HCV-co-infected patients – French ANRS CO13 HEPAVIH cohort

Accepted Manuscript Efficacy and safety of direct-acting antiviral regimens in HIV/HCV-coinfected patients - French ANRS CO13 HEPAVIH cohort Lionel Piroth, Linda Wittkop, Karine Lacombe, Eric Rosenthal, Camille Gilbert, Patrick Miailhes, Patrizia Carrieri, Julie Chas, Isabelle Poizot-Martin, Anne Gervais, Stéphanie Dominguez, Didier Neau, David Zucman, Eric Billaud, Philippe Morlat, Hugues Aumaitre, Caroline Lascoux-Combe, Anne Simon, Olivier Bouchaud, Elina Teicher, Firouzé Bani-Sadr, Laurent Alric, Daniel Vittecoq, François Boué, Claudine Duvivier, Marc-Antoine Valantin, Laure Esterle, François Dabis, Philippe Sogni, Dominique Salmon, for the ANRS CO13 HEPAVIH study group, PII: DOI: Reference:

S0168-8278(17)30107-1 http://dx.doi.org/10.1016/j.jhep.2017.02.012 JHEPAT 6428

To appear in:

Journal of Hepatology

Received Date: Revised Date: Accepted Date:

31 August 2016 7 February 2017 9 February 2017

Please cite this article as: Piroth, L., Wittkop, L., Lacombe, K., Rosenthal, E., Gilbert, C., Miailhes, P., Carrieri, P., Chas, J., Poizot-Martin, I., Gervais, A., Dominguez, S., Neau, D., Zucman, D., Billaud, E., Morlat, P., Aumaitre, H., Lascoux-Combe, C., Simon, A., Bouchaud, O., Teicher, E., Bani-Sadr, F., Alric, L., Vittecoq, D., Boué, F., Duvivier, C., Valantin, M-A., Esterle, L., Dabis, F., Sogni, P., Salmon, D., for the ANRS CO13 HEPAVIH study group, Efficacy and safety of direct-acting antiviral regimens in HIV/HCV-coinfected patients - French ANRS CO13 HEPAVIH cohort, Journal of Hepatology (2017), doi: http://dx.doi.org/10.1016/j.jhep.2017.02.012

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Efficacy and safety of direct-acting antiviral regimens in HIV/HCV-coinfected patients French ANRS CO13 HEPAVIH cohort Lionel Piroth*1,2, Linda Wittkop*3,4, Karine Lacombe5,6, Eric Rosenthal7,8, Camille Gilbert3, Patrick Miailhes9, Patrizia Carrieri10, Julie Chas11, Isabelle Poizot-Martin12, Anne Gervais13, Stéphanie Dominguez14, Didier Neau15, David Zucman16, Eric Billaud17, Philippe Morlat18, Hugues Aumaitre19, Caroline Lascoux-Combe20, Anne Simon21, Olivier Bouchaud22,23, Elina Teicher24, Firouzé Bani-Sadr25,26, Laurent Alric27,28, Daniel Vittecoq29,30, François Boué29,31, Claudine Duvivier32, Marc-Antoine Valantin33, Laure Esterle3, François Dabis3,4, Philippe Sogni34,35,36, and Dominique Salmon37 for the ANRS CO13 HEPAVIH study group (*equal contributions, co-first authors) Affiliations: 1: Centre Hospitalier Universitaire de Dijon, Département d’Infectiologie, Dijon, France ; 2: Université de Bourgogne, Dijon, France; 3: Univ. Bordeaux, ISPED, Inserm, Bordeaux Population Health Research Center, team MORPH3EUS, UMR 1219, CIC-EC 1401, F-33000 Bordeaux, France ; 4: CHU de Bordeaux, Pole de sante publique, Service d’information medicale, F-33000 Bordeaux, France ; 5: Assistance Publique des Hôpitaux de Paris, Hôpital Saint-Antoine, Service Maladies infectieuses et tropicales, Paris, France ; 6: UMPC (Université Pierre et Marie Curie), UMR S1136, Institut Pierre Louis d'Epidémiologie et de Santé Publique, Paris, France ; 7: Centre Hospitalier Universitaire de Nice, Service de Médecine Interne, Hôpital l’Archet, Nice, France ; 8: Université de Nice-Sophia Antipolis, Nice, France ; 9: Service des Maladies Infectieuses et Tropicales, CHU Lyon, Hôpital de la Croix Rousse, Lyon, France ; 10: Aix Marseille Univ, INSERM, IRD, SESSTIM, Sciences Economiques & Sociales de la Santé & Traitement de l’Information Médicale, Marseille, France ; 11: Assistance Publique des Hôpitaux de Paris, Hôpital Tenon, Service Maladies infectieuses et tropicales, Paris, France ;12: Aix Marseille Univ, APHM SainteMarguerite, Service d’Immuno-hématologie clinique,Marseille, France ; 13: Assistance Publique des Hôpitaux de Paris, Hôpital Bichat Claude Bernard, Service des maladies infectieuses et tropicales, Paris, France ; 14: Assistance Publique des Hôpitaux de Paris, Hôpital Henri Mondor, Service Immunologie clinique et maladies infectieuses, Immunologie clinique, Créteil, France ; 15: Centre Hospitalier Universitaire de Bordeaux, Service Maladies infectieuses et tropicales Bordeaux, Hôpital Pellegrin, Bordeaux, France ; 16: Hôpital Foch, unité VIH, Suresnes, France ; 17: Centre Hospitalier Universitaire de Nantes, Service Maladies infectieuses et tropicales, Nantes, France ; 18: Centre Hospitalier Universitaire de Bordeaux, Service de médecine interne, hôpital SaintAndré, Bordeaux, France ; 19: Centre Hospitalier de Perpignan, Service Maladies infectieuses et tropicales, Perpignan, France ; 20: Assistance Publique des Hôpitaux de Paris, Hôpital Saint-Louis, Service Maladies infectieuses et tropicales, Paris, France ; 21: Assistance Publique des Hôpitaux de Paris, Hôpital Pitié-Salpétrière, Département de Médecine Interne et Immunologie Clinique, Paris, France ; 22: Assistance Publique des Hôpitaux de Paris, Hôpital Avicenne, Service Maladies infectieuses et tropicales, Bobigny, France ; 23: Université Paris 13 Nord, Bobigny, France ; 24: Assistance Publique des Hôpitaux de Paris, GH Paris Sud : Service Médecine Interne et Immunologie clinique, Hôpital Bicêtre, Le Kremlin-Bicêtre ; Centre Hépato-Biliaire, Hôpital PaulBrousse,Villejuif, France ; 25: Centre Hospitalier Universitaire de Reims, Service de médecine interne, maladies infectieuses et immunologie clinique, Reims, France ; 26: Université de Reims, Champagne-Ardenne, Reims, France ; 27: Centre Hospitalier Universitaire de Toulouse, Hôpital Purpan, Service Médecine interne-Pôle Digestif, Toulouse, France ; 28: UMR 152 IRD Université Toulouse III, Paul Sabatier, Toulouse, France ; 29: Université Paris Sud, Le Kremlin-Bicêtre, France ; 30: Assistance Publique des Hôpitaux de Paris, Hôpital Bicêtre, Hôpitaux universitaires Paris Sud, Service Maladies infectieuses et tropicales, Le Kremlin-Bicêtre, France ; 31: Assistance Publique des Hôpitaux de Paris, Groupe Hospitalier Paris Sud, Hôpital Antoine-Béclère, Service Médecine interne et immunologie, Clamart, France ; 32: Assistance Publique des Hôpitaux de Paris, Hôpital Necker-Enfants Malades, Service de Maladies Infectieuses et Tropicales, Centre d'infectiologie Necker-Pasteur, IHU Imagine, Paris, France ; 33: Assistance Publique des Hôpitaux de Paris, Hôpital Pitié-Salpétrière, Service Maladies infectieuses et tropicales, Paris, France ; 34: Assistance Publique des Hôpitaux de Paris, Hôpital Cochin, Service d’Hépatologie, Paris, France ; 35: INSERM U-1223 – Institut Pasteur, Paris, France ; 36: Université Paris Descartes, Sorbonne Paris Cité, Paris, France ; 37: Assistance Publique des Hôpitaux de Paris, Hôpital Cochin, Service Maladies infectieuses et tropicales, Paris, France

Corresponding author: Dr Linda Wittkop, MD, PhD Inserm center U1219 Bordeaux Population Health, Université de Bordeaux/ISPED Bordeaux School of Public Health, CHU de Bordeaux, 146 rue Léo-Saignat, 33076 Bordeaux cedex, France. [email protected] Phone: +33(0)5 57 57 45 26 Fax: +33(0)5 56 24 00 81

Word count: Title: 105 characters, Electronic word count: 2719 words, 6 Tables, 4 Figures; Supplementary Material: 1 Figure and 6 Tables 1

Keywords: HIV/HCV co-infection, all-oral DAA, sustained virological response Conflict of interst Dr Piroth reports personal fees from Bristol Myers Squibb, Gilead, Viiv Healthcare, MSD, Pfizer, Gilead, Janssen Cilag, outside the submitted work; Dr Wittkop reports grants from ANRS, during the conduct of the study; grants from Inserm Aviesan, personal fees from BMS, Janssen, Gilead and MSD outside the submitted work; Dr Lacombe reports personal fees from Gilead, Janssen, Abbvie, Merck, outside the submitted work; Dr Morlat reports personal fees from Gilead, MSD, ViiV health care, Janssen, non-financial support from Gilead, MSD, ViiV healthcare outside the submitted work; Dr Aumaître reports personal fees from BMS, non-financial support from Gilead during the conduct of the study; Dr Alric reports grants, personal fees and non-financial support from Gilead, grants and nonfinancial support from BMS, grants and personal fees from MSD, grants from Janssen, grants from Abbvie, during the conduct of the study; Dr Bouchaud reports grants and non-financial support from ANRS, during the conduct of the study; personal fees and other from Gilead, grants and other from MSD, grants from GSK VIIVH, other from Janssen, outside the submitted work; Dr Chas reports personal fees from Abbvie, BMS and Gilead outside the submitted work. Financial support : ANRS (France REcherche Nord&Sud Sida-HIV Hépatites)

Author contributions: All members of the ANRS HEPAVIH study group participated in discussions on the design of the study, the choice of statistical analyses and data interpretation, and were involved in the preparation and review of the submitted manuscript. L. Piroth and L. Wittkop drafted the manuscript. C. Gilbert and L. Wittkop did the statistical analyses, act as guarantors for the analyses, and had full access to the dataset. All coauthors approved the final version of the manuscript.

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Abstract

Background & Aims: Few data are available on the use of new oral direct-acting antiviral (DAA) regimens to treat HIV/HCV-coinfected patients in real-life settings. Methods: HIV/HCV-coinfected patients enrolled in the ANRS CO13 HEPAVIH observational cohort were included if they began an all-oral DAA-based regimen before 1 May 2015 (12-week regimens) or 1 February 2015 (24-week regimens). Treatment success (SVR12) was defined by undetectable HCV-RNA 12 weeks after treatment cessation. Exact logistic regression analysis was used to identify factors associated with SVR12. Results: We included 323 patients (74% men) with a median age of 53 years, 99% of whom were on combination antiretroviral therapy (cART). HIV-RNA load was <50 copies/mL in 88% of patients, the median CD4 cell count was 540/mm3, 60% of patients were cirrhotic, and 68% had previously received unsuccessful anti-HCV treatment. cART was protease inhibitor (PI)based in 23%, non nucleoside reverse transcriptase inhibitor (NNRTI)-based in 15%, and integrase inhibitor (II)-based in 38%, while 24% of patients received other regimens. The SVR12 rate was 93.5% overall (95% CI: 90.2-95.9), 93.3% (88.8-96.4) in cirrhotic and 93.8% (88.1-97.3) in non-cirrhotic patients. The SVR12 rates were respectively 93.1% (84.5-97.7), 91.8% (80.4-97.7) and 95.8% (90.5-98.6) in patients receiving PI-based, NNRTI-based and II-based cART. In adjusted analysis, SVR12 was not associated with HIV-RNA load, the cART regimen, cirrhosis, prior anti-HCV treatment, the duration of anti-HCV therapy, or ribavirin use. The most common adverse effects were fatigue and digestive disorders. Conclusions: New all-oral DAA regimens were well tolerated and yielded high SVR12 rates in HIV/HCV-coinfected patients.

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Lay summary: We evaluated efficacy and safety of all-oral DAA regimen in a large French nationwide observational cohort study of HIV/HCV co-infected patients. Sustained virological response 12 weeks after treatment cessation was 93.5% overall. The all-oral DAA regimens were well tolerated and most common adverse effects were fatigue and digestive disorders.

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Introduction Hepatitis C virus (HCV) coinfection is frequent among people living with HIV, with a reported prevalence of 15% to 30% [1-3] and up to 82% among injecting drug users [4]. HCV coinfection has become a major cause of illness and death in the era of combination antiretroviral therapy (cART) [5]. Sustained virological responses (SVR) to interferon-based anti-HCV therapy used to be less frequent in case of HIV coinfection [6-8]. Since 2011, the treatment of chronic hepatitis C has improved dramatically with the advent of direct-acting antiviral (DAA) drugs [9]. The SVR rate now seems to be similar in HIV/HCV-coinfected and HCV-monoinfected patients. With most combinations, SVR rates exceed 90% in clinical trials [10-16] and even reached 95-100% in a recent 12-week trial [15].

However, participants in clinical trials are not always fully representative of patients followed in cohort studies. For example, only 6.3%, 8.3% and 43% of patients in a recent Canadian real-life cohort study [17] would have been eligible for the Turquoise-1 [13], Ion-4 [11], and Ally-2 [16] trials, respectively. Some recent studies in the real-life setting have given promising SVR rates for coinfected patients [18-20]. Although SVR rates obtained with brief, simple and well-tolerated DAA-based treatments are expected to be similar, data on HIV/HCV-coinfected patients in real-life settings are still scarce and come mainly from small studies.

HCV treatment recommendations for HIV/HCV-coinfected patients have evolved rapidly. New DAAs were first made available in France through compassionate-use programs, with sofosbuvir (SOF), simeprevir (SMV) and daclatasvir (DCV) available in 2014 and ledipasvir (LDV) available in 2015. Several oral, DAA-combinations could have been used to treat HIV/HCV-coinfected patients in routine practice, depending for example on the co-prescribed antiretroviral regimen, which can interact with anti-HCV drugs [21-23].

Here we report the efficacy and safety of all-oral DAA-based regimens in HIV/HCVcoinfected patients enrolled in the French nationwide ANRS CO13 HEPAVIH observational 5

cohort, with a special focus on dual-DAA regimens and on efficacy according to the concomitant cART regimen.

Patients and methods

Study population

Patients enrolled in ANRS CO13 HEPAVIH, a French nationwide multicenter hospital-based cohort of HIV/HCV-coinfected patients with prospective data collection [14], were eligible and gave a written consent. In addition, patients from the 28 centers participating in the ANRS CO13 HEPAVIH cohort, who were not initially included in the cohort but who gave their consent for specific follow-up during and after DAA treatment, were also eligible. All eligible patients were included in this analysis if they started an all-oral DAA-based regimen before 1 May 2015 (12 weeks of treatment) or 1 February 2015 (24 weeks of treatment). All patients gave their consent for study participation and the ANRS CO13 HEPAVIH cohort has received approval by an Institutional Review board (CPP Ile de France III). Patients who participated in completed and published clinical trials were included in the analysis. Patients were not included if they were participating in an ongoing clinical trial (including those completed but not yet published) of combinations including Peg-interferon (PegIFN), or if follow-up after the end of treatment was insufficient to assess virological responses. The DAA regimen was chosen by each patient's physician [21-23].

Data collection and definitions

The following data were collected prospectively by each participating center, using an electronic case report form (eCRF): age, sex, HCV genotype, previous anti-HCV treatment, HIV-related characteristics (CDC class, HIV-RNA load, CD4 cell count, ARV treatment), start and end dates of DAA treatment, initial doses of anti-HCV and anti-HIV drugs and any changes during follow-up, and HCV-RNA load at each time point (baseline, week (W)2, W4, W8, end of treatment (EOT), follow-up W4 (FU-W4) and FU-W12. 6

Treatment success was defined as HCV-RNA negativity (below the detection limit of 15 IU/mL or 12 IU/mL, depending on the assay) at FU-W12 (SVR12) or thereafter. Relapse was defined as detectable HCV-RNA post-treatment after undetectable HCV-RNA at the end of treatment. Virological failure was defined as detectable HCV-RNA at both EOT and FU-W12.

Cirrhotic status was based on liver biopsy (METAVIR fibrosis stage F4), liver stiffness ≥12.5 kPa (FibroScan®; Echosens, France), a FibroTest® value ≥0.75 (Biopredictive, France) or physical and biological signs of end-stage liver disease, as previously published [24, 25]. Adverse events were collected throughout the study period and were categorised as being due to liver disease, HIV infection, cART, or DAA.

Statistical analysis

Variables were described as numbers, percentages, or the median and interquartile range [IQR], as appropriate. Patient characteristics are reported at initiation of DAA treatment. For SVR rates, 95% confidence intervals were calculated. We used univariable and multivariable (adjusted) exact logistic regression models to identify independent baseline variables associated with SVR12. For these analyses, patients receiving SOF + RBV were excluded because one objective was to test the benefit of adding RBV to a dual-DAA regimen. We tested the following variables selected a priori: treatment duration (24 versus 12 weeks), ribavirin co-administration (yes/no), age (for each additional 10 years), gender, cirrhosis (yes/no), the HCV genotype (1 versus others), HIV RNA viral load (undetectable versus detectable), the HCV treatment history (pre-treated versus naïve) and the cART regimen at DAA initiation. We tested the following baseline characteristics in models adjusted for ribavirin use, treatment duration, sex and age: the anti-HCV treatment history (model 1), genotype (model 2), cirrhosis (model 3), HIV RNA load (model 4), and the cART regimen at DAA initiation (model 5). Furthermore, model 6 for DAA combination was further adjusted for cirrhosis and the variables listed above. SAS software version 9.3 (SAS Institute Inc., Cary, North Carolina) was used for all analyses. 7

Role of the funding source

The ANRS CO13 HEPAVIH cohort study is sponsored by Inserm-ANRS (French National Institute for Health and Medical Research – ANRS/France REcherche Nord&Sud Sida-hiv Hépatites). The sponsor had no role in data collection, data analysis, data interpretation, or writing of the report. Other funders had no role in the study design, data collection, data analysis, data interpretation, or writing of the report.

Results

Patient characteristics at DAA initiation

A total of 323 HIV/HCV-coinfected patients treated with all-oral DAA regimens were included in this study (supplementary material Figure 1). Eleven patients were excluded from all analyses because of insufficient follow-up after end of treatment (supplementary material Table 1). One of these 11 patients died from variceal bleeding between FU-W4 and FU-W12, with undetectable HCV-RNA at the end of treatment and at FU-W4. The characteristics of the patients at DAA initiation are reported in Table 1. Median age at DAA initiation was 53 years, and 74% of the participants were male. Almost all participants were on cART (98.8%), consisting mainly of integrase inhibitor-based regimens (37.6%), and 88.5% of patients had undetectable HIV-RNA. The median CD4 cell count was 540/mm3. Most patients were at CDC stage A (42.6%) or B (27.1%). Cirrhosis was present in 60.2% of patients, at ChildPugh A in 160 cases, Child-Pugh B in 13 cases and Child Pugh C in 3 cases; this information was missing for 18 patients. Median HCV viral load was 6.0 (5.5-6.4) log10 IU/mL and most patients had HCV genotype 1 infection (56.5%), followed by genotype 4 (24.5%), genotype 3 (14.3%) genotype 2 (4.3%) and HCV genotype 6 (one patient). Most patients (68.4%) had previously received unsuccessful anti-HCV therapy, consisting of interferon/Peg-interferon + ribavirin in 181 cases and triple-drug regimens including either telaprevir or boceprevir in 29 cases.

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SOF + DCV ± RBV was prescribed to 56.0% of patients, followed by SOF + LDV ± RBV in 20.4% of cases, SOF + RBV in 15.8%, and SOF + SMV ± RBV in 5.9%. Six patients received other combinations (Table 1). Most patients (88%) receiving ribavirin-based regimens were anti-HCV treatment-experienced; the regimens used with RBV were SOF+DCV (n=25), SOF+LDV (n=10) and SOF+SMV (n=2) (supplementary material Table 3). Of the 164 cirrhotic patients receiving at least two DAAs, 26 patients (16%) received a ribavirincontaining regimen for 12 weeks (n=9) or 24 weeks (n=17). Fifteen non-cirrhotic patients (14%) received a dual-DAA + ribavirin regimen for 12 weeks (n=11) or 24 weeks (n=4) (supplementary material Table 4).

Response to HCV therapy (Figure 1a - 1d and supplementary Table 2)

Factors associated with the treatment response in the adjusted exact logistic regression analysis are shown in Table 2a and 2b.

Overall response to HCV therapy SVR12 was achieved in 302 patients overall (93.5%, 95% CI: 90.2-95.9). The SVR rate ranged from 86.3% (95% CI: 73.7-94.3) with SOF + RBV to 95.5% (95% CI: 87.3-99.1) with SOF + LDV ± RBV. We observed no significant difference in SVR12 according to the initial DAA regimen, after adjustment for ribavirin use, the treatment duration, previous HCV therapy, and cirrhosis.

Responses according to cirrhotic status and the HCV genotype There was no difference in SVR12 between patients with and without cirrhosis (93.3% (95% CI: 88.8-96.4) and 93.8% (95% CI: 88.1-97.3), respectively). SVR12 rates were 94.4% (95% CI: 89.6-97.4) and 81.3% (95% CI: 54.4-96.0), respectively, among patients with Child-Pugh A (of whom 29.4% received RBV) and Child-Pugh B/C (of whom 18.8% received RBV) (P=0.08). There was no significant difference in SVR12 between HCV genotype 1 infection and other genotypes. Respective SVR12 rates among patients with HCV genotype 1, 3 and 9

4 infection were 92.3% (95% CI: 87.4-95.7), 95.7% (85.5-99.5) and 96.2% (89.2-99.2). The SVR12 was 85.7% (95% CI: 57.2-98.2) among the 14 patients with genotype 2 infection, of whom 12 received SOF + RBV and 7 were cirrhotic.

Responses according to previous anti-HCV treatment The SVR12 was 94.1% (95% CI: 87.6-97.8) in anti-HCV-naïve patients, and 93.2% (95% CI: 89.1-96.2) in experienced patients (Table 2b). Neither the intended treatment duration nor initial HCV viral load was associated with SVR12.

Responses according to ribavirin use Forty-one patients received a dual-DAA regimen that included ribavirin (see supplementary material Tables 3 and 4). Their SVR12 was 92.7% (95% CI: 80.1-98.5), compared to 95.2% (95% CI: 91.6-97.6) in patients who received a dual-DAA regimen that did not include ribavirin. Most patients (56.0%) received SOF + DCV, and 25 of them also received ribavirin (supplementary material Table 5). The SVR12 was 95.0% (95% CI: 90.8-97.7) overall among patients who received SOF + DCV, and respectively 92.0% (74.0-99.0) and 95.5% (91.098.2) in those who did and did not receive ribavirin. Similar results were obtained in patients who received SOF+LDV with or without RBV (supplementary Table 2). Overall, among patients who received at least two DAAs, the SVR12 was similar whether or not they received ribavirin (Table 2a). These results were confirmed by a robustness analysis based on a propensity score (data not shown).

Response according to the cART regimen The SVR12 was respectively 93.1% (84.5-97.7), 91.8% (80.4-97.7) and 95.8% (90.5-98.6) among patients receiving PI-based, NNRTI-based and II-based cART (Table 3 and Figure 1c).

A more detailed descriptive analysis of SVR12 according to the DAA and cART

regimens showed similar SVR12 rates with all possible combinations, although some were prescribed to very few patients (Table 3). 10

Treatment failure

Treatment failure occurred in 21 patients: 15 patients had a virological relapse, 4 patients experienced virological failure, one patient had detectable viral load 12 weeks after treatment cessation but no available data at the end of treatment, and one patient died during treatment. Characteristics of patients in whom treatment failed are summarized in supplementary material Table 6. Most of them (71.4%) were male; median age was 54 years; HIV viral load was below 50 copies/mL in 76.2% of cases; and the median CD4 cell count was 447/mm3. Most of these patients (66.7%) had HCV genotype 1 infection and 13 (62%) had cirrhosis.

Safety

Adverse effects related to HCV therapy were reported in 94 patients (30%) (Table 4). Anemia occurred in 16 patients, of whom 11 received RBV. Eleven patients stopped their HCV therapy prematurely, two for intolerance and one for lack of virological response (reasons unknown in the other 8 patients). HCV treatment modifications were reported for 36 patients, of whom 10 stopped ribavirin and one stopped daclatasvir. Dose modifications were reported for 32 patients and for the following drugs: daclatasvir (n=14), ribavirin (n=13), simeprevir (n=2), asunaprevir (n=1), sofosbuvir (n=1) and ledipasvir (n=1). The reasons for treatment modification were intolerance (n=6), underdosing (n=8: 7 patients receiving DCV and one receiving RBV), and unknown (n=22). Complications related to HIV infection or cART, and complications related to liver disease, are summarized in Tables 5 and 6.

Discussion

In this French nationwide observational cohort study of HIV/HCV-coinfected patients treated with all-oral DAA-based HCV therapy, we observed a high overall SVR12 of 93.5% (95% CI:

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90.2-95.9) in real-life settings. Neither the HCV genotype nor cirrhotic status influenced the SVR12 rate. Nonetheless, as this was an observational cohort study, this high rate of SVR12 might be due to more intensive treatment of selected patients.

This study provides important information on HIV/HCV-coinfected patients who are often omitted from clinical trials [17]. In particular, we included far more patients with genotype 3 or 4 infection than did the ALLY-2 [16] and ASTRAL-5 trials [15]. The SVR12 rate was low in patients with genotype 2 infection, almost all of whom were treated with SOF+RBV, which is known to be less potent than other regimens. Our results are similar to those reported for HCV genotype 2-monoinfected patients treated with SOF+RBV [26].

In patients infected with genotype 1, we observed no difference in efficacy between SOF + DCV and SOF + LDV. The shift from DCV to LDV observed between 2014 and 2015 was not driven by efficacy considerations, as SVR rates were also high with SOF + DCV, whatever the HCV genotype. Rather, this shift probably reflects a preference for a single-tablet regimen allowed by the SOF + LDV combination, as well as economic considerations.

A potential benefit of adding ribavirin to a dual-DAA combination has been reported in HCVmonoinfected patients with advanced cirrhosis receiving 12-week courses of SOF + LDV [27] or SOF + DCV [28]. As patients in our cohort who received RBV may have had more severe HCV disease and more baseline predictors of failure, we used multivariable logistic regression models that take such characteristics into account. We also used a propensity score-based approach. Finally, neither the use of ribavirin nor the type of DAA combination was associated with treatment outcome, even in patients with Child Pugh B/C cirrhosis. Our results are concordant with other real-world studies of HIV/HCV-coinfected patients, in whom ribavirin had no benefit when added to SOF + SMV [18] or SOF + DCV [29]. The theoretical benefit of ribavirin may be offset by adverse effects, which can be anticipated since many HIV/HCV-coinfected patients have already been treated with ribavirin in the past.

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We are aware of no other observational cohort studies of HCV treatment outcomes according to the type of concomitant antiretroviral therapy in HIV-coinfected patients. We found no impact of the cART combination on the SVR12 rate, whereas previous studies suggested that many patients experience significant drug-drug interactions which preclude the use of some antiretroviral drugs [17, 30]. However, the patients' physicians probably chose the anti-HCV regimen in view of their patients' antiretroviral treatment: for example, none of the patients prescribed SOF+SMV was on PI-based cART.

Very few patients stopped their treatment prematurely, confirming the good tolerability of current anti-HCV combinations. Hepatic complications mainly occurred in cirrhotic patients. The virological failure rate was also low, and further analyses are underway to determine whether or not the emergence of resistance precludes retreatment.

Several limitations of this study must be pointed out. First, treatment was not based on a predefined protocol but depended on drug availability and known efficacy on the different HCV genotypes. Thus, in the absence of randomisation, we cannot rule out the possibility that the absence of risk factors was due to bias, especially an indication bias. However, after adjustment for age, ribavirin use and gender, we found that the treatment duration, type of treatment and cirrhosis did not influence treatment outcomes, as confirmed by robustness analysis. Because the number of patients experiencing treatment failure was small, the lack of significant associations might also be explained by a lack of statistical power. In addition, as we do not yet have the genotyping results at treatment failure, we cannot exclude the possibility that some treatment failures were due to re-infection.

In conclusion, in this real-life observational cohort with prospective data collection, new alloral DAA regimens were well tolerated and had excellent virological efficacy in HIV/HCVcoinfected patients. Thus, neither antiretroviral therapy, nor advanced liver disease, appears to undermine the anti-HCV treatment response in HIV/HCV-coinfected patients.

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Author contributions:

All members of the ANRS HEPAVIH study group participated in discussions on the design of the study, the choice of statistical analyses and data interpretation, and were involved in the preparation and review of the submitted manuscript. L. Piroth and L Wittkop drafted the manuscript. C. Gilbert and L Wittkop did the statistical analyses, acted as guarantors for the analyses, and had full access to the dataset. All co-authors approved the final version of the manuscript.

Acknowledgements:

The HEPAVIH cohort population

Scientific Committee of the ANRS CO13 HEPAVIH Study Group: D. Salmon (coordinating investigator), F. Dabis (co-coordinating investigator), L. Wittkop (scientific and methodological coordinator), L. Esterle (project manager), P. Sogni, P. Trimoulet, J. Izopet, L. Serfaty, V. Paradis, B. Spire, P. Carrieri, M.A. Valantin, G. Pialoux, J. Chas, I. Poizot-Martin, K. Barange, A. Naqvi, E. Rosenthal, A. Bicart-See, O. Bouchaud, A. Gervais, C. LascouxCombe, C. Goujard, K. Lacombe, C. Duvivier, D. Vittecoq, D. Neau, P. Morlat, F. Bani-Sadr, L. Meyer, F. Boufassa, S. Dominguez, B. Autran, A.M. Roque, C. Solas, H. Fontaine, D. Costagliola, L. Piroth, A. Simon, D. Zucman, F. Boué, P. Miailhes, E. Billaud, H. Aumaître, D. Rey, S. Couffin-Cadiergues, and L. Marchand.

Clinical centres and participating physicians: APHP Cochin, Paris (Médecine Interne et Maladies Infectieuses: D. Salmon, L. Alagna; Hépato-gastro-entérologie: P. Sogni; Anatomo14

pathologie: B. Terris; Virologie: A. Krivine); APHP Pitié-Salpétrière, Paris (Maladies Infectieuses et Tropicales: C. Katlama, M.A. Valantin, H. Stitou; Hépato-gastro-entérologie: Y. Benhamou; Anatomo-pathologie: F. Charlotte; Virologie: S. Fourati); APHP Pitié-Salpétrière, Paris (Médecine Interne: A. Simon, P. Cacoub, S. Nafissa); APHM Sainte-Marguerite, Marseille (Service d'Immuno-Hématologie Clinique - CISIH: I. Poizot-Martin, O. Zaegel, M. Porcher; Virologie: C. Tamalet); APHP Tenon, Paris (Maladies Infectieuses et Tropicales: G. Pialoux, J. Chas, L. Slama; Anatomo-pathologie: P. Callard, F. Bendjaballah; Virologie: C. Le Pendeven); CHU Purpan, Toulouse (Maladies Infectieuses et Tropicales: B. Marchou; Hépato-gastro-entérologie: L. Alric, K. Barange, S. Metivier; Anatomo-pathologie: J. Selves; Virologie: F. Larroquette); CHU Archet, Nice (Médecine Interne: E. Rosenthal; Infectiologie: Alissa Naqvi; Anatomo-pathologie: J. Haudebourg, M.C. Saint-Paul; Virologie: C. Partouche); APHP Avicenne, Bobigny (Médecine Interne – Unité VIH: O. Bouchaud; Anatomo-pathologie: M. Ziol; Virologie: Y. Baazia); Hôpital Joseph Ducuing, Toulouse (Médecine Interne: M. Uzan, A. Bicart-See, D. Garipuy, M.J. Ferro-Collados; Anatomo-pathologie: J. Selves; Virologie: F. Nicot); APHP Bichat – Claude-Bernard, Paris (Maladies Infectieuses:, A. Gervais, Y. Yazdanpanah; Anatomo-pathologie: H. Adle-Biassette; Virologie: G. Alexandre); APHP Saint-Louis, Paris (Maladies infectieuses: C. Lascoux-Combe, J.M. Molina,; Anatomopathologie: P. Bertheau, J. Duclos; Virologie: P. Palmer); APHP Saint-Antoine (Maladies Infectieuses et Tropicales:, K. Lacombe, P. Campa; P.M. Girard, Anatomo-pathologie: D. Wendum, P. Cervera, J. Adam; Virologie: C. Viala); APHP Bicêtre, Paris (Médecine Interne: C. Goujard, Elina Teicher; Virologie: C. Pallier; Maladies Infectieuses: D. Vittecoq); APHP Necker, Paris (Maladies Infectieuses et Tropicales: O. Lortholary, C. Duvivier,C. Rouzaud, J. Lourenco, F. Touam, C. Louisin: Virologie: A. Mélard); CHU Pellegrin, Bordeaux (Maladies Infectieuses et Tropicales: D. Neau, A. Ochoa, E. Blanchard, S. Castet-Lafarie, C. Cazanave, D. Malvy, M. Dupon, H. Dutronc, F. Dauchy, L. Lacaze-Buzy; Anatomo-pathologie: P. Bioulac-Sage; Virologie: P. Trimoulet, S. Reigadas); Hôpital Saint-André, Bordeaux (Médecine Interne et Maladies Infectieuses: P. Morlat, D. Lacoste, F. Bonnet, N. Bernard, M. Bonarek Hessamfar, J. Roger-Schmeltz, P. Gellie, P. Thibaut, F. Paccalin, C. Martell, M. 15

Carmen Pertusa, M. Vandenhende, P. Mercier, D. Malvy, T. Pistone, M.C. Receveur, S. Caldato; Anatomo-pathologie: P. Bioulac-Sage; Virologie: P. Trimoulet, S. Reigadas); Hôpital du Haut-Levêque, Bordeaux (Médecine Interne: J.L. Pellegrin, J.F. Viallard, E. Lazzaro, C. Greib; Anatomo-pathologie: P. Bioulac-Sage; Virologie: P. Trimoulet, S. Reigadas); Hôpital FOCH, Suresnes (Médecine Interne: D. Zucman, C. Majerholc; Virologie: F. Guitard); APHP Antoine Béclère, Clamart (Médecine Interne: F. Boué, J. Polo Devoto, I. Kansau, V. Chambrin, C. Pignon, L. Berroukeche, R. Fior, V. Martinez; Virologie: C. Deback); CHU Henri Mondor, Créteil (Immunologie Clinique: Y. Lévy, S. Dominguez, J.D. Lelièvre, A.S. Lascaux, G. Melica); CHU Hôtel Dieu, Nantes (Maladies Infectieuses et Tropicales: E. Billaud, F. Raffi, C. Alavena; Virologie: A. Rodallec); Hôpital de la Croix Rousse, Lyon (Maladies Infectieuses et Tropicales: P. Miailhes, D. Peyramond, C. Chidiac, , F. Ader, F. Biron, A. Boibieux, L. Cotte, T. Ferry, T. Perpoint, J. Koffi, F. Zoulim, F. Bailly, P. Lack, M. Maynard, S. Radenne, M. Amiri; Virologie: T.T. Le-Thi); CHU Dijon, Dijon (Département d'infectiologie:, L. Piroth, P. Chavanet M. Duong Van Huyen, M. Buisson, A. Waldner-Combernoux, S. Mahy, R. Binois, A.L. Simonet-Lann, D. Croisier-Bertin); CH Perpignan, Perpignan (Maladies infectieuses et tropicales: H. Aumaître); CHU Robert Debré, Reims (Médecine interne, maladies infectieuses et immunologie clinique: F. Bani-Sadr, D. Lambert, Y Nguen, C. Rouger, J.L. Berger); CHRU Strasbourg (Le Trait d’Union: D Rey, M Partisani, ML Batard, C Cheneau, M Priester, C Bernard-Henry, E de Mautort, Virologie: P Gantner et S Fafi-Kremer)

Data collection: D. Beniken, O. Braik, C. Lupin, C. Lions, A.-S. Ritleng, P. Honoré, V. Payssan, S. Breau, A. Joulie, M. Mole, C. Bolliot, F. Touam, F. André, H. Hue, L. Larmet, C. Brochier, V. Thoirain, M. Raho-Moussa, S Ogoudjobi, M Azar, D. Bornarel, S. Gohier, C. Chesnel, G. Maradan, C. Taieb, S. Hadjoudj, M. Malet, I. Kmiec, P. Fischer, A. Palacin, M.P. Pietri, V. Le Baut, P. Guet, S. Le Puil, , M. Mebarki, A. Fior, A. Adda-Lievin

Data monitoring, data management and statistical analyses:

16

V. Conte, J. Delaune, L. Dequae Merchadou, N. Douiri, S. Gillet, C. Gilbert, A. Jacquet, R. Kherraz, M. Pouyles, F. Marcellin, M. Mora, F. Paraina, C. Protopopescu

Funding: ANRS (France REcherche Nord&Sud Sida-HIV Hépatites)

Co-funding: Roche, Schering Plough, GSK, BMS, Merck-Serono

17

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21

Table 1: Characteristics at initiation of DAA-regimen, ANRS CO13 HEPAVIH, 2014-2015 (n=323) Characteristics Age, years Male sex CD4, cells/mm3 HIV-RNA < 50 copies/mL CDC stage** A B C cARTa Type of cART Non Nucleoside Reverse Transcriptase Inhibitor -based (all) Efavirenz-based Rilpivirine-based Protease-Inhibitor-based (all) Atazanavir/r based Darunavir/r based Integrase Inhibitor-based (all) Other HCV genotype*** 1a 1b 1 without precision 2 3 4 6 Cirrhosis***

Statistics * 53 (50-56) 240 (74.3) 540 (360-773) 286 (88.5) 135 (42.6) 86 (27.1) 96 (30.3) 319 (98.8) 49 (15.4) 18 (36.7) 28 (57.1) 72 (22.6) 22 (30.6) 41 (56.9) 120 (37.6) 78 (24.5) 123 (38.2) 38 (11.8) 21 (6.5) 14 (4.3) 46 (14.3) 79 (24.5) 1 (0.3) 194 (60.2)

Elastometry (measured by Fibroscan®, kPa)**** 12.6 (8.0-20.2) Failure to previous HCV treatment 221 (68.4) HCV viral load, log10 UI/mL*** 6.0 (5.5-6.4) Prescribed DAA regimen Sofosbuvir + Daclatasvir ± Ribavirin 181 (56.0) Sofosbuvir + Ribavirin 51 (15.8) Sofosbuvir + Ledipasvir ± Ribavirin 66 (20.4) Sofosbuvir + Simeprevir ± Ribavirin 19 (5.9) Otherb 6 (1.9) Intended treatment duration 12 weeks 138 (42.7) 24 weeks 180 (55.7) Legend: *Continuous variables are reported as median (IQR) and categorical variables as n (%),**Missing data for 6 patients, *** Missing data for one patient,**** Data available for 149 patients, acombination antiretroviral therapy,bone patient received daclatasvir+asunaprevir+ribavirin, one patient sofosbuvir+daclatasvir+simeprevir, one patient sofosbuvir+ledipasvir+daclatasvir, two patients ombitasvir+paritaprevir+ritonavirboosted+ribavirin and one patient received ombitasvir+paritaprevir+ritonavirboosted+dasabuvir+ribavirin.

1

Table 2a: Results from univariable and multivariable exact logistic regression models for treatment success excluding patients receiving the combination sofosbuvir + ribavirin (n=272). Variable

Multivariable – Model 7

Univariable OR (95% CI)

P-value

OR (95% CI)

P-value

Age (for each additional 10 years)

0.47 [0.20 ; 1.16]

0.0998

0.479 [0.193 ; 1.184]

0.1109

Ribavirin containing regimen (Yes versus No)

0.64 [0.16 ; 3.70]

0.7095

0.627 [0.158 ; 2.488]

0.5068

Sex (Male versus Female)

1.24 [0.27 ; 4.48]

0.9340

1.119 [0.325 ; 3.850]

0.8590

Treatment duration (24 weeks versus 12 weeks)

2.07 [0.60 ; 8.08]

0.3060

2.939 [0.763 ; 11.326]

0.1173

Treatment history (Experienced versus naïve)

0.67 [0.12 ; 2.62]

0.7845

-

Genotype (1 versus others)

0.26 [0.03 ; 1.22]

0.1054

-

Cirrhosis (Yes versus No)

0.85 [0.22 ; 2.90]

1.0000

0.794 [0.234 ; 2.699]

HCV RNA (for each additional IU/mL)

0.92 [0.47; 1.77]

0.7922

-

2.42 [0.41 ; 10.01]

0.3547

-

PI-based

0.66 [0.11 ; 4.69]

0.8682

-

NNRTI-based

1.37 [0.13 ; 69.39]

1.0000

-

Other

0.39 [0.08 ; 1.72]

0.2579

-

0.91 [0.15 ; 3.80]

1.0000

0.501 [0.110 ; 2.273]

HIV RNA (<50 vs ≥ 50 copies/mL)

0.7115

cART at DAA initiation (ref=II-based)

DAA treatment (ref=SOF/LDV) SOF + DCV

0.3702

SOF + SMV 0.41 [0.04 ; 5.28] 0.6201 0.359 [0.052 ; 2.489] 0.2998 Legend: PI: protease inhibitor; II: integrase inhibitor; NNRTI: Non Nucleoside Reverse Transcriptase Inhibitor; cART: combination antiretroviral therapy; DAA: direct acting antiviral; SOF: Sofosbuvir; DCV: Daclatasvir; SMV: Simeprevir; LDV: Ledipasvir. OR (95% confidence intervals) and p-values (Wald test) were calculated using exact logistic regression.

2

Table 2b: Results from multivariable exact logistic regression models for treatment success excluding patients receiving the combination sofosbuvir + ribavirin (n=272). Variable Model 1* Treatment history (Experienced versus naïve) Model 2* Genotype (1 versus others) Model 3* Cirrhosis (Yes versus No) Model 4* HIV RNA (<50 vs ≥ 50 copies/mL) Model 5* cART at DAA initiation (ref=II-based) PI-based NNRTI-based Other Model 6* DAA treatment (ref=SOF/LDV) SOF + DCV SOF + SMV

Multivariable OR [95% CI] P-value 0.637 [0.165 ; 2.457]

0.5129

0.251 [0.054 ; 1.164]

0.0773

0.681 [0.201 ; 2.311]

0.5375

2.914 [0.704 ; 12.069]

0.1402

0.681 [0.145 ; 3.209] 1.438 [0.153 ; 13.557] 0.416 [0.110 ; 1.575]

0.6274 0.7509 0.1965

0.493 [0.109 ; 2.219] 0.342 [0.051 ; 2.320]

0.3566 0.2722

Legend: * all multivariable models have been adjusted for ribavirin use, treatment duration, sex and age. PI: protease inhibitor; II: integrase inhibitor; NNRTI: Non Nucleoside Reverse Transcriptase Inhibitor; cART: combination antiretroviral therapy; DAA: direct acting antiviral; SOF: Sofosbuvir; DCV: Daclatasvir; SMV: Simeprevir; LDV: Ledipasvir. OR (95% confidence intervals) and p-values (Wald test) were calculated using exact logistic regression.

3

Table 3: Description of efficacy according to prescribed DAA-regimen and prescribed cART at DAA initiation (number of patients with SVR / number of patients receiving the specific combination, (%SVR12), [95% Confidence intervals]). Anti-HCV treatment received All DAA regimen SOF+RBV SOF+DCV±RBV SOF+LDV±RBV SOF+SMV±RBV (n=323) (n=51) (n=181) (n=66) (n=19) All (n=72) 67/72 15/17 39/40 12/14 (93.1) (88.2) (97.5) (85.7) [84.5-97.7] [63.6-98.5] [86.8-99.9] [57.2-98.2] Darunavir-based 37/41 8/10 21/22 7/8 PI-based (n=41) (90.2) (80.0) (95.5) (87.5) [76.9-97.3] [44.4-97.5] [77.2-99.9] [47.3-99.7] Atazanavir-based 21/22 4/4 12/12 5/6 (n=22) (95.5) (100.0) (100.0) (83.3) [77.2-99.9] [39.8-100.0] [73.5-100.0] [35.9-99.6] All 45/49 9/12 20/21 12/12 4/4 (n=49) (91.8) (75.0) (95.2) (100.0) (100.0) [80.4-97.7] [42.8-94.5] [76.2-99.9] [73.5-100.0] [39.8-100.0] NNRTIbased* Rilpivirine-based 25/28 2/4 11/12 8/8 4/4 (n=28) (89.3) (50.0) (91.7) (100.0) (100.0) [71.8-97.7] [6.8-93.2] [61.5-99.8] [63.1-100.0] [39.8-100.0] All 115/120 10/11 71/73 19/20 11/12 II-based (n=120) (95.8) (90.9) (97.3) (95.0) (91.7) [90.5-98.6] [58.7-99.8] [90.5-99.7] [75.1-99.9] [61.5-99.8] All 71/78 10/11 40/45 19/19 1/2 Other (n=78) (91.0) (90.9) (88.9) (100.0) (50.0) [82.4-96.3] [58.7-99.8] [75.9-96.3] [82.4-100.0] [1.3-98.7] Legend: DCV: daclatasvir; LDV: ledipasvir; RBV: ribavirin; SMV: simeprevir; SOF: sofosbuvir; PI: protease inhibitor; II: integrase inhibitor; NNRTI: Non Nucleoside Reverse Transcriptase Inhibitor. *Efavirenz-based NNRTI regimen could not be broken down due to small numbers.

4

Table 4: Secondary effects allocated to all-oral DAA treatments during the study period, in 323 HIV-HCV coinfected patients, the ANRS CO13 HEPAVIH cohort, 20142015 Reported secondary effect

Number of patients*

Fatigue

30

Anemia

16

Digestive disorders

19

Skin disorders

14

Mood disorders

8

Insomnia

10

Headache

18

Cough

2

Articular pain

3

Muscular pain

6

Diminution of libido

3

Gynecomastia, Crisis of epilepsia, Anorexia

1 each

* A patient can experience more than one secondary effect

5

Table 5: Complications related to HIV or cART in 13 of the 323 HIV-HCV coinfected patients, the ANRS CO13 HEPAVIH cohort, 2014-2015 Reported complication

Number of patients*

Gynecomastia

1

Renal insufficiency

1

Mucositis

1

Oral candidiasis

3

Vaginal candidiasis

1

Odynophagia

1

Lipohypertrophy

1

Canker sore

1

Skin disorders

1

Non-defined dysplasia

1

Herpes

2

Bronchitis

1

Rhinopharyngitis

1

*for some patients more than one complication was reported

6

Table 6: Complications related to liver disease in 19 of the 323 HIV-HCV coinfected patients, the ANRS CO13 HEPAVIH cohort, 2014-2015 Reported complication

Cirrhotic Child

Cirrhotic Child

Non cirrhotic

Pugh A

Pugh B or C

patients

patients

patients (n=16)

(n=128)

(n=160) Hepatocellular carcinoma

1

1

Ascites

1

1

Gastrointestinal bleeding

1

Liver decompensation

Undefined

2

Asthenia

1

Anicteric cholestasis

1

Late-onset cutaneous porphyria

1

Esophageal varices

1

Gastritis

1

1

2

Thrombocytopenic purpura

1

Heavy right costal pain

1

Heterogenic nodular lesions of

1

hepatic lobe IV

7

100% 95.5%

80

95.0%

93.5%

89.5%

% of SVR12

86.3% 60

40

20 302/323

44/51

172/181

63/66

17/19

0

Figure 1a: Frequency of sustained virological (vertical bars represent 95% confidence intervals calculated using the exact binomial distribution) response 12 weeks after the end of therapy according to prescribed DAA regimen which has been evaluated in adjusted exact logistic regression analysis (see table 2a and b).

Duration of treatment 93.5%

92.0%

95.0%

95.2%

92.7%

93.8%

93,3%

94.1%

93.2%

302/ 323

127/ 138

171/ 180

220/ 231

38/ 41

120/ 128

181/ 194

96/ 102

206/ 221

24 weeks

No

Yes

No

Yes

Naïve

Experienced

Previous treatment

12 weeks

% of SVR12

80

Cirrhosis

All

100%

Use of Ribavirin*

60 40 20 0

Figure 1b: Frequency of sustained virological (vertical bars represent 95% confidence intervals calculated using the exact binomial distribution) response 12 weeks after the end of therapy according to the selected covariables which have been evaluated in adjusted exact logistic regression analysis (see table 2a and b). *Patients receiving SOF + RBV have been excluded from this analysis.

HCV genotype

cART

Genotype 4

91.0%

115/ 120

45/ 49

67/ 72

71/ 78

Others

75/ 78

93.1%

PI-based

45/ 47

91.8%

NNRTI-based

12/ 14

95.8%

II-based

96.2%

Genotype 3

% of SVR12

80

92.3%

95.7%

Genotype 2

100% 85.7%

60 40 20

168/ 182

Genotype 1

0 289/ 310

Figure 1c: Frequency of sustained virological response (vertical bars represent 95% confidence intervals calculated using the exact binomial distribution) 12 weeks after the end of therapy according to the selected covariables which have been evaluated in adjusted exact logistic regression analysis (see table 2a and b).

Overall

With cirrhosis

100%

100.0% 92.0%

95.0%

88.9%

93.0%

95.4%

94.7%

100.0% 100.0%

81.8%

60

62/ 65

4/4

26/ 26

Without RBV

9/11

With RBV*

89/ 94

Without RBV

17/ 17

With RBV*

40/ 43

Without RBV

8/9

With RBV*

171/ 180

Without RBV

0

127/ 138

With RBV*

20

24 weeks

40

12 weeks

% of SVR12

80

Without cirrhosis

12 weeks 24 weeks

*Patients receiving SOF + RBV have been excluded from this analysis.

Figure 1d: Frequency of sustained virological response (95% confidence intervals confidence intervals calculated using the exact binomial distribution) 12 weeks after the end of therapy according to the selected covariables which have been evaluated in adjusted exact logistic regression analysis (see table 2a and b).

*Graphical Abstract

Data from 323 HIV/HCV co-infected patients treated with all-oral DAA regimen and included in the French nationwide ANRS CO13 HEPAVIH cohort showed high frequencies of sustained virological response.

Overall

With cirrhosis

Without cirrhosis

100%

60

62/ 65

4/4

26/ 26

Without RBV

9/11

With RBV*

89/ 94

Without RBV

17/ 17

With RBV*

40/ 43

Without RBV

8/9

With RBV*

171/ 180

Without RBV

0

127/ 138

With RBV*

20

24 weeks

40

12 weeks

% of SVR12

80

12 weeks 24 weeks

*Patients receiving SOF + RBV have been excluded from this analysis.

Frequency of sustained virological response (95% confidence intervals) 12 weeks after the end of therapy according to the selected covariables which have been evaluated in adjusted logistic regression analysis.