The Take Home

2016 International Liver Congress

The 2016 International Liver Congress again focused heavily on new therapies, real-world data and options for practice management in the field of hepatitis C. More than 10,000 attendees gathered in Barcelona, Spain, from April 13 to 18 to hear the research from leaders in the field.

HCV Next board members and experts in attendance offered varying viewpoints on the data presented. Co-Chief Medical Editor, Ira M. Jacobson, MD, chair of the department of medicine at Mount Sinai Beth Israel Medical Center in New York City; Zobair Younossi, MD, MPH, chairman of the department of medicine, Inova Fairfax Hospital, and vice president for research of Inova Health System; Eric J. Lawitz, MD, vice president of scientific and research development at The Texas Liver Institute and clinical professor of medicine at the University of Texas Health Science Center; and Jordan J. Feld, MD, MPH, associated professor of medicine and research director of gastroenterology at the Toronto Centre for Liver Disease and HCV Next Editorial Board member shared their insights into the most compelling data and topics discussed at this year’s meeting.

Ira M. Jacobson, MD

One of the most important presentations given during The International Liver Congress 2016 was one by Massimo Colombo, MD, from Italy.

This phase 2, open-label study looked at post-kidney transplant patients with or without cirrhosis randomly assigned to receive ledipasvir/sofosbuvir (Harvoni, Gilead Sciences) without ribavirin for either 12 weeks (n = 57) or 24 weeks (n = 57).

Ira M. Jacobson

Colombo showed 100% cure rates in patients who finished their medication — no virologic failures. This offers a whole new world of hope for these very needy patients and it raises many fascinating questions.

If there is a nearly 100% chance of curing a patient of HCV after a transplant, and a dialysis patient has a poor quality of life and a high risk for premature morbidity and mortality, transplant an HCV positive kidney now.

The much shorter waiting period for HCV-positive kidneys opens up an opportunity to use such kidneys in HCV-positive patients on dialysis. The contribution of death in young drug addicts in leading to this relative overabundance of HCV-positive kidneys a societal tragedy that cries out for amelioration but it is an opportunity for people with end-stage kidney disease.

Additionally, we were previously reluctant to treat existing HCV in a patient on the kidney transplant list who had advanced hepatic fibrosis for fear of the potential for more rapidly progressive liver disease that may occur after a kidney transplant.

Now we can transplant these patients and treat afterward.

The other ramification of this study is that it adds to the data in liver transplant recipients, with their very high cure rates with antiviral therapy, in indicating that potent direct-acting antiviral agents can overcome whatever adverse impact immunosuppression might theoretically have on the efficacy of such treatment. Indeed, kidney transplant recipients are generally more immunosuppressed pharmacologically than liver transplant recipients.

One can then extrapolate a little bit to patients with inflammatory bowel disease or those with rheumatologic conditions like psoriatic arthritis who are also on immunosuppressants. We have previously wondered if the immunosuppressant would undermine the efficacy of the HCV drugs and the answer seems to be that it’s unlikely.

I regard this study as being of historical importance in its transformative potential for this patient population. We’ve opened a new chapter in the field.

In other difficult-to-treat groups, there were some very important papers on decompensated cirrhotics and the impact of treating them. One, in particular, from Luca S. Belli, MD, looked into how many of these patients, once treated, are delisted from transplant lists.

The retrospective study, conducted in 11 liver transplant centers from February 2014 to February 2015, reported on 134 consecutive patients with HCV-related decompensated cirrhosis without hepatocellular carcinoma who were treated with direct-acting antivirals. At the time of presentation, 34 patients were inactivated and 21 patients were delisted, according to Belli. These patients showed significant improvement in their clinical characteristics from MELD to ascites.

This gets to the question of who should be treated and who shouldn’t, as Belli reminded the audience that we don’t yet know how long these clinical improvements will last. We continue to search for an identifiable inflection point to identify which decompensated patients should have antiviral therapy deferred until after liver transplantation. At present, there are some experts who argue that all patients should be treated, while others who favor withholding treatment from patients with Child-Pugh Class C or very high MELD scores.

In another real-world look at existing regimens, Michael R. Charlton, MD, a fellow HCV Next Editorial Board member, presented a resistance analysis for ledipasvir/sofosbuvir in patients with advanced liver disease or post-transplant. This is a composite analysis from SOLAR-1 and SOLAR-2 that showed very sustained virologic response rates when using ledipasvir/sofosbuvir plus ribavirin for treatment.

It basically shows no impact of resistance associated variants (RAVs) in that population, perhaps because we use ribavirin. It adds to the conversation about how ribavirin helps to control resistance variance.

On the RAVs topic, this meeting also provided an intriguing glimpse of the future regimens and how they may play a role in salvaging non-responders.

This could be considered the “breakout” meeting for ABT-493 and ABT-530 (AbbVie). With three oral presentations and many posters, it looks extremely encouraging in both genotype 3 and patients with RAVs.

Specifically, Fred Poordad, MD, showed that this combination used in patients with genotype 1 produced SVR12 in 100% of those with only NS3 RAVs, 90% of those with only NS5A RAVs and 94% of those with both. Poordad also reported that 92% of patients with two or more RAVs reached SVR12.

There’s also the triplet regimen of sofosbuvir/velpatasvir/GS-9857 (Gilead) showing new hope for DAA failures. Lawitz presented the latest data on that and it seems salvage regimens aren’t too far off.

Sofosbuvir/velpatasvir will be likely available to U.S. physicians in the second half of 2016. What is unclear is how it will be positioned relative to sofosbuvir/ledipasvir. Will it act as a replacement in genotype 1 patients, in whom an eight-week option will not be available, or be used predominantly in other genotypes like 2 or 3? Sofosbuvir/velpatasvir will almost certainly become the treatment of choice in genotype 2, because in the ASTRAL-2 study, it was superior to sofosbuvir and ribavirin, and will — at the very least — be competitive with daclatasvir (Daklinza, Bristol-Myers Squibb) and sofosbuvir for genotype 3, appearing to require no ribavirin or extension of therapy beyond 12 weeks to attain results in cirrhotics at least comparable to those attained with daclatasvir and sofosbuvir. Now it has also shown excellent results in DAA failures, which is a real-world issue.

In other real-world situations, Nezam H. Afdhal, MD, presented a poster in which data from the TRIO database with a somewhat different message from those presented from TARGET at The Liver Meeting 2015 regarding proton pump inhibitor use with ledipasvir.

The take-home from TARGET showed there was a 5% decrement in response to ledipasvir/sofosbuvir, presumably because ledipasvir needs acid for optimal absorption. The TRIO data, on the other hand, showed no significant effect on SVR with once daily PPIs, though the SVR rates with twice daily PPIs trended lower, prompting “caution” with the use of such PPI dosing

Mattias Mandorfer, MD, also showed that the interferon-free regimens we use today ameliorated portal hypertension both in patients with significant baseline portal hypertension and those with lesser diagnoses. They answered the question of whether you can cure or mitigate portal hypertension. The answer is yes.

Lastly, we again saw the exciting concept of shortening treatment through the new mechanism of action offered by RG-101 (Regulus), which targets miR-122.

The results are dramatic with the potential for a 4-week regimen with a single injection of this novel drug concomitant with initiation of with ledipasvir/sofosbuvir, simeprevir (Olysio, Janssen Therapeutics) or daclatasvir, and another dose of the miR-122 inhibitor on day 29 followed by cessation of all treatment.

In this interim report, HCV RNA levels were below the lower limit of quantification at week 12 post-dosing in 100% of patients (14/14) treated with RG-101 and ledipasvir/sofosbuvir, 93.3% (14/15) of those treated with RG-101 and simeprevir and 100% of those treated with RG-101 and daclatasvir.

Right now, when we talk about the potential to shorten therapy to 4 weeks, we’ve basically given up on DAAs. No matter how much weaponry you level at it, you can’t do it. But if you have a novel agent with a novel mechanism of action, with its demonstrated ability to confer long-term viral suppression after a limited exposure, maybe it’s possible.

Zobair Younossi, MD, MPH

What we are seeing here at ILC 2016, as we saw at The Liver Meeting, is that hepatitis C drug regimens are becoming less and less complicated with shorter, better tolerated and more genotypic regimens. In fact, most regimens will not exceed 12 weeks and they could be even shorter in the future. Although ribavirin may be important for some subgroups, most HCV patients will do just fine with ribavirin-free regimens.

Zobair Younossi

There is also increasing evidence that, in general, most of these drugs, especially the newer ones, are safe for most patients. Nevertheless, the regimens containing protease inhibitors drugs are still not safe in those with advanced liver disease and, for some drugs, we still have issues for patients who have significant renal disease.

In some of these difficult-to-treat groups of patients, these challenges may be overcome with the addition of ribavirin or extending the duration of treatment. This is especially pertinent for patients with decompensated cirrhosis and patients who have RAVS.

In fact, the data that have been presented (both at this meeting and previously) assessed the efficacy of velpatasvir/sofosbuvir with or without ribavirin in patients with decompensated liver disease. The SVR from ASTRAL-4 is very, very high — over 95% when you add ribavirin to a 12-week regimen.

The data presented here for patients with RAVs are also very promising. The data suggest that by using regimens that target different part of the virus, we may be able to get around RAV issues. This may be another scenario in which the addition of ribavirin to these regimens may be helpful. This is an era of “miracles” in HCV treatment. In fact, over a relatively short period, a number of regimens have been developed with very high cure rates for HCV.

Another interesting study came from an ASTRAL-5 presentation by David Wyles, MD. These data confirm the fact that HIV/HCV coinfected individuals should be treated the same as everyone else as the medications have a high efficacy and great tolerability. In this case, those medications were sofosbuvir and velpatasvir, but the story is consistent with other recent regimens

Another area that is really important is developing a comprehensive approach to hepatitis C as a disease. In fact, hepatitis C is a systemic disease with hepatic manifestations, extra hepatic manifestations and what I call patient experience manifestations.

This comprehensive approach to the systemic disease of hepatitis C requires that we not only look at efficacy as SVR but we also look at improvement in patient reported outcomes (PRO). That means quality of life, fatigue, work productivity, etc., and then we should also look at the third piece of this comprehensive approach to HCV, which is the economics of hepatitis C disease burden and its treatment.

The current evidence suggests that we have dealt with the first part of this comprehensive approach to HCV — the high efficacy rates from clinical trials have been accomplished. Another important issue is the improvement in effectiveness of the new regimens in real-world practices. In fact, data from both Europe and the United States suggest that the difference seen between SVR rates obtained from the efficacy trials and effectiveness (real-world practices) that were seen with previous anti-HCV regimens, is no longer applicable to the new regimens. In fact, a great deal of real-world data has been reported from Israel and Germany with paritaprevir/ritonavir/ombitasvir, dasabuvir with or without ribavirin; from Scandinavia with sofosbuvir-containing regimens; from the United States with ledipasvir/sofosbuvir in patients with cirrhosis; and from Germany with multiple regimens used in retreatment.

In summary, all of these data suggest that the new regimens have very similar efficacy and effectiveness across various populations of people. So we have resolved this issue of SVR rate.

After assessing efficacy and effectiveness, it is important to assess the impact of these new regimens on PROs. Historically, interferon caused severe impairment of quality of life during treatment. After removing interferon from the regimen, we now know that ribavirin caused a modest and reversible impairment of patient quality of life. In contrast, the new regimens free of interferon and ribavirin (ledipasvir/sofosbuvir or velpatasvir/sofosbuvir) actually improve PROs during treatment. This suggests that some of the quality of life impairment in HCV patients is related to the virus and PRO improvement occurs as the virus is suppressed and then eradicated.

In fact, once you achieve SVR, you actually have much better quality of life, including fatigue and some aspects of work productivity. This makes patients feel better, which could also positively enhance adherence to the drug.

At this meeting, for the first time, we reported PRO data from the randomized placebo controlled data of ASTRAL-1. This analysis clearly showed patients receiving placebo did not have any improvement of PROs while the treatment with sofosbuvir/velpatasvir improved PRO scores during treatment and after achieving SVR. If you follow patients through 24 weeks of follow-up, the PROs continue to improve.

We don’t yet know when these patients are going to get to their maximum PRO benefit, but I suspect it will be some time before we see the maximum benefit. The interesting thing is that the improvement in PROs is not seen just in quality of life scores. It’s quality of life, fatigue and work productivity, which is not just something that impacts the patient but also their families and the society by reducing presenteeism. In fact, if you follow these patients even longer, there is some evidence that the absenteeism aspect of work productivity may also improve. Improving both components of work productivity may lead in major positive impact to the economy. Although the data were initially obtained from the U.S., we are now seeing similar results in Asian and European countries.

The last piece of this comprehensive approach to HCV is the economic story of hepatitis C. Here, you have conflicting data. The data presented at this meeting focused primarily on the budgetary impact of these medications. Since these drugs are expensive, their cost could impact governmental budgets and other private payers or health insurance companies. In fact, this is a relatively narrow way of looking at HCV disease and its treatment. Although budgetary impact of HCV treatment is very relevant to providing access, it is also very important to perform economic analysis of hepatitis C from the society perspective.

From a society perspective, you have to take a longer view. Let’s take the situation in the United States. If the payers in the United States don’t cover these patients with hepatitis C and if Medicaid or the state payers don’t cover them, these patients are going to either develop end-stage liver disease or become disabled and Medicare will have to pay for them. So, the United States government or the U.S. society will have to pay for this disease one way or another and, in fact, they may have to pay for untreated patients with more severe liver disease, which will be more expensive later on.

When you look at it from the long-term societal perspective, these drugs are cost-effective no matter the threshold you use for cost effectiveness. If you use the old standard of $50,000 per quality-adjusted life year (QALY), they are cost effective. If you increase it to the willingness to pay threshold to $150,000 per QALY, they are even more cost effective.

One of the most talked-about studies presented here came from Australia’s James Freeman, MD, who analyzed the chemical components and efficacy of generic HCV medications. While he showed they were chemically similar and had high efficacy, it is not only about this one study.

It’s about quality control with generics because it’s a question of if we will actually be comfortable that the drug you’re giving will have the same RAV profile, the same side effect profile. We have seen disasters in the past when quality control in different countries is not followed as strictly as we would follow it. And patients are harmed.

In that context, we don’t have clear-cut data that the quality control of those drugs are equivalent to the quality control of drugs that are the standard in Europe and the United States. Until these data are widely available, I remain cautious.

Additionally, a lot of these new drugs are being made available to the rest of the world at deep discounts. That would take care of some of these issues of cost. Nevertheless, it is important to remember that what is cost effective for the United States certainly may not be cost effective for European countries and other places in the world. In this context, each country has to do its due diligence in terms of economic analysis. Furthermore, it is critical that pharmaceutical companies and the governments and the payers negotiate to provide access to these incredible drugs to all patients with HCV. In fact, as a result of these negotiations, no one in the United States is paying full price now. The more drugs we have in this space, the market competition will take care of the cost issue in time.

Finally, our biggest challenge is not going to be drugs or their efficacy. Our challenge will be screening and finding patients with HCV and then giving them these highly effective regimens in an affordable manner. And, as we treat the liver disease of hepatitis C, there’s going to be more emphasis on the extra-hepatic side effects of hepatitis C, which have been completely ignored.

Another issue is the other non-liver aspects of HCV. There are very little data in terms of efficacy of drugs for mixed cryoglobulinemia of HCV. Other interesting questions will be whether treatment will impact HCV-related type 2 diabetes? Will achieving SVR impact the neurocognitive abnormalities seen in patients with HCV? There is going to be a lot of effort and interesting data in that arena.

A final issue is the care of liver disease after achieving HCV cure. When you cure hepatitis C in the Western world, probably the whole world, a large number of these patients will have underlying fatty liver disease. In fact, you have a prevalence of fatty liver disease of 24% in the world. The fact is when you’re curing hepatitis C, it doesn’t always mean you got rid of all liver disease. I’m seeing a lot of these patients coming back without hepatitis C, but now with underlying NASH and a tendency toward progression.

Getting patients to treatment is fantastic. Getting these very high cure rates are very good. But, because of this high prevalence of fatty liver disease, we have to think about the two diseases that coexisted that push your patient to cirrhosis. If you cure hepatitis C with cirrhosis, but the patient has underlying NASH with cirrhosis, that patient may still require liver transplantation or develop liver cancer.

Eric J. Lawitz, MD

At this meeting, the DAA failure space is clearly in focus with three studies utilizing two second-generation regimens. My own presentation focused on the “triple therapy” of sofosbuvir, velpatasvir, and GS-9857, a protease inhibitor, data and Poordad’s presentation looked at the ABT-493 and ABT-530 regimen.

Both of these studies looked at single and multi-class DAA exposed patients; the main difference in these populations were the presence of patients with cirrhosis in the sofosbuvir/valpatasvir/GS-9857 trial while the ABT-493/ABT-530 trial evaluated noncirrhotics while cirrhotics will be studied in the second part of the current trial.

Eric J. Lawitz

My study showed the new generation of agents seem to be universally successful with a SVR12 of 99% (127/128) in genotypes 1 through 6, treatment-experienced patients, including DAA-exposed, with half of the enrolled patients having compensated cirrhosis. This is encouraging as previously we have not had studies showing any reliable way to retreat patients with DAA failure with high rates of success. Now, for the first time, we see two regimens demonstrating high rates of success in these patients.

Poordad’s presentation showed the combination of ABT-493/ABT-530 in DAA exposed noncirrhotic genotype 1 patients had a mITT of 96% (45/47), the ITT was 90% (45/50) with 3 patients’ failing for non virologic reasons.

The ABT-493/ABT-530 also produced good results in genotype 3, as Andrew J. Muir, MD, showed with his presentation. In this study, 29 treatment-naive patients with HCV genotype 3 without cirrhosis were given a once-daily combination for 8 weeks and, of these, 97% achieved SVR12 (n = 28).

In a second study presented by Paul Y. Kwo, MD, 48 patients with HCV genotype 3, who were treatment-naive with cirrhosis were randomized to the same once-daily combination with or without 800 mg of ribavirin for 12 weeks. Of these, all 48 in both treatment groups achieved SVR12 (100%).

As mentioned, Afdahl addressed the question of PPI use with ledipasvir. The TARGET data set from AASLD suggested a 5% decline in efficacy in the setting of concurrent PPI use. The current study from the TRIO database showed there was no difference in outcome regardless of presence or absence of concurrent PPI use, except in those taking twice-daily PPIs, which demonstrated a trend for lower rates of SVR. We should continue to watch for data in this area; obviously, a prospective randomized trial would definitively answer the question. Until then, we continue to monitor observational outcomes.

We understand the pharmacologic effect of pH on solubility of ledipasvir, but how that translates into clinical outcome still needs study. It is certainly likely that the effect would be most obvious in those patients with “stacked” negative baseline factors like cirrhosis, baseline resistance. and less robust innate immune responses, where if there was an effect this would be the population where the difference may best demonstrated. In the subgroup of patients with high medical need for therapy, I avoid concurrent high-dose PPI therapy with ledipasvir in my practice.

Overall, the real world data as mentioned by Younossi is looking much like the registration data. One question in my mind is whether the current “real-world data” will hold up over time. Right now, even the real-world data focuses on motivated patients, who make it through the process of navigating busy practices and taking necessary steps (usually many steps) to access medications. As we move to treating patients less motivated and energetic for a cure, I wonder if we will we see a decline in efficacy because these patients need more care? It will be interesting to track “real world” data over the next few years as the demographics of patients entering therapy may differ from patients being treated today.

A pleasant surprise thus far has been the consistent “real world” data across patient types, countries and clinics. Unlike previous generations of therapies where we couldn’t reproduce clinical trial results in the community, we are consistently seeing results that mirror the registration data.

At this meeting, we were also privy to a small study from Sanjay Bansal, MD, looking at ledipasvir/sofosbuvir in pediatrics and adolescents. It’s great data to have and will allow hopefully for a future approval for treating younger patients and preventing potential systemic complications down the road for them. It would be valuable to extend the label and have patients under the age of 18 getting access to the drugs if possible.

In a presentation given by Sarah Kattakuzhy, MD, adherence to appointments was better with primary care physicians and nurse practitioners than hepatologists. Inherently, this makes sense as primary care doctors are the face of the patients’ medical care whereas specialists are more removed. The better relationship you have with the patient, the more likely you are to be successful no matter what disease state you are treating.

This raises the question of who is best positioned to treat hepatitis C. Ultimately, doctors who are motivated and interested in hepatitis C are the optimal providers irrespective of their specialty.

Lastly, as Jacobson mentioned, the idea of shortening the duration of DAAs with the long-acting miR-122 target is intriguing. We have been completely unsuccessful shortening down to 4 weeks with DAAs. Many have tried, all have failed, unless we find 30% to 40% an acceptable rate of SVR12. The trial presented by Mihaly Makara, MD, showed the “sandwich” approach of 2 doses of RG-101 28 days apart with either single or dual-class DAA therapy between RG-101 doses. This produced results showing 40/41 (98%) patients on the lower limit of quantification 12 weeks after completion of therapy. The development of jaundice in one patient underscores the need for additional safety data on this drug.

This trial lays the groundwork for further study of this regimen in larger populations with a 4 week course of therapy.

Jordan J. Feld, MD, MPH

There were a lot of interesting developments this year at the International Liver Congress but for me, perhaps the most surprising was the next generation combination regimen of ABT-493 and ABT-530. They had a number of different presentations, as mentioned above, and all of them produced very good results, clearly proving that a nucleotide polymerase inhibitor is not absolutely necessary to achieve very high cure rates across many patient populations. They look to be safe and effective and have the added benefit of being safe in renal patients, which will be important for non-genotype 1 patients with chronic kidney disease.

Jordan J. Feld

In addition to this combination, I was impressed with the triplet regimens. A number of small studies reported high rates of SVR, even in retreatment studies, which gives us good confidence that we will be able to treat most, if not all, of the few patients who fail first attempts at treatment.

It looks like there were a lot of small studies on resistance, such as those from Lawitz with the triplet regimen and Poordad with the ABT combination, but they looked pretty outstanding. They were able to treat almost everyone, even with retreatment.

These three-drug regimens will be a very good answer for people who have failed a first course of therapy. One of the questions will be whether we use three-drug regimens up front or reserve them as salvage for the few that fail.

You can argue both ways, but I might make the argument that it’s good to reserve them. The argument to use them first is to give the best therapy right up front. But the reasons for failure are not always virological. It may be because people aren’t adherent. Having these as an option for a secondary treatment might be best.

One study in which I participated was a study looking at ledipasvir/sofosbuvir with ribavirin in genotype 3. We actually conducted the study because we were skeptical of the original data showing positive results in this population. We were pleasantly surprised to see that it was effective, similar to what has been reported with sofosbuvir/daclatasvir, despite the fact that ledipasvir is not active against genotype 3 in the replicon model.

We had a total of 111 patients and each patient received sofosbuvir/ledipasvir plus ribavirin for 12 weeks. The overall SVR rate was 89% but without cirrhosis, SVR was 94% (66/70) while cirrhosis was 79% (31/39).

That’s similar to what is reported with sofosbuvir/daclatasvir, and arguably better in patients with cirrhosis. It suggests when you put these drugs in vivo, maybe the replicon assay is not that reliable in predicting the outcome. Clearly, this is more active than expected. If we believe that lack of activity of ledipasvir in the replicon, one would expect this regimen to be similar to sofosbuvir/ribavirin alone, but clearly the results are superior to sofosbuvir/ribavirin alone, particularly with only 12 weeks of treatment. It suggests that ledipasvir is more active against genotype 3 than one might have predicted.

It raises the question of whether the replicon is a good way to measure the success of a regimen. Maybe it’s a moot point given all of the great options, but the question of whether your in vitro assay is a good reflection of what happens in patients is still interesting for antiviral drug development both in HCV and potentially in other infections.

Realistically, sofosbuvir/velpatasvir is likely going to be a better option, so this is not suggesting that sofosbuvir/ledipasvir should be a treatment for genotype 3, but a proof of concept that you can get activity you didn’t anticipate.

Another interesting area for me at this meeting was Acute HCV. The German acute HCV study was interesting as it showed 6 weeks of ledipasvir/sofosbuvir was quite effective in treating the acute infection.

In the monoinfected patients, SVR was 100%. It’s not a huge study, but that’s still really useful because it gives you an option. We’ve been arguing that you shouldn’t treat acute HCV because you can see if people spontaneously clear and just treat if they become chronic. You could still make that argument, but at least this shows what you can do. Especially in the face of ongoing transmission risks, it might be worthwhile to treat.

Previously, the sofosbuvir/ribavirin studies that looked at 6 weeks and 12 weeks were not very effective. Most people thought if you just suppress the virus, you’d be successful treating acute HCV, but it seems you need potent suppression and if you have that, then 6 weeks appears to be enough, at least for most patients.

Another interesting issue that came up centered on the PPI effect with sofosbuvir/ledipasvir. We’ve already discussed the fact that the TRIO evaluation didn’t support what was found by the HCV-TARGET analysis. When you have different studies and they find different results, which do you trust? The methodologies are different and it’s important to look carefully at exactly what was done in each case.

One important difference between them: TRIO is using pharmacy data, which one would think would be more accurate in terms of which drugs are being taken, but an important point to consider is that it captures only prescription drugs and a lot of the PPI use in the U.S. is over the counter. That would make me concerned that they missed a lot the PPI use. HCV-TARGET reviewed the medical records, which also has its downfalls as it only records what clinicians ask about and note in the chart. Both methodologies have their pros and cons and it is hard to be certain that one is more accurate than the other. I am somewhat biased toward the HCV-TARGET result, perhaps because we participate in the study and I know the rigor of the data collection. That being said, even in HCV-TARGET, the effect on SVR is relatively small.

However, my own belief is that it’s a very plausible effect and we really want to maximize SVR if at all possible. So, from my perspective it’s best not to take PPI with ledipasvir if it can be avoided. I stress this particularly in the first 4 weeks of therapy before the virus is suppressed when drug levels are likely more important. I have yet to have a patient who could not stop the PPI for at least the first 4 weeks of treatment. Overall, the ILC was another interesting chapter in the evolving story of HCV.

Disclosures: Feld reports receiving support for research and/or honoraria for scientific consulting for AbbVie, Abbott, Bristol-Myers Squibb, Gilead, Janssen, Merck, Theravance and Trek. Jacobson reports various financial relationships with AbbVie, Achillion, Alnylam, Bristol-Myers Squibb, Enanta, Gilead Sciences, Janssen Therapeutics, Merck and Tobira. Lawitz reports financial relationships with AbbVie, Achillion Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Enanta Pharmaceuticals, Gilead Sciences, GlaxoSmithKline, Janssen, Merck & Co., Novartis, Regulus, Roche, Salix, Santaris Pharmaceuticals, Tacere, and Theravance. Younossi reports being on the advisory committees or review panels of Janssen, Salix and Vertex and consulting for Coneatus, Enterome and Gilead.

The 2016 International Liver Congress again focused heavily on new therapies, real-world data and options for practice management in the field of hepatitis C. More than 10,000 attendees gathered in Barcelona, Spain, from April 13 to 18 to hear the research from leaders in the field.

HCV Next board members and experts in attendance offered varying viewpoints on the data presented. Co-Chief Medical Editor, Ira M. Jacobson, MD, chair of the department of medicine at Mount Sinai Beth Israel Medical Center in New York City; Zobair Younossi, MD, MPH, chairman of the department of medicine, Inova Fairfax Hospital, and vice president for research of Inova Health System; Eric J. Lawitz, MD, vice president of scientific and research development at The Texas Liver Institute and clinical professor of medicine at the University of Texas Health Science Center; and Jordan J. Feld, MD, MPH, associated professor of medicine and research director of gastroenterology at the Toronto Centre for Liver Disease and HCV Next Editorial Board member shared their insights into the most compelling data and topics discussed at this year’s meeting.

Ira M. Jacobson, MD

One of the most important presentations given during The International Liver Congress 2016 was one by Massimo Colombo, MD, from Italy.

This phase 2, open-label study looked at post-kidney transplant patients with or without cirrhosis randomly assigned to receive ledipasvir/sofosbuvir (Harvoni, Gilead Sciences) without ribavirin for either 12 weeks (n = 57) or 24 weeks (n = 57).

Ira M. Jacobson

Colombo showed 100% cure rates in patients who finished their medication — no virologic failures. This offers a whole new world of hope for these very needy patients and it raises many fascinating questions.

If there is a nearly 100% chance of curing a patient of HCV after a transplant, and a dialysis patient has a poor quality of life and a high risk for premature morbidity and mortality, transplant an HCV positive kidney now.

The much shorter waiting period for HCV-positive kidneys opens up an opportunity to use such kidneys in HCV-positive patients on dialysis. The contribution of death in young drug addicts in leading to this relative overabundance of HCV-positive kidneys a societal tragedy that cries out for amelioration but it is an opportunity for people with end-stage kidney disease.

Additionally, we were previously reluctant to treat existing HCV in a patient on the kidney transplant list who had advanced hepatic fibrosis for fear of the potential for more rapidly progressive liver disease that may occur after a kidney transplant.

Now we can transplant these patients and treat afterward.

The other ramification of this study is that it adds to the data in liver transplant recipients, with their very high cure rates with antiviral therapy, in indicating that potent direct-acting antiviral agents can overcome whatever adverse impact immunosuppression might theoretically have on the efficacy of such treatment. Indeed, kidney transplant recipients are generally more immunosuppressed pharmacologically than liver transplant recipients.

One can then extrapolate a little bit to patients with inflammatory bowel disease or those with rheumatologic conditions like psoriatic arthritis who are also on immunosuppressants. We have previously wondered if the immunosuppressant would undermine the efficacy of the HCV drugs and the answer seems to be that it’s unlikely.

I regard this study as being of historical importance in its transformative potential for this patient population. We’ve opened a new chapter in the field.

In other difficult-to-treat groups, there were some very important papers on decompensated cirrhotics and the impact of treating them. One, in particular, from Luca S. Belli, MD, looked into how many of these patients, once treated, are delisted from transplant lists.

The retrospective study, conducted in 11 liver transplant centers from February 2014 to February 2015, reported on 134 consecutive patients with HCV-related decompensated cirrhosis without hepatocellular carcinoma who were treated with direct-acting antivirals. At the time of presentation, 34 patients were inactivated and 21 patients were delisted, according to Belli. These patients showed significant improvement in their clinical characteristics from MELD to ascites.

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This gets to the question of who should be treated and who shouldn’t, as Belli reminded the audience that we don’t yet know how long these clinical improvements will last. We continue to search for an identifiable inflection point to identify which decompensated patients should have antiviral therapy deferred until after liver transplantation. At present, there are some experts who argue that all patients should be treated, while others who favor withholding treatment from patients with Child-Pugh Class C or very high MELD scores.

In another real-world look at existing regimens, Michael R. Charlton, MD, a fellow HCV Next Editorial Board member, presented a resistance analysis for ledipasvir/sofosbuvir in patients with advanced liver disease or post-transplant. This is a composite analysis from SOLAR-1 and SOLAR-2 that showed very sustained virologic response rates when using ledipasvir/sofosbuvir plus ribavirin for treatment.

It basically shows no impact of resistance associated variants (RAVs) in that population, perhaps because we use ribavirin. It adds to the conversation about how ribavirin helps to control resistance variance.

On the RAVs topic, this meeting also provided an intriguing glimpse of the future regimens and how they may play a role in salvaging non-responders.

This could be considered the “breakout” meeting for ABT-493 and ABT-530 (AbbVie). With three oral presentations and many posters, it looks extremely encouraging in both genotype 3 and patients with RAVs.

Specifically, Fred Poordad, MD, showed that this combination used in patients with genotype 1 produced SVR12 in 100% of those with only NS3 RAVs, 90% of those with only NS5A RAVs and 94% of those with both. Poordad also reported that 92% of patients with two or more RAVs reached SVR12.

There’s also the triplet regimen of sofosbuvir/velpatasvir/GS-9857 (Gilead) showing new hope for DAA failures. Lawitz presented the latest data on that and it seems salvage regimens aren’t too far off.

Sofosbuvir/velpatasvir will be likely available to U.S. physicians in the second half of 2016. What is unclear is how it will be positioned relative to sofosbuvir/ledipasvir. Will it act as a replacement in genotype 1 patients, in whom an eight-week option will not be available, or be used predominantly in other genotypes like 2 or 3? Sofosbuvir/velpatasvir will almost certainly become the treatment of choice in genotype 2, because in the ASTRAL-2 study, it was superior to sofosbuvir and ribavirin, and will — at the very least — be competitive with daclatasvir (Daklinza, Bristol-Myers Squibb) and sofosbuvir for genotype 3, appearing to require no ribavirin or extension of therapy beyond 12 weeks to attain results in cirrhotics at least comparable to those attained with daclatasvir and sofosbuvir. Now it has also shown excellent results in DAA failures, which is a real-world issue.

In other real-world situations, Nezam H. Afdhal, MD, presented a poster in which data from the TRIO database with a somewhat different message from those presented from TARGET at The Liver Meeting 2015 regarding proton pump inhibitor use with ledipasvir.

The take-home from TARGET showed there was a 5% decrement in response to ledipasvir/sofosbuvir, presumably because ledipasvir needs acid for optimal absorption. The TRIO data, on the other hand, showed no significant effect on SVR with once daily PPIs, though the SVR rates with twice daily PPIs trended lower, prompting “caution” with the use of such PPI dosing

Mattias Mandorfer, MD, also showed that the interferon-free regimens we use today ameliorated portal hypertension both in patients with significant baseline portal hypertension and those with lesser diagnoses. They answered the question of whether you can cure or mitigate portal hypertension. The answer is yes.

Lastly, we again saw the exciting concept of shortening treatment through the new mechanism of action offered by RG-101 (Regulus), which targets miR-122.

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The results are dramatic with the potential for a 4-week regimen with a single injection of this novel drug concomitant with initiation of with ledipasvir/sofosbuvir, simeprevir (Olysio, Janssen Therapeutics) or daclatasvir, and another dose of the miR-122 inhibitor on day 29 followed by cessation of all treatment.

In this interim report, HCV RNA levels were below the lower limit of quantification at week 12 post-dosing in 100% of patients (14/14) treated with RG-101 and ledipasvir/sofosbuvir, 93.3% (14/15) of those treated with RG-101 and simeprevir and 100% of those treated with RG-101 and daclatasvir.

Right now, when we talk about the potential to shorten therapy to 4 weeks, we’ve basically given up on DAAs. No matter how much weaponry you level at it, you can’t do it. But if you have a novel agent with a novel mechanism of action, with its demonstrated ability to confer long-term viral suppression after a limited exposure, maybe it’s possible.

Zobair Younossi, MD, MPH

What we are seeing here at ILC 2016, as we saw at The Liver Meeting, is that hepatitis C drug regimens are becoming less and less complicated with shorter, better tolerated and more genotypic regimens. In fact, most regimens will not exceed 12 weeks and they could be even shorter in the future. Although ribavirin may be important for some subgroups, most HCV patients will do just fine with ribavirin-free regimens.

Zobair Younossi

There is also increasing evidence that, in general, most of these drugs, especially the newer ones, are safe for most patients. Nevertheless, the regimens containing protease inhibitors drugs are still not safe in those with advanced liver disease and, for some drugs, we still have issues for patients who have significant renal disease.

In some of these difficult-to-treat groups of patients, these challenges may be overcome with the addition of ribavirin or extending the duration of treatment. This is especially pertinent for patients with decompensated cirrhosis and patients who have RAVS.

In fact, the data that have been presented (both at this meeting and previously) assessed the efficacy of velpatasvir/sofosbuvir with or without ribavirin in patients with decompensated liver disease. The SVR from ASTRAL-4 is very, very high — over 95% when you add ribavirin to a 12-week regimen.

The data presented here for patients with RAVs are also very promising. The data suggest that by using regimens that target different part of the virus, we may be able to get around RAV issues. This may be another scenario in which the addition of ribavirin to these regimens may be helpful. This is an era of “miracles” in HCV treatment. In fact, over a relatively short period, a number of regimens have been developed with very high cure rates for HCV.

Another interesting study came from an ASTRAL-5 presentation by David Wyles, MD. These data confirm the fact that HIV/HCV coinfected individuals should be treated the same as everyone else as the medications have a high efficacy and great tolerability. In this case, those medications were sofosbuvir and velpatasvir, but the story is consistent with other recent regimens

Another area that is really important is developing a comprehensive approach to hepatitis C as a disease. In fact, hepatitis C is a systemic disease with hepatic manifestations, extra hepatic manifestations and what I call patient experience manifestations.

This comprehensive approach to the systemic disease of hepatitis C requires that we not only look at efficacy as SVR but we also look at improvement in patient reported outcomes (PRO). That means quality of life, fatigue, work productivity, etc., and then we should also look at the third piece of this comprehensive approach to HCV, which is the economics of hepatitis C disease burden and its treatment.

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The current evidence suggests that we have dealt with the first part of this comprehensive approach to HCV — the high efficacy rates from clinical trials have been accomplished. Another important issue is the improvement in effectiveness of the new regimens in real-world practices. In fact, data from both Europe and the United States suggest that the difference seen between SVR rates obtained from the efficacy trials and effectiveness (real-world practices) that were seen with previous anti-HCV regimens, is no longer applicable to the new regimens. In fact, a great deal of real-world data has been reported from Israel and Germany with paritaprevir/ritonavir/ombitasvir, dasabuvir with or without ribavirin; from Scandinavia with sofosbuvir-containing regimens; from the United States with ledipasvir/sofosbuvir in patients with cirrhosis; and from Germany with multiple regimens used in retreatment.

In summary, all of these data suggest that the new regimens have very similar efficacy and effectiveness across various populations of people. So we have resolved this issue of SVR rate.

After assessing efficacy and effectiveness, it is important to assess the impact of these new regimens on PROs. Historically, interferon caused severe impairment of quality of life during treatment. After removing interferon from the regimen, we now know that ribavirin caused a modest and reversible impairment of patient quality of life. In contrast, the new regimens free of interferon and ribavirin (ledipasvir/sofosbuvir or velpatasvir/sofosbuvir) actually improve PROs during treatment. This suggests that some of the quality of life impairment in HCV patients is related to the virus and PRO improvement occurs as the virus is suppressed and then eradicated.

In fact, once you achieve SVR, you actually have much better quality of life, including fatigue and some aspects of work productivity. This makes patients feel better, which could also positively enhance adherence to the drug.

At this meeting, for the first time, we reported PRO data from the randomized placebo controlled data of ASTRAL-1. This analysis clearly showed patients receiving placebo did not have any improvement of PROs while the treatment with sofosbuvir/velpatasvir improved PRO scores during treatment and after achieving SVR. If you follow patients through 24 weeks of follow-up, the PROs continue to improve.

We don’t yet know when these patients are going to get to their maximum PRO benefit, but I suspect it will be some time before we see the maximum benefit. The interesting thing is that the improvement in PROs is not seen just in quality of life scores. It’s quality of life, fatigue and work productivity, which is not just something that impacts the patient but also their families and the society by reducing presenteeism. In fact, if you follow these patients even longer, there is some evidence that the absenteeism aspect of work productivity may also improve. Improving both components of work productivity may lead in major positive impact to the economy. Although the data were initially obtained from the U.S., we are now seeing similar results in Asian and European countries.

The last piece of this comprehensive approach to HCV is the economic story of hepatitis C. Here, you have conflicting data. The data presented at this meeting focused primarily on the budgetary impact of these medications. Since these drugs are expensive, their cost could impact governmental budgets and other private payers or health insurance companies. In fact, this is a relatively narrow way of looking at HCV disease and its treatment. Although budgetary impact of HCV treatment is very relevant to providing access, it is also very important to perform economic analysis of hepatitis C from the society perspective.

From a society perspective, you have to take a longer view. Let’s take the situation in the United States. If the payers in the United States don’t cover these patients with hepatitis C and if Medicaid or the state payers don’t cover them, these patients are going to either develop end-stage liver disease or become disabled and Medicare will have to pay for them. So, the United States government or the U.S. society will have to pay for this disease one way or another and, in fact, they may have to pay for untreated patients with more severe liver disease, which will be more expensive later on.

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When you look at it from the long-term societal perspective, these drugs are cost-effective no matter the threshold you use for cost effectiveness. If you use the old standard of $50,000 per quality-adjusted life year (QALY), they are cost effective. If you increase it to the willingness to pay threshold to $150,000 per QALY, they are even more cost effective.

One of the most talked-about studies presented here came from Australia’s James Freeman, MD, who analyzed the chemical components and efficacy of generic HCV medications. While he showed they were chemically similar and had high efficacy, it is not only about this one study.

It’s about quality control with generics because it’s a question of if we will actually be comfortable that the drug you’re giving will have the same RAV profile, the same side effect profile. We have seen disasters in the past when quality control in different countries is not followed as strictly as we would follow it. And patients are harmed.

In that context, we don’t have clear-cut data that the quality control of those drugs are equivalent to the quality control of drugs that are the standard in Europe and the United States. Until these data are widely available, I remain cautious.

Additionally, a lot of these new drugs are being made available to the rest of the world at deep discounts. That would take care of some of these issues of cost. Nevertheless, it is important to remember that what is cost effective for the United States certainly may not be cost effective for European countries and other places in the world. In this context, each country has to do its due diligence in terms of economic analysis. Furthermore, it is critical that pharmaceutical companies and the governments and the payers negotiate to provide access to these incredible drugs to all patients with HCV. In fact, as a result of these negotiations, no one in the United States is paying full price now. The more drugs we have in this space, the market competition will take care of the cost issue in time.

Finally, our biggest challenge is not going to be drugs or their efficacy. Our challenge will be screening and finding patients with HCV and then giving them these highly effective regimens in an affordable manner. And, as we treat the liver disease of hepatitis C, there’s going to be more emphasis on the extra-hepatic side effects of hepatitis C, which have been completely ignored.

Another issue is the other non-liver aspects of HCV. There are very little data in terms of efficacy of drugs for mixed cryoglobulinemia of HCV. Other interesting questions will be whether treatment will impact HCV-related type 2 diabetes? Will achieving SVR impact the neurocognitive abnormalities seen in patients with HCV? There is going to be a lot of effort and interesting data in that arena.

A final issue is the care of liver disease after achieving HCV cure. When you cure hepatitis C in the Western world, probably the whole world, a large number of these patients will have underlying fatty liver disease. In fact, you have a prevalence of fatty liver disease of 24% in the world. The fact is when you’re curing hepatitis C, it doesn’t always mean you got rid of all liver disease. I’m seeing a lot of these patients coming back without hepatitis C, but now with underlying NASH and a tendency toward progression.

Getting patients to treatment is fantastic. Getting these very high cure rates are very good. But, because of this high prevalence of fatty liver disease, we have to think about the two diseases that coexisted that push your patient to cirrhosis. If you cure hepatitis C with cirrhosis, but the patient has underlying NASH with cirrhosis, that patient may still require liver transplantation or develop liver cancer.

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Eric J. Lawitz, MD

At this meeting, the DAA failure space is clearly in focus with three studies utilizing two second-generation regimens. My own presentation focused on the “triple therapy” of sofosbuvir, velpatasvir, and GS-9857, a protease inhibitor, data and Poordad’s presentation looked at the ABT-493 and ABT-530 regimen.

Both of these studies looked at single and multi-class DAA exposed patients; the main difference in these populations were the presence of patients with cirrhosis in the sofosbuvir/valpatasvir/GS-9857 trial while the ABT-493/ABT-530 trial evaluated noncirrhotics while cirrhotics will be studied in the second part of the current trial.

Eric J. Lawitz

My study showed the new generation of agents seem to be universally successful with a SVR12 of 99% (127/128) in genotypes 1 through 6, treatment-experienced patients, including DAA-exposed, with half of the enrolled patients having compensated cirrhosis. This is encouraging as previously we have not had studies showing any reliable way to retreat patients with DAA failure with high rates of success. Now, for the first time, we see two regimens demonstrating high rates of success in these patients.

Poordad’s presentation showed the combination of ABT-493/ABT-530 in DAA exposed noncirrhotic genotype 1 patients had a mITT of 96% (45/47), the ITT was 90% (45/50) with 3 patients’ failing for non virologic reasons.

The ABT-493/ABT-530 also produced good results in genotype 3, as Andrew J. Muir, MD, showed with his presentation. In this study, 29 treatment-naive patients with HCV genotype 3 without cirrhosis were given a once-daily combination for 8 weeks and, of these, 97% achieved SVR12 (n = 28).

In a second study presented by Paul Y. Kwo, MD, 48 patients with HCV genotype 3, who were treatment-naive with cirrhosis were randomized to the same once-daily combination with or without 800 mg of ribavirin for 12 weeks. Of these, all 48 in both treatment groups achieved SVR12 (100%).

As mentioned, Afdahl addressed the question of PPI use with ledipasvir. The TARGET data set from AASLD suggested a 5% decline in efficacy in the setting of concurrent PPI use. The current study from the TRIO database showed there was no difference in outcome regardless of presence or absence of concurrent PPI use, except in those taking twice-daily PPIs, which demonstrated a trend for lower rates of SVR. We should continue to watch for data in this area; obviously, a prospective randomized trial would definitively answer the question. Until then, we continue to monitor observational outcomes.

We understand the pharmacologic effect of pH on solubility of ledipasvir, but how that translates into clinical outcome still needs study. It is certainly likely that the effect would be most obvious in those patients with “stacked” negative baseline factors like cirrhosis, baseline resistance. and less robust innate immune responses, where if there was an effect this would be the population where the difference may best demonstrated. In the subgroup of patients with high medical need for therapy, I avoid concurrent high-dose PPI therapy with ledipasvir in my practice.

Overall, the real world data as mentioned by Younossi is looking much like the registration data. One question in my mind is whether the current “real-world data” will hold up over time. Right now, even the real-world data focuses on motivated patients, who make it through the process of navigating busy practices and taking necessary steps (usually many steps) to access medications. As we move to treating patients less motivated and energetic for a cure, I wonder if we will we see a decline in efficacy because these patients need more care? It will be interesting to track “real world” data over the next few years as the demographics of patients entering therapy may differ from patients being treated today.

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A pleasant surprise thus far has been the consistent “real world” data across patient types, countries and clinics. Unlike previous generations of therapies where we couldn’t reproduce clinical trial results in the community, we are consistently seeing results that mirror the registration data.

At this meeting, we were also privy to a small study from Sanjay Bansal, MD, looking at ledipasvir/sofosbuvir in pediatrics and adolescents. It’s great data to have and will allow hopefully for a future approval for treating younger patients and preventing potential systemic complications down the road for them. It would be valuable to extend the label and have patients under the age of 18 getting access to the drugs if possible.

In a presentation given by Sarah Kattakuzhy, MD, adherence to appointments was better with primary care physicians and nurse practitioners than hepatologists. Inherently, this makes sense as primary care doctors are the face of the patients’ medical care whereas specialists are more removed. The better relationship you have with the patient, the more likely you are to be successful no matter what disease state you are treating.

This raises the question of who is best positioned to treat hepatitis C. Ultimately, doctors who are motivated and interested in hepatitis C are the optimal providers irrespective of their specialty.

Lastly, as Jacobson mentioned, the idea of shortening the duration of DAAs with the long-acting miR-122 target is intriguing. We have been completely unsuccessful shortening down to 4 weeks with DAAs. Many have tried, all have failed, unless we find 30% to 40% an acceptable rate of SVR12. The trial presented by Mihaly Makara, MD, showed the “sandwich” approach of 2 doses of RG-101 28 days apart with either single or dual-class DAA therapy between RG-101 doses. This produced results showing 40/41 (98%) patients on the lower limit of quantification 12 weeks after completion of therapy. The development of jaundice in one patient underscores the need for additional safety data on this drug.

This trial lays the groundwork for further study of this regimen in larger populations with a 4 week course of therapy.

Jordan J. Feld, MD, MPH

There were a lot of interesting developments this year at the International Liver Congress but for me, perhaps the most surprising was the next generation combination regimen of ABT-493 and ABT-530. They had a number of different presentations, as mentioned above, and all of them produced very good results, clearly proving that a nucleotide polymerase inhibitor is not absolutely necessary to achieve very high cure rates across many patient populations. They look to be safe and effective and have the added benefit of being safe in renal patients, which will be important for non-genotype 1 patients with chronic kidney disease.

Jordan J. Feld

In addition to this combination, I was impressed with the triplet regimens. A number of small studies reported high rates of SVR, even in retreatment studies, which gives us good confidence that we will be able to treat most, if not all, of the few patients who fail first attempts at treatment.

It looks like there were a lot of small studies on resistance, such as those from Lawitz with the triplet regimen and Poordad with the ABT combination, but they looked pretty outstanding. They were able to treat almost everyone, even with retreatment.

These three-drug regimens will be a very good answer for people who have failed a first course of therapy. One of the questions will be whether we use three-drug regimens up front or reserve them as salvage for the few that fail.

You can argue both ways, but I might make the argument that it’s good to reserve them. The argument to use them first is to give the best therapy right up front. But the reasons for failure are not always virological. It may be because people aren’t adherent. Having these as an option for a secondary treatment might be best.

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One study in which I participated was a study looking at ledipasvir/sofosbuvir with ribavirin in genotype 3. We actually conducted the study because we were skeptical of the original data showing positive results in this population. We were pleasantly surprised to see that it was effective, similar to what has been reported with sofosbuvir/daclatasvir, despite the fact that ledipasvir is not active against genotype 3 in the replicon model.

We had a total of 111 patients and each patient received sofosbuvir/ledipasvir plus ribavirin for 12 weeks. The overall SVR rate was 89% but without cirrhosis, SVR was 94% (66/70) while cirrhosis was 79% (31/39).

That’s similar to what is reported with sofosbuvir/daclatasvir, and arguably better in patients with cirrhosis. It suggests when you put these drugs in vivo, maybe the replicon assay is not that reliable in predicting the outcome. Clearly, this is more active than expected. If we believe that lack of activity of ledipasvir in the replicon, one would expect this regimen to be similar to sofosbuvir/ribavirin alone, but clearly the results are superior to sofosbuvir/ribavirin alone, particularly with only 12 weeks of treatment. It suggests that ledipasvir is more active against genotype 3 than one might have predicted.

It raises the question of whether the replicon is a good way to measure the success of a regimen. Maybe it’s a moot point given all of the great options, but the question of whether your in vitro assay is a good reflection of what happens in patients is still interesting for antiviral drug development both in HCV and potentially in other infections.

Realistically, sofosbuvir/velpatasvir is likely going to be a better option, so this is not suggesting that sofosbuvir/ledipasvir should be a treatment for genotype 3, but a proof of concept that you can get activity you didn’t anticipate.

Another interesting area for me at this meeting was Acute HCV. The German acute HCV study was interesting as it showed 6 weeks of ledipasvir/sofosbuvir was quite effective in treating the acute infection.

In the monoinfected patients, SVR was 100%. It’s not a huge study, but that’s still really useful because it gives you an option. We’ve been arguing that you shouldn’t treat acute HCV because you can see if people spontaneously clear and just treat if they become chronic. You could still make that argument, but at least this shows what you can do. Especially in the face of ongoing transmission risks, it might be worthwhile to treat.

Previously, the sofosbuvir/ribavirin studies that looked at 6 weeks and 12 weeks were not very effective. Most people thought if you just suppress the virus, you’d be successful treating acute HCV, but it seems you need potent suppression and if you have that, then 6 weeks appears to be enough, at least for most patients.

Another interesting issue that came up centered on the PPI effect with sofosbuvir/ledipasvir. We’ve already discussed the fact that the TRIO evaluation didn’t support what was found by the HCV-TARGET analysis. When you have different studies and they find different results, which do you trust? The methodologies are different and it’s important to look carefully at exactly what was done in each case.

One important difference between them: TRIO is using pharmacy data, which one would think would be more accurate in terms of which drugs are being taken, but an important point to consider is that it captures only prescription drugs and a lot of the PPI use in the U.S. is over the counter. That would make me concerned that they missed a lot the PPI use. HCV-TARGET reviewed the medical records, which also has its downfalls as it only records what clinicians ask about and note in the chart. Both methodologies have their pros and cons and it is hard to be certain that one is more accurate than the other. I am somewhat biased toward the HCV-TARGET result, perhaps because we participate in the study and I know the rigor of the data collection. That being said, even in HCV-TARGET, the effect on SVR is relatively small.

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However, my own belief is that it’s a very plausible effect and we really want to maximize SVR if at all possible. So, from my perspective it’s best not to take PPI with ledipasvir if it can be avoided. I stress this particularly in the first 4 weeks of therapy before the virus is suppressed when drug levels are likely more important. I have yet to have a patient who could not stop the PPI for at least the first 4 weeks of treatment. Overall, the ILC was another interesting chapter in the evolving story of HCV.

Disclosures: Feld reports receiving support for research and/or honoraria for scientific consulting for AbbVie, Abbott, Bristol-Myers Squibb, Gilead, Janssen, Merck, Theravance and Trek. Jacobson reports various financial relationships with AbbVie, Achillion, Alnylam, Bristol-Myers Squibb, Enanta, Gilead Sciences, Janssen Therapeutics, Merck and Tobira. Lawitz reports financial relationships with AbbVie, Achillion Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Enanta Pharmaceuticals, Gilead Sciences, GlaxoSmithKline, Janssen, Merck & Co., Novartis, Regulus, Roche, Salix, Santaris Pharmaceuticals, Tacere, and Theravance. Younossi reports being on the advisory committees or review panels of Janssen, Salix and Vertex and consulting for Coneatus, Enterome and Gilead.