News from the 2016 AASLD Liver Meeting

This edition of the bulletin focuses on news from The Liver Meeting, organised by the American Association for the Study of Liver Diseases (AASLD), which was held in Boston from 11-15 November 2016.

New pangenotypic combinations

Stefan Zeuzem, presenting at AASLD 2016. Photo by Liz Highleyman,

Drug combinations which treat each genotype of hepatitis C with similar rates of success are on the horizon.

A new combination of direct-acting antivirals (DAAs) designed to treat all genotypes of hepatitis C cured 99% of people with genotypes 1, 2, 4, 5 and 6, and in a separate study cured between 91 and 96% of people with genotype 3 infection. Glecaprevir and pibrentasvir (G/P) are being developed by AbbVie as a once-daily, single-pill combination regimen that can be dosed without ribavirin. Both drugs in the combination are highly active against all genotypes of hepatitis C.

Results from three phase III studies of glecaprevir and pibrentasvir were presented at The Liver Meeting:

  • ENDURANCE-1 tested the combination in people without cirrhosis with genotype 1 infection. Participants received the combination for 8 or 12 weeks. The study found that 99% or more of participants in both study arms achieved sustained virologic response (SVR12).
  • ENDURANCE-2 tested the combination in previously untreated or treatment-experienced people with genotype 2 infection. The study found that 99% of participants achieved SVR12.
  • ENDURANCE-4 tested the combination in previously untreated or treatment-experienced people with genotypes 4, 5 or 6, without cirrhosis. The study found that 99% of participants achieved SVR12.

In the SURVEYOR-II study, a phase II trial testing various durations of treatment, the experimental combination cured between 91 and 96% of treatment-experienced people and/or people with cirrhosis. (See Hepatitis C genotype 3 below for further details).

Based on these results the glecaprevir and pibrentasvir pill will be submitted for marketing approval before the end of 2016 in the United States and in early 2017 in the European Union and Japan and is likely to receive approval in 2017.

Gilead Sciences presented results of phase III studies of the three-drug regimen of sofosbuvir, velpatasvir and voxilaprevir.

Sofosbuvir and velpatasvir are already available as a combination pill, Epclusa, which received marketing approval earlier this year in the United States and European Union. Voxilaprevir is a protease inhibitor active against all genotypes of hepatitis C virus (HCV). The phase III studies tested a combination of the three drugs, dosed as a single pill, once a day.

The studies showed:

  • 8 weeks of the triple regimen was inferior to 12 weeks of sofosbuvir/velpatasvir in genotype 1a infection. In all other genotypes there was no difference between the three-drug and the two-drug regimen. Sustained response rates for the triple regimen were 92% for genotype 1a, 97% for 1b, 97% for genotype 2, 99% for genotype 3, 92% for genotype 4, 94% for genotype 5 and 100% for genotype 6; all genotypes had SVR12 rates in the 97-100% range using the dual regimen.
  • In people with genotype 3, the POLARIS-3 study reported SVR12 rates of 96% in both the 8-week sofosbuvir/velpatasvir/voxilaprevir arm and the 12-week sofosbuvir/velpatasvir arm.
  • In people with genotypes 1-4 not previously cured of hepatitis C by DAA regimens, the triple regimen cured 97% of people compared to 90% of those who received sofosbuvir/velpatasvir. This study found that the triple regimen was superior to dual therapy. The difference in efficacy was more pronounced in people with cirrhosis, and the triple regimen was more effective than the dual regimen in people with genotype 1a in this study.
  • In people with previous experience of ledipasvir, daclatasvir or ombitasvir (part of the AbbVie 3D regimen) the triple regimen cured 96% of people with genotypes 1-4.

Gilead Sciences plans to seek marketing approval for the combination in the United States by the end of 2016 and shortly afterwards in the European Union.

Merck is evaluating a once-daily fixed-dose co-formulation containing its approved HCV protease inhibitor grazoprevir (part of the Zepatier co-formulation with elbasvir), the investigational nucleotide NS5B polymerase inhibitor MK-3682 and the next-generation NS5A inhibitor ruzasvir (formerly MK-8408). The combination is active against all genotypes.

Phase II studies presented at The Liver Meeting showed:

  • The combination was highly effective as an 8-week, 12-week or 16-week regimen for people with HCV genotypes 1, 2 or 3, with sustained response rates of 86 to 100% depending on treatment duration.
  • A 16-week regimen with added ribavirin was highly effective in people who had experienced failure of the 8-week regimen.
  • MK-3682/grazoprevir/ruzasvir with ribavirin for 16 weeks or alone for 24 weeks was highly effective in people who had experienced failure of sofosbuvir/ledipasvir (Harvoni) or grazoprevir/elbasvir (Zepatier).

Hepatitis C genotype 3

Graham Foster, presenting at AASLD 2016. Photo by Liz Highleyman,

People with genotype 3 hepatitis C are at higher risk of developing advanced liver fibrosis and hepatocellular carcinoma than people who have other genotypes, and people with prior treatment experience have fewer interferon-free treatment options than those who have other genotypes.

Professor Graham Foster of Queen Mary University in London called treatment-experienced people with genotype 3 and cirrhosis the "toughest of the tough." Currently approved regimens for this group include sofosbuvir/velpatasvir (Epclusa) with ribavirin for 12 weeks or sofosbuvir plus daclatasvir (Daklinza) with ribavirin for 12 or 24 weeks, but until recently direct-acting antiviral (DAA) combinations with pegylated interferon were still considered an option for these challenging patients.

Three studies presented at The Liver Meeting showed that genotype 3 can now be treated successfully in the vast majority of people using new drug combinations. Treatment-experienced people and those with cirrhosis were cured at similar rates to those seen in previously untreated people with other genotypes.

A triple regimen of grazoprevir/elbasvir (Zepatier) plus sofosbuvir (Sovaldi) without ribavirin cured 96% of previously untreated and 97% of treatment-experienced people with hepatitis C virus genotype 3 and liver cirrhosis, matching rates seen in easier-to-treat patient groups, according to results from the C-ISLE study.

AbbVie’s pangenotypic combination of glecaprevir and pibrentasvir cured almost all of the hardest-to-treat people with genotype 3 – those with cirrhosis and/or previous treatment experience – in a phase II trial. The study found that between 91 and 96% of participants were cured, depending on the duration of treatment. In this study all cases of treatment failure occurred in people with very high baseline viral loads.

Gilead Sciences’s triple regimen of sofosbuvir, velpatasvir and voxilaprevir was highly effective in people with genotype 3 and compensated cirrhosis, curing 96% of participants in the POLARIS-3 study. The combination also cured 99% of people with genotype 3 infection in the POLARIS-2 study and 94% of people with genotype 3 infection and previous treatment experience with DAAs in the POLARIS-4 study.

All of these regimens can be given without ribavirin, offering the prospect of treatment that is both interferon-free and ribavirin-free for people with genotype 3 infection.

Real world treatment performance matches the best clinical trial results

Direct-acting antiviral (DAA) treatment is curing people of hepatitis C infection in clinics at similar rates to those seen in clinical trials, and there don’t seem to be major differences between drug regimens, according to results of a large population study presented at The Liver Meeting.

Clinical trials tend to show the best-case scenario for efficacy of new drugs. People in clinical trials are carefully selected from populations who are already attending clinics – by definition, a highly motivated group of patients. Furthermore, people recruited to clinical trials cost money to recruit and monitor so they will be followed up carefully, and in many cases people are getting free treatment, maximising the incentive to stay in care. All these factors tend to promote better outcomes in clinical trial populations than in subsequent 'real world' clinic populations.

A review of the Veterans Affairs Cohort – military veterans receiving care through US Veterans Affairs’ (VA) clinics – finds that people receiving DAA treatment in those hospitals are being cured of hepatitis C at similar rates to those seen in clinical trials of the drug combinations in widespread use today.

Cure rates were highest in people with genotype 1 infection, and in people with genotypes 2 and 3 without cirrhosis. The study also found that an 8-week course of sofosbuvir/ledipasvir (Harvoni) for those eligible was just as effective as a 12-week course in those who did not qualify.

Treatment scale-up and the continuum of care

If sufficient money is available to pay for direct-acting antivirals (DAAs), the US Veterans Affairs (VA) could cure the majority of veterans under its care of hepatitis C within three years, and has already shown it has the capacity to initiate almost 7000 people on treatment in a single month, George Ioannou of University of Washington, Seattle, reported at The Liver Meeting.

Data from Australia presented at the conference showed what happens when another big health system begins scaling up treatment. Since March 2016, 26,000 people are estimated to have begun DAA treatment in Australia, according to research carried out by researchers at the Kirby Institute, University of New South Wales. Almost two-thirds of people with hepatitis C and cirrhosis are estimated to have been cured already.

Although these rates of treatment initiation are impressive, elimination of hepatitis C – or even just preventing an increase in liver-related morbidity and mortality will require substantial improvements in hepatitis C testing and linkage to care. Grave weaknesses in hepatitis C screening and linkage to care are still widespread in the United States and threaten to leave a large proportion of baby boomers with hepatitis C untreated, presentations at the The Liver Meeting showed.

The birth cohort approach to screening for hepatitis C was adopted by the Centers for Disease Control and Prevention due to the high prevalence of hepatitis C virus in American baby boomers and the cost-effectiveness of screening in an older population. Three quarters of all chronic hepatitis C cases in the US are estimated to be in baby boomers, and older people infected several decades ago are at higher risk of complications arising from advanced liver damage.

Liver cancer in people treated with direct-acting antivirals

Hepatitis C infection can be cured with a course of direct-acting antiviral (DAA) treatment, but eliminating the infection may not heal the liver sufficiently to prevent the development of liver cancer. Furthermore, there is evidence that people with cirrhosis previously treated for liver cancer have a high rate of recurrence of liver cancer. Two studies, conducted in Italy and Spain, both found that around 30% of people previously treated for liver cancer experienced a recurrence of liver cancer within a median of six months of completing hepatitis C treatment. Both research groups considered the rate of recurrence in their patients to be unusual and warned doctors to be on the lookout for liver cancer recurrence.

Two studies investigating the risk of liver cancer presented at the The Liver Meeting have shown that the risk of liver cancer is not increased in people who are cured of hepatitis C after a course of DAA treatment.

However, Italian researchers found that those people who did develop liver cancer during or shortly after antiviral treatment were more likely to develop an aggressive form of liver cancer, perhaps because of changes in immune surveillance in the liver as a result of treatment.

Hepatitis B treatment

Image: Gilead Sciences

Tenofovir alafenamide (TAF), a new lower-dose pro-drug, matches the older tenofovir disoproxil fumarate (TDF) for antiviral activity against hepatitis B virus but causes less bone mineral loss, according to a study presented at The Liver Meeting in Boston. Last week the US Food and Drug Administration (FDA) approved stand-alone TAF for hepatitis B treatment and a European Medicines Agency (EMA) committee issued a positive opinion.

TAF is a new pro-drug formulation that produces high levels of the active drug (tenofovir diphosphate) in hepatocytes and CD4 T-cells with smaller doses than TDF, which means lower concentrations in the blood and less drug exposure for the kidneys, bones and other organs and tissues.

Last week the US FDA approved Vemlidy (TAF 25mg), allowing it to be used to treat hepatitis B in people with compensated liver disease. The EMA's Committee for Medicinal Products for Human Use has also issued a positive opinion on Gilead's application for market authorisation.

Generic hepatitis C drugs

Use of generic versions of direct-acting antivirals (DAAs) resulted in high cure rates for people who obtained the products through three buyers’ clubs, indicating that the generic products are effective, according to three presentations at the International Congress on Drug Therapy in HIV Infection (HIV Glasgow) in October.

Generic versions of DAAs are manufactured in India under voluntary license from Gilead Sciences, and by other Indian companies who are not licensees, and in other countries such as Bangladesh where patents on the products do not exist. The lack of patent protection allows generic manufacturers to produce their own versions of the drugs. In many countries it is legal to import drugs for personal use by ordering them online. In other countries imports of generic drugs are either forbidden or restricted to those carried through customs by individuals in quantities sufficient for personal use.

Concerns have been expressed as to whether people who obtain generic versions of DAAs are buying high-quality, effective drugs. One of the studies presented last month comes from a population in which all drugs ordered were subjected to tests for the active ingredients. That study found no cases in which people received inactive pills.

The three studies were carried out among the customers of buyers’ clubs based in Australia, South-East Asia and Eastern Europe. The drug combinations used were sofosbuvir/ribavirin, sofosbuvir/daclatasvir and sofosbuvir/ledipasvir. Cure rates for these regimens ranged from 81 to 100% but the studies consistently found lower cure rates (below 80%) among people with genotype 3 infection. The cohorts were too small to find any differences between drug regimens or cirrhosis status. The studies report on 888 people, not all of whom have completed treatment or 12-week post-treatment follow-up visits.

The World Hepatitis Alliance recently hosted a webinar on the subject of generic hepatitis C medicines. You can watch the webinar on YouTube and view the webinar presentation slides as a PDF.

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