EASL 2013: New Wave of Hepatitis C Treatments On the Way

May 13, 2013, by Liz Highleyman

Studies presented at the EASL International Liver Congress, held April 24–28 in Amsterdam, confirm the expectation that a new generation of safer and more effective therapies for hepatitis C will be available within the next few years. These include both better add-ons to interferon and the first interferon-free combinations of direct-acting antivirals (DAAs).

An estimated three million people in the U.S. have hepatitis C, but most do not know they’re infected. The CDC this week reiterated its recommendation that all “baby boomers” born between 1945 and 1965 get a test for HCV antibodies and, if positive, a viral load test to determine if they’re still infected. “You may not remember what you did in the 60s and 70s, but your liver does,” said CDC director Thomas Frieden.

Testing is crucial because chronic HCV infection can lead to cirrhosis, liver cancer, and death. Now is a good time because better hepatitis C treatments that can stop liver disease progression are on the way.

Interferon Add-Ons

The current standard of care adds one of the first approved DAAs—boceprevir (Victrelis) or telaprevir (Incivek)—to pegylated interferon and ribavirin. Triple therapy works better than interferon/ribavirin alone, but comes with added side effects.

Some people with advanced liver disease cannot wait for better options, but data presented at the EASL meeting show that these regimens carry a high risk of serious complications for patients with cirrhosis and liver transplant recipients.

For people who can wait a bit longer, several studies showed promising outcomes when adding more effective and better-tolerated second-generation DAAs to interferon-based therapy:

• Daclatasvir (HCV NS5A inhibitor)
• Faldaprevir (HCV protease inhibitor)
• MK-5172 (HCV protease inhibitor)
• Simeprevir (HCV protease inhibitor)
• Sofosbuvir (nucleotide analog HCV polymerase inhibitor)
• Vaniprevir (HCV protease inhibitor)

These new drugs produced cure rates in the 80% to 90% range even for difficult-to-treat patients. They can often shorten treatment to three to six months (down from six months to a year) and generally do not cause more side effects than interferon and ribavirin alone. (For more detailed coverage of this study and others presented at EASL 2013, visit HIVandHepatitis.com.)

“DAAs are ready for prime time,” EASL Secretary General Mark Thursz said at an April 24 press conference kicking off the congress.

The first new DAAs are expected to become available by late 2013 or early 2014, initially for use with interferon. Simeprevir and sofosbuvir were submitted for FDA approval in March and April, with a review timeline of six months.

“Interferon is not dead yet,” Thursz emphasized. “Twelve weeks of an interferon triple regimen is tolerable for a large number of patients…and it may be better than waiting another year for a suitable all-oral regimen.”

Interferon-Free Combos

People with early or stable liver disease may be able to wait for all-oral regimens that eliminate interferon, which can cause flu-like symptoms and depression. Some combos also dispense with ribavirin, which can cause anemia.

All-oral regimens have gotten the lion’s share of attention at recent conferences (including the Conference on Retroviruses and Opportunistic Infections in March). While several interferon-free regimens continue to look good, enthusiasm at EASL was somewhat tempered by setbacks among difficult-to-treat patients.

A quad regimen containing DAAs developed by AbbVie (formerly Abbott)—HCV protease inhibitor ABT450 boosted with ritonavir + NS5A inhibitor ABT-267 + non-nucleoside polymerase inhibitor ABT-333 + ribavirin—cured 96% of treatment-naive patients with HCV genotype 1 and 93% of prior interferon non-responders treated for 12 weeks in the Aviator study.

This combo is especially promising because it worked for more than 90% of previously untreated or treatment-experienced patients, people with harder-to-treat HCV subtype 1a or easier-to-treat 1b, and those with mild or moderate liver fibrosis, though people with cirrhosis—who have the poorest response—were excluded.

AbbVie announced this week that the FDA has given this regimen a “breakthrough therapy” designation, intended to speed development and review of promising drugs for serious or life-threatening conditions.

Gilead’s sofosbuvir/ribavirin 12-week dual regimen previously demonstrated 100% sustained virological response (SVR) for previously untreated people with HCV genotypes 2 or 3 and no liver cirrhosis. SVR at 12 or 24 weeks after completing treatment (known as SVR12 and SVR24) is considered a cure.

But researchers at EASL reported lower cure rates in the larger treatment-naive FISSION and treatment-experienced FUSION trials, in which 20%–30% of participants had cirrhosis. SVR12 rates were 67% using a 12-week regimen in FISSION, and 50% with a 12-week regimen or 73% with a 16-week regimen in FUSION.

The major surprise was that people with genotype 2 and genotype 3—usually considered together as a single “easier-to-treat” category compared with genotype 1—responded differently.

Among those with genotype 2, SVR rates were excellent: 97% in FISSION and 86%–94% in FUSION. People with genotype 3 did not fare as well, with cure rates of 56% and 30%–62%—no better than pegylated interferon/ribavirin. The difference was even more pronounced among people with cirrhosis, with cure rates falling as low as 34% in FISSION and 19% in FUSION.

Presenter Edward Gane from Auckland City Hospital suggested that genotypes 2 and 3 should no longer be lumped together, as genotype 3 is “behaving as a harder-to-treat virus.”

Turning to genotype 1, further results from the ELECTRON trial confirmed that sofosbuvir/ribavirin alone is not adequate for such patients. Adding the NS5A inhibitor ledipasvir, however, raised the cure rate to 100% for both treatment-naives and prior null responders.

Gilead announced last week that a coformulation of sofosbuvir/ledipasvir without ribavirin for eight or 12 weeks led to 95%–100% sustained response at four or eight weeks post-treatment—promising, but too soon to declare a cure.

Study findings reported in 2012 showed that sofosbuvir plus Bristol-Myers Squibb’s NS5A inhibitor daclatasvir cured 100% of treatment-naive genotype 1 patients. Gilead decided not to pursue this combination in Phase 3 trials in favor of its own ledipasvir, but some smaller studies have gone forward.

Mark Sulkowski from Johns Hopkins University reported that sofosbuvir plus daclatasvir cured all previously treated genotype 1 patients who did not respond to interferon-based triple therapy using boceprevir or telaprevir, providing some of the first data on “rescue therapy” after failure of the current standard-of-care.

Finally, a three-drug DAA combo containing daclatasvir, the HCV protease inhibitor asunaprevir, and the non-nucleoside polymerase inhibitor BMS-791325, taken for 12 or 24 weeks, cured 88%–94% of previously untreated genotype 1 patients without cirrhosis, with treatment “failures” mostly due to missing data rather than viral breakthrough or relapse.

Taken together, these findings add to the evidence that effective and well-tolerated DAA therapy will be able to cure most people with chronic hepatitis C within the coming years.

“If a patient has early stage [liver disease], lots of physicians are recommending their patients wait” for all-oral regimens, Thursz summarized. For those with more advanced disease, “treating with the standard of care is probably the way to go”—unless they have very advanced disease, in which case they have “significant risk of dying from septic complications” if treated with current triple therapy.

Liz Highleyman (liz (at) hivandhepatitis.com) is a freelance medical writer and editor-in-chief of HIVandHepatitis.com.

Selected Sources

AbbVie. AbbVie’s Investigational HCV Regimen Receives Breakthrough Therapy Designation from the U.S. Food and Drug Administration. Press release. May 6, 2013.

Bristol-Myers Squibb. High Rates of SVR Demonstrated in Phase II Study with Investigational Triple DAA Regimen of Daclatasvir, Asunaprevir and BMS-791325 in Treatment-Naive Patients with Genotype 1 Chronic Hepatitis C Infection. Press release. April 23, 2013.

Everson, G. and others. Interim analysis of an interferon (IFN)- and ribavirin (RBV)-free regimen of daclatasvir (DCV), asunaprevir (ASV), and BMS-791325 in treatment-naive, hepatitis C virus genotype 1-infected patients. 48th Annual Meeting of the European Association for the Study of the Liver (EASL 2013). Amsterdam. April 24–28, 2013. Abstract 1423.

Ferenci, P. and others. Faldaprevir plus pegylated interferon alfa-2A and ribavirin in chronic HCV genotype-1 treatment-naive patients: final results from STARTVerso1, a randomised double blind placebo-controlled phase III trial. Abstract 1416.

Fontaine, H. and others. SVR12 rates and safety of triple therapy including telaprevir or boceprevir in 221 cirrhotic non responders treated in the French Early Access Program (ANRS CO20-CUPIC). EASL 2013. Abstract 60.

Gane, E. and others. Phase 3 randomized controlled trial of all-oral treatment with sofosbuvir+ribavirin for 12 weeks compared to 24 weeks of peg+ribavirin in treatment-naive GT2/3 HCV-infected patients (FISSION). EASL 2013. Abstract 5.

Gane, E. and others. All-oral sofosbuvir-based 12-week regimens for the treatment of chronic HCV infection: the ELECTRON study. EASL 2013. Abstract 14.

Gilead Sciences. Gilead reports interim data from Phase 2 LONESTAR study. Press release. May 2, 2013.

Jacobson, I. and others. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. New England Journal of Medicine. April 23, 2013 (Epub ahead of print).

Jacobson, I. and others. Treatment with sofosbuvir+ribavirin for 12 weeks achieves SVR12 of 78% in GT2/3 interferon-ineligible, -intolerant, or -unwilling patients: results of the phase 3 POSITRON trial. EASL 2013. Abstract 61.

Jacobson, I. and others. Simeprevir (TMC435) with peginterferon/ribavirin for treatment of chronic HCV genotype 1 infection in treatment-naïve patients: results from QUEST-1 a phase III trial. EASL 2013. Abstract 1425.

Kowdley, K. and others. Safety and efficacy of interferon-free regimens of ABT-450/r, ABT-267 and ABT-33 +/- ribavirin in patients with chronic genotype 1 infection: results from the Aviator study. EASL 2013. Abstract 3.

Lawitz, E. and others. Sofosbuvir for previously untreated chronic hepatitis C infection. New England Journal of Medicine. April 23, 2013 (Epub ahead of print).

Lawitz, E. and others. Sofosbuvir + peginterferon + ribavirin for 12 weeks achieves 90% SVR12 in genotype 1, 4, 5, or 6 HCV infected patients: the NEUTRINO study. EASL 2013. Abstract 1411.

Manns, M. and others. High sustained viral response at 12- and 24-week follow-up of MK-5172 with pegylated interferon alfa-2b and ribavirin (PR) in HCV genotype 1 treatment-naive non-cirrhotic patient. EASL 2013. Abstract 66.

Manns, M. and others. Simeprevir (TMC435) with peginterferon/ribavirin for treatment of chronic HCV genotype 1 infection in treatment-naive patients: results from QUEST-2 a phase III trial. EASL 2013. Abstract 1413.

Nelson, D. and others. All oral therapy with sofosbuvir+ribavirin for 12 or 16 weeks in treatment experienced GT2/3 HCV-infected patients: results of the phase 3 FUSION trial. EASL 2013. Abstract 6.

Rutter, K. and others. Safety of triple therapy with telaprevir or boceprevir in hepatitis C patients with advanced liver disease – predictive factors for sepsis. EASL 2013. Abstract 65.

Sulkowski, M. and others. Sustained virologic response with daclatasvir plus sofosbuvir +/-± ribavirin (RBV) in chronic HCV genotype (GT) 1-infected patients who previously failed telaprevir (TVR) or boceprevir (BOC). EASL 2013. Abstract 1417.

Verna, E. and others. A multicenter study of protease inhibitor-triple therapy in HCV-infected liver transplant recipients: report from the CRUSH-C group EASL 2013. Abstract 23.

Source

Hepatitis C in the USA and Europe: two problems, one solution

The Lancet, Volume 381, Issue 9879, Page 1688, 18 May 2013

doi:10.1016/S0140-6736(13)61059-4 Cite or Link Using DOI

Original Text

The Lancet

Nearly half of Americans who test positive for hepatitis C virus (HCV) infection with an initial antibody test do not receive the follow-up RNA testing that is necessary to show whether they have recovered or have an ongoing infection. If left untreated, ongoing infection could lead to serious liver disease and death. This worrying finding comes from a new study by the US Centers for Disease Control and Prevention (CDC). In about 20% of cases, the body clears HCV infection unaided, but most people need treatment—typically pegylated interferon and ribavirin. About 3 million Americans are thought to have hepatitis C, but because the disorder can be asymptomatic for years, only a quarter know that they are infected. In Europe, an estimated 9 million people are infected, but only half have been diagnosed.

The CDC study examined surveillance data from eight US sites for 2005—11. Another key finding was that most new cases—67% of those with ongoing infection—were in people who were born between 1945 and 1965 (so-called baby-boomers). The CDC now recommends that all baby boomers receive routine HCV testing.

In Europe, the heterogeneity of the population means that although baby boomers might still have a role, other groups are more at risk. Many of these groups—including injecting drug users, dialysis patients, sex workers, prison inmates, and migrants from endemic regions such as sub-Saharan Africa and the Middle East—are already on the edges of society, and strong advocacy is needed to ensure that they receive appropriate diagnosis and care. France and Germany have HCV screening programmes that target many of these groups, but a Europe-wide approach will be needed if control is to be achieved.

Promising new drugs are in the pipeline, with some, such as sofosbuvir, achieving sustained virological responses in 90% of patients when combined with interferon alfa and ribavirin in phase 2 trials. Substantial decreases in HCV infection are within reach, but only if governments worldwide act together to implement policies and provide funding for effective screening, follow-up, and treatment.

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Combination Therapy With Telaprevir for Chronic Hepatitis C Virus Genotype 1 Infection in Patients With HIV: A Randomized Trial

Original Research | 17 May 2013

Mark S. Sulkowski, MD; Kenneth E. Sherman, MD, PhD; Douglas T. Dieterich, MD; Mohammad Bsharat, PhD; Lisa Mahnke, MD, PhD; Jürgen K. Rockstroh, MD; Shahin Gharakhanian, MD, DPH; Scott McCallister, MD; Joshua Henshaw, PhD; Pierre-Marie Girard, MD, PhD; Bambang Adiwijaya, PhD; Varun Garg, PhD; Raymond A. Rubin, MD; Nathalie Adda, MD; and Vincent Soriano, MD, PhD

[+-] Article and Author Information

Ann Intern Med. Published online 17 May 2013 doi:10.7326/0003-4819-159-2-201307160-00654

Background: Telaprevir (TVR) plus peginterferon-α2a (PEG-IFN-α2a) and ribavirin substantially increases treatment efficacy for genotype 1 chronic hepatitis C virus (HCV) infection versus PEG-IFN-α2a–ribavirin alone. Its safety and efficacy in patients with HCV and HIV-1 are unknown.

Objective: To assess the safety and efficacy of TVR plus PEG-IFN-α2a–ribavirin in patients with genotype 1 HCV and HIV-1 and evaluate pharmacokinetics of TVR and antiretrovirals during coadministration.

Design: Phase 2a, randomized, double-blind, placebo-controlled study. (ClinicalTrials.gov: NCT00983853)

Setting: 16 international multicenter sites.

Patients: 62 patients with HCV genotype 1 and HIV-1 who were HCV treatment–naive and taking 0 or 1 of 2 antiretroviral regimens were randomly assigned to TVR plus PEG-IFN-α2a–ribavirin or placebo plus PEG-IFN-α2a–ribavirin for 12 weeks, plus 36 weeks of PEG-IFN-α2a–ribavirin.

Measurements: HCV RNA concentrations.

Results: Pruritus, headache, nausea, rash, and dizziness were higher with TVR plus PEG-IFN-α2a–ribavirin during the first 12 weeks. Serious adverse events occurred in 5% (2 in 38) of those receiving TVR plus PEG-IFN-α2a–ribavirin and 0% (0 in 22) of those receiving placebo plus PEG-IFN-α2a–ribavirin; the same number in both groups discontinued treatment due to adverse events. Sustained virologic response occurred in 74% (28 in 38) of patients receiving TVR plus PEG-IFN-α2a–ribavirin and 45% (10 in 22) of patients receiving placebo plus PEG-IFN-α2a–ribavirin. Rapid HCV suppression was seen with TVR plus PEG-IFN-α2a–ribavirin (68% [26 in 38 patients] vs. 0% [0 in 22 patients] undetectable HCV RNA levels by week 4). Two patients had on-treatment HCV breakthrough with TVR-resistant variants. Patients treated with antiretroviral drugs had no HIV breakthroughs; antiretroviral exposure was not substantially modified by TVR.

Limitation: Small sample size and appreciable dropout rate.

Conclusion: In patients with HCV and HIV-1, more adverse events occurred with TVR versus placebo plus PEG-IFN-α2a–ribavirin; these were similar in nature and severity to those in patients with HCV treated with TVR. With or without concomitant antiretrovirals, sustained virologic response rates were higher in patients treated with TVR versus placebo plus PEG-IFN-α2a–ribavirin.

Primary Funding Source: Vertex Pharmaceuticals and Janssen Pharmaceuticals

Source

HCV patients with late viral breakthrough have similar characteristics

Provided by Healio

May 19, 2013

ORLANDO, Fla. — Viral breakthrough during the interferon/ribavirin phase of hepatitis C triple therapy was associated with genotype 1a and advanced liver fibrosis, similar to findings in previous clinical trials, according to study data presented here at Digestive Disease Week.

“We’ve noticed that there are patients who were experiencing viral breakthrough later in treatment,” Kali Zhou, MD, a resident in the department of medicine at the University of California, Los Angeles, told Infectious Disease News. “We did see later viral breakthrough in clinical trials, but we haven’t evaluated whether the characteristics of our breakthrough patients were similar to those who broke through in clinical trials.”

Zhou and colleagues conducted a retrospective analysis that included 55 patients who were treated from June 2011 to June 2012 and evaluated characteristics of patients who experienced viral breakthrough. Patients were treated with either boceprevir (Victrelis, Merck) or telaprevir (Incivek, Vertex).

Nine patients had viral breakthrough and all of those received telaprevir. Eight of those patients broke through during the interferon/ribavirin phase of treatment, with a mean time to breakthrough of 21.3 weeks. Six patients had genotype 1a, and six of the patients had stage 3-4 fibrosis on liver biopsy. Six patients were prior null responders and one was a prior relapse. Resistance patterns were detected in six of eight patients who underwent resistance testing, and the six patients also had cross-resistance to boceprevir.

“Right now, the recommended frequency of testing viral load is weeks 4, 12, 24 and 48 for patients receiving telaprevir, and one more test at week 8 for patients receiving boceprevir,” Zhou said. “Because most of the patients broke through after week 12, patients at high risk should probably have viral load testing monthly.”

Zhou K. #Sa1040. Characteristics of Viral Breakthrough With Direct Acting Agents for Chronic Hepatitis C Treatment in Clinical Practice. Presented at: Digestive Disease Week; May 18-21, 2013; Orlando, Fla.

Disclosure: Zhou reports no relevant financial disclosures.

Source

HBV may increase risk for non-Hodgkin lymphoma

Provided by Healio

May 18, 2013

ORLANDO, Fla. — Infection with hepatitis B virus may be a risk factor for non-Hodgkin lymphoma, according to data presented here at Digestive Disease Week 2013.

Researchers from the Marshfield Clinic in Wisconsin conducted a meta-analysis that included 19 case-control studies performed throughout the world. The analysis included a total of 13,947 cases and 1,559,448 controls. In nine of the studies, the controls were non-lymphoma cancer/hospital patients; eight studies incorporated healthy controls, and two studies included both types of controls. In most of the studies (17), patients were diagnosed with hepatitis B by detection of HBsAg, while hepatitis B was self-reported in the remaining two studies. All incidences of non-Hodgkin lymphoma (NHL) were diagnosed with histopathology.

Among the patients with NHL, 1,205 had hepatitis B infection and among the controls, there were 40,592 cases of infection. The risk of hepatitis B was higher for patients with NHL compared with controls (OR=2.53; 95% CI, 2.10-3.03). Significant heterogeneity was not observed across the evaluated studies.

The increased risk of hepatitis B infection was present in both developing and developed countries in subgroup analysis. There was also no difference in risk among controls based in the hospital- and population-based controls.

For more information:

Kanth R. #Sa1020. Presented at: Digestive Disease Week; May 18-21, 2013; Orlando.

Disclosure: The researchers report no relevant financial disclosures.

Source

HCV prevalence higher among Asian-Americans

Provided by Healio

May 19, 2013

ORLANDO, Fla. — There was a higher prevalence of hepatitis C infection among Asian-Americans than among non-Asians who received care at a free community clinic, researchers reported at Digestive Disease Week.

“Among non-Asians, the prevalence of HCV was similar to what was seen in NHANES data,” Mindie Nguyen, MD, associate professor of medicine at Stanford University, told Infectious Disease News. “Worldwide, a large amount of the HCV burden is in Asia, and we lacked data on whether Asian-Americans have a higher HCV prevalence that is similar to that in their countries of origin. We found that the prevalence of HCV among Asian-Americans was similar to the reported prevalence in many parts of Asia and Southeast Asia.”

Nguyen and colleagues conducted a cross-sectional study that included patients who were seen from July 2011 to October 2012 at a free community primary care clinic, where HCV screening is recommended for all patients seeking routine care. The researchers collected clinical and risk factor data by reviewing medical records.

Of the 691 consecutive patients seen during the timeframe, 436 were screened for HCV with antibody testing. Fourteen of the patients had a positive antibody test and of those 11 were Asian, which resulted in an HCV prevalence of 4.5% for Asians (95% CI, 1.9-7.1), compared with a prevalence of 1.6% for non-Asians (95% CI, 0.21-3.3).

Of the three non-Asians with HCV, two had a history of illicit drug use. Among the Asian patients, one had a history of illicit drug use and one had a history of blood transfusion. The HCV risk factors for four patients were unknown. The remaining five Asians had only a history of prior surgery and uncertain risk factors. In addition, most of the Asians with HCV were foreign-born.

“A large majority of the Asian patients with positive HCV antibodies did not have any of the well-known risk factors for HCV infection,” Nguyen said. “Given the high prevalence, screening for HCV should be done for foreign-born Asian-Americans coming from endemic areas, as hepatitis B virus screening is currently recommended by the CDC for those coming from areas with an HBV prevalence of 2% or higher.”

Lin O. #Sa1069. High Prevalence of Hepatitis C Virus Infection (HCV) in Asian Americans in a Community Primary Care Clinic. Presented at: Digestive Disease Week; May 18-21, 2013; Orlando, Fla.

Disclosure: Nguyen reports financial relationships with Bristol-Myers Squibb, Gilead, Onyx, Novartis, Vertex, Dynavax Technologies and Hoffman-LaRoche.

Source

Patients with Medicaid less likely to receive HCV treatment

Provided by Healio

May 18, 2013

ORLANDO — Although diagnosed hepatitis C infection was more common among people with Medicaid insurance, the treatment rates were lower compared with people who had commercial insurance, research presented here at Digestive Disease Week suggests.

“These results were pretty much what we expected,” Jenny Griffith, PharmD, senior manager of clinical epidemiology at AbbVie, told Infectious Disease News. “We knew that people who have Medicaid insurance are typically sicker, and we expected to find the same thing in HCV. The one thing that was unexpected was that the rate of diagnosed HCV was double in the Medicaid group. One hypothesis for this is that people with Medicaid typically have a lower socioeconomic status, and according to NHANES data, there is a higher prevalence of HCV among those with a lower socioeconomic status.”

Griffith and colleagues conducted a retrospective analysis that included approximately 28 million commercial beneficiaries from Jan. 2000 to Dec. 2009 and 3.2 million Medicaid beneficiaries from July 1999 to June 2009. They evaluated the prevalence of HCV and treatment estimates, as well as comorbidities and possible contraindications to treatment.

The 10-year prevalence of HCV was 302 per 100,000 among people with commercial insurance and 663 per 100,000 among people with Medicaid. The prevalence of treatment, however, was 26.5% among patients with commercial insurance and 19.5% among Medicaid beneficiaries. Those with Medicaid had higher rates of most evaluated comorbidities, including drug abuse, ascites, COPD, depression, autoimmune disease and pregnancy. More patients on Medicaid also had possible contraindications to treatment with ribavirin and/or interferon.

“The take-home message is that if you have someone who has Medicaid insurance, they are more than likely to be sicker and have more comorbidities that will make it more difficult to treat them,” Griffith said. “The development of interferon-free treatment may increase eligibility for treatment and hopefully eliminate this gap.”

For more information:

Griffith J. #Sa1066. Presented at: Digestive Disease Week; May 18-21, 2013; Orlando.

Disclosure: Griffith is an employee of AbbVie.

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