High efficacy of glecaprevir/pibrentasvir for HCV-infected individuals with active drug use

Depósito de investigación de la Universidad de Sevilla https://idus.us.es/ “This is an Accepted Manuscript of an article published by Elsevier in: JOURNAL OF INFECTION on 2022, available at: https://doi.org/10.1016/j.jinf.2022.06.005” 1 High efficacy of Glecaprevir/Pibrentasvir for HCV-Infected 1 individuals with active drug use 2 3 Alejandro González-Serna1,2,3,4, Juan Macias1,3,4,5, Anaïs Corma-Gomez1,3,4, 4 Francisco Tellez6, Josep Cucurull7, Luis M Real1,3,4,8, Rafael Granados9, Antonio 5 Rivero-Juarez10, José Hernandez-Quero11, Dolores Merino12, Rosario Palacios13, 6 Maria José Ríos14, Antonio Collado15, Juan A. Pineda1,3,4,5, for 7 HEPAVIR/GEHEP-001 study group RIS-HEP07. 8 9 1. Unidad de Gestión Clínica de Enfermedades Infecciosas y Microbiología 10 (UCEIM), Hospital Universitario de Valme, Sevilla, Spain. 11 2. Departamento de Fisiología, Facultad de Farmacia, Universidad de Sevilla, 12 Sevilla, Spain. 13 3. Instituto de Biomedicina de Sevilla (IBiS), Sevilla, Spain. 14 4. Centro de Investigación Biomédica en Red de Enfermedades Infecciosas 15 (CIBERINFEC). 16 5. Departamento de Medicina, Universidad de Sevilla, Sevilla, Spain. 17 6. Hospital Universitario de Puerto Real, Puerto Real. 18 7. Fundacio Salut Emporda (Fundació Privada), Figueres. 19 8. Departamento de Especialidades Quirúrgicas, Bioquímica e Inmunología. 20 Facultad de Medicina, Universidad de Málaga, Málaga, Spain. 21 9. Hospital de Gran Canaria Dr. Negrín, Las Palmas de Gran Canarias. 22 10. Hospital Universitario Reina Sofía, Córdoba. 23 11. Hospital Universitario de San Cecilio de Granada, Granada. 24 2 12. Hospital Juan Ramón Jiménez, Huelva. 25 13. Hospital Clínico Universitario Virgen de la Victoria, Málaga. 26 14. Hospital Universitario Virgen Macarena, Sevilla. 27 15. Hospital Universitario Torrecárdenas, Almería. 28 29 Short tittle: High efficacy of G/P for active drug users 30 31 Word count: 2018 32 33 Total number of tables and figures: 5 34 35 *Corresponding author: Juan Macías. Infectious Diseases and Microbiology Unit, 36 Hospital Universitario de Valme, Avda Bellavista s/n, 41014-Seville, Spain. Tel: 37 +34 955015736. Email: [email protected] 38 39 Lay Summary/Key Points: 40 • Active drug use is independently associated with lower SVR rates to G/P. 41 • Voluntary dropout in patients with active drug users is up to 4-fold higher 42 compared to those with past drug use and up to 11-fold compared to those who 43 never used drugs. 44 • G/P could be particularly beneficial in this scenario but specific strategies 45 designed to increase the retention in care of active drug users are needed. 46 47 3 48 Ethical aspects: Both the study design and development complied with the 49 Helsinki declaration and was approved by the local Ethics Committee of the 50 Hospital Universitario Virgen de Valme (Seville). All patients gave their written 51 informed consent to participate in the study. 52 53 Permission to reproduce material from other sources is not necessary. 54 4 Abstract 55 56 Objectives: Real world data on glecaprevir/pibrentasvir (G/P) among active drug 57 users are scarce. We evaluated the sustained virological response (SVR) rates of 58 G/P among individuals with and without active drug use in routine clinical 59 practice. 60 Methods: Two ongoing prospective multicenter cohorts of individuals starting 61 G/P were analyzed. Overall SVR intention-to-treat (ITT), discontinuations due to 62 adverse effects and dropouts were evaluated. Results in patients with active, 63 past and without active drug use were compared. 64 Results: Overall, 644 individuals started G/P and have reached the date of SVR 65 evaluation. Of them, 613 (95.2%) individuals achieved SVR. There were two 66 (0.3%) relapses, one (0.2%) discontinuation due to side effects and 35 (5.4%) 67 dropouts. SVR rates for patients with active drug use, past drug use and those 68 who never used drugs were 85.4%(n/N=70/82), 96.1%(n/N=320/333) and 69 97.4%(n/N=223/229) respectively (p<0.001). After adjustment by sex, age, HCV 70 genotype and opioid agonist therapy, active drug use was the only factor 71 independently associated with SVR (ITT) [adjusted OR (95%confidence interval): 72 0.29(0.09-0.99),p=0.048]. 73 Conclusions: Active drug use was independently associated with lower SVR 74 rates to G/P, mainly due to voluntary dropout. G/P could be particularly beneficial 75 in this scenario but specific strategies designed to increase the retention in care 76 are needed. 77 5 78 Keywords: Glecaprevir/pibrentasvir; HCV therapy; Drug use; Opiate Agonist 79 Therapy; PWID. 80 81 6 INTRODUCTION 82 83 Elimination of viral hepatitis was adopted by The World Health Assembly 84 as a public health objective by 2030.1 This ambitious target needs sufficient 85 coverage for a number of core interventions in order to be reached.2 HCV 86 treatment and cure was one of those interventions. HCV infection has become a 87 curable disease in nearly all patients thanks to highly effective and safe direct- 88 acting antiviral (DAA) combinations. However, drug users, currently or previously, 89 have far higher prevalence of hepatitis C virus (HCV) infection than the general 90 population.3, 4 Unfortunately, uptake of treatment is still low among drug users5 91 and even today, some clinicians are hesitant to prescribe DAAs to people who 92 inject drugs (PWID) due to concerns over poor adherence, reduced tolerability, 93 and the risk of HCV reinfection.6 94 Lower sustained viral response (SVR) rates in drug users with DAA may 95 be found in clinical practice compared to clinical trials, mainly due to a greater 96 likelihood of losses to follow-up and lower adherence. We found that HCV- 97 infected PWID with active drug use had the lowest SVR rate to DAA 98 combinations in clinical practice.7 Higher rates of discontinuations due to adverse 99 events and, especially, of losses to follow-up were the main factors responsible 100 for those lower SVR rates. SVR rates among PWID and patients who never used 101 drugs were similar when active drug use was accounted for.7 These results were 102 obtained before Glecaprevir/Pibrentasvir (G/P) was widely available. 103 7 G/P has demonstrated high efficacy and tolerability in a variety of 104 settings.8-12 In the setting of drug use, G/P is supported by a meta-analysis from 105 patients with HCV genotypes 1-6 who were treated with G/P for 8, 12, or 16 106 weeks in eight Phase 2 and 3 trials showing that G/P is highly efficacious and 107 well tolerated in HCV-infected patients receiving opioid agonist therapy (OAT) .13 108 Sustained viral response (SVR) was high and no HCV reinfections occurred 109 through post-treatment week 12. However, real world data on G/P in the setting 110 of drug use are still scarce. Furthermore, post-hoc analyses of data from clinical 111 trials showed that virologic failure was not associated with G/P treatment 112 interruption, which may be related to its high drug forgiveness.14 It is not known 113 whether the efficacy of G/P in the setting of clinical trials may be replicated 114 among active drug users in clinical practice. 115 For these reasons, our aim was to compare the rates of SVR to G/P 116 among HCV-Infected individuals with ongoing drug use, previous drug use and 117 those who never injected drugs in daily practice. 118 8 METHOD 119 120 Patients and study design 121 122 The HEPAVIR-DAA cohort (NCT02057003), which includes HIV/HCV- 123 coinfected patients, and the GEHEP-MONO cohort (NCT02333292), which 124 recruits HCV monoinfected individuals, are ongoing prospective multicenter 125 cohorts of patients receiving DAA combinations prescribed in clinical practice, 126 outside clinical trials. Patients included in these cohorts with chronic HCV 127 infection who started G/P and achieved the SVR evaluation date were included in 128 the present analysis. Patients taking at least one dose of the combination were 129 eligible. Cirrhosis was diagnosed with a liver biopsy showing fibrosis stage 4, or 130 with liver stiffness ≥12.5 kPa, or with a previous hepatic decompensation. 131 132 Medications and follow-up 133 134 G/P was used as prescription medication to treat HCV infection in routine 135 clinical practice in the cohorts. The standard duration of the combination G/P was 136 8 weeks for treatment-naïve patients without cirrhosis.15 Since 2019, treatment- 137 naïve patients with compensated cirrhosis could be treated for 8 weeks. The 138 achievement of plasma HCV RNA below the limit of detection 12 weeks after the 139 end of therapy with G/P was defined as SVR. The efficacy of therapy was 140 assessed by the SVR rate. Discontinuations due to adverse effects, dropouts and 141 15 therapy in the same location,19 peer support or a helping hand from people in 251 recovery,20 and cash incentives.21 252 Another possible reason for the lower SVR rates in drug users, in addition 253 to dropouts, could be the higher proportion of individuals with HCV genotype 3 254 infection.22 In the SURVEYOR-II trial the efficacy of G/P was 91.7% in treatment- 255 experienced patients with genotype 3 infection without cirrhosis.23 In our study, 256 HCV genotype 3 was more frequent in drug users. This could be expected given 257 the high prevalence of HCV genotype 3 among PWID globally.24 Lower rates of 258 SVR in genotype 3-infected patients could explain the response rates found for 259 active drug users. However, there were no virologic failures among active drug 260 users in our study. In addition, active drug use independently associated with 261 response after adjustment by HCV genotype 3. 262 G/P is recommended for individuals without cirrhosis or with compensated 263 cirrhosis and contraindicated for patients with decompensated cirrhosis.25, 26 In 264 agreement with previous reported meta-analysis of G/P treatment,27, 38 in clinical 265 practice we found no difference in SVR rates according to cirrhosis status, even 266 though SVR rates were slightly higher in individuals without cirrhosis. There was 267 only one of interruption due to adverse effects in the cohorts in a cirrhotic patient 268 HCV with genotype 3 infection and Child-Pugh Score B7, treated with G/P by 269 decision of his physician. Despite of this, high response rates were found for 270 cirrhotic patients in this study. 271 In this study we report the efficacy and safety of G/P in patients included in 272 real-world multicenter cohorts. The overall efficacy of G/P among drug users 273 16 found in a previous meta-analysis was replicated in this real-world sample of 274 patients.18 However, this study may have certain limitations. First, drug use was 275 self-reported and thus, it was likely underestimated. Second, reinfections were 276 not systematically evaluated and might have gone unnoticed in the study 277 population. However, reinfections were recently analyzed in these same cohorts 278 finding a frequency lower than 0.2% for the period of DAAs administration.2 279 Therefore, we assume that unnoticed reinfections should not change 280 substantially the conclusions of this study. 281 In conclusion, G/P is effective in individuals with and without active drug 282 use. Spain was on track to meet the 2030 HCV elimination targets by WHO, 283 before the SARS-CoV-2 pandemic. To attain the national HCV elimination goal, 284 specific strategies designed to increase the retention in care of active drug users 285 are needed. G/P as a short treatment with high SVR rates in active drug users 286 could be particularly beneficial in this scenario. 287 17 Abbreviations 288 289 Sustained virological response (SVR), direct-acting antiviral (DAA), 290 Glecaprevir/Pibrentasvir (G/P), intention-to-treat analysis (ITT), per-protocol (PP), 291 hepatitis C virus (HCV), opioid agonist therapy (OAT), people who inject drugs 292 (PWID). 293 294 Acknowledgements 295 296 All collaborators and patients included in the study. 297 298 Authorship 299 300 AGS and JM performed the acquisition, analysis, or interpretation of data 301 for the work. JAP and JM designed the research study. ACG, FT, JC, LMR, RG, 302 ARJ, JHQ, DM, RP, MJR and AC contributed essential reagents or tools. AGS 303 and JM analyzed the data and wrote the paper. 304 305 Financial support 306 307 This study has been funded by Instituto de Salud Carlos III through the 308 project “PI018/00606" (Co-funded by European Regional Development 309 Fund/European Social Fund "A way to make Europe"/"Investing in your future"). 310 18 This work was supported by the Ministry of Science, Innovation and Universities 311 of Spain for A.G.-S who is recipient of a Miguel Servet Research Contract 312 (CP18/00146), co-financed by the FSE ‘El Fondo Social Europeo invierte en tu 313 futuro’. A.C.-G. has received a Rıo Hortega grant from the Instituto de Salud 314 Carlos III (CM19/00251). J.A.P. has received a research extension grant from the 315 Programa de Intensificacion de la Actividad de Investigacion del Servicio 316 Nacional de Salud Carlos III (3SNS). 317 318 Conflict of interest 319 320 A.C.-G. has received lecture fees from Gilead. 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Trickey A, Fraser H, Lim AG, Peacock A, Colledge S, Walker JG, et al. The 456 contribution of injection drug use to hepatitis C virus transmission globally, 457 regionally, and at country level: a modelling study. Lancet Gastroenterol Hepatol. 458 2019;4:435-444. 459 31 Figure 2. Global SVR rates to G/P 480 481