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EASL Issues New Hepatitis C Treatment Recommendations For All Genotypes


The European Association for the Study of the Liver (EASL) released its latest recommendations on treatment of hepatitis C at a special meeting last week in Paris. The updated guidelines now include highly effective interferon-free options for all hepatitis C virus (HCV) genotypes and for the most challenging patients.

EASL usually releases revised recommendations at its International Liver Congress in the spring, but this year the guidelines panel decided to hold off the release to wait for European approval of 2 newer direct-acting antiviral regimens, grazoprevir/elbasvir (Zepatier) and sofosbuvir/velpatasvir (Epclusa). The recommendations were presented at an evening session preceding a special meeting, New Perspectives in Hepatitis C Virus Infection - The Roadmap for Cure.

Panel coordinator Jean-Michel Pawlotsky presented a summary of the recommendations, followed by a discussion with panel members Alessio Aghemo, David Back, Geoffrey Dusheiko, Xavier Forns, and Massimo Puoti, along with EASL Secretary General Laurent Castera and Francesco Negro of the EASL governing board; member Christoph Sarrazin was absent.

The guidelines -- now in press in the Journal of Hepatology and available on the EASL website -- are designed to be flexible enough to be relevant in countries with different approval mechanisms and funding systems.

"EASL is committed to making recommendations that every country can use," Pawlotsky said. "We hope these guidelines can help people all over the world."

Treatment Goal and Indications

The goal of hepatitis C treatment is to cure HCV infection to prevent liver cirrhosis, decompensation (liver failure), hepatocellular carcinoma (liver cancer), severe extra-hepatic manifestations, and death, according to the guidelines. Sustained virological response (SVR), or undetectable HCV at 12 or 24 weeks post-treatment, is considered a cure.

The guidelines call for universal access to hepatitis C treatment, stating that, "All treatment-naive and treatment-experienced patients with compensated or decompensated chronic liver disease due to HCV must be considered for therapy."

"EASL was the first to say that every patient with HCV has the right to treatment," Pawlotsky noted.

Acknowledging that treatment may not be immediately available to all due to cost and other factors, the recommendations stress that some patients should be treated without delay, including those with significant liver fibrosis or cirrhosis (Metavir stage F2 or higher), those with clinically significant extra-hepatic manifestations, and those with HCV recurrence after a liver transplant. This is broader than the 2015 recommendations, which prioritized patients at stage F3 or higher.

The new guidelines also call for prioritization of individuals at risk for transmitting HCV, including active injection drug users, gay and bisexual men with high-risk sexual practices, women who wish to get pregnant, kidney dialysis patients, and people in prison.

Recommended Regimens

Factors to consider when choosing a regimen include HCV genotype, prior treatment experience, severity of liver disease, comorbidities, and the potential for drug-drug interactions with other medications.

For all genotypes, interferon-free direct-acting antiviral (DAA) regimens are the best options due to their high efficacy, good tolerability, and ease of use, according to the guidelines.

All recommended regimens now include at least 2 DAAs. For the first time no interferon-containing regimens are listed among the recommended options, though Pawlotsky said these are not forbidden if that's all that's available in a given country.

Ribavirin still plays a role in helping prevent relapse in difficult-to-treat patients such as those with genotype 3, prior treatment failure, cirrhosis, or high viral load.

Pawlotsky recommended ribavirin for patients who are likely to fail treatment. "It's very important with DAAs that patients respond immediately," he said. "We can't just try the simplest regimen and retreat if needed."

The guidelines list recommended regimens by genotype, in no preferential order, broken down by whether patients are previously untreated or prior non-responders, and whether they are non-cirrhotic or have compensated cirrhosis (people with decompensated cirrhosis are treated as a special population).

Genotype 1a:

  • Sofosbuvir/ledipasvir (Harvoni) +/- ribavirin
  • Sofosbuvir/velpatasvir (Epclusa)
  • Sofosbuvir (Sovaldi) + daclatasvir (Daklinza) +/- ribavirin
  • Paritaprevir/ritonavir/ombitasvir + dasabuvir (3D; Viekira Pak, Viekira XR, or Viekirax/Exviera) + ribavirin
  • Grazoprevir/elbasvir (Zepatier) +/- ribavirin

Genotype 1b:

  • Sofosbuvir/ledipasvir
  • Sofosbuvir/velpatasvir
  • Sofosbuvir + daclatasvir
  • Paritaprevir/ritonavir/ombitasvir + dasabuvir
  • Grazoprevir/elbasvir

Genotype 2:

  • Sofosbuvir/velpatasvir
  • Sofosbuvir + daclatasvir

Genotype 3:

  • Sofosbuvir/velpatasvir +/- ribavirin
  • Sofosbuvir + daclatasvir +/- ribavirin

Genotype 4:

  • Sofosbuvir/ledipasvir +/- ribavirin
  • Sofosbuvir/velpatasvir
  • Sofosbuvir + daclatasvir +/- ribavirin
  • Sofosbuvir + simeprevir (Olysio) +/- ribavirin
  • Paritaprevir/ritonavir/ombitasvir (2D; Technivie or Viekirax) + ribavirin
  • Grazoprevir/elbasvir +/- ribavirin

Genotype 5:

  • Sofosbuvir/ledipasvir +/- ribavirin
  • Sofosbuvir/velpatasvir
  • Sofosbuvir + daclatasvir +/- ribavirin

Genotype 6:

  • Sofosbuvir/ledipasvir +/- ribavirin
  • Sofosbuvir/velpatasvir
  • Sofosbuvir + daclatasvir +/- ribavirin

Most regimens are taken for 12 weeks, but previously untreated patients without cirrhosis and low HCV viral load can be cured with sofosbuvir/ledipasvir (genotype 1a or 1b) or the paritaprevir-based 3D regimen (genotype 1b only) for 8 weeks. Conversely, genotype 1a patients with cirrhosis should extend treatment with the 3D regimen to 24 weeks and those with high viral load should take grazoprevir/elbasvir for 16 weeks.

Some regimens also call for adjusting treatment duration or adding ribavirin based on the presence of HCV resistance mutations, but routine resistance testing before starting treatment is not recommended and DAA regimens can be optimized without it. However, providers who have easy access to reliable NS5A resistance testing can use it to guide their decisions.

"If we recommended HCV resistance testing the only consequence would be denial of treatment," Pawlotsky emphasized. "The only risk is that you will slightly over-treat some patients -- some patients will receive ribavirin when they don't really need it."

Notable changes from the 2015 recommendations include the addition of grazoprevir/elbasvir and sofosbuvir/velpatasvir, omission of sofosbuvir plus ribavirin alone for genotypes 2 and 3, removal of sofosbuvir plus simeprevir for genotype 1, and removal of sofosbuvir or simeprevir plus pegylated interferon and ribavirin for any genotype.

The approval of sofosbuvir/velpatasvir now offers a single-tablet option for genotype 3, which remains a bit more difficult to treat. However, the panel decided that all treatment-experienced genotype 3 patients should use it with ribavirin (differing from U.S. recommendations, which only recommend ribavirin for treatment-experienced cirrhotics).

"With genotype 3 we're getting close to what we have for other genotypes, but it's still a tricky genotype," said Aghemo. "There's still not an optimal regimen, meaning 8 to 12 weeks without ribavirin for all patients." However, he continued, "I'm not saying we should wait for better drugs -- I wouldn’t count on having new drugs soon, so we have to optimize the drugs we have."

Recommendations for Specific Populations

HIV/HCV coinfected people can use the same regimens as HIV-negative patients -- and cure rates are the same for both groups -- but they need to take into account the potential for drug-drug interactions with antiretroviral therapy. Sofosbuvir-based regimens and daclatasvir have fewer interactions than other HCV regimens, though sofosbuvir/velpatasvir should not be taken with most NNRTIs including the widely used efavirenz (Sustiva).

People coinfected with HCV and hepatitis B virus (HBV) can be treated for hepatitis C according to the general recommendations, but they should be carefully monitored because HBV may become more active once HCV is eliminated, and they may need to start HBV antivirals such as tenofovir (Viread) or entecavir (Baraclude).

People with decompensated cirrhosis remain one of the most challenging groups to treat. Those who are not on a waiting list for a liver transplant should be treated urgently, according to the guidelines. However, those with current or past decompensation (Child-Pugh class B and C) should not use HCV protease inhibitors (grazoprevir, paritaprevir, or simeprevir), as they can lead to worsening liver failure and death. The recommended regimens for these patients are sofosbuvir/ledipasvir, sofosbuvir/velpatasvir, or sofosbuvir plus daclatasvir, all with ribavirin if tolerated.

Patients with decompensated cirrhosis without HCC who are awaiting a liver transplant should be treated for hepatitis C if they have a MELD score below 18-20. In some cases they may improve enough that they no longer need a transplant. Those with higher MELD scores should receive a transplant first and be treated afterwards, unless their expected waiting time is more than 6 months. People on the transplant list with HCC should be treated before transplantation if possible.

If HCV recurs after a liver transplant, treatment should be started as soon as possible once the patient is stabilized after surgery. Recommended regimens are sofosbuvir/ledipasvir or sofosbuvir plus daclatasvir, both with ribavirin. Sofosbuvir/velpatasvir may become an option once its interactions with immune-suppressing drugs are known.

People with chronic kidney disease who have an estimated glomerular filtration rate (eGFR) >30 mL/mincan be treated according to the general recommendations. Those with worse kidney disease or receiving kidney dialysis should use sofosbuvir with caution. Patients with genotypes 1 or 4 can use the paritaprevir-based 3D regimen or grazoprevir/elbasvir; those with other genotypes can use sofosbuvir-based regimens with close monitoring of kidney function.

Patients who were not cured with prior DAA treatment are generally easy to treat using the recommended regimens if they were not previously exposed to NS5A inhibitors (daclatasvir, ledipasvir, or velpatasvir). Those who were so exposed can try regimens containing sofosbuvir plus 2 or 3 other DAAs and ribavirin -- for example sofosbuvir plus the 3D regimen or grazoprevir/elbasvir -- but these off-label combinations are expensive and have very limited safety data.

"The experience of the panel is that only these kinds of combinations can work, and even these combinations do not always work when you retreat patients who have selected NS5A-resistant viruses," Pawlotsky cautioned. "This is another reason to optimize therapy from the very beginning."

For people who inject drugs -- both active injectors and people on opioid substitution therapy -- decisions about treatment should be made on a case-by-case basis. "HCV treatment must be considered for [people who inject drugs] who are willing to receive treatment, are able and willing to maintain regular appointments and adherence, and accept to undergo integrated management of their substance abuse, including syringe exchange program, substitution therapy and other general harm reduction strategies," the guidelines advise.

The C-EDGE CO-STAR trial found that people on opioid substitution therapy treated with grazoprevir/elbasvir had response rates, adherence, and side effects similar to those of non-drug users in other studies. Modeling studies suggest that hepatitis C treatment for people who inject drugs could reduce transmission when combined with other prevention measures.

For people with acute HCV infection, the panel recommended sofosbuvir/ledipasvir, sofosbuvir/velpatasvir, or sofosbuvir plus daclatasvir without ribavirin, generally for 8 weeks, but extended to 12 weeks for HIV-positive patients or those with high HCV viral load.

Other Considerations


While the "gold standard" for determining a cure has been undetectable HCV RNA (<15 IU/mL) at 12 or 24 weeks after the end of treatment, the revised guidelines also include undetectable HCV core antigen as an alternative endpoint for sustained virological response where HCV viral load tests are not available or not affordable.

Viral monitoring is not necessary during treatment, as direct-acting antiviral therapy has high response rates and does not rely on response-guided treatment adjustments. Monitoring can be simplified by measuring HCV RNA or HCV core antigen only before starting treatment and at 12 or 24 weeks after completing therapy.

However, people who are at ongoing risk for hepatitis C -- including people who inject drugs and men who have sex with men -- should be tested at least annually for reinfection. Individuals who continue to inject drugs "should not be excluded from treatment on the basis of perceived risk of reinfection," the guidelines state.

Patients with liver cirrhosis should receive ongoing ultrasound monitoring for HCC every 6 months, as successful hepatitis C treatment reduces but does not eliminate the risk of liver cancer.

Panel members discussed the unexpectedly high recurrence of liver cancer seen in some studies after DAA therapy.

"At this point we don't have enough data -- it may be true, it may not be true, time will tell," said Forns. "We need to be aware of this potential risk. If it is true, it's telling us we have to treat patients early before they develop cirrhosis."

Finally, the panel addressed how high hepatitis C drug prices are limiting treatment access worldwide and the role of generics.

"The safety and efficacy of generics was shown to be close to optimal," said Aghemo. "It’s a way to shoot for universal treatment."



JM Pawlotsky et al (European Association for the Study of the Liver). EASL Recommendations on Treatment of Hepatitis C 2016. Journal of Hepatology, 2016 (in press).

UPDATE: JM Pawlotsky et al (European Association for the Study of the Liver). EASL Recommendations on Treatment of Hepatitis C 2016. Journal of Hepatology 66(1):153-194. January 2017.