Pediatr Transplantation 2014: 18: E64–E68

© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Pediatric Transplantation DOI: 10.1111/petr.12223

Liver transplantation in a child with multifocal hepatocellular carcinoma hepatitis C and management of post-transplant viral recurrence using boceprevir Malik S, Dekio F, Wen JW. Liver transplantation in a child with multifocal hepatocellular carcinoma hepatitis C and management of post-transplant viral recurrence using boceprevir. Abstract: HCV infection is the leading cause of liver transplantation in the adult population in the United States. HCV infection occurs in 0.2– 0.4% of the pediatric population and progression to HCC is uncommon. Liver transplantation for HCV in children is rare. In this report, we present a case of pediatric patient with HCV and multifocal HCC at the age of 13 who underwent successful liver transplantation. While good graft function was initially observed, at one month after transplant, he experienced significant hepatitis C recurrence. He was treated with low-accelerating dose regimen antiviral therapy of PEGIFN and RBV, followed by addition of a protease inhibitor, boceprevir, which led to viral clearance. To our knowledge, this is the first case report describing the post-transplant course of a child transplanted for HCV and HCC, and the first pediatric case report on using the triple therapy for management of post-liver transplant recurrence of HCV. This case report demonstrates the need for increased vigilance of surveillance for HCC during childhood.

HCV infection in children occurs in 0.2% of children 6–11 yr old and 0.4% of children 12–19 yr old (1), and most children acquire the infection through vertical transmission from their mothers. Even though HCV is the most common indication for liver transplantation in the adult population, progression to end-stage liver disease is relatively uncommon during childhood (2–4). Only 67 pediatric patients between 1988 and 2006 received liver transplantation for HCV in the United States (1). Development of HCC with HCV in the pediatric population is extremely Abbreviations: ADA-SCID, adenosine deaminase deficiencysevere combined immunodeficiency; AFP, alpha-fetoprotein; GI, gastrointestinal; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; PBSCT, peripheral blood stem-cell transplant; PEG-IFN, pegylated interferon; RBV, ribavirin; SCID, severe combined immunodeficiency syndrome; SVR, sustained virological response; TACE, transarterial chemoembolization.

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Saloni Malik1, Fumiko Dekio2 and Jessica W. Wen1,3 1

Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA, 2Department of Pathology, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA, 3Division of Gastroenterology, Hepatology and Nutrition, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA Key words: pediatric liver transplantation – carcinoma – viral infection Jessica W. Wen, Division of Gastroenterology, Hepatology & Nutrition, The Children’s Hospital of Philadelphia, 34th St & Civic Center Blvd, Philadelphia, PA 19104, USA Tel.: 215 590 9146 Fax: 215 590 3680 E-mail: [email protected] Accepted for publication 9 December 2013

rare, and it is associated with poor prognosis, mainly due to delay in diagnosis (5). In this report, we present a case of pediatric patient with HCV and multifocal HCC at the age of 13 who underwent successful liver transplantation. This patient developed clinically significant recurrent hepatitis C post-transplant and was successfully managed with newly available direct-acting antiviral medication boceprevir, in addition to standard treatment for HCV. To our knowledge, this is the first case report describing the post-transplant course of a child transplanted for HCV and HCC and the first case report describing the use of boceprevir in combination with PEG-IFN/RBV following liver transplantation in a child. The diagnostic evaluation and treatment strategies for such patients are discussed. This case report demonstrates the need for increased vigilance for surveillance of HCC occurrence in children.

Pediatric liver transplant in multifocal HCC and Hep C Case report

The patient was born with SCID, diagnosed after presentation of lung infection and failure to thrive at one month of age. He was subsequently diagnosed with adenosine deaminase deficiency or ADA-SCID. At six wk of age, he received PBSCT from his mother after conditioning with three daily doses of antithymocyte globulin. His mother was HIV negative but found to have hepatitis C infection during donor screening. The patient had undetectable HCV RNA prior to transplant. Due to the urgent need of stem-cell transplant, the decision was made to proceed with his mother as the donor. Following PBSCT, the patient was on cyclosporine as graft-vs.-hostdisease prophylaxis for several months. He was completely off of any immune suppression after completing the course of cyclosporine and was judged to have a fully reconstituted immune system. He did not receive any hepatitis C treatment after PBSCT and had unremarkable liver enzymes. At age 8, the patient was found to have evidence of chronic HCV infection, likely acquired from his mother either via vertical transmission or as a result of PBSCT, and was referred for GI care. He presented with increased liver enzymes and an increased alpha-fetoprotein level of 96.3 ng/mL (normal range 0.6–3.9 ng/mL). Physical examination revealed no ascites or masses present. He was found to have hepatitis C genotype 1a. Imaging studies and treatment for HCV was recommended. However, the patient was lost to follow-up, as his family relocated to another country. He returned at age 13 with evidence of compensated cirrhosis. In particular, the increased AFP level of 246 ng/mL raised concern for development of HCC. His HCV diagnosis with cirrhosis was supported by biopsy and confirmed as genotype 1a, with favorable IL28B polymorphism. MRI imaging found multiple nodules involving both lobes of the liver. Initial biopsy of one of the nodules showed changes consistent with chronic active hepatitis with cirrhosis, with no areas suggestive of HCC. However, repeat biopsy of the largest nodule, measuring 2 cm in the right hepatic lobe on imaging, showed characteristic changes of HCC. The patient had a 0.5cm lung nodule detected by CT that was found to be granulomatous inflammation due to histoplasmosis on wedge biopsy and serology. No other metastases were noted from MRI of the brain, abdomen and bone scan. Because of the multifocal nature of the cancer and underlying

cirrhosis, surgical resection was not an appropriate treatment option. The patient received a single TACE procedure and was placed on the waiting list for liver transplant. His last CT scan before transplant showed two lesions, 1.2 cm and 0.8 cm in size post-TACE. The patient underwent deceased pediatric donor whole-liver graft transplant just prior to his 14th birthday from an EBV/CMV serologynegative donor of matching blood type. The surgery proceeded without complications, and he had an uneventful recovery. The explanted liver revealed a 2-cm lesion in the mid-lower right lobe, which was histologically consistent with HCC. The background liver demonstrated diffuse micronodular cirrhosis and regenerative nodules with marked hepatocellular cholestasis. The patient was discharged home on postoperative day 8 with standard immunosuppressive regimen of tacrolimus and prednisone as well as antimicrobial and antiviral prophylactic medications. While he initially did well with good graft function, at one month post-transplant, he presented with increased liver enzymes, raising concern for acute cellular rejection. A liver biopsy (Fig. 1) revealed changes compatible with mild acute rejection, which was treated with pulse steroids. The biopsy also had findings consistent with recurrent hepatitis C. A second biopsy was performed a week later for continued rise in liver enzymes, increased bilirubin with total bilirubin peaking at 4 mg/dL (normal 0.6–1.4 mg/dL) and high HCV viral load (69 million IU/mL), which revealed ongoing recurrent hepatitis with severe lobulitis and resolution of rejection (Fig. 2). At that time, the decision was made to treat the patient with a gradually accelerating dosage regimen of antiviral therapy of PEG-interferon (PEG-IFN) and RBV. PEG-IFN (goal 1.5 mcg/ kg/wk) and RBV (goal 15 mg/kg/day divided twice daily) were both started at reduced dose with 50% dose of PEG-IFN and 33% dose of RBV. The two medications were then increased in alternating weeks, with 15–20% increase in PEG-IFN every two wk and 33% increase in RBV every two wk until reaching full dose. Tolerance to dose increase was assessed weekly. Initially, the patient was able to reach full dose of both medications. However, he later developed anemia and depression requiring dose reduction. He was eventually able to tolerate full dose RBV with concomitant use of erythropoietin and 80% dose of PEG-IFN. He had clear biochemical response with normalization of bilirubin and liver enzymes on this regimen, so the treatment was continued despite inability to achieve viral clearance (Fig. 3). After a year of E65

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Fig. 1. Liver allograft at four wk post-transplant. Recurrence of hepatitis C and acute cellular rejection. Top left: Portal inflammation. Top right: Perivenulitis. Bottom left: Hepatocytic changes compatible with hepatitis. Bottom right: Positive HCV immunostain.

Fig. 3. Post-transplant transaminases. Fig. 2. Liver allograft at five wk post-transplant. Resolution of acute cellular rejection but significant lobular hepatitis. (Inset: mild peri-portal inflammation).

treatment, boceprevir, a protease inhibitor used as treatment against genotype 1 HCV, was added to the treatment regimen with a weight-based dosing of approximately 34 mg/kg/day divided three times per day. Due to known drug–drug interactions between boceprevir and tacrolimus, the dosage of tacrolimus was lowered to 0.5 mg at the start of boceprevir treatment. And tacrolimus trough levels were followed closely until within the range of 4–7 prior to redosing. This patient was on tacrolimus with daily dosing schedule 2–3 times per week during his treatment. Other than continued need for erythropoietin, boceprevir was well tolerated in this patient without significant side effects. The patient completed 44 wk of the triple therapy. At week four of triple therapy, there was detected viral RNA but below the level E66

of quantification (lower detectable limit of 43 IU/mL). By week 8, the patient has had undetectable viral load and normalization of liver enzymes (Figs. 3 and 4), and remained HCV RNA negative at the end of treatment, 4 and 12 wk post-treatment. A repeat MRI of abdomen at two yr post-liver transplant shows no recurrence of HCC. Discussion

Here, we describe the case of a young adolescent with HCV infection since early infancy who developed cirrhosis and HCC by age 13; the patient was successfully transplanted with deceased donor liver graft. HCV in children rarely leads to progression of cirrhosis or HCC during childhood. This case highlights the importance of remaining vigilant for the possibility of pediatric HCC in the setting of chronic hepatitis C infection. There have been very limited reports of HCC and liver transplantation in the pediatric

HCV RNA Quant PCR (million IU/mL)

Pediatric liver transplant in multifocal HCC and Hep C Post-Transplant viral load 80

PEG-IFN + RBV

PEG-IFN + RBV + Boceprevir

60 40 20 * Not detected

0 0

20

40

60

80

100

Weeks after transplant

Fig. 4. Post-transplant HCV viral load.

population. In 2009, Gonzalez-Peralta et al. (5) described two cases in which young adolescents were infected with HCV leading to HCC. Both cases were detected at late stage with multifocal HCC. Neither patient fared well; one patient was considered for transplant, but expired prior to the procedure, while the other did not survive the transplant operation. HCV is known to be a significant risk factor for the development of HCC, and studies have suggested that periodic surveillance of these patients leads to earlier diagnosis with improved survival (6, 7). Surveillance is generally most strongly recommended for populations who are most highly at risk; there have been no studies describing benefit of screening for HCC in a pediatric population (8). Radiologic method with ultrasound every six months is the preferred method for surveillance, and confirmation of diagnosis is made without need for biopsy if the typical finding of intense arterial uptake, followed by “washout” of contrast in the venous phase is present on a 4-phase contrasted crosssectional imaging study (8–11). While late diagnosis of HCC have poor prognosis, there are treatment options for HCC if detected early. The preferred treatment for HCC is surgical resection. The five-yr survival of tumor resection exceeds 50% (8, 12–15). However, surgical resection is not an option if tumor size is too great, the HCC is bi-lobar, or if there is presence of vasculature invasion, or significant cirrhosis. Radiofrequency ablation, radioembolization, or transarterial chemo-embolization can be considered in such cases. Liver transplantation is considered if patient has advanced liver disease or tumors that are unresectable but fit within the Milan criteria: solitary HCC less than or equal to 5 cm in diameter, or up to three lesions 3 cm or less in diameter, without vascular invasion or metastases. The five-yr survival of patients within

Milan criteria receiving a liver transplant for HCC is estimated to be 70% (8). While there are too few pediatric patients who have been transplanted for HCV and HCC to generate a knowledge base about the nature of the postoperative course, in the adult population, HCV is the most common indication for liver transplant, and the postoperative course has been extensively studied (16). HCV is understood to recur universally and immediately in liver transplant recipients, unless there is viral clearance prior to transplant (3, 16–20). Recurrence progresses to cirrhosis in 20% of patients within five yr, and HCV genotype 1 is known to be particularly aggressive. Although HCV takes decades to progress to cirrhosis and HCC pretransplant, the rates of progression from cirrhosis to de-compensation, and death are accelerated after liver transplantation, often requiring re-transplantation. We know less about the postoperative course of HCV in children than we do in adults, however, by any measure, this patient’s clinically significant recurrence within one month post-transplant is an accelerated and aggressive form of recurrence. It is especially interesting to note that his mother, from whom he contracted the disease, remains untreated and asymptomatic. He shares an immune system with his mother, due to his bone marrow transplant, but his course of disease has been dramatically different from his mother’s. We do not know how the diagnosis of SCID and PBSCT with associated immune suppression immediately post stem-cell transplant might have altered the natural history of HCV in this patient. However, given that he did not have a detectable viral load prior to PBSCT and he was transplanted early in infancy, it is less likely that SCID by itself with a lack of adaptive immune response during the first month of life had contributed to the more rapid progression of hepatitis C in this child. But perhaps the conditioning regimen, brief immune suppression after PBSCT and a recovering adaptive immune response post-PBSCT led to the more aggressive course later on in life. When HCV does recur in the adult population, the decision-making process about how and whether to treat the disease with antiviral therapy depends on how aggressive the recurrence is; antiviral therapy is recommended if there is evidence of HCV-related progression to fibrosis. Although not all post-transplant patients can tolerate full-dose antiviral treatment, this therapy has nevertheless been shown to be effective, with reported SVR rates of 50% in patients with HCV genotype 2 or 3, and 13% SVR in those with genotype 1 (17). SVR is very strongly associated E67

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with improved long-term survival. In our patient, we were able to achieve biochemical response with resolution of jaundice and normalization of liver enzymes with PEG-IFN/RBV, and only achieved viral clearance once boceprevir was added. The currently approved first generation NS3 protease inhibitors are only genotype 1 specific and associated with significant side effects, such as anemia and skin rash in addition to the typical side effects associated with PEG-IFN/ RBV. With the availability of newer direct-acting antivirals that are developing in the pipeline, some of which are pan genotypic, and with the prospect of interferon-free regimens in the horizon, the outcomes for post-transplant HCV recurrence may be further improved in the future. This case demonstrates that although transplantation for HCV and HCC in children is rare, a successful outcome is possible. We suggest increased awareness of the possibility of HCC occurring in adolescent patients with chronic hepatitis C, particularly in those with bridging fibrosis or cirrhosis. We believe that greater vigilance may lead to improved outcomes for these patients. Authors’ contributions Saloni Malik: Participated in concept/design, data collection, and drafting the article. Fumiko Dekio: Participated in data collection, and revision of the article. Jessica Wen: Participated in concept/design, critical revision of the article, and approval of the article.

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5. GONZALEZ-PERALTA RP, LANGHAM MR Jr, ANDRES JM, et al. Hepatocellular carcinoma in 2 young adolescents with chronic hepatitis C. J Pediatr Gastroenterol Nutr 2009: 48: 630–635. 6. MCMAHON BJ, BULKOW L, HARPSTER A, et al. Screening for hepatocellular carcinoma in Alaska natives infected with chronic hepatitis B: A 16-year population-based study. Hepatology 2000: 32: 842–846. 7. WONG LL, LIMM WM, SEVERINO R, WONG LM. Improved survival with screening for hepatocellular carcinoma. Liver Transpl 2000: 6: 320–325. 8. BRUIX J, SHERMAN M. Management of hepatocellular carcinoma: An update. Hepatology 2011: 53: 1020–1022. 9. KOJIRO M. Focus on dysplastic nodules and early hepatocellular carcinoma: An Eastern point of view. Liver Transpl 2004: 10: S3–S8. 10. YU JS, KIM KW, KIM EK, LEE JT, YOO HS. Contrast enhancement of small hepatocellular carcinoma: Usefulness of three successive early image acquisitions during multiphase dynamic MR imaging. AJR Am J Roentgenol 1999: 173: 597–604. 11. MUELLER GC, HUSSAIN HK, CARLOS RC, NGHIEM HV, FRANCIS IR. Effectiveness of MR imaging in characterizing small hepatic lesions: Routine versus expert interpretation. AJR Am J Roentgenol 2003: 180: 673–680. 12. FONG Y, SUN RL, JARNAGIN W, BLUMGART LH. An analysis of 412 cases of hepatocellular carcinoma at a Western center. Ann Surg 1999: 229: 790–799; discussion 9-800. 13. INTERNATIONAL CONSENSUS GROUP FOR HEPATOCELLULAR NEOPLASIA. Pathologic diagnosis of early hepatocellular carcinoma: A report of the international consensus group for hepatocellular neoplasia. Hepatology 2009: 49: 658–664. 14. GRAZI GL, ERCOLANI G, PIERANGELI F, et al. Improved results of liver resection for hepatocellular carcinoma on cirrhosis give the procedure added value. Ann Surg 2001: 234: 71–78. 15. ISHIZAWA T, HASEGAWA K, AOKI T, et al. Neither multiple tumors nor portal hypertension are surgical contraindications for hepatocellular carcinoma. Gastroenterology 2008: 134: 1908–1916. 16. SELZNER N, RENNER EL, SELZNER M, et al. Antiviral treatment of recurrent hepatitis C after liver transplantation: Predictors of response and long-term outcome. Transplantation 2009: 88: 1214–1221. 17. TERRAULT NA. Hepatitis C therapy before and after liver transplantation. Liver Transpl 2008: 14(Suppl 2): S58–S66. 18. GANE EJ. The natural history of recurrent hepatitis C and what influences this. Liver Transpl 2008: 14(Suppl 2): S36–S44. 19. GONZALEZ SA. Management of recurrent hepatitis C following liver transplantation. Gastroenterology & Hepatology 2010: 6: 637–645. 20. VENTURI C, BUENO J, CASTELLS L, et al. Long-term outcome of hepatitis C virus infections acquired after pediatric liver transplantation. Liver Transpl 2011: 17: 1474–1480.

Liver transplantation in a child with multifocal hepatocellular carcinoma hepatitis C and management of post-transplant viral recurrence using boceprevir.

HCV infection is the leading cause of liver transplantation in the adult population in the United States. HCV infection occurs in 0.2-0.4% of the pedi...
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