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EARLY ON-TREATMENT RESPONSES DURING PEGYLATED INTERFERON PLUS RIBAVIRIN ARE INCREASED FOLLOWING 13 DAYS OF COMBINATION NUCLEOSIDE POLYMERASE (RG7128) AND PROTEASE (RG7227) INHIBITOR THERAPY (INFORM-1)
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Reported by Jules Levin
EASL Apr 14-18 2010 Vienna Austria
"the profound viral suppression achieved with combination DAA therapy may reduce the high levels of interferon gamma-inducible protein (IP-10 or CXCL10) associated with chronic HCV infection, thereby reducing endogenous interferon activation levels.3 Thus, potent DAA combination regimens have the potential to not only block viral replication by arresting HCV RNA replication, but also to reconstitute innate host immune responses, thereby increasing the potential of long-term cure with finite DAA therapy.
.......These encouraging results suggest that, when given at optimal doses, a short course of dual combination therapy does enhance on-treatment response rates."
E. Gane1, S. Roberts2, C. Stedman3, P. Angus4, B. Ritchie5, R. Elston6, D. Ipe6, P. Morcos6, L. Baher6, I. Najera6, T. Chu6, M. Mannino6, M. Berry7, W. Bradford8, M. Laughlin6, N. Shulman6, P. Smith6
1Auckland Clinical Studies, Auckland, New Zealand; 2Gastroenterology, The Alfred Hospital, Melbourne, VIC, Australia; 3Christchurch Clinical Studies, Christchurch, New Zealand; 4Gastroenterology, Austin Hospital, Melbourne, VIC, Australia; 5Gastroenterology, Royal Adelaide Hospital, Adelaide, SA, Australia; 6Roche Palo Alto LLC, Palo Alto, CA, USA; 7Pharmasset Inc., Princeton, NJ, USA; 8InterMune, Inc., Brisbane, CA, USA
Conclusions
The interferon-free dual oral combination regimen of RG7128/RG7227 produced rapid and profound suppression of HCV RNA replication through 13 days of dosing. These initial reductions in circulating HCV RNA prior to initiating treatment with peginterferon alfa-2a (40KD) plus ribavirin enhanced on-treatment virological responses at week 4 and 12 of treatment and end-of-treatment responses.
The 13-day combination regimen contributed to higher end of treatment virological response rates in groups B, C and D compared with the shorter and lower dose combination regimen in group A. The highest end-of-treatment response rate in treatment-naive individuals (100%) was achieved in patients treated with the highest dosage combination of RG7128/RG7227 (1000/900 mg bid). All patients achieved an RVR at week 4 of treatment with the SOC and were assigned to an abbreviated 24-week regimen. These encouraging results suggest that, when given at optimal doses, a short course of dual combination therapy does enhance on-treatment response rates.
Final SVR-24 results in all cohorts are awaited with great interest.
Longer-term follow-up for SVR and larger studies will be needed to assess the clinical merits of combination DAA induction therapy prior to treatment with the SOC. However, such an approach is unlikely to benefit patients with contraindications to interferon, those intolerant of interferon, and individuals who have not responded to previous treatment with the SOC. In these populations, longer duration interferon-free combination DAA studies are planned.
Introduction
Induction therapy with potent direct acting antiviral (DAA) combination regimens could potentially enhance the efficacy and decrease the duration of treatment with the current standard of care (SOC) for chronic hepatitis C (peginterferon plus ribavirin).1
There are at least three possible mechanisms through which DAAs may enhance the activity of the standard of care. First, inhibitors of the viral RNA polymerase and serine protease have potent antiviral efficacy and when combined with SOC should increase the rate of rapid virological response. These two classes of DAA target different steps of HCV replication and when combined, should provide synergistic viral suppression and protection from antiviral resistance. Second, the virus encodes proteins that inhibit host induction of type I interferons. For example, HCV protease blocks dsRNA-induced interferon production by interfering with phosphorylation of interferon regulatory factor-3 (IRF -3).2 Third, the profound viral suppression achieved with combination DAA therapy may reduce the high levels of interferon gamma-inducible protein (IP-10 or CXCL10) associated with chronic HCV infection, thereby reducing endogenous interferon activation levels.3 Thus, potent DAA combination regimens have the potential to not only block viral replication by arresting HCV RNA replication, but also to reconstitute innate host immune responses, thereby increasing the potential of long-term cure with finite DAA therapy.
Objective
The objective of this analysis is to determine the early on-treatment virological responses after week 4 and 12 of peginterferon alfa-2a (40KD) plus ribavirin therapy and sustained virological response at 12 (SVR-12)4 and 24 (SVR-24) weeks post-treatment in patients who received a 7- or 14-day interferon-free dual combination regimen comprised of an HCV polymerase inhibitor (RG7128) and HCV protease inhibitor (RG7227) in the INFORM-1 study.
Methods
Patients
Eligible patients had chronic hepatitis C virus genotype 1 infection with a baseline HCV RNA level of at least 105 IU/mL. Both interferon-naive patients and interferon treatment-experienced patients were recruited. However, patients were entered into treatment cohorts on the basis of their treatment history as shown in Figure 1.
Treatment
INFORM-1 was a randomized, double-blind, placebo-controlled trial of the combination of an orally administered nucleoside polymerase inhibitor (RG7128; Roche/Pharmasset) plus an orally administered protease inhibitor (RG7227; Roche/InterMune). Treatment-naive (Cohorts A-D, and G), -experienced non-null (Cohort E), or null responder (Cohort F) patients were randomised to escalating doses of RG7128 (500 or 1000 mg bid) and RG7227 (100 mg or 200 mg tid, or 600 mg or 900 mg bid) for 7 or 13 days, after which, patients were switched to the SOC (peginterferon alfa-2a (40KD) plus ribavirin) (Figure 1).
Figure 1. INFORM-1 Study design. Non-null = relapse or partial response to previous treatment. Null = <1-log reduction at week 4 and/or <2-log reduction at week 12 of previous treatment
Virological outcomes
Serum HCV RNA was quantified (COBAS® Ampliprep / COBAS® TaqMan® HCV test; detection limit 15 IU/mL, Roche Diagnostics). Rapid virological response (RVR) was defined as undetectable HCV RNA at study day 42 (week 4 of SOC) and complete early virological response (cEVR) was defined as undetectable HCV RNA (<15 IU/mL) at study day 98 (week 12 of SOC) after patients were switched to the standard of care.
The duration of SOC was determined by previous treatment history and the early on-treatment response. Treatment-naive patients who achieved an RVR were assigned to 24 weeks of SOC, whilst those without an RVR were assigned to 48 weeks of SOC. All treatment-experienced patients were assigned to 48 weeks of SOC. The usual stopping rules were applied: SOC was stopped after 12 weeks in the absence of an EVR (<2 log reduction in HCV RNA from baseline) and after 24 weeks if HCV RNA remained detectable.
Sustained virological response (SVR) was defined as undetectable HCV RNA after 24 weeks of untreated follow-up (study week 24 or 48).
Results
The mean reduction in HCV RNA at the end of interferon-free treatment is shown in Figure 2.
Figure 2. Mean reductions in HCV RNA levels over baseline at the end of the interferon-free dual combination DAA treatment period. 95% confidence intervals are shown in brackets. Oral twice daily doses of RG7128/RG7227 are shown
Figure 3. Patients with undetectable HCV RNA at week 4 (RVR) and week 12 (cEVR) of treatment with the SOC in patients treated with the highest dose regimens of RG7128/RG7227
The number of patients with unquantifiable and undetectable HCV RNA at the end of interferon-free DAA treatment is shown in Table 1.
Table 1. Patients with unquantifiable or undetectable HCV RNA after 13 days of interferon-free DAA combination therapy
The percentage of treatment-naive patients with undetectable HCV RNA at week 4 and 12 of treatment with the SOC after treatment for 13 days with any dosage regimen of RG7128/RG7227 or placebo is shown in Figure 4.
Figure 4. Patients with undetectable HCV RNA at week 4 (RVR) and week 12 (cEVR) of treatment with the SOC in all treatment-naive patients treated for 13 days with RG7128/RG7227 or placebo (groups B-D and G combined)
Figure 5. End-of-treatment virological response in treatment-naive patients who received RG7128/RG7227 then the SOC in groups A-D. End-of-treatment responses in all naive patients combined are also shown.
End-of-treatment response data are available for all treatment-naive patients enrolled in groups A to D and a subset of patients enrolled in groups E-G (Figure 5). The responses were higher in patients who received a full two weeks of treatment in groups B, C and D (range 63% to 75%).
Seven of eight patients in group G have completed treatment. All had achieved an RVR at week 4 of SOC and thus were assigned to an abbreviated 24-week regimen. All seven patients (100%) have achieved an end-of-treatment-response.
SVR-12 results are available for 39 patients in groups A through D. A total of 14 of these individuals (36%) were HCV RNA negative at week 12 of untreated follow-up. Three of nine placebo recipients (33%) have also achieved an SVR-12. One patient in group G has completed 12 weeks of untreated follow-up and has achieved an SVR-12.
Among patients who received 13 days of RG7128/RG7227, 23 have SVR-12 results available, of whom 10 (44%) were HCV RNA-negative at week 12 of un-treated follow-up.
There was no evidence of treatment-emergent resistance in any of the 55 patients who received 13 days of interferon-free DAA combination therapy.
References
1. Ghany MG, Strader DB, Thomas DL, Seeff LB. Diagnosis, management, and treatment of hepatitis C: An update. Hepatology 2009;49:1335-1374.
2. Foy E, Li K, Wang C, Sumpter R, Jr., Ikeda M, Lemon SM, Gale M, Jr. Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease. Science 2003;300:1145-1148.
3. Shulman N, Smith P, Ipe D, et al. Reduction of IP10, a biomarker of endogenous IFN, during therapy with two direct-acting antiviral agents (DAA-combo) in INFORM-1 suggests that reducing HCV RNA with IFN-free therapy may enhance response to Interferons. 16th International Symposium on HCV and Related Viruses, October 3-7 2009, Nice, France.
4. Martinot-Peignoux M, Stern C, Maylin S, et al. Twelve weeks Posttreatment Follow-up Is as Relevant as 24 Weeks to Determine the Sustained Virologic Response in Patients with Hepatitis C Virus Receiving Pegylated Interferon and Ribavirin. Hepatology 2010;51:1122-1126.
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