Therapy with telaprevir, peginterferon, and ribavirin should be stopped in both treatment-naive and treatment-experienced patients with hepatitis C virus infection if HCV RNA levels are greater than 1,000 IU/mL at week 4 or 12 of treatment, according to new futility rules developed using phase II and III trial data.

The rules are important for preventing needless drug exposure and to minimize the development of drug-resistant variants in patients with little or no chance of achieving sustained virologic response, reported Dr. Nathalie Adda of Vertex Pharmaceuticals Inc., Cambridge, Mass., and her colleagues.

The futility rules were initially developed during clinical trials of telaprevir combination therapy and were instituted along with standard peginterferon/ribavirin (Peg-IFN/RBV) futility rules; phase II trial data were analyzed to determine whether the telaprevir rules could differentiate patients likely to experience viral breakthrough and patients likely to achieve sustained virologic response, and it was found that the majority of viral breakthroughs occurred within the first 4 weeks of treatment. Thus, a futility rule was implemented at week 4 in studies of telaprevir combination therapy as has long been the case for studies of Peg-IFN/RBV therapy (Clin. Gastroenterol. Hepatol. 2012 Nov. 16 [doi: 10.1016/j.cgh.2012.10.045]).

For treatment-naive patients, a level of 1,000 IU/mL at week 4 was used; for treatment-experienced patients, a more conservative level of 100 IU/mL at week 4 (and at weeks 6 and 8) was used.

These rules were further analyzed based on phase III studies of patients who were treated with 12 weeks of telaprevir, Peg-IFN/RBV followed by 12 or 36 weeks of Peg-IFN/RBV alone. This allowed for refinement of the optimal thresholds and time points for identifying patients unlikely to achieve sustained virologic response.

"In this analysis, we also sought to harmonize the futility rules for all patient populations (treatment-naive and -experienced)," the investigators wrote.

They found that 1.7% of 844 treatment-naive patients, 0.7% of 138 prior relapsers, and 0% of 46 prior partial responders had HCV RNA levels greater than 1,000 IU/mL at week 4, compared with 14% of 70 prior nonresponders. None of the 25 patients with HCV RNA levels above the 1,000 IU/mL level at week 4 achieved sustained virologic response with continued therapy. Among those who had HCV RNA levels between 100 and 1,000 IU/mL at week 4, a small subset achieved sustained virologic response with continued treatment: 25% of treatment-naive and 14% of treatment-experienced patients.

The 1,000 IU/mL threshold was retained, as it was found to maximize the likelihood of achieving sustained virologic response, they said.

"Furthermore, 13/14 (93%) treatment-naive and 10/11 (91%) treatment-experienced patients with HCV RNA levels greater than 1,000 IU/mL at week 4 reached their HCV RNA nadir prior to week 4, typically by week 2, with subsequent increase in HCV RNA by week 4, meeting the definition of viral breakthrough," they wrote.

Additionally, the investigators reassessed previously-established Peg-IFN/RBV treatment futility rule of a 2 log₁₀ decrease or greater in HCV RNA at week 12 in the context of a telaprevir-based regimen, and implemented a futility rule for treatment-naive patients of greater than 1,000 IU/mL HCV RNA at the end of the telaprevir dosing period to avoid unnecessary Peg-IFN/RBV exposure in those unlikely to achieve SVR.

This rule was met by 1.5% of 605 treatment naive patients who completed week 12. Similar rules were implemented at weeks 6, 8, and 12 for treatment-experienced patients, but few patients met the week 6 and 8 futility rules (5 and 2 of 266 patients, respectively), and the HCV RNA assessment at these time points was replaced by the week 12 assessment.

"In conclusion, data from phase II and III trials confirmed that a futility rule of greater than 1,000 IU/mL at week 4 accurately and specifically identified patients unlikely to achieve sustained virologic response. Less than 2% of treatment-naive, prior relapse, and prior partial response, and 14% of prior null response patients met the above criterion, and none achieved sustained virologic response after stopping telaprevir, with continued Peg-IFN/RBV," the investigators wrote, noting that the vast majority of these patients were already experiencing viral breakthrough by week 4.

The new rules prevent unnecessary drug exposure in those unlikely to achieve sustained virologic response, and, importantly, they minimize additional HCV RNA testing, because the futility time points coincide with those used to guide total treatment duration.

"This strategy will avoid additional adverse effects of continued treatment and will help minimize the evolution, enrichment, or protracted persistence of resistant variants, which could adversely impact patient candidacy for potential treatment with subsequent antiviral regimens," they concluded.

Several authors are employees of Janssen Pharmaceuticals and stock owners of Johnson and Johnson. One author reported receiving consulting fees, lecture fees, and/or grant/research support from many companies involved in hepatitis C virus therapeutics.

Futility rules defined for telaprevir-based HCV therapy