Guest Editorial

Pangenotypic Regimen: A Step Forward in HCV Treatment

It’s been an amazing few years for hepatitis C in general, and the development of various treatment regimens is moving at a rapid pace. The nice thing is that for most patients, we have highly effective therapies. One of the newest therapies is the pangenotypic regimen, which was most recently investigated in the ASTRAL clinical trials.

The unique element about the ASTRAL clinical trials is the pangenotypic nature of the drugs involved. In ASTRAL-1, ASTRAL-2 and ASTRAL-3, 1,035 patients with HCV genotypes 1 to 6 were assigned a fixed dose combination of sofosbuvir (Sovaldi, Gilead Sciences) and velpatasvir (Gilead Sciences) for 12 weeks. Of these patients, 21% had compensated cirrhosis and 28% failed prior treatments. In the ASTRAL-4 study, 267 patients with decompensated cirrhosis were randomly assigned to a regimen of sofosbuvir and velpatasvir with or without ribavirin for 12 weeks, or sofosbuvir and velpatasvir for 24 weeks.

Jordan J. Feld

There are two major advantages here with the pangenotypic regimen. One, is you have a therapy available that works across all genotypes. The big advantage of that is it allows the possibility to move treatment, at least for many patients, outside of specialty care. If we as hepatologists and infectious disease specialists are going to address the public health burden of this disease, we’re going to have to move treatment outside of specialty clinics, at least for many patients. For straightforward patients without advanced liver disease, there’s no reason primary care physicians, nurses and mid-level providers can’t manage and treat this effectively.

Treating hepatitis C is definitely not one-size-fits-all. However, it is one-size-fits-most. That is a huge benefit, but we have to make sure non-specialist providers recognize when they need to provide a specialist to a patient. For instance, anyone with cirrhosis or complicated medical histories should be seen by providers with more experience, but the vast majority of patients are still treatment-naive and non-cirrhotic and this takes away one more barrier in terms of simplifying treatment.

The other major benefit of this regimen is that it is a great option for genotype 3, which has been one area where currently approved therapies leave a bit to be desired. A regimen of sofosbuvir and ribavirin for 24 weeks is not ideal. Real-world data from the HCV TARGET registry have shown sustained virologic response rates to be particularly dismal in patients with cirrhosis. The SVR rates were down to 58% for treatment-naive patients with cirrhosis and down to 44% for treatment-experienced cirrhotics. This is not ideal for a 6-month regimen that includes the use of ribavirin.

On the other hand, you have a regimen of sofosbuvir and daclatasvir (Daklinza, Bristol-Myers Squibb) that has raised a lot of excitement as a possible ribavirin-free and interferon-free regimen. Unfortunately, data are limited among patients with cirrhosis. There is some real-world data from Europe showing 24 weeks of this regimen is not bad, but it is an incredibly expensive regimen with no real clinical trial data to support its efficacy.

The ASTRAL studies provided high quality clinical trial data. In the ASTRAL-1 study, we had a placebo element that allowed the comparison of safety. Sometimes people don’t understand why there is a placebo arm involved, but it is critical to get a true sense of the safety. In my own experience conducting the trial, we had many patients who were on active treatment say ‘I must be on the placebo because I don’t feel anything’ because the side effects were very minimal. In this trial, it does look like a very good regimen. The results are hard to argue with—only two virologic failures out of 624 patients. It is pretty remarkable.

In ASTRAL-2, there were 134 patients in the sofosbuvir and velpatasvir arm and 132 in the sofosbuvir and ribavirin arm. SVR rates 12 weeks’ post-treatment were 99% for the sofosbuvir/velpatasvir group and 94% for the sofosbuvir/ribavirin group. In fact, the only patient not to achieve SVR12 in the velpatasvir arm was lost to follow-up. The velpatasvir regimen yielded SVR12 rates at or near 100% among cirrhotics, compared with 96% among cirrhotics treated with sofosbuvir/ribavirin.

In the ASTRAL-3 study, results showed SVR rates above 90% across the board, including those with cirrhosis, and 89% in treatment-experienced cirrhotics. This is pretty solid data. Rates were still not quite as high as we’ve seen in other areas, but I think this provides a great option for patients with genotype 3, particularly those with cirrhosis.

With the ASTRAL-4 study, we figured out that this is not the end of the road. In decompensated patients, it looked like adding ribavirin was still helpful and that raises a question about why that’s true — it seems ribavirin just does not want to go away. Personally, I believe ribavirin probably has most of its effect by being a so-called mutagen and causing the virus to have more mutations. This limits the virus’ ability to escape from the pressure of the drug or the immune response. You end up having less quasispecies diversity and the consequence of that is less breakthrough, which leads to less resistant variants emerging and less variants that evade specific immune responses. This is hard to prove, but more and more data show it delays and/or prevents the onset of resistance.

This also matters more in the decompensated patient because these patients may have unequal drug distribution due to shunting in the liver. Ribavirin provides a cushion to deal with resistance. It’s hard to prove, but there are reasonable data to support this. It raises the question of whether ribavirin will have a role down the road. I think we will be able to get rid of it for most patients.

Overall, it is a huge step forward having a panogenotypic regimen. There is still room for improvement in shortening therapy, handling patients who failed therapy, among other elements to consider. There is still a little bit of work to do, but the data across the trials pretty much speak for themselves.

Jordan J. Feld, MD, MPH
Associate Professor of Medicine
Research Director, Toronto Centre for Liver Disease
Toronto General Hospital, University Health Network
University of Toronto

Disclosure: Feld reports associations with AbbVie and Boehringer Ingelheim.

It’s been an amazing few years for hepatitis C in general, and the development of various treatment regimens is moving at a rapid pace. The nice thing is that for most patients, we have highly effective therapies. One of the newest therapies is the pangenotypic regimen, which was most recently investigated in the ASTRAL clinical trials.

The unique element about the ASTRAL clinical trials is the pangenotypic nature of the drugs involved. In ASTRAL-1, ASTRAL-2 and ASTRAL-3, 1,035 patients with HCV genotypes 1 to 6 were assigned a fixed dose combination of sofosbuvir (Sovaldi, Gilead Sciences) and velpatasvir (Gilead Sciences) for 12 weeks. Of these patients, 21% had compensated cirrhosis and 28% failed prior treatments. In the ASTRAL-4 study, 267 patients with decompensated cirrhosis were randomly assigned to a regimen of sofosbuvir and velpatasvir with or without ribavirin for 12 weeks, or sofosbuvir and velpatasvir for 24 weeks.

Jordan J. Feld

There are two major advantages here with the pangenotypic regimen. One, is you have a therapy available that works across all genotypes. The big advantage of that is it allows the possibility to move treatment, at least for many patients, outside of specialty care. If we as hepatologists and infectious disease specialists are going to address the public health burden of this disease, we’re going to have to move treatment outside of specialty clinics, at least for many patients. For straightforward patients without advanced liver disease, there’s no reason primary care physicians, nurses and mid-level providers can’t manage and treat this effectively.

Treating hepatitis C is definitely not one-size-fits-all. However, it is one-size-fits-most. That is a huge benefit, but we have to make sure non-specialist providers recognize when they need to provide a specialist to a patient. For instance, anyone with cirrhosis or complicated medical histories should be seen by providers with more experience, but the vast majority of patients are still treatment-naive and non-cirrhotic and this takes away one more barrier in terms of simplifying treatment.

The other major benefit of this regimen is that it is a great option for genotype 3, which has been one area where currently approved therapies leave a bit to be desired. A regimen of sofosbuvir and ribavirin for 24 weeks is not ideal. Real-world data from the HCV TARGET registry have shown sustained virologic response rates to be particularly dismal in patients with cirrhosis. The SVR rates were down to 58% for treatment-naive patients with cirrhosis and down to 44% for treatment-experienced cirrhotics. This is not ideal for a 6-month regimen that includes the use of ribavirin.

On the other hand, you have a regimen of sofosbuvir and daclatasvir (Daklinza, Bristol-Myers Squibb) that has raised a lot of excitement as a possible ribavirin-free and interferon-free regimen. Unfortunately, data are limited among patients with cirrhosis. There is some real-world data from Europe showing 24 weeks of this regimen is not bad, but it is an incredibly expensive regimen with no real clinical trial data to support its efficacy.

The ASTRAL studies provided high quality clinical trial data. In the ASTRAL-1 study, we had a placebo element that allowed the comparison of safety. Sometimes people don’t understand why there is a placebo arm involved, but it is critical to get a true sense of the safety. In my own experience conducting the trial, we had many patients who were on active treatment say ‘I must be on the placebo because I don’t feel anything’ because the side effects were very minimal. In this trial, it does look like a very good regimen. The results are hard to argue with—only two virologic failures out of 624 patients. It is pretty remarkable.

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In ASTRAL-2, there were 134 patients in the sofosbuvir and velpatasvir arm and 132 in the sofosbuvir and ribavirin arm. SVR rates 12 weeks’ post-treatment were 99% for the sofosbuvir/velpatasvir group and 94% for the sofosbuvir/ribavirin group. In fact, the only patient not to achieve SVR12 in the velpatasvir arm was lost to follow-up. The velpatasvir regimen yielded SVR12 rates at or near 100% among cirrhotics, compared with 96% among cirrhotics treated with sofosbuvir/ribavirin.

In the ASTRAL-3 study, results showed SVR rates above 90% across the board, including those with cirrhosis, and 89% in treatment-experienced cirrhotics. This is pretty solid data. Rates were still not quite as high as we’ve seen in other areas, but I think this provides a great option for patients with genotype 3, particularly those with cirrhosis.

With the ASTRAL-4 study, we figured out that this is not the end of the road. In decompensated patients, it looked like adding ribavirin was still helpful and that raises a question about why that’s true — it seems ribavirin just does not want to go away. Personally, I believe ribavirin probably has most of its effect by being a so-called mutagen and causing the virus to have more mutations. This limits the virus’ ability to escape from the pressure of the drug or the immune response. You end up having less quasispecies diversity and the consequence of that is less breakthrough, which leads to less resistant variants emerging and less variants that evade specific immune responses. This is hard to prove, but more and more data show it delays and/or prevents the onset of resistance.

This also matters more in the decompensated patient because these patients may have unequal drug distribution due to shunting in the liver. Ribavirin provides a cushion to deal with resistance. It’s hard to prove, but there are reasonable data to support this. It raises the question of whether ribavirin will have a role down the road. I think we will be able to get rid of it for most patients.

Overall, it is a huge step forward having a panogenotypic regimen. There is still room for improvement in shortening therapy, handling patients who failed therapy, among other elements to consider. There is still a little bit of work to do, but the data across the trials pretty much speak for themselves.

Jordan J. Feld, MD, MPH
Associate Professor of Medicine
Research Director, Toronto Centre for Liver Disease
Toronto General Hospital, University Health Network
University of Toronto

Disclosure: Feld reports associations with AbbVie and Boehringer Ingelheim.