Sustained Virologic Response (SVR)
A sustained virologic response (SVR) is an undetectable HCV RNA level using a sensitive assay (typically with a lower limit of 25 IU/ml) 12 weeks after completion of therapy for hepatitis C (Figure 1). This is typically referred to as the SVR12 and achieving an SVR12 is the goal of therapy. Among persons who achieve an SVR12, more than 99% go on to achieve an SVR24. Trial outcomes with SVR time frames of shorter duration (SVR8, and SVR4) have been presented in an effort to expedite conclusions from these trials, but SVR4 and SVR8 are not the standard in clinical practice.
Durability of SVR
Long-term follow-up of patients who achieve an SVR24 has shown that nearly 100% remain HCV RNA negative years after therapy.[3,4,5] The largest studies have shown a minimal relapse rate, between 0 to 1%. Thus, an undetectable HCV RNA 24 weeks after antiviral therapy can be considered a virologic cure.
Impact of SVR on Liver Histology
Patients who achieve an SVR are more likely to have an improvement in liver inflammation and fibrosis than those who do not achieve an SVR. In a pooled analysis of patients who had paired liver biopsies before and 1 months to 6 years after treatment with standard interferon monotherapy, peginterferon monotherapy, or peginterferon with ribavirin, those patients who had an SVR were twice as likely to have lower necroinflammatory scores after treatment, compared to patients who relapsed (67% versus 32%). In the same study, improvement in baseline scores were more likely to occur in those who had longer periods of undetectable HCV RNA. In some cases, there was complete regression of liver fibrosis. Multiple studies have confirmed this long-term histologic benefit.[3,4,5,8]
Impact of SVR on Survival and Natural History
Clearance of HCV RNA with treatment has been shown to have a beneficial impact on a variety of clinical outcomes, both liver and non-liver related [Pearlman, Mira, Kutala, Dieperick].[6,9,10,11] One study demonstrated that U.S. veterans with chronic hepatitis C with age-matched controls without hepatitis C, investigators demonstrated that hepatitis C infection increased the risk of death by approximately 37%. However, veterans with chronic hepatitis C infection who received at least 48 weeks of peginterferon and ribavirin had a 60% reduction in mortality compared with untreated veterans (Figure 2). In a study involving the general population, patients with advanced fibrosis who underwent antiviral therapy and achieved an SVR had reduction in overall mortality, liver-related death, liver failure, and hepatocellular carcinoma when compared with those who did not achieve an SVR (Figure 3). Most of this survival benefit appeared to result from the marked reduction in liver failure, but a number of studies have also demonstrated the benefit of an SVR to all-cause mortality[14,15] and non-liver-related deaths. In a recent meta-analysis of 35 studies, investigators showed a clear benefit in 5-year overall survival with HCV treatment, including patients with cirrhosis and with HIV coinfection (Figure 4).
Impact of SVR on Other Medical Conditions
Hepatitis C can cause a myriad of extrahepatic complications, including membranoproliferative glomerulonephritis and Non Hodgkin's lymphoma. Chronic hepatitis C infection is associated with a higher prevalence of insulin resistance and diabetes mellitus. In some patients, successful treatment of hepatitis C is associated with improvement or remission of these underlying conditions.[18,19] In addition, achieving an SVR has been shown to reduce the chance of impaired fasting glucose and diabetes development by 50%, an effect that is independent of other established risk factors for diabetes, such as age and body mass index.