at three months after its initiation in cases where HCV viremia remains positive. Finally, HCV-positive patients who had cleared HCV RNA after α-IFN and who then underwent renal transplantation suffered no subsequent relapse despite immunosuppression (54–56). Hence, any HCV-positive patients on dialysis who are candidates for a renal transplant should be offered anti-HCV therapy, regardless of the results of the liver biopsy or HCV genotype. The treatment is α-IFN 3 MU SC three times a week for 48 weeks independently of HCV genotype, because less relapses were observed in patients treated during 48 weeks as compared to those treated for 24 weeks (51, 56, 57). The patient is not candidate for a renal transplant during this period. Nevertheless, patients with persisting HCV viremia should be maintained on the waiting list and should undergo a kidney transplantation. Alpha-IFN therapy might be contemplated for those HCV(+)/RNA(+) dialysis patients who are not candidate for renal transplantation, provides their life expectancy is reasonable (greater than 5 years) because survival of HCV-negative dialysis patients is significantly higher than that in HCV-positive dialysis patients (1, 2).

Dialysis patients tolerate α-IFN less well than patients with normal renal function. Interferon therapy interruption was observed in up to 60% of dialysis patients. The major side effects can be flulike symptoms, malaise, myalgia, asthenia, loss of weight, cardiovascular disorders, hematological abnormalities, and neurological disorders.

The difference in efficacy and side effects of α-IFN in HCV-positive dialysis patients compared to that observed in patients with normal renal function might be related to differences in α-IFN pharmacokinetics. The use of ribavirin is contraindicated in dialysis patients as it may result in severe hemolytic anemia. However, some authors have used a combination of α-IFN and ribavirin to treat these patients (58–60). They found that the virological response was similar to that obtained using α-IFN alone, apart from the finding that patients who were given ribavirin experienced severe anemia (59) unless ribavirin plasma concentrations were monitored (60–62). Levovirin, the L-isomer of ribavirin, and viramidine, a ribavirin pro-drug, seem to induce less hemolytic anemia compared to ribavirin. To date, both drugs, as well as protease inhibitors are under evaluation outside the hemodialysis and posttransplantation settings. Finally, no data are available on the use of amantadine to treat HCV-positive dialysis patients.

In conclusion, because there is a lack of an effective anti-HCV therapy for renal-transplant patients, we strongly recommend treating HCV RNA-positive patients with α-IFN alone before undergoing renal transplantation. This also holds for patients who are not candidates for renal transplantation, providing their life expectancy is reasonable, so as to prevent the evolution of cirrhosis.

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Keywords:

Renal transplantation; Hepatitis C virus; Ribavirin; Alpha interferon; Amantadine; Acute rejection

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