June 16, 2014

Hepatitis C Treatment: Hope on the Horizon

Medscape Gastroenterology

Digestive Disease Week (DDW) 2014

Donald M. Jensen, MD, Lauri R. Graham

June 16, 2014

Editor's Note: The treatment for hepatitis C is evolving rapidly, and interferon-free options are now finally possible, with impressive sustained viral response (SVR) rates. Medscape spoke with Donald M. Jensen, MD, Professor of Medicine and Director of the Department of Hepatology at the University of Chicago, about the new and forthcoming treatment options for hepatitis C, some of which were presented at the recent Digestive Disease Week (DDW) meeting; the collaboration of care among providers in the treatment of patients; and an assessment of the cost now versus the prior standard of care.

Interferon-Free Options At Last

Medscape: The ION, SAPPHIRE, TURQUOISE, and PEARL studies were for hepatitis C genotype 1 and tested interferon-free regimens in specific patient populations (such as treatment-naive, treatment-experienced, and cirrhotic patients). The results of these studies have now been shared, some of which were presented at DDW. Could you briefly describe the highlights from each study? Let's start with ION-1 and ION-2.

Dr. Jensen: Historically, hepatitis C genotype 1 has been one of our more difficult-to-treat patient populations -- and 70% of the US population with hepatitis C has genotype 1 -- so most of the studies focused on interferon-free therapies for this genotype.

The ION studies use an interferon-free combination of sofosbuvir plus ledipasvir, with and without ribavirin. Sofosbuvir is a nucleotide inhibitor, and ledipasvir is an NS5A inhibitor. ION-1 and ION-2[1-2] compared 2 different regimens: ION-1 in treatment-naive patients, 16% of whom had cirrhosis, and ION-2 in treatment-experienced patients in whom a pegylated interferon and ribavirin-based therapy, with or without a protease inhibitor, had previously failed.

The regimens were similar in both of these ION studies. They compared 12 or 24 weeks of sofosbuvir and ledipasvir, with or without ribavirin. ION-1 had over 200 patients in each of the 4 arms, and ION-2 had over 100 patients in each of the 4 arms.

In ION-1, the SVR rate, or cure rate, for treatment-naive patients varied between 97% and 99%. These are truly remarkable cure rates in this patient population. In ION-2, patients in whom therapy had previously failed demonstrated SVR rates between 94% and 99%, which are almost as impressive as in ION-1.

ION-2 showed that it did not seem to matter whether patients had failed prior protease inhibitor treatment. Ribavirin really didn't add anything to the success of any of the arms in either of the 2 clinical trials.

The difference between 12 and 24 weeks was also not readily apparent. In the patients in ION-2, there was a slight numerical advantage at 24 weeks with 99%, but it was 94% and 96% in the 12-week arms.

A subanalysis of ION-2 examined treatment-experienced patients who had cirrhosis. Patients given sofosbuvir and ledipasvir with or without ribavirin for 12 weeks had a response rate of 82%-86%, whereas when they received it for 24 weeks, they did much better -- with an SVR of 100%. This will raise the issue of whether cirrhotic patients in whom previous therapy failed might do better with 24 weeks of treatment as opposed to just 12 weeks.

This was not a statistically significant difference, but certainly this point needs to be further assessed. The number of patients with cirrhosis in each of these arms is relatively small (only 22 patients in each arm), so maybe more robust numbers will give a better indication of whether a longer duration is needed in this patient population.

Medscape: What were some of the highlights from ION-3?

Dr. Jensen: ION-3[3] -- which was presented at this year's DDW meeting -- compared treatment durations of 8 weeks vs 12 weeks with a sofosbuvir and ledipasvir combination in treatment-naive, noncirrhotic patients with hepatitis C genotype 1. There were over 200 patients in each of the 3 arms: sofosbuvir and ledipasvir for 8 weeks; sofosbuvir, ledipasvir, and ribavirin for 8 weeks; and sofosbuvir and ledipasvir for 12 weeks. The SVR rate was between 93% and 95% in all of the arms. In the 8-week arms, it was 94% with sofosbuvir and ledipasvir and 93% with sofosbuvir, ledipasvir, and ribavirin; in the 12-week arm, it was 95% with sofosbuvir and ledipasvir.

This suggests that 8 weeks might be just as good as 12 weeks in treatment-naive patients with genotype 1. But a word of caution: There were no cirrhotic patients, and all were treatment-naive. There were no treatment-experienced participants.

So will 8 weeks become the standard, or is this an option only for some patients? Going forward, I think 8 weeks looks like it may be an option for treatment-naive patients with mild hepatitis C genotype 1, but it remains to be seen whether those with more complicated disease can benefit from a shorter treatment duration.

Medscape: Have shorter treatment durations, such as this one of 8 weeks, been looked at in other studies?

Dr. Jensen: An arm of the ELECTRON trial[4] investigated an even shorter duration -- 6 weeks of sofosbuvir and ledipasvir and ribavirin -- the thought being that if 8 weeks was as good as 12 weeks, what about 6 weeks? There were 25 patients in that arm, and they were treatment-naive and without cirrhosis. The SVR rate was only 68%.

So, it looks like you need more than 6 weeks, but 8 weeks looks like it's as good as 12 weeks. Eight weeks is probably the shortest duration that we can think about in treatment-naive patients with genotype 1 with this combination.

Medscape: Let's talk about some of the other studies. What are the highlights of SAPPHIRE and TURQUOISE?

Dr. Jensen: In SAPPHIRE and TURQUOISE, 3 direct-acting antiviral agents were combined with ribavirin. These agents were ABT450, which is a protease inhibitor and boosted with ritonavir; ABT267, which is an NS5A inhibitor now known as ombitasvir; and ABT333, which is a non-nucleoside inhibitor now known as dasabuvir.

SAPPHIRE I[5] included noncirrhotic patients with hepatitis C genotype 1 who had not been previously treated. They were treated with this so-called 3D combination plus ribavirin. An SVR rate of 96% was achieved in those treated for 12 weeks. So, again, this is very comparable to what we saw with the ION-1 study, but here there were no cirrhotic patients.

In SAPPHIRE II,[6] treatment-experienced noncirrhotic patients with hepatitis C genotype 1 were treated with 12 weeks of the 3D combination plus ribavirin, and they also achieved an SVR rate of 96%. There were 297 patients, which is a very robust number.

To answer the question of whether cirrhotic patients did differently, TURQUOISE II[7] was done in 380 patients with cirrhosis; both treatment-naive and treatment-experienced patients were included. One arm of 208 patients received 12 weeks of the 3D combination plus ribavirin, and in the other arm, 172 patients received 24 weeks of the 3D combination plus ribavirin. The SVR rate in the 12-week arm was 92%, and it was 96% in the 24-week arm. These are very good response rates in cirrhotic patients.

Medscape: Moving on to PEARL, these studies were undertaken to analyze genotype 1a and 1b separately. Could you share the highlights?

Dr. Jensen: There was a lingering question about whether genotype 1a and 1b respond similarly. Previous data from the SAPPHIRE studies had shown that genotype 1a responded a little less well than genotype 1b -- so, yes, the PEARL studies were undertaken to analyze genotype 1a and 1b separately.

PEARL III[8] included 419 patients with hepatitis C genotype 1b who were treatment-naive. They were given the 3D combination without ribavirin for 12 weeks, or the 3D combination with ribavirin for 12 weeks. It only studied a 12-week duration. The SVR rates were 99% in both arms, so it was extremely good in genotype 1b.

PEARL IV[8] examined genotype 1a, the subtype of genotype 1 that didn't respond quite as well as genotype 1b in prior studies. In this study, they had about 200 patients in the 3D combination without ribavirin and 100 patients in the 3D combination with ribavirin. The SVR rate was 90% in the 3D combination without ribavirin, and 97% in the 3D combination with ribavirin. So again, this is a high success rate -- a little less than PEARL III, but these were not head-to-head studies. What it suggests, however, is that patients do very well with this 3D combination with and without ribavirin. Genotype 1a may benefit a little more with ribavirin.

It's amazing that we're even saying that 90% is inferior, compared with where we were not that long ago. But this is where we're going with genotype 1, as you can see from all of the studies we discussed.

Hope and Promise for Patients With Genotype 1

Medscape: In your opinion, what do these interferon-free treatment options mean for providers and also for patients with hepatitis C genotype 1?

Dr. Jensen: I think it gives a lot of hope and promise for patients with genotype 1 -- both for those who have been waiting for these new therapies, and also for those who haven't even touched therapy yet.

For patients in whom previous therapy has failed, it's even more promising. I think those patients have been the most worried. They've failed 1 or 2 courses of an interferon-based treatment, and they've been to hell and back with those therapies. They are worried that they will develop cirrhosis, that they will need a liver transplant, or that they will develop liver cancer.

I think having these high cure rates -- even in previously difficult-to-treat populations -- is really all about hope. As providers, we can offer our patients something both better and safer.

Medscape: What's also striking about these treatment options is how well they are tolerated. What are your thoughts?

Dr. Jensen: I think that is one of the biggest things. The fact that virtually all of the patients were able to complete the trials, and very few dropped out due to side effects, is impressive. The only side effects of most of these new drugs were headache and nausea, but nothing like what was experienced with the interferon-based therapies in the past.

Getting rid of ribavirin would be another huge step forward, and it looks like that may be possible from many of these studies. Ribavirin is associated with anemia and does have some teratogenicity, so women of childbearing age have to be careful.

Besides the fact that these therapies are well tolerated, we also know that a shorter duration and less pill burden does improve patient compliance and adherence.

Options for Patients With Genotypes 2 and 3

Medscape: What's on the treatment horizon for patients with hepatitis C genotypes 2 and 3?

Dr. Jensen: In a study[9] presented at DDW, patients with hepatitis C genotype 2 or 3 in whom prior treatment with sofosbuvir and ribavirin had failed were successfully retreated with a sofosbuvir-containing regimen. These patients were treated with either 12 weeks of sofosbuvir plus pegylated interferon and ribavirin or 24 weeks of sofosbuvir plus ribavirin, and the SVR12 rates were then compared.

The 12-week treatment arm (sofosbuvir plus pegylated interferon and ribavirin) had 34 patients, and the 24-week treatment arm (sofosbuvir plus ribavirin) had 73 patients. This was an interim analysis, because only 26 of the 34 patients in the 12-week arm and 40 of the 73 patients in the 24-week arm completed therapy. The SVR12 rate for the 12-week arm was 92%, and in the 24-week sofosbuvir plus ribavirin arm, it was 63% (50% in genotype 2 and 63% in genotype 3). Because both genotypes 2 and 3 performed equally in the 24-week arm, it suggests that we probably need something more than just longer retreatment with sofosbuvir and ribavirin -- perhaps interferon is not totally dead.

So for patients in whom treatment has failed in previous 12-week studies of sofosbuvir and ribavirin, this suggests that if they were to be retreated, they probably would do better with 12 weeks of sofosbuvir, pegylated interferon, and ribavirin than with sofosbuvir and ribavirin for 24 weeks. This might change once we have NS5A inhibitors to combine with sofosbuvir, but for now, this may be an option for these patients going forward.

No More "Difficult to Treat" Populations

Medscape: Where are we at in the treatment of coinfected patients? Are these newer drugs effective in this patient population as well?

Dr. Jensen: There have been studies[10-13] in coinfected patients with several of the different combinations, such as sofosbuvir and ribavirin; sofosbuvir and ledipasvir; and simeprevir, pegylated interferon, and ribavirin. What has come out of these studies is that the response rates in coinfected patients (regardless of genotype) are very similar to that seen in similar studies of monoinfected patients.

I think the big news is that this previously "difficult to treat" patient population with HIV and HCV is probably not going to be so difficult to treat moving forward. If their HIV is under control, patients seem to respond just as well to these new direct-acting antiviral combinations as patients without HIV. I think that is terrific news.

The same can also be said for many patients with cirrhosis, in that it is probably not as difficult to treat anymore. They are responding reasonably well, though not quite as well as noncirrhotic patients.

So, we are learning that these previously difficult-to-treat populations are probably not going to be so difficult to treat with these new agents.

Challenges to Treatment May Still Remain

Medscape: There's a lot of good news now surrounding the treatment of hepatitis C. Let's talk about some of the challenges. What about patients in whom therapy with these new drugs fails? Where are we at with resistance and rescue strategies, or are those still to be determined?

Dr. Jensen: Earlier, we discussed the study that looked at the retreatment of patients with hepatitis C genotypes 2 and 3 in whom prior treatment with sofosbuvir and ribavirin had failed.

The LONESTAR-2 trial[14] also included patients with genotypes 2 and 3 in whom prior treatment with pegylated interferon and ribavirin had failed. They received sofosbuvir plus pegylated interferon and ribavirin. This suggests that pegylated interferon and ribavirin with sofosbuvir may play a role.

I think we are going to have more data in the next several months so we can analyze it better. In the short term, though, it looks like pegylated interferon and ribavirin, along with a direct-acting antiviral, may still be in play for some patients who have failed treatment.

The LONESTAR study[15] examined patients with hepatitis C genotype 1 who failed prior treatment with a protease-inhibitor regimen. They were given sofosbuvir and ledipasvir, with and without ribavirin. We will find out whether this combination works for these patients with treatment failure. My hunch is that it will.

There has been a lot of concern in the past several years about viral resistance, in part because of the protease inhibitors telaprevir and boceprevir. I think what we are finding now is resistance really isn't such an issue when you get to these high SVR rates. I think the jury is still out on patients in whom therapy fails, in terms of whether we should measure resistance or not. But clearly, it will be an issue with only a very few patients. With multiple classes of drugs, which should cover resistance to any one class of drugs, it shouldn't be a big issue.

What's Coming Down the Pipeline

Medscape: We've heard about more agents in the pipeline for hepatitis C. What additional approvals might we expect to come within the next 6-18 months?

Dr. Jensen: There are other agents in the pipeline, with a few approvals expected in late 2014 or early 2015. As we discussed earlier, there is the combination of sofosbuvir and ledipasvir, which has been submitted to the US Food and Drug Administration (FDA) for approval. Also submitted to the FDA for approval is the all-oral combination of ABT-450 and ritonavir coformulated with ombitasvir, plus dasabuvir with or without ribavirin.

The combination of daclatasvir, an NS5A replication complex inhibitor, and asunaprevir, a NS3 protease inhibitor, has also been recently submitted. This combination of daclatasvir and asunaprevir works better in hepatitis C genotype 1b than genotype 1a.

Daclatasvir is also being studied in combination with asunaprevir and BMS-791325 (a non-nucleoside inhibitor), which has shown good activity against both genotypes 1a and 1b. However, this regimen has not yet been submitted to the FDA.

A little further behind is a combination of MK-5172 (protease inhibitor) and MK-8742 (NS5A inhibitor), which is currently being studied with and without ribavirin in treatment-naive, noncirrhotic patients with hepatitis C genotype 1 in the C-WORTHy study. Although there are small numbers of patients in this phase 2 clinical trial, the interim results show very good sustained response rates of 89%-100%. This also has not yet been submitted to the FDA.

Medscape: With these upcoming treatment options, would you advise providers to treat now or wait?

Dr. Jensen: The promise that these therapies will be available soon (last quarter of 2014 and early 2015) is certainly hopeful. Currently, the only approved treatments for hepatitis C genotype 1 include pegylated interferon and ribavirin; simeprevir plus pegylated interferon and ribavirin; and sofosbuvir plus pegylated interferon and ribavirin. So for a patient with hepatitis C genotype 1 and mild disease who can wait until later this year, we will probably have the option of an interferon-free treatment.

The American Association for the Study of Liver Diseases/Infectious Diseases Society of America practice guidelines[16] have recommended a combination of simeprevir and sofosbuvir without pegylated interferon and ribavirin for interferon-ineligible patients with genotype 1. This offers an alternate treatment option for patients with hepatitis C genotype 1; however, it is not approved by the FDA and would be considered an off-label combination.

For patients with hepatitis C genotypes 2 and 3, we have good options right now that are interferon-free. For genotype 2, 12 or 24 weeks of sofosbuvir and ribavirin is terrific. For genotype 3, 24 weeks of sofosbuvir and ribavirin looks very good. It's unlikely that sofosbuvir and ledipasvir will offer much in the way of an advantage for these 2 patient groups.

So I think waiting offers an advantage for patients with genotype 1, but probably not as much of an advantage for patients with genotype 2 or 3.

Collaboration of Care Between Primary Care Providers and Specialists

Medscape: With the call for all baby boomers to be screened for hepatitis C, there will be an increased number of patients receiving diagnoses. Will the availability of these new drugs and treatment regimens make it easier for those outside of gastroenterology/hepatology to treat patients with hepatitis C?

Dr. Jensen: First, we have a lot of work to do in terms of screening patients. Only 50% have been tested for hepatitis C. It has been estimated that 2.7-3.2 million people in the United States, without including the homeless or incarcerated, have hepatitis C; if you include homeless and incarcerated persons, it puts this figure closer to 4-5 million people. Among patients diagnosed with hepatitis C, only 1-1.2 million were referred to care, and of those, only 600,000-700,000 have been HCV RNA tested.

Because 75% of hepatitis C patients are baby boomers born between 1945 and 1965, this birth cohort screening is a one-time test for hepatitis C that could identify a significant number. It has been estimated that over 800,000 people would be potential candidates for treatment if they had a one-time test for hepatitis C. So there is a huge need to just get people tested.

With therapies that are relatively -- or potentially -- easy, can a primary care physician or a first-line provider not only screen patients but also treat them? Personally, I think that is an option that not only is viable, but also is going to be necessary to have an impact on the downstream effects of hepatitis C.

Remember, the average age of a patient with hepatitis C is mid- to late 50s. If we delay screening and treatment, more people will develop cirrhosis; more will develop liver cancer; more will need liver transplants; more will die of end-stage liver disease; and more will die of complications, not necessarily due to hepatitis C but to indirect causes of morbidity and mortality down the road. So identifying and treating patients sooner rather than later is imperative.

This ties in to what we talked about earlier -- whether to treat now or wait. For patients with advanced fibrosis, they need to be treated now! We need to get on top of those. For patients with mild disease, can they wait a little bit? Sure; they can wait for perhaps better, cheaper therapies in the future, but not too long.

Medscape: About 25% of patients with hepatitis C have cirrhosis already. Even if we cure these patients, they will still need to be monitored, because their cirrhosis puts them at risk for liver cancer in the future. What role might primary care providers play in the care of these patients?

Dr. Jensen: That is the rub in all of this: Can we educate providers who want to treat patients with hepatitis C to do fibrosis testing, and to continue surveillance for hepatocellular carcinoma? Some have suggested that one could use a relatively simple decision point as to when to refer patients on to specialists (eg, hepatologists, gastroenterologists).

That decision point might be a platelet count. We know that patients who have a low platelet count are more likely to have advanced fibrosis, and it is something that a primary care provider could easily obtain in their patients. It could be as simple as a platelet count or an assessment of fibrosis by calculating the AST-to-platelet ratio index (APRI), which is a combination of the aspartate aminotransferase level and platelet count.

The rationale is to identify the patients with advanced fibrosis and to refer them to a specialist. We'll have to figure this out, because I don't think there are enough hepatologists to treat the 800,000 baby boomers who should be uncovered by this screening -- and to leave patients untreated would be a tragedy.

Medscape: How would you suggest simplifying the decision point in terms of when to refer a patient from a primary care provider to a specialist?

Dr. Jensen: We know it can't be a complicated decision point. It's got to be simple, cheap, and reliable. The one question here is the reliability: How reliable is a low platelet count for identifying patients with advanced fibrosis? It doesn't catch everybody, but you could even make that cut-off point for the platelet count very conservative.

The normal platelet count is 150,000 platelets/µL; you could raise it up to 200,000 per µL. You could set it to where the sensitivity is good enough that patients with advanced fibrosis are referred and those with milder fibrosis are treated by primary care. It needs to be worked on, but we don't have much time to do a lot of long-term studies.

Fortunately, there are many good surrogate markers for fibrosis that don't require liver biopsy; FibroScan is one. There are blood tests: for example, FibroSURE, FibroTest, Fib 4, APRI, and FIBROSpect. Many are readily available and provide good sensitivity and specificity for identifying patients with advanced fibrosis.

The Cost Per Cure

Medscape: The high cost of these new drugs for hepatitis C has been well publicized. Could you talk about the cost, and how it compares with the cost of the prior standard of care?

Dr. Jensen: It's not just looking at the cost of the drugs, but assessing the cost per cure -- or the cost per SVR. The previous standard of triple therapy (pegylated interferon and ribavirin plus telaprevir or boceprevir) involved a lot of nursing visits and laboratory tests; many patients required blood transfusions, erythropoietin injections for anemia, and rash treatment. When you take all of the global costs associated with therapy -- not just the drug, but also the care costs -- and divide it by the success rate of that therapy, which was only 70%, you get a value that is anywhere between $172,000-$189,000 per successful treatment course. Remember, the treatments were longer too -- 24-48 weeks -- and more toxic. When you look at the cost per success, or the cost per SVR, those therapies are actually very expensive.

If you compare it with the most expensive treatment that we use today -- the off-label combination of sofosbuvir plus simeprevir, which is around $150,000 -- and even add in a couple of nursing visits and blood tests at baseline and 4, 12, and 24 weeks, it comes to about $164,000 per cure or per SVR. The success rate of this therapy is 93%. It is cheaper in terms of cost per cure than what we had before.

I'm not justifying the price of $84,000 for 12 weeks of the drug sofosbuvir by any stretch of the imagination, but I think it's short-sighted to think that these patients should instead be treated with telaprevir plus pegylated interferon and ribavirin because the cost of the drug is cheaper; I think that is a mistake. Do we need cheaper alternatives? Absolutely, we need cheaper alternatives, but we need to think about the end result as well.

Medscape: What advice can you give to providers when it comes to cost in counseling patients about their treatment options for hepatitis C?

Dr. Jensen: I don't have direct advice, but I can tell you what I do for my patients -- we do discuss the cost of these medications. Every insurance provider is a little different. Patients need to check with their insurance provider (or have their specialty pharmacy check with their insurance provider) about what their obligation is in those costs.

We don't know whether the costs will get cheaper in the future; historically, with any new therapy, they have not. Further down the line, there could be cheaper alternatives, but it's probably not going to be tremendously cheaper and probably not soon. We have to have a strategy where patients with mild disease might wait and see whether there are cheaper alternatives. Many insurance providers are also reassessing their coverage for patients with mild disease, so it may be out of our hands about treating patients with mild disease anyway. I have less of a problem there.

The issue is patients with advanced disease. They need to be treated now, and I think we need to find a way to get them treated without waiting and without significant out-of-pocket expenses, but that is going to be the challenge.

Medscape: Speaking of advanced disease, what is the cost of care involved with these patients?

Dr. Jensen: The annual healthcare cost per patient with hepatitis C is around $20,000. Specifically, for a noncirrhotic patient with hepatitis C, the annual healthcare cost is about $17,000 per year; it's about $22,000 per year if they have compensated cirrhosis. If they develop complications, such as ascites, jaundice, or encephalopathy, it jumps up to $60,000 per year. A liver transplant is $577,000 just for the procedure itself, and then there is the added cost of the medications associated with it.

Letting these patients with advanced disease go untreated is not a cheap alternative. We need to come up with a strategy of how we are going to deal with these millions of patients with hepatitis C who haven't been identified or treated in order to avoid these downstream costs, which will be expensive.

Medscape: Is there anything else you'd like to share with Medscape's clinical audience about today's treatment of hepatitis C?

Dr. Jensen: It's an exciting time in the treatment of hepatitis C, and I think that is a big message. The therapy, particularly interferon-based therapy, has been so brutal in the past. There is huge hope for these new therapies in that they will be so tolerable yet effective, and that it will encourage all providers to test their patients for hepatitis C, knowing that they can be cured with a relatively easy therapy.

The recommended baby-boomer screening hasn't really been embraced yet. There are a lot of strategies being used to improve it; for example, when patients go in for their colonoscopy screening, it is suggested that they are also tested for hepatitis C.

My hunch is that by getting out the message of a new, relatively easy therapy for hepatitis C, it will increase awareness, and people will get screened and then linked to proper care. I hope that is going to be what happens.

References

1. Afdhal N, Zeuzem S, Kwo P, et al; ION-1 Investigators. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med. 2014;370:1889-1898.

2. Afdhal N, Reddy KR, Nelson DR, et al; ION-2 Investigators. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med. 2014;370:1483-1493.

3. Kowdley KV, Gordon SC, Reddy KR, et al; ION-3 Investigators. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med. 2014;370:1879-1888.

4. Gane EJ, Stedman CA, Hyland RH, et al. Once daily sofosbuvir/ledipasvir fixed dose combination with or without ribavirin: the ELECTRON trial. Program and abstracts of the 64th Annual Meeting of the American Association for the Study of Liver Diseases 2013; November 1-5, 2013; Washington, DC. Abstract 73.

5. Feld JJ, Kowdley KV, Coakley E, et al. Treatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin. N Engl J Med. 2014;370:1594-1603.

6. Zeuzem S, Jacobson IM, Baykal T, et al. Retreatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin. N Engl J Med. 2014;370:1604-1614.

7. Poordad F, Hezode C, Trinh R, et al. ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis. N Engl J Med. 2014;370:1973-1982.

8. Ferenci P, Bernstein D, Lalezari J, et al. ABT-450/r-ombitasvir and dasabuvir with or without ribavirin for HCV. N Engl J Med. 2014;370:1983-1992.

9. Nyberg L, Lalezari J, Ni L, et al. Successful retreatment with sofosbuvir-containing regimens for HCV genotype 2 or 3 infected patients who failed prior sofosbuvir plus ribavirin therapy. Program and abstracts of Digestive Disease Week 2014; May 3-6, 2014; Chicago, Illinois. Abstract 239.

10. Sulkowski MS, Rodriguez-Torres M, Lalezari JP, et al. All-oral therapy with sofosbuvir plus ribavirin for the treatment of HCV genotype 1, 2, and 3 infection in patients co-infected with HIV (PHOTON-1). Program and abstracts of the 64th Annual Meeting of the American Association for the Study of Liver Diseases 2013; November 1-5, 2013; Washington, DC. Abstract 212.

11. Dieterich D, Rockstroh J, Orkin C, et al. Simeprevir (TMC435) plus peginterferon/ribavirin in patients co-infected with HCV genotype-1 and HIV-1: primary analysis of the C212 study. Program and abstracts of the 14th European AIDS Conference (EACS 2013); October 16-19, 2013; Brussels, Belgium. Abstract LBPS9/5.

12. Rodriguez-Torres M, Rodriguez-Orengo J, Gaggar A, et al. Sofosbuvir and peginterferon alfa-2a/ribavirin for treatment-naive genotype 1-4 HCV infected patients who are HIV coinfected with HIV. Program and abstracts of ID Week 2013; October 2-6, 2013; San Francisco, California. Abstract 714.

13. Naggie S, Sulkowski M, Lelazeri J, et al. Sofosbuvir plus ribavirin for HCV genotype 1-3 infection in HIV coinfected patients (PHOTON-1). Program and abstracts of the 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014); March 3-6, 2014; Boston, Massachusetts. Abstract 26.

14. Lawitz E, Poordad F, Brainard DM, et al. Sofosbuvir in combination with pegIFN and ribavirin for 12 weeks provides high SVR rates in HCV-infected genotype 2 or 3 treatment experienced patients with and without compensated cirrhosis: results from the LONESTAR-2 study. Program and abstracts of the 64th Annual Meeting of the American Association for the Study of Liver Diseases 2013; November 1-5, 2013; Washington, DC. Abstract LB-4.

15. Lawitz E, Poordad FF, Pang PS, et al. Sofosbuvir and ledipasvir fixed-dose combination with and without ribavirin in treatment-naive and previously treated patients with genotype 1 hepatitis C virus infection (LONESTAR): an open-label, randomised, phase 2 trial. Lancet. 2014;383:515-523. Abstract

16. American Association for the Study of Liver Diseases; Infectious Diseases Society of America. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org/ Accessed June 4, 2014.

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Benefits of Screening for Liver Cancer Remain in Question

Provided by news@JAMA

By Jill Jin, MD, MPH on June 16, 2014

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Screening for liver cancer in individuals with chronic liver disease may not be beneficial. Image: ©iStock.com/choja

The ultimate goal of cancer screening is to reduce one’s risk of cancer-related death. In the case of screening for liver cancer, the story is still evolving, but new studies continue to suggest that it may not achieve this goal.

Screening tests for different types of cancer have presented a mixed picture on the overall utility of screening. Some, such as Papanicolaou (Pap) smears to screen for cervical cancer, have clear value in detecting cervical cancers at a earlier, more treatable stages and improving long-term survival. Others, such as prostate-specific antigen (PSA) levels to screen for prostate cancer, are more in doubt, as studies indicate that the benefits of PSA testing are small at best, and the harms of unnecessary treatment can be significant.

A systematic review released today in the Annals of Internal Medicine about screening tests for liver cancer in high-risk individuals (those with liver cirrhosis or chronic hepatitis B infection) found that overall, the evidence is of low quality and offers no proof that screening these individuals offers any advantage in extending life or in decreasing mortality from the disease.

This review, funded by the US Department of Veterans Affairs, included 18 observational studies and 4 clinical trials that studied the issue. After a careful assessment of the methods and results of all the studies, the authors concluded that the 2 largest randomized clinical trials, both conducted in China, had “substantial methodological flaws” that threatened the validity of their results. One study showed that routine screening with liver ultrasound and alpha-fetoprotein testing was associated with reduced liver cancer mortality, but the other showed no effect. Furthermore, most of the patients in these 2 studies had chronic hepatitis B infection as the cause of the their chronic liver disease, whereas the majority of people in the United States with chronic liver disease have chronic hepatitis C infection or alcoholic liver disease.

The 18 observational studies included a wider range of geographic settings and more patients with hepatitis C infection; however, the results on mortality reduction resulting from screening were still mixed. Given the inherent bias present in observational studies, the authors state that these studies “do not contribute substantially to the strength of evidence.” Overall, the results did suggest that liver cancers diagnosed as a result of screening tended to be at an earlier stage than those diagnosed clinically in the absence of screening, but the “lead time bias” in these findings makes any true effects on mortality questionable. In other words, people may perceive they are living longer because of a longer period between diagnosis and death, but that longer period may simply be the result of earlier diagnosis and not of extending lifespan.

None of the studies examined the harms of screening, which can include psychological stress, needle-track “seeding” of cancer cells as a result of biopsy, and overdiagnosis, a concept that refers to finding very slow-growing tumors that never would have otherwise caused problems in a patient’s lifetime.

Current guidelines by the American Association of Liver Diseases recommend screening for liver cancer with ultrasound every 6 months for all individuals with cirrhosis, and for some individuals with chronic hepatitis B infection in the absence of cirrhosis. The US Preventive Services Task Force has not released official guidelines on the topic. The authors suggest that there are still major evidence gaps that need to be addressed before more solid guidelines can be created, but also recognize that conducting large-scale randomized trials in the United States or Europe that focus on this specific clinical question in this patient population may not be feasible.

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Journal of Hepatology

Volume 61, Issue 1, Pages 7–14, July 2014

Sylvie Deuffic-Burban, Michaël Schwarzinger, Dorothée Obach, Vincent Mallet, Stanislas Pol, Georges-Philippe Pageaux, Valérie Canva, Pierre Deltenre, Françoise Roudot-Thoraval, Dominique Larrey, Daniel Dhumeaux, Philippe Mathurin, Yazdan Yazdanpanah

Received: August 22, 2013; Received in revised form: February 4, 2014; Accepted: March 6, 2014; Published Online: March 17, 2014

DOI: http://dx.doi.org/10.1016/j.jhep.2014.03.011

Abstract

Background & Aims

In treatment-naive patients mono-infected with genotype 1 chronic HCV, treatments with telaprevir/boceprevir (TVR/BOC)-based triple therapy are standard-of-care. However, more efficacious direct-acting antivirals (IFN-based new DAAs) are available and interferon-free (IFN-free) regimens are imminent (2015).

Methods

A mathematical model estimated quality-adjusted life years, cost and incremental cost-effectiveness ratios of (i) IFN-based new DAAs vs. TVR/BOC-based triple therapy; and (ii) IFN-based new DAAs initiation strategies, given that IFN-free regimens are imminent. The sustained virological response in F3–4/F0–2 was 71/89% with IFN-based new DAAs, 85/95% with IFN-free regimens, vs. 64/80% with TVR/BOC-based triple therapy. Serious adverse events leading to discontinuation were taken as: 0–0.6% with IFN-based new DAAs, 0% with IFN-free regimens, vs. 1–10% with TVR/BOC-based triple therapy. Costs were €60,000 for 12 weeks of IFN-based new DAAs and two times higher for IFN-free regimens.

Results

Treatment with IFN-based new DAAs when fibrosis stage ⩾F2 is cost-effective compared to TVR/BOC-based triple therapy (€37,900/QALY gained), but not at F0–1 (€103,500/QALY gained). Awaiting the IFN-free regimens is more effective, except in F4 patients, but not cost-effective compared to IFN-based new DAAs. If we decrease the cost of IFN-free regimens close to that of IFN-based new DAAs, then awaiting the IFN-free regimen becomes cost-effective.

Conclusions

Treatment with IFN-based new DAAs at stage ⩾F2 is both effective and cost-effective compared to TVR/BOC triple therapy. Awaiting IFN-free regimens and then treating regardless of fibrosis is more efficacious, except in F4 patients; however, the cost-effectiveness of this strategy is highly dependent on its cost.

Keywords: Boceprevir, Chronic hepatitis C, Cost-effectiveness analysis, Direct-acting antivirals, Genotype 1, Interferon-free regimens, Model-based analysis, Telaprevir, Treatment initiation

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Provided by NICE (National Institute for Health and Care Excellence)

In draft recommendations published today healthcare guidance body NICE is asking Gilead Sciences for more information on its product sofosbuvir (Sovaldi), for the treatment of chronic hepatitis C.

Hepatitis C is a virus that infects the liver. It is spread by contact with infected blood, usually as a result of using contaminated needles for injecting drugs. The virus can cause inflammation of, and damage to the liver, preventing it from working properly.

Although 15 to 20% of people infected with the hepatitis C virus naturally clear their infections within 6 months, the remainder develop chronic hepatitis which can be life-long.

Figures from 2012 suggest that around 160,000 people are chronically infected with the hepatitis C virus in the England. More than half of people with chronic hepatitis C do not know they are infected because often, they only have mild symptoms or no symptoms at all for a long period of time.

About 1 in 3 people infected with the hepatitis C virus will eventually develop liver cirrhosis, where normal liver tissue is replaced by scar tissue.

A small percentage of people with chronic hepatitis C and cirrhosis also develop liver cancer.

The aims of treatment are to clear the virus from the blood to prevent progression of liver disease, and to prevent the transmission of the hepatitis C virus. Sofosbuvir is an oral antiviral drug used to prevent hepatitis C viral replication in infected cells.

Commenting on the draft guidance Professor Carole Longson, Director of the NICE Centre for Health Technology Evaluation, said: “Poor diagnosis rates, combined with a high number of new infections annually means that chronic hepatitis C presents a major public health challenge.

“The problem is made worse because the potential side-effects of current treatments, such as interferon, which often needs to be given for a long period of time, mean that many people with the disease either don't complete the full course, or are reluctant to seek treatment in the first place.

“The availability of new treatments, like sofosbuvir, that can shorten the duration of interferon-based therapy or which in some cases don't need to be taken with interferon at all, would potentially encourage more people to seek treatment.

“The available evidence shows that sofosbuvir is an effective treatment for chronic hepatitis C in certain patients. However, evidence is lacking for some subgroups of patients with chronic hepatitis C, and there are also substantial uncertainties in the evidence base presented by the manufacturer. The Committee has therefore requested further information from the manufacturer before it can decide whether sofosbuvir is a cost-effective use of NHS resources.”

Consultees are now able to comment on the preliminary recommendations which are available for public consultation. Comments received during this consultation will be fully considered by the Committee at the next meeting, and following this meeting the next draft guidance will be issued. The closing date for comments on the draft guidance is 4 July 2014.

This is draft guidance; NICE has not yet issued final guidance to the NHS. Until then, NHS bodies should make decisions locally on the funding of specific treatments.

Ends

Notes to Editors

References

About the draft guidance

1. The draft guidance on is available from the NICE website. Consultation on the draft guidance closes on 4 July 2014.

2. The draft guidance states that:

1.1 The Committee is minded not to recommend sofosbuvir within its marketing authorisation for treating chronic hepatitis C in adults.

1.2 The Committee recommends that NICE requests further analyses from the manufacturer for sofosbuvir in combination with ribavirin, with or without peginterferon alfa compared with peginterferon alfa and ribavirin in people with genotype 1 and genotype 3 chronic hepatitis C, to be made available for the second Appraisal Committee meeting, as follows:

  • Revised cost-effectiveness analyses presented separately for people with and without cirrhosis, with and without HIV-co-infection, and by treatment history. The analyses should incorporate the following assumptions:
    • a transition from the sustained virological response-cirrhotic health state to the hepatocellular carcinoma health state, using the transition probability estimates from Cardoso et al. (2010)
    • alternative sustained virological response estimates for peginterferon alfa and ribavirin including those from Hadziyannis et al. (2004) (see section 4.14)
    • alternative utility increments after sustained virological response including SF-36 values from the trials collected at 24 weeks post-treatment, and Vera-Llonch et al. (2013) (see section 4.18)
    • alternative costs for ribavirin in the model (see section 4.15)
  • Sensitivity analyses that include the above mentioned assumptions and also explore the effect on the incremental cost-effectiveness ratios (ICERs) of the following:
    • assuming that up to 100% of people with genotype 3 HCV receive sofosbuvir plus ribavirin for 24 weeks (see section 4.16)
    • assuming an increased proportion of interferon-eligible people may be unwilling to have interferon treatment and therefore receive sofosbuvir plus ribavirin for 24 weeks (see section 4.17)
    • allowing people aged 35 and 55 years to enter the model (see section 4.12)
    • variation in all-cause mortality by assuming the population entering the model comprises 61% men and 39% women, in line with estimates from Wright et al. (2006) (see section 4.12).
  • For all the above analyses:
    • report probabilistic ICERs
    • use a discount rate of 3.5% for costs and benefits in line with the NICE reference case
    • provide a revised fully executable economic model to check the above revisions.
About chronic hepatitis C

1. There are 6 major genotypes and several subtypes of the hepatitis C virus, the prevalence of each vary geographically.

2. Genotypes 1 and 3 account for the majority of chronic hepatitis C cases in England (46% and 43% respectively).

3. People with genotype 2 hepatitis C generally respond to treatment better than those with genotype 1, 3, 4, 5 or 6.

4. For people with mild disease, a ‘watchful waiting' approach may be agreed, on an individual basis, between the patient and clinician.

5. Current NICE guidance (NICE technology appraisal 75 and NICE technology appraisal 106) recommends that standard treatment for the majority of people with chronic hepatitis C is peginterferon alfa and ribavirin combination therapy. Monotherapy with peginterferon alfa-2a or peginterferon alfa-2b is recommended for patients who are unable to tolerate ribavirin or for whom ribavirin is contraindicated.

6. Other NICE guidance on hepatitis C (NICE technology appraisal 200) also recommends that people who have been previously treated with peginterferon alfa and ribavirin or with peginterferon alfa monotherapy have an option to receive further courses of peginterferon alfa and ribavirin.

7. Shortened courses of peginterferon alfa and ribavirin are also recommended as an option for certain patient subgroups (NICE technology appraisal 200).

8. For people with genotype 1 chronic hepatitis C, who have not been previously treated or who have been previously treated, NICE guidance also recommends telaprevir in combination with peginterferon alfa and ribavirin (NICE technology appraisal 252) or boceprevir in combination with peginterferon alfa and ribavirin (NICE technology appraisal 253).

About sofosbuvir

1. Sofosbuvir (Sovaldi, Gilead Sciences) is an antiviral drug used to prevent hepatitis C viral replication in infected cells. It is administered orally.

2. Sofosbuvir has a UK marketing authorisation for use ‘in combination with other medicinal products for treating chronic hepatitis C in adults'. The recommended dose is one 400mg tablet daily. The summary of product characteristics for sofosbuvir states that peginterferon alfa and ribavirin, or ribavirin only, are the recommended co-administered medicinal products for use with sofosbuvir.

3. The average duration of treatment is 12 or 24 weeks depending on the patient's hepatitis C virus genotype and history of prior treatment with interferon.

4. Sofosbuvir combination treatment regimens without peginterferon alfa for patients with genotype 1, 4, 5 and 6 hepatitis C virus infection have not been investigated in phase 3 studies. According to the summary of product characteristics for sofosbuvir, treatment regimens without peginterferon alfa should only be used for patients with genotype 1, 4, 5 and 6 hepatitis C virus infection if they are intolerant to or ineligible for peginterferon alfa therapy and are in urgent need of treatment.

5. The summary of product characteristics for sofosbuvir also states that for all genotypes, consideration should be given to potentially extending the duration of therapy from 12 weeks up to 24 weeks especially for subgroups of people who have one or more factors historically associated with lower response rates to interferon-based therapies (such as people with advanced liver fibrosis or cirrhosis, high baseline viral concentrations, prior unresponsiveness to peginterferon alfa and ribavirin combination therapy, or a non-CC nucleotide polymorphism near their IL28B gene [that is, people without the CC genotype IL28B polymorphism]; or for people of African and Caribbean family origin).

6. The cost of sofosbuvir is £11,660.98 per 28-tablet pack of 400 mg tablets (excluding VAT, ‘British national formulary' [BNF] May 2014). The cost of a 12-week course of treatment is £34,982.94 and a 24-week course is £69,965.88 (both excluding VAT), not including the cost for ribavirin and peginterferon alfa. Costs may vary in different settings because of negotiated procurement discounts.

7. In April 2014 NHS England issued an interim clinical commissioning policy stating that it would commission sofosbuvir in combination with daclatasvir or ledipasvir with or without ribavirin for patients who meet specific criteria and are considered to be at significant risk of death or irreversible damage within the next 12 months, irrespective of genotype. The combination of sofosbuvir and daclatasvir or ledipasvir with or without ribavirin is not being considered in this ongoing appraisal.

About NICE

The National Institute for Health and Care Excellence (NICE) is the independent body responsible for driving improvement and excellence in the health and social care system. We develop guidance, standards and information on high-quality health and social care. We also advise on ways to promote healthy living and prevent ill health.

Formerly the National Institute for Health and Clinical Excellence, our name changed on 1 April 2013 to reflect our new and additional responsibility to develop guidance and set quality standards for social care, as outlined in the Health and Social Care Act (2012).

Our aim is to help practitioners deliver the best possible care and give people the most effective treatments, which are based on the most up-to-date evidence and provide value for money, in order to reduce inequalities and variation.

Our products and resources are produced for the NHS, local authorities, care providers, charities, and anyone who has a responsibility for commissioning or providing healthcare, public health or social care services.

To find out more about what we do, visit our website: www.nice.org.uk and follow us on Twitter: @NICEComms.

This page was last updated: 16 June 2014

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NICE rejection looms for Sovaldi

gilead_-sciences_3

Published on 16/06/14 at 10:35am

In a draft recommendation published today NICE is asking Gilead for more information on its new hepatitis C pill Sovaldi (sofosbuvir) – and is currently not minded to recommend the treatment for NHS England funding.

Professor Carole Longson, director of the NICE centre for health technology evaluation, explains: “The availability of new treatments, like sofosbuvir, that can shorten the duration of [older injectable drug therapy] interferon, or which in some cases don’t need to be taken with interferon at all, would potentially encourage more people to seek treatment.

“The available evidence shows that sofosbuvir is an effective treatment for chronic hepatitis C in certain patients. However, evidence is lacking for some sub-groups of patients with chronic hepatitis C, and there are also substantial uncertainties in the evidence base presented by the manufacturer.

“The [NICE] Committee has therefore requested further information from the manufacturer before it can decide whether sofosbuvir is a cost-effective use of NHS resources.”

Specifically, NICE wants further analyses from Gilead for its drug, in combination with Roche’s ageing injectable treatment Copegus (ribavirin), with or without Roche’s other medicine Pegasys (peginterferon alfa), compared with the two treatments in people with genotype 1 and genotype 3 chronic hepatitis C.

It also wants revised cost-effectiveness analyses presented separately for people with and without cirrhosis, with and without HIV-co-infection, and by treatment history.

Consultees are now able to comment on these initial recommendations, which are also available for public consultation.

Comments received during this consultation will be fully considered by the Committee at the next meeting, NICE says, and following this the next draft guidance will be issued. The closing date for comments on the draft guidance is 4 July.

The drug’s price tag is £11,660 per 28-tablet pack of 400mg tablets, meaning the cost of a 12-week course of treatment is £34,982, and a 24-week course is £69,965 (but this does not include the cost for Roche’s medicines, which may also factor).

This is an eye-watering price tag that has come under much scrutiny in recent months, but oddly NICE seems less concerned with cost than it does with some fairly minor technical efficacy data.

Overall, the drug has impressed in late-stage studies, with recent clinical trial data showing that Sovaldi can effectively cure the disease in over 90% of patients in just 12 weeks.

This is compared to other treatments such as Vertex’ Incivek (telaprevir) and Merck’s Victrelis (boceprevir), which take double the amount of time to treat and have cure rates of around 75 per cent.

Sovaldi is expected to reach around $10 billion in sales by next year and is on course to become the biggest selling medicine in the world.

Funding streams

This comes after the Scottish Medicines Consortium, which is essentially the Scottish NICE, approved funding north of the border for the drug last week, although with some restrictions.

But despite the NICE appraisal still in transition, some hep C patients are already receiving Sovaldi via public funding in England.

This is because in April, NHS England said it would pay out as much as £18.7 million for Sovaldi, in combination with Bristol-Myers Squibb’s hep C drug daclatasvir or Gilead’s other treatment ledipasvir – with or without Copegus – for patients who meet specific criteria and are considered to be at significant risk of death or irreversible damage within the next year. 

This is believed to be able to help around 500 patients in England. This combination is not, however, being considered by NICE in this ongoing appraisal.

Ben Adams

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