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Updated Hepatitis C Treatment Guidelines Add New Therapies, Hard-to-Treat Patients

The American Association for the Study of Liver Diseases (AASLD), Infectious Diseases Society of America (IDSA), and International Antiviral Society-USA (IAS-USA) recently updated their hepatitis C treatment guidelines to add newly approved interferon-free direct-acting antiviral regimens and to provide more information about treating patients with HIV/HCV coinfection and decompensated liver disease. The evolving guidelines are available online at HCVguidelines.org.

On December 19 several sections of the guidelines were updated. The most notable change was the addition of Gilead Science's sofosbuvir/ledipasvir coformulation (Harvoni) and AbbVie's paritaprevir/ritonavir/ombitasvir plus dasabuvir regimen (Viekira Pak), which received U.S. Food and Drug Administration approval in October and December, respectively.

Initial Hepatitis C Genotype 1 Treatment

The guidelines now state that "3 options with similar efficacy in general" are recommended for previously untreated patients with HCV genotype 1a:

• Sofosbuvir/ledipasvir coformulation without ribavirin for 12 weeks, regardless of liver cirrhosis status;
• Paritaprevir regimen plus weight-based ribavirin for 12 weeks for people without cirrhosis or 24 weeks for those with cirrhosis;
• Sofosbuvir (Gilead's Sovaldi) plus simeprevir (Janssen's Olysio) with or without weight-based ribavirin for 12 weeks for non-cirrhotic or 24 weeks for cirrhotic patients.

For people with easier-to-treat HCV subtype 1b, there are also 3 options with similar efficacy:

• Sofosbuvir/ledipasvir coformulation without ribavirin for 12 weeks;
• Paritaprevir regimen without ribavirin for 12 weeks for people without cirrhosis or with ribavirin for those with cirrhosis;
• Sofosbuvir plus simeprevir without ribavirin for 12 for non-cirrhotic or 24 weeks for cirrhotic patients.

The prescribing information for Harvoni notes that a treatment duration of 8 weeks may be considered for previously untreated patients without cirrhosis who have a low pre-treatment HCV viral load (<6 million IU/mL). The ION-3 trial showed that sofosbuvir/ledipasvir for 8 weeks worked as well as 12 weeks for easier-to-treat patients. The revised guidelines, however, do not recommend the shorter duration.

These treatment options all have cure rates above 90% -- substantially higher than the previous interferon-based therapy standard of care, even with the addition of the first generation HCV protease inhibitors telaprevir (Vertex's now discontinued Incivek) or boceprevir (Merck's Victrelis).

Genotype 1 Re-treatment

For genotype 1a and 1b patients without cirrhosis who were previously treated with pegylated interferon plus ribavirin, the guidelines recommend the same options as for treatment-naive patients.

Treatment-experienced genotype 1a and 1b patients with compensated cirrhosis, can either take sofosbuvir/ledipasvir alone for 24 weeks or with ribavirin for 12 weeks, the paritaprevir regimen with ribavirin for 12 (genotype 1a) or 24 (genotype 1b) weeks, or sofosbuvir plus simeprevir for 24 weeks.

For treatment-experienced people without advanced fibrosis who were not cured using a prior sofosbuvir-containing regimen, the guidelines suggest that patients "defer antiviral therapy pending additional data or consider treatment within clinical trial settings."

For those with advanced fibrosis who cannot wait, the recommendation is sofosbuvir/ledipasvir with or without ribavirin for 24 weeks. Further recommendations are provided for people who previously failed interferon-based triple therapy including telaprevir or boceprevir.

Not Recommended

The revised guidelines state that regimens not recommended for treatment-naive or treatment-experienced genotype 1 patients include sofosbuvir plus ribavirin alone (previously an alternative for genotype 1 patients who could not take interferon) and regimens containing pegylated interferon plus ribavirin, either alone or with sofosbuvir, simeprevir, telaprevir, or boceprevir.

Treatment-experienced people who previous tried interferon-based therapy with an HCV protease inhibitor also should not use interferon-free regimens containing the newer HCV protease inhibitors simeprevir or paritaprevir.

Many patients and providers will be glad to see the elimination of interferon-based therapy, which lasts up to 48 weeks, can cause difficult side effects, and does not cure as many people as the new interferon-free regimens.

Other Genotypes

Recommendations for people with HCV genotype 4 are generally similar to those for people with genotype 1. Sofosbuvir/ledipasvir for 12 weeks is recommended for people with genotype 6.

Guidelines for people with HCV genotypes 2 or 3 have not changed substantially from the initial version -- sofosbuvir plus ribavirin for 12 to 24 weeks -- as ledipasvir and the paritaprevir regimen are not effective against these genotypes.

HIV/HCV Coinfection

Recommendations for initial hepatitis C treatment and re-treatment are the same for HIV/HCV coinfected patients as for HIV negative people with HCV alone, although drug-drug interactions with antiretrovirals need to be taken into account.

Ledipasvir is known to increase levels of tenofovir (Viread, also in the Truvada, Atripla, Complera, and Stribild coformulations), so kidney function should be monitored and it should not be used by people with creatinine clearance below 60 mL/min.

The paritaprevir regimen should be used with antiretroviral drugs known not to interact, including raltegravir (Isentress), probably dolutegravir (Tivicay), enfuvirtide (Fuzeon), tenofovir, emtricitabine (Emtriva), lamivudine (Epivir), and atazanavir (Reyataz). The dose of ritonavir used to boost HIV protease inhibitors may need to be adjusted or dropped since the paritaprevir coformulation already contains ritonavir.

Several contraindications are listed for using specific HIV and HCV drugs together. The guidelines emphasize that antiretroviral therapy should not be interrupted in order to use a non-recommended or interacting HCV drug.

Decompensated Cirrhosis and Post-Transplant

On December 29 the guidelines were updated again to include information for treatment of people with decompensated cirrhosis -- moderate or severe liver impairment with Child-Turcotte-Pugh class B or C.

People with HCV genotypes 1 or 4 and decompensated cirrhosis may be treated with sofosbuvir/ledipasvir plus ribavirin for 12 weeks. Ribavirin should be started at a low dose of 600 mg and increased as tolerated. Patients with anemia or ribavirin intolerance can drop ribavirin and extend treatment duration to 24 weeks. This regimen "should be used only by highly experienced HCV practitioners," the guidelines emphasize.

Treatment-naive or -experienced liver transplant recipients with HCV genotypes 1, 3, or 4 -- including those with compensated cirrhosis -- can be treated with sofosbuvir/ledipasvir plus weight-based ribavirin for 12 weeks, or without ribavirin for 24 weeks if unable to take it. The paritaprevir regimen plus ribavirin for 24 weeks, or sofosbuvir plus simeprevir for 12 weeks, are additional alternatives for transplant recipients with genotype 1.

For transplant recipients with decompensated cirrhosis, sofosbuvir/ledipasvirwith a low escalating dose of ribavirin for 12 weeks is recommended for those with genotypes 1, 3, or 4, while sofosbuvir plus ribavirin for 24 weeks is recommended for those with genotype 2.

Regimens containing pegylated interferon, simeprevir, the paritaprevir regimen, telaprevir, or boceprevir are not recommended for transplant recipients with decompensated liver disease.

The AASLD/IDSA/IAS-USA guidelines will be frequently updated as new study data and information from real-world use become available.

1/12/15

Reference

AASLD, IDSA, and IAS-USA. Recommendations for Testing, Managing, and Treating Hepatitis C. http://www.hcvguidelines.org.