Hepatology
Table 1: Definitions of Virologic Response Response
Definition
RVR EVR
cEVR pEVR Undetectable HCV RNA levels at week 4 of treatment
HCV RNA ≥2 log10 reduction in HCV RNA level from baseline at week 12 of treatment
Absence of HCV RNA in the serum at week 12 of treatment
A ≥2 log decline in HCV RNA level but the virus remains detectable at week 12 of treatment
Partial response HCV RNA levels decline (≥2 log10) but did not become undetectable at any time during treatment
Null response Slow responder
EOT SVR Relapse Breakthrough A <2 log10 decrease in HCV RNA by week 12
A partial EVR (≥2 log decrease in HCV RNA by week 12), followed by delayed viral negativity until week 24 of therapy
Undetectable HCV RNA levels at the completion of 82treatment
Undetectable HCV RNA levels 24 weeks after completion of treatment
Recurrence of detectable virus during the 24 weeks of follow-up period after achieving an EOT response
Recurrence of detectable virus on therapy after achieving viral negativity
EOT = end-of-treatment response; EVR = early virologic response; HCV = hepatitis C virus; RVR = rapid virologic response.
Table 2: Factors Affecting Response Viral Factors
Genotype Viral load
Definitions of Treatments
It is important for clinicians to understand the various definitions of virologic response to not only assess patient responses but also interpret the results of clinical studies. While not all definitions are standardized, the following have been used widely in clinical trials.
Rapid virologic response (RVR) is defined as HCV RNA levels that are undetectable at week 4 of treatment. Early virologic response (EVR) is
defined as a ≥2 log10 reduction in HCV RNA level from baseline at week 12 of treatment. EVR can be further categorized as complete EVR (cEVR), which is the absence of HCV RNA in the serum at week 12 of treatment, or partial EVR (pEVR), which is a ≥2 log decline in HCV RNA level but the virus remains detectable at week 12 of treatment. A partial response is
when HCV RNA levels decline by ≥2 log10 but never become undetectable at any time during treatment. A null-response is a <2 log10 decrease in HCV RNA by week 12. A slow responder is a patient who achieves a pEVR,
Host Factors Male sex
Age at infection Duration of infection Race or ethnicity Presence of steatosis Genetic factors Immune response
EU approved interferon alfa-2b as a treatment for chronic HCV infection. The second major advance in HCV therapy came with the addition of ribavirin to interferon. Ribavirin is a nucleoside analog that is known to have activity against several flaviviruses and was developed as a potential therapy for HIV infection, but found to be ineffective against HIV. Initial studies demonstrated that ribavirin alone had little effect on serum HCV RNA levels, but led to improved serum aminotranferase levels.12,14
Importantly, when combined with interferon alfa the rate of sustained virologic response (SVR) (mixed genotypes) increased to approximately 40% when given for 48 weeks, a substantial improvement over that of interferon alone.12,14,15
interferon alfa-2b therapy for hepatitis C treatment in 1998.
A third advance in therapy came with the introduction of pegylated forms of interferon that allowed treatment with once-weekly (rather than thrice- weekly) injections. Pegylated interferon yielded higher rates of SVR than standard interferon, as seen in two landmark trials with 54 to 56% of individuals achieving SVR rates after a 48-week course of peginterferon alfa and ribavirin.12,16
genotype. Since the initial approval of peginterferon and ribavirin in 2001, 82 Ribavirin was approved for use with
which is a ≥2 log decrease in HCV RNA by week 12, followed by delayed viral negativity until week 24 of therapy. End-of-treatment response (EOT) is undetectable HCV RNA levels at the completion of treatment, which is generally 48 weeks for patients with genotypes 1 and 4 and 24 weeks for patients with genotypes 2 and 3. A SVR is undetectable HCV RNA levels 24 weeks after the completion of treatment and is the best definition of cure at this time. Achieving an SVR is the goal of therapy. Relapse is recurrence of detectable virus during the 24 weeks of follow-up after achieving an EOT response, and breakthrough is recurrence of detectable virus on therapy after achieving viral negativity17–22
(see Table 1). Factors Affecting Response
The likelihood of achieving an SVR can be predicted by viral or host factors. Viral factors include most importantly the genotype followed by the viral level. There are six major HCV genotypes.23
The genotype does not predict
the natural history of infection; it does however predict the likelihood of treatment response, and, in many cases, determines the duration of treatment. In all prospective studies genotype is the strongest predictor of response. SVR rates were higher in patients who had genotypes 2 or 3 and lower pre-treatment HCV RNA levels. Host factors include male sex, age at infection, duration of infection, race or ethnicity, the presence of hepatic steatosis, genetic factors, and the patient’s immune response. It has also been noted that African-American and Hispanic patients have lower SVR rates than in Caucasians12,16,24–27
(see Table 2).
Use of Viral Kinetics for Tailoring Hepatitis C Treatment
Studies have shown that viral load in hepatitis C reaches a steady state based on the equilibrium between production of and clearance of HCV.29,30
The response rates varied according to HCV RNA then follows a biphasic slope.30,32,33
Quantitative measurement of hepatitis C has been used to assess hepatitis C treatment response and the likelihood of a sustained viral response.28
This level remains relatively stable within a range
of 1 log10 until the introduction of anti-viral agents to treat the infection, which is aimed at halting the production of virus.31
The decline of HCV The first phase is typically seen within eight hours of administration of interferon, with a rapid decline of US GASTROENTEROLOGY & HEPATOLOGY REVIEW
additional advances in treatment have been primarily through refinement of peginterferon and ribavirin doses as well as incorporating viral kinetics for response-guided therapy to determine treatment duration.
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