Baseline resistance-guided therapy does not enhance the response to interferon-free treatment of HCV infection in real life

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HEPAVIR Baseline resistance-guided therapy does not enhance the response to interferon-free treatment of HCV infection in real life Luis M. Real 1, Juan Macías 1, Ana B.

1 HEPAVIR Baseline resistance-guided therapy does not enhance the response to interferon-free treatment of HCV infection in real life Luis M. Real 1, Juan Macías 1, Ana B. Pérez 2, Dolores Merino 3, Rafael Granados 4, Luis Morano 5, Marcial Delgado 6, María J. Ríos 7, Carlos Galera 8, Miguel G. Deltoro 9, Nicolás Merchante 1, Federico García 2, Juan A. Pineda 1, on behalf of HEPAVIR and GEHEP study groups. 1 Hospital Universitario de Valme, Sevilla, Spain 2 Complejo Hospitalario Universitario de Granada-Hospital PTS, Granada, Spain 3 Hospital Universitario Juan Ramón Jiménez, Huelva, Spain 4 Hospital Universitario de Gran Canaria Dr. Negrín. Las Palmas de Gran Canaria, Spain 5 Hospital Universitario Alvaro Conqueiro,Vigo, Spain 6 Hospital Regional de Málaga, Málaga, Spain 7 Hospital Universitario Virgen Macarena, Sevilla, Spain 8 Hospital Virgen de la Arrixaca, Murcia, Spain 9 Consorcio Hospital General Universitario de Valencia, Valencia, Spain

2 Background A low proportion of naïve HCV-infected patients treated with directacting antiviral (DAA) combinations fail to achieve sustained virological response 1-3. The presence of Resistance-Associated Substitutions (RASs) in the NS5A gene may be associated with lower rates of sustained virological response (SVR) in naïve patients treated with DAA combinations. There is limited information on the potential impact of RAS testing on the outcome of HCV treatment in DAA-naïve patients in real life. 1. Pawlotsky JM. Gastroenterology. 2014;146: Pawlotsky JM. Gastroenterology. 2015;148: Curry MP, et al. N Engl J Med. 2015;373:

3 Objective To assess whether the treatment guided by RASs increases the rate of SVR in naïve HCV-infected patients in daily clinical practice.

4 Patients and methods (I) Design: prospective observational study. Inclusion criteria: HCV-infected patients who were recruited into the HEPAVIR 1 or GEHEP 2 cohorts. All patients treated with interferon (IFN)-free DAA based regimens between March 2016 and May 2017 in 17 Spanish hospitals. Patients who never had been treated before with DAAs, with the exception of sofosbuvir with or without ribavirin alone or plus interferon. Patients with premature discontinuations or who had missing SVR data were excluded. 1 HEPAVIR (clinicaltrials.gov ID: NCT ) 1 GEHEP-MONO (clinicaltrials.gov ID: NCT )

5 Patients and methods (II) In the subgroup of patients collected in one of the participating hospitals (Valme University Hospital), NS5A-RASs were tested by Sanger techniques. This subgroup was called resistance guided treatment (RGT) population. Patients from the rest of hospitals constituted the control population (without RASs testing) Treatments followed the recommendations of the Spanish guidelines. In the RGT population, patients with NS5A-RASs were treated with a DAA combination containing a protease inhibitor when possible, or, alternatively, adding ribavirin and/or extending treatment. Rates of SVR 12 in the RGT and control populations were compared.

6 Results I Disposition of the study populations RGT population Control population 129 HCVinfected patients 5 (3.8%) voluntarily dropped out 525 HCVinfected patients 11 (2.1%) voluntarily dropped out 3 (2.3%) lost to follow up 1 (0.8 %) adverse events 2 (0.4 %) adverse events 120 (93.0%) Patients with evaluable SVR 512 (97.5%) Patients with evaluable SVR

7 Variables Results II RGT: Resistance-guided treatment; * Mean (Quartil 1 Quartil 3); Among 511 individuals. Among 507 individuals. Main baseline characteristics of patients. RGT population n=120 Control population n=512 p-value Age, years* 50 (47-54) 51 (46-54) Male gender, n (%) 101 (84.2) 356 (69.5) HIV coinfection, n (%) 75 (62.5) 251 (49.0) Cirrhotics, n (%) 25 (20.8) 130 (25.4) Viral load > IU/µL, n (%) 85 (70.8) 361 (71.2) Pre-treated, n (%) 28 (23.3) 133 (26.0) HCV genotype a, n (%) 50 (41.7) 171 (33.4) 1b, n (%) 30 (25.0) 143 (27.9) 1a/b, n (%) 0 19 (3.7) 2, n (%) 0 7 (1.4) 3, n (%) 17 (14.2) 75 (14.6) 4, n (%) 23 (19.2) 94 (18.4) 5, n (%) 0 2 (0.4) Indeterminate, n (%) 0 1 (0.2)

8 Results III DAA combinations used RGT population Control population 8 (6.7%) 1 (0.8%) 51 (10%) 9 (7.5%) SOF/LDV 9 (7.5%) 9 (7.5%) 12 (10%) 72 (60%) 78 (15.2%) 16 (3.1%) 15 (2.9%) 262 (51.2%) ProD Pro EBR/GZR SOF/VEL SOF/DCV 90 (17.6%) SOF+SMV SOF: Sofosbubir; RBV: ribavirin; DCV: daclastavir; SMV simeprevir; PrOD: paritaprevir-ritonavir/ombitasvir plus dasabuvir; PrO: paritaprevir-ritonavir/ombitasvir; LDV: ledipasvir; VEL: Velpatasvir; EBR: Elbasvir; GZR: grazoprevir.

9 Results IV Prevalence of patients with NS5A-RASs in the RGT population (N=120) 9 (7.5%) Patients with RASs 111 (92.5%%) Patients without RASs

10 Results V Patients from RGT population who showed RASs Patient HCV-GT NS5A RAS Cirrhosis HIV DAA regimen RBV use Duration (Weeks) 1 1a Y93L No Yes SOF/LDV No a M28V No No PrOD Yes b P58S No No PrOD No b L31V No Yes PrOD No b L31M No Yes PrOD No b L31M Yes Yes PrOD Yes Y93H Yes Yes SOF/VEL Yes Y93H Yes Yes SOF/VEL Yes A30K Yes No SOF/DCV Yes 24 SOF: Sofosbubir; LDV: ledipasvir; DCV: daclastavir; PrOD: paritaprevir-ritonavir/ombitasvir plus dasabuvir; VEL: Velpatasvir. RBV: ribavirin.

11 Rate of SVR 12 (%) Results VI SVR 12 rates in the RGT population according to the presence of NS5A-RASs p= % 97,3% 9 9 Patients with RASs relapses 3 relapses Patients without RASs

12 Rate of SVR 12 (%) Results VII SVR 12 rates in both RGT and control populations % 98.8% RGT population p= relapses 6 relapses Control population

13 Conclusions The rate of SVR achieved by the non-guided treatment is so high, that no benefit is added by treatment guided by RASs. The few relapses observed in the RGT population were not driven by the presence of RASs.

14 Acknowledgements HEPAVIR-DAA cohort: Antonio Collado (H Torrecárdenas); Josep Cucurull (H de Figueres); Marcial Delgado (HR Málaga); Carlos Galera (H Virgen de la Arrixaca); Juan Luis Gómez (HU de Gran Canaria); Rafael Granados (HU de Gran canaria Dr Negrín); Manuel Márquez, Rosario Palacios, Jesús Santos (HU Virgen de la Victoria); Dolores Merino, Miguel Raffo (H Juan Ramón Jiménez); Luis E. Morano, Eva Prado (CHU de Vigo); Mohamed Omar, María A. Gómez Vidal (CH de Jaén); Inés Pérez (H Poniente); Monsterrat Pérez (HU La Línea de la Concepción); María José Ríos, Inmaculada López Montesinos (HU Macarena); Antonio Rivero-Juárez, Antonio Rivero (HU Reina Sofía); Ignacio de Los Santos (HU La Princesa); Francisco Téllez (HU Puerto Real); Francisco J. Vera, Lorena Martínez (H Santa Lucía); Juan A. Pineda, Juan Macías (HU Valme). GEHEP-MONO cohort: Marcial Delgado (HR Málaga); Miguel García-Deltoro (HGU de Valencia); Juan Luis Gómez (HU de Gran Canaria); Rafael Granados (HU de Gran canaria Dr Negrín); Félix Gutiérrez (H de Elche); Manuel Márquez, Rosario Palacios, Jesús Santos (HU Virgen de la Victoria); Dolores Merino, Miguel Raffo (CH de Huelva); Luis E. Morano, Eva Prado (CHU de Vigo); Inés Pérez (H Poniente); Monsterrat Pérez (HU La Línea de la Concepción); María José Ríos, Inmaculada López Montesinos (HU Macarena); Sergio Reus (HGU Alicante); Antonio Rivero-Juárez, Antonio Rivero (HU Reina Sofía); Francisco Téllez (HU Puerto Real); Francisco J. Vera, Lorena Martínez (H Santa Lucía); Juan A. Pineda, Juan Macías (HU Valme). This work was supported by grants from: Plan Nacional R+D+I cofinanciad by the Subdirección General de Evaluación from ISCIII and the Fondo Europeo de Desarrollo Regional FEDER-(RD16/0025/0040 and RD12/0017/0012). Fundación Progreso y Salud from the Junta de Andalucía (PI and PI-0001/2017) Grupo de Estudio de Hepatitis Víricas from the Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica GEHEP-SEIMC (GEHEP-004).

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