The Take Home

The Take Home: International Liver Congress

International Liver Congress

The International Liver Congress 2014 featured some of the most up-to-date findings in the rapidly evolving field of hepatitis C virus therapies. Nearly 10,000 attendees gathered in London from April 9 to 13 to hear the latest research on novel direct-acting antiviral therapies that are changing the face of this disease. This year’s meeting was more popular than ever, with a record-breaking number of abstracts submitted.

Jordan J. Feld, MD 

Jordan J. Feld

Jordan J. Feld, MD, MPH, assistant professor of medicine and research director of gastroenterology at Toronto Western Hospital Liver Center and HCV Next Editorial Board member; Giorgina Mieli-Vergani, MD, PhD, professor of pediatric hepatology at King’s College Hospital in London and honorary president of the International Liver Congress; Anu Osinusi, MD, MPH, assistant professor of medicine in the Institute of Human Virology at University of Maryland; and Stefan Wiktor, MD, team leader of the Global Hepatitis Program at WHO, shared their thoughts on the most compelling data and topics discussed at this year’s meeting.

New WHO Guidelines

Wiktor: These guidelines are different [than other recent guidelines] because they are focusing on [treatment of HCV in] low- and middle-income countries. In these countries, most people who have HCV are not being treated, and in some countries they are receiving standard interferon, which is substandard care. So for our guidelines, the group that was convened represented a number of low- and middle-income countries. We felt that it was important to include recommendations for all existing treatments, from interferon to the newest direct-acting antiviral (DAA) therapies. For example, we recommend pegylated interferon over standard interferon, which seems like a backward-looking recommendation, but we know that in a number of countries, like Pakistan, they use standard interferon. We wanted to state clearly that these countries should use pegylated interferon. But we did not want to leave out the opportunity for countries to use the new DAAs such as sofosbuvir (Sovaldi, Gilead) and simeprevir (Olysio, Janssen Therapeutics), so we had to rush and reconvene our group to include recommendations for those two drugs.

As we heard from Egypt, some countries have been able to negotiate price reductions with the manufacturers that enable patients to be treated with these drugs.

A big question comes up with regard to who should be treated. We took a resource use consideration in our guideline. Although we do not have a formal recommendation, we state that patients with more advanced fibrosis — those in stage F3 and F4 — should be prioritized for treatment. In many countries, the number of patients who will be able to be treated because of economic considerations will be limited, so among that pool of patients, we wanted those at the highest risk for [developing] cancer or cirrhosis to be treated, as they will benefit most. This is the most cost-effective approach.

ELECTRON-2

Feld: The most impressive take-home message from ILC 2014 was seeing data that patients who had previously failed a sofosbuvir-containing regimen and then were treated with sofosbuvir/ledipasvir demonstrated very high rates of sustained virologic response.

Edward J. Gane, MD, from Auckland Clinical Studies in New Zealand, showed this in the ELECTRON-2 study, which investigated the safety and efficacy of combination therapy with ledipasvir (Gilead) and sofosbuvir in three patient cohorts: patients with advanced liver disease; patients with HCV genotype 3; and patients who failed on earlier DAA regimens. Results demonstrated SVR in 19 patients with HCV genotype 1 infection who previously failed on sofosbuvir treatment, including eight patients who had relapsed on a shorter course of ledipasvir and sofosbuvir.
Results like these give us the option of re-treating patients for longer or using a second drug combination with sofosbuvir. It gives us the confidence that failing a regimen is not putting you in bad shape for future treatment.

ION-1

Osinusi: The ION-1 study included 865 patients treated with sofosbuvir plus ledipasvir with or without ribavirin for 12 or 24 weeks. This included 136 (16%) patients with compensated cirrhosis. Results demonstrated very high cure rates upward of 97%. The regimen was very well tolerated with few serious adverse events. Extension to 24 weeks of therapy did not lead to added benefit. Ribavirin use was associated with additional anemia and marginal increase in SVR rates in cirrhotic patients.

Anu Osinusi, MD 

Anu Osinusi

The sofosbuvir/ledipasvir fixed-dose combination evaluated will likely be the first interferon- and ribavirin-free DAA therapy approved for patients with HCV genotype 1 infection, which accounts for more than 75% of infected individuals in the United States. The potential that a 12-week, single, daily pill with a favorable safety profile for treatment of HCV will be readily available in the near future represents a major advancement in the field.

ION-3

Mieli-Vergani: One presentation at the general session by Kris V. Kowdley, MD, from Virginia Mason Medical Center, showed remarkable results with the combination of sofosbuvir and ledipasvir in patients who were not only treatment-naive but in patients with cirrhosis and those who have not responded to previous treatment. [This analysis included 647 patients who were randomly assigned in a 1:1:1 ratio to a fixed-dose combination of sofosbuvir 400 mg plus ledipasvir 90 mg for 8 weeks (n=215); combination therapy plus ribavirin for 8 weeks (n=216); or combination therapy without ribavirin for 12 weeks (n=216). The SVR12 rate was 94% with 8-week sofosbuvir/ledipasvir without ribavirin, 93% with 8-week sofosbuvir/ledipasvir with ribavirin and 95% with 12-week sofosbuvir/ledipasvir without ribavirin.]

Giorgina Mieli-Vergani, MD 

Giorgani Mieli-Vergani

It is important that patients only have to take one tablet per day with no interferon or ribavirin with this regimen. The study had an arm with ribavirin treatment, but the results were not better than the arm without ribavirin treatment. This would make treatment easier, decrease nonadherence and improve quality of life for the patients. Also, the side effects are minimal. This is confirmed by other studies at this same congress showing that the response to this drug combination is excellent.

SAPPHIRE-I

Feld: I presented results of the SAPPHIRE-I study. This was a study of a 12-week interferon-free regimen of the NS3/4A protease inhibitor ABT-450 with ritonavir (ABT-450/r; AbbVie) and the NS5A inhibitor ombitasvir plus the NS5B RNA polymerase inhibitor dasabuvir (both from AbbVie) with ribavirin. Patients were randomly assigned in a 3:1 ratio to a single-table co-formulation of ABT-450/r-ombitasvir (150 mg/100 mg/25 mg once daily) and dasabuvir (250 mg twice daily) with weight-based ribavirin (n=472) or to matching placebo (n=158).

The SVR rates were remarkable, 96.2% overall, 98% in patients with HCV genotype 1b and 95.3% in genotype 1a. There was one on-treatment breakthrough, which is good news, as there has been concern with this regimen that we might have viral breakthrough and resistance. Only seven patients relapsed after treatment. That is a pretty low virologic failure rate.

SAPPHIRE-I was a placebo-controlled trial, which has an advantage over some of the other trials because it provides a true evaluation of safety and tolerability compared with nothing. That is important because when you look at the data, although there were more side effects in the patients taking active drug, 73% of patients treated with placebo had an adverse event. So it looks like 85% experienced an adverse event using the active therapy, but 73% of patients taking nothing (placebo) had an adverse event. In addition, there were no grade 3 hemoglobin drops, nothing worse than 10 g/dL, which is pretty tolerable. Everything else was mild. This is a well-tolerated regimen.

TURQUOISE-II

Osinusi: TURQUOISE-II is the largest dedicated study to date of interferon-free DAA-only regimens for the treatment of patients with HCV genotype 1 infection and compensated cirrhosis. In this study, it was shown that it is possible to cure about 94% of patients (SVR12 92% in the 12-week arm and 96% in the 24-week arm) with 12 to 24 weeks of ABT-450/r and ombitasvir plus dasabuvir with ribavirin. The regimen was safe, with similar tolerability as in patients without cirrhosis.

The population that most providers are concerned about for now and the near future includes patients with advanced liver disease, particularly cirrhotics. As such, this is a very important study. This regimen significantly advances the cure rates in this difficult population without the excessive high rates and complications observed in the past with interferon-based therapies. However, clinicians will still remain concerned about side effects associated with ribavirin, particularly anemia. There are also still concerns about drug-drug interactions attributable to ritonavir use with this regimen.

RESTORE

Mieli-Vergani: Simeprevir is a NS3/4A protease inhibitor for the treatment of HCV genotypes 1 and 4 in adults with compensated liver disease, including all stages of liver fibrosis. Taken as one pill once daily, simeprevir works by blocking the protease enzyme that enables HCV to replicate in host cells.

In the phase 3 RESTORE study, conducted in Belgium and France, 107 patients with chronic HCV genotype 4 received once-daily simeprevir with pegylated interferon and ribavirin for 12 weeks. Treatment-naive patients and prior relapsers received response-guided therapy with pegylated interferon and ribavirin continued for up to 24 or 48 weeks. Prior partial responders and prior null responders continued to receive pegylated interferon and ribavirin for up to 48 weeks.

Overall, 65.4% of patients achieved SVR12. The SVR12 rates in the IL28B CT and TT patient subgroups were 65.6% and 59.5%, and 65.6% and 62.2% demonstrated a rapid virologic response (RVR), respectively. Among those patients with more severe liver fibrosis (METAVIR F4), 46.7% and 62.1% achieved SVR12 and RVR, respectively. Among those patients meeting response-guided therapy criteria, none experienced on-treatment failure, and three patients experienced viral relapse (two treatment-naive patients, one relapser). Overall, simeprevir was well tolerated. Most adverse events were grade 1 or 2. Serious adverse events were infrequent (five patients [4.7%]; no deaths) and considered unrelated to simeprevir. The most frequent adverse events (>30% of patients) included influenza-like illness, asthenia and fatigue.

NEUTRINO

Mieli-Vergani: This study involved treatment-naive and treatment-experienced patients of Egyptian ancestry with chronic HCV genotype 4, including those who were interferon-ineligible, interferon-intolerant and interferon failures.

Sofosbuvir plus ribavirin was shown to provide a simple, effective and well-tolerated interferon-free regimen. After 12 weeks of treatment with sofosbuvir plus ribavirin, the SVR12 rate in treatment-naive patients was 79%, and in treatment-experienced patients was 59%. Extending treatment duration to 24 weeks resulted in higher SVR12 rates in both treatment-naive and treatment-experienced patients: 100% and 87%, respectively.

Most adverse events were mild or moderate in severity and consistent with the known side effects of ribavirin.

General Comments

Feld: There is one caveat with all of these successful treatments: We need to figure out what is going to happen to those small numbers of patients who do end up failing because they had resistance to at least one agent. Are they going to have other regimens? There are drugs in development but we need to make sure we watch this patient population.

Mieli-Vergani: The major take-home message of this meeting is the treatment of HCV. The results of some of the phase 3 trials presented are absolutely outstanding. It is clear that we can now cure HCV. The major problem that remains is the cost of the treatment. What we should concentrate on now is to abate the cost of this treatment worldwide. At the American Association for the Study of Liver Diseases’ The Liver Meeting in November, it was suggested that it would cost $80,000 per year. Of course, $80,000 per year is less expensive than having a liver transplant, but many countries will not have the money to do it because there are so many patients infected. Theoretically, the patients should be treated before they get very severe liver disease. So I think the issue remains of how we treat these patients, and who should be treated. We do not want to have to stratify patients based on money, essentially on whether someone can afford it or whether they cannot.

References:
Afdhal N. N Engl J Med. 2014;370:1889-1898.
Feld JJ. N Engl J Med. 2014;370:1594-1603.
Kowdley KV. N Engl J Med. 2014;370:1879-1888.
Poordad F. N Engl J Med. 2014 370:1973-1982.
World Health Organization. Guidelines for the screening, care and treatment of persons with hepatitis C infection. www.who.int/hiv/pub/hepatitis/hepatitis-c-guidelines/en/. Accessed on May 8, 2014.
Disclosures: Feld reports associations with AbbVie and Boehringer Ingelheim. Mieli-Vergani reports associations with Bristol-Myers Squibb, Novartis and Roche. Osinusi and Wiktor report no relevant financial disclosures.

International Liver Congress

The International Liver Congress 2014 featured some of the most up-to-date findings in the rapidly evolving field of hepatitis C virus therapies. Nearly 10,000 attendees gathered in London from April 9 to 13 to hear the latest research on novel direct-acting antiviral therapies that are changing the face of this disease. This year’s meeting was more popular than ever, with a record-breaking number of abstracts submitted.

Jordan J. Feld, MD 

Jordan J. Feld

Jordan J. Feld, MD, MPH, assistant professor of medicine and research director of gastroenterology at Toronto Western Hospital Liver Center and HCV Next Editorial Board member; Giorgina Mieli-Vergani, MD, PhD, professor of pediatric hepatology at King’s College Hospital in London and honorary president of the International Liver Congress; Anu Osinusi, MD, MPH, assistant professor of medicine in the Institute of Human Virology at University of Maryland; and Stefan Wiktor, MD, team leader of the Global Hepatitis Program at WHO, shared their thoughts on the most compelling data and topics discussed at this year’s meeting.

New WHO Guidelines

Wiktor: These guidelines are different [than other recent guidelines] because they are focusing on [treatment of HCV in] low- and middle-income countries. In these countries, most people who have HCV are not being treated, and in some countries they are receiving standard interferon, which is substandard care. So for our guidelines, the group that was convened represented a number of low- and middle-income countries. We felt that it was important to include recommendations for all existing treatments, from interferon to the newest direct-acting antiviral (DAA) therapies. For example, we recommend pegylated interferon over standard interferon, which seems like a backward-looking recommendation, but we know that in a number of countries, like Pakistan, they use standard interferon. We wanted to state clearly that these countries should use pegylated interferon. But we did not want to leave out the opportunity for countries to use the new DAAs such as sofosbuvir (Sovaldi, Gilead) and simeprevir (Olysio, Janssen Therapeutics), so we had to rush and reconvene our group to include recommendations for those two drugs.

As we heard from Egypt, some countries have been able to negotiate price reductions with the manufacturers that enable patients to be treated with these drugs.

A big question comes up with regard to who should be treated. We took a resource use consideration in our guideline. Although we do not have a formal recommendation, we state that patients with more advanced fibrosis — those in stage F3 and F4 — should be prioritized for treatment. In many countries, the number of patients who will be able to be treated because of economic considerations will be limited, so among that pool of patients, we wanted those at the highest risk for [developing] cancer or cirrhosis to be treated, as they will benefit most. This is the most cost-effective approach.

ELECTRON-2

Feld: The most impressive take-home message from ILC 2014 was seeing data that patients who had previously failed a sofosbuvir-containing regimen and then were treated with sofosbuvir/ledipasvir demonstrated very high rates of sustained virologic response.

Edward J. Gane, MD, from Auckland Clinical Studies in New Zealand, showed this in the ELECTRON-2 study, which investigated the safety and efficacy of combination therapy with ledipasvir (Gilead) and sofosbuvir in three patient cohorts: patients with advanced liver disease; patients with HCV genotype 3; and patients who failed on earlier DAA regimens. Results demonstrated SVR in 19 patients with HCV genotype 1 infection who previously failed on sofosbuvir treatment, including eight patients who had relapsed on a shorter course of ledipasvir and sofosbuvir.
Results like these give us the option of re-treating patients for longer or using a second drug combination with sofosbuvir. It gives us the confidence that failing a regimen is not putting you in bad shape for future treatment.

ION-1

Osinusi: The ION-1 study included 865 patients treated with sofosbuvir plus ledipasvir with or without ribavirin for 12 or 24 weeks. This included 136 (16%) patients with compensated cirrhosis. Results demonstrated very high cure rates upward of 97%. The regimen was very well tolerated with few serious adverse events. Extension to 24 weeks of therapy did not lead to added benefit. Ribavirin use was associated with additional anemia and marginal increase in SVR rates in cirrhotic patients.

Anu Osinusi, MD 

Anu Osinusi

The sofosbuvir/ledipasvir fixed-dose combination evaluated will likely be the first interferon- and ribavirin-free DAA therapy approved for patients with HCV genotype 1 infection, which accounts for more than 75% of infected individuals in the United States. The potential that a 12-week, single, daily pill with a favorable safety profile for treatment of HCV will be readily available in the near future represents a major advancement in the field.

PAGE BREAK

ION-3

Mieli-Vergani: One presentation at the general session by Kris V. Kowdley, MD, from Virginia Mason Medical Center, showed remarkable results with the combination of sofosbuvir and ledipasvir in patients who were not only treatment-naive but in patients with cirrhosis and those who have not responded to previous treatment. [This analysis included 647 patients who were randomly assigned in a 1:1:1 ratio to a fixed-dose combination of sofosbuvir 400 mg plus ledipasvir 90 mg for 8 weeks (n=215); combination therapy plus ribavirin for 8 weeks (n=216); or combination therapy without ribavirin for 12 weeks (n=216). The SVR12 rate was 94% with 8-week sofosbuvir/ledipasvir without ribavirin, 93% with 8-week sofosbuvir/ledipasvir with ribavirin and 95% with 12-week sofosbuvir/ledipasvir without ribavirin.]

Giorgina Mieli-Vergani, MD 

Giorgani Mieli-Vergani

It is important that patients only have to take one tablet per day with no interferon or ribavirin with this regimen. The study had an arm with ribavirin treatment, but the results were not better than the arm without ribavirin treatment. This would make treatment easier, decrease nonadherence and improve quality of life for the patients. Also, the side effects are minimal. This is confirmed by other studies at this same congress showing that the response to this drug combination is excellent.

SAPPHIRE-I

Feld: I presented results of the SAPPHIRE-I study. This was a study of a 12-week interferon-free regimen of the NS3/4A protease inhibitor ABT-450 with ritonavir (ABT-450/r; AbbVie) and the NS5A inhibitor ombitasvir plus the NS5B RNA polymerase inhibitor dasabuvir (both from AbbVie) with ribavirin. Patients were randomly assigned in a 3:1 ratio to a single-table co-formulation of ABT-450/r-ombitasvir (150 mg/100 mg/25 mg once daily) and dasabuvir (250 mg twice daily) with weight-based ribavirin (n=472) or to matching placebo (n=158).

The SVR rates were remarkable, 96.2% overall, 98% in patients with HCV genotype 1b and 95.3% in genotype 1a. There was one on-treatment breakthrough, which is good news, as there has been concern with this regimen that we might have viral breakthrough and resistance. Only seven patients relapsed after treatment. That is a pretty low virologic failure rate.

SAPPHIRE-I was a placebo-controlled trial, which has an advantage over some of the other trials because it provides a true evaluation of safety and tolerability compared with nothing. That is important because when you look at the data, although there were more side effects in the patients taking active drug, 73% of patients treated with placebo had an adverse event. So it looks like 85% experienced an adverse event using the active therapy, but 73% of patients taking nothing (placebo) had an adverse event. In addition, there were no grade 3 hemoglobin drops, nothing worse than 10 g/dL, which is pretty tolerable. Everything else was mild. This is a well-tolerated regimen.

TURQUOISE-II

Osinusi: TURQUOISE-II is the largest dedicated study to date of interferon-free DAA-only regimens for the treatment of patients with HCV genotype 1 infection and compensated cirrhosis. In this study, it was shown that it is possible to cure about 94% of patients (SVR12 92% in the 12-week arm and 96% in the 24-week arm) with 12 to 24 weeks of ABT-450/r and ombitasvir plus dasabuvir with ribavirin. The regimen was safe, with similar tolerability as in patients without cirrhosis.

The population that most providers are concerned about for now and the near future includes patients with advanced liver disease, particularly cirrhotics. As such, this is a very important study. This regimen significantly advances the cure rates in this difficult population without the excessive high rates and complications observed in the past with interferon-based therapies. However, clinicians will still remain concerned about side effects associated with ribavirin, particularly anemia. There are also still concerns about drug-drug interactions attributable to ritonavir use with this regimen.

RESTORE

Mieli-Vergani: Simeprevir is a NS3/4A protease inhibitor for the treatment of HCV genotypes 1 and 4 in adults with compensated liver disease, including all stages of liver fibrosis. Taken as one pill once daily, simeprevir works by blocking the protease enzyme that enables HCV to replicate in host cells.

In the phase 3 RESTORE study, conducted in Belgium and France, 107 patients with chronic HCV genotype 4 received once-daily simeprevir with pegylated interferon and ribavirin for 12 weeks. Treatment-naive patients and prior relapsers received response-guided therapy with pegylated interferon and ribavirin continued for up to 24 or 48 weeks. Prior partial responders and prior null responders continued to receive pegylated interferon and ribavirin for up to 48 weeks.

Overall, 65.4% of patients achieved SVR12. The SVR12 rates in the IL28B CT and TT patient subgroups were 65.6% and 59.5%, and 65.6% and 62.2% demonstrated a rapid virologic response (RVR), respectively. Among those patients with more severe liver fibrosis (METAVIR F4), 46.7% and 62.1% achieved SVR12 and RVR, respectively. Among those patients meeting response-guided therapy criteria, none experienced on-treatment failure, and three patients experienced viral relapse (two treatment-naive patients, one relapser). Overall, simeprevir was well tolerated. Most adverse events were grade 1 or 2. Serious adverse events were infrequent (five patients [4.7%]; no deaths) and considered unrelated to simeprevir. The most frequent adverse events (>30% of patients) included influenza-like illness, asthenia and fatigue.

PAGE BREAK

NEUTRINO

Mieli-Vergani: This study involved treatment-naive and treatment-experienced patients of Egyptian ancestry with chronic HCV genotype 4, including those who were interferon-ineligible, interferon-intolerant and interferon failures.

Sofosbuvir plus ribavirin was shown to provide a simple, effective and well-tolerated interferon-free regimen. After 12 weeks of treatment with sofosbuvir plus ribavirin, the SVR12 rate in treatment-naive patients was 79%, and in treatment-experienced patients was 59%. Extending treatment duration to 24 weeks resulted in higher SVR12 rates in both treatment-naive and treatment-experienced patients: 100% and 87%, respectively.

Most adverse events were mild or moderate in severity and consistent with the known side effects of ribavirin.

General Comments

Feld: There is one caveat with all of these successful treatments: We need to figure out what is going to happen to those small numbers of patients who do end up failing because they had resistance to at least one agent. Are they going to have other regimens? There are drugs in development but we need to make sure we watch this patient population.

Mieli-Vergani: The major take-home message of this meeting is the treatment of HCV. The results of some of the phase 3 trials presented are absolutely outstanding. It is clear that we can now cure HCV. The major problem that remains is the cost of the treatment. What we should concentrate on now is to abate the cost of this treatment worldwide. At the American Association for the Study of Liver Diseases’ The Liver Meeting in November, it was suggested that it would cost $80,000 per year. Of course, $80,000 per year is less expensive than having a liver transplant, but many countries will not have the money to do it because there are so many patients infected. Theoretically, the patients should be treated before they get very severe liver disease. So I think the issue remains of how we treat these patients, and who should be treated. We do not want to have to stratify patients based on money, essentially on whether someone can afford it or whether they cannot.

References:
Afdhal N. N Engl J Med. 2014;370:1889-1898.
Feld JJ. N Engl J Med. 2014;370:1594-1603.
Kowdley KV. N Engl J Med. 2014;370:1879-1888.
Poordad F. N Engl J Med. 2014 370:1973-1982.
World Health Organization. Guidelines for the screening, care and treatment of persons with hepatitis C infection. www.who.int/hiv/pub/hepatitis/hepatitis-c-guidelines/en/. Accessed on May 8, 2014.
Disclosures: Feld reports associations with AbbVie and Boehringer Ingelheim. Mieli-Vergani reports associations with Bristol-Myers Squibb, Novartis and Roche. Osinusi and Wiktor report no relevant financial disclosures.