Accepted Manuscript Title: Boceprevir plus Peginterferon/Ribavirin to retreat HCV genotype-1 in HIV-HCV coinfected patients. Final results of BOC HIV-HCV Spanish Study. Author: M. Laguno M.A. Von Wichmann E. Van den Eynde J. Navarro C. Cifuentes J. Murillas S. Veloso M. Mart´ınez-Rebollar J.M. Guardiola A. Jou J.L. G´omez- Sirvent M. Cervantes J.A. Pineda S. L´opez-Calvo A. Carrero M.L. Montes E. Deig A. Tapiz J.D. Ruiz-Mesa A. Cruceta E. de Lazzari J. Mallolas PII: DOI: Reference:
S1201-9712(16)31212-7 http://dx.doi.org/doi:10.1016/j.ijid.2016.10.028 IJID 2759
To appear in:
International Journal of Infectious Diseases
Received date: Revised date: Accepted date:
13-7-2016 13-10-2016 25-10-2016
Please cite this article as: Laguno M, Von Wichmann MA, Van den Eynde E, Navarro J, Cifuentes C, Murillas J, Veloso S, Mart´ınez-Rebollar M, Guardiola JM, Jou A, Sirvent JLG-, Cervantes M, Pineda JA, L´opez-Calvo S, Carrero A, Montes ML, Deig E, Tapiz A, Ruiz-Mesa JD, Cruceta A, de Lazzari E, Mallolas J, Boceprevir plus Peginterferon/Ribavirin to retreat HCV genotype-1 in HIV-HCV coinfected patients. Final results of BOC HIV-HCV Spanish Study., International Journal of Infectious Diseases (2016), http://dx.doi.org/10.1016/j.ijid.2016.10.028 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Highlights for review:
Prospective, randomized clinical trial
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Safety and efficacy of RGT with BOC + pegylated interferon alpha 2a/ribavirin
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Retreatment of HCV-HIV coinfected patients with genotype-1 who were non-responders or relapsers to P/R therapy.
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Overall sustained virological reponse of 67% up to 80% in previously relapsed or breakthrough to P/R.
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Cost-effective alternative treatment in non available DAA settings.
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Boceprevir plus Peginterferon/Ribavirin to retreat HCV genotype-1 in HIV-HCV coinfected patients. Final results of BOC HIV-HCV Spanish Study. EudraCT number: 2012-003984-23
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M. Laguno1 , MA Von Wichmann2, E Van den Eynde3, J Navarro4, C Cifuentes5, J Murillas6, S Veloso7, M Martínez-Rebollar1, JM Guardiola8, A Jou9, JL Gómez- Sirvent10, M. Cervantes11, JA Pineda12, S López-Calvo13, A Carrero14, ML Montes15, E Deig16, A Tapiz17, JD Ruiz-Mesa18, A Cruceta1, E de Lazzari1, J Mallolas1 .
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1Hospital Clínic de Barcelona/IDIBAPS. Barcelona. Spain. 2Hospital Universitario de Donostia. Donosti. Spain. 3Hospital Universitari de Bellvitge. Bellvitge. Spain. 4Hosital Universitari Vall d’Hebrón. Barcelona. Spain. 5Hospital Son Llàtzer. Palma de Mallorca. Spain. 6Hospital Son Espases. Palma de Mallorca. Spain. 7Hospital Universitari Joan XXIII. Tarragona. Spain. 8Hospital de la Santa Creu i Sant Pau. Barcelona. Spain. 9Hospital Universitari Germans Trias i Pujol. Bardalona. Spain. 10Hospital Universitario de Canarias. Tenerife. Spain. 11Corporació Sanitària Parc Taulí. Sabadell. Spain. 12 Hospital Universitario de Valme. Sevilla. Spain. 13Hospital Universitario A Coruña. La Coruña. Spain. 14Hospital Universitario Gregorio Marañón. Madrid. Spain. 15Hospital Universitario de La Paz. Madrid. Spain 16Hospital de Granollers. Granollers. Spain. 17Fundació Althaia. Manresa. Spain. 18Hospital Regional. Málaga. Spain.
Short Title: P/R+BOC to retreat HCV-HIV patients
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Key words: P/R+BOC therapy, HCV-HIV experienced patients, HCV genotype 1, retreatment María Martínez-Rebollar Infectious Diseases Unit Hospital Clinic Villarroel 170 08036 BARCELONA Spain Tel. +34-93- 2275574 e-mail:
[email protected]
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ABSTRACT
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Introduction: Boceprevir (BOC) is one of the first developed oral inhibitors of HCVNS3 protease. This study assessed the safety and efficacy of BOC + pegylated interferon 2a/ribavirin (P/R) in the retreatment of HCV-HIV coinfected patients with genotype 1. Methods: This is a phase III prospective trial. HCV/HIV-GT1 coinfected patients from 16 hospitals in Spain were included to receive 4 weeks of P/R (lead-in), then responseguided therapy with P/R plus BOC (fixed 44 weeks was indicated in case of cirrhosis). The primary endpoint was sustained virological response (SVR) rates at 24 weeks posttreatment. We evaluated efficacy and safety in all patients who received at least one dose of study drug. Results: From June 2013 to April 2014 we enrolled 102 patients, 98 of whom received at least one treatment dose. 73% were male, 34% cirrhotic, 23% IL-28b CC, 65% genotype 1a and 41% were previous null responders. The overall SVR was 67%. Previous null-responders and cirrhotic patients had lower SVR rates (57% and 51% respectively). Seventy six patients (78%) completed the therapy scheme and the most common reasons for discontinuation were lack of response at week 12 (12 patients) and adverse events (6 patients). Conclusions: Response-guided therapy with BOC in combination with P/R leads to overall SVR rates of 67% but only 51% in patients with cirrhosis. The therapy was generally well tolerated. Although the current standards of care do not include BOC + P/R, we believe that this combination can be beneficial where new Direct Antiviral Agents against HCV interferon-free therapies are not available yet.
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Introduction:
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Liver disease caused by chronic hepatitis C virus (HCV) infection is a leading cause of morbidity and mortality among human immunodeficiency virus (HIV)-infected patients in the developed world and represents an important health care problem in this population 1,2. HCV genotype 1 is the most prevalent in this population. The standard treatment for HCV infection until 2009 was the combination of peginterferon plus ribavirin for 48 weeks. However, with this combination the rate of sustained virological response (SVR) achieved in patients with genotype 1 is low, less than 40 % 3,4,5,6. Therefore, more than half of the patients fail to respond and should be retreated. In recent years, several drugs with direct HCV antiviral activity (DAA) have been developed. The first group of DAA used in combination therapy with PEG-interferon + Ribavirin (P/R) is the protease inhibitors (PI) of HCV NS3 telaprevir and boceprevir (BOC). The results of clinical trials with triple therapy in both mono 7,8 and HIV coinfected patients 9,10,11 are good; however there are few data on the efficacy of this regimen in patients who do not respond to previous P/R therapy 12,13,14,15,16,17. Although triple therapy achieves higher rates of SVR than conventional therapies, it may be more toxic and is clearly more expensive. There are data indicating that the Response-guided therapy (RGT) (32 weeks of triple therapy) in previous failure to P/R therapy in HCV monoinfected patients can be as effective as the standard triple therapy (44 weeks) but with lower toxicity and cost 14. Some studies have evaluated the efficacy and safety of triple therapy with PI in HIV HCV coinfected patients previously treated with P/R 18,19, and one have evaluated RGT20. This phase III study assessed the safety and efficacy of RGT with BOC + pegylated interferon alpha 2a/ribavirin in the retreatment of HIV-HCV/GT1 who were nonresponders or relapsers to P/R therapy.
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Study Design and Participating Centers The study was a phase III, prospective, multicenter, open-label, single-arm trial carried out in the specialized HIV units of 16 hospitals of Spain. The study was conducted in accordance with the principles of Good Clinical Practice. The institutional ethics committee of Hospital Clinic of Barcelona (coordinator center) and AEMPS (Drug Spanish Agency), having taken into account the opinions of the other CEICs involved in the project (16 hospitals in Spain). All patients provided written informed consent before entering the study. The clinical trial was registered in EudraCT (number: 2012-003984-23) The study design is illustrated in Figure 1 Patients HIV-HCV coinfected patients who received medical care for HIV infection in any of the hospitals participating in the study were enrolled from June 2013 to April 2014. The patients had to fulfill the following inclusion criteria: previous nonresponders or relapsers to P/R therapy; HIV infection with CD4 cell count above 100 cells/mm3 and plasma HIV viral load undetectable (12,5Kpa. Exclusion criteria included: hepatitis B or any other cause 4 Page 4 of 17
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of clinically significant liver disease, decompensated liver disease, a severe psychiatric disorder and active substance abuse. Treatment and monitoring Peginterferon alfa-2a was administered subcutaneously at a dose of 180 μg once weekly, ribavirin was administered twice a day at a dose of 800 to 1200 mg per day on the basis of body weight and boceprevir (BOC) was administered at a dose of 800 mg three times daily. During the 4-week lead-in period, all patients received peginterferon plus ribavirin (P/R). Subsequent treatment varied according to degree of liver fibrosis and viral response at this point: a) Patients with HCV-RNA decrease
