Treatment-induced SVR is a long-term HCV cure

Posted on April 15, 2015

Study indicates that a treatment-induced SVR corresponds to a cure for Hepatitis C, and that the clinical significance of any residual trace amounts of HCV RNA seems limited

A sustained viral response (SVR), defined as undetectable HCV RNA in serum 24 weeks after the end of treatment, is regarded as a cure from HCV infection. However, it has been hypothesized that residual foci of HCV infected cells with low HCV replication may still be present but kept under control by the immune system. This could potentially enable reactivation of the infection in immunosuppressed patients, and HCV reactivation after SVR has been described in case reports. Results of a comprehensive study to better understand the natural history of chronic hepatitis C infection after SVR following treatment with interferon or peginterferon alpha-2b ± ribavirin, were recently published in the journal Alimentary Pharmacology and Therapeutics (Hedenstierna M et al. Aliment Pharmacol Ther 2015; 41: 532–543). Five to twenty years after SVR, 54 patients (29 females and 25 males) received a full clinical and histological work-up and an evaluation of humoral and cellular immune responses to HCV. These patients were also screened for HCV RNA traces in plasma, PBMCs and liver.

  • Patients had a median age of 52.1 years at follow up, the median follow-up time was 9.8 years (range 5–20) post-SVR, and the median duration of infection prior to SVR was 18.4 years.
  • Clinical, biochemical and histological parameters indicating liver disease were compared between samples taken at baseline (before the start of treatment) and at follow up. Comparative analyses showed that 5–20 years after SVR, the degree of liver disease had regressed and in the majority normalized according to all measured clinical, biological and histological markers.
  • All patients were HCV seropositive at follow-up and 50/54 patients had a positive confirmation test with RIBA. Confirmation tests with RIBA were intermediate in 4/54 patients but these patients had a follow-up time of at least 10 years, supporting that antibody titers had decreased over time.
  • An inverse correlation between the NS3 antibody endpoint titer and the time after SVR (P = 0.0002) indicated that while successfully treated patients can maintain HCV antibodies for up to 15 years after SVR, the levels of HCV antibodies decrease with the time after SVR, which supports the notion that the virus has been eradicated.
  • Successfully treated patients may maintain HCV-specific T-cell responses for up to 20 years after HCV eradication but the magnitude of the responses decreases with the time after SVR.

Plasma (all 54 patients), PBMCs (all 54 patients) and liver biopsies (40/54 patients) from treatment-recovered patients were tested for HCV RNA in a highly sensitive combined ultracentrifugation/RT-PCR method. Although all plasma and liver biopsy samples tested negative for HCV RNA at follow up, three PBMC samples (6%) tested positive.

  • These 3 patients with residual HCV RNA in their PBMCs did not have similar characteristics, such as gender, age, HCV genotype, IL-28B genotype or route of infection, and the authors noted that, surprisingly, they only had a very mild liver disease in the follow-up.
  • All 3 patients with residual HCV RNA in their PBMCs had HCV-specific T cells and NS3 antibodies, but no cross-neutralizing antibodies. The presence of detectable HCV-specific T-cell responses suggests that trace amounts of HCV RNA may generate enough HCV antigens to stimulate HCV-specific T cells. However, the authors noted that some patients with undetectable levels of HCV RNA had equally strong or even stronger HCV-specific T-cell responses, indicating that additional factors are involved in the maintenance of the HCV-specific T-cell responses.

The time between the end of HCV therapy and the follow-up sample for the 3 patients with residual HCV RNA in their PBMCs was noted to be 9 years or less (8, 5 and 9 years). Three new blood samples taken 5, 5, and 4 years after the RNA-positive samples all tested negative for HCV RNA, which supports the conclusion that the probability to detect HCV RNA traces in PBMCs of treatment-recovered patients decreases with the time after successful HCV therapy. This study demonstrates that in general, the decrease in immunological and liver disease parameters after SVR indicates the clearance of the immune stimulus and suggests a complete HCV cure. The authors concluded the following: “residual HCV RNA can be detected up to 9 years after SVR in a minority of the patients. This low-level HCV RNA may sustain HCV-specific immune responses but does not cause detectable liver disease. Taken together, our data indicate that a treatment-induced SVR corresponds to a cure and that the clinical significance of any residual trace amounts of HCV RNA seems limited.”

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