November 5, 2013

Sofosbuvir and ledipasvir stop virus replicating in 97% of patients in study reported in the Lancet journal

Alok Jha
theguardian.com, Tuesday 5 November 2013 13.44 EST

Hepatitis-C-Virus-008

Hepatitis C virus seen through an electron microscope. Photograph: UIG/Getty

Scientists have reported the successful eradication of hepatitis C in patients using two new antiviral drugs, raising hopes of a possible cure.

In the trial, the virus was eliminated from almost all the patients involved, including those who had not previously responded to existing drugs.

Hepatitis C is caused by a virus that spreads via bodily fluids and ends up damaging the liver. Unlike other forms of hepatitis, there is no vaccine and the only treatments include powerful combinations of drugs known as interferons and protease inhibitors. But the treatments have many side-effects, are complex to administer and, in the common type of hepatitis C known as genotype 1, the drugs do not work. If an infection cannot be cured, it can lead to liver cancer.

The new treatment, reported in medical journal the Lancet on Tuesday , consists of the experimental drugs sofosbuvir and ledipasvir. In the trial, 100 patients with genotype 1 hepatitis C were split into groups and given the drugs in a single pill for either eight or 12 weeks. Forty of the participants had previously failed to respond to drugs and half of this group had cirrhotic livers.

After 12 weeks, 97% of the participants had what scientists called a "sustained virological response", which meant that the hepatitis C virus was not replicating inside them. The patients suffered varying amounts of side-effects, including nausea, anaemia, respiratory tract infections and headaches, but none were considered to be serious.

Professor Eric Lawitz of the University of Texas, who led the study, said the results offered hope to people currently without treatment options: "The results of this trial suggest that the fixed-dose combination of sofosbuvir and ledipasvir could offer patients a short, all-oral treatment that might be highly effective and safe in patients who tend not to respond well to existing therapies, including individuals with cirrhosis, or black race, resistant strains of the virus."

Charles Gore, chief executive of the Hepatitis C Trust, said the new drug combination was great news. "We were concerned that those with advanced hepatitis C would remain difficult to treat, but these new direct antivirals are incredibly potent. The results suggest that even the most difficult to treat people will in fact be extremely treatable. It now looks as if almost no one will be excluded from benefiting from treatment, which is an incredible achievement.

"There are a number of exciting new drugs on the horizon. However, of the 215,000 people estimated to be living with the virus in the UK, less than half have been diagnosed. In England, only 3% of hepatitis C patients receive treatment each year. There is no point having these treatments if we can't use them, so we must ensure that we diagnose more people who can avail of them."

In 2010, a total of 7,834 new hepatitis C cases were reported in England, though the true figure is probably much higher. Rates of infection are greater in people of African descent than in other ethnic groups.

The virus is present in the blood and, to a much lesser extent, the saliva and semen or vaginal fluid of an infected person.

It is most likely to be transmitted through blood-to-blood contact. Intravenous drug users who share their needles are known to be especially vulnerable.

Professor Margaret Hellard of the Burnet Institute in Melbourne, Australia, who co-authored a linked comment on the research published in the Lancet, said: "As a proof of concept study, [this] demonstrates very high response rates, regardless of the presence of cirrhosis, prior treatment failure, or [resistant] genotype."

She cautioned, however, that the study was small, based at a single location and only had a short follow-up, which she said raised concerns about how representative the sample was and whether early clinical trial results could be generalised to real-world settings. "Whilst giving cause for optimism, the full implications of these results need to be tempered for now," she wrote.

Source

Also See: Sofosbuvir and ledipasvir fixed-dose combination with and without ribavirin in treatment-naive and previously treated patients with genotype 1 hepatitis C virus infection (LONESTAR): an open-label, randomised, phase 2 trial

11/05/13

By: ELIZABETH MECHCATIE, Family Practice News Digital Network

WASHINGTON – Treatment with the hepatitis C antiviral drug sofosbuvir plus ribavirin resulted in high response rates in a study of 182 treatment-naive patients co-infected with hepatitis C and HIV, who were being treated with a variety of antiretroviral regimens, Dr. Mark Sulkowski said at the annual meeting of the American Association for the Study of Liver Disease.

The sustained virologic response rates 12 weeks after treatment (SVR12), the primary endpoint, were similar to the SVR12 rates in studies of patients infected with hepatitis C virus (HCV) only, who were treated with an interferon-free regimen of sofosbuvir plus ribavirin for 12-24 weeks, said Dr. Sulkowski, medical director of the viral hepatitis center in the divisions of infectious diseases and gastroenterology/hepatology at Johns Hopkins University, Baltimore.

"More importantly, sofosbuvir-ribavirin was effectively coadministered with multiple antiretroviral regimens, and there was no evidence of an adverse effect on the HIV disease," he said. The antiretroviral therapy (ART) regimens included HIV-1 protease inhibitors, reverse transcriptase (non-nucleoside and nucleoside) inhibitors, and integrase inhibitors.

The population of patients coinfected with HIV and HCV "has a high medical need" for an effective, interferon-free oral regimen that can be safely administered with ART, and drug interaction studies have shown that sofosbuvir can be administered with many antiretroviral drugs, Dr. Sulkowski said.

Sofosbuvir is an orally administered HCV-specific nucleotide polymerase inhibitor, with potent antiviral activity against HCV genotypes 1 through 6; it is taken once a day at a dose of 400 mg. A Food and Drug Administration advisory panel recently recommended that it be approved for treatment-naive adults with genotype 1 and 4 infections (in combination with pegylated interferon and ribavirin) and for treatment of adults with genotype 2 and 3 infections (in combination with ribavirin); approval is expected in December.

The study evaluated treatment with sofosbuvir,with 1,000-1,200 mg ribavirin a day, in HIV-positive patients coinfected with HCV: 114 patients with HCV genotype 1 infections treated for 24 weeks and 68 patients with genotypes 2 or 3 treated for 12 weeks. The study had broad inclusion criteria, and included patients with cirrhosis, with no platelet level cut off, treated with a wide range of antiretroviral therapy regimens (85%-98% were on ART). Their mean age was 48-49 years, 81%-82% were male, and most were white.

The SVR12 rates were 76% among patients with HCV genotype 1, 88% among genotype 2 patients, and 67% among genotype 3 patients, which were similar to the rates observed for patients infected with hepatitis C only, Dr. Sulkowski said. The two patients with HCV viral breakthrough were documented to be noncompliant with treatment, and there was no evidence of sofosbuvir resistance in the cases of virologic failures. In other studies of patients with HCV infection only, who were treated with sofosbuvir plus ribavirin without interferon, SVR12 rates have ranged from 68% among genotype 1 patients treated for 24 weeks to 97% among genotype 2 patients and 56% among genotype 3 patients treated for 12 weeks, Dr. Sulkowski said.

Overall, treatment was well tolerated, with a low rate of discontinuations from adverse events. Fatigue, headache, and insomnia were the most common adverse effects, and were similar in frequency and severity to that observed in studies of patients with HCV infection only. The rate of serious adverse events was 7%. There was one death, a suicide, in a patient treated for 12 weeks, who had a history of mental illness. There was no evidence of sofosbuvir resistance in the virologic failures.

About 21% of the patients treated for 24 weeks developed anemia, a known adverse effect of ribavirin, and 25% of those patients required a reduction in ribavirin dose.

As for HIV safety, there was no evidence of HIV breakthrough, Dr. Sulkowski said. Two patients with transient HIV viral breakthrough were not adhering to ART. There was no drop in the CD4 T-cell percentage values; there was a drop in absolute CD4 T cells, which he said is consistent with a known ribavirin-mediated decrease in lymphocytes.

Dr. Sulkowski disclosed that the study was funded by Gilead Sciences, the manufacturer of sofosbuvir.

emechcatie@frontlinemedcom.com

Source

Also See: Gilead Announces Phase 3 Results for an All-Oral, Sofosbuvir-Based Regimen for the Treatment of Hepatitis C in Patients Co-Infected With HIV

Dr. Xavier Forns

Spain

Disclosure: X. Forns: Gilead, Janssen, MSD; R.J. Fontana: Gilead, GSK, Tibotec, Vertex; D. Moonka; Gilead; J.G. McHutchison, W.T. Symonds, J. Denning, P. Chang, and V. Kivett are employees of and own stock in Gilead; L. McNair: Gilead; M. Shiffman: Gilead, Abbott, Achillion, Bayer, Beckman-Colter, BMS, Boehringer Ingelheim, Gen-Probe, GlobeImmune, GSK, Idenix, Intercept, Janssen, Merck, Mochida, Novartis, Roche/Genentech, Salix, Vertex; M. Charlton: Gilead, AbbVie, Biotest, BMS, Genentech, Novartis, Vertex.

ABSTRACT FINAL ID: 1084
CURRENT CATEGORY: Viral Hepatitis C
CURRENT DESCRIPTORS: S06. HCV Therapy and Trials: New Agents (phase 2 -3)
SESSION TYPE: Poster
SESSION TITLE: HCV Therapeutics: New Agents
ABSTRACT FINAL ID: Initial Evaluation of the Sofosbuvir Compassionate Use Program for Patients with Severe Recurrent HCV Following Liver Transplantation
PRESENTER: Kellie Chu

AUTHOR/INSTITUTIONS: X. Forns, Liver Unit, Hospital Clinic, Barcelona, SPAIN|R.J. Fontana, University of Michigan, Ann Arbor, Michigan, UNITED STATES|D. Moonka, Henry Ford Health System, Detroit, Michigan, UNITED STATES|J.G. McHutchison, W.T. Symonds, J.M. Denning
SPONSORSHIP: Gilead Sciences, Inc.

ABSTRACT BODY:
Background: Patients with severe, recurrent hepatitis C (HCV) after liver transplantation (LT), who have either failed to respond to or are unable to tolerate antiviral therapies, have no effective treatment options. The polymerase inhibitor sofosbuvir (SOF) has been shown to be effective in combination with ribavirin (RBV), with or without peginterferon (PEG), in patients with HCV infection of all genotypes (GT).

Methods: SOF was provided in an IRB-approved compassionate use protocol (eIND or expanded access protocol) to treat patients with severe recurrent HCV infection following LT, including patients with fibrosing cholestatic hepatitis (FCH). The regimen included SOF 400 mg/day for up to 48 weeks, with appropriate doses of RBV and/or PEG at the physician’s discretion. Treating physicians provide periodic updates of clinical status, lab tests, and serious adverse events (SAEs).

Results: As of APR2013, 115 patients have been approved for compassionate use and 63 have started treatment. Of these, 45 have received ≥4 weeks of a SOF-containing regimen (36 SOF + RBV, 9 SOF+PEG/RBV). Baseline features of these 45 patients were: 33 GT1, 5 GT3, 7 other GTs; 29% female; mean age 55 years; mean baseline bilirubin 6.0 mg/dL (range 0.4-25.8) albumin 3.1 g/dL (2.0-4.8), INR 1.26 (0.96-2.07) and platelets 103 x 103/uL (27-316 x 103). Nineteen of the 45 (42%) had histologically-documented FCH. At week 4 of therapy, 28 of 36 patients (78%) who had reported HCV RNA levels were less than the limit of detection or quantification and 2 patients who received only 12 weeks of treatment have achieved SVR 12. The clinical condition of 32 of the 45 patients (71%) rapidly improved according to investigators’ narratives (eg, normalization of ALT and/or bilirubin levels, resolution of ascites which had been refractory to diuretics or requiring paracentesis, resolution/improvement of encephalopathy, increased muscle mass) within 1-4 weeks after the start of treatment. Another six patients (13%) were reported to have stabilized from their prior decompensation. Seven patients (16%) died after initiating therapy, with all deaths attributed to progression of liver disease or associated complications. Forty-seven SAEs have been reported in 23 patients. None were attributed to study drug.

PostTX_VR

Conclusions: In patients with severe post-LT HCV recurrence, a compassionate use regimen containing SOF and RBV (with or without PEG) has been well-tolerated and has demonstrated strong antiviral activity. The SOF-based regimen has resulted in notable clinical improvement and/or disease stabilization in many patients. Results will be updated at the time of presentation.

Source

JAMA Internal Medicine Releases for November 05, 2013

EMBARGOED FOR RELEASE: 11:30 A.M. (CT), TUESDAY, NOVEMBER 5, 2013

Media Advisory: To contact author Jeffrey McCombs, Ph.D., call Sadena Thevarajah at 213-821-7978 or email thevaraj@healthpolicy.usc.edu.

CHICAGO – In a study of Veterans Affairs patients with hepatitis C (HCV), only a minority were willing to start treatment and fewer still achieved the undetectable viral loads that appear to be associated with decreased rates of illness and death, according to a study published by JAMA Internal Medicine, a JAMA Network publication.

HCV is estimated to affect as many as 170 million people worldwide and an estimated 3.2 million people in the United States. Patients with HCV are at risk of developing liver-related complications such as cirrhosis, liver failure and the cancer hepatocellular carcinoma (HCC), the authors write in the study background. However, sometimes patients with HCV go untreated because of adverse effects from available treatments.

Jeffrey McCombs, Ph.D., of the University of Southern California School of Pharmacy, Los Angeles, and colleagues sought to describe the progression of HCV in clinical practice by examining the time to liver-related clinical events and death in a group of 28,769 patients from the Veterans Affairs (VA) HCV clinical registry.

Of the patients, only 24.3 percent were willing to start treatment, and 16.4 percent of treated patients achieved an undetectable viral load. The study reports that death rates were 6.8 per 1,000 person-years for patients who achieved viral suppression vs. 21.8 per 1,000 person-years in patients who did not meet that goal. Patients who achieved undetectable viral loads also reduced their risk of liver-related events by 27 percent, according to the results.

“While antiviral therapy can lead to viral eradication and reduced event risk, its effectiveness under real-world clinical conditions is limited by adverse effects and other factors. In this study, only 1 in 4 patients with HCV and a detectable viral load were willing to initiate treatment. Once treated, only a fraction of patients achieved the minimum treatment response of a single undetectable viral load test,” the authors write.

(JAMA Intern Med. Published online November 5, 2013. doi:10.1001/jamainternmed.2013.12505. Available pre-embargo to the media at http://media.jamanetwork.com.)

Editor’s Note: Financial support for this research was provided by Bristol-Myers Squibb. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Editor’s Note: Stuck Between a Rock and a Hard Place

In a related editor’s note, Mitchell Katz, M.D., a JAMA Internal Medicine deputy editor, writes: “The authors demonstrate that patients who do achieve viral suppression, which almost always required treatment, fared significantly better. The critical issue going forward is whether the new drugs that have been released (e.g. hepatitis C protease inhibitors) or are likely to be approved soon (e.g. hepatitis C nucleotide polymerase inhibitor) can achieve sustained viral suppression in a high percentage of patients without serious adverse effects. And can these treatments be made available without breaking the bank of safety net health systems across the country that care for large numbers of patients with hepatitis C? I certainly hope so.”

#  #  #

For more information, contact JAMA Network Media Relations at 312-464-JAMA (5262) or email mediarelations@jamanetwork.org.

Source

This article can be found in the following collections: Gastroenterology (Hepatobiliary disease); Infectious Diseases (Anti-infective therapy)

Copyright © 2013 Elsevier Ltd All rights reserved.

Original Text

Prof Eric Lawitz MD a, Prof Fred F Poordad MD a, Phillip S Pan MD b, Robert H Hyland DPhil b, Xiao Ding PhD b, Hongmei Mo PhD b, William T Symonds PharmD b, John G McHutchison MD b, Fernando E Membreno MD a

Summary

Background

Interferon-based treatment is not suitable for many patients with hepatitis C virus (HCV) infection because of contraindications such as psychiatric illness, and a high burden of adverse events. We assessed the efficacy and safety of an interferon-free regimen—a fixed-dose combination of the nucleotide polymerase inhibitor sofosbuvir (400 mg) and the HCV NS5A inhibitor ledipasvir (90 mg), with and without ribavirin--in patients with genotype-1 hepatitis C infection who were treatment-naive or previously treated with a protease-inhibitor regimen.

Methods

For this open-label study, we enrolled 100 adult patients (>18 years) with HCV infection at a centre in the USA between Nov 2, 2012, and Dec 21, 2012. In cohort A, we used a computer-generated sequence to randomly assign (1:1:1; stratified by HCV genotype [1a vs 1b]) 60 non-cirrhotic, treatment-naive patients to receive sofosbuvir plus ledipasvir for 8 weeks (group 1), sofosbuvir plus ledipasvir and ribavirin for 8 weeks (group 2), or sofosbuvir plus ledipasvir for 12 weeks (group 3). In cohort B, we randomly allocated (1:1; stratified by genotype and presence or absence of cirrhosis) 40 patients who previously had virological failure after receiving a protease inhibitor regimen to receive sofosbuvir plus ledipasvir for 12 weeks (group 4) or sofosbuvir plus ledipasvir and ribavirin for 12 weeks (group 5). 22 (55%) of 40 patients in cohort B had compensated cirrhosis. The primary endpoint was sustained virological response 12 weeks after treatment (SVR12), analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01329978.

Results

In cohort A, SVR12 was achieved by 19 (95%) of 20 patients (95% CI 75—100) in group 1, by 21 (100%) of 21 patients (84--100) in group 2, and by 18 (95%) of 19 patients (74--100) in group 3. In cohort B, SVR12 was achieved by 18 (95%) of 19 patients (74—100) in group 4 and by all 21 (100%) of 21 patients (84--100) in group 5. Two patients had viral relapse; one patient was lost to follow-up after achieving sustained virological response 8 weeks after treatment. The most common adverse events were nausea, anaemia, upper respiratory tract infection, and headache. One patient in group five had a serious adverse event of anaemia, thought to be related to ribavirin treatment.

Interpretation

These findings suggest that the fixed-dose combination of sofosbuvir-ledipasvir alone or with ribavirin has the potential to cure most patients with genotype-1 HCV, irrespective of treatment history or the presence of compensated cirrhosis. Further clinical trials are needed to establish the best treatment duration and to further assess the contribution of ribavirin.

Funding Gilead Sciences.

Source

Also See: Once Daily Sofosbuvir/Ledipasvir Fixed Dose Combination with or without Ribavirin Resulted in ≥95% Sustained Virologic Response In Patients with HCV Genotype 1, Including Patients with Cirrhosis: the LONESTAR trial

HCV Yields to Combo, While HIV Stays Suppressed

Meeting Coverage

Published: Nov 5, 2013 | Updated: Nov 5, 2013

By Ed Susman , Contributing Writer, MedPage Today

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Action Points

  • Note that 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

WASHINGTON -- Combination therapy to treat patients co-infected with HIV and hepatitis C virus (HCV) can achieve a high percentage of virologic end-of-treatment response to the hepatitis infection without affecting suppression of the HIV, researchers reported here.

At 48 weeks, 83% of patients had a sustained response to hepatitis infection with the combination of telaprevir (Incivek)-pegylated interferon and ribavirin, and maintained suppression of HIV to less than 50 copies/mL, said Laurent Cotte, MD, co-ordinator of the study for the French National Agency for Research (ANRS), and a physician at Centre Hospitalier Universitaire de Lyon.

More than half the patients with HIV in France are co-infected with hepatitis C virus making this population of patients difficult to treat, Cotte told MedPage Today at the annual meeting of the American Association for the Study of Liver Diseases.

"Despite a high discontinuation rate related to toxicity (20.3%), a very high virological response rate was achieved at Week 48 with the combination therapy in patients who were already experienced with pegylated-ribavirin HIV co-infected patients," Cotte said at his poster presentation.

Cotte and his colleagues began dosing a cohort of 69 patients; 8 discontinued treatment before 16 weeks because of adverse events and 10 discontinued between 16 weeks and the end of the study.

At Week 16, 88% of the patients in the intention-to-treat analysis had achieved a virologic response to the telaprevir-based combination.

By the end of the study, 83% of the intention-to-treat population had maintained that response, he said. Cotte noted that the patients are being followed to determine if they can sustain the response and, in effect, cure the patient of the hepatitis C infection.

All the patients were treated with highly active anti-retroviral therapy and had controlled their HIV to undetectable levels using the 50-copies/mL assay. "We had one patient who recorded one reading of 59 copies/mL but that was just a blip," Cotte said. "Otherwise there was no problem in these patients staying HIV-suppressed,"

Cotte acknowledged the sweeping advances being made in treatment for HCV, noting that pegylated interferon and ribavirin may soon be obsolete drugs. "When we started this study, this was the standard of care treatment," he said. "But even with these newer regimens, this study will be the set point that shows what we will need for this population. It shows that these patients can be treated effectively."

"We had a very good virological response -- 83% of the patients achieving that by week 48. We also had significant adverse events, notably anemia, the need for erythropoietin, the need for blood transfusion and reduction in ribavirin dosing. Over the course of 48 weeks, about 70% of patients experienced those Grade 3 or Grade 4 events."

The median age of the patients in the study was 50. About 85% of the patients were non-black; 80% were men; about 55% were injecting drug users.

"About 30% of the 1 million patients infected with HIV in the United States are co-infected with hepatitis C virus," said Raymond Chung, MD, director of hepatology and associate professor of medicine at Massachusetts General Hospital/Harvard Medical School. "These are difficult patients to treat. We first have to make sure that the antiretroviral drugs used in treatment of HIV do not have drug-drug-interactions with the antiviral medication."

In the study 49% of the patients were on the antiretroviral atazanavir (Reyataz) in combination with ritonavir; 19% were on efavirenz (Sustiva) and 17% were on raltegravir (Isentress), Cotte reported.

Chung told MedPage Today that in Cotte's study the patients were taking those medications. "Historically, we were able to reach a sustained virologic response in about 50% of patients with infection with HCV alone. But if patients were co-infected with HIV, the success rate was about 35%."

"What these new combinations have shown is that we can level the playing field for HIV co-infected patients," Chung said. "We now expect to achieve about a 75% sustained virologic response with drugs such as telaprevir. This study fits into that formula."

He said that new all-oral regimens are expected to further change treatment to benefit these patients.

Cotte had no disclosures.

Chung disclosed commercial relationships with Idenix, Enanta, Gilead, Merck and Mass Biologic.

Primary source: American Association for the Study of Liver Diseases
Source reference: Cotte L, et al "High end-of-treatment (EOT) response rate with telaprevir-pegIFN-RBV in treatment-experienced HIV co-infected patients with HCV genotype 1: ANRS HC26 telapreVIH study" AASLD 2013.

Source

Interferon-Free HCV Tx Benefits Mentally Ill

Meeting Coverage

Published: Nov 5, 2013

Coverage of Hepatitis C Virus is supported in part by an independent educational grant from AbbVie Pharmaceuticals.

This report is part of a 12-month Clinical Context series.

By Michael Smith, North American Correspondent, MedPage Today

Reviewed by F. Perry Wilson, MD, MSCE; Instructor of Medicine, Perelman School of Medicine at the University of Pennsylvania

abbvie-logo-175

WASHINGTON -- Hepatitis C (HCV) patients with mental comorbidities, such as depression or bipolar disorder, can be successfully treated with an interferon-free drug regimen, a phase II trial showed.

The combination of ribavirin and the investigational agent sofosbuvir was equally effective in patients with and without significant mental health disorders, according to Amy Nelson, RN, of the National Institute of Allergy and Infectious Diseases in Bethesda, Md.

Importantly, both groups of patients were equally likely to adhere to the medication and to appear for study visits, she told MedPage Today at the annual meeting of the American Association for the Study of Liver Diseases.

The finding is important because it opens the door to effective therapy for people with mental illnesses, for whom standard therapy has been contraindicated, Nelson said.

The standard treatment for HCV for several years has been based on a combination of ribavirin and pegylated interferon, but the latter drug has psychiatric side effects that make it unsuitable for many patients who already have mental illness, she explained.

"A lot of people haven't been treated" because of that issue, Nelson said, adding that the finding gives "a lot of hope as we move away from interferon ... that [the] whole group that hasn't been treated can clear the virus."

Sofosbuvir is one of several so-called direct-acting agents in the development pipeline -- drugs that target parts of the HCV genome rather than boosting the immune system, as interferon does -- and is one of the most advanced in the regulatory process.

An FDA advisory panel has recommended it be approved for use in combination with ribavirin for patients with genotypes 2 and 3 of HCV. In those with genotypes 1 and 4, the panel recommended using it with interferon and ribavirin. The agency is not obliged to follow the advice of its committees, but usually does.

In the SPARE study, Nelson and colleagues treated 60 HCV patients, all with genotype 1 disease, for 24 weeks with daily sofosbuvir (at 400 mg) and either low-dose or weight-based ribavirin.

Of those, 23 had an active mental health disorder, defined as requiring pharmacotherapy for major depression, bipolar disorder, schizophrenia, anxiety, or depression with anxiety.

Nelson and colleagues found that patients with mental health disorders attended 97% of required study visits, compared with 98% by the remaining participants.

Also, among those that finished the 24 weeks of treatment, 83% of both groups missed fewer than four doses of sofosbuvir.

And 61% of those with a mental health disorder had undetectable virus 12 weeks after the end of therapy, compared with 68% of those in the rest of the cohort. The difference was not significant.

The prevalence of mental health issues among HCV patients is "quite high," commented Michael Fried, MD, of the University of North Carolina Chapel Hill, who was not part of the study.

"So there is a very high rate of patients who, when they first come to see you, have poorly controlled mental health issues and they are not candidates for antiviral therapy that is peginterferon based," he told MedPage Today.

But the study by Nelson and colleagues shows that those patients are "quite a treatable population" if doctors have interferon-free regimens available.

He noted that, if sofosbuvir is approved, the indication for genotype 1 patients will include interferon and ribavirin.

But other combinations of drugs under clinical investigation -- including the pairing of sofosbuvir and ledipasvir, which blocks the action of the viral nonstructural protein 5A -- can be used without interferon to treat genotype 1 patients.

The study was supported by the National Institute of Allergy and Infectious Diseases.

Nelson reported no conflicts of interest. Two co-authors were employees of Gilead.

Fried reported financial links with Gilead, Vertex, Bristol-Myers Squibb, Merck, Genentech, Janssen, and Abbott.

Primary source: American Association for the Study of Liver Diseases
Source reference: Nelson A, et al "Impact of pre-existing mental health disorders on adherence and sustained virologic response with an interferon-free trial of sofosbuvir and ribavirin for chronic Hepatitis C" AASLD 2013; Abstract 319.

Source

Hepatitis C, a Silent Killer, Meets Its Match

05HEPC1-articleLarge

Edward Linsmier for The New York Times
Arthur Rubens, 63, of Naples, Fla., was cured of hepatitis C after taking part in a clinical trial for a new drug.

By ANDREW POLLACK

Published: November 4, 2013

Determined to get rid of the hepatitis C infection that was slowly destroying his liver, Arthur Rubens tried one experimental treatment after another. None worked, and most brought side effects, like fever, insomnia, depression, anemia and a rash that “felt like your skin was on fire.”

But this year, Dr. Rubens, a professor of management at Florida Gulf Coast University, entered a clinical trial testing a new pill against hepatitis C. Taking it was “a piece of cake.” And after three months of treatment, the virus was cleared from his body at last.

“I had a birthday in September,” Dr. Rubens, 63, said. “I told my wife I don’t want anything. It would take away from the magnitude of this gift.”

Medicine may be on the brink of an enormous public health achievement: turning the tide against hepatitis C, a silent plague that kills more Americans annually than AIDS and is the leading cause of liver transplants. If the effort succeeds, it will be an unusual conquest of a viral epidemic without using a vaccine.

“There is no doubt we are on the verge of wiping out hepatitis C,” said Dr. Mitchell L. Shiffman, the director of the Bon Secours Liver Institute of Virginia and a consultant to many drug companies.

Over the next three years, starting within the next few weeks, new drugs are expected to come to market that will cure most patients with the virus, in some cases with a once-a-day pill taken for as little as eight weeks, and with only minimal side effects.

That would be a vast improvement over current therapies, which cure about 70 percent of newly treated patients but require six to 12 months of injections that can bring horrible side effects.

The latest data on the experimental drugs is being presented at The Liver Meeting in Washington, which ends Tuesday.

But the new drugs are expected to cost from $60,000 to more than $100,000 for a course of treatment. Access could be a problem, particularly for the uninsured and in developing countries. Even if discounts or generic drugs are offered to poor countries, there are no international agencies or charities that buy hepatitis C medications, as there are for H.I.V. and malaria drugs.

And some critics worry that the bill will be run up when huge numbers of people who would have done fine without them turn to the drugs. That is because many people infected with hepatitis C never suffer serious liver problems.

“The vast majority of patients who are infected with this virus never have any trouble,” said Dr. Ronald Koretz, emeritus professor of clinical medicine at the University of California, Los Angeles.

It is impossible to tell in advance whether an infected individual will go on to suffer serious consequences. For patients who can afford them, the temptation to take the new drugs before trouble arises will be powerful.

A Heavy Toll

An estimated three to four million Americans are infected with hepatitis C, and about 150 million worldwide — three to five times the number who have H.I.V. Most people who are infected do not know it, because it can take decades for the virus to damage the liver sufficiently to cause symptoms.

In the United States, the number of new infections has fallen to about 17,000 a year, from more than 200,000 per year in the 1980s, according to the Centers for Disease Control and Prevention. There has been a recent rise in cases among young people who inject pain medicines or heroin.

About 16,600 Americans had hepatitis C listed as a cause of death on death certificates in 2010, though that might vastly understate the mortality linked to the disease, according to the C.D.C.  Although there are fewer new infections, the number of deaths is expected to keep rising as the infections incurred years ago increasingly take their toll.

Hepatitis C is spread mainly by the sharing of needles, though it can also be acquired during sex. The virus was transmitted through blood transfusions before testing of donated blood began in 1992. Dr. Rubens, the recently cured patient, believes he was infected when he worked as a paramedic long ago.

The main treatment has been interferon alfa, given in weekly injections for 24 or 48 weeks, combined with daily tablets of ribavirin. Neither drug was developed specifically to treat hepatitis C. The combination cures about half the patients, but the side effects — flulike symptoms, anemia and depression — can be brutal.

The new drugs, by contrast, are specifically designed to inhibit the enzymes the hepatitis C virus uses to replicate, the same approach used to control H.I.V. As with H.I.V., two or more hepatitis C drugs will be used together to prevent the virus from developing resistance.

One big difference is that H.I.V. forms a latent reservoir in the body, so H.I.V. drugs must be taken for life to prevent the virus from springing back. Hepatitis C does not form such a reservoir, so it can be eliminated permanently.

If no virus is detectable in the blood 12 weeks after treatment ends — a measure known as a sustained virologic response — there is almost no chance the virus will come back and the patient is considered essentially cured. The damaged liver can then heal itself somewhat, doctors say.

Yet even if the virus is cleared, people who were once infected may still have an increased risk of liver cancer, especially if cirrhosis, a scarring of the liver, has set in.

The new drugs now moving to market can achieve sustained viral responses in 80 to 100 percent of patients with treatment durations of 12 to 24 weeks, possibly shorter.

For Tom Espinosa, a building inspector in Oakland, Calif., the new treatments cannot arrive fast enough. Mr. Espinosa, 59, has advanced cirrhosis and some spots on his liver that might be cancer. He is so fatigued that he spends all weekend in bed. He has tried all available treatments and nothing worked, making him envious of other patients who were cured.

“I became resentful for a little while, but I got over it,” he said. With time possibly running out, he plans to try the first new drug to hit the market.

To be sure, many of the new drug combinations have not been extensively tested yet. Side effects might still show up. And the drugs are not expected to work as well for patients with severe cirrhosis or those co-infected with H.I.V.

“I just don’t think we know the answer until we get more widespread clinical experience,” said Charles M. Rice, a hepatitis C expert at Rockefeller University. “We may be in for some surprises still.”

New Direction

Researchers and patients have been disappointed before, when the first two direct-acting antiviral pills, telaprevir and boceprevir, reached the market in 2011. The drugs, which inhibited the virus’s protease enzyme, still required interferon and ribavirin, but they raised the cure rate to about 70 percent.

There was a huge rush to treatment. But doctors now say that side effects were worse than expected, in part because the sickest patients had been excluded from the clinical trials of the drugs.

“A lot of that didn’t come to light until after the drugs were approved,” said Dr. Brian R. Edlin, an associate professor of public health and medicine at Weill Cornell Medical College. “Then it turns out they were just horrible.”

Among the new drugs, the one garnering the most excitement is sofosbuvir, from Gilead Sciences, which is expected to be approved by the Food and Drug Administration by Dec. 8. It inhibits the virus’s polymerase enzyme, which builds new genomes out of RNA so the virus can replicate.

Sofosbuvir is an evil decoy of sorts. It looks like a building block of RNA. But once it is mistakenly incorporated into the RNA chain, the chain cannot grow and the virus cannot reproduce.

The effectiveness of the new drugs can vary depending on which strain of hepatitis C, known as genotypes, the patient has.

People infected with hepatitis C genotypes 2 and 3 — which account for 20 to 25 percent of cases in the United States — will take sofosbuvir with ribavirin but without interferon, making this the first all-oral treatment for hepatitis C. Treatment for genotype 2 will be 12 weeks, but for genotype 3 it will probably be 24 weeks.

Genotype 1, which accounts for more than 70 percent of patients in the United States, will still require interferon and ribavirin along with sofosbuvir, but only for 12 weeks. In a clinical trial, about 90 percent of previously untreated patients taking this combination achieved a sustained virologic response. The combination is expected to be somewhat less effective in those for whom previous treatments did not work.

Gilead hopes to have an all-oral treatment for genotype 1 approved by the end of 2014. It would be a once-a-day pill containing both sofosbuvir and another experimental Gilead drug, ledipasvir. This combination, used along with ribavirin, is what cured Dr. Rubens.

Other companies, including AbbVie, Merck and Bristol-Myers Squibb, are in a heated race to also bring all-oral combinations to market in the next two years or so.

Liver specialists will be able to put together an all-oral regimen for genotype 1 very soon, however, by prescribing both sofosbuvir and simeprevir, a Johnson & Johnson protease inhibitor that is expected to win approval soon. One study has shown this combination to be extremely effective, though insurers may balk at paying for two expensive drugs.

Awaiting Better Options

These new drugs are likely to alter the calculus about who gets treated and when.

Many doctors are now “warehousing” their hepatitis C patients — urging them to forgo treatment until the new drugs are approved.

“There’s no way I’m going to put them on an interferon regimen when we’re a year away from having interferon-free regimens,” said Dr. Scott Friedman, the chief of liver diseases at the Icahn School of Medicine at Mount Sinai. “It’s rare you have to pull the trigger and get them on treatment in that period of time.”

Gilead estimates that only 58,000 Americans with hepatitis C are now undergoing treatment, a small fraction even of those who know they are infected. Wanting to avoid interferon’s side effects, some patients without symptoms try to monitor their liver and start treatment only if it shows signs of deterioration.

But with the new more tolerable treatments, some experts say, it makes sense to treat early-stage disease to prevent cirrhosis and the accompanying risk of liver cancer.

And it is likely that more pre-symptomatic patients will be found through wider screening. Both the United States Preventive Services Task Force and the C.D.C. have recently begun to recommend that all baby boomers — people born from 1946 to 1964 — be tested for infection with hepatitis C, since they represent about three quarters of all cases.

“It will be test and treat,” said Dr. Eugene Schiff, the director of the liver diseases center at the University of Miami, who is a consultant to drug companies.

Pharmaceutical companies, of course, have a financial interest in seeing that more people get screened and treated, and they have been providing support for hepatitis C awareness campaigns and sponsoring studies on the benefits of screening and treatment.

The all-oral regimens also may make it more feasible to treat the people who are most likely to spread the virus — intravenous drug users, the homeless and prison inmates, many of whom also have mental health problems.

“I can’t treat an unstable patient safely with interferon,” said Dr. Diana Sylvestre, who runs a clinic in Oakland, Calif. that treats illicit drug users and former users. “But I can sure as hell give them a few pills.”

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