Current Approved Therapies in Hepatitis C Virus Infection
hepatitis C viral levels determined by the efficacy of interferon alfa at preventing viral production.30,32,34
The second phase of virus elimination
is highly variable with the rate of decay being based on the two factors noted above, namely the intrinsic viral clearance as well as the continued effectiveness of the therapy in inhibiting viral replication.30
As
noted above, this model can be used to explain the differences in treatment efficacy between different genotypes and may also be used to explain racial difference in response rates.
The current treatment for patients with HCV is the combination of pegylated interferon and ribavirin for 24–48 weeks. This approach is highly effective for patients with HCV genotypes 2 or 3, who have SVR of approximately 80%, with the majority requiring 24 weeks of treatment. This treatment algorithm is less effective for patients with genotype 1, as these patients have SVR rates of 40–50% after standard treatment of 48 weeks, with higher SVR rates with 48 weeks rather than with 24 weeks of treatment.
Treatment of Genotypes 2 and 3
Peginterferon with ribavirin therapy for a total of 24 weeks remains the standard duration for genotypes 2 and 3. Several recent studies have suggested that a shorter duration of treatment of 12–16 weeks may be possible in a specific subset of patients undergoing RVR.12,26,35–42
weeks to avoid an increased risk for virologic relapse. However, patients with a low pre-treatment viral load (≤400,000IU/ml) and an RVR (as determined by a highly sensitive assay) have the highest probability of achieving an SVR with a shorter duration of therapy. Such a regimen may be a reasonable option for these patients, especially if tolerability of longer treatment may be a concern. As with genotype 1, baseline viral load should be determined in two samples, taken at least four weeks apart. If trying to shorten treatment duration it is our practice to use weight-based ribavirin compared with flat dose ribavirin (800mg).26,35–41,43
Treatment for Genotype 1
The current 48-week treatment duration, recommended for HCV genotype 1-infected patients, may also be tailored by viral response using viral kinetics.49
A recent prospective trial demonstrated that
patients with genotype 1 baseline HCV RNA levels (≤600,000IU/ml) who undergo RVR achieve an SVR rate of up to 90%.42,50
In addition a
retrospective review of several large trials by Jensen et al. noted nearly a quarter (23%) of HCV genotype 1 patients treated with peginterferon plus RBV achieved RVR,42,51
and, of these patients, 89% demonstrated
SVR after treatment duration of only 24 weeks. Similar to those with genotypes 2 and 3 with RVR, treatment may be tailored to 24 weeks, though these individuals most likely will have low viral levels.
These
studies also suggest that genotype 3-infected patients with high viral load and those with advanced fibrosis may require longer duration of therapy of 48 weeks.
A study by Mangia et al. compared a standard 24-week course of pegylated interferon alfa-2b and weight-based ribavirin (1,000–1,200mg) with a variable course of therapy based on achieving RVR at week four in which these patients received 12 weeks of therapy and those who failed to clear virus at week four received 24 weeks of therapy.37
In those who
cleared virus at week four, an overall SVR of 85% was seen in the 12-week treatment group undergoing RVR, which was not different from the overall sustained response rate seen in those treated for 24 weeks. Higher response rates were seen in genotype 2 patients compared with genotype 3 patients. Baseline HCV RNA levels also influence SVR rates and patients with low pre-treatment serum HCV RNA levels and RVR have been reported to respond equally well with both 16 and 24 weeks of therapy (SVR rates of 82–100 and 81–100%, respectively).35,37,38,42,43
It is
possible, therefore, that these patients may be considered for shorter treatment duration. Other studies have demonstrated that genotype 3-infected patients have a lower response rate to therapy compared with those infected with genotype 2 hepatitis C.35,44,45
While the precise
mechanism remains unclear, possible explanations include differences in viral kinetics as well as the degree of steatosis associated with hepatitis C genotype 3. Previous studies using standard interferon or pegylated interferon with ribavirin have demonstrated that 48 weeks of therapy was not superior to 24 weeks of therapy in those with genotypes 2 and 3.26 There is evidence that patients with HCV genotype 2 or 3 and higher baseline viral load have lower rates of SVR and higher relapse rates after 24 weeks of treatment than those with lower HCV RNA baseline levels,35,42,43,46,47
In general, patients infected with HCV genotypes 2 or 3 should not be routinely treated for less than the currently recommended 24
US GASTROENTEROLOGY & HEPATOLOGY REVIEW
and that, in patients without RVR, the lowest rates of relapse are obtained with 48 weeks of treatment and a higher RBV dose.42,48
Patients who may need to be considered for longer treatment duration than 24 weeks include those who have a baseline viral load of 600,000IU/ml, cirrhosis, co-infection with HIV, or are immunosuppressed. Several recent studies have suggested that extending treatment beyond 48 weeks may lead to improved SVR rates in some genotype 1 patients.14,52–54
In those who fail to achieve SVR, there is either a pattern of non-response (failure to clear the virus from the serum), relapse where HCV RNA is cleared from the serum and returns after therapy is discontinued, or breakthrough where the virus reappears after clearance from the serum. With the use of pegylated interferon and ribavirin, improving SVR rates is achieved by ‘minimizing relapse’. The two large randomized registration trials by Manns et al. and Fried et al. evaluated combination therapy with pegylated interferon and ribavirin and revealed similar relapse rates of 18 and 19%, respectively, when treatment was continued for 48 weeks.16,24
Patients with a delayed virologic response to
HCV therapy have a lower likelihood of achieving SVR with 48 weeks of treatment than those with a more rapid decline in viral load.26
Some studies have demonstrated that the probability of attaining SVR has been shown to be greater with a longer period of undetectable serum HCV RNA during treatment.55
Two recent studies have helped
provide insight into extending treatment. Berg et al. compared therapy extension for 72 weeks with standard duration of 48 weeks in genotype 1 HCV patients who received interferon-based therapy and found no overall difference in SVR (54 versus 53%) or relapse rates (21 versus 29%) between the two groups.53
However, in a subgroup analysis in patients
who were late responders (virus level HCV RNA <6,000IU/ml at 12 weeks but undetectable virus at 24 weeks), extending the duration of treatment to 72 weeks from 48 weeks decreased the relapse rate significantly. Patients who did not have a serum HCV RNA <6,000IU/ml at 12 weeks had a high rate of relapse regardless of treatment duration. Of note, there was a higher incidence of drop-outs in the 72-week treatment arm than the 48-week treatment arm, particularly between weeks 48 and 72,
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