What to do when DAA treatment fails

Chronic hepatitis C infection (HCV) is a major public health problem affecting more than 71 million patients worldwide including more than 3.5 million patients in the United States.1 With the introduction of direct acting antiviral agents (DAAs), it is now possible to cure hepatitis C infection even in patients with advanced fibrosis, cirrhosis and HCV / HIV co-infection. In addition, current regimens are significantly better tolerated with higher rates of response and minimal adverse effects as compared to older interferon-based regimens. Four main classes of DAAs targeting hepatitis C virus replication are available and have proven highly effective in eradication of hepatitis C infection: NS5A inhibitors (ledipasvir, ombitasvir, daclatasvir, elbasvir, velpatasvir, pibrentasvir), nucleoside NS5B polymerase inhibitors (sofosbuvir), non-nucleoside NS5B polymerase inhibitors (dasabuvir), and NS3/4A protease inhibitors (simeprevir, bocepevir, teleprevir, paritaprevir, grazoprevir, glecaprevir). Combination therapies with these agents have been shown to improve efficacy and prevent emergence of HCV resistance associated substitutions (RASs).2

DAA regimens to treat HCV have shown high sustained virologic response rates (SVR) approaching 98 percent in various real-world cohorts. However, treatment may be unsuccessful in a small number of patients. The most common cause of virologic failure is relapse which is defined as undetectable HCV RNA at the end of treatment followed by a rebound once antiviral therapy is discontinued. Very few patients fail via virologic breakthrough on treatment. Treatment failure although infrequent, has been associated with development of RASs.3 An integrated analysis of approximately 2,100 patients treated with sofosbuvir / ledipasvir showed that virological failure occurred in 2.4 percent of patients. NS5A RASs were present in 74 percent of patients who relapsed. RASs were detected at several positions: M28T, Q30R, H58D and Y93H.4 Recent studies have demonstrated that newer DAA combinations are effective for treatment-experienced patients.5,6 An overview of retreatment options for treatment experienced patients is summarized in the table below.

Table 1. Retreatment options for Hepatitis C after DAA’s failure.

NS3 protease inhibitors [PIs] (teleprevir, boceprevir or simeprevir) + peg-interferon / ribavirin experienced patients

Multiple treatment regimens are available for patients who relapsed after treatment with first generation PI’s (telepravir, boceprevir or simeprevir) and interferon. The current recommended regimens for HCV GT-1 patients without cirrhosis includes ledipasvir / sofosbuvir for 12 weeks, sofosbuvir / velpatasvir for 12 weeks or glevaprevir / pibrentasvir for 12 weeks. SVR rates were with the 12-week ledipasvir / sofosbuvir, 12- week sofosbuvir / velpatasvir and 12-week glecaprevir / pibrentasvir were 94 percent, 100 percent and 92 percent respectively.7

NS5B inhibitors + ribavirin experienced patients

Sofosbuvir plus ribavirin is no longer used for HCV patients because of suboptimal response. However, it was a viable option in the past especially for treatment naïve GT-2 and GT-3 patients. The recommended regimens available for this group of patients includes sofosbuvir / velpatasvir / voxilaprevir for 12 weeks, glecaprevir / pibrentasvir for 12 weeks or sofosbuvir / velpatasvir for 12 weeks.5,6

NS5A inhibitors experienced patients

The ledipasvir / sofosbuvir combination is now widely used and has high SVR rates. However, patients with advanced liver disease, including cirrhosis and multiple comorbid conditions, have relatively low SVR rates. The recommended regimens for these patients are sofosbuvir / velpatasvir / voxilaprevir for 12 weeks or glecaprevir / pibrentasvir for 16 weeks. However, the glecaprevir / pibrentasvir regimen is not recommended in patients who relapsed after treatment with second generation NS3/4A PI’s (e.g, grazoprevir) patients with hepatic impairment (Child-Pugh class B and C cirrhosis).5

Discussion

Retreatment options after DAA failure in patients with HCV depends on multiple factors including causes of treatment failure, prior regimen used, presence of baseline RASs, comorbid conditions and severity of liver disease. Patients who have relapsed after peg-interferon and ribavirin can be retreated with any current DAA regimen. Patients who have relapsed after a regimen including a first-generation PI (telaprevir, boceprevir, simeprevir) should generally not be retreated with a DAA regimen that contains a PI. The best option for retreatment for such patients is a DAA regimen that contains an NS5A inhibitor (e.g, ledipasvir, velpatasvir) and NS5B inhibitor (e.g, sofosbuvir). However, a second-generation PI (grazoprevir, glecaprevir) may be used in prior PI failures. RASs related to NS5A inhibitors persist over time and have an impact on the choice and efficacy of future treatment as compared to NS5B RASs, which will disappear after few weeks or months. Presence of the Q80K substitution in the NS3 protease is associated with a reduced SVR rate in HCV GT 1a patients especially with cirrhosis and relapse after pegylated interferon based treatment.8 The glecaprevir / pibrentasvir regimen is not recommended in patients who relapsed after a second generation NS3/4A PI (e.g., grazoprevir) combination regimen and also those with hepatic impairment (Child-Pugh class B and C cirrhosis). Treatment experienced (except HCV GT-3) patients following a sofosbuvir containing regimen (but not NS3/4A PI or NS5A inhibitor) and without cirrhosis can be treated with an eight week course of glecaprevir / pibrentasvir.5 For patients previously treated with an NS5A inhibitor-containing regimen, the best available option is the recently approved triple drug combination of velpatasvir, sofosbuvir and voxilaprevir.6 In summary, retreatment strategies with salvage regimens including sofosbuvir / velpatasvir / voxilaprevir and glecaprevir / pibrentasvir can lead to SVR in most patients who did not achieve SVR with previous DAA regimens, including those with NS5A RASs.

Dr. Kowdley is a consultant or part of the advisory board for AbbVie, Allergan, Arena, Conatus, Corcept, Dova, Gilead, Intercept, Mavupharma, Merck, Trio Health and Verlyx. He is part of AbbVie, Gilead and Intercept’s speaker’s bureau. Dr. Kowdley sits on the editorial board of Annals of Hepatology, and Hepatology Communications.

Dr. Jhaveri is a member of AACP, AMA, APHA and AASLD.

References

1. Gower, E., Estes, C., Blach, S., Razavi-Shearer, K., Razavi, H. Global epidemiology and genotype distribution of the hepatitis C virus infection. J Hepatol. 2014;61(1 Suppl):S45-57.
2. Bartenschlager, R., Lohmann, V., Penin, F. The molecular and structural basis of advanced antiviral therapy for hepatitis C virus infection. Nat Rev Microbiol. 2013;11(7):482-496.
3. Poveda, E., Wyles, D.L., Mena, A., Pedreira, J.D., Castro-Iglesias, A., Cachay, E. Update on hepatitis C virus resistance to direct-acting antiviral agents. Gastrointest Endosc. Antiviral Res. 2014;108:181-191.
4. Wyles, D., Pockros, P., Morelli, G. et al, Ledipasvirsofosbuvir plus ribavirin for patients with genotype 1 hepatitis C virus previously treated in clinical trials of sofosbuvir regimens. Hepatology. 2015;61(6):1793-1797.
5. Asselah, T., Kowdley, K.V., Zadeikis, N. et al, Efficacy of Glecaprevir/Pibrentasvir for 8 or 12 Weeks in Patients With Hepatitis C Virus Genotype 2, 4, 5, or 6 Infection Without Cirrhosis. Clin Gastroenterol Hepatol. 2018;16(3):417-426.
6. Bourliere, M., Gordon, S.C., Flamm, S.L. et al, Sofosbuvir, Velpatasvir, and Voxilaprevir for Previously Treated HCV Infection. N Engl J Med. 2017;376(22):2134-2146.
7. Afdhal, N., Reddy, K.R., Nelson, D.R. et al, Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med. 2014;370(16):1483-1493.
8. Sarrazin, C., Lathouwers, E., Peeters, M. et al, Prevalence of the hepatitis C virus NS3 polymorphism Q80K in genotype 1 patients in the European region. Antiviral Res. 2015;116:10-16.

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