Therapy with boceprevir or telaprevir in HIV/ hepatitis C virus co-infected patients to treat recurrence of hepatitis C virus infection after liver transplantation Teresa Maria Antoninia,b,c,i, Valerie Furland,i, Elina Teichera,e,i, Stephanie Haim-Boukobzab,c,f,i, Mylene Sebaghb,c,g,i, Audrey Coillya,b,c,i, Laurence Bonhomme-Faivreh,i, Anne-Marie Roque-Afonsob,c,f,i, Daniel Vittecoqe,i, Didier Samuela,b,c,i, Anne-Marie Taburetd,i and Jean-Charles Duclos-Valle´ea,b,c,i Objective: Severe hepatitis C virus (HCV) recurrence affects post-transplant survival in HIV/HCV co-infected patients. This article describes the results of triple anti-HCV therapy with boceprevir or telaprevir in seven HIV/HCV co-infected patients following liver transplantation. Methods: All patients had severe HCV recurrence [fibrosis stage F2 or acute hepatitis A2 (n ¼ 5) or fibrosing cholestatic hepatitis (n ¼ 2)] associated with genotype 1a (n ¼ 4) or 1b (n ¼ 3). Patients were treated with Peg-interferon/ribavirin and boceprevir (n ¼ 2) or telaprevir (n ¼ 5) immediately (n ¼ 3) or after a 4-week lead-in phase (n ¼ 4). Immunosuppression included either cyclosporine (n ¼ 5) or tacrolimus (n ¼ 2). Prior to introducing telaprevir, combined antiretroviral therapy was switched in one patient to prevent drug–drug interactions. Results: At 24 weeks after the end of treatment, sustained virological response was observed in 60% (3/5) of the patients treated with telaprevir; no responders were observed in the boceprevir group. Triple anti-HCV therapy was prematurely discontinued in six patients [treatment failure (n ¼ 2), infection (n ¼ 2), acute rejection (n ¼ 1) and myocardial infarction (n ¼ 1)]. Anaemia occurred in all patients, requiring erythropoietin, ribavirin dose reduction and red blood cell transfusions in five patients. Average cyclosporine doses were reduced by 50–84% after telaprevir initiation and by 33% after boceprevir initiation. Tacrolimus doses were reduced by 95% with telaprevir. Conclusion: Our data suggest that in HIV/HCV co-infected patients, triple anti-HCV therapy with telaprevir greatly improved efficacy despite poor tolerability. Significant decreases in cyclosporine or tacrolimus doses are necessary prior to introduction of boceprevir or telaprevir. Close monitoring is essential to prevent drug–drug interactions among antiretroviral therapy, immunosuppressive agents and anti-HCV therapy. ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
AIDS 2015, 29:53–58 a AP-HP Hoˆpital Paul-Brousse, Centre He´pato-Biliaire, bUniversity Paris-Sud, UMR-S 785, cInserm, Unite´ 785, Villejuif, dAP-HP, Hoˆpital Kremlin-Biceˆtre, HUPS, Pharmacie Clinique, eAP-HP Hoˆpital Kremlin-Biceˆtre, Service de Me´decine Interne, Immunologie et Maladies Infectieuses, Le Kremlin-Biceˆtre, fAP-HP Hoˆpital Paul-Brousse, Service Virologie, gAP-HP Hoˆpital PaulBrousse, Service Anatomie Pathologique, hAP-HP, Hoˆpital Paul-Brousse, Pharmacie Clinique, and iDHU Hepatinov, Villejuif, France. Correspondence to Professor Jean-Charles Duclos-Valle´e, Centre He´pato-Biliaire, Hoˆpital Paul-Brousse, 12, avenue Paul Vaillant Couturier, 94800 Villejuif, France. E-mail: [email protected] Received: 3 July 2014; revised: 1 October 2014; accepted: 9 October 2014.
DOI:10.1097/QAD.0000000000000516
ISSN 0269-9370 Q 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
53
54
AIDS
2015, Vol 29 No 1
Keywords: boceprevir, hepatitis C virus, HIV, immunosuppression, liver transplantation, telaprevir
Introduction Liver transplantation in HIV-infected patients is feasible [1–4]. Our experience has shown that 2 and 5-year survival rates of co-infected patients are poorer than those of hepatitis C virus (HCV) mono-infected patients: 73 and 51% in HIV/HCV patients vs. 91 and 81% in HCV alone [2]. This is the consequence of more rapidly developing HCV fibrosis in the graft and of fibrosing cholestatic hepatitis (FCH) in a significant number of patients (19%) associated with a 15% survival rate at 3 years [2–5]. Standard anti-HCV therapy peg-interferon (Peg-IFN) þ ribavirin (RBV) rarely yields a sustained virological response (SVR). After anti HCV therapy with Peg-IFN and RBV, SVR was observed in only 18% of patients with a severe HCV recurrence following liver transplantation [5]. The addition of protease inhibitors, the first-generation direct-acting antivirals (DAAs), such as boceprevir (BOC) or telaprevir (TVR), has enhanced the efficacy of PegIFN þ RBV therapy in genotype 1-naive and non-naı¨ve non-transplanted patients from 38 to 66% and 21 to 66%, respectively [6,7]. In HIV/HCV co-infected noncirrhotic patients treated with BOC or TVR, SVR 24 weeks (W) was obtained in 63 and 73% of the treated patients, respectively [8,9]. Moreover, we recently demonstrated that DAAs Peg-IFN and RBV (DAAPR) are effective in HCV mono-infected patients following liver transplantation. Sustained virological response at week 24 post-treatment follow-up (SVR 24) was 71% in patients treated with BOC and 20% in those treated with TVR [10]. In this study, we report our initial experience with antiHCV triple therapy following liver transplantation, including BOC or TVR in seven HIV/HCV coinfected patients.
Patients and methods Patient characteristics Seven HIV/HCV co-infected patients (six men, one woman) were treated using triple anti-HCV therapy, associating Peg-IFN þ RBV with BOC (n ¼ 2) or TVR (n ¼ 5) following liver transplantation. The indications for liver transplantation were end-stage liver disease (n ¼ 5) and hepatocellular carcinoma (n ¼ 2). Anti-HCV triple therapy was initiated upon severe HCV
recurrence in the graft, as defined by fibrosis stage at least F2 or acute hepatitis stage at least A2, determined by the METAVIR score (n ¼ 5) [11] or the presence of FCH (n ¼ 2) [12].
Virological monitoring Hepatitis C virus RNA was quantified using Abbott Real Time HCV PCR assay [limit of quantification (LOQ): 12 IU/ml; Abbott Diagnostics, Chicago, Illinois, USA]. Plasma HIV viral load was quantified using Cobas Taqman AmpliPrep/Cobas Taqman v2 (LOQ of 20 copies/ml; Roche Molecular Diagnostics, Mannheim, Germany). Direct sequencing of the NS5B region was used to determine the HCV genotype, as described elsewhere [13]. Interleukin (IL)28B polymorphism rs12979860 (IL28B) of recipients and donors was determined using ABI TaqMan allelic discrimination kit and ABI7900HT Sequence Detection System (Applied Biosystems, Carlsbad, California, USA). Rapid virological response (RVR) was defined as undetectable serum HCV RNA at week 4 of the triple therapy. At week 12, early virological response (EVR) was defined as a 2-log decrease from baseline HCV RNA level. Complete EVR (cEVR) was defined as undetectable serum HCV RNA at W24 of the triple therapy. The HCV viral load was monitored at baseline, W2 and then monthly until the end of treatment. In the event of virological response, the viral load was monitored each month until 6 months after treatment (SVR 24). In the event of virological failure, resistance to TVR or BOC was proven as previously described [14].
Anti-hepatitis C virus regimen Two patients were treated with BOC and five with TVR. A 4-week lead-in phase was performed in all patients receiving BOC and in two patients receiving TVR. All patients received Peg-IFN a2a (Pegasys; Roche) (n ¼ 2) or Peg-IFN a2b (Viraferon-Peg; Schering-Plough, Kemlworth, New Jersey, USA) (n ¼ 5). The initial dose of Peg-IFN a2b was 135 mg/week in two patients and 180 mg/week in three patients. The initial dose of Peg-IFN a2a was 90 and 100 mg/week, respectively. Mean initial dose of RBV (Copegus from Roche, or Rebetol from Schering-Plough) as adjusted to renal function was 714 mg/day (600–1000). Boceprevir (800 mg three times a day) was initiated after a 4-week lead-in phase of Peg-IFN þ RBV therapy. TVR
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Triple anti-hepatitis C virus therapy Antonini et al.
(750 mg three times a day) was introduced simultaneously or after a 4-week lead-in phase of Peg-IFN þ RBV therapy. In the latter group, lead-in phase served to assess Peg-IFN þ RBV tolerability. Failure to achieve HCV RNA levels less than 100 IU/ml at week 12 in the BOC group and less than 1000 IU/ml at week 4 or 12 in the TVR group led to stopping of therapy.
CNI drug concentrations were closely monitored at initiation, during combined treatment and following DAA-PR therapy. CNI drug dosing regimens, according to the duration since liver transplantation, were adjusted to therapeutic target ranges between 50 and 150 ng/ml for cyclosporine and between 5 and 10 ng/ml for tacrolimus (TAC).
Histological examination Liver biopsies were fixed in acet acid-formaline-aldehyde, paraffin-embedded and stained with Hematein Eosin Safran, Picrosirius and Perls. Acute and chronic rejections were diagnosed according to Banff classifications [15]. A diagnosis of ‘biliary obstruction’ was based on a combination of portal oedematous fibrosis, ductular proliferation, portal mixed inflammatory infiltrate, cholangiolitis and cholestasis [16]. Chronic hepatitis was evaluated using the METAVIR scoring system [11].
Clinical and biological data were collected for all patients throughout the triple therapy and follow-up. Erythropoietin (EPO) (Neorecormon; Roche), at a maximum dose of 40 000 IU weekly, was administered when haemoglobin levels either dropped below 10 g/dl, were above 1 g/dl per week or were below 12 g/dl before initiating triple therapy. When the neutrophil count was below 500 cells/ml, the Peg-IFN dose was reduced. Granulocyte colony-stimulating factor (G-CSF) (Neupogen; Amgen Europe BV, Breda, The Netherlands) at a maximum dose of 300 g weekly was introduced when neutrophil counts remained low. Eltrombopag (Revolade; Glaxosmithkline, Research Triangle Park, North Carolina, USA) was initiated at 25 mg once daily when the platelet count was below 50 109/l, despite reduced Peg-IFN doses. Creatinine clearance was estimated using the Cockcroft–Gault formula.
Fibrosing cholestatic hepatitis was defined according to the histological criteria described by Davies et al. [12]: presence of extensive, dense portal fibrosis with immature fibrous bands extending into the sinusoidal spaces, ductular proliferation, cholestasis and moderate mononuclear inflammation.
Safety assessment Patients were hospitalized the day before protease inhibitor initiation or a combination antiretroviral therapy (cART) switch (if needed), for clinical monitoring and assays of trough blood concentrations of calcineurin inhibitors (CNI) drugs. In line with available data concerning drug–drug interaction studies conducted in healthy volunteer participants, and based on our experience with HCV mono-infected patients, trough
Results Patient characteristics at baseline The mean time between liver transplantation and antiHCV triple therapy introduction was 28 months (range 2–77 months). Patient characteristics upon initiating anti-HCV triple therapy are described in Table 1. Mean
Table 1. Clinical and biological characteristics of HIV/hepatitis C virus co-infected patients before the introduction of triple anti-hepatitis C virus therapy. N Sex Age (years) MELD score Months after LT Total bilirubin (mmol/l) g-GT (IU/l) Creatinine clearance (ml/min) CD4þ (cells/ml) CD4þ/CD8þ (%) HCV RNA (log 10 IU/ml) HCV genotype IL28b recipient HCV treatment (naive) HCV RNA (log 10 copies/ml) cART (before anti-HCV therapy) Immunosupressive therapy Liver biopsy (before anti-HCV therapy)
1
2
3
4
5
6
7
F 52 20 7 163 1135 72 289 0.3 8.6 1b CT Yes
AIDS 2015, 29:53–58 a AP-HP Hoˆpital Paul-Brousse, Centre He´pato-Biliaire, bUniversity Paris-Sud, UMR-S 785, cInserm, Unite´ 785, Villejuif, dAP-HP, Hoˆpital Kremlin-Biceˆtre, HUPS, Pharmacie Clinique, eAP-HP Hoˆpital Kremlin-Biceˆtre, Service de Me´decine Interne, Immunologie et Maladies Infectieuses, Le Kremlin-Biceˆtre, fAP-HP Hoˆpital Paul-Brousse, Service Virologie, gAP-HP Hoˆpital PaulBrousse, Service Anatomie Pathologique, hAP-HP, Hoˆpital Paul-Brousse, Pharmacie Clinique, and iDHU Hepatinov, Villejuif, France. Correspondence to Professor Jean-Charles Duclos-Valle´e, Centre He´pato-Biliaire, Hoˆpital Paul-Brousse, 12, avenue Paul Vaillant Couturier, 94800 Villejuif, France. E-mail: [email protected] Received: 3 July 2014; revised: 1 October 2014; accepted: 9 October 2014.
DOI:10.1097/QAD.0000000000000516
ISSN 0269-9370 Q 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
53
54
AIDS
2015, Vol 29 No 1
Keywords: boceprevir, hepatitis C virus, HIV, immunosuppression, liver transplantation, telaprevir
Introduction Liver transplantation in HIV-infected patients is feasible [1–4]. Our experience has shown that 2 and 5-year survival rates of co-infected patients are poorer than those of hepatitis C virus (HCV) mono-infected patients: 73 and 51% in HIV/HCV patients vs. 91 and 81% in HCV alone [2]. This is the consequence of more rapidly developing HCV fibrosis in the graft and of fibrosing cholestatic hepatitis (FCH) in a significant number of patients (19%) associated with a 15% survival rate at 3 years [2–5]. Standard anti-HCV therapy peg-interferon (Peg-IFN) þ ribavirin (RBV) rarely yields a sustained virological response (SVR). After anti HCV therapy with Peg-IFN and RBV, SVR was observed in only 18% of patients with a severe HCV recurrence following liver transplantation [5]. The addition of protease inhibitors, the first-generation direct-acting antivirals (DAAs), such as boceprevir (BOC) or telaprevir (TVR), has enhanced the efficacy of PegIFN þ RBV therapy in genotype 1-naive and non-naı¨ve non-transplanted patients from 38 to 66% and 21 to 66%, respectively [6,7]. In HIV/HCV co-infected noncirrhotic patients treated with BOC or TVR, SVR 24 weeks (W) was obtained in 63 and 73% of the treated patients, respectively [8,9]. Moreover, we recently demonstrated that DAAs Peg-IFN and RBV (DAAPR) are effective in HCV mono-infected patients following liver transplantation. Sustained virological response at week 24 post-treatment follow-up (SVR 24) was 71% in patients treated with BOC and 20% in those treated with TVR [10]. In this study, we report our initial experience with antiHCV triple therapy following liver transplantation, including BOC or TVR in seven HIV/HCV coinfected patients.
Patients and methods Patient characteristics Seven HIV/HCV co-infected patients (six men, one woman) were treated using triple anti-HCV therapy, associating Peg-IFN þ RBV with BOC (n ¼ 2) or TVR (n ¼ 5) following liver transplantation. The indications for liver transplantation were end-stage liver disease (n ¼ 5) and hepatocellular carcinoma (n ¼ 2). Anti-HCV triple therapy was initiated upon severe HCV
recurrence in the graft, as defined by fibrosis stage at least F2 or acute hepatitis stage at least A2, determined by the METAVIR score (n ¼ 5) [11] or the presence of FCH (n ¼ 2) [12].
Virological monitoring Hepatitis C virus RNA was quantified using Abbott Real Time HCV PCR assay [limit of quantification (LOQ): 12 IU/ml; Abbott Diagnostics, Chicago, Illinois, USA]. Plasma HIV viral load was quantified using Cobas Taqman AmpliPrep/Cobas Taqman v2 (LOQ of 20 copies/ml; Roche Molecular Diagnostics, Mannheim, Germany). Direct sequencing of the NS5B region was used to determine the HCV genotype, as described elsewhere [13]. Interleukin (IL)28B polymorphism rs12979860 (IL28B) of recipients and donors was determined using ABI TaqMan allelic discrimination kit and ABI7900HT Sequence Detection System (Applied Biosystems, Carlsbad, California, USA). Rapid virological response (RVR) was defined as undetectable serum HCV RNA at week 4 of the triple therapy. At week 12, early virological response (EVR) was defined as a 2-log decrease from baseline HCV RNA level. Complete EVR (cEVR) was defined as undetectable serum HCV RNA at W24 of the triple therapy. The HCV viral load was monitored at baseline, W2 and then monthly until the end of treatment. In the event of virological response, the viral load was monitored each month until 6 months after treatment (SVR 24). In the event of virological failure, resistance to TVR or BOC was proven as previously described [14].
Anti-hepatitis C virus regimen Two patients were treated with BOC and five with TVR. A 4-week lead-in phase was performed in all patients receiving BOC and in two patients receiving TVR. All patients received Peg-IFN a2a (Pegasys; Roche) (n ¼ 2) or Peg-IFN a2b (Viraferon-Peg; Schering-Plough, Kemlworth, New Jersey, USA) (n ¼ 5). The initial dose of Peg-IFN a2b was 135 mg/week in two patients and 180 mg/week in three patients. The initial dose of Peg-IFN a2a was 90 and 100 mg/week, respectively. Mean initial dose of RBV (Copegus from Roche, or Rebetol from Schering-Plough) as adjusted to renal function was 714 mg/day (600–1000). Boceprevir (800 mg three times a day) was initiated after a 4-week lead-in phase of Peg-IFN þ RBV therapy. TVR
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Triple anti-hepatitis C virus therapy Antonini et al.
(750 mg three times a day) was introduced simultaneously or after a 4-week lead-in phase of Peg-IFN þ RBV therapy. In the latter group, lead-in phase served to assess Peg-IFN þ RBV tolerability. Failure to achieve HCV RNA levels less than 100 IU/ml at week 12 in the BOC group and less than 1000 IU/ml at week 4 or 12 in the TVR group led to stopping of therapy.
CNI drug concentrations were closely monitored at initiation, during combined treatment and following DAA-PR therapy. CNI drug dosing regimens, according to the duration since liver transplantation, were adjusted to therapeutic target ranges between 50 and 150 ng/ml for cyclosporine and between 5 and 10 ng/ml for tacrolimus (TAC).
Histological examination Liver biopsies were fixed in acet acid-formaline-aldehyde, paraffin-embedded and stained with Hematein Eosin Safran, Picrosirius and Perls. Acute and chronic rejections were diagnosed according to Banff classifications [15]. A diagnosis of ‘biliary obstruction’ was based on a combination of portal oedematous fibrosis, ductular proliferation, portal mixed inflammatory infiltrate, cholangiolitis and cholestasis [16]. Chronic hepatitis was evaluated using the METAVIR scoring system [11].
Clinical and biological data were collected for all patients throughout the triple therapy and follow-up. Erythropoietin (EPO) (Neorecormon; Roche), at a maximum dose of 40 000 IU weekly, was administered when haemoglobin levels either dropped below 10 g/dl, were above 1 g/dl per week or were below 12 g/dl before initiating triple therapy. When the neutrophil count was below 500 cells/ml, the Peg-IFN dose was reduced. Granulocyte colony-stimulating factor (G-CSF) (Neupogen; Amgen Europe BV, Breda, The Netherlands) at a maximum dose of 300 g weekly was introduced when neutrophil counts remained low. Eltrombopag (Revolade; Glaxosmithkline, Research Triangle Park, North Carolina, USA) was initiated at 25 mg once daily when the platelet count was below 50 109/l, despite reduced Peg-IFN doses. Creatinine clearance was estimated using the Cockcroft–Gault formula.
Fibrosing cholestatic hepatitis was defined according to the histological criteria described by Davies et al. [12]: presence of extensive, dense portal fibrosis with immature fibrous bands extending into the sinusoidal spaces, ductular proliferation, cholestasis and moderate mononuclear inflammation.
Safety assessment Patients were hospitalized the day before protease inhibitor initiation or a combination antiretroviral therapy (cART) switch (if needed), for clinical monitoring and assays of trough blood concentrations of calcineurin inhibitors (CNI) drugs. In line with available data concerning drug–drug interaction studies conducted in healthy volunteer participants, and based on our experience with HCV mono-infected patients, trough
Results Patient characteristics at baseline The mean time between liver transplantation and antiHCV triple therapy introduction was 28 months (range 2–77 months). Patient characteristics upon initiating anti-HCV triple therapy are described in Table 1. Mean
Table 1. Clinical and biological characteristics of HIV/hepatitis C virus co-infected patients before the introduction of triple anti-hepatitis C virus therapy. N Sex Age (years) MELD score Months after LT Total bilirubin (mmol/l) g-GT (IU/l) Creatinine clearance (ml/min) CD4þ (cells/ml) CD4þ/CD8þ (%) HCV RNA (log 10 IU/ml) HCV genotype IL28b recipient HCV treatment (naive) HCV RNA (log 10 copies/ml) cART (before anti-HCV therapy) Immunosupressive therapy Liver biopsy (before anti-HCV therapy)
1
2
3
4
5
6
7
F 52 20 7 163 1135 72 289 0.3 8.6 1b CT Yes
