The standard duration of therapy with PEG-IFN alfa/ribavirin combinations is 48 weeks for patients with HCV G1 infection. However, several factors – positively or negatively – affect treatment outcome. Among these factors, viral load before treatment and HCV RNA decline during early therapy are most important for prediction of SVR (14).
Therefore, HCV RNA levels are monitored before initiation of treatment and during the first 12 weeks of therapy. Early virologic response (EVR) is defined as either a≥2 log10 reduction (partial EVR, pEVR) or undetectable serum HCV RNA at 12 weeks (complete EVR, cEVR), determined by a sensitive molecular test.
Fried et al. first recognized the prognostic value of EVR (6). Their pivotal observation acknowledged that not attaining EVR at week 12 was associated with failure to attain SVR in 97% of patients (negative predictive value [NPV]). Conversely, the positive predictive value (PPV) of the week 12 EVR (the proportion of patients with EVR who attain SVR) was 65% (6). Similarly, a retrospective analysis of data from the Manns et al. study revealed that the overall PPV of patients attaining EVR was 72%, whereas the overall NPV for patients attaining EVR was 100% (15). Based on these data, failure to reach EVR at week 12 is currently used for early identification of non-responders to therapy and for early treatment discontinuation in these patients (16–22).
Shortening treatment duration
More recently, virologic response at 4 weeks (RVR; defined as undetectable serum HCV RNA by sensitive molecular test at week 4) was evaluated as a method for identifying rapid responders in whom shorter duration of treatment may be appropriate (23–27).
Up to 47% of patients with HCV genotype 1 infection – and especially those with a low baseline viremia – achieve RVR during antiviral therapy with PEG-IFN alfa and ribavirin (12–47%) (23–30). Jensen et al. (24) reported in a post hoc analysis of the data of Hadziyannis et al. (7) that approximately one third of patients with HCV G1 can be successfully treated with a 24-week regimen. Overall, 89% of patients who attained RVR attained SVR. Among the variable treatment regimens investigated in this analysis, SVR rates ranged between 73% (in patients receiving PEG-IFN alfa 2a 180 μg/week plus ribavirin 800 mg/d for 48 weeks) and 91% (PEG-IFN alfa 2a 180 μg/week plus ribavirin 1000–1200 mg/d for 48 weeks) in patients who attained RVR. In contrast, SVR rates were in the range of 16% (PEG-IFN alfa 2a 180 μg/week plus ribavirin 800 mg/d for 24 weeks) to 44% (PEG-IFN alfa 2a 180 μg/week plus ribavirin 1000–1200 mg/d for 48 weeks) in patients who did not attain RVR. In this study, the principal difference between patients who attained RVR and those who did not was the incidence of relapse after completion of treatment. Though end-of-treatment response rates were similar to SVR rates in patients who attained RVR (73–97 vs 73–91%), in patients who did not attain RVR, there was a marked decrease in response rates from end of treatment to end of follow-up (56–70 vs 16–44%) (24). In accordance with these data, a recent prospective trial by Ferenci et al. reported a SVR rate of 80% in patients with an RVR and a HCV genotype 1 or HCV genotype 4 infection treated with PEG-IFN alfa 2a 180 μg/week plus ribavirin 1000/1200 mg/day for 24 weeks (23). In this trial, comparison of baseline characteristics revealed significant differences between patients with or without RVR. A younger age, lower body weight, genotype 4 and a low baseline HCV RNA were significantly associated with an RVR. Among patients with RVR no additional baseline predictors for SVR could be identified. A baseline viral load of more than 800 000 IU/ml appeared associated with treatment failure in patients with RVR, although this trend was not statistically significant (23).
Two further studies also suggest, that baseline viremia has an important impact on treatment outcome in patients with RVR and treatment duration for 24 weeks (25, 26). Mangia et al. reported lower rates for SVR in patients with RVR and a baseline viral load ≥400 000 IU/ml with 24 weeks compared with 48 weeks of PEG-IFN alfa 2a/b plus ribavirin (73% [57/78] versus 87% [33/38], P=0.14). In patients with RVR and a baseline viral load <400 000 IU/ml SVR rates were comparable between both treatment groups (84% [38/45] and 83% [20/24] for 24 and 48 weeks of treatment, respectively; P=0.83 (25). Yu et al. (26) also observed similar SVR rates between the 24-week and 48-week arms of therapy with PEG-IFN alfa 2a (180 μg/week) plus ribavirin (1000/1200 mg/d) in patients with RVR and a baseline HCV RNA <400 000 IU/ml (96 and 100%, respectively). When SVR rates of all patients with RVR irrespective of their baseline viral load were compared, the shorter treatment duration was inferior to the 48-week regimen mainly due to a higher relapse rate (89 versus 100%, P=0.056).
So far, no consensus has been established which cutoff for baseline HCV RNA might discriminate best between patients with RVR who are sufficiently treated with 24 weeks and these who will need 48 weeks of PEG-IFN alfa 2a/b and ribavirin to optimise treatment outcome. While the latter two trials report a cutoff at 400 000 IU/ml, another trial used a cutoff at 600 000 IU/ml (27) and the trial by Ferenci et al. (23) applied a cutoff at 800 000 IU/ml for baseline HCV RNA. This question needs to be addressed prospectively in future clinical trials.
Lengthening treatment duration
The possible benefits of extending treatment beyond 48 weeks to improve SVR rates in patients with HCV genotype 1 were investigated in several recent studies (25, 28, 30, 31). In a multicenter, prospective, randomized trial Berg et al. evaluated the relative efficacy of 48 versus 72 weeks of treatment with PEG-IFN alfa-2a (180 μg/week) plus ribavirin (800 mg/d) in 455 treatment-naïve patients with HCV G1 infection. The overall rate of SVR did not differ between 48 or 72 weeks of treatment (53 vs 54%, P=0.80). Patients who attained RVR or EVR attained excellent SVR rates, ranging from 76–84%, independent of treatment duration. Patients who had detectable HCV RNA at week 12 showed significantly higher SVR rates when treated for 72 weeks than when treated for 48 weeks (29 vs 17%, P=0.04). The benefit of extending treatment duration was most obvious in slow virologic responders (patients who had detectable HCV RNA at week 12 but undetectable HCV RNA at week 24), with relapse rates of 40% (72-week treatment) versus 64% (48-week treatment) (P=0.021). Overall, the authors concluded that extended treatment, though not generally recommended for patients with HCV genotype 1 infection, may be appropriate for the subset of patients who are slow virologic responders.
A recent study by Pearlman and colleagues reported similar observations in HCV genotype 1 infected “slow responder” patients (31). In this study, treatment-naïve patients with chronic hepatitis C were treated with 1.5 μg/kg/week PEG-IFN alfa-2b and weight-based ribavirin (800–1400 mg/day). Patients (n=101) considered slow virological responders, defined as patients who achieved at least a 2-log reduction in HCV RNA from baseline, yet, had detectable HCV RNA at 12 weeks (PCR, TaqMan, Roche, detection limit 10 IU/ml) were randomized 1:1 to continue treatment for a total of 48 or 72 weeks. Overall SVR rates were significantly higher in the 72-week treatment group than in the 48-week treatment group (38 vs 18%, respectively; P=0.026). The SVR rate observed in the 72-week treatment group is remarkable considering that, in addition to being infected with HCV G1, these patients had several other negative prognostic factors at baseline, including African American race (48%), high baseline viral load (78%), F3/4 fibrosis (26%) and high BMI (≥30 kg/m2; 34%).
Whereas the above described studies evaluated treatment extension in patients with pEVR but slow response at week 12, TeraViC-4 examined treatment extension for patients without RVR (HCV RNA >50 IU/ml) at week 4 (30). In this study, treatment-naïve patients without RVR were randomly assigned to continue receiving PEG-IFN alfa-2a (180 μg/week) plus RBV (800 mg/d) for a total of 48 (group A, n=165) or 72 weeks (group B, n=161). Patients with undetectable HCV RNA were allocated to standard treatment according to genotype and baseline viral load: G2/3 patients and G1 patients with baseline viral load ≤800 000 IU/ml continued treatment for an additional 20 weeks (group C, n=148) and patients with HCV genotypes 1/4 and baseline viral load >800 000 IU/ml continued for an additional 44 weeks (group D, n=36). Randomly assigned patients (groups A and B) were included in the efficacy analysis. End-of-treatment response was identical in groups A and B (61%); however, higher relapse significantly affected SVR rates in patients with the shorter treatment regimen. Relapse rates were significantly higher (48 vs 26%; P=0.003) and SVR rates consequently were significantly lower (32 vs 45%; P=0.014) in patients receiving treatment for 48 weeks than in those treated for 72 weeks. These differences remained significant when only G1 patients or only patients with low baseline viral load (≤800 000 IU/ml) were analyzed. When only patients with high baseline viral load were considered, there was a difference in SVR rates between the 48-week and 72-week regimens which did, however, not reach statistical significance.
Moreover, this study questioned the clinical validity of the week 12 stopping rule for patients who do not attain EVR (undetectable HCV RNA or a 2 log10 decrease) (30). As expected, not attaining EVR at week 12 was associated with a high NPV for patients randomly assigned to 48 weeks of treatment (92%). However, in patients treated for 72 weeks, the week 12 NPV decreased to 85%, suggesting that a small population of patients who do not attain EVR may still attain SVR if given an extended duration of therapy. In total, 4 (8%) of 51 patients receiving treatment for 48 weeks and 6 (15%) of 41 patients treated for 72 weeks did not attain EVR yet still reached SVR. A week 24 stopping rule (undetectable HCV RNA or a 2 log10 decrease) was more reliable in this study with NPVs of 94 and 95% for the 48- and 72-week regimens (30).
In a recently published trial (25), Mangia et al. investigated treatment extension to 72 weeks in a subgroup of HCV genotype 1 infected patients who first became HCV RNA negative at week 12 of treatment with PEG-IFN alfa 2a/b plus weight-based ribavirin. After 72 weeks of treatment 33/52 (63.5%) showed an SVR as compared with 8/21 (38.1%) after 48 weeks of therapy (P=0.068).
The above described data demonstrate that a significant number of patients may benefit from extended duration of therapy. However, so far there is no consensus for whom treatment extension should be applied – for patients without RVR or cEVR – and also how long treatment should be extended. This area clearly merits further research.
Individualized treatment duration
The DITTO-HCV study used a dynamically individualized approach to treatment of hepatitis C, basing decisions regarding choice of therapy and treatment duration on initial decline in HCV RNA (32). Among patients with RVR, end-of-treatment responses were 91% in patients receiving combination therapy for 24 weeks and 92% in those treated for the standard (control) 48 weeks. SVR rates were also similar between the 24-week and 48-week regimens (79 vs 85%). However, in G1 patients, SVR rates were lower for the 24-week regimen than for the 48-week regimen, though the difference between these groups was not statistically significant (65 vs 83%). When further stratifying this sample according to baseline HCV RNA, it becomes clear that, in G1 patients with high baseline viral load (>800 000 IU/ml), the 24-week regimen is significantly inferior to the 48-week regimen; however, in G1 patients with low baseline viral load (≤800 000 IU/ml), there was no significant difference in SVR rates between the two treatment durations. In G1 patients with slow partial response, SVR rates were similar in patients who received combination therapy for 72 weeks or 48 weeks (50 vs 43%), whereas, in flat, and null responders, the number of G1 patients in each group was too low (<10) for meaningful comparisons (32).
Berg et al. recently reported on the use of individualized treatment strategies in G1 patients (33). In this study, patients received PEG-IFN alfa-2b (1.5 μg/kg/week) plus weight-based ribavirin (800–1400 mg/d) for 48 weeks or according to an individualized treatment strategy based on time to HCV RNA <615 IU/ml. Patients attaining HCV RNA levels <615 IU/ml at weeks 3, 4, 5, 6, 7, or 8 were treated for 18, 24, 32, 36, 42, or 48 weeks, respectively. Overall, the individualized treatment strategy was less effective than the standard treatment approach, with SVR rates of 34% in patients randomly assigned to the individualized approach and of 48% in patients receiving 48-week standard therapy (P=0.004). The lower SVR rates in the individualized therapy group were attributed to the higher incidence of relapse (32 vs 14%). Among patients undergoing the individualized treatment approach, SVR rates were 63, 57, 41, 35, and 12% in patients treated for 18, 24, 30, 36–42, and 48 weeks, respectively.
In conclusion, to date no valid recommendations for complete individualization of treatment regimens can be given. Further investigations regarding optimal criteria for determination of treatment duration are needed.