Friday, January 13, 2017

Real-world use, effectiveness, safety of anti-viral treatment in chronic hepatitis C genotype 3

Original Article
Alimentary Pharmacology & Therapeutics
Early View, Version of Record online: 12 JAN 2017

Real-world use, effectiveness and safety of anti-viral treatment in chronic hepatitis C genotype 3 infection
Authors M. Cornberg, J. Petersen, A. Schober, S. Mauss, K. H. W. Böker, R. Link, R. Günther, Y. Serfert, H. Pfeiffer-Vornkahl, M. P. Manns, C. Sarrazin, D. Hüppe, T. Berg, C. Niederau
First published: 12 January 2017
Full publication history DOI: 10.1111/apt.13925

Treatment of chronic hepatitis C genotype 3 (GT3) is more challenging compared with other genotypes. Since 2014, several new treatment regimens have been approved but sometimes based on limited data.

To validate the use, effectiveness and safety of anti-viral treatment in chronic hepatitis C genotype 3 infection under real-word conditions.

The German Hepatitis C-Registry is a large national non-interventional real-world study for patients with chronic hepatitis C. A total of 1322 GT3 patients were enrolled (211 untreated and 1111 treated patients).

Between February 2014 and September 2015, five different treatment strategies have been used (PegIFN+RBV, PegIFN+RBV+SOF, SOF+RBV, DCV+SOF±RBV, LDV/SOF±RBV). Treatment uptake and use of treatment concepts changed markedly and rapidly during the study influenced by new approvals, guideline recommendations, and label updates. PegIFN-based therapies constantly declined while DCV-based therapies increased with one interruption after the approval of LDV/SOF, which was frequently used until new guidelines recommended not using this combination for GT3. Per-protocol SVR ranged from 80.9% in the PegIFN+RBV group to 96.1% in PegIFN+RBV+SOF treated patients. Treatment-experienced patients with cirrhosis showed a suboptimal SVR of 68% for SOF+RBV but a high SVR of 90–95% for DCV+SOF±RBV. The safety analysis showed more adverse events and a stronger decline of haemoglobin for RBV containing regimens.

Real-world data can validate the effectiveness and safety for treatment regimens that had previously been approved with limited data, in particular for specific subgroups of patients. The present study demonstrates how rapid new scientific data, new treatment guidelines, new drug approvals and label changes are implemented into routine clinical practice today.

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Treatment of chronic hepatitis C has markedly been improved with the introduction of IFN-free DAA therapies in 2014. In contrast to genotype 1, there have still been more challenges for treatment of patients with GT3.[5] Several DAA had not been approved for GT3 and for several combinations, that is, PegIFN+RBV+SOF, DCV+SOF+RBV and LDV/SOF+RBV data had been limited.[8-10, 13] The present real-world study shows that the use of DAA combinations has significantly changed several times within a short period of 20 months. Despite the approval of SOF+RBV in January 2014, 22% of patients still received dual PegIFN+RBV in the first time period of the present study. More than 93% of patients treated with PegIFN+RBV at that time were therapy-naïve patients without cirrhosis. In fact, response-guided therapy with PegIFN+RBV for 16–24 weeks in therapy-naïve noncirrhotic patients was at that time a reasonable alternative compared to 24 weeks SOF+RBV in particular when considering costs.[14] The most frequently used regimen with >50% of all patients treated during the first 7 months after approval of SOF was 12 weeks PegIFN+RBV+SOF. Interestingly, this treatment showed numerically the best SVR among all regimens. Thus, the present real-world data confirms the efficacy of PegIFN+RBV+SOF reported in the BOSON phase III trial[15] and is in line with other recent real-world data.[16, 17] Based on our data, treatment with PegIFN+RBV+SOF for 12 weeks can achieve a PP SVR >95% in patients without cirrhosis and a SVR >85% in patients with cirrhosis. Thus, this combination is an effective option if other DAA are not available or not recommended due to economical considerations, which is the reality in many countries up to now, i.e. in Poland.[18] After the approval of DCV, the use of PegIFN-based therapies declined constantly in this German study probably also because the German Guidelines published in October 2014 recommended not to use IFN anymore.[19] Despite limited data for GT3, uptake for DCV-based therapies was fast and reached almost 50% in the 3 months period following EMA approval and more than 80% after the label update for noncirrhotic patients. More than 120 noncirrhotic patients have been treated with the recommended 12 weeks DCV+SOF regimen. The SVR of 93% was comparable to the result from the ALLY3 phase III trial.[11] However, 12 week DCV+SOF+RBV reached even 100% SVR in patients without cirrhosis. In general, RBV should be avoided if possible because it is associated with a higher frequency of AEs and anaemia as confirmed in this study. For GT3 it may, however, remain a cornerstone, if baseline NS5A resistant associated substitutions (RAS) are present[20] or patients have unfavourable baseline characteristic. This appears to be true even for the recently approved combination of velpatasvir and sofosbuvir (VEL/SOF), which has become another new standard therapy for GT3.[21, 22] The current EASL clinical practice guidelines recommend treating IFN treatment-experienced GT3 patients without cirrhosis with VEL/SOF or DCV+SOF plus RBV if baseline NS5A RAS testing is not available.[23] However, we have only observed a small (3%) but not significant difference between naïve and IFN treatment-experienced noncirrhotic patients who have been treated with 12 weeks DCV+SOF, but there may be a bias because physicians may have selected RBV or longer treatment durations for more difficult-to-treat patients. In fact, only 27% of all 12-week DCV+SOF treated patients were treatment-experienced but 42% of 12-week DCV+SOF+RBV treated patients.
Patients with well-compensated compensated cirrhosis achieved excellent SVR with 12 weeks DCV+SOF+RBV like in the ALLY3+ trial[24] although the number of cirrhotic patients treated with this regimen was small in the present registry. For patients with advanced cirrhosis, we suggest 24 weeks DCV+SOF with or without RBV; the SVR was nominally higher in the RBV containing cohort but the limitations of a non-interventional registry have to be considered before recommending to add RBV in all patients with advanced cirrhosis. However, addition of RBV with a rapid dose reduction in the case of AEs may be a reasonable approach.
Costs and availability will remain major factors for the decision between a one-pill-fits-all concept and an individualised approach.[25] However, economic considerations can be problematic if newly approved therapies are used too fast without robust data available. This had been the case for the use of LDV/SOF, which had a lower price, compared with the use of DCV+SOF. After the approval of LDV/SOF there was a rapid uptake in the real-world setting accounting for almost 30% of all GT3 therapies although the study data were based on limited phase II data showing a SVR between 64 and 100%.[13] However, not a single patient in recent studies received LDV/SOF+RBV for 24 weeks as recommended in the label. Our data show that treatment with LDV/SOF+RBV for just 12 weeks is suboptimal and only reaches the SVR seen with SOF/RBV. Our present data are similar to the data of the UK early access program (EAP), which showed a SVR of only 61% for 12 weeks LDV/SOF±RBV in patients with advanced cirrhosis.[26] Interestingly, sequence analysis of GT3-infected patients with failure to LDV/SOF-based therapy from a large European Resistance Databank showed no selection of NS5A RAS.[27] This indicates a low anti-viral activity of LDV against GT3 isolates. However, patients treated according to the label for 24 weeks with LDV/SOF+RBV showed a SVR >90% in difficult-to-treat patients, which may be explained by some additional efficacy of the administration of LDV, if given for a longer period despite a low anti-viral activity against GT3. Retrospectively, the label recommendation proved to be appropriate but a treatment period of 24 weeks with LDV/SOF+RBV may only be considered if no other NS5A inhibitor is available. One more interesting aspect of our data is that the use of LDV/SOF dramatically declined after the International Liver Congress of EASL in 2015 at which the UK EAP data and the new EASL guidelines recommended not to use LDV/SOF in GT3.[28] This clearly demonstrates the importance of scientific meetings and guidelines for the real-world setting and also shows how rapid such recommendations are implemented into clinical practice today.
One important aim of the real-world registry was to validate the data of treatment with SOF+RBV for 24 weeks, which became available as the first IFN-free therapy for GT3 after the approval of SOF in January 2014. However, SOF+RBV was only used in approximately one quarter of patients and this figure did not show dramatic changes over time. The uncertainty of data in difficult-to-treat patients and the high costs were probably main reasons for the hesitant use of SOF+RBV. In fact, our data confirm that the SVR is suboptimal for that regimen in IFN-experienced patients with cirrhosis. This observation was similar in other real-world studies.[16, 17] Thus, SOF+RBV should not be used if VEL/SOF or DCV+SOF are available.
The suboptimal effectiveness of SOF+RBV in difficult-to-treat patients and the lack of robust data for other therapies might be a reason why treatment has been delayed in GT3 patients more often when compared with GT1 patients in the present German cohort. The frequency of patients who were screened but not treated was higher for GT3 when compared with the non-GT3 cohort. In addition, GT3 patients were underrepresented in this study with around 15% of all HCV patients when compared with 28% seen in a former large German real-life registry.[29] Patients in the nontreated cohort were younger and more often treatment-naïve; they also had less frequently cirrhosis but more frequently had an opiate substitution therapy. These characteristics may have been reasons to delay treatment until more reliable data or better treatment options became available. Indeed, shortly after the GT3 12 week label update of DCV the frequency of nontreated patients dropped from 18% to 4%.
A strength of the present study is the fact that it included almost 200 sites with many of them treating <10 patients. Thus, the present registry reflects not a multicentre study of academic centres but a true real-world cohort covering more than 30% of all therapies initiated in Germany during that time period. The present study shares the limitations of all real-world studies with data not as complete and controlled when compared with phase II/III studies.
In conclusion, the present analysis shows that real-world data can validate the effectiveness and safety for treatment regimens that had previously been approved with limited data in particular for subgroups of patients. The present study also demonstrates how rapid new scientific data, new treatment guidelines, new drug approvals and label changes are implemented into routine clinical practice today.

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