© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Transplant Infectious Disease, ISSN 1398-2273

Review

Hepatitis C recurrence: the Achilles heel of liver transplantation J. Howell, P. Angus, P. Gow. Hepatitis C recurrence: the Achilles heel of liver transplantation. Transpl Infect Dis 2014: 16: 1–16. All rights reserved Abstract: Hepatitis C virus (HCV) infection is the most common indication for liver transplantation worldwide; however, recurrence post transplant is almost universal and follows an accelerated course. Around 30% of patients develop aggressive HCV recurrence, leading to rapid fibrosis progression (RFP) and culminating in liver failure and either death or retransplantation. Despite many advances in our knowledge of clinical risks for HCV RFP, we are still unable to accurately predict those most at risk of adverse outcomes, and no clear consensus exists on the best approach to management. This review presents a critical overview of clinical factors shown to influence the course of HCV recurrence post transplant, with particular focus on recent data identifying the important role of metabolic factors, such as insulin resistance, in HCV recurrence. Emerging data for genetic markers of HCV recurrence and their usefulness for predicting adverse outcomes will also be explored.

J. Howell1,2, P. Angus1,2, P. Gow1,2 1

Liver Transplant Unit, Austin Hospital, Melbourne, Australia, 2Department of Medicine, University of Melbourne, Melbourne, Australia Key words: hepatitis C; viral hepatitis; diabetes; metabolic syndrome; liver fibrosis; living donor transplantation; immunosuppression Correspondence to: Dr Jessica Howell, Liver Transplant Unit, Austin Hospital, Studley Rd, Heidelberg, Victoria 3084, Australia Tel: 61 3 94965000 Fax: 61 3 94963487 E-mails: [email protected]; [email protected]

Received 8 February 2013, revised 12 June 2013, accepted for publication 3 August 2013 DOI: 10.1111/tid.12173 Transpl Infect Dis 2014: 16: 1–16

The problem of hepatitis C virus (HCV) recurrence post liver transplantation HCV infection is the most common indication for liver transplantation in Western nations, accounting for >50% of transplants performed in Europe and the USA. Over 180 million people are estimated to be infected with HCV worldwide, and the somber prediction is for the health burden from HCV to steadily increase. By 2020, it is projected that untreated patients with HCV developing cirrhosis will increase by 30%, the number of patients with HCV liver cirrhosis will double, and the number of patients with HCV cirrhosis developing hepatocellular carcinoma will increase by 80% (1). Referrals for liver transplantation for HCV-related liver disease are also predicted to double by 2020 (2). In patients transplanted for HCV infection, recurrence of HCV in the graft is universal. This recurrence

results in significantly diminished survival post liver transplantation in HCV patients compared with patients without HCV infection. One study described 5-year survival rates of 66% in HCV-negative patients compared with 57% in HCV-positive patients. Approximately 30% of patients transplanted for HCV liver disease develop acute severe recurrent hepatitis, leading to rapid progression to cirrhosis and graft failure (3, 4). The median time to cirrhosis, estimated from clinical studies, is >30 years in immunocompetent individuals with HCV. By contrast, approximately 10–30% of HCV patients develop cirrhosis within 5 years post transplant, with the majority of HCV patients developing graft cirrhosis by 9–12 years post transplant (5–7). These patients also develop liver decompensation more quickly than their non-transplanted HCV-infected counterparts, with approximately 50% of patients with HCV graft cirrhosis experiencing an episode of decompensation during 12 months of follow up, and 6 log IU/mL at 2 weeks post transplant and IL-28 rs12979860 non-C/C genotype (14).

HCV rapid fibrosis progression (RFP) post transplant: definitions and methods of measuring fibrosis progression One critical clinical question is how to best measure fibrosis progression in HCV recurrence post transplant, to identify those with aggressive disease early and implement changes in management to prevent further progression (8). Early detection is crucial, as HCVinfected patients post transplant appear to respond better to early antiviral therapy, while early referral for retransplantation before the onset of renal impairment and infectious complications leads to improved posttransplant outcomes (6, 15–18). The current clinical standard is for protocol liver biopsies to be performed every 1–2 years post liver transplantation, to identify those with RFP over time, who are at increased risk of HCV-mediated graft cirrhosis (19). The degree of

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fibrosis on liver biopsy is scored using well-established categorical scores, such as the Ishak or Metavir score, combined with trichrome staining (20, 21). How best to define RFP remains a key area of debate. A variety of definitions of RFP post transplant have been used in clinical studies over the last decade. Fibrosis rate (calculated as fibrosis stage on most recent liver biopsy over time post transplant, measured in fibrosis units/year) (22, 23), fibrosis stage F1 or greater on the first-year liver biopsy (1, 24), and time to F2 stage fibrosis (measured in years) (25) are the 3 commonly used methods in studies examining fibrosis progression post transplant. However, true validation and comparison of the ability of these different measures of fibrosis progression to identify patients at risk of developing rapid fibrosis and graft cirrhosis have not been established. In practice, progression of fibrosis stage on consecutive annual liver biopsies is considered to represent clinically significant fibrosis progression and heralds the need for intervention.

Non-invasive measures of fibrosis progression Liver biopsy has historically been the ‘gold standard’ for determining the degree of HCV-related liver fibrosis post transplant. However, in recent years, there has been great interest in developing non-invasive measures of HCV fibrosis progression. Transient elastography is in widespread clinical use in many countries, but its validity in post-transplant HCV is not yet clearly established. Preliminary studies suggest that yearly measures of liver stiffness by transient elastography are a surrogate marker for HCV-mediated fibrosis progression, and can identify those with RFP who are at risk for cirrhosis post transplantation (26, 27). However, accuracy of transient elastography readings is significantly reduced in the context of high transaminase levels, which are common post transplant because of copathologies such as acute cellular rejection (ACR), biliary obstruction, or infection. Furthermore, graft steatosis and obesity are both common post liver transplantation and these factors also affect the accuracy of transient elastography readings (28–31). Therefore, further validation of transient elastography in HCV-mediated fibrosis post transplant is needed, before its use replaces liver biopsy. Other non-invasive measures of HCV recurrence have also been developed to identify those with RFP, but are not yet used in routine practice (32). Benlloch et al. (32) and Cross et al. (33) have developed noninvasive indices for identifying those who have fibrosis

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post transplant using international normalized ratio, aspartate aminotransferase, time post transplant, and either albumin/total protein ratio or platelet count. However, these indices have primarily been used to rationalize the number of patients requiring liver biopsy, and have not been validated in larger populations. See Summary 1. Summary points: Hepatitis C virus (HCV) recurrence post liver transplantation ● HCV recurrence post liver transplantation is universal, with 30% developing rapid HCV-mediated fibrosis progression and poor outcomes. ● Survival after retransplantation is poor (50% survival at 3 years). ● Fibrosing cholestatic hepatitis is a severe form of HCV recurrence characterized by rapid onset of cholestasis post transplant with very poor survival and minimal response to treatment. ● Protocol liver biopsies every 1–2 years help to identify those most at risk of rapid fibrosis progression. ● Transient elastography has an emerging role in liver fibrosis assessment, but remains to be validated in large studies of HCV recurrence post transplant.

Summary 1

Early markers of RFP A key focus of research in HCV recurrence is early identification to determine patients at risk of rapid HCV recurrence and to stratify the need for liver biopsies. Several early markers of RFP have been identified; these are outlined in Table 1 (10, 34–48). However, it is important to note that none of these markers have been extensively validated in large studies, and are not yet in widespread clinical use.

Serum markers A relationship between high alanine aminotransferase (ALT) levels in the first year post transplant and development of graft cirrhosis has been described; however, ALT can be normal in significant HCV recurrence, and is generally a poor marker of histologic severity (7). Total bilirubin (both peak >3.5 mg/dL, and mean level post transplant) more convincingly has been shown to predict severity of HCV recurrence. Early-onset cholestasis is an independent negative predictor of graft and patient survival in recurrent HCV, and in many cases heralds FCH (34). Other serum markers that may prove useful for predicting adverse HCV-related outcomes, when measured in the first 6 months post liver transplantation, include tumor

Early markers of rapid hepatitis C virus (HCV)-mediated fibrosis post liver transplantation Clinical factor

First author (reference)

Explant liver HCV negative: positive strand ratio

Lin (39)

Cholestasis – blood

Iacob (34), Ueda (40)

Cholestasis – liver biopsy

Pessoa (38)

Pre-transplant HCV viral load

Everhart (41), Charlton (42, 43), Condron (44), Doughty (45), Feray (46)

Post-transplant HCV viral load

Papatheodoridis (47), Gane (10), Shackel (48)

Serum MCP-1, VCAM-1, IP-10 levels

Micheloud (36)

Serum hyaluronic acid level

Pungpapong (37)

Serum TNFa and IL-6

Green (35)

HCV, hepatitis C; MCP-1, monocyte chemotactic protein-1; VCAM-1, vascular cell adhesion protein-1; IP-10, interferon-gamma-inducing protein-10; TNFa, tumor necrosis factor alpha; IL-6, interleukin 6.

Table 1

necrosis factor alpha (TNFa) and interleukin (IL)-6 (35), monocyte chemotactic protein-1, vascular cell adhesion molecule-1, interferon-inducing gamma protein-10, chitinase YKL:40, and hyaluronic acid (36, 37).

Histopathology Reflecting the predictive importance of early-onset biochemical cholestatic hepatitis, cholestasis and ballooning degeneration of hepatocytes on liver biopsy are more prevalent in HCV-infected grafts that develop cirrhosis, compared with those that do not (3). Furthermore, the degree of inflammatory activity and liver damage on the first-year liver biopsy post transplant predicts the trajectory of HCV recurrence, with early acute hepatitis associated with worse graft survival (3, 7). A high histologic grade of inflammation on explant histology also predicts aggressive HCV recurrence post transplant (49). The ratio of liver HCV RNA-negative strands to positive strands on immunohistochemical staining of the explant specimen reflects viral replication, and correlates with severity of HCV recurrence in the new graft (38, 39, 50).

Risks for HCV-related RFP Many clinical studies have sought to identify risks for HCV RFP post liver transplantation. Considerable

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discrepancy remains in the variables identified in these studies. In part, this is a result of the lack of uniformity and consensus in definitions of RFP post liver transplantation. However, some risks have been identified in multiple, well-designed studies that are now considered established risks for HCV RFP. These clinical risk factors are outlined in Table 2 (7, 10, 23–25, 36, 37, 42, 44, 48, 51–106).

Viral factors Post-transplant viral load is an important marker of disease severity (41, 43, 45, 46). Papatheodoridis et al. (47) found a correlation between liver fibrosis and HCV RNA levels at 12 months post-transplant, whereas Gane et al. (10) and Duvoux et al. (107) similarly found an association between peak HCV RNA levels and histologic severity of HCV recurrence. Shackel et al. (48) demonstrated that a peak post-transplant HCV viral load >107 IU/mL was an independent predictor of graft loss, including HCV-related graft loss (48). All patients in their study, with peak post-transplant HCV viral loads >108 IU/mL, died (48). This study was pivotal in suggesting the need for routine early viral-load testing post-transplant, to identify those most at risk of adverse outcomes, who would benefit from reduction in immunosuppression. Evidence also suggests that pre-transplant viral load predicts more severe HCV recurrence post transplant (41, 43, 44). Interestingly, negative HCV viral load at the time of transplantation does not preclude HCV recurrence in the liver graft, with up to 55% of this patient group developing HCV recurrence. However, virologic and histologic recurrence is delayed in patients who are HCV RNA negative by PCR at the time of transplantation (108). Viral genotype 1b is associated with greater RFP in HCV recurrence, independent of treatment response (10, 51, 52). Greater homogeneity of viral quasispecies pre-transplant is also associated with more severe HCV recurrence, likely reflecting reduced viral immune pressure (53).

well-established risk factor for HCV RFP (23, 24, 44, 55– 57, 109). Berenguer et al. (54) demonstrated that advanced donor age had a relative risk of 1.05 for HCV-mediated graft cirrhosis and 1.02 for patient mortality in HCV patients who underwent liver transplantation, with the highest probability of developing graft cirrhosis in those who received grafts from donors who were ≥60 years of age. Wali et al. (23) similarly found that advanced donor graft age was associated with RFP in HCV post transplant, with the interval to cirrhosis being 10 years in patients whose graft donor age was 30% dropout rates because of side effects. ● Although SVR data are minimal for new direct-acting antiviral agents, preliminary evidence suggests that triple therapy with boceprevir or telaprevir is efficacious post liver transplant, taking into consideration potential calcineurin inhibitor drug interactions. ● Preliminary data for daclatasvir and sofosbuvir (GS-7977) also look promising in the treatment of HCV recurrence post-transplant.

Summary 1

Howell et al: HCV recurrence post liver transplant

Conclusion Many important advances have been made in our understanding of risks for rapid HCV fibrosis post transplant. Advanced donor age, prolonged warm ischemia time, ACR, and high viral load early post transplant are all established risk factors for rapid HCVmediated graft fibrosis. Recent studies have also identified the metabolic syndrome as an important risk factor for HCV RFP. Strategies to reduce rapid graft fibrosis in HCV post-transplant include avoidance of ACR through adequate immunosuppression early post transplant, titrating immunosuppression to HCV viral load, optimizing glycemic control and metabolic factors, and, where possible, minimizing warm ischemia times, and avoiding use of older donors in older HCVinfected recipients. However, further studies are urgently needed to optimize these strategies.

Acknowledgements: Grant support: Dr Jessica Howell received scholarship funds for stipend from the Gastroenterological Society of Australia (GESA). Author disclosures: No author had any disclosures to make relevant to this manuscript.

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