- Email: [email protected]
Sofosbuvir and ribavirin for genotype 2 HCV infected patients with cirrhosis: A real life experience
Accepted Manuscript Sofosbuvir and Ribavirin for genotype 2 HCV infected patients with cirrhosis: a real life experience Alessandra Mangia, Simone Susser, Valeria Piazzolla, Ernesto Agostinacchio, Giulio De Stefano, Vincenzo Palmieri, Giancarlo Spinzi, Immacolata Carraturo, Domenico Potenza, Ruggero Losappio, Andrea Arleo, Maria Miscio, Rosanna Santoro, Christoph Sarrazin, Massimiliano Copetti PII: DOI: Reference:
S0168-8278(16)30707-3 http://dx.doi.org/10.1016/j.jhep.2016.12.002 JHEPAT 6353
To appear in:
Journal of Hepatology
Received Date: Revised Date: Accepted Date:
2 August 2016 30 November 2016 4 December 2016
Please cite this article as: Mangia, A., Susser, S., Piazzolla, V., Agostinacchio, E., De Stefano, G., Palmieri, V., Spinzi, G., Carraturo, I., Potenza, D., Losappio, R., Arleo, A., Miscio, M., Santoro, R., Sarrazin, C., Copetti, M., Sofosbuvir and Ribavirin for genotype 2 HCV infected patients with cirrhosis: a real life experience, Journal of Hepatology (2016), doi: http://dx.doi.org/10.1016/j.jhep.2016.12.002
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Sofosbuvir and Ribavirin for genotype 2 HCV infected patients with cirrhosis: a real life experience
Alessandra Mangia1, Simone Susser2,Valeria Piazzolla1, Ernesto Agostinacchio3, Giulio De Stefano4, Vincenzo Palmieri5, Giancarlo Spinzi6, Immacolata Carraturo 7, Domenico Potenza8, Ruggero Losappio9, Andrea Arleo 1, Maria Miscio1, Rosanna Santoro1, Christoph Sarrazin10, Massimiliano Copetti11
1
Liver Unit, IRCCS “Casa Sollievo della Sofferenza” San Giovanni Rotondo, Italy
2
Johann Wolfgang Goethe-University Medical Center, Frankfurt am Main, Germany
3
Internal Medicine Clinica “Mater Dei” Bari, Italy
4
Infectious Diseases Unit, Presidio ospedaliero Madonna delle Grazie, Matera, Italy
5
Medical Clinic “A. Murri”, Policlinico di Bari, Italy
6
Gastroenterology Unit, Ospedale Valduce, Como, Italy
7
Infectious Diseases Unit, Ospedale “Vito Fazzi” Lecce, Italy
8
Interventional ultrasound Unit, Ospedale “Perrino” Brindisi, Italy
9
Infectious Diseases Unit, Presidio Opedaliero Bisceglie
10
11
Medizinische Klinik 1, Goethe University Hospital, Frankfurt, Germany
Biostatic Unit, IRCCS “Casa Sollievo della Sofferenza” San Giovanni Rotondo, Italy
Corresponding Author: Alessandra Mangia Liver Unit IRCCS “Casa Sollievo della Sofferenza” 71013 San Giovanni Rotondo, ITALY Phone: 0039-882-416375 Fax: 0039-882-416270 Email: [email protected]
Electronic word count: words.
figures and tables.
•
Keywords
•
A HCV
•
B Genotype 2
•
C Sofosbuvir
•
D Ribavirin
•
E Cirrhosis
Abbreviations Direct Antiviral Agents (DAA), genotype (GT), sofosbuvir (SOF), ribavirin (RBV), treatment naïve (TN), treatment experienced (TE), ABBOTT RealTime (ART), adverse events (AE), hemoglobin (Hb), confidence intervals (CIs), Child Turcotte Pugh (CTP), intention to treat (ITT), per protocol analysis (PP).
Introduction
HCV genotype still represents the most important viral factor for selection of appropriate Direct Antiviral Agents (DAA) regimen and duration in chronic HCV infection. In the era of Interferon-based therapies, genotype 2 (GT2) was considered easy to treat. Indeed, the first interferon free treatment, based on the combination of Sofosbuvir (SOF) 400 mg + Ribavirin (RBV) 1000-1200 mg daily, was investigated in patients infected with this genotype and until very recently [1] has represented the standard of care [2]. The newly approved combination of SOF and Velpatasvir (VEL) [2,3], has been recommended as the new standard, but is not yet available in all the European countries [4,5]. Real life experience attained with SOF and weight-based RBV combination will inform clinicians and patients about the limitations of the past regimens and will help to better understand the advantages of the new ones. In phase III trials, the combination of SOF and weight-based RBV was associated with 90% rates of SVR [6,7]. More recently, real life studies suggested that SVR might be lower. It was observed that the higher the proportion of cirrhotic patients included into the cohorts, the lower the SVR rate [8,9]. However, it should be noticed that, according to evidence generated by phase III studies [7], international guidelines advise to extend the duration of treatment - longer than 20 weeks - in patients with cirrhosis [1,10]. Whether the lower SVR registered in observational cohorts is related to the higher proportion of patients with cirrhosis, or whether it can be attributed to the duration of 12 weeks adopted in real life despite the longer 12-20 weeks duration recommended by EASL for cirrhotic patients [1], can be object of debate. Indeed, in a study based on the German cohort [8] and in the Target study [9] the vast majority of patients received 12 weeks of treatment. Moreover, in the German cohort, only 75% were treated inside guidelines with regard to RBV dosages also [9]. An alternative explanation for the lower SVR registered in real life has been considered: the presence of a recombinant HCV genotype 2k/1b strain, not recognized by the commonly used
genotyping assay, Innolipa, unable to amplify both the 5’and 3’ regions of the HCV genome, and associated with suboptimal response to SOF and RBV. This chimera virus, firstly described in Georgia [11], has been investigated in countries as Germany and Israel, destination of migratory flows from the former Soviet Union in the mid 1990’s. In these countries the chimera virus has been discovered at a prevalence of 13% and 25%, respectively [12]. Italy was not a priority country for this migratory phenomenon and, as shown in a collaborative study, none of the 52 patients with GT2 from our center carried this chimera virus[12]. Based on 9 prior treatment failure patients with cirrhosis and previous failure history in the Fusion trial, in the registration studies in monoinfected patients the maximum duration of SOF and RBV treatment for GT2 has been 16 weeks.. Extending the treatment of GT2 patients with cirrhosis up to 20 weeks could associated with an increase in the response rate. We evaluated this hypothesis and the role of the 2k/1b variant as a possible explanation for virological failures in consecutively observed GT2 infected patients.
The
candidates to treatment have been selected according to the Italian reimbursement criteria that prioritise patients with advanced fibrosis or cirrhosis [5]. A course of 12 weeks was adopted in the presence of bridging fibrosis, while 16 or 20 weeks were prescribed when cirrhosis was diagnosed. Our aim is to identify a balance between treatment duration and maximum SVR in order to inform clinicians and patients from countries where the combination of SOF and RBV is available, whereas the very recently approved combination of SOF and VEL is not.
Patients and Methods
Study design
This is an open label prospective observational study on HCV GT2 patients with advanced liver fibrosis or cirrhosis treated with SOF and RBV combination therapy at 6 different centers in Italy. The first patient started treatment on January 30, 2015. All patients completed post-treatment
week 12 evaluation by the end of May 2016. Patients were between 18 and 87 years and had severe documented fibrosis or cirrhosis. Patients with active HBV infection were considered not eligible, as well as patients with history of a previous DAA course. Patients with decompensated liver diseases were not excluded. Key exclusion criteria, in accordance with the Italian Medicine Agency (AIFA), were: active HCC or presence of systemic diseases with short life expectancy. Untreated patients and patients who had failed a previous course of Interferon and RBV received SOF 400 mg once a day, orally, in combination with RBV 1000 or 1200 mg daily, based on the body weight ≤ or > 75 Kg for 12 weeks, if cirrhosis was absent, and for 16 or 20 weeks, if cirrhosis was present. As this was not a randomised trial, the duration of 16 or 20 weeks was selected by physicians in accordance with local guidelines and patients characteristics. Patients with cirrhosis were not treated for less than 16 weeks. Patients were assessed for biochemistry, hematology and virology at baseline, every 4 weeks on treatment and 4 and 12 weeks after the end of treatment.
Assessment of disease severity
The presence of cirrhosis or advanced fibrosis (F3/F4) was defined by Fibroscan and/or liver biopsy with the only exception of patients with clinical evidence of cirrhosis complications. Liver specimens were obtained by liver biopsy only in 39 patients. Cirrhosis was diagnosed at histology according to Metavir score=4. Transient elastography threshold to define cirrhosis was ≥12.5 KPa, to define bridging fibrosis 10.1 KPa.
Laboratory assessments
Screening assessment included serum HCV RNA levels and IL28B genotyping in addition to standard laboratory clinical tests. HCV RNA levels were measured using ABBOTT RealTime
(ART) assay with a LLQ of 12 IU/ml and a LLOD of 10-12 IU/ml. HCV genotype and subtype were determined by using Innolipa 2.0 assay. IL28B was determined by PCR amplification and sequencing of the rs12979860 single-nucleotide polymorphism [13]. On treatment assessment included standard laboratory testing, serum HCV RNA, vital signs and physical examination. The type of previous response to PegIFN and Ribavirin treatment was defined by standard criteria [14].
Sequencing for recombinant genotype 2k/1b strain
Initial genotyping of the samples was performed using the Innolipa 2.0 assay, which is limited in identifying recombinant HCV strains. In case of 2k/1b chimeras, genotyping with the hybridization assay leads to a genotype 2 call. Thus, serum samples of patients who experienced a relapse, matched by age and disease severity with samples of patients with SVR, were re-genotyped and checked for incidence of the recombinant genotype 2k/1b by a Sanger sequencing approach, as gold-standard for genotype calling. The regions encoding HCV core, the NS2/NS3 junction, and the NS3 protease gene were amplified by nested polymerase chain reaction, and population-based sequenced. To confirm chimeric strains and to exclude dual infection, the recombination site, which is located at the NS2/NS3 junction, was included in the investigation. Analysis was performed using BLASTN interface [15]. Results of genotyping by sequencing were compared to the original. Sequencing and data analysis were done at the Biomedical Research Laboratory at the University Hospital Frankfurt/Main, Germany.
Efficacy end points
The study evaluated SVR rates in patients with GT2 and advanced fibrosis or cirrhosis in real life at post-treatment week 12. Results were compared with those reported in patients with cirrhosis and previous history of treatment failure, included in the registration studies [6,7].
Safety assessment
Data on safety issues were collected during the treatment period and during 12 weeks of follow up, including laboratory assessments, physical examination and reporting of adverse events (AE). Anemia was defined as an AE as follows: mild, Hemoglobin (Hb) values between 10.0 and 12.5 g/dl, moderate Hb between 8.5 and 10 g/dl, and severe Hb below 8.5 g/dl. Anemia developing during treatment was managed by 200 mg RBV dose reduction. Use of blood transfusion and erythropoietin were allowed.
Statistical methods
Demographic and clinical data were reported as mean and standard deviation on frequencies and percentages for continuous and categorical variables, respectively. Group comparisons were performed using Mann-Whitney U-test and Person chi-square or Fisher exact test for continuous and categorical variables, respectively. Point estimates of rates of SVR12 along their exact 95% Confidence Intervals (CIs) were estimated. Statistical analyses were performed by using SAS version 9.3 (SAS Institute Inc., Cary, NC, USA).
Results
Patients’ characteristics
In total, 352 patients with bridging fibrosis or cirrhosis infected with GT2 and candidate for treatment in the participating centers were evaluated. Since 15% were ribavirin intolerant and are not included in this analysis, 299 were offered treatment, 6 of them were excluded due to active HBV infection and 2 patients died before starting treatment. Therefore, 291 patients were treated and had a complete follow up by the end of May 2016. Demographic and baseline characteristics of the ITT population are shown in Table 1. Among 291 patients, 134 (46.1%) were male, 123 (42.3%) were classified as F3, and 168 (57.7%) as F4. The median age was 68 years (18-87), median HCV RNA 1,834,598 IU/ml (23-31,827,592). In total, 163 (56.0%) patients were naïve. In 145 of 168 patients with cirrhosis who had liver fibrosis assessed by means of Transient elastography (TE), the minimum value was 12.5 KPa and the maximum 75 KPa. Among cirrhotic patients, median MELD score was 7 (6-19). Of 168 patient with cirrhosis, 149 had a Child Turcotte Pugh (CTP) score A 5-6 (89.9%) the remaining had CTP score B 7-9. 50 patients had platelets <100,000μl and 62 had albumin levels <3,5 g/dl. Patients with cirrhosis received either 16 weeks of treatment according to phase III studies’ results or 20 weeks of treatment in accordance with European guidelines. IL28B genotyping showed non CC genotype in 66% of the 143 cases who were tested for. Diabetes was observed in 15% of patients, the majority of whom were also overweight or obese (Fig.1). Table 2 shows baseline characteristics of patients with cirrhosis by treatment duration.
Although mean platelets count was comparable between the two treatment groups a higher mean stiffness value was found among patients receiving 20 weeks of treatment, suggesting that physicians assigned a longer treatment course to patients with higher TE results. All the other characteristics, including Child Pugh score were comparable between 16 and 20 weeks of treatment duration.
Virologic response
A total of 278 patients (95,53%, 95%CI=92,48-97,60) achieved SVR12. At intention to treat (ITT) population analysis, SVR12 was achieved by 99,15% (95%CI=97,50-100,00) of patients with advanced fibrosis and by 93,06% (95%CI=88,20-93,36) of patients with cirrhosis. Overall, 97,55% (95%CI=93,84-99,33) treatment naïve achieved SVR12; response rates for treatment experienced patients with a previous non response was 91,18% (95%CI=83,91-95,86), for previous relapsers was 100% (95%CI=86,77-100,00). The reason for treatment failure was relapse in all but 2 patients who discontinued treatment due to esophageal variceal bleeding and cerebral hemorrhage respectively, and were considered non responders. For both of them, treatment duration of 20 weeks was planned. After the virologic relapse, their baseline samples were sequenced. Of the 5 non responders, treated for 20 weeks, 2 were found associated with genotype non 2 (one was 1b and another was 4). All the other patients who experienced a relapse were confirmed to be GT2 infected. To exclude reinfection, serum samples of the patients who experienced a relapse collected at week 4 or later during the follow up were sequenced confirming GT2 infection.
SVR by severity of liver disease and treatment duration
Among cirrhotic patients, subgroup analysis by treatment duration of 16 or 20 weeks showed SVR12 of 94,51% (95%CI=87,64-98,19) after 16 weeks and of 91.46% (95%CI=83,2096,50) after 20 weeks (p=0.31).
Characteristics of patients with virologic failure and analysis of treatment completers with post-treatment week12 HCV RNA results
Among 168 cirrhotic patients, 7 out of 82 subjects treated for 20 weeks and 5 of 91 treated for 16 weeks had a failure. In detail, 5/7 patients experienced a relapse and 2 were considered non responders at ITT analysis due to an early discontinuation. Reasons to discontinue treatment were esophageal variceal bleeding after 2 weeks from the start of treatment and cerebral hemorrhage at week 19 of treatment. Three out of 5 patients had a relapse after a 16 week course. Among 5 patients with relapse treated for 20 weeks, one in CTP B class in the waiting list for OLT underwent sequencing of a basal stored sample after the virus reappearance and was discovered to be GT4 infected, while a second was found GT1 instead of GT2. Of the remaining 3, one was a patient with renal failure after kidney transplant who had to reduce RBV 4 weeks after the start of treatment, and 2 were patients with liver cirrhosis in CPT class A. Among 5 patients with cirrhosis who received 16 weeks of treatment and experienced a relapse, 2 were patients with CTP class A and one was a patient with decompensated cirrhosis. Of 123 non cirrhotic patients, a patient who did not achieve SVR was a young patient without apparent reasons not to respond. According with these evidences, the analysis of treatment completers with post-treatment week 12 HCV RNA available results was performed and showed SVR12 of 94,51% (95%CI=87,6498,19) and 94,94% (95%CI=87,54-98,60), after 16 and 20 weeks, respectively (p=1.00 by fisher exact test). Therefore, keeping in mind that the two treatment duration groups are not matched and
that this study was not powered to compare efficacy between 16 or 20 weeks duration, it is difficult to imagine that rates of response higher than those above reported can be achieved in real life with a longer course of therapy.
Predictors of SVR
Multiple parameters were tested for possible association with SVR12 in patients with cirrhosis. They included baseline KPa values, baseline platelets, baseline MELD, presence of ascites, presence of esophageal varices, history of HCC, baseline viremia levels, baseline AST and ALT values, baseline albumin values, co-morbidities as diabetes and obesity. By univariate analysis, predictive of lower SVR12 rates were low PLT count, presence of ascites, presence of esophageal varices and higher baseline CTP score.
Multivariate analysis
Multivariate analysis included treatment history, ascites, esophageal varices, BMI, treatment duration, PLT count and presence of ascites. Among them, the following independent predictors of lower SVR rates were identified: low PLT count (OR 7,2; 95% CI 1,67-31,25; p value =0.0022) and esophageal varices (OR 0,1; 95% CI 0,01-0,72; p=0.0079).
Safety
The most common adverse events (AEs), occurring in at least 20% of subjects, were fatigue, anemia, nausea, insomnia and headache (Table 3). As previously described, the most common
serious AEs was by far anemia [7]. Safety profile was consistent with RBV related known side effects, namely anemia and rash (Table 3). Anemia was defined by Hb levels <12.5 g/dl in both men and women (Table 3). Anemia was mild in 12.5% of cases overall and moderate in 3.6% of cases. Hb levels <8.5 g/dl were observed in 2.6% of our patients. Nevertheless, no patients discontinued treatment due to anemia. All the patients with severe anemia received blood transfusion and were managed by step by step 200 mg RBV dose reductions. Percentage of patients developing anemia among cirrhotic patients who received 16 or 20 weeks of treatment is reported in Table 2. Median baseline Hb levels were 13.51± 1.54. When compared to median end of treatment levels of 12.47±1.68 a percentage difference decline of 8.31±10.61 was observed. Severe anemia was observed only in female patients with cirrhosis who completed the assigned treatment duration and it developed right after the start of treatment (Fig.2). RBV dose reduction was requested in 23 patients, overall. No difference in SVR was observed between patients receiving full or reduced doses of RBV. None of the discontinuations due to AEs were deemed related to SOF.
Discussion
In this study, the combination of SOF and weight-based RBV, representing the standard of care for treatment of patients with GT2 infection until very recently, was associated with SVR12 rates in patients with advanced fibrosis and cirrhosis higher than those reported either in the registration studies [1, 2, 6,7], or in other real life studies [8,9]. Overall, only 13 patients (4,47%) experienced a failure. Of note, our patients with cirrhosis received SOF and RBV combination treatment for a period longer than 12 weeks. Indeed, 91 of 168 patients with cirrhosis received 16 weeks, while 82 received 20 weeks of therapy. Among cirrhotic patients, SVR12 was 93,06% at ITT and 94,70% at the analysis of treatment completers with available post treatment results at week 12. GT2 is the third most common genotype in the world, although it represents about 10-15% of the HCV infected population in Europe and US [16, 17]. SOF/VEL as single pill, fixed dose combination represents the new standard of treatment and will ensure extremely high rates of SVR without the addition of RBV [3]. This new treatment is not yet available in some European countries including Switzerland, Sweden and Italy [4,5,18], and the findings of this study show that
individualising SOF and weight-based RBV duration in GT2 patients with cirrhosis in case of lack of SOF/VEL access, may improve SVR. SVR12 of 98,8% reported in 161 treatment naïve patients with cirrhosis after 16 or 20 weeks of treatment in this study were higher than the 91% reported in phase III FISSION study [6], where only 11 cirrhotic patients were included. Moreover, in our study 90,59% of 77 previous non responder subjects with cirrhosis achieved SVR after 16 or 20 weeks of therapy. The corresponding rates, in 10 cirrhotic patients enrolled to 12 weeks, and in 9 enrolled to 16 weeks in the Fusion study were 60% and 78% [7]. Racial difference might play a role in studies performed in US, equally it is possible that a higher prevalence of female patients, included in our study as a result of ribavirin intolerance in the era of IFN-based treatments, led to higher SVR rates in our study. The different genetic background of patients should also be taken into account when examining the results of a phase III study on GT2 treatment performed in Japan. In that study, SVR12 was 89% after 12 weeks of treatment [19]. However, of 14 GT2 patients with cirrhosis, 94% attained SVR12. Although Asian origin prevents a direct comparison with European patients, these results confirm that SOF/RBV is associated with SVR12 higher than 90% in GT2, even in the presence of cirrhosis. In the Valence study, performed in Europe but focusing on GT3 rather than on GT2, only 11 cirrhotic GT2 patients were enrolled. SVR were 100% for 2/2 naïve and 77.8% for 9 treatment experienced after 12 weeks [20]. While phase III trials included small numbers of patients with cirrhosis, real life cohorts as Target, TRIO and Valor-HCV focused on patients with more advanced liver disease [9,21,22]. In an extremely large cohort of VA including 2131 GT2 who received 12 weeks of therapy, a lower rate of SVR was observed in cirrhotic patients as compared to non cirrhotic (89.1% vs 77.3%) [23]. In the real life Target cohort, of the 86 patients with cirrhosis included, 62 received 12 weeks and 24 received 16 weeks of treatment, they achieved 79% and 83% SVR rates, respectively. However, after 12 weeks 71.9% of naïve and 86.7% of treatment experienced patients with cirrhosis attained SVR; while after 16 weeks 100% of naïve and 76.5% of treatment experienced cleared the virus.
These findings suggest that for patients with a prior treatment experience and cirrhosis an extended duration might be of benefit [9]. Viral sequencing performed both, in stored basal samples after the virologic failure and in samples collected during follow up showed the absence of a chimera 2k/1b virus and confirmed the absence of re-infection. The 2k/1b recombinant strain recently identified in patients from East Europe [11] and shown associated with poor response rates to SOF/RBV combination in patients with GT2 infection from German and Israeli [12] was not found among our GT2 infected patients. These results highlight the impact of this genetic variation as a local phenomenon rather than a general explanation for lower SVR rates, in patients with GT2 infection. Moreover, our data suggest that genotyping at baseline is of utmost importance in patients with GT2 treated with SOF and RBV due to the high risk to perform suboptimal treatments in patients uncorrectely genotyped as GT2. The use of a pangenotypic regimen as that based on SOF/VEL will overcome this issue in the future. A merit of this study is the inclusion of patients with very advanced liver disease. About 20% of our patients showed pre-treatment features similar to those reported in the CUPIC cohort(PLT <100,000 /µl and albumin levels <3.5 g/dl) [24]. Low PLT count represented the second independent predictor of relapse. By contrast, diabetes or obesity did not show impact on SVR12. It could be debated whether the higher SVR rate observed in our study can be attributed to the extended duration in a subgroup of patients with features of portal hypertension, including 11% in CTP class B. Although, as shown by the analysis of treatment completers, SVR12 rates after 16 or 20 weeks duration were similar, we acknowledge that the study is not powered for these subgroup analyses. We calculated that given the extremely high rates of SVR attainable with this regimen, the comparison of 16 with 20 weeks of treatment would have required the enrolment of not less than 754 subjects per arm, to demonstrate a statistically significant difference with a power of 80% and an alpha error of 5%. However, given our high rates of response after 20 weeks, it is highly conceivable that 24 weeks may represent an overtreatment.
Finally, we should consider that the longer the treatment the higher the risk of anemia. It is important to notice that the side effect profile of the standard combination in this study was overall favourable. Although RBV related anemia resulted manageable by dose reductions a higher number of female patients with cirrhosis developed anemia in particular after longer treatment courses. Nevertheless, SVR12 rates were not influenced by RBV dose reduction. Of course, the option based on SOF/VEL, as ribavirin free regimen [3] will be the optimal solution to sparing anemia and all the RBV related side effects. This is not a randomized controlled study. However, all GT2 patients candidate to treatment were prospectively and consecutively enrolled at each participating center. It should also be kept in mind that in the few cases of patients who failed to achieve SVR, successful re-treatment strategies based on NS5 inhibitors can now be adopted [25]. Hence, the option of re-treating a few failures with SOF/VEL may probably represent an interesting cost effective alternative in some countries. In conclusion, the present study shows in GT2 patients with cirrhosis, either naïve or treatment experienced, SVR12 higher than 95% after SOF and weight-based RBV for 16 or 20 weeks. In a real life population of GT2 patients with cirrhosis, when access to SOF/VEL is not possible, a treatment of individualised duration with SOF/RBV is associated with comparable rates of responses after 16 or 20 treatment weeks and good tolerability, although a slightly increase of anemia can be observed after longer treatment. Correct genotyping at baseline is mandatory.
Table 3.0 Overall adverse events, among patients with cirrhosis and by treatment duration
SOF+RBV
SOF+RBV
SOF+RBV
SOF+RBV
Total
Cirrhotic
16 weeks
20 weeks
(N=291)
(N=168)
(N=91)
(N=82)
Fatigue
177 (61,0%)
106 (63,6%)
49 (53,8%)
57 (69,5%)
Headache
69 (23,7%)
58 (34,5%)
34 (37,3%)
24 (29,2%)
Nausea
54 (18,5%)
49 (28,5%)
25 (27,4%)
24 (29,2%)
Insomnia
51 (17,5%)
31 (18,4%)
14 (15,3%)
17 (20,7%)
Rash
6 (2,06%)
4 (2,3%)
3 (3,2%)
1 (1,2%)
Hemoglobin <12.5 g/dl
24/192
11 (6,5%)
5 (5,4%)
6 (7,3%)
(12,5%)
Hemoglobin <10.5 g/dl
7/192 (3,6%)
7 (4,1%)
3 (3,2%)
4 (4,8%)
<8.5 g/dl
5/192 (2,6%)
5 (2,9%)
2 (2,1%)
3 (3,6%)
Neutrophils <750/mm3
0/291
0/186
0/91
0/82
Platelets <50,000/mm3
0/291
0/168
0/91
0/82
Hemoglobin
Table 1. Overall demographic characteristics of patients and by treatment duration
Patients with Patients by treatment duration Characteristics
advanced fibrosis or cirrhosis SOF-RBV for
SOF-RBV for
SOF-RBV for
12-20 weeks
12 weeks
16-20 weeks
(N=291) (%)
(N=123) (%)
(N=168) (%)
Mean Age, years
68,0
66,0
69,7
Range
18-87
18-82
36.9-87
Male sex, n (%)
134 (46,0)
47 (38,2)
63 (55,0)
BMI
26,50±3,98
25,88±4,51
27,00±3,48
Liver stiffness, Mean KPa
15,27±9,32
9,71±2,09
18,78±9,30
Cirrhosis, n (%)
168 (57.7)
0
168
Mean HCV RNA, log10 2,869212±3,669,940 2,994,498±3,814,380
2,792,051±3,584,309
IU/ml±SD Mean ALT levels
80,09±80.49
60,58±61.15
95,19±90.08
Mean AST levels
67,57±63,66
46,18±40,07
83,72±73,09
50 (17,1)
n.a.
50 (29,7)
CC
61
16
43
CT
79
38
41
TT
33
23
10
CTP A
149
3
146
CTP B
14
0
14
Na
5
0
5
MELD score
8,28±2,38
n.a.
8,28±2,38
Albumin <3.5 g/dl, n (%)
62 (21,3)
n.a.
62 (36,9)
PLT <100,000 u/l, n (%)
HCV treatment experience, n (%) Naïve
163 (56,01)
81
81
Previously treated
130
42
86
Prior non response
26
2
24
Prior relapse
101
40
61
167,58±82,20
212,26±86,96
136,33±61,74
Platelets count
Table 2. Characteristics of patients with cirrhosis by treatment duration
Characteristics
SOF-RBV for
SOF-RBV for
16 weeks
20 weeks
(N=90) (%)
(N=82) (%)
70
69
37-86
36.9-87
47 (52,2)
43 (52,44)
BMI
27,12±3.73
26,58±3.23
Liver stiffness, Mean
15,06±5.54*
22,73±12.16
Mean Age, years Range Male sex, n (%)
KPa
Mean
HCV
RNA, 2,623,171±3,825,5 2,887,072,051±3,1
log10 IU/ml±SD
25
98,588
Mean ALT levels
96,31±86,32
92,31±91,19
Mean AST levels
83,87±72,90
83,10±72,05
26 (29,5)
23 (29,5)
CC
20
25
CT
13
29
PLT <100,000 u/l, n (%)
TT
3
8
CTP A
77
69
CTP B
7
9
Na
6
4
MELD score
7,95±2,05
8,59±2,58
Albumin <3.5 g/dl, n
3,90±0,71
3,73±0,86
Naïve
41
45
Previously treated
31
31
140,76±60,90
132,86±62,80
(%)
HCV
treatment
experience, n (%)
Platelets count
* P value <0,0001
References
1) European Association for the study of the liver. EASL Recommendations on treatment of Hepatitis C 2015. J Hepatol 2015 Jul;63(1):199-236. doi: 10.1016/j.jhep.2015.03.025. 2) European Association for the study of the liver EASL Recommendations on treatment of hepatitis C 2016 J Hepatol 2016 http://dx.doi.org/10.1016/j.jhep.2016.09.001 3) Foster GR, Afdhal N, Roberts SK, Bräu N, Gane EJ, Pianko S et al. Sofosbuvir and Velpatasvir for HCV Genotype 2 and 3 Infection. N Engl J Med. 2015 Dec 31;373(27):2608-17 4)SASL www.hepatitis-schweiz.ch Treatment of chronic Hepatitis C September 2016 update SASLSSI expert opinion Statement 5) Aghemo A, Bruno R, Ciancio A, Coco B, Petta S, Toniutto P, et al. Documento di indirizzo dell’Associazione Italiana per lo Studio del Fegato per l’uso razionale di antivirali diretti di seconda generazione nelle categorie di pazienti affetti da epatite C cronica ammesse alla rimborsabilità in Italia;
(2014,
reviewed
in
September
2015 th).
Retrieved
from:
http://www.webaisf.org/media/33882/documento_hcv_22set.2015.pdf 6) Lawitz E, Mangia A, Wyles D, Rodriguez-Torres M, Hassanein T, Gordon SC, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013 May 16;368(20):187887. 7)Jacobson IM, Gordon SC, Kowdley KV, Yoshida EM, Rodriguez-Torres M, Sulkowski MS, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N. Engl. J. Med. 2013 May 16;368(20):1867-77. 8)Tacke F, Gunther R, Buggish P, Klinker H, Schober A, John C et al Treatment of HCV genotype 2 with sofosbuvir and ribavirin results in lower SVR rates in real life than expected from clinical trials. Liver Intern 2016. DOI:10.111/liv.13206 9)Welzel TM, Nelson DR, Morelli G, Di Bisceglie AM, Reddy KR, Kuo A et al. Effectiveness and safety of Sofosbuvir and Ribavirin for the Treatment of HCV Genotype 2 infection: results of the
real-world, clinical practice HCV-TARGET Study. GUT 2016 doi:10.1136/gutjnl-2016-311609 10)American Association for the Study of Liver Diseases, Infectious Diseases Society of America. HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. Retrieved from: http://www.hcvguidelines.org/ 11)Karchava M, Waldenström J, Parker M, Hallack R, Sharvadze L, Gatserelia L et al. High incidence of the hepatitis C virus recombinant 2k/1b in Georgia: Recommendations for testing and treatment. Hepatol Res. 2015 Dec;45(13):1292-8 12)Susser S, Dietz J, Barak M, Schlevogt B, Daniel R, Piazzolla V et al. Prevalence and clinical importance of hepatitis C virus genotype 2K/1B chimeras. Abstract presented at the International Liver Congress EASL - European Association for the Study of the Liver Barcelona, Spain 13-17 April 2016 13) Mangia A, Thompson AJ, Santoro R, Piazzolla V,Tilmann HL, Patel K, et al An IL28B polymorphism determines treatment response of hepatitis C virus genotype 2 or 3 patients who do not achieve a radid virologic response. Gastroenterology 2010;139:821-7 14) Ghany MG, Strader DB, Thomas DL, Seeff LB; American Association for the Study of Liver Diseases. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology. 2009 Apr;49(4):1335-74. 15) Johnson M, Zaretskaya I, Raytselis Y, Merezhuk Y, McGinnis S, Madden TL. NCBI BLAST: a better web interface. Nucleic Acids Res. 2008 Jul 1;36(Web Server issue):W5-9. 16) World Health Organization. Hepatitis C virus. World Health organization (WHO). Retrieved from: http:// http://www.who.int/mediacentre/factsheets/fs164/en/ 17) Cornberg M, Razavi HA, Alberti A, Bernasconi E, Buti M, Cooper C, et al. A systematic review of hepatitis C virus epidemiology in Europe, Canada and Israel. Liver Int. 2011 Jul;31 Suppl 2:30-60. 18) Lagging M, Wejstal R, Norkrans G, Kalstrom O, Aleman S, Weiland O, et al Treatment of hepatitis C virus infection for adult and childran: Updated Swedish consensus
recommendations. Infect Dis (Lond) 2016: 48; 251-261 19) Omata M, Nishiguchi S, Ueno Y, Mochizuki H et al Sofosbuvir plus ribavirin in Japanese patients with chronic genotype 2 HCV infection, an open-label phase 3 trial. J Viral Hep 2014;762-8 20) Zeuzem S, Dusheiko GM, Salupere R, Mangia A, Flisiak R, Hyland RH, et al. Sofosbuvir in Genotypes 2 or 3 VALENCE Trial. N Engl J Med. 2014 May 22. 370:1993-2001. 21) Dieterich D, Bacon B, Flamm S, Kowdley K, Milligan S, Tsai N et al. Evaluation of sofosbuvir and simeprevir-based regimens in the TRIO network - Academic and community treatment of a real-world, heterogeneous population. Presented at the 65th Annual Meeting of the American Association for the Study of Liver Diseases: The Liver Meeting 2014, Boston MA; Nov 7-11 2014; J Hepatol 2015; 62, suppl 2. S621 22) Ho SB, Monto A, Peyton A, Kaplan DE, Byrne S Moon S et al Efficacy of sofosbuvir plus ribavirin in Veterans with hepatitis C viruss genotype 2 infection compensated cirrhosis and multiple comorbidities. Clin Gastroenterol Hepatol 2016 doi: 10.1016/j.cgh.2016.05.024 [Epub ahead of print]. 23) Ioannou GN, Beste LA, Chang MF, Green PK, Lowy E, Tsui JI et al Effectiveness of Sofosbuvir, Ledipasvir/Sofosbuvir, or Paritaprevir/Ritonavir/Ombitasvir and Dasabuvir regimens for treatment of patients with hepatitis C inn the Veterans Affairs National Health Care System. Gastroenterology 2016;151:457-471 24) Hezode C, Fontaine H, Darival C, Carney D, Zoulim F et al Triple therapy in treatmentexperienced patients with HCV cirrhosis in a multicenter cohort of the Freanch early access programme (ANRS CUPIC) J Hepatol 2013; 434-41 25) Lawitz E, Poordaad F, Wells J, Hyland RH et al High efficacy of sofosbuvir/velpatasvir /GS9857 with or without RBV for 12 weeks in direct acting antiviral experienced patients with genotype 1 HCV infection. J Hepatol 2016;64 suppl 2, PS021
Table
Table 1. Overall demographic characteristics of patients and by treatment duration
Patients with Patients by treatment duration Characteristics
advanced fibrosis or cirrhosis SOF-RBV for
SOF-RBV for
SOF-RBV for
12-20 weeks
12 weeks
16-20 weeks
(N=291) (%)
(N=123) (%)
(N=168) (%)
Mean Age, years
68,0
66,0
69,7
Range
18-87
18-82
36.9-87
Male sex, n (%)
134 (46,05)
47 (38,21)
63 (55,00)
BMI
26,50±3,98
25,88±4,51
27,00±3,48
Liver stiffness, Mean KPa
15,27±9,32
9,71±2,09
18,78±9,30
Cirrhosis, n (%)
168 (57.73)
0
168
Mean HCV RNA, log10 2,869212±3,669,940 2,994,498±3,814,380
2,792,051±3,584,309
IU/ml±SD Mean ALT levels
80,09±80.49
60,58±61.15
95,19±90.08
Mean AST levels
67,57±63,66
46,18±40,07
83,72±73,09
50 (17,1)
n.a.
50 (29,7)
PLT <100,000 u/l, n (%)
CTP A
149 (88,8)
3 (0,2)
146 (88,6)
CTP B
14 (8,2)
0
14 (8,3)
Unknown
5 (2,9)
0
5 (2,9)
MELD score
8,28±2,38
n.a.
8,28±2,38
Albumin <3.5 g/dl, n (%)
62 (21,3)
n.a.
62 (36,9)
Naïve
163 (56,0)
81 (65,8)
81 (48,8)
Previously treated
130 (44,0)
42 (34,2)
86 (51,2)
Prior non response
27 (20,8)
2 (4,9)
24 (27,9)
Prior relapse
103 (79,2)
40 (95,4)
62 (72,1)
167,58±82,20
212,26±86,96
136,33±61,74
HCV treatment experience, n (%)
Platelets count
Table 2. Characteristics of patients with cirrhosis by treatment duration
Characteristics
SOF-RBV for 16 weeks (N=90) (%)
SOF-RBV for 20 weeks (N=82) (%)
Mean Age, years (range)
70 (37-86)
69 (36.9-87)
Male sex, n (%)
47 (52.2)
43 (52.44)
BMI (mean±SD)
27.12±3.73
26.58±3.23
Liver stiffness,Mean KPa±SD
15,06±5.54*
22,73±12.16
Mean HCV RNA, log10 IU/ml±SD
2,623,171± 3,825,525
2,887,072,051± 3,198,588
Mean ALT levels±SD
96.31±86,32
92.31±91,19
Mean AST levels±SD
83.87±72.90
83.10±72.05
PLT <100,000 u/l n, (%)
26 (29.5)
23 (29.5)
CTP A n, (%) CTP B n, (%) Unknown n (%)
77 (85.5) 7 (7.7) 6 (6.6)
69 (84.1) 9 (10.9) 4 (4.8)
MELD score mean±SD
7,95±2,05
8,59±2,58
Albumin <3.5 g/dl, n (%)
7 (7.7)
7 (8.5)
HCV treatment experience, n (%)
Naïve, n (%)
45 (50)
41(50)
Previously treated, n (%)
45 (50)
41(50)
Platelets count mean±SD
140,76±60,90 132,86±62,80
* P value <0,0001
Table 3.0 Overall adverse events, among patients with cirrhosis and by treatment duration
SOF+RBV
SOF+RBV
SOF+RBV
SOF+RBV
Total
Cirrhotic
16 weeks
20 weeks
(N=291)
(N=168)
(N=91)
(N=82)
Fatigue
177 (61,0%)
106 (63,6%) 49 (53,8%)
57 (69,5%)
Headache
69 (23,7%)
58 (34,5%)
34 (37,3%)
24 (29,2%)
Nausea
54 (18,5%)
49 (28,5%)
25 (27,4%)
24 (29,2%)
Insomnia
51 (17,5%)
31 (18,4%)
14 (15,3%)
17 (20,7%)
Rash
6 (2,06%)
4 (2,3%)
3 (3,2%)
1 (1,2%)
Hemoglobin <12.5 g/dl
24/192
11 (6,5%)
5 (5,4%)
6 (7,3%)
7/192 (3,6%)
7 (4,1%)
3 (3,2%)
4 (4,8%)
<8.5 g/dl
5/192 (2,6%)
5 (2,9%)
2 (2,1%)
3 (3,6%)
Neutrophils <750/mm3
0/291
0/186
0/91
0/82
Platelets <50,000/mm3
0/291
0/168
0/91
0/82
(12,5%) Hemoglobin <10.5 g/dl
Hemoglobin
Ethic Statement This study was conducted in accordance with the Declaration of Helsinki. As it is an observational study conducted in accordance with the Italian Medicine Agency, patients were not required to sign any informed consent.
Figure1
Figure2
*Graphical Abstract
Graphical abstract N=123
Patients with HCV GT2 infection = 291
SVR12
patients with advanced fibrosis
N=168
91 patients with cirrhosis
99,1
94,5
82 patients with cirrhosis 91,5
0
4
8
12
16
20
24 weeks
S0168-8278(16)30707-3 http://dx.doi.org/10.1016/j.jhep.2016.12.002 JHEPAT 6353
To appear in:
Journal of Hepatology
Received Date: Revised Date: Accepted Date:
2 August 2016 30 November 2016 4 December 2016
Please cite this article as: Mangia, A., Susser, S., Piazzolla, V., Agostinacchio, E., De Stefano, G., Palmieri, V., Spinzi, G., Carraturo, I., Potenza, D., Losappio, R., Arleo, A., Miscio, M., Santoro, R., Sarrazin, C., Copetti, M., Sofosbuvir and Ribavirin for genotype 2 HCV infected patients with cirrhosis: a real life experience, Journal of Hepatology (2016), doi: http://dx.doi.org/10.1016/j.jhep.2016.12.002
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Sofosbuvir and Ribavirin for genotype 2 HCV infected patients with cirrhosis: a real life experience
Alessandra Mangia1, Simone Susser2,Valeria Piazzolla1, Ernesto Agostinacchio3, Giulio De Stefano4, Vincenzo Palmieri5, Giancarlo Spinzi6, Immacolata Carraturo 7, Domenico Potenza8, Ruggero Losappio9, Andrea Arleo 1, Maria Miscio1, Rosanna Santoro1, Christoph Sarrazin10, Massimiliano Copetti11
1
Liver Unit, IRCCS “Casa Sollievo della Sofferenza” San Giovanni Rotondo, Italy
2
Johann Wolfgang Goethe-University Medical Center, Frankfurt am Main, Germany
3
Internal Medicine Clinica “Mater Dei” Bari, Italy
4
Infectious Diseases Unit, Presidio ospedaliero Madonna delle Grazie, Matera, Italy
5
Medical Clinic “A. Murri”, Policlinico di Bari, Italy
6
Gastroenterology Unit, Ospedale Valduce, Como, Italy
7
Infectious Diseases Unit, Ospedale “Vito Fazzi” Lecce, Italy
8
Interventional ultrasound Unit, Ospedale “Perrino” Brindisi, Italy
9
Infectious Diseases Unit, Presidio Opedaliero Bisceglie
10
11
Medizinische Klinik 1, Goethe University Hospital, Frankfurt, Germany
Biostatic Unit, IRCCS “Casa Sollievo della Sofferenza” San Giovanni Rotondo, Italy
Corresponding Author: Alessandra Mangia Liver Unit IRCCS “Casa Sollievo della Sofferenza” 71013 San Giovanni Rotondo, ITALY Phone: 0039-882-416375 Fax: 0039-882-416270 Email: [email protected]
Electronic word count: words.
figures and tables.
•
Keywords
•
A HCV
•
B Genotype 2
•
C Sofosbuvir
•
D Ribavirin
•
E Cirrhosis
Abbreviations Direct Antiviral Agents (DAA), genotype (GT), sofosbuvir (SOF), ribavirin (RBV), treatment naïve (TN), treatment experienced (TE), ABBOTT RealTime (ART), adverse events (AE), hemoglobin (Hb), confidence intervals (CIs), Child Turcotte Pugh (CTP), intention to treat (ITT), per protocol analysis (PP).
Introduction
HCV genotype still represents the most important viral factor for selection of appropriate Direct Antiviral Agents (DAA) regimen and duration in chronic HCV infection. In the era of Interferon-based therapies, genotype 2 (GT2) was considered easy to treat. Indeed, the first interferon free treatment, based on the combination of Sofosbuvir (SOF) 400 mg + Ribavirin (RBV) 1000-1200 mg daily, was investigated in patients infected with this genotype and until very recently [1] has represented the standard of care [2]. The newly approved combination of SOF and Velpatasvir (VEL) [2,3], has been recommended as the new standard, but is not yet available in all the European countries [4,5]. Real life experience attained with SOF and weight-based RBV combination will inform clinicians and patients about the limitations of the past regimens and will help to better understand the advantages of the new ones. In phase III trials, the combination of SOF and weight-based RBV was associated with 90% rates of SVR [6,7]. More recently, real life studies suggested that SVR might be lower. It was observed that the higher the proportion of cirrhotic patients included into the cohorts, the lower the SVR rate [8,9]. However, it should be noticed that, according to evidence generated by phase III studies [7], international guidelines advise to extend the duration of treatment - longer than 20 weeks - in patients with cirrhosis [1,10]. Whether the lower SVR registered in observational cohorts is related to the higher proportion of patients with cirrhosis, or whether it can be attributed to the duration of 12 weeks adopted in real life despite the longer 12-20 weeks duration recommended by EASL for cirrhotic patients [1], can be object of debate. Indeed, in a study based on the German cohort [8] and in the Target study [9] the vast majority of patients received 12 weeks of treatment. Moreover, in the German cohort, only 75% were treated inside guidelines with regard to RBV dosages also [9]. An alternative explanation for the lower SVR registered in real life has been considered: the presence of a recombinant HCV genotype 2k/1b strain, not recognized by the commonly used
genotyping assay, Innolipa, unable to amplify both the 5’and 3’ regions of the HCV genome, and associated with suboptimal response to SOF and RBV. This chimera virus, firstly described in Georgia [11], has been investigated in countries as Germany and Israel, destination of migratory flows from the former Soviet Union in the mid 1990’s. In these countries the chimera virus has been discovered at a prevalence of 13% and 25%, respectively [12]. Italy was not a priority country for this migratory phenomenon and, as shown in a collaborative study, none of the 52 patients with GT2 from our center carried this chimera virus[12]. Based on 9 prior treatment failure patients with cirrhosis and previous failure history in the Fusion trial, in the registration studies in monoinfected patients the maximum duration of SOF and RBV treatment for GT2 has been 16 weeks.. Extending the treatment of GT2 patients with cirrhosis up to 20 weeks could associated with an increase in the response rate. We evaluated this hypothesis and the role of the 2k/1b variant as a possible explanation for virological failures in consecutively observed GT2 infected patients.
The
candidates to treatment have been selected according to the Italian reimbursement criteria that prioritise patients with advanced fibrosis or cirrhosis [5]. A course of 12 weeks was adopted in the presence of bridging fibrosis, while 16 or 20 weeks were prescribed when cirrhosis was diagnosed. Our aim is to identify a balance between treatment duration and maximum SVR in order to inform clinicians and patients from countries where the combination of SOF and RBV is available, whereas the very recently approved combination of SOF and VEL is not.
Patients and Methods
Study design
This is an open label prospective observational study on HCV GT2 patients with advanced liver fibrosis or cirrhosis treated with SOF and RBV combination therapy at 6 different centers in Italy. The first patient started treatment on January 30, 2015. All patients completed post-treatment
week 12 evaluation by the end of May 2016. Patients were between 18 and 87 years and had severe documented fibrosis or cirrhosis. Patients with active HBV infection were considered not eligible, as well as patients with history of a previous DAA course. Patients with decompensated liver diseases were not excluded. Key exclusion criteria, in accordance with the Italian Medicine Agency (AIFA), were: active HCC or presence of systemic diseases with short life expectancy. Untreated patients and patients who had failed a previous course of Interferon and RBV received SOF 400 mg once a day, orally, in combination with RBV 1000 or 1200 mg daily, based on the body weight ≤ or > 75 Kg for 12 weeks, if cirrhosis was absent, and for 16 or 20 weeks, if cirrhosis was present. As this was not a randomised trial, the duration of 16 or 20 weeks was selected by physicians in accordance with local guidelines and patients characteristics. Patients with cirrhosis were not treated for less than 16 weeks. Patients were assessed for biochemistry, hematology and virology at baseline, every 4 weeks on treatment and 4 and 12 weeks after the end of treatment.
Assessment of disease severity
The presence of cirrhosis or advanced fibrosis (F3/F4) was defined by Fibroscan and/or liver biopsy with the only exception of patients with clinical evidence of cirrhosis complications. Liver specimens were obtained by liver biopsy only in 39 patients. Cirrhosis was diagnosed at histology according to Metavir score=4. Transient elastography threshold to define cirrhosis was ≥12.5 KPa, to define bridging fibrosis 10.1 KPa.
Laboratory assessments
Screening assessment included serum HCV RNA levels and IL28B genotyping in addition to standard laboratory clinical tests. HCV RNA levels were measured using ABBOTT RealTime
(ART) assay with a LLQ of 12 IU/ml and a LLOD of 10-12 IU/ml. HCV genotype and subtype were determined by using Innolipa 2.0 assay. IL28B was determined by PCR amplification and sequencing of the rs12979860 single-nucleotide polymorphism [13]. On treatment assessment included standard laboratory testing, serum HCV RNA, vital signs and physical examination. The type of previous response to PegIFN and Ribavirin treatment was defined by standard criteria [14].
Sequencing for recombinant genotype 2k/1b strain
Initial genotyping of the samples was performed using the Innolipa 2.0 assay, which is limited in identifying recombinant HCV strains. In case of 2k/1b chimeras, genotyping with the hybridization assay leads to a genotype 2 call. Thus, serum samples of patients who experienced a relapse, matched by age and disease severity with samples of patients with SVR, were re-genotyped and checked for incidence of the recombinant genotype 2k/1b by a Sanger sequencing approach, as gold-standard for genotype calling. The regions encoding HCV core, the NS2/NS3 junction, and the NS3 protease gene were amplified by nested polymerase chain reaction, and population-based sequenced. To confirm chimeric strains and to exclude dual infection, the recombination site, which is located at the NS2/NS3 junction, was included in the investigation. Analysis was performed using BLASTN interface [15]. Results of genotyping by sequencing were compared to the original. Sequencing and data analysis were done at the Biomedical Research Laboratory at the University Hospital Frankfurt/Main, Germany.
Efficacy end points
The study evaluated SVR rates in patients with GT2 and advanced fibrosis or cirrhosis in real life at post-treatment week 12. Results were compared with those reported in patients with cirrhosis and previous history of treatment failure, included in the registration studies [6,7].
Safety assessment
Data on safety issues were collected during the treatment period and during 12 weeks of follow up, including laboratory assessments, physical examination and reporting of adverse events (AE). Anemia was defined as an AE as follows: mild, Hemoglobin (Hb) values between 10.0 and 12.5 g/dl, moderate Hb between 8.5 and 10 g/dl, and severe Hb below 8.5 g/dl. Anemia developing during treatment was managed by 200 mg RBV dose reduction. Use of blood transfusion and erythropoietin were allowed.
Statistical methods
Demographic and clinical data were reported as mean and standard deviation on frequencies and percentages for continuous and categorical variables, respectively. Group comparisons were performed using Mann-Whitney U-test and Person chi-square or Fisher exact test for continuous and categorical variables, respectively. Point estimates of rates of SVR12 along their exact 95% Confidence Intervals (CIs) were estimated. Statistical analyses were performed by using SAS version 9.3 (SAS Institute Inc., Cary, NC, USA).
Results
Patients’ characteristics
In total, 352 patients with bridging fibrosis or cirrhosis infected with GT2 and candidate for treatment in the participating centers were evaluated. Since 15% were ribavirin intolerant and are not included in this analysis, 299 were offered treatment, 6 of them were excluded due to active HBV infection and 2 patients died before starting treatment. Therefore, 291 patients were treated and had a complete follow up by the end of May 2016. Demographic and baseline characteristics of the ITT population are shown in Table 1. Among 291 patients, 134 (46.1%) were male, 123 (42.3%) were classified as F3, and 168 (57.7%) as F4. The median age was 68 years (18-87), median HCV RNA 1,834,598 IU/ml (23-31,827,592). In total, 163 (56.0%) patients were naïve. In 145 of 168 patients with cirrhosis who had liver fibrosis assessed by means of Transient elastography (TE), the minimum value was 12.5 KPa and the maximum 75 KPa. Among cirrhotic patients, median MELD score was 7 (6-19). Of 168 patient with cirrhosis, 149 had a Child Turcotte Pugh (CTP) score A 5-6 (89.9%) the remaining had CTP score B 7-9. 50 patients had platelets <100,000μl and 62 had albumin levels <3,5 g/dl. Patients with cirrhosis received either 16 weeks of treatment according to phase III studies’ results or 20 weeks of treatment in accordance with European guidelines. IL28B genotyping showed non CC genotype in 66% of the 143 cases who were tested for. Diabetes was observed in 15% of patients, the majority of whom were also overweight or obese (Fig.1). Table 2 shows baseline characteristics of patients with cirrhosis by treatment duration.
Although mean platelets count was comparable between the two treatment groups a higher mean stiffness value was found among patients receiving 20 weeks of treatment, suggesting that physicians assigned a longer treatment course to patients with higher TE results. All the other characteristics, including Child Pugh score were comparable between 16 and 20 weeks of treatment duration.
Virologic response
A total of 278 patients (95,53%, 95%CI=92,48-97,60) achieved SVR12. At intention to treat (ITT) population analysis, SVR12 was achieved by 99,15% (95%CI=97,50-100,00) of patients with advanced fibrosis and by 93,06% (95%CI=88,20-93,36) of patients with cirrhosis. Overall, 97,55% (95%CI=93,84-99,33) treatment naïve achieved SVR12; response rates for treatment experienced patients with a previous non response was 91,18% (95%CI=83,91-95,86), for previous relapsers was 100% (95%CI=86,77-100,00). The reason for treatment failure was relapse in all but 2 patients who discontinued treatment due to esophageal variceal bleeding and cerebral hemorrhage respectively, and were considered non responders. For both of them, treatment duration of 20 weeks was planned. After the virologic relapse, their baseline samples were sequenced. Of the 5 non responders, treated for 20 weeks, 2 were found associated with genotype non 2 (one was 1b and another was 4). All the other patients who experienced a relapse were confirmed to be GT2 infected. To exclude reinfection, serum samples of the patients who experienced a relapse collected at week 4 or later during the follow up were sequenced confirming GT2 infection.
SVR by severity of liver disease and treatment duration
Among cirrhotic patients, subgroup analysis by treatment duration of 16 or 20 weeks showed SVR12 of 94,51% (95%CI=87,64-98,19) after 16 weeks and of 91.46% (95%CI=83,2096,50) after 20 weeks (p=0.31).
Characteristics of patients with virologic failure and analysis of treatment completers with post-treatment week12 HCV RNA results
Among 168 cirrhotic patients, 7 out of 82 subjects treated for 20 weeks and 5 of 91 treated for 16 weeks had a failure. In detail, 5/7 patients experienced a relapse and 2 were considered non responders at ITT analysis due to an early discontinuation. Reasons to discontinue treatment were esophageal variceal bleeding after 2 weeks from the start of treatment and cerebral hemorrhage at week 19 of treatment. Three out of 5 patients had a relapse after a 16 week course. Among 5 patients with relapse treated for 20 weeks, one in CTP B class in the waiting list for OLT underwent sequencing of a basal stored sample after the virus reappearance and was discovered to be GT4 infected, while a second was found GT1 instead of GT2. Of the remaining 3, one was a patient with renal failure after kidney transplant who had to reduce RBV 4 weeks after the start of treatment, and 2 were patients with liver cirrhosis in CPT class A. Among 5 patients with cirrhosis who received 16 weeks of treatment and experienced a relapse, 2 were patients with CTP class A and one was a patient with decompensated cirrhosis. Of 123 non cirrhotic patients, a patient who did not achieve SVR was a young patient without apparent reasons not to respond. According with these evidences, the analysis of treatment completers with post-treatment week 12 HCV RNA available results was performed and showed SVR12 of 94,51% (95%CI=87,6498,19) and 94,94% (95%CI=87,54-98,60), after 16 and 20 weeks, respectively (p=1.00 by fisher exact test). Therefore, keeping in mind that the two treatment duration groups are not matched and
that this study was not powered to compare efficacy between 16 or 20 weeks duration, it is difficult to imagine that rates of response higher than those above reported can be achieved in real life with a longer course of therapy.
Predictors of SVR
Multiple parameters were tested for possible association with SVR12 in patients with cirrhosis. They included baseline KPa values, baseline platelets, baseline MELD, presence of ascites, presence of esophageal varices, history of HCC, baseline viremia levels, baseline AST and ALT values, baseline albumin values, co-morbidities as diabetes and obesity. By univariate analysis, predictive of lower SVR12 rates were low PLT count, presence of ascites, presence of esophageal varices and higher baseline CTP score.
Multivariate analysis
Multivariate analysis included treatment history, ascites, esophageal varices, BMI, treatment duration, PLT count and presence of ascites. Among them, the following independent predictors of lower SVR rates were identified: low PLT count (OR 7,2; 95% CI 1,67-31,25; p value =0.0022) and esophageal varices (OR 0,1; 95% CI 0,01-0,72; p=0.0079).
Safety
The most common adverse events (AEs), occurring in at least 20% of subjects, were fatigue, anemia, nausea, insomnia and headache (Table 3). As previously described, the most common
serious AEs was by far anemia [7]. Safety profile was consistent with RBV related known side effects, namely anemia and rash (Table 3). Anemia was defined by Hb levels <12.5 g/dl in both men and women (Table 3). Anemia was mild in 12.5% of cases overall and moderate in 3.6% of cases. Hb levels <8.5 g/dl were observed in 2.6% of our patients. Nevertheless, no patients discontinued treatment due to anemia. All the patients with severe anemia received blood transfusion and were managed by step by step 200 mg RBV dose reductions. Percentage of patients developing anemia among cirrhotic patients who received 16 or 20 weeks of treatment is reported in Table 2. Median baseline Hb levels were 13.51± 1.54. When compared to median end of treatment levels of 12.47±1.68 a percentage difference decline of 8.31±10.61 was observed. Severe anemia was observed only in female patients with cirrhosis who completed the assigned treatment duration and it developed right after the start of treatment (Fig.2). RBV dose reduction was requested in 23 patients, overall. No difference in SVR was observed between patients receiving full or reduced doses of RBV. None of the discontinuations due to AEs were deemed related to SOF.
Discussion
In this study, the combination of SOF and weight-based RBV, representing the standard of care for treatment of patients with GT2 infection until very recently, was associated with SVR12 rates in patients with advanced fibrosis and cirrhosis higher than those reported either in the registration studies [1, 2, 6,7], or in other real life studies [8,9]. Overall, only 13 patients (4,47%) experienced a failure. Of note, our patients with cirrhosis received SOF and RBV combination treatment for a period longer than 12 weeks. Indeed, 91 of 168 patients with cirrhosis received 16 weeks, while 82 received 20 weeks of therapy. Among cirrhotic patients, SVR12 was 93,06% at ITT and 94,70% at the analysis of treatment completers with available post treatment results at week 12. GT2 is the third most common genotype in the world, although it represents about 10-15% of the HCV infected population in Europe and US [16, 17]. SOF/VEL as single pill, fixed dose combination represents the new standard of treatment and will ensure extremely high rates of SVR without the addition of RBV [3]. This new treatment is not yet available in some European countries including Switzerland, Sweden and Italy [4,5,18], and the findings of this study show that
individualising SOF and weight-based RBV duration in GT2 patients with cirrhosis in case of lack of SOF/VEL access, may improve SVR. SVR12 of 98,8% reported in 161 treatment naïve patients with cirrhosis after 16 or 20 weeks of treatment in this study were higher than the 91% reported in phase III FISSION study [6], where only 11 cirrhotic patients were included. Moreover, in our study 90,59% of 77 previous non responder subjects with cirrhosis achieved SVR after 16 or 20 weeks of therapy. The corresponding rates, in 10 cirrhotic patients enrolled to 12 weeks, and in 9 enrolled to 16 weeks in the Fusion study were 60% and 78% [7]. Racial difference might play a role in studies performed in US, equally it is possible that a higher prevalence of female patients, included in our study as a result of ribavirin intolerance in the era of IFN-based treatments, led to higher SVR rates in our study. The different genetic background of patients should also be taken into account when examining the results of a phase III study on GT2 treatment performed in Japan. In that study, SVR12 was 89% after 12 weeks of treatment [19]. However, of 14 GT2 patients with cirrhosis, 94% attained SVR12. Although Asian origin prevents a direct comparison with European patients, these results confirm that SOF/RBV is associated with SVR12 higher than 90% in GT2, even in the presence of cirrhosis. In the Valence study, performed in Europe but focusing on GT3 rather than on GT2, only 11 cirrhotic GT2 patients were enrolled. SVR were 100% for 2/2 naïve and 77.8% for 9 treatment experienced after 12 weeks [20]. While phase III trials included small numbers of patients with cirrhosis, real life cohorts as Target, TRIO and Valor-HCV focused on patients with more advanced liver disease [9,21,22]. In an extremely large cohort of VA including 2131 GT2 who received 12 weeks of therapy, a lower rate of SVR was observed in cirrhotic patients as compared to non cirrhotic (89.1% vs 77.3%) [23]. In the real life Target cohort, of the 86 patients with cirrhosis included, 62 received 12 weeks and 24 received 16 weeks of treatment, they achieved 79% and 83% SVR rates, respectively. However, after 12 weeks 71.9% of naïve and 86.7% of treatment experienced patients with cirrhosis attained SVR; while after 16 weeks 100% of naïve and 76.5% of treatment experienced cleared the virus.
These findings suggest that for patients with a prior treatment experience and cirrhosis an extended duration might be of benefit [9]. Viral sequencing performed both, in stored basal samples after the virologic failure and in samples collected during follow up showed the absence of a chimera 2k/1b virus and confirmed the absence of re-infection. The 2k/1b recombinant strain recently identified in patients from East Europe [11] and shown associated with poor response rates to SOF/RBV combination in patients with GT2 infection from German and Israeli [12] was not found among our GT2 infected patients. These results highlight the impact of this genetic variation as a local phenomenon rather than a general explanation for lower SVR rates, in patients with GT2 infection. Moreover, our data suggest that genotyping at baseline is of utmost importance in patients with GT2 treated with SOF and RBV due to the high risk to perform suboptimal treatments in patients uncorrectely genotyped as GT2. The use of a pangenotypic regimen as that based on SOF/VEL will overcome this issue in the future. A merit of this study is the inclusion of patients with very advanced liver disease. About 20% of our patients showed pre-treatment features similar to those reported in the CUPIC cohort(PLT <100,000 /µl and albumin levels <3.5 g/dl) [24]. Low PLT count represented the second independent predictor of relapse. By contrast, diabetes or obesity did not show impact on SVR12. It could be debated whether the higher SVR rate observed in our study can be attributed to the extended duration in a subgroup of patients with features of portal hypertension, including 11% in CTP class B. Although, as shown by the analysis of treatment completers, SVR12 rates after 16 or 20 weeks duration were similar, we acknowledge that the study is not powered for these subgroup analyses. We calculated that given the extremely high rates of SVR attainable with this regimen, the comparison of 16 with 20 weeks of treatment would have required the enrolment of not less than 754 subjects per arm, to demonstrate a statistically significant difference with a power of 80% and an alpha error of 5%. However, given our high rates of response after 20 weeks, it is highly conceivable that 24 weeks may represent an overtreatment.
Finally, we should consider that the longer the treatment the higher the risk of anemia. It is important to notice that the side effect profile of the standard combination in this study was overall favourable. Although RBV related anemia resulted manageable by dose reductions a higher number of female patients with cirrhosis developed anemia in particular after longer treatment courses. Nevertheless, SVR12 rates were not influenced by RBV dose reduction. Of course, the option based on SOF/VEL, as ribavirin free regimen [3] will be the optimal solution to sparing anemia and all the RBV related side effects. This is not a randomized controlled study. However, all GT2 patients candidate to treatment were prospectively and consecutively enrolled at each participating center. It should also be kept in mind that in the few cases of patients who failed to achieve SVR, successful re-treatment strategies based on NS5 inhibitors can now be adopted [25]. Hence, the option of re-treating a few failures with SOF/VEL may probably represent an interesting cost effective alternative in some countries. In conclusion, the present study shows in GT2 patients with cirrhosis, either naïve or treatment experienced, SVR12 higher than 95% after SOF and weight-based RBV for 16 or 20 weeks. In a real life population of GT2 patients with cirrhosis, when access to SOF/VEL is not possible, a treatment of individualised duration with SOF/RBV is associated with comparable rates of responses after 16 or 20 treatment weeks and good tolerability, although a slightly increase of anemia can be observed after longer treatment. Correct genotyping at baseline is mandatory.
Table 3.0 Overall adverse events, among patients with cirrhosis and by treatment duration
SOF+RBV
SOF+RBV
SOF+RBV
SOF+RBV
Total
Cirrhotic
16 weeks
20 weeks
(N=291)
(N=168)
(N=91)
(N=82)
Fatigue
177 (61,0%)
106 (63,6%)
49 (53,8%)
57 (69,5%)
Headache
69 (23,7%)
58 (34,5%)
34 (37,3%)
24 (29,2%)
Nausea
54 (18,5%)
49 (28,5%)
25 (27,4%)
24 (29,2%)
Insomnia
51 (17,5%)
31 (18,4%)
14 (15,3%)
17 (20,7%)
Rash
6 (2,06%)
4 (2,3%)
3 (3,2%)
1 (1,2%)
Hemoglobin <12.5 g/dl
24/192
11 (6,5%)
5 (5,4%)
6 (7,3%)
(12,5%)
Hemoglobin <10.5 g/dl
7/192 (3,6%)
7 (4,1%)
3 (3,2%)
4 (4,8%)
<8.5 g/dl
5/192 (2,6%)
5 (2,9%)
2 (2,1%)
3 (3,6%)
Neutrophils <750/mm3
0/291
0/186
0/91
0/82
Platelets <50,000/mm3
0/291
0/168
0/91
0/82
Hemoglobin
Table 1. Overall demographic characteristics of patients and by treatment duration
Patients with Patients by treatment duration Characteristics
advanced fibrosis or cirrhosis SOF-RBV for
SOF-RBV for
SOF-RBV for
12-20 weeks
12 weeks
16-20 weeks
(N=291) (%)
(N=123) (%)
(N=168) (%)
Mean Age, years
68,0
66,0
69,7
Range
18-87
18-82
36.9-87
Male sex, n (%)
134 (46,0)
47 (38,2)
63 (55,0)
BMI
26,50±3,98
25,88±4,51
27,00±3,48
Liver stiffness, Mean KPa
15,27±9,32
9,71±2,09
18,78±9,30
Cirrhosis, n (%)
168 (57.7)
0
168
Mean HCV RNA, log10 2,869212±3,669,940 2,994,498±3,814,380
2,792,051±3,584,309
IU/ml±SD Mean ALT levels
80,09±80.49
60,58±61.15
95,19±90.08
Mean AST levels
67,57±63,66
46,18±40,07
83,72±73,09
50 (17,1)
n.a.
50 (29,7)
CC
61
16
43
CT
79
38
41
TT
33
23
10
CTP A
149
3
146
CTP B
14
0
14
Na
5
0
5
MELD score
8,28±2,38
n.a.
8,28±2,38
Albumin <3.5 g/dl, n (%)
62 (21,3)
n.a.
62 (36,9)
PLT <100,000 u/l, n (%)
HCV treatment experience, n (%) Naïve
163 (56,01)
81
81
Previously treated
130
42
86
Prior non response
26
2
24
Prior relapse
101
40
61
167,58±82,20
212,26±86,96
136,33±61,74
Platelets count
Table 2. Characteristics of patients with cirrhosis by treatment duration
Characteristics
SOF-RBV for
SOF-RBV for
16 weeks
20 weeks
(N=90) (%)
(N=82) (%)
70
69
37-86
36.9-87
47 (52,2)
43 (52,44)
BMI
27,12±3.73
26,58±3.23
Liver stiffness, Mean
15,06±5.54*
22,73±12.16
Mean Age, years Range Male sex, n (%)
KPa
Mean
HCV
RNA, 2,623,171±3,825,5 2,887,072,051±3,1
log10 IU/ml±SD
25
98,588
Mean ALT levels
96,31±86,32
92,31±91,19
Mean AST levels
83,87±72,90
83,10±72,05
26 (29,5)
23 (29,5)
CC
20
25
CT
13
29
PLT <100,000 u/l, n (%)
TT
3
8
CTP A
77
69
CTP B
7
9
Na
6
4
MELD score
7,95±2,05
8,59±2,58
Albumin <3.5 g/dl, n
3,90±0,71
3,73±0,86
Naïve
41
45
Previously treated
31
31
140,76±60,90
132,86±62,80
(%)
HCV
treatment
experience, n (%)
Platelets count
* P value <0,0001
References
1) European Association for the study of the liver. EASL Recommendations on treatment of Hepatitis C 2015. J Hepatol 2015 Jul;63(1):199-236. doi: 10.1016/j.jhep.2015.03.025. 2) European Association for the study of the liver EASL Recommendations on treatment of hepatitis C 2016 J Hepatol 2016 http://dx.doi.org/10.1016/j.jhep.2016.09.001 3) Foster GR, Afdhal N, Roberts SK, Bräu N, Gane EJ, Pianko S et al. Sofosbuvir and Velpatasvir for HCV Genotype 2 and 3 Infection. N Engl J Med. 2015 Dec 31;373(27):2608-17 4)SASL www.hepatitis-schweiz.ch Treatment of chronic Hepatitis C September 2016 update SASLSSI expert opinion Statement 5) Aghemo A, Bruno R, Ciancio A, Coco B, Petta S, Toniutto P, et al. Documento di indirizzo dell’Associazione Italiana per lo Studio del Fegato per l’uso razionale di antivirali diretti di seconda generazione nelle categorie di pazienti affetti da epatite C cronica ammesse alla rimborsabilità in Italia;
(2014,
reviewed
in
September
2015 th).
Retrieved
from:
http://www.webaisf.org/media/33882/documento_hcv_22set.2015.pdf 6) Lawitz E, Mangia A, Wyles D, Rodriguez-Torres M, Hassanein T, Gordon SC, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013 May 16;368(20):187887. 7)Jacobson IM, Gordon SC, Kowdley KV, Yoshida EM, Rodriguez-Torres M, Sulkowski MS, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N. Engl. J. Med. 2013 May 16;368(20):1867-77. 8)Tacke F, Gunther R, Buggish P, Klinker H, Schober A, John C et al Treatment of HCV genotype 2 with sofosbuvir and ribavirin results in lower SVR rates in real life than expected from clinical trials. Liver Intern 2016. DOI:10.111/liv.13206 9)Welzel TM, Nelson DR, Morelli G, Di Bisceglie AM, Reddy KR, Kuo A et al. Effectiveness and safety of Sofosbuvir and Ribavirin for the Treatment of HCV Genotype 2 infection: results of the
real-world, clinical practice HCV-TARGET Study. GUT 2016 doi:10.1136/gutjnl-2016-311609 10)American Association for the Study of Liver Diseases, Infectious Diseases Society of America. HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. Retrieved from: http://www.hcvguidelines.org/ 11)Karchava M, Waldenström J, Parker M, Hallack R, Sharvadze L, Gatserelia L et al. High incidence of the hepatitis C virus recombinant 2k/1b in Georgia: Recommendations for testing and treatment. Hepatol Res. 2015 Dec;45(13):1292-8 12)Susser S, Dietz J, Barak M, Schlevogt B, Daniel R, Piazzolla V et al. Prevalence and clinical importance of hepatitis C virus genotype 2K/1B chimeras. Abstract presented at the International Liver Congress EASL - European Association for the Study of the Liver Barcelona, Spain 13-17 April 2016 13) Mangia A, Thompson AJ, Santoro R, Piazzolla V,Tilmann HL, Patel K, et al An IL28B polymorphism determines treatment response of hepatitis C virus genotype 2 or 3 patients who do not achieve a radid virologic response. Gastroenterology 2010;139:821-7 14) Ghany MG, Strader DB, Thomas DL, Seeff LB; American Association for the Study of Liver Diseases. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology. 2009 Apr;49(4):1335-74. 15) Johnson M, Zaretskaya I, Raytselis Y, Merezhuk Y, McGinnis S, Madden TL. NCBI BLAST: a better web interface. Nucleic Acids Res. 2008 Jul 1;36(Web Server issue):W5-9. 16) World Health Organization. Hepatitis C virus. World Health organization (WHO). Retrieved from: http:// http://www.who.int/mediacentre/factsheets/fs164/en/ 17) Cornberg M, Razavi HA, Alberti A, Bernasconi E, Buti M, Cooper C, et al. A systematic review of hepatitis C virus epidemiology in Europe, Canada and Israel. Liver Int. 2011 Jul;31 Suppl 2:30-60. 18) Lagging M, Wejstal R, Norkrans G, Kalstrom O, Aleman S, Weiland O, et al Treatment of hepatitis C virus infection for adult and childran: Updated Swedish consensus
recommendations. Infect Dis (Lond) 2016: 48; 251-261 19) Omata M, Nishiguchi S, Ueno Y, Mochizuki H et al Sofosbuvir plus ribavirin in Japanese patients with chronic genotype 2 HCV infection, an open-label phase 3 trial. J Viral Hep 2014;762-8 20) Zeuzem S, Dusheiko GM, Salupere R, Mangia A, Flisiak R, Hyland RH, et al. Sofosbuvir in Genotypes 2 or 3 VALENCE Trial. N Engl J Med. 2014 May 22. 370:1993-2001. 21) Dieterich D, Bacon B, Flamm S, Kowdley K, Milligan S, Tsai N et al. Evaluation of sofosbuvir and simeprevir-based regimens in the TRIO network - Academic and community treatment of a real-world, heterogeneous population. Presented at the 65th Annual Meeting of the American Association for the Study of Liver Diseases: The Liver Meeting 2014, Boston MA; Nov 7-11 2014; J Hepatol 2015; 62, suppl 2. S621 22) Ho SB, Monto A, Peyton A, Kaplan DE, Byrne S Moon S et al Efficacy of sofosbuvir plus ribavirin in Veterans with hepatitis C viruss genotype 2 infection compensated cirrhosis and multiple comorbidities. Clin Gastroenterol Hepatol 2016 doi: 10.1016/j.cgh.2016.05.024 [Epub ahead of print]. 23) Ioannou GN, Beste LA, Chang MF, Green PK, Lowy E, Tsui JI et al Effectiveness of Sofosbuvir, Ledipasvir/Sofosbuvir, or Paritaprevir/Ritonavir/Ombitasvir and Dasabuvir regimens for treatment of patients with hepatitis C inn the Veterans Affairs National Health Care System. Gastroenterology 2016;151:457-471 24) Hezode C, Fontaine H, Darival C, Carney D, Zoulim F et al Triple therapy in treatmentexperienced patients with HCV cirrhosis in a multicenter cohort of the Freanch early access programme (ANRS CUPIC) J Hepatol 2013; 434-41 25) Lawitz E, Poordaad F, Wells J, Hyland RH et al High efficacy of sofosbuvir/velpatasvir /GS9857 with or without RBV for 12 weeks in direct acting antiviral experienced patients with genotype 1 HCV infection. J Hepatol 2016;64 suppl 2, PS021
Table
Table 1. Overall demographic characteristics of patients and by treatment duration
Patients with Patients by treatment duration Characteristics
advanced fibrosis or cirrhosis SOF-RBV for
SOF-RBV for
SOF-RBV for
12-20 weeks
12 weeks
16-20 weeks
(N=291) (%)
(N=123) (%)
(N=168) (%)
Mean Age, years
68,0
66,0
69,7
Range
18-87
18-82
36.9-87
Male sex, n (%)
134 (46,05)
47 (38,21)
63 (55,00)
BMI
26,50±3,98
25,88±4,51
27,00±3,48
Liver stiffness, Mean KPa
15,27±9,32
9,71±2,09
18,78±9,30
Cirrhosis, n (%)
168 (57.73)
0
168
Mean HCV RNA, log10 2,869212±3,669,940 2,994,498±3,814,380
2,792,051±3,584,309
IU/ml±SD Mean ALT levels
80,09±80.49
60,58±61.15
95,19±90.08
Mean AST levels
67,57±63,66
46,18±40,07
83,72±73,09
50 (17,1)
n.a.
50 (29,7)
PLT <100,000 u/l, n (%)
CTP A
149 (88,8)
3 (0,2)
146 (88,6)
CTP B
14 (8,2)
0
14 (8,3)
Unknown
5 (2,9)
0
5 (2,9)
MELD score
8,28±2,38
n.a.
8,28±2,38
Albumin <3.5 g/dl, n (%)
62 (21,3)
n.a.
62 (36,9)
Naïve
163 (56,0)
81 (65,8)
81 (48,8)
Previously treated
130 (44,0)
42 (34,2)
86 (51,2)
Prior non response
27 (20,8)
2 (4,9)
24 (27,9)
Prior relapse
103 (79,2)
40 (95,4)
62 (72,1)
167,58±82,20
212,26±86,96
136,33±61,74
HCV treatment experience, n (%)
Platelets count
Table 2. Characteristics of patients with cirrhosis by treatment duration
Characteristics
SOF-RBV for 16 weeks (N=90) (%)
SOF-RBV for 20 weeks (N=82) (%)
Mean Age, years (range)
70 (37-86)
69 (36.9-87)
Male sex, n (%)
47 (52.2)
43 (52.44)
BMI (mean±SD)
27.12±3.73
26.58±3.23
Liver stiffness,Mean KPa±SD
15,06±5.54*
22,73±12.16
Mean HCV RNA, log10 IU/ml±SD
2,623,171± 3,825,525
2,887,072,051± 3,198,588
Mean ALT levels±SD
96.31±86,32
92.31±91,19
Mean AST levels±SD
83.87±72.90
83.10±72.05
PLT <100,000 u/l n, (%)
26 (29.5)
23 (29.5)
CTP A n, (%) CTP B n, (%) Unknown n (%)
77 (85.5) 7 (7.7) 6 (6.6)
69 (84.1) 9 (10.9) 4 (4.8)
MELD score mean±SD
7,95±2,05
8,59±2,58
Albumin <3.5 g/dl, n (%)
7 (7.7)
7 (8.5)
HCV treatment experience, n (%)
Naïve, n (%)
45 (50)
41(50)
Previously treated, n (%)
45 (50)
41(50)
Platelets count mean±SD
140,76±60,90 132,86±62,80
* P value <0,0001
Table 3.0 Overall adverse events, among patients with cirrhosis and by treatment duration
SOF+RBV
SOF+RBV
SOF+RBV
SOF+RBV
Total
Cirrhotic
16 weeks
20 weeks
(N=291)
(N=168)
(N=91)
(N=82)
Fatigue
177 (61,0%)
106 (63,6%) 49 (53,8%)
57 (69,5%)
Headache
69 (23,7%)
58 (34,5%)
34 (37,3%)
24 (29,2%)
Nausea
54 (18,5%)
49 (28,5%)
25 (27,4%)
24 (29,2%)
Insomnia
51 (17,5%)
31 (18,4%)
14 (15,3%)
17 (20,7%)
Rash
6 (2,06%)
4 (2,3%)
3 (3,2%)
1 (1,2%)
Hemoglobin <12.5 g/dl
24/192
11 (6,5%)
5 (5,4%)
6 (7,3%)
7/192 (3,6%)
7 (4,1%)
3 (3,2%)
4 (4,8%)
<8.5 g/dl
5/192 (2,6%)
5 (2,9%)
2 (2,1%)
3 (3,6%)
Neutrophils <750/mm3
0/291
0/186
0/91
0/82
Platelets <50,000/mm3
0/291
0/168
0/91
0/82
(12,5%) Hemoglobin <10.5 g/dl
Hemoglobin
Ethic Statement This study was conducted in accordance with the Declaration of Helsinki. As it is an observational study conducted in accordance with the Italian Medicine Agency, patients were not required to sign any informed consent.
Figure1
Figure2
*Graphical Abstract
Graphical abstract N=123
Patients with HCV GT2 infection = 291
SVR12
patients with advanced fibrosis
N=168
91 patients with cirrhosis
99,1
94,5
82 patients with cirrhosis 91,5
0
4
8
12
16
20
24 weeks