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ledipasvir/sofosbuvir in NS3/4A protease
inhibitor-experienced individuals with hepatitis C virus
genotype 1 and HIV coinfection with and without
cirrhosis (ANRS HC31 SOFTRIH study)
E. Rosenthal, C Fougerou-Leurent, A. Renault, Mp. Carrieri, F. Marcellin, R
Garraffo, E. Teicher, H Aumaitre, K. Lacombe, F. Bailly, et al.
To cite this version:
E. Rosenthal, C Fougerou-Leurent, A. Renault, Mp. Carrieri, F. Marcellin, et al.. Efficacy, safety
and patient-reported outcomes of ledipasvir/sofosbuvir in NS3/4A protease inhibitor-experienced
in-dividuals with hepatitis C virus genotype 1 and HIV coinfection with and without cirrhosis (ANRS
HC31 SOFTRIH study). HIV Medicine, Wiley, 2018, 19 (3), pp.227-237. �10.1111/hiv.12571�.
�hal-01740817�
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ficacy, safety and patient-reported outcomes of
ledipasvir/sofosbuvir in NS3/4A protease
inhibitor-experienced individuals with hepatitis C virus
genotype 1 and HIV coinfection with and without cirrhosis
(ANRS HC31 SOFTRIH study)
E Rosenthal,1C Fougerou-Leurent ,2,3A Renault,3,4MP Carrieri,5,6F Marcellin,5,6R Garraffo,7E Teicher,8
H Aumaitre,9K Lacombe,10F Bailly,11E Billaud,12S Chevaliez,13S Dominguez,14MA Valantin,15J Reynes,16A Naqvi,17 L Cotte,18S Metivier,19V Leroy,20M Dupon,21T Allegre,22P De Truchis,23V Jeantils,24J Chas,25D Salmon-Ceron,26 P Morlat,27D Neau,28P Perre,29L Piroth,30S Pol,31M Bourliere,32GP Pageaux,33L Alric,34D Zucman,35PM Girard,10 I Poizot-Martin,36,37Y Yazdanpanah,38F Raffi,12E Le Pabic,2,3C Tual,2,3A Pailhe,39I Amri39E Bellissant2,3,4and JM Molina40for the ANRS HC31 SOFTRIH Study Group*
1Internal Medicine Department, CHU de Nice, H^opital Archet 1, Nice, France,2
Pharmacology Department, CHU Rennes, Rennes, France,3Inserm, CIC1414, Rennes, France,4Pharmacology Laboratory, Faculte de Medecine, Univ Rennes 1, Rennes, France,5Sciences Economiques & Sociales de la Sante & Traitement de l’Information Medicale, Inserm, IRD, Aix Marseille Univ, Marseille, France,6Observatoire Regional de la Sante Provence-Alpes-C^ote d’Azur, Marseille, France, 7
Clinical Pharmacology and Toxicology Department, CHU de Nice, Nice, France,8Infectious Diseases Department, APHP, H^opital Bic^etre, Le Kremlin Bic^etre, France,9Infectious and Tropical Diseases Department, H^opital de Perpignan, Perpignan, France,10Infectious Diseases Department, APHP, H^opital Saint Antoine, Paris, France,11Hepatology Department, HCL, H^opital de la Croix-Rousse, Lyon, France,12
Infectious Diseases Department, CHU Nantes, Nantes, France,13Virology Department, APHP, H^opital Henri Mondor, Creteil, France,14Clinical Immunology Department, APHP, H^opital Henri Mondor, Creteil, France,15Infectious Diseases Department, APHP, H^opital La Pitie Salp^etriere, Paris, France,16Infectious Diseases Department, CHU Montpellier, Montpellier, France,17Infectious Diseases
Department, CHU de Nice, H^opital Archet 1, Nice, France,18Infectious Diseases Department, HCL, H^opital de la Croix-Rousse, Lyon, France,19Hepatogastroenterology Department, CHU Toulouse, Toulouse, France,20Hepatogastroenterology Department, CHU Grenoble, Grenoble, France,21Infectious Diseases Department, CHU Bordeaux, Bordeaux, France, 22
Hemato Oncology Department, CH du Pays d’Aix, Aix-en-Provence, France,23Infectious Diseases Department, APHP, H^opital R Poincare, Garches, France,24Infectious Diseases Department, APHP, H^opital J Verdier, Bondy, France, 25Infectious and Tropical Diseases Department, APHP, H^opital Tenon, Paris, France,26Infectious Diseases Department, APHP, H^opital Cochin, Paris, France,27
Internal Medicine and Infectious Diseases Department, CHU Bordeaux,
Bordeaux, France,28Infectious and Tropical Diseases Department, CHU Bordeaux, Bordeaux, France,29Internal Medicine Department, CHD Vendee, La Roche sur Yon, France,30
Infectious Diseases Department, CHU Dijon, Dijon, France, 31Hepato-Gastroenterology Department, APHP, H^opital Cochin, Paris, France,32
Hepatogastroenterology Department, H^opital Saint Joseph, Marseille, France,33
Hepatogastroenterology Department, CHU Montpellier, Montpellier, France, 34
Internal Medicine Department, CHU Toulouse, Toulouse, France,35Internal Medicine Department, H^opital Foch, Suresne, France,36Immuno and Clinical Hematology department, APHM Sainte-Marguerite, Aix Marseille Univ, Marseille, France,37Inserm U912 (SESSTIM), Marseille, France,38Infectious and Tropical Diseases Department, APHP, H^opital Bichat, Paris, France,39Unite de Recherche Clinique et Fondamentale sur les Hepatites Virales, ANRS (France Recherche Nord & Sud Sida-hiv Hepatites), Paris, France and40Hepatogastroenterology Department, APHP, H^opital Saint Louis, Paris, France
Correspondence: Professor Eric Rosenthal, Service de Medecine Interne, H^opital Archet 1, CHU de Nice, 06200 Nice, France. Tel: +33 492 035 861; fax: +33 492 035 896; e-mail: rosenthal.e@chu-nice.fr
*7A complete list of the ANRS HC31 SOFTRIH study group is provided in Appendix S1.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduc-tion in any medium, provided the original work is properly cited and is not used for commercial purposes.
Objectives
Studies evaluating the efficacy and safety of the fixed-dose combination ledipasvir (LDV)/ sofosbuvir (SOF) in patients coinfected with HIV-1 and hepatitis C virus (HCV) have mainly included treatment-na€ıve patients without cirrhosis. We aimed to evaluate the efficacy and safety of this combination in treatment-experienced patients with and without cirrhosis.
Methods
We conducted a multicentre, open-label, double-arm, nonrandomized study in patients coinfected with HIV-1 and HCV genotype 1 with and without cirrhosis, who had good viral suppression on their antiretroviral regimens. All patients were pretreated with a first-generation NS3/4A protease inhibitor (PI) plus pegylated interferon/ribavirin. Patients received a fixed-dose combination of LDV/SOF for 12 weeks, or for 24 weeks if cirrhosis was present. The primary endpoint was a sustained virological response (SVR) 12 weeks after the end of therapy. Secondary endpoints included safety, pharmacokinetics and patient-reported outcomes.
Results
Of the 68 patients enrolled, 39.7% had cirrhosis. Sixty-five patients [95.6%; 95% confidence interval (CI): 87.6–99.1%; P < 0.0001] achieved an SVR, with similar rates of SVR in those with and without cirrhosis. Tolerance was satisfactory, with mainly grade 1 or 2 adverse events. Among patient-reported outcomes, only fatigue significantly decreased at the end of treatment compared with baseline [odds ratio (OR): 0.36; 95% CI: 0.14–0.96; P = 0.04]. Mean tenofovir area under the plasma concentration–time curve (AUC) at week 4 was high, with mean SD AUC variation between baseline and week 4 higher in cirrhotic than in noncirrhotic patients (3261.57 1920.47 ng/mL vs. 1576.15 911.97 ng/mL, respectively; P = 0.03). Mild proteinuria (54.4%), hypophosphataemia (50.0%), blood bicarbonate decrease (29.4%) and hypokalaemia (13.2%) were reported. The serum creatinine level was not modified.
Conclusions
LDV/SOF provided a high SVR rate in PI-experienced subjects coinfected with HCV genotype 1 and HIV-1, including patients with cirrhosis.
Keywords: coinfection, hepatitis C virus, HIV, ledipasvir, sofosbuvir, treatment
Accepted 19 October 2017
Introduction
To date, most of the studies evaluating the efficacy and safety of the fixed-dose combination of ledipasvir [LDV; an inhibitor of nonstructural protein 5A (NS5A)] and sofosbuvir (SOF; a nucleotide NS5B polymerase inhibi-tor) in patients coinfected with HIV-1 and hepatitis C virus (HCV) have mainly included individuals without cirrhosis and with no previous exposure to direct-acting antiviral agents (DAAs). Overall, these studies showed high rates of sustained virological response (SVR) in HIV/HCV-coinfected patients with genotype 1 or 4 [1,2]. The phase 2 ERADICATE study showed that, after 12 weeks of LDV/SOF in 50 treatment-na€ıve, noncir-rhotic patients coinfected with HCV genotype 1 and HIV-1, the rate of SVR 12 weeks after the end of the therapy (SVR12) was 98% [1]. The ION-4 phase 3 study evaluated the single fixed-dose combination for 12 weeks in 335 HIV-seropositive patients with both
HCV genotype 1 and genotype 4 coinfections, including 185 HCV treatment-experienced individuals (53 patients exposed to NS3/4A PIs) and 67 patients with cirrhosis. Overall, this study showed a 96.1% response rate in terms of SVR12 (96.6% vs. 94.0% in noncirrhotic and cirrhotic patients, respectively; difference not significant) [2]. These studies also showed that LDV/SOF in HIV/ HCV-coinfected patients produced a similar SVR rate to that in HCV-monoinfected patients [3]. Nevertheless, rel-ative to HCV-monoinfected patients, drug interactions with antiretrovirals may complicate treatment of coin-fected patients and expose them to secondary events, particularly in patients with cirrhosis.
The SOFTRIH study aimed to evaluate the efficacy, safety and patient-reported outcomes (PROs) of combined treat-ment with LDV/SOF in a population of patients coinfected with HIV-1 and HCV genotype 1 who had virological fail-ure on or were intolerant to NS3/4A protease inhibitors (PIs), including subjects with compensated cirrhosis.
Methods
Study design and setting
This study was a nonrandomized, double-arm, open-label phase II pilot trial conducted between August 2014 and December 2015 in 30 French centres. The sponsor [Inserm-Agence Nationale de Recherche sur le Sida et les Hepatites Virales (ANRS)] designed and conducted the study, and collected, monitored and analysed the data. Study drugs were kindly provided by Gilead Sciences, Inc. (Foster City, CA, USA). The study protocol (EUDRACT number 2013-002607-33) was approved by Ethical Com-mittee CPP-Sud-Mediterranee-1 (Marseille, France) and by the French Regulatory Authority Agence nationale de securite du medicament et des produits de sante (ANSM) (Saint-Denis, France). It was registered in the ClinicalTri-als.gov database under reference NCT02125500. The study was conducted in compliance with the Declaration of Helsinki and Good Clinical Practice Guidelines and regulatory requirements. All participants provided written informed consent.
Patients
Patients enrolled in the study had to be HIV/HCV geno-type 1-coinfected adults, with a screening level of HCV RNA of at least 1000 IU/mL. Other inclusion criteria were: virological failure or premature discontinuation for intolerance of a previous triple therapy with pegylated (peg)-interferon/ribavirin and a first-generation PI; pre-vious anti-HCV treatment interrupted for at least 3 months; stable antiretroviral treatment (combination of permitted molecules: tenofovir, emtricitabine, lamivu-dine, efavirenz, raltegravir, rilpivirine and enfuvirtide; as insufficient data on drug–drug interactions with LDV were available at this time, dolutegravir was not allowed) for at least 4 weeks before screening; HIV RNA < 50 HIV-1 RNA copies/mL for at least 3 months; CD4 count of > 100 cells/lL and CD4 percentage > 15%. The main noninclusion criteria were Child–Pugh B or C cirrhosis or a history of cirrhosis decompensation, coinfection with hepatitis B virus and any organ transplantation. As a result of the interaction between LDV and tenofovir leading to an increase in tenofovir exposure, a minimum creatinine clearance of 60 mL/ min, as calculated with the Modification of Diet in Renal Disease (MDRD) formula, was required for enrolment. Full eligibility criteria are given in the Appendix S1. Fibrosis was evaluated at screening in all patients with the assessment of the presence or absence of cirrhosis based on:
•
previous liver biopsy exhibiting cirrhotic lesions,•
and/or significant liver biopsy (cumulative length ≥ 15 mm or ≥ 5 portal spaces) within the past 18 months,•
and/or significant and reliable liver stiffness assess-ment (Fibroscanâ, Echosens, Paris, France) within the past 6 months [at least 10 measures with interquartile range (IQR) < 30% of the median value and a success rate of≥ 70%].Cirrhosis was defined as a METAVIR score of F4 on the liver puncture biopsy and/or hepatic impulse elastometry ≥ 14.5 kPa.
Procedures
Cirrhotic patients received 24 weeks of the LDV/SOF (90/ 400 mg) fixed-dose combination once daily. Noncirrhotic patients received the same regimen for 12 weeks. The study treatment had to be interrupted in the case of: (1) virological failure, defined as a confirmed breakthrough (an increase from nonquantifiable to quantifiable HCV RNA or to≥ 1 log10 IU/mL above nadir); (2) intolerance, defined as a confirmed increase of alanine aminotrans-ferase (ALT) to 5 times the nadir and ALT > upper limit of normal.
Outcomes and measurements
The primary efficacy endpoint was an SVR12 (unde-tectable HCV RNA). Key secondary efficacy endpoints were SVR4, SVR24 and virological response measured at weeks 1, 2, 4, 12, 16, 20, 24, 30, 36, and 42 plus week 48 in cirrhotic patients. Plasma HCV RNA levels were quan-tified in virology laboratories local to the sites using one of the following techniques: the COBAS AmpliPrep/ COBAS TaqMan HCV test, version 2.0 (Roche Molecular Systems, Pleasanton, CA, USA) with a lower limit of quantification (LLOQ) of 15 IU/mL or the Abbott Real-Time HCV Assay (Abbott Molecular, Des Plaines, IL, USA) with an LLOQ of 12 IU/mL.
Safety endpoints included the frequency and severity of adverse events, discontinuations of study treatment and safety laboratory changes (including HIV virological assessment). All study participants were monitored fre-quently for adverse events and clinical laboratory results were recorded throughout the study. Adverse events were graded by investigators according to the Inserm-ANRS Scale for Scoring of Adverse Events Seriousness (v6; 9 September 2003). HIV RNA was measured with the Abbott RealTime HIV-1 Assay (Abbott Molecular) or the COBAS AmpliPrep/COBAS TaqMan-HIV Test, version 2
(Roche Molecular Systems). HIV viral load (VL) was con-sidered detectable if> 50 copies/mL. HIV virological fail-ure was defined as at least one HIV VL over this threshold, confirmed within 2 weeks.
Moreover, repeated assessments of PROs were sched-uled throughout the follow-up, including assessments of adherence to HIV and HCV treatments (using the Inserm-ANRS self-administered questionnaire [4]), self-reported symptoms [using the ANRS AC24 questionnaire derived from the AIDS Clinical Trials Group (ACTG) Symptom Distress Module [5]] as indicators of patients’ subjective experience with treatments, perceived level of fatigue and associated discomfort (using three items from the Piper Fatigue Scale [6]) and health-related quality of life (HRQL) (using the Medical Outcomes Study (MOS) SF-12 scale [7]). These PROs were evaluated at follow-up visits at day 0, week 12 and week 24 for noncirrhotic patients and day 0, week 12, week 24 and week 36 for cirrhotic patients.
Pharmacokinetics
Twenty subjects receiving an antiretroviral treatment con-sisting of the combination of tenofovir, emtricitabine and raltegravir were enrolled in an intensive 10-h pharma-cokinetics (PK) substudy. PK profiles were obtained at hours 0, 1, 2, 3, 6, 8 and 10. Plasma samples from these patients were analysed for antiretroviral drug concentra-tions at day 0 and week 4 (liquid chromatography coupled with tandem mass spectrometry; Medical Pharmacology and Toxicology Unit, Pasteur University Hospital, Nice, France). Quantification limits were 10lg/L for tenofovir and 25lg/L for raltegravir. SOF, GS-331007 (the predom-inant circulating metabolite of SOF) and LDV concentra-tions were analysed at week 4 (Gilead Sciences, Inc.).
Statistical analysis
Qualitative data are presented as number and percentage and quantitative data are presented as median and IQR or mean and standard deviation (SD), as appropriate.
The primary efficacy endpoint was the SVR12 rate measured at week 36 for cirrhotic patients and week 24 for noncirrhotic patients. For analysis of the main end-point, an intention-to-treat (ITT) analysis was performed with a test comparing an observed to a theoretical pro-portion using a unilateral formulation with a type I error of 5%. The rate of SVR12 below which the therapy would be considered inefficient was fixed at 50% (null hypothe-sis). The rate of SVR12 above which the therapy would bring a real benefit was fixed at 70% (alternative hypoth-esis). To guarantee 95% power to detect such a 20%
benefit, and considering the statistical hypotheses, a min-imum of 39 (out of 64) participants with an SVR12 were required to conclude that the SVR rate was> 50%.
The time needed to obtain HCV undetectability was compared between noncirrhotic and cirrhotic patients using a log rank test with a significance level of P< 0.05. The evolution of pharmacokinetic parameters (week 0–4) was compared with a paired Wilcoxon test.
The number of patients with adverse events in the non-cirrhotic group was compared with that in the non-cirrhotic group using av2test or Fisher’s exact test with a signifi-cance level of P < 0.05.
Changes in PROs with time were analysed using mixed linear and logistic regression models (for continuous and binary outcomes, respectively). Variables tested in the models included time, gender, age and cirrhosis status as potential modifiers of PROs. All tests were two-sided, with a significance levela fixed at 0.05.SAS9.4 software
(SAS Institute Inc, Cary, NC, USA) andSTATA/SE 12.1
soft-ware for Windows (Stata Corp. LP, College Station, Texas, USA) were used for the analyses.
Results
Study patients
A total of 74 patients from 30 participating centres were screened for enrolment between August 2014 and March 2015. Six patients were not enrolled for the following reasons: cirrhosis Child–Pugh B (one patient), liver biopsy refused by the patient although needed for cirrhosis sta-tus documentation (one patient), MDRD creatinine clear-ance < 60 mL/min (two patients), haematological exploration being performed (one patient) and HIV treatment regimen including dolutegravir (one patient). Sixty-eight patients were enrolled and started the treat-ment. Demographic characteristics of these 68 patients at baseline are presented in Table 1. Among the 27 patients with cirrhosis, the median baseline albumin level was 40 g/dL, the median platelet count was 132 G/L and the median international normalized ratio was 1.1.
Efficacy
Among the 68 patients who were enrolled and treated, 65 [95.6%; 95% confidence interval (CI): 87.6–99.1%; P< 0.0001] had an SVR12 and SVR24 (Fig. 1). Despite achieving SVR12 and SVR24, three patients were regarded as having treatment failure: one noncirrhotic patient had never been exposed to HCV PIs, and so devi-ated from the inclusion criteria; one patient with cirrhosis prematurely discontinued study drugs at week 2, as
planned in the protocol, for gastrointestinal bleeding needing proton-pump inhibitor treatment, and secondar-ily started the treatment again; and nonscheduled rib-avirin was introduced at week 12 in one patient with cirrhosis for persistently detectable HCV RNA. Regarding HCV kinetics, although not significant, our data suggest a trend for more rapidly undetectable HCV viral load in noncirrhotic patients compared with patients with cirrho-sis (Fig. S1).
Safety
One of the 68 patients in the study discontinued the treat-ment prematurely, as planned in the protocol, because
of gastrointestinal bleeding needing a proton-pump inhi-bitor treatment, which is known to interact with LDV. All the patients (100%) presented at least one adverse event; most of them were mild to moderate in severity (Table 2). Eleven patients had serious adverse events, including thrombocytopaenia in one patient, considered to be drug-related by the investigator. Study investigators reported mild proteinuria, hypophosphataemia, blood bicarbonate decrease and hypokalaemia in 54.4%, 50.0%, 29.4% and 13.2% of patients, respectively. They reported blood bicarbonate decrease more frequently in patients with cir-rhosis than in noncirrhotic patients (44.4% vs. 19.5%, respectively; P= 0.03). In contrast, no change in serum creatinine clearance level (Fig. S2), blood bicarbonate,
Table 1 Demographic characteristics of the patients at baseline
Characteristic Noncirrhotic patients (n= 41) Cirrhotic patients (n= 27) All patients (n= 68)
Age (years) [mean (SD)] 52 (7) 53 (5) 52 (6)
Male [n (%)] 35 (85.4) 19 (70.4) 54 (79.4)
HCV genotype [n (%)]
1a 34 (82.9) 22 (81.5) 56 (82.4)
1b 5 (12.2) 4 (14.8) 9 (13.2)
HCV RNA (log10IU/mL) [median (IQR)] 6.2 (5.9–6.4) 6.1 (5.6–6.5) 6.2 (5.8–6.5)
HIV RNA< 50 copies/mL or < LLOQ* [n (%)] 41 (100.0) 27 (100.0) 68 (100.0) CD4 cell count (cells/lL) [median (IQR)] 657 (484–875) 537 (462–754) 629 (466–853) HIV antiretroviral regimen [n (%)]
Raltegravir+ FTC + TDF 33 (80.5) 16 (59.3) 49 (72.1)
Rilpivirine+ FTC + TDF 4 (9.8) 3 (11.1) 7 (10.3)
Efavirenz+ FTC + TDF 0 (0.0) 2 (7.4) 2 (2.9)
Other regimen 4 (9.8) 6 (22.2) 10 (14.7)
HCV treatment history [n (%)]
Previous treatment courses for HCV infection≥ 3 7 (17.1) 16 (59.3) 23 (33.8)
Previous failure on HCV PI 32 (78.0) 21 (77.8) 53 (77.9)
Previous premature discontinuation of HCV PI for intolerance 9 (22.0) 6 (22.2) 15 (22.1)
SD, standard deviation; HCV, hepatitis C virus; IQR, interquartile range; PI, protease inhibitor; TDF, tenofovir disoproxil fumarate; FTC, emtricitabine. *Two patients had HIV RNA< the lower limit of quantification (LLOQ) of 80 copies/mL at baseline.
Non-cirrhotic patients (n = 41) Cirrhotic patients (n = 27)
Fig. 1 Hepatitis C virus (HCV) RNA during treatment and sustained virological response (SVR), by cirrhosis status, in the 68 patients evaluable for virological efficacy.pOne patient was regarded as having virological failure from week 1 (W1). kOne patient was regarded as having virological failure from W4.*One patient was regarded as having virological failure from W20. ♮Missing data for one patient. EOT, end of treatment.
phosphate, potassium or urinary protein was noted in the whole population (data not shown), and no quantitative change in creatinine level, blood bicarbonate, phosphate or potassium was noted during the study duration among patients with investigator-reported renal events (Figs S3– S6). CD4 cell counts were stable throughout treatment and the follow-up phase. One patient had a confirmed HIV virological rebound post discontinuation of antiretroviral treatment at week 28. A second patient dis-played a confirmed low-level HIV RNA rebound at week 12 (73 copies/mL) with undetectability obtained after anti-HIV treatment modification.
Patient-reported outcomes
Patients showed high levels of adherence to both antiretro-viral and HCV treatments during follow-up (Table 3). The median (IQR) number of self-reported symptoms was 5 (2, 9) at week 0 and remained relatively stable during follow-up. Figure 2 presents the type of symptoms reported at the end of HCV treatment (EOT) for noncirrhotic and cirrhotic patients. In the univariable analyses, female gender and the presence of cirrhosis were significantly associated with a higher number of self-reported symptoms causing discom-fort and poorer physical quality of life. After adjustment for study visit (week 0, EOT and SVR12), the presence of cirrho-sis was independently associated with a higher number of self-reported symptoms causing discomfort during follow-up (model coefficient 1.61; 95% CI: 0.27, 2.96; P = 0.02), poorer physical HRQL (model coefficient 6.94; 95% CI: 10.81, 3.07; P< 0.001) and greater fatigue (model coef-ficient 1.14; 95% CI: 0.13, 2.14; P= 0.03). No significant change with time was observed for the different PROs anal-ysed, except for the discomfort associated with fatigue, which significantly decreased compared with week 0 both at EOT [odds ratio (OR): 0.36; 95% CI: 0.14, 0.96; P= 0.04] and 12 weeks later (OR: 0.35; 95% CI: 0.13, 0.95; P= 0.04).
Pharmacokinetics
PK parameters evaluated for LDV, SOF, GS-331007, teno-fovir and raltegravir are presented in Table 4. AUC24 values for tenofovir and raltegravir were not different in cirrhotic and noncirrhotic patients (Table S1), neither at baseline nor
Table 2 Adverse events and discontinuations
Event n (%) All patients (n= 68) Noncirrhotic patients (n= 41) Cirrhotic patients (n= 27) Discontinuation of treatment
because of adverse event
1 (1.5) 0 1 (3.7)
Death 0 0 0
Any adverse event 68 (100.0) 41 (100.0) 27 (100.0) Common adverse events*
Fatigue 18 (26.5) 6 (14.6) 12 (44.4)
Hypertension 14 (20.6) 10 (24.4) 4 (14.8)
Headache 8 (11.8) 4 (9.8) 4 (14.8)
Serious adverse events
Any 11 (16.2) 6 (14.6) 5 (18.5)
Grade 3–4 laboratory abnormality
7 (10.3) 6 (14.6) 1 (3.7)
*Listed are adverse events that were reported in at least 10% of patients. Patients could have more than one adverse event or serious adverse event.
Table 3 Distribution of patient-reported outcomes during follow-up
Week 0 Week 12 Week 24
Week 36 (a)n= 41 (b)n= 27 (a)n= 38 (b)n= 25 (a)n= 36 (b)n= 25 (b)n= 25 Adherence to treatment*
Adherence to ART (%) 70 70 65 88 81 80 78
Adherence to HCV treatment (%) 72 92 – 76
Self-reported symptoms†
Total number of symptoms reported [median (IQR)] 4 (2; 7) 7 (3; 12) 5 (3; 8) 4 (2; 7) 5 (2; 6) 5 (3; 10) 4 (1; 11) Number of symptoms causing discomfort [median (IQR)] 1 (0; 3) 2 (1; 5) 1 (0; 2) 2 (1; 5) 1 (0; 3) 1 (0; 7) 2 (0; 6) Health-related quality of life‡,§
Physical dimension (PCS score) [median (IQR)] 49 (45; 55) 39 (30; 48) 50 (43; 53) 44 (38; 50) 48 (41; 54) 41 (34; 48) 43 (40; 49) Mental dimension (MCS score) [median (IQR)] 42 (36; 51) 42 (33; 55) 46 (30; 53) 43 (35; 56) 46 (41; 56) 44 (33; 52) 50 (39; 56) Perceived fatigue¶
Global level of fatigue [median (IQR)] 3 (1; 5) 5 (2; 7) 3 (0; 5) 6 (1; 7) 3 (0; 5) 4 (2; 6) 4 (2; 5)
Fatigue perceived as discomforting (%) 35 54 28 48 30 26 21
ART, antiretroviral therapy; HCV, hepatitis C virus; IQR, interquartile range; MCS, mental component summary; PCS, physical component summary. (a) Noncirrhotic patients; (b) cirrhotic patients. Percentages are computed for complete data.
*Inserm-Agence Nationale de Recherche sur le Sida et les Hepatites Virales (ANRS) self-administered questionnaire.
†ANRS AC24 questionnaire (list of 25 symptoms) derived from the AIDS Clinical Trials Group (ACTG) Symptom Distress Module.
‡Aggregated physical component summary (PCS) and mental component summary (MCS) scores from the MOS SF-12 scale (range 0–100; higher scores
denote better health-related quality of life).
§Proportion of missing values> 25%.
A Non-cirrhotic patients B Cirrhotic patients a b c d a b c d
Fig. 2 Self-reported symptoms at the end of hepatitis C virus (HCV) treatment. (A) Noncirrhotic patients. (B) Cirrhotic patients. The symptoms are ordered according to their prevalence (self-report) at week 0 (W0). (a) List of symptoms reported by> 20% of patients at W0; (b) list of symptoms reported by 10–20% of patients at W0; (c) list of symptoms reported by 5–10% of patients at W0; (d) list of symptoms reported by < 5% of patients at W0.
at week 4. In contrast, for tenofovir, the AUC variation between baseline and week 4 was significantly higher in patients with cirrhosis than in noncirrhotic patients, with a mean (SD) difference of 3261.57 1920.47 and 1576.15 911.97 ng/mL (P = 0.03) in cirrhotic and non-cirrhotic patients, respectively. No association was found between tenofovir exposure and reporting of mild protein-uria, hypophosphataemia, blood bicarbonate decrease or hypokalaemia by the investigators.
Discussion
In this nonrandomized, double-arm, open-label phase II pilot trial, the combination of LDV and SOF was associated with high rates of SVR in participants coinfected with HCV genotype 1 and HIV, independent of the presence of cirrhosis. The participants included in this study had many
factors previously described as being associated with a poor prognosis, including male sex (79.4%), genotype 1a infection (82.4%) and cirrhosis (39.7%). All the patients had previously been exposed to triple therapy with peg-interferon/ribavirin and a PI, and 59.3% of patients with cirrhosis had previously received more than three treat-ment courses for HCV infection. Previous studies showed that LDV/SOF for 12 weeks without ribavirin provided high rates of SVR in patients with HCV genotype 1, including (1) those coinfected with HIV-1, (2) those with previous treatment failure while receiving regimens that included DAA drugs, and (3) those with cirrhosis [2,8]. In our study, 24 weeks’ duration of LDV/SOF was chosen to maximize the SVR rate in heavily pretreated patients with cirrhosis, and allowed patients to achieve high rates of SVR. Viral efficacy of 12 weeks’ duration of therapy with LDV/SOF without ribavirin in the cirrhotic patients enrolled in our study cannot be predicted. As previously shown for HCV genotype 3 [9], our data suggest that patients with cirrhosis had a slower virological response as compared with noncirrhotic patients. Several studies indi-cated that residual viraemia during highly effective inter-feron (IFN)-free combination therapy was not predictive of virological failure [9–11]. In contrast, a recent publication suggested that use of early viral kinetic analysis has the potential to individualize the duration of DAA agent ther-apy [12]. Both an integrated analysis of 513 patients and the results of the SIRIUS study showed that LDV/SOF for 24 weeks and LDV/SOF plus ribavirin for 12 weeks pro-vided similarly high SVR rates in previous nonresponders with HCV genotype 1 and compensated cirrhosis, LDV/ SOF without ribavirin for 12 weeks demonstrating lower SVR rates in these patients [13,14]. Based on these data, both American and European guidelines recommend 24 weeks of the fixed-dose combination of LDV/SOF with-out ribavirin, or alternatively 12 weeks of the same com-bination with ribavirin, in treatment-experienced patients with compensated (Child–Pugh A) cirrhosis who failed to achieve an SVR, including patients having received treat-ment with pegylated IFN-a, ribavirin and either telaprevir or boceprevir [15,16]. In HIV-coinfected patients, the ION-4 study showed that LDV/SOF for 12 weeks showed high SVR rates, including in treatment-experienced subjects and those with compensated cirrhosis. Studies from real life investigating all-oral DAA regimens in people coin-fected with HIV/HCV, in particular results from the prospective ANRS CO-13-HEPAVIH cohort study [17], showed no difference between 12 and 24 weeks’ DAA treatment durations or between regimens with and without ribavirin. However, in this observational study, the alloca-tion of different regimens was not based on a predefined protocol but depended on physician choice. Consequently,
Table 4 Pharmacokinetics (PK) of sofosbuvir (SOF), GS-331007, ledi-pasvir (LDV), tenofovir and raltegravir in a subset of patients. (a) SOF, GS-331007 and LDV pharmacokinetic parameters at week 4; (b) exposure to tenofovir and raltegravir at baseline and week 4
(a) PK parameter Mean (% CV) (n= 20*) SOF AUC (ng h/mL) 2170 (61.3) Cmax(ng/mL) 1500 (49.5) GS-331007 AUC (ng h/mL) 14 900 (37.4) Cmax(ng/mL) 1020 (30.0) LDV AUC (ng h/mL) 6000 (43.8) Cmax(ng/mL) 332 (41.5) Ctau(ng/mL) 190 (48.4) (b)
Variable n AUC day 0 AUC week 4 P (RS)
Tenofovir AUC (ng h/mL) (mean SD) 18 2135.2 973.9 4366.7 2116 < 0.0001 Tenofovir concentration (ng/mL) (min, median, max) 945.1, 1869.1, 4368.5 1167.6, 3798.4, 9687 Raltegravir AUC (ng h/mL) (mean SD) 18 12 132.5 8504 10 299.7 5846 0.1815 Raltegravir concentration (ng/mL) (min, median, max) 956.6, 11 959.7, 27 374.5 2493, 9987.2, 21 401.5
% CV, coefficient of variablility; AUC, area under the plasma concentra-tion–time curve during the dosing interval; Cmax, maximum
concentra-tion; RS, Wilcoxon signed rank test: Ctau: concentration at the end of
the dosing interval.
*One patient was excluded from PK analysis based upon the subject’s dosing record, which showed that the PK substudy dose of LDV/SOF was administered approximately 8 h after the previous dose of LDV/SOF.
comparison regarding treatment duration or the use of rib-avirin could not be performed. Our results provide further data in HIV-coinfected patients and support the adminis-tration of LDV/SOF for 24 weeks in treatment-experienced patients with compensated cirrhosis.
In this study, most adverse events associated with combined LDV/SOF were mild (grade 1–2) and clinically managed. There were no deaths or medication discontinu-ations attributable to the study drug. Previous studies showed that, compared with HCV-monoinfected patients, HIV/HCV-coinfected patients from the PHOTON 1 and 2 studies had more impairment of PROs prior to the initia-tion of treatment [18]. In addiinitia-tion, compensated cirrhosis negatively impact PROs in patients with chronic hepatitis C [19]. In our study, a higher number of self-reported symptoms were also observed, and, as previously reported in HIV/HCV-coinfected patients [20], the individuals included in the SOFTRIH trial showed significant improvement for discomfort associated with fatigue, which significantly decreased during treatment and after treatment cessation. This may account for the high level of adherence to HCV treatment observed in our study.
LDV/SOF has limited potential for clinically significant drug interactions with most antiretroviral agents [21,22]. However, results from phase 1 evaluations showed that concomitant administration of LDV/SOF and tenofovir disoproxil fumarate as a component of an antiretroviral regimen resulted in a modest increase (approximately 40%) in the exposure to tenofovir, as compared with an antiretroviral regimen alone [21,22]. In our study, LDV, SOF and GS-331007 exposures were generally within the ranges (minimum to maximum) of exposures observed in the populations of LDV/SOF phase 2/3 studies (Gilead, per-sonal communication). In contrast, in this trial, administra-tion of emtricitabine plus tenofovir disoproxil fumarate with LDV/SOF in patients coinfected with HCV and HIV-1 resulted in a 50% higher tenofovir exposure than previ-ously reported with antiretroviral regimens alone [21], especially in patients with cirrhosis. In addition, the over-exposure to tenofovir was slightly higher than that reported in the LDV/SOF package insert [21]. Our study showed no significant change in creatinine clearance, nor any relationship between tenofovir exposure and renal proximal tubulopathy reported signs. It is not unlikely that more systematic intensive renal monitoring might have revealed treatment-emergent proximal tubule dysfunction. In the ION-4 study, 5.67% of patients had a creatinine clearance decrease > 25% and 34.0% had an incident increase in urine proteinuria from negative/trace to ≥ 1 during LDV/SOF treatment. In these patients, baseline levels of retinol-binding protein-4, a urinary biomarker of proximal tubule dysfunction, were higher for patients with
incident proteinuria (P< 0.001) and increased from base-line to EOT [23]. There was a positive correlation with teno-fovir exposure, and the authors proposed dosing of retinol-binding protein-4 to identify patients at risk of tubular tox-icity who have increased exposures to tenofovir.
Limitations of this study include its noncomparative open-label design and the restriction of permitted antiretroviral regimens. In addition, use of ritonavir-boosted HIV-1 PIs or cobicistat-ritonavir-boosted elvitegravir with tenofovir disoproxil fumarate was not permitted in our study because of the potential for additional increases in tenofovir exposure. The potential effects of these anti-retroviral treatments combined with LDV/SOF therapy on renal function should be addressed in future studies.
In conclusion, we found that a fixed-dose combination of LDV/SOF provided high rates of SVR in subjects with HCV genotype 1 who were coinfected with HIV-1 and with previ-ous treatment failure on or intolerance to triple therapy with peg-interferon/ribavirin and a PI. While 12 weeks’ treat-ment duration is highly effective in noncirrhotic patients, 24 weeks’ duration of LDV/SOF may be better in heavily pretreated cirrhotic patients to achieve the highest SVR rates, as recommended in recent guidelines [15,16].
Acknowledgements
Financial support was provided by the Agence Nationale de Recherche sur le Sida et les Hepatites Virales (ANRS), with the participation of Gilead Sciences.
Dr Hugues Aumaitre, Dr Laurence Gerard, Pr Michel Dupon, Pr. Laurent Alric, Dr Claudine Duvivier, Dr Elina Teicher, Dr Thierry Allegre, Dr Alain Lafeuillade, Dr Pierre de Truchis, Dr Vincent Jeantils, Dr Julie Chas, Dr Dominique Batisse, Pr Dominique Salmon-Ceron, Dr David Zucman, Dr Emmanuel Mortier, Dr Stephanie Dominguez, Dr Marc-Antoine Valantin, Dr Anne Simon, Pr. Pierre-Marie Girard, Pr. Jean-Michel Molina, Pr. Philippe Morlat, Pr. Didier Neau, Dr Djamila Makhloufi, Dr Isabelle Poizot-Martin, Pr. Yazdan Yazdanpanah, Pr. Jacques Reynes, Pr. Francßois Raffi, Dr Philippe Perre, Dr Alissa Naqvi, Pr. Eric Rosenthal, Pr. Christian Michelet, Pr. Lionel Piroth, Dr Antoine Cheret, Pr. Thierry May, Dr Laurent Cotte, Pr. Jacques Moreau, Pr. Stanislas Pol, Pr. Victor de Ledinghen, Dr Marc Bour-liere, Pr. Georges-Philippe Pageaux, Dr Sophie Metivier, Pr. Vincent Leroy, Pr. Ghassan Riachi, Pr. Jean-Charles Duclos-Vallee, Pr. Isabelle Rosa. We also acknowledge the investigators of the GERMIVIC Study Group (Groupe d’Etude et de Recherche en Medecine Interne et Maladies Infectieuses) for their continuing effort in enrolling patients and the assistance provided by the clinical research associ-ates and data-manager: Mustapha Ahmim, Julie Raimon, Regine Thierry and Amelie Martin.
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Supporting Information
Additional Supporting Information may be found in the online version of this article at the publisher’s web-site: Appendix S1. List of the ANRS HC31 SOFTRIH Study group.
Table S1. Exposure to tenofovir and raltegravir in cirrhotic and in non-cirrhotic patients.
Fig. S1. HCV undetectability time curves according to the cirrhosis status.
Fig. S2. Creatinine clearance level during and after treat-ment, by cirrhosis status.
Fig. S3. Evolution of serum creatinine level (lmol/L) in patients with reported renal events (n= 61).
Fig. S4. Evolution of serum bicarbonate level (mmol/L) in patients with reported renal events (n= 61).
Fig. S5. Evolution of serum phosphate level (mmol/L) in patients with reported renal events (n= 61).
Fig. S6. Evolution of serum potassium level (mmol/L) in patients with reported renal events (n= 61).
