Competition affects who gets a liver transplant: study

A surgeon holds the liver during an operation to extract the liver and the kidneys from a brain-dead women at the Unfallkrankenhaus Berlin (UKB) hospital in Berlin January 12, 2008.

Credit: Reuters/Fabrizio Bensch

Sun Jan 6, 2013 8:54pm EST

(Reuters) - More competition between medical centers that perform liver transplants may mean sicker patients get lower-quality donor organs, according to a U.S. study.

When more than one center has patients on the same donor list, the centers have an incentive to get organs for as many of their own patients as possible, wrote researchers, whose report appeared in Liver Transplantation.

So doctors are more likely to take the first available organ when their patient is at the top of the transplant list, whether or not that pairing has the best chance to succeed, rather than risk the organ will go to another center.

"There is the question whether competition decreases the ability of a center to better match donor and recipient characteristics," wrote John Paul Roberts, from the University of California, San Francisco, and colleagues.

They analyzed data on more than 38,000 liver recipients who had transplants from non-living donors between 2003 and 2009. The transplants were done at 112 medical centers in 47 so-called distribution areas - some covered by only one center and some that relayed organs to multiple transport centers.

Roberts and his colleagues found "clinically important differences" showing patients who received organs were initially worse off, with a higher risk of dying or having their transplant fail, in areas that had more medical centers in competition for the same organs.

For example, 10 percent of patients who received organs at centers with no competition had the worst scores for liver disease severity pre-transplant, compared to more than 28 percent of those in the high-competition distribution areas.

Areas with high competition also transplanted more organs that were considered at higher risk of failing, according to the new findings.

Although that might not be the best way of distributing organs on a society-wide scale, it could be considered a plus for the people who otherwise wouldn't get an organ or for livers that would otherwise be considered too low quality and be discarded.

"If you're a sick, high-risk patient... then it's in your interest that somebody will take more of a risk on you. The alternative is not surviving," said Michael Charlton, a liver disease researcher from the Mayo Clinic Transplant Center in Rochester, Minnesota.

Competition does increase access for patients, he said. So people who are very sick and turned away by a center that's the only place for transplants in its distribution area might have better luck elsewhere if they can afford to travel.

"The practice, in terms of choosing patients who can undergo liver transplantation and accepting organs that are already listed for transplantations, varies significantly between centers," said Charlton, who wasn't involved in the study, to Reuters Health.

But he cautioned that the way researchers measured competition - comparing the market shares for each transplant center in a given area - doesn't account for the effect of a center's reputation for good outcomes.

In that situation, a popular, higher-volume center would experience less competition from other centers and might also have better transplant records, so pure competition might not be the only explanation for outcomes. SOURCE: bit.ly/X6pLMq

(Reporting by Elaine Lies)

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9 & Soon 11 New HCV Drugs in Phase 3

Provided by NATAP

Shortly before AASLD Abbott announced the start of their phase 3 studies which will examine the coformulation of ABT450/r (protease) + ABT267 (NS5A) + their non-nuc + rbv. In addition Gilead is starting a phase 3 study looking at their coformulation of GS7977+ GS5885 (NS5A) + rbv.

• Abbott Phase 3 Study - (10/17/12)
• AASLD: A 12-week Interferon-free Treatment Regimen With ABT-450/r, ABT 267, ABT-333, and Ribavirin Achieves SVR12 Rates (Observed Data) of 99% in Treatment-naïve Patients and 93% in Prior Null Responders With HCV Genotype 1 Infection - (11/13/12)
• AASLD: Once Daily Sofosbuvir (GS-7977) Regimens in HCV Genotype 1-3: The ELECTRON Trial - (11/14/12)
• BMS052 HCV-NS5A Monotherapy in Phase 3 Now
• GS-7977 HCV Nucleotide in Phase 3 Now
• Peginterferon Lambda: new interferon in phase 3 now
• BI1335 HCV Protease in Phase 3 Now
• TMC-435 HCV Protease in Phase 3 -
• BMS032 HCV Protease in Phase 3 Now -

"Rapid progress has been made with the HCV Research Program and we now have a comprehensive Phase III development program" John Martin CEO Gilead........"In May and June of this year, discussions were held with the U.S. FDA and 3 European regulatory agencies, and agreement has been achieved on a comprehensive Phase III development plan for GS-7977 and on a Phase III plan for GS-7977 in combination with the NS5A inhibitor, GS-5885.......we anticipate being able to file for regulatory approvals for GS-7977 by the middle of next year.......If successful, the initial indication will for 12 to 16 weeks of treatment with GS-7977 and Ribavirin in genotype 2/3 infected patients, and for 12 weeks of treatment with GS-7977, peg-interferon and Ribavirin in genotype 1, 4, 5 and 6 infected patients......we plan to advance the fixed dose combination of GS-7977 and 5885, currently in Phase I clinical testing, into Phase III in the fourth quarter of this year.....GS-7977 and GS-5885 were successfully co-formulated into a single pill, fixed dose combination......The fixed dose combination regulatory filings could, in that case, follow the initial GS-7977 filings a year later by mid-2014"....."The Food and Drug Administration is allowing a nonstandard-of-care controlled phase III study for 7977/5885" from Barron's online [we know the FDA is allowing this for all IFN-free therapy development studies from all companies]

Gilead Begins Single Pill Hepatitis C Study for 2014 Approval - (07/27/12)

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Trying to halt hepatitis C's molecular hijacking

Public release date: 27-Dec-2012

Contact: Dan Meyers
dan.meyers@ucdenver.edu
303-724-5377
University of Colorado Denver

AURORA, Colo. (Dec. 27, 2012) – Researchers at the University of Colorado School of Medicine have figured out intimate details of how the hepatitis C virus takes over an invaded cell, a breakthrough that could point to way for new treatments for the virus.

Hep C hijacks the machinery by which a cell makes proteins and uses it instead to create proteins for the virus. Over the last two decades, researchers have figured out that Hep C uses an RNA molecule to do this. Now they're trying to fill in the details.

One key detail is reported in a paper published online Dec. 23 in Nature Structural and Molecular Biology. It's written by Jeffrey Kieft, PhD, an associate professor at the CU medical school's Department of Biochemistry and Molecular Genetics and an Early Career Scientist of the Howard Hughes Medical Institute, and his former graduate student, Megan Filbin, PhD, a graduate of the Program in Molecular Biology.

Working with researchers from the lab of Tamir Gonen at the Janelia Farm Research Campus of the Howard Hughes Medical Institute, Kieft used ultra high-power electron microscopes to take images of individual RNA molecules from Hep C as they interacted with the cell's machinery. The researchers combined those images with a variety of other experiments and these clues led them to identify a new way that the virus' RNAs takes over the cell's machinery.

Specifically, the researchers focused on how a ribosome, the cell's protein-making factory, can be manipulated by the Hep C RNA to affect a part of the protein process called translocation. And they saw something else – that even very small changes in the interactions important for that hijacking process can be blocked.

"This points the way to developing drugs to fight hepatitis C in ways that current therapies do not," Kieft says.

###

Faculty at the University of Colorado School of Medicine work to advance science and improve care. These faculty members include physicians, educators and scientists at University of Colorado Hospital, Children's Hospital Colorado, Denver Health, National Jewish Health, and the Denver Veterans Affairs Medical Center. The school is located on the Anschutz Medical Campus, one of four campuses in the University of Colorado system. To learn more about the medical school's care, education, research and community engagement, please visit its web site. For additional news and information, please visit the University of Colorado Denver newsroom.

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Sustained Virological Response Lowers Mortality Risk in Hep C

All-cause, liver-related mortality down with SVR for patients with chronic hepatitis C, hepatic fibrosis

Last Updated: December 28, 2012.

FRIDAY, Dec. 28 (HealthDay News) -- Sustained virological response (SVR) is associated with lower all-cause mortality in patients with chronic hepatitis C virus (HCV) and advanced hepatic fibrosis, according to a study published in the Dec. 26 issue of the Journal of the American Medical Association.

To examine the correlation between SVR and mortality, Adriaan J. van der Meer, M.D., from the Erasmus MC University Medical Center in Rotterdam, Netherlands, and colleagues analyzed long-term follow-up data from 530 patients with chronic HCV infection started on an interferon-based treatment regimen (from 1990 to 2003) at five large tertiary care hospitals in Europe and Canada.

The researchers found that, over a median follow-up of 8.4 years, 192 patients (36 percent) achieved SVR. One hundred patients without SVR and 13 patients with SVR died. The 10-year cumulative all-cause mortality rate was significantly lower with SVR (8.9 versus 26.0 percent). SVR correlated with a significantly reduced risk of all-cause mortality (hazard ratio [HR], 0.26) and of liver-related mortality or transplantation (HR, 0.06), which was observed in three patients with SVR and 103 without SVR. For liver-related mortality or transplantation, the 10-year cumulative incidence rate was significantly lower with SVR (1.9 versus 27.4 percent).

"In conclusion, our study indicates that SVR was associated with improved overall survival in patients with chronic HCV infection and advanced hepatic fibrosis," the authors write.

Several authors disclosed financial ties to the pharmaceutical industry.

Abstract
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HCV Studies Give Hope for Interferon-Free Therapy

By Michael Smith, North American Correspondent, MedPage Today

Published: January 02, 2013

Reviewed by F. Perry Wilson, MD, MSCE; Instructor of Medicine, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner

Investigational agents that act directly against the hepatitis C virus (HCV) may allow previously untreated patients to avoid interferon therapy, long a standard of care, researchers said.

Two phase IIa studies, reported in the Jan. 3 issue of the New England Journal of Medicine, found promising results with different agents, either without interferon or with reduced use of the drug.

Both studies also found less impressive outcomes among patients previously treated unsuccessfully with the standard combination of ribavirin and pegylated interferon.

The development of so-called direct-acting agents, delivered orally, has held the promise of eliminating the need for treatment with interferon, which is difficult to tolerate and must be administered by subcutaneous injection.

"The development of an interferon-free, all-oral treatment regimen would represent an important advance," argued researchers led by Edward Gane, MD, of Auckland City Hospital in Auckland, New Zealand.

In an open-label study, Gane and his colleagues gave the nucleotide polymerase inhibitor sofosbuvir combined with ribavirin for up to 12 weeks to eight groups of HCV patients:

• 40 previously untreated patients with HCV genotype 2 or 3 infection were randomly assigned, in groups of 10, to get the combination, with three groups also getting peginterferon alfa-2a for 4, 8, or 12 weeks, respectively
• two additional groups, each of 10 previously untreated patients also with genotypes 2 or 3, got sofosbuvir monotherapy for 12 weeks or sofosbuvir, peginterferon alfa-2a, and ribavirin for 8 weeks
• two groups of patients with HCV genotype 1 received sofosbuvir and ribavirin for 12 weeks -- 10 patients with no response to prior treatment and 25 with no previous treatment.

Gane and colleagues have previously reported some of the promising results in the genotype 2 and 3 patients but early outcomes among those with genotype 1, regarded as more difficult to cure, were disturbing.

Specifically, as they reported in the journal, 9 of 10 who had previously failed interferon-based treatment relapsed quickly after the end of treatment with sofosbuvir and ribavirin.

On the other hand, all of the patients in the first four groups achieved a sustained virologic response at 24 weeks (SVR₂₄) – defined as no detectable HCV RNA 24 weeks after the end of therapy – which is usually regarded as a cure.

And all 10 patients who got sofosbuvir, peginterferon alfa-2a, and ribavirin for 8 weeks achieved SVR₂₄, as did 6 of 10 who got sofosbuvir monotherapy.

Importantly, 21 of 25 previously untreated patients with HCV genotype 1 – or 84% -- achieved SVR₂₄ after 12 weeks of treatment therapy with sofosbuvir and ribavirin.

Taken together, Gane and colleagues concluded, the data suggest that 12 weeks of the all-oral combination of sofosbuvir and ribavirin is likely to be effective regardless of genotype, as long as patients have not previously been treated with interferon and ribavirin.

The results "potentially pave the way" to an all-oral, short-duration regimen that does not use interferon, Gane and colleagues concluded, arguing that the combination of sofosbuvir and ribavirin deserves further study.

Investigators on the second study, led by Fred Poordad, MD, of the University of Texas Health Science Center in San Antonio, came to similar conclusions about a different regimen.

In a 12-week open-label study, a combination of two direct-acting agents, along with ribavirin, yielded good results in treatment-naïve patients with genotype 1 virus, but did less well among those who had previously been treated with interferon and ribavirin.

The investigational drugs were ABT-450, an inhibitor of the viral NS3 protease, boosted with low-dose ritonavir, and ABT-333, a non-nucleoside NS5B polymerase inhibitor.

All patients got ABT-333 and ribavirin, as well as one of two doses of ABT-450/r -- 250 or 150 mg daily, with 100 mg of ritonavir in either case – for 12 weeks and were followed for 48 weeks after the end of therapy.

The primary endpoint was the proportion of patients who reached a so-called extended rapid virologic response, defined as undetectable viral RNA from week 4 through week 12.

By that token, Poordad and colleagues reported:

• 17 of 19 treatment-naïve patients who got the high dose of ABT-450/r (89%) reached the primary endpoint
• Among treatment-naïve patients, 11 of 14 (79%) who got the lower dose achieved an extended rapid virologic response
• In those two groups, all patients who completed treatment had a sustained virologic response at 12 weeks after treatment -- 18 of the 19 in the first group and 13 of 14 in the second.
• In the third group of therapy-experienced patients, treatment with the low dose of ABT-450/r along with ABT-33 and ribavirin led to an initial decline of viral load in all patients.
• 10 of 17 patients (59%) had an extended rapid virologic response, six had virologic breakthrough during treatment, three had a relapse after treatment, and eight (47%) had a sustained virologic response 12 weeks after the end of therapy.

Poordad and colleagues argued that the findings suggest the regimen will do well among previously untreated patients with genotype 1 infection, but added that larger studies are needed to confirm the results.

The study by Gane and colleagues was supported by Pharmasset and Gilead Sciences.

Gane reported financial links with Roche, Pharmasset, Gilead, Novartis, Janssen-Cilag, Tibotec, and Boehringer Ingelheim.

The study by Poordad and colleagues was supported by Abbott.

Poordad reported financial links with Abbott, Vertex, Merck, Anadys Pharmaceuticals, Achillion, BMS, Gilead, Novartis, Genentech, Theravance, Onyx, Salix, Pharmasset, Idenix, Tibotec/Janssen, GlaxoSmithKline, Boehringer Ingelheim, and Pfizer.

Primary source: New England Journal of Medicine
Source reference:
Gane EJ, et al "Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C" N Engl J Med 2013; 368: 34-44.

Additional source: New England Journal of Medicine
Source reference:
Poordad F, et al "Exploratory study of oral combination antiviral therapy for hepatitis C" N Engl J Med 2013; 368 :45-53.

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Interferon-Free Regimens for Chronic HCV Infection: Getting Closer

Published in Journal Watch Gastroenterology January 2, 2013

Several regimens with polymerase or protease inhibitors plus ribavirin achieved high sustained virologic response rates without interferon.

A major drawback of current therapies for chronic hepatitis C virus (HCV) infection is poor tolerability of adverse effects, mainly caused by peginterferon. Previous studies of interferon-free HCV regimens were early phase trials (JW Gastroenterol Jan 18 2012 and JW Gastroenterol Sep 30 2011); now results are available from two industry-sponsored, open-label, phase 2a trials in patients with HCV genotypes 1, 2, and 3.

In the first study, investigators randomized 40 treatment-naive patients with genotype 2 or 3 in a 1:1:1:1 ratio to four groups, all of which received sofosbuvir — an oral nucleotide HCV polymerase inhibitor — (400 mg daily) and ribavirin (1000–1200 mg daily) for 12 weeks. Three groups also received peginterferon (180 µg weekly) for 4, 8, and 12 weeks, respectively. Subsequently added study groups included the following: 10 patients with genotypes 2 or 3 who received sofosbuvir monotherapy for 12 weeks; 10 patients with genotypes 2 or 3 who received sofosbuvir, ribavirin, and peginterferon for 8 weeks; and 25 genotype 1, treatment-naive patients and 10 genotype 1 null responders to previous peginterferon/ribavirin treatment who received sofosbuvir and ribavirin for 12 weeks. The primary end point of sustained virologic response at 24 weeks post-therapy was achieved by all 40 patients who received sofosbuvir plus ribavirin with or without peginterferon, 6 of the 10 patients who received sofosbuvir monotherapy, 21 of the 25 genotype 1, treatment-naive patients who received sofosbuvir and ribavirin, and only 1 of the 10 genotype 1, treatment-experienced patients who received sofosbuvir and ribavirin. No mutations were observed in the other 9 patients. Adverse effects were mild.

In the second study, investigators sequentially enrolled patients with HCV genotype 1. All patients received ABT-333 — a nonnucleoside NS5B polymerase inhibitor — (400 mg twice daily), ribavirin (1000–1200 mg daily), and one of two daily doses of ABT-450/r (ABT-450, an NS3 protease inhibitor, combined with 100 mg of ritonavir daily) for 12 weeks. Groups of 19 and 14 treatment-naive patients received 250 mg and 150 mg of ABT-450/r, respectively, and a third group of 17 treatment-experienced patients received 150 mg of ABT-450/r. The primary end point was extended rapid virologic response (undetectable HCV RNA from weeks 4 through 12), which was achieved in 89%, 79%, and 59% of the three groups, respectively. Sustained virologic response was achieved in 95%, 93%, and 47%, respectively. Resistant variants in NS3 and NS5B were observed in 8 of the 9 patients who had virologic failure in group three. Side effects were mild.

Comment: These findings suggest that we are close to realizing the ideal HCV treatment — an interferon-free, simple regimen of short duration with minimal adverse effects and low resistance rates. Patients with genotypes 2 or 3 and treatment-naive patients with genotype 1 will be the first to benefit. Ribavirin seems to be here to stay, at least for now. Unfortunately, difficult-to-treat patients such as genotype 1, treatment-experienced patients will likely continue to require interferon as part of their regimens.

— Atif Zaman, MD, MPH

Citation(s):

Gane EJ et al. Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J Med 2013 Jan 3; 368:34.

Poordad F. Exploratory study of oral combination antiviral therapy for hepatitis. N Engl J Med 2013 Jan 3; 368:45.

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Estrogen Modulating Therapy for HCV Infection in Postmenopausal Women

Published in Journal Watch Gastroenterology December 14, 2012

Adding raloxifene hydrochloride to standard therapy significantly increased response, but only among women with IL28B genotype TT.

Studies of hepatitis C virus (HCV) infection treatment have shown that response to interferon-based therapy is lower in postmenopausal women than in premenopausal women. This could be caused by declining estrogen levels in menopause. To test that hypothesis, investigators evaluated whether the addition of raloxifene hydrochloride (RLX) — a selective estrogen receptor modulator — improved the efficacy of standard therapy with peginterferon and ribavirin in this group.

Investigators randomized 123 postmenopausal Japanese women aged 50 to 73 years with genotype 1b HCV infection to receive 60 mg of RLX daily plus standard therapy with 180 µg of peginterferon weekly and 600 to 1000 µg of ribavirin daily or standard therapy only for 48 weeks. The primary end point was sustained virologic response (SVR), defined as undetectable serum HCV RNA after 24 weeks of treatment. The mean length of time since menopause was 10.2 years (range, 2–22 years). Baseline characteristics of the two groups did not differ.

SVR was significantly higher in the RLX group than the standard therapy group overall (61.3% vs. 34.4%; P=0.005) and in a subgroup with IL28B genotype TT (72.5% vs. 39.2%; P=0.001), but not in patients with IL28B genotype CC or TC. Only one patient discontinued RLX after developing a rash during week 2 of treatment.

Comment: These results suggest that the addition of RLX as adjuvant therapy to peginterferon and ribavirin in postmenopausal women with genotype 1b HCV infection significantly improves SVR. The improvement was limited to women with IL28B genotype TT. The mechanism by which RLX improves SVR is unclear but could involve the improvement of estradiol levels and reduction of oxidative stress or inhibition of inflammatory cytokine production. Regardless, further study of the use of RLX and other, similar agents as adjuvant therapy to HCV regimens is warranted.

— Atif Zaman, MD, MPH

Citation(s):

Furusyo N et al. Raloxifene hydrochloride is an adjuvant antiviral treatment of postmenopausal women with chronic hepatitis C: A randomized trial. J Hepatol 2012 Dec; 57:1186. (http://dx.doi.org/10.1016/j.jhep.2012.08.003)

Medline abstract (Free)

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Telaprevir Linked to Potentially Fatal Skin Reaction

Robert Lowes

Dec 19, 2012

The label for the hepatitis C drug telaprevir ( Incivek, Vertex Pharmaceuticals) now features a boxed warning on the risk for serious and sometimes fatal skin reactions, the US Food and Drug Administration (FDA) announced today.

Patients must stop taking telaprevir along with its partner drugs peginterferon and ribavirin if they experience a serious skin reaction, particularly a rash with systemic symptoms, or a progressive severe rash, according to the label change that the FDA approved on December 14.

In combination with peginterferon and ribavirin, telaprevir is indicated for the treatment of chronic genotype 1 hepatitis C virus infection in adults with compensated liver disease, including cirrhosis, who are treatment-naive or who already have received interferon-based medications.

The boxed warning states that patients receiving telaprevir in combination treatment have experienced skins reactions that include Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms, and toxic epidermal necrolysis. The fatal cases occurred in patients who continued to take the drug after developing a progressive rash and systemic symptoms.

Vertex Pharmaceuticals stated in a press release that in phase 3 clinical trials, less than 1% of patients receiving telaprevir combination treatment experienced a serious skin reaction. All were hospitalized, and all recovered.

More information about today's announcement is available on the FDA's Web site.

To report adverse events related to telaprevir, contact MedWatch, the FDA's safety information and adverse event reporting program, by telephone at 1-800-FDA-1088; online at https://www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htm; or with postage-paid FDA form 3500, available at http://www.fda.gov/MedWatch/getforms.htm; or by mail to MedWatch, 5600 Fishers Lane, Rockville, Maryland 20852-9787.

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Hepatitis C Treated With Oral Nucleotide Inhibitor

Joe Barber Jr, PhD

Jan 03, 2013

Twelve weeks of sofosbuvir and ribavirin treatment may be sufficient for sustained antiviral activity in untreated and pretreated patients with hepatitis C virus (HCV) genotype 1, 2, or 3, according to the findings of an open-label, phase 2 trial.

Edward J. Gane, MD, from the New Zealand Liver Transplant Unit, Auckland City Hospital and the Gastroenterology Department, Christchurch Hospital, both in New Zealand, and colleagues published their findings in the January 3 issue of the New England Journal of Medicine.

"The results from this study confirm that sofosbuvir, an oral nucleotide analogue polymerase inhibitor, combined with ribavirin, is a very effective treatment in patients infected with both genotype 1 and non–genotype 1 HCV, without cirrhosis," Dr. Gane told Medscape Medical News by email. "This regimen is very well tolerated: all oral, short-duration (only 12 weeks), and without any significant drug interactions or specific toxicity."

In the study, the authors treated patients as follows: 4 groups of 10 previously untreated patients with HCV genotype 2 or 3 infection each received sofosbuvir plus ribavirin for 12 weeks, with 3 groups also receiving peginterferon alpha-2a for 4, 8 or 12 weeks (groups 1 - 4); a group of 10 previously untreated patients with HCV genotype 2 or 3 infection received sofosbuvir alone for 12 weeks (group 5); a group of 10 previously untreated patients with HCV genotype 2 or 3 infection received sofosbuvir plus peginterferon alpha-2a and ribavirin for 8 weeks (group 6); a group of 10 patients with HCV genotype 1 infection who did not respond to previous treatment and a group of 25 previously untreated patients with HCV genotype 1 infection both received sofosbuvir plus ribavirin for 12 weeks (groups 7 and 8).

Among the patients in groups 1 to 4, all 40 patients had undetectable HCV serum levels up to 48 weeks after treatment. In addition, all patients in group 6 had a sustained virologic response (SVR) at 12 weeks after the end of treatment and all 9 patients for whom data were available had an SVR at 24 weeks.

The authors excluded patients with positive tests for hepatitis B surface antigen, hepatitis B core immunoglobulin M antibodies, or HIV antibodies. In total, 6 (60%) of 10 patients in group 5 and 21 (84%) of 25 patients in group 8 had an SVR at 24 weeks after treatment, whereas only 1 (10%) of 10 patients in group 7 had an SVR.

Among the patients without SVRs at 24 weeks, deep sequencing revealed the presence of the S282T mutation in only 1 patient; no other mutations at conserved sites were identified.

No patient was forced to discontinue treatment because of adverse events. The most common adverse events included headache, fatigue, insomnia, and nausea.

Regarding hematologic events, sofosbuvir monotherapy was associated with modest (0.54 g/dL) decreases in hemoglobin levels. Patients who received peginterferon were more likely to experience hematologic abnormalities, and the degree of changes in hemoglobin levels was more severe among these patients.

Similarly, neutropenia and thrombocytopenia were only observed in patients who received interferon. No grade 3 or 4 elevations of bilirubin levels were observed, and only a single patient (in group 8) relapsed within 2 weeks after the end of treatment and displayed increased alanine aminotransferase levels.

Remaining Questions

In an email to Medscape Medical News, Dr. Gane identified several questions that remain to be addressed: "Will the excellent efficacy and tolerability in this phase 2 study be confirmed in the larger phase 3 studies, which contain patients with cirrhosis?" Dr Gane asked. "Which other antiviral agent should be combined with sofosbuvir to improve efficacy in treatment-experienced patients? Can such short-duration, all-oral therapy be administered in the community, thereby increasing treatment access?"

Donald M. Jensen, MD, director of the Center for Liver Diseases, the University of Chicago, Illinois, who was not involved in the study, noted that the treatment groups were small and fairly homogenous, thus requiring validation in larger, more representative cohorts. "We also need to know why prior interferon treatment failure predisposes to relapse but not on-treatment response and why this is more common in genotype 1a subjects (though few genotype 1b subjects were included in the present investigation)."

Dr. Jensen told Medscape Medical News by email: "Can this be overcome with longer treatment durations or combination with other antivirals? We also need to understand how ribavirin prevents relapse…a question that has plagued us for decades."

Ira M. Jacobsen, MD, chief of the Division of Gastroenterology and Hepatology from Cornell University in New York, also noted that the mechanism of ribavirin's role remains unclear. "Whether 12 weeks of sofosbuvir plus ribavirin will really provide 100% SVR rates in genotypes 2 and 3 remains to be answered by larger trials that are ongoing," Dr. Jacobson told Medscape Medical News by email. "Also unanswered is what will be required to achieve satisfactory SVR rates, preferably similar to naive patients, in nonresponders to previous peginterferon and ribavirin therapy. Optimization in genotype 1–naive patients is also a question."

The study was supported by Pharmasset and Gilead Sciences. Several coauthors are employed by Pharmasset, Chimerix, and/or Gilead. Dr. Gane's institution received funding from Pharmasset and Gilead, and he has received payment for board membership, lectures, and/or travel from Roche, Pharmasset, Gilead, Novartis, Janssen-Cilag, Tibotec, and Boehringer Ingelheim. One coauthor's institution received funding from Pharmasset and Gilead, and she received payment for advisory board membership and/or travel from Janssen-Cilag, Roche, and Gilead. Dr. Jensen has received grant funding from Abbott/AbbVie, Boehringer Ingelheim, BMS, Genentech/Roche, Gilead/Pharmasset, and Merck, and he serves as an advisor/consultant with Abbott/AbbVie, Astex, Biotica, Boehringer Ingelheim, BMS, Genentech/Roche, Gilead/Pharmasset, Merck, and Vertex. Dr. Jacobson has received grant funding from Abbott, Achillion, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Novartis, Pfizer, Roche/Genentech, Schering/Merck, Tibotec/Janssen, and Vertex, and he serves as a speaker and/or advisor/consultant with Abbott, Achillion, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Novartis, Roche/Genentech, Schering/Merck, Tibotec/Janssen, Enanta, Idenix, Kadmon, Presidio, and Vertex.

N Engl J Med. 2013;368:34-44. Abstract

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Few hepatitis C patients receive complete treatment

Published on December 31, 2012 at 5:15 PM

By Lauretta Ihonor, medwireNews reporter

Less than 10% of patients with hepatitis C (HCV) receive the treatment they need to achieve a sustained virologic response (SVR), results from a systematic review show.

The review, which included 25 studies conducted in the US, Canada, and Australia, revealed that 19% of HCV-infected and 16% of HCV/HIV-coinfected patients are considered eligible for treatment.

And only 3% and 6% of HCV-infected and HCV/HIV-coinfected patients, respectively, continue with treatment until a SVR is achieved, say the authors in General Hospital Psychiatry.

The authors highlight that recently developed direct-acting antivirals are very effective at curing HCV when used in combination with pegylated interferon and ribavirin.

But the side effects associated with these drugs are greater than those of traditional antiviral therapy and this may deter patients from seeking treatment, add Carol North (The University of Texas Southwestern Medical Center, Dallas, USA) and team.

They therefore recommend that researchers and physicians address such treatment concerns "so that the benefits of emerging scientific achievements can be realized in the care of HCV in the community."

The review identified four barriers to receipt of care: medical ineligibility, patient-related barriers, provider-related barriers, and medical care system barriers.

Medical and psychosocial problems, such as substance misuse, psychiatric illness, and medical comorbidity, were found to hinder receipt of treatment in up to one third of HCV patients.

"Management of these problems in patients with psychiatric and/or substance-use problems has the potential to improve their treatment readiness and likelihood of successfully completing HCV treatment," say North et al.

Only studies performed in real-life, non-clinical trial settings were included in the systematic review to ensure that a true impression of "real-world" HCV treatment practices was obtained.

In all studies, patient flow through the HCV care pathway was recorded in terms of the percentage of HCV patients presenting for care who were deemed eligible for treatment, started treatment, completed treatment, and achieved a SVR.

North and colleagues conclude that the findings from the current review illustrate that new interventions are required to encourage HCV patients to "engage in treatment and achieve success in completing treatment."

Licensed from medwireNews with permission from Springer Healthcare Ltd. ©Springer Healthcare Ltd. All rights reserved. Neither of these parties endorse or recommend any commercial products, services, or equipment.

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