Based on the phase 3 study designs for BOC and TVR, it is likely that response-guided therapy will be the new paradigm for treatment-naïve patients. However, the paradigms are quite different. The BOC treatment will be a 4-week lead-in with PEG/RBV followed by 24 weeks of PEG/RBV/BOC and no further treatment for patients who became negative by week 8 and remain so until week 24. Patients who had detectable virus at any point between weeks 8 and 24, will stop BOC at week 28, but will continue PEG/RBV until week 48. Hence, all patients will have 24 weeks of BOC, and rapid responders will have total treatment duration of 28 weeks, whereas slow responders will have an extra 20-week extension of PEG/RBV. The treatment-experienced population will also likely have response-guided therapy with a lead-in and 36 weeks of PEG/RBV/BOC, with or without an additional 12 weeks of PEG/RBV for those patients who had detectable virus at week 8. Previously treated patients with detectable virus at week 12 will discontinue therapy for futility.
The TVR response-guided protocol for treatment-naïve patients will require viral negativity at weeks 4 and 12 for the total treatment duration to be 24 weeks, with TVR given over the first 12 weeks only. If patients do not have undetectable virus at both 4- and 12-week time points, they will require a total duration of 48 weeks of PEG/RBV. The paradigm for treatment-experienced patients will not be response-guided based on the design of the REALIZE trial. Patients will receive 12 weeks of TVR and 48 weeks of PEG/RBV.
In both the BOC and TVR phase 3 trials, the SVR in patients with a poor response to interferon, whether it was by historical assessment of 12-week lab values from referring doctors’ records, or lack of a 1-log decline at the end of the lead-in period, was very low, ranging from 29% to 34%. This population is perhaps not ideally served by either of these compounds, and further assessment of more potent compounds or more novel regimens is warranted. Until such time, it is likely that patients with null responses to interferon will be retreated with BOC and TVR, but retreatment should be done with great care, because viral breakthrough and relapse rates are high.
In distinction to this population, treatment-naïve patients, partial responders, and relapsers appear to have much better response rates and clearly are the prime groups to target for treatment. Patients with HIV coinfection, pre-transplant patients with low platelet counts, decompensated liver disease, or renal failure, and liver transplant recipients have yet to be studied. Although these patients represent very important subsets of the HCV population, treatment of these groups will have to await study results prior to any recommendations.
The study designs of BOC and TVR are quite different. The differences of these new treatment paradigms will require clinicians to apply different laboratory monitoring strategies based on the regimen being used. Although a learning curve is inevitable, the concept of individualization of therapy is beneficial for the patient and ultimately is designed to prevent over- and under-treatment. There are no head-to-head comparisons of these two compounds, but both BOC and TVR are being evaluated with both pegylated interferon alfa-2a and 2b to determine if the interferons can be used interchangeably with either drug.