Daclatasvir plus sofosbuvir works well for people with genotype 3 hepatitis C and advanced liver disease in real-world clinical practice

Tania Welzel, presenting at AASLD 2015. Photo by Liz Highleyman, hivandhepatitis.com

Interferon-free treatment with daclatasvir plus sofosbuvir, with or without ribavirin, led to sustained virological response in a majority of people with genotype 3 hepatitis C virus (HCV) and advanced liver disease treated in a real-world setting in compassionate use programs in Europe, according to a pair of studies presented at the 2015 AASLD Liver Meeting last week in San Francisco, USA.

While interferon-free direct-acting antiviral therapy has revolutionised treatment for chronic hepatitis C, better options are still needed for people with HCV genotype 3. This genotype, which accounts for an estimated 30% of all hepatitis C cases worldwide, is associated with faster liver disease progression and is more likely than other genotypes to lead to cirrhosis and liver cancer.

Researchers reported findings from studies looking at people with genotype 3 who were treated with Bristol-Myers Squibb's pangenotypic HCV NS5A replication complex inhibitor daclatasvir (Daklinza) and Gilead Sciences' HCV polymerase inhibitor sofosbuvir (Sovaldi), with or without ribavirin, in two compassionate use programmes. Compassionate use allows people with urgent medical needs and no other treatment options to receive experimental therapies prior to regulatory approval.

Glossary

sustained virological response (SVR)

The continued, long-term suppression of a virus as a result of treatment. In hepatitis C, refers to undetectable hepatitis C RNA after treatment has come to an end. Usually SVR refers to RNA remaining undetectable for 12 or 24 weeks after ending treatment and is considered to be a cure (SVR12 or SVR24).

cirrhosis

Severe fibrosis, or scarring of organs. The structure of the organs is altered, and their function diminished. The term cirrhosis is often used in relation to the liver. 

compassionate use

The release of an experimental drug by its manufacturer to people who are unable to obtain it in a clinical trial.

hepatic

To do with the liver.

oral

Refers to the mouth, for example a medicine taken by mouth.

In the previous ALLY-3 study, daclatasvir plus sofosbuvir taken for 12 weeks led to a 12-week post-treatment sustained virological response (SVR12) rate of 96% for people without cirrhosis, but only 63% for those with cirrhosis. As reported at the Liver Meeting, the follow-up ALLY-3+ study found that adding ribavirin increased cure rates to 88% with 12 weeks and 92% with 16 weeks of treatment. But good outcomes in clinical trials are not always reflected in real-world settings where patients may be more difficult to treat.

European Union compassionate use

Tania Welzel of Goethe University in Frankfurt, Germany, presented findings from a multicentre compassionate use programme in the European Union (AI444-237).

This analysis included 102 people with genotype 3 chronic hepatitis C, considered at high risk of hepatic decompensation or death within 12 months if they did not receive treatment. All were included in the safety analysis and 82 were included in the efficacy analysis (20 did not reach the 12-week post-treatment analysis or had missing data).

Nearly 70% were men, 88% were white and the median age was 55 years; 15% had HIV co-infection and 5% also had hepatitis B. Over half (59%) had received prior hepatitis C treatment. Most (85%) had liver cirrhosis, of whom 47% had Child-Pugh (CP) class A, 39% had class B and 13% had class C. The median MELD score – a measure of liver function impairment – was 10, and 10% had a score greater than 15. The group included eight liver transplant recipients.

Participants were treated with 60mg daclatasvir and 400mg sofosbuvir. Physicians had the option to add ribavirin, and this was done in 39% of cases. Most people were treated for 24 weeks but providers could opt for a shorter duration.

At 12 weeks post-treatment, 86% of people treated with daclatasvir and sofosbuvir alone, and 88% who added ribavirin achieved SVR12 in an intention-to-treat analysis. There was one viral breakthrough during treatment, six relapses, one discontinuation due to an adverse event and three deaths.

Response rates were 91% without and 100% with ribavirin for treatment-naive patients, and 82% and 81%, respectively, for those treated previously. SVR12 rates were 86% without and 71% with ribavirin for the small number of people treated for only 12 weeks. Response rates for people with HIV and HCV co-infection were 83% without and 100% with ribavirin, and all transplant recipients were cured either with or without ribavirin, but these numbers were small.

Response rates were about the same for people with cirrhosis treated with or without ribavirin – 86% vs 88%, respectively – but there were some differences according to liver disease severity. Among those using daclatasvir and sofosbuvir alone, SVR12 rates were 100% for CP class A, 80% for class B and 75% for class C. Conversely, among those who added ribavirin, response rates were 85%, 86% and 100%, respectively. A similar pattern was seen according to MELD scores.

Liver function generally improved with treatment, with ALT and total bilirubin levels falling on average, while albumin levels and platelet counts rose.

A majority of participants in the study experienced adverse events – as expected for such a sick population – but treatment-related serious adverse events were uncommon (3% without and 5% with ribavirin). There were six adverse events leading to treatment discontinuation or death. No one experienced severe ALT or AST liver enzyme or creatinine elevations. Three people in the daclatasvir plus sofosbuvir arm and four who added ribavirin developed anaemia.

"In a real-life clinical setting, [daclatasvir + sofosbuvir with or without ribavirin] achieved high SVR rates (87%) in HCV genotype 3-infected patients at high risk of hepatic decompensation or death," the researchers concluded. "These findings suggest that [daclatasvir + sofosbuvir with or without ribavirin] is an effective and well-tolerated oral treatment for patients with genotype 3 infection, including those with most advanced disease."

French Compassionate Use

Christophe Hézode from Centre Hospitalier Universitaire Henri-Mondor in Créteil, France, presented findings from a similar analysis of the large French Temporary Authorization for Use (ATU) compassionate use programme.

Patients eligible for the programme either had Metavir fibrosis scores of F3 of higher, or had severe extra-hepatic (beyond the liver) manifestations of HCV infection, post-liver transplant HCV recurrence or an indication for liver or kidney transplantation.

In this study, the safety analysis included 468 people with genotype 3 from more than 200 centres in France, while the efficacy analysis included 284 people (excluding 184 who had not yet reached 12 weeks of post-treatment follow-up).

This group was broadly similar to the European Union study population, but had less advanced liver disease overall. Three-quarters were men and the median age was 54 years; 14% had HIV and 7% had hepatitis B co-infection. A majority (73%) were treatment-experienced. Liver cirrhosis was present in 78%, of whom most (83%) had CP class A, 14% had class B and just 3% had class C. There were 24 liver transplant recipients and 25 people awaiting liver or kidney transplants.

Again, the recommended regimen was 60mg daclatasvir plus 400mg sofosbuvir for 24 weeks, but physicians could add ribavirin or shorten treatment duration at their discretion. More than half (n = 166) used daclatasvir and sofosbuvir alone for 24 weeks, 20% (n = 58) used the dual regimen for 12 weeks, 18% (n = 53) used daclatasvir, sofosbuvir, and ribavirin for 24 weeks, and 2% (n = 5) used the triple regimen for 12 weeks. People treated for just 12 weeks had less advanced disease.

Overall, SVR12 rates were 81% and 89%, respectively, for the dual regimen taken for 12 and 24 weeks, and 100% and 81% for the triple regimen taken for 12 and 24 weeks. Irrespective of duration, the two-drug regimen cured 87% and the three-drug regimen cured 83%. Irrespective of regimen, 83% were cured with 12 weeks of treatment and 87% with 24 weeks.

People with stage F3 fibrosis had high response rates using daclatasvir and sofosbuvir alone regardless of duration (96% with 12 weeks and 100% with 24 weeks). Response rates with the dual regimen were lower for people with cirrhosis (70% and 86% respectively); however, adding ribavirin to 24-week treatment did not improve response (81%). People with CP class A had higher SVR rates than those with class B or C – 87%, 67% and 50%, respectively – with the greatest difference seen with the shorter treatment duration; only 33% of class B and C patients treated for 12 weeks were cured.

In this analysis, 9% of patients experienced serious adverse events, only two of which were considered treatment-related (liver decompensation and allergic dermatitis); three people discontinued treatment due to adverse events.

"In this real-world setting, [daclatasvir + sofosbuvir with or without ribavirin] for 12 or 24 weeks was well-tolerated and achieved high SVR12 in genotype 3 patients with advanced liver disease," the investigators concluded. "These results show the pangenotypic, all-oral regimen of [daclatasvir + sofosbuvir with or without ribavirin] is an effective and well-tolerated option for patients with genotype 3 infection and advanced liver disease."

References

Welzel TM et al. Safety and efficacy of daclatasvir plus sofosbuvir with or without ribavirin for the treatment of chronic HCV genotype 3 infection: Interim results of a multicenter European compassionate use program. AASLD Liver Meeting, abstract 37, 2015.

Hézode C et al. Daclatasvir plus sofosbuvir with or without ribavirin in genotype 3 patients from a large French multicenter compassionate use program. AASLD Liver Meeting, abstract 206, 2015.