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♦CASO CLÍNICO
Successful treatment with telaprevir of
post-transplant fibrosing cholestatic hepatitis C
in an HIV co-infected patient
Sebastián Marciano,1 Omar Andrés Galdame,1 Laura Alicia Barcan,2 Adrián Carlos Gadano1
Sección de Hepatología,
Sección de Infectología,
Hospital Italiano, Buenos Aires, Argentina.
1
2
Acta Gastroenterol Latinoam 2015;45:076-079
Summary
Hepatitis C recurrence is the main cause of graft loss in liver transplant patients co-infected with human immunodeficiency virus (HIV). These patients have higher risk of
fibrosing cholestatic hepatitis, which is the most severe type
of hepatitis C recurrence. Until direct antiviral agents were
released, only a minority of patients could be satisfactorily
treated. We describe the successful treatment with pegylatedinterferon, ribavirin and telaprevir of an hepatitis C virus
(HCV)/HIV co-infected patient who developed fibrosing
cholestatic hepatitis after liver transplantation. A 40-yearold male (HCV genotype 1a; IL-28 CC) underwent liver
transplantation for decompensated cirrhosis. On post-transplant day 60, he rapidly developed progressive jaundice,
worsening of liver function tests and ascites. A transjugular
liver biopsy confirmed the diagnosis of fibrosing cholestatic
hepatitis. Treatment with pegylated-interferon, ribavirin
and telaprevir was indicated for 48 weeks, achieving sustained virological response at 12 weeks of follow-up. The rapid
negativization of the viral load observed during the first 4
weeks of treatment was associated with regression of ascites
and jaundice. Red blood cell transfusions, erythropoietin and
filgrastim were required for the management of anemia and
neutropenia. Triple therapy with telaprevir might be indicated for the treatment of severe HCV recurrence in selected
Correspondencia: Sebastián Marciano
Valentín Virasoro 2470
Barrio Virasoro Village (Lote 16)
San Isidro (CP: 1643), Buenos Aires, Argentina
Phone: 54-9-11-50066086
Fax: 54-11-49590346
E-mail: [email protected]
76 Acta Gastroenterol Latinoam 2015;45(1)076-079
HCV/HIV co-infected patients, especially in countries with
limited access to pegylated-interferon-free regimens.
Key words. Direct antiviral agents, graft loss, hepatitis C
recurrence, protease inhibitors.
Hepatitis C fibrosante colestásica tratada
con telaprevir luego del trasplante hepático
en un paciente co-infectado con HIV
Resumen
La recurrencia de la hepatitis C post-trasplante hepático es la
principal causa de pérdida del injerto en los pacientes coinfectados con el virus de la inmunodeficiencia humana (HIV).
Estos pacientes presentan un riesgo elevado de recurrencia de
la hepatitis C en su forma más grave, hepatitis colestásica fibrosante. En la era previa a los antivirales de acción directa,
el tratamiento de la misma era ineficaz, pudiendo rescatar
una minoría de los pacientes afectados. Presentamos el caso
de un paciente coinfectado que desarrolló una recurrencia de
hepatitis C colestásica fibrosante luego del trasplante, la cual
fue tratada con éxito con interferón pegilado, ribavirina y
telaprevir. Un paciente de 40 años de edad [virus de la hepatitis C (HCV) genotipo 1a; IL-28 CC] coinfectado con
HIV fue sometido a un trasplante hepático por cirrosis descompensada. En el día 60 post-trasplante desarrolló ictericia
progresiva y ascitis severa. La biopsia hepática transyugular
confirmó el diagnóstico de recurrencia de hepatitis C colestásica fibrosante. Se realizó tratamiento con interferón pegilado, ribavirina y telaprevir por 48 semanas, logrando respuesta virológica sostenida a 12 semanas de finalizado el mismo.
La negativización de la viremia en las primeras 4 semanas de
tratamiento se asoció con resolución de la ascitis y la ictericia.
Durante el tratamiento requirió eritropoyetina, filgrastim y
Post-transplant telaprevir in HCV/HIV co-infection
transfusiones de glóbulos rojos para el manejo de la anemia y
neutropenia. La triple terapia con telaprevir podría indicarse
para el tratamiento de la recurrencia severa de la hepatitis C en
pacientes coinfectados con HIV, especialmente en países en los
que la accesibilidad a esquemas libres de interferón sea limitada.
Palabras claves. Antivirales de acción directa, pérdida del
injerto, recurrencia de hepatitis C, inhibidores de proteasa.
Abbreviations
HCV: Hepatitis C virus.
HIV: Human immunodeficiency virus.
SVR: Sustained virological response.
PEG-INF: Pegylated-interferon.
RBV: Ribavirin.
DAA: Direct antiviral agents.
Re-infection of the graft is the main cause of death and
graft loss in patients with hepatitis C virus (HCV) infection undergoing liver transplantation.1–5 In some patients,
HCV recurrence is characterized by an accelerated fibrosis
process.6 Once cirrhosis of the graft develops, decompensation occurs in more than two thirds of the recipients,
ultimately leading to re-transplantation or death.6, 7
A sub-group of patients who experience HCV recurrence develops an aggressive variant known as fibrosing
cholestatic hepatitis, which is characterized by severe cholestasis, ballooning, perisinusoidal fibrosis and very high
HCV viral load. Its prognosis is dismal, almost invariably
characterized by rapid deterioration of liver function.2, 8, 9
Outcomes after liver transplantation are poorer in
HCV patients co-infected with the human immunodeficiency virus (HIV) than in HCV mono-infected patients.10–12 These patients are at higher risk of rapid fibrosis progression and fibrosing cholestatic hepatitis.13, 14
The management of HCV recurrence in co-infected
patients is challenging. The global sustained virological
response (SVR) rates are low in patients treated with
pegylated-interferon (PEG-INF) plus ribavirin (RBV),15
especially in patients with fibrosing cholestatic hepatitis. Since the introduction of the direct antiviral agents
(DAAs) boceprevir and telaprevir, higher SVR rates were
reported for the treatment of HCV genotype 1 recurrence in mono-infected patients.16 However, this strategy is
challenged by treatment-related toxicity and significant drug
to drug interactions.16 Recently, sofosbuvir and simeprevir
were recommended for the treatment of post-transplant
HCV recurrence.17 However, access to these new DDAs is
still limited in most countries. At the time this case-report
Sebastián Marciano y col
was submitted, there was a single published case describing
the use of telaprevir in combination with PEG-INF plus
RBV in an HCV/HIV co-infected patient with severe HCV
recurrence after liver transplantation.18
We report the successful treatment with telaprevir in
combination with PEG-INF and RBV in an HCV/HIV
co-infected liver transplant recipient with severe fibrosing
cholestatic HCV recurrence.
Case report
A 40-year-old Hispanic male patient co-infected with
HCV (genotype 1a; IL-28 CC) and HIV underwent liver
transplantation for decompensated cirrhosis. He had been a
prior partial responder to PEG-INF plus RBV 4 years before liver transplantation. At the time of that treatment he had
compensated cirrhosis and an anti-retroviral therapy consisting of ritonavir-boosted lopinavir, tenofovir and emtricitabine (HIV viral load was undetectable and the CD4+ cell count
was 265/mm3). The MELD score at the time of transplantation was 32 and the Child-Pugh C-10. The HCV viral load
was 13,900 IU/mL, HIV was undetectable and CD4 cell
count was 279/mm3. Anti-retrovirals remained unchanged.
A 53 year old, heart-beating deceased female donor
was used. The cause of death was an hemorrhagic cerebrovascular accident. The body mass index was 35. The
cold ischemia time was 7 hours. The transplant was uneventful with a total duration of 6 hours. Induction was
performed with basiliximab and steroids. The immediate
postoperative course was complicated by arterial hypertension and a urinary tract infection, both successfully
controlled with appropriate treatment. Tacrolimus was
initiated on postoperative day 1, achieving blood though
levels between 7-12 ng/ml together with mycophenolate
mofetil. Anti-retrovirals were re-initiated on post transplant day 40 with the same pre-transplant regimen. On
post-transplant day 60, the patient rapidly developed
progressive jaundice, worsening of liver function tests
and tense ascites. Blood tests revealed significant liver
dysfunction: total bilirubin 17.8 mg/dL, prothrombin
concentration 62% and alanine aminotransferase 175
IU/L (Table 1). Liver ultrasography was normal. A transjugular liver biopsy was performed, which showed features of fibrosing cholestatic HCV recurrence: severe cholestasis, ballooning and perisinusoidal fibrosis.
After written consent was obtained, the patient was
admitted for 2 weeks to start treatment with PEG-INF
alfa-2a (180 ug/week), RBV (1,000 mg/day) and telaprevir (750 mg three times daily). Anti-retrovirals were
switched to raltegravir, tenofovir and emtricitabine.
Tacrolimus dose was carefully adjusted to obtain blood
Acta Gastroenterol Latinoam 2015;45(1)076-079
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Post-transplant telaprevir in HCV/HIV co-infection
Sebastián Marciano y col
Table 1. Laboratory characteristics before, during and after treatment.
trough levels of 8 to 12 ng/ml. Mycophenolate mofetil
was discontinued. Pre-treatment HCV viral load was higher than 69,000,000 IU/mL (Cobas TaqMan; lower limit
of quantification 43 IU/mL, lower limit of detection 26
IU/mL, higher limit of quantification 69,000,000 IU/
mL). Most significant treatment related adverse events
were flu-like symptoms, anemia and neutropenia. Red
blood cell transfusions (three units in two separate days),
erythropoietin and filgrastim were required for the management of cytopenias. A progressive decline in CD4
cell count was observed during the treatment, requiring
prophylaxis with azithromycin and trimethoprim-sulfamethoxazole. HIV viral load was persistently undetectable. Two therapeutic paracentesis were performed during
the first 4 weeks of treatment. Ascites and jaundice resolved during the first 4 weeks of treatments and did not
recur. Thereafter, treatment tolerability was optimal.
The patient was treated for 48 weeks, receiving telaprevir, PEG-INF plus RBV during the first 12 weeks, and
PEG-INF plus RBV thereafter. The HCV viral load was
detectable but unquantifiable at treatment week 4, and
undetectable at treatment weeks 12, 24 and 48. Adherence to treatment was optimal and no dose reductions were
required in any of the medications. The patient achieved
SVR at 12 weeks after the end of therapy (SVR-12) and is
currently asymptomatic, with normal liver function tests.
A transient elastography (Fibroscan®) was performed at
end of treatment showing a 6.7 Kpa, corresponding to a
fibrosis stage grade of 0-1.
78 Acta Gastroenterol Latinoam 2015;45(1)076-079
Discussion
The presentation of this case illustrates the successful
treatment of fibrosing cholestatic HCV recurrence with telaprevir, PEG-INF and RBV in an HIV co-infected patient.
Fibrosing cholestatic hepatitis after liver transplantation is an unfortunate situation. In patients who do
not respond to treatment, re-transplantation is the only
remaining choice once liver failure develops. However,
re-transplantation of HCV/HIV co-infected patients is
associated with poor outcomes and is controversial.19
Prior studies have shown that co-infected patients have
higher HCV viral loads after transplantation, higher rate of
fibrosing cholestatic hepatitis and a more rapid progression
of fibrosis.20 Our patient had several risks factors for developing severe HCV recurrence. The donor was 53 years old
and had a BMI of 35. Moreover, the MELD at transplantation was 32. These characteristics have been previously
described to be associated with worse outcomes.20
There is not general agreement on the optimal immunosuppression for co-infected patients after liver
transplantation. Our patient received induction with
basiliximab and steroids. Maintenance immunosuppression consisted of tacrolimus, mycophenolate mofetil and
steroids. We chose this immunosuppression regimen for
two reasons. First, because rejection was described to
be more frequent in co-infected than in mono-infected
patients.20 Second, because it has been described that
treatment of rejection (steroid boluses) is associated with
more severe HCV disease.20
Post-transplant telaprevir in HCV/HIV co-infection
We decided to initiate triple therapy with PEG-INF,
RBV and telaprevir. Anti-retrovirals were switched to minimize drug interactions and tacrolimus dose was property adjusted. Mycophenolate was discontinued in order
to lower the risk of treatment-induced cytopenias. The
rapid reduction in HCV viral load induced by the triple
therapy was associated with resolution of the ascites and
normalization of liver function tests. Moreover, SVR-12
was achieved after 48 weeks of therapy.
Daclatasvir and sofosbuvir successful treatment of fibrosing cholestatic HCV recurrence in an HCV mono-infected patient has already been reported.21 Sofosbuvir and
simeprevir were recently recommended for the treatment
of HCV in different settings.17 The combination of these
DAAs with or without RBV would have been the ideal
treatment for the patient we report. However, these
drugs might not be widely available in the near future.
Meanwhile, we believe that different strategies should be
implemented to prevent and treat the aggressive HCV
recurrence in co-infected patients: from adequate donorrecipient matching to antiviral treatment, even in cases in
whom marginal treatment tolerability is anticipated.
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