Hepatitis C virus: Management of recurrent disease

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Although the successful treatment of hepatitis C virus (HCV) does improve survival after liver transplantation (LT), antiviral treatment for patients awaiting transplantation or on immunosuppression after transplantation continues to be hindered by significant toxicities and disappointing response rates. However, in this era of rapidly evolving HCV therapy, strategies for eradicating the virus in the pre‐and post‐LT settings will play a key role in improving outcomes.

Early Post‐Transplant Antiviral Therapy

Perioperative therapies such as HCV immunoglobulin formulations have not been successful in eradicating or controlling infection. In addition, the prophylactic and preemptive use of pegylated interferon (PEG‐IFN) and ribavirin before histologically significant recurrent disease is generally poorly tolerated, as fewer than half of patients have the clinical and hematological stability to start treatment in the first several months after LT.1 Preemptive treatment is also of uncertain benefit. In the most comprehensive randomized controlled trial comparing preemptive treatment to the treatment of histologically recurrent disease, there were no differences in clinically important outcomes, including significant recurrence and patient or graft survival.2 As a result, treatment is currently recommended only for patients with histologically significant recurrence, who are generally defined as individuals with at least grade 2 of 4 necroinflammation, stage 2 of 4 fibrosis, significant cholestasis, and/or the cholestatic variant of HCV.3

Abbreviations.

HCV

hepatitis C virus

IFN

interferon

LT

liver transplantation

mTOR

mammalian target of rapamycin

PEG‐IFN

pegylated interferon

SVR

sustained virological response

Monitoring for Significant Recurrence and Staging of Disease

The assessment of fibrosis progression in LT patients with HCV is central to their management. Fibrosis is accelerated in comparison to the non‐transplant setting and is nonlinear. In addition, there is a poor correlation between serological liver tests and liver histology, and there is no accurate noninvasive method for differentiating HCV from rejection. Finally, treatment is currently recommended for those patients with histologically significant recurrence. For these reasons, many centers perform post‐LT liver biopsy annually, although the ideal surveillance frequency is unknown.

Liver biopsy also has limitations, including procedural complications, sampling error, and the complexities of biopsy interpretation after LT. Therefore, there is great interest in the development and validation of noninvasive markers of fibrosis. Traditional indirect markers, such as platelets, albumin, gamma‐glutamyltransferase, and liver enzymes, are less specific after LT because they may be abnormal for other reasons, including medication toxicities, proteinuria, bile duct complications, and rejection, respectively. Several combinations of serologies and markers of extracellular matrix turnover have been tested with variable accuracy in determining the stage of disease or predicting progression.4, 5 However, none of these are routinely used in the clinic.

Ultrasound and magnetic resonance elastography may be more promising, and they have now been shown in several studies to correlate well with liver histology and portal pressure measurements both before and after LT. In a recent systematic review of ultrasound elastography in post‐LT patients with HCV, a pooled analysis revealed a sensitivity of 83% and a specificity of 83% for the diagnosis of significant fibrosis and a sensitivity of 98% and a specificity of 84% for the diagnosis of cirrhosis.6 In addition, serial measurements within the first year after LT and/or the use of elastography in conjunction with noninvasive serological markers may lead to even greater diagnostic accuracy.

Although significant progress has been made, at this time, these noninvasive tests should be used in conjunction with standard liver biopsy. This is especially important when making decisions about HCV treatment, evaluating the degree of necroinflammation, and excluding other causes of liver test elevations.

Antiviral Therapy for the Treatment of Significant Recurrent HCV

HCV treatment with a sustained virological response (SVR) is an important goal of post‐LT management because it leads to disease stabilization and/or regression7 and improves survival (Fig. 1).7, 8 Combination therapy with PEG‐IFN and ribavirin remains the recommended regimen after LT because SVR rates are higher than those with interferon (IFN)‐based dual therapy or PEG‐IFN alone. Unfortunately, studies of post‐LT treatment have generally led to disappointing SVR rates because of the high proportions of patients with genotype 1 and previous nonresponse, the poor tolerability of PEG‐IFN and ribavirin, and concomitant immunosuppression, which affects viral kinetics and renders the interpretation of traditional stopping rules complex.9 When more than 40 treatment trials of PEG‐IFN or IFN with ribavirin were pooled, the composite SVRs were 27% and 24%, respectively.10 The pooled discontinuation rates were 24% and 26%, respectively. With only approximately one‐quarter of patients achieving SVR, there is an urgent need to bring novel HCV therapies to the transplant population.

Figure 1.

After the initiation of HCV treatment, survival is higher for HCV‐positive LT recipients who achieve SVR (with 1‐, 3‐, and 5‐year survival rates of 96%, 94%, and 94%, respectively) versus nonresponders (97%, 73%, and 68%, respectively; P = 0.012, log‐rank test). Reprinted with permission from Journal of Hepatology.7 Copyright 2012, Elsevier.

Directly Acting Antivirals and Novel HCV Treatment Regimens

Many new directly active antiviral agents are currently in clinical trials. The two approved protease inhibitors, telaprevir and boceprevir, have led to marked improvements in SVR rates and truncated therapy for some patients in the non‐transplant setting. However, these agents are approved only for genotype 1 infection and must be administered with PEG‐IFN and ribavirin. Therefore, although the response rates may be higher, the goals of improved safety and tolerability for post‐LT patients are unlikely to be met by these agents.

No formal clinical trials of protease inhibitor‐based triple therapy after LT have been completed, and the protease inhibitors are not approved by the Food and Drug Administration for post‐LT patients. However, off‐label use of triple therapy after LT has begun at many centers with significant caution because of the interactions between the protease inhibitors and calcineurin inhibitors (Fig. 2)11 and, to a lesser extent, prednisone. Formal trials with full pK analyses in transplant patients are ongoing (ClinicalTrials.gov identifier NCT01467505), but preliminary data are emerging from observational cohorts throughout the world.12, 13 A multicenter, observational cohort recently reported the treatment of 101 patients with high early on‐treatment response rates (HCV RNA was undetectable in 72% at 12 weeks), although the final SVR data have not yet been reported. Calcineurin inhibitor dosing was dramatically altered with the protease inhibitor (the mean daily doses before and on treatment were 10 and 0.06 mg, respectively, for tacrolimus and 200 and 50 mg, respectively, for cyclosporine), and adverse events included two deaths, acute rejection (18%), and an increase in the creatinine level ≥ 0.5 mg/dL (33%).13

Figure 2.

(A) Dose‐normalized mean (standard deviation) blood concentration–time profiles for cyclosporine after the administration of cyclosporine alone or with telaprevir (a log‐linear scale). (B) Dose‐normalized mean (standard deviation) blood concentration–time profiles for tacrolimus after the administration of tacrolimus alone or with telaprevir (a log‐linear scale). Reprinted with permission from Hepatology.11 Copyright 2011, American Association for the Study of Liver Diseases.

On the basis of promising results in non‐LT settings,14, 15, 16 several new IFN‐free directly active antiviral regimens are now in clinical trials in with post‐LT patients. There is an open‐label trial of 12 weeks of sofosbuvir (polymerase inhibitor) and ribavirin in patients with all genotypes (NCT01687270) with results are expected in 2014. In addition, an open‐label trial of ritonavir‐boosted ABT‐450 (NS, nonstructural 3 protease inhibitor), ABT‐267 (a nonstructural 5A inhibitor), ABT‐333 (a nonnucleoside nonstructural 5B polymerase inhibitor), and ribavirin for genotype 1 patients with recurrent HCV is now recruiting (NCT01782495). Both physicians and patients await the efficacy and safety results from these trials with great anticipation. It is now likely a reality that an IFN‐free regimen will be available to these difficult‐to‐treat patients in the near future.

Immunosuppression in Patients With Recurrent HCV

High‐intensity immunosuppression such as OKT3 and the treatment of acute rejection with bolus steroids are associated with severe HCV recurrence,17, 18, 19 and rejection is associated with diminished survival for HCV‐positive (but not HCV‐negative) LT recipients.20 Therefore, the initial treatment of mild acute rejection now typically includes modulation of the baseline immunosuppression when this is possible. However, the ideal maintenance immunosuppression regimen for striking a balance between viral control and suppression of rejection continues to be debated.

Although many aim to limit steroid exposure in HCV patients, rapid fluctuations in the levels of immunosuppression with steroid tapering may also negatively affect outcomes,21 and data are limited on steroid‐free regimens. As for the choice of calcineurin inhibitor, although cyclosporine appears to have in vitro antiviral activity22 and may be associated with an improved antiviral therapy response, in vivo viral suppression has not been demonstrated, and most trials and meta‐analyses have shown similar rates of HCV recurrence with cyclosporine and tacrolimus.23 Additionally, a nonrandomized United Network for Organ Sharing database analysis revealed superior overall survival for patients on tacrolimus‐based regimens (Fig. 3).24 Mycophenolate mofetil may also have in vitro antiviral properties and, when used as long‐term maintenance with low‐dose calcineurin inhibitors, may decrease the risk of fibrosis progression.25 Finally, there has been great interest in the use of mammalian target of rapamycin (mTOR) inhibitors because of their reported antifibrotic properties. There are no large, prospective randomized controlled trials looking at mTOR inhibitors specifically in HCV patients, although single‐center retrospective data were initially promising for sirolimus use.26 However, a Scientific Registry of Transplant Recipients data analysis revealed concern for overall increased mortality in HCV patients on mTOR‐based regimens.27 An analysis of HCV patients enrolled in the prospective everolimus studies is also ongoing, and prospective, randomized data are needed.

Figure 3.

The cumulative hazard of graft failure due to recurrent disease is higher in patients who receive tacrolimus as their primary immunosuppression versus patients who receive cyclosporine (hazard ratio = 1.4, P = 0.007) in the United Network for Organ Sharing database. Reprinted with permission from American Journal of Transplantation.24 Copyright 2011, American Society of Transplantation and American Society of Transplant Surgeons.

Therefore, clear evidence to support any particular maintenance regimen remains elusive, and recommendations for adjustments in the setting of significant HCV recurrence should focus on lowering the overall level of immunosuppression.

Future Directions

Antiviral therapy with SVR improves survival for LT patients with HCV. Combinations of potent oral directly active antivirals that achieve excellent SVR rates with shorter treatment duration and less toxicity will soon be a reality and will radically change the field. In the long term, these regimens will hopefully lead to fewer patients who require LT for HCV, and in the short term, they will significantly alter our ability to eradicate the virus in both the pre‐ and post‐LT settings.