Comment
Worldwide mortality from hepatitis C virus (HCV) infection is rising and, without increases in the number of individuals who are successfully treated, rates are predicted to rise further.1 A response to therapy (undetectable viraemia 12 weeks after treatment ends) reduces disease progression, but therapy has long involved unpalatable interferon and ribavirin regimens given for 6 months, with extended durations for some genotypes (eg, genotype 1).2 Given the side-effects of interferon, long treatment duration, and low response rates (ie, less than 80%) most patients choose to defer therapy. However, new oral drug combinations that have higher than 90% response rates and few side-effects have encouraged patients and their doctors to reconsider therapy. For patients with genotype 1 HCV infection, two strategies have emerged—one involves combinations of at least three potent, low-resistance-barrier drugs (a protease, an NS5A inhibitor, and a non-nucleoside inhibitor)3 and the other uses the high-resistance-barrier nucleotide sofosbuvir, with either an NS5A inhibitor (such as ledipasvir) or a protease inhibitor (simeprevir).4,5 For the triple, non-nucleotide regimen, therapy for 12 weeks is needed,3 but for sofosbuvir and ledipasvir, 8 weeks is sufficient for patients without cirrhosis,4 although 6 weeks of therapy is less effective.6 Ribavirin is a weak antiviral drug that might improve response rates but adds side-effects; researchers increasingly avoid it. In The Lancet, Anita Kohli and colleagues7 report results from a ribavirin-free, single-centre, open-label, phase 2A study of sofosbuvir and ledipasvir combinations that include either the non-nucleoside inhibitor GS-9669 or the protease inhibitor GS-9451. 20 patients per treatment group were allocated to 12 weeks of sofosbuvir and ledipasvir, 6 weeks of sofosbuvir and ledipasvir plus GS-9669, or 6 weeks of sofosbuvir and ledipasvir plus GS-9451. All patients allocated to receive sofosbuvir and ledipasvir for 12 weeks achieved a sustained virological response at 12 weeks (SVR12), and 19 of 20 patients in each of the triple-therapy groups had SVR12 in a rigid intention-to-treat analysis. The triple-therapy combinations seemed to allow even shorter treatment regimens, with most patients achieving SVR after only 6 weeks of treatment. One of the many questions posed by the study is the value of
such regimens—8 weeks of therapy is acceptable and a reduction to 6 weeks might be of little value. However, many patients with HCV have continuing comorbidities (eg, injection drug use, psychiatric and social comorbidities) that reduce compliance and so shorter treatments might be easier to give; reduced treatment durations could make depot preparations possible to allow single-shot treatments for such individuals. Kohli and colleagues7 show that HCV clearance with 6 weeks of treatment is possible and, with high response rates seen when sofosbuvir and ledipasvir were combined with either a non-nucleoside or a protease inhibitor, the nature of the third drug seems to be unimportant. However, the study was relatively small (20 patients per group), sequentially assigned rather than randomised, and the conclusions are therefore far from robust. Patients with cirrhosis were excluded from the short-duration groups and it is not clear whether very short treatments can be used in such patients— studies of sofosbuvir and non-sofosbuvir regimens comparing 12 weeks of treatment and 24 weeks of treatment in patients with cirrhosis suggest that extension of the duration of the regimen might have some benefits, although these were significant only in some subsets of patients.8,9 The duration of HCV treatment is often established through assessment of the rate of virological response,10 necessitating early assessment of HCV RNA. Kohli and colleagues’ findings7 indicate that the rate of viral response might be slightly faster in patients receiving triple therapy, with kinetic modelling showing fitted HCV RNA concentrations significantly lower at days 7, 14, and 21 in patients receiving sofosbuvir, ledipasvir, and GS-9451, which could assist in future modelling studies to optimise treatment duration. An unexpected finding was that six patients with very low viraemia at the end of treatment went on to achieve SVR12. The mechanism underlying this paradoxical outcome will no doubt provoke heated debate and experimentation among virologists. Hepatitis C is prone to the rapid development of drug resistance11 and short durations of therapy that might be ineffective are a concern. It is reassuring that resistance was not an issue in this study, but one patient who failed to respond had post-treatment
www.thelancet.com Published online January 13, 2015 http://dx.doi.org/10.1016/S0140-6736(14)61600-7
Ramon Andrade 3DCIENCIA/Science Photo Library
Shorter treatments for hepatitis C: another step forward?
Published Online January 13, 2015 http://dx.doi.org/10.1016/ S0140-6736(14)61600-7 See Online/Articles http://dx.doi.org/10.1016/ S0140-6736(14)61228-9
1
Comment
virological variants associated with reduced responses to NS5A inhibitors. The importance of these polymorphisms is unclear, but vigilance will be needed in future studies to avoid long-term drug resistance. Treatment for HCV has quickly moved from poorly tolerated interferon-based therapies to extraordinarily effective, side-effect-free drug combinations that cure almost all compliant patients. The demonstration that even shorter durations of treatment could be effective should lead to larger trials of potent drug combinations combined with sofosbuvir for very short periods. It remains unclear whether other highresistance-barrier drugs will also work in shorter treatment durations, but it is unlikely that the effects will be limited to sofosbuvir. Current data comparing 12 weeks and 24 weeks of treatment9 suggest that patients with cirrhosis might be poor candidates for short duration therapies, although randomised trials addressing this issue have not been done; those tempted to delay introduction of treatment to patients without evidence of advanced disease would be advised to consider the costs of delaying therapy until severe disease has developed. Despite the progress that has been made, early identification and treatment of patients before they have developed cirrhosis must remain the priority.
2
Graham R Foster The Blizard Institute, Queen Mary’s University of London, London E1 2AT, UK [email protected] I have received personal fees from AbbVie, Boehringer Igelheim, BMS, Merck, Novartis, and Janssen; grants and personal fees from Roche and Gilead; and grants from Springbank. 1
2 3 4 5
6
7
8 9 10
11
Razavi H, Waked I, Sarrazin C, et al. The present and future disease burden of hepatitis C virus (HCV) infection with today’s treatment paradigm. J Viral Hepat 2014; 21 (suppl 1): 34–59. D’Souza R, Foster GR. Diagnosis and treatment of hepatitis C. J R Soc Med 2004; 97: 223–25. Kowdley KV, Lawitz E, Poordad F, et al. Phase 2b trial of interferon-free therapy for hepatitis C virus genotype 1. N Engl J Med 2014; 370: 222–32. 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. Lawitz E, Sulkowski MS, Ghalib R, et al. Simeprevir plus sofosbuvir, with or without ribavirin, to treat chronic infection with hepatitis C virus genotype 1 in non-responders to pegylated interferon and ribavirin and treatment-naive patients: the COSMOS randomised study. Lancet 2014; 384: 1756–65. Gane EJ, Stedman CA, Hyland RH, et al. Efficacy of nucleotide polymerase inhibitor sofosbuvir plus the NS5A inhibitor ledipasvir or the NS5B non-nucleoside inhibitor GS-9669 against HCV genotype 1 infection. Gastroenterology 2014; 146: 736–43. Kohli A, Osinusi A, Sims Z, et al. Virological response after 6 week triple-drug regimens for hepatitis C: a proof-of-concept phase 2A cohort study. Lancet 2014; published online Jan 13. http://dx.doi.org/10.1016/ S0140-6736(14)61228-9. Poordad F, Hezode C, Trinh R, et al. ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis. N Engl J Med 2014; 370: 1973–82. 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. Ferenci P. Response guided therapy in patients with chronic hepatitis C—yesterday, today and tomorrow. Best Pract Res Clin Gastroenterol 2012; 26: 463–69. Sarrazin C, Kieffer TL, Bartels D, et al. Dynamic hepatitis C virus genotypic and phenotypic changes in patients treated with the protease inhibitor telaprevir. Gastroenterology 2007; 132: 1767–77.
www.thelancet.com Published online January 13, 2015 http://dx.doi.org/10.1016/S0140-6736(14)61600-7
Worldwide mortality from hepatitis C virus (HCV) infection is rising and, without increases in the number of individuals who are successfully treated, rates are predicted to rise further.1 A response to therapy (undetectable viraemia 12 weeks after treatment ends) reduces disease progression, but therapy has long involved unpalatable interferon and ribavirin regimens given for 6 months, with extended durations for some genotypes (eg, genotype 1).2 Given the side-effects of interferon, long treatment duration, and low response rates (ie, less than 80%) most patients choose to defer therapy. However, new oral drug combinations that have higher than 90% response rates and few side-effects have encouraged patients and their doctors to reconsider therapy. For patients with genotype 1 HCV infection, two strategies have emerged—one involves combinations of at least three potent, low-resistance-barrier drugs (a protease, an NS5A inhibitor, and a non-nucleoside inhibitor)3 and the other uses the high-resistance-barrier nucleotide sofosbuvir, with either an NS5A inhibitor (such as ledipasvir) or a protease inhibitor (simeprevir).4,5 For the triple, non-nucleotide regimen, therapy for 12 weeks is needed,3 but for sofosbuvir and ledipasvir, 8 weeks is sufficient for patients without cirrhosis,4 although 6 weeks of therapy is less effective.6 Ribavirin is a weak antiviral drug that might improve response rates but adds side-effects; researchers increasingly avoid it. In The Lancet, Anita Kohli and colleagues7 report results from a ribavirin-free, single-centre, open-label, phase 2A study of sofosbuvir and ledipasvir combinations that include either the non-nucleoside inhibitor GS-9669 or the protease inhibitor GS-9451. 20 patients per treatment group were allocated to 12 weeks of sofosbuvir and ledipasvir, 6 weeks of sofosbuvir and ledipasvir plus GS-9669, or 6 weeks of sofosbuvir and ledipasvir plus GS-9451. All patients allocated to receive sofosbuvir and ledipasvir for 12 weeks achieved a sustained virological response at 12 weeks (SVR12), and 19 of 20 patients in each of the triple-therapy groups had SVR12 in a rigid intention-to-treat analysis. The triple-therapy combinations seemed to allow even shorter treatment regimens, with most patients achieving SVR after only 6 weeks of treatment. One of the many questions posed by the study is the value of
such regimens—8 weeks of therapy is acceptable and a reduction to 6 weeks might be of little value. However, many patients with HCV have continuing comorbidities (eg, injection drug use, psychiatric and social comorbidities) that reduce compliance and so shorter treatments might be easier to give; reduced treatment durations could make depot preparations possible to allow single-shot treatments for such individuals. Kohli and colleagues7 show that HCV clearance with 6 weeks of treatment is possible and, with high response rates seen when sofosbuvir and ledipasvir were combined with either a non-nucleoside or a protease inhibitor, the nature of the third drug seems to be unimportant. However, the study was relatively small (20 patients per group), sequentially assigned rather than randomised, and the conclusions are therefore far from robust. Patients with cirrhosis were excluded from the short-duration groups and it is not clear whether very short treatments can be used in such patients— studies of sofosbuvir and non-sofosbuvir regimens comparing 12 weeks of treatment and 24 weeks of treatment in patients with cirrhosis suggest that extension of the duration of the regimen might have some benefits, although these were significant only in some subsets of patients.8,9 The duration of HCV treatment is often established through assessment of the rate of virological response,10 necessitating early assessment of HCV RNA. Kohli and colleagues’ findings7 indicate that the rate of viral response might be slightly faster in patients receiving triple therapy, with kinetic modelling showing fitted HCV RNA concentrations significantly lower at days 7, 14, and 21 in patients receiving sofosbuvir, ledipasvir, and GS-9451, which could assist in future modelling studies to optimise treatment duration. An unexpected finding was that six patients with very low viraemia at the end of treatment went on to achieve SVR12. The mechanism underlying this paradoxical outcome will no doubt provoke heated debate and experimentation among virologists. Hepatitis C is prone to the rapid development of drug resistance11 and short durations of therapy that might be ineffective are a concern. It is reassuring that resistance was not an issue in this study, but one patient who failed to respond had post-treatment
www.thelancet.com Published online January 13, 2015 http://dx.doi.org/10.1016/S0140-6736(14)61600-7
Ramon Andrade 3DCIENCIA/Science Photo Library
Shorter treatments for hepatitis C: another step forward?
Published Online January 13, 2015 http://dx.doi.org/10.1016/ S0140-6736(14)61600-7 See Online/Articles http://dx.doi.org/10.1016/ S0140-6736(14)61228-9
1
Comment
virological variants associated with reduced responses to NS5A inhibitors. The importance of these polymorphisms is unclear, but vigilance will be needed in future studies to avoid long-term drug resistance. Treatment for HCV has quickly moved from poorly tolerated interferon-based therapies to extraordinarily effective, side-effect-free drug combinations that cure almost all compliant patients. The demonstration that even shorter durations of treatment could be effective should lead to larger trials of potent drug combinations combined with sofosbuvir for very short periods. It remains unclear whether other highresistance-barrier drugs will also work in shorter treatment durations, but it is unlikely that the effects will be limited to sofosbuvir. Current data comparing 12 weeks and 24 weeks of treatment9 suggest that patients with cirrhosis might be poor candidates for short duration therapies, although randomised trials addressing this issue have not been done; those tempted to delay introduction of treatment to patients without evidence of advanced disease would be advised to consider the costs of delaying therapy until severe disease has developed. Despite the progress that has been made, early identification and treatment of patients before they have developed cirrhosis must remain the priority.
2
Graham R Foster The Blizard Institute, Queen Mary’s University of London, London E1 2AT, UK [email protected] I have received personal fees from AbbVie, Boehringer Igelheim, BMS, Merck, Novartis, and Janssen; grants and personal fees from Roche and Gilead; and grants from Springbank. 1
2 3 4 5
6
7
8 9 10
11
Razavi H, Waked I, Sarrazin C, et al. The present and future disease burden of hepatitis C virus (HCV) infection with today’s treatment paradigm. J Viral Hepat 2014; 21 (suppl 1): 34–59. D’Souza R, Foster GR. Diagnosis and treatment of hepatitis C. J R Soc Med 2004; 97: 223–25. Kowdley KV, Lawitz E, Poordad F, et al. Phase 2b trial of interferon-free therapy for hepatitis C virus genotype 1. N Engl J Med 2014; 370: 222–32. 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. Lawitz E, Sulkowski MS, Ghalib R, et al. Simeprevir plus sofosbuvir, with or without ribavirin, to treat chronic infection with hepatitis C virus genotype 1 in non-responders to pegylated interferon and ribavirin and treatment-naive patients: the COSMOS randomised study. Lancet 2014; 384: 1756–65. Gane EJ, Stedman CA, Hyland RH, et al. Efficacy of nucleotide polymerase inhibitor sofosbuvir plus the NS5A inhibitor ledipasvir or the NS5B non-nucleoside inhibitor GS-9669 against HCV genotype 1 infection. Gastroenterology 2014; 146: 736–43. Kohli A, Osinusi A, Sims Z, et al. Virological response after 6 week triple-drug regimens for hepatitis C: a proof-of-concept phase 2A cohort study. Lancet 2014; published online Jan 13. http://dx.doi.org/10.1016/ S0140-6736(14)61228-9. Poordad F, Hezode C, Trinh R, et al. ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis. N Engl J Med 2014; 370: 1973–82. 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. Ferenci P. Response guided therapy in patients with chronic hepatitis C—yesterday, today and tomorrow. Best Pract Res Clin Gastroenterol 2012; 26: 463–69. Sarrazin C, Kieffer TL, Bartels D, et al. Dynamic hepatitis C virus genotypic and phenotypic changes in patients treated with the protease inhibitor telaprevir. Gastroenterology 2007; 132: 1767–77.
www.thelancet.com Published online January 13, 2015 http://dx.doi.org/10.1016/S0140-6736(14)61600-7
