Thursday, January 5, 2017

Hepatitis C: efficacy and safety in real life

Special Issue: Liver International
Proceedings of the 10th Paris Hepatitis Conference. International Conference on the Management of Patients with Viral Hepatitis undefined

Volume 37, Issue S1
January 2017
Pages 7–12

Hepatitis C: efficacy and safety in real life (pages 26–32)
Robert Flisiak, Joanna Pogorzelska and Marta Flisiak-Jackiewicz
Version of Record online: 3 JAN 2017 | DOI: 10.1111/liv.13293


Interferon-free combinations were registered in 2014 and 2015 for the treatment of chronic HCV infection. As a result, real-world experience has been gathered in the last year and this paper presents data available in September 2016. Real-world studies on the efficacy of the ledipasvir/sofosbuvir (LDV/SOF)±ribavirin (RBV) regimen showed a sustained virologic response (SVR) rate of between 91% and 98%. The SVR rate in the 13858 patients included in this paper was 94%, and 92% in the 3506 patients with cirrhosis. In a number of recently published real-world studies evaluating ombitasvir/paritaprevir/ritonavir (OBV/PTV/r)±dasabuvir (DSV)±RBV, the SVR rate was between 92% and 100%. The SVR rate of the 4260 patients included in the studies in this paper was 97% and the rate was the same in the 1647 patients with cirrhosis. Recently, data evaluating SOF/simeprevir±RBV showed an SVR rate >90%, while in combination with daclatasvir this rate reached approximately 95%. The safety data available for LDV/SOF±RBV and OBV/PTV/r±DSV±RBV show that discontinuation due to adverse events was necessary in no more than 3% of patients and the frequency of serious adverse events was between 0 and 11%, in particular in real-world studies. Because of the similar efficacy and safety, real-world data support the use of either the LDV/SOF±RBV or OBV/PTV/r±DSV±RBV regimen in patients with genotypes 1 or 4. There is still not enough real-world data in patients with genotype 3 and other genotypes.

Key points

  • Current real-world experience supports the use of either LDV/SOF±RBV or OBV/PTV/r±DSV±RBV in genotype 1 and 4 infected patients whatever the severity of fibrosis.
  • HCV treatment history, HIV coinfection and previous liver or kidney transplantation do not influence the efficacy and safety of these two regimens.
  • The efficacy of the SOF+SMV±RBV regimen was relatively low in real-world results.
  • There is still not enough real-world data in patients infected with genotype 3 and other genotypes.

1 Introduction
The only therapeutic option for the treatment of HCV infection before 2011 was pegylated interferon alfa (PegIFNa) and ribavirin (RBV) for 24-48 weeks resulting in a sustained virologic response (SVR) rate in 40%-70% depending on the genotype (G) and the population.[1, 2] The first generation direct-acting antivirals (DAA), the protease inhibitors boceprevir and telaprevir, were added to the standard regimen resulting in improved SVR rates of approximately 70%.[3-5] The use of these “triple” regimens was limited to genotype 1 patients and it was still ineffective in nonresponders to PegIFNa+RBV, patients with cirrhosis, and patients with IL28B non-CC genotypes. Moreover, safety, especially in patients with advanced liver fibrosis, was not improved.[6] The development of pangenotypic, highly effective and safe interferon-free (IFN-free) medications based on combinations of 2-3 DAA quickly changed the landscape of HCV treatment.[7, 8] The new DAA are protease (NS3/4A), polymerase (NS5B) and NS5A inhibitors. In clinical trials, their combinations provided SVR rates >90% whatever the severity of fibrosis and the treatment history. In addition, they were safe and made it possible to shorten treatment to at least 12 weeks in most patients. The first IFN-free combination was registered in 2014, but in most countries this highly effective therapy was introduced in 2015. Thus, data from real-world experience became available only quite recently. The efficacy of real-world data is usually lower than that of clinical trials, because included patients are more diversified and adherence is usually poorer in the general population of patients, but this is not the case with IFN-free regimens.
This paper is a “snapshot” of real-world efficacy and safety data available in September 2016, after 2 years of DAA in interferon-free regimens. New data continue to be gathered and will probably be available before the final publication of this paper, but these can be obtained during the 10th Paris Hepatology Conference in January 2017.

2 LDV/SOF±RBV: sustained virologic response of 91%-98%
The combination of the NS5A inhibitor, ledipasvir and the polymerase inhibitor sofosbuvir (LDV/SOF), was registered by both the US Food and Drug Administration (FDA) and the European Medicines Agency as the first single pill, interferon-free regimen in 2014.[9] Therefore, some real-world data on LDV/SOF were already presented at the annual American Association for the Study of Liver Diseases meeting in November 2015, but most results were presented at the European Association for the Study of the Liver (EASL) meeting in 2016.
Real-world efficacy data are presented in Table 1 and show that LDV/SOF±RBV treatment resulted in an SVR rate of between 91% and 98%. The SVR rate of the 13858 patients with G1 infection was 94% and it was 92% in the 3506 patients with cirrhosis. Patients were mostly treated for 12 weeks with RBV or for 24 weeks without RBV (Table 1). This is similar to the report by Curry et al. in G1, treatment-experienced patients with cirrhosis.[10] The SVR rate was higher in phase 2/3 clinical trials (n=421, SVR=96%) than in real-world studies (n=503, SVR=91%).

Table 1. Overview on efficacy in real-world studies with LDV/SOF±RBV in HCV infection
ReferenceCountryNumber of patients, nCirrhosis, nSVR 12 in all patients, n (%)SVR 12 in cirrhosis, n (%)
  1. a Patients with FIB-4>3.5.
Terrault et al.[18]USA10441008 (96)
Afdhal et al.[13]USA19796791936 (98)654 (96)
Buggisch et al.[16]Germany19561923 (98)
Crespo et al.[17]Spain15048141436 (95)779 (96)
Latt et al.[20]USA1053983 (93)
Qureshi et al.[47]USA338331 (98)
Flisiak et al.[19]Poland864381 (94)37 (86)
Fuchs et al.[48]USA273167249 (97)161 (96)
Backus et al.[11]USA53901641a4911 (91)1436 (88)a
Cheung et al.[43]UK162162147 (91)147 (91)
Aghemo et al.[49]Italy7368 (93)
Overall13858350613073 (94)3214 (92)
The largest single study including 5390 patients with G1 infection treated with the LDV/SOF regimen was the cohort from US Veterans Administration register.[11] In this study an SVR rate of 91% was obtained in all patients and 88% was obtained in patients with cirrhosis. This large population allowed a highly reliable analysis of subpopulations. There were no differences related to the use of RBV, genotype subtype, age, gender, HIV, decompensation or treatment experience. Significantly, lower efficacy was demonstrated in patients with advanced liver fibrosis (87.5% vs 92.7%) and those receiving proton pump inhibitors (PPI), particularly if they were administered with RBV (86.5% vs 91.9%).[11] Lower efficacy in patients with cirrhosis (92%) vs those without (98%) was demonstrated in the Portuguese Universal Coverage Program.[12] The same tendency was also confirmed by Curry et al.[10] with an 85% SVR rate in patients with cirrhosis after 12 weeks of treatment without RBV in a comparative analysis of registration and real-world studies. According to that study the reduced efficacy of the 12-week regimen with LDV/SOF could be improved by adding RBV and/or extending therapy to 24 weeks.[10]

The reduced efficacy of LDV/SOF when combined with PPI has been shown in previous studies including the US Veterans Administration cohort. However, it was not confirmed in 454 patients receiving PPI from the large TRIO study including 1979 patients.[13]

Another analysis from the US Veterans Administration performed in 4365 treatment-naive patients with G1 infection (mostly 1a) showed a significantly lower SVR rate in patients with low grade fibrosis and low viral load, treated according to the current label for 8 weeks (93.2%) compared to the 12-week regimen (96.6%).[14] On the other hand, results from the TRIO database including 895 patients, supported possible shortening of the LDV/SOF regimen to 8 weeks in patients with G1b infection.[15] No difference was found in relation to the length of treatment in 1956 patients in the German Hepatitis-C Registry or in 423 patients from the Spanish HEPA-C cohort who qualified for a 8-week regimen.[16, 17] In the 323 patients from HCV-Target study who received a shorter regimen, 131 received 8 weeks of LDV/SOF resulting in a 97% SVR rate that was the same as that in patients treated for 12 weeks.[18]

Unfortunately, safety is not well documented in most real-world studies (Table 2). Analyses from Spanish, Polish and USA studies showed serious adverse events in no more than 6% of patients and discontinuations due to adverse events in 0.8%-2.3%.[17, 19, 20] Discontinuation due to adverse events were also rare (<1%) in transplant recipients treated with LDV/SOF, but severe adverse events in this difficult population were reported in 9.4% and 11% of American and European populations respectively.[21, 22]

Table 2. Available safety data of interferon-free regimens in real-world experience
RegimenReferenceDiscontinued due to adverse events (%)Serious Adverse Events (%)
  1. a Liver or kidney recipients.
LDV/SOF±RBVCrespo et al.[17]1.75.6
Latt et al.[20]0.80.8
Flisiak et al.[19]2.30
Reddy et al.[21],a0.89.4
Colombo et al.[22],a0.911
OBV/PTV/r±DSV±RBVCalleja et al.[28]1.75.9
Flisiak et al.[29]2.43.8
Hinrichsen et al.[52]1.42.3
Hunyady et al.[31]04.9
Lubel et al.[32]1.75.4
Zuckerman et al.[30]33.8
SMV+SOF±RBVSulkowski et al.[24]35

3 Other sofosbuvir containing combinations have a slightly lower efficacy
The combination of SOF+SMV±RBV was the first available interferon-free regimen, but it was only marketed in several countries because it was very expensive. Most real-world experience comes from the USA and the largest cohort was found at the US Veterans Health Administration. A recent analysis including 3068 patients treated with SOF+SMV±RBV reported an SVR rate of 87%, compared to 93% in patients treated with LDV/SOF±RBV (n=5524) or ombitasvir/paritaprevir/ritonavir (OBV/PTV/r)±dasabuvir (DSV)±RBV (n=1012). However, it should be mentioned that SOF+SMV±RBV was administered to patients with more advanced liver disease because this was the first regimen that they could receive.[23] Similar results were observed in the HCV-Target study. The SVR rate in the 802 patients with G1 infection was 84% and patients with cirrhosis had a lower chance of achieving an SVR, in particular those with a history of decompensation and those previously treated with protease inhibitors.[24] The SVR with SOF+SMV±RBV was 5%-13% lower than that of LDV/SOF±RBV in specific groups of patients.[25]
Data from the German Hepatitis C-Registry showed that the efficacy of SOF+SMV±RBV was 86% in 284 patients, which was significantly lower than SOF+DCV±RBV (n=528), LDV/SOF±RBV (n=1836) or OBV/PTV/r±DSV±RBV (n=390), which resulted in an SVR of 94%-95%.[26] In the largest published French cohort to date including 768 patients with G1 infection treated with SOF+DCV±RBV, the SVR rate was 95%.[27] RBV had no statistically significant effect and a 12-week regimen was sufficient in patients without cirrhosis. However, treatment for 24 weeks in 563 patients with cirrhosis resulted in a significantly higher SVR (95%) than 12 weeks (88%) of treatment.[27]

4 OBV/PTV/r±DSV±RBV: sustained virologic response in 92%-100% of patients
OBV/PTV/r±DSV±RBV was registered a few months after LDV/SOF, and the first real-world data became available in 2016 for the EASL meeting. In a number of recently presented studies included in Table 3, OBV/PTV/r±DSV±RBV treatment has resulted in an SVR rate ranging from 92% to 100%. The SVR rate of the 4260 patients in this study, mainly with G1 infection was 97% and it was the same in the 1647 patients with cirrhosis (Table 3).
Table 3. Overview on efficacy in real-world studies with OBV/PTV/r±DSV±RBV in genotype 1 and 4 HCV infection
ReferenceCountryNumber of patients, nCirrhosis, nSVR 12 in all patients, n (%)SVR 12 in cirrhosis, n (%)
Aghemo et al.[49]Italy424241 (98)41 (98)
Calleja et al.[28]Spain14227321376 (97)710 (97)
Christensen et al.[50]Germany8783 (95)
Derbala et al.[51]Qatar422441 (98)24 (100)
Flisiak et al.[29]Poland209119207 (99)117 (98)
G√≥mez et al.[40]Spain3131 (100)
Hinrichsen et al.[52]Germany558127539 (97)129 (95)
Hunyady et al.[31]Hungary6160 (98)
Lubel et al.[32]Australia167167 (92)(91)
McCombs et al.[23]USA1012350945 (93)329 (94)
Ouzan et al.[53]France2020 (100)
Teti et al.[54]Italy193188 (97)
Zuckerman et al.[30]Israel416253413 (99)251 (99)
Overall426016474111 (97)1601 (97)

The multicenter Spanish study included the largest number of patients.[28] The analysis was based on 1422 patients with G1 (mostly genotype1b) infection, 49% treatment experienced, and 47% with cirrhosis. The SVR rate after 12 weeks was 97% and on multivariate analysis the probability of achieving an SVR was associated with low baseline albumin concentrations. There were no statistical differences related to genotype, age or fibrosis. The most frequent severe adverse event was anaemia associated with RBV (24 patients, 1.5%). Severe adverse events were related to the MELD score, high fibroscan values and advanced age. Another large study from the United States Veterans Health's Administration included 1012 patients with a final SVR rate of 93%.[23] Finally, previously published data from the Polish AMBER study showed an SVR rate at week 12 of 99%, but the most important result was that the risk of on-treatment decompensation was related to a history of decompensation before treatment and baseline impaired liver function.[29] The same rate of efficacy (SVR rate 99%) and safety were reported in a population of Israeli patients, mostly with cirrhosis and G1 infection. This study also showed that the most significant predictive factor of on-treatment decompensation was a history of decompensation.[30] An SVR rate of 97% was also reported in 142 patients who had not responded to a previous interferon-based triple regimen containing first generation protease inhibitors (boceprevir or telaprevir), who were enrolled in four studies including the largest one from Hungary.[31]

Unfortunately, safety data were only provided in a few studies. As shown in Table 3 the frequency of discontinuation due to adverse events, which can be considered to be a universal indicator of clinically significant adverse events, did not exceed 2.4%. Serious adverse events were reported in no more than 6% of patients. Anaemia and hyperbilirubinaemia usually occurred in patients with cirrhosis receiving RBV.[32] Since RBV is no longer a part of the regimen recommended for G1b patients, including those with cirrhosis, these adverse events should not be a problem.

5 HIV/HCV coinfection does not seem to influence the results
HIV coinfection did not significantly influence the likelihood of achieving an SVR. Similar efficacy was found between monoinfected and coinfected patients with OBV/PTV/r±DSV (93% vs 89%), LDV/SOF (93% vs 93%) and SOF+SMV (87% vs 88%) in the large US Veterans Health Administration cohort including 9604 and 408 patients respectively.[33] The efficacy of LDV/SOF±RBV in the 150 coinfected patients in the TRIO study was 98% and was not affected by the length of treatment, viral load, cirrhosis, subgenotypes, race or PPI.[34] Similar results (97%) were reported in 288 coinfected patients treated with LDV/SOF±RBV in the Portuguese Universal Coverage Program.[12]

6 Transplant recipients also have excellent response rates
Administration of LDV/SOF±RBV to 262 liver or/and kidney transplant recipients from the HCV-Target cohort resulted in a 95% SVR rate. Safety analysis showed <1% discontinuation and serious adverse events in 9%.[21] Similar efficacy (98%) was obtained in 114 Italian kidney transplant patients who received LDV/SOF±RBV for 12 or 24 weeks.[22] Analysis of results from the TRIO cohort showed an SVR rate of 96% in 67 post-liver transplant patients on the LDV/SOF±RBV regimen.[35]

An efficacy of 100% and no unexpected safety issues were observed in the AMBER-CEE study including 35 liver transplant recipients treated with OBV/PTV/r±DSV±RBV.[36] Another group of 22 liver transplant patients were treated with this regimen after transplantation in an Israeli study. The SVR rate in this study was 86% and there were no adverse events.[30]

7 Kidney function is a safety issue
As shown by Rosenblatt et al.[37] patients with pre-existing moderate renal impairment are at a higher risk of having their kidney disease worsen during LDV/SOF treatment and creatinine clearance worsened during treatment in 42% of those with abnormal baseline renal function. Certain safety issues, including early withdrawal and death were also reported in patients with moderate to severe chronic kidney disease treated with the SOF based regimen, and the SVR rate was only 79%.[38] In the large French CUPILT study, renal dysfunction developed in 83/139 (60%) liver transplant patients during treatment with a SOF based regimen and renal function did not improve in 22 of these after treatment was discontinued.[39] On the other hand, LDV/SOF did not affect renal function in post-kidney transplant patients treated for as long as 24 weeks in the Italian study.[22]
There is limited real-world experience with OBV/PTV/r±DSV±RBV in patients with kidney disease. In the Spanish muliticenter study, a 100% SVR rate was reported in 33 patients with end-stage renal disease (stage 4 and 5) treated with OBV/PTV/r±DSV±RBV with no discontinuation due to adverse events. It should be mentioned that a dose reduction or interruption was necessary in the treatment with RBV in 5/14 patients.[40]

8 Hepatocellular carcinoma after IFN-free therapy: to be further studied
The first report on the potential risk of hepatocellular carcinoma (HCC) associated with DAA therapy was published by Reig et al.[41] In that study, the incidence of recurrent HCC (patients had a history of HCC) immediately following DAA was 27.6%. In another large, retrospective cohort study Buonfiglioli et al.[42] showed that HCC developed in 26/344 (7.6%) patients with cirrhosis treated with DAA within 24 weeks after treated had stopped. However, it should be mentioned that 65% of patients with post-treatment HCC had a previous diagnosis of HCC. One possible explanation of these unexpected results is the presence of small HCC before antiviral treatment is begun in patients with a previous history of HCC. Another explanation could be the reconstitution of innate immunity and the downregulation of the endogenous interferon system following rapid disappearance of HCV. Thus, insufficient interferon activation can promote the growth of malignant cells, which did not occur with immunomodulatory, interferon-based regimens.

On the other hand, the rate of the development of HCC during and after treatment (24 weeks follow-up) in 119 patients with cirrhosis in the AMBER study was only 1.7%, and the English Access Program also reported a lower risk of development of HCC during and after treatment in patients with cirrhosis (4.6%) compared to those without (8%).[29, 43] Finally, analysis of data from three prospective French cohorts including more than 6000 patients did not confirm any increase in recurrent HCC following DAA. This study included 267 patients with a prior history of HCC and the rate of recurrence after DAA was similar to those who did not receive this regimen (0.73 vs 0.66 per 100 person-months).[44] Thus, for the moment there are no conclusive data supporting an increased risk of HCC following treatment with DAA in patients with or without a previous history of HCC including those with advanced hepatic fibrosis.

9 Genotype 3: real-world data still limited
The real-world data on the treatment of patients with G3 infection, which is currently considered to be the most difficult to cure genotype, are limited. The most effective treatment in 172 patients with G3 infection and decompensated cirrhosis from the English Access Program, was achieved with SOF+DCV+RBV (71%, [n=105]) while the LDV/SOF+RBV regimen resulted in a 65% SVR rate in 57, and in the remaining 10 patients these two therapeutic options without RBV only cured 50% patients.[43] In the HCV-Target study, 178 patients were treated with SOF+RBV and 60% achieved an SVR (42% in patients with cirrhosis who had not responded to prior therapy), compared to 84% in 19 patients treated with SOF+PegIFN+RBV.[45] In a recently published German study, an SVR of 92% was obtained in 36 patients treated with SOF+DCV±RBV, 100% in 10 treated with LDV/SOF±RBV, and 83% in 12 who received SOF+RBV.[46]

10 Conclusion
Because of similar efficacy and safety, existing real-world experience in the treatment of HCV infection with interferon-free regimens supports the use of either LDV/SOF±RBV or OBV/PTV/r±DSV±RBV in patients with G1 infection whatever the severity of fibrosis. HCV treatment history, HIV coinfection and previous liver or kidney transplantation do not affect the efficacy or safety of these two leading regimens. Because of less effective results in real-world data, SOF+SMV±RBV will probably not be widely used in the future. Real-world data are still insufficient in patients with G3 infection and other genotypes.

Conflicts of Interest
Robert Flisiak was an advisor or speaker for AbbVie, BMS, Gilead, Janssen, Merck, Novartis, Roche; Joanna Pogorzelska and Marta Flisiak-Jackiewicz have no conflicts of interest.

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