Sustained virologic response

Chronic HCV infection is curable, and cure is the goal of antiviral therapy. Successful treatment is characterized by a sustained virological response (SVR), defined by undetectable HCV RNA in a sensitive assay (detection limit < 50 international units (IU)/ml) 6 months after the end of therapy. Recent large-scale follow-up studies have shown no relapse or recurrence after 4-6 year s in more than 99% of patients who have an SVR (McHutchison et al. 2006 Swain et al. 2007). 

The antiviral efficacy of IFN-p administered for 24 weeks at a dose of 3 million units daily has been studied in a small series of HBeAg-positive patients. HBe seroconversion was observed in half the patients and ALT normalization in four patients out of five (Kagawa et al. 1993). Sequential therapy with lamivudine and IFN-p has been tested in HBeAg-positive patients (Enomoto et al. 2007). A sustained virological response was achieved in only 7 (29%) of the 24 patients, 24 weeks after the end of therapy. In a pilot study of IFN-p therapy in 29 patients in whom IFN-a therapy had failed, HBV DNA became undetectable in 6 patients (21%) (Munoz et al. 2002). 

Ribavirin is a guanosine analog synthesized more than 35 years ago, which possesses broad-spectrum antiviral activity against several RNA and DNA viruses in vitro (Sidwell et al. 1972). When administered as monotherapy in patients with chronic hepatitis C, ribavirin induces a decline of serum alanine aminotransferase (ALT) levels while no effect on sustained virologic response is detectable (Di Bisceglie et al. 1992). 

Fig. 1 Sustained virologic response rates from pivotal trials in patients with chronic hepatitis C according to treatment regimen and HCV genotype. For references see text...

The development of pegylated (peg) interferons that possess a sustained absorption, a slower rate of clearance, and a longer half life than unmodified interferons led to further improvement of sustained virologic response rates especially for patients infected with genotype 1 (Fig. 1) (Fried et al. 2002 Manns et al. 2001 Zeuzem et al. 2000). 

Patients infected with HCV genotype 1,4, 5 or 6 are treated with peginterferon-a in combination with ribavirin for 48 weeks (Table 3). In the pivotal trials, sustained virologic response rates achieved with patients infected with these genotypes were 46-51% with peginterferon-a2a and ribavirin and 42-48% with peginterferon-a2b and ribavirin. Different baseline parameters (female gender, age <40 years, low body... 

Further reduction of treatment duration to gain even better tolerability and lower side effects without compromising the sustained virologic response rates was... 

To further improve sustained virologic response rates, different treatment approaches are currently under investigation. For example, individualized therapy durations on the basis of the HCV RNA concentration at baseline and early during therapy are the subject of clinical studies (Berg et al. 2006 Zeuzem et al. 2005a). In addition, triple therapy with other antiviral compounds, such as amantadine, has been evaluated in multiple studies, leading to contradictory results (Mangia et al. 2004). 

Interferon alfa-2a (Roferon A), interferon alfa-2b (Intron-A), and interferon alfacon-1 (Infergen) are approved for chronic hepatitis C. However, they are not prescribed alone because only 12% to 16% of patients achieve a sustained virologic response (SVR). Adding ribavirin, a synthetic guanosine analogue that inhibits viral polymerase, increases the SVR rate to 35% to 45%. 

Encourage medication compliance with viral hepatitis treatments to increase sustaining virologic response. 

Several factors correlate with improved response to IFN therapy, including increased alanine transaminases and HBV DNA levels, high histologic activity score at biopsy, and being non-Asian. Treatment for a minimum of 12 months is associated with greater sustained virologic response rates than treatment for 4 to 6 months. Conventional IFN therapy has been... 

The current standard of treatment for chronic HCV infection is a combination of once-weekly PEG-IFN and a daily oral dose of ribavirin. Sustained virologic response rates are 54% to 56%. Therapy is optimized based on genotype, patient weight, and response to therapy. Recommended treatment regimens for HCV infection are given in Table 25-8 and Fig. 25-3. 

Subsequent analysis of stored serum samples showed reduction of HCV RNA levels during treatment and durable eradication of virus in some cases [38]. These early results were confirmed by randomized controlled trials in patients with chronic hepatitis C [39-41]. Durable viral eradication (termed sustained virologic response, or SVR) was achieved in 6% to 15% of patients after six months of treatment with recombinant interferon at doses of 3 to 6 MU administered subcutaneously three times per week. SVR increased to 13% to 25% if treatment was extended to 12 months [41]. The combination of the oral nucleoside analogue ribavirin with recombinant interferon increased SVR to 41% [42-44]. Ribavirin, however, is potentially embryotoxic and induces a dose-dependent hemolytic anemia, a situation that calls for close monitoring during therapy. 

Efficacy appears to be superior to therapy with nonpegylated interferons in controlled clinical trials, particularly as regards the proportion of patients with sustained virologic responses. As with the nonpegylated interferon alfa agents, combination therapy of the pegylated interferon alfa compounds with ribavirin is more effective than monotherapy. 

Perihepatic lymphadenopathy This symptom was observed in chronic hepatitis in 1994 by K. Lyttkens et al. using sonography. It is common in chronic hepatitis C (60-100% of cases) as well as B - even with normal liver values. (102) There is a correlation between lymph node volume and hepatic inflammatory activity or viraemia. A decrease in the total volume of lymph nodes is associated with a sustained virological response and an improvement in liver histology. (81, 116, 143, 147)... 

The combination of interferon and ribavirin has a significant benefit on sustained virologic response (the absence of detectable HCV RNA more than 6 months after treatment), biochemical response (normalization of transaminases), and liver histology in patients with hepatitis C compared with interferon by itself. Ribavirin is ineffective by itself and should not be used as monotherapy. 

Less than 3% chance of sustained virological response some continue treatment to 24 weeks and reevaluate. 

Occasionally, different time points are used to record results as end-of-therapy responses or as sustained virologic response (SVR at least 6 months after therapy). SVR has been acknowledged as thebest predictor of a long-term clinical outcome. 

The safety and efficacy of sofosbuvir were evaluated in five phase 3 trials (NEUTRINO, FISSION, POSITRON, FUSION, and VALENCE) including a total of 1724 HCV mono-infected subjects with genotypes 1-6 CHC and one phase 3 trial (PHOTON-1) with 223 HCV/HIV-1 co-infected subjects with genotype 1, 2, or 3 CHC. The primary endpoint in these studies was sustained virologic response 12 weeks after completion of therapy (SVR12). 

Clearly, an immediate goal in the treatment of chronic hepatitis C infection is the eradication of the vims from the semm. A sustained virological response is defined as the inability to detect hepatitis C vims in the serum 6 months after treatment has been completed. The antiviral effect of IFN in patients with chronic hepatitis C infection is well established. The standard therapeutic schedule of IFN consists of 3 MIU adnoinistered subcutaneously three times a week for up to 48 weeks. IFN therapy alone produces a sustained virological response in less than 20% of patients. ... 

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