September 16, 2013

'Quad' PIll OK for Older HIV Patients

Published: Sep 15, 2013 | Updated: Sep 16, 2013

By Michael Smith, North American Correspondent, MedPage Today

Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner

Action Points

  • This study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
  • A four-drug pill quad pill (containing elvitegravir, cobicistat, emtricitabine, and tenofovir) for HIV works as well in older patients as it does in those under 50.
  • Note that the older patients (50 and 0ver) taking the quad pill had significantly less dizziness and fewer abnormal dreams compared to those getting efavirenz, emtricitabine, and tenofovir.

DENVER -- A four-drug "quad" pill for HIV works as well in older patients as it does in those under 50, a researcher said.

The quad pill (approved last year and marketed as Stribild) has been shown in several clinical trials to have equivalent efficacy and safety to major first-line HIV regimens, according to Joel Gallant, MD, of the Southwest CARE Center in Santa Fe.

But as the HIV-positive population ages, it becomes important to study the efficacy and safety of medications in older patients specifically, he argued here at the annual Interscience Conference on Anti-Microbial Agents and Chemotherapy.

To address the issue, the authors analyzed two randomized phase III clinical trials in treatment-naïve patients divided by age -- under 50 or 50 and over.

In one of the two trials, the quad pill (containing elvitegravir, cobicistat, emtricitabine, and tenofovir) was compared with the single-pill combination of efavirenz, emtricitabine, and tenofovir (Atripla).

In the second, the quad was compared with boosted atazanavir (Reyataz) and the single-pill combination of emtricitabine and tenofovir (Truvada).

In both cases, efficacy, defined as the ability of the regimen to control viral replication, was similar after 96 weeks of therapy -- 84% and 83%, respectively, for the quad and 82% in both studies for the comparator regimen.

In both studies, tolerability was slightly better for the quad, Gallant noted.

For this analysis, Gallant and colleagues combined the efficacy and safety data from both studies, but compared how older patients stacked up against their younger counterparts.

The proportion of men 50 or older ranged from 14% to 16% in the four original study arms, Gallant said.

For those 50 and older in the quad-Atripla study, efficacy was identical at 96 weeks at 82%. By comparison, the quad pill did slightly better in those under 50 -- 85% versus 81% -- but the difference was not significant.

Results were similar in the other study -- 82% and 81% for those under 50 and 90% in both arms for those 50 and older.

Over the 2 years of the studies, only two patients developed resistance, Gallant noted.

In both age groups, treatment led to a recovery of the immune response that was slightly blunted among those 50 and older but did not differ between treatment arms.

On the adverse events front, the older patients taking the quad:

  • Had significantly less dizziness and fewer abnormal dreams compared to those getting Atripla.
  • Had an early increase in serum creatinine that stabilized through week 96, was greater than with Atripla, but similar to that experienced by patients on atazanavir/emtricitabine/tenofovir.
  • Had similar median increases in lipid parameters to those taking the other comparator regimens.

The study adds to the "comfort level" of clinicians prescribing the quad pill to older patients, commented Joseph Eron, MD, of the University of North Carolina Chapel Hill, who was not involved in the study but who co-moderated the session at which the data was presented.

"You didn't see any peculiar toxicities among the older group," Eron told MedPage Today. "It was reassuring."

It's also gratifying that the analysis could be done at all, Eron said, adding that "it's good to see that we have enough older patients to do the study."

The study was supported by Gilead Sciences. Gallant reported financial links with Bristol-Myers Squibb, Gilead Sciences, Janssen Therapeutics, Merck and Co, and Takara Bio. Several authors are employees of Gilead.

Eron previously disclosed financial relationships with Bristol-Myers Squibb, GlaxoSmithKline, Merck, Tibotec, and ViiV Healthcare.

Primary source: Interscience Conference on Anti-Microbial Agents and Chemotherapy
Source reference: Gallant JE, et al "Elvitegravir/Cobicistat/Emtricitabine/Tenofovir DF (E/C/F/TDF) demonstrates comparable efficacy and favorable tolerability to efavirenz (EFV)/FTC/TDF and to ritonavir-boosted atazanavir (ATV+RTV) plus FTC/TDF in subjects 50 years and older at week 96" ICAAC 2013; Abstract H-1459.

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PRNewswire

Updated Overall Survival in Large Subgroup Continues to Show Positive Clinical Benefit

Company Sponsors Symposium on Directions in Early-Intermediate HCC

LAWRENCEVILLE, N.J., Sept. 16, 2013 /PRNewswire/ -- Celsion Corporation (NASDAQ: CLSN) announced today that Ronnie T.P. Poon, MD, MS, PhD, FRCS (Edin), FACS, Professor of Surgery at the University of Hong Kong and Lead Asia Pacific Principal Investigator for Celsion's Phase III HEAT Study of ThermoDox® in hepatocellular carcinoma (HCC) reviewed the official clinical trial results from the HEAT Study including findings from the HEAT Study post-hoc analysis at the International Liver Cancer Association 7th Annual Conference held on September 13-15, 2013 in Washington D.C.  Following Professor Poon's presentation on September 14, 2013, the Company sponsored a symposium of leading liver cancer experts to discuss new directions in the treatment of early-intermediate HCC.

Professor Poon's oral presentation, titled "Phase 3 Randomized, Double-Blind, Dummy Controlled Trial of Radiofrequency Ablation (RFA) + Lyso-Thermosensitive Liposomal Doxorubicin for Hepatocellular Carcinoma (HCC) Lesions 3-7 cm," was held on September 14, 2013 at 12:00 p.m. (local time) during the Plenary Session.  Professor Poon's presentation also included the most recent Overall Survival data from the HEAT Study post-hoc analysis which continues to suggest positive progression-free survival (PFS) and Overall Survival (OS) in ThermoDox® treated patients when heating cycles from the radiofrequency ablation (RFA) procedure were optimized.

The data from the HEAT Study post-hoc analysis presented by Professor Poon demonstrate that ThermoDox® markedly improves Overall Survival, when compared to the control group, in patients if their lesions undergo RFA for 45 minutes or more.  These findings apply to single HCC lesions (63% of the HEAT Study population) from both size cohorts of the HEAT Study (3-5 cm and 5-7 cm) and represent a subgroup of approximately 300 patients (42% of the patients in the HEAT Study).

  • In the patient subgroup treated in the ThermoDox® arm whose RFA procedure lasted longer than 45 minutes and was completed within 90 minutes (40% of single lesion patients) Overall Survival improved by 71% (Hazard Ratio of 0.585) when compared to the control arm of RFA treatment only.
  • In the patient subgroup treated in the ThermoDox® arm whose RFA procedure lasted longer than 90 minutes (23% of single lesion patients), Overall Survival improved by similar 71% (Hazard Ratio of 0.584) when compared to the control arm of RFA treatment only.
  • When combined, these two subgroups show clinical results that indicate a 61% improvement in Overall Survival, a Hazard Ratio of 0.623 and a P-value = 0.058.
  • In contrast, the patient subgroup treated with ThermoDox® whose RFA procedure lasted less than 45 minutes in duration (37% of single lesion patients) indicated that the control arm had a slightly improved Overall Survival benefit when compared to the ThermoDox® arm.
  • The Hazard Ratio reported above should be viewed with caution since they are not statistically significant and the HEAT Study has not reached its median point for Overall Survival analysis.  Celsion continues to follow all patients in the HEAT Study to the secondary endpoint, Overall Survival, and will update the subgroup analysis based on RFA heating duration.

Celsion also sponsored a symposium in conjunction with the ILCA conference moderated by Professor Riccardo Lencioni, MD, FSIR, EBIR, the Director of the Division of Diagnostic Imaging and Intervention at Pisa University School of Medicine in Italy.   Participants included Professor Josep Llovet, MD, PhD, Professor of Medicine and Director, Mount Sinai Liver Cancer Program, Mount Sinai School of Medicine; Ghassan K. Abou-Alfa MD, PhD, Associate Attending Memorial Sloan-Kettering Cancer Center, New York, NY, Associate Professor, Weill Medical College at Cornell University, New York, NY, and Associate Professor, Gastrointestinal Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, NY; and Professor Ronnie T.P. Poon, MD, PhD.  The discussion focused on new developments in the treatment of early-intermediate HCC including the updated data from the Company's HEAT Study post-hoc analysis as well as computer modeling with supplementary preclinical animal studies supporting the relationship between heating duration and clinical outcomes.

  • Results from a finite element method model that simulates temperature, perfusion contours with RFA treatments and allow prediction of drug deposition contour maps with the combined use of RFA and ThermoDox®, show a direct correlation with heating time and amount of drug deposited to the tumor margin, where both adequate heat and tissue perfusion exist.
  • Results from recently completed large animal studies (21 subject porcine study) demonstrate that longer RFA heating (dwell) time results in higher local tissue concentrations of ThermoDox® in the surrounding ablation zone.  

Professor Riccardo A. Lencioni commented, "After reviewing the complete and subgroup analysis of the Phase III HEAT Study as well as the recently completed porcine study, I am convinced ThermoDox® demonstrates clinical activity in a highly responsive population of single lesion patients.  The duration of heat from the RFA procedure is an important factor in a successful clinical outcome when combined with ThermoDox® as demonstrated by the growing body of clinical and non-clinical data generated by the Company.  These findings build a solid scientific foundation of understanding that increased perfusion and longer heating duration are key factors for ensuring that the heat-sensitive liposomes are activated to deposit high concentrations of doxorubicin in the tumor and the surrounding liver tissue."

ILCA has selected the HEAT Study presentation to be webcast as part of an online educational program of the ILCA 2013 Annual Conference.  Professor Poon's presentation will also be available on Celsion's website at http://investor.celsion.com/events.cfm.

The International Liver Cancer Association is the only international organization devoted exclusively to liver cancer research for experts from all related disciplines – medical, interventional and surgical oncology as well as hepatology.  ILCA's Executive Committee consists of Dr. Josep M. Llovet (President); Professor Riccardo Lencioni and Dr. Morris Sherman.  Celsion notes that Professors Lencioni and Poon and Dr. Sherman are principal investigators on the HEAT Study.

About Celsion Corporation

Celsion is dedicated to the development and commercialization of innovative cancer drugs, including tumor-targeting treatments using focused heat energy in combination with heat-activated liposomal drug technology.  Celsion has research, license or commercialization agreements with leading institutions, including the National Institutes of Health, Duke University Medical Center, University of Hong Kong, the University of Pisa, the UCLA Department of Medicine, the Kyungpook National University Hospital, the Beijing Cancer Hospital and the University of Oxford.  For more information on Celsion, visit our website: http://www.celsion.com.

Celsion wishes to inform readers that forward-looking statements in this release are made pursuant to the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995.  Readers are cautioned that such forward-looking statements involve risks and uncertainties including, without limitation, unforeseen changes in the course of research and development activities and in clinical trials; the significant expense, time, and risk of failure of conducting clinical trials; HEAT Study data is subject to further verification and review by the HEAT Study Data Management Committee; the need for Celsion to evaluate its future development plans; termination of the Technology Development Contract or collaboration between Celsion and HISUN at any time; possible acquisitions or licenses of other technologies, assets or businesses or the possible failure to make such acquisitions or licenses; possible actions by customers, suppliers, competitors, regulatory authorities; and other risks detailed from time to time in the Celsion 's periodic reports and prospectuses filed with the Securities and Exchange Commission.  Celsion assumes no obligation to update or supplement forward-looking statements that become untrue because of subsequent events, new information or otherwise.

Investor Contact
Jeffrey W. Church
Senior Vice President and
Chief Financial Officer
609-482-2455
jchurch@celsion.com

SOURCE Celsion Corporation

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New Hope for H.I.V. Vaccine

17MONK-popup

Ed Jones/Agence France-Presse — Getty Images

A new vaccine tested in rhesus monkeys generated a muted, long-lasting immune response to the simian version of H.I.V.

By DONALD G. McNEIL Jr.

Published: September 16, 2013

“Kafkaesque” is not a word normally used to describe immune responses, but it’s how Dr. Louis J. Picker described what his experimental vaccine did to his rhesus monkeys: “It’s like their T-cells were turned into the East German secret police, hunting down infected cells until there were none left.”

Recent work by Dr. Picker, a vaccine expert at Oregon Health & Science University, has shaken up the long, frustrating search for an AIDS vaccine. His latest study, published in Nature last week, has scientists scratching their heads, wondering if it might open up a new avenue for research.

Dr. Picker tested his vaccine in 16 monkeys who were then infected with simian immunodeficiency virus, a close relative of H.I.V., which normally would have sent them spiraling rapidly down to a miserable death. The experimental vaccine protected only nine of them, but it also did something never seen before: these monkeys slowly “cleared” the virus and now appear to be cured. “Three years later, you can’t tell them from other monkeys,” Dr. Picker said.

Dr. Anthony S. Fauci, the head of the National Institute for Allergy and Infectious Diseases, said the effect was “unique.”

And Dr. Barton F. Haynes, the director of the Human Vaccine Institute at Duke University’s medical school, said it was “potentially extremely important to understand how this happened.”

Scientists often test ideas for potential AIDS vaccines by creating similar ones against S.I.V. Never before has one eliminated an existing infection. In that sense, the effect of Dr. Picker’s vaccine was less like that of a measles or flu shot and more like that of the AIDS cures used in two famous cases, known as the Berlin patient and the Mississippi baby.

The Berlin patient, Timothy Ray Brown, was infected with H.I.V. and cured only by obliterating his immune system to defeat his leukemia, and then injecting bone marrow from a donor with a rare H.I.V.-blocking mutation. The unidentified baby was born to an infected mother in Mississippi and apparently infected with H.I.V., but then cured with early and large doses of antiretroviral drugs.

Both now appear to have no H.I.V. lurking deep in their bodies, but it is impossible to be sure because not every bit of their tissue can be tested.

Because he works with monkeys, Dr. Picker was able to do something that would be unthinkable with human patients — necropsy them, grind up every organ and take 240 samples from each to be sure that they harbored no hidden virus.

Making vaccines by simply weakening the virus that causes AIDS has failed because the virus mutates a hundred times faster than even the fast-mutating flu virus. In Dr. Picker’s vaccine, S.I.V. genes are fused to those of another virus, the cytomegalovirus. (The name means “big cell,” and it is in the herpes family but different from its relatives that cause lip and genital sores, chickenpox and shingles.)

H.I.V. fusion has been tried with adenoviruses and others, but cytomegalovirus seems to work better. It’s not entirely clear why, but one theory is that cytomegalovirus has a very long history of infecting primates — so much so that 100 percent of monkeys and about 80 percent of humans get it in their lifetimes.

Therefore, we primates have adapted to it. Although the virus can be lethal to fetuses and to those with immune systems suppressed by AIDS or transplant drugs, in most victims it causes no symptoms.

The body responds to cytomegalovirus more slowly and calmly than it does, for example, to a flu.

As in any infection, the thymus gland generates new white blood cells called T cells — in this case, CD8 hunter-killer cells — primed to target the specific virus. But in the case of Dr. Picker’s vaccine, those cells stay in an unusual “half-alert” state. A full-blown immune response eventually exhausts itself, and can even be dangerous. For example, the rare humans who catch H5N1 bird flu often die of the immune response itself; they drown in the flood of CD8s and other would-be saviors pouring into the lung tissue, spoiling for a fight.

That “half-alert” state is the “Kafkaesque” element: unactivated CD8s wander around aimlessly, while fully activated ones behave like storm troopers. But the half-activated CD8s persist in tissues, eliminating their targets quietly without triggering inflammation or even a mild fever.

When S.I.V. genes are fused to the cytomegalovirus spine, the CD8s kill S.I.V.-infected cells too.

Since it protected only some monkeys, the new technique might be best used in combination approaches. For example, Dr. Fauci said, it could be given with a vaccine that generates antibodies against H.I.V. “and maybe eliminate the cells that sneak past the antibody shield.”

Alternatively, the vaccine might be given to infected patients who are on antiretroviral drugs to see if it can “mop up” lingering reservoirs of virus.

It should take up to three years to get a human version ready for trials, Dr. Picker estimated.

“Now the outstanding question is, ‘Why only half?’ ” said Dr. Mike McCune, an AIDS researcher at the University of California, San Francisco, referring to the monkeys who were protected in Dr. Picker’s trial.

Too often, AIDS advances that work in lots of monkeys don’t work in many humans.

“Not all monkeys are the same,” Dr. McCune said. “They’re not as inbred as mice, but they’re sometimes from the same families, they get the same diets... Who knows what will happen if this goes into humans?”

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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration

Food and Drug Administration 
[Docket No. FDA-2013-N-0001]
Antiviral Drugs Advisory Committee; Notice of Meeting
AGENCY:  Food and Drug Administration, HHS.
ACTION:  Notice.

This notice announces a forthcoming meeting of a public advisory committee of the Food and Drug Administration (FDA).  The meeting will be open to the public.

Name of Committee: Antiviral Drugs Advisory Committee.

General Function of the Committee: To provide advice and recommendations to the Agency on FDA's regulatory issues.

Date and Time: The meeting will be held on October 24, 2013, from 8 a.m. to 5 p.m.

Location: Sheraton Silver Spring Hotel, Cypress Ballroom, 8777 Georgia Ave., Silver Spring, MD.  The hotel phone number is 301-589-0800.

Contact Person: Karen Abraham-Burrell, Center for Drug Evaluation and Research,
Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 31, rm. 2417, Silver Spring,
MD 20993-0002, 301-796-9001, FAX: 301-847-8533, email: AVAC@fda.hhs.gov, or FDA
Advisory Committee Information Line, 1-800-741-8138 (301-443-0572 in the Washington, DC
area). 

A notice in the Federal Register about last minute modifications that impact a previously announced advisory committee meeting cannot always be published quickly enough to provide
timely notice.  Therefore, you should always check the Agency's Web site at
http://www.fda.gov/AdvisoryCommittees/default.htm and scroll down to the appropriate advisory committee meeting link, or call the advisory committee information line to learn about possible modifications before coming to the meeting.

Agenda:  The committee will discuss new drug application (NDA) 205123, simeprevir (a hepatitis C virus protease inhibitor), manufactured by Janssen Pharmaceutical Co., with a
proposed indication for the treatment of chronic hepatitis C genotype 1 infection, in combination
with peginterferon alfa and ribavirin (two medicines approved to treat chronic hepatitis C) in
adult patients with compensated liver disease (including cirrhosis) who are treatment-naïve or
who have failed previous interferon therapy (pegylated or non-pegylated) with or without ribavirin. Compensated liver disease is a stage in which the liver is damaged but maintains ability to function. 

FDA intends to make background material available to the public no later than 2 business
days before the meeting.  If FDA is unable to post the background material on its Web site prior to the meeting, the background material will be made publicly available at the location of the advisory committee meeting, and the background material will be posted on FDA's Web site after the meeting.  Background material is available at
http://www.fda.gov/AdvisoryCommittees/Calendar/default.htm. Scroll down to the appropriate
advisory committee meeting link.

Procedure:  Interested persons may present data, information, or views, orally or in writing, on issues pending before the committee.  Written submissions may be made to the contact person on or before October 9, 2013.  Oral presentations from the public will be scheduled between approximately 1 p.m. and 2 p.m.  Those individuals interested in making formal oral presentations should notify the contact person and submit a brief statement of the general nature of the evidence or arguments they wish to present, the names and addresses of proposed participants, and an indication of the approximate time requested to make their presentation on or before October 1, 2013.  Time allotted for each presentation may be limited.  If the number of registrants requesting to speak is greater than can be reasonably accommodated during the scheduled open public hearing session, FDA may conduct a lottery to determine the speakers for the scheduled open public hearing session.  The contact person will notify interested persons regarding their request to speak by October 2, 2013.

Persons attending FDA's advisory committee meetings are advised that the Agency is not
responsible for providing access to electrical outlets.

FDA welcomes the attendance of the public at its advisory committee meetings and will
make every effort to accommodate persons with physical disabilities or special needs. If you
require special accommodations due to a disability, please contact Karen Abraham-Burrell at
least 7 days in advance of the meeting.

FDA is committed to the orderly conduct of its advisory committee meetings.  Please visit our Web site at http://www.fda.gov/AdvisoryCommittees/AboutAdvisoryCommittees/ucm111462.htm for
procedures on public conduct during advisory committee meetings.

Notice of this meeting is given under the Federal Advisory Committee Act (5 U.S.C. app.

Dated:  September 11, 2013. 
Jill Hartzler Warner, Acting Associate Commissioner for Special Medical Programs.   
[FR Doc. 2013-22546 Filed 09/16/2013 at 8:45 am; Publication Date: 09/17/2013]

Screen All Boomers for Hep C? Two Docs Disagree

Medscape Family Medicine > Roundtable in Primary Care

Robert W. Morrow, MD, Charles P. Vega, MD

Sep 16, 2013

Editor's Note: The Centers for Disease Control and Prevention (CDC) and the US Preventive Services Task Force (USPSTF) have recommended that all baby boomers (those born between 1945 and 1965) should be screened for hepatitis C virus (HCV). We asked Charles P. Vega, MD, and Robert W. Morrow, MD, Medscape family physician advisors, how realistic these recommendations are in primary care practice. We received 2 different opinions.[1,2]

Dr. Vega: Screening These Adults Is Important, and I'm On Board

The age range described in the recommendations fit the majority of my patient panel: those who have an average of 6 chronic conditions. Getting health maintenance completed can be a struggle, given other competing priorities. So I was highly skeptical about checking hepatitis C status on these sweet older adults.

However, on examining the evidence, this is the generation that bears a disproportionate burden of HCV infection, morbidity, and mortality. Moreover, trials of anti-HCV treatment did include, if not focus on, older adults. These are the studies that demonstrated that sustained virologic response improved cancer and mortality outcomes.

Why hadn't I learned this stuff before? Who knows. But I'm on board. One-time screening is more than reasonable and will save lives.

However, the overall incidence of HCV infection appears to have declined over the past 10 years. This screening recommendation is for a limited time only. (Now, there's a potential new marketing gimmick for the USPSTF!) We should keep that in mind moving forward.

Dr. Morrow: Where's the Evidence Supporting Benefits vs Risks of Screening?

Like most of the subjects raised in these roundtables, this one has some substance that was not initially apparent.

Generally, we screen for a disease when the benefit exceeds the risk. In other words, if we randomize the population to those screened and unscreened, the unscreened group should do worse than the screened group using some objective, patient-centered measure, even if that is the quality-adjusted life-year.

As a disease becomes less likely or prevalent, false-positive findings become more common than true-positives.

For example, a polymerase chain reaction test with high sensitivity and specificity might still yield a rather high false-positive result. We see false-positives with Pap tests for women older than 40 years, and for purified protein derivative tests in general; in the first case, as women get older cervical cancer becomes very rare, and in the other case, tuberculosis is less present in the general population.

A false-positive rate of 1/1000 seems small until after the first million studied!

OK, we don't have the information that the tested group does better than the untested group in measures important to patients. So is this an emergency, and therefore we can't wait for a patient-centered study? We need to see the numbers of measures important to patients. Do screened patients die later, transmit less disease to bystanders, or have less disability compared with unscreened people? Right now, that is assumed but not known.

Aside from fatigue for months, I have several patients in my practice with injury from HCV treatment, including hyperthyroidism. One patient had to have surgery for refractory hyperthyroidism after radioactive iodine, and now has lost much of her voice due to injury during intubation.

Regardless, anecdotes suck, so where are the numbers that are patient-centered, not pharma-centered?

I suppose if we had a real healthcare system, we could conduct this study in a few months of analysis of population databases. Hello, Kaiser, what do you know? Until then, did your laboratory have a new technician who made a methods error that resulted in false-positives, owing to contamination of a hypersensitive test? I think that's why I see several inexplicable HPV-positive tests in women older than 50 years, which go away on repeat tests -- and yes, I don't order the test, but laboratories often run HPV tests without a request.

Show me the analysis, so I can understand why this expensive and not necessarily faultless test -- which can lead to treatments that are expensive and not necessarily faultless or successful -- is truly patient-centered. Until then, we should spend the funds on prevention strategies that work, such as needle exchanges and careful histories.

Dr. Vega: False-Positives Are Rare, and We Can't Wait for Studies

Bob is completely accurate in pointing out how every screening test has both a downside and a potential benefit. In fact, he lists some screening tests, such as for tuberculosis in the general population, that do not make sense because the potential harms outweigh the advantages of testing.

HCV screening for this specific age population is not in that class of testing. The prevalence of HCV among persons born between 1945 and 1965 is 3.25%, which sounds small until one realizes that this represents approximately three quarters of cases of chronic HCV infection in the United States. The infection is underrecognized by clinicians treating these patients, and that is a huge contributor to the overall morbidity and mortality of HCV.

With regard to the potential harms of screening, false-positive HCV antibody tests are extremely rare. New-generation anti-HCV screening yields specificity levels above 99%. Advancements in the evaluation of patients with chronic HCV infection have reduced the need for liver biopsy, which incurred the majority of major complications in the work-up of HCV. Complications from HCV treatment are common, but serious complications are rare. The reductions in the risks for cirrhosis and death with HCV treatment generally outweigh the risks of therapy.

It would be wonderful to have a randomized screening trial with thousands of participants to fully evaluate screening for HCV. But Bob knows that such a study is impractical and won't ever happen. First, it will require years to even set up the research, and many, many more to complete it. Remember that we didn't well understand the basic natural history of chronic HCV infection until study cohorts were followed for decades. Persons born between 1945 and 1965 simply do not have that kind of time to wait.

To respond to another couple issues, screening for HCV only works if patients found to be positive can be quickly referred for further evaluation and therapy. Otherwise, it is a waste of healthcare resources that may be better used elsewhere.

Regarding the timing of HCV screening: Between regular blood testing for the diabetes, hyperlipidemia, and assorted other chronic illnesses common among my middle-age and older adult patients, I don't think it will be a challenge to recommend an anti-HCV antibody test at some point. Simple decision-support software can facilitate reminders regarding such screening. We have had strong success in our practice in using this strategy to implement universal screening for HIV infection.

Dr. Morrow: Forget RCTs; Look at Large Data Sets

Thanks for your thoughtful comments, Charles.

I am certainly not going to joust with the epidemiology folks at the CDC, but a different number for prevalence among blood donors from 2010 shows a falling rate of HCV antibody prevalence by the less specific test methods, down to 0.072%.[3]

My general sense is that we have many ways of estimating the expected rates of transmission and liver failure, and because prior transmission was likely owing to sharing of needles and blood transfusions, we do have good preventive measures.

Prospective randomized controlled trials (RCTs) are but one of the methods to analyze risk vs benefits, and often not the best. Could someone step forward and look at these numbers in large data sets systematically before embarking on a campaign?

As an aside, RCTs to a large measure have gotten us into the mess in which you look for answers to clinical questions in the research literature, and questions that are not answered are found far more commonly using this research method, largely because of the linear nature of the process. If you look at A to B, do you get C more commonly than by chance?

In truth, modern analytics, such as Bayesian approaches, are far more predictive than frequentist methods alone. This is simply to say that someone should be funded to look at whether screening large groups of baby boomers for HCV would lead to predictably better outcomes that matter to patients. Yes, indeed, this can be done with many different large data sets using contemporary analytic methods (but please don't ask this community doc for the details!). Think about how Google tells us about traffic on the highways by looking at the number of cell phones and how fast they are travelling and mapping this to the roadways: instantly and clearly, but indirectly.

From my seat in my family medicine office, as well as an educator: We are told not to screen for domestic violence due to lack of outcomes evidence, and not to screen for gun ownership due to politics, and not to screen for chronic alcoholism (only unsafe behaviors) due to difficulty in treatment. We don't screen for Helicobacter pylori. We don't screen men for Chlamydia and gonorrhea.

Why hepatitis C, and why now?

Dr. Vega: It's Time to Screen Now

Good points. I'd just add that Bob is right: The prevalence of HCV is falling, and this may be due to greater public knowledge and interventions to prevent bloodborne transmission. But the more advanced statistical analyses on screening for HCV has been done, and one study showed that age-based screening was actually more cost-effective than screening on the basis of risk factors.[4] At the end of the day, the screening is imperative now because these older adults are in a time window when screening and treatment should add substantially more years of quality living. That window will not stay open forever, and we as primary care physicians need to understand when it is getting ready to close.

The news that HCV treatment is simplifying and may eventually move to the primary care office should only add to the weight of this recommendation. But that's a topic for a different time.

References

  1. Garcia J. Hepatitis C: USPSTF recommends all baby boomers be screened. Medscape. June 24, 2013. http://www.medscape.com/viewarticle/806836 Accessed September 5, 2013.

  2. Teo CG. Testing for hepatitis C: new guidance. Medscape. July 29, 2013. http://www.medscape.com/viewarticle/808327 Accessed September 5, 2013.

  3. Murphy EL, Fang J, Tu Y, et al. Hepatitis C virus prevalence and clearance among US blood donors, 2006-2007: associations with birth cohort, multiple pregnancies, and body mass index. J Infect Dis. 2010;202:576-584. Abstract

  4. Liu S, Cipriano LE, Holodniy M, Goldhaber-Fiebert JD. Cost-effectiveness analysis of risk-factor guided and birth-cohort screening for chronic hepatitis C infection in the United States. PLoS One. 2013;8:e58975.

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stigma-300x300

CREDIT: The Stigma Project

By Tara Culp-Ressler on September 16, 2013 at 8:59 am

A public school district in Arkansas has removed three siblings from school because administrators suspect they may be infected with HIV, according to a local disability rights organization. Under the Americans with Disabilities Act, public schools may not ban children simply based on their HIV status.

The three siblings — two of whom have disabilities — are living with a foster family and attending the Pea Ridge Public School District. But school district officials recently found documentation that suggested the birth mother and one of the kids are both HIV-positive, and told the foster family that none of the children could return to school until they provided proof that they don’t have the virus. When the kids were sent to school the next day anyway, they were “set aside until the foster parents picked them up,” according to a local news outlet.

The Disability Rights Center of Arkansas is accusing the school district of illegally discriminating against the children. They say that school officials have no right to demand medical testing at whim — particularly since, even if the children did test positive for HIV, they would still have the right to attend public school.

“The fact that the foster families have to provide documentation that the children are HIV negative before entering the school is unlawful and immoral,” the group said in a statement last week. “It stigmatizes individuals with disabilities — or their ‘perceived’ disabilities, as there is no indication these individuals have HIV. There is only an unlawful fear that they do.”

The Disability Rights Center is fighting to ensure that the three kids will be placed back in their school. The superintendent of the Pea Ridge district has declined to offer a statement on the controversy, but has indicated the school sought legal counsel before making their decision.

Last year, a private school in Pennsylvania sparked widespread protests after denying admission to an HIV-positive boy. Advocates pointed out that children shouldn’t be denied education opportunities simply because they have HIV. The school eventually reversed its decision after a legal battle with the U.S. Department of Justice, and agreed to provide staff with additional HIV sensitivity training.

Despite significant medical advances that help HIV-positive Americans live increasingly longer and healthier lives, many people still have widespread misconceptions about how the virus is actually spread. That lack of education has contributed to a pervasive stigma surrounding HIV — and a reluctance to integrate HIV-positive individuals with other people who don’t have the virus. Ultimately, that type of stigmatization only helps maintains the epidemic by hampering HIV prevention and outreach efforts.

Source

Journal of Hepatology

Article in Press

Coilly Audrey, Roche Bruno, Dumortier Jérôme, Leroy Vincent, Botta-Fridlund Danielle, Radenne Sylvie, Pageaux Georges-Philippe, Si-Ahmed Si-Nafaa, Guillaud Olivier, Antonini Teresa Maria, Haim-Boukobza  Stéphanie,Roque-Afonso Anne-Marie, Samuel Didier, Duclos-Valleem, Jean-Charles,

Received 18 February 2013; received in revised form 16 July 2013; accepted 15 August 2013. published online 30 August 2013.
Accepted Manuscript

Abstract

Background

Protease inhibitors (PI) with peg-interferon/ribavirin have significantly improved SVR rates in HCV G1 patients. Their use to treat HCV recurrence after liver transplantation (LT) is a challenge.

Methods

This cohort study included 37 liver transplant recipients (male: 92%, age 57±11years), treated with boceprevir (n=18) or telaprevir (n=19). The indication for therapy was HCV recurrence (fibrosis stage > then or equal to F2 (n=31, 83%) or fibrosing cholestatic hepatitis (n=6, 16%).

Results

Eighteen patients were treatment-naive, five were relapsers and 14 were non-responders to dual therapy after LT. Twenty-two patients received cyclosporine and 15 tacrolimus. After 12 weeks of PI therapy, a complete virological response was obtained in 89% of patients treated with boceprevir, and 58% with telaprevir (P=0.06). The end of treatment virological response rate was 72% (13/18) in the boceprevir group and 40% (4/10) in the telaprevir group (P=0.125). A sustained virological response 12 weeks after treatment discontinuation was observed in 20% (1/5) and 71% (5/7) of patients in the telaprevir and boceprevir groups, respectively (P=0.24). Treatment was discontinued in 16 patients (treatment failures (n=11), adverse events (n=5)). Infections occurred in ten patients (27%), with three fatal outcomes (8%). The most common adverse effect was anemia (n=34, 92%), treated with erythropoietin and/or a ribavirin dose reduction; thirteen patients (35%) received red blood cell transfusions. The cyclosporine dose was reduced by 1.8±1.1-fold and 3.4±1.0-fold with boceprevir and telaprevir, respectively. The tacrolimus dose was reduced by 5.2±1.5-fold with boceprevir and 23.8±18.2-fold with telaprevir.

Conclusions

Our results suggest that triple therapy is effective in LT recipients, particularly those experiencing a severe recurrence. The occurrence of anemia and drug-drug interactions, and the risk of infections, require close monitoring.

Abbreviations: ALT, alanine aminotransferase, AFEF, French Association for the Study of the Liver, AUC, area under the curve, BID, twice daily (bis in die), BOC, boceprevir, cEVR, complete early virological response, CNI, calcineurin inhibitors, CYP, cytochrome P450, EPO, erythropoietin, EOT, end of treatment response rate, EVR, early virological response, F, female, FCH, fibrosing cholestatic hepatitis, G1, genotype 1, GGT, gamma-glutamyl transferase, HBV, hepatitis B virus, HCC, hepatocellular carcinoma, HCV, hepatitis C virus, HIV, human immunodeficiency virus, IL, interleukin, INR, International Normalized Ratio, IS, immunosuppressive drugs, Kg, Kilogram, LT, liver transplantation, M, male, MELD, Model for End-stage Liver Disease, MMF, mycophenolate mofetil, NA, not available, NR, non-response, PCR, polymerase chain reaction, PEG-IFN, pegylated interferon, PI, protease inhibitors, QD, once a day (quaque die), RBV, ribavirin, RVR, rapid virological response, SVR12, sustained virological response 12 weeks after the end of therapy, TBC, trough blood concentration, TID, three times a day (ter in die), TVR, telaprevir, VB, virological breakthrough, VL, viral load, VR, virological response

Keywords: Hepatitis C, Boceprevir, Telaprevir, Protease inhibitors, HCV recurrence, Liver transplantation, Early virological response, Drug-drug interaction, Sustained virological response

No full text is available. To read the body of this article, please view the PDF online.

PII: S0168-8278(13)00613-2

doi:10.1016/j.jhep.2013.08.018

© 2013 Published by Elsevier Inc.

Source

Hepatol Res. 2013 Aug;43(8):836-45. doi: 10.1111/hepr.12025. Epub 2013 Feb 28.

Ogura S, Saitoh S, Kawamura Y, Sezaki H, Hosaka T, Akuta N, Kobayashi M, Suzuki F, Suzuki Y, Arase Y, Ikeda K, Kumada H.

Department of Hepatology, Toranomon Hospital, Tokyo, Japan.

Abstract

AIM: Laparoscopy-guided liver biopsy is the most accurate method for assessing liver fibrosis but have several limitations. We designed a non-invasive method, called magnetic resonance laparoscopy (MRL), based on gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging, to assess liver fibrosis in patients with chronic hepatitis B and C virus.

METHODS: We prospectively analyzed 49 patients with normal liver and 353 patients with chronic viral hepatitis, laparoscopic liver biopsy was performed on 109 patients and 244 patients were diagnosed as having liver cirrhosis clinically. The MRL findings of the liver surface were classified into three categories: (i) smooth (essentially smooth surface of the entire liver or with limited areas of depression); (ii) partially irregular (several interconnected depressions on the surface mainly in the left lobe of the liver); and (iii) diffusely irregular (nodules present on the liver surface). Patients with diffusely irregular liver surface was diagnosed as liver cirrhosis.

RESULTS: The liver surface changed with the progression of liver fibrosis from smooth, partially irregular to diffusely irregular, irrespective of viral type. The sensitivity, specificity, positive and negative predictive values for the diagnosis of cirrhosis according to the surface findings on MRL were 96%, 100%, 95% and 95%, respectively. The cirrhotic liver showed: (i) disappearance of impression of the right ribs; (ii) enlargement of the lateral segment; and (iii) atrophy of the right lobe according to Child-Pugh classification.

CONCLUSION: Our data indicated that MRL is a potentially useful non-invasive examination for evaluation of liver fibrosis associated with viral hepatitis.

© 2012 The Japan Society of Hepatology.

KEYWORDS: chronic hepatitis, gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid, laparoscopy, multiple resonance imaging, multiple resonance laparoscopy

PMID: 23445460 [PubMed]

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HEPATOLOGY, June 2013

Mark S. Sulkowski,1 Tarik Asselah,2 Jacob Lalezari,3 Peter Ferenci,4 Hugo Fainboim,5 Barbara Leggett,6 Fernando Bessone,7 Stefan Mauss,8 Jeong Heo,9 Yakov Datsenko,10 Jerry O. Stern,11 George Kukolj,12Joseph Scherer,11 Gerhard Nehmiz,10 Gerhard G. Steinmann,10 and Wulf O. Bocher10

In this large, phase 2 study of faldaprevir QD, in combination with PegIFN/RBV, cure of infection (SVR) was achieved in up to 84% of HCV GT-1 patients, with more than 80% meeting VR criteria for shortened treatment duration (24 weeks). Overall, the treatment regimen was safe and tolerable. Confirmatory phase 3 trials testing 120 and 240 mg QD faldaprevir without LI, in combination with PegIFN/RBV, are ongoing in treatment-naïve and -experienced patients, as well as patients with HCV/HIV coinfection.

Abstract

Faldaprevir (BI 201335) is a potent, hepatitis C virus (HCV) NS3/4A protease inhibitor with pharmacokinetic properties supportive of once-daily (QD) dosing. Four hundred and twenty-nine HCV genotype (GT)-1 treatment-naïve patients without cirrhosis were randomized 1:1:2:2 to receive 24 weeks of pegylated interferon alfa-2a and ribavirin (PegIFN/RBV) in combination with placebo, faldaprevir 120 mg QD with 3 days of PegIFN/RBV lead-in (LI), 240 mg QD with LI, or 240 mg QD without LI, followed by an additional 24 weeks of PegIFN/RBV. Patients in the 240 mg QD groups achieving maintained rapid virologic response (mRVR; viral load [VL] <25 IU/mL at week 4 and undetectable at weeks 8-20) were rerandomized to cease all treatment at week 24 or continue receiving PegIFN/RBV up to week 48. VL was measured by Roche TaqMan. Sustained virologic response (SVR) rates were 56%, 72%, 72%, and 84% in the placebo, faldaprevir 120 mg QD/LI, 240 mg QD/LI, and 240 mg QD groups. Ninety-two percent of mRVR patients treated with faldaprevir 240 mg QD achieved SVR, irrespective of PegIFN/RBV treatment duration. Eighty-two percent of GT-1a patients who received faldaprevir 240 mg QD achieved SVR versus 47% with placebo. Mild gastrointestinal disorders, jaundice resulting from isolated unconjugated hyperbilirubinemia, and rash or photosensitivity were more common in the active groups than with placebo. Discontinuations resulting from adverse events occurred in 4%, 11%, and 5% of patients treated with 120 mg QD/LI, 240 mg QD/LI, and 240 mg QD of faldaprevir versus 1% with placebo. Conclusion: Faldaprevir QD with PegIFN/RBV achieved consistently high SVR rates with acceptable tolerability and safety at all dose levels. The 120 and 240 mg QD doses are currently undergoing phase 3 evaluation.

(Click on image to enlarge)

figure1

Figure 4. Difference in rates of SVR between the treatment and control groups, according to subgroups. Treatment of hepatitis C infection has advanced since its initial characterization.1 Hepatitis C virus (HCV) genotype (GT)-1 represents the most common GT in many parts of the world and, historically, has been less responsive to peginterferon alfa-2A (PegIFN) and ribavirin (RBV), compared with other HCV GTs, despite longer treatment duration (48 weeks) and higher-dose RBV. Since the proof-of-concept study with the HCV NS3/4A peptidomimetic protease inhibitor (PI), BILN 2061,2 multiple PIs have entered clinical development. Two PIs, the α-ketoamide derivatives boceprevir and telaprevir, have been approved for treatment in many regions of the world. Taken three times daily in combination with PegIFN/RBV, both boceprevir and telaprevir have significantly improved sustained virologic response (SVR) rates and shortened treatment duration in approximately half of treated HCV GT-1 patients, as compared with PegIFN/RBV alone.3-6 However, both agents carry a high pill burden and add significant side effects to those of PegIFN/RBV, including severe skin rashes/pruritus (telaprevir), anal discomfort (telaprevir), dysgeusia (boceprevir), and anemia (telaprevir and boceprevir).

Faldaprevir is a potent, once-daily (QD), HCV NS3/4A PI7 with antiviral activity in in vitro HCV subgenomic replicon assays, as well as NS3 protease assays derived from HCV GT-1, -4, -5, and -6.8 Preclinical and human pharmacokinetic (PK) studies suggested that faldaprevir has a long half-life, consistent with QD dosing.9 Phase 1b studies demonstrated that faldaprevir QD combined with PegIFN/RBV was well tolerated and induced strong antiviral responses in treatment-naïve and -experienced HCV GT-1 patients.10 Here, we report on the results of a phase 2b, multicenter, randomized, double-blind study of faldaprevir or placebo in combination with PegIFN/RBV in treatment-naïve, HCV GT-1-infected patients (SILEN-C1; Safety, and antIviraL Effect of faldaprevir iN hepatitis C).

Abbreviations

AE, adverse event; ALT, alanine aminotransferase; BMI, body mass index; CI, confidence interval; DRESS, drug rash with eosinophilia and systemic symptoms; EVR, early virologic response; GGT, gamma-glutamyl transferase; GT, genotype; HCV, hepatitis C virus; HIV, human immunodeficiency virus; IVRS, interactive voice response system; LI, lead-in; LLOD, lower limit of detection; LLOQ, lower limit of quantification; mRVR, maintained rapid virologic response; OR, odds ratio; PCR, polymerase chain reaction; PegIFN, pegylated interferon alfa-2a; PI, protease inhibitor; PK, pharmacokinetic; PR, peginterferon/ribavirin; QD, once-daily; RBV, ribavirin; RGT, response-guided therapy; SJS, Stevens-Johnson syndrome; SVR, sustained virologic response; UGT, uridine diphosphate glucuronosyltransferase; ULN, upper limit of normal; VL, viral load; VR, virologic response.

Results

Patient Disposition and Baseline Characteristics.

Of 581 patients screened, 429 were randomized to treatment, whereas 152 did not meet entry criteria (Fig. 2). Of the 429 treated patients, 74 prematurely discontinued the trial medication (faldaprevir or placebo). Reasons for treatment discontinuation included AEs (n = 28), lack of efficacy (n = 23), refusal to continue the trial medication (n = 8), noncompliance with the protocol (n = 5), loss to follow-up (n = 3), and other reasons (n = 7). Patients were evenly distributed over all dose groups with respect to gender, race, HCV RNA, GT, age, BMI, and IL28B GT (Table 1). Patients were predominantly male (55%), mean age was 46 ± 11 years, mean BMI was 26.0 ± 4.6, and mean HCV RNA was 6.39 ± 0.61 log10 IU/mL. Analysis of IL28B GT (rs12979860) was performed retrospectively in 223 patients (the remaining patients did not provide consent for testing); of those tested, 27% were CC and 73% were non-CC. Six patients enrolled into the study and received study drug based on initial testing, but were found not to be infected with GT-1 by sequencing (GT-3, n = 2; GT-4, n = 1; GT-6, n = 3); all non-GT-1 patients achieved SVR. These patients are included in the safety analysis, but were excluded from the efficacy analysis.

Efficacy.

SVR was achieved by 56% of patients in the placebo arm, compared to 72% of patients in the 120 mg QD/LI arm (P = 0.054), 72% of patients in the 240 mg QD/LI arm (P = 0.021), and 84% of patients in the 240 mg QD arm (P = 0.001; Fig. 3). The majority of patients treated with faldaprevir achieved mRVR with rates of 15%, 80%, 78%, and 87% in the placebo, 120 mg QD/LI, 240 mg QD/LI, and 240 mg QD dose groups, respectively (Fig. 3). Virologic response (VR) is summarized in Table 2. In the placebo group, 11 of 71 patients (15%) relapsed. Thirty-one of 352 patients (9%) treated with faldaprevir relapsed: five of 69 (7%) in the 120 mg QD/LI group, 15 of 141 (11%) in the 240 mg QD/LI group, and 11 of 142 (8%) in the 240 mg QD group.

In the 240 mg QD/LI and 240 mg QD dose groups, 78% and 87% of patients, respectively, achieved mRVR and were eligible for rerandomization to either 24 or 48 weeks of PegIFN/RBV (Fig. 3). High rates of SVR (81% to 96%) were observed in patients with mRVR. In the 240 mg QD/LI arm, lower SVR (81% versus 96%; P = 0.051) and higher relapse (17% versus 4%) rates were observed in patients who achieved mRVR and were treated for 24 weeks, compared with those treated for 48 weeks. In contrast, 107 of 116 patients (92%) in the 240 mg QD dose group achieved SVR, irrespective of the duration of treatment (24 versus 48 weeks; P = 1.000); rates of relapse were also similar (5% versus 2%).

In patients who received the 240 mg QD dose without LI, SVR rates were consistently high across a wide range of patient subgroups (Fig. 4). Notably, the SVR rate for GT-1a patients was 82% (compared with 47% on PegIFN/RBV; P = 0.0013). All 22 patients (100%) with IL28B GT CC achieved SVR, compared with 82% with PegIFN/RBV alone. In this arm, the percentage of patients achieving mRVR and thus eligible for 24 weeks overall treatment duration was 87%, with similar rates across all subgroups, including non-CC patients. A univariate logistic regression analysis of baseline predictors of SVR in patients in the 240 mg QD dose group, considering IL28B GT, ALT, GGT, HCV VL, gender, BMI, and time since diagnosis, indicated that only GGT (P = 0.013, odds ratio [OR; 95% CI] = 3.32 [1.29, 8.59]) and IL28B (P = 0.154) achieved the predefined significance level for multivariate testing. However, because 100% of patients with the IL28B CC GT achieved SVR, multiple variable regression was not performed. Within the 48 non-CC GT patients, the effect of GGT was slightly reduced (OR [95% CI] = 2.03 [0.56, 7.3]).

Rates of virologic breakthrough during faldaprevir treatment were comparable (3%-6%) with that observed in the placebo group (3%), but, in contrast to the placebo group, were predominantly associated with the selection of NS3 R155K or D168V variants for GT-1a or GT-1b patients, respectively. Three patients (1%) in the active arms experienced virologic rebound during PegIFN/RBV therapy after stopping faldaprevir therapy, including one R155K change (GT-1a), one without detectable resistant mutant (GT-1a), and one (GT-1a) with mixed substitutions at R155 and D168. Post-treatment rebound in the active arms from the nonresponder group was characterized by two R155K substitutions (one GT-1a in each 240 mg dose group) and the lack of detectable resistant mutants in the other five patients. Relapses among the faldaprevir treatment groups were observed in 31 of 352 patients (9%) with an undetectable VL at the end of treatment; viral sequencing of this patient group was characterized by predominant selection of R155K variants in GT-1a patients (eight of 12) and D168V variants in GT-1b patients (11 of 19). Notably, five of six patients in the faldaprevir treatment groups with resistance substitutions detectable before treatment (two R155K in GT-1a and four D168 in GT-1b) achieved SVR.

Safety.

Most AEs observed during or up to 30 days after the end of treatment with faldaprevir were those commonly related to PegIFN/RBV therapy (Table 3). Serious AEs were reported in two patients (3%) in the placebo group and 33 (9%) treated with faldaprevir (all serious AEs are described in the footnote of Table 3). Discontinuation of treatment resulting from an AE was lower for patients treated with placebo versus faldaprevir: one of 71 (1%) discontinued treatment in the control group, compared to three of 69 (4%), 16 of 140 (11%), and eight of 149 (5%) patients treated with 120 mg QD/LI, 240 mg QD/LI, and 240 mg QD faldaprevir (Table 3). Of the 28 patients who discontinued faldaprevir or placebo because of AEs, 25 also discontinued PegIFN/RBV.

The primary AEs attributed to faldaprevir were mild gastrointestinal disorders (nausea, diarrhea, and vomiting), jaundice, pruritus, and rash. All AEs resolved during or after end of treatment. Rash and photosensitivity were higher in the 240 mg groups, compared to placebo and the 120 mg group. Probability of occurrence of rash or photosensitivity reactions tended to increase with increasing median trough plasma levels of faldaprevir. Rashes had an erythematous, macular, or papular morphology, preferentially affecting the trunk, arms, and legs, and usually occurred during the first 12 weeks of treatment. Mucus membranes and other organs were not affected in any patient. There were no cases of Stevens-Johnson syndrome (SJS), erythema multiforme, or drug rash with eosinophilia and systemic symptoms (DRESS). The majority of cases were mild and were managed without treatment interruption, in most cases, by applying topical treatments and, rarely, systemic corticosteroids (<5%). Photosensitivity mostly manifested as mild erythema limited to sun-exposed areas of the body and led to one discontinuation. Severe rash events were observed in 11 patients (3% in the faldaprevir groups): five patients (4%) in the 240 mg QD/LI group and six (4%) in the 240 mg QD group. Ten patients in the 240 mg dose groups (3%) discontinued faldaprevir because of rash, which was classified as severe in eight of these cases.

At the higher doses of 240 mg QD, 20% to 25% of patients experienced jaundice (usually mild) as a result of dose-dependent, isolated, unconjugated hyperbilirubinemia associated with faldaprevir; rates of mild jaundice were similar for placebo and 120 mg QD (Table 3). Hyperbilirubinemia was rapidly reversible (bilirubin normalized in all patients subsequent to cessation of faldaprevir dosing) and not associated with liver injury, hemolysis, or any other clinical symptoms. Changes in safety laboratory values were consistent with those observed with PegIFN/RBV (Table 4). Importantly, there was no additional effect of faldaprevir on hemoglobin levels or white blood cells, compared to the control group; the rate of erythropoietin was similar in the placebo and active arms (5% to 12%).

Discussion

The PI faldaprevir, dosed QD in combination with PegIFN and RBV, increased SVR rates of treatment-naïve GT-1 patients from 56% in the placebo group to as high as 84% with 240 mg faldaprevir. SVR rates were similar with this dose in patients with historically less-favorable IL82B GT and HCV GT-1a. Interestingly, patients in the 120 mg QD/LI group had similar EVR and SVR rates to those in the 240 mg QD/LI group, suggesting a lack of a dose effect on VR at the higher dose. Furthermore, although not directly compared, SVR rates observed with all dose regimens of faldaprevir and PegIFN/RBV appear at least similar to those reported with the recently approved PIs boceprevir and telaprevir (68% and 73%, respectively).3, 5

Response-guided therapy (RGT) was assessed in both 240 mg dose groups, where 78% and 87% of patients with or without LI achieved mRVR, respectively, defined as HCV RNA < LLOQ at week 4 and < LLOD at weeks 8 to 20. Thus, the majority of patients met the response criteria for rerandomization to either stopping all treatment after 24 weeks or continuation of PegIFN/RBV to week 48. All patients who were not eligible for rerandomization continued PegIFN/RBV to week 48. Importantly, patients achieving mRVR who stopped all treatment at week 24 in the 240 mg QD dose group showed equivalent SVR rates as those who continued PegIFN/RBV to week 48. Because these data were derived in a randomized fashion, they support the application of RGT with 24 weeks of overall treatment duration for treatment-naïve GT-1 patients achieving mRVR.

Clinical trials of boceprevir and telaprevir also included the option for shortened treatment duration, but incorporated more-stringent criteria (which included HCV RNA < LLOD at week 4) than this study.3, 5 When the criteria used in the telaprevir studies to identify patients eligible for shortened treatment duration (HCV RNA < LLOD at weeks 4 and 12) were applied to this data set, up to 75% met the criteria, suggesting that the majority of patients treated with faldaprevir plus PegIFN/RBV may be eligible for 24 weeks of therapy. Furthermore, these data support the application of less-stringent criteria at treatment week 4 (<25 IU/mL detected or undetected), which may be acceptable for the determination of patients who can be treated for shorter duration with faldaprevir plus PegIFN/RBV.

HCV NS3/4A PIs have been shown to rapidly select for the emergence of resistance mutations when administered as monotherapy.10, 12 Therefore, the effect of 3 days of pretreatment of patients with PegIFN and RBV before adding faldaprevir was assessed directly by comparing 240 mg QD dose groups with or without LI. The rationale was that the short delay of the first intake of faldaprevir would prevent the possibility of functional PI monotherapy. Surprisingly, the administration of a 3-day LI with PegIFN/RBV before initiation of faldaprevir resulted in approximately 10% lower rates of mRVR and SVR, compared with faldaprevir initiated simultaneously with PegIFN/RBV. A similar negative effect was observed in a second independent phase 2 trial of faldaprevir in patients who had nonresponse to previous PegIFN/RBV treatment.13 Although the reasons for poor response with short LI are unknown, rapid and profound inhibition of HCV replication might restore IFN responsiveness, as suggested by the decrease of plasma levels of IFN-inducible protein 10, a lymphocyte chemokine indicative of endogeneous activation of host IFN pathways, in HCV patients treated with IFN-free regimens.14 However, further research is required to test this hypothesis. Although the reasons for lower response rates with 3-day LI are not fully understood, this strategy was not selected for further investigation. Breakthroughs and relapses in the faldaprevir treatment groups were rare and usually associated with the selection of common NS3 PI-resistant variants, whereas patients failing PegIFN/RBV had wild-type NS3 sequences detected, with the exception of one patient who had selected for a D168E mutant, a previously observed natural polymorphism that also shifts potency of some PIs. Faldaprevir selected NS3 mutants predominantly encoded for R155K and D168V in GT-1a and GT-1b, respectively. Patients who experienced postfaldaprevir treatment rebound (either relapser and rebound from nonresponse) selected for similar NS3 amino acid changes, although 29% of isolates across the faldaprevir treatment groups encoded for virus that lacked known resistance mutants. In vitro studies have demonstrated 100-fold to 500-fold reduced sensitivity of various viral GT-1a strains carrying the R155K substitution, whereas D168V substitutions in GT-1b strains conferred >1,000-fold reduced sensitivity to faldaprevir.15 The clinical data indicate that these shifts in sensitivity cannot be offset by the increase in faldaprevir exposure achieved by dose doubling from 120 to 240 mg QD. The most frequent AEs were those typical for PegIFN/RBV therapy. Although 120 mg QD faldaprevir had a safety profile similar to PegIFN/RBV (only pruritus and vomiting increased), higher frequencies were reported for skin rash, photosensitivity, jaundice, nausea, and diarrhea with the 240 mg QD dose. However, the vast majority of events were mild or moderate in intensity and only 4% to 11% of patients discontinued faldaprevir at 120 or 240 mg QD. Jaundice was, in all but one case, the result of isolated increases of unconjugated bilirubin (one patient with normal plasma bilirubin), was rapidly reversible after cessation of faldaprevir, and was not associated with signs of liver toxicity or excess hemolysis; patients had no other symptoms, and only one patient in the trial discontinued because of jaundice. In vitro studies demonstrated that faldaprevir mediated inhibition of the bilirubin-conjugating enzyme UGT1A1 and, to a lesser extent, the organic anion-transporting polypeptide 1 and multidrug-resistant protein 2 transporters, which appear to be the key drivers of this finding.16 This effect is comparable with that of other PIs in development for HCV17 or in clinical use for HIV (e.g., atazanavir) treatment, which is not considered a sign of hepato- or hematotoxicity.18 Skin rash and photosensitivity reactions, which were more frequent with the 240 mg QD dose, were usually mild and could be managed without treatment modifications, in most instances. There were few discontinuations resulting from skin events and no cases of DRESS syndrome, SJS, or erythema multiforme. Of note, there was no effect of faldaprevir on hemoglobin levels, red blood cell counts, or leukocyte counts, suggesting that anemia and leukocytopenia reported for some other PIs are not a class effect, but rather compound-specific side effects.

A potential limitation of this trial was the exclusion of patients with liver cirrhosis; this was because of the lack of phase 1 safety data in this patient population at the initiation of this study. However, tolerability, safety, and efficacy of 240 mg QD faldaprevir with PegIFN/RBV given for four weeks in patients with compensated liver cirrhosis (Child-Pugh score) was demonstrated to be similar to patients without cirrhosis in recently completed phase 1 and 2 trials.19, 20 Importantly, the PK characteristics were unchanged in patients with cirrhosis. In addition, degree of liver fibrosis was not collected prospectively in this study, precluding any analysis of the association of fibrosis stage on the efficacy and safety of faldaprevir. Lastly, because of the inclusion of RGT in some, but not all, treatment arms, the study was only fully blinded up to treatment week 24.

In this large, phase 2 study of faldaprevir QD, in combination with PegIFN/RBV, cure of infection (SVR) was achieved in up to 84% of HCV GT-1 patients, with more than 80% meeting VR criteria for shortened treatment duration (24 weeks). Overall, the treatment regimen was safe and tolerable. Confirmatory phase 3 trials testing 120 and 240 mg QD faldaprevir without LI, in combination with PegIFN/RBV, are ongoing in treatment-naïve and -experienced patients, as well as patients with HCV/HIV coinfection.

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Hepatology June 2013

Mark S. Sulkowski,1 Marc Bourlie` re,2 Jean-Pierre Bronowicki,3 Tarik Asselah,4 Jean-Michel Pawlotsky,5 Stephen D. Shafran,6 Stanislas Pol,7 Stefan Mauss,8 Dominique Larrey,9 Yakov Datsenko,10 Jerry O. Stern,11George Kukolj,12 Joseph Scherer,11 Gerhard Nehmiz,10 Gerhard G. Steinmann,10 and Wulf O. Bocher13

Abstract

Faldaprevir (BI 201335) is a potent, hepatitis C virus (HCV) NS3/4A protease inhibitor. In all, 290 noncirrhotic HCV genotype (GT)-1 patients with prior null (<1 log10 viral load [VL] drop at any time on treatment) or partial response (≥1 log10 VL drop but never undetectable on treatment) were randomized 2:1:1 to receive 48 weeks of peginterferon alfa-2a and ribavirin (PegIFN/RBV) in combination with faldaprevir 240 mg once daily (QD) with 3 days PegIFN/RBV lead-in (LI), 240 mg QD without LI, or 240 mg twice daily (BID) with LI.

Patients in the 240 mg QD/LI group achieving maintained rapid virologic response (mRVR; VL <25 IU/mL [Roche TaqMan] at week 4 and undetectable at weeks 8 to 20) were rerandomized to cease all treatment at week 24 or continue PegIFN/RBV up to week 48. Sustained virologic response (SVR) rates were 32%, 50%, and 42% in prior partial responders, and 21%, 35%, and 29% in prior null responders in the faldaprevir 240 mg QD/LI, 240 mg QD, and 240 mg BID/LI groups, respectively. In the 240 mg QD/LI group, a significantly higher proportion of mRVR patients rerandomized to 48 weeks' treatment achieved SVR compared with those assigned to 24 weeks treatment (72% versus 43%; P = 0.035). Rates of gastrointestinal disorders, jaundice, dry skin, and photosensitivity were increased at 240 mg BID compared with the 240 mg QD dose. Faldaprevir discontinuations owing to adverse events occurred in 6%, 4%, and 23% of patients in the 240 mg QD/LI, 240 mg QD, and 240 mg BID/LI groups, respectively. Conclusion: Faldaprevir 240 mg QD with PegIFN/RBV was safe and tolerable and produced substantial SVR rates in prior null and partial responders. The 240 mg QD dose is currently undergoing phase 3 evaluation.

Hepatitis C represents one of the most common chronic infectious diseases, affecting 150 to 170 million people worldwide. Of the described hepatitis C virus (HCV) genotypes (GT), GT-1 is most common in many parts of the world.

Historically, GT-1 has been less responsive to peginterferon alfa (PegIFN) and ribavirin (RBV) treatment, with around 50% to 60% of treatment-naïve patients failing to achieve a sustained virologic response (SVR). Treatment options for these patients were previously limited to a repeated course of PegIFN/RBV, with a low chance of cure (15% SVR).1, 2 Recent approval of the HCV NS3/4A protease inhibitors (PIs) boceprevir and telaprevir has resulted in significantly improved SVR rates in GT-1-infected patients including those who failed to respond to prior PegIFN/RBV treatment.3, 4 However, both agents add significant side effects to those of PegIFN/RBV, including severe skin rashes/pruritus (telaprevir), anal and digestive discomfort (telaprevir), anemia (telaprevir and boceprevir), nausea (telaprevir and boceprevir), and dysgeusia (boceprevir), are dosed thrice-daily, and carry a high pill burden.

Faldaprevir (BI 201335) is a peptidomimetic linear PI which has a long half-life, as demonstrated by preclinical and human pharmacokinetic studies, allowing once-daily (QD) dosing.5 In phase 1b studies, faldaprevir combined with PegIFN/RBV demonstrated strong antiviral responses and was well tolerated in treatment-naïve and treatment-experienced HCV GT-1 patients.6 In a phase 2b study of faldaprevir (SILEN-C1), up to 84% of treatment-naïve GT-1 patients achieved SVR and the safety and tolerability profile of faldaprevir was found to be favorable.7 Moreover, up to 87% of patients achieved the criterion of a maintained rapid virologic response (mRVR; HCV RNA <25 IU/mL at week 4 and undetectable from week 8 to week 20) and qualified for shortened treatment duration with 24 weeks of overall treatment. Here we report the results of a phase 2b multicenter, randomized, double-blind study of faldaprevir in combination with PegIFN/RBV in HCV GT-1-infected patients with nonresponse to prior PegIFN/RBV (SILEN-C2; Safety and antIviraL Effect of faldaprevir iN hepatitis C).

Patients and Methods

Patients
Patients were enrolled at 73 centers in 14 countries (Australia, Austria, Canada, Czech Republic, France, Germany, Republic of Korea, The Netherlands, Portugal, Romania, Spain, Switzerland, United Kingdom, and United States). Eligible patients were 18 to 65 years of age, had chronic HCV GT-1 infection, had previously received at least 12 weeks of combination treatment with an approved dose of PegIFN alfa-2a or alfa-2b combined with RBV, and had detectable HCV RNA at the end of previous treatment. At the time that the protocol was developed and approved, there was no standard definition of null or partial response. Accordingly, virologic failure was defined as either a <1 log10 maximum reduction in HCV RNA at any time during treatment (null response), or a maximal reduction in HCV RNA at any timepoint ≥1 log10 but never having achieved HCV RNA below the level of detection (partial response). Relapsers, who experienced undetectable HCV RNA during and/or at the end of prior HCV treatment followed by viral rebound, were specifically excluded from the trial. Other key inclusion criteria included an HCV viral load (VL) of ≥100,000 IU/mL at screening and a liver biopsy within 24 months prior to enrollment; patients with histologic cirrhosis were excluded. Patients with evidence of other liver disease, HCV of mixed GT, hepatitis B virus, human immunodeficiency virus, decompensated liver disease, contraindication to PegIFN or RBV, or hyperbilirubinemia (>1.5 x upper limit of normal [ULN]) were excluded; patients with Gilbert's polymorphism were accepted. Due to the potential for drug interactions, concomitant treatment with medications that are substrates of P-gp, UGT1A1, CYP3A4 or 2C9, with a narrow therapeutic range, were excluded. All patients provided written informed consent prior to trial participation. The study protocol was reviewed and approved by the appropriate Institutional Ethics Committees and health authorities.

Study Design

This was a phase 2b, multicenter, randomized, double-blind trial (NCT00774397). Eligible treatment-experienced patients were randomized to one of three treatment groups in a 2:1:1 ratio: 240 mg faldaprevir QD combined with PegIFN alfa-2a and RBV for 24 weeks, starting with a 3-day lead-in (LI) phase of placebo plus PegIFN/RBV, and followed by an additional 24 weeks of PegIFN/RBV (240 mg QD/LI); 240 mg faldaprevir QD combined with PegIFN alfa-2a and RBV for 24 weeks, followed by an additional 24 weeks of PegIFN/RBV (240 mg QD); 240 mg faldaprevir twice daily (BID) combined with PegIFN alfa-2a and RBV for 24 weeks, starting with a 3-day LI phase of placebo plus PegIFN/RBV, and followed by an additional 24 weeks of PegIFN/RBV (240 mg BID/LI). The rationale for the 3-day LI phase was that short delay of the first intake of faldaprevir would allow sufficient levels of PegIFN and RBV to be achieved prior to the administration of faldaprevir to prevent the possibility of functional faldaprevir monotherapy.

Three days was thought to be sufficient based on the observation that the antiviral effect of interferon can be observed within 1 to 2 days of dosing.8 For all patients, a loading dose of 480 mg faldaprevir was administered on the morning of the first day of faldaprevir treatment. In the 240 mg QD/LI treatment group, all patients achieving mRVR, defined as HCV VL below the lower limit of quantification (LLOQ) at week 4 (HCV RNA <25 IU/mL) and undetectable from week 8 to week 20 (HCV RNA <17 IU/mL), were rerandomized at week 24, at a ratio of 1:1, to either continue PegIFN/RBV up to week 48 or stop all treatment at week 24. PegIFN alfa-2a was administered subcutaneously at a dose of 180 μg per week, and RBV was given orally at a dose of 1,000 mg/day (body weight <75 kg) or 1,200 mg/day (body weight ≥75 kg) in two divided doses. Faldaprevir and RBV were administered with food. Hematopoietic growth factors were not provided but allowed at the discretion of the investigator for the management of anemia and neutropenia. Stopping criteria for virologic failure were as follows: HCV VL rebound by ≥1,000 IU/mL after previous VL below the lower limit of detection (LLOD), in two consecutive visits at least 2 weeks apart; lack of early virologic response, defined as an absence of drop by ≥2 log10 from baseline VL at week 12; or absence of VL below the LLOD at week 24. There were no protocol-specified laboratory or clinical stopping rules for bilirubin elevations.

Efficacy Assessments

Efficacy Endpoints

The primary efficacy endpoint of the study was SVR, defined as HCV RNA below the LLOD 24 weeks after the end of all anti-HCV therapy. Secondary efficacy endpoints included mRVR (defined in the study design section) and the occurrence of rebound, in particular breakthrough and relapse. End of treatment response (EoTR) was defined as HCV RNA not detected at end of treatment. Rebound was defined as HCV RNA >1 log10 from nadir, or ≥100 IU/mL after previous VL below the LLOD in two consecutive visits at least 2 weeks apart. Breakthrough was defined as HCV RNA rebound during faldaprevir/placebo treatment or subsequent PegIFN/RBV treatment. Relapse was defined as HCV RNA undetectable at the end of treatment but detectable during the follow-up period. Nonresponse was used to define patients who did not achieve SVR, but did not experience a virologic breakthrough or relapse.

Analysis of Plasma HCV RNA and GT

Plasma HCV RNA levels were measured using the Roche COBAS TaqMan HCV/HPS (v. 2.0) assay at a central laboratory, with an LLOQ of 25 IU/mL and an LLOD of 17 IU/mL. HCV GT for screening and randomization was determined using the Trugene HCV assay (Bayer, Leverkusen, Germany); due to the technical limitations of this genotyping assay,9 definitive HCV GTs and subtypes used for all analyses were based on complete NS3/4A sequencing and phylogenetic analyses for all randomized patients.

Genotypic and Phenotypic Resistance Monitoring

Samples for genotyping the HCV NS3/4A protease were collected at all patient visits. Retrospective viral genotyping was performed for all patients at baseline, for patients who discontinued study treatment due to virologic failure or who had VL plateaus above the LLOQ, or VL rebounds during or after the end of treatment. Viral RNA was isolated from plasma using the QiaAmp Viral RNA extraction kit. cDNA was synthesized using Superscript III one-step reverse transcription polymerase chain reaction system with platinum Taq DNA polymerase using GT-specific primers. The length of amplified product potentially limits the detection to samples with VL >103 IU/mL. The NS3/4A protease nucleotide sequence was obtained by direct DNA sequencing of the amplified product using Big Dye Terminator V3.1 and the ABI 3130x1 Genetic Analyzer (Applied Biosystems) detection system that allows for the detection of variants present at ≥30%.

Safety Assessments

A written record of all adverse events (AEs), including time of onset, end time, and intensity of the event, as well as any treatment or action required for the event and its outcome, was kept by each investigator. All AEs, including rash, were graded based on tolerability until the introduction of a rash management plan, defined as follows: mild (localized), moderate (diffuse, 30% to <70% body surface area), or severe (diffuse generalized, >70% body surface area or mucous membrane involvement or organ dysfunction or signs of anaphylaxis or life threatening). The intensity of all other AEs was judged based on a patient's tolerability of the event as being mild (easy to tolerate), moderate (interference with usual activity), or severe (incapacitating or causing inability to work or to perform usual activities). Vital signs and electrocardiograms were also evaluated, as were routine laboratory parameters.

Statistical Assessments

Descriptive statistics for efficacy and safety endpoints were reported. All P-values reported are 2-sided and were calculated using Fisher's exact test. All efficacy and safety results relate to all treated patients (Fig. 1). The sample size in this phase 2 trial was based on an optimization approach for the probability of correctly selecting the most efficacious dose for phase 3.

Results

Patient Disposition and Baseline Characteristics

Of 355 patients enrolled in the trial, 290 patients were randomized to treatment (Fig. 1). Of these, 288 patients received at least one dose of treatment; 192 patients completed treatment with faldaprevir, while 96 patients prematurely discontinued for reasons including AEs (n = 27), lack of efficacy (n = 51), refusal to continue the study medication (n = 11), noncompliance with the protocol (n = 3), and other reasons (n = 4) including one patient lost to follow-up. Following completion of the faldaprevir dosing phase, PegIFN/RBV was continued in 162 patients and completed in 114 patients, while 30 were rerandomized to stop all therapy (Fig. 1).

Baseline characteristics were similar among the three treatment groups (Table 1); 67% of patients were male, mean age was 49 years, 5% of patients were black (Hispanic patients were classed as white), and mean log10 HCV RNA was 6.58 IU/mL. As expected for prior nonresponders, only 4% of patients (among those with available IL28B GT data) had the CC polymorphism (rs12979860) (Table 1). Among all patients, 51% were infected with GT-1a and 47% with GT-1b. The majority of patients were documented null responders (47%; using stringent criteria of <1 log10 reduction in HCV RNA at any time during previous treatment) or prior partial responders (36%) to previous treatment (Table 1).

Efficacy

Overall, SVR was achieved by 28% of patients in the 240 mg QD/LI group, 41% in the 240 mg QD group, and 31% in the 240 mg BID/LI group (Fig. 2A). Compared with patients with prior null response, the rate of SVR was higher in patients with prior partial response (Fig. 2B), as expected. SVR was achieved by 32%, 50%, and 42% of prior partial responders in the 240 mg QD/LI, 240 mg QD, and 240 mg BID/LI treatment groups, respectively; corresponding rates in prior null responders were 21%, 35%, and 29%. SVR rates among patients infected with GT-1a tended to be lower than among patients infected with GT-1b virus.

Protocol-defined mRVR was achieved by 43%, 45%, and 47% of patients in the 240 mg QD/LI, 240 mg QD, and 240 mg BID/LI treatment groups, respectively (Fig. 2A). In the 240 mg QD/LI group, 59 patients who achieved mRVR were rerandomized to complete 24 or 48 weeks of PegIFN/RBV (total duration); the rate of SVR was significantly higher in patients treated for 48 weeks (72%) compared with those treated for 24 weeks (43%; P = 0.035) and virologic relapse was significantly lower in patients treated for 48 weeks (21%) compared with those treated for 24 weeks (57%; P = 0.0073) (Fig. 2C). Relapse occurred in 27% of patients with 240 mg QD/LI, 12% of patients with 240 mg QD, and 20% of patients with 240 mg BID/LI. The higher relapse rate in the 240 mg QD/LI group was mainly driven by frequent relapses in patients who obtained mRVR and were rerandomized to shortened treatment duration.

Breakthrough was observed in 24% of patients on faldaprevir treatment, with GT-1a viruses largely encoding NS3 R155 mutants and GT-1b viruses encoding only D168 changes (Table 2). The median time for faldaprevir breakthrough was 30 days (range 14 to 169). Of note, the viral breakthrough rate was lower in patients treated with 240 mg BID/LI (17%) and substitutions at position 155 were not observed in patients infected with GT-1a. After discontinuation of faldaprevir, virologic breakthrough during PegIFN/RBV therapy occurred in 6% of patients and was mainly associated with R155K mutations. Other nonresponse and relapse within all faldaprevir treatment arms was observed in 33% of patients and was characterized by R155K (37/51) substitutions for GT-1a virus and D168V (23/43) changes for GT-1b. However, in these groups 23% (22/94) had viruses that lacked known resistant mutations.

Safety

The most frequent AEs were those typical of PegIFN/RBV treatment, and in most cases were mild or moderate in intensity. Table 3 lists the most common AEs reported at an incidence of >20% in any group during the 24 weeks of treatment with faldaprevir or placebo and PegIFN/RBV. Based on prior studies, gastrointestinal disorders (nausea, diarrhea, and vomiting), skin events (rash and photosensitivity), and jaundice associated with elevated unconjugated bilirubin levels were considered to be potentially related to faldaprevir; these events were frequently observed during the initial weeks of therapy (Table 3). The rates of gastrointestinal disorders, jaundice, dry skin, and photosensitivity were higher in the 240 mg BID group compared with the 240 mg QD dose groups, suggestive of a dose-response relationship.

Serious AEs were more common in patients in the 240 mg BID/LI group (19%) compared with those in the 240 mg QD/LI and 240 mg QD groups (7% in both groups) and included anemia (4%, 1%, and 0%, respectively), gastrointestinal disorders (6%, 1%, and 0%, respectively), and skin and subcutaneous tissue disorders (7%, 0%, and 3%, respectively). No deaths were observed. Discontinuations due to AEs were rather frequent in the 240 mg BID/LI group (23%) but low with the 240 mg QD/LI group (6%) and the 240 mg QD group (4%). AEs leading to discontinuation were mainly rash (10%, 0%, and 0%, respectively), asthenia (4%, 0%, and 0%, respectively), nausea (3%, 1%, and 0%, respectively), vomiting (4%, 1%, and 1%, respectively), increased bilirubin (3%, 1%, and 0%, respectively), and jaundice (1%, 1%, and 0%, respectively). Some patients had more than one AE at the time of discontinuation.

Changes in laboratory values were generally consistent with those commonly reported for PegIFN/RBV. Decreases in hemoglobin, platelets, and white blood cell count were observed at frequencies similar to those observed with PegIFN/RBV and descriptive analysis did not reveal any clinically relevant differences between dose groups (no statistical analyses were conducted; Table 4).10 Erythropoietin was received by 6% to 14% of patients (two patients received transfusions; one in the 240 mg QD arm and one in the 240 mg BID/LI arm). Increases in total bilirubin, characterized by predominance of the unconjugated (indirect) fraction, were common during faldaprevir therapy and rapidly returned to pretreatment levels in all patients after faldaprevir was discontinued. Elevations in bilirubin were not associated with increases in serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels, or other markers of liver injury (Supporting Table 1).

Discussion

Treatment with the PI, faldaprevir 240 mg QD, in combination with PegIFN and RBV, led to virologic cure (SVR) in 35% and 50% of HCV GT-1 patients with strictly defined prior null or partial response to PegIFN/RBV. Interestingly, higher SVR rates were not observed in patients treated with 3-day LI of PegIFN/RBV compared with those treated with all three drugs simultaneously from the start. While 240 mg BID/LI was associated with lower rates of virologic breakthrough, the SVR rate achieved with this regimen was lower than the rate achieved with 240 mg QD, largely due to higher rates of treatment discontinuation due to AEs.

This trial excluded patients with liver cirrhosis and used a more stringent definition of null (<1 log10 reduction in HCV RNA at any time during previous treatment) and partial response (≥1 log10 reduction in VL but never undetectable on treatment) than clinical trials with other HCV PIs plus PegIFN/RBV in treatment-experienced patients.3, 4, 11 The manner in which prior HCV treatment response was collected in this study did not permit retrospective analysis of the current definitions of null (<2 log10 reduction in HCV RNA at week 12) and partial response (≥2 log10 reduction in HCV RNA at week 12 but with detectable HCV RNA at week 24). Accordingly, cross-study comparison of these data with other published studies is not possible.12 A phase 3 trial of faldaprevir plus PegIFN/RBV in treatment-experienced patients classified according to current definitions of null and partial response is ongoing. Prior relapsers are also being assessed in the phase 3 study. While these data are not yet available, this study suggests that, similar to other HCV PIs, prior PegIFN/RBV treatment response impacts the likelihood of response to retreatment with faldaprevir plus PegIFN/RBV.

For telaprevir and boceprevir, shortened response-guided therapy (RGT) provided to patients with rapid virologic response is the standard approach for treatment-naïve patients and prior relapsers (telaprevir). In the US, prior partial responders with RVR are eligible for shortened therapy with boceprevir regimens (but this is not included in the EU label); however, RGT has not been assessed in prior null responders. In this study, virologic relapse occurred in 60% of prior partial and null responders treated with 240 mg QD/LI who achieved mRVR, and were randomly assigned to stop treatment after 24 weeks. Although it is possible that RGT may have been more effective in patients treated with faldaprevir 240 mg QD without the PegIFN/RBV 3-day LI, we believe that these data provide convincing evidence that RGT should not be considered in this difficult-to-cure patient population. Thus, this concept was abandoned for previous null and partial responders in the ongoing phase 3 clinical trial program.

Importantly, even with longer PegIFN/RBV therapy, SVR rates were lower in patients with prior null response compared with those with prior partial response. In addition, the rate of virologic failure with HCV variants resistant to faldaprevir was higher in null responders, likely reflecting the inability of PegIFN/RBV to eradicate variants with decreased susceptibility to faldaprevir. This finding is consistent with those in clinical trials of boceprevir and telaprevir.3, 4 However, some differences in patterns of resistant variants detected in patients failing faldaprevir were observed compared with those previously reported in patients who failed to respond to telaprevir and boceprevir. Most cases of breakthrough and relapse were due to selection of the well-described resistance mutations R155K (GT-1a) and D168V (GT-1b).

Interestingly, a lower breakthrough rate was observed (17%, 12/70) with 240 mg BID/LI, where both GT-1a and GT-1b breakthrough virus encoded D168 mutants exclusively, indicating that the sensitivity shifts of R155K mutants might partially be covered by the increased faldaprevir exposure at this dose level; however, overall efficacy was offset by a higher discontinuation rate in the BID dose group. Wild-type sequence without detectable resistant mutants was found in 23% of nonresponders other than breakthrough (relapsers, other non-SVR) across all arms.

HCV PIs are known to rapidly select for resistant variants when administered as monotherapy.6, 13 Based on the rationale that a short delay in the first intake of a PI may prevent the possibility of functional monotherapy, the effect of a 3-day PegIFN/RBV LI period before initiation of faldaprevir therapy was assessed for the 240 mg QD dose. Consistent with phase 2 results reported in treatment-naïve patients,7, administration of a 3-day LI with PegIFN/RBV prior to faldaprevir treatment resulted in SVR rates around 10% lower than when the same dose of faldaprevir and PegIFN/RBV were initiated simultaneously. This observation remained valid after sensitivity analysis, which involved the removal of the 30 patients with mRVR who were rerandomized to what was found to be a suboptimal treatment duration (24 weeks). The finding that initiation of PegIFN/RBV prior to HCV PI had a negative effect was unexpected. Interestingly, in two randomized controlled trials (one with boceprevir; one with telaprevir), addition of HCV PI after 4 weeks of PegIFN/RBV therapy (LI) was not associated with a decrease or increase in the proportion of patients achieving SVR. The underlying mechanism for impaired viral response with the 3-day LI in our study is not known; further investigation is ongoing. Given the observed negative effect of 3-day PegIFN/RBV LI, simultaneous start of faldaprevir and PegIFN/RBV will be incorporated into current and future studies of this agent.

Faldaprevir was well tolerated at the 240 mg QD dose. At this dose, the main faldaprevir-related AEs were mild-to-moderate skin rash, photosensitivity reactions, and gastrointestinal events, which tended to occur during the first weeks after faldaprevir initiation up to week 12. Only 6% and 4% of patients discontinued faldaprevir due to AEs in the 240 mg QD/LI and 240 mg QD treatment groups, respectively. However, a much higher rate of discontinuation due to AEs was observed with the 240 mg BID dose (23%) without improved efficacy; thus, this dose will not be investigated in phase 3 studies.

Faldaprevir is associated with incidences of jaundice related to increases in unconjugated bilirubin. Similar to some other HCV PIs in development,14 faldaprevir-mediated inhibition of normal bilirubin uptake (OATP-1), processing (UGT1A1), and elimination (MRP-2) appear to drive this event.15 Jaundice was rapidly reversible after cessation of faldaprevir and was not associated with increases in serum ALT, AST, or other markers of liver injury; only three patients discontinued the trial due to jaundice and indirect bilirubin elevation. Skin rash in the 240 mg QD dose groups was mainly mild to moderate and managed without treatment modifications in most instances. In the 240 mg QD dose groups, only one patient discontinued treatment due to rash; however, 10 patients discontinued treatment with the 240 mg BID dose because of rash. In conclusion, addition of 240 mg QD faldaprevir for 24 weeks to 48-week PegIFN/RBV therapy was safe and tolerable and produced SVR rates of up to 50% in even the hardest-to-cure patients, i.e., GT-1 patients with null or partial response to prior PegIFN/RBV. Phase 3 trials testing 120 mg and 240 mg QD faldaprevir without LI, in combination with PegIFN/RBV, for treatment-naïve patients and patients with prior treatment failure are ongoing.

Source