First published 14 October 2015

Approved indication: hepatitis C
Harvoni (Gilead)
90 mg/400 mg tablets
Australian Medicines Handbook section 5.5

Sofosbuvir (Aust Prescr 2014;37:177-8) is a nucleotide analogue antiviral drug that is used in combination with other drugs to treat chronic hepatitis C. As the effectiveness of regimens containing interferon can be limited by adverse effects, there is interest in studying other drugs to use in combination with sofosbuvir.

Ledipasvir is an antiviral drug aimed at a protein (NS5A) in the hepatitis C virus. As this protein is involved in viral replication, ledipasvir will reduce the amount of virus in infected patients. Ledipasvir is rapidly absorbed. As the solubility of ledipasvir is pH-dependent, antacids, proton pump inhibitors and H2-receptor antagonists can decrease absorption. Ledipasvir is minimally metabolised with most of the dose being excreted unchanged in the faeces. The median half-life is 47 hours. No dose adjustment is required in patients with hepatic impairment.

The fixed-dose combination of ledipasvir and sofosbuvir has mainly been studied in patients with genotype 1 infection. Its approval is based on open-label clinical trials which assessed the virological response (see Table). A sustained virological response was defined as a viral RNA in the patient’s serum below 25 IU/mL 12 weeks after the end of treatment. However, the World Health Organization has previously considered a sustained response to be the absence of viral RNA six months after the end of treatment.

Table - Efficacy of ledipasvir and sofosbuvir in hepatitis C

 

Trial Patients Sustained virological response for patients taking 12-week regimens
Ledipasvir/sofosbuvir    Ledipasvir/sofosbuvir plus ribavirin
ION- 11           865 previously untreated patients 99% (211/214) 97% (211/217)
ION-22 440 previously treated patients 94% (102/109) 96% (107/111)
ION-33 647 previously untreated patients without cirrhosis 95% (206/216) -
ION-44 335 patients coinfected with HIV 96% (322/335) -
 Primary outcome was the proportion of patients who had no quantifiable RNA in their sera 12 weeks after treatment

In ION-1, 865 previously untreated patients were randomised to take the combination, with or without ribavirin, in either 12- or 24-week regimens. There was a sustained viral response in 97–99% of the patients. This response was achieved by 94–100% of the patients who had cirrhosis (16% of the trial participants).1

The ION-2 trial used the same four treatment regimens as ION-1, but studied 440 patients who had not responded to other treatments for genotype 1 infections. Approximately 20% of these patients had cirrhosis. Twelve weeks after completing 12 weeks of treatment, there was a virological response of 94–96%. In patients who were treated for 24 weeks a viral RNA below 25 IU/mL was achieved in 99%. The response rate was significantly lower in patients with cirrhosis who were treated for 12 weeks compared with 24 weeks (82–86% vs 100%).2

The ION-3 trial assessed the efficacy of a shorter treatment regimen in previously untreated patients without cirrhosis. It randomised 647 patients to take the combination of ledipasvir and sofosbuvir, with or without ribavirin, for eight weeks, or the combination alone for 12 weeks. There was a sustained virological response in 94% of the patients who took the combination for eight weeks (93% with ribavirin) compared with 95% who took it for 12 weeks.3 An eight-week regimen can therefore be considered in previously untreated patients without cirrhosis who have pre-treatment viral RNA concentrations below 6 million IU/mL.

ION-4 was an open-labelled study involving 335 patients who were infected with hepatitis C virus and HIV. Using a 12-week regimen, a sustained response against hepatitis C was achieved by 96% of the patients. Results were similar irrespective of the treatments used for HIV in the trial, and whether or not the patients had cirrhosis.4

Less than 1% of the patients treated with ledipasvir and sofosbuvir had to stop treatment because of adverse effects. Without ribavirin, the most frequent adverse events with the combination were fatigue, headache, nausea and insomnia. There are no human data in pregnancy and lactation, but the combination had no effect on fetal development in animal studies.

Drug interactions can occur with one or both components of the combination, so it is best to check the product information before prescribing. Its efficacy could be reduced by inducers of P-glycoprotein such as rifampicin and St John’s wort. There is a potentially fatal interaction with amiodarone. Other interactions include digoxin, antiepileptic drugs, and statins particularly rosuvastatin. There is no known interaction with oral contraception.

Resistance to ledipasvir can develop during treatment. This should be considered in patients who do not have a sustained virological response.

A once-daily, interferon-free treatment, which in most cases only needs to be taken for 12 weeks, that has very high efficacy is an advance. While further research is needed for other genotypes, the combination of ledipasvir and sofosbuvir is probably the treatment of choice for genotype 1 hepatitis C infection in 2015. However, until similar antiviral drugs arrive, cure comes with a high cost.5 The Pharmaceutical Benefits Advisory Committee estimates that the cost of treatment in Australia will exceed $3 billion over five years.6

manufacturer provided the product information

The Transparency Score is explained in New drugs: transparency, Vol 37 No 1, Aust Prescr 2014;37:27.

At the time the comment was prepared, information about this drug was available on the web site of the Food and Drug Administration in the USA (www.fda.gov).

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).

References

  1. Afdhal N, Zeuzem S, Kwo P, Chojkier M, Gitlin N, Puoti M, et al.; ION-1 Investigators. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med 2014;370:1889-98.
  2. Afdhal N, Reddy KR, Nelson DR, Lawitz E, Gordon SC, Schiff E, et al.; ION-2 Investigators. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med 2014;370:1483-93.
  3. Kowdley KV, Gordon SC, Reddy KR, Rossaro L, Bernstein DE, Lawitz E, et al.; ION-3 Investigators. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med 2014;370:1879-88.
  4. Naggie S, Cooper C, Saag M, Workowski K, Ruane P, Towner WJ, et al.; ION-4 Investigators. Ledipasvir and sofosbuvir for HCV in patients coinfected with HIV-1. N Engl J Med 2015;373:705-13.
  5. Hoofnagle JH, Sherker AH. Therapy for hepatitis C--the costs of success. N Engl J Med 2014;370:1552-3.
  6. Pharmaceutical Benefits Scheme. March 2015 PBAC Meeting – positive recommendations. Canberra: Australian Government Department of Health; 2015. www.pbs.gov.au/info/industry/listing/elements/pbac-meetings/pbac-outcomes/2015-03 [cited 2015 Oct 2]

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.