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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