Not that in North America we have seen Dacla (a NS5A) and Asunaprevir (a NS3/4A) being used as a double, but in Japan they have made use of this double. Multiple Japanese studies have fairly recently been coming out about the prevalent use of this combo and various notes they are making about it.
This study was interesting, in various ways, but I especially liked it because, even if we are not doing this particular double over here, the study lends support to the concept that thorough/repeated/prolonged VL testing beyond SVR12 and even beyond SVR 24 is a good important thing (even if late failures after SVR 24 is such a very rare thing)!
Journal of Viral Hepatitis
Late Relapse of Hepatitis C Virus in Patients With Sustained Virological Response After Daclatasvir and Asunaprevir Therapy
The optimal term of follow-up for patients who achieve sustained virological responses (SVR) is an important topic because of the widespread use of direct-acting antivirals (DAA), which achieve a high SVR rate. Investigations of long-term follow-up among patients with SVR after interferon (IFN) therapy have reported that approximately 80%-100% of patients maintained SVR. However, the long-term durability of SVR to DAA treatment is unknown. The aim of this study was to evaluate the incidence of late relapse in patients who achieved SVR with daclatasvir (DCV) and asunaprevir (ASV).
... Four hundred and thirteen patients infected with hepatitis C virus (HCV) genotype 1b who completed ASV and DCV treatment and achieved SVR were selected. Patients who were persistently negative for serum HCV RNA at 24 weeks after withdrawal of DCV and ASV were considered to have SVR24. Mean follow-up period was 21.5 months (range, 4.8-30.3 months) after SVR24. Four patients redeveloped HCV RNA in serum at 6, 12, 12 and 26 months, respectively, after achieving SVR24 ...
Results of molecular analysis by phylogenetic tree of HCV nonstructural protein 3 and 5A regions from late relapse indicated that the same strain was present at pretreatment and late relapse. In conclusion, late relapse by the original HCV strain was confirmed by direct sequencing in 4 of 413 patients with SVR to ASV and DCV. Although a few patients may develop late relapse, SVR achieved with all oral DAA therapy is as durable as that with IFN therapy.
Discussion
Late relapse of HCV refers to detection of HCV RNA in serum after determination of SVR and has only been reported from studies with IFN-based therapy. The long-term durability of SVR with all oral direct-acting antivirals (DAA) treatment needs to be evaluated. DAA as well as IFN could achieve SVR, but DAA therapy directly acts on HCV eradication, whereas IFN therapy uses the immune system to eradicate HCV. The impacts of each agent on immune status may not be similar. Thus, several differences exist between the effect of DAA and IFN in terms of the clinical course such as incidence of HCC and HBV reactivation during and after eradication of HCV.[9-13] Whether DAA therapy causes late relapse to the same extent as IFN therapy is unknown and needs careful evaluation of late relapse rate in patients who achieved SVR by DAA. Sarrazin investigated late relapse after SVR12 by DAA therapy and found that five patients had detectable HCV RNA between SVR12 and SVR24.[14] Our study observed longer follow-up period (mean 21.5 months) after SVR24 and found four patients with late relapse by DAA therapy, as confirmed by direct sequencing analysis. Rates of late relapse with DAA therapy thus appear similar to those with IFN-based therapy. Late relapse is a rare eventthat occurs within 26 months after SVR. In the meantime, our result indicates that successful HCV eradication needs to be reconfirmed up to at least 26 months after SVR. The mechanism of late relapse is still unknown. HCV RNA is undetectable in serum but small quantities of virus persist in hepatocytes or lymphocytes and macrophages.[15] We speculated that these persistence of HCV allows for the possibility of late relapse. However, it remains unclear why reappearance of HCV occurs in patients without immunocompromised status. To accurately distinguish late relapse from reinfection in SVR patients, we performed direct sequencing of HCV NS3 and NS5A regions and phylogenetic analyses at pretreatment and at the time of reappearance of HCV. HCV relapse by the presence of the original strain was confirmed by direct sequencing and phylogenetic analyses of both NS3 and NS5A regions. Reinfection found in high-risk populations such as PWID could be supported by this analysis, but there are limitations in some cases.[16] Patients in special populations may become reinfected by the initial source and differentiating late relapse from reinfection from the initial source is difficult. None of the four late-relapse cases lacked reinfection risk factors. Reinfection from the initial source could be excluded using this clinical information. However, three of four cases had acquired RAS at the time of late relapse. Late relapse would be able to be clearly defined when emergence of RAS is identified at HCV recurrence. The mechanism of late relapse is unknown and investigation of the patterns of RAS emergence may help elucidate the processes by which late relapse of HCV arises. RAS that emerged at the time of late relapse in cases without RAS at baseline were NS3-D168, NS5A-L31 and NS5A-Y93, which have frequently been reported in relapse and breakthrough cases.[2,3] This emergence pattern of RAS was not unique and resembled that seen in the majority of relapse and breakthrough cases. However, one case with RAS at baseline did not acquire these triple RAS at the time of late relapse. Pre-existing RAS contributed more significantly to appearance of new RAS than wild-type strain at virologic failure[17] and this emergence pattern of RAS would be unique. This case showed late relapse at 26 months after SVR, but the other cases which showed emergence of the triple RAS represented late relapse within 12 months after SVR. RAS could impact variant replicative fitness and the long-term dynamics of viral RNA suppression. These RAS have effects on replication rate that might influence the timing of relapse. We thus speculated that these different patterns of RAS acquisition would impact virologic treatment failure. The small number of patients examined prevented identification of statistical correlations between RAS and late relapse. The relevance of pre-existing RAS to the occurrence of late relapse to DAA therapies remains unclear and requires further study.
Identification of factors predicting late relapse is likely to prove useful in reducing the costs and efforts associated with long-term follow-up. Comparison of NS3 and NS5A regions between SVR and late relapse was performed, and NS3-150, NS5A-153 and NS5A-183 are candidate predictors of the risk of late relapse. However, the small number of patients with late relapse greatly limited the statistical power of this comparison. Further studies of the long-term durability of SVR by DAA treatment are needed to overcome this limitation.
In conclusion, although a small proportion of patients will develop a late relapse, SVR by ASV and DCV therapy is usually maintained.
Not that in North America we have seen Dacla (a NS5A) and Asunaprevir (a NS3/4A) being used as a double, but in Japan they have made use of this double. Multiple Japanese studies have fairly recently been coming out about the prevalent use of this combo and various notes they are making about it.
This study was interesting, in various ways, but I especially liked it because, even if we are not doing this particular double over here, the study lends support to the concept that thorough/repeated/prolonged VL testing beyond SVR12 and even beyond SVR 24 is a good important thing (even if late failures after SVR 24 is such a very rare thing)!
Late Relapse of Hepatitis C Virus in Patients With Sustained Virological Response After Daclatasvir and Asunaprevir Therapy
Kazuhiko Hayashi; Masatoshi Ishigami; Yoji Ishizu; Teiji Kuzuya; Takashi Honda; Yoshiki Hirooka; Hidenori Toyoda; Takashi Kumada; Masashi Hattori; Yoshiaki Katano; Hidemi Goto
DISCLOSURES
J Viral Hepat. 2018;25(12):1446-1451.
(Excerpts)
Abstract
The optimal term of follow-up for patients who achieve sustained virological responses (SVR) is an important topic because of the widespread use of direct-acting antivirals (DAA), which achieve a high SVR rate. Investigations of long-term follow-up among patients with SVR after interferon (IFN) therapy have reported that approximately 80%-100% of patients maintained SVR. However, the long-term durability of SVR to DAA treatment is unknown. The aim of this study was to evaluate the incidence of late relapse in patients who achieved SVR with daclatasvir (DCV) and asunaprevir (ASV).
... Four hundred and thirteen patients infected with hepatitis C virus (HCV) genotype 1b who completed ASV and DCV treatment and achieved SVR were selected. Patients who were persistently negative for serum HCV RNA at 24 weeks after withdrawal of DCV and ASV were considered to have SVR24. Mean follow-up period was 21.5 months (range, 4.8-30.3 months) after SVR24. Four patients redeveloped HCV RNA in serum at 6, 12, 12 and 26 months, respectively, after achieving SVR24 ...
Results of molecular analysis by phylogenetic tree of HCV nonstructural protein 3 and 5A regions from late relapse indicated that the same strain was present at pretreatment and late relapse. In conclusion, late relapse by the original HCV strain was confirmed by direct sequencing in 4 of 413 patients with SVR to ASV and DCV. Although a few patients may develop late relapse, SVR achieved with all oral DAA therapy is as durable as that with IFN therapy.
Discussion
Late relapse of HCV refers to detection of HCV RNA in serum after determination of SVR and has only been reported from studies with IFN-based therapy. The long-term durability of SVR with all oral direct-acting antivirals (DAA) treatment needs to be evaluated. DAA as well as IFN could achieve SVR, but DAA therapy directly acts on HCV eradication, whereas IFN therapy uses the immune system to eradicate HCV. The impacts of each agent on immune status may not be similar. Thus, several differences exist between the effect of DAA and IFN in terms of the clinical course such as incidence of HCC and HBV reactivation during and after eradication of HCV.[9-13] Whether DAA therapy causes late relapse to the same extent as IFN therapy is unknown and needs careful evaluation of late relapse rate in patients who achieved SVR by DAA. Sarrazin investigated late relapse after SVR12 by DAA therapy and found that five patients had detectable HCV RNA between SVR12 and SVR24.[14] Our study observed longer follow-up period (mean 21.5 months) after SVR24 and found four patients with late relapse by DAA therapy, as confirmed by direct sequencing analysis. Rates of late relapse with DAA therapy thus appear similar to those with IFN-based therapy. Late relapse is a rare event that occurs within 26 months after SVR. In the meantime, our result indicates that successful HCV eradication needs to be reconfirmed up to at least 26 months after SVR. The mechanism of late relapse is still unknown. HCV RNA is undetectable in serum but small quantities of virus persist in hepatocytes or lymphocytes and macrophages.[15] We speculated that these persistence of HCV allows for the possibility of late relapse. However, it remains unclear why reappearance of HCV occurs in patients without immunocompromised status. To accurately distinguish late relapse from reinfection in SVR patients, we performed direct sequencing of HCV NS3 and NS5A regions and phylogenetic analyses at pretreatment and at the time of reappearance of HCV. HCV relapse by the presence of the original strain was confirmed by direct sequencing and phylogenetic analyses of both NS3 and NS5A regions. Reinfection found in high-risk populations such as PWID could be supported by this analysis, but there are limitations in some cases.[16] Patients in special populations may become reinfected by the initial source and differentiating late relapse from reinfection from the initial source is difficult. None of the four late-relapse cases lacked reinfection risk factors. Reinfection from the initial source could be excluded using this clinical information. However, three of four cases had acquired RAS at the time of late relapse. Late relapse would be able to be clearly defined when emergence of RAS is identified at HCV recurrence. The mechanism of late relapse is unknown and investigation of the patterns of RAS emergence may help elucidate the processes by which late relapse of HCV arises. RAS that emerged at the time of late relapse in cases without RAS at baseline were NS3-D168, NS5A-L31 and NS5A-Y93, which have frequently been reported in relapse and breakthrough cases.[2,3] This emergence pattern of RAS was not unique and resembled that seen in the majority of relapse and breakthrough cases. However, one case with RAS at baseline did not acquire these triple RAS at the time of late relapse. Pre-existing RAS contributed more significantly to appearance of new RAS than wild-type strain at virologic failure[17] and this emergence pattern of RAS would be unique. This case showed late relapse at 26 months after SVR, but the other cases which showed emergence of the triple RAS represented late relapse within 12 months after SVR. RAS could impact variant replicative fitness and the long-term dynamics of viral RNA suppression. These RAS have effects on replication rate that might influence the timing of relapse. We thus speculated that these different patterns of RAS acquisition would impact virologic treatment failure. The small number of patients examined prevented identification of statistical correlations between RAS and late relapse. The relevance of pre-existing RAS to the occurrence of late relapse to DAA therapies remains unclear and requires further study.
Identification of factors predicting late relapse is likely to prove useful in reducing the costs and efforts associated with long-term follow-up. Comparison of NS3 and NS5A regions between SVR and late relapse was performed, and NS3-150, NS5A-153 and NS5A-183 are candidate predictors of the risk of late relapse. However, the small number of patients with late relapse greatly limited the statistical power of this comparison. Further studies of the long-term durability of SVR by DAA treatment are needed to overcome this limitation.
In conclusion, although a small proportion of patients will develop a late relapse, SVR by ASV and DCV therapy is usually maintained.