Showing posts with label Viekira Pak. Show all posts
Showing posts with label Viekira Pak. Show all posts

Monday, February 27, 2017

AbbVie Receives CHMP Positive Opinion for eight-week regimen of VIEKIRAX + EXVIERA for HCV genotype 1b

AbbVie Receives CHMP Positive Opinion for Eight-Week Treatment Option with VIEKIRAX® (ombitasvir/paritaprevir/ritonavir tablets) + EXVIERA® (dasabuvir tablets) for Patients with Genotype 1b Chronic Hepatitis C

Feb 27, 2017

- CHMP opinion brings AbbVie one step closer to approval of an eight-week regimen of VIEKIRAX + EXVIERA for previously untreated genotype 1b (GT1b) chronic hepatitis C virus (HCV) patients with minimal to moderate fibrosis*
- AbbVie's EMA label expansion is supported by 98 percent cure rate in the dedicated Phase 3b GARNET study[1]
- GT1b is the most common subtype globally and accounts for 47 percent of the nine million people infected with chronic HCV in Europe[2],[3],[4]

NORTH CHICAGO, Ill., Feb. 27, 2017 /PRNewswire/ -- AbbVie (NYSE: ABBV), a global biopharmaceutical company, announced today that the European Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has granted a positive opinion for a shorter, eight-week treatment of VIEKIRAX® (ombitasvir/paritaprevir/ritonavir tablets) + EXVIERA® (dasabuvir tablets) as an option for previously untreated adult patients with genotype 1b (GT1b) chronic hepatitis C virus (HCV) and minimal to moderate fibrosis*.

VIEKIRAX + EXVIERA is currently approved in the European Union for use as a 12-week treatment for GT1b chronic HCV-infected patients without cirrhosis or with compensated cirrhosis.

"AbbVie continuously strives to expand the utility of our HCV treatments, including investigating a shorter path to virologic cure for people living with HCV," said Michael Severino, M.D., executive vice president, research and development and chief scientific officer, AbbVie. "With this positive CHMP opinion, we will bring an eight-week treatment option for the many HCV patients with GT1b."

Approximately 160 million people worldwide are infected with HCV, with GT1b being the most common subtype globally.2,5 In Europe, this subtype accounts for 47 percent of the nine million people infected with chronic HCV across the continent.3,4

"Nearly half of the people living with chronic hepatitis C in Europe are infected with genotype 1b," said Dr. Tania Mara Welzel, M.H.Sc., study author and Medical Lead of the Clinical Study Center at the Department of Medicine at J.W. Goethe University in Frankfurt, Germany. "VIEKIRAX + EXVIERA has demonstrated high cure rates with only eight weeks of treatment in GT1b patients with minimal to moderate fibrosis."

The CHMP positive opinion is supported by data from the dedicated Phase 3b GARNET study. Results showed that with eight weeks of treatment with VIEKIRAX + EXVIERA, 98 percent (n=160/163) of previously untreated GT1b chronic HCV infected patients without cirrhosis achieved sustained virologic response at 12 weeks post-treatment (SVR12).1 The most commonly reported adverse events, occurring at rate equal to or greater than 5 percent, were headache (21 percent), fatigue (17 percent), nasopharyngitis (8 percent), pruritus (8 percent), nausea (6 percent) and asthenia (5 percent).

* When assessing severity of liver disease using non-invasive methods, additional blood tests improve accuracy and should be undertaken prior to 8-week treatment in all patients with moderate fibrosis.

About the GARNET Study1
The Phase 3b GARNET study is a multicenter, open-label, single-arm study investigating the safety and efficacy of eight weeks of treatment with VIEKIRAX + EXVIERA without ribavirin in treatment-naïve patients with GT1b chronic HCV infection without cirrhosis.1 The study enrolled 166 patients across 20 sites around the world. Of the 166 patients enrolled, 163 patients had GT1b chronic HCV infection without cirrhosis and three patients with other HCV genotypes were excluded from the efficacy analysis. The primary endpoint is the percentage of patients who achieved SVR12.

Two patients experienced post-treatment relapse and one discontinued due to noncompliance. Less than one percent of patients experienced serious adverse events or clinically significant (Grade ?3) laboratory abnormalities. One patient discontinued treatment on Day 45 due to an adverse event but achieved SVR12.

Additional information about the GARNET study can be found on www.clinicaltrials.gov.

VIEKIRAX® + EXVIERA®
VIEKIRAX + EXVIERA is approved in the European Union for the treatment of genotype 1 (GT1) chronic hepatitis C virus (HCV) infection, including patients with compensated cirrhosis. VIEKIRAX is approved in the European Union for the treatment of genotype 4 (GT4) chronic HCV infection.

VIEKIRAX tablets consist of the fixed-dose combination of paritaprevir 150mg (NS3/4A protease inhibitor) and ritonavir 100mg with ombitasvir 25mg (NS5A inhibitor), dosed once daily. EXVIERA tablets consist of dasabuvir 250mg (non-nucleoside NS5B polymerase inhibitor) dosed twice daily. VIEKIRAX + EXVIERA is taken with or without ribavirin (RBV), dosed twice daily based on patient type. VIEKIRAX + EXVIERA is taken for 12 weeks with or without RBV, except in genotype 1a patients with compensated cirrhosis (Child-Pugh A), who should take it for 24 weeks with RBV.

Paritaprevir was discovered during the ongoing collaboration between AbbVie and Enanta Pharmaceuticals (NASDAQ: ENTA) for hepatitis C protease inhibitors and regimens that include protease inhibitors. Paritaprevir has been developed by AbbVie for use in combination with AbbVie's other investigational medicines for the treatment of chronic hepatitis C.

Additional information about AbbVie's hepatitis C development program can be found on www.clinicaltrials.gov.

EU Indication
VIEKIRAX is indicated in combination with other medicinal products for the treatment of chronic hepatitis C (CHC) in adults. EXVIERA is indicated in combination with other medicinal products for the treatment of CHC in adults.

Important EU Safety Information
Contraindications:
VIEKIRAX + EXVIERA are contraindicated in patients with severe hepatic impairment (Child-Pugh C). Patients taking ethinyl estradiol-containing medicinal products must discontinue them and switch to an alternative method of contraception prior to initiating VIEKIRAX + EXVIERA. Do not give VIEKIRAX with certain drugs that are sensitive CYP3A substrates or strong inhibitors of CYP3A. Do not give VIEKIRAX and EXVIERA with strong or moderate enzyme inducers. Do not give EXVIERA with certain drugs that are strong inhibitors of CYP2C8.

Special warnings and precautions for use:
VIEKIRAX and EXVIERA are not recommended as monotherapy and should be used in combination with other medicinal products for the treatment of hepatitis C infection.

Risk of Hepatic Decompensation and Hepatic Failure in Patients with Cirrhosis
VIEKIRAX and EXVIERA are not recommended in patients with moderate hepatic impairment (Child-Pugh B). Patients with cirrhosis should be monitored for signs and symptoms of hepatic decompensation, including hepatic laboratory testing at baseline and during treatment.

ALT elevations
Transient elevations of ALT to >5x ULN without concomitant elevations of bilirubin occurred in clinical trials with VIEKIRAX + EXVIERA and were more frequent in a subgroup who were using ethinyl estradiol-containing contraceptives.

Pregnancy and concomitant use with ribavirin
Extreme caution must be taken to avoid pregnancy in female patients and female partners of male patients when VIEKIRAX with or without EXVIERA is taken in combination with ribavirin, see section 4.6 and refer to the Summary of Product Characteristics for ribavirin for additional information.

Use with concomitant medicinal products
Use caution when administering VIEKIRAX with fluticasone or other glucocorticoids that are metabolized by CYP3A4. A reduction in colchicine dosage or interruption in colchicine is recommended in patients with normal renal or hepatic function. VIEKIRAX with or without EXVIERA is expected to increase exposure of statins so certain statins need to be discontinued or dosages reduced. Low dose ritonavir, which is part of VIEKIRAX, may select for PI resistance in HIV co-infected patients without ongoing antiretroviral therapy. HIV co-infected patients without suppressive antiretroviral therapy should not be treated with VIEKIRAX.

Adverse Reactions
Most common (>20 percent) adverse reactions for VIEKIRAX + EXVIERA with RBV were fatigue and nausea.

Full summary of product characteristics is available at www.ema.europa.eu

Sunday, February 19, 2017

APASL 2017 - Triple DAA combo containing ritonavir effective, safe for HCV GT1b in Asians


Triple DAA combo containing ritonavir effective, safe for HCV GT1b in Asians
13 hours ago, Pearl Toh
A combination of the direct-acting antiviral agents (DAAs) ombitasvir/paritaprevir/ritonavir (OBV/PTV/r) and dasabuvir (DSV) resulted in sustained virologic response at post-treatment week 12 (SVR12) in almost all Asian adult patients with genotype 1b (GT1b) chronic hepatitis C virus (HCV) infection without cirrhosis, according to the ONYX-I* study presented at the recent Asian Pacific Association for the Study of the Liver Annual Meeting (APASL 2017) held in Shanghai, China.

July 25, 2016

Thursday, January 26, 2017

Hepatitis C Virus Genotype 4: Genotype 1's Little Brother

2017 Jan;24(1):4-12. doi: 10.1111/jvh.12620. Epub 2016 Dec 1.

Hepatitis C Virus Genotype 4: Genotype 1's Little Brother
J. Llaneras; M. Riveiro-Barciela; M. Buti; R. Esteban


Introduction
Chronic hepatitis C virus (HCV) infection affects approximately 130-150 million individuals worldwide.[1] Twenty per cent of chronic HCV infections are caused by HCV genotype 4 (GT4).[2] Infection by this genotype is more common (and highly prevalent), in the Middle East and Africa, where GT4 is responsible for more than 80% of HCV infections. In some Mediterranean European countries, especially Italy, France, Greece and Spain, the prevalence of GT4 has increased, accounting for 10%-20% of HCV infections. This genotype is usually seen in intravenous drugs users, HCV/HIV co-infected patients and immigrants from Africa or the Middle East.[3, 4] The prevalence of this infection in the United States is estimated at around 1%.[5]

In the last 5 years, HCV treatment has undergone a major change due to emergence of the new direct-acting antiviral (DAA) agents. Various therapeutic strategies have been designed to treat several HCV genotypes with these drugs.

The Food and Drug Administration (FDA) and the European Medicines Agency (EMA) recently approved several drugs for the treatment of chronic HCV GT4 infection. The classical therapies for GT4, such as pegylated alpha interferon 2a or 2b (PegIFN) and ribavirin (RBV), are giving way to the new DAA agents. The following combinations have been approved for GT4 therapy: sofosbuvir (SOF), an NS5B polymerase inhibitor[6] plus ribavirin; sofosbuvir plus simeprevir (SMV), an NS3/4A protease inhibitor[7]; sofosbuvir plus daclatasvir (DCV), an NS5A protease inhibitor[8]; ombitasvir (OBV), an NS5A protein inhibitor, plus paritaprevir, another NS3/4A protease inhibitor, boosted with ritonavir (PTV/r)[9]; the fixed-dose combination of sofosbuvir with ledipasvir (LDV), an NS5A protease inhibitor[10]; the fixed-dose combination of elbasvir (EBR), an NS5A inhibitor, and grazoprevir (GZR), an NS3/4A protease inhibitor[11]; and sofosbuvir with velpatasvir (VEL), an NS5A protein inhibitor.[12]

As compared with HCV genotype 1 (GT1), few trials have been performed in GT4 patients, and the samples studied are smaller. All the various DAA combinations have demonstrated effectiveness and safety in the treatment of patients with GT4 infection. However, the AASLD and EASL guidelines do not recommended them all, and rating of the evidence differs because of the type of studies performed, the safety profiles reported, drug–drug interactions, the availability across different countries and the cost of treatment.[13, 14] As in other HCV genotypes, the new DAA agents have led to improvements in the efficacy and safety of treatment in GT4 and have displaced PegIFN combined therapies to a secondary position (Tables 1 and 2).

Table 1. EASL recommended therapies for chronic HCV gentoype 4[13]
RecommendationRegimen and daily dosingDuration (weeks)
  1. DCV, daclatasvir; LDV, ledipasvir; OBV, ombitasvir; PTR/r, paritaprevir/ritonavir; RBV, ribavirin; SMV, simeprevir; SOF, sofosbuvir.
  2. a Patients with compensated cirrhosis with contraindications to the use of ribavirin on treatment should receive the fixed-dose combination of sofosbuvir and ledipasvir for 24 weeks without ribavirin.
IFN-free regimens in treatment-naive patients with or without cirrhosis
A1LDV/SOF (90 mg/400 mg)12
A1SOF/VEL (400 mg/100 mg)12
A1OBV/PTV/r (25 mg/150 mg/100 mg) + weight-based RBV12
A1EBR/GZR (50 mg/100 mg)12
A1SOF + SMV (400 mg/150 mg)12
B2SOF + DCV (400 mg/60 mg)12
IFN-free regimens in treatment-experienced patients with or without cirrhosis
B1LDV/SOF (90 mg/400 mg) + weight-based RBV12a
A1SOF/VEL (400 mg/100 mg)12
A1OBV/PTV/r (25 mg/150 mg/100 mg) + weight-based RBV24
B1SOF + SMV (400 mg/150 mg) + weight-based RBV12a
B2SOF + DCV (400 mg/60 mg) + weight-based12a

Table 2. American Association for the Study of Liver Diseases (AASLD) recommended therapies for chronic hepatitis C virus (HCV) genotype 4

RecommendationRegimen and daily dosingDuration (weeks)
  1. a Patients with prior on-treatment virological failure should be treated with 16 weeks and adding weight-based ribavirin.
Treatment-naive or treatment-experienced with or without cirrhosis recommended regimens[14]
A1OBV/PTV/r (25/150/100 mg) + weight-based RBV12
A1SOF/VEL (400/100 mg)12
B2EBR/GZR (50/100 mg)12a
B2LDV/SOF (90/400 mg)12
This article reviews the currently available data and the new treatments under development for patients with chronic HCV GT4 infection.

2 Historical Situation
2.1 Interferon-based therapies
Four IFN-based therapies have been approved by the FDA and the European Medicines Agency (EMA). Currently, none of them are recommended by the American Association for the Study of Liver Diseases (AASLD) or the European Association for the Study of the Liver (EASL) guidelines because of the superiority of IFN-free therapies in terms of efficacy and safety.

2.1.1 Pegylated interferon plus ribavirin
The first treatment for GT4 patients was PegINF plus ribavirin (RBV), which provided a sustained virological response (SVR) rate of around 45% in treatment-naive patients receiving pegylated alpha interferon (2a or 2b) plus RBV for 24-48 weeks.[15-17] In a large real-world cohort study, PROPHESYS, 317 patients with chronic HCV GT4 infection received this regimen.[18] The overall SVR24 rate (sustained virological response at week 24) was 41%, with a lower value (27%) in patients with cirrhosis. The limitations of this therapy are the lengthy duration, adverse events associated with PegINF, and low applicability in patients with advanced liver disease.

2.1.2 Sofosbuvir plus pegylated interferon plus ribavirin
Sofosbuvir is a potent nucleotide analogue inhibitor of the HCV NS5B polymerase with activity against all HCV genotypes.[6] SOF plus PegINF and RBV for 12 weeks was evaluated in the NEUTRINO trial,[19] a phase-III study that included 28 patients infected by HCV GT4. SVR12 (sustained virological response at week 12) was achieved in 27 of the 28 patients (96%). The limitation of this regimen is that it is PegIFN-based, with all that this implies.

2.1.3 Simeprevir plus pegylated interferon plus ribavirin
Simeprevir, an NS3/4 inhibitor, is active against genotypes 1, 2 and 4.[7] The RESTORE study evaluated the efficacy and safety of SMV plus PegIFN plus RBV for 12 weeks followed by PegIFN and RBV for an additional period of 12 or 36 weeks in 107 patients HCV infected with GT4, including treatment-naïve and treatment-experienced patients.[20] Overall, 65.4% (70/107) of patients achieved SVR12, with a lower rate in treatment-experienced patients.

2.1.4 Daclatasvir plus pegylated interferon plus ribavirin
Daclatasvir is an NS5A inhibitor with activity against all HCV genotypes.[8] In the phase-III COMMAND-4 study, 124 GT4 patients were randomized to receive DCV plus PegIFN plus RBV for 24-48 weeks or PegIFN plus RBV for 48 weeks.[21] SVR12 rates were 82% (67/82) with DCV plus PegIFN plus RBV vs 43% (18/42) with PegIFN plus RBV.
Although SVR12 rates are higher in DAA plus PegIFN regimens than in PegIFN plus RBV, DAA plus PegIFN regimens do not achieve higher SVR12 rates than the currently available IFN-free combinations, which have the additional advantages of a shorter treatment duration and fewer adverse events.

3 Interferon-Free Therapies
Direct-acting antiviral agents have brought about a revolution in the efficacy and safety of HCV treatment and have enabled treatment of more complex cases: patients with advanced liver disease or decompensated disease, those with IFN contraindications or intolerance and those unwilling to receive IFN treatment.

Among IFN-free therapies, four combinations are recommended in the new, updated AASLD guidelines[14] for treating naïve and experienced patients (with or without cirrhosis): two NS5B inhibitor plus NS5A inhibitor combinations, sofosbuvir/ledipasvir and sofosbuvir/velpatasvir; and two NS5A inhibitor plus NS3/4 inhibitor combinations, ombitasvir/paritaprevir/ritonavir (with RBV) and elbasvir/grazoprevir. In most cases, all these combinations are used in 12-week regimens (Table 3).

Table 3. Interferon-free combination regimens with new DAA agents with activity in GT4

NS3/4NS5BNS5A
  1. a Fixed-dose combination.
 SofosbuvirLedipasvira
 SofosbuvirVelpatasvira
 SofosbuvirDaclatasvir
SimeprevirSofosbuvir 
Paritaprevir/r Ombitasvira
Grazoprevir Elbasvira

3.1 NS5B inhibitor plus NS5A inhibitor
3.1.1 Sofosbuvir/ledipasvir
The NIAID SYNERGY study, a phase-IIA trial, evaluated the combination of SOF/LDV in a cohort of 21 HCV GT4-infected patients.[22] The regimen was SOF 400 mg combined with LDV 90 mg in one pill, once daily for 12 weeks. The cohort included 13 (62%) treatment-naïve patients and eight (38%) treatment-experienced patients; three patients had moderate–severe liver fibrosis (F3 in 2 and F4 in 1). Twenty (95%) patients achieved SVR12 (100% in the protocol analysis). One patient did not complete the 12-week treatment regimen because of nonadherence. There were no treatment discontinuations due to adverse events. The most common side effects were diarrhoea, fatigue, nausea and upper respiratory tract infection. This controlled study showed that this one-pill once-daily treatment was highly effective and safe in GT4-infected patients. Further studies are needed to expand the recommendations for difficult-to-treat patients with GT4 infection.

Abergel et al.[23] evaluated SOF/LDV for 12 weeks in 44 patients infected by HCV GT4, including 10 (23%) with cirrhosis and 22 (50%) who were treatment-experienced. The overall SVR12 rate was 93%. As to NS5A resistance-associated substitutions (RASs), 22 of 27 (89%) patients with NS5A RASs and all those without RASs achieved SVR12. L30R was the most prevalent NS5A resistant-associated substitution (RAS) in the cohort. NS5B RASs were not detected at baseline. Three patients relapsed within the first 4 weeks after completion of treatment. Two were treatment-experienced, and none had cirrhosis. The most common side effects were similar to those seen in other cohorts (asthenia, headache and fatigue).

3.1.2 Sofosbuvir/velpatasvir
Velpatasvir is a pangenotypic HCV NS5A inhibitor with antiviral activity against genotypes 1-6. The EMA and FDA have authorized use of the SOF 400 mg plus VEL 100 mg fixed combination in one pill daily.[12]

Sofosbuvir/velpatasvir was evaluated in ASTRAL-1, a phase-III study that enrolled 624 patients with HCV infection, including some cirrhotic and treatment-experienced patients.[24] Patients previously treated with DAA agents were excluded. Overall, 116 (19%) patients had genotype 4 infection, 121 (19%) had cirrhosis, and 423 (68%) were treatment-naïve. All patients received a 12-week regimen of SOF/VEL. SVR12 rates were 100% (116/116) in GT4-infected patients, regardless of their fibrosis status or whether they had previously received treatment. At baseline, 50 GT4-infected patients had NS5A RASs, but all achieved SVR12. No significant differences were observed in adverse event rates between the SOF/VEL regimen and placebo. The most frequent adverse effects were headache, fatigue and nasopharyngitis.

Although the GT4-infected sample size was small, this 12-week combination regimen was easy to comply with, highly effective, and safe, even in those with advanced liver fibrosis and treatment-experienced patients.

3.2 NS5A inhibitor plus NS3/4 inhibitor
3.2.1 Ombitasvir/paritaprevir/ritonavir
Ombitasvir is a NS5A inhibitor and paritaprevir a NS3/4A protease inhibitor that is coadministered with low-dose ritonavir to increase paritaprevir serum levels.[9] This combination was analysed in the multicentre phase-IIb, PEARL-I study[25] including 135 noncirrhotic GT4 patients, 86 (63.7%) of whom were treatment-naïve. Treatment-experienced patients had failed PegINF plus RBV. Treatment-naïve patients were randomly assigned to a 12-week regimen of OBV plus PTV/r with or without weight-based RBV. All treatment-experienced patients received a 12-week regimen of OBV plus PTV/r with weight-based RBV. In treatment-naïve patients, SVR12 rates were 100% (42/42) in the RBV-containing regimen and 91% (40/44) in the RBV-free regimen, with no significant differences. All treatment-experienced patients achieved SVR12 (49/49). Two patients in the treatment-naïve group with an RBV-free regimen prematurely discontinued treatment: one was lost to follow-up and the other experienced viral breakthrough at week 8 of treatment. Two other patients in the same group relapsed within 12 weeks post-treatment. All were subtype GT4d, and all had RASs at the time of failure that were not present at baseline. The predominant NS3 RAS was D168V, and the NS5A RASs were L28S or L28V. The regimen was found to be safe. The most common adverse effect was headache, but there were no adverse event-related discontinuations or dose interruptions.
The efficacy and safety of this regimen in cirrhotic patients was evaluated in the multicentre, phase-III AGATE-I study,[26] including HCV GT4-infected treatment-naïve or treatment-experienced patients with compensated cirrhosis. Patients were randomized into two arms; one received a 12-week regimen of OBV plus PTV/R with weight-based RBV once daily and the other a 16-week regimen with the same combination. Preliminary results showed SVR12 rates of 97% (57/59) in patients with the 12-week regimen vs 98% (60/61) with the 16-week regimen. One patient receiving the 12-week regimen who did not achieve SVR12 had discontinued treatment on day 1. The other was a man with HCV subtype GT4a and a previous null response to PegINF plus RBV. At baseline, he had the P58L NS5A RAS and no NS3 RASs. At failure, he showed newly emergent NS5A RASs: L28M and Y93H. Thirty-six patients in the AGATE-I cohort had RASs at baseline, and all but one achieved SVR12. In the 16-week regimen arm, SVR12 results could not be reported for one patient because of missing data. This combination was well tolerated, with no discontinuations due to adverse events. The most important events recorded were asthenia, fatigue, headache and anaemia, which were more common in the lengthier, 16-week arm.

AGATE-II is a phase-III trial carried out in Egypt, evaluating OBV plus PTV/r with RBV for GT4-infected patients, including those with compensated cirrhosis.[27] In total, 160 patients were enrolled, 100 noncirrhotic and 60 compensated cirrhotic patients. Half were treatment-experienced (61% prior null responders, 24% prior relapsers and 15% partial responders). Noncirrhotic patients received co-formulated OBV plus PTV/R once daily plus weight-based RBV for 12 weeks. Patients with compensated cirrhosis were randomized into two arms with the same regimen for 12 weeks and 24 weeks, respectively. SVR12 rates were high 94% (94/100) in the noncirrhotic arm: one patient failed while on treatment, one discontinued by withdrawing consent, data were missing in another, and three patients relapsed. SVR12 in the 12-week cirrhotic arm was 97% (30/31), with a single patient failing on treatment, and SVR12 in the 24-week arm was 96% (27/29), with missing data in one patient during follow-up and one on-treatment failure. The most common adverse events were fatigue (12%) and headache (15%). Extension of therapy to 24 weeks did not provide any additional benefits in cirrhotic patients, and there were more adverse events and a higher haemoglobin decrease in this arm.

3.2.2 Elbasvir plus grazoprevir
Elbasvir is an NS5A inhibitor, active against genotypes 1, 2a, 3, 4, 5 and 6. Grazoprevir is an NS3/4 protease inhibitor that is active against HCV genotypes 1, 2, 4, 5 and 6.[11]
The C-EDGE treatment-naïve study was an international, randomized, blinded, placebo-controlled trial investigating the combination of EBR 50 mg plus GZR 100 mg in one daily pill for 12 weeks in treatment-naive cirrhotic and noncirrhotic patients with chronic HCV genotype 1, genotype 4 and genotype 6 infection.[28] The overall SVR12 rate for all genotypes was 95%. SVR12 in GT4 treatment-naive patients was 100% (18/18). RASs were analysed in GT4 patients at baseline. NS3 RASs were present in seven of 18 (39%) patients, NS5A RASs in nine of 18 (50%) patients, and both RASs (NS5A and NS3) were found in two patients. In this study, the presence of RASs did not have an impact on SVR12 in GT4 patients. The most common adverse events in the cohort were headache (17%), fatigue (16%) and nausea (9%).

The C-EDGE treatment-experienced study evaluated the efficacy of a 12-week or 16-week regimen in HCV-infected patients who had failed PegIFN treatment. Patients received a one-pill regimen of EBR plus GZR with or without weight-based RBV.[29] SVR12 rates in GT4 patients receiving the 12-week regimen without or with RBV were 78% (7/9) and 93% (14/15), respectively. SVR12 rates in those receiving the 16-week regimen without or with RBV were 60% (3/5) and 100% (8/8), respectively. Baseline RASs and subgenotypes did not seem to have an impact on SVR12 rates.
Asselah et al.[30] reported data from phase-II and phase-III studies including a total of 103 GT4-infected patients treated with EBR/GZR. Sixty-six treatment-naïve patients were enrolled to receive EBR/GZR for 12 weeks and another 10 patients received the same regimen plus weight-based RBV for 12 weeks. Ninety-six (54/56) patients achieved SVR12 in the RBV-free regimen, one patient was lost to follow-up, and other relapsed. In the RBV regimen, SVR12 rates were 100% (10/10). Treatment-experienced patients were divided into four arms, 12 weeks or 16 weeks of treatment with or without weight-based RBV. SVR12 rates were higher in the 16-week regimens and RBV-associated regimens than in the 12-week regimens or RBV-free regimens. Two patients in the 12-week regimen relapsed, one in the RBV-associated regimen and the other in the RBV-free regimen. The other two patients failed on treatment in the 16-week regimen without RBV. All treatment-naive patients who had NS5A RASs at baseline achieved SVR12. In total, 81% (13/16) of treatment-experienced patients who achieved SVR12 had NS5A RASs at baseline, and 100% of treatment-experienced patients with NS3 RASs at baseline achieved SVR12.

The 12-week regimen without RBV is an attractive combination for treatment-naïve patients and PegIFN relapsers, including patients with compensated cirrhosis. In treatment-failed patients, 16-week therapy duration is associated with a higher SVR12 (Table 4).

Table 4. (a) SVR12 in GT4 hepatitis C virus (HCV)-infected patients without liver cirrhosis treated with IFN-free regimens. (b) SVR12 in GT4 HCV-infected patients with liver cirrhosis treated with IFN-free regimens. (c) SVR12 in GT4 HCV-infected patients with and without liver cirrhosis treated with IFN-free regimens
Treatment regimenDuration (weeks)NoPrior HCV treatmentSVR12 rate % (no SVR/total)Virological failures (no of cases)
  1. EBR, elbasvir; GZR, grazoprevir; LDV, ledipasvir; OBV, ombitasvir; PTR/R, paritaprevir/ritonavir; RBV, ribavirin; SOF, sofosbuvir; TE, treatment-experienced patients; TN, treatment-naive patients; VEL, velpatasvir.
  2. a Regimen without ribavirin.
  3. b Regimen with ribavirin.
(a) NS5B/NS5A
SOF/VEL (ASTRAL-1)[24]1289Treatment-experienced Treatment-naive100% (89/89)
SOF/LDV (NIAID SYNERGY)[22]1214Treatment-experienced Treatment-naive93% (13/14)
SOF/LDV Abergel et al.[23]1234Treatment-experienced Treatment-naive91% (31/34)Relapsers: 3
NS5A/NS3/4
OBV/PTV/r (PEARL-1)[25]12135Treatment-experienced Treatment-naive91% (40/44) TNaVirological breakthrough: 1 Relapsers: 2
100% (42/42) TNb
100% (49/49) TEb
OBV/PTV/r + RBV (AGATE-II)[27]12100Treatment-experienced Treatment-naive94% (94/100)Breakthrough: 1 Relapsers: 3
(b) NS5B/NS5A
SOF/VEL (ASTRAL-1)[24]1227Treatment-experienced Treatment-naive100% (27/27)
SOF/LDV (NIAID SYNERGY)[22]127Treatment-experienced Treatment-naive100% (7/7)
SOF/LDV Abergel et al.[23]1210Treatment-experienced Treatment-naive100% (10/10)
NS5A/NS3/4
OBV/PTV/r + RBV (AGATE-I)[26]12
16
120Treatment-naive
Treatment-experienced
97% (57/59) 12 weeks
98% (60/61) 16 weeks
Virological breakthrough: 1
OBV/PTV/r + RBV (AGATE-II)[27]12
24
60Treatment-naive
Treatment-experienced
97% (30/31) 12 weeks
96% (27/29) 24 weeks
Virological breakthrough: 2
(c) NS5A/NS3/4
GZR/EBR (C-EDGE TN)[28]1218Treatment-naive100% (18/18)
GZR/EBR (C-EDGE TE)[29]12
16
37Treatment-experienced78% (7/9) 12 weeksa
93% (14/15) 12 weeksb
60% (3/5) 16 weeksa
100% (8/8) 16 weeksb
GZR/EBR Asselah et al.[30]12
16
103Treatment-experienced Treatment-naiveTN
96% (54/56) 12 weeksa
100% (10/10) 12 weeksb
TE
78% (7/9) 12 weeksa
93% (14/15) 12 weeksb
66% (3/5) 16 weeksa
100% (8/8) 16 weeksb
Relapsers: 3 Virological breakthrough: 2

3.3 Other interferon-free regimens accepted for treating HCV GT4 infection
3.3.1 Sofosbuvir plus ribavirin
Sofosbuvir plus RBV was the first IFN-free therapy used for GT4 infection, but it is no longer recommended. In a phase-II study, 60 patients of Egyptian ancestry with chronic HCV GT4 infection received a combination of SOF plus RBV.[31] Half of the patients had been previously treated. Patients were randomly allotted 1:1 to receive SOF 400 mg and weight-based RBV in both groups, but with treatment durations of either 12 or 24 weeks. SVR12 was achieved in 68% of patients in the 12-week group and 93% in the 24-week group. The most common adverse events were headache, insomnia and fatigue. A larger number of adverse events were reported in the 24-week group due to the longer treatment duration. This study had a limited sample, and it included only a few difficult-to-treat patients.

Another trial carried out in Egypt analysed the efficacy and safety of the same combination in 103 patients,[32] 52% treatment-experienced and 17% with cirrhosis at baseline. Patients were randomly assigned to one of two arms: SOF 400 mg and a weight-based daily dose of RBV for 12 or 24 days. SVR12 was 90% in the 24-week group and 77% in the 12-week group. Patients with cirrhosis had lower SVR12 rates than those without cirrhosis in both arms.
Despite the favourable SVR12 rates at 24 weeks, this combination is suboptimal compared with combinations including two DAAs, which allow shorter duration and show fewer associated side effects, particularly in patients with cirrhosis.

3.3.2 Sofosbuvir plus simeprevir
PLUTO is a multicentre Spanish study including 40 patients with HCV GT4 infection.[33] This single-arm study evaluated the efficacy and safety of a 12-week regimen of SOF 400 mg plus SMV 150 mg daily. All patients achieved SVR12 regardless of their baseline characteristics (18% cirrhosis and 68% treatment-experienced). Adverse events occurred in 50%; all were grade 1 and grade 2. The most common adverse event was headache (20%).

The preliminary efficacy results of the phase-IIa OSIRIS study are in line with those seen in the PLUTO study.[34] OSIRIS is being conducted in Egypt and includes 63 treatment-naïve or experienced patients with and without cirrhosis. All have HCV GT4 infection and are under treatment with SMV 150 mg plus SOF 400 mg daily. High SVR4 rates (95%-100%) have been seen with 12 weeks of treatment regardless of the prior PegIFN plus RBV response or cirrhosis stage. The initial safety data show no discontinuations due to adverse events, and no grade 3 or 4 treatment-related adverse events. The study remains open pending SVR12.

The SOF plus SMV regimen has also been evaluated in the real world. In the French HEPATHER cohort, 34 HCV GT4 patients (82% with compensated cirrhosis and 73% treatment-experienced) were treated with SOF 400 mg plus SMV for 12 or 24 weeks with or without RBV.[35] SVR12 was attained in all patients receiving RBV in their regimen. In a study conducted in the Netherlands, HCV GT4-infected patients were treated with SOF plus SMV (with or without RBV) for 12 weeks. Treatment-naive and treatment-experienced patients were included, and SVR12 was achieved in 49 of 53 patients (92%).[36]

Regarding these results, SOF plus SMV would be a combination option for HCV GT4 infected patients. RBV addition could be considered in treatment-experienced patients.

3.3.3 Sofosbuvir plus daclatasvir
The ATU study investigated a French cohort including 215 patients with HCV GT4 infection and characteristics associated with a low response to treatment, such as moderate liver fibrosis, extrahepatic manifestations, recurrence following liver transplantation and placement on the liver or kidney transplant lists.[37] Among the total, 110 (52%) patients were treated with a 24-week regimen including SOF 400 mg and DCV 30 mg daily, and 63 (30%) patients received the same regimen for 12 weeks. RBV was added in eight patients in the 12-week regimen group and in 31 patients receiving the 24-week regimen. The overall SRV12 rate in HCV GT4 patients was around 91%. SVR12 in patients with cirrhosis (including decompensated cirrhosis) was 90%. The 12-week regimen group showed the highest number of treatment failures. This is a safe regimen with few discontinuations (1%), and the most common adverse event was asthenia in 10% of patients.

4 Treatment of Decompensated Cirrhosis
There are few available studies using the new DAA agents in GT4-infected patients with decompensated cirrhosis. The phase-II SOLAR-I study enrolled GT1- and GT4-infected patients with cirrhosis and moderately or severely impaired liver function, and liver transplant recipients with or without cirrhosis and mild, moderate or severe liver impairment, or fibrosing cholestatic hepatitis.[38] Patients were randomized into two arms to receive 12 or 24 weeks of LDV/SOF plus RBV, respectively. In total, 337 patients were enrolled, and 1% (4/337) had HCV GT4. Overall SVR12 rates in patients with moderate hepatic impairment were 87% in the 12-week regimen and 88% in the 24-week regimen. In liver transplant recipients, SVR12 was lower in those in Child–Turcotte–Pugh class C, with 60% and 75% in the 12- and 24-week regimens, respectively, compared noncirrhotic transplant recipients, with SVR12 rates of 96% and 98%, respectively. Treatment had to be discontinued prematurely in 4% patients because of adverse events. Ten patients died, mainly from complications related to hepatic decompensation. LDV/SOF plus weight-based RBV was associated with high SVR12 rates and good tolerance in decompensated and severe liver impairment, but there were only four GT4 patients in the cohort.

SOLAR-II was a multicentre study that extended data on the LDV/SOF plus RBV regimen in GT4 decompensated cirrhotic patients.[39] In total, 333 patients with advanced liver impairment were enrolled, 37 of whom (11%) were HCV GT4. LDV/SOF plus weight-based RBV were administered in 12- or 24-week regimens. SVR12 rates in GT4 were 78% (14/18) in the group receiving a 12-week regimen and 94% (16/17) in those treated for 24 weeks. The discontinuation rates were similar to those of SOLAR-I. Seventeen patients died due to complications of hepatic decompensation.
The phase-III study, ASTRAL-4, enrolled treatment-naive and treatment-experienced patients with decompensated cirrhosis infected with HCV genotypes 1 (78%), 2 (4%), 3 (15%), 4 (3%) and 6 (<1%).[40] Patients were randomized at a 1:1:1 ratio to receive SOF/VEL once daily for 12 weeks, SOF plus RBV once daily for 12 weeks or SOF/VEL once daily for 24 weeks. Overall SVR12 rates were 83% in patients receiving 12 weeks SOF/VEL (100%, 4/4 in GT4 patients), 94% in those receiving SOF/VEL plus RBV (100%, 2/2 in GT4 patients) and 86% in those with 24 weeks of SOF/VEL (100%, 2/2 in GT4 patients). All GT4-infected patients achieved SVR12. There were no significant differences in SVR rates between the three groups. NS5A RASs were detected in 72 of 255 patients (28%). Of these 72 patients, 64 (89%) achieved SVR12 compared with 169 of 183 patients (92%) without RASs. Serious adverse events were observed in approximately 16%-18% of patients in each group.

Real-life data are scarce in GT4-infected patients with decompensated cirrhosis. Welzel et al.[41] reported on 49 decompensated HCV patients receiving SOF plus DCV with or without RBV. The overall SVR12 was 92% (45/49). Three patients had GT4 infection, and all achieved SVR12. According to the Child–Turcotte–Pugh scoring system for cirrhosis, 15 were classified as B and eight as C. SVR12 rates in these patients were 80% and 88%, respectively. Please note the low representation of genotype 4 in this cohort.
The benefits of this treatment are unclear, particularly in patients with an advanced Child–Turcotte–Pugh score, because viral clearance seems to have little impact on liver impairment or liver complications.

5 HCV/HIV Co-Infected Patients
The efficacy and safety of treatment for HCV GT4 infection in the HIV co-infected population has been evaluated in a few studies.

ION-4 is a multicentre study involving patients co-infected with HIV-1 and HCV genotypes 1 or 4.[42] All patients received an antiretroviral regimen of tenofovir and emtricitabine with efavirenz, rilpivirine or raltegravir. In addition, all received LDV 90 mg plus SOF 400 mg in a single pill once daily for 12 weeks. In total, 335 patients were enrolled, 20% had cirrhosis, and 55% had received prior HCV treatment. SVR12 was achieved in 96% of the total cohort and in all patients (8/8) with GT4 infection. SVR12 rates were similar in the various subgroups regardless of treatment experience or cirrhosis stage. There were no cases of HIV-1 virological rebound, and none of the patients discontinued treatment because of adverse events.

The ALLY-2 study analysed 203 HCV/HIV co-infected patients (three patients had GT4) receiving 12 or 8 weeks of SOF 400 mg plus DCV 60 mg, daily.[43] SVR12 rates were 97% after 12 weeks of treatment and 76% after 8 weeks. All GT4-infected patients achieved SVR12.
A subanalysis by antiretroviral regimen class reported that SVR12 was 97% and was similar across the antiretroviral regimens included.[44] SOF plus DCV is an attractive combination for HCV/HIV co-infected patients, but further data in GT4-infected patients are needed.

The phase-III C-EDGE CO-INFECTION study is a multicentre trial including HIV patients co-infected with HCV genotypes 1, 4 and 6.[45] In total, 218 patients were enrolled and all received GZR/EBR for 12 weeks. The SVR12 rate in patients with GT4 infection was 96% (27/28), with only one relapse, occurring in a noncirrhotic patient. This RBV-free combination achieved a high SVR12 in HCV/HIV co-infected patients without RBV adverse events.

There is little information on GT4 HCV/HIV co-infected patients treated with ombitasvir and paritaprevir regimens. This would likely be an effective, safe combination, as indicated in genotype 1 by the TURQUOISE-I study,[46] but additional data are needed to recommend this combination in this specific population.

6 DAA Failures
6.1 Genotype 4. Resistance-associated substitutions
Only 2% to 5% of HCV GT4 patients fail DAA treatment. Pawlosky et al. reviewed the profiles of patients who experienced treatment failure in each of the major studies using any type of combination therapy. Most of the information came from HCV GT1-infected patients and very little from HCV GT4.

The emergence of HCV RASs is determined by the genetic barrier to the drug, the fitness of the resistant viral population and blood levels of the drug. The dynamics of RASs after discontinuation of DAAs differs depending on the antiviral agent. NS3/4 protease inhibitor RASs disappear within some time after completion of treatment. However, NS5A RASs persist for years and could impact on the selection of retreatment strategies.[47]

RASs to NS5A inhibitors at baseline did not demonstrate a significant impact on SVR12 in combination regimens of SOF/LDV, SOF/VEL or SOF plus DCV, except in treatment-experienced GT1a patients, with or without cirrhosis, in whom lower SVR12 rates were observed. Very limited data are available in GT4 infection. In patients with NS5A RASs failing DAA treatment, the current recommendation is to extend treatment to 24 weeks and add RBV. This is based on the findings from small studies showing a higher SVR12.[48] Although there are no available data in GT4 infection, NS5A inhibitor resistance did not have an impact on SVR12 in GT1 patients receiving an OBV/PTV/R regimen with RBV. Similar results were found for the EBR/GZR combination, with the exception of GT1a patients and treatment-experienced GT1b patients, in whom SVR12 rates were lower. Hence, associated RBV and 16-week or 18-week duration are required in these patients. Again, no resistance data are available in GT4 for this combination. NS3 RASs at baseline do not appear have impact on SVR12.

Presence of the Q80K NS3 resistance substitution does not affect SVR12 in GT4 infection, unlike what occurs in GT1a patients, especially treatment-experienced ones.[49]
Some re-treatment strategies after failing DAAs have been explored in a small number of patients. In a recent study, 15 GT1- and GT4-infected patients who failed a DCV-based regimen (DCV plus PegIFN plus RBV, with or without asunaprevir) received SOF plus SMV without RBV for 12 weeks. Thirteen (87%) achieved SVR12, including all those with GT4 infection.[50] Further data on re-treatment of GT4 patients are needed before a strong recommendation can be established. In the meantime, one re-treatment approach could be a combination of SOF with a DAA of a different class than that previously used plus RBV, and extending therapy to 24 weeks.

7 Summary
In summary, the treatment options for HCV GT4 are now continually growing. The lower SVR rates reported in the past have been eliminated since the development of the new DAA agents. The NS5B-inhibitor, sofosbuvir, has been and remains the cornerstone of the current IFN-free therapies, achieving high SVR12 rates with a good safety profile. Combinations of NS5B inhibitors with NS5A or NS3/4 may be optimal strategies for the treatment of GT4-infected patients with compensated cirrhosis and those previously treated with PegIFN/RBV regimens. Nonetheless, other combinations without NS5B inhibitors, such as NS5A plus NS3/4-inhibitors, have shown SVR rates and safety profiles similar to those of the sofosbuvir combination. Despite the paucity of studies in HCV GT4 infection, some cohorts have provided information of promising SVR12 rates and safety profiles in special populations, such as HCV/HIV co-infected patients and patients with decompensated cirrhosis. These limited data encourage more aggressive use of DAA agents in these populations.
Unfortunately, data on re-treatment strategies for GT4-infected patients who fail IFN-free therapy are nonexistent. We need a greater representation of GT4 patients in real-life studies to provide GT4 infection with a proper identity and remove it from the shadow of GT1.

Disclosures
Maria Buti and Rafael Esteban have received grant for Gilead, MSD, Abbvie and BMS. Mar Riveiro-Barciela has received grant for Gilead. Jordi Llaneras has no personal interests to declare.

References
Source - http://onlinelibrary.wiley.com/doi/10.1111/jvh.12620/full

Friday, September 30, 2016

On eve of rollout, fears under-funding may restrict hep C treatment

Regular news from the New Zealand Doctor newsroom

On eve of rollout, fears under-funding may restrict hep C treatment
Cliff Taylorctaylor@nzdoctor.co.nz
Friday 30 September 2016, 3:20PM

The RNZCGP fears under-funding threatens a ground-breaking hepatitis C treatment even as GPs prepare to start prescribing it from tomorrow.

The college has written an urgent letter to the Ministry of Health saying it supports the treatment, but extensive GP input is needed and the cost “will have a significant impact on patient’s ability to obtain a cure”.

It is urging the ministry to consider funding options, including direct funding for free GP visits.

GPs have been preparing for three months for the rollout of Viekira Pak, shown in trials to cure more than 95 per cent of patients with hepatitis C genotype 1. The drug was financially out of reach for most people, until it was funded by Pharmac from 1 July.

Patients will be knocking on GPs’ doors

Pharmac and drug company Abbvie have been preparing GPs for the rollout with educational materials and seminars. Pharmac’s deputy medical director for primary care, GP Bryan Betty, says it is one of the biggest changes in general practice prescribing in decades.

Auckland liver specialist Ed Gane says GPs should expect to have patients “knocking on their door” from tomorrow.

“GPs need to ensure they are educated about this new treatment,” Professor Gane says in a media release. “This is our chance to offer a life-changing cure to many people living with hepatitis C.”

College endorses training but queries cost

RNZCGP chief executive Helen Morgan-Banda is in Australia today and unable to be interviewed. She sent an email saying the college is endorsing both face-to-face training via DHBs and an online module for GPs prescribing Viekira Pak. It is also promoting the training via its weekly e-newsletter to members.

Ms Morgan-Banda wrote to the ministry last Friday saying the college welcomes the new treatment as a great development that will have positive benefits for a large number of New Zealanders.

But she says the college is very concerned the cost of GP visits will present a barrier to patients. She suggested two alternative avenues for funding:

* direct funding for free visits, such as the ministry currently provides for dioxin exposed people, and

* funding through a DHB Primary Options for Acute Care (POAC) programme.

“Our view is that whichever model is deemed appropriate, action needs to be taken urgently to ensure that it is in place and funding is available as soon as possible after the 1 October date when access to treatment becomes available,” she wrote in the letter.

In today’s email, Ms Morgan-Banda says the medicines have been funded, but GP appointments have not. The college is concerned this will affect the success of the programme.

She says patients with hepatitis C tend to be more deprived than the general population and are also often transient. She is concerned the lack of funding will result in inequity of access to treatment.

New Zealand Doctor sought comment from the ministry, but did not receive a reply before deadline.

‘Game-changing’ – despite the cost

ProCare associate clinical director and GP Jamie Shepherd says the issue of cost has been discussed at the PHO and he understands why the college has concerns.

But he says he and colleagues are well prepared and excited about being able to offer the treatment.

“We would love to have it funded, but we recognise as a GP it’s our role to deliver this as best we can. We have been aware of the rollout since July. It will be a big change for general practice, but it’s been well highlighted.

“This is game-changing for people with hepatitis C in New Zealand.”

Huge improvement in treatment

Professor Gane is hailing the new drug’s efficacy. Viekira Pak is taken orally, usually for 12 weeks and will cure over 95 per cent of patients, he says. It is also well tolerated, with 99 per cent of people completing treatment.

“This is a huge improvement compared to previous Interferon treatments, which consisted of weekly injections for a year, associated with bad side effects. Almost 20 per cent of people had to stop the treatment and less than half were cured.”

However, he says an effective oral treatment is still needed for almost half of the New Zealanders infected with hepatitis C who have other genotypes (2, 3, 4, 5 and 6).

Buyers’ Club an option for some

He is calling for Pharmac to fund other pan-genotypic drugs, but says in the meantime personal importation of generic versions could be a viable option.

He says to date more than 500 New Zealanders and Australians have accessed generics through the Fix Hep C Buyers’ Club run by Australian GP James Freeman.
“The generic medications cured more than 95 per cent of patients and were extremely safe, proving that these generic drugs are the real deal,” Professor Gane says. “These medications cost less than five per cent of the price of brand drugs — which is about $2,100.”

Related link
October 1: a momentous day for many people living with hepatitis C in New Zealand - The Hepatitis Foundation of New Zealand

Friday, September 23, 2016

AbbVie Presents Data on Eight-Week Treatment of VIEKIRAX® for Genotype 1b

AbbVie Presents Data on Eight-Week Treatment of VIEKIRAX® (ombitasvir/paritaprevir/ritonavir tablets) + EXVIERA® (dasabuvir tablets) in Patients with Genotype 1b Chronic Hepatitis C

- 98 percent of previously untreated genotype 1b (GT1b) chronic hepatitis C virus (HCV) infected patients without cirrhosis achieved SVR12 in Phase 3b GARNET study1

- First study evaluating 8 weeks of VIEKIRAX (ombitasvir/paritaprevir/ritonavir tablets) + EXVIERA (dasabuvir tablets)1

- GT1b is the most common subtype globally,2 accounting for 47 percent of the nine million people infected with chronic HCV in Europe alone3,4

- GARNET study results on 8-week treatment duration included in newly published 'EASL Recommendations on Treatment of Hepatitis C'

NORTH CHICAGO, Ill., Sept. 23, 2016 /PRNewswire/ -- AbbVie (NYSE: ABBV), a global biopharmaceutical company, today announced new data showing high response rates with just eight weeks of VIEKIRAX® (ombitasvir/paritaprevir/ritonavir tablets) + EXVIERA® (dasabuvir tablets) treatment. In the Phase 3b GARNET study, 98 percent (n=160/163) of previously untreated patients with genotype 1b (GT1b) chronic hepatitis C virus (HCV) infection without cirrhosis achieved sustained virologic response rates at 12 weeks post-treatment (SVR12).1 These data were presented today at the 2016 EASL Special Conference: New Perspectives in Hepatitis C Virus Infection – The Roadmap for Cure, in Paris, France and included in the newly published 'EASL Recommendations on Treatment of Hepatitis C.' VIEKIRAX + EXVIERA is currently approved in the European Union for GT1b patients without cirrhosis or with compensated cirrhosis for 12 weeks.

"VIEKIRAX + EXVIERA has already achieved high cure rates with 12 weeks of treatment," said Stefan Zeuzem, M.D., study author and Chief of the Department of Medicine at the J.W. Goethe University Hospital in Frankfurt, Germany. "These results now show the potential for cure in just eight weeks with VIEKIRAX + EXVIERA in HCV genotype 1b infected patients without liver cirrhosis. The efficacy in this population is particularly important as GT1b is the most common subtype of hepatitis C virus globally."

Approximately 160 million people worldwide are infected with HCV.5 Genotype 1 is the most prevalent of the six major HCV genotypes, affecting an estimated 83 million people worldwide.6 In Europe, GT1b is the most predominant subtype accounting for 47 percent of the nine million people infected with chronic HCV.3,4,6

"AbbVie remains focused on continuing to explore and understand the expectations of HCV care, including a shorter treatment duration with VIEKIRAX + EXVIERA in GT1b patients," said Rob Scott, M.D., Vice President, Development and Chief Medical Officer, AbbVie.

In the GARNET study, the most commonly reported adverse events (≥5 percent) were headache (21 percent), fatigue (17 percent), nasopharyngitis (8 percent), pruritus (8 percent), nausea (6 percent) and asthenia (5 percent). These adverse events were mostly mild, with one patient discontinuing treatment due to adverse events.1

About the GARNET Study1
The Phase 3b GARNET study is a multicenter, open-label, single-arm study, investigating the safety and efficacy of eight weeks of treatment with VIEKIRAX + EXVIERA without ribavirin in treatment-naïve patients with GT1b chronic HCV infection without cirrhosis.1 The study enrolled 166 patients across 20 sites around the world. Of the 166 patients enrolled, 163 patients had GT1b chronic HCV infection without cirrhosis and three patients with other HCV genotypes were excluded from the efficacy analysis. The primary endpoint is the percentage of patients who achieved a sustained virologic response 12 weeks after treatment (SVR12).

Two patients experienced post-treatment relapse and one subject discontinued due to noncompliance. Less than one percent of patients experienced serious adverse events or clinically significant (Grade ≥3) laboratory abnormalities. One patient discontinued treatment on Day 45 due to an adverse event but achieved SVR12.

Additional information about the GARNET study can be found on www.clinicaltrials.gov.

VIEKIRAX® + EXVIERA®
VIEKIRAX + EXVIERA is approved in the European Union for the treatment of genotype 1 (GT1) chronic hepatitis C virus (HCV) infection, including patients with compensated cirrhosis. VIEKIRAX is approved in the European Union for the treatment of genotype 4 (GT4) chronic HCV infection.

VIEKIRAX tablets consist of the fixed-dose combination of paritaprevir 150mg (NS3/4A protease inhibitor) and ritonavir 100mg with ombitasvir 25mg (NS5A inhibitor), dosed once daily. EXVIERA tablets consist of dasabuvir 250mg (non-nucleoside NS5B polymerase inhibitor) dosed twice daily. VIEKIRAX + EXVIERA are taken with or without ribavirin (RBV), dosed twice daily based on patient type. VIEKIRAX + EXVIERA is taken for 12 weeks with or without RBV, except in genotype 1a patients with compensated cirrhosis (Child-Pugh A), who should take it for 24 weeks with RBV.

Paritaprevir was discovered during the ongoing collaboration between AbbVie and Enanta Pharmaceuticals (NASDAQ: ENTA) for hepatitis C protease inhibitors and regimens that include protease inhibitors. Paritaprevir has been developed by AbbVie for use in combination with AbbVie's other investigational medicines for the treatment of chronic hepatitis C.

Additional information about AbbVie's hepatitis C development program can be found on www.clinicaltrials.gov.

EU Indication
VIEKIRAX is indicated in combination with other medicinal products for the treatment of chronic hepatitis C (CHC) in adults. EXVIERA is indicated in combination with other medicinal products for the treatment of CHC in adults.

Important EU Safety Information
Contraindications:
VIEKIRAX + EXVIERA are contraindicated in patients with severe hepatic impairment (Child-Pugh C). Patients taking ethinyl estradiol-containing medicinal products must discontinue them and switch to an alternative method of contraception prior to initiating VIEKIRAX + EXVIERA. Do not give VIEKIRAX with certain drugs that are sensitive CYP3A substrates or strong inhibitors of CYP3A. Do not give VIEKIRAX and EXVIERA with strong or moderate enzyme inducers. Do not give EXVIERA with certain drugs that are strong inhibitors of CYP2C8.

Special warnings and precautions for use:
VIEKIRAX and EXVIERA are not recommended as monotherapy and should be used in combination with other medicinal products for the treatment of hepatitis C infection.

Risk of Hepatic Decompensation and Hepatic Failure in Patients with Cirrhosis
VIEKIRAX and EXVIERA are not recommended in patients with moderate hepatic impairment (Child-Pugh B). Patients with cirrhosis should be monitored for signs and symptoms of hepatic decompensation, including hepatic laboratory testing at baseline and during treatment.

ALT elevations
Transient elevations of ALT to >5x ULN without concomitant elevations of bilirubin occurred in clinical trials with VIEKIRAX + EXVIERA and were more frequent in a subgroup who were using ethinyl estradiol-containing contraceptives.

Pregnancy and concomitant use with ribavirin
Extreme caution must be taken to avoid pregnancy in female patients and female partners of male patients when VIEKIRAX with or without EXVIERA is taken in combination with ribavirin, see section 4.6 and refer to the Summary of Product Characteristics for ribavirin for additional information.

Use with concomitant medicinal products
Use caution when administering VIEKIRAX with fluticasone or other glucocorticoids that are metabolized by CYP3A4. A reduction in colchicine dosage or interruption in colchicine is recommended in patients with normal renal or hepatic function. VIEKIRAX with or without EXVIERA is expected to increase exposure of statins so certain statins need to be discontinued or dosages reduced. Low dose ritonavir, which is part of VIEKIRAX, may select for PI resistance in HIV co-infected patients without ongoing antiretroviral therapy. HIV co-infected patients without suppressive antiretroviral therapy should not be treated with VIEKIRAX.

Adverse Reactions
Most common (>20 percent) adverse reactions for VIEKIRAX + EXVIERA with RBV were fatigue and nausea.

Full summary of product characteristics is available at www.ema.europa.eu

Friday, August 26, 2016

Hepatitis C/Effectiveness of Sofosbuvir, Ledipasvir/Sofosbuvir, or Paritaprevir/Ritonavir/Ombitasvir and Dasabuvir

September 2016 Gastroenterology.
Volume 151, Issue 3, Pages 457–471.e5

Effectiveness of Sofosbuvir, Ledipasvir/Sofosbuvir, or Paritaprevir/Ritonavir/Ombitasvir and Dasabuvir Regimens for Treatment of Patients With Hepatitis C in the Veterans Affairs National Health Care System

George N. Ioannou, Lauren A. Beste, Michael F. Chang, Pamela K. Green, Elliott Lowy, Judith I. Tsui, Feng Su, Kristin Berry

DOI: http://dx.doi.org/10.1053/j.gastro.2016.05.049

Background & Aims
We investigated the real-world effectiveness of sofosbuvir, ledipasvir/sofosbuvir, and paritaprevir/ritonavir/ombitasvir and dasabuvir (PrOD) in treatment of different subgroups of patients infected with hepatitis C virus (HCV) genotypes 1, 2, 3, or 4.

Methods
We performed a retrospective analysis of data from 17,487 patients with HCV infection (13,974 with HCV genotype 1; 2131 with genotype 2; 1237 with genotype 3; and 135 with genotype 4) who began treatment with sofosbuvir (n = 2986), ledipasvir/sofosbuvir (n = 11,327), or PrOD (n = 3174), with or without ribavirin, from January 1, 2014 through June 20, 2015 in the Veterans Affairs health care system. Data through April 15, 2016 were analyzed to assess completion of treatments and sustained virologic response 12 weeks after treatment (SVR12). Mean age of patients was 61 ± 7 years, 97% were male, 52% were non-Hispanic white, 29% were non-Hispanic black, 32% had a diagnosis of cirrhosis (9.9% with decompensated cirrhosis), 36% had a Fibrosis-4 index score >3.25 (indicator of cirrhosis), and 29% had received prior antiviral treatment.

Results
An SVR12 was achieved by 92.8% (95% confidence interval [CI], 92.3%–93.2%) of subjects with HCV genotype 1 infection (no significant difference between ledipasvir/sofosbuvir and PrOD regimens), 86.2% (95% CI, 84.6%–87.7%) of those with genotype 2 infection (treated with sofosbuvir and ribavirin), 74.8% (95% CI, 72.2%–77.3%) of those with genotype 3 infection (77.9% in patients given ledipasvir/sofosbuvir plus ribavirin, 87.0% in patients given sofosbuvir and pegylated-interferon plus ribavirin, and 70.6% of patients given sofosbuvir plus ribavirin), and 89.6% (95% CI 82.8%–93.9%) of those with genotype 4 infection. Among patients with cirrhosis, 90.6% of patients with HCV genotype 1, 77.3% with HCV genotype 2, 65.7% with HCV genotype 3, and 83.9% with HCV genotype 4 achieved an SVR12. Among previously treated patients, 92.6% with genotype 1; 80.2% with genotype 2; 69.2% with genotype 3; and 93.5% with genotype 4 achieved SVR12. Among treatment-naive patients, 92.8% with genotype 1; 88.0% with genotype 2; 77.5% with genotype 3; and 88.3% with genotype 4 achieved SVR12. Eight-week regimens of ledipasvir/sofosbuvir produced an SVR12 in 94.3% of eligible patients with HCV genotype 1 infection; this regimen was underused.

Conclusions
High proportions of patients with HCV infections genotypes 1–4 (ranging from 75% to 93%) in the Veterans Affairs national health care system achieved SVR12, approaching the results reported in clinical trials, especially in patients with genotype 1 infection. An 8-week regimen of ledipasvir/sofosbuvir is effective for eligible patients with HCV genotype 1 infection and could reduce costs. There is substantial room for improvement in SVRs among persons with cirrhosis and genotype 2 or 3 infections.

Discussion Only
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LDV/SOF, PrOD, and SOF-based antiviral regimens resulted in remarkably high SVR rates in the VA national health care system, approaching the rates reported in clinical trials. This is in contrast to previous interferon-based regimens, which consistently resulted in much lower SVR rates in real-world clinical practice than in clinical trials.12, 13, 14, 15, 16, 17 SVR rates were higher in genotype 1– (SVR 92.8%) and genotype 4–infected patients (SVR 89.6%) than genotype 2– (SVR 86.2%) or 3–infected patients (SVR 74.8%), and these differences were even greater among cirrhotic and treatment-experienced patients. Among genotype 1–infected patients, there was no significant difference in SVR rates between LDV/SOF and PrOD regimens in either unadjusted or multivariable, propensity-score-adjusted analyses, and SVR rates >90% were achieved even in subgroups such as treatment-experienced or cirrhotic patients. The short, 8-week LDV/SOF monotherapy regimen resulted in excellent SVR rate (94.3%), but was used in only 48.6% of genotype 1–infected patients eligible for 8-week therapy (ie, treatment-naïve patients with viral load <6 million IU/mL, without cirrhosis). Long, 24-week regimens did not result in higher SVR rates and were rarely used, despite being FDA-approved and American Association for the Study of Liver Diseases/Infectious Diseases Society of America–recommended32 for certain genotype 1 patients with cirrhosis.

Among a total of 17,487 patients, our study included 5250 patients with a diagnosis of cirrhosis and 5960 with a FIB-4 score >3.25 (which is highly suggestive of cirrhosis), who achieved surprisingly high overall SVR rates of 86.8% and 87.4%, respectively. These high SVR rates were driven by genotype 1–infected cirrhotic patients who had much higher SVR (90.6%; 95% CI, 89.7%–91.5%) than genotype 2 (77.3%; 95% CI 73.3%–80.9%) or genotype 3 (65.7%; 95% CI, 61.2%–69.8%). To our knowledge, this is the largest study of DAAs in cirrhotic patients and the SVR rates in genotype 1–infected patients are the highest reported in real-world clinical practice. LDV/SOF, PrOD, and SOF regimens have allowed patients with cirrhosis to be cured of HCV in substantial numbers and proportions for the first time ever. Longer follow-up of these patients is necessary to determine whether patients with cirrhosis who achieve SVR by DAAs are protected from developing progressive liver dysfunction, liver failure, or HCC and, whether they are capable of liver remodeling and regression of cirrhosis.

American Association for the Study of Liver Diseases/Infectious Diseases Society of America guidelines during the time period of our study,32 as well as the LDV/SOF package insert,33 recommend that LDV/SOF regimens should extend for 12 or 24 weeks, with the single exception of a short, 8-week LDV/SOF monotherapy regimen that “can be considered,”33 “with caution and at the discretion of the practitioner”32 in treatment-naïve, genotype 1–infected patients without cirrhosis with an HCV viral load <6 million IU/mL. This is based on a post-hoc analysis of the ION-3 clinical trial showing higher relapse rates in those treated for 8 weeks who had a viral load ≥6 million (9 of 92 [10%]) compared with those with a viral load <6 million IU/mL (2 of 123 [2%]).3 VA treatment guidelines explicitly recommended 8 weeks of treatment for this subgroup of patients.34 Indeed, our study confirmed that 8 weeks of LDV/SOF monotherapy had similarly high SVR rates (94.8%) as 12 weeks (95.3%) in this favorable subgroup. However, our results also showed that treatment was unnecessarily extended beyond 8 weeks in 1833 of 4066 patients in this subgroup, dramatically increasing the cost of treatment without increasing SVR. Our results should offer reassurance to treatment providers that 8 weeks of LDV/SOF monotherapy is sufficient duration in this subgroup.

VA treatment guidelines during the study period designated PrOD as the preferred regimen in genotype 1–infected patients except for prior null responders, those previously treated with protease inhibitors, and patients with Child’s B or C cirrhosis (in whom the preferred regimen was LDV/SOF and ribavirin for 12 weeks) and except for treatment naïve, non-cirrhotics with a viral load <6 million (in whom 8-week LDV/SOF and 12-week PrOD regimens were equally preferred). This was due to the lower cost of 12 weeks of PrOD ($22,850) compared with 12 weeks of LDV/SOF ($37,157) in the VA system during the study period and the absence of evidence that one is more effective than the other in the subgroups for which PrOD was preferred. Our data support the VA treatment recommendations because we found no difference in SVR between PrOD and LDV/SOF regimens in either adjusted or unadjusted analyses, in the entire population or in clinically relevant subgroups (cirrhosis or not, treatment-experienced or naïve). Despite these recommendations and the higher cost, LDV/SOF regimens constituted 77% and PrOD only 23% of regimens in genotype-1–infected patients. This could be due to higher prevalence of drug–drug interactions, higher pill burden, and more frequent requirement for co-prescription of ribavirin in PrOD regimens compared with LDV/SOF regimens.

After the end of the study period, and after FDA approval of elbasvir/grazoprevir as an additional regimen for genotype 1 HCV on January 28, 2016, regimen costs in the VA were further reduced dramatically, to approximately $17,000 per 12-week course for LDV/SOF, PrOD, and elbasvir/grazoprevir and treatment recommendations changed to “equally recommend” all 3 agents as of March 2016.

Genotype 3–infected patients had the lowest SVR rates in our study, just as in clinical trials. We found that the non-FDA–approved regimen of LDV/SOF and ribavirin had a higher SVR rate (77.9%; 95% CI, 73.1%–82.0%) than the longer and more expensive FDA-approved regimen of SOF and ribavirin for 24 weeks (70.6%; 95% CI, 66.9%–74.1%). However, the highest SVR rate in genotype 3–infected patients was observed in the regimen that included PEG together with SOF and ribavirin (87.0%; 95% CI, 80.0%–91.8%), the only interferon-containing regimen that is still recommended.32
Few large real-world studies of interferon-free regimens are currently available for comparison with ours. The HCV-TARGET, a prospective cohort study of patients undergoing HCV treatment in routine clinical care in academic centers, reported SVR rate to SOF and simeprevir in genotype 1–infected patients of 88% among 151 transplant recipients and 84% among 836 non-transplant recipients.35, 36 This regimen has been superseded by LDV/SOF and PrOD-based regimens. Among 487 patients with decompensated cirrhosis treated in the United Kingdom under an Expanded Access Programme with SOF, LDV/SOF, or daclatasvir, SVR was achieved in 90.5% of genotype 1– and 68.8% of genotype 3–infected patients37—very similar to our findings. A smaller VA study looked at only treatment-naïve, genotype 1–infected patients treated with LDV/SOF and reported SVR rates almost identical to ours among this subgroup.38 The TRIO Network, which compiles data from participating “real-world” academic and community HCV treatment clinics in the United States, reported in an abstract an SVR rate of 94% among 1521 genotype 1–infected patients treated with LDV/SOF monotherapy.39
The main limitation of our study was that SVR data were unavailable in 9% of patients, which can lead to overestimated SVR rates among those with available SVR data. We think this is unlikely for 2 reasons. First, patients with missing SVR data were similar to those with available SVR data (Supplementary Table 2). Although early discontinuation of treatment in <8 weeks was more common in patients with missing SVR data (25% vs 4.4%), the majority of patients with missing SVR completed 8 or more weeks of treatment, demonstrating that patients with missing SVR data were not patients who “dropped out” of treatment or were “lost to follow-up,” but rather patients (or physicians) who were simply delinquent in getting their SVR viral load measured after the end of their treatment—not an uncommon phenomenon outside of clinical trials. Second, we used comprehensive multiple imputation models that included duration of treatment in addition to baseline, pretreatment characteristics to impute the missing SVR data and found only a non-substantial reduction in SVR after imputation (Table 5), suggesting that it is unlikely that our results of observed SVR are biased toward overestimation due to the missing SVR data. Important strengths of the study include the complete ascertainment of filled pharmacy prescriptions and the utilization of complete electronic medical records since 1999 from a national health care system that treats the greatest number of HCV-infected patients in the United States.

Our results demonstrate that LDV/SOF, PrOD, and SOF regimens can achieve remarkably high SVR rates in real-world clinical practice, especially in genotype 1–infected patients. The main obstacle to curing HCV infection in the maximum possible number of patients is currently the cost of HCV antiviral regimens. It is expected that cost will decline dramatically as more antiviral regimens become FDA-approved, resulting in competition between manufacturers. In fact, costs decreased dramatically within the VA after the completion of our study and after the FDA approval of elbasvir/grazeprevir in January 2016. The VA health care system has budgeted $1.5 billion nationally for antiviral medications for fiscal year 2016, while every health care organization in the United States is faced with similar budgetary constraints due to the cost of antiviral medications. We hope that our results will be used to determine the most cost-effective ways to treat HCV-infected patients and to reassure patients, clinicians, and health care systems that current treatments for HCV, though costly, appear to be effective in the real-world setting.

Acknowledgments
Author contributions: George Ioannou: Study concept and design, acquisition of data, statistical analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript, obtained funding. Pamela Green: Analysis of data. Elliott Lowy: Analysis of data. Kristin Berry: Study design and analysis of data. Feng Su: Study design and critical revision of the manuscript. Michael F. Chang: Study design and critical revision of the manuscript. Judith Tsui: Study design and critical revision of the manuscript. Lauren Beste: Study design and critical revision of the manuscript. George Ioannou is the guarantor of this paper. All authors approved the final version of the manuscript.

Article Outline
  1. Methods
    1. Data Source: The Veterans Affairs Corporate Data Warehouse
    2. Study Population and Antiviral Regimens
    3. Baseline Characteristics
    4. Sustained Virologic Response
    5. Statistical Analysis
  2. Results
    1. Treatment Regimens by Genotype
    2. Patient Characteristics
    3. Early Discontinuation of Treatment
    4. Overall Sustained Virologic Response Rates by Genotype
    5. Utilization and Sustained Virologic Response Rates of 8-Week Ledipasvir/Sofosbuvir Regimens
    6. Utilization and Sustained Virologic Response Rates of 24-Week Ledipasvir/Sofosbuvir and Paritaprevir/Ritonavir/Ombitasvir Regimens
    7. Sustained Virologic Response Rates in Patients With Cirrhosis
    8. Sustained Virologic Response Rates in Treatment-Experienced vs Treatment-Naïve Patients
    9. Independent Predictors of Sustained Virologic Response
    10. Impact of Missing Sustained Virologic Response Data and Imputation for Missing Sustained Virologic Response
  3. Discussion
  4. Supplementary Material
  5. References