Treatment of hepatitis C in renal failure

c l i n i c a l q u e r i e s : n e p h r o l o g y 1 ( 2 0 1 2 ) 2 3 6 e2 4 0

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Review article

Treatment of hepatitis C in renal failure Samir Mohindra a,*, Narayan Prasad b a b

Associate Professor, Department of Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India Additional Professor, Department of Nephrology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, India

article info

abstract

Article history:

Hepatitis C is a common infection, seen frequently in patients on renal replacement

Received 27 June 2012

therapy and is responsible for an adverse outcome in patients on dialysis as well as

Accepted 7 July 2012

potential renal transplant (RT) recipients. HCV infection is the fourth leading cause of post-

Available online 13 August 2012

transplantation death, and leading cause of post-transplantation liver dysfunction. HCV infection is both a cause as well as a complication in patients of chronic kidney disease

Keywords:

(CKD). Therefore, prompt recognition and appropriate timely treatment is essential to

Hepatitis C

salvage these patients. Lack of safe and effective drugs to treat HCV infection in CKD

Renal failure

patients is a major concern. The presently available drugs, interferon and ribavirin, have

Interferon

altered pharmacokinetics in patients with renal failure; therefore, these have potential

Renal transplantation

adverse effect on graft function and survival. This article reviews the recent advances in

Ribavirin

evaluation; discusses the available therapeutic options and their limitations. Copyright ª 2012, Reed Elsevier India Pvt. Ltd. All rights reserved.

1.

Introduction

More than 170 million people worldwide are chronically infected with hepatitis C virus (HCV), responsible for more than 1 million deaths from end stage liver disease and hepatocellular carcinoma.1 HCV infection and chronic kidney disease are common medical conditions linked in multiple ways. CKD patients on renal replacement therapy have higher prevalence of HCV infection than general population.2 HCV infection is known to have adverse outcome in patients on RRT and post-transplantation phase.3 Despite advances, management of CKD patients with HCV infection is a complex problem, which includes role of antiviral therapy in dialysis and post-transplantation patients, and treatment of HCV infection-related kidney disease. The lack of safe and effective drug therapy is an area of major concern. Moreover in absence of large-scale clinical trials in these patients, clear-cut guidelines for treatment are still awaited.

2.

Epidemiology

The prevalence of hepatitis C infection has been studied extensively and reported prevalence in dialysis patients has been found to be high, varying between 5e50%.4,5 In renal transplant recipients, prevalence rate is reported to be as high as 5e46%, higher level of HCV positivity seen in developing nations. Table 1 shows prevalence of anti-HCV positivity in dialysis patients in developing countries where prevalence is much higher possibly due to higher nosocomial spread, incomplete screening of blood and blood products and possibly higher prevalence in general population.6,7 The prevalence levels have remained high despite screening, mainly due to nosocomial spread. The prevalence of anti-HCV positivity in dialysis units tends to be influenced by factors like race, type of dialysis (peritoneal vs. hemodialysis), number of dialysis sessions before transplantation, and number of blood transfusions received.8,9 Acute HCV infection

* Corresponding author. E-mail addresses: [email protected], [email protected] (S. Mohindra). 2211-9477/$ e see front matter Copyright ª 2012, Reed Elsevier India Pvt. Ltd. All rights reserved. http://dx.doi.org/10.1016/j.cqn.2012.06.004

c l i n i c a l q u e r i e s : n e p h r o l o g y 1 ( 2 0 1 2 ) 2 3 6 e2 4 0

Table 1 e Prevalence of HCV infection in hemodialysis units. Country New Zealand Poland South Africa Thailand Saudi Arabia Germany Netherlands Spain United States France Japan Italy United Kingdom Belgium India Tunisia Brazil Iran

HCV prevalence

Year of study

5% 42% 21% 20% 68% 7% 3% 22% 14% 15% 20% 22% 3% 7% 12e42% 20% 17% 9%

1992 1992 1994 1994 1994 1996e1997 1997 1997e2001 1997e2001 1997e2001 1997e2001 1997e2001 1997e2001 2000 2001 2001e2003 2002e2005 2004

in dialysis settings can be characterized only by modest and transient increase in transaminases.10 Patients with chronic renal failure and chronic HCV infection, usually have lowgrade hepatitis, characterized by increased or even normal transaminases, despite persistent viremia and histological progression.11 Patients on hemodialysis tend to have lower viral load and milder histological abnormalities, as compared to patients of CRF not on hemodialysis.12 The data on longterm effect of HCV infection on renal transplant is conflicting, though majority of studies indicate reduced graft as well as patient survival.13 Factors like viral load, genotype, pretransplant liver pathology and type of immunosuppression used can affect outcome.14 Post renal transplantation HCV positive patients can have rapid progression of liver disease, leading to liver failure which is the fourth leading cause of mortality in long-term survivors.15 Inspite of high liver and infectionrelated mortality, renal transplantation in HCV-infected patients does give a survival benefit.16 With the screening of blood for blood borne infection, implementation of infection control practices, risk of transmission of HCV infection in dialysis units has started to show a declining trend in developed world.17

3.

Diagnosis of HCV

Serological detection of antibody to HCV antigen by enzymelinked immunoassay (ELISA) is the initial test to detect HCV infection in CRF patients. The third generation ELISA is a very sensitive and specific test for detecting HCV infection.3 Treatment decision depends on confirmation of viremia, assessment of viral load and genotype. PCR-based tests are more accurate in patients with HCV infection in renal failure patients and therefore are preferred. Samples for HCV RNA detection should be taken prior to hemodialysis session as heparin can interfere with detection and secondly there can be a transient lowering of HCV RNA in the post dialysis period.

3.1.

237

Nosocomial spread of HCV infection in dialysis unit

Since the dramatic reduction in post transfusion HCV infection in 1990s, nosocomial transmission in dialysis units is the common mode of acquiring HCV infection. Failure of the dialysis units to follow standard infection prevention and control practices is considered to be the main culprit. Dialyzer reusage is not considered to be a risk factor in dialysis units.18 The CDC currently does not recommend patient isolation or designated machines in HD units.19 Prospective studies have indicated that following infection control practices, transmission of HCV infection is reduced. Current infection control practices to prevent HCV infection in dialysis units is possible by following universal precautions and standard HD unit precautions. Periodic anti-HCV testing in dialysis units is advised as an infection control practice.

3.2.

Natural history of HCV infection in dialysis units

Accurate assessment of natural history of HCV infection in dialysis patients is difficult because of lack of symptoms of liver disease and more indolent course. The natural history of HCV infection spans over decades and because of higher morbidity and mortality due to associated co morbid conditions, it is difficult to judge the consequences of chronic HCV infection in these patients. However studies with adequate number of patients and reasonable follow up nevertheless indicate reduced survival in HCV positive patients. A recent meta-analysis of observational studies involving 11,589 unique patients on maintenance dialysis demonstrated that the presence of anti-HCV antibody was an independent and significant risk factor for death; adjusted relative risk (allcause mortality) was 1.34 (95% CI, 1.13e1.59). Liver dysfunction was incriminated in a lower survival of seropositive patients. The study estimate for relative risk of liver-related mortality was 5.89 (95% CI, 1.93e17.99).20 The presence of anti-HCV antibody is an independent predictor of mortality (relative risk, 1.37; 95% CI, 1.15e1.62; P value ¼ .003) in the Japanese HD cohort, according to the Asia-Pacific Dialysis Registry data on dialysis.21 A more recent association between HCV positivity and cardiovascular-related mortality has been found, relative risk was 1.80.22

3.3.

Therapy of HCV infection in dialysis patients

The risks and benefits of interferon-based regimens in HCV positive dialysis patients have been evaluated in many studies. A meta-analysis which included 24 clinical trials enrolling 429 patients on maintenance dialysis who received conventional IFN monotherapy sustained virologic response rate was 39% (95% CI, 32e46) and dropout rate was 19% (95% CI, 13e26).23 Paradoxically viral response to monotherapy with standard IFN in maintenance HD patients is higher than that observed in patients with chronic hepatitis C and normal kidney function (response rate 39% vs. 7e16%) who received conventional IFN monotherapy.24,25 Several mechanisms may explain the relatively higher response to IFN in patients receiving regular HD. Dialysis patients with HCV usually have a lower viral load, the infection is frequently associated with milder forms of liver disease, clearance of IFN is lower in

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(one case) and urosepsis (two cases).35 Antiviral therapy with interferon should be considered only in patients in whom the risk of severe HCV-related liver disease like fibrosing cholestatic hepatitis is there and there is a possibility of loss of the allograft. Various regimens using alternative drugs like amantadine, ribavirin monotherapy or their combination have been used but with little proven efficacy.36e38

dialysis than in non-CKD patients, and release of endogenous IFN from circulating white blood cells during HD procedures has been reported.26 The ability of patients on dialysis to tolerate interferon therapy is lower with the dropout rate as high as 19%. In addition to flu like symptoms, dialysis patients have more frequent gastro-intestinal (18%) and neurological (21%) symptoms.23 The altered pharmacokinetics of IFN including longer half-life in dialysis patients can explain higher rates of side effects and consequent dropouts. Additional causes could be higher age and associated co morbid conditions in HD patients.27 The current standard of care therapy of HCV infection is pegylated interferon and ribavirin combination. The long acting pegylated IFNs, due to longer half-life are administered in weekly dose. Data on pegylated IFN as monotherapy in HD patients is limited to few small studies. These studies indicate that viral efficacy of plain IFN and pegylated IFN is similar in HD patients.28e30 Data on usage of combination antiviral therapy (IFN and ribavirin) is limited though encouraging regarding safety and efficacy as shown in Table 2.31,32 Ribavirin, when used has a propensity to get accumulated and cause hemolytic anemia in dialysis patients who are already predisposed to anemia. If, a decision to use ribavirin is made certain precautions like using lower dosage, monitoring with weekly hemoglobin estimation and aggressive use of erythropoietin to treat anemia need to be taken.33

3.5.

Treatment of acute HCV infection in CKD patients

Though large, multicentric trials are lacking, there are two meta-analyses which indicate that treatment of acute HCV infection in CKD patients is safe and effective. This analysis suggested that these patients tolerated shortened IFN-based therapy very well with reasonably high-sustained virological response rates.39,40 However, despite increasing evidence in favor of treating these patients, there is no consensus regarding timing of treatment initiation, optimal dosing and duration schedule. The German network for viral hepatitis (HEP-NET) in their randomized trial that evaluated immediate therapy for asymptomatic patients and immediate versus delayed (12 weeks from onset of symptoms) therapy for those with symptomatic hepatitis the intent-to-treat analysis suggested lower SVR rates for those undergoing delayed treatment (78% vs. 54%), but dropout during the observation phase of the delayed treatment group. The SVR rates remained excellent for those who adhered to therapy in all arms; SVR rates were similar after immediate treatment for symptomatic hepatitis (arm A, n-536; SVR 87%), delayed treatment for symptomatic hepatitis (arm B, n-537; SVR 100%), and immediate treatment for asymptomatic hepatitis (arm C, n-516; SVR 100%). Although this trial confirmed the efficacy of delayed therapy, the investigators suggested that this strategy should only be applied if adherence can be ensured.41 Several studies have indicated 12 weeks of Peg IFN-based regimen to be optimal with viral clearance rates of 72e75%.42,43 Rapid biological response (RVR: negative HCV RNA by sensitive PCR assays at 4 weeks) should be used as a predictor of viral clearance with 12 weeks of therapy. However, patients with genotype 1 and no RVR should receive 24 weeks of therapy. With the evidence of better efficacy with Peg IFN in chronic hepatitis C, regimen use Peg IFN in dosage of 1.33e1.5 mg/kg. Addition of ribavirin, though well tolerated confers no advantage.

3.4. Treatment of HCV infection in renal transplant recipients Presently there is no safe and effective therapy for the treatment of chronic HCV in renal transplant recipients. A meta-analysis of clinical trials of IFN-based therapy (interferon alone or with ribavirin) in RT recipients with chronic hepatitis C showed that the estimate for SVR and dropout rate was 18.0% (95% CI, 7.0e29%) and 35% (95% CI, 20e50%), respectively.34 The most frequent side-effect requiring cessation of therapy was graft dysfunction, usually acute rejection refractory to corticosteroid therapy. Few studies have used combination antiviral therapy (interferon plus ribavirin). Shu et al treated 11 RT recipients with chronic HCV with a very low dose of IFN-a (1 MU by subcutaneous route three times weekly) for 48 weeks. Out of these, three patients stopped the therapy prematurely because of acute graft failure

Table 2 e Pegylated interferon in combination with ribavirin in patients with chronic hepatitis C on maintenance hemodialysis: clinical trials. Authors Bruchfeld et al, 2006

Antiviral agent 44

Rendina et al, 200745 Schmitz et al, 2007 Carriero et al, 200846 van Leusen et al, 200832 Liu et al, 200931

Peg-IFN alfa-2a (N 5 2) or peg-IFN alfa-2b (N 5 4) plus ribavirin Peg-IFN alfa-2a plus ribavirin Peg-IFN alfa-2b plus ribavirin Peg-IFN alfa-2a plus ribavirin Peg-IFN alfa-2a plus ribavirin Peg-IFN alfa-2a plus ribavirin

Results have been calculated according to an intention to-treat analysis. Abbreviations: IFN, interferon; SVR, sustained virologic response.

% SVR 50 (3/6) 97 50 29 71 60

(34/35) (3/6) (4/14) (4/7) (21/35)

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3.6.

Treatment of HCV-related glomerulonephritis (GN)

The role of HCV infection in causing glomerular disease has been demonstrated in both native as well as transplanted kidneys. The most common lesion seen in HCV infection is Type 1 membranoproliferative glomerulonephritis. Use of antiviral treatment in HCV-GN has shown relationship between SVR and improvement in renal function. A recent meta-analysis showed that usage of antiviral therapy is more effective than immunosuppressive therapy in patients with HCV-related GN.47 Role of rituximab, chimeric humane mouse monoclonal antibody in HCV-related GN has been encouraging.

4.

Conclusions

HCV infection can either be an etiology or complication of chronic kidney disease. HCV infection in CKD patients is a major clinical problem in dialysis patients; in potential renal transplant recipients as well as in post-transplant patients. HCV positivity is associated with higher mortality in these patients. Current available antiviral therapies are of limited efficacy and associated with significant side effects. With the newer protease and polymerase inhibitors to be introduced in near future, more therapeutic options are on the anvil for the high-risk CKD patients.

Conflicts of interest All authors have none to declare.

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