Comment
Cavallini James/BSIP/Science Photo Library
A pill a day keeps HCV away
Published Online April 9, 2015 http://dx.doi.org/10.1016/ S1473-3099(15)70127-1 See Articles page 645
616
In The Lancet Infectious Diseases, Masashi Mizokami and colleagues1 reported the results of a phase 3 trial that assessed the safety and efficacy of an interferon-free, all-oral, anti-hepatitis C virus combination of the directacting antivirals sofosbuvir and ledipasvir (given as a fixed-dose combination) with or without ribavirin for 12 weeks in 341 patients with hepatitis C virus genotype 1 infection in Japan. Chronic hepatitis C virus infection is a major cause of liver cirrhosis, hepatocellular carcinoma, and death. WHO estimates that about 150 million people are chronically infected with hepatitis C virus worldwide and that up to half a million die annually from hepatitis C virus-related diseases.2 In some patients, the infection can be eradicated with antiviral therapy. An undetectable plasma viral load 12 weeks after therapy completion (sustained virological response 12 [SVR12]) is regarded as complete eradication of the infection.3,4 SVR12 is also associated with improved survival and a low rate of progression to advanced disease.5,6 Until recently, available hepatitis C virus treatments were far from optimum. In fact, all therapies contained interferon, which is poorly tolerated and is contraindicated in patients with decompensated disease. A breakthrough for these patients, and all patients with hepatitis C virus, came with the synthesis of antihepatitis C virus direct-acting antiviral drugs. These protease inhibitors, nucleotide or non-nucleotide polymerase inhibitors, and NS5A inhibitors target different hepatitis C virus proteins. However, only some combinations of these antivirals have been proven to be active and safe.7,8 One of the most active combinations against hepatitis C virus genotype 1 is the association of the nucleotide polymerase inhibitor sofosbuvir and the NS5A inhibitor ledipasvir, whose efficacy and safety are addressed in the study by Mizokami and colleagues.1 Patients enrolled in the study by Mizokami and colleagues had a mean age of 59 years and almost all (97%) were infected with hepatitis C virus subtype 1b. Roughly half the patients had received previous antiviral treatment, 76 (22%) had cirrhosis, and 76 (22%) had baseline mutations conferring resistance to NS5A inhibitors. The number of patients who achieved SVR12 was high (100% in the ribavirin-free group and 98% in the ribavirin-containing group). These results are
particularly impressive in view of the high mean age of the patients and the presence of factors associated with antiviral failure (namely, cirrhosis, baseline NS5Aresistant variants, and previous treatment) in a nonnegligible portion of patients. Both combinations were well tolerated and safe. However, two patients in the group receiving ribavirin had serious cardiac adverse events (acute myocardial infarction and cardiac arrest). Although these events were possibly related to the study drugs, both have an alternative explanation (pre-existing disease and infection). Furthermore, neither sofosbuvir nor ledipasvir were associated with cardiac toxic effects in three earlier pivotal studies.9–11 Mizokami and colleagues also reported a higher rate of adverse events in the group receiving ribavirin than in the ledipasvir-sofosbuvir only. Two immediate considerations arise from the results obtained in Japanese patients. First, ribavirin did not add to the efficacy of the ledipasvir-sofosbuvir combination and even increased the adverse event rate. Second, the 100% SVR12 response achieved in the ledipasvir-sofosbuvir only group marks the end of the era when hepatitis C virus studies were dominated by predictors of the antiviral response rate. A limitation of this study is the low rate of patients with subtype 1a infection, which might weaken generalisation of the results to all patients with hepatitis C virus genotype 1, which is the most common genotype worldwide. However, efficacy did not differ between subtype 1a and 1b in the other phase 3 studies that recruited a large proportion of patients infected with subtype 1a.9–11 The battle against hepatitis C virus has reached a turning point, but much is still to be investigated. For example, little is known about the efficacy, safety, and optimum regimen of antiviral therapies for patients with very advanced disease. Moreover, the advantage of viral clearance in terms of survival and the quality of life of these patients remains to be established. Finally, in some non-1 genotypes, such as genotype 3, the therapeutic combinations available are not optimum, especially in treatment-experienced patients with cirrhosis. In summary, the study by Mizokami and colleagues1 in Japanese patients supported the excellent results www.thelancet.com/infection Vol 15 June 2015
Comment
of the sofosbuvir-ledipasvir combination obtained in pivotal trials of the treatment of genotype 1 infection done in the USA and Europe.9–11 In view of the absence of significant drug-drug interactions, the high efficacy, even in difficult-to-treat patients—eg, patients with cirrhosis and antiviral-treatment experienced patients— and the excellent safety and tolerability profile,12,13 the sofosbuvir-ledipasvir combination is a powerful weapon in the fight against genotype 1 hepatitis C virus infection and could eradicate worldwide hepatitis C virus.
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8
*Ivan Gentile, Guglielmo Borgia Department of Clinical Medicine and Surgery, University of Naples, Naples 80131, Italy [email protected] IG has received funding for a grant from Gilead. GB declares no competing interests. 1
2
Mizokami M, Yokosuka O, Takehara T, et al. Ledipasvir and sofosbuvir fixeddose combination with and without ribavirin for 12 weeks in treatmentnaïve and previously treated Japanese patients with genotype 1 hepatitis C: an open-label, randomized, phase 3 trial. Lancet Infect Dis 2015; published online April 9. http://dx.doi.org/10.1016/S1473-3099(15)70099-X WHO. Hepatitis C. 2014. http://www.who.int/mediacentre/factsheets/ fs164/en/ (accessed July 2, 2014).
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10 11
12
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Chen J, Florian J, Carter W, et al. Earlier sustained virologic response end points for regulatory approval and dose selection of hepatitis C therapies. Gastroenterology 2013; 144: 1450–55. AASLD, IDSA. Recommendations for testing, managing, and treating hepatitis C. 2014. http://www.hcvguidelines.org/fullreport (accessed July 4, 2014). Omland LH, Krarup H, Jepsen P, et al. Mortality in patients with chronic and cleared hepatitis C viral infection: a nationwide cohort study. J Hepatol 2010; 53: 36–42. Bruno S, Stroffolini T, Colombo M, et al. Sustained virological response to interferon-alpha is associated with improved outcome in HCV-related cirrhosis: a retrospective study. Hepatology 2007; 45: 579–87. Gentile I, Buonomo AR, Zappulo E, Borgia G. Interferon-free therapies for chronic hepatitis C: toward a hepatitis C virus-free world? Expert Rev Anti Infect Ther 2014; 12: 763–73. Gentile I, Buonomo AR, Zappulo E, Borgia G. Discontinued drugs in 2012–2013: hepatitis C virus infection. Expert Opin Investig Drugs 2015; 24: 239–51. Kowdley KV, Gordon SC, Reddy KR, et al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med 2014; 370: 1879–88. Afdhal N, Zeuzem S, Kwo P, et al. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med 2014; 370: 1889–98. Afdhal N, Reddy KR, Nelson DR, et al. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med 2014; 370: 1483–93. Gentile I, Buonomo AR, Borgia F, Castaldo G, Borgia G. Ledipasvir: a novel synthetic antiviral for the treatment of HCV infection. Expert Opin Investig Drugs 2014; 23: 561–71. Gentile I, Borgia F, Buonomo AR, Castaldo G, Borgia G. A novel promising therapeutic option against hepatitis C virus: an oral nucleotide NS5B polymerase inhibitor sofosbuvir. Curr Med Chem 2013; 20: 3733–42.
Oseltamivir (Tamiflu), a neuraminidase inhibitor, is the most widely used anti-influenza drug. However its effectiveness has been hotly debated1 and its optimum use in pandemics is unclear.2 A large, double-blind, randomised, placebo-controlled trial, comprised of 1190 patients with influenza (referred to as index patients) and their households with 4694 members, was done in Kamalapur, a suburb of Dhaka, Bangladesh from May, 2008, to December, 2010. The trial addressed direct and indirect protection from illness after giving oseltamivir to index patients.3,4 In the first report from the trial published in Lancet Infectious Diseases,3 Alicia Fry and colleagues analysed the direct effects of oseltamivir on index patients, 89% of whom were younger than 18 years, who had influenza confirmed by a rapid diagnostic test. The index patients had a slight reduction from 4 to 3 days in the duration of their symptoms after receiving oseltamivir treatment. No significant differences were noted when results were stratified by the time of treatment (ie,
Cavallini James/BSIP/Science Photo Library
A pill a day keeps HCV away
Published Online April 9, 2015 http://dx.doi.org/10.1016/ S1473-3099(15)70127-1 See Articles page 645
616
In The Lancet Infectious Diseases, Masashi Mizokami and colleagues1 reported the results of a phase 3 trial that assessed the safety and efficacy of an interferon-free, all-oral, anti-hepatitis C virus combination of the directacting antivirals sofosbuvir and ledipasvir (given as a fixed-dose combination) with or without ribavirin for 12 weeks in 341 patients with hepatitis C virus genotype 1 infection in Japan. Chronic hepatitis C virus infection is a major cause of liver cirrhosis, hepatocellular carcinoma, and death. WHO estimates that about 150 million people are chronically infected with hepatitis C virus worldwide and that up to half a million die annually from hepatitis C virus-related diseases.2 In some patients, the infection can be eradicated with antiviral therapy. An undetectable plasma viral load 12 weeks after therapy completion (sustained virological response 12 [SVR12]) is regarded as complete eradication of the infection.3,4 SVR12 is also associated with improved survival and a low rate of progression to advanced disease.5,6 Until recently, available hepatitis C virus treatments were far from optimum. In fact, all therapies contained interferon, which is poorly tolerated and is contraindicated in patients with decompensated disease. A breakthrough for these patients, and all patients with hepatitis C virus, came with the synthesis of antihepatitis C virus direct-acting antiviral drugs. These protease inhibitors, nucleotide or non-nucleotide polymerase inhibitors, and NS5A inhibitors target different hepatitis C virus proteins. However, only some combinations of these antivirals have been proven to be active and safe.7,8 One of the most active combinations against hepatitis C virus genotype 1 is the association of the nucleotide polymerase inhibitor sofosbuvir and the NS5A inhibitor ledipasvir, whose efficacy and safety are addressed in the study by Mizokami and colleagues.1 Patients enrolled in the study by Mizokami and colleagues had a mean age of 59 years and almost all (97%) were infected with hepatitis C virus subtype 1b. Roughly half the patients had received previous antiviral treatment, 76 (22%) had cirrhosis, and 76 (22%) had baseline mutations conferring resistance to NS5A inhibitors. The number of patients who achieved SVR12 was high (100% in the ribavirin-free group and 98% in the ribavirin-containing group). These results are
particularly impressive in view of the high mean age of the patients and the presence of factors associated with antiviral failure (namely, cirrhosis, baseline NS5Aresistant variants, and previous treatment) in a nonnegligible portion of patients. Both combinations were well tolerated and safe. However, two patients in the group receiving ribavirin had serious cardiac adverse events (acute myocardial infarction and cardiac arrest). Although these events were possibly related to the study drugs, both have an alternative explanation (pre-existing disease and infection). Furthermore, neither sofosbuvir nor ledipasvir were associated with cardiac toxic effects in three earlier pivotal studies.9–11 Mizokami and colleagues also reported a higher rate of adverse events in the group receiving ribavirin than in the ledipasvir-sofosbuvir only. Two immediate considerations arise from the results obtained in Japanese patients. First, ribavirin did not add to the efficacy of the ledipasvir-sofosbuvir combination and even increased the adverse event rate. Second, the 100% SVR12 response achieved in the ledipasvir-sofosbuvir only group marks the end of the era when hepatitis C virus studies were dominated by predictors of the antiviral response rate. A limitation of this study is the low rate of patients with subtype 1a infection, which might weaken generalisation of the results to all patients with hepatitis C virus genotype 1, which is the most common genotype worldwide. However, efficacy did not differ between subtype 1a and 1b in the other phase 3 studies that recruited a large proportion of patients infected with subtype 1a.9–11 The battle against hepatitis C virus has reached a turning point, but much is still to be investigated. For example, little is known about the efficacy, safety, and optimum regimen of antiviral therapies for patients with very advanced disease. Moreover, the advantage of viral clearance in terms of survival and the quality of life of these patients remains to be established. Finally, in some non-1 genotypes, such as genotype 3, the therapeutic combinations available are not optimum, especially in treatment-experienced patients with cirrhosis. In summary, the study by Mizokami and colleagues1 in Japanese patients supported the excellent results www.thelancet.com/infection Vol 15 June 2015
Comment
of the sofosbuvir-ledipasvir combination obtained in pivotal trials of the treatment of genotype 1 infection done in the USA and Europe.9–11 In view of the absence of significant drug-drug interactions, the high efficacy, even in difficult-to-treat patients—eg, patients with cirrhosis and antiviral-treatment experienced patients— and the excellent safety and tolerability profile,12,13 the sofosbuvir-ledipasvir combination is a powerful weapon in the fight against genotype 1 hepatitis C virus infection and could eradicate worldwide hepatitis C virus.
3
4
5
6
7
8
*Ivan Gentile, Guglielmo Borgia Department of Clinical Medicine and Surgery, University of Naples, Naples 80131, Italy [email protected] IG has received funding for a grant from Gilead. GB declares no competing interests. 1
2
Mizokami M, Yokosuka O, Takehara T, et al. Ledipasvir and sofosbuvir fixeddose combination with and without ribavirin for 12 weeks in treatmentnaïve and previously treated Japanese patients with genotype 1 hepatitis C: an open-label, randomized, phase 3 trial. Lancet Infect Dis 2015; published online April 9. http://dx.doi.org/10.1016/S1473-3099(15)70099-X WHO. Hepatitis C. 2014. http://www.who.int/mediacentre/factsheets/ fs164/en/ (accessed July 2, 2014).
9
10 11
12
13
Chen J, Florian J, Carter W, et al. Earlier sustained virologic response end points for regulatory approval and dose selection of hepatitis C therapies. Gastroenterology 2013; 144: 1450–55. AASLD, IDSA. Recommendations for testing, managing, and treating hepatitis C. 2014. http://www.hcvguidelines.org/fullreport (accessed July 4, 2014). Omland LH, Krarup H, Jepsen P, et al. Mortality in patients with chronic and cleared hepatitis C viral infection: a nationwide cohort study. J Hepatol 2010; 53: 36–42. Bruno S, Stroffolini T, Colombo M, et al. Sustained virological response to interferon-alpha is associated with improved outcome in HCV-related cirrhosis: a retrospective study. Hepatology 2007; 45: 579–87. Gentile I, Buonomo AR, Zappulo E, Borgia G. Interferon-free therapies for chronic hepatitis C: toward a hepatitis C virus-free world? Expert Rev Anti Infect Ther 2014; 12: 763–73. Gentile I, Buonomo AR, Zappulo E, Borgia G. Discontinued drugs in 2012–2013: hepatitis C virus infection. Expert Opin Investig Drugs 2015; 24: 239–51. Kowdley KV, Gordon SC, Reddy KR, et al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med 2014; 370: 1879–88. Afdhal N, Zeuzem S, Kwo P, et al. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med 2014; 370: 1889–98. Afdhal N, Reddy KR, Nelson DR, et al. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med 2014; 370: 1483–93. Gentile I, Buonomo AR, Borgia F, Castaldo G, Borgia G. Ledipasvir: a novel synthetic antiviral for the treatment of HCV infection. Expert Opin Investig Drugs 2014; 23: 561–71. Gentile I, Borgia F, Buonomo AR, Castaldo G, Borgia G. A novel promising therapeutic option against hepatitis C virus: an oral nucleotide NS5B polymerase inhibitor sofosbuvir. Curr Med Chem 2013; 20: 3733–42.
Oseltamivir (Tamiflu), a neuraminidase inhibitor, is the most widely used anti-influenza drug. However its effectiveness has been hotly debated1 and its optimum use in pandemics is unclear.2 A large, double-blind, randomised, placebo-controlled trial, comprised of 1190 patients with influenza (referred to as index patients) and their households with 4694 members, was done in Kamalapur, a suburb of Dhaka, Bangladesh from May, 2008, to December, 2010. The trial addressed direct and indirect protection from illness after giving oseltamivir to index patients.3,4 In the first report from the trial published in Lancet Infectious Diseases,3 Alicia Fry and colleagues analysed the direct effects of oseltamivir on index patients, 89% of whom were younger than 18 years, who had influenza confirmed by a rapid diagnostic test. The index patients had a slight reduction from 4 to 3 days in the duration of their symptoms after receiving oseltamivir treatment. No significant differences were noted when results were stratified by the time of treatment (ie,
![[An avocado a day keeps the doctor away].](/assets/img/hold.png)
