The Take Home

The Take Home: International Liver Congress 2018

As we in the United States look ahead to Digestive Disease Week coming up and further to our fall meetings, the International Liver Congress gives us an opportunity to hear the latest from our colleagues around the world as well as those at home.

This year, although there was much buzz about hepatitis B virus (HBV) and nonalcoholic steatohepatitis, hepatitis C virus (HCV) still held a prominent place in the oral presentations. As clinicians, we can take home some new data about 8-week regimens, real-world data, treatment failures and retreatments and how sustained virologic response affects both hepatocellular carcinoma risk as well as the risk for extrahepatic malignancies.

Continued 8-week Speculation

Nancy S. Reau

Tarik Asselah, MD, University Paris Diderot, presented data looking at genotype 1b and genotype 4 treatment-naive participants with mild to moderate fibrosis who received Zepatier (elbasvir/grazoprevir; Merck) for 8 weeks (n = 53) or 12 weeks (n = 64).

In the 8-week group, two virologic relapses occurred and, overall, the regimen showed an excellent safety profile with no serious adverse events, discontinuations or elevation of alanine aminotransferase or aspartate aminotransferase levels, he said.

SVR was 99% in genotype 1B, however genotype 4 patients achieved SVR at a numerically lower rate than genotype 1B. As an 8-week option, elbasvir/grazoprevir offers high efficacy in genotype 1b, but likely is not your first choice for treating genotype 4 patients. Although it does give clinicians the reassurance that high cure rates occur in those that truncate therapy at an earlier time point.

Additionally, Alison Boyle, a pharmacist from Scotland, presented data on 8 weeks of Epclusa (sofosbuvir/velpatasvir; SOF/VEL, Gilead Sciences) in patients with varied drug use and genotype 3. In the original 90 people included in the study, 93% achieved SVR. Two were lost to follow up, two discontinued treatment prematurely, one died and one reinfected. Excluding those, the 84 who finished treatment all achieved SVR.

Broken down further, all participants with F3 (n = 23), viral load greater than 6 million (n = 5), HIV coinfection (n = 2) and quantifiable end of treatment (n = 7) achieved SVR. By drug use, 100% of IV drug users and 100% of those who tested positive on the drug screen achieved SVR. One patient with self-reported non-IV drug use was reinfected (93.3%) and in the daily supervised methadone group, one participant was lost to follow up, one prematurely discontinued treatment and one was reinfected but spontaneously cleared (92.1%).

These data are encouraging and assure us of high SVR rates in genotype 3, however a 12-week course of SOF/VEL is still recommended by guidelines. You want every patient to have the highest possibility of effective treatment. With the Achilles heel of genotype 3 in a high fibrosis population, you should aim to treat for all 12 weeks. This study reassures us of high expected efficacy in patients that truncate therapy at 8 weeks but may not, yet, be able to change standard of care.

Real-World Data

Two European registries – one in Italy and one in Germany – showed how Mavyret (glecaprevir/pibrentasvir; GP, AbbVie) is faring outside of clinical trials, which is something we have not yet seen presented in the U.S.

In NAVIGATOR-II, Roberta D’Ambrosio, MD, and colleagues looked at 723 Italian patients with HCV treated with GP and presented the interim results from this retrospective, longitudinal study. At baseline, 639 patients received treatment for 8 weeks and 84 received treatment for 16 weeks, mainly due to advanced fibrosis. There was only one relapse out of the 347 patients in the 8-week treatment group (99.7% SVR). Those results included 24 patients who were HIV-positive and eight with advanced chronic kidney disease, none of whom were the relapse patient.

The German registry study is an ongoing non-interventional, multicenter, prospective registry study. Thomas Berg, MD, presented the results at the meeting. This group collected data from 638 patients at 104 sites in Germany between July 28, 2017, and February 9, 2018, where patients received treatment with GP. This interim report included 96 patients, 93 of whom achieved SVR and three of whom discontinued due to other causes.

Failures, Retreatments

Although rare in both clinical trials and real-world cohorts, salvage strategies for GP failures remain poorly defined. Looking at retreatment in this population is important as clinicians need the reassurance that even with the ridiculously low failure rates, you know what your options are if a patient fails.

David Wyles

David L. Wyles, MD, presented MAGELLEN-3, which focused on retreatment of GP virologic failures with either a 12-week regimen (n = 2) or a 16-week regimen (n = 21) of GP plus Sovaldi (sofosbuvir, Gilead Sciences) and ribavirin, depending on patient and virus characteristics. To receive 12 weeks of retreatment, patients could not have genotype 3, cirrhosis or previous exposure to NS3 or NS5 DAAs other than GP. Only 2 patients met these criteria, both of which were genotype 2. All other participants received 16 weeks.

Fibrosis was restaged before retreatment, with two patients having newfound cirrhosis. Although no NS3 resistance associated substitutions (RASs) were found alone, only in combination with NS5a RASs, the disbursement of RASs differed slightly between each genotype group.

Overall, Wyles showed 100% SVR in the 12-week group and 95% SVR in the 16-week group. There was one virologic failure in a genotype 1a participant who had previously failed sofosbuvir/ledipasvir and was retreated with GP. This individual experienced breakthrough on GP plus sofosbuvir and ribavirin. This regimen showed 100% SVR in all genotype 3 patients. Wyles concluded that GP plus sofosbuvir and ribavirin is an effective retreatment strategy after GP failure.

In another presentation, Anna S. Lok, MD, FAASLD, presented a phase 3b randomized, open-label study of GP with or without ribavirin for patients with genotype 1 who previously failed an NS5a inhibitor plus sofosbuvir. Lok’s study does not include prior therapy with both a protease inhibitor and NS5Ai or decompensated cirrhosis.

She presented data on 167 patients. Lok and colleagues randomly assigned those without cirrhosis (n = 122) to either GP for 12 weeks (n = 71) or 16 weeks (n = 45) then they randomly assigned those with cirrhosis to either GP plus ribavirin for 12 weeks (n = 21) or GP for 16 weeks (n = 24).

She showed that there were high SVR4 rates in all groups: 96% in non-cirrhotics receiving GP for 12 weeks and 16 weeks; 86% in cirrhotics receiving GP plus ribavirin for 12 weeks; and 100% in cirrhotics receiving GP for 16 weeks.

Lok concluded that these preliminary data show a 95% overall SVR4 rate despite a high prevalence of baseline NS5a RAS, although there was lower efficacy and tolerability in the ribavirin retreatment group.

Retreatment with GP with or without RBV offers another option for patients who fail prior therapies.

Cancer: Liver and Other

Sarah Shili, from France, presented a study in which researchers asked whether liver stiffness measurement and its regression can predict a lower risk for hepatocellular carcinoma.

Using Fibroscan (Echosens), Shili and colleagues analyzed 828 patients with valid liver stiffness measurement (LSM) and no history of HCC. They showed that there was a change in LSM of –3.6 kPa over a median 6-month follow-up (P < .0001). Yet there were two deaths and 22 incidences of HCC (2.8%).

Anna S. Lok

In looking at the factors associated with HCC occurrence, Shili showed that those patients without diabetes and a baseline LSM of less than 12.5 kPa or between 8 kPa and 12.5 kPa had a lower risk for HCC and may not require HCC screening. She also showed that the presence of diabetes – regardless of baseline LSM – points to a need for HCC screening as 8% of those patients and 3.5% of those without cirrhosis developed HCC.

But the change in LSM from pre- to posttreatment did not impact the need for HCC screening.

We should know this because while liver stiffness is validated pretreatment, we do not yet understand what the change in this noninvasive measure means once a patient loses some of the inflammatory components upon which it’s been validated. Rather, we must use the staging assessment for fibrosis to dictate which factors to follow long-term. You cannot restage them after a cure.

Certainly, curing the HCV lowers the overall HCC risk, but that does not eliminate the need to monitor cured patients. This study suggests that improvement in LSM does not change HCC screening strategy.

Liver cancer is not the only malignancy linked to HCV. In a poster presented by Alvaro Mena de Cea, MD, PhD, of the Institute of Biomedical Research and La Coruña University Hospital Complex in Spain, the researchers found that the standard incidence rate (SIR) of all diagnosed lymphomas in HIV-monoinfected and HIV/HCV-coinfected patients was 15 (95% CI, 9.1-24.7). The SIR of Hodgkin lymphoma and non-Hodgkin lymphoma in HIV monoinfection and HIV/HCV coinfection was 17.2 (95% CI, 5-60.3) and 15.6 (95% CI, 9.4-29.7), respectively. The SIR of HL in HIV/HCV-coinfected patients was 28.4 (95% CI, 8.3-98.8) — an incidence the researchers called “remarkable” — and the SIR of NHL in the same population was 12.1 (95% CI, 6.8-23.4).

They hypothesized that eradication of HCV in coinfected persons should decrease the incidence of lymphoma in virally suppressed individuals living with HIV.

In another presentation, Anand P. Chokkalingam, PhD, of Gilead Sciences presented a study that looked at the incidence or prevalence of non-hepatic cancers in patients treated for HCV, both with interferon and DAAs. This study comes after the REVEAL HCV database showed an uptick in multiple malignancies – prostate, thyroid, lymphomas – in the HCV population.

This new analysis showed a significant reduction in risk for total non-hepatic cancers in the DAA group vs. the interferon group (adjusted HR = 0.86; 95% CI, 0.8-0.93). In NHL and bile duct cancers there was a non-significant reduction, but in leukemia, prostate, bladder and lung cancers, they saw a significant reduction in the DAA group. Breast, esophagus and pancreatic cancers did not show the same effect.

This study supports the REVEAL HCV findings but goes one step further. HCV eradication in a population lowers the incidence of several cancers that were present at a higher rate in the HCV population. Chokkalingam hypothesized that we observed these reductions due to the long-term impact of successful HCV treatment at a population level.

Screening Outside Birth Cohorts

The last interesting study that I’d like to call to attention to is one presented by Stuart Flanagan, MD, who presented data from HepFree, a screening organization in the United Kingdom. Specifically, in the study presented at ILC, Flanagan showed us that our migrant populations will require a different approach for HCV screening, meaning that country of origin will impact screening strategy.

In comparing the control practices in Scotland with an intervention study in which they sent educational letters to an immigrant population, Flanagan showed an increase in testing at 1.7% in the control group and 19.5% in the intervention group (P = .014) and a 31.8% uptake in the screening for Indian populations and a 27.8% uptake among those older than 40 years. In the traditional screening method, 0.75% of the Indian population were screened and just 1.5% of those older than 40.

With approximately 90% engagement in care once testing positive for hepatitis, Flanagan stated that screening immigrants is cost effective and results in 13.49 prevented deaths per 10,000 patients screened. He suggested that focusing on immigrants older than 40 years is most clinically and cost effective.

Birth cohort-based screening plays an important role in identifying individuals at risk for HCV, especially those with advanced fibrosis. However, screening strategies must change with an evolving population. We recognize that in the U.S. that we have bimodal cohorts with the opioid epidemic and our previously defined birth cohort. Migrant populations, as seen here in the U.K., will bring different factors into this already complex equation. And many of the regions from which they come are not well characterized by risk factor for HCV.

Beyond HCV

The HBV therapeutics and diagnostics are becoming an exciting area of interest. Clinicians are being tempted by investigational therapies that look like they might ultimately become approved products offering curative options. New diagnostics might help identify patients best suited for these new treatment options.

It definitely looks exciting and Ira Jacobson, MD, discusses a bit more in those fields in his editorial.

As we in the United States look ahead to Digestive Disease Week coming up and further to our fall meetings, the International Liver Congress gives us an opportunity to hear the latest from our colleagues around the world as well as those at home.

This year, although there was much buzz about hepatitis B virus (HBV) and nonalcoholic steatohepatitis, hepatitis C virus (HCV) still held a prominent place in the oral presentations. As clinicians, we can take home some new data about 8-week regimens, real-world data, treatment failures and retreatments and how sustained virologic response affects both hepatocellular carcinoma risk as well as the risk for extrahepatic malignancies.

Continued 8-week Speculation

Nancy S. Reau

Tarik Asselah, MD, University Paris Diderot, presented data looking at genotype 1b and genotype 4 treatment-naive participants with mild to moderate fibrosis who received Zepatier (elbasvir/grazoprevir; Merck) for 8 weeks (n = 53) or 12 weeks (n = 64).

In the 8-week group, two virologic relapses occurred and, overall, the regimen showed an excellent safety profile with no serious adverse events, discontinuations or elevation of alanine aminotransferase or aspartate aminotransferase levels, he said.

SVR was 99% in genotype 1B, however genotype 4 patients achieved SVR at a numerically lower rate than genotype 1B. As an 8-week option, elbasvir/grazoprevir offers high efficacy in genotype 1b, but likely is not your first choice for treating genotype 4 patients. Although it does give clinicians the reassurance that high cure rates occur in those that truncate therapy at an earlier time point.

Additionally, Alison Boyle, a pharmacist from Scotland, presented data on 8 weeks of Epclusa (sofosbuvir/velpatasvir; SOF/VEL, Gilead Sciences) in patients with varied drug use and genotype 3. In the original 90 people included in the study, 93% achieved SVR. Two were lost to follow up, two discontinued treatment prematurely, one died and one reinfected. Excluding those, the 84 who finished treatment all achieved SVR.

Broken down further, all participants with F3 (n = 23), viral load greater than 6 million (n = 5), HIV coinfection (n = 2) and quantifiable end of treatment (n = 7) achieved SVR. By drug use, 100% of IV drug users and 100% of those who tested positive on the drug screen achieved SVR. One patient with self-reported non-IV drug use was reinfected (93.3%) and in the daily supervised methadone group, one participant was lost to follow up, one prematurely discontinued treatment and one was reinfected but spontaneously cleared (92.1%).

PAGE BREAK

These data are encouraging and assure us of high SVR rates in genotype 3, however a 12-week course of SOF/VEL is still recommended by guidelines. You want every patient to have the highest possibility of effective treatment. With the Achilles heel of genotype 3 in a high fibrosis population, you should aim to treat for all 12 weeks. This study reassures us of high expected efficacy in patients that truncate therapy at 8 weeks but may not, yet, be able to change standard of care.

Real-World Data

Two European registries – one in Italy and one in Germany – showed how Mavyret (glecaprevir/pibrentasvir; GP, AbbVie) is faring outside of clinical trials, which is something we have not yet seen presented in the U.S.

In NAVIGATOR-II, Roberta D’Ambrosio, MD, and colleagues looked at 723 Italian patients with HCV treated with GP and presented the interim results from this retrospective, longitudinal study. At baseline, 639 patients received treatment for 8 weeks and 84 received treatment for 16 weeks, mainly due to advanced fibrosis. There was only one relapse out of the 347 patients in the 8-week treatment group (99.7% SVR). Those results included 24 patients who were HIV-positive and eight with advanced chronic kidney disease, none of whom were the relapse patient.

The German registry study is an ongoing non-interventional, multicenter, prospective registry study. Thomas Berg, MD, presented the results at the meeting. This group collected data from 638 patients at 104 sites in Germany between July 28, 2017, and February 9, 2018, where patients received treatment with GP. This interim report included 96 patients, 93 of whom achieved SVR and three of whom discontinued due to other causes.

Failures, Retreatments

Although rare in both clinical trials and real-world cohorts, salvage strategies for GP failures remain poorly defined. Looking at retreatment in this population is important as clinicians need the reassurance that even with the ridiculously low failure rates, you know what your options are if a patient fails.

David Wyles

David L. Wyles, MD, presented MAGELLEN-3, which focused on retreatment of GP virologic failures with either a 12-week regimen (n = 2) or a 16-week regimen (n = 21) of GP plus Sovaldi (sofosbuvir, Gilead Sciences) and ribavirin, depending on patient and virus characteristics. To receive 12 weeks of retreatment, patients could not have genotype 3, cirrhosis or previous exposure to NS3 or NS5 DAAs other than GP. Only 2 patients met these criteria, both of which were genotype 2. All other participants received 16 weeks.

PAGE BREAK

Fibrosis was restaged before retreatment, with two patients having newfound cirrhosis. Although no NS3 resistance associated substitutions (RASs) were found alone, only in combination with NS5a RASs, the disbursement of RASs differed slightly between each genotype group.

Overall, Wyles showed 100% SVR in the 12-week group and 95% SVR in the 16-week group. There was one virologic failure in a genotype 1a participant who had previously failed sofosbuvir/ledipasvir and was retreated with GP. This individual experienced breakthrough on GP plus sofosbuvir and ribavirin. This regimen showed 100% SVR in all genotype 3 patients. Wyles concluded that GP plus sofosbuvir and ribavirin is an effective retreatment strategy after GP failure.

In another presentation, Anna S. Lok, MD, FAASLD, presented a phase 3b randomized, open-label study of GP with or without ribavirin for patients with genotype 1 who previously failed an NS5a inhibitor plus sofosbuvir. Lok’s study does not include prior therapy with both a protease inhibitor and NS5Ai or decompensated cirrhosis.

She presented data on 167 patients. Lok and colleagues randomly assigned those without cirrhosis (n = 122) to either GP for 12 weeks (n = 71) or 16 weeks (n = 45) then they randomly assigned those with cirrhosis to either GP plus ribavirin for 12 weeks (n = 21) or GP for 16 weeks (n = 24).

She showed that there were high SVR4 rates in all groups: 96% in non-cirrhotics receiving GP for 12 weeks and 16 weeks; 86% in cirrhotics receiving GP plus ribavirin for 12 weeks; and 100% in cirrhotics receiving GP for 16 weeks.

Lok concluded that these preliminary data show a 95% overall SVR4 rate despite a high prevalence of baseline NS5a RAS, although there was lower efficacy and tolerability in the ribavirin retreatment group.

Retreatment with GP with or without RBV offers another option for patients who fail prior therapies.

Cancer: Liver and Other

Sarah Shili, from France, presented a study in which researchers asked whether liver stiffness measurement and its regression can predict a lower risk for hepatocellular carcinoma.

Using Fibroscan (Echosens), Shili and colleagues analyzed 828 patients with valid liver stiffness measurement (LSM) and no history of HCC. They showed that there was a change in LSM of –3.6 kPa over a median 6-month follow-up (P < .0001). Yet there were two deaths and 22 incidences of HCC (2.8%).

Anna S. Lok

In looking at the factors associated with HCC occurrence, Shili showed that those patients without diabetes and a baseline LSM of less than 12.5 kPa or between 8 kPa and 12.5 kPa had a lower risk for HCC and may not require HCC screening. She also showed that the presence of diabetes – regardless of baseline LSM – points to a need for HCC screening as 8% of those patients and 3.5% of those without cirrhosis developed HCC.

PAGE BREAK

But the change in LSM from pre- to posttreatment did not impact the need for HCC screening.

We should know this because while liver stiffness is validated pretreatment, we do not yet understand what the change in this noninvasive measure means once a patient loses some of the inflammatory components upon which it’s been validated. Rather, we must use the staging assessment for fibrosis to dictate which factors to follow long-term. You cannot restage them after a cure.

Certainly, curing the HCV lowers the overall HCC risk, but that does not eliminate the need to monitor cured patients. This study suggests that improvement in LSM does not change HCC screening strategy.

Liver cancer is not the only malignancy linked to HCV. In a poster presented by Alvaro Mena de Cea, MD, PhD, of the Institute of Biomedical Research and La Coruña University Hospital Complex in Spain, the researchers found that the standard incidence rate (SIR) of all diagnosed lymphomas in HIV-monoinfected and HIV/HCV-coinfected patients was 15 (95% CI, 9.1-24.7). The SIR of Hodgkin lymphoma and non-Hodgkin lymphoma in HIV monoinfection and HIV/HCV coinfection was 17.2 (95% CI, 5-60.3) and 15.6 (95% CI, 9.4-29.7), respectively. The SIR of HL in HIV/HCV-coinfected patients was 28.4 (95% CI, 8.3-98.8) — an incidence the researchers called “remarkable” — and the SIR of NHL in the same population was 12.1 (95% CI, 6.8-23.4).

They hypothesized that eradication of HCV in coinfected persons should decrease the incidence of lymphoma in virally suppressed individuals living with HIV.

In another presentation, Anand P. Chokkalingam, PhD, of Gilead Sciences presented a study that looked at the incidence or prevalence of non-hepatic cancers in patients treated for HCV, both with interferon and DAAs. This study comes after the REVEAL HCV database showed an uptick in multiple malignancies – prostate, thyroid, lymphomas – in the HCV population.

This new analysis showed a significant reduction in risk for total non-hepatic cancers in the DAA group vs. the interferon group (adjusted HR = 0.86; 95% CI, 0.8-0.93). In NHL and bile duct cancers there was a non-significant reduction, but in leukemia, prostate, bladder and lung cancers, they saw a significant reduction in the DAA group. Breast, esophagus and pancreatic cancers did not show the same effect.

This study supports the REVEAL HCV findings but goes one step further. HCV eradication in a population lowers the incidence of several cancers that were present at a higher rate in the HCV population. Chokkalingam hypothesized that we observed these reductions due to the long-term impact of successful HCV treatment at a population level.

PAGE BREAK

Screening Outside Birth Cohorts

The last interesting study that I’d like to call to attention to is one presented by Stuart Flanagan, MD, who presented data from HepFree, a screening organization in the United Kingdom. Specifically, in the study presented at ILC, Flanagan showed us that our migrant populations will require a different approach for HCV screening, meaning that country of origin will impact screening strategy.

In comparing the control practices in Scotland with an intervention study in which they sent educational letters to an immigrant population, Flanagan showed an increase in testing at 1.7% in the control group and 19.5% in the intervention group (P = .014) and a 31.8% uptake in the screening for Indian populations and a 27.8% uptake among those older than 40 years. In the traditional screening method, 0.75% of the Indian population were screened and just 1.5% of those older than 40.

With approximately 90% engagement in care once testing positive for hepatitis, Flanagan stated that screening immigrants is cost effective and results in 13.49 prevented deaths per 10,000 patients screened. He suggested that focusing on immigrants older than 40 years is most clinically and cost effective.

Birth cohort-based screening plays an important role in identifying individuals at risk for HCV, especially those with advanced fibrosis. However, screening strategies must change with an evolving population. We recognize that in the U.S. that we have bimodal cohorts with the opioid epidemic and our previously defined birth cohort. Migrant populations, as seen here in the U.K., will bring different factors into this already complex equation. And many of the regions from which they come are not well characterized by risk factor for HCV.

Beyond HCV

The HBV therapeutics and diagnostics are becoming an exciting area of interest. Clinicians are being tempted by investigational therapies that look like they might ultimately become approved products offering curative options. New diagnostics might help identify patients best suited for these new treatment options.

It definitely looks exciting and Ira Jacobson, MD, discusses a bit more in those fields in his editorial.

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