Patients feel stigma, discrimination when living with hepatitis

Provided by Healio

April 23, 2015

VIENNA — After receiving their diagnoses, patients with viral hepatitis report suffering stigma and discrimination at the hands of family, friends, employers and even health care practitioners, according to a survey presented at the 2015 International Liver Congress.

“Viral hepatitis is not only a silent disease, but also a silencing event,” Marcelo Naveira, MD, of Brazil’s Ministry of Health, said during a press conference at the congress. “There is a need for a broad campaign targeting hepatitis awareness and fight against stigma and discrimination. Given the recent advances in therapy, one can be assured that no true progress has been achieved while those infected by viral hepatitis still have to face stigma and discrimination. These effects might last long after virologic response is achieved.”

Grupo Otimismo, a support group for people with hepatitis and a nongovernmental organization in Brazil, used an online tool to survey 1,217 people infected with hepatitis B or C, Naveira explained. The 12-question survey looked at discrimination and stigma experienced by patients.

When asked who they informed, 94.1% of respondents told family, 73.7% told friends, 57.4% told a partner and 46.1% told coworkers, but only 31.4% told support groups, 9.1% told a social network and 2.1% told no one. Although 72.45% of patients reported those they told had some comprehension of their diagnosis, 48.9% reported overall indifference.

After diagnosis, 55.8% of patients reported an effect on self-esteem and 41.4% reported feeling shame. More than 40% of respondents reported their diagnoses affected their jobs, friends and sexual relationships; approximately 10% of respondents were dismissed from their jobs due to their hepatitis. Of those that told family members, 24.6% reported family then avoided physical contact and of those who told friends, 23.8% said those friends stopped inviting them to social events.

While 70% of health professionals were reported to treat patients properly, 24.6% reported the practitioners kept a certain distance and 6.9% of respondents were denied care. Patients reported that those places in which discrimination took place were the dentist (21.2%), while getting a manicure/pedicure (17.1%), undergoing tests at a lab (10.8%) or at the gym (4.4%).

“Protection against the damage inflicted by viral hepatitis is a matter of public health and basic human rights,” Naveira said. “It troubles us in Brazil — it worries us a lot — that even in a society so open to change, people still have to deal with consequences of disease like viral hepatitis. We assume in other societies that people face those same consequences.” – by Katrina Altersitz

For More Information:

Varaldo CN. Abstract P1275. Presented at: International Liver Congress; April 22-26, 2015; Vienna.

Disclosure: Naveira and Varaldo report no relevant financial relationships.

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Shorter HCV Tx Works in Advanced Disease

Provided by MedPage Today

Twelve weeks of treatment yielded high efficacy rates in hepatitis C (HCV) patients with advanced liver disease or recurrent HCV after transplant.

by Michael Smith
North American Correspondent, MedPage Today

VIENNA -- In hepatitis C virus (HCV) patients with advanced liver disease or recurrent HCV after transplant, 12 weeks of treatment yielded high efficacy rates, a researcher said here.

Efficacy did not differ greatly among patients randomly assigned to 12 or 24 weeks of treatment with the fixed-dose combination of ledipasvir/sofosbuvir (Harvoni) given with ribavirin, according to Michael Manns, MD, of Hannover Medical School in Hannover, Germany.

And the combination was generally well-tolerated -- an important consideration among the seriously ill patients in the so-called SOLAR-2 trial, Manns told reporters here at the annual meeting of the European Association for the Study of the Liver.

The study evaluated the safety and efficacy of the therapy in patients with Child-Pugh scores of B and C either pre- or post-transplant, or in those whose disease had recurred after transplant but who were Child-Pugh A or had fibrosis scores of F0 through F3.

The goal was to compare outcomes with 12 weeks of therapy with those after 24 weeks -- the recommended duration for such patients in Europe, Manns said.

For most patients with conditions similar to those in the trial, Manns said, "I would feel comfortable treating for 12 weeks."

But most of the 328 patients had genotype 1 disease, and the handful of patients in the study with genotype 4 HCV did not do as well, he noted. For those patients, he said, he would continue to aim for 24 weeks of therapy "depending on tolerability."

What to do with the difficult-to-treat patients in the study is a tough question, commented Markus Peck-Radosavljevic, MD, of the Medical University of Vienna and current Secretary General of EASL.

On one hand, Peck-Radosavljevic told MedPage Today, the study does show that the treatment "is not endangering" the patients and can lead to cures in most cases.

But on the other hand, he said, "there might be a point where you don't do them a favor by making them virus-free."

It could happen, he said, that treatment might cure a patient of HCV, leaving him or her ineligible for a transplant but still with a seriously damaged liver.

In many cases, he said, it might be better to go ahead with a transplant and count on being able to cure recurrent HCV afterward.

Patients in the trial, Manns said, had either genotype 1 or 4 and were stratified into six groups:

• Patients without transplant and either Child-Pugh B or Child-Pugh C cirrhosis -- groups 1 and 2
• Patients with recurrent HCV after liver transplantation and either without cirrhosis or with Child-Pugh A, B, or C cirrhosis -- groups 3 through 6

The endpoint of the study was sustained virologic response 12 weeks after the end of treatment (SVR₁₂).

Overall, Manns reported, post-transplant patients without fibrosis or with Child-Pugh A status did equally well with 12 or 24 weeks of therapy -- SVR₁₂ rates were 95% and 98%, respectively.

Patients with Child-Pugh B or C cirrhosis, regardless of transplant status, did less well but, again, treatment duration seemed to have little effect -- 85% with SVR₁₂ at 12 weeks and 88% at 24 weeks, Manns reported.

Differences appeared when the patients were broken down by genotype, however.

Among patients with genotype 1 disease, 12- and 24-week SVR₁₂ rates were 96% and 98% if they had low fibrosis scores or Child-Pugh A cirrhosis, and 88% and 89%, respectively, for those with Child-Pugh B or C cirrhosis.

The 18 patients with genotype 4 and less advanced liver damage had SVR₁₂ rates of 91% and 100% after 12 and 24 weeks of therapy, respectively.

But among the 14 patients with genotype 4 and Child-Pugh B and C cirrhosis, 12- and 24-week SVR₁₂ rates were 57% and 86%, respectively.

Most patients reported at least one adverse event, with rates of between 92% and 95%, Manns said, but serious adverse events were much less common -- reported by between 14% and 28% of patients, with more seen among those with more advanced disease.

There were no treatment-related adverse events in patients without cirrhosis and nine among those with cirrhosis, including five reports of anemia and one each of falling, vomiting, diarrhea, and hyperbilirubinemia.

Although there were 10 deaths, none was considered related to treatment, Manns said.

The study was supported by Gilead Sciences. Manns disclosed relevant relationships with AbbVie, BI, BMS, Gilead, Janssen, Merck, Novartis, Roche, Idenix, and GSK. Some authors are employees of Gilead.

Reviewed by Henry A. Solomon, MD, FACP, FACC Clinical Associate Professor, Weill Cornell Medical College

Primary Source: European Association for the Study of the Liver

Source Reference: Manns M, et al "Ledipasvir/sofosbuvir with ribavirin is safe and efficacious in decompensated and post liver transplantation patients with HCV infection: Preliminary results of the prospective SOLAR 2 trial" EASL 2015; Abstract G02.

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Also See: Gilead’s Harvoni and Sovaldi Demonstrate Efficacy and Safety among Chronic Hepatitis C Patients with Advanced Liver Disease

Study reveals impact of delaying HCV treatment

Published on April 23, 2015 at 4:01 AM

Data revealed today at The International Liver Congress™ 2015 highlights the impact of delaying treatment for the hepatitis C virus (HCV). Researchers found that treatment delays have a serious detrimental effect on treatment efficacy, increasing the risk of morbidity and mortality among patients.

The study was conducted using retrospective patient data from the Veterans Administration in the USA to estimate the impact on risk of morbidity and death depending on whether treatment was initiated before or after a patient's FIB4 levels became elevated. The FIB4 index is a simple formula used to predict liver damage (fibrosis) based on standard biochemical values and age.

Researchers found that delaying treatment until after a patient's FIB4 level exceeds 3.25 has a clear detrimental effect on treatment effectiveness. Delaying therapy until after the patient's FIB4 level exceeds 1.45 or 1.00 has a smaller detrimental effect on treatment effectiveness.

The study demonstrates that delaying HCV treatment in an attempt to save costs has a serious adverse impact on patients, with the most serious effect being the speeding up of time to death. Once HCV diagnosis has been confirmed the most suitable treatment should be initiated as soon as feasible balancing budgetary cash-flow issues against adverse impacts on patients.

Source: European Association for the Study of the Liver

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Janssen Announces SVR12 Rates with Twelve Weeks of Treatment with All-Oral, Once-Daily Regimen of Simeprevir Plus Sofosbuvir in Genotype 1 HCV Patients With and Without Cirrhosis

- Data from OPTIMIST-1 and OPTIMIST-2 Trials Showing SVR12 Rates of 97 Percent and 84 Percent to be Presented at The International Liver Congress™ 2015 of the European Association for the Study of the Liver -

CORK, Ireland, April 23, 2015 /PRNewswire/ -- Janssen Sciences Ireland UC, one of the Janssen Pharmaceutical Companies of Johnson & Johnson (Janssen), today announced results for its hepatitis C treatment simeprevir at The International Liver Congress™ 2015 of the European Association for the Study of the Liver (EASL) in Vienna. Late-breaking results from the Phase 3 OPTIMIST-1 and OPTIMIST-2 trials highlight the clinical outcomes of simeprevir in an all-oral combination regimen in a wide range of patients with hepatitis C virus (HCV) infection.

"The new data for simeprevir presented at The International Liver Congress™ confirms its efficacy when combined with sofosbuvir in an all-oral, ribavirin-free regimen for HCV patients, including those who are treatment-naive and treatment-experienced, both with and without cirrhosis," said Gaston Picchio, hepatitis disease area leader, Janssen. "These data further demonstrate the role of simeprevir within the HCV treatment landscape, as it provides patients with an important therapeutic option."

The results from the OPTIMIST-1 and OPTIMIST-2 trials are the first Phase 3 data to be presented on simeprevir in combination with sofosbuvir (SMV/SOF) in patients with genotype 1 chronic HCV infection, both with and without cirrhosis. Sofosbuvir is a nucleotide analog NS5B polymerase inhibitor developed by Gilead Sciences, Inc.

OPTIMIST-1¹

• OPTIMIST-1 is a Phase 3, randomized, open-label trial to investigate the efficacy and safety of the all-oral regimen of SMV/SOF among treatment-naive and treatment-experienced genotype 1 chronic HCV-infected patients without cirrhosis. The primary objective was to show superior sustained virologic response (SVR) at 12 weeks after treatment (SVR12) with 12 and eight weeks of treatment with SMV/SOF versus a historical control (patients previously treated with approved regimens containing a direct-acting antiviral, pegylated interferon and ribavirin).
• Ninety-seven (97) percent of patients treated with SMV/SOF for 12 weeks (n=150/155) achieved SVR12, which was superior to the SVR12 rate of 87 percent among the historical control.
  • SVR12 rates of 100 percent were seen among patients with IL28B CC genotype (n=43/43) and those with baseline NS5A and NS3 Q80K polymorphisms (n=9/9).
• Patients treated with eight weeks of SMV/SOF achieved an SVR12 rate of 83 percent (n=128/155), which was not superior to the SVR12 rate of 83 percent in the historical control.
  • High SVR12 rates were seen among patients with baseline HCV RNA <4 million IU/mL (96 percent; n=46/48), IL28B CC genotype (93 percent; n=38/41), patients with genotype 1b HCV infection (92 percent; n=36/39) and patients without baseline NS5A and Q80K polymorphisms (89 percent; n=78/88).
• The most frequently reported adverse events in the 12-week and eight-week treatment arms were headache (14 and 17 percent, respectively), fatigue (12 and 15 percent, respectively) and nausea (15 and 9 percent, respectively).

OPTIMIST-2²

• OPTIMIST-2 is a Phase 3, open-label, single-arm trial to investigate the efficacy and safety of SMV/SOF in treatment-naive and treatment-experienced genotype 1 chronic HCV-infected patients with cirrhosis. The primary objective was to show superior SVR12 with 12 weeks of treatment with SMV/SOF versus a historical control.
• Twelve (12) weeks of treatment with SMV/SOF resulted in SVR12 rates of 84 percent (n=86/103), which was superior to the SVR12 rate of 70 percent in the historical control.
• Higher SVR12 rates were seen in patients with baseline NS5A polymorphisms with or without NS3 Q80K polymorphisms (100 percent, n=13/13), patients with albumin ≥4 g/dL (94 percent; n=47/50) and treatment-naïve patients (88 percent; n=44/50).
• The most common adverse events were fatigue (20 percent), headache (20 percent) and nausea (11 percent).

"Chronic HCV infection is a leading cause of cirrhosis, and once it is developed, these patients can be very difficult to cure. The results of the OPTIMIST-2 study demonstrate the safety and efficacy of the all-oral regimen of simeprevir and sofosbuvir for genotype 1 chronic HCV patients with cirrhosis," said Eric Lawitz, M.D., Texas Liver Institute, principal investigator of the OPTIMIST-2 study.

About Hepatitis C
Hepatitis C, a blood-borne infectious disease of the liver and a leading cause of chronic liver disease, is a major global public health concern. Approximately 170 million people are infected with hepatitis C worldwide and 350,000 people per year die from the disease globally. When left untreated, hepatitis C can cause significant damage to the liver, including cirrhosis. Additionally, hepatitis C may increase the risk of developing complications from cirrhosis, which may include liver failure.

About Janssen's HCV Development Program
The goal of the Janssen hepatitis C virus (HCV) clinical development program is to provide physicians with multiple treatment options in order to offer patients the best possible chance at successful therapy.

Ongoing studies focus on the investigation of the NS3/4A protease inhibitor simeprevir in a number of different treatment combinations and HCV patient populations, including those who are difficult to cure.

Janssen's HCV pipeline also includes JNJ-56914845, an investigational NS5A replication complex inhibitor currently in Phase 2 studies, and following the acquisition of Alios BioPharma by Johnson & Johnson in November 2014, AL-335, a uridine-based nucleotide analog in Phase 1 development, and AL-516, a guanosine-based nucleotide analog NS5B polymerase inhibitor in pre-clinical development.

These compounds are being developed with the intent of targeting critical steps of the HCV replication cycle.

About Simeprevir (OLYSIO^®)
Simeprevir is an NS3/4A protease inhibitor which has been developed by Janssen Sciences Ireland UC in collaboration with Medivir AB.

In November 2013, simeprevir was initially approved by the U.S. Food and Drug Administration, and in May 2014, it was granted marketing authorization by the European Commission. Subsequent marketing authorizations have followed in several other countries around the world. Indications vary by market.

Janssen is responsible for the global clinical development of simeprevir and has exclusive, worldwide marketing rights, except in the Nordic countries. Medivir AB retains marketing rights for simeprevir in these countries under the marketing authorization held by Janssen-Cilag International NV.

About Janssen Pharmaceutical Companies of Johnson & Johnson
At Janssen, we are dedicated to addressing and solving some of the most important unmet medical needs of our time in oncology, immunology, neuroscience, infectious diseases and vaccines, and cardiovascular and metabolic diseases. Driven by our commitment to patients, we develop innovative products, services and healthcare solutions to help people throughout the world. Janssen R&D Ireland is part of the Janssen Pharmaceutical Companies of Johnson & Johnson. Please visit http://www.janssenrnd.com for more information.

INDICATIONS
OLYSIO^® is a hepatitis C virus (HCV) NS3/4A protease inhibitor indicated for the treatment of chronic hepatitis C (CHC) genotype 1 infection as a component of a combination antiviral treatment regimen.

Limitations of Use:

• OLYSIO^® monotherapy is not recommended.
• OLYSIO^® efficacy in combination with peginterferon alfa (Peg‑IFN‑alfa) and ribavirin (RBV) is substantially reduced in patients infected with HCV genotype 1a with an NS3 Q80K polymorphism at baseline compared to patients infected with hepatitis C virus (HCV) genotype 1a without the Q80K polymorphism. Screening patients with HCV genotype 1a infection for the presence of virus with the NS3 Q80K polymorphism at baseline is strongly recommended. Alternative therapy should be considered for patients infected with HCV genotype 1a containing the Q80K polymorphism.
• OLYSIO^® is not recommended in patients with moderate or severe hepatic impairment (Child‑Pugh Class B or C).
• OLYSIO^® is not recommended in patients who have previously failed therapy with a treatment regimen that included OLYSIO^® or other HCV protease inhibitors.

IMPORTANT SAFETY INFORMATION

Contraindications:

• There are no specific contraindications to OLYSIO^®. The contraindications to other antiviral drugs administered with OLYSIO^® for the treatment of CHC infection also apply to OLYSIO^® combination treatment.  Prescribers should consult the complete prescribing information for these drugs for a description of contraindications.

Warnings and Precautions:

• Serious Symptomatic Bradycardia When Co-administered with Sofosbuvir and Amiodarone:  Postmarketing cases of symptomatic bradycardia and cases requiring pacemaker intervention have been reported when amiodarone is co-administered with sofosbuvir in combination with another HCV direct acting antiviral, including OLYSIO^®. A fatal cardiac arrest was reported in a patient receiving a sofosbuvir-containing regimen (ledipasvir/sofosbuvir). Bradycardia has generally occurred within hours to days, but cases have been observed up to 2 weeks after initiating 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 co-administration of amiodarone. Bradycardia generally resolved after discontinuation of HCV treatment. The mechanism for this bradycardia effect is unknown. 
  Co-administration of amiodarone with OLYSIO^® in combination with sofosbuvir is not recommended. For patients taking amiodarone who have no other alternative treatment options, and who will be co-administered OLYSIO and sofosbuvir: 
           o    Counsel patients about the risk of serious symptomatic bradycardia
           o    Cardiac monitoring in an in-patient setting for the first 48 hours of
                 co-administration is recommended, after which outpatient or self-monitoring
                 of the heart rate should occur on a daily basis through at least the first 2
                 weeks of treatment.
  Patients who are taking sofosbuvir in combination with OLYSIO^® who need to start amiodarone therapy due to no other alternative treatment options should undergo similar cardiac monitoring as outlined above.
  Due to amiodarone's long elimination half-life, patients discontinuing amiodarone just prior to starting sofosbuvir in combination with OLYSIO^® should also undergo similar cardiac monitoring as outlined above.
  Patients who develop signs or symptoms of bradycardia should seek medical evaluation immediately. Symptoms may include near-fainting or fainting, dizziness or lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pain, confusion or memory problems.
• Hepatic Decompensation and Hepatic Failure:  Hepatic decompensation and hepatic failure, including fatal cases, have been reported postmarketing in patients treated with OLYSIO^® in combination with Peg‑IFN‑alfa and RBV or in combination with sofosbuvir.  Most cases were reported in patients with advanced and/or decompensated cirrhosis who are at increased risk for hepatic decompensation or hepatic failure.  Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between treatment with OLYSIO^® and these events has not been established.
  OLYSIO^® is not recommended for patients with moderate or severe hepatic impairment (Child-Pugh Class B or C).
  In clinical trials of OLYSIO^®, modest increases in bilirubin levels were observed without impacting hepatic function. Postmarketing cases of hepatic decompensation with markedly elevated bilirubin levels have been reported.  Monitor liver chemistry tests before and as clinically indicated during OLYSIO^® combination therapy.  Patients who experience an increase in total bilirubin to greater than 2.5 times the upper limit of normal should be closely monitored:
  • Patients should be instructed to contact their healthcare provider if they have onset of fatigue, weakness, lack of appetite, nausea and vomiting, jaundice or discolored feces.
  • Discontinue OLYSIO if elevation in bilirubin is accompanied by liver transaminase increases or clinical signs and symptoms of hepatic decompensation.
• Risk of Serious Adverse Reactions Associated With Combination Treatment: OLYSIO^® should be used in combination with other antiviral drugs for the treatment of CHC infection. Therefore, consult the prescribing information for these drugs before starting therapy with OLYSIO^®.
• Photosensitivity: Photosensitivity reactions have been observed with OLYSIO^® combination therapy. Serious photosensitivity reactions resulting in hospitalization have been observed with OLYSIO^® in combination with Peg‑IFN‑alfa and RBV. Photosensitivity reactions occurred most frequently in the first 4 weeks of treatment, but can occur at any time during treatment. Photosensitivity may present as an exaggerated sunburn reaction, usually affecting areas exposed to light (typically the face, "V" area of the neck, extensor surfaces of the forearms, and dorsa of the hands). Manifestations may include burning, erythema, exudation, blistering, and edema.
  Use sun protective measures and limit sun exposure during treatment with OLYSIO^®. Avoid use of tanning devices during treatment with OLYSIO^®. Discontinuation of OLYSIO^® should be considered if a photosensitivity reaction occurs and patients should be monitored until the reaction has resolved. If a decision is made to continue OLYSIO^® in the setting of a photosensitivity reaction, expert consultation is advised.
• Rash: Rash has been observed with OLYSIO^® combination therapy. Rash occurred most frequently in the first 4 weeks of treatment, but can occur at any time during treatment. Severe rash and rash requiring discontinuation of OLYSIO^® have been reported in subjects receiving OLYSIO^® in combination with Peg‑IFN‑alfa and RBV. Most of the rash events in OLYSIO^®‑treated patients were of mild or moderate severity. Patients with mild to moderate rashes should be followed for possible progression of rash, including the development of mucosal signs (e.g., oral lesions, conjunctivitis) or systemic symptoms. If the rash becomes severe, OLYSIO^® should be discontinued. Patients should be monitored until the rash has resolved.
• Sulfa Allergy: OLYSIO^® contains a sulfonamide moiety. In subjects with a history of sulfa allergy (n=16), no increased incidence of rash or photosensitivity reactions has been observed. However, there are insufficient data to exclude an association between sulfa allergy and the frequency or severity of adverse reactions observed with the use of OLYSIO^®.
• Risk of Adverse Reactions or Reduced Therapeutic Effect Due to Drug Interactions: Co‑administration of OLYSIO^® with substances that are moderate or strong inducers or inhibitors of cytochrome P450 3A (CYP3A) is not recommended as this may lead to significantly lower or higher exposure of simeprevir, respectively, which may result in reduced therapeutic effect or adverse reactions.

Adverse Reactions

• Use with Peg-IFN-alfa and RBV: Adverse reactions (all grades, at least 3% higher frequency) for OLYSIO^® with Peg-IFN-alfa and RBV vs. Peg-IFN-alfa and RBV alone in the first 12 weeks were rash (including photosensitivity) (28% vs. 20%), pruritus (22% vs. 15%), nausea (22% vs. 18%), myalgia (16% vs. 13%), and dyspnea (12% vs. 8%).

• Use with sofosbuvir: The most common (> 10%) adverse reactions reported during 12 weeks treatment with OLYSIO^® in combination with sofosbuvir without RBV were fatigue (25%), headache (21%), nausea (21%), insomnia (14%) and pruritus (11%). Rash and photosensitivity were reported in 11% and 7% of subjects, respectively. During 24 weeks treatment with OLYSIO^® in combination with sofosbuvir, dizziness (16%), and diarrhea (16%) were also commonly reported.

Use in Specific Populations

• Pregnancy Category C: Adequate and well-controlled trials with OLYSIO^® have not been conducted in pregnant women. OLYSIO^® should be used during pregnancy only if the potential benefit justifies the potential risk. Female patients of childbearing potential should use an effective contraceptive method.

• Race: Patients of East Asian ancestry exhibit higher simeprevir exposures. In clinical trials, higher simeprevir exposures have been associated with increased frequency of adverse reactions, including rash and photosensitivity. There are insufficient safety data to recommend an appropriate dose for patients of East Asian ancestry. The potential risks and benefits of OLYSIO^® should be carefully considered prior to use in patients of East Asian ancestry.

• Renal Impairment:  No dose adjustment of OLYSIO^® is required in patients with mild, moderate or severe renal impairment. The safety and efficacy of OLYSIO^® have not been studied in HCV‑infected patients with severe renal impairment (creatinine clearance below 30 mL/min) or end‑stage renal disease, including patients requiring dialysis. Simeprevir is highly protein-bound; therefore, dialysis is unlikely to result in significant removal of simeprevir.

• Hepatic Impairment: No dose adjustment of OLYSIO^® is required in patients with mild hepatic impairment (Child‑Pugh Class A). The safety and efficacy of OLYSIO^® have not been established in HCV‑infected patients with moderate or severe hepatic impairment (Child‑Pugh Class B or C). OLYSIO^® is not recommended for patients with moderate or severe hepatic impairment (Child‑Pugh Class B or C). There have been postmarketing reports of hepatic decompensation, hepatic failure, and death in patients with advanced or decompensated cirrhosis receiving OLYSIO^® combination therapy. Simeprevir exposures are increased in patients with moderate or severe hepatic impairment (Child‑Pugh Class B or C). In clinical trials, higher simeprevir exposures have been associated with increased frequency of adverse reactions, including increased bilirubin, rash and photosensitivity.

• Other HCV Genotypes: The safety and efficacy of OLYSIO^® have not been established in patients infected with other HCV genotypes.

• Liver Transplantation: The safety and efficacy of OLYSIO^® have not been studied in liver transplant patients.

Not a complete list of Uses in Specific Populations.

Consult the PI for Peg-IFN-alfa and RBV or sofosbuvir before starting therapy with OLYSIO^®.  Safety information related to these drugs also applies to their use in OLYSIO^® combination treatment.

Please see full Prescribing Information and Patient Information for more details.

This press release contains "forward-looking statements" as defined in the Private Securities Litigation Reform Act of 1995 regarding product development. The reader is cautioned not to rely on these forward-looking statements. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or known or unknown risks or uncertainties materialize, actual results could vary materially from the expectations and projections of Janssen R&D Ireland and/or Johnson & Johnson. Risks and uncertainties include, but are not limited to: challenges and uncertainties inherent in new product development, including the uncertainty of clinical success and of obtaining regulatory approvals; competition, including technological advances, new products and patents attained by competitors; challenges to patents; changes to applicable laws and regulations, including global health care reforms; and trends toward health care cost containment. A further list and description of these risks, uncertainties and other factors can be found in Johnson & Johnson's Annual Report on Form 10-K for the fiscal year ended December 28, 2014, including in Exhibit 99 thereto, and the company's subsequent filings with the Securities and Exchange Commission. Copies of these filings are available online at www.sec.gov, www.jnj.com or on request from Johnson & Johnson. None of the Janssen Pharmaceutical Companies or Johnson & Johnson undertakes to update any forward-looking statement as a result of new information or future events or developments.

References

¹ A Phase 3, randomised, open-label study to evaluate the efficacy and safety of 12 and 8 weeks of treatment with simeprevir plus sofosbuvir in treatment-naive and -experienced patients with chronic HCV genotype 1 infection without cirrhosis: The OPTIMIST-1 study. Presented at The International Liver Congress™ 2015.

² A Phase 3, open-label, single-arm study to evaluate the efficacy and safety of 12 weeks of simeprevir plus sofosbuvir in treatment-naive or –experienced patients with chronic hepatitis c virus genotype 1 infection and cirrhosis: The OPTIMIST-2 study. Presented at The International Liver Congress™ 2015.

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Merck Announces Results from Phase 2/3 Study of Investigational Chronic Hepatitis C Therapy Grazoprevir/Elbasvir in Patients with Advanced Chronic Kidney Disease

C-SURFER Trial is First to Investigate an All-Oral Ribavirin-Free Hepatitis C Treatment Regimen in Treatment-Naïve and Treatment-Experienced Patients with Advanced Chronic Kidney Disease Infected with Hepatitis C Virus Genotype 1

Thursday, April 23, 2015 3:30 am EDT

VIENNA--(BUSINESS WIRE)--Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced the first presentation of data from C-SURFER, the company’s Phase 2/3 clinical trial evaluating the investigational once-daily treatment regimen of grazoprevir (100mg) and elbasvir (50mg) in patients with advanced chronic kidney disease (CKD) infected with chronic hepatitis C virus (HCV) genotype 1 (GT1).¹ Treatment-naïve patients and patients who failed prior pegylated interferon HCV therapy, with or without cirrhosis, all of whom had CKD stages 4 or 5, were enrolled.² Following 12 weeks of treatment with grazoprevir and elbasvir, 99 percent (115/116) of patients in the pre-specified primary population for analysis of efficacy data achieved a sustained virologic response 12 weeks after the completion of treatment (SVR12).³ These data will be presented today at The International Liver Congress^TM 2015 – the 50^th annual congress of the European Association for the Study of the Liver (late breaking E-Poster #LP02).

“There is an unmet medical need to treat chronic hepatitis C virus infection in patients with advanced chronic kidney disease,” said Dr. Howard Monsour, Jr., chief of hepatology, Houston Methodist Hospital, Houston, Texas. “In this trial, the first to investigate an all-oral ribavirin-free treatment regimen in treatment-naïve and treatment-experienced CKD patients, treatment with grazoprevir and elbasvir for 12 weeks was effective in this study population with HCV genotype 1 infection.”

The ongoing C-SURFER Phase 2/3 clinical trial is a randomized, parallel-group, placebo-controlled study evaluating patients infected with chronic HCV GT1 with advanced CKD with or without liver cirrhosis. Patients were randomized to one of two study arms:

• Immediate treatment group (ITG), grazoprevir plus elbasvir (blinded) once-daily for 12 weeks (n=111);
• Deferred treatment group (DTG), initially placebo (control arm) for 12 weeks followed by a four week follow-up period and then treatment with grazoprevir plus elbasvir (open label) once-daily for 12 weeks (n=113).

In addition, 11 patients received grazoprevir plus elbasvir (open label) once-daily for 12 weeks with intensive pharmacokinetic sampling.

Of the 122 patients who received grazoprevir plus elbasvir, 83 percent were treatment-naïve, 36 percent had diabetes, 18 percent had stage 4 CKD, 82 percent had stage 5 CKD, 75 percent were receiving hemodialysis and 45 percent were African-American. Among those patients who received at least one dose of grazoprevir plus elbasvir, five percent (6/122) were excluded from the pre-specified primary efficacy analysis population, or modified full analysis set, due to missing data caused by death or early discontinuation for reasons unrelated to study drug. In the modified full analysis set, 99 percent (115/116) of patients receiving grazoprevir plus elbasvir achieved SVR12. One GT1b infected, non-cirrhotic, interferon-intolerant patient showed a viral relapse at follow-up week 12. Within the modified full analysis set, efficacy was consistent across the patient sub-populations assessed. In a supportive analysis of all 122 patients who received at least one dose of grazoprevir plus elbasvir in the ITG arms, including patients who did not complete the study for reasons not related to study drug, 94 percent (115/122) of patients achieved SVR12.

“Merck’s broad clinical development program includes studies dedicated to bringing a once-daily regimen to diverse populations of patients infected with chronic HCV, including certain types of patients with co-morbidities, such as advanced chronic kidney disease,” said Dr. Eliav Barr, vice president, infectious diseases, Merck Research Laboratories. “These data highlight how emerging innovations in chronic hepatitis C treatment may lead to new options for patient populations in which it historically has been difficult to achieve high rates of sustained viral clearance.”

No patients in the ITG arms discontinued treatment due to adverse events (AEs), while four percent (5/113) of patients in the comparator placebo phase of the DTG arm discontinued treatment due to AEs. The rates of serious AEs reported were 14 percent (16/111) in the ITG arms and 17 percent (19/113) in the placebo control DTG arm. The most common treatment-related AEs in the ITG arms and DTG arm (placebo) were headache (17%, 17%), nausea (15%, 16%) and fatigue (10%, 15%), respectively. There were four deaths reported during the initial treatment phase and the first 14 days of study follow-up. One patient (1%) in the open label arm died from cardiac arrest (not considered related to study medicine) and three patients (2%) in the placebo group died from aortic aneurysm, pneumonia and an unknown cause.

On April 8, 2015, the company announced that the U.S. Food and Drug Administration (FDA) had granted Breakthrough Therapy designation to grazoprevir/elbasvir for the treatment of patients infected with chronic HCV GT1 with end-stage renal disease on hemodialysis and patients infected with chronic HCV GT4. Breakthrough Therapy designation is intended to expedite the development and review of a candidate that is planned for use, alone or in combination, to treat a serious or life-threatening disease or condition when preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints.

About C-SURFER

C-SURFER is a Phase 2/3 clinical trial evaluating Merck’s investigational grazoprevir plus elbasvir in patients infected with chronic HCV GT1 and with advanced chronic kidney disease (stages 4 and 5, including patients on hemodialysis) with or without liver cirrhosis, which are among those with HCV infection who are most difficult to treat, over 12 weeks.

About Chronic HCV Infection and Chronic Kidney Disease

Chronic HCV infection is both a cause and complication of the treatment of CKD. In patients with CKD, chronic HCV infection is associated with an increased risk of accelerated loss of remaining kidney function, kidney transplant failure and death. Furthermore, patients with chronic HCV infection and advanced CKD represent an unmet need due to a lack of demonstrated HCV treatment options for this group.

About Grazoprevir/Elbasvir

Grazoprevir/elbasvir is an investigational, once-daily single tablet regimen consisting of grazoprevir (NS3/4A protease inhibitor) and elbasvir (NS5A replication complex inhibitor). As part of Merck’s broad clinical trials program, grazoprevir/elbasvir is being studied in multiple HCV genotypes and in patients with difficult-to-treat conditions such as HIV/HCV co-infection, advanced chronic kidney disease, inherited blood disorders, liver cirrhosis and those on opiate substitution therapy.

Merck’s Commitment to HCV

For nearly 30 years, Merck has been at the forefront of the response to the HCV epidemic. Merck employees are dedicated to applying their scientific expertise, resources and global reach to deliver innovative health care solutions that support people living with HCV worldwide.

About Merck

Today’s Merck is a global health care leader working to help the world be well. Merck is known as MSD outside the United States and Canada. Through our prescription medicines, vaccines, biologic therapies and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to health care through far-reaching policies, programs and partnerships. For more information, visit www.merck.com and connect with us on Twitter, Facebook and YouTube.

Forward-Looking Statement

This news release includes “forward-looking statements” within the meaning of the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995. These statements are based upon the current beliefs and expectations of Merck’s management and are subject to significant risks and uncertainties. There can be no guarantees with respect to pipeline products that the products will receive the necessary regulatory approvals or that they will prove to be commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements.

Risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; global trends toward health care cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; Merck’s ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of Merck patents and other protections for innovative products; and the exposure to litigation, including patent litigation, and/or regulatory actions.

Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise except as required by applicable law. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in Merck’s 2014 Annual Report on Form 10-K and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site (www.sec.gov).

¹ In Phase 2 studies, grazoprevir/elbasvir are administered as two separate tablets

² Stages 4 and 5 chronic kidney disease are defined as severely or very severely reduced kidney function, based on estimated glomerular filtration rate <30 mL/min/1.73m²

³ Includes patients who received ≥1 dose of study drug and excluded those with missing data because of death or early discontinuation for reasons unrelated to study drug

Contact:

Media:
Doris Li, 908-246-5701
or
Sarra Herzog, 201-669-6570
or
Investors:
Joe Romanelli, 908-740-1986
or
Justin Holko, 908-740-1879

Source

Civacir can effectively prevent HCV recurrence following liver transplants

Published on April 23, 2015 at 6:50 AM

New data from an ongoing Phase III trial revealed today at The International Liver CongressTM 2015 show that the use of hepatitis C immune globulin (HCIG, Civacir®) can effectively prevent hepatitis C virus (HCV) recurrence in patients following a liver transplant (LT). The data demonstrate that intravenous Civacir given both peri- and post-LT prevents HCV-reinfection in patients who also received antiviral therapy (AVT) before their transplant operation.

Civacir is a hepatitis C immune globulin (HCIG) produced from pooled plasma from hundreds of screened donors who have high antibody titers against HCV. In this trial, patients received AVT before their LT and those in the active treatment groups received 16 infusions of Civacir in the peri- and immediate post-LT period for 10 weeks. The control group received current standard of care (no treatment) post-LT.

The preliminary results suggest that Civacir provides an effective alternative approach as compared to current standard of care to prevent HCV recurrence in post-LT patients. Civacir was well tolerated with no drug-related serious adverse events observed during the study.

Hepatitis C virus (HCV) remains the leading cause for liver transplantation (LT) and recurrent HCV disease is the most frequent cause of graft loss. Prevention of recurrence independent of genotype and severity of cirrhosis is highly desirable because it simplifies post-LT management.

Source: European Association for the Study of the Liver

Source

All-oral 12-week treatment with daclatasvir plus sofosbuvir in patients with hepatitis C virus genotype 3 infection: ALLY-3 phase III study

Hepatology

Volume 61, Issue 4
April 2015
Pages 1127–1135

David R. Nelson, James N. Cooper, Jacob P. Lalezari, Eric Lawitz, Paul J. Pockros, Norman Gitlin, Bradley F. Freilich, Ziad H. Younes, William Harlan, Reem Ghalib, Godson Oguchi, Paul J. Thuluvath, Grisell Ortiz-Lasanta, Mordechai Rabinovitz, David Bernstein, Michael Bennett, Trevor Hawkins, Natarajan Ravendhran, Aasim M. Sheikh, Peter Varunok, Kris V. Kowdley, Delphine Hennicken, Fiona McPhee, Khurram Rana, Eric A. Hughes, on behalf of the ALLY-3 Study Team

First published: 10 March 2015

DOI: 10.1002/hep.27726

Potential conflict of interest: Dr. Nelson received grants from Bristol-Myers Squibb, Gilead, and Merck. Dr. Lawitz consults, advises, is on the speakers' bureau for, and received grants from AbbVie, Gilead, Janssen, Merck, and Vertex. He consults, advises, and received grants from Achillion, Bristol-Myers Squibb, Idenix, Novartis, Santaris, and Theravance. He consults and advises BioCryst, Biotica, and Regulus. He is on the speakers' bureau for Kadmon. He received grants from Boehringer Ingelheim, GlaxoSmithKline, Presidio, and Roche. Dr. Pockros consults, advises, is on the speakers' bureau for, and received grants from Bristol-Myers Squibb, Gilead, and Janssen. Dr. Gitlin is on the speakers' bureau for and received grants from Bristol-Myers Squibb and Gilead. Dr. Freilich received grants from Bristol-Myers Squibb. Dr. Younes is on the speakers' bureau for and received grants from Vertex, Gilead, and AbbVie. He received grants from Bristol-Myers Squibb, Idenix, and Merck. Dr. Ghalib received grants from Gilead, AbbVie, Bristol-Myers Squibb, Merck, Pfizer, Salix, Pharmasset, Boehringer Ingelheim, Anadys, Janssen, Evoke, Idenix, Takeda, Vertex, Virochem, Achillion, and Debio. Dr. Thuluvath is on the speakers' bureau and received grants from Gilead and AbbVie. He is on the speakers' bureau for Onyx. He received grants from Salix and Bristol-Myers Squibb. Dr. Bernstein consults, advises, is on the speakers' bureau for, and received grants from Gilead and AbbVie. He consults and received grants from Bristol-Myers Squibb. Dr. Hawkins consults, advises, is on the speakers' bureau for, and received grants from Gilead, AbbVie, and Janssen. He is on the speakers' bureau and received grants from ViiV. He received grants from Bristol-Myers Squibb. Dr. Ravendhran advises, is on the speakers' bureau for, and received grants from Gilead and AbbVie. He is on the speakers' bureau for Salix and Onyx. He received grants from Bristol-Myers Squibb and Merck. Dr. Sheikh advises, is on the speakers' bureau for, and received grants from Gilead. He advises and is on the speakers' bureau for AbbVie. He received grants from Bristol-Myers Squibb, Idenix, Merck, Achillion, Vertex, Genentech, and Hologic. Dr. Kowdley advises and received grants from AbbVie, Gilead, Merck, and Bristol-Myers Squibb. He advises Achillion and Trio Health. He received grants from Beckman, Boehringer Ingelheim, Ikaria, Intercept, Janssen, Mochida, Novartis, and Vertex. Dr. Hennicken is employed by Bristol-Myers Squibb. Dr. McPhee is employed by and owns stock in Bristol-Myers Squibb. Dr. Rana is employed by Bristol-Myers Squibb. Dr. Hughes is employed by Bristol-Myers Squibb.

This study was funded by Bristol-Myers Squibb.

Abstract

Treatment options for patients with hepatitis C virus (HCV) genotype 3 infection are limited, with the currently approved all-oral regimens requiring 24-week treatment and the addition of ribavirin (RBV). This phase III study (ALLY-3; ClinicalTrials.gov: NCT02032901) evaluated the 12-week regimen of daclatasvir (DCV; pangenotypic nonstructural protein [NS]5A inhibitor) plus sofosbuvir (SOF; pangenotypic NS5B inhibitor) in patients infected with genotype 3. Patients were either treatment naïve (n = 101) or treatment experienced (n = 51) and received DCV 60 mg plus SOF 400 mg once-daily for 12 weeks. Coprimary endpoints were the proportions of treatment-naïve and treatment-experienced patients achieving a sustained virological response (SVR) at post-treatment week 12 (SVR12). SVR12 rates were 90% (91 of 101) and 86% (44 of 51) in treatment-naïve and treatment-experienced patients, respectively; no virological breakthrough was observed, and ≥99% of patients had a virological response (VR) at the end of treatment. SVR12 rates were higher in patients without cirrhosis (96%; 105 of 109) than in those with cirrhosis (63%; 20 of 32). Five of seven patients who previously failed treatment with an SOF-containing regimen and 2 of 2 who previously failed treatment with an alisporivir-containing regimen achieved SVR12. Baseline characteristics, including gender, age, HCV-RNA levels, and interleukin-28B genotype, did not impact virological outcome. DCV plus SOF was well tolerated; there were no adverse events (AEs) leading to discontinuation and only 1 serious AE on-treatment, which was unrelated to study medications. The few treatment-emergent grade 3/4 laboratory abnormalities that were observed were transient. Conclusion: A 12-week regimen of DCV plus SOF achieved SVR12 in 96% of patients with genotype 3 infection without cirrhosis and was well tolerated. Additional evaluation to optimize efficacy in genotype 3–infected patients with cirrhosis is underway. (Hepatology 2015;61:1127–1135)

Chronic infection with hepatitis C virus (HCV) genotype 3 is common throughout the world and remains a significant disease burden for many patients.[1, 2] Infection with HCV genotype 3 has been associated with an increased risk of progression to cirrhosis, as well as development of steatosis or hepatocellular carcinoma (HCC), compared with other HCV genotypes.[3-5] In an observational cohort study, analysis of real-world data from the Veterans Affairs HCV clinical registry found that the risks of cirrhosis, HCC, liver-related hospitalization, and death were significantly higher in genotype 3–infected patients, compared with genotype 1–infected patients,[6] underscoring the medical need for safe, effective treatment options for patients with genotype 3 infection. Recent advances have led to the approval of interferon (IFN)-free and/or ribavirin (RBV)-free therapies for chronic infection with HCV genotypes 1, 2, 3, and 4. However, for both treatment-naïve and treatment-experienced patients with genotype 3 infection, IFN- and RBV-free therapy options are currently limited.

Therapies approved in the United States and Europe for treatment of genotype 3 infection include a 24-week, all-oral regimen of sofosbuvir (SOF; a pangenotypic nonstructural protein [NS]5B inhibitor) in combination with RBV[7, 8] and a 24-week regimen of pegylated IFN (Peg-IFN) plus RBV.[9, 10] In addition, a 12-week, IFN-based regimen of SOF plus Peg-IFN and RBV[8] is approved in Europe for treating genotype 3 infection, as are all-oral, 24-week regimens of daclatasvir (DCV; a potent, pangenotypic NS5A inhibitor) plus SOF with RBV[11] and ledipasvir (LDV; an NS5A inhibitor) plus SOF with RBV[12] for patients with compensated cirrhosis and/or previous treatment experience. The all-oral combination of SOF plus RBV requires 24 weeks of treatment because 12- and 16-week treatment durations were associated with lower response rates (30%-61% and 62%, respectively) in genotype 3–infected patients.[7, 13, 14] With 24-week treatment, lower response rates were observed in genotype 3–infected patients who were treatment experienced (77%), particularly those with cirrhosis (60%), compared with those who were treatment naïve (93%).[7, 15] In addition, there was an increased incidence of anemia, which is consistent with the hemolytic anemia known to occur with RBV treatment.[15, 16] Thus, patients with genotype 3 infection have a need for improved treatment options, preferably with therapies of shorter duration and without the addition of Peg-IFN or RBV.

DCV was evaluated in combination with SOF in a phase II study.[17] Treatment for 24 weeks with DCV plus SOF, with or without the addition of RBV, resulted in an 89% rate of sustained virological response (SVR) at post-treatment week 12 (SVR12) among 18 treatment-naïve patients with genotype 3 infection.[11, 17] Of 5 genotype 3–infected patients who had ≥F3 fibrosis (based on FibroTest scores), all 5 achieved SVR12.¹¹ In this phase III study, the efficacy and safety of 12-week, RBV-free treatment with DCV plus SOF were evaluated in treatment-naïve and treatment-experienced patients chronically infected with HCV genotype 3.

Patients and Methods

Study Design and Patients

This was an open-label, two-cohort phase III study (ClinicalTrials.gov: NCT02032901) of a 12-week regimen of DCV plus SOF in genotype 3 infection. Eligible patients were males and females ≥18 years of age with chronic genotype 3 infection who were either treatment naïve or treatment-experienced and had HCV-RNA levels ≥10,000 IU/mL at screening. Treatment-naïve patients had no previous exposure to any IFN formulation, RBV, or any HCV direct-acting antiviral (DAA) agent, whereas treatment-experienced patients received previous therapy with IFN-α (with or without RBV), SOF plus RBV, or other anti-HCV agents, such as inhibitors of cyclophilin or microRNA. Patients who received previous therapy with NS5A inhibitors and those who previously discontinued treatment with SOF plus RBV prematurely because of intolerance (other than exacerbation of anemia) were excluded. All permitted previous anti-HCV therapies must have been completed or discontinued at least 12 weeks before screening.

Patients with compensated cirrhosis were eligible (up to 50% in each cohort), with cirrhosis determined by liver biopsy (Metavir F4) at any time before screening, FibroScan (>14.6 kilopascals [kPa]) within 1 year of baseline (day 1), or a FibroTest score ≥0.75 coupled with an aspartate aminotransferase (AST) to platelet ratio index (APRI) >2. Per the study protocol, FibroTest assessments (scores determined by BioPredictive) were performed during screening; a FibroTest score ≤0.74 corresponded to a fibrosis stage of F0-F3, and a score >0.74 corresponded to a fibrosis stage of F4. Key patient exclusion criteria included chronic liver disease other than that related to HCV infection, infection with HCV genotypes other than genotype 3 or with mixed genotypes, coinfection with human immunodeficiency virus (HIV) or hepatitis B virus, documented or suspected HCC, or evidence of hepatic decompensation.

All patients received open-label treatment with DCV 60 mg plus SOF 400 mg once-daily for 12 weeks, with a subsequent 24-week follow-up. The study was conducted in accord with the ethical principles that originated in the Declaration of Helsinki, and the study protocol was approved by the institutional review board or independent ethics committee at each study site. All patients provided written informed consent before participation in the study.

Study Assessments

Adherence to study treatment was assessed at each study visit based on tablet counts and dosing information recorded in patient diaries. HCV-RNA levels were determined at baseline; on-treatment weeks 1, 2, 4, 6, 8, and 12; and post-treatment weeks 4, 12, and 24 using the COBAS TaqMan HCV test (version 2.0; Roche Molecular Systems, Pleasanton, CA), with a lower limit of quantitation (LLOQ) of 25 IU/mL. HCV genotype or subtype was determined using the RealTime HCV genotype II assay (Abbott Molecular, Abbott Park, IL) and confirmed by viral sequence analysis. Interleukin-28B (IL28B) genotype (rs12979860 single-nucleotide polymorphism) was determined by polymerase chain reaction amplification and sequencing. Resistance testing was performed by population-based sequencing of plasma samples from all patients at baseline and from patients with virological failure (VF) who had HCV-RNA levels of ≥1,000 IU/mL. VFs included virological breakthrough (VBT), defined as a confirmed, on-treatment HCV-RNA increase of ≥1 log₁₀ IU/mL from nadir or a confirmed HCV-RNA measurement of ≥LLOQ following a previous measurement of <LLOQ; relapse, defined as a confirmed HCV-RNA measurement of ≥LLOQ post-treatment following an undetectable HCV-RNA measurement at the end of treatment; and HCV-RNA measurement of ≥LLOQ at any time point not meeting the definition of VBT or relapse. Safety and tolerability were assessed based on adverse event (AE) reporting, clinical laboratory tests, vital signs, and physical examinations.

Statistical Analyses

The coprimary endpoints were the proportions of treatment-naïve and treatment-experienced patients achieving SVR12 (defined as HCV-RNA levels <LLOQ, either detectable or undetectable). Target sample sizes of 100 treatment-naïve and 50 treatment-experienced patients would provide 95% confidence intervals (CI) for the observed SVR12 rates of within 9.7% and 14.2%, respectively, when the observed SVR12 rates were ≥75%. In the treatment-naïve cohort, a target sample size of 100 patients would provide a 95% CI lower bound of >76% with an observed SVR12 rate of 85%. In the treatment-experienced cohort, a target sample size of 50 patients would provide a 95% CI lower bound of >73% with an observed SVR12 rate of 86%.

Secondary efficacy endpoints included the proportion of patients achieving HCV-RNA levels <LLOQ, detectable or undetectable, at on-treatment weeks 1, 2, 4, 6, and 8, the end of treatment, and post-treatment weeks 4 and 24; the proportion achieving HCV-RNA levels <LLOQ, undetectable, at on-treatment weeks 1, 2, 4, 6, and 8 and the end of treatment; and SVR12 rates by baseline cirrhosis status and IL28B genotype. Efficacy analyses included all patients who received ≥1 dose of study medications, and response rates and two-sided 95% exact binomial CI were estimated by cohort for efficacy endpoints.

Results

Patients

A total of 152 patients received ≥1 dose of study medications; of these, 101 (66%) were treatment naïve and 51 (34%) were treatment experienced. Treatment-experienced patients included those who had previously failed treatment with IFN-based therapies or other anti-HCV therapies, including SOF- and alisporivir (ALV)-containing regimens (Table 1). One hundred (99%) treatment-naïve patients and all 51 (100%) treatment-experienced patients completed 12 weeks of treatment; 1 treatment-naïve patient discontinued treatment after week 8 because of pregnancy, but achieved SVR12.

Table 1. Demographic and Baseline Disease Characteristics

Overall, patients were 90% white and 59% male, with a median age of 55 years; the majority of patients had baseline HCV-RNA levels of ≥800,000 IU/mL (71%) and a non-CC IL28B genotype (61%; Table 1). All patients were chronically infected with HCV genotype 3. Cirrhosis, as determined by liver biopsy, FibroScan, or FibroTest/APRI per protocol, was present in 21% of patients overall (treatment naïve, 19%; treatment experienced, 25%). Fibrosis stage was also determined using FibroTest scores, based on which, 119 (78%) patients had a fibrosis stage of F0-F3 and 30 (20%) had a fibrosis stage of F4; FibroTest scores were not reported for 3 patients (all 3 achieved SVR12). Baseline albumin levels were similar in patients with cirrhosis (median, 41 g/L; range, 33-47) and without cirrhosis (median, 44 g/L; range, 36-53); baseline platelet (PLT) counts were lower in patients with cirrhosis (median, 124.5 × 10⁹/L; range, 62-382) than in those without cirrhosis (median, 200 × 10⁹/L; range, 89-334).

Virological Response

DCV plus SOF for 12 weeks achieved SVR12 rates of 90% in treatment-naïve patients and 86% in treatment-experienced patients with genotype 3 infection, with an overall SVR12 rate of 89% (Table 2). Rapid and sustained reductions from baseline in HCV-RNA levels were observed, with mean decreases of 4.3-4.5 log₁₀ IU/mL at on-treatment week 1 and 4.7-4.9 log₁₀ IU/mL at on-treatment week 2. The proportion of patients achieving HCV-RNA levels <LLOQ, detectable or undetectable, at early on-treatment time points in the treatment-naïve and treatment-experienced cohorts, respectively, was 40% and 24% for week 1, 77% and 69% for week 2, and 94% and 98% for week 4. HCV-RNA levels were undetectable at end of treatment in ≥99% of patients.

Table 2. Virological Response

The relationship between virological response (VR) at early on-treatment time points and achievement of SVR12 was assessed. SVR12 was achieved by 94% of patients with HCV-RNA levels <LLOQ, detectable or undetectable, and 86% of patients with HCV-RNA levels ≥LLOQ, at week 1; 92% and 79% of patients with HCV-RNA levels <LLOQ, detectable or undetectable, or ≥LLOQ, respectively, at week 2 achieved SVR12. Among patients with HCV-RNA levels <LLOQ, detectable or undetectable, at week 4, 90% achieved SVR12, compared with 71% of patients with HCV-RNA levels ≥LLOQ. When VR at week 4 was assessed based on undetectable HCV-RNA levels, the proportion of patients with a week 4 response who achieved SVR12 was 91%.

Analysis of SVR12 in patient subgroups based on baseline characteristics showed no notable differences by gender, age, HCV-RNA levels, or IL28B genotype (Fig. 1). Among treatment-experienced patients, SVR12 was achieved by 25 of 31 patients with previous relapse and by all 7 null responders, 2 partial responders, and 2 patients who experienced VBT with past treatment. In addition, all 6 patients who were intolerant of past treatment achieved SVR12, as did 2 of 3 patients with other types of past treatment failure (HCV-RNA never undetectable on treatment or indeterminate). SVR12 was achieved in 5 of 7 patients who previously failed treatment with an SOF-containing regimen and in both patients who previously failed treatment with an ALV-containing regimen.

Figure 1. VR by baseline characteristics. ^aHCV RNA <LLOQ (25 IU/mL), detectable or undetectable; error bars reflect 95% CI.

SVR12 rates were higher in patients without cirrhosis (96%) than in patients with cirrhosis (63%; Fig. 2A), although high response rates at end of treatment were noted both in patients with and without cirrhosis (97% and 100%, respectively). A similar trend was observed when SVR12 was analyzed by fibrosis stage, based on FibroTest scores, of F0-F3 (93%) and F4 (70%; Fig. 2B). Overall, results by cirrhosis status or by fibrosis stage based on FibroTest scores were generally consistent between the treatment-naïve and treatment-experienced cohorts. VR at early on-treatment time points did not appear to impact SVR12 rates in patients with cirrhosis, given that the proportion of patients with cirrhosis who achieved SVR12 was the same among those who did or did not have undetectable HCV-RNA levels at on-treatment week 4 (10 of 16 patients with undetectable HCV-RNA levels at week 4 and 10 of 16 patients without undetectable HCV-RNA levels at week 4 achieved SVR12).

Figure 2. VR in patients with (A) cirrhosis or (B) fibrosis stage of F4 (FibroTest). ^aHCV RNA <LLOQ (25 IU/mL), detectable or undetectable; error bars reflect 95% CI. ^bAmong 32 patients with cirrhosis, 11 (34%) had baseline PLT counts ≤100 × 10⁹ cells/mL. ^cCirrhosis status determined in 141 patients by liver biopsy (Metavir F4), FibroScan (>14.6 kPa), or FibroTest score ≥0.75 and APRI >2; for 11 patients, cirrhosis status was missing or inconclusive (FibroTest score >0.48 to <0.75 or APRI >1 to ≤2). ^dPer the study protocol, FibroTest assessments were performed during screening (FibroTest scores not available for 3 treatment-naïve patients); F0-F3 defined as FibroTest score of ≤0.74 and F4 defined as FibroTest score of >0.74.

The relationship between resistance-associated variants (RAVs) at NS5A amino acid positions M28, A30, L31, and Y93 at baseline and SVR12 was assessed. No patients had L31 polymorphisms at baseline; 1 patient without cirrhosis had M28V at baseline and achieved SVR12. NS5A-A30 polymorphisms were detected in 14 of 147 patients at baseline. Of the 14 patients with A30 polymorphisms, 9 of 9 without cirrhosis and 1 of 5 with cirrhosis achieved SVR12. Among the 4 patients with cirrhosis with baseline A30 polymorphisms who did not achieve SVR12, 2 also had Y93H at baseline, 1 had A30T, which has no effect on DCV potency in vitro, and 1 had A30K, which was associated with SVR12 in the 5 remaining patients with this polymorphism.[18] NS5A-Y93H was detected in 13 of 147 patients who had NS5A sequence at baseline; of these 13 patients, 6 of 9 without cirrhosis and 1 of 4 with cirrhosis achieved SVR12. No NS5B RAVs were detected at amino acid positions associated with resistance to SOF (159, 282, or 321) at baseline.

Virologic Failure

Occurrence of VF was low, with no VBTs observed (Table 2). One treatment-naïve patient with cirrhosis had a quantifiable HCV-RNA level of 53 IU/mL at end of treatment; this event did not meet the protocol definition of VBT, which required on-treatment confirmation of the HCV-RNA measurement. The patient was a slow responder through week 4 and had a low baseline PLT count (83 × 10⁹ cells/L), reflecting advanced cirrhosis. Sixteen patients (9 treatment naïve and 7 treatment experienced) had post-treatment relapse, of whom 11 (7 treatment naïve and 4 treatment experienced) had cirrhosis at baseline. All of the relapses occurred by post-treatment week 4 except for 1, which occurred between post-treatment week 4 and post-treatment week 12 in a treatment-naïve patient without cirrhosis. Factors that may have contributed to treatment failure in this patient included a very high baseline HCV-RNA level (27.5 × 10⁶ IU/mL), presence of the NS5A-Y93H RAV at baseline, and incomplete treatment adherence (93% adherent), although no relapses occurred among the other 4 patients who were not completely adherent to treatment (3 with 90%-95% adherence and 1, who discontinued after week 8 because of pregnancy, with 66% adherence). The NS5A-Y93H RAV emerged in 9 of 16 patients with relapse; of the remaining 7 patients with relapse, 6 had NS5A-Y93H at baseline and 1 had emergent NS5A-L31I. NS5B RAVs at amino acid positions associated with resistance to SOF (159, 282, or 321) were not detected at relapse.

Safety and Tolerability

DCV plus SOF was well tolerated, with no AEs leading to discontinuation of treatment (Table 3). There were no deaths and only 1 serious AE (SAE) was reported on-treatment: an event of gastrointestinal hemorrhage that was considered not related to study medications. The most common AEs (in >10% of patients) were headache, fatigue, and nausea, and the incidence of grade 3 AEs was low (2%), with no grade 4 AEs reported.

Table 3. Safety and Tolerability

Few treatment-emergent grade 3/4 laboratory abnormalities were observed with DCV plus SOF, with such events reported only for absolute lymphocytes, PLTs, international normalized ratio (INR), and lipase. Incidences of these grade 3/4 laboratory abnormalities were low (≤2% each), and none led to clinically significant bleeding or pancreatitis or to treatment discontinuation. Moreover, these abnormalities were primarily transient increases or decreases that were not present for prolonged periods during treatment. No treatment-emergent grade 3/4 abnormalities were observed in hemoglobin (Hgb) or liver-related parameters, including alanine aminotransferase (ALT) and AST and total bilirubin.

Discussion

In patients chronically infected with HCV genotype 3, the all-oral, 12-week regimen of DCV plus SOF achieved SVR12 rates of 90% in treatment-naïve patients and 86% in treatment-experienced patients; SVR12 was achieved in 96% of patients without cirrhosis and in 63% of patients with cirrhosis. No VBTs were observed, and all but 1 patient achieved a VR at end of treatment. The combination of DCV plus SOF was well tolerated, with a low incidence of SAEs, no deaths or AEs leading to discontinuation, and few treatment-emergent grade 3/4 laboratory abnormalities. These results are generally consistent with those from a phase II study demonstrating the efficacy and tolerability of DCV plus SOF, with or without RBV, in patients with genotype 3 infection.[17] Overall, findings from the present study show that in genotype 3–infected patients without cirrhosis, a 12-week treatment with DCV plus SOF is efficacious, compared with the current 24-week, all-oral regimens containing RBV.

SVR12 rates were comparable across subgroups based on gender, age, baseline HCV-RNA levels, and IL28B genotype. Notably, this study included patients who previously failed treatment with SOF- or ALV-containing regimens, of whom 71% and 100%, respectively, achieved SVR12. A limitation of the study is that the impact of race on SVR12 rates could not be fully assessed owing to the high proportion of white patents enrolled (90% overall); however, all 6 of the black patients enrolled in the study achieved SVR12.

SVR12 rates with DCV plus SOF were higher in patients without cirrhosis than in those with cirrhosis, and in patients with a fibrosis stage (based on FibroTest scores) of F0-F3 than in those with F4. However, the 63% SVR12 rate in patients with cirrhosis is comparable to that achieved with 16 (61%) or 24 weeks (67%) of SOF plus RBV, with the advantages of an IFN-free and shorter-duration regimen.[7] On-treatment and end-of-treatment response rates were similar in patients with or without cirrhosis, with relapse accounting for all but one of the treatment failures: among the 16 patients with relapse, 11 had cirrhosis. Relapse was more frequent in the 4 patients with cirrhosis who had Y93H RAVs at baseline, although these RAVs did not measurably affect on-treatment response. Other possible reasons for the higher relapse rate in genotype 3–infected patients with cirrhosis remain uncertain. Given that high relapse rates have also been observed with other all-oral regimens after treatment of genotype 3 infection,[14, 18] this HCV genotype may be more difficult than others to eradicate with DAAs, particularly in patients with cirrhosis. Multiple factors may contribute to this effect and require further study.

The robust on-treatment VR with DCV plus SOF, with nearly all VFs the result of post-treatment relapse, suggests that optimizing treatment outcomes in patients with cirrhosis could include the addition of RBV or a longer treatment duration. A randomized study has been initiated (clinicaltrials.gov: NCT02319031)[19] in which patients with genotype 3 infection and compensated advanced cirrhosis are receiving DCV in combination with SOF and RBV for 12 or 16 weeks, with the objective of determining whether adding RBV and extending treatment will improve the durability of response post-treatment. This strategy has been successful with other all-oral regimens. A recent report regarding a phase II study of SOF plus GS-5816, with or without RBV, suggests that the addition of RBV improves response rates in genotype 3–infected patients with cirrhosis. In treatment-experienced patients with cirrhosis treated for 12 weeks, SVR12 rates were higher with SOF plus GS-5816 with the addition of RBV (85%-96%) than with sofosbuvir plus GS-5816 alone (58%-88%).[20] The combination of LDV plus SOF with RBV for 12 weeks has been reported to provide SVR12 rates of 89% in genotype 3–infected, treatment-experienced patients without cirrhosis and a lower rate of 77% in those with cirrhosis.[21] Because DCV has shown greater potency in vitro against genotype 3, compared with LDV,[11, 22-24] the combination of DCV plus SOF, with the addition of RBV, may be expected to provide improved response rates relative to the current results in patients with cirrhosis. DCV plus SOF, with or without RBV, is also being evaluated in additional patient populations with high unmet medical needs in other studies of the ALLY phase 3 program. These include patients who have cirrhosis or who are post–liver transplant (ALLY-1; ClinicalTrials.gov: NCT02032875) and patients who are coinfected with HIV (ALLY-2; ClinicalTrials.gov: NCT02032888). DCV has been approved in combination with other anti-HCV agents in Europe and Japan.

DCV plus SOF was associated with a favorable safety profile. Incidences of SAEs and grade 3/4 AEs were low, and no deaths or AEs leading to discontinuation were reported. Few grade 3/4 laboratory abnormalities were reported, and the events that were observed were primarily transient changes and did not lead to treatment discontinuation. No grade 3/4 abnormalities in Hgb emerged during treatment, whereas previous studies have reported reductions in Hgb levels with the combination of SOF plus RBV.[14, 15] Overall, no notable safety concerns were observed with the combination of DCV plus SOF.

In summary, a 12-week regimen of DCV plus SOF achieved SVR12 in 96% of treatment-naïve and treatment-experienced patients with genotype 3 infection without cirrhosis and was well tolerated. This regimen, without the addition of RBV and with a shorter treatment duration relative to currently approved all-oral regimens, demonstrated high SVR12 rates across patient subgroups, except in patients with cirrhosis and regardless of past treatment response. These findings support the 12-week regimen of DCV plus SOF as an efficacious, well-tolerated treatment option. Additional evaluation to optimize efficacy in genotype 3–infected patients with cirrhosis is underway.[19]

References

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FDA to revisit its policies on homeopathic products

Provided by The Washington Post

Homeopathic remedies, derived from plants, minerals and other substances, often are tailored to individual patients. (iStock)

By Brady Dennis April 18

Homeopathy has long been a magnet for controversy, earning a devoted following among patients who insist its remedies are safe and effective, while attracting criticism from many doctors and researchers who say its treatments offer no more help than a placebo.

After problems within the industry in recent years, the Food and Drug Administration says it wants to revisit how it oversees homeopathic products, which can be manufactured and marketed without prior approval from regulators.

Should the FDA regulate homeopathic remedies such as Cold-Eeze the same way it does over-the-counter drugs such as Advil? Should it hold products such as Zicam, which contains small amounts of zinc, to the same safety and efficacy standards that it requires for Tylenol?

Hundreds of public comments have poured in to the FDA ahead of two days of hearings that begin Monday. The agency said it wants more data to “better assess the risks and benefits” of homeopathic remedies, which have become a mainstay on modern pharmacy shelves, often sold alongside over-the-counter pharmaceutical drugs. Stores such as Whole Foods feature sections of homeopathic remedies aimed at treating conditions including allergies and heartburn.

The FDA has not made any decisions about whether to change how it approaches homeopathic products, said Cynthia Schnedar, director of the Office of Compliance at the FDA’s Center for Drug Evaluation and Research. “At this stage,” she said, “we are gathering information about whether to adjust our current enforcement policy.”

The FDA has issued nearly 40 warning letters since 2009 to companies making homeopathic products, Schnedar said.

Last month, the agency warned consumers not to rely on over-the-counter asthma products labeled as homeopathic, saying they have not been evaluated for safety and effectiveness. In 2009, the FDA warned consumers to stop using several types of Zicam cold remedies after reports of more than 130 cases of people losing their sense of smell; the company issued a recall. The following year, Hyland’s Teething Tablets were recalled after reports of reactions in some children; the tablets later were reintroduced with a new formulation.

Homeopathic medicines have had the same legal status as regular pharmaceuticals since 1938, when then-New York Sen. Royal Copeland, who was a trained homeopath, helped shepherd a landmark food and drug law through Congress.

In the 1970s, lawmakers directed the FDA to review the safety and effectiveness of over-the-counter medications. But the agency deferred reviewing homeopathic treatments at the time and last evaluated its policies in 1988. It has allowed most prescription and non-prescription homeopathic products to go to market without prior approval.

Homeopathy traces its founding back two centuries to German doctor and chemist Samuel Hahnemann — whose statue, incidentally, has been in downtown Washington, east of Scott Circle, since 1900.

A key principle underpinning the practice of homeopathy is the notion that “like cures like,” or that substances that create certain symptoms in a healthy person can help to cure diseases with similar symptoms. Homeopathic remedies, derived from plants, minerals and other substances, often are tailored to individual patients. Many treatments are diluted to the point that there is little or no active ingredient remaining. The dilution, which homeopaths believe triggers an immune response in the body, has led skeptics to claim that the practice amounts to little more than selling water and wishful thinking.

The National Institutes of Health has said that there is “little evidence to support homeopathy as an effective treatment for any specific condition,” and that “several key concepts of homeopathy are inconsistent with fundamental concepts of chemistry and physics.”

Last month, Australia’s National Health and Medical Research Council concluded that “there are no health conditions for which there is reliable evidence that homeopathy is effective.” The organization found that there were “no good-quality, well-designed studies with enough participants” to determine whether such treatments were more effective than a placebo.

Edzard Ernst, an emeritus professor at the University of Exeter in England and an outspoken homeopathy critic, said in an e-mail, “There is an appalling amount of misinformation out there, targeted at the often naive consumer.”

He said that the FDA should require homeopathic products to meet the same standards as other medications. “This is a most dangerous situation, and has to be corrected in the interest of public safety,” he said.

Given such criticisms, the FDA’s decision to revisit the issue has worried advocates of homeopathy, who fear that any broad new regulations might unfairly cripple the industry.

“Obviously, people are alarmed and wondering what the FDA is up to,” said Jennifer Jacobs, who practiced homeopathy for 30 years and is now a clinical assistant professor of epidemiology at the University of Washington School of Public Health. “It seems to me that they have bigger fish to fry.”

Jacobs said that homeopathic remedies have a long history of overall safety, particularly when compared with the harmful side effects caused by many conventional drugs. In addition, she said, homeopathic remedies shouldn’t be dismissed merely because science lacks a clear explanation for why they have helped patients.

“It’s foolish to think we understand everything about physics and chemistry at this point in time,” Jacobs said. “Just because we don’t understand exactly how they work doesn’t mean we won’t be able to in the future.”

Ronald Whitmont, a homeopathic doctor in New York and president of the American Institute of Homeopathy, said his organization supports the FDA’s actions to crack down on poor manufacturing practices. “There are always bad apples in the manufacturing world, and they need to be policed just like in any other industry,” he said. “We are behind the FDA. Their concern is our concern.”

But he said he hopes the hearing doesn’t turn into a debate about the legitimacy of homeopathy itself, which has a long safety record and a growing list of ardent patients nearly two centuries after it began.

“Since homeopathy has been in existence, there have been detractors who said this couldn’t possibly work,” Whitmont said. “If it doesn’t work, why is it used worldwide by millions of people? Why isn’t it going away?”

Brady Dennis is a national reporter for The Washington Post, focusing on food and drug issues.

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