Dr. E Lebovics: Post-EASL 2015 HCV Interview

Posted on June 2, 2015

During our last interview, you mentioned that extending the use of all oral, interferon-free, hepatitis C regimens to special populations including those with decompensated cirrhosis, post-transplant, and renal failure is an area of great interest. We would like to hear your thoughts on relevant clinical data presented at The International Liver Congress™ 2015, 50th annual meeting of the European Association for the Study of the Liver, in Vienna, Austria, April 22-26, 2015.

For more information on the selected EASL 2015 HCV abstracts discussed below, please click here to review the Congress abstract e-book.

Abstract G02: Ledipasvir/Sofosbuvir with Ribavirin is Safe And Efficacious in Decompensated and Post Liver Transplantation Patients with HCV Infection: Preliminary Results of the Prospective SOLAR 2 Trial. Manns M, et al.

Could you please discuss the importance of this type of study to the management of special populations with HCV infection?

Dr. Lebovics: The populations with arguably the most pressing need for anti-viral therapy are the decompensated cirrhotics and post-transplant patients. These patients were generally not eligible for interferon-based therapy because of the side-effect profile. With the emergence of safe and effective oral agents, these patients can now be offered therapy. The burning questions are as follows: will they respond as well as patients with less advanced disease (recalling that cirrhosis is a negative predictor of response)? will the liver disease improve with response?

Please summarize your key takeaways from the results of this study?

Dr. Lebovics: The regimen of sofosbuvir, ledipasvir, and ribavirin was very effective, with SVR in the 12 week arms of 95% for F0-3 and Childs A post-transplant and 85% in Childs B or C pre- or post-transplant. The regimen was also very well tolerated with very few discontinuations even with the use of ribavirin. MELD score fell in most patients, and Childs score fell from B to A in 35% and C to B in 48% of patients. However, most of the improvement was attributable to a drop in bilirubin and a rise in albumin.

Based on your understanding of the SOLAR-2 preliminary study data, what questions would you have for the study investigators?

Dr. Lebovics: I would want to know if signs of decompensation improved in responders. Did encephalopathy disappear? Did ascites resolve? It could be a pyrrhic victory if eradication of the HCV reduced the MELD score without reversing liver failure, as the opportunity for transplant might actually be delayed.

What questions regarding the safety and efficacy of DAA combinations in decompensated and post liver transplantation patients with HCV infection do you hope will be addressed in future meetings?

Dr. Lebovics: I would like to see a clear benefit of therapy in the decompensated cirrhotic patient, so that infection of a future graft is avoided – although this is not as great a victory as it may have been in the past, now that post-transplant therapy is a reality. The question remains regarding whether overall outcome and survival is improved. It is now evident that all patients should be treated post-transplant to clear HCV.

How do you envision that current practice habits in the US will be changed based on the results of this study? What, if any, barriers will prevent such a change in practice?

Dr. Lebovics: For a decompensated patient who is not a transplant candidate, anti-viral therapy would certainly be appropriate unless the patient’s chance for short-term survival is poor. For decompensated cirrhotics awaiting transplant, I think that in practice most hepatologists will opt for therapy on the assumption that eradicating HCV can only help. Again, the overall survival benefit is yet unproven. I am aware that some transplant surgeons have argued to delay therapy till post-transplant in patients who are irreversibly headed to transplant. Cost is generally not a barrier in this population except in uninsured patients.

What are your thoughts on the continued use of ribavirin in DAA therapies? Is ribavirin really necessary?

Dr. Lebovics: Ribavirin in this regimen enables curtailing of the duration of therapy from 24 to 12 weeks in difficult to treat patients. Importantly, this reduces costs. For some regimens and for some populations it remains essential. The concern with ribavirin is tolerability due to hemolysis. Also it is difficult to use in the setting of renal failure and its use necessitates contraception. We keep hoping to “bury” ribavirin but studies such as this one show that it still has a role.

 

Abstract LO8: Daclatasvir, Sofosbuvir, and Ribavirin Combination For HCV Patients With Advanced Cirrhosis or Posttransplant Recurrence: Phase 3 ALLY-1 Study. Poordad F, et al.

Please summarize your key takeaways from the results of this study?

Dr. Lebovics: This study also involved patients with advanced cirrhosis and patients who were post-transplant. Therapy with daclatasvir, sofosbuvir and ribavirin for 12 weeks was highly effective for the post-transplant patients with an SVR of 94%. The patients with Childs A and B cirrhosis also had excellent results with SVRs of 92 and 94% respectively. The Childs C cirrhotics did not fare as well with an SVR in only 56%.

Based on your understanding of the ALLY-1 study data, what questions would you have for the study investigators?

Dr. Lebovics: I was intrigued by the finding that an albumin of <2.8 seemed to be a negative predictor of response, more so than the presence of ascites or encephalopathy or the level of bilirubin. It would be interesting to see if this turns out to be a predictor with other regimens as well. I’d also want to know whether BMS will pursue other studies with variation of this regimen for the Childs C patients.

Aside from the use of daclatasvir instead of ledipavir, could you please outline what you consider to be similarities and differences between the results of this study and those of the SOLAR-1 study?

Dr. Lebovics: The patient population is similar other than that the Ally study includes genotypes 2 and 3 owing to the pangenotypic range of daclatasvir. The SOLAR study lumped Childs B and C into a single group whereas the ALLY study reported them separately. These factors make it difficult to compare the results directly. Yet, it seems the Childs C genotype 1 cirrhotics did better in SOLAR than in ALLY.

What challenges do you think daclatasvir will face should it be approved for use in the US given the current availability of approved DAAs such as ledipasvir/sofosbuvir?

Dr. Lebovics: Daclatasvir will definitely fill a void for genotype 2 and 3 patients, although the initial approval is anticipated to be only for genotype 3. The combination of daclatasvir and sofosbuvir is not a single pill, as is the case for ledipasvir and sofosbuvir. An issue that is emerging is the importance of resistance associated variants or RAVs involving the NS5A region. This is not unique to daclatasvir.  It remains to be determined whether baseline RAVs are important enough that testing for RAVs should be done prior to initiating therapy. Also, it appears the treatment-associated NS5A RAVs hang around for a long time, so your first shot with an NS5A inhibitor is your best shot. Coming into the market after ledipasvir, this may prove to be an issue for daclatasvir in NS5A-experienced patients.

  

Abstract O007: All Oral HCV Therapy is Safe and Effective in Patients with Decompensated Cirrhosis: Interim Report From the HCV-TARGET Real World Experience. Reddy R, et al.

Please summarize your key takeaways from the results of this study?

Dr. Lebovics: TARGET is an international registry reporting real world experience with DAAs. This report focuses on treatment of decompensated cirrhotics defined as having a MELD score >10. Most genotype 1 patients were treated sofosbuvir plus simeprevir. For this regimen, the SVR was 74%. Essentially, all genotype 2 and 3 patients were treated with sofosbuvir plus ribavirin. SVR for G2 was 81% and the SVR for G3 was 39%. Higher bilirubin was a negative predictor and higher albumin was a positive predictor of response.

Based on your understanding of this real world HCV study data, what questions would you have for the study investigators?

Dr. Lebovics: Well, as the authors state, further follow-up will be needed to assess the reversibility of decompensation in responders. As we already discussed, a key question is the impact on timing and need for transplantation, and survival. Of note, for genotypes 2 and 3, the regimen of sofosbuvir plus ribavirin will be replaced by the ALLY-1 regimen of sofosbuvir, daclatasvir and ribavirin, as the preferred regimen in the near future.

Please outline what you perceive to be the strengths and weaknesses of real world HCV treatment data?

Dr. Lebovics: The experience with interferon-based regimens was that response rates in the real world were substantially worse than in clinical trials because of poor tolerability. Real world studies have shown that this is not the case for DAAs. These agents are very well tolerated by patients, and adherence tends to be excellent. Real world studies also allow reporting of large numbers of patients pooled from many centers in a short period of time. The drawback is that the treatment protocols and reliability of reporting may vary from center to center rendering the data difficult to tease apart for interpretation. Overall, I find these studies quite valuable.

 

Abstract O008: Efficacy and Safety of Grazoprevir and Elbasvir in Hepatitis C Genotype 1-Infected Patients With Child–Pugh Class B Cirrhosis (C-SALT Part A). Jacobson IM, et al.

Could you please discuss the importance of this type of study to the management of Hepatitis C genotype 1-infected patients with cirrhosis?

Dr. Lebovics: This is another study addressing the decompensated cirrhotic population. For grazoprevir and elbasvir, the study was limited to Childs B and used a reduced dose of grazoprevir because of its hepatic metabolism.

Please summarize your key takeaways from the results of this study?

Dr. Lebovics: This single pill, ribavirin-free regimen was highly effective with 90% SVR. There was no hepatotoxicity and the regimen was well tolerated. Childs scores improved in most patients.

Based on your understanding of the C-SALT study data, what questions would you have for the study investigators?

Dr. Lebovics: With such impressive results in Childs B cirrhotics, will Merck be daring enough to pursue this regimen in Childs C cirrhotics? The concern, of course, is hepatotoxicity.

Based on your knowledge of available clinical data, do you see the combination of grazoprevir and elbasvir finding a usage niche in the US once approved?

Dr. Lebovics: Absolutely. I think it will be the preferred regimen for renal failure patients. Also, it will be very competitive as a single pill, ribavirin-free regimen for genotypes 1 and 4.

 

Abstract G15: The Association of Sofosbuvir and Daclatasvir For Treating Severe Recurrence of HCV Infection After Liver Transplantation: Results From a Large French Prospective Multicentric ANRS CO23 CUPILT Cohort. Coilly A, et al.

Please summarize your key takeaways from the results of this study, and potential implications to the treatment of post-transplant patients in the US?

Dr. Lebovics: This was a French and Belgian multicenter study of post-transplant patients of any genotype treated with sofosbuvir plus daclatasvir with or without ribavirin for 12 or 24 weeks as per the decision of the investigator. Response rates were fantastic, with only 2 virologic failures out of 130 patients treated. Addition of ribavirin did not confer any added efficacy. Improvement in biochemical parameters such as bilirubin and albumin were seen. MELD scores improved in most patients. However, a decline in renal function was seen and about half of the patients required dose adjustment of their immunosuppressive regimen.

Based on your understanding of the ANRS CO23 CUPILT Cohort study data, what questions would you have for the study investigators?

Dr. Lebovics: The effects of this regimen on renal function and on the post-transplant immunosuppressive drug dosing are unexpected. It would be important to know whether these changes differ from a control population of non-HCV infected post-transplant patients at a similar point in their post-transplant course.

 

Abstract LO1: Safety of Ombitasvir/Paritaprevir/Ritonavir Plus Dasabuvir For Treating HCV GT1 Infection in Patients with Severe Renal Impairment or End-Stage Renal Disease: The RUBY-I Study. Pockros PJ, et al.

Please summarize your key takeaways from the results of this study?

Dr. Lebovics: Patients with renal failure have not been served well with anti-viral therapy for hepatitis C to date. The 3 DAA regimen is not renally metabolized but does require ribavirin, which is renally metabolized, for genotype 1A patients. This is an interim report primarily focused on the safety of this regimen in renal failure patients including those on dialysis. Genotype 1A patients were started on ribavirin 200 mg daily or 4 hours prior to dialysis. 8 of 13 patients had to interrupt dosing of ribavirin because of anemia. Only 1 had a drop in hemoglobin below 8. Four were treated with erythropoietin and none required transfusion. At the time of the report, 10 of 10 patients who reached 4 weeks of follow-up achieved an SVR4.

Based on your understanding of the RUBY-I study data, what questions would you have for the study investigators?

Dr. Lebovics: Well, full results of efficacy are pending. It is somewhat moot because the ribavirin-free regimen of grazoprevir plus elbasvir will become the preferred regimen for renal failure patients when available.

Have you used 3 DAA combinations in your practice? If yes, how often and in what types of patients? Does the use of multiple DAA combinations pose a problem to your practice and patients with regards to access/reimbursement?

Dr. Lebovics: Absolutely. It is a highly effective and well-tolerated regimen for genotypes 1 and 4 (for genotype 4 dasabuvir is omitted). The need for multiple pills does not seem to be an issue for adherence. The choice of regimen is largely dictated by payers currently. As the therapeutic options expand it will remain to be seen how payers will handle a clinician’s preference to mix different drugs for specific indications.

In your practice, how often do you see HCV-infected patients with “clinical trial defined” symptoms of severe renal Impairment or end-stage renal disease? In clinical practice, do these symptoms correlate with liver disease and/or other complicating factors?

Dr. Lebovics: Between 5% and 15% of dialysis patients are hepatitis C infected so it’s quite common. The population this trial is addressing are patients with compensated hepatitis C who have coincident renal failure. Certainly renal failure can be a complication of end-stage liver disease, often but not always in the form of the hepatorenal syndrome. That’s not what we’re talking about here.

 

During our last interview, you also mentioned that you would like to see data from the ILC-EASL meeting focusing on pre-HCV treatment assessment and post-treatment follow-up. We would like to hear your thoughts on the following ILC-EASL presentations.

Abstract O003: Can Hepatitis C Treatment Be Safely Delayed? Evidence From the Veterans Administration Healthcare System. McCombs JS, et al.

Please summarize your key takeaways from the results of this study, as well as the implications to the management of patients chronically infected with HCV?

Dr. Lebovics: These authors had performed a statistical analysis of the VA database and previously showed that HCV suppression decreases the risk of liver-related adverse events and death. They also showed that the FIB-4 test, a composite test that measures liver fibrosis, can be used to monitor the risk of liver-related adverse events and death. The question addressed in this study is: does delaying therapy until FIB-4 levels rise decrease efficacy of therapy in preventing liver-related adverse events and death? In a word, the answer was yes. The implications of this finding are significant. Some payers in the U.S. and many in other countries are limiting therapy to patients with advanced disease defined as F3 or F4 fibrosis. This study indicates that such a policy will increase liver-related adverse events and deaths and is therefore unjustifiable.

Please outline what you perceive to be the strengths and weaknesses of this study?

Dr. Lebovics: The strength is the statistical analysis of a huge database. The weakness is inherent to any retrospective database analysis – the population may not be representative of the general population, data may not have been accurately entered, etc. On balance, it’s a very valuable study.

How do you envision that current practice habits in the US will be changed based on the results of this study? What, if any, barriers/rationales will prevent such a change in practice?

Dr. Lebovics: I think this is yet another piece of evidence that promotes viral eradication in all HCV-infected patients. The barrier to universally activating this policy is, of course, cost. Hopefully, with more competition in the market, costs will decrease significantly.

 

Abstract O063: HCV Reinfection Cases in Phase 3 Studies of  Sofosbuvir. Svarovskaia E, et al.

Please summarize your key takeaways from the results of this study, as well as the implications to the management of patients chronically infected with HCV?

Dr. Lebovics: Concordance between SVR12 and SVR24 in 5 phase 3 Gilead studies was 99.7%. For 12 identified discordant cases, deep sequencing of NS5B was done and indicated that 7 of the so-called relapse cases were in fact reinfections with a new virus. This study highlights the fact that apparent relapse may in fact more commonly be reinfection. It would be important to identify the risk factors for reinfection in these patients. If active IV drug use is found to be responsible, and if the prevalence of reinfection is determined to be significant over time, reevaluation of whether such patients should be offered therapy would be appropriate. For now, it seems to be a rare occurrence.

What do the results of this study say about the use of SVR12 versus SVR24 in clinical trials? How do these results relate to your clinical experiences? How do you define treatment success in your practice?

Dr. Lebovics: I think this study strengthens the conclusion that SVR12 is an acceptable indicator of cure. That is what I use in my practice although a week 24 follow-up HCV RNA should be obtained as well. I have yet to see a discordant SVR12 and SVR24.

 

Abstract O120: Advanced Fibrosis is Common in Individuals Whose Hepatitis C Has Not Been Diagnosed: Results From the National Health and Nutrition Examination Survey 2001–2012. Udompap P, et al.

Please summarize your key takeaways from the results of this study, as well as the implications to the management of patients chronically infected with HCV?

Dr. Lebovics: About 75% of HCV-infected persons in the U.S. are unaware of their infection until screened. This study looked at the degree of liver fibrosis, as measured by FIB-4 or APRI scores, in this unaware screened population compared to those with known hepatitis C. It turned out that the 2 populations were about the same – about 20% with advanced fibrosis and 10% with cirrhosis.

How would you address the potential implication that the results of this study strengthen the argument for reserving costly new DAA therapies for those with advanced fibrosis?

Dr. Lebovics: The implication of this study is to underscore the need to screen patients for hepatitis C. A significant percentage of unaware patients are at short-term risk for complications of liver disease, so time is of the essence in bringing them to medical attention.

Thank you Dr. Lebovics for providing your opinions on key presentations of interest from the 2015 ILC-EASL Congress. I have a couple of final questions:

Please highlight the most important unanswered and/or new clinical practice questions you have based on the wealth of HCV clinical data presented at this year’s ILC-EASL meeting?

Dr. Lebovics: What’s most exciting is the outlook for multiple, different, effective, all-oral regimens for hepatitis C including all genotypes, treatment-experienced patients, HIV-coinfected patients, renal failure patients, decompensated cirrhotics, and post-transplant patients. Identifying the ideal regimen for each patient subtype will require data that will emerge in the coming years. A major issue that is now coming to attention is the impact of resistance and whether testing for RAVs prior to choosing a regimen will become necessary. Just recently, we were talking about how simple managing hepatitis C has become and whether it should be undertaken by primary care physicians. Now, at least for some patient subtypes, it’s becoming complicated again.

What future meetings are important to you with regards to HCV education? Which other meetings are you planning to attend this year?

Dr. Lebovics: The next major Hepatology meeting is AASLD in November. I hope to be there.

For more information on the selected EASL 2015 HCV abstracts discussed above, please click here to review the Congress abstract e-book.

 


No Replies to "Dr. E Lebovics: Post-EASL 2015 HCV Interview"


    Join the discussion

    Some html is OK