Hepatitis C Late Relapse in Patients With Directly Acting Antiviral-related Sustained Virological Response at Week 12

Mariantonietta Pisaturo; Carmine Minichini; Mario Starace; Mara Caroprese; Margherita Macera; Giuseppina Brancaccio; Stefania De Pascalis; Antonella Santonicola; Alfonso Galeota Lanza; Rosa Zampino; Gaetano Cotticelli; Evangelista Sagnelli; Giovanni Battista Gaeta; Nicola Coppola


Liver International. 2019;39(5):844-853. 

In This Article


Few data are available in the literature from real-life studies on the patients with DAA failure, and an exhaustive description of the clinical characteristics of these patients is still largely lacking. The present real-life study showed that a DAA failure was observed in about 4% of 3259 patients treated with DAA regimen; we underlined that 35% of failed patients were treated with a non-active or suboptimal DAA regimen against HCV genotype. Moreover, our study demonstrated that most HCV patients who failed DAA therapy experienced a virological relapse, but a late relapse was observed only in 7 (0.2% of all DAA-treated patients).

The durability of the virological response is a key issue in the management of patients with an SVR. In the interferon era, when the SVR was defined as HCV-RNA negativity at week 24 after stopping treatment, a late relapse was described as very low. The cumulative data of eight studies of interferon treatment for chronic hepatitis C showed a late relapse rate of 4.7% (95% confidence interval [CI] 2.0-7.4) in 286 patients with an SVR.[18]

In the DAA era, SVR12 is used as a surrogate of SVR24 with a concordance of at least 99.5%.[19,20]

However, Sarrazin et al[12] evaluating 12 patients with a late relapse (at week 24 after stopping sofosbuvir and ledipasvir therapy) found by phylogenetic analyses of the NS5B region that five patients had minimal genetic changes between baseline and post-treatment sequences, suggesting a true late relapse; for the other seven patients, the virus identified at baseline was significantly unrelated to that present at the late relapse, suggesting a re-infection.

The identification of a re-infection has important implications for the choice of optimal retreatment strategies, since it is potentially simpler to treat owing to the lack of exposure of the current viral quasispecies to therapy, whereas virological relapse cases may have selected viral variants with reduced susceptibility. Re-infection is a particular concern in patients with ongoing high-risk behaviours, such as injecting drug users, patients with HIV coinfection and men who have sex with men.[21,22] In a retrospective analysis of the NEAT network, the HCV re-infection incidence was 7.3/100 persons-year (95% CI 6.2-8.6) in 606 HIV-positive men who have sex with men (MSM) who cleared HCV spontaneously or after successful treatment.[26] In a large French AIDS cohort on 3406 patients, HCV re-infections occurred in 73 with an incidence of 2.52%-2.90% patients-year.[27] In a large population-based cohort (British Columbia Hepatitis Testers Cohort) enrolling 4114 individuals, 40 subjects experienced an HCV re-infection.[28] Finally, of great interest were the results of a meta-analysis evaluating the risk of late relapse or HCV re-infection after achieving a sustained virological response: in the 43 studies evaluating 7969 HCV-monoinfected patients, the pooled recurrence rate was 1.85/1000 events/person per year of follow-up (PYFU; 95% confidence interval [CI]: 71-3.35); in the 14 studies evaluating 771 HCV-monoinfected "high-risk" patients (intravenous drug users or prisoners), the pooled recurrence rate was 22.32/1000 PYFU (95% CI, 13.07-33.46); in the four studies evaluating 309 HIV/HCV coinfected patients, the pooled recurrence rate was 32.02/1000 PYFU (95% CI, 0.00-123.49).[29]

In our study in the two of the seven patients with a late relapse for whom a serum sample collected at baseline was available, the phylogenetic analysis of the NS3, NS5A and NS5b regions demonstrated the presence of the same virus, indicating a true late relapse. For four patients, since all harboured the same genotype before and after DAA failure and none was at a high risk for re-infection, a re-infection seems improbable, but cannot be excluded. Moreover, our population was at low probability of re-infection, since the presumed duration of HCV infection was very long (at least 12 years). Instead, patient #6 harboured different HCV 1 subgenotypes (1b and 1a respectively) before the start of the DAA regimen and at relapse; therefore, in this case, we can hypothesize a re-infection with another subgenotype of HCV, although an erroneous identification of the HCV subgenotype before the start of DAA may also be possible.[17]

The clinical significance of a late relapse remains unclear; it suggested that some patients thought to have achieved an SVR may still harbour HCV. In some studies, despite serum HCV-RNA negativity after interferon treatment, patients may occasionally present low levels of detectable virus in the liver tissue during a follow-up period of 1-2 years after the end of treatment,[30,31] a condition that has been demonstrated to be a predictor of a later recurrence of HCV infection.[32] Moreover, it has previously been shown that HCV-RNA can persist after the achievement of an SVR;[33] small amounts of HCV-RNA (<15 IU/mL) can be found in circulation after an SVR is reached. In another report, HCV sequences could be detected in the liver in 2% of patients with an SVR.[34]

Another important issue is that HCV is not a strictly hepatotropic virus, and there is evidence that it can also replicate in peripheral blood mononuclear cells (PBMCs).[35] Persistence of extrahepatic sites of HCV replication could potentially play a role in late recurrence after treatment. Radkowski et al[36] showed that in patients with SVR after therapy, small quantities of HCV-RNA could persist in the liver or macrophages and lymphocytes for up to 9 years, and this continuous viral presence could result in a persistence of humoral and cellular immunity for many years after therapy and could present a potential risk for a late relapse. The findings of the continuing presence of HCV-RNA years after successful antiviral treatment are compatible with findings by Pham et al,[37] who were able to amplify viral sequences from follow-up sera or PBMC in 11 of 11 SVR patients for up to 5 years after therapy.

This study has some limitations. First, as a real-life study we did not exclude that some patients with DAA failure had dropped out. Second, the unavailability of a serum collected before the DAA regimen and thus a re-infection cannot be excluded in five of the seven patients with a late relapse. Third, a conclusion on the management of patients with SVR12 may be reached analysing a more extensive cohort.

In conclusion, our real-life study demonstrates that a late relapse may occur in patients who had obtained an SVR12 with DAA treatment. This is in good agreement with the data recently published by Sarrazin et al[12] but partially disagrees with the indication of the international guidelines[38] suggesting a post-treatment follow-up of 12 weeks. Thus, further studies on a larger patient population are needed to clarify this topic.