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Durability of SVR in chronic hepatitis C patients treated with peginterferon-α2a/ribavirin in combination with a direct-acting anti-viral
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Alimentary Pharmacology & Therapeutics July 2013
K. Rutter*, H. Hofer*, S. Beinhardt*, M. Dulic, M. Gschwantler, A. Maieron, H. Laferl, A. F. Stattermayer*,T.-M. Scherzer*, R. Strassl, H. Holzmann, P. Steindl-Munda* & P. Ferenci*
*Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria. Department of Internal Medicine IV, Wilhelminenspital, Vienna, Austria. Hospital Elisabethinen, Linz, Austria. Department of Internal Medicine, Kaiser-Franz-Josef-Spital, Vienna, Austria. Department of Clinical Virology, Medical University of Vienna, Vienna, Austria.

The introduction of direct-acting anti-virals has increased sustained virological response (SVR) rates in chronic hepatitis C genotype 1 infection. At present, data on long-term durability of viral eradication after successful triple therapy are lacking.
To evaluate the long-term durability of viral eradication in patients treated with triple therapy, including direct-acting anti-virals.
Patients who participated in randomised, controlled trials or an extended access programme of treatment with peginterferon-α2a/ribavirin in combination with a direct-acting anti-viral (telaprevir, danoprevir, faldaprevir, simeprevir, mericitabine, balapiravir) were followed after achieving SVR. The median follow-up after the patients was 21 (range: 7-64) months.
One hundred and three patients with chronic hepatitis C genotype 1 infection [f/m: 34/69; GT-1b: 67 GT-1a: 34, GT-4: 2; mean age: 47.6 years (45.5-49.7; 95% CI)] achieving a SVR triple therapy were followed. Two cases of late relapses (2/103, 1.9%; 95% CI: 0.24-6.8) were observed. One patient was cirrhotic, both carried the genotype 1b and completed the prescribed treatment. The relapses occurred 8 and 12 months after cessation of anti-viral treatment. Cloning sequencing revealed identical sequence in both patients. Resistance analysis revealed no presence of viral resistance.
Like the SVR after peginterferon-α2/ribavirin combination treatment, HCV eradication after triple therapy remains durable after long-term follow-up.
Eradication of HCV is the ultimate goal of anti-viral therapy. The commonly used parameter for viral eradication is a sustained virological response defined by undetectable HCV-RNA 6 months after end of successful therapy. Sustained virological response is commonly considered as parameter for cure of chronic hepatitis C. Long-term follow-up studies in patients treated by peginterferon/ribavirin have shown that HCV eradication is durable with follow-up periods of more than 20 years.[1-5] Achieving a SVR prevents progression to end stage liver disease and occurrence of hepatocellular carcinoma.[6-8] Moreover, successful treatment of HCV is associated with reduced hepatic morbidity, liver related deaths and improvement of health-related quality of life.[7-11] Recent reports even documented a reversal of cirrhosis many years after achieving sustained virological response (SVR).[12-14] Currently we are witnessing the development of potent anti-viral drugs for treatment of chronic hepatitis C. The first two licensed protease inhibitors almost doubled the rate of SVR both in treatment-naïve[15, 16] and treatment-experienced patients.[17, 18] It is unknown whether the encouraging long-term data of dual combination therapy can be extrapolated to triple therapy with direct-acting anti-virals. So far, no data on the long-term outcome of patients with SVR following triple therapy have been reported. Aim of our study was to analyse virological follow-up of a large cohort of SVR patients participating in phase 2 or 3 trials or an extended access programme treated with peginterferon/ribavirin in combination with different direct-acting anti-virals.
Patients and methods

Patients participated in prospective randomised trials of treatment with pegylated interferon-alfa, ribavirin (PEGIFN/RBV) with a direct-acting anti-viral[15, 18-20] or in a named patient early access programme for telaprevir and were routinely invited for follow-up examinations.[3] Patients were selected according to the inclusion and exclusion criteria of the respective trial. All patients were Caucasians. Patients receiving placebo or no ribavirin were excluded from this analysis. A total of 103 out of 113 patients (91.2%) with SVR after DAA containing therapy attended follow-up visits at the out-patient clinics of the 4 participating tertiary referral centres. SVR was achieved in 43 patients receiving telaprevir, 30 on faldaprevir,[21, 22] 20 on simeprevir[23], 3 on danoprevir, 5 on ritonavir boosted danoprevir, 5 on mericitabine[24],3 on ritonavir boosted danoprevir and mericitabine and 2 on balapiravir.[25] For details see Table 1.


Virological tests
HCV was quantified during the studies in central laboratories using different PCR assays described in subscript Table 1. During follow-up, viral load of HCV was quantified by real-time PCR (COBAS TaqMan HCV Test Version 2; Roche Diagnostics, Pleasanton, CA, USA) in all patients. Genotyping of HCV was determined by Versant genotype assay (LiPA 2.0; Bayer HealthCare LLC, Subsidiary of Bayer Corporation, Tarrytown, NY, USA). Sequencing of HCV-RNA was performed for one patient by Bohringer-Ingelheim Canada (by Marquis Martin) using the ABI 3730 Genetic Analyzer (Applied Biosystems) detection system. The second sequencing of HCV-RNA was performed by the department of virology (HH) using the ABI 3130XL Genetic Analyzer (Applied Biosystems).
Clinical follow-up
All patients were asked to return to follow-up visits after 6 months and then at least once a year. Out of 113 patients, 103 patients returned to follow-up visits. At the clinical visits, routine blood tests, including alfa-1-fetoprotein and quantitative HCV-RNA determination (by TaqMan HCV Test), were obtained. Patients with pre-treatment cirrhosis were asked to perform a liver ultrasound examination prior to the visit. If necessary [in case of hepatic decompensation or suspicion for hepatocellular carcinoma (HCC)], further examinations were performed as needed. The institutional review board approved this retrospective non-interventional analysis.
Statistical analysis
Database management and statistical analysis were performed using commercially available software systems (Microsoft Office Excel 2010; Microsoft Corporation, USA and SPSS 2006 for Windows version 16). Quantitative variables were expressed as mean with the 95% confidence interval or as median (range). Data were analysed by using Student's t-test for Gaussian variables, Mann-Whitney U-test for non-Gaussian variables as well as Chi-squared test. To determine, whether variables were normally distributed or not, the Kolmogorow-Smirnow test was applied. All P-values were two-tailed and assumed to be statistically significant if P ≤ 0.05.
Characteristics of patients

A total of one hundred and three patients (f/m = 34/69, age: 47.6 8.7; years s.d.) with a sustained virological response (SVR) were evaluated. Patient's characteristics are shown in Table 2. A total of 23 patients (17 Nonresponder/6 Relapser) were treatment experienced, while 80 were treatment naive. One hundred and one patients were chronically infected with HCV-genotype 1 (HCV-1a: 34; HCV-1b: 67), two patients with HCV-genotype 4 (both received mericitabine). Ninety-three patients with HCV-genotype 1 received a protease inhibitor, seven patients a NS5B inhibitor (balapiravir or mericitabine) and three patients a combination of protease and NS5B inhibitor together with pegylated interferon-alfa and ribavirin at the four Austrian study sites (for details see Table 1).
Two relapses (2/103, 1.9%) occurred during follow-up after achieving a sustained virological response: One late relapse was seen in a 51-year-old female noncirrhotic patient (Fibroscan: 5.8 0.5 kPa) infected with genotype 1b. She was a carrier of the IL-28B rs12979860 T/C genotype. She was treatment naïve and received triple therapy (3 days lead in with peginterferon/ribavirin followed by peginterferon/ribavirin/faldaprevir 120 mg daily) for 12 weeks and peginterferon/ribavirin for a total of 24 weeks. HCV-RNA became undetectable at week 4 and remained undetectable throughout the whole therapy. She was HCV-RNA negative after 24 weeks of follow-up (SVR24) and had aminotransferases in normal range. Two months later, she came to the out-patient unit because of abdominal pain. Laboratory test showed detectable HCV-RNA (=8 months after end of treatment; viral load: 1.33 E5 IU/mL). The positive HCH RNA was confirmed several times.
Cloning sequencing in this patient showed the same sequence in the sample taken after relapse as in the sample obtained at screening. Resistance analysis revealed no presence of viral resistance. She received a retreatment with pegIFN/RBV and telaprevir for a total of 24 weeks and was HCV-RNA undetectable at end of treatment. She is currently on treatment-free follow-up. The second late relapse occurred in a 59-year-old treatment-naïve, cirrhotic, male patient, who was chronically infected by HCV-genotype 1b and carrier of IL-28B genotype rs12979860 T/C. He received triple therapy (peginterferon/ribavirin/faldaprevir 120 mg daily for 24 weeks and peginterferon/ribavirin for a total of 48 weeks). HCV-RNA became undetectable at week 4 and remained undetectable throughout the whole therapy. After 24 weeks of follow-up, HCV-RNA was not detected (SVR24) and aminotransferases were normal. At a routine control examination 12 months after end of treatment, increased ALT was detected. HCV quantification revealed a viral load of 288 IU/mL. The genotype of the pre-treatment and the postrelapse sample was HCV-1b and cloning sequencing revealed identical sequence in both samples. Resistance analysis revealed no presence of viral resistance. No signs of hepatic decompensation or HCC occurrence were observed.
In both patients, HCV-RNA increased to pre-treatment levels within the next months. Of the remaining 101 patients, 90 (89.1%) had aminotransferases within the normal range at the last follow-up. AFP levels were available in 60 patients and were within the normal range in 54/60 (90%) patients. In the patients with slight increase AFP levels abdominal ultrasound revealed no signs of hepatic mass. No patient took immunosuppressive medication in the posttreatment follow-up period.
This study confirms that SVR equals permanent HCV eradication by whatever interferon-based anti-viral treatment it was achieved. Our data indicate that the favourable long-term outcome reported after peginterferon/ribavirin combination therapy seems to hold true for patients treated with a triple therapy with peginterferon/ribavirin in combination with a direct anti-viral agent. To the best of our knowledge, this is the first study reporting long-term virological outcomes in patients with hepatitis C after successful anti-viral triple therapy.
There are theoretical concerns regarding the durability of HCV eradication after successful direct-acting anti-viral-based triple therapy. During direct-acting anti-viral treatment resistance-associated variants with reduced replication fitness compared with the wild type virus may emerge. If these resistance-associated variants cannot be eliminated by the required peginterferon/ribavirin backbone, strains with reduced replication fitness may persist in low concentration and may account for late relapses. In the ADVANCE study, 1 of 357 patients evaluated had a confirmed late relapse after early discontinuation of treatment (randomised to the arm 8 weeks of telaprevir followed by dual therapy) at week 12.[15] In the PROVE 2 study, 2 late relapses were observed 36 and 48 weeks after the end of treatment.[19] In a phase 2 trial of an interferon-free regime (ritonavir boosted protease inhibitor ABT-450 combined with the nonnucleoside inhibitor of HCV NS5B polymerase ABT-072), one patient had a late relapse 36 weeks after end of treatment.[27] Thus data on longer follow-up are of major importance in the era of direct-acting anti-virals in HCV treatment.
In our study, two patients with a sustained virological response (SVR24) experienced a relapse 2 and 6 months later. Both patients completed a full course of anti-viral treatment without dose modifications or discontinuations of medications with peginterferon/ribavirin and faldaprevir. The serum samples of both patients (taken at baseline and after relapse) revealed no viral resistance and showed viral homology to samples collected at screening. Neither of the two patients showed a risk behaviour regarding HCV infection before reappearance of HCV. Thus, in both patients a late relapse rather than a newly acquired infection seems to be the reason for reappearance of hepatitis C virus. Obviously, an ongoing occult HCV infection cannot be excluded with certainty.[28]
Overall, our data show that it seems appropriate to extrapolate the encouraging long- term data of dual combination therapy to triple therapy with direct-acting anti-virals. The late relapse rate was 1.9% (95% CI: 0.24-6.8) as compared to 0.18% (0.004-1.01) in a much larger cohort of patients with SVR after dual therapy.[29] As all patients treated with direct-acting anti-virals in combination with PEGIFN/RBV achieving similar rates of SVR were followed prospectively, a potential selection bias is unlikely. However, in parallel to reported late relapses after successful dual therapy), late relapses after triple therapy - although a rare event - seem to occur within the first months after SVR like in the cases in our cohort. The fact that both relapses were observed in patients receiving faldaprevir occurred possibly just by chance, as the mode of action and the efficacy of the protease inhibitors are similar. Nevertheless, it seems advisable to confirm a successful HCV eradication within the first year of follow-up after achieving a sustained virological response. From our data, no impact on the durability of SVR after interferon-free treatments can be inferred.
In conclusion, our study shows that HCV eradication by triple therapy remains durable and confirms an excellent long-term prognosis of HCV patients with SVR. To assess the long-term clinical benefit of triple therapy, studies with a longer follow-up and larger patient numbers are needed.
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