Combination Ledipasvir/Sofosbuvir With or Without Ribavirin for ≥ 12 Weeks Reported to Have Sustained Virologic Response Rates > 90% in Adults With Chronic HCV Genotype 1 Infection

EBM Focus - Volume 9, Issue 16

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Reference: N Engl J Med 2014 Apr 11 early online (level 3 [lacking direct] evidence)

When to start treatment for chronic hepatitis C is a controversial and uncertain area. In patients with HCV and advanced liver disease, treatment that achieves a sustained virologic response is associated with lower rates of liver-related morbidity and mortality, and treatment is generally recommended. For patients without advanced liver disease, guidelines suggest individualized decision-making. In this group, the absolute rates of adverse clinical events are low with a long time to develop, so the relative benefit of early treatment is uncertain compared to monitoring and starting treatment later as needed.

For patients in whom therapy is being considered, the combination of recombinant human interferon alfa as weekly injections and weight-based oral ribavirin has historically been a mainstay of treatment. However, both agents are limited by established adverse reactions: interferon is associated with various flu-like symptoms, depression, and cytopenia, while ribavirin is associated with hemolytic anemia, fatigue, pruritus, and rash. A recent joint treatment guideline from the American Society for the Study of Liver Disease and the Infectious Diseases Society of America includes recommendations for newer direct-acting antiviral agents (AASLD/IDSA 2014 Feb PDF); however, these recommendations were based on small phase 2 studies. Now, 2 large phase 3 trials have evaluated an oral fixed-dose combination of an HCV nonstructural protein 5A inhibitor (ledipasvir) and a nucleotide polymerase inhibitor (sofosbuvir) in adults with chronic HCV genotype 1 infection.

The first trial (ION-1) included previously untreated patients, whereas the second trial (ION-2) included patients previously treated with peginterferon plus ribavirin (53% also received a protease inhibitor) who had not had a sustained virologic response (serum HCV RNA < 25 units/mL). In both trials, patients were randomized to ledipasvir/sofosbuvir 90 mg/400 mg orally once daily for 12 weeks vs. 24 weeks vs. ledipasvir/sofosbuvir at the same dosage plus weight-based ribavirin for 12 weeks vs. 24 weeks.

In ION-1, 870 adults (mean age 53 years, 16% with cirrhosis) were randomized and > 99% completed treatment and were included in analyses. The rates of sustained virologic response at 12 weeks after end of treatment were 99% with ledipasvir/sofosbuvir for 12 weeks, 98% with ledipasvir/sofosbuvir for 24 weeks, 97% with ledipasvir/sofosbuvir plus ribavirin for 12 weeks, and 99% with ledipasvir/sofosbuvir plus ribavirin for 24 weeks. The rate of discontinuation of ledipasvir/sofosbuvir was low in all groups: 0% with ledipasvir/sofosbuvir for 12 weeks, 2% with ledipasvir/sofosbuvir for 24 weeks, 0% with ledipasvir/sofosbuvir plus ribavirin for 12 weeks, and 3% with ledipasvir/sofosbuvir plus ribavirin for 12 weeks. The most common adverse events were fatigue, headache, insomnia, and nausea

In ION-2, 441 adults (mean age 56 years, 20% with cirrhosis) were randomized and > 99% completed treatment and were included in analyses. The rates of sustained virologic response at 12 weeks after end of treatment were 94% with ledipasvir/sofosbuvir for 12 weeks, 98% with ledipasvir/sofosbuvir for 24 weeks, 96% with ledipasvir/sofosbuvir plus ribavirin for 12 weeks, and 99% with ledipasvir/sofosbuvir plus ribavirin for 24 weeks. No patients discontinued treatment due to adverse events, and the most common adverse events were fatigue, headache, and nausea.

Sofosbuvir recently became the first drug approved by the U.S. Food and Drug Administration to treat certain types of HCV infection without coadministration of interferon (FDA Press Release 2013 Dec 6). The ION-1 and ION-2 trials demonstrate that an all-oral fixed-dose combination of ledipasvir/sofosbuvir for 12-24 weeks is associated with sustained virologic response rates > 90%, without the need for interferon or ribavirin. This was true even in patients who had not had a sustained virologic response to interferon-based therapy, a group considered more difficult to treat. These results are the basis for a new drug application for the ledipasvir/sofosbuvir combination. Other direct-acting antiviral agents have also shown promising results in early trials, and similarly are easy to administer with short duration of treatment, few contraindications, and minimal side effects reported. The arrival of these agents will almost certainly reshape the management of patients with hepatitis C infection.

However, the very high cost of treatment for these new agents (estimated to exceed $90,000 USD per course in some cases) represents a serious limitation to their use in clinical practice, particularly in developing countries. This new study does not address the issue of at what stage to initiate treatment for patients with chronic hepatitis C, but after having decided to treat with antiviral therapy, this new evidence suggests a less toxic but expensive combination can achieve very high rates of sustained virologic response.

For more information see the Hepatitis C topic in DynaMed.


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