US hepatitis C guidelines updated to include new therapies

The American Association for the Study of Liver Diseases (AASLD), Infectious Diseases Society of America and International Antiviral Society-USA have updated their hepatitis C guidelines to add newly approved direct-acting antiviral (DAA) regimens, offering more options for people with hepatitis C virus (HCV) genotypes other than 1 or 4. The full guidance is available online at HCVguidelines.org.

The biggest change was the addition of Gilead Science's newly approved sofosbuvir/velpatasvir coformulation (Epclusa). The previous guidelines revision in February added Merck's recently approved grazoprevir/elbasvir (Zepatier) combination.

The European Association for the Study of the Liver (EASL) announced at the International Liver Congress in April that it will release an update to its hepatitis C guidelines at a special meeting in September, by which time these co-formulations are expected to also be approved in Europe.

Sofosbuvir/velpatasvir is now a recommended regimen for previously untreated and treatment-experienced people with HCV genotypes 1, 2, 3, 4, 5 and 6.

This pangenotypic regimen makes it feasible to treat all people with the same regimen without the need for genotypic testing. However, the guidelines still state that "Testing for HCV genotype is recommended to guide selection of the most appropriate antiviral regimen."

Genotype 1: People with HCV genotype 1a or 1b and no liver cirrhosis have the most recommended options, including sofosbuvir/velpatasvir, sofosbuvir/ledipasvir (Harvoni), sofosbuvir plus simeprevir (Olysio), sofosbuvir plus daclatasvir (Daklinza), grazoprevir/elbasvir and AbbVie's paritaprevir/ritonavir/ombitasvir plus dasabuvir regimen (Viekirax/Exviera or '3D'), all taken for 12 weeks.

Sofosbuvir/velpatasvir, sofosbuvir/ledipasvir and grazoprevir/elbasvir are also recommended for people with genotype 1 with compensated cirrhosis, with the paritaprevir regimen included for those with subtype 1b but not 1a.

Genotype 2: Sofosbuvir/velpatasvir for 12 weeks is recommended for people with genotype 2 with either no cirrhosis or compensated cirrhosis, and sofosbuvir plus daclatasvir is also included for people without cirrhosis. Sofosbuvir plus ribavirin alone is no longer recommended.

Genotype 3: Sofosbuvir/velpatasvir and sofosbuvir plus daclatasvir for 12 weeks are again recommended regimens for people with genotype 3 without cirrhosis or with compensated cirrhosis, with the addition of ribavirin as an option for people with cirrhosis.

Genotype 4: The recommended options are sofosbuvir/velpatasvir, sofosbuvir/ledipasvir, grazoprevir/elbasvir and paritaprevir/ritonavir/ombitasvir plus ribavirin (without dasabuvir) for 12 weeks for people without cirrhosis or with compensated cirrhosis.

Genotype 5 and 6: Sofosbuvir/velpatasvir and sofosbuvir/ledipasvir for 12 weeks are recommended for both people with cirrhosis and those with compensated cirrhosis.

Notably, none of the current recommended first-line regimens include pegylated interferon, and most do not include ribavirin, both of which can cause numerous side-effects that can interfere with treatment success.

Recommendations for people who previously were not cured with interferon-based therapy are generally similar to those for initial treatment, but adding ribavirin is more often advised for those with cirrhosis, and people with genotype 1a should be tested for resistant virus before using grazoprevir/elbasvir.

The guidelines also include recommendations for people who previously did not respond to prior treatment attempts using the first-generation HCV protease inhibitors boceprevir (Victrelis) or telaprevir (Incivo) or other older DAA regimens.

Treatment duration is now usually 12 weeks for all groups. Although studies have shown that 8 weeks of sofosbuvir/ledipasvir works well for people with genotype 1 without cirrhosis who are treatment-naive, this shorter duration is not recommended in the guidelines. In a few cases treatment duration extends to 24 weeks for people with prior DAA treatment experience.

The guidelines include updated recommendations for people with hepatitis C with decompensated cirrhosis, those with kidney impairment, people with HIV/HCV co-infection and those who develop recurrent HCV infection after liver transplantation.

For people with decompensated cirrhosis (Child-Pugh B or C, indicating moderate or severe liver function impairment), the recommended regimens are 12 weeks of sofosbuvir/velpatasvir, sofosbuvir/ledipasvir or sofosbuvir plus daclatasvir, all with ribavirin. Those who cannot tolerate ribavirin can use the DAAs alone for 24 weeks.

People with mild-to-moderate kidney impairment can use most recommended regimens without dose adjustment. For those with severe impairment (creatinine clearance < 30 ml/min) or end-stage renal disease who have an urgent need for treatment, grazoprevir/elbasvir or the paritaprevir combination are recommended for genotype 1, while pegylated interferon/ribavirin – the old standard of care – is still recommended for genotypes 2, 3, 5 and 6.

Unlike interferon-based therapy, new DAA regimens have similar efficacy for HIV-positive and HIV-negative people, and the recommended regimens are the same for people with HIV/HCV co-infection as for those with HCV alone. However, some antiretroviral drugs should be avoided and some dose adjustment may be necessary to manage potential drug-drug interactions.

"Antiretroviral drug switches, when needed, should be done in collaboration with the HIV practitioner," the guidelines recommend.

One notable caveat is that sofosbuvir/velpatasvir should not be used with efavirenz (Sustiva, also in Atripla), and both velpatasvir and ledipasvir can raise levels of tenofovir – a component of several HIV co-formulations – and therefore require close kidney function monitoring.

The issuing organisations stress that this guidance should be considered a "living document" that will be updated frequently as new information and treatments become available. They add that the choice of treatment may, in the future, be further guided by data from cost-effectiveness studies as these become available.

The forthcoming European guidelines are expected to give greater emphasis to cost considerations than the American guidance and will include a range of treatment options to reflect the fact that not all drugs are approved for coverage in all countries.