Editorial

Exciting Real-World Data, New Regimens Emerge

Several major themes regarding hepatitis C virus emerged from The Liver Meeting in San Francisco this year, ranging from real-world efficacy data reinforcing our pivotal trials to new regimens and treatment strategies.

First, data presented from real-world databases like TARGET and TRIO shed light on how closely the extraordinary efficacy data, in particular those from the trials, correspond to daily practice.

On a whole, they are indeed confirmed. There’s no significant drop in our expectations based on what we are seeing in our real-world observational studies. Perhaps one of the most important affirmations is the demonstration that treatment-naive, genotype 1, non-cirrhotic patients with HCV RNA levels below 6 million IU/mL can be treated with just 8 weeks of ledipasvir/sofosbuvir (Harvoni, Gilead Sciences) without sacrificing SVR. Even initial doubters like myself have come around and we now have sufficient data supplementing the ION-3 study to stop agonizing over this issue. Despite the presentation of a Veterans Affairs database study suggesting a difference in sustained viral response between 8 and 12 weeks, the preponderance of the evidence, including three other real-world studies, enumerated in more detail in our Take Home, suggests that we can now reassure patients — with confidence — that we are not short changing them or sacrificing a finite chance of SVR on the altar of saving resources, but rather that we think this is consistent with good medical practice.

Ira M. Jacobson

The highly anticipated grazoprevir/elbasvir (Merck) regimen continues to be evaluated substantively in traditionally challenging populations, such as active drug users and those with HIV/HCV co-infection. With regard to co-infected patients, they are no longer difficult to cure with this or the previously approved regimens. With regard to injection drug users, although that risk of re-infection has to be acknowledged, we think it can be controlled adequately with proper collaboration with addiction medicine specialists and, more importantly, that the downstream benefit of preventing new infection in countless other people outweighs the relatively low risk that exists of re-infection.

Additional data brought me to the conclusion that grazoprevir/elbasvir for 12 weeks may very well be the optimal therapy for treatment-naive patients or relapsers with cirrhosis, while those who failed to respond to interferon-based therapy are optimally served with 16 weeks of the regimen and adding ribavirin.

There was also an analysis of resistance associated variants (RAVs) and their impact on SVR with grazoprevir/elbasvir. If you believe that baseline RAVs do impact SVR and can be addressed with a change in your treatment strategy, namely extension of therapy with the addition of ribavirin, we now know which types of assays are needed and which variants matter.

We await approval of this regimen, which is expected in late January by the FDA, and we will find out if there is a stipulation about whether baseline RAV testing is officially recommended. Even if not, clinicians will have to use their judgement as to what they think is best for individual patients.

One series of presentations was little short of breathtaking, conferring the feeling amongst listeners that one was witnessing the progression to another plateau in the evolution of HCV therapy: the ASTRAL studies on sofosbuvir (Sovaldi, Gilead Sciences) and velpatasvir (GS-5816, Gilead Sciences), the latter a pangenotypic NS5A inhibitor.

With 99% or higher SVR in all genotypes except genotype 3, including the largest cohort of genotype 5 patients in a pivotal trial, and only two posttreatment relapses, ASTRAL-1 vindicated the classification of velpatasvir as a pangenotypic drug and this as a pangenotypic regimen.

Additionally, with 95% SVR in genotype 3, it looks like velpatasvir/sofosbuvir is likely to become a preferred regimen for this genotype. A transition from sofosbuvir and ribavirin to a combined direct-acting antiviral regimen has already occurred recently with daclatasvir/sofosbuvir, but the SVR rates with sofosbuvir/velpatasvir are even higher, especially in cirrhotics treated with a 12-week regimen.

The expected approval is June 2016.

Lastly, the second-generation protease and NS5A inhibitors, ABT-493 and ABT-530 (AbbVie), showed promise in treatment as first-line pangenotypic therapy and also with great efficacy against patients harboring baseline RAVs or have RAVs emerge on a prior course of therapy.

This appears to be a very promising pangenotypic regimen that is currently in phase 3 trials.

Looking at other presented studies, it’s beginning to appear that we may eventually have a choice of 8-week triplet regimens containing a nucleotide polymerase inhibitor or 12-week dual regimens. Then the issue will be the potential disadvantages of using a third drug with potential side effects or drug-drug interactions vs. the advantage of being able to shorten therapy. It’s not clear there would be significant cost differences since a shorter regimen with an extra drug may entail a similar cost.

Our readers can expect to see large bodies of data emerging from already initiated advanced trials of triplet regimens of a protease, polymerase and nucleotide inhibitor, whether it’s sofosbuvir, another nucleotide inhibitor called MK-3682 (Merck) or perhaps yet others earlier in development. These regimens may prove to be particularly powerful tools for patients who have failed first generation DAA regimens.

Increasingly, we must ask: are we witnessing the approaching ‘end of history’ with regard to HCV therapy, which would be a scenario in which we have the weapons we need to cure just about everybody? Do we move on or are there still novel approaches that might alter the paradigm? See our Take Home for my breakdown of the presented data, including a presentation on a miR-122 inhibitor, which may be that novel approach.

Ira M. Jacobson, MD
Co-Chief Medical Editor
HCV Next 

Several major themes regarding hepatitis C virus emerged from The Liver Meeting in San Francisco this year, ranging from real-world efficacy data reinforcing our pivotal trials to new regimens and treatment strategies.

First, data presented from real-world databases like TARGET and TRIO shed light on how closely the extraordinary efficacy data, in particular those from the trials, correspond to daily practice.

On a whole, they are indeed confirmed. There’s no significant drop in our expectations based on what we are seeing in our real-world observational studies. Perhaps one of the most important affirmations is the demonstration that treatment-naive, genotype 1, non-cirrhotic patients with HCV RNA levels below 6 million IU/mL can be treated with just 8 weeks of ledipasvir/sofosbuvir (Harvoni, Gilead Sciences) without sacrificing SVR. Even initial doubters like myself have come around and we now have sufficient data supplementing the ION-3 study to stop agonizing over this issue. Despite the presentation of a Veterans Affairs database study suggesting a difference in sustained viral response between 8 and 12 weeks, the preponderance of the evidence, including three other real-world studies, enumerated in more detail in our Take Home, suggests that we can now reassure patients — with confidence — that we are not short changing them or sacrificing a finite chance of SVR on the altar of saving resources, but rather that we think this is consistent with good medical practice.

Ira M. Jacobson

The highly anticipated grazoprevir/elbasvir (Merck) regimen continues to be evaluated substantively in traditionally challenging populations, such as active drug users and those with HIV/HCV co-infection. With regard to co-infected patients, they are no longer difficult to cure with this or the previously approved regimens. With regard to injection drug users, although that risk of re-infection has to be acknowledged, we think it can be controlled adequately with proper collaboration with addiction medicine specialists and, more importantly, that the downstream benefit of preventing new infection in countless other people outweighs the relatively low risk that exists of re-infection.

Additional data brought me to the conclusion that grazoprevir/elbasvir for 12 weeks may very well be the optimal therapy for treatment-naive patients or relapsers with cirrhosis, while those who failed to respond to interferon-based therapy are optimally served with 16 weeks of the regimen and adding ribavirin.

There was also an analysis of resistance associated variants (RAVs) and their impact on SVR with grazoprevir/elbasvir. If you believe that baseline RAVs do impact SVR and can be addressed with a change in your treatment strategy, namely extension of therapy with the addition of ribavirin, we now know which types of assays are needed and which variants matter.

We await approval of this regimen, which is expected in late January by the FDA, and we will find out if there is a stipulation about whether baseline RAV testing is officially recommended. Even if not, clinicians will have to use their judgement as to what they think is best for individual patients.

One series of presentations was little short of breathtaking, conferring the feeling amongst listeners that one was witnessing the progression to another plateau in the evolution of HCV therapy: the ASTRAL studies on sofosbuvir (Sovaldi, Gilead Sciences) and velpatasvir (GS-5816, Gilead Sciences), the latter a pangenotypic NS5A inhibitor.

With 99% or higher SVR in all genotypes except genotype 3, including the largest cohort of genotype 5 patients in a pivotal trial, and only two posttreatment relapses, ASTRAL-1 vindicated the classification of velpatasvir as a pangenotypic drug and this as a pangenotypic regimen.

Additionally, with 95% SVR in genotype 3, it looks like velpatasvir/sofosbuvir is likely to become a preferred regimen for this genotype. A transition from sofosbuvir and ribavirin to a combined direct-acting antiviral regimen has already occurred recently with daclatasvir/sofosbuvir, but the SVR rates with sofosbuvir/velpatasvir are even higher, especially in cirrhotics treated with a 12-week regimen.

The expected approval is June 2016.

Lastly, the second-generation protease and NS5A inhibitors, ABT-493 and ABT-530 (AbbVie), showed promise in treatment as first-line pangenotypic therapy and also with great efficacy against patients harboring baseline RAVs or have RAVs emerge on a prior course of therapy.

This appears to be a very promising pangenotypic regimen that is currently in phase 3 trials.

Looking at other presented studies, it’s beginning to appear that we may eventually have a choice of 8-week triplet regimens containing a nucleotide polymerase inhibitor or 12-week dual regimens. Then the issue will be the potential disadvantages of using a third drug with potential side effects or drug-drug interactions vs. the advantage of being able to shorten therapy. It’s not clear there would be significant cost differences since a shorter regimen with an extra drug may entail a similar cost.

Our readers can expect to see large bodies of data emerging from already initiated advanced trials of triplet regimens of a protease, polymerase and nucleotide inhibitor, whether it’s sofosbuvir, another nucleotide inhibitor called MK-3682 (Merck) or perhaps yet others earlier in development. These regimens may prove to be particularly powerful tools for patients who have failed first generation DAA regimens.

Increasingly, we must ask: are we witnessing the approaching ‘end of history’ with regard to HCV therapy, which would be a scenario in which we have the weapons we need to cure just about everybody? Do we move on or are there still novel approaches that might alter the paradigm? See our Take Home for my breakdown of the presented data, including a presentation on a miR-122 inhibitor, which may be that novel approach.

Ira M. Jacobson, MD
Co-Chief Medical Editor
HCV Next