HCV Research and News: AASLD 2011

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April 16, 2012

Updated AASLD HCV Guideline Aims To Simplify Use of DAAs

Gastroenterology & Endoscopy News

ISSUE: APRIL 2012 | VOLUME: 63:4

by Christina Frangou

The American Association for the Study of Liver Diseases (AASLD) recently published an updated practice guideline on the treatment of chronic infection with hepatitis C virus (HCV) genotype 1 (Ghany MG et al. Hepatology 2011;54:1433-1444).

The guideline, authored by members of the AASLD practice guideline committee, was issued in response to the development of new direct-acting antivirals (DAAs) and the identification of several single nucleotide polymorphisms associated with spontaneous and treatment-induced clearance of HCV infection. The report makes 18 recommendations for clinicians who are considering using the new DAAs to treat patients with HCV. The two currently approved DAAs have complex prescribing rules, including outlines for response-guided therapy and unusual stopping rules, and many clinicians question how and when the agents are best used.

“We have entered into a very different treatment paradigm. I’d suggest that everyone read the guideline from the AASLD. It’s a very good overview of where we are today,” said David R. Nelson, MD, a study author and professor of medicine, Division of Gastroenterology, Hepatology and Nutrition at the University of Florida College of Medicine, in Jacksonville, during a presentation at The Liver Meeting last year.

The authors outline the current state of evidence regarding treatment with boceprevir and telaprevir, and provide some guidance on much-debated issues such as treatment of patients with cirrhosis and the role of interleukin-28B (IL28B) testing.

The guidelines are “very important and very helpful,” said Michal R. Charlton, MD, professor of medicine and head of the hepatobiliary section at Mayo Clinic, in Rochester, Minn. “The guidelines provide a lens through which clinicians can look to see the optimal approach to managing patients with HCV infection.”

Inside the Recommendations

According to the authors of the report, the DAAs, in combination with peginterferon alfa and ribavirin, are now the “optimal therapy” for treating HCV genotype 1 chronic infection. Both therapies must be given with peginterferon and ribavirin, which limits selection of resistant variants and improves antiviral response. Furthermore, boceprevir and telaprevir should not be used to treat patients infected with HCV genotype 2 or 3.

The authors reiterated the FDA recommendation that treatment-naive patients with cirrhosis treated with either boceprevir or telaprevir in combination with interferon and ribavirin should receive therapy for 48 weeks instead of on a response-guided basis. However, the authors added that this recommendation is “based on limited data and requires further study.”

The report also specifies that the stopping rules differ for telaprevir and boceprevir in treatment-naive patients. Treatment with telaprevir, peginterferon alfa and ribavirin should be stopped if the HCV RNA level is greater than 1,000 IU/mL at treatment weeks 4 or 12 and/or detectable at treatment week 24. Treatment with boceprevir, peginterferon and ribavirin should be stopped if the HCV RNA level is greater than 100 IU/mL at treatment week 12 or detectable at treatment week 24. For both therapies, the evidence for the discontinuation rules is considered Class 2a, meaning the weight of evidence is in favor of the usefulness of this rule, but there is limited evidence.

Patients who previously received and failed therapy with interferon and ribavirin remain a conundrum with regard to starting DAA therapy. Studies have shown that patients’ response to triple therapy regimens in both boceprevir and telaprevir trials was strongly influenced by the outcome of their earlier treatment with peginterferon and ribavirin. The decision to re-treat patients should depend on their previous response to peginterferon and ribavirin and on reasons why they may have failed, such as inadequate drug dosing or side-effect management, the report said. The authors call on physicians to review old treatment records to document previous treatment response.

This updated document is the first to clarify treatment for patients who fail DAA therapy. The authors say that patients who do not have a virologic response, who experience virologic breakthrough or who relapse on one protease inhibitor (PI) should not be retreated with the other PI.

Although the evidence is limited, the AASLD did make some recommendations for managing treatment-experienced patients. The AASLD suggests retreatment with boceprevir or telaprevir, together with peginterferon alfa and weight-based ribavirin, “be considered” for patients who had a virologic relapse or who were partial responders after a previous course of treatment with standard interferon alfa or peginterferon alfa and/or ribavirin.

“Relapsers and partial responder patients can expect relatively high sustained virologic response rates to retreatment with a PI-containing triple regimen and should be considered candidates for retreatment,” the authors wrote.

For previously null responders, telaprevir may be considered but boceprevir cannot be recommended, the committee found. This finding differs from the FDA label, which indicates that boceprevir can be used in null responders. Null responders were excluded from Phase III trials of boceprevir (Poordad F et al. N Engl J Med 2011;364:1195-1206).

“Given the lack of definitive information for Phase III data, caution is advised in the use of [boceprevir] in null responders until further supportive evidence becomes available,” according to the AASLD.

Additionally, the decision to re-treat a null responder with telaprevir should be individualized, particularly in patients with cirrhosis, because less than one-third of null responder patients in the telaprevir trial achieved a sustained virologic response (SVR). Moreover, the authors caution that a majority of null responders developed resistance to DAAs.

“Any potential benefit from treating nonresponders must be weighed against the risk for development of antiviral resistance and for serious side effects, and the high cost of therapy,” the report said.

The AASLD acknowledged uncertainty about the benefit of the lead-in strategy required for treatment with boceprevir. Theoretically, the lead-in may improve efficacy by lowering HCV RNA levels, thus reducing the rate of viral breakthrough when the PI is introduced. The authors noted, however, that poor responders during the lead-in period can still achieve SVR.

“Thus, a poor response during the lead-in phase should not be used to deny patients access to PI therapy,” the authors said. Patients who develop anemia on PI therapy should be managed by reducing the ribavirin dose, they added.

The report also specified that IL28B genotype is a significant treatment predictor of response to therapy, but data are insufficient to determine whether IL28B testing can be used to recommend either interferon and ribavirin alone or a triple therapy with a PI.

“Consideration should be given to ordering the test when it is likely to influence either the physician’s or patient’s decision to initiate therapy,” the authors said.

Telaprevir and boceprevir are not recommended for use in children and adolescents younger than 18 years because safety and efficacy has not been established in this group.

Additionally, the guidelines do not address several important questions about DAAs, Dr. Charlton said. The report, for example, does not provide detailed and practical information about drug–drug interactions, managing HIV/HCV co-infection and managing side effects, he said.

“Perhaps the highest-impact omission, which was unavoidable, is whether in light of the spectacular report of efficacy and tolerability of PSI-7977 in combination with ribavirin without interferon, patients with early stages of liver disease should be treated at all with boceprevir or telaprevir,” he said. “In our practice, we are already beginning to advise many patients to wait. … A strong case could be made for waiting for the results of the Phase III interferon-free studies.”

The committee cautions that the guidelines are “based on data that are presently limited” and the recommendations may need revision as additional data become available.

“There is a paucity of information for many of the subgroups with the greatest unmet need for treatment (e.g., patients co-infected with HIV and HCV, with decompensated cirrhosis and after liver transplantation),” the committee said.

Dr. Nelson receives research support from Bayer/Onyx, Bristol-Myers Squibb, Genentech/Roche, Gilead, Merck, Pharmasset, Tibotec and Vertex Pharmaceuticals; he serves on the advisory boards of Bayer/Onyx, Genentech/Roche, Gilead, Merck, Pharmasset and Tibotec; and he is a consultant for Vertex Pharmaceuticals. Dr. Charlton receives research support from Bristol-Myers Squibb, Genentech/Roche, Merck and Vertex Pharmaceuticals; he is a consultant for Bristol-Myers Squibb, Genentech/Roche Gilead, Merck and Vertex Pharmaceuticals.

Source

January 13, 2012

Response to Comments on An Update on Treatment of Genotype 1 Chronic Hepatitis C Virus Infection

An Update on Treatment of Genotype 1 Chronic Hepatitis C Virus Infection: 2011 Practice Guideline by the American Association for the Study of Liver Diseases

These evidence-based guidelines are developed and updated regularly by a committee of hepatology experts and include recommendations of preferred approaches to the diagnostic, therapeutic, and preventive aspects of care.

You will need Adobe Acrobat Reader to view these documents.

Response to Comments on An Update on Treatment of Genotype 1 Chronic Hepatitis C Virus Infection

1) I think the guidelines are fine. I do have a question as to follow up of a Genotype 1 patient who does not want treatment and also the Genotype 1 patient who fails triple therapy?

Response:
Monitoring of patients with all genotypes who do not warrant or want treatment was not addressed in the guidelines. Frequency of monitoring should be based on underlying disease severity. Patients with mild disease could be seen every six months while those with more advanced disease should be seen every three to four months; this recommendation is based on expert opinion. Patients with cirrhosis need to be considered for periodic surveillance for esophageal varices and hepatocellular carcinoma as per AASLD guidelines on Management of Esophageal Varices and Hepatocellular Carcinoma.
2) There is no consideration for IL28B testing to determine if some patients are good candidates for double therapy with Pegylated Interferon with Ribavirin vs. triple therapy. Since, compliance is a major issue with the triple therapy, providing an option with double therapy to patients who would respond well based on IL28B should be addressed.

Response:
The advantages of using PI-based treatment even in persons with IL28B genotype CC are that more persons will qualify for abbreviated therapy with telaprevir and possibly boceprevir, and there are higher SVR rates than double therapy. The advantages of treating IL28B genotype CC patients with peginterferon and ribavirin alone are fewer side effects, fewer drug-drug interactions, and lower cost. However, until cost effectiveness studies are published, we recommend the PI-based approach in most patients.

3) I am surprised there is so little commentary on which patients warrant treatment. This is a significant omission. Future guidelines and commentary should include a balanced discussion framing the pros and cons of treatment according to typical patient scenarios. These therapies are still prone to many side effects, and many patients have little urgency to treat, yet are feeling pressured to participate.

Response:
This question was beyond the scope of our mandate and will be reconsidered in the next full update to the guidelines. The issue is a highly controversial one with many different opinions. Many factors go into the decision regarding whom to treat including disease severity, likelihood of response, benefits and risks of treatment, as well as the likelihood of new therapeutic options. As efficacy and safety of therapy improves many of these factors may become less important and it is likely that most patients will become candidates for therapy.

4) The #16 recommendation of the guideline is somewhat contradictory to the #9 recommendation: In #9, the futility rule is described as the following: "telaprevir, peginterferon alfa and ribavirin should be stopped if the HCVRNA level is >1,000 IU/ml at treatment weeks 4 or 12". But in #16 it says that "the protease inhibitor should be discontinued if virological breakthrough (>1 log increase in serum HCVRNA above nadir) is observed". If telaprevir was used, there are occasions HCVRNA measured 10 times higher from nadir (e.g. Around 10 IU/ml to the hundreds but well within 1000 IU/ml futility limit) during telaprevir dosing period. If the clinician follows #9, telaprevir should be continued but if #16 was followed, telaprevir needs to be stopped. Therefore, this inconsistency needs to be addressed.

Response:
The two statements are not contradictory. To clarify, the stopping rule in #9 applies to patients who reach a virological plateau after which continued therapy would significantly increase the risk for antiviral resistance. Recommendation #16 deals with compliant patients who experience virological breakthrough signifying the emergence of antiviral resistance. Although the author is correct, among the patients with virological breakthrough, their HCV RNA may increase from undetected to 100 IU/ml and still be under the 1,000 IU/ml rule; the important point is the change from a negative to a positive test.

Source

January 4, 2012

Gene-Targeting Therapy Shows Promise Against Hepatitis C

Provided by Hep Magazine

November 9, 2011

Miravirsen, a novel injectable drug targeting a “microRNA” known as miR-122 responsible for the accumulation of hepatitis C virus (HCV) in the liver, had long-lasting activity against the virus when used without other medications in a preliminary clinical trial presented Monday, November 7, at the 62nd annual meeting of the American Association for the Study of Liver Diseases (AASLD) in San Francisco.

New clinical data from the early stage Phase II study demonstrate that four out of nine participants treated with the highest dose of miravirsen—7 milligrams per kilogram (mg/kg) of body weight—saw their HCV viral loads decrease to undetectable levels with just four weeks of treatment.

These findings, said study presenter Harry Janssen, MD, PhD, of Erasmus MC University Hospital in Rotterdam, Netherlands, suggest that miravirsen’s unique mechanism-of-action offers a high barrier to viral resistance and the potential for cure, used either alone or with other medications. He also noted that miravirsen was well tolerated in people living with HCV, signaling a possible advantage over today’s standard pegylated interferon–based treatment.

Continue Reading Here ...

January 3, 2012

AASLD: Sustained Response is Durable among Hepatitis C Patients Treated with Telaprevir

Provided by HIVandHepatitis.com

Published on Tuesday, 03 January 2012 00:00

Written by Liz Highleyman

Almost all chronic hepatitis C patients who achieved sustained virological response (SVR) using the recently approved HCV protease inhibitor telaprevir (Incivek) plus pegylated interferon and ribavirin continued to have undetectable viral load nearly 2 years later, according to data presented at the recent American Association for the Study of Liver Disease (AASLD) Liver Meeting in San Francisco.

The ADVANCE, REALIZE, and ILLUMINATE trials demonstrated that adding telaprevir to standard therapy significantly increased the rate of sustained response, or continued undetectable HCV RNA at 24 weeks after the completion of therapy.

Investigators with the EXTEND Study Team looked at whether treatment response was durable with longer follow-up. EXTEND is a 3-year study of participants who received at least 1 dose of telaprevir in selected Phase 2 and 3 trials including ADVANCE (genotype 1 treatment-naive) and REALIZE (genotype 1 previously treated).

Kenneth Sherman presented findings from the second interim analysis at the Liver Meeting. This analysis included 223 patients who achieved SVR (followed for a median 21 months) and 185 non-responders who did not achieve SVR (followed for a median of 29 months). A total of 228 were originally in Phase 2 studies and 180 were in Phase 3 trials; 162 were treatment-naive and 246 were treatment-experienced.

Results

> 99% of patients -- all but 1 -- maintained SVR during follow-up.
1 individual experienced late relapse 48 weeks after prematurely discontinuing therapy (after 10 weeks total treatment time).
The recurring virus matched the prior strain, indicating relapse rather than reinfection.
Among 162 patients who did not achieve SVR and had available genetic sequencing data, 85% no longer had detectable telaprevir-resistant HCV variants, which had been replaced by wild-type virus.
More people with HCV subtype 1b had wild-type virus at their last study visit compared to those with subtype 1a (95% vs 77%, respectively).
Looking at specific resistance mutations, replacement with wild-type virus ranged from 82% to 100%.
No patients with long-term SVR experienced liver-related clinical events, compared with 4 non-responders (2 with transplants due to liver cancer, 1 with hepatic encephalopathy, 1 with ascites).

"In this interim analysis, SVR after telaprevir-based therapy was durable," the researchers concluded. "In patients who did not achieve SVR during telaprevir-based therapy, resistant variants were replaced by wild-type."

1/3/12

Reference

KE Sherman, MS Sulkowski, F Zoulim, et al. (EXTEND Study Team). Follow-up of SVR Durability and Viral Resistance in Patients with Chronic Hepatitis C Treated with Telaprevir-Based Regimens: Interim Analysis of the EXTEND Study. 62nd Annual Meeting of the American Association for the Study of Liver Disease (AASLD 2011). San Francisco, November 4-8. 2011. Abstract 248.

Source

Silymarin Flops in Treatment of Chronic Hepatitis C

By: SUSAN LONDON, Family Practice News Digital Network

SAN FRANCISCO – Oral silymarin, an extract of milk thistle, is well tolerated but not efficacious for treating chronic hepatitis C virus infection, according to results from a randomized phase II trial reported at the annual meeting of the American Association for the Study of Liver Diseases.

After 24 weeks, patients taking high doses of the botanical agent – which is known to have anti-inflammatory, immunomodulatory, and antiviral activity in vitro – did not show improvement in serum levels of alanine aminotransferase (ALT) compared with their counterparts taking placebo.

A botanical agent – and milk thistle extract – has been proven ineffective for treating chronic hepatitis C.

There were also no significant differences between groups in a variety of measures of symptoms and quality of life.

"We must conclude that oral silymarin used at higher-than-customary doses did not significantly alter biochemical or virological markers of disease activity in hepatitis C patients previously treated with interferon-based regimens," said first author Dr. Michael W. Fried, director of hepatology at the University of North Carolina at Chapel Hill. But he added that "this was a fairly difficult group – these were nonresponders [to conventional therapy] – they were older."

The study is noteworthy for its many strengths, such as its use of a well characterized silymarin product, prolonged treatment, excellent adherence, and focus on a specific liver disease, he said.

Recent studies finding a benefit of silymarin in treating HCV infection used a different, intravenous formulation, according to Dr. Fried. That formulation contains a succinate moiety that may be important and likely achieves blood levels of silybin A, a major active component, higher than can be achieved with the oral formulation.

The oral doses used in the trial were probably not sufficient to inhibit the virus’ replicative enzymes, but giving higher doses was not practical. "We had to balance that with the pill burden: These were five capsules given three times a day, so we were not able to push the dose currently," he explained. "There may be attempts to try higher[-dose] formulations. There is also some way, interestingly, that’s being investigated to try to boost the silymarin levels with other botanical products ... because of their interactions on metabolism."

Dr. T. Jake Liang, president of the AASLD and chief of the liver diseases branch at the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Md., noted that the market for herbal and related products "is a big business in this country, about $30 billion, and it’s really not that well regulated, and there are a lot of unsubstantiated claims."

He pointed out that the trial focused on a more modest disease outcome. "The goal was not so much to see whether silymarin can eradicate the hepatitis C virus; the goal was really to see whether it could improve the damage to the liver," he explained in a press conference.

"I think this study clearly shows that the use of milk thistle is not effective in treating patients with hepatitis C. It’s a very important negative study – I think that’s key. We really want to make sure that we prevent any unwarranted use of herbal products despite the [health claims]," Dr. Liang concluded.

The trial, known as SyNCH and funded by the National Institutes of Health, enrolled 154 adult patients from four U.S. centers with chronic HCV who had not had a sustained virologic response to prior interferon-based therapy, had quantifiable HCV RNA, and had an ALT level of at least 65 IU/L.

Patients who had decompensated cirrhosis or moderate to severe steatosis or steatohepatitis were excluded, as were those who were positive for HIV or hepatitis B surface antigen, or who had used silymarin in the past month.

The patients were assigned to double-blind treatment in three groups: silymarin 420 mg three times daily, silymarin 700 mg three times daily, or matching placebo three times daily. The silymarin product used was a standardized preparation (Legalon, manufactured and supplied by Rottapharm Madaus in Monza, Italy, and Cologne, Germany) that is approved as a prescription drug in some European and Asian countries. Doses three- to fivefold higher than the customary one were chosen to achieve the highest likelihood of finding a benefit, according to Dr. Fried.

The patients studied were about 55 years old, on average, and three-fourths were white. Their mean ALT was 125 IU/L. Forty-four percent had used silymarin previously.

"Adherence throughout the treatment trial was quite excellent," he reported; across groups, 92%-98% of participants took more than 80% of planned doses. And random testing confirmed that patients in the silymarin group had silybin A in plasma while those in the placebo group did not.

However, final intent-to-treat analyses showed no significant difference between groups at 24 weeks in the primary end point, defined as achievement of a serum ALT level of 45 IU/L or lower (approximately the upper limit of normal) or a drop in serum ALT level of at least 50% to less than 65 IU/L (approximately 1.5 times the upper limit of normal).

Just 3.8% of patients in the placebo group met this end point, as did 4% in the silymarin 420-mg group and 3.8% in the silymarin 700-mg group.

"We really looked at many different subpopulations, and we could not find any signal at all," Dr. Fried said; additionally, the findings were much the same in per-protocol analyses.

The treatment groups were also statistically indistinguishable with respect to the changes from baseline in ALT levels and in HCV RNA levels, and with respect to changes from baseline in scores on questionnaires assessing depression, physical and mental health, and quality of life specific to chronic liver disease.

"Silymarin was well tolerated with an adverse event profile similar to placebo," Dr. Fried said. The three treatment groups did not differ significantly with respect to rates of adverse events (most of which were mild or moderate) or serious adverse events.

Dr. Fried reported that he is a consultant to Genentech, Tibotec, Vertex, Merck, Abbott, and Pharmasset; receives grant or research support from Genentech, Tibotec, Vertex, Merck, Anadys, Abbott, and Bristol-Myers Squibb; is an adviser or reviewer for GlaxoSmithKline; and has stock in Pharmasset. Dr. Liang reported that he had no relevant conflicts of interest.

Source

December 27, 2011

AASLD: Fever Signals Responsiveness to Pegylated Interferon for Hepatitis C

Liz Highleyman | Content provided by hivandhepatitis.com

Published Tuesday, 27 December 2011

People who have an increase in body temperature soon after starting interferon-based therapy for chronic hepatitis C virus (HCV) infection are more likely to experience early virological response, according to a presentation at the American Association for the Study of Liver Disease (AASLD) Liver Meeting last month in San Francisco.

Rather than directly targeting HCV, interferon works by stimulating the body's immune response. This can lead to a variety of flu-like symptoms including fever, loss of appetite, and muscle aches. But it is not known how these side effects relate to antiviral activity.

Hwalih Hanand colleagues from the National Institutes of Health evaluated whether temperature changes after starting interferon reflect responsiveness to pegylated interferon, as assessed by viral kinetics, serum cytokine levels, and treatment response.
The study included 60 previously untreated chronic hepatitis C patients who started standard therapy using pegylated interferon plus ribavirin. Half were men, nearly 60% were white, about 20% each were black and Asian, and the mean age was 52 years. A majority (57%) had difficult-to-treat HCV genotype 1, one-third had genotypes 2 or 3, and 10% had genotypes 4, 5, or 6.

The researchers measured body temperature with an oral thermometer before the first injection of pegylated interferon and at 8, 16, and 24 hours thereafter, and determined the maximum temperature increase from baseline within the first 24 hours, or Tmax.

Serum HCV viral load was measured at baseline, at 6, 24, 48, and 72 hours, and then weekly for the first 4 weeks of treatment, and used to calculate the first and second phase slope of HCV decline. Levels of interferon gamma-inducible protein 10 (IP-10) were also assessed for a subset of patients at baseline and at 6 and 24 hours after treatment initiation.
Results

The average maximum temperature increase after starting interferon was 1.1°C.
The average peak temperature was 37.9°C, and 33% of patients experienced fevers above 38.0°C within 24 hours.
Overall, 42% of participants experienced rapid virological response (RVR) at week 4, 83% showed early virological response (EVR) at week 12, and 38% achieved sustained virological response (SVR) at 24 weeks after the end of treatment.
There was a strong and significant positive correlation between maximum temperature (Tmax) and the first phase of viral decline.
However, Tmax did not correlate with the second phase of viral decline.
The correlation between Tmax and first phase viral decline was similar for people with genotype 1 and those with genotypes 2 or 3, with no difference in average Tmax across viral genotypes.
There was a significant positive correlation between Tmax and IP-10 induction at 6 and 24 hours.
Tmax was significantly higher on average for participants with the favorable IL28B rs129790860 "CC" gene pattern -- a known predictor of treatment response -- compared to those with the unfavorable "CT" or "TT" patterns (1.43 vs 0.84°C, respectively).
Tmax predicted RVR at week 4 and EVR at week 12, though the correlation was weak.

"Temperature increase after the initial injection of pegylated interferon is closely associated with interferon responsiveness, as reflected by the correlation with serum IP-10 increase, virological decline, and IL28B genotype," the researchers concluded. "The lack of difference between genotypes pinpoints its association with host-responsiveness factors."

As an easily measurable marker, they suggested, temperature "may be incorporated as a surrogate of more expensive and elaborate tests in future models of responsiveness to interferon-based treatment."

Investigator affiliation: Liver Diseases Branch, NIDDK, NIH, Bethesda, MD.

12/27/11

Reference

H Han, M Noureddin, YJ Park, et al. Changes in Oral Temperature After the Initial Injection of Peginterferon Alfa-2a in Patients with Chronic Hepatitis C Reflect Host-Interferon Responsiveness. 62nd Annual Meeting of the American Association for the Study of Liver Disease (AASLD 2011). San Francisco, November 4-8. 2011. Abstract 487.

Source

AASLD: Upping Ribavirin Dose Does Not Increase Interferon Effectiveness in HIV/HCV Coinfected Patients

Liz Highleyman | Content provided by hivandhepatitis.com

Published Tuesday, 22 November 2011

Starting hepatitis C treatment with a double dose of ribavirin plus erythropoietin to manage anemia did not lead to higher rates of sustained response to interferon-based therapy in HIV/HCV coinfected people, researchers reported at the American Association for the Study of Liver Diseases Liver Meeting (AASLD 2011) this month in San Francisco.

An estimated one-third of HIV positive people are coinfected with hepatitis C virus (HCV), and dual infection is associated with faster liver disease progression and poorer response to interferon-based therapy.

Vincent Soriano from Hospital Carlos III in Madrid and colleagues conducted a study to determine whether increasing the usual dose of ribavirin might improve virological response in this patient population.

Ribavirin promotes sustained virological response (SVR) because it reduces the risk of relapse after the end of treatment. Studies have shown that 1000-1200 mg/day weight-adjusted ribavirin works better than a fixed 800 mg/day dose, but the effect of even higher doses is not well understood. Ribavirin can cause hemolytic anemia (destruction of red blood cells), so higher-than-normal doses must be used with caution.

The PERICO study included 357 HIV/HCV coinfected participants who had not previously received interferon for hepatitis C. About three-quarters were men and the average age was 43 years. About 60% had HCV genotype 1, 19% had genotype 3, 17% had genotype 4, and only 6% had genotype 2. About half had advanced liver fibrosis/cirrhosis, 43% had the favorable IL28B CC gene pattern, and 72% had high baseline HCV RNA > 500,000 IU/mL. Most were on antiretroviral therapy with undetectable HIV viral load, and the mean CD4 T-cell count was about 550 cells/mm³.

All participants received the standard 180 mcg/week dose of pegyalted interferon alfa-2a (Pegasys). In addition, they were randomly assigned to receive either standard 1000-1200 mg/day weight-adjusted ribavirin for the full course of treatment, or else a 2000 mg/day induction dose for the first 4 weeks along with weekly subcutaneous injections of 50,000 IU erythropoietin (Procrit or Epogen), then dropping down to the standard ribavirin dose and discontinuing erythropoietin.

Patients with rapid virological response (RVR) at week 4 were treated for the standard duration of 24 weeks for genotypes 2 and 3 or 48 weeks for genotypes 1 and 4. People without RVR were treated for 48 or 72 weeks, respectively. Participants with inadequate response at weeks 12 or 24 stopped treatment early.

Results

In an intent-to-treat analysis, 43% of participants in the high-dose ribavirin induction arm achieved SVR 24 weeks after the end of treatment, compared with 47% in the standard therapy arm, not a significant difference.
In an on-treatment analysis, the corresponding rates were 53% vs 57%, again not a significant difference.
Premature treatment discontinuation occurred with similar frequency in both arms -- 51% vs 53%, respectively -- mostly due to virological failure.
Other response predictors were associated with higher sustained response rates, as expected:
- HCV genotype: 82% for genotypes 2 and 3, 42% for genotype 1b, 34% for genotype 4, and 31% for genotype 1a;
- IL28B gene pattern: 74% for CC vs 35% for CT or TT;
- Treatment completion: 80% for completion vs 31% for early discontinuation.
In a multivariate analysis, SVR was significantly associated with HCV genotypes 2 and 3, IL28B CC, and low baseline HCV RNA.
RVR was the best predictor of SVR.
Despite differing doses, ribavirin plasma trough levels (lowest between doses) at week 4 were the same in both arms, at 2.3 mcg/mL.

Based on these findings, the investigators concluded, "Induction therapy with high ribavirin dosing along with erythropoietin does not improve SVR rates in HIV/HCV coinfected patients."

To explain the unexpected similar ribavirin levels regardless of dose, they suggested that pre-emptive erythropoietin "might blunt the benefit of ribavirin overdosing by enhancing erythrocyte uptake of plasma ribavirin."

Investigator affiliations: Infectious Diseases, Hospital Carlos III, Madrid, Madrid, Spain; Hospital Clínico San Cecilio, Granada, Spain; Hospital San Pablo, Barcelona, Spain; Hospital Gregorio Marañón, Madrid, Spain; Hospital 12 de Octubre, Madrid, Spain; Hospital Clinico San Carlos, Madrid, Spain; Hospital Virgen de La Victoria, Malaga, Spain; H Virgen Macarena, Sevilla, Spain; Hospital Universitario de Valme, Sevilla, Spain; Hospital Txagorritxu, Vitoria, Spain; Hospital Gral de Jerez, Jerez, Spain; Hospital do Meixoeiro, Vigo, Spain; Hospital Xeral-Cies, Vigo, Spain; Hospital Cruces, Bilbao, Spain; Hospital La Princesa, Madrid, Spain; Hospital Central de Asturias, Oviedo, Spain.

11/22/11

Reference

P Labarga, M Téllez, P Barreiro, V Soriano, et al. The Perico Trial: A Multicenter Randomized Controled Trial Comparing High Ribavirin (RBV) Induction vs Standard RBV Dosing in the Treatment of Chronic Hepatitis C in HIV-Coinfected Patients. 62nd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2011). San Francisco, November 4-8. 2011. Abstract 247.

Source

December 16, 2011

A 'Newer' Era of HCV Therapy Begins?

William F. Balistreri, MD

Posted: 12/16/2011

Dawning of Another New Era

In an editorial appearing in the New England Journal of Medicine^[1] in March of this year, Jensen suggested that a new era of therapy for hepatitis C virus (HCV) infection was dawning with the development of 2 effective protease inhibitors -- telaprevir and boceprevir. These direct-acting antiviral (DAA) agents, used in combination with peginterferon and ribavirin, were shown to be effective in patients infected with HCV genotype 1. Now an even newer era may be on the horizon!

New Compounds, New Hope

Several investigational drug trials were presented at The Liver Meeting 2011 -- the annual meeting of the American Association for the Study of Liver Diseases. Two groups reported the apparently remarkable preliminary results of an investigational agent for the treatment of infection with HCV.^[2,3] An interferon-free regimen of PSI-7977 plus ribavirin achieved strikingly high rates of sustained viral response (SVR); this drug offers the potential solution to a long sought after goal -- the ability to delete noisome interferon injections from treatment strategies.

PSI-7977 is a uridine nucleotide analog polymerase inhibitor that is administered orally once daily. This agent has previously demonstrated robust activity in patients infected with HCV genotype 1 when used in combination with pegylated-interferon and ribavirin, and activity when used as a monotherapy has also been reported.

Promising Antiviral Activity

Two phase 2 studies of this investigational compound were presented at The Liver Meeting 2011.

The aim of the first (ELECTRON) trial was to determine the shortest duration of interferon, if any, that was required to achieve SVR when PSI-7977 plus ribavirin are coadministered.^[2] Forty treatment-naive, noncirrhotic patients infected with HCV genotype 2 or 3were randomly assigned to receive PSI-7977 400 mg plus ribavirin for 12 weeks -- this was combined with either no interferon or interferon for 4, 8, or 12 weeks. All patients achieved a rapid virologic response (RVR); > 80% had nondetectable HCV RNA at 2 weeks and all patients had undetectable levels at 3 weeks. All patients achieved an end-of-treatment (ETR) response and normalization of alanine aminotransferase levels. No serious adverse events were attributed to PSI-7977, and as expected, safety and tolerability were highest in the interferon-free treatment group. Buoyed by these results, the investigators carried out a small trial of open-label PSI-7977 monotherapy for 12 weeks; the response rates were similar to the combination therapy results.

A similar study (PROTON), a double-blind, placebo-controlled, dose-ranging study of PSI-7977, enrolled 121 treatment-naive patients with HCV genotype 1.^[3] Patients were randomly assigned to receive either 12 weeks of interferon/ribavirin plus PSI-7977 (200 mg or 400 mg), or placebo. Duration of therapy was response guided. The control group received the interferon/ribavirin standard combination for 48 weeks. The RVR for the 200 mg and the 400 mg dose was 98%, with an ETR at 24 weeks of 91%. The RVR in the placebo group was 19%, and the ETR was 50%. Of specific note, all patients with the difficult-to-treat interleukin 28B single-nucleotide polymorphism T/T mutation had an RVR -- all became HCV-negative by week 3 and 100% went on to achieve an SVR.

The studies suggest that PSI-7977 exhibits high-potency antiviral activity against a broad range of HCV genotypes and has a high barrier to resistance; the agent reduced the duration of therapy for HCV clearance in half. The impact may be significant -- offering a shorter, interferon-free regimen that is effective even in difficult-to-treat patients. A newer era indeed!

The potent antiviral efficacy in association with a promising safety profile, support the continued exploration of PSI-7977 with abbreviated interferon duration, as monotherapy, or with other DAA in patients with all HCV genotypes. These further studies will hopefully confirm this optimism and document the spectrum of potential adverse effects of this drug.

References

Jensen DM. A new era of hepatitis C therapy begins. N Engl J Med. 2011;364:1272-1274.
Gane EJ, Stedman CA, Hyland RH, et al. Once daily PSI-7977 plus RBV: pegylated interferon-ALFA not required for complete rapid viral response in treatment-naïve patients with HCV GT2 or GT3. Program and abstracts of The Liver Meeting 2011: American Association for the Study of Liver Diseases (AASLD) 62nd Annual Meeting; November 9-13, 2011; Boston, MA. Abstract 34.
Lawitz E, Lalezar JP, Hassanein T, et al. Once-daily PSI-7977 plus Peg/RBV in treatment-naïve patients with HCV GT1: robust end of treatment response rates are sustained post-treatment. Program and abstracts of The Liver Meeting 2011: American Association for the Study of Liver Diseases (AASLD) 62nd Annual Meeting; November 9-13, 2011; Boston, MA. Abstract 225.

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December 7, 2011

Enoxaparin May Prevent Portal Vein Thrombosis in Advanced Cirrhosis

By: M. ALEXANDER OTTO, Internal Medicine News Digital Network

SAN FRANCISCO – The anticoagulant enoxaparin appears to prevent portal vein thrombosis in patients with advanced cirrhosis, based on a small Italian study presented at the annual meeting of the American Association for the Study of Liver Diseases.

In this trial, 6 of 36 patients (17%) randomized to placebo developed partial or complete portal vein thrombosis (PVT) within a year, whereas none of the 34 patients (0%) randomized to 4,000 IU daily of the low-molecular-weight heparin developed PVT.

The analysis indicated that enoxaparin had a significant protective effect (HR 0.218; 95% CI, 0.048-0.994, P = .049) in these patients with advanced cirrhosis.

At enrollment, none of the patients had PVT. The treatment and placebo groups had no significant differences in terms of biochemical or demographic factors at the outset of the trial, which was the first to prospectively investigate whether anticoagulation prevents PVT.

At the meeting, lead investigator Dr. Erica Villa, professor of gastroenterology at the University of Modena and Reggio Emilia in Modena, Italy, said that the results need to be confirmed in larger studies.

All of the subjects had cirrhosis classified as Child-Pugh B7 to C10. The mean age in both groups was 57 years, and the mean MELD (Model for End-Stage Liver Disease) score was approximately 14. Men made up more than 60% of both arms.

Enoxaparin appeared to provide significant protection against decompensation – defined as new-onset ascites, hepatic encephalopathy, or variceal bleeding – and death. Four enoxaparin patients (12%) decompensated during treatment, whereas 22 (61%) in the placebo arm decompensated. The difference persisted even after treatment with enoxaparin ended at 12 months.

Similarly, although 10 patients died in the enoxaparin group – 4 from sepsis, 2 from progressive liver failure, 3 from hepatocellular carcinoma, and 1 from variceal bleeding – 16 died in the placebo group. These deaths were due to sepsis in seven patients, progressive liver failure in another seven, hepatocellular carcinoma in one, and variceal bleeding in one.

There were no hemorrhagic or other treatment-related adverse events in the enoxaparin group, although asymptomatic thrombocytopenia led to the withdrawal of one patient 3 months into the trial. Three enoxaparin patients had liver transplants while on the drug, and Dr. Villa noted that they did not need extra blood transfusions.

Dr. Villa said she had no disclosures. She said the study was funded internally, and not by a company that makes enoxaparin.

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A Possible Sea Change in Cirrhosis Treatment

Enoxaparin "could certainly become a treatment for people who are at high risk for portal vein thrombosis. We don’t know enough about this; there may be side effects just like with other drugs, but [the findings are] exciting," said Dr. Jake Liang.

If this approach holds up to additional testing, it would signal "a sea change" in the treatment of advanced cirrhosis. "We treat thousands of people with cirrhosis; this would advocate that you should put them on this very expensive medicine" even if there’s no evidence of PVT, said Dr. Willscott Naugler.

Dr. Naugler is assistant professor of medicine at Oregon Health and Science University in Portland. Dr. Liang is president of the American Association for the Study of Liver Diseases and chief of the liver diseases branch of the National Institute of Diabetes and Digestive and Kidney Diseases

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December 6, 2011

Telaprevir Effective in Hard-to-Treat Cirrhotic HCV

Neil Canavan

December 6, 2011 (San Francisco, California) — Adding the recently approved protease inhibitor telaprevir to pegylated interferon (peginterferon) plus ribavirin therapy achieved a 47% sustained viral response (SVR) in hard-to-treat patients with hepatitis C virus (HCV) infection and cirrhosis who had previously failed the standard 2-drug regimen. This finding comes from a subset analysis of the phase 3 REALIZE trial, presented here at The Liver Meeting 2011: American Association for the Study of Liver Diseases 62nd Annual Meeting.

The REALIZE investigators originally looked at telaprevir in combination with peginterferon plus ribavirin in patients with HCV genotype 1 who had had a previous null or partial response, or who had relapsed after treatment with the 2-drug regimen. REALIZE had 3 treatment groups — 2 with different schedules of triple therapy and a third with placebo plus the 2-drug regimen.

Stanislas Pol, MD, PhD, from the Université Paris Descartes, Institut National de la Santé et de la Recherche Médicale, and Assistance Publique-Hôpitaux de Paris, Cochin Hospital, France, and colleagues performed the subanalysis of the REALIZE trial to gauge the effect of triple therapy on a subset of patients with Child class A cirrhosis who had responded poorly to the 2-drug regimen. "For this analysis, we pooled the 2 telaprevir arms since there was no difference in safety and efficacy" between the 2, he explained.

The REALIZE study population consisted of 169 patients with cirrhosis (stage F4) and 493 patients without cirrhosis (stages F0 to F3). For the entire cohort, median age was 52 years, 93% was white, 88% had an HCV RNA level of at least 800,000 IU/mL, and median body mass index was 28 kg/m². Just more than half of the patients were infected with HCV genotype 1a.

There were more null responders in the group with cirrhosis (36% vs 25%), but fewer relapsers (43% vs 57%).

Results showed that in patients with no, minimal, or portal fibrosis (F0 to F2), SVR was achieved in 75% of patients receiving telaprevir and in 22% of those receiving placebo.

"If we consider SVR according to fibrosis stage and prior response, we see no clear impact of fibrosis stage on the overall SVR rate of around 85%. For prior partial responders, there was a significant impact by fibrosis stage, with a decrease in SVR rate from 77% to 56% in patients with mild fibrosis, declining to 34% in those patients with cirrhosis," Dr. Pol told Medscape Medical News.

In previous null responders, the SVR rate after triple therapy was 41% in the patients without cirrhosis, 42% in those with mild fibrosis, and 14% in those with cirrhosis.

More than half (53%) of these previously treated patients with cirrhosis did not achieve an SVR with the addition of telaprevir, compared with 27% of patients without cirrhosis.

Regarding safety, the prevalence of rash was higher in patients with than without cirrhosis (67% vs 53%), but other rates for common adverse events were similar. For hematologic events, anemia was more frequent in patients with cirrhosis (42% vs 34%). In addition, neutropenia was higher (25% vs 17%) and, "as might be expected, platelet counts were lower in the cirrhotic subset," Dr. Pol noted.

Can Early Responders Stop Treatment?

The relatively high response rate in patients with cirrhosis and HCV who had failed previous treatment with peginterferon and ribavirin raises the question of whether treatment can be stopped early with triple therapy.

Michael Bernstein, MD, director of the hepatitis clinic at the Coney Island Hospital, Brooklyn, New York, asked: "If they had an extended RVR [rapid virologic response], if they were negative for virus at week 4 and again at week 12, for which there was evidence in REALIZE, then perhaps they could get just 24 weeks of treatment. That's called response-guided therapy."

Dr. Bernstein's reasoning is that in patients without cirrhosis, an extended RVR is indicative of a greater than 90% SVR rate.

"The current recommendation is to treat these patients for 48 weeks, whether they have an extended RVR or not. In this study, this is a special subgroup of patients — even a sub-subgroup — because it is not just cirrhotics, but cirrhotics who have not responded previously to treatment.... It may be feasible to stop [treatment] at 24 weeks if they have this very favorable RVR," he told Medscape Medical News. As phase 4 data accrue, evidence might support doing so.

Dr. Pol reports being a consultant for Bristol-Myers Squibb, Boehringer Ingelheim, Tibotec, Novartis, and Gilead; and receiving grants for research from Bristol-Meyers Squibb, Gilead, Roche, and Schering-Plough/Merck. Dr. Bernstein has disclosed no relevant financial relationships.

The Liver Meeting 2011: American Association for the Study of Liver Diseases (AASLD) 62nd Annual Meeting. Abstract 31. Presented November 6, 2011.

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Telaprevir Not Cost Effective in All Patients With HCV

Neil Canavan

December 6, 2011 (San Francisco, California) — The recently approved and highly effective hepatitis C virus (HCV) protease inhibitor telaprevir was shown not to be cost effective for the treatment of patients with HCV genotype 1 and the (CC) interleukin (IL)-28B polymorphism, a genetic variant that predicts a favorable response to treatment with the standard dual regimen of pegylated interferon (peginterferon) and ribavirin.

This cost analysis was reported here at The Liver Meeting 2011: American Association for the Study of Liver Diseases (AASLD) 62nd Annual Meeting.

"IL-28B is the strongest pretreatment predictor of sustained virologic response in genotype 1 patients," said study presenter Ziad Gellad, MD, MPH, from the Department of Medicine–Gastroenterology, Duke University Medical Center, Durham, North Carolina. "In genotype 1 patients with the favorable (CC) IL-28B polymorphism, dual therapy with peginterferon and ribavirin is effective in the majority of patients."

That said, telaprevir in combination with peginterferon plus ribavirin has demonstrated significantly increased sustained viral response rates, compared with peginterferon plus ribavirin alone in phase 3 studies of treatment-naive and treatment-experienced genotype 1 patients with HCV.

Dr. Gellad asked: Is the addition of telaprevir cost effective in the subpopulation of patients with IL-28B (CC)? The answer, he said, is no.

"One of the potential benefits of tailoring therapy is decreasing cost," Dr. Gellad said. The current wholesale cost of the 2-drug regimen is $18,336 at 24 weeks and $36,672 at 48 weeks; for the 3-drug regimen, the cost is $67,536 at 12 weeks and $85,872 at 36 weeks.

Because the addition of telaprevir more than doubles the cost of treatment, Dr. Gellad designed a cost-effectiveness model to determine whether the added expense is really worth it for a patient with the favorable genotype 1 (CC) IL-28B profile.

The model is based on a number of assumptions: that societal perspective is limited, that no patients would have a coinfection with other viruses that accelerate liver-related death or prevent treatment, "and importantly, that nonresponders or relapsers after dual therapy are retreated with a 48-week course of telaprevir."

The researchers developed a decision model that evaluated 3 treatment strategies:

peginterferon plus ribavirin for 48 weeks, with a 12-week stopping rule for nonresponse; patients who did not respond or who relapsed would be treated with telaprevir
a response-guided treatment approach with peginterferon plus ribavirin, in which those who achieved a rapid viral response (undetectable at week 4) would receive 24 weeks of dual therapy alone, and those with still-detectable viral loads at week 4 were treated for 48 weeks; nonresponsive or relapsed patients received telaprevir.
12 weeks of telaprevir in combination with 24 or 48 weeks of peginterferon plus ribavirin based on the extended rapid virologic response.

Treatment outcomes generated by the model were based on outcomes data derived from the IDEAL, REALIZE, and ADVANCE clinical trials.

A theoretical cohort of patients with 10,000 iterations was performed. The end point assumed 1 of 2 health states: sustained virologic response (cure) or fibrosis progression. Dr. Gellad's team assessed the cost of each. "As patients progressed through the model, they accumulated costs, which were expressed in [quality-adjusted life-years]," Dr. Gellad explained.

"The key point is that the efficacy of all 3 strategies is similar, but when you consider point estimates, telaprevir is dominated by the interferon/ribavirin strategies, and this preference is driven by the cost of therapy," Dr. Gellad told Medscape Medical News.

Costs generated by the model were $46,785 for peginterferon plus ribavirin given as response-guided therapy, $54,931 for peginterferon plus ribavirin (not response-guided), and $68,788 for telaprevir plus peginterferon plus ribavirin.

"We then investigated the impact of the cost of telaprevir on the probability of cost effectiveness, and assumed a weekly cost of $3321 [the current cost of the drug].... If the cost dropped below $1433, a triplet with telaprevir became the preferred strategy," he reported.

Dr. Gellad concluded that in treatment-naïve patients with HCV genotype 1 and the (CC) IL-28B polymorphism, initial therapy with a telaprevir-based regimen is unlikely to be cost effective under current cost and efficacy conditions.

Comparison Shopping

"What this group from Duke did is very important because, with resources dwindling, we need to figure out whether a particular treatment is more cost effective than another," said AASLD president T. Jake Liang, MD, tenured senior investigator and chief of the Liver Diseases Branch at the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland. "This is somewhat related to so-called personalized medicine because it uses a genetic marker to identify patients who will respond well to a certain treatment."

Major genetic studies conducted over the past several years have indicated that (CC) IL-28B is a genetic marker highly associated with treatment response to interferon-based therapy. "This is a great marker — probably the best genetic marker we have so far — to gauge how a person will respond to treatment," Dr. Liang said.

The analysis by Dr. Gellad's team "suggests that this could be a way to save some money for patients with the favorable IL-28B genotype," he noted. Certainly, there is excitement about the recent availability of direct-acting antivirals, such as telaprevir, which greatly enhance treatment response, "but then again, maybe not one size fits all. In the spirit of personalized medicine, this may be one way we can reduce costs and, at the same time, retain the same success rate treating patients with HCV."

Dr. Gellad reports consulting for Merck & Co and receiving grants or research support from Merck & Co and PENTAX Medical. Dr. Liang has disclosed no relevant financial relationships.

The Liver Meeting 2011: American Association for the Study of Liver Diseases (AASLD) 62nd Annual Meeting. Abstract 118. Presented November 7, 2011.

Source

December 5, 2011

Boceprevir Often Successful as Rescue Treatment in HCV

Neil Canavan

November 30, 2011 (San Francisco, California) — Patients with hepatitis C virus (HCV) infection who previously failed combination treatment with pegylated interferon alfa-2a (peginterferon) and ribavirin achieved up to a 50% sustained viral response (SVR) with the recently approved protease inhibitor boceprevir. This finding, from the preliminary results of the ongoing PROVIDE study, was reported here at The Liver Meeting 2011: American Association for the Study of Liver Diseases 62nd Annual Meeting.

"This study was designed to give boceprevir treatment to patients who were null responders in the control arms of our previous pivotal trials," said Michelle Treitel, PhD, from Merck Research Laboratories in Kenilworth, New Jersey.

Patients were rolled over from the SPRINT-1, SPRINT-2, RESPOND-2, and PEG 2a/BOC studies into PROVIDE. "These are patients who had either met the futility rule or who had relapsed after the end of treatment with peginterferon and ribavirin. After failure, they were immediately started on 44 weeks of boceprevir/peginterferon/ribavirin triple therapy." The aim of the study was to assess SVR after boceprevir, peginterferon, and ribavirin treatment in nonresponders.

Overall, 168 patients from the 4 studies were enrolled in PROVIDE. Patients were eligible if they received 12 or more weeks of peginterferon plus ribavirin treatment and failed to achieve a SVR (HCV RNA levels below the lower limit of detection of +9.3 IU/mL at treatment week 12 in treatment-experienced patients or at treatment week 24 in treatment-naïve patients), had a virologic breakthrough, or relapsed after the end of treatment (undetectable HCV RNA at the end of treatment but no SVR).

The subanalysis presented by Dr. Treitel involved 48 patients from the SPRINT-2 and RESPOND trials.

Patients were treated with boceprevir 800 mg orally twice daily, peginterferon 1.5 µg/kg subcutaneously once daily, and ribavirin 600 to 1400 mg/day (based on weight) orally in 2 divided doses. All patients received 4 weeks of peginterferon plus ribavirin induction therapy prior to receiving boceprevir. Patients received the boceprevir, peginterferon, ribavirin combination for up to 44 weeks, and were followed for an additional 24 weeks to determine SVR.

The PROVIDE cohort was 64.6% male, 68.8% white, had mean age of 51.0 years, and had a mean body mass index of 26.8 kg/m². Among the patients, 87.5% had a baseline viral load greater than 800,000 IU/mL, 64.6% were infected with HCV genotype 1a, and 4.2% had detectable cirrhosis.

The primary end point of PROVIDE was undetectable HCV RNA 24 weeks after therapy.

In this nonresponder subpopulation, 38% of patients treated with the triple combination achieved a SVR. The achievement of SVR differed by race (27% of black subjects and 42% of nonblack subjects), age (50% of those younger than 50 years and 29% of those older than 50 years), alanine transaminase levels (50% of those with normal levels and 34% of those with elevated levels), and genotype (41% of those infected with genotype 1a and 33% of those with genotype 1b).

"The difference by genotype is the reverse of what you would expect," said Dr. Treitel. "That most likely has to do with the small sample size."

The magnitude of decline in HCV RNA after 4 weeks of peginterferon plus ribavirin induction therapy was positively related to the rate of SVR. Dr. Treitel reported a 50% SVR for patients who experienced a reduction of at least 1 log in HCV RNA, compared with 34% SVR for patients who experienced a reduction of less than 1 log.

"This null group has not been specifically studied for boceprevir before, and these patients are really poor interferon responders," said Dr. Treitel. "In these traditionally very hard-to-treat subjects, we're still showing that you can get a 38% SVR."

Taking It to the Street

"I was very interested to see the rate of response to triple therapy in patients who have previously failed treatment or who were nonresponders," said Abu Hamour, MBBS, MSc, FRCP, from the University Hospital of Northern British Columbia in Prince George, Canada.

The lack of patients with cirrhosis in the study was a sticking point for Dr. Hamour. Although this does not reflect the population of patients he sees in his practice, the conclusions give him something valuable to take home.

"I have this information that I can give to my patients — a prognosis," he said. After treatment with this triple therapy, I can tell patients "who failed treatment with peginterferon/ribavirin or who were nonresponders...[that] if you have a more than a 1 log drop, you have a 50% chance of response; if you have less than a 1 log drop, then your response is much lower, around 35%. Patients can then make choices based on that information."

Dr. Treitel is an employee of Merck Research Laboratory. Dr. Hamour has disclosed no relevant financial relationships.

The Liver Meeting 2011: American Association for the Study of Liver Diseases (AASLD) 62nd Annual Meeting. Abstract 931. Presented November 7, 2011.

Source

November 23, 2011

New HCV Drugs at AASLD

November 18, 2011

AASLD: HCV Testing by Birth Cohort Cost-Effective

By Charles Bankhead, Staff Writer, MedPage Today
Published: November 04, 2011
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

SAN FRANCISCO -- Birth-cohort screening for hepatitis C virus (HCV) infection proved highly cost-effective, even when adjusted for universal treatment with direct-acting antiviral therapy, according to a study reported here.

Universal HCV testing in people born from 1945 to 1965 would detect 800,000 new cases of HCV infection and prevent 82,000 deaths at a cost of $15,700 per quality-adjusted life year (QALY) gained.

Assuming treatment with pegylated interferon and ribavirin would prevent an estimated 121,000 deaths at a cost of $35,700 per QALY, still well within the generally accepted range for cost effectiveness.

The findings were reported simultaneously here at the American Association for the Study of Liver Diseases meeting and online in Annals of Internal Medicine.

"Without new case identification strategies, the adverse consequences of chronic HCV infection are forecasted to result in an increasing public health burden over the next two decades," David P. Rein, PhD, of the National Opinion Research Center at the University of Chicago, and co-authors wrote in conclusion.

"Birth-cohort screening appears to be a reasonable strategy to identify asymptomatic cases of HCV," they added.

More than four million Americans have antibodies to HCV, which leads to chronic infection in about 75% of cases. HCV infection occurs most often in adults born between 1945 and 1965, most of whom acquire infection 20 to 40 years before diagnosis, the authors wrote in their introduction.

Estimates of HCV-related mortality ranged between 7,000 and 13,000 deaths in 2005. Without changes in the current approach to case identification, the number of HCV deaths will increase to 35,000 a year by 2030, the authors continued.

Clinical trials of pegylated interferon and ribavirin have demonstrated efficacy in 46% of patients infected with HCV genotype 1 (which accounts for 70% of infected white patients and 90% of African Americans in the U.S.) and 81% of patients infected with genotype 2 or 3.

The CDC recommends antibody testing for individuals with a history of behaviors, exposures, or health indicators associated with HCV infection (such as intravenous drug use and hemodialysis). Even so, as many as 50% of HCV-infected individuals may be unaware of their status, the authors wrote.

Expanding screening recommendations to the birth cohort covering 1945 to 1965 offers one potential means to increase detection and treatment of HCV infection. Such a strategy would increase healthcare costs, but whether the additional cost would offset potential benefits of expanded screening is unclear.

To address the issue, Rein and colleagues performed an analysis based on data derived from the National Health and Nutrition Examination Survey, census data, Medicare reimbursement information, and published sources.

The analytic model included the estimated cost of HCV testing in the 67 million Americans born from 1945 through 1965 who had at least one visit to a primary care provider in 2006. The authors also calculated the lifetime cost of treating the estimated 2.4 million patients with HCV-positive test results, illness-related lost productivity, increased loss of QALYs, and other relevant factors.

As compared with the current approach to identification of HCV infection, birth-cohort screening would identify 808,580 additional cases of HCV infection at a cost of $2,874 per case. Treatment of the additional cases would result in an additional 348,800 QALYs gained at a total cost of $5.5 billion, resulting in incremental cost-effectiveness ratio (ICER) of $15,700 per QALY.

Expanding the definition of treatment to consist of a direct-acting antiviral, pegylated interferon, and ribavirin results in an additional 532,200 QALYs gained at a cost of $19 billion and an ICER of $35,700 per QALY saved.

Sensitivity analysis yielded a stable ICER that was most sensitive to discounting and QALY losses assigned to disease states, the authors wrote.

Acknowledging limitations of their analysis, Rein and colleagues cited a scarcity of empirical data on screening and treatment with a direct-acting antiviral in real-world clinical settings. Nonetheless, they concluded, "birth-cohort screening for HCV in primary-care settings was highly cost-effective."

The study was supported by the CDC.

The authors had no relevant disclosures.

Primary source: Annals of Internal Medicine
Source reference:

Rein DB, et al "The cost-effectiveness of birth cohort hepatitis C antibody screening in U.S. primary care settings" Ann Intern Med 2011; 155(9): epub.

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Adverse CNS Effects of HCV Treatment Discourage Adherence

Neil Canavan

November 18, 2011 (San Francisco, California) — Patients infected with hepatitis C virus (HCV) can experience a marked decline in neuropsychological cognitive function in the first 14 weeks of combination pegylated interferon and ribavirin therapy. This poses a potential treat to treatment adherence, said clinical psychologist Jeffrey J. Weiss, PhD, MS, from Mount Sinai School of Medicine in New York City, here at The Liver Meeting 2011: American Association for the Study of Liver Diseases 62nd Annual Meeting.

These data are from a large prospective study looking at early treatment discontinuation and the onset of neuropsychiatric symptomatology in HCV monoinfected and HCV/HIV coinfected treatment-naïve patients receiving combination pegylated interferon/ribavirin therapy, Dr. Weiss explained.

"A lot of work has focused on depression, and not to the decrements in cognitive function," said Dr. Weiss. A host of neuropsychiatric symptoms should be considered when initiating a new treatment.

"In this era of direct-acting antivirals, when we're asking patients to take medications 3 times a day (every 6 to 9 hours)..., we need to be aware that, just at baseline, 40% to 50% of patients...[have] substantial deficits in cognitive functioning."

This investigation established the degree of neurocognitive decline during the first 12 and 48 weeks of treatment. Both HCV-infected and HCV/HIV-coinfected patients were evaluated. Neuropsychological instruments were used to explore which domains of cognitive functioning are most affected by combination pegylated interferon/ribavirin treatment, and whether being coinfected with HIV adds to the decrements in cognitive functioning.

There were no significant differences at baseline between the HCV-infected and HCV/HIV-coinfected cohorts for age, sex distribution, ethnicity, HCV RNA viral load, HCV genotype, or stage of liver disease. There were also no differences between the 2 groups at baseline for neuropsychological scores. However, although the same percentage of patients in the HCV and HCV/HIV cohorts reported depression, HCV patients had significantly worse depression scores.

After treatment, global neuropsychological function declined significantly in HCV patients during the first 24 weeks of HCV treatment. Domains with the greatest declines were memory, executive function, and motor function. "The HCV monoinfected group also had a greater decline in neuropsychological function than the coinfected group in the first 12 weeks," said Dr. Weiss. "This is probably due to more depression among HCV patients at baseline."

How a patient's declining neuropsychological function affects their behavior is key, and can depend on clinical history, Dr. Weiss explained. "Patients who have a history of cognitive dysfunction might respond less to the onset of new symptoms. Patients with a significant pathology who are already well engaged in psychiatric treatment tend to do quite well on [antiretroviral] treatment because they are familiar with the symptoms and are being well managed." Those who are high functioning at baseline will have more trouble; to be successfully managed, the healthcare provider must be aware of the potential for central nervous system (CNS)-related treatment nonadherence.

CNS and the Hepatologist

Raymond T. Chung, MD, vice chief of the gastrointestinal unit and medical director of the liver transplant program at Massachusetts General Hospital in Boston, agrees that the hepatologist must be part psychiatrist. "We field these patients rather then pass them off since there can often be overlap with true advanced hepatic disease and hepatic encephalopathy."

He is mindful of the potential impact of HCV medications. "It has been a modest issue with both HCV/HIV and HCV alone." Symptoms are often called "brain fog," Dr. Chung explained. "This fog does get in the way, in high-functioning individuals, of their ability to carry out intricate calculative functions and memory at work, for instance." It would not be surprising for such a patient to become frustrated and consider forgoing medication, he observed.

Dr. Chung considers the issue manageable if it is proactively addressed. However, like many clinicians at the meeting, he's looking more toward preventing than managing adverse effects by eliminating pegylated interferon from standard HCV treatment.

Dr. Weiss reports being a consultant for Vertex Pharmaceuticals and Kadmon Pharmaceuticals. Dr. Chung has disclosed no relevant financial relationships.

The Liver Meeting 2011: American Association for the Study of Liver Diseases (AASLD) 62nd Annual Meeting. Abstract 972. November 6, 2011.

Source

Two New Drugs Poised to Replace Interferon in HCV Treatment

Neil Canavan

November 18, 2011 (San Francisco, California) — Two new compounds — a protease inhibitor and a polymerase inhibitor — have the potential to replace pegylated interferon in standard treatment regimens for hepatitis C virus (HCV), according to late-breaking data reported here at The Liver Meeting 2011: American Association for the Study of Liver Diseases (AASLD) 62nd Annual Meeting.

In an interim analysis of the open-label phase 2b SOUND-C2 study, investigators looked at the novel protease inhibitor BI 201335 (BI35, Boehringer Ingelheim) and the novel polymerase inhibitor BI 207127 (BI27, Boehringer Ingelheim).

The analysis involved 362 treatment-naïve patients with HCV genotype 1. In the cohort, 52% were male, 98% were white, 85% had an HCV RNA viral load of at least 800,000 IU/mL at baseline, 39% had HCV genotype 1a, 10% showed evidence of compensated cirrhosis, and 26% carried the interleukin (IL)28B polymorphism C/C genotype.

The 5 treatment groups, which all received BI35 120 mg once daily, were:

• BI27 600 mg 3 times a day plus ribavirin for 16 weeks, for 28 weeks, or for 40 weeks (thrice-daily groups)

• BI27 600 mg twice daily plus ribavirin for 28 weeks (twice-daily group)

• BI27 600 mg 3 times daily without ribavirin for 28 weeks (no-ribavirin group).

"Having 2 investigational compounds in 1 trial is a bit unusual," noted Federico Mensa, MD, from the division of clinical research in virology at Boehringer Ingelheim Pharmaceuticals in Ridgefield, Connecticut.

"The idea is to take interferon out of the regimen equation. That treatment is associated with so many adverse events that many patients don't even want to start treatment," Dr. Mensa noted. It's thought that the combination of 2 of the so-called direct-acting antiviral agents will also prevent the emergence of resistance prior to sustained virologic response, he added.

The interim analysis was performed after all patients completed 12 weeks of treatment. Data for the 238 patients in the 16-week and 28-week thrice-daily groups were combined, since those patients received the same treatment for the first 12 weeks.

Results at week 4 show that response to antiviral treatment (HCV RNA viral load below the lower limit of quantification) ranged from 88% for the thrice-daily groups to 72% for the no-ribavirin group.

At week 12, responses ranged from 76% for the twice-daily group to 57% for the no-ribavirin group.

At weeks 4 and 8, virologic failure occurred in 3.4%, 1.3%, and 4.3% of patients in the thrice-daily, twice-daily, and no-ribavirin groups, respectively.

Virologic breakthrough at 12 weeks occurred in 13.4%, 20.5%, and 32.6% of patients in the twice-daily, thrice-daily, and no-ribavirin groups, respectively.

Patients infected with HCV genotype 1a had a lower response rate than others in the study, particularly those in the no-ribavirin group. The lowest rate of response was for IL28B non-C/C patients in the no-ribavirin group (22%); it was 100% in patients with the C/C genotype in the no-ribavirin group. Excellent response was seen in genotype 1b patients, regardless of IL28B status.

"Viral response rates at 12 weeks of up to 76% were comparable to complete early virologic responses achieved with first-generation protease inhibitors plus pegylated interferon," said Dr. Mensa.

How do low response rates observed for patients with HCV genotype 1a, IL28B non-C/C stack up? "This is an important question. Right now my understanding is that we have not seen that data published — the response rates for genotype 1a patients with the unfavorable C/C IL28b variant are not available, to my knowledge, for boceprevir or telaprivir. So it is hard to make a comparison," said Dr. Mensa.

There were some early discontinuations recorded for reasons other than virologic failure, including adverse events and patients lost to follow-up — 17% in the thrice-daily groups, 6% in the twice-daily group, and 13% in the no-ribavirin group. The most common adverse events were mild to moderate gastrointestinal or skin events.

Discussions are ongoing regarding the treatment protocol for a planned phase 3 study using these agents.

What Took So Long?

"Clearly, the protease inhibitors have shot ahead of the nonnukes [polymerase inhibitors], especially because the structural chemistry was understood earlier," said David R. Nelson, MD, associate dean for clinical research in the division of gastroenterology, hepatology, and nutrition at the University of Florida College of Medicine in Gainesville. "Protease inhibitors have also been much more potent than the typical nonnukes. There were some in development prior to protease inhibitors, but the potency of these drugs early on is what limited clinical trial results."

Dr. Nelson is the lead investigator of the ZENITH trial, in which the polymerase inhibitor VX-222 (Vertex Pharmaceuticals) is being combined with the recently approved protease inhibitor telaprevir in a population of treatment-naïve patients infected with HCV genotype 1.

The ZENITH trial is looking at the efficacy and tolerability of VX-222, telaprevir, and ribavirin with and without pegylated interferon. Response rates for the pegylated-interferon-free group will be reported at the 2012 meeting of the European Association of the Study of the Liver.

Dr. Mensa reports being an employee of Boehringer Ingelheim. Dr. Nelson reports being a consultant for Bayer HealthCare, Biolex, and Roche; and receiving grants and research support from Abbott, Anadys Pharmaceuticals, Bayer HealthCare, BMS, Gilead Sciences, Human Genome Sciences, Merck, Novartis, Roche, and Vertex Pharmaceuticals.

The Liver Meeting 2011: American Association for the Study of Liver Diseases (AASLD) 62nd Annual Meeting. Late-breaking abstract 15, presented November 7, 2011. Abstract 14, presented November 9, 2011.

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