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Efficacy of Re-treatment With TMC435 as Combination Therapy in Hepatitis C Virus-Infected Patients Following TMC435 Monotherapy
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Gastroenterology Aug 8 2012
Article in Press
OLIVER LENZ,* JOEP DE BRUIJNE, LEEN VIJGEN,* THIERRY VERBINNEN,* CHRISTINE WEEGINK,
HERWIG VAN MARCK,* INA VANDENBROUCKE,* MONIKA PEETERS,* KENNETH SIMMEN,* GREG FANNING,*
RENE VERLOES,* GASTON PICCHIO, and HENDRIK REESINK
*Janssen Infectious Diseases, Beerse, Belgium; Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands; and
Janssen Research and Development, Titusville, New Jersey
Received 14 December 2011; accepted 27 July 2012. published online 10 August 2012.
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"The data presented here suggest that in some patients the frequency of emerging resistant viral variants may decrease over time, in the absence of selective pressure imposed by a direct-acting antiviral, to levels that do not negatively affect outcome on subsequent re-treatment with a regimen containing the same direct-acting antiviral. However, in other patients, resistant variants might persist at low levels, potentially below the detection limit of deep sequencing assays, which may affect the efficacy of a second course of treatment. The impact of preexisting resistant variants on treatment outcome is intimately linked to the intrinsic PegIFN/RBV responsiveness of the patient, as shown in this and other studies, because their sole presence does not automatically translate into treatment failure.12, 13 The significance of preexisting variants on sustained virologic response may be different when considering interferon-free regimens."
In the TMC435-C101 study, 6 patients infected with hepatitis C virus genotype 1 were treated with the protease inhibitor TMC435 (200 mg once daily) as monotherapy for 5 days. Approximately 1.5 years later, 5 of these patients were re-treated with TMC435 (200 mg once daily) plus pegylated interferon alfa-2a and ribavirin (PegIFNα-2a and RBV) for 4 weeks, followed by PegIFNα-2a and RBV until week 48 (in the Optimal Protease inhibitor Enhancement of Response to therApy [OPERA-1] study). TMC435-resistant variants, which emerged in all 5 patients during the TMC435-C101 study, were no longer detected at the beginning of the OPERA-1 study based on virus population sequencing. During the OPERA-1 study, 3 patients had a sustained virologic response; deep sequencing indicated low-level persistence of resistant variants in the remaining 2 patients, which might have affected their response to re-treatment. Clinical trials.gov Number, NCT00561353.
New treatments for patients infected with hepatitis C virus (HCV) genotype 1 are now available, including HCV NS3/4A protease inhibitors (PIs).1, 2 Drug-resistant viral variants can emerge in patients treated with direct-acting antivirals who do not achieve a sustained virologic response.3, 4 Although it has been described that variants become undetectable after treatment failure in most patients, it is unclear whether low-level variants persist and affect re-treatment options.5, 6
TMC435 is an investigational HCV PI administered orally once daily.7, 8, 9 In study TMC435-C101, 6 patients infected with HCV genotype 1 received TMC435 (200 mg once daily) as monotherapy for 5 days.10 Approximately 1.5 years later, 5 of the 6 patients participated in the Optimal Protease inhibitor Enhancement of Response to TherApy (OPERA-1; TMC435-C201) study and were treated with TMC435 (200 mg once daily) plus peginterferon alfa-2a/ribavirin (PegIFNα-2a/RBV) for 4 weeks, followed by PegIFNα-2a/RBV up to week 48 (Supplementary Materials and Methods and Supplementary Figure 1). Patients were white men previously treated with interferon-based therapy who did not respond to treatment or experienced a relapse (Table 1).
In TMC435-C101, all patients had a rapid and pronounced decline in HCV RNA during TMC435 monotherapy.10 Although no viral breakthrough was observed, mutations at NS3 amino acid positions 80, 155, 156, and/or 168 emerged in all patients. Deep sequencing at baseline of TMC435-C101 showed that there had been no additional preexisting NS3 mutations at positions known to affect TMC435 activity in vitro (80, 155, 156, and 168).11 At baseline of OPERA-1, these variants that emerged during C101 were no longer detectable using population sequencing (Supplementary Table 1). With deep sequencing, Q80L and R155G were observed at baseline of OPERA-1 at low frequency (1%-2%) in 2 of 3 patients (patients 140 and 144, respectively) who achieved undetectable HCV RNA after 4 weeks of triple therapy and ultimately achieved a sustained virologic response (Table 1 and Supplementary Figures 2A and 3). Q80L had been previously detected in patient 140 as an emerging minority variant in TMC435-C101 (frequency <5%), while in patient 144, R155G had not been previously observed.
In the remaining 2 patients who did not achieve a sustained virologic response and who were previous nonresponders to PegIFN/RBV and of IL28B TT genotype (polymorphism rs12979860), decreases in HCV RNA levels from baseline were slower in OPERA-1, in which TMC435 was given in combination with PegIFN/RBV, compared with TMC435-C101, in which TMC435 was given alone. In patient 141, decreases at day 7 were -2.8 IU/mL (OPERA-1) vs -3.5 log10 IU/mL (TMC435-C101) (Supplementary Figure 1B). In patient 142, decreases at day 3 were -2.9 IU/mL (OPERA-1) vs -3.7 log10 IU/mL (TMC435-C101) (Supplementary Figure 2B).
Patient 142 achieved an HCV RNA level <25 IU/mL at the end of triple therapy (OPERA-1) and experienced viral breakthrough at week 28 during PegIFN/RBV treatment. Population sequencing identified emerging D168A/V and R155K mutations during TMC435-C101 and R155K at day 7, day 14, and time of viral breakthrough in OPERA-1. Based on deep sequencing (Figure 1), R155K became detectable (frequency of 9%) at day 3 of TMC435-C101 before becoming the major variant and was detected 4 weeks after the end of TMC435 dosing (frequency of 64%). R155K was still detectable at baseline of OPERA-1 (frequency of 1%) and became the major variant from day 7 to time of viral breakthrough, 24 weeks after the end of TMC435 dosing. The ability of R155K to persist is consistent with reports showing the relatively high fitness of variants harboring this mutation. In addition to R155K, multiple mutations emerged at position 80 and 168 (Q80L, K, R and D168V, A, E, H, N, G) as well as in TMC435-C101 and/or OPERA-1 as minor variants.
Patient 141 had a TMC435 dose reduction at day 10 from 200 to 100 mg once daily and stopped all treatment at day 14 due to elevated bilirubin levels. HCV RNA levels did not decline further from day 7 until day 14. Q80R + D168E and Q80K + D168E mutations were detected at day 7 and 4 weeks after the end of the 14-day treatment period in OPERA-1, respectively. In TMC435-C101, population-based sequencing showed the emergence of D168V (Supplementary Table 1). Based on deep sequencing (Figure 1), D168V became detectable (frequency of 2%) at day 4 of TMC435-C101 before becoming the major variant, and D168E emerged (frequency of 6%) at the last follow-up visit, 4 weeks after the end of dosing with TMC435. At baseline of OPERA-1, only the wild-type residue aspartate was observed at position 168, while during OPERA-1 D168E became the major variant (frequency of 83% at day 7) and D168V was only transiently detectable (frequency of 12% at day 7). In parallel to the emergence of D168E, Q80R and subsequently Q80K became detectable. This suggests that previous exposure to TMC435 facilitated the emergence of a Q80R/K + D168E double mutant variant, which confers a similar level of resistance to TMC435 as the single D168V mutation but displays higher fitness.
In summary, although only 5 patients were analyzed and their first exposure to TMC435 was short, all patients had TMC435-resistant variants at the end of their first treatment that were no longer detectable (by population sequencing) at baseline of a second study 1.5 years later. A similar pattern may occur in patients who fail to respond to a PI-based regimen and are later evaluated for re-treatment. The data presented here suggest that in some patients the frequency of emerging resistant viral variants may decrease over time, in the absence of selective pressure imposed by a direct-acting antiviral, to levels that do not negatively affect outcome on subsequent re-treatment with a regimen containing the same direct-acting antiviral. However, in other patients, resistant variants might persist at low levels, potentially below the detection limit of deep sequencing assays, which may affect the efficacy of a second course of treatment. The impact of preexisting resistant variants on treatment outcome is intimately linked to the intrinsic PegIFN/RBV responsiveness of the patient, as shown in this and other studies, because their sole presence does not automatically translate into treatment failure.12, 13 The significance of preexisting variants on sustained virologic response may be different when considering interferon-free regimens. (Supplementary Figure 3).
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