Caroline Rochon, MD, FACS
Transplant and Hepatobiliary Surgeon
Because the treatment of HCV recurrence after liver transplantation, a major cause of graft loss, has shown such disappointing results over the years, transplant programs have tried to attack the recurrence problem with prevention strategies first and desperate therapeutic attempts second. Transplant surgeons anticipate HCV recurrence even before the surgery begins. Several donor factors have been identified with higher potential for HCV recurrence post transplantation and most transplant centers will not accept the same organs for HCV positive recipients that they would for recipients with other indications for transplant.
Many studies have identified multiple donor factors as being associated with higher/earlier HCV recurrence, the most important being increased donor age and higher percentage of steatosis in the graft. The decision to avoid transplanting HCV recipients with older/fatter grafts varies from center to center. How old is too old and how fat is too fat is a matter of preference, but the practice remains universal: prevent recurrence by judicious graft selection. As a consequence, HCV positive candidates can have a longer wait for transplant or a lower transplant rate than candidates without the disease. Other strategies employed in the post-transplant setting involve avoidance of over immunosuppression or episodes of acute rejection (easier said than done).
In theory, HCV positive liver transplant recipients can be treated with a pre-emptive approach immediately following transplantation or with a recurrence-based approach when liver damage is diagnosed. The advantages of pre-emptive or early post-transplant treatment are that serum HCV-RNA levels are characteristically low and significant histological graft damage is virtually absent. Although these factors predict a favorable response, this therapeutic approach had traditionally been difficult to manage because of poor tolerability and reduced efficacy of the pegylated interferon/ribavirin combination. Thus, the preferred strategy is usually to delay antiviral treatment until histological evidence of recurrent post-transplant HCV-related chronic hepatitis is established. This evidence is sometimes found on biopsies ordered to investigate clinical abnormalities or on protocol biopsies often done at 1 year post transplantation. The algorithms for care vary greatly between institutions but most centers will treat patients with clinical and histological signs of recurrence and at least Grade 3 or 4 inflammation or stage II fibrosis in the liver graft tissue. In this setting, treatment with a combination of Pegylated Interferon plus ribavirin is associated with an overall sustained virological response (SVR) of about 30% (1).
The recent introduction of direct-acting antivirals, including drugs that inhibit protease, polymerase and other non-structural proteins, heralds a new era in HCV treatment. In the post-transplant phase, triple therapy, with either telaprevir or boceprevir faces multiple challenges. (2) Post-transplant HCV recipients are often “difficult to treat” patients, either because they were prior non responders or they had a high blood HCV RNA. Still, improved outcomes are expected with the new drugs. Triple therapy with these agents is now being investigated. While the data are still very preliminary, reports show that 70 to 90% of patients are virus free at 12 weeks. (3) Infectious and hematologic complications are frequent and drug levels need to be monitored very carefully due to drug-drug interactions between calcineurin inhibitors and protease inhibitors.
Therefore, from my perspective, the increased risk of HCV recurrence post-transplant with older, more steatotic donor grafts is offset by the better ability we now have to treat recurrent disease, even if recurrence is still considered an off label indication.
We also have to wonder, in the era of these new drugs, whether it is wise to wait a full year before protocol biopsies and whether it is worth waiting for stage 2 fibrosis on biopsy to treat. Outcomes may be improved with earlier treatment of HCV recurrence; one might even talk of “recurrence prevention.” As we develop expertise with interferon-free direct acting antiviral therapy, like with sofosbuvir for example, lowering the feared risk of rejection while on treatment, we should all discuss how ethical it is to let the virus damage any graft at all and whether all HCV recipients should be treated preemptively post transplantation. (4) Such approaches seem particularly appropriate if the team decided to forfeit the traditional prevention strategies likes avoidance of older donor grafts. In short, the fight against HCV may be won by breaking the barriers to transplantation, being more liberal with graft acceptance and treating preemptively all grafts before the virus begins to damage the new liver…from my perspective.
- Roche B, Samuel D. Hepatitis C virus treatment pre- and post-liver transplantation. Liver Int 2012; 32( suppl 1): 120-128.
- Werner CR1, Egetemeyr DP, Lauer UM, Nadalin S, Königsrainer A, Malek NP, Berg CP Telaprevir-based triple therapy in liver transplant patients with hepatitis C virus: a 12-week pilot study providing safety and efficacy data. Liver Transpl. 2012 Dec;18(12):1464-70.
- Punpapong S, Murphy JL, Henry TM, Ryland K, Satyanaravana R, Rosser B, Yataco ML, Keaveny A. Preliminary experience using Telaprevir with Peginterferon and Ribavirin for treatment of HCV genotype 1 after liver transplantation. Liver Transpl. 2013 2013 Jul;19(7):690-700.
- Charlton M, Gane E, Manns MP, Brown RS Jr, Curry MP, Kwo PY, Fontana RJ, Gilroy R, Teperman L, Muir AJ, McHutchison JG, Symonds WT, Brainard D, Kirby B, Dvory-Sobol H, Denning J, Arterburn S Samuel D, Forns X, Terrault NA. Sofosbuvir and Ribavirin for Treatment of Compensated Recurrent Hepatitis C Virus Infection After Liver Transplantation. Gastroenterology. 2014 Oct 7. [Epub ahead of print]
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