The goal of treatment is a virological cure (sustained virological response). This is defined as undetectable viral RNA in plasma 24 weeks after treatment has finished. A sustained virological response prevents the development of cirrhosis. In patients who already have cirrhosis, a sustained virological response reduces the risks of liver failure and hepatocellular carcinoma.
The approved treatment combinations for hepatitis C in Australia are summarised in Tables 2 and 3. Currently, all PBS-subsidised regimens involve peginterferon plus ribavirin.
TABLE 3 TGA-approved interferon-free regimens for hepatitis C
Viral genotype
|
Treatment regimen*
|
Patient characteristics
|
Response rates†
|
No cirrhosis
|
Cirrhosis
|
Cirrhosis + treatment-experienced
|
1a/b
|
Sofosbuvir + ledipasvir
|
12 weeks‡
|
12 weeks
|
24 weeks§
|
≥95%
|
1a
|
Paritaprevir + ritonavir + ombitasvir + dasabuvir
|
12 weeks + ribavirin
|
12 weeks + ribavirin
|
12 weeks + ribavirin#
|
≥95%
|
1b
|
12 weeks
|
12 weeks + ribavirin¶
|
12 weeks + ribavirin¶
|
1a/b
|
Sofosbuvir + daclatasvir ± ribavirin
|
12 weeks
|
12 weeks + ribavirin OR 24 weeks**
|
12 weeks + ribavirin OR 24 weeks**††
|
≥95%
|
1b
|
Asunaprevir + daclatasvir
|
24 weeks
|
24 weeks
|
24 weeks
|
90%
|
2
|
Sofosbuvir + ribavirin
|
12 weeks
|
12 weeks‡‡
|
12 weeks‡‡
|
F0-3 >90%
F4 >80%
|
3
|
Sofosbuvir + ribavirin
|
24 weeks
|
24 weeks
|
24 weeks
|
F0-3 >80%
F4 62-82%§§
|
3
|
Sofosbuvir + daclatasvir ± ribavirin
|
12 weeks
|
12 weeks + ribavirin OR 24 weeks##
|
12 weeks + ribavirin OR 24 weeks##
|
F0-3 >90%
F4 >80%##
|
The widespread use of peginterferon-containing regimens has been limited by treatment-related toxicity, as well as disappointing efficacy in patients with advanced liver disease. Direct-acting antiviral drugs targeting multiple steps in the viral life cycle have been developed and used in combination to successfully treat hepatitis C infection. These interferon-free regimens have very high efficacy, short duration (8–12 weeks) and minimal toxicity. They are suitable for patients who cannot tolerate interferon combinations or who are ineligible. These patients previously had no treatment options. The PBAC has recently made positive recommendations to list these regimens on the PBS.
Interferon-containing regimens
The combination of subcutaneous peginterferon plus oral ribavirin has been the backbone of treatment for hepatitis for the past decade.
Genotype 2 and 3 hepatitis C is treated with peginterferon plus ribavirin for 24 weeks (Table 2). Response rates are over 70%, but are lower in patients with cirrhosis.
Protease inhibitors
Treatment regimens for genotype 1 infection can include a protease inhibitor such as simeprevir, telaprevir or boceprevir (Table 2).
Simeprevir was approved in late 2014 and is now the first-line protease inhibitor for genotype 1 infections. It is also approved for genotype 4 infections. Compared to telaprevir or boceprevir, it offers the benefit of a single daily dose and an improved toxicity profile. Also, the majority of patients will qualify for shorter duration therapy (24 vs 48 weeks). Treatment-naïve patients are eligible for short-duration therapy if they have undetectable viral RNA at week four of treatment (Table 2).
In patients with genotype 1 infection, triple therapy with a protease inhibitor has been associated with response rates of over 70%. However, some patient subgroups remain harder to cure, including those with cirrhosis, and those who have previously failed treatment with peginterferon plus ribavirin. Cure rates are less than 50% in these patients.
A fourth protease inhibitor, asunaprevir, has been approved by the TGA in combination with daclatasvir (an inhibitor of the nonstructural protein NS5A). This is a quadruple therapy regimen with peginterferon and ribavirin for genotype 1 (and genotype 4) infections (Table 2). It has not yet been listed on the PBS.
Sofosbuvir
More recently, sofosbuvir, an NS5B nucleotide polymerase inhibitor, has been approved for use by the TGA but is not yet listed on the PBS. For patients with genotypes 1, 4, 5 or 6, sofosbuvir plus peginterferon and ribavirin for 12 weeks is associated with response rates of approximately 90%. Response rates among patients with cirrhosis are 80%.
For genotype 3 infections, sofosbuvir can be added to peginterferon and ribavirin in a 12-week regimen or to ribavirin alone in a 24-week regimen. The response rate for 12 weeks of triple therapy was higher than for 24 weeks of sofosbuvir plus ribavirin (93% vs 84%).12 For genotype 2 infections, sofosbuvir without ribavirin for 12 weeks is associated with response rates over 90%.
Interferon-free regimens
Multiple interferon-free treatment regimens have recently been approved for genotype 1, 2 and 3 hepatitis C infections (Table 3). The first-line regimens for genotype 1 include:
- sofosbuvir and ledipasvir (an NS5A inhibitor)6,7
- paritaprevir (a protease inhibitor that requires ritonavir boosting), ombitasvir (NS5A inhibitor) and dasabuvir (NS5B polymerase non-nucleoside inhibitor) with or without ribavirin.16-18
For both regimens, response rates are over 95% across all patient groups including those with cirrhosis and those who have previously failed on peginterferon plus ribavirin. Treatment duration is 12 weeks for most patients. The pill burden is low and the regimens are well tolerated.
A third regimen, sofosbuvir plus daclatasvir, was very effective in a phase II study of patients with genotype 1 infection who had previously failed protease inhibitor-based triple therapy.
Interferon-free treatment regimens for genotype 3 infection include sofosbuvir plus ribavirin for 24 weeks, and the combination of sofosbuvir plus daclatasvir for 12 weeks12-14 (Table 3). These regimens are very effective in patients who do not have cirrhosis.
Genotype 3 remains harder to cure in patients with cirrhosis, particularly in those who have previously failed peginterferon and ribavirin. In this subgroup, triple therapy with sofosbuvir plus peginterferon and ribavirin for 12 weeks produces better response rates than sofosbuvir plus ribavirin for 24 weeks. A prospective study is evaluating the benefit of adding ribavirin to the 12-week regimen of sofosbuvir plus daclatasvir versus prolonging treatment duration of sofosbuvir plus daclatasvir. Preliminary data from an early-access program in Europe suggest that sustained virological response rates are over 85% among cirrhotic patients treated with sofosbuvir plus daclatasvir for 24 weeks.15
The approved interferon-free treatment regimen for genotype 2 infection is sofosbuvir plus ribavirin for 12 weeks (Table 3). The combination of sofosbuvir plus ledipasvir is effective for genotype 4 and 6 infections. Paritaprevir/ritonavir plus ombitasvir plus ribavirin is effective for genotype 4 infections.