First published 1 October 2015
Some of the views expressed in the following notes on newly approved products should be regarded as preliminary, as there may have been limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Executive Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer's approved product information, a drug information centre or some other appropriate source.
Approved indication: hepatitis C
Daklinza (Bristol-Myers Squibb)
30 mg tablets
Australian Medicines Handbook section 5.5
Hepatitis C can be classified into six main genotypes (1–6). These can be further subdivided into subtypes (e.g. 1a, 1b). In Australia, genotype 1a and 1b account for 54% of hepatitis C cases and genotype 3a for 37%. Up until recently, patients were offered a combination of peginterferon and ribavirin and patients with genotype 1 disease could add a protease inhibitor. However, many people cannot tolerate interferon-based regimens or are not eligible because they have contraindications.
Several new drugs have been approved in Australia for hepatitis C.1 Daclatasvir, a nucleotide polymerase inhibitor, adds to this list. It is a direct-acting antiviral that works by inhibiting the non-structural 5A protein involved in viral replication. Daclatasvir has been approved for use in combination with other drugs, such as sofosbuvir and asunaprevir, in patients with compensated liver disease (including cirrhosis).
The recommended dose of daclatasvir is 60 mg per day. After oral administration, daclatasvir is absorbed within 1–2 hours and steady state is reached after four days. Its terminal half-life is 12–15 hours and most of the dose is excreted in the faeces. Dose adjustment is not required in hepatic or renal impairment.
Table 1: Efficacy of daclatasvir and sofosbuvir in hepatitis C
|Study||Viral genotype||Treatment regimen||Sustained virological response‡|
|Treatment-naïve patients||Treatment-experienced patients|
|Sulkowski2||1||daclatasvir + sofosbuvir§||100% (70/70)||100% (21/21)|
|daclatasvir + sofosbuvir + ribavirin§||98% (55/56)||100% (20/20)|
|2 or 3||daclatasvir + sofosbuvir§||93% (28/30)||—|
|daclatasvir + sofosbuvir + ribavirin§||93% (13/14)||—|
|Nelson3||3||daclatasvir + sofosbuvir#||Overall
|Patients with cirrhosis
|Patients with cirrhosis
‡ Defined as proportion of patients with viral RNA less than the lower limit of quantification in serum, measured 12 weeks after the end of treatment.
§ Treatment given for 12 or 24 weeks in treatment-naïve patients and for 24 weeks in treatment-experienced patients.
# Treatment given for 12 weeks.
Table 2: Efficacy of daclatasvir and asunaprevir in hepatitis C
|Study||Viral genotype||Treatment regimen (24 weeks)||Sustained virological response‡|
|Treatment-naïve patients||Treatment-experienced patient||Intolerant/ ineligible patients|
|Manns5||1b||daclatasvir + asunaprevir||90% (182/203)||82% (168/205)||82% (192/235)|
|Kumada6||—||80% (70/87)||88% (119/135)|
|Jensen7||1||daclatasvir + asunaprevir + peginterferon + ribavirin||—||Overall
|Patients with cirrhosis
|Patients with cirrhosis
‡ Defined as proportion of patients with viral RNA less than the lower limit of quantification in serum measured 12 weeks after the end of treatment.
Daclatasvir and sofosbuvir
Daclatasvir combined with sofosbuvir has also been investigated in patients co-infected with HIV. Most of them had genotype 1a or 1b, and some had previously been treated for hepatitis C. After a 12-week course of daclatasvir and sofosbuvir, most of them (149/153) had a sustained virological response.4
Daclatasvir and asunaprevir
Daclatasvir has also been combined with asunaprevir (100 mg twice daily) in an open-label study of patients with genotype 1b infection.5 Asunaprevir is another direct-acting hepatitis C drug. Although approved by the Therapeutic Goods Administration, it is not currently available on prescription in Australia. It selectively inhibits the viral non-structural protein 3/4A protease.
In the trial, participants were divided into three groups:
- treatment-naïve patients
- patients who had not responded or only partially responded to previous peginterferon and ribavirin
- patients intolerant to, and/or ineligible for, peginterferon and ribavirin (this included patients with depression, anaemia or neutropenia, or compensated advanced fibrosis or cirrhosis with thrombocytopenia).
Patients with cirrhosis were present in all three groups (16%, 31% and 47%). After 24 weeks of daclatasvir and asunaprevir, most patients had a sustained virological response (see Table 2). Response rates were similar in patients with cirrhosis and without cirrhosis (84% vs 85%). A high viral titre at baseline (≥800 000 IU/mL) or the presence of viral variants associated with non-structural 5A protein resistance predicted a poor response to treatment.5
A Japanese trial also enrolled 222 patients with genotype 1b disease.6 They were classified as non-responders to previous interferon and ribavirin or as intolerant to, or ineligible for, interferon-based treatment. Around 10% of patients had cirrhosis. They were given 24 weeks of daclatasvir and asunaprevir. Up to 88% of participants had a sustained viral response (see Table 2), including 20 of the 22 patients with cirrhosis.6
Another trial investigated daclatasvir and asunaprevir with peginterferon and ribavirin in 398 patients with genotype 1 or 4 infection.7 Participants had been previously treated with peginterferon and ribavirin but had either not responded or had only partially responded. After 24 weeks of treatment with the new regimen, most of them had a sustained virological response (see Table 2).7
Safety and precautions
In the safety cohort of 1679 patients, the most common adverse events included fatigue, diarrhoea, nausea and headache. In one of the trials with daclatasvir and sofosbuvir, one patient discontinued because of fibromyalgia, and another because of a stroke. The ribavirin dose had to be reduced in five patients because of anaemia.2 In a trial of daclatasvir and asunaprevir, 10 patients discontinued because of an adverse event. Reasons included increased liver enzymes (7 patients), prolonged QT interval (1), constipation (1), hypertransaminasaemia (1), brain cancer (1) and bronchiectasis (1).5 In the Japanese trial of patients who were intolerant to or ineligible for interferon, 10 patients discontinued because of elevations in liver enzymes and one because of myasthenia gravis.6 When peginterferon and ribavirin were added to daclatasvir and asunaprevir, 18 patients discontinued. The most common reasons were rash, malaise, neutropenia and vertigo (2 cases of each).7
Cardiac arrhythmias, including severe bradycardia, have been reported in patients taking amiodarone with daclatasvir and sofosbuvir, so close monitoring is recommended with this combination.
Daclatasvir should not be used in pregnancy. In animal studies, it has been shown to cross the placenta, and maternal and embryofetal toxicity have been observed at high doses. Contraception should be used during treatment and for five weeks afterwards. Daclatasvir is also excreted in milk and breastfeeding is not recommended.
The safety and efficacy of daclatasvir in people who are co-infected with hepatitis B have not been established as these patients were generally excluded from the trials.
Resistance to daclatasvir can occur. If patients experience an increase in viral RNA during treatment, the regimen should be discontinued.
Daclatasvir is mainly metabolised by cytochrome P450 (CYP) 3A4. It is contraindicated in combination with strong inducers of CYP3A4 (e.g. phenytoin, carbamazepine, rifampicin, dexamethasone and St John’s wort), as these drugs may lower daclatasvir exposure. The daily daclatasvir dose should be increased to 90 mg with moderate CYP3A4 inducers. Conversely, the dose should be reduced to 30 mg per day with strong CYP3A4 inhibitors (e.g. clarithromycin, boceprevir, telaprevir, atazanavir, ritonavir, ketoconazole).
As daclatasvir inhibits P-glycoprotein, co-administered digoxin and other P-glycoprotein substrates with a narrow therapeutic index, such as dabigatran, should be used with caution. Care is also urged with the statins as rosuvastatin concentrations are increased with daclatasvir.
In general, daclatasvir-containing regimens were very effective at clearing hepatitis C virus in patients with chronic disease. This included those who had not adequately responded to previous treatments and patients who were co-infected with HIV. With the daclatasvir and sofosbuvir combination, adding ribavirin did not seem to give further benefit. Patients with genotype 3 infection who had cirrhosis were less likely to have a sustained response after 12 weeks of daclatasvir and sofosbuvir compared to those who did not have cirrhosis. This combination was not assessed in patients with genotype 1 disease and cirrhosis. The combination of daclatasvir and asunaprevir (with or without peginterferon and ribavirin) was effective in a range of patients with genotype 1 or 4 infection.
Daclatasvir regimens were generally well tolerated but prescribers should be mindful of adverse reactions to other drugs in the treatment regimen. As daclatasvir is metabolised by CYP3A4, there are numerous drug interactions that need to be considered. Most importantly, concomitant use of strong CYP3A4 inducers is contraindicated as this may reduce the efficacy of daclatasvir.
The Transparency Score () is explained in New drugs: transparency, Vol 37 No 1, Aust Prescr 2014;37:27.
Note on references
At the time the comment was prepared, a scientific discussion about this drug was available on the website of the European Medicines Agency (www.emea.europa.eu).
- Thompson A, Holmes J. Treating hepatitis C – what’s new. Aust Prescr 2015. Epub ahead of print.
- Sulkowski MS, Gardiner DF, Rodriguez-Torres M, Reddy KR, Hassanein T, Jacobson I, et al.; AI444040 Study Group. Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med 2014;370:211-21.
- Nelson DR, Cooper JN, Lalezari JP, Lawitz E, Pockros PJ, Gitlin N, et al.; ALLY-3 Study Team. All-oral 12-week treatment with daclatasvir plus sofosbuvir in patients with hepatitis C virus genotype 3 infection: ALLY-3 phase III study. Hepatology 2015;61:1127-35.
- Wyles DL, Ruane PJ, Sulkowski MS, Dieterich D, Luetkemeyer A, Morgan TR, et al.; ALLY-2 Investigators. Daclatasvir plus sofosbuvir for HCV in patients coinfected with HIV-1. N Engl J Med 2015;373:714-25.
- Manns M, Pol S, Jacobson IM, Marcellin P, Gordon SC, Peng CY, et al.; HALLMARK-DUAL Study Team. All-oral daclatasvir plus asunaprevir for hepatitis C virus genotype 1b: a multinational, phase 3, multicohort study. Lancet 2014;384:1597-605.
- Kumada H, Suzuki Y, Ikeda K, Toyota J, Karino Y, Chayama K, et al. Daclatasvir plus asunaprevir for chronic HCV genotype 1b infection. Hepatology 2014;59:2083-91.
- Jensen D, Sherman KE, Hézode C, Pol S, Zeuzem S, de Ledinghen V, et al.; HALLMARK-QUAD Study Team. Daclatasvir and asunaprevir plus peginterferon alfa and ribavirin in HCV genotype 1 or 4 non-responders. J Hepatol 2015;63:30-7.