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HIV Coinfection Predicts Failure of Ledipasvir/Sofosbuvir in Treatment-Naïve Non-Cirrhotic Patients with HCV genotype 1

HIV Coinfection Predicts Failure of Ledipasvir/Sofosbuvir in Treatment-Naïve Non-Cirrhotic... Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz214/5486493 by Ed 'DeepDyve' Gillespie user on 07 May 2019 HIV Coinfection Predicts Failure of Ledipasvir/Sofosbuvir in Treatment-Naïve Non-Cirrhotic Patients with HCV genotype 1 1,2 3,4,5,6 7,8 9 Juan Berenguer , José Luis Calleja , María Luisa Montes , Ángela Gil , Ana 10,11 1,2,6,12 1,2 Moreno , Rafael Bañares , Teresa Aldámiz-Echevarría , Agustín 6,10,11,13 14,15 6,7,8 16,17 Albillos , María Jesús Téllez , Antonio Olveira , Lourdes Domínguez , 16,17 6,7,8 5,18 Inmaculada Fernández , Javier García-Samaniego , Benjamín A Polo , 18 2,19 19 14,15 Beatriz Álvarez , Pablo Ryan , José Barrio , María J Devesa , Laura Benítez 3,4 20,21 20,21 13,22 13,22 , Ignacio Santos , Luisa García Buey , José Sanz , Elvira Poves , Juan E 23,24 23,24 25 9, Losa , Conrado Fernández-Rodríguez , Inmaculada Jarrín , María J Calvo , 7,8 Juan González-García . 1 2 Hospital General Universitario Gregorio Marañón, Madrid, Spain. Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain. Hospital Universitario Puerta de Hierro, Madrid, Spain. Instituto de Investigación Sanitaria Puerta de Hierro, Madrid, Spain. Universiad Autónoma de Madrid (UAM), Madrid, Spain. Centro de Investigación Biomédica en Red en el Área Temática de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain. Hospital Universitario La Paz, Madrid, Spain. Instituto de Investigación Hospital Universitario La Paz (IdiPAZ), Subdirección General de Farmacia y Productos Sanitarios/SERMAS, Madrid, Spain. Hospital Universitario Ramón y Cajal, Madrid, Spain. Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain. © The Author(s) 2019. Published by Oxford University Press on behalf of Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by- nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz214/5486493 by Ed 'DeepDyve' Gillespie user on 07 May 2019 12 13 Universidad Complutense de Madrid (UCM), Madrid, Spain. Universidad de Alcalá (UAH), Madrid, Spain. Hospital Clínico San Carlos, Madrid, Spain. 15 16 Instituto de Investigación Sanitaria San Carlos (IdiSSC), Madrid, Spain. Hospital Universitario 12 de Octubre, Madrid, Spain. Instituto de Investigación Hospital 12 de Octubre (i+12), Madrid, Spain. Fundación Jiménez Díaz, Madrid, Spain. 19 20 Hospital Universitario Infanta Leonor, Madrid, Hospital Universitario de la Princesa, Madrid, Spain. Instituto de Investigación del Hospital Universitario La Princesa, Madrid, Spain. Hospital Universitario Príncipe de Asturias, Alcalá de 23 24 Henares. Hospital Fundación Alcorcón, Alcorcón. Universidad Rey Juan Carlos, Alcorcón. Instituto de Salud Carlos III, Madrid, Spain. Keywords Antiviral Agents/administration & dosage/*therapeutic use Hepatitis C, Chronic/*complications/*drug therapy HIV Infections/*complications Sustained Virologic Response DAA Running title: HIV and treatment failure to DAAs Contact information Juan Berenguer, MD, PhD Unidad de Enfermedades Infecciosas/VIH (4100) Hospital Gregorio Marañón, Doctor Esquerdo 46 28007 Madrid Telephone: +34 91 586 8592 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz214/5486493 by Ed 'DeepDyve' Gillespie user on 07 May 2019 Fax: +34 91 426 5177 jbb4@me.com Alternative corresponding author Juan González-García, MD, PhD Unidad de VIH, Servicio de Medicina Interna Instituto de Investigación Sanitaria La Paz (IdiPAZ) Paseo de la Castellana 261. 28046. Madrid, Spain. Telephone: +34 91 207 1676. Fax: +34 91 729 0033. Email: juangonzalezgar@gmail.com Article´s main point The results of this large real-world study suggest that HIV infection is a predictor of treatment failure to ledipasvir/sofosbuvir, in patients with chronic hepatitis C. and supports the use of newer simplified and pan-genotypic anti-HCV regimens among coinfected patients. Juan Berenguer and Juan González-García contributed equally to this study Initial data from this analysis were presented at the Conference on Retroviruses and Opportunistic Infections (CROI). March 4-7, 2018. Boston, MA. (Presentation # 607). Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz214/5486493 by Ed 'DeepDyve' Gillespie user on 07 May 2019 Abstract Background: The efficacy of licensed DAA regimens is assumed to be the same for HCV-monoinfected patients (HCV-Mono) and HIV/HCV-coinfected patients (HCV- Co). However, the high SVR rates of DAA regimens and the small number of HIV- infected patients included in registration trials have made it difficult to identify predictors of treatment failure, including the presence of HIV. Methods: We compared treatment outcomes for LDV/SOF against HCV G1 in treatment-naïve HCV-Mono and HCV-Co without cirrhosis in a prospective registry of individuals receiving DAAs for HCV. Results: Up to September 2017, a total of 17,269 patients were registered, and 1,358 patients (1,055 HCV-Mono/303 HCV-Co) met the inclusion criteria. Significant differences between HCV-Mono and HCV-Co were observed for age, gender, and G1 subtype distribution. Among HCV-Co, 99.0% were receiving antiretroviral therapy. SVR rates for LDV/SOF at 8 wk did not differ significantly between HCV-Mono and HCV-Co (96.9% vs. 94.0%; P=.199). However, the SVR rate for LDV/SOF at 12 wk was significantly higher for HCV-Mono than HCV-Co (97.2% vs. 91.8%; P=.001). A multivariable logistic regression model including age, sex, liver stiffness, G1 subtype, HCV-RNA, HIV, and treatment duration showed the factors associated with treatment failure to be male sex (adjusted odds ratio [aOR] 2.49; 95%CI 1.27-4.91; P=.008) and HIV infection (aOR 2.23; 95%CI 1.13-4.38; P=.020). Conclusions: The results of this large prospective study analyzing outcomes for LDV/SOF against HCV G1 in treatment-naïve non-cirrhotic patients suggest that HIV infection is a predictor of treatment failure in patients with chronic hepatitis C. Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz214/5486493 by Ed 'DeepDyve' Gillespie user on 07 May 2019 Introduction The licensure of direct-acting antiviral agents (DAAs) marked a turning point in the treatment of infection by hepatitis C virus (HCV) [1]. This therapeutic innovation offered new prospects for the treatment of individuals coinfected by HCV and the human immunodeficiency virus (HIV), a difficult-to-treat population in the interferon plus ribavirin (RBV) era, with lower sustained viral response (SVR) rates and higher frequencies of serious adverse events than patients monoinfected with HCV [2-4]. Currently, it is recommended that coinfected persons receive the same treatment as monoinfected individuals, assuming that the efficacy of approved DAA regimens does not differ between the groups [5, 6]; although this is not entirely the case for AASLD/IDSA guidelines in the U.S in which ledipasvir and sofosbuvir (LDV/SOF) for 8 weeks is not recommended for patients with HIV/HCV coinfection, regardless of baseline HCV RNA level [6]. However, whether or not HIV infection is a predictor of treatment response to DAA regimens is difficult to assess owing to the high SVR rates associated with most licensed all-oral DAA-based regimens against HCV and the low number of clinical trials with DAA including both monoinfected and coinfected patients [7, 8]. As for real-world case series, some have found an association between HIV coinfection and lower SVR rates [9, 10], whereas in others, SVR rates were not significantly different between monoinfected and coinfected individuals [11-14]. We aimed to assess whether or not HIV infection is associated with failure of DAA therapy. Therefore, we focused on previously untreated non-cirrhotic patients infected with HCV genotype 1, with or without HIV, who were treated with Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz214/5486493 by Ed 'DeepDyve' Gillespie user on 07 May 2019 LDV/SOF. We adopted this approach because it provided a large enough sample size of patients and because we could easily control for some predictors of response including genotype, type of regimen, presence of cirrhosis, previous exposure to anti-HCV therapy, and use of RBV. Patients and Methods Design and patient selection Patients were selected for this study from the Madrid Registry of Use of DAA for HCV (RUA-VHC), a compulsory prospective registry of individuals receiving DAAs for HCV infection in the region of Madrid created in November 2014 by the Madrid Regional Health Service (SERMAS). Providing baseline data for this online registry is mandatory for the retrieval of DAAs in hospital pharmacies. Likewise, providing exhaustive follow-up data is a condition for reimbursement. The decision to treat was taken and the regimen selected by the treating physician according to current guidelines. Data collected prospectively in RUA-VHC have been reported in depth elsewhere [15]. In summary, baseline data included demographics, whether the patient was HIV-infected and was receiving antiretroviral therapy (ART), HCV genotype and subtype, HCV RNA load, prior history of anti-HCV therapy, liver fibrosis stage, and presence or absence of cirrhosis. The date of initiation and type of DAA regimen, use of RBV, and planned treatment duration were also recorded. In September 2016, a case report form was used to collect the following HIV- related variables offline: HIV transmission category, Centers for Disease Control and Prevention (CDC) clinical category, baseline and nadir CD4+ T-cell counts, and Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz214/5486493 by Ed 'DeepDyve' Gillespie user on 07 May 2019 baseline HIV viral load. In March 2017, the online registry was modified to include all the variables related to HIV infection mentioned above. Since then, this information has been registered prospectively. The study protocol was approved by the ethics committee of Hospital Universitario La Paz for the analysis of anonymous routine clinical data without written informed consent for purposes of scientific publication. In this analysis, patients included in RUA-VHC were eligible if they were 18 years or older, were infected with HCV genotype 1, were non-cirrhotic and previously untreated, were treated with LDV/SOF without ribavirin for 8 or 12 weeks and were scheduled to finish treatment on or before September 31, 2017. Measurements Fibrosis stage and cirrhosis were determined by liver biopsy or transient elastography (FibroScan, Echo-Sens, Paris, France). Cirrhosis was defined as liver stiffness > 12.5 kPa or clinical evidence of liver decompensation. The remaining liver stiffness cutoffs were as follows: ≤ 7 kPa, the cutoff to rule out null or mild fibrosis; < 9.5 kPa, the cutoff to rule out advanced fibrosis-cirrhosis [16]. HCV RNA was measured at baseline, at the end of therapy, and 12 weeks after completion of treatment. Real-time PCR assays for the quantification of HCV RNA included Roche COBAS AmpliPrep/COBAS TaqMan HCV (Roche Molecular Systems, Pleasanton, California, USA; lower limit of detection [LLOD] 15 IU/mL), Abbott RealTime HCV assay (Abbott Laboratories, Abbott Park, Illinois, USA; LLOD 12 IU/mL), or Siemens Versant HCV RNA version 1.0 (Siemens Healthcare GmbH, Erlangen, Germany; LLOD 15 IU/mL). Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz214/5486493 by Ed 'DeepDyve' Gillespie user on 07 May 2019 Outcomes Follow-up data in the online registry included the following: i) SVR, defined as undetectable plasma HCV RNA at 12 weeks after completion of treatment; ii) relapse, defined as detectable post-treatment HCV RNA after undetectable HCV RNA at the end of therapy; and iii) viral breakthrough, defined as detectable HCV RNA at the end of therapy and at week 12. Discontinuations due to adverse events or for reasons other than adverse events, losses to follow-up, and deaths were also registered. Statistical analysis When analyzing treatment effectiveness, any patient who initiated LDV/SOF therapy without confirmed SVR or missing outcome data were considered as treatment failures. Three multivariable logistic regression models were used to identify independent baseline factors associated with treatment failure. The first model included variables that were associated with treatment failure in univariable analysis with P < .05. The second model included variables that were associated with treatment failure in univariable analysis with P < .1. The third model was a fully adjusted model including age, sex, liver stiffness, HCV genotype, HCV RNA load, HIV infection, and treatment duration. Analyses were performed for the entire data set and for subgroups of treatment duration (8 and 12 weeks). Wald tests were used to derive P values. The analyses were performed using Stata version 14 (Stata Corp, College Station, Texas, USA). Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz214/5486493 by Ed 'DeepDyve' Gillespie user on 07 May 2019 Results Patient characteristics Up to September 2017, a total of 17,269 patients (13,720 monoinfected patients and 3,549 coinfected patients) initiated all-oral DAAs for treatment of HCV infection in 25 hospitals in the region of Madrid. Of these, 1,358 patients (1,055 monoinfected patients and 303 coinfected patients) met the inclusion criteria (Supplementary material – Figure S1). A total of 272 of the 1,358 patients (20.0%) included in this study were also included in a paper describing real-world outcomes of all oral DAA-based therapy in 2,369 HIV/HCV-coinfected patients [15]. The baseline characteristics of the 1,358 patients categorized by LDV/SOF treatment duration and by type of patient (monoinfected patients or coinfected patients) are shown in Table 1. Overall, 497 patients were treated with LDV/SOF for 8 weeks (36.6%), and 861 patients were treated with LDV/SOF for 12 weeks (63.4%). A higher percentage of monoinfected patients (39.2%) than coinfected patients (27.4%) were treated with LDV/SOF for 8 weeks. In brief, 55.1% were men, and the median age was 56 years. The HCV subtype distribution was: 1a (40.9%), 1b (55.7%), and 1 not subtyped (3.5%). The median HCV RNA was 6.2 Log IU/mL, and 17.2% of patients had an HCV RNA > 6 million IU/mL. A total of 1,320 (97.2%) patients underwent transient elastography at baseline. The median liver stiffness value was 8.8 kPa, and 494 (37.4%) patients had a liver stiffness value ≥ 9.5 kPa (but ≤ 12.5 kPa), which was indicative of advanced fibrosis. Statistically significant differences between monoinfected patients and coinfected patients were observed at baseline for age, gender, and Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz214/5486493 by Ed 'DeepDyve' Gillespie user on 07 May 2019 genotype 1 subtype distribution (Table 1). At baseline, 99.0% of coinfected patients were on ART. Full data on HIV-related characteristics were available for analysis from approximately half of the coinfected patients. No statistically significant differences were found between patients with complete HIV data and patients with incomplete HIV data for age, HCV genotype distribution, and HCV RNA load. However, patients with incomplete HIV data were more frequently male and had a lower liver stiffness value (Supplementary material – Table S1). Differences in mechanism of acquisition of HIV were found between coinfected patients treated for 8 or 12 weeks, with a lower proportion of injection drug use and a higher frequency of men who have sex with men among the former group (Table 2). Treatment response LDV/SOF for 8 weeks Treatment responses to LDV/SOF for 8 weeks are shown in Figure 1A. A total of 497 patients (414 monoinfected patients and 83 coinfected patients) received SOF/LDV without RBV for 8 weeks. Overall, the SVR rate of 8 weeks of therapy with SOF/LDV was 96.4%, without significant differences in SVR rates found between monoinfected patients and coinfected patients 96.9% vs. 94.0%, P = .199. There were no viral breakthroughs. The overall relapse rate was 2.8%, and no statistically significant differences in relapse rates were found between monoinfected patients and coinfected patients (2.2% vs. 6.0%, P = .06). Only 1 patient discontinued SOF/LDV owing to adverse events, and 3 patients discontinued therapy for reasons not related to adverse events. All 4 were monoinfected patients. Outcomes for 8 weeks’ treatment with LDV/SOF without Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz214/5486493 by Ed 'DeepDyve' Gillespie user on 07 May 2019 RBV for HCV genotype 1a and 1b analysis are shown in Figure 2A. LDV/SOF for 12 weeks Treatment response to LDV/SOF for 12 weeks is shown in Figure 1B. A total of 861 patients (641 monoinfected patients and 220 coinfected patients) received SOF/LDV without RBV for 12 weeks. Overall, the SVR rates of 12 weeks of therapy with SOF/LDV was 95.8%. Statistically significant differences in SVR rates were found between monoinfected patients and coinfected patients (97.2% vs. 91.8%, P = .001). Again, there were no viral breakthroughs. The overall relapse rate was 1.6%, and no statistically significant differences in relapse rates were found between monoinfected patients and coinfected patients (1.1% vs. 3.2%, P = .06). Five patients (0.6%) discontinued SOF/LDV owing to adverse events (2 monoinfected patients [0.3%] and 3 [1.4%] coinfected patients, P = .11). Fifteen patients (1.7%) discontinued therapy for reasons not related to adverse events (9 monoinfected patients [1.4%] and 6 [2.7%] coinfected patients, P = .23). Two coinfected patients died before SVR could be assessed: both died from complications of acute exacerbation of chronic obstructive pulmonary disease. Outcomes for 12 weeks’ treatment with LDV/SOF without RBV for HCV genotype 1a and 1b are shown in Figure 2B. Variables associated with treatment failure The results of the univariable and multivariable logistic regression models to identify baseline variables associated with treatment failure for the full data set are shown in Table 3. In the univariable analysis, male sex and the presence of HIV infection were the only variables significantly associated with increased odds of treatment failure. In all 3 multivariable models, male sex and HIV infection were Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz214/5486493 by Ed 'DeepDyve' Gillespie user on 07 May 2019 the only variables significantly associated with increased odds of treatment failure. In the fully adjusted model, the adjusted odds ratio (aOR) of treatment failure for males in comparison with females was 2.49 (95%CI 1.27-4.91; P=.008). Likewise, the aOR of treatment failure for coinfected patients in comparison with monoinfected patients was 2.23 (95%CI 1.13-4.38; P=.020). We also performed separate analyses to identify baseline variables associated with treatment failure according to treatment duration. Among patients treated for 8 weeks, male sex was the only variable independently associated with treatment failure (Supplementary material – Table S2). Among patients treated for 12 weeks, HIV infection was the only variable independently associated with treatment failure (Supplementary material – Table S3). Discussion Whether or not HIV infection is associated with treatment failure of DAA therapy is a controversial issue. The C-WORTHY and the C-EDGE CO-STAR studies, 2 of the few clinical trials with DAA that included both monoinfected and coinfected patients, revealed similar rates of sustained virological response to grazoprevir and elbasvir in both groups [7, 8]. These results are not easy to interpret owing to issues of study design in the C-WORTHY study (different treatment durations, different doses of elbasvir, and the addition or not of ribavirin) [7] and the low number of coinfected patients included in the C-EDGE CO-STAR study [8]. Some real-world practice studies have found lower SVR rates with all-oral DAA-based therapy in coinfected patients than in monoinfected patients [9, 10], whereas in other studies, SVR rates were not significantly different between monoinfected and coinfected individuals [11-14]. Again, the results of these studies are difficult to Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz214/5486493 by Ed 'DeepDyve' Gillespie user on 07 May 2019 interpret owing to the lack of homogeneity in essential variables such as HCV genotype, liver disease severity, prior exposure to anti-HCV therapy, and DAA- regimen used. We answered our research question by analyzing a large and homogeneous group of HCV genotype 1–infected treatment-naïve non-cirrhotic patients treated with LDV/SOF. We found lower SVR rates for LDV/SOF in coinfected patients than in monoinfected patients, with most of the treatment failures in both groups being viral relapses. The independent association between HIV and treatment failure was found after adjustment for age, sex, liver stiffness, HCV subtype, HCV RNA load, and treatment duration. Interestingly, when we carried out separate analyses according to treatment duration, we found an association between HIV and treatment failure among patients treated for 12 weeks but not among patients treated for 8 weeks. This could be due to a type 2 error, as the number of HIV-infected patients treated for 8 weeks was substantially lower than the number treated for 12 weeks (83 vs. 220). However, it must be considered that in comparison with patients treated for 8 weeks, those treated for 12 weeks, irrespective of whether or not they were HIV- infected, had a significantly higher frequency of both HCV-RNA above 6 million IU/mL and a liver stiffness value equal to or higher than 9.5 kPa, which is indicative of advanced fibrosis. Moreover, among HIV-infected individuals, the proportion of MSM was higher in those treated for 8 weeks than in those treated for 12 weeks. Given the recent ongoing outbreak of HCV among HIV-infected MSM, it is conceivable that more recent HCV infections were included in the former group than in the latter. This, in turn, could have influenced SVR rates, as Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz214/5486493 by Ed 'DeepDyve' Gillespie user on 07 May 2019 treatment of acute or early HCV infection has been associated with very high SVR rates [17]. For these reasons, any potential disadvantageous influence of HIV infection on treatment response would be more easily detected in patients treated for 12 weeks than in patients treated for 8 weeks. The reason why HIV infection influenced treatment response could not be ascertained from our data. However, this observation could be explained by some characteristics of coinfected patients, such as a CD4+ count < 200 cells/mm and prior clinical AIDS, which are indicative of immunosuppression and have been associated with failure of all-oral DAA-based therapy in coinfected patients [15]. Of note, 82 of the 188 (43.6%) coinfected patients for which the CDC clinical category was known had a prior diagnosis of AIDS. Likewise, 9 of the 158 (5.7%) coinfected patients with known CD4+ cell counts at baseline, had < 200 CD4+ cells/mm . There is some evidence that the host immune response may play a role in HCV clearance even during DAA-based therapies, possibly through the recognition and elimination by T cells of viral variants with resistance-associated substitutions (RASs) [18]. Of note, in a recent analysis of clinical trials of patients with genotype 1 HCV infection treated with LDV/SOF, NS5A RASs were present in 8-16% of patients before treatment and had a negative impact on treatment outcome [19]. If less effective clearance of resistant viral variants by the immune system is the reason why HIV infection negatively affected treatment response, then the newer pan-genotypic drug regimens that include NS5A inhibitors with a high barrier to resistance (eg sofosbuvir/velpatasvir or glecaprevir/pibrentasvir) could be a preferred option over other recommended regimens in coinfected patients with a prior diagnosis of AIDS and/or a CD4+ cell count < 200 CD4+ cells/mm . Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz214/5486493 by Ed 'DeepDyve' Gillespie user on 07 May 2019 Our study is limited by the lack of data on adherence and on concomitant medication, including proton pump inhibitors [20]. Another limitation is the absence of information on pre-existing viral variants with RASs, which prevented us from analyzing their prevalence among groups and assessing their impact on treatment outcomes. Our study is also limited by the fact that full data on HIV- related characteristics at the time of the data analysis were available for only half of the patients. This precluded the performance of additional comparative analyses between monoinfected patients and coinfected patients with a baseline CD4+ cell count below and above 200 cells/mm , or with and without a prior diagnosis of clinical AIDS, for better assessment of the effect of immunosuppression on treatment response among coinfected individuals. Finally, another limitation is the absence of information about the mechanism of transmission of HCV in HCV- monoinfected persons. Nevertheless, to our knowledge, ours is the largest real-world study comparing treatment outcomes between monoinfected and coinfected patients in which there was no variability according to HCV genotype, liver disease severity, exposure to previous anti-HCV therapy, and DAA-based regimen. In conclusion, the results of this study analyzing treatment outcomes for LDV/SOF against HCV genotype 1 in treatment-naïve non-cirrhotic patients suggest that HIV infection is a predictor of treatment failure in patients with chronic hepatitis C. This finding cannot be used to support the notion that HIV/HCV-coinfected individuals are a difficult-to-treat population in the era of all-oral DAA-based therapy. However, it does argue in favor of prioritizing the use of newer simplified and pan-genotypic anti-HCV regimens among coinfected patients to lessen the Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz214/5486493 by Ed 'DeepDyve' Gillespie user on 07 May 2019 possibility of treatment failure due to suboptimal adherence or presence of resistant viral variants. Funding This work was supported by the Spanish AIDS Research Network [RD16/0025/0017] that is included in the Spanish I+D+I Plan and is co-financed by ISCIII-Subdirección General de Evaluacion and European Funding for Regional Development (FEDER), and the Fondo de Investigación de Sanidad en España (FIS)/Instituto de Salud Carlos III (Spanish Health Research Funds) [PI17/00657]. Acknowledgements The authors thank Thomas O’Boyle for writing assistance. References 1. Liang TJ, Ghany MG. Therapy of hepatitis C--back to the future. N Engl J Med 2014; 370(21): 2043-7. 2. Torriani FJ, Rodriguez-Torres M, Rockstroh JK, et al. Peginterferon Alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. N Engl J Med 2004; 351(5): 438-50. 3. Carrat F, Bani-Sadr F, Pol S, et al. Pegylated interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic hepatitis C in HIV-infected patients: a randomized controlled trial. JAMA 2004; 292(23): 2839-48. 4. McHutchison JG, Lawitz EJ, Shiffman ML, et al. Peginterferon alfa-2b or alfa- 2a with ribavirin for treatment of hepatitis C infection. N Engl J Med 2009; 361(6): 580-93. Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz214/5486493 by Ed 'DeepDyve' Gillespie user on 07 May 2019 5. European Association for the Study of the Liver. EASL Recommendations on Treatment of Hepatitis C 2016. J Hepatol 2017; 66(1): 153-94. 6. AASLD-IDSA. HCV Guidance: Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. [Date accessed, April 8, 2019]. Available at: http://www.hcvguidelines.org. 7. Sulkowski M, Hezode C, Gerstoft J, et al. Efficacy and safety of 8 weeks versus 12 weeks of treatment with grazoprevir (MK-5172) and elbasvir (MK- 8742) with or without ribavirin in patients with hepatitis C virus genotype 1 mono-infection and HIV/hepatitis C virus co-infection (C-WORTHY): a randomised, open-label phase 2 trial. The Lancet 2015; 385(9973): 1087-97. 8. Dore GJ, Altice F, Litwin AH, et al. Elbasvir-Grazoprevir to Treat Hepatitis C Virus Infection in Persons Receiving Opioid Agonist Therapy: A Randomized Trial. Ann Intern Med 2016; 165(9): 625-34. 9. Arias A, Aguilera A, Soriano V, et al. Rate and predictors of treatment failure to all-oral HCV regimens outside clinical trials. Antivir Ther 2017; 22(4): 307-12. 10. Neukam K, Morano-Amado LE, Rivero-Juarez A, et al. HIV-coinfected patients respond worse to direct-acting antiviral-based therapy against chronic hepatitis C in real life than HCV-monoinfected individuals: a prospective cohort study. HIV Clin Trials 2017; 18(3): 126-34. 11. Ingiliz P, Christensen S, Kimhofer T, et al. Sofosbuvir and Ledipasvir for 8 Weeks for the Treatment of Chronic Hepatitis C Virus (HCV) Infection in HCV- Monoinfected and HIV-HCV-Coinfected Individuals: Results From the German Hepatitis C Cohort (GECCO-01). Clin Infect Dis 2016; 63(10): 1320-4. Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz214/5486493 by Ed 'DeepDyve' Gillespie user on 07 May 2019 12. Montes ML, Olveira A, Ahumada A, et al. Similar effectiveness of direct- acting antiviral against hepatitis C virus in patients with and without HIV infection. AIDS 2017; 31(9): 1253-60. 13. Bruno G, Saracino A, Scudeller L, et al. HCV mono-infected and HIV/HCV co- infected individuals treated with direct-acting antivirals: to what extent do they differ? Int J Infect Dis 2017; 62: 64-71. 14. Bischoff J, Mauss S, Cordes C, et al. Rates of sustained virological response 12 weeks after the scheduled end of direct-acting antiviral (DAA)-based hepatitis C virus (HCV) therapy from the National German HCV registry: does HIV coinfection impair the response to DAA combination therapy? HIV Med 2018; 19(4): 299-307. 15. Berenguer J, Gil-Martin A, Jarrin I, et al. All-oral direct-acting antiviral therapy against hepatitis C virus (HCV) in human immunodeficiency virus/HCV- coinfected subjects in real-world practice: Madrid coinfection registry findings. Hepatology 2018; 68(1): 32-47. 16. Singh S, Muir AJ, Dieterich DT, Falck-Ytter YT. American Gastroenterological Association Institute Technical Review on the Role of Elastography in Chronic Liver Diseases. Gastroenterology 2017; 152(6): 1544-77. 17. Rockstroh JK, Bhagani S, Hyland RH, et al. Ledipasvir–sofosbuvir for 6 weeks to treat acute hepatitis C virus genotype 1 or 4 infection in patients with HIV coinfection: an open-label, single-arm trial. The Lancet Gastroenterology & Hepatology 2017; 2(5): 347-53. 18. Ahlen G, Frelin L, Brenndorfer ED, et al. Containing "The Great Houdini" of viruses: combining direct acting antivirals with the host immune response for the treatment of chronic hepatitis C. Drug Resist Updat 2013; 16(3-5): 60-7. Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz214/5486493 by Ed 'DeepDyve' Gillespie user on 07 May 2019 19. Zeuzem S, Mizokami M, Pianko S, et al. NS5A resistance-associated substitutions in patients with genotype 1 hepatitis C virus: Prevalence and effect on treatment outcome. J Hepatol 2017; 66(5): 910-8. 20. Tapper EB, Bacon BR, Curry MP, et al. Evaluation of proton pump inhibitor use on treatment outcomes with ledipasvir and sofosbuvir in a real-world cohort study. Hepatology 2016; 64(6): 1893-9. Figure legends Figure 1. A) Outcomes for 8 weeks’ treatment with sofosbuvir/ledipasvir without ribavirin for HCV genotype 1 in treatment-naïve, non-cirrhotic patients. B) Outcomes for 12 weeks’ treatment with sofosbuvir/ledipasvir without ribavirin for HCV genotype 1 in treatment-naïve, non-cirrhotic patients P-values derived from the Pearson’s chi-squared test. HCV-Mono, HCV monoinfected patients; HCV-Co, HIV/HCV-coinfected patients; No., number of patients; SVR, sustained viral response (number [%]);CI, confidence interval; DC, treatment discontinuations (number [%]); AE, adverse events. Figure 2. A) Treatment outcomes for 8 weeks’ treatment with sofosbuvir/ledipasvir without ribavirin for HCV genotype 1a and 1b in treatment- naïve, non-cirrhotic patients. (B) Treatment outcomes for 12 weeks’ treatment with sofosbuvir/ledipasvir without ribavirin for HCV genotype 1a and 1b in Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz214/5486493 by Ed 'DeepDyve' Gillespie user on 07 May 2019 treatment-naïve, non-cirrhotic patients. P-values derived from the Pearson’s chi-squared test. MoP, HCV monoinfected patients; Coinfected patients, HIV/HCV-coinfected patients; No., number of patients; SVR, sustained viral response (number [%]);CI, confidence interval; DC, treatment discontinuations (number [%]); AE, adverse events. Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz214/5486493 by Ed 'DeepDyve' Gillespie user on 07 May 2019 Appendix. Physicians and Hospital Pharmacists of the Madrid Registry of Use of DAA for HCV (RUA-VHC). Hospital General Universitario Gregorio Marañón: Ahumada, Adriana; Ais Larisgoitia, Arantza; Aldámiz Echevarría Lois, María Teresa; Bañares Cañizares, Rafael; Berenguer Berenguer, Juan; Blanco Sánchez, Germán; Chamorro De Vega, Esther; Clemente Ricote, Gerardo; Collado Borell, Roberto; Díaz Fontenla, Fernando; Escudero Vilaplana, Vicente; Eworo Ndongo, Alia; Fernández Cruz, Ana; Flores Fernandez, Virginia; García González, Xandra; García Sánchez, Raquel; Gijón Vidaurreta, Paloma; Giménez Manzorro, Álvaro; Herranz Alonso, Ana; Ibáñez García, Sara; Lallana Sainz, Elena; Lobato Matilla, María Elena; López Bernaldo De Quirós, Juan Carlos; Manrique Rodríguez, Silvia; Martínez Fernandez-Llamazares, Cecilia; Martínez Ortega, Pilar; Miralles Martin, Pilar; Montilla De Mora, Pedro; Padilla Ortega, Belén; Parras Vázquez, Francisco; Pérez Valderas, María Dolores; Revuelta Herrero, José Luis; Ribed Sánchez, Almudena; Rincón Rodríguez, Diego; Rodríguez González, Carmen; Romero Cristóbal, Mario; Romero Jiménez, Rosa; Ruiz Martínez, Cristina; Salcedo Plaza, Magdalena; Sánchez Somolinos, Mar; Sarobe González, Camino; Valerio Minero, Maricela. Hospital Universitario La Paz: Baladé Martinez, Laura; Barreiro García, Pablo; Benítez García, Beatriz; Bernardino De La Serna, José; Castillo Grau, Pilar; De Sebastián Rueda, María; Erdozain Sosa, José Carlos; Freire González, Mercedes; Gabaldón Garnica, Paloma; García Sánchez, Araceli; García-Samaniego Rey, Francisco; González Del Valle, Luis; González Fernández, María Ángeles; González García, Juan J. ; Jiménez Nacher, Inmaculada; Jiménez Vicente, Carlos; Lucena Martinez; Patricia; Martín Carbonero, Luz; Molina Cabezuelo, Marta; Montes Ramírez, Mª Luisa; Moreno Celda, Victoria; Moreno Palomino, Marta; Moreno Ramos, Francisco; Olveira Martín, Antonio; Parrilla, Mercedes; Pérez Valero, Ignacio; Rodríguez Martín, Elena; Rodríguez Nava, José Luis; Romero Portales, Miriam; Rossignoli Montero, Ana; Ruiz De Hoyos, Marta; Sobrino Jiménez, Carmen; Soriano Vázquez, Vicente; Valencia Ortega, Eulalia; Varela Fernandez, Hugo Adolfo. Hospital Ramón y Cajal: Albillos Martinez, Agustín; Anguita Ruiz, Eva; Arocena Aranguren, Carlos; Casado Osorio, José; Díaz De Santiago, Alberto; Fortún Abete, Jesús; García González, Miguel; Gea Rodríguez, Francisco; Gómez De Salazar López De Silanes, María Esther; Gramage Caro, Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz214/5486493 by Ed 'DeepDyve' Gillespie user on 07 May 2019 Teresa; Graus Morales, Javier; Moreno Guillen, Santiago; Moreno Zamora, Ana María; Navas Elorza, Enrique; Pérez Elías, María Jesús; Pérez Molina, José Antonio; Quereda Rodríguez-Navarro, Carmen; Rodríguez Sagrado, Miguel Ángel; Serrano Villar, Sergio Daniel; Vélez Díaz-Palleres, Manuel; Vivancos Gallego, María Jesús. Hospital Doce de Octubre: Campo Angora, Mercedes; Castellano Tortajada, Gregorio; De Lagarde Sebastián, María; Fernández Vázquez, Inmaculada; Gómez Valbuena, Isabel; Manzano Alonso, María Luisa; Martin Algíbez, Ana María; Matarranz Del Amo, Mariano; Muñoz Gómez, Raquel; Pinar López, Oscar; Pulido Ortega, Federico; Rubio García, Rafael; Serrano Garrote, Olga. Hospital Clínico de San Carlos: Benítez Giménez, María Teresa; Cabello Clotet, Noemí; Cuenca Alarcón, Francisca; Devesa Medina, María José; Estrada Pérez, Vicente; Izquierdo Rubio, Sonia; Maroto Castellanos, Maite; Núñez Orantos, María José; Rodríguez Del Rio, Elena; Sáenz De Tejada López, Marta; Sánchez-Pobre Bejarano, Pilar; Santiago Pérez, Alejandro; Téllez Molina, María Jesús; Vergas García, Jorge. Hospital Fundación Jiménez Díaz: Álvarez Álvarez, Beatriz; Arias Moya, María Ángeles; Becares Martínez, Francisco Javier; Bonilla Porras, Macarena; Cabello Úbeda, Alfonso; Calvo Hernández, Rocío; González Guirado, Agustina; Górgolas Hernández, Miguel De; Hernández Segurado, Marta; Moran Ortiz-Desolorzano, Marta; Morón Merchante, Francisco Javier; Polo Lorduy, Benjamín Arturo; Porres Cubero, Juan Carlos; Tortajada Esteban, Elena Victoria; Varela Silva, Andrés L. Hospital Infanta Leonor: Barrio Antoranz, José; Barrueco Fernandez, Nélida; Cañamares Orbis, Irene; Carrión Alonso, Gemma; Cuevas Tascón, Guillermo; Escobar Rodríguez, Ismael; Esteban Alba, Concepción; Izquierdo García, Elsa; Liras Medina, Ángel; Lozano Maya, María Del Mar; Marino Martínez, Carolina; Ryan Murúa, Pablo; Sáez De La Fuente, Javier; Sánchez Rubio, Luis; Such Díaz, Ana; Tejedor Prado, Pilar; Troya García, Jesús; Villa Poza, José Carlos. Hospital de Puerta de Hierro: Arias Milla, Ana; Baños Pérez, Isolina; Benítez Gutiérrez, Laura María; Calleja Panero, José Luis; Cuervas Mons Martínez, Valentín; Duca, Ana María; Folguera Olías, Carlos; Menchén Viso, Belén; De La Revilla Negro, Juan; Ruiz Gutiérrez, Julia; Sánchez Guerrero, Amelia; Santiago Prieto, María Elvira. Hospital La Princesa: Alañón Plaza, Estefanía; Gallego Aranda, Tomás; García Buey, Luisa Consuelo; González Moreno, Leticia; Ibáñez Zurriaga, Amparo; Marinero Martinez-Lázaro, Almudena; Martinez Nieto, Concepción; Morell Baladrón, Alberto; Pérez Abanades, Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz214/5486493 by Ed 'DeepDyve' Gillespie user on 07 May 2019 María; Ramírez Herráiz, Esther; Real Martinez, Yolanda; Santos Gil, Ignacio De Los; Hospital U. Príncipe de Asturias: Arranz Caso, José Alberto; Beceiro Pedreño, Inmaculada; Borrego Rodríguez, Gloria; Casas García, Esperanza; Costero Pastor, Ana Belén; De Miguel Prieto, Julio; Del Pozo Prieto, David; Fernández Pacheco Garcia-Valdecasas, María; Ginés Palomares, Ana; Hernández Gutiérrez, Cristina; Herranz Muñoz, Clara; Herrero Fernández, Marta; Lebrero García, Alberto; Novella Mena, María; Ortiz Campos, María; Pérez Pérez, Diana; Poves Martinez, Elvira; Santolaya Perrín, María Rosario; Sanz Moreno, José; Víctor Palomares, Virginia; Hospital Fundación de Alcorcón: Alonso López, Sonia; Bartolomé García, Emma; Fernández Rodríguez, Conrado; Gutiérrez García, Mª Luisa; Henríquez Camacho, Cesar Augusto; Hervás Gómez, Rafael; Losa García, Juan Emilio; Moreno Núñez, Leonor; Pérez Encinas, Montserrat; Polanco Paz, María Del Mar; Sanmartín Fenollera, Patricia; Velasco Arribas, María. Hospital Infanta Sofía: Albertos Rubio, Sonia; Beltrán Castaño, Rocío; Comas Redondo, Carmen; García Yubero, Cristina; González-Ruano Pérez, Patricia; Hidalgo Aguirre, Lorena; Malmierca Corral, Eduardo; Martinez Hernández, Alicia; Pérez Álvarez, Mónica; Portillo Horcajada, Laura; Suárez García, Inés María. Hospital de Fuenlabrada: Andrés Rosado, Ana; Canalejo Castrillero, Eduardo; Candel García, Beatriz; Carrasco Torrents, América; De La Poza Gómez, Gema; García Rebolledo, Eva María; Hernández Muniesa, Belén; Hinojosa Mena-Bernal, Juan; Mondejar Gutiérrez, Gemma María; Ontanon Nasarre, Ana; Piqueras Alcohol, Belén; Ruiz Giardin, José Manuel; Ruiz, Justo; San Martin López, Juan Víctor; Valer López-Fando, María Paz. Hospital Universitario de Getafe: Diez Fernandez, Raúl; Esteban Fernandez, Francisco Javier; Gaspar Alonso-Vega, Gabriel; Gil Ares, Fernando; Gómez Rubio, Mariano; Molina García, Teresa; Negro Vega, Eva; Pérez Caballero, Gloria; Sánchez Ayuso, Javier; Sánchez-Rubio Ferrández, Javier. Hospital Severo Ochoa: Agud Aparicio, José Luis; Aguirre Losada, Alberto Ángel; Castro Urda, José Luis; Cervero Jiménez, Miguel; Díaz Gómez, Estrella; Domínguez Gozalo, Andrea; García Benayas, Elena; Jusdado Ruiz-Capillas, Juan José; Muñoz Romero, Javier; Torres Perea, Rafael. Hospital de Móstoles: Barros Aguado, Carlos Antonio; Corrales Pérez, Laura; Crespo Robledo, Paloma; González Alonso, Raquel; Mañes Sevilla, Mireya; Merino Morales, Francisco; Moreno Sánchez, Diego; Moriel Sánchez, Carmen; Rubio Cebrián, Beatriz. Hospital del Henares: Campos Fernández De Sevilla, María De Los Ángeles; De Lorenzo Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz214/5486493 by Ed 'DeepDyve' Gillespie user on 07 May 2019 Pinto, Ana; Delgado Téllez De Cepeda, Laura; Egües Lugea, Amaia; Gallego Úbeda, Marta; Ibáñez Pinto, Alberto; Sánchez Gómez, Argeme; Sanz Rojas, Patricia; Serrano Herranz, Regino; Tovar Pozo, María; Valbuena González, Marta. Hospital Infanta Cristina: Botella Mateu, Belén; Cuenca Morón, Beatriz De; De Guzmán García-Monge, María Teresa; Domingo Senra, Daniel; Domínguez García, Nuria; Esteban Fernandez-Zarza, Carlos; Martínez Consuegra, José Antonio; Matilla García, Elena; Melero Bermejo, José Antonio; Moreno Díaz, Raquel; Ortiz Duran, María; Pérez Quero, José Luis; Rodríguez Vargas, Blanca. Hospital del Sureste: Buendía Bravo, Silvia; Calvo Ramos, Irina; Capilla Montes, Cristina; Cruz Cruz, María Teresa; Díaz Sánchez, Antonio; Fernández Amago, María Teresa; García Benayas, María Teresa; González Alonso, María Rosario; Marzal Alfaro, Belén; Moya Valverde, Eloísa; Peñalver Cifuentes, Rafael; Rivero Fernández, Miguel. Hospital Rey Juan Carlos: García Barquero, Margarita; García García, Almudena; Gotuzzo Altez, Luis Ricardo; Huertas Velasco, María Antonia; Marcos Rojas Rodríguez De Quesada, Jorge; Nistal Juncos, Sara; Pérez Rial, Gabriel. Hospital Infanta Elena: Alarcón Del Amo, Cristina; Alcalde Rodríguez, Daniel; Barranco Cao, Raquel; Calvache Rodríguez, Almudena; Chico Álvarez, Inmaculada; Collados Arroyo, Virginia; Del Portillo Rubí, Álvaro; Delgado Galán, María; López Martin, María Del Carmen; Rodríguez Rodríguez, Raquel; Tejedor Bravo, Marta; Vegas Serrano, Ana. Hospital de Torrejón: Achécar Justo, Linette María; Arponen, Sari; Blasco Guerrero, Marta; Del Rio Izquierdo, María; Esteva Jiménez, Laura; Gimeno García, Alejandra; González Pino, Andrea; Montero Hernández, María Carmen; Morales Martínez, Lorena; Sáez Bertrand, Catalina. Hospital del Tajo: Alonso Grandes, Elena; Fernández Esteban, Eva; Lo Iacono, Oreste; Monsalvo Arroyo, Raquel; Pedraza Cezón, Luis Antonio; Soto Fernández, Susana; Terrancle Juan, Ignacio. Hospital Gómez Ulla: García Mayor, María De Los Ángeles; López Honduvilla, Francisco José; Menéndez Martínez, María Antonia; Pérez Moran, María José; Prats Olivan, Pilar. Hospital Collado Villalba: Abad Guerra, Javier; Arias Rivera, María Luisa; Bejerano Domínguez, Alicia; Correa Abanto, Lizbeth Milagros; Ferrere González, Federico; Gómez Pérez, Marta; Olivares Valles, Ana. Hospital El Escorial: Aguilar Guisado, Carolina; Belda Bilbao, Luis Miguel; Calvo Fernández, Santiago; García De Aguinaga, Mª Luisa; García Gimeno, María Mercedes; Gongorra López, Andrea; Jaime Sánchez, Belén; Montero Jiménez, Francisco Javier; Sánchez Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz214/5486493 by Ed 'DeepDyve' Gillespie user on 07 May 2019 Suárez, Susana. Hospital Central de La Cruz Roja: Fuentes Irigoyen, Raquel; Iborra Herrera, Jerónimo; Navarrete García, Elena; Tejada González, Pilar. Hospital Infantil Niño Jesús: García Rodríguez, María Del Pilar; Muñoz Codoceo, Rosa Ana. Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz214/5486493 by Ed 'DeepDyve' Gillespie user on 07 May 2019 Fig 1. Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz214/5486493 by Ed 'DeepDyve' Gillespie user on 07 May 2019 Fig 2. Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz214/5486493 by Ed 'DeepDyve' Gillespie user on 07 May 2019 Table 1. Baseline characteristics of 1,358 previously untreated non-cirrhotic patients infected with HCV genotype 1 and treated with LDV/SOF 8 weeks 12 weeks TOTAL Total Monoinfected Coinfected P* Total Monoinfected Coinfected P* Monoinfected and Patients Patients Patients Patients Coinfected Patients Variables N=497 N=414 N=83 N=861 N=641 N=220 N=1,358 Age – median (IQR) 56 (49-66) 59 (50-68) 50 (46-54) <0.001 56 (50-68) 61 (52-71) 51 (48-54) <0.001 56 (50-67) Male sex – n (%) 258 (51.9) 192 (46.4) 66 (79.5) <0.001 491 (57.0) 325 (50.7) 166 (75.4) <0.001 749 (55.1) HCV genotype/subtype – n (%) <0.001 <0.001 1a 160 (32.2) 95 (22.9) 65 (78.3) 395 (45.9) 224 (34.9) 171 (77.7) 555 (40.9) 1b 322 (64.8) 311 (75.1) 11 (13.2) 434 (50.4) 398 (62.1) 36 (16.4) 756 (55.7) 1 not subtyped 15 (3.0) 8 (1.9) 7 (8.4) 32 (3.7) 19 (3.0) 13 (5.9) 47 (3.5) HCV RNA – n (%) Log IU/mL – Median (IQR) 5.9 (5.4-6.4) 5.9 (5.4-6.3) 6.1 (5.6-6.5) 0.033 6.4 (6.0-6.8) 6.4 (5.9-6.8) 6.5 (6.0-6.8) 0.070 6.2 (5.7-6.6) > 6 million IU/mL – n (%) 18 (3.6) 12 (2.9) 6 (7.2) 0.054 216 (25.1) 154 (24.0) 62 (28.2) 0.220 234 (17.2) Transient elastography – n (%) No 8 (1.6) 8 (1.9) 0 30 (3.5) 30 (4.7) 0 38 (2.8) Yes 489 (98.4) 406 (98.1) 83 (100.0) 831 (96.5) 611 (95.3) 220 (100.0) 1,320 (97.2) Stiffness kPa – Median (IQR) 8.6 (7.9-9.4) 8.6 (7.9-9.3) 8.6 (7.8-10.0) 0.582 9.1 (8.1-10.4) 9.1 (8.1-10.4) 9.0 (8.1-10.3) 0.534 8.8 (8.0-10.1) ≥ 9.5 kPa – n (%) 121 (24.7) 94 (23.1) 27 (32.5) 0.071 373 (44.9) 284 (46.5) 89 (40.4) 0.123 494 7.4) *P-values derived from the Pearson’s chi-squared test or the nonparametric Mann-Whitney test for differences in categorical or continuous variables, respectively. Abbreviations: HCV, hepatitis C virus; LDV/SOF, ledipasvir/sofosbuvir; IQR, interquartile range; HCV, hepatitis C virus; RNA, ribonucleic acid. Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz214/5486493 by Ed 'DeepDyve' Gillespie user on 07 May 2019 Table 2. Baseline HIV-related characteristics of 303 previously untreated non-cirrhotic HIV/HCV-coinfected with HCV genotype 1 and treated with LDV/SOF Variable 8 weeks 12 weeks Total P* Variables n = 83 n = 220 n = 303 HIV risk factor – n (%) 0.021 Injection drug use 39 (47.0) 120 (54.5) 159 (52.5) Men who have sex with men 8 (9.6) 4 (1.8) 12 (4.0) Heterosexual relations 5 (6.0) 8 (3.6) 13 (4.3) Transfusions 0 2 (0.9) 2 (0.7) Unknown 31 (37.3) 86 (39.1) 117 (38.6) CDC clinical category – n (%) 0.305 A 21 (25.3) 38 (17.3) 59 (19.5) B 9 (10.8) 38 (17.3) 47 (15.5) C 22 (26.5) 60 (27.3) 82 (27.1) Unknown 31 (37.3) 84 (38.2) 115 (37.9) Nadir CD4+/mm – n (%) 0.622 > 500 8 (9.6) 14 (6.4) 22 (7.3) 200 - 499 17 (20.5) 38 (17.3) 55 (18.1) < 200 27 (32.5) 84 (38.2) 111 (36.6) Unknown 31 (37.3) 84 (38.2) 115 (38.0) Baseline CD4+/mm – n (%) > 500 22 (26.5) 75 (34.1) 97 (32.0) 0.057 200 - 499 9 (10.8) 43 (19.5) 52 (17.2) < 200 2 (2.4) 7 (3.2) 9 (3.0) Unknown 50 (60.2) 95 (43.2) 145 (47.9) Known 33 (39.8) 125 (56.8) 158 (52.1) 0.008 Median (IQR) 632 595 607 0.474 (474 – 847) (372 – 819) (389 – 822) ART – n (%) 0.285 No 0 3 (1.4) 3 (1.0) Yes 83 (100.0) 217 (98.6) 300 (99.0) HIV-RNA – n (%) Unknown 31 (37.3) 81 (36.8) 112 (37.0) 0.932 Known 52 (62.6) 139 (63.2) 191 (63.0) Detectable 5 (9.6) 7 (5.0) 12 (6.3) 0.246 Undetectable 47 (90.4) 132 (95.0) 179 (93.7) *P-values derived from the Pearson’s chi-squared test or the nonparametric Mann- Whitney test for differences in categorical or continuous variables, respectively. Abbreviations: HIV, human immunodeficiency virus; HCV, hepatitis C virus; CDC, Centers for Disease Control and Prevention; ART, antiretroviral therapy; RNA, ribonucleic acid. Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz214/5486493 by Ed 'DeepDyve' Gillespie user on 07 May 2019 Table 3. Results from univariable and multivariable logistic regression models to identify independent baseline factors predictive of treatment failure considering the whole data set (Monoinfected, Coinfected, 8 and 12 weeks) – 1,358 Treatment Univariable Multivariable Multivariable Multivariable † ‡ § failures Model 1 Model 2 Model 3 Variable N (%) OR (95% CI) P OR (95% CI) P OR (95% CI) P OR (95% CI) P Age 0.473 0.441 4 (2.9) 1.00 1 <45 23 (4.8) 1.69 (0.58 – 4.98) 1.64 (0.55 – 4.89) 45-54 27 (3.6) 1.27 (0.44 – 3.67) 2.03 (0.67 – 6.15) ≥55 Sex 0.001 0.008 0.010 0.008 Female 12 (2.0) 1.00 1.00 1.00 1.00 42 (5.6) 2.96 (1.54 – 5.67) 2.47 (1.27 – 4.82) 2.43 (1.24 – 4.77) 2.49 (1.27 – 4.91) Male Liver stiffness – kPa 0.300 0.399 28 (3.4) 1.00 1 < 9.5 25 (5.1) 1.52 (0.88 – 2.64) 1.48 (0.84 – 2.61) ≥ 9.5 1 (2.6) 0.77 (0.10 – 5.82) 1.19 (0.15 – 9.27) Unknown HCV genotype 0.079 0.879 0.722 1b 22 (2.9) 1.00 1.00 1 30 (5.4) 1.91 (1.09 – 3.34) 1.15 (0.60 – 2.19) 1.27 (0.65 – 2.49) 1a 2 (4.3) 1.48 (0.34 – 6.50) 0.89 (0.19 – 4.07) 0.89 (0.19 – 4.10) 1 not subtyped HCV RNA IU/mL 0.911 0.676 < 6,000,000 45 (4.0) 1.00 1 9 (3.8) 0.96 (0.46 – 1.99) 0.85 (0.40 – 1.82) ≥ 6,000,000 HIV-infection <0.001 0.007 0.024 0.020 No 31 (2.9) 1.00 1.00 1.00 1.00 23 (7.6) 2.71 (1.56 – 4.73) 2.20 (1.24 – 3.89) 2.08 (1.10 – 3.94) 2.23 (1.13 – 4.38) Yes Treatment duration 0.612 0.850 12 weeks 36 (4.2) 1.00 1 18 (3.6) 0.86 (0.48 – 1.53) 1.06 (0.57 – 1.96) 8 weeks Multivariable model 1 includes variables with a P-value <0.05 in the univariable analysis. Multivariable model 2 includes variables with a P-value <0.1 in the univariable analysis. Multivariable model 3 is a fully adjusted one, including every variable detailed in the first column. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Open Forum Infectious Diseases Oxford University Press

HIV Coinfection Predicts Failure of Ledipasvir/Sofosbuvir in Treatment-Naïve Non-Cirrhotic Patients with HCV genotype 1

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Oxford University Press
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© The Author(s) 2019. Published by Oxford University Press on behalf of Infectious Diseases Society of America.
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10.1093/ofid/ofz214
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Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz214/5486493 by Ed 'DeepDyve' Gillespie user on 07 May 2019 HIV Coinfection Predicts Failure of Ledipasvir/Sofosbuvir in Treatment-Naïve Non-Cirrhotic Patients with HCV genotype 1 1,2 3,4,5,6 7,8 9 Juan Berenguer , José Luis Calleja , María Luisa Montes , Ángela Gil , Ana 10,11 1,2,6,12 1,2 Moreno , Rafael Bañares , Teresa Aldámiz-Echevarría , Agustín 6,10,11,13 14,15 6,7,8 16,17 Albillos , María Jesús Téllez , Antonio Olveira , Lourdes Domínguez , 16,17 6,7,8 5,18 Inmaculada Fernández , Javier García-Samaniego , Benjamín A Polo , 18 2,19 19 14,15 Beatriz Álvarez , Pablo Ryan , José Barrio , María J Devesa , Laura Benítez 3,4 20,21 20,21 13,22 13,22 , Ignacio Santos , Luisa García Buey , José Sanz , Elvira Poves , Juan E 23,24 23,24 25 9, Losa , Conrado Fernández-Rodríguez , Inmaculada Jarrín , María J Calvo , 7,8 Juan González-García . 1 2 Hospital General Universitario Gregorio Marañón, Madrid, Spain. Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain. Hospital Universitario Puerta de Hierro, Madrid, Spain. Instituto de Investigación Sanitaria Puerta de Hierro, Madrid, Spain. Universiad Autónoma de Madrid (UAM), Madrid, Spain. Centro de Investigación Biomédica en Red en el Área Temática de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain. Hospital Universitario La Paz, Madrid, Spain. Instituto de Investigación Hospital Universitario La Paz (IdiPAZ), Subdirección General de Farmacia y Productos Sanitarios/SERMAS, Madrid, Spain. Hospital Universitario Ramón y Cajal, Madrid, Spain. Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain. © The Author(s) 2019. Published by Oxford University Press on behalf of Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by- nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz214/5486493 by Ed 'DeepDyve' Gillespie user on 07 May 2019 12 13 Universidad Complutense de Madrid (UCM), Madrid, Spain. Universidad de Alcalá (UAH), Madrid, Spain. Hospital Clínico San Carlos, Madrid, Spain. 15 16 Instituto de Investigación Sanitaria San Carlos (IdiSSC), Madrid, Spain. Hospital Universitario 12 de Octubre, Madrid, Spain. Instituto de Investigación Hospital 12 de Octubre (i+12), Madrid, Spain. Fundación Jiménez Díaz, Madrid, Spain. 19 20 Hospital Universitario Infanta Leonor, Madrid, Hospital Universitario de la Princesa, Madrid, Spain. Instituto de Investigación del Hospital Universitario La Princesa, Madrid, Spain. Hospital Universitario Príncipe de Asturias, Alcalá de 23 24 Henares. Hospital Fundación Alcorcón, Alcorcón. Universidad Rey Juan Carlos, Alcorcón. Instituto de Salud Carlos III, Madrid, Spain. Keywords Antiviral Agents/administration & dosage/*therapeutic use Hepatitis C, Chronic/*complications/*drug therapy HIV Infections/*complications Sustained Virologic Response DAA Running title: HIV and treatment failure to DAAs Contact information Juan Berenguer, MD, PhD Unidad de Enfermedades Infecciosas/VIH (4100) Hospital Gregorio Marañón, Doctor Esquerdo 46 28007 Madrid Telephone: +34 91 586 8592 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz214/5486493 by Ed 'DeepDyve' Gillespie user on 07 May 2019 Fax: +34 91 426 5177 jbb4@me.com Alternative corresponding author Juan González-García, MD, PhD Unidad de VIH, Servicio de Medicina Interna Instituto de Investigación Sanitaria La Paz (IdiPAZ) Paseo de la Castellana 261. 28046. Madrid, Spain. Telephone: +34 91 207 1676. Fax: +34 91 729 0033. Email: juangonzalezgar@gmail.com Article´s main point The results of this large real-world study suggest that HIV infection is a predictor of treatment failure to ledipasvir/sofosbuvir, in patients with chronic hepatitis C. and supports the use of newer simplified and pan-genotypic anti-HCV regimens among coinfected patients. Juan Berenguer and Juan González-García contributed equally to this study Initial data from this analysis were presented at the Conference on Retroviruses and Opportunistic Infections (CROI). March 4-7, 2018. Boston, MA. (Presentation # 607). Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz214/5486493 by Ed 'DeepDyve' Gillespie user on 07 May 2019 Abstract Background: The efficacy of licensed DAA regimens is assumed to be the same for HCV-monoinfected patients (HCV-Mono) and HIV/HCV-coinfected patients (HCV- Co). However, the high SVR rates of DAA regimens and the small number of HIV- infected patients included in registration trials have made it difficult to identify predictors of treatment failure, including the presence of HIV. Methods: We compared treatment outcomes for LDV/SOF against HCV G1 in treatment-naïve HCV-Mono and HCV-Co without cirrhosis in a prospective registry of individuals receiving DAAs for HCV. Results: Up to September 2017, a total of 17,269 patients were registered, and 1,358 patients (1,055 HCV-Mono/303 HCV-Co) met the inclusion criteria. Significant differences between HCV-Mono and HCV-Co were observed for age, gender, and G1 subtype distribution. Among HCV-Co, 99.0% were receiving antiretroviral therapy. SVR rates for LDV/SOF at 8 wk did not differ significantly between HCV-Mono and HCV-Co (96.9% vs. 94.0%; P=.199). However, the SVR rate for LDV/SOF at 12 wk was significantly higher for HCV-Mono than HCV-Co (97.2% vs. 91.8%; P=.001). A multivariable logistic regression model including age, sex, liver stiffness, G1 subtype, HCV-RNA, HIV, and treatment duration showed the factors associated with treatment failure to be male sex (adjusted odds ratio [aOR] 2.49; 95%CI 1.27-4.91; P=.008) and HIV infection (aOR 2.23; 95%CI 1.13-4.38; P=.020). Conclusions: The results of this large prospective study analyzing outcomes for LDV/SOF against HCV G1 in treatment-naïve non-cirrhotic patients suggest that HIV infection is a predictor of treatment failure in patients with chronic hepatitis C. Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz214/5486493 by Ed 'DeepDyve' Gillespie user on 07 May 2019 Introduction The licensure of direct-acting antiviral agents (DAAs) marked a turning point in the treatment of infection by hepatitis C virus (HCV) [1]. This therapeutic innovation offered new prospects for the treatment of individuals coinfected by HCV and the human immunodeficiency virus (HIV), a difficult-to-treat population in the interferon plus ribavirin (RBV) era, with lower sustained viral response (SVR) rates and higher frequencies of serious adverse events than patients monoinfected with HCV [2-4]. Currently, it is recommended that coinfected persons receive the same treatment as monoinfected individuals, assuming that the efficacy of approved DAA regimens does not differ between the groups [5, 6]; although this is not entirely the case for AASLD/IDSA guidelines in the U.S in which ledipasvir and sofosbuvir (LDV/SOF) for 8 weeks is not recommended for patients with HIV/HCV coinfection, regardless of baseline HCV RNA level [6]. However, whether or not HIV infection is a predictor of treatment response to DAA regimens is difficult to assess owing to the high SVR rates associated with most licensed all-oral DAA-based regimens against HCV and the low number of clinical trials with DAA including both monoinfected and coinfected patients [7, 8]. As for real-world case series, some have found an association between HIV coinfection and lower SVR rates [9, 10], whereas in others, SVR rates were not significantly different between monoinfected and coinfected individuals [11-14]. We aimed to assess whether or not HIV infection is associated with failure of DAA therapy. Therefore, we focused on previously untreated non-cirrhotic patients infected with HCV genotype 1, with or without HIV, who were treated with Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz214/5486493 by Ed 'DeepDyve' Gillespie user on 07 May 2019 LDV/SOF. We adopted this approach because it provided a large enough sample size of patients and because we could easily control for some predictors of response including genotype, type of regimen, presence of cirrhosis, previous exposure to anti-HCV therapy, and use of RBV. Patients and Methods Design and patient selection Patients were selected for this study from the Madrid Registry of Use of DAA for HCV (RUA-VHC), a compulsory prospective registry of individuals receiving DAAs for HCV infection in the region of Madrid created in November 2014 by the Madrid Regional Health Service (SERMAS). Providing baseline data for this online registry is mandatory for the retrieval of DAAs in hospital pharmacies. Likewise, providing exhaustive follow-up data is a condition for reimbursement. The decision to treat was taken and the regimen selected by the treating physician according to current guidelines. Data collected prospectively in RUA-VHC have been reported in depth elsewhere [15]. In summary, baseline data included demographics, whether the patient was HIV-infected and was receiving antiretroviral therapy (ART), HCV genotype and subtype, HCV RNA load, prior history of anti-HCV therapy, liver fibrosis stage, and presence or absence of cirrhosis. The date of initiation and type of DAA regimen, use of RBV, and planned treatment duration were also recorded. In September 2016, a case report form was used to collect the following HIV- related variables offline: HIV transmission category, Centers for Disease Control and Prevention (CDC) clinical category, baseline and nadir CD4+ T-cell counts, and Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz214/5486493 by Ed 'DeepDyve' Gillespie user on 07 May 2019 baseline HIV viral load. In March 2017, the online registry was modified to include all the variables related to HIV infection mentioned above. Since then, this information has been registered prospectively. The study protocol was approved by the ethics committee of Hospital Universitario La Paz for the analysis of anonymous routine clinical data without written informed consent for purposes of scientific publication. In this analysis, patients included in RUA-VHC were eligible if they were 18 years or older, were infected with HCV genotype 1, were non-cirrhotic and previously untreated, were treated with LDV/SOF without ribavirin for 8 or 12 weeks and were scheduled to finish treatment on or before September 31, 2017. Measurements Fibrosis stage and cirrhosis were determined by liver biopsy or transient elastography (FibroScan, Echo-Sens, Paris, France). Cirrhosis was defined as liver stiffness > 12.5 kPa or clinical evidence of liver decompensation. The remaining liver stiffness cutoffs were as follows: ≤ 7 kPa, the cutoff to rule out null or mild fibrosis; < 9.5 kPa, the cutoff to rule out advanced fibrosis-cirrhosis [16]. HCV RNA was measured at baseline, at the end of therapy, and 12 weeks after completion of treatment. Real-time PCR assays for the quantification of HCV RNA included Roche COBAS AmpliPrep/COBAS TaqMan HCV (Roche Molecular Systems, Pleasanton, California, USA; lower limit of detection [LLOD] 15 IU/mL), Abbott RealTime HCV assay (Abbott Laboratories, Abbott Park, Illinois, USA; LLOD 12 IU/mL), or Siemens Versant HCV RNA version 1.0 (Siemens Healthcare GmbH, Erlangen, Germany; LLOD 15 IU/mL). Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz214/5486493 by Ed 'DeepDyve' Gillespie user on 07 May 2019 Outcomes Follow-up data in the online registry included the following: i) SVR, defined as undetectable plasma HCV RNA at 12 weeks after completion of treatment; ii) relapse, defined as detectable post-treatment HCV RNA after undetectable HCV RNA at the end of therapy; and iii) viral breakthrough, defined as detectable HCV RNA at the end of therapy and at week 12. Discontinuations due to adverse events or for reasons other than adverse events, losses to follow-up, and deaths were also registered. Statistical analysis When analyzing treatment effectiveness, any patient who initiated LDV/SOF therapy without confirmed SVR or missing outcome data were considered as treatment failures. Three multivariable logistic regression models were used to identify independent baseline factors associated with treatment failure. The first model included variables that were associated with treatment failure in univariable analysis with P < .05. The second model included variables that were associated with treatment failure in univariable analysis with P < .1. The third model was a fully adjusted model including age, sex, liver stiffness, HCV genotype, HCV RNA load, HIV infection, and treatment duration. Analyses were performed for the entire data set and for subgroups of treatment duration (8 and 12 weeks). Wald tests were used to derive P values. The analyses were performed using Stata version 14 (Stata Corp, College Station, Texas, USA). Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz214/5486493 by Ed 'DeepDyve' Gillespie user on 07 May 2019 Results Patient characteristics Up to September 2017, a total of 17,269 patients (13,720 monoinfected patients and 3,549 coinfected patients) initiated all-oral DAAs for treatment of HCV infection in 25 hospitals in the region of Madrid. Of these, 1,358 patients (1,055 monoinfected patients and 303 coinfected patients) met the inclusion criteria (Supplementary material – Figure S1). A total of 272 of the 1,358 patients (20.0%) included in this study were also included in a paper describing real-world outcomes of all oral DAA-based therapy in 2,369 HIV/HCV-coinfected patients [15]. The baseline characteristics of the 1,358 patients categorized by LDV/SOF treatment duration and by type of patient (monoinfected patients or coinfected patients) are shown in Table 1. Overall, 497 patients were treated with LDV/SOF for 8 weeks (36.6%), and 861 patients were treated with LDV/SOF for 12 weeks (63.4%). A higher percentage of monoinfected patients (39.2%) than coinfected patients (27.4%) were treated with LDV/SOF for 8 weeks. In brief, 55.1% were men, and the median age was 56 years. The HCV subtype distribution was: 1a (40.9%), 1b (55.7%), and 1 not subtyped (3.5%). The median HCV RNA was 6.2 Log IU/mL, and 17.2% of patients had an HCV RNA > 6 million IU/mL. A total of 1,320 (97.2%) patients underwent transient elastography at baseline. The median liver stiffness value was 8.8 kPa, and 494 (37.4%) patients had a liver stiffness value ≥ 9.5 kPa (but ≤ 12.5 kPa), which was indicative of advanced fibrosis. Statistically significant differences between monoinfected patients and coinfected patients were observed at baseline for age, gender, and Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz214/5486493 by Ed 'DeepDyve' Gillespie user on 07 May 2019 genotype 1 subtype distribution (Table 1). At baseline, 99.0% of coinfected patients were on ART. Full data on HIV-related characteristics were available for analysis from approximately half of the coinfected patients. No statistically significant differences were found between patients with complete HIV data and patients with incomplete HIV data for age, HCV genotype distribution, and HCV RNA load. However, patients with incomplete HIV data were more frequently male and had a lower liver stiffness value (Supplementary material – Table S1). Differences in mechanism of acquisition of HIV were found between coinfected patients treated for 8 or 12 weeks, with a lower proportion of injection drug use and a higher frequency of men who have sex with men among the former group (Table 2). Treatment response LDV/SOF for 8 weeks Treatment responses to LDV/SOF for 8 weeks are shown in Figure 1A. A total of 497 patients (414 monoinfected patients and 83 coinfected patients) received SOF/LDV without RBV for 8 weeks. Overall, the SVR rate of 8 weeks of therapy with SOF/LDV was 96.4%, without significant differences in SVR rates found between monoinfected patients and coinfected patients 96.9% vs. 94.0%, P = .199. There were no viral breakthroughs. The overall relapse rate was 2.8%, and no statistically significant differences in relapse rates were found between monoinfected patients and coinfected patients (2.2% vs. 6.0%, P = .06). Only 1 patient discontinued SOF/LDV owing to adverse events, and 3 patients discontinued therapy for reasons not related to adverse events. All 4 were monoinfected patients. Outcomes for 8 weeks’ treatment with LDV/SOF without Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz214/5486493 by Ed 'DeepDyve' Gillespie user on 07 May 2019 RBV for HCV genotype 1a and 1b analysis are shown in Figure 2A. LDV/SOF for 12 weeks Treatment response to LDV/SOF for 12 weeks is shown in Figure 1B. A total of 861 patients (641 monoinfected patients and 220 coinfected patients) received SOF/LDV without RBV for 12 weeks. Overall, the SVR rates of 12 weeks of therapy with SOF/LDV was 95.8%. Statistically significant differences in SVR rates were found between monoinfected patients and coinfected patients (97.2% vs. 91.8%, P = .001). Again, there were no viral breakthroughs. The overall relapse rate was 1.6%, and no statistically significant differences in relapse rates were found between monoinfected patients and coinfected patients (1.1% vs. 3.2%, P = .06). Five patients (0.6%) discontinued SOF/LDV owing to adverse events (2 monoinfected patients [0.3%] and 3 [1.4%] coinfected patients, P = .11). Fifteen patients (1.7%) discontinued therapy for reasons not related to adverse events (9 monoinfected patients [1.4%] and 6 [2.7%] coinfected patients, P = .23). Two coinfected patients died before SVR could be assessed: both died from complications of acute exacerbation of chronic obstructive pulmonary disease. Outcomes for 12 weeks’ treatment with LDV/SOF without RBV for HCV genotype 1a and 1b are shown in Figure 2B. Variables associated with treatment failure The results of the univariable and multivariable logistic regression models to identify baseline variables associated with treatment failure for the full data set are shown in Table 3. In the univariable analysis, male sex and the presence of HIV infection were the only variables significantly associated with increased odds of treatment failure. In all 3 multivariable models, male sex and HIV infection were Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz214/5486493 by Ed 'DeepDyve' Gillespie user on 07 May 2019 the only variables significantly associated with increased odds of treatment failure. In the fully adjusted model, the adjusted odds ratio (aOR) of treatment failure for males in comparison with females was 2.49 (95%CI 1.27-4.91; P=.008). Likewise, the aOR of treatment failure for coinfected patients in comparison with monoinfected patients was 2.23 (95%CI 1.13-4.38; P=.020). We also performed separate analyses to identify baseline variables associated with treatment failure according to treatment duration. Among patients treated for 8 weeks, male sex was the only variable independently associated with treatment failure (Supplementary material – Table S2). Among patients treated for 12 weeks, HIV infection was the only variable independently associated with treatment failure (Supplementary material – Table S3). Discussion Whether or not HIV infection is associated with treatment failure of DAA therapy is a controversial issue. The C-WORTHY and the C-EDGE CO-STAR studies, 2 of the few clinical trials with DAA that included both monoinfected and coinfected patients, revealed similar rates of sustained virological response to grazoprevir and elbasvir in both groups [7, 8]. These results are not easy to interpret owing to issues of study design in the C-WORTHY study (different treatment durations, different doses of elbasvir, and the addition or not of ribavirin) [7] and the low number of coinfected patients included in the C-EDGE CO-STAR study [8]. Some real-world practice studies have found lower SVR rates with all-oral DAA-based therapy in coinfected patients than in monoinfected patients [9, 10], whereas in other studies, SVR rates were not significantly different between monoinfected and coinfected individuals [11-14]. Again, the results of these studies are difficult to Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz214/5486493 by Ed 'DeepDyve' Gillespie user on 07 May 2019 interpret owing to the lack of homogeneity in essential variables such as HCV genotype, liver disease severity, prior exposure to anti-HCV therapy, and DAA- regimen used. We answered our research question by analyzing a large and homogeneous group of HCV genotype 1–infected treatment-naïve non-cirrhotic patients treated with LDV/SOF. We found lower SVR rates for LDV/SOF in coinfected patients than in monoinfected patients, with most of the treatment failures in both groups being viral relapses. The independent association between HIV and treatment failure was found after adjustment for age, sex, liver stiffness, HCV subtype, HCV RNA load, and treatment duration. Interestingly, when we carried out separate analyses according to treatment duration, we found an association between HIV and treatment failure among patients treated for 12 weeks but not among patients treated for 8 weeks. This could be due to a type 2 error, as the number of HIV-infected patients treated for 8 weeks was substantially lower than the number treated for 12 weeks (83 vs. 220). However, it must be considered that in comparison with patients treated for 8 weeks, those treated for 12 weeks, irrespective of whether or not they were HIV- infected, had a significantly higher frequency of both HCV-RNA above 6 million IU/mL and a liver stiffness value equal to or higher than 9.5 kPa, which is indicative of advanced fibrosis. Moreover, among HIV-infected individuals, the proportion of MSM was higher in those treated for 8 weeks than in those treated for 12 weeks. Given the recent ongoing outbreak of HCV among HIV-infected MSM, it is conceivable that more recent HCV infections were included in the former group than in the latter. This, in turn, could have influenced SVR rates, as Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz214/5486493 by Ed 'DeepDyve' Gillespie user on 07 May 2019 treatment of acute or early HCV infection has been associated with very high SVR rates [17]. For these reasons, any potential disadvantageous influence of HIV infection on treatment response would be more easily detected in patients treated for 12 weeks than in patients treated for 8 weeks. The reason why HIV infection influenced treatment response could not be ascertained from our data. However, this observation could be explained by some characteristics of coinfected patients, such as a CD4+ count < 200 cells/mm and prior clinical AIDS, which are indicative of immunosuppression and have been associated with failure of all-oral DAA-based therapy in coinfected patients [15]. Of note, 82 of the 188 (43.6%) coinfected patients for which the CDC clinical category was known had a prior diagnosis of AIDS. Likewise, 9 of the 158 (5.7%) coinfected patients with known CD4+ cell counts at baseline, had < 200 CD4+ cells/mm . There is some evidence that the host immune response may play a role in HCV clearance even during DAA-based therapies, possibly through the recognition and elimination by T cells of viral variants with resistance-associated substitutions (RASs) [18]. Of note, in a recent analysis of clinical trials of patients with genotype 1 HCV infection treated with LDV/SOF, NS5A RASs were present in 8-16% of patients before treatment and had a negative impact on treatment outcome [19]. If less effective clearance of resistant viral variants by the immune system is the reason why HIV infection negatively affected treatment response, then the newer pan-genotypic drug regimens that include NS5A inhibitors with a high barrier to resistance (eg sofosbuvir/velpatasvir or glecaprevir/pibrentasvir) could be a preferred option over other recommended regimens in coinfected patients with a prior diagnosis of AIDS and/or a CD4+ cell count < 200 CD4+ cells/mm . Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz214/5486493 by Ed 'DeepDyve' Gillespie user on 07 May 2019 Our study is limited by the lack of data on adherence and on concomitant medication, including proton pump inhibitors [20]. Another limitation is the absence of information on pre-existing viral variants with RASs, which prevented us from analyzing their prevalence among groups and assessing their impact on treatment outcomes. Our study is also limited by the fact that full data on HIV- related characteristics at the time of the data analysis were available for only half of the patients. This precluded the performance of additional comparative analyses between monoinfected patients and coinfected patients with a baseline CD4+ cell count below and above 200 cells/mm , or with and without a prior diagnosis of clinical AIDS, for better assessment of the effect of immunosuppression on treatment response among coinfected individuals. Finally, another limitation is the absence of information about the mechanism of transmission of HCV in HCV- monoinfected persons. Nevertheless, to our knowledge, ours is the largest real-world study comparing treatment outcomes between monoinfected and coinfected patients in which there was no variability according to HCV genotype, liver disease severity, exposure to previous anti-HCV therapy, and DAA-based regimen. In conclusion, the results of this study analyzing treatment outcomes for LDV/SOF against HCV genotype 1 in treatment-naïve non-cirrhotic patients suggest that HIV infection is a predictor of treatment failure in patients with chronic hepatitis C. This finding cannot be used to support the notion that HIV/HCV-coinfected individuals are a difficult-to-treat population in the era of all-oral DAA-based therapy. However, it does argue in favor of prioritizing the use of newer simplified and pan-genotypic anti-HCV regimens among coinfected patients to lessen the Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz214/5486493 by Ed 'DeepDyve' Gillespie user on 07 May 2019 possibility of treatment failure due to suboptimal adherence or presence of resistant viral variants. Funding This work was supported by the Spanish AIDS Research Network [RD16/0025/0017] that is included in the Spanish I+D+I Plan and is co-financed by ISCIII-Subdirección General de Evaluacion and European Funding for Regional Development (FEDER), and the Fondo de Investigación de Sanidad en España (FIS)/Instituto de Salud Carlos III (Spanish Health Research Funds) [PI17/00657]. Acknowledgements The authors thank Thomas O’Boyle for writing assistance. References 1. Liang TJ, Ghany MG. Therapy of hepatitis C--back to the future. N Engl J Med 2014; 370(21): 2043-7. 2. Torriani FJ, Rodriguez-Torres M, Rockstroh JK, et al. Peginterferon Alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. N Engl J Med 2004; 351(5): 438-50. 3. Carrat F, Bani-Sadr F, Pol S, et al. Pegylated interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic hepatitis C in HIV-infected patients: a randomized controlled trial. JAMA 2004; 292(23): 2839-48. 4. McHutchison JG, Lawitz EJ, Shiffman ML, et al. Peginterferon alfa-2b or alfa- 2a with ribavirin for treatment of hepatitis C infection. N Engl J Med 2009; 361(6): 580-93. Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz214/5486493 by Ed 'DeepDyve' Gillespie user on 07 May 2019 5. European Association for the Study of the Liver. EASL Recommendations on Treatment of Hepatitis C 2016. J Hepatol 2017; 66(1): 153-94. 6. AASLD-IDSA. HCV Guidance: Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. [Date accessed, April 8, 2019]. Available at: http://www.hcvguidelines.org. 7. Sulkowski M, Hezode C, Gerstoft J, et al. Efficacy and safety of 8 weeks versus 12 weeks of treatment with grazoprevir (MK-5172) and elbasvir (MK- 8742) with or without ribavirin in patients with hepatitis C virus genotype 1 mono-infection and HIV/hepatitis C virus co-infection (C-WORTHY): a randomised, open-label phase 2 trial. The Lancet 2015; 385(9973): 1087-97. 8. Dore GJ, Altice F, Litwin AH, et al. Elbasvir-Grazoprevir to Treat Hepatitis C Virus Infection in Persons Receiving Opioid Agonist Therapy: A Randomized Trial. Ann Intern Med 2016; 165(9): 625-34. 9. Arias A, Aguilera A, Soriano V, et al. Rate and predictors of treatment failure to all-oral HCV regimens outside clinical trials. Antivir Ther 2017; 22(4): 307-12. 10. Neukam K, Morano-Amado LE, Rivero-Juarez A, et al. HIV-coinfected patients respond worse to direct-acting antiviral-based therapy against chronic hepatitis C in real life than HCV-monoinfected individuals: a prospective cohort study. HIV Clin Trials 2017; 18(3): 126-34. 11. Ingiliz P, Christensen S, Kimhofer T, et al. Sofosbuvir and Ledipasvir for 8 Weeks for the Treatment of Chronic Hepatitis C Virus (HCV) Infection in HCV- Monoinfected and HIV-HCV-Coinfected Individuals: Results From the German Hepatitis C Cohort (GECCO-01). Clin Infect Dis 2016; 63(10): 1320-4. Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz214/5486493 by Ed 'DeepDyve' Gillespie user on 07 May 2019 12. Montes ML, Olveira A, Ahumada A, et al. Similar effectiveness of direct- acting antiviral against hepatitis C virus in patients with and without HIV infection. AIDS 2017; 31(9): 1253-60. 13. Bruno G, Saracino A, Scudeller L, et al. HCV mono-infected and HIV/HCV co- infected individuals treated with direct-acting antivirals: to what extent do they differ? Int J Infect Dis 2017; 62: 64-71. 14. Bischoff J, Mauss S, Cordes C, et al. Rates of sustained virological response 12 weeks after the scheduled end of direct-acting antiviral (DAA)-based hepatitis C virus (HCV) therapy from the National German HCV registry: does HIV coinfection impair the response to DAA combination therapy? HIV Med 2018; 19(4): 299-307. 15. Berenguer J, Gil-Martin A, Jarrin I, et al. All-oral direct-acting antiviral therapy against hepatitis C virus (HCV) in human immunodeficiency virus/HCV- coinfected subjects in real-world practice: Madrid coinfection registry findings. Hepatology 2018; 68(1): 32-47. 16. Singh S, Muir AJ, Dieterich DT, Falck-Ytter YT. American Gastroenterological Association Institute Technical Review on the Role of Elastography in Chronic Liver Diseases. Gastroenterology 2017; 152(6): 1544-77. 17. Rockstroh JK, Bhagani S, Hyland RH, et al. Ledipasvir–sofosbuvir for 6 weeks to treat acute hepatitis C virus genotype 1 or 4 infection in patients with HIV coinfection: an open-label, single-arm trial. The Lancet Gastroenterology & Hepatology 2017; 2(5): 347-53. 18. Ahlen G, Frelin L, Brenndorfer ED, et al. Containing "The Great Houdini" of viruses: combining direct acting antivirals with the host immune response for the treatment of chronic hepatitis C. Drug Resist Updat 2013; 16(3-5): 60-7. Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz214/5486493 by Ed 'DeepDyve' Gillespie user on 07 May 2019 19. Zeuzem S, Mizokami M, Pianko S, et al. NS5A resistance-associated substitutions in patients with genotype 1 hepatitis C virus: Prevalence and effect on treatment outcome. J Hepatol 2017; 66(5): 910-8. 20. Tapper EB, Bacon BR, Curry MP, et al. Evaluation of proton pump inhibitor use on treatment outcomes with ledipasvir and sofosbuvir in a real-world cohort study. Hepatology 2016; 64(6): 1893-9. Figure legends Figure 1. A) Outcomes for 8 weeks’ treatment with sofosbuvir/ledipasvir without ribavirin for HCV genotype 1 in treatment-naïve, non-cirrhotic patients. B) Outcomes for 12 weeks’ treatment with sofosbuvir/ledipasvir without ribavirin for HCV genotype 1 in treatment-naïve, non-cirrhotic patients P-values derived from the Pearson’s chi-squared test. HCV-Mono, HCV monoinfected patients; HCV-Co, HIV/HCV-coinfected patients; No., number of patients; SVR, sustained viral response (number [%]);CI, confidence interval; DC, treatment discontinuations (number [%]); AE, adverse events. Figure 2. A) Treatment outcomes for 8 weeks’ treatment with sofosbuvir/ledipasvir without ribavirin for HCV genotype 1a and 1b in treatment- naïve, non-cirrhotic patients. (B) Treatment outcomes for 12 weeks’ treatment with sofosbuvir/ledipasvir without ribavirin for HCV genotype 1a and 1b in Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz214/5486493 by Ed 'DeepDyve' Gillespie user on 07 May 2019 treatment-naïve, non-cirrhotic patients. P-values derived from the Pearson’s chi-squared test. MoP, HCV monoinfected patients; Coinfected patients, HIV/HCV-coinfected patients; No., number of patients; SVR, sustained viral response (number [%]);CI, confidence interval; DC, treatment discontinuations (number [%]); AE, adverse events. Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz214/5486493 by Ed 'DeepDyve' Gillespie user on 07 May 2019 Appendix. Physicians and Hospital Pharmacists of the Madrid Registry of Use of DAA for HCV (RUA-VHC). Hospital General Universitario Gregorio Marañón: Ahumada, Adriana; Ais Larisgoitia, Arantza; Aldámiz Echevarría Lois, María Teresa; Bañares Cañizares, Rafael; Berenguer Berenguer, Juan; Blanco Sánchez, Germán; Chamorro De Vega, Esther; Clemente Ricote, Gerardo; Collado Borell, Roberto; Díaz Fontenla, Fernando; Escudero Vilaplana, Vicente; Eworo Ndongo, Alia; Fernández Cruz, Ana; Flores Fernandez, Virginia; García González, Xandra; García Sánchez, Raquel; Gijón Vidaurreta, Paloma; Giménez Manzorro, Álvaro; Herranz Alonso, Ana; Ibáñez García, Sara; Lallana Sainz, Elena; Lobato Matilla, María Elena; López Bernaldo De Quirós, Juan Carlos; Manrique Rodríguez, Silvia; Martínez Fernandez-Llamazares, Cecilia; Martínez Ortega, Pilar; Miralles Martin, Pilar; Montilla De Mora, Pedro; Padilla Ortega, Belén; Parras Vázquez, Francisco; Pérez Valderas, María Dolores; Revuelta Herrero, José Luis; Ribed Sánchez, Almudena; Rincón Rodríguez, Diego; Rodríguez González, Carmen; Romero Cristóbal, Mario; Romero Jiménez, Rosa; Ruiz Martínez, Cristina; Salcedo Plaza, Magdalena; Sánchez Somolinos, Mar; Sarobe González, Camino; Valerio Minero, Maricela. Hospital Universitario La Paz: Baladé Martinez, Laura; Barreiro García, Pablo; Benítez García, Beatriz; Bernardino De La Serna, José; Castillo Grau, Pilar; De Sebastián Rueda, María; Erdozain Sosa, José Carlos; Freire González, Mercedes; Gabaldón Garnica, Paloma; García Sánchez, Araceli; García-Samaniego Rey, Francisco; González Del Valle, Luis; González Fernández, María Ángeles; González García, Juan J. ; Jiménez Nacher, Inmaculada; Jiménez Vicente, Carlos; Lucena Martinez; Patricia; Martín Carbonero, Luz; Molina Cabezuelo, Marta; Montes Ramírez, Mª Luisa; Moreno Celda, Victoria; Moreno Palomino, Marta; Moreno Ramos, Francisco; Olveira Martín, Antonio; Parrilla, Mercedes; Pérez Valero, Ignacio; Rodríguez Martín, Elena; Rodríguez Nava, José Luis; Romero Portales, Miriam; Rossignoli Montero, Ana; Ruiz De Hoyos, Marta; Sobrino Jiménez, Carmen; Soriano Vázquez, Vicente; Valencia Ortega, Eulalia; Varela Fernandez, Hugo Adolfo. Hospital Ramón y Cajal: Albillos Martinez, Agustín; Anguita Ruiz, Eva; Arocena Aranguren, Carlos; Casado Osorio, José; Díaz De Santiago, Alberto; Fortún Abete, Jesús; García González, Miguel; Gea Rodríguez, Francisco; Gómez De Salazar López De Silanes, María Esther; Gramage Caro, Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz214/5486493 by Ed 'DeepDyve' Gillespie user on 07 May 2019 Teresa; Graus Morales, Javier; Moreno Guillen, Santiago; Moreno Zamora, Ana María; Navas Elorza, Enrique; Pérez Elías, María Jesús; Pérez Molina, José Antonio; Quereda Rodríguez-Navarro, Carmen; Rodríguez Sagrado, Miguel Ángel; Serrano Villar, Sergio Daniel; Vélez Díaz-Palleres, Manuel; Vivancos Gallego, María Jesús. Hospital Doce de Octubre: Campo Angora, Mercedes; Castellano Tortajada, Gregorio; De Lagarde Sebastián, María; Fernández Vázquez, Inmaculada; Gómez Valbuena, Isabel; Manzano Alonso, María Luisa; Martin Algíbez, Ana María; Matarranz Del Amo, Mariano; Muñoz Gómez, Raquel; Pinar López, Oscar; Pulido Ortega, Federico; Rubio García, Rafael; Serrano Garrote, Olga. Hospital Clínico de San Carlos: Benítez Giménez, María Teresa; Cabello Clotet, Noemí; Cuenca Alarcón, Francisca; Devesa Medina, María José; Estrada Pérez, Vicente; Izquierdo Rubio, Sonia; Maroto Castellanos, Maite; Núñez Orantos, María José; Rodríguez Del Rio, Elena; Sáenz De Tejada López, Marta; Sánchez-Pobre Bejarano, Pilar; Santiago Pérez, Alejandro; Téllez Molina, María Jesús; Vergas García, Jorge. Hospital Fundación Jiménez Díaz: Álvarez Álvarez, Beatriz; Arias Moya, María Ángeles; Becares Martínez, Francisco Javier; Bonilla Porras, Macarena; Cabello Úbeda, Alfonso; Calvo Hernández, Rocío; González Guirado, Agustina; Górgolas Hernández, Miguel De; Hernández Segurado, Marta; Moran Ortiz-Desolorzano, Marta; Morón Merchante, Francisco Javier; Polo Lorduy, Benjamín Arturo; Porres Cubero, Juan Carlos; Tortajada Esteban, Elena Victoria; Varela Silva, Andrés L. Hospital Infanta Leonor: Barrio Antoranz, José; Barrueco Fernandez, Nélida; Cañamares Orbis, Irene; Carrión Alonso, Gemma; Cuevas Tascón, Guillermo; Escobar Rodríguez, Ismael; Esteban Alba, Concepción; Izquierdo García, Elsa; Liras Medina, Ángel; Lozano Maya, María Del Mar; Marino Martínez, Carolina; Ryan Murúa, Pablo; Sáez De La Fuente, Javier; Sánchez Rubio, Luis; Such Díaz, Ana; Tejedor Prado, Pilar; Troya García, Jesús; Villa Poza, José Carlos. Hospital de Puerta de Hierro: Arias Milla, Ana; Baños Pérez, Isolina; Benítez Gutiérrez, Laura María; Calleja Panero, José Luis; Cuervas Mons Martínez, Valentín; Duca, Ana María; Folguera Olías, Carlos; Menchén Viso, Belén; De La Revilla Negro, Juan; Ruiz Gutiérrez, Julia; Sánchez Guerrero, Amelia; Santiago Prieto, María Elvira. Hospital La Princesa: Alañón Plaza, Estefanía; Gallego Aranda, Tomás; García Buey, Luisa Consuelo; González Moreno, Leticia; Ibáñez Zurriaga, Amparo; Marinero Martinez-Lázaro, Almudena; Martinez Nieto, Concepción; Morell Baladrón, Alberto; Pérez Abanades, Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz214/5486493 by Ed 'DeepDyve' Gillespie user on 07 May 2019 María; Ramírez Herráiz, Esther; Real Martinez, Yolanda; Santos Gil, Ignacio De Los; Hospital U. Príncipe de Asturias: Arranz Caso, José Alberto; Beceiro Pedreño, Inmaculada; Borrego Rodríguez, Gloria; Casas García, Esperanza; Costero Pastor, Ana Belén; De Miguel Prieto, Julio; Del Pozo Prieto, David; Fernández Pacheco Garcia-Valdecasas, María; Ginés Palomares, Ana; Hernández Gutiérrez, Cristina; Herranz Muñoz, Clara; Herrero Fernández, Marta; Lebrero García, Alberto; Novella Mena, María; Ortiz Campos, María; Pérez Pérez, Diana; Poves Martinez, Elvira; Santolaya Perrín, María Rosario; Sanz Moreno, José; Víctor Palomares, Virginia; Hospital Fundación de Alcorcón: Alonso López, Sonia; Bartolomé García, Emma; Fernández Rodríguez, Conrado; Gutiérrez García, Mª Luisa; Henríquez Camacho, Cesar Augusto; Hervás Gómez, Rafael; Losa García, Juan Emilio; Moreno Núñez, Leonor; Pérez Encinas, Montserrat; Polanco Paz, María Del Mar; Sanmartín Fenollera, Patricia; Velasco Arribas, María. Hospital Infanta Sofía: Albertos Rubio, Sonia; Beltrán Castaño, Rocío; Comas Redondo, Carmen; García Yubero, Cristina; González-Ruano Pérez, Patricia; Hidalgo Aguirre, Lorena; Malmierca Corral, Eduardo; Martinez Hernández, Alicia; Pérez Álvarez, Mónica; Portillo Horcajada, Laura; Suárez García, Inés María. Hospital de Fuenlabrada: Andrés Rosado, Ana; Canalejo Castrillero, Eduardo; Candel García, Beatriz; Carrasco Torrents, América; De La Poza Gómez, Gema; García Rebolledo, Eva María; Hernández Muniesa, Belén; Hinojosa Mena-Bernal, Juan; Mondejar Gutiérrez, Gemma María; Ontanon Nasarre, Ana; Piqueras Alcohol, Belén; Ruiz Giardin, José Manuel; Ruiz, Justo; San Martin López, Juan Víctor; Valer López-Fando, María Paz. Hospital Universitario de Getafe: Diez Fernandez, Raúl; Esteban Fernandez, Francisco Javier; Gaspar Alonso-Vega, Gabriel; Gil Ares, Fernando; Gómez Rubio, Mariano; Molina García, Teresa; Negro Vega, Eva; Pérez Caballero, Gloria; Sánchez Ayuso, Javier; Sánchez-Rubio Ferrández, Javier. Hospital Severo Ochoa: Agud Aparicio, José Luis; Aguirre Losada, Alberto Ángel; Castro Urda, José Luis; Cervero Jiménez, Miguel; Díaz Gómez, Estrella; Domínguez Gozalo, Andrea; García Benayas, Elena; Jusdado Ruiz-Capillas, Juan José; Muñoz Romero, Javier; Torres Perea, Rafael. Hospital de Móstoles: Barros Aguado, Carlos Antonio; Corrales Pérez, Laura; Crespo Robledo, Paloma; González Alonso, Raquel; Mañes Sevilla, Mireya; Merino Morales, Francisco; Moreno Sánchez, Diego; Moriel Sánchez, Carmen; Rubio Cebrián, Beatriz. Hospital del Henares: Campos Fernández De Sevilla, María De Los Ángeles; De Lorenzo Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz214/5486493 by Ed 'DeepDyve' Gillespie user on 07 May 2019 Pinto, Ana; Delgado Téllez De Cepeda, Laura; Egües Lugea, Amaia; Gallego Úbeda, Marta; Ibáñez Pinto, Alberto; Sánchez Gómez, Argeme; Sanz Rojas, Patricia; Serrano Herranz, Regino; Tovar Pozo, María; Valbuena González, Marta. Hospital Infanta Cristina: Botella Mateu, Belén; Cuenca Morón, Beatriz De; De Guzmán García-Monge, María Teresa; Domingo Senra, Daniel; Domínguez García, Nuria; Esteban Fernandez-Zarza, Carlos; Martínez Consuegra, José Antonio; Matilla García, Elena; Melero Bermejo, José Antonio; Moreno Díaz, Raquel; Ortiz Duran, María; Pérez Quero, José Luis; Rodríguez Vargas, Blanca. Hospital del Sureste: Buendía Bravo, Silvia; Calvo Ramos, Irina; Capilla Montes, Cristina; Cruz Cruz, María Teresa; Díaz Sánchez, Antonio; Fernández Amago, María Teresa; García Benayas, María Teresa; González Alonso, María Rosario; Marzal Alfaro, Belén; Moya Valverde, Eloísa; Peñalver Cifuentes, Rafael; Rivero Fernández, Miguel. Hospital Rey Juan Carlos: García Barquero, Margarita; García García, Almudena; Gotuzzo Altez, Luis Ricardo; Huertas Velasco, María Antonia; Marcos Rojas Rodríguez De Quesada, Jorge; Nistal Juncos, Sara; Pérez Rial, Gabriel. Hospital Infanta Elena: Alarcón Del Amo, Cristina; Alcalde Rodríguez, Daniel; Barranco Cao, Raquel; Calvache Rodríguez, Almudena; Chico Álvarez, Inmaculada; Collados Arroyo, Virginia; Del Portillo Rubí, Álvaro; Delgado Galán, María; López Martin, María Del Carmen; Rodríguez Rodríguez, Raquel; Tejedor Bravo, Marta; Vegas Serrano, Ana. Hospital de Torrejón: Achécar Justo, Linette María; Arponen, Sari; Blasco Guerrero, Marta; Del Rio Izquierdo, María; Esteva Jiménez, Laura; Gimeno García, Alejandra; González Pino, Andrea; Montero Hernández, María Carmen; Morales Martínez, Lorena; Sáez Bertrand, Catalina. Hospital del Tajo: Alonso Grandes, Elena; Fernández Esteban, Eva; Lo Iacono, Oreste; Monsalvo Arroyo, Raquel; Pedraza Cezón, Luis Antonio; Soto Fernández, Susana; Terrancle Juan, Ignacio. Hospital Gómez Ulla: García Mayor, María De Los Ángeles; López Honduvilla, Francisco José; Menéndez Martínez, María Antonia; Pérez Moran, María José; Prats Olivan, Pilar. Hospital Collado Villalba: Abad Guerra, Javier; Arias Rivera, María Luisa; Bejerano Domínguez, Alicia; Correa Abanto, Lizbeth Milagros; Ferrere González, Federico; Gómez Pérez, Marta; Olivares Valles, Ana. Hospital El Escorial: Aguilar Guisado, Carolina; Belda Bilbao, Luis Miguel; Calvo Fernández, Santiago; García De Aguinaga, Mª Luisa; García Gimeno, María Mercedes; Gongorra López, Andrea; Jaime Sánchez, Belén; Montero Jiménez, Francisco Javier; Sánchez Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz214/5486493 by Ed 'DeepDyve' Gillespie user on 07 May 2019 Suárez, Susana. Hospital Central de La Cruz Roja: Fuentes Irigoyen, Raquel; Iborra Herrera, Jerónimo; Navarrete García, Elena; Tejada González, Pilar. Hospital Infantil Niño Jesús: García Rodríguez, María Del Pilar; Muñoz Codoceo, Rosa Ana. Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz214/5486493 by Ed 'DeepDyve' Gillespie user on 07 May 2019 Fig 1. Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz214/5486493 by Ed 'DeepDyve' Gillespie user on 07 May 2019 Fig 2. Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz214/5486493 by Ed 'DeepDyve' Gillespie user on 07 May 2019 Table 1. Baseline characteristics of 1,358 previously untreated non-cirrhotic patients infected with HCV genotype 1 and treated with LDV/SOF 8 weeks 12 weeks TOTAL Total Monoinfected Coinfected P* Total Monoinfected Coinfected P* Monoinfected and Patients Patients Patients Patients Coinfected Patients Variables N=497 N=414 N=83 N=861 N=641 N=220 N=1,358 Age – median (IQR) 56 (49-66) 59 (50-68) 50 (46-54) <0.001 56 (50-68) 61 (52-71) 51 (48-54) <0.001 56 (50-67) Male sex – n (%) 258 (51.9) 192 (46.4) 66 (79.5) <0.001 491 (57.0) 325 (50.7) 166 (75.4) <0.001 749 (55.1) HCV genotype/subtype – n (%) <0.001 <0.001 1a 160 (32.2) 95 (22.9) 65 (78.3) 395 (45.9) 224 (34.9) 171 (77.7) 555 (40.9) 1b 322 (64.8) 311 (75.1) 11 (13.2) 434 (50.4) 398 (62.1) 36 (16.4) 756 (55.7) 1 not subtyped 15 (3.0) 8 (1.9) 7 (8.4) 32 (3.7) 19 (3.0) 13 (5.9) 47 (3.5) HCV RNA – n (%) Log IU/mL – Median (IQR) 5.9 (5.4-6.4) 5.9 (5.4-6.3) 6.1 (5.6-6.5) 0.033 6.4 (6.0-6.8) 6.4 (5.9-6.8) 6.5 (6.0-6.8) 0.070 6.2 (5.7-6.6) > 6 million IU/mL – n (%) 18 (3.6) 12 (2.9) 6 (7.2) 0.054 216 (25.1) 154 (24.0) 62 (28.2) 0.220 234 (17.2) Transient elastography – n (%) No 8 (1.6) 8 (1.9) 0 30 (3.5) 30 (4.7) 0 38 (2.8) Yes 489 (98.4) 406 (98.1) 83 (100.0) 831 (96.5) 611 (95.3) 220 (100.0) 1,320 (97.2) Stiffness kPa – Median (IQR) 8.6 (7.9-9.4) 8.6 (7.9-9.3) 8.6 (7.8-10.0) 0.582 9.1 (8.1-10.4) 9.1 (8.1-10.4) 9.0 (8.1-10.3) 0.534 8.8 (8.0-10.1) ≥ 9.5 kPa – n (%) 121 (24.7) 94 (23.1) 27 (32.5) 0.071 373 (44.9) 284 (46.5) 89 (40.4) 0.123 494 7.4) *P-values derived from the Pearson’s chi-squared test or the nonparametric Mann-Whitney test for differences in categorical or continuous variables, respectively. Abbreviations: HCV, hepatitis C virus; LDV/SOF, ledipasvir/sofosbuvir; IQR, interquartile range; HCV, hepatitis C virus; RNA, ribonucleic acid. Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz214/5486493 by Ed 'DeepDyve' Gillespie user on 07 May 2019 Table 2. Baseline HIV-related characteristics of 303 previously untreated non-cirrhotic HIV/HCV-coinfected with HCV genotype 1 and treated with LDV/SOF Variable 8 weeks 12 weeks Total P* Variables n = 83 n = 220 n = 303 HIV risk factor – n (%) 0.021 Injection drug use 39 (47.0) 120 (54.5) 159 (52.5) Men who have sex with men 8 (9.6) 4 (1.8) 12 (4.0) Heterosexual relations 5 (6.0) 8 (3.6) 13 (4.3) Transfusions 0 2 (0.9) 2 (0.7) Unknown 31 (37.3) 86 (39.1) 117 (38.6) CDC clinical category – n (%) 0.305 A 21 (25.3) 38 (17.3) 59 (19.5) B 9 (10.8) 38 (17.3) 47 (15.5) C 22 (26.5) 60 (27.3) 82 (27.1) Unknown 31 (37.3) 84 (38.2) 115 (37.9) Nadir CD4+/mm – n (%) 0.622 > 500 8 (9.6) 14 (6.4) 22 (7.3) 200 - 499 17 (20.5) 38 (17.3) 55 (18.1) < 200 27 (32.5) 84 (38.2) 111 (36.6) Unknown 31 (37.3) 84 (38.2) 115 (38.0) Baseline CD4+/mm – n (%) > 500 22 (26.5) 75 (34.1) 97 (32.0) 0.057 200 - 499 9 (10.8) 43 (19.5) 52 (17.2) < 200 2 (2.4) 7 (3.2) 9 (3.0) Unknown 50 (60.2) 95 (43.2) 145 (47.9) Known 33 (39.8) 125 (56.8) 158 (52.1) 0.008 Median (IQR) 632 595 607 0.474 (474 – 847) (372 – 819) (389 – 822) ART – n (%) 0.285 No 0 3 (1.4) 3 (1.0) Yes 83 (100.0) 217 (98.6) 300 (99.0) HIV-RNA – n (%) Unknown 31 (37.3) 81 (36.8) 112 (37.0) 0.932 Known 52 (62.6) 139 (63.2) 191 (63.0) Detectable 5 (9.6) 7 (5.0) 12 (6.3) 0.246 Undetectable 47 (90.4) 132 (95.0) 179 (93.7) *P-values derived from the Pearson’s chi-squared test or the nonparametric Mann- Whitney test for differences in categorical or continuous variables, respectively. Abbreviations: HIV, human immunodeficiency virus; HCV, hepatitis C virus; CDC, Centers for Disease Control and Prevention; ART, antiretroviral therapy; RNA, ribonucleic acid. Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofz214/5486493 by Ed 'DeepDyve' Gillespie user on 07 May 2019 Table 3. Results from univariable and multivariable logistic regression models to identify independent baseline factors predictive of treatment failure considering the whole data set (Monoinfected, Coinfected, 8 and 12 weeks) – 1,358 Treatment Univariable Multivariable Multivariable Multivariable † ‡ § failures Model 1 Model 2 Model 3 Variable N (%) OR (95% CI) P OR (95% CI) P OR (95% CI) P OR (95% CI) P Age 0.473 0.441 4 (2.9) 1.00 1 <45 23 (4.8) 1.69 (0.58 – 4.98) 1.64 (0.55 – 4.89) 45-54 27 (3.6) 1.27 (0.44 – 3.67) 2.03 (0.67 – 6.15) ≥55 Sex 0.001 0.008 0.010 0.008 Female 12 (2.0) 1.00 1.00 1.00 1.00 42 (5.6) 2.96 (1.54 – 5.67) 2.47 (1.27 – 4.82) 2.43 (1.24 – 4.77) 2.49 (1.27 – 4.91) Male Liver stiffness – kPa 0.300 0.399 28 (3.4) 1.00 1 < 9.5 25 (5.1) 1.52 (0.88 – 2.64) 1.48 (0.84 – 2.61) ≥ 9.5 1 (2.6) 0.77 (0.10 – 5.82) 1.19 (0.15 – 9.27) Unknown HCV genotype 0.079 0.879 0.722 1b 22 (2.9) 1.00 1.00 1 30 (5.4) 1.91 (1.09 – 3.34) 1.15 (0.60 – 2.19) 1.27 (0.65 – 2.49) 1a 2 (4.3) 1.48 (0.34 – 6.50) 0.89 (0.19 – 4.07) 0.89 (0.19 – 4.10) 1 not subtyped HCV RNA IU/mL 0.911 0.676 < 6,000,000 45 (4.0) 1.00 1 9 (3.8) 0.96 (0.46 – 1.99) 0.85 (0.40 – 1.82) ≥ 6,000,000 HIV-infection <0.001 0.007 0.024 0.020 No 31 (2.9) 1.00 1.00 1.00 1.00 23 (7.6) 2.71 (1.56 – 4.73) 2.20 (1.24 – 3.89) 2.08 (1.10 – 3.94) 2.23 (1.13 – 4.38) Yes Treatment duration 0.612 0.850 12 weeks 36 (4.2) 1.00 1 18 (3.6) 0.86 (0.48 – 1.53) 1.06 (0.57 – 1.96) 8 weeks Multivariable model 1 includes variables with a P-value <0.05 in the univariable analysis. Multivariable model 2 includes variables with a P-value <0.1 in the univariable analysis. Multivariable model 3 is a fully adjusted one, including every variable detailed in the first column.

Journal

Open Forum Infectious Diseases – Oxford University Press

Published: May 1, 2019

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