Side effects associated with different hepatitis C direct-acting antiviral drugs

Aim - To evaluate the adverse effects associated with the different direct-acting antiviral drug (DAA) regimens in Egyptian patients. Patients received sofosbuvir (SOF)/ribavirin (RBV), SOF/simeprevir, SOF/daclatasvir (DCV), SOF/DCV/RBV, and paritaprevir/ombitasvir/ritonavir/RBV. SOF/RBV regimen showed the highest rate of side effects while SOF/DCV showed the least.

The adverse effects of interferon-free regimens in 149 816 chronic hepatitis C treated Egyptian patients

D. Attia, K. El Saeed, W. Elakel, T. Elbaz, A. Omar, A. Yosry, M. H. Elsayed, M. El Raziky, M. Anees, W. Doss, Y. El Shazly, H. Wedemeyer and G. Esmat

Version of Record online: 5 MAR 2018 | DOI: 10.1111/apt.14538

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Summary
Background
Interferon-free regimens are associated with high sustained virological response; however, associated adverse effects have yet to be fully reported.

Aim
To evaluate the adverse effects associated with the different direct-acting antiviral drug (DAA) regimens in Egyptian patients.

Methods
This multicenter retrospective study included all adverse effects during and after treatment with DAA regimens of 149 816 chronic hepatitis C treated Egyptian patients. Patients received sofosbuvir (SOF)/ribavirin (RBV) (n = 21 835), SOF/simeprevir (n = 24 215) SOF/daclatasvir (DCV) (n = 58 477), SOF/DCV/RBV (n = 45 188) and paritaprevir/ombitasvir/ritonavir/RBV (n = 101). The duration of treatment varied between 12 and 24 weeks. All changes in the treatment regimens, discontinuation, mortality, and serious side effects were reported.

Results
Adverse effects developed in 2475 (1.7%) (mean age [54 ± 9], male gender [53%]) patients. Serious side effects developed in 68% of these patients, and SOF/RBV was the most common causing regimen (73%, P < 0.001). Anaemia and hyperbilirubinemia were the most common side effects (731/149816, 0.5% and 463/149816, 0.3%, respectively) and SOF/RBV (588/21835, 3% and 353/21835, 1.6%, respectively) showed the highest incidence in the treated patients. Hepatocellular carcinoma and mortality were reported in 0.02% and 0.06% of all treated patients, respectively. Patients with liver cirrhosis showed higher incidence of serious side effects (Log rank P = 0.045) and mortality (Log rank P = 0.025) than patients without liver cirrhosis. Male gender (P = 0.012), lower haemoglobin (P < 0.001), platelets (P < 0.001) and albumin (P = 0.001), higher bilirubin (P = 0.002) and cirrhosis (P < 0.001) were factors associated with serious side effects development.

Conclusion
Adverse effects associated with DAAs are few, anemia being the most common. SOF/RBV regimen showed the highest rate of side effects while SOF/DCV showed the least.

Discussion

View full-text article @ Alimentary Pharmacology & Therapeutics

To our knowledge, this is the first study with such a large cohort of chronic HCV-infected patients treated with DAAs who reported associated adverse effects and related death. This study revealed that interferon-free regimens are associated with minimal side effects, which are mostly non-serious. The most common side effects were haematological complications, with anaemia being the dominant one, particularly with respect to the SOF/RBV regimen. The serious haematological adverse effects were managed with haematopoietic agents, treatment discontinuation or reduction in RBV dose with prolongation of treatment duration. The SOF/RBV regimen showed the highest rate of side effects, with anaemia being the prominent one. The SOF/SIM regimen was associated with hyperbilirubinemia; however, this was not significant and did not require treatment discontinuation or a change in drug dosage. DCV-containing regimens showed the lowest side effects among all regimens. This study also showed that death was highest in the SOF/RBV regimen and pre-treatment thrombocytopenia and higher Child score were the dominant pre-treatment associated pathologies. In this study, HCC was reported in 33 patients, and this was mostly with the SOF/RBV regimen; however, this was not significant. Serious adverse effects as well as death were prominent with liver cirrhosis under the interferon-free regimens irrespective of the regimen.

The initial approval of DAAs by the Egyptian Council Committee of Viral Hepatitis had dramatically improved the SVR rate in Egyptian chronic HCV-infected patients, from 60% to almost 100% in some studies.[5, 8, 10] Our study showed that SVR24 reached 88% in those who developed side effects. Although the majority of the study cohort were cirrhotic patients (81%), side effects development was minimal (1.7%), in comparison to other studies, the entire cohort of which were cirrhotic patients and reported 24% side effects.[16] Serious side effects that led to reduction in the RBV dose and prolongation of the treatment duration or even treatment discontinuation, were observed in only (1.1%) of cases. Anaemia was the most common serious side effect, and was mostly associated with the SOF/RBV regimen. The rate of serious side effects was lower in comparison to that of the Guard-C study, which reported 5.9% serious side effects, while the incidence of anaemia in our study was higher (29.5% vs 25%).[17] Interestingly, our multivariate analysis confirmed that pre-treatment HB (<12.6 g/dL) and lower platelets (124 × 103/μL) were associated with post-treatment serious side effects development, as previously mentioned.[18] Our large cohort also revealed that the pre-treatment higher Child-Pugh score represented in lower albumin <35 g/dL and higher bilirubin >1.2 μmol/dL were also factors associated with post-treatment serious side effects development. Lower albumin was also described by Maan et al and Foster et al as factors associated with post-treatment serious side effects development.[16, 17]

The second common serious side effect was hyperbilirubinemia, which was not significant and was only prominent in the SOF/RBV regimen. Non-specific side effects such as fatigue, headache and abdominal discomfort were the most commonly reported in all regimens, which is line with all previously published data.[5, 7, 8, 10, 16, 19, 20]

Death was reported in only 0.06% of all treated patients, and was mainly associated with the SOF/RBV regimen. Death was in most of the cases secondary to hepatic decompensation. Three patients died due to diabetic coma and one due to myocardial infarction under the SOF/RBV regimen.

Hepatocellular carcinoma was also reported in 0.02% of all treated patients, and most cases were reported in the SOF/RBV regimen. This incidence is, however, lower when compared to other studies.[21, 22] The incidence of HCC on this regimen can be explained by the associated liver cirrhosis in 89% of patients, which is line with previous published data,[23] and 22% were Child-Pugh B, which may favour disease progression and the presence of regenerative nodules before the start of treatment. It is to be noted, that the presence of cirrhosis was associated with increased death rate and was also the common factor detected in all regimens associated with serious side effects development.

The incidence of serious side effects, death and HCC development was highest in the SOF/RBV regimen. This can be explained by the fact that this regimen was the first approved regimen for DAAs, and all patients treated with this regimen were the most sick (lower platelets and higher Child-Pugh score B). On the other hand, SOF/DCV showed the lowest incidence of side effects in comparison to the other regimens.

This study was conducted on a large cohort of Egyptian patients, more than 90% of which are infected with genotype 4.[7] Egypt is one of the countries with the highest prevalence with HCV infection, and the urgency to treat chronic HCV patients is associated with reduction in prevalence, which already started to appear, with 29% reduction in prevalence in 2015.[4] This study has several limitations; although we are reporting the adverse effects of several regimens, many of these regimens may no longer be used in several countries (eg SOF/RBV combination is no longer recommended in the European and American guidelines). Moreover, SIM is also rarely in use today, not due to efficacy but because of economic reasons. We must highlight that SIM is still used in many regions including Egypt. Another point to highlight is that these data were excluded from the database which were reported by the treating physicians. There may be an underreporting of adverse effects because there was no soft data verification by independent physicians; however, this is also accepted in large cohort studies.

In conclusion, the use of PEG-IFN/RBV combination was limited due to eligibility, tolerability and treatment efficacy (40%-69%).[24, 25] The use of interferon-free regimens increased the SVR rate and improved the tolerability and eligibility of treatment. The use of interferon-free regimens is safe and tolerable, with a higher cure rate in patients with genotype 4 than the previously used regimen. Cirrhotic patients are in particularly urgent need of treatment and those regimens are the most safely used, but this requires close monitoring and the use of haematopoietic agents to avoid anaemia, especially with RBV-containing regimens. Regular sonographic assessment for early detection of HCC is also of great importance in patients with liver cirrhosis. Future worldwide studies are required to address the adverse effects caused by the new regimens used today, such as SOF/velpatasvir, grazopervir/elbasvir and glecaprevir/pibrentasvir.

View full-text article - http://onlinelibrary.wiley.com/doi/10.1111/apt.14538/full

Response Tailored Protocol Versus the Fixed 12 Weeks of Dual Sofosbuvir/Daclatasvir Treatment in Egyptian Patients With Chronic Hepatitis C Genotype-4 Infection

Response Tailored Protocol Versus the Fixed 12 Weeks of Dual Sofosbuvir/Daclatasvir Treatment in Egyptian Patients With Chronic Hepatitis C Genotype-4 Infection: A Randomized, Open-label, Non-inferiority Trial
Mostafa Yakoot Correspondence information about the author Mostafa Yakoot Email the author Mostafa Yakoot , Alaa M. Abdo, Siham Abdel-Rehim, Sherine Helmy

Highlights
It would be prudent to consider vRVR to therapy at week 2 before shortening HCV treatment duration with SOF/DCV to 8 weeks.

This will consider the variability of response as a factor at individualized level not just a point of estimate at a population level.

Response-tailored duration of 8 or 12 weeks based on achieving vRVR was non-inferior to the fixed 12 weeks course.

The decision of shortening the duration of therapy of non-cirrhotic chronic hepatitis C genotype-4 patients with dual sofosbuvir plus daclatasvir to 8 weeks instead of the recommended 12 weeks, if based on achieving viral negativity in serum at week 2 as an on-treatment qualifier, could provide a prudent basis to avoid unnecessary long treatment courses. This could not only reduce the drug exposure and the risk of adverse drug reactions, but also cut the cost of full treatment course with such expensive medications by one third.

View full text article, here.

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

Summary
Background
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.

Aim

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

Methods

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).

Results

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.

Conclusions

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.

Discussion Only

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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.

http://onlinelibrary.wiley.com/doi/10.1111/apt.13925/full

Health Canada Approves DAKLINZA™ (daclatasvir) for Difficult-to-Treat Hepatitis C Patient Populations

Health Canada Approves DAKLINZA™ (daclatasvir) for Difficult-to-Treat Hepatitis C Patient Populations

SOURCE Bristol-Myers Squibb Canada

DAKLINZA™ is approved in Canada in combination with other agents for the treatment of chronic hepatitis C Patients with HIV co-infection, advanced cirrhosis and post-liver transplant HCV recurrence

MONTREAL, May 24, 2016 /CNW/ - Bristol-Myers Squibb Canada today announced Health Canada's approval of DAKLINZA™ (daclatasvir), in combination with sofosbuvir (with or without ribavirin) for 12 weeks in the treatment of chronic hepatitis C (CHC) in adult patients with hepatitis C virus (HCV) genotypes 1, 2 or 3 in three difficult-to-treat populations, including patients with HIV-1 co-infection, patients with compensated or decompensated cirrhosis and patients with HCV recurrence after liver transplantation.1

Both co-infected and post-transplant patient populations, historically, have been difficult to treat, in large part due to potential drug-to-drug interactions between the antiviral therapy regimens for HIV or anti-rejection drugs for post-transplant.2,3

"Chronic hepatitis C patients who have advanced disease, are co-infected with HIV or who have a recurrence of HCV after receiving a new liver pose complex treatment challenges to physicians," said Dr. Curtis Cooper, Director, The Ottawa Hospital and Regional Hepatitis Program. "These new indications for DAKLINZA™ give physicians more treatment options. We can now offer safe and highly curative HCV treatment to even the most complex and medically challenging of patients."

HCV and HIV co-infection is not rare. Approximately 20 per cent of Canadians with HIV have both infections.4 HCV progresses more rapidly to liver damage in people who are co-infected than in those who only have HCV.2 Currently, liver disease related to HCV is the leading cause of death among people with co-infection.2

"As part of our commitment to the HCV community, we have strived to make new treatment options available for patients with different genotypes, including those who are amongst the most difficult-to-treat," said Dr. Nawal Peacock, President and General Manager, Bristol-Myers Squibb Canada. "With this expanded label for DAKLINZA™, we are proud to provide an option that helps bridge what has been a challenging treatment gap for these patients."

The new indications are based on data from the ALLY-1 clinical trial (in post-transplant patients and patients with advanced cirrhosis) and the ALLY-2 clinical trial (in HIV-1 co-infected patients). In ALLY-1, DAKLINZA in combination with sofosbuvir and ribavirin achieved a cure rate of 94 per cent in patients with post-liver transplant and 92 to 94 per cent in patients with advanced cirrhosis.3 In ALLY-2, the DAKLINZA™ plus sofosbuvir combination achieved a 97 per cent cure rate in treatment naive co-infected patients and 98 per cent in treatment experienced co-infected patients.2

"As people in the advanced stages of the disease can attest, HCV can be a devastating illness," Dr. Morris Sherman, hepatologist and chair of the Canadian Liver Foundation, who has treated patients with hepatitis C for more than 20 years. "These patients are in great need of a cure so they can recover and enjoy their life again. The HCV community welcomes each new treatment option that can help to cure this illness, and bring us closer to seeing a day when HCV is gone for good."

DAKLINZA™, a potent, pan-genotypic NS5A replication complex was approved by Health Canada in August 2015 for use in combination with other agents for the treatment of adult patients with HCV genotypes 1, 2, or 3 and compensated liver disease, including cirrhosis.1 In Canada, genotypes 1, 2 and 3 account for 65 per cent, 14 per cent and 20 per cent of HCV infections respectively.5

About Bristol-Myers Squibb Canada Co.
Bristol-Myers Squibb Canada is an indirect wholly-owned subsidiary of Bristol-Myers Squibb Company, a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information about Bristol-Myers Squibb global operations, visit www.bms.com. Bristol-Myers Squibb Canada has been delivering innovative medicines for serious diseases to Canadian patients in the areas of cardiovascular health, oncology, neuroscience, immunoscience and virology for over 80 years. Bristol-Myers Squibb Canada employs over 300 people across the country. For more information, please visit www.bmscanada.ca.

Additional Information:

About ALLY-1 Clinical Trial1
In the trial, the DAKLINZA™ plus sofosbuvir and ribavirin regimen demonstrated overall SVR12 in 94 per cent of post-liver transplant patients and 83 per cent of patients in the advanced cirrhosis cohort, including 92 to 94 per cent of patients with compensated cirrhosis (Child-Pugh A or B). In the cirrhosis cohort, four subjects with hepatocellular carcinoma underwent liver transplantation after 1 to 71 days of treatment; three of the four subjects received 12 weeks of post-liver transplant treatment extension and one subject, treated for 23 days before transplantation, did not receive treatment extension. All four subjects achieved SVR12.

In the ALLY 1 trial, the most common adverse reactions (frequency of 10% or greater) among the 113 subjects were headache, anemia, fatigue and nausea. Most adverse reactions were mild to moderate in severity. Fifteen (13%) subjects experienced an SAE; all SAEs were considered unrelated to treatment. Of the 15 (13%) subjects who discontinued study drug for adverse events, 13 (12%) subjects discontinued ribavirin only and 2 (2%) subjects discontinued all study drugs.

About ALLY-2 Clinical Trial1
In ALLY-2, the DAKLINZA™ plus sofosbuvir regimen demonstrated overall SVR12 in 97 per cent in treatment-naive patients and 98 per cent in treatment-experienced patients, including 100 per cent in genotype 3 (n=10). SVR12 rates were high regardless of combination antiretroviral therapy (cART) regimens, including boosted-protease inhibitor-, NNRTI-, and integrase inhibitor-based therapies. In the trial, 2 per cent of subjects experienced SAEs and no discontinuations due to AEs. The most common adverse reaction (=10% or greater) was fatigue (14%).

References
1 Bristol-Myers Squibb Canada DAKLINZA™ Product Monograph. Revised: May 13, 2016.
2 Wyles DL, et al. Daclatasvir plus Sofosbuvir for HCV in Patients Coinfected with HIV-1. N Engl J Med. 2015;373:714-25.
3 Poordad, F., Schiff, E.R., Vierling, J.M., et al, Daclatasvir, sofosbuvir, and ribavirin combination for HCV patients with advanced cirrhosis or posttransplant recurrence: phase 3 ALLY-1 study. J Hepatol. 2015;62:261.
4 Centre for Communicable Diseases and Infection Control Infectious Disease Prevention and Control Branch Public Health Agency of Canada. Hepatitis C in Canada: 2005-2010 Surveillance Report. 2012. Page 25.
5 RP Myers, RP, Shah KW, Cooper, C, et al. An update on the management of chronic hepatitis C: 2015 consensus guidelines from the Canadian Association for the Study of the Liver. Can J Gastroenterol Hepatol 2015.

AASLD: Bristol-Myers To Present Data From Multiple Studies Of Difficult-To-Treat Chronic Hepatitis C Patients

Bristol-Myers Squibb (BMY) To Present Data From Multiple Studies Of Difficult-To-Treat Chronic Hepatitis C Patients At American Association for Study of Liver Diseases

Real-world use of Daklinza-based regimens complements clinical findings across various HCV patient populations

Results of ALLY-3+ trial in genotype 3 HCV patients with cirrhosis to provide new insights into treating this patient population

PRINCETON, N.J.--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE:BMY) announced today that 17 abstracts have been accepted for presentation at The Liver Meeting® 2015, the annual meeting of The American Association for the Study of Liver Diseases (AASLD) 2015, taking place in San Francisco, CA., from November 13 – 17.

“The data to be presented at this year’s AASLD conference reinforces Bristol-Myers Squibb’s ongoing commitment to investigating Daklinza-based treatments that could address the still-challenging needs of many patients living with chronic viral hepatitis C”

Highlights include:
Real-world data in chronic hepatitis C (HCV) populations, including genotype 3 patients, post-liver transplant patients, patients with advanced liver disease (including decompensated cirrhosis) and those coinfected with HIV.
Late-breaking data from the ALLY-3+ clinical trial, a study of Daklinza (daclatasvir) and sofosbuvir with ribavirin in genotype 3 HCV patients with cirrhosis.

“The data to be presented at this year’s AASLD conference reinforces Bristol-Myers Squibb’s ongoing commitment to investigating Daklinza-based treatments that could address the still-challenging needs of many patients living with chronic viral hepatitis C,” said Douglas Manion, M.D., head of Specialty Development, Bristol-Myers Squibb. “We are aiming to ultimately help a diverse range of hepatitis C patient populations.”

The complete list of Bristol-Myers Squibb data presentations follows. More information is available at http://www.aasld.org/.

Title			Date/Time
Oral Presentation: All-Oral Treatment With Daclatasvir (DCV) Plus Sofosbuvir (SOF) Plus Ribavirin (RBV) for 12 or 16 Weeks in HCV Genotype (GT) 3-Infected Patients With Advanced Fibrosis or Cirrhosis: The ALLY-3+ Phase 3 Study			Session: Late-breaking Abstract Session Date: November 16, 2015 Session Time: 3:00 – 4:30 p.m. Publication Number: LB-3
Oral Presentation: Safety and efficacy of daclatasvir plus sofosbuvir with or without ribavirin for the treatment of chronic HCV genotype 3 infection: Interim results of a multicenter European compassionate use program			Session: Parallel 5: Hepatitis C: Pre-Approval Clinical  Studies I Date: November 15, 2015 Session Time: 3:00 - 4:30 p.m. Presentation Time: 3:00 - 3:15 p.m. Location: General Session/3000 (Moscone Center) Publication Number: 37
Oral Presentation: Daclatasvir plus sofosbuvir with or without ribavirin in genotype 3 patients from a large French multicenter compassionate use program			Session: Viral Hepatitis Plenary Date: November 17, 2015 Session Time: 8:00 - 9:30 a.m. Presentation Time: 8:15 - 8:30 a.m. Location: Room 3000 (Moscone Center) Publication Number: 206
Oral Presentation: Daclatasvir and Sofosbuvir in Patients with Recurrent HCV Following Liver Transplantation and Advanced Fibrosis or Cirrhosis: United States Multicenter Treatment Protocol			Session: Parallel 32: Clinical Aspects of HCV Virology, Pathogenesis, and Immunology Date: November 17, 2015 Session Time: 11:15 a.m. -12:45 p.m. Presentation Time: 12:00 -12:15 p.m.* Location: Room 3014 (Moscone Center) Publication Number: 217 * Presentation time expected to change, TBC
Oral Presentation: Daclatasvir in combination with sofosbuvir with or without ribavirin is safe and efficacious in liver transplant recipients with HCV recurrence: Interim results of a multicenter compassionate use program			Session: Parallel 37: Hepatitis C: Pre-Approval Clinical Studies II Date: November 17, 2015 Session Time: 11:15 a.m. - 12:45 p.m. Presentation Time: 12:30 - 12:45 p.m. Location: General Session/3000 (Moscone Center) Publication Number: 252
Presidential Poster of Distinction:702 Short-duration therapy with daclatasvir/asunaprevir/beclabuvir fixed-dose combination plus sofosbuvir in patients with chronic hepatitis C genotype 1 (FOURward Study)			Session: Therapeutics: New Agents (not approved, Phase 2-3) Date: November 14, 2015 Presentation Time: 2:00 – 7:30 p.m. Location: Poster Hall Publication Number: 702
Presidential Poster of Distinction:Daclatasvir plus sofosbuvir with or without ribavirin for the treatment of chronic HCV in patients coinfected with HIV: Interim results of a multicenter compassionate use program			Session: Hepatitis C: Therapeutics /Approved Agents Date: November 15, 2015 Presentation Time: 8:00 a.m. – 5:30 p.m. Location: Poster Hall Publication Number: 1058
Poster: Improvement in liver disease parameters following treatment with daclatasvir + sofosbuvir and ribavirin in patients with chronic HCV infection and advanced cirrhosis			Session: Therapeutics: New Agents  (not approved, Phase 2-3) Date: November 14, 2015 Presentation Time: 2:00 – 7:30 p.m. Location: Poster Hall Publication Number: 706
Poster: Baseline HCV NS5A resistance-associated variants do not impact SVR12 rates in non-cirrhotic and post-liver transplant patients with genotype 1 infection treated with daclatasvir and sofosbuvir with or without ribavirin for 12 weeks: An integrated analysis			Session: Therapeutics: New Agents  (not approved, Phase 2-3) Date: November 14, 2015 Presentation Time: 2:00 – 7:30 p.m. Location: Poster Hall Publication Number: 709
Poster: Comparative Efficacy and Tolerability of Daclatasvir + Sofosbuvir versus Sofosbuvir + Ribavirin in Patients with Chronic Hepatitis C Coinfected with HIV: A Matching-Adjusted Indirect Comparison			Session: Therapeutics: New Agents (not approved, Phase 2-3) Date: November 14, 2015 Presentation Time: 2:00 – 7:30 p.m. Location: Poster Hall Publication Number: 711
Poster: An integrated safety analysis of daclatasvir + sofosbuvir, with or without ribavirin, in patients with chronic HCV infection			Session: Therapeutics: New Agents  (not approved, Phase 2-3) Date: November 14, 2015 Presentation Time: 2:00 – 7:30 p.m. Location: Poster Hall Publication Number: 716
Poster: Daclatasvir exposure does not explain lower sustained virologic response rates in cirrhotic patients with HCV genotype 3 following 12 weeks of daclatasvir plus sofosbuvir treatment			Session: Therapeutics: New Agents  (not approved, Phase 2-3) Date: November 14, 2015 Presentation Time: 2:30 – 7:00 p.m. Location: Poster Hall Publication Number: 720
Poster: Integrated Safety Analysis of Daclatasvir Plus Sofosbuvir, With or Without Ribavirin, in Patients With HCV Genotype 3 Infection			Session: Therapeutics: New Agents (not approved, Phase 2-3) Date: November 14, 2015 Presentation Time: 2:00 – 7:30 p.m. Location: Poster Hall Publication Number: 726
Poster: Daclatasvir exposure alone does not explain HCV relapse in HIV-HCV coinfected patients receiving daclatasvir plus sofosbuvir with ritonavir-boosted darunavir in the ALLY-2 study			Session: Therapeutics: New Agents  (not approved, Phase 2-3) Date: November 14, 2015 Presentation Time: 2:00 – 7:30 p.m. Location: Poster Hall Publication Number: 728
Poster: Daclatasvir and asunaprevir in non-Japanese Asian patients with chronic HCV genotype 1b infection who are ineligible for or intolerant to interferon-alfa therapies with or without ribavirin: Phase 3 SVR12 interim results			Session: Late-breaking Poster Session Date: November 16, 2015 Session Time: 8:00 a.m. – 5:30 p.m. Presenters available: 12:30 – 2:00 p.m. Location: Poster Hall Publication Number: LB-18
Poster: Impact of Daclatasvir-Sofosbuvir Combination Treatment on Medical Events and Costs in Patients Infected with Genotype 3 Hepatitis C Virus			Session: Cost-Effectiveness and Economics of Care Date: November 16, 2015 Presentation Time: 8:00 a.m. – 5:30 p.m. Location: Poster Hall Publication Number: 1456
Poster: Cost-effectiveness of Daclatasvir in Combination with Sofosbuvir for the Treatment of Subjects with Genotype 3 Chronic Hepatitis C Infection in the United States			Session: Cost-Effectiveness and Economics of Care Date: November 16, 2015 Presentation Time: 8:00 a.m. – 5:30 p.m. Location: Poster Hall Publication Number: 1461

About Bristol-Myers Squibb in HCV

Bristol-Myers Squibb’s research efforts are focused on advancing compounds to deliver the most value to HCV patients with high unmet needs. At the core of our portfolio isDaklinza, a NS5A complex inhibitor which continues to be investigated in multiple treatment regimens and in patients with high disease burden.

In July 2014, Japan became the first country in the world to approve the use of aDaklinza-based regimen for the treatment of chronic HCV. Since then, Daklinza-based regimens have been approved in more than 50 countries, including the United States, across Europe, and in numerous other countries in Central and South America, the Middle East and the Asia-Pacific region.

Indication and Important Safety Information - Daklinza™ (daclatasvir)

INDICATION

Daklinza™ (daclatasvir) is indicated for use with sofosbuvir for the treatment of patients with chronic hepatitis C virus (HCV) genotype 3 infection.

Limitations of Use:
Sustained virologic response (SVR) rates are reduced in HCV genotype 3-infected patients with cirrhosis receiving Daklinza in combination with sofosbuvir for 12 weeks.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS
Drugs Contraindicated with Daklinza: strong inducers of CYP3A that may lead to loss of efficacy of Daklinza include, but are not limited to:
Phenytoin, carbamazepine, rifampin, St. John’s wort (Hypericum perforatum).

WARNINGS and PRECAUTIONS

-- Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions: Coadministration of Daklinza and other drugs may result in known or potentially significant drug interactions. Interactions may include the loss of therapeutic effect of Daklinza and possible development of resistance, dosage adjustments for other agents or Daklinza, possible clinically significant adverse events from greater exposure for the other agents or Daklinza.
Serious Symptomatic Bradycardia When Coadministered with Sofosbuvir and Amiodarone: Post-marketing cases of symptomatic bradycardia and cases requiring pacemaker intervention have been reported when amiodarone is coadministered with sofosbuvir in combination with another direct-acting antiviral, including Daklinza. A fatal cardiac arrest was reported with ledipasvir/sofosbuvir.
Coadministration of amiodarone with Daklinza in combination with sofosbuvir is not recommended. For patients taking amiodarone who have no alternative treatment options, patients should undergo cardiac monitoring, as outlined in Section 5.2 of the prescribing information.
Bradycardia generally resolved after discontinuation of HCV treatment.
Patients also taking beta blockers or those with underlying cardiac comorbidities and/or advanced liver disease may be at increased risk for symptomatic bradycardia with coadministration of amiodarone.

ADVERSE REACTIONS
The most common adverse reactions were (≥ 5%): headache (14%), fatigue (14%), nausea (8%), and diarrhea (5%).

DRUG INTERACTIONS
CYP3A: Daklinza is a substrate. Moderate or strong inducers may decrease plasma levels and effect of Daklinza. Strong inhibitors (e.g., clarithromycin, itraconazole, ketoconazole, ritonavir) may increase plasma levels of Daklinza.
P-gp, OATP 1B1 and 1B3, and BCRP: Daklinza is an inhibitor, and may increase exposure to substrates, potentially increasing or prolonging their adverse effect.
See Section 7 of the Full Prescribing Information for additional established and other potentially significant drug interactions and related dose modification recommendations.

Daklinza in Pregnancy: No data with Daklinza in pregnant women are available to inform a drug-associated risk. Animal studies of Daklinza at exposure above the recommended human dose have shown maternal and embryofetal toxicity. Consider the benefits and risks of Daklinza when prescribing Daklinza to a pregnant woman.

Nursing Mothers: Daklinza was excreted into the milk of lactating rats; it is not known if Daklinza is excreted into human milk. Consider the benefits and risks to the mother and infant when breastfeeding.

Please click here for the Daklinza full prescribing information

About Bristol-Myers Squibb

Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information please visit www.bms.com or follow us on Twitter athttp://twitter.com/bmsnews.

Bristol-Myers Squibb Forward Looking Statement

This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995 regarding the research, development and commercialization of pharmaceutical products. Such forward-looking statements are based on current expectations and involve inherent risks and uncertainties, including factors that could delay, divert or change any of them, and could cause actual outcomes and results to differ materially from current expectations. No forward-looking statement can be guaranteed. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Bristol-Myers Squibb's business, particularly those identified in the cautionary factors discussion in Bristol-Myers Squibb's Annual Report on Form 10-K for the year ended December 31, 2014 in our Quarterly Reports on Form 10-Q and our Current Reports on Form 8-K. Bristol-Myers Squibb undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise.

NICE Recommends Daklinza (daclatasvir) for Treatment of Certain Patients with Chronic Hepatitis C Genotypes 1, 3 and 4

NICE Recommends Daklinza (daclatasvir) for Treatment of Certain Patients with Chronic Hepatitis C Genotypes 1, 3 and 4

"The burden of genotype 3 hepatitis C in the United Kingdom is one of the highest anywhere in Europe"

PRINCETON, N.J.--(BUSINESS WIRE)--Bristol-Myers Squibb (NYSE:BMY) today announced that the National Institute for Health and Care Excellence (NICE) has recommended Daklinza (daclatasvir) in England and Wales for the treatment of adult patients with chronic hepatitis C virus (HCV) infection. Specifically, NICE recommended Daklinza, an oral, once-daily medication used in combination with other agents, to treat certain patients with HCV genotypes 1, 3 and 4. Approximately 214,000 people in the UK are thought to have chronic HCV, and roughly 100,000 of those patients are estimated to have genotype 3, a difficult-to-treat and often aggressive form of chronic HCV.

“It is a challenge to treat patients with hepatitis C virus infection, including the significant number of patients with genotype 3, whose condition tends to progress rapidly,” said Anna Maria Geretti, Professor of Virology and Infectious Diseases, University of Liverpool. “In the past there have been limited treatment options available and therefore this decision is an important milestone. Daclatasvir in combination with other agents represents a much needed oral treatment regimen that has been shown to cure the infection in the majority of patients, and we have already seen positive results in the real-life setting in patients with advanced disease.”

HCV genotype 3 is associated with accelerated progression of fibrosis compared to other genotypes, which can make treatment time critical. Recent research has also shown that the risk of cirrhosis for patients infected with HCV genotype 3 is 31% greater than for those with HCV genotype 1.

“The burden of genotype 3 hepatitis C in the United Kingdom is one of the highest anywhere in Europe,” said Douglas Manion, M.D., head of Specialty Development, Bristol-Myers Squibb. “England has now joined Italy, France, The Netherlands, Sweden, Belgium, Switzerland, Denmark, Scotland and Ireland in recognizing the value of Daklinza for the treatment of genotype 3 HCV, and we are excited to make it available to help address what is still a significant unmet need among the UK HCV population.”

In the EU, Daklinza is indicated in combination with other medicinal products for the treatment of chronic hepatitis C virus (HCV) infection in adults. In genotype 3 HCV, Daklinza is currently approved in combination with sofosbuvir for 12 weeks in patients without cirrhosis and for 24 weeks in patients with cirrhosis with the optional use of ribavirin based on clinical assessment of the patient. Until recently, treatment options for genotype 3 patients in England were limited, and included interferon. Daklinza plus sofosbuvir, with or without ribavirin, is currently one of only two all-oral treatment regimens recommended by the European Association for the Study of the Liver’s (EASL) treatment guidelines for patients with HCV genotype 3.

About the NICE guidance
Following a submission by Bristol-Myers Squibb, NICE has issued final guidance on the use of Daklinza, in combination with other medicinal products, for use within NHS England as an option for the treatment of chronic HCV infection in adults. NICE has recommended its use as specified in the following table.

For further information on the guidance, please visit: https://www.nice.org.uk/.

About the Bristol-Myers Squibb HCV portfolio
Bristol-Myers Squibb’s research efforts are focused on advancing compounds to deliver the most value to HCV patients with high unmet needs. At the core of our portfolio is daclatasvir, an NS5A complex inhibitor which continues to be investigated in multiple treatment regimens and in patients with high disease burden, such as pre- and post-transplant patients and HIV/HCV coinfected patients, as part of the ongoing ALLY Program.

In July 2014, Japan became the first country in the world to approve the use of a daclatasvir-based regimen for the treatment of chronic HCV. Since then, daclatasvir-based regimens have been approved in more than 50 countries, including the United States, several countries across Europe, and in numerous other countries in North, Central and South America, the Middle East and the Asia-Pacific region.

U.S. Indication and Important Safety Information (ISI) - Daklinza™ (daclatasvir)
The following ISI is based on information from U.S. Prescribing Information for Daklinza. Please consult the full Prescribing Information for all labeled safety information.

INDICATION
Daklinza™ (daclatasvir) is indicated for use with sofosbuvir for the treatment of patients with chronic hepatitis C virus (HCV) genotype 3 infection.
Limitations of Use:

• Sustained virologic response (SVR) rates are reduced in HCV genotype 3-infected patients with cirrhosis receiving Daklinza in combination with sofosbuvir for 12 weeks.

IMPORTANT SAFETY INFORMATION
CONTRAINDICATIONS

• Drugs Contraindicated with Daklinza: strong inducers of CYP3A that may lead to loss of efficacy of Daklinza include, but are not limited to:
  • Phenytoin, carbamazepine, rifampin, St. John’s wort (Hypericum perforatum).

WARNINGS and PRECAUTIONS

• Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions: Coadministration of Daklinza and other drugs may result in known or potentially significant drug interactions. Interactions may include the loss of therapeutic effect of Daklinza and possible development of resistance, dosage adjustments for other agents or Daklinza, possible clinically significant adverse events from greater exposure for the other agents or Daklinza.

• Serious Symptomatic Bradycardia When Coadministered with Sofosbuvir and Amiodarone: Post-marketing cases of symptomatic bradycardia and cases requiring pacemaker intervention have been reported when amiodarone is coadministered with sofosbuvir in combination with another direct-acting antiviral, including Daklinza. A fatal cardiac arrest was reported with ledipasvir/sofosbuvir.
  • Coadministration of amiodarone with Daklinza in combination with sofosbuvir is not recommended. For patients taking amiodarone who have no alternative treatment options, patients should undergo cardiac monitoring, as outlined in Section 5.2 of the prescribing information.
  • Bradycardia generally resolved after discontinuation of HCV treatment.
  • Patients also taking beta blockers or those with underlying cardiac comorbidities and/or advanced liver disease may be at increased risk for symptomatic bradycardia with coadministration of amiodarone.

ADVERSE REACTIONS

• The most common adverse reactions were (≥ 5%): headache (14%), fatigue (14%), nausea (8%), and diarrhea (5%).

DRUG INTERACTIONS

• CYP3A: Daklinza is a substrate. Moderate or strong inducers may decrease plasma levels and effect of Daklinza. Strong inhibitors (e.g., clarithromycin, itraconazole, ketoconazole, ritonavir) may increase plasma levels of Daklinza.
• P-gp, OATP 1B1 and 1B3, and BCRP: Daklinza is an inhibitor, and may increase exposure to substrates, potentially increasing or prolonging their adverse effect.

See Section 7 of the Full Prescribing Information for additional established and other potentially significant drug interactions and related dose modification recommendations.
Daklinza in Pregnancy: No data with Daklinza in pregnant women are available to inform a drug-associated risk. Animal studies of Daklinza at exposure above the recommended human dose have shown maternal and embryofetal toxicity. Consider the benefits and risks of Daklinza when prescribing Daklinza to a pregnant woman.
Nursing Mothers: Daklinza was excreted into the milk of lactating rats; it is not known if Daklinza is excreted into human milk. Consider the benefits and risks to the mother and infant when breastfeeding.

Please click here for the Daklinza full prescribing information.

About Bristol-Myers Squibb
Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information, please visit http://www.bms.com or follow us on Twitter at http://twitter.com/bmsnews.

Bristol-Myers Squibb Forward Looking Statement
This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995 regarding the research, development and commercialization of pharmaceutical products. Such forward-looking statements are based on current expectations and involve inherent risks and uncertainties, including factors that could delay, divert or change any of them, and could cause actual outcomes and results to differ materially from current expectations. No forward-looking statement can be guaranteed. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Bristol-Myers Squibb's business, particularly those identified in the cautionary factors discussion in Bristol-Myers Squibb's Annual Report on Form 10-K for the year ended December 31, 2014 in our Quarterly Reports on Form 10-Q and our Current Reports on Form 8-K. Bristol-Myers Squibb undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise.

Contact:

Bristol-Myers Squibb
Media:
Robert Perry, 407-492-4616
rob.perry@bms.com
or
Investors:
Ranya Dajani, 609-252-5330
ranya.dajani@bms.com
or
Bill Szablewski, 609-252-5894
william.szablewski@bms.com