Telaprevir is a recently approved direct-acting antiviral against hepatitis C virus (HCV) that works through inhibition of the NS3/4A serine protease inhibitor.Phase 2b and 3 studies have shown marked increase in sustained virological response rates in both treatment- naïve and treatment-experienced patients with HCV genotype 1 treated with a telaprevir-containing regimen compared with pegylated interferon (PEG-IFN) and ribavirin alone. The most commonly observed side effects of telaprevir therapy are anaemia to a greater degree than that observed with PEG-IFN/ribavirin alone; eczematous rash, which can be severe in a minority of patients; and anorectal discomfort.
Approximately 3–4 million persons in the United States and 170 million worldwide are infected with the hepatitis C virus (HCV) , and up to 75% of new infections progress to chronic infection, which is a major cause of chronic liver disease [2, 3]. Hepatitis C is the leading cause of death from liver disease and the most frequent indication for liver transplant in the United States .
For a decade, standard of care therapy for chronic hepatitis C genotype 1 (G1) consisted of pegylated interferon (PEG-IFN) alfa-2a or PEG-IFN alfa-2b, combined with ribavirin, for 48 weeks in patients with genotype 1 HCV or 24 weeks with genotype 2 or 3 . Despite the improvement in efficacy over previous regimens when this therapy was introduced, the overall sustained virological response (SVR) rate in patients with HCV G1 was still only 40–50% .
Telaprevir – mechanism of action
Determination of the structure of HCV proteins, the development of a subgenomic replicon system and a cell culture model that enables productive HCV infection have facilitated the development of direct-acting antiviral agents (DAAs) [7, 8]. Such agents have the potential to substantially increase rates of SVR and to truncate the duration of therapy .
Each step of the HCV life cycle offers a potential target for DAA therapy. Polyprotein processing is one such step. Two viral peptidases are involved in the post-translational processing of HCV proteins- NS2 and NS3/4A. NS3 is a multifunctional viral protein containing a serine proteinase domain in its N-terminal third (approximately 180 amino acids) and a helicase/NTPase domain in its C-terminal two-thirds. NS3 has a typical chymotrypsin-like fold, and NS4A is a cofactor of its proteinase activity. The NS3/4A serine protease catalyses HCV polyprotein cleavage. NS3 needs to assemble with its cofactor NS4A to catalyse cis-cleavage at the NS3–NS4A junction and trans-cleavage at all downstream junctions including NS4A-NS4B, NS4B-NS5A, and NS5A-NS5B. The cleavage sites recognized by NS3-NS4A proteinase have in common the following sequence: Asp/Glu/XXXXCys/Thr-Ser/Ala with trans-cleavage occurring downstream of a cysteine residue and the cis-cleavage occurring downstream of a threonine residue . Telaprevir, is an NS3/4A serine protease inhibitor produced by Vertex Pharmaceuticals (Cambridge, Massachusetts). Telaprevir is a potent covalent orally bioavailable peptidomimetic inhibitor of NS3/4A with an alpha ketoamide moiety that anchors at the enzyme active site.
Phase 1 studies
The phase 1 clinical trials for telaprevir were initially conducted at two collaborative sites in The Netherlands and one in Germany in 2004–2005 in two parts. In the first part of the initial trial, 24 healthy subjects received doses of 450 or 750 mg every 8 h (q8h), or 1250 mg of telaprevir every 12 h (q12h) for 5 days. Telaprevir was well-tolerated, and no serious adverse events were reported. The second part of the trial was conducted to evaluate the safety and tolerability of ascending multiple doses of telaprevir in patients with chronic hepatitis C and to investigate its pharmacokinetics and antiviral activity. Median HCV RNA levels in the telaprevir dose groups substantially and rapidly decreased. The median maximum change was −3.46 log10 IU/ml in the 450-mg q8h group, −4.77 log10 IU/ml in the 750-mg q8h group, and −3.49 log10 IU/ml in the 1250-mg q12h group. All subjects in the telaprevir groups had at least a 2-log10 decrease from baseline in HCV RNA. All subjects in the 750-mg q8h group had at least a 3-log10 decrease. All three telaprevir dose groups showed similar declines in median HCV RNA up to day 3 of dosing. A further decrease was not evident in the 450-mg q8h and 1250-mg q12h groups, and median HCV RNA levels in those two dose groups increased at the end of the dosing period.
The initial rapid decline in HCV RNA was related to maximal exposure to telaprevir, and the second phase of the viral decline was sustained by trough concentrations (Ctrough) of telaprevir. Subjects who received the 750-mg q8h regimen had an average Ctrough of 1054 ng/ml and >/ = 4-log10 decrease in HCV RNA, whereas subjects who received the 450-mg q8h regimen had an average Ctrough of 781 ng/ml with a >/ = 3-log10 decrease in HCV RNA, and subjects who received the 1250-mg q12h regimen had an average Ctrough of 676 ng/ml with a >/ = 3-log10 decrease in HCV RNA .
On the basis of these data, telaprevir at a dose of 750 mg q8h emerged as the lead dosing regimen for further trials. The virological breakthroughs that occurred during the dosing period were related to selection of viral variants with decreased sensitivity to telaprevir and confirmed that telaprevir would need to be utilized in combination therapy .
The resistant variants were well characterized in subsequent studies, which differentiated high-level from low-level-resistant variants and defined a generally inverse relationship between degree of resistance conferred by a mutation and the replicative fitness of the resulting viral variant .
Further study was undertaken to evaluate telaprevir monotherapy vs. combination therapy with telaprevir and PEG-IFN. Twenty HCV G1 treatment-naïve patients were randomized to one of three treatment regimens: placebo q8h orally for 14 days and PEG-IFN weekly for 2 weeks (four patients); telaprevir q8h orally for 14 days (eight patients); or telaprevir q8h orally for 14 days and PEG-IFN weekly for 2 weeks (eight patients). Telaprevir was dosed at 1250 mg once and then subsequent doses were 750 mg q8h. Telaprevir/PEG-IFN combination therapy resulted in a more significant viral decline during the study period with a median change in HCV RNA from baseline to day 15 of −5.49log10 vs. −3.99log10 for telaprevir monotherapy, and −1.09log10 for PEG-IFN monotherapy [11, 12]. Analysis of viral kinetics during the study period revealed a biphasic viral decline. The rapid first phase was similar in the PEG-IFN/telaprevir and the telaprevir group. The second phase of decline was more sustained in the combo PEG-IFN/telaprevir combination group. In the telaprevir monotherapy group, 4 patients had continued decline, and 4 had viral decline followed by rebound . In the 4 patients who had viral rebound on telaprevir alone, R155K/T and A156V/T-resistant variants were detected by sequence analysis during the initial steep decline, but were replaced by V36(M/A)/R155(K/T) double mutant variants during the rebound phase. This V36(M/A)/R155(K/T) double mutant variant had been shown in in vitro analysis to confer both higher levels of resistance and higher relative fitness . All patients enrolled in the trial were offered continued therapy off study with PEG-IFN and RBV after the study period, of which 19 accepted. All 8 patients initially treated in the combo PEG-IFN/telaprevir group had undetectable HCV RNA at week 12 while receiving standard of care with PEG-IFN/RBV vs. 5 of 8 patients initially treated with telaprevir monotherapy. At week 24 on standard therapy all patients who had initially received PEG-IFN/telaprevir or telaprevir alone had achieved undetectable HCV RNA, thereby illustrating that telaprevir-resistant variants are sensitive to PEG-IFN and ribavirin (RBV) [11, 12].
In logical progression, further phase 1 study was then conducted utilizing telaprevir in combination with the current standard of care therapy of PEG-IFN/RBV. Twelve treatment-naïve subjects with chronic G1 HCV were treated with telaprevir 750 mg q8h, PEG-IFN 180 µg/week and RBV 1000 or 1200 mg/day for 28 days and then could continue treatment with PEG-IFN/RBV for up to 44 weeks. All 12 subjects had a decrease from baseline of at least 4-log10 and 10 subjects had a decrease greater than 5-log10. There was no viral breakthrough. Viral sequencing analysis showed no evidence of previously identified telaprevir-resistant mutations in 10 subjects during study drug dosing. Although resistant mutations were noted in 2 subjects their viral load continued to decline, again indicating sensitivity to PEG-IFN/RBV. Two subjects had undetectable HCV RNA within 8 days and all were undetectable at 28 days. Twelve subjects went on to continue therapy, 8 of who achieved an SVR, 2 of who had viral breakthrough and 2 of who were lost to follow-up. All subjects had at least one adverse event with the most frequent including influenza-like illness, fatigue, headache, nausea, anaemia, depression and pruritis .
Upon this background, the PROVE (PROtease inhibition for Viral Evaluation) phase 2 trials were initiated.
Phase 2 studies
PROVE 1 studied the safety and efficacy of telaprevir in combination with PEG-IFN and RBV (PR) in noncirrhotic treatment-naïve HCV G1 subjects in the United States . It was designed as a Phase 2b, randomized double-blind, placebo-controlled, and multi-centre (37) study. The study population included treatment-naïve chronic G1 HCV-infected subjects aged 18–65 years in the US. Exclusion criteria included infection with hepatitis B virus (HBV) or human immunodeficiency virus (HIV), cirrhosis on biopsy within 2 years, decompensated liver disease, hepatocellular carcinoma (HCC), another cause of clinically significant liver disease, absolute neutrophil count <1500/mm3, and platelets <90 000/mm3. Most study subjects were middle-aged (mean 48 years old) white (77%) males (63%), and 87% had a viral load >800 000 IU/ml. Subjects were stratified by weight (> or </ = 75kg) and ethnicity (black or other). The study design included 4 treatment groups: (i) T12PR12 (telaprevir 1250 mg on day 1 and then 750 mg q8h thereafter for 12 weeks as well as PEG IFN 180 µg/week and RBV 1000–1200 mg/day for the same 12 weeks, n = 17); (ii) T12PR24 (telaprevir 1250 mg on day 1 and then 750 mg q8h thereafter for 12 weeks with PEG-IFN and RBV and then an additional 12 weeks PEG-IFN and RBV, n = 79); (iii) T12PR48 (telaprevir 1250 mg on day 1 and then 750 mg q8h thereafter for 12 weeks with PEG-IFN and RBV, and then additional 36 weeks PEG-IFN and RBV, n = 79); (iv) PR48 (control group-standard of care, n = 75). Standard stopping rules applied in the PR48 control group (2 log10 decline in HCV RNA by week 12 of treatment and undetectable viral load at week 24). Subjects in the T12PR24, T12PR12 were required to have a rapid virological response (RVR, HCV RNA undetectable) to stop therapy at 24 or 12 weeks respectively. If they did not achieve RVR, they were treated for 48 weeks. If breakthrough occurred (>100 IU/ml after being undetectable or increase in RNA of 1 log10 unit) during the first 12 weeks, then telaprevir or placebo was discontinued and the standard of care was continued. If breakthrough did occur and the viral load was greater than 1000 IU/ml, then sequencing of the NS3/4A region was performed.
SVR rates were 41% for the standard of care regimen (PR48), 35% in T12PR12, 61% for T12PR24 and 67% for T12PR48. Rates of RVR were also better in telaprevir-treated subjects: PR48 8% vs. T12PR12 59%, T12PR24 81%, T12PR48 81%. Relapse was less common in subjects who received telaprevir and who were treated for at least 24 weeks: T12PR24 2%, T12PR48 6% vs. T12PR12 33%, PR48 23%. The rate of virological breakthrough in telaprevir-treated patients was 7%, with most of the breakthroughs occurring in patients who had never cleared HCV RNA completely. In patients with breakthrough, resistant variants were detected with mutations including V36M, R155K (genotype 1a) or A156T (genotype 1b). As shown previously, V36M and R155K/T variants are observed in patients with genotype 1a because of a lower genetic barrier as these mutations require only 1 nucleotide change in the triplet codon at the 36 and 155 positions compared with 2 changes required in genotype 1b . The V36M and R155K/T variants are more fit than the A156T variant noted in genotype 1b patients .
There was a higher rate of discontinuation of the overall treatment regimen for adverse events (21%) in telaprevir-based groups vs. (11%) control patients, with an increased frequency of rash, pruritus, nausea, diarrhoea, and anaemia noted. Twelve patients (7%) who received telaprevir developed severe rash and discontinued therapy vs. 1(1%) control patient. Erythropoiesis-stimulating agents were prohibited for the first 12 weeks of treatment. The mean decline in haemoglobin (Hb) was 3 gm/dl in the control group with an incremental rate of haemoglobin decline of 0.5–1 gm/dl more in telaprevir-treated patients. After telaprevir was discontinued, the haemoglobin increased. PROVE 1 demonstrated superiority of combination therapy over standard of care and illustrated that with combination therapy a shorter treatment course could be considered. It raised RVR as a required criterion for stopping therapy at earlier time points than the standard 48 weeks. Rash and anaemia emerged as the most common side effects of therapy .
PROVE 2 was the European counterpart to PROVE 1. It evaluated the safety and efficacy of telaprevir in combination with PEG-IFN with or without RBV in noncirrhotic treatment-naïve HCV genotype 1 patients . It was designed as a multicentre, randomized, partially double-blind placebo-controlled phase 2b trial.
There were four treatment groups (total n = 334) including- T12PR12, T12PR24, T12P12 (telaprevir and PEG-IFN only) and standard of care regimen PR48. This RBV free arm (T12P12) was distinct from PROVE 1, as was the equivalent number of patients in all four treatment arms. An RVR was not required for patients to stop therapy at the predefined stopping point defined in each treatment arm. Instead, patients in the T12PR24, T12PR12 and T12P12 groups were required to have undetectable HCV RNA levels at the last study visit before the planned end of treatment, which was week 10 for T12PR12 and T12P12 and week 20 for T12PR24 group or they went on to continue PEG-IFN/RBV for 48 weeks. SVR rates were 46% in the control group (PR), 36% in the T12P12, 60% in T12PR12 and 69% in T12PR24. RVR rates were PR48 13%, T12P12 50%, T12PR24 69% and T12PR12 80%. Relapse occurred in 22% of controls, 48% of patients treated without RBV (T12P12), 14% of the T12PR24 group, and 30% of the T12PR12 group. A multivariate analysis showed that treatment group and baseline HCV RNA were the only two variables significantly associated with SVR.
Hepatitis C virus with low-level resistance was found at baseline in 1% of subjects. Among subjects with viral breakthrough who had sequencing performed, wild-type virus was noted in 5%, low-level resistance in 41%, and high-level resistance in 55%. Among subjects with relapse who had sequencing performed, wild-type virus was noted in 5%, low-level resistance in 79%, and high-level resistance in 17%.
The median time to appearance of rash of any severity in the telaprevir-based groups was 9–12 days. Severe (grade 3) rash was found in 7% of patients (6 of 81) in the T12PR24 group, 6% (5 of 82) in the T12PR12 group, and 3% (2 of 78) in the T12P12 group, but was not seen in the PR48 group. Twelve of the 163 patients (7%) in the combined T12PR24 and T12PR12 groups discontinued treatment because of rash.
PROVE 2 confirmed that telaprevir is effective and has an acceptable tolerability profile in combination therapy for the treatment of HCV genotype1 treatment-naïve subjects and that the clinical viral breakthrough that occurred during the dosing period was related to selection of viral variants with decreased sensitivity to telaprevir. It highlighted the importance of ribavirin in the treatment regimen. It revealed that baseline viral load was predictive of response even with telaprevir therapy .
PROVE 3 was undertaken to evaluate telaprevir's efficacy in patients with HCV infection who had not had a sustained response to an initial full course of treatment with PEG-IFN and RBV, i.e. prior treatment failures . It was an international randomized, partially placebo-controlled, partially double-blind, phase 2 study. The study population included subjects with HCV genotype 1 age 18–70 who had been previously been treated with PEG-IFN/RBV for at least 12 weeks and did not have SVR. They were stratified by type of treatment failure: nonresponse, relapse and breakthrough. Fifty seven per cent of subjects were considered to previously have had nonresponse, 36% relapse and 7% breakthrough. Exclusion criteria included chronic HBV, HIV, cirrhosis on biopsy within 2 years, decompensated liver disease, HCC, another cause of clinically significant liver disease, absolute neutrophil count <1500/mm3, platelets <100 000/mm3. Subjects were required to have had a liver biopsy within 3 years. Unlike PROVE 1 and 2, PROVE 3 included cirrhotics, who comprised 16% of the study population. There were four treatment groups: (i) T12PR24; (ii) T24PR48; (iii) T24PR24; and (iv) PR48. Those in the control group (PR48) were allowed to roll over and receive telaprevir after study conclusion. Telaprevir was dosed 1125 mg on day 1 and then 750 mg p.o. q8h. Stopping rules included: breakthrough between weeks 4 and 24; <1 log10 drop by week 4 in the control group; HCV >30 IU/ml at week 4 in the telaprevir-treated subjects; <2 log10 decline at week 12; and detectable virus at week 24.
The T12PR24 and T24PR48 regimens were most efficacious and not statistically different from one another, with SVR rates of 51 and 53% respectively, vs. 24% with T24P24 and 14% with PR48. However, discontinuation of therapy because of adverse events was less common in the T12PR24 group than in the T24PR48 group. Rates of SVR were higher among subjects who had previously had a relapse (T12PR24 69%; T24PR48 76%; T24P24 42%; and PR48 20%) than among those who had not had a response to previous treatment (T12PR24 39%, T24PR48 38%, T24P24 11%, PR48 9%). There was less relapse among the subjects in the T12PR24 and T24PR48 arms with relapse rates of 30 and 13% respectively vs. 53% in both the T24P24 and PR48 groups. For subjects in the T24PR48 group who actually completed treatment, relapse rates were 4% overall, 4% for patients with no previous response, and 0% for patients with a previous relapse. There were more breakthroughs with genotype 1a then 1b, with rates of 24% vs. 11%. In a subanalysis, cirrhotics had equivalent rates of SVR in this study compared with noncirrhotics.
Logistic regression analysis showed that a sustained virological response was significantly associated with assignment to the T12PR24 or T24PR48 group, an undetectable HCV RNA level during a previous period of treatment with peginterferon alfa and ribavirin, and low baseline viral load (<800 000 IU/ml). The majority of subjects who discontinued therapy because of a stopping rule had the V36M/R155K double variant; all but one of the subjects had infection with HCV genotype 1a.
Again, relapse occurred less frequently with the T24PR48 regimen than with the T12PR24 regimen and rates of SVR were similar in the T12PR24 and T24PR48 groups. However, discontinuation of therapy because of adverse events was less common in the T12PR24 group than in the T24PR48 group. The overall efficacy and safety results indicate that the T12PR24 regimen appeared to provide a better risk–benefit profile than the T24PR48 group . This left open the question of whether selected patients who are tolerating treatment and have a significant risk of relapse (e.g. genotype 1a patients) might optimize their treatment with a total of 48 weeks of therapy, perhaps with an initial 12 weeks of telaprevir. This is, in fact, what was studied in phase 3 (see below; Figs 1–3).
Phase 3 studies
ADVANCE was the larger of two phase 3 trials of telaprevir in treatment-naïve G1-infected patients . In addition to establishing the safety and efficacy of telaprevir for purposes of registration, it had two important goals: first, to explore an 8-week rather than 12-week course of telaprevir to assess whether the incidence or severity of side effects, particularly rash, could be reduced while preserving efficacy; second, to assess the capacity to truncate therapy to 24 weeks in patients with robust viral responses and still attain high rates of SVR with minimal relapse.
ADVANCE was a three-arm double-blind, randomized study, which was placebo-controlled for telaprevir. The study population (n = 1088) consisted of treatment-naïve G1 HCV subjects and included subjects with advanced fibrosis (21%) i.e. bridging fibrosis or compensated cirrhosis. Patients in the telaprevir arms received either 12 or 8 weeks of telaprevir at a dose of 750 mg q8h, PEG-IFN and RBV, followed by PEG-IFN and RBV alone (T8PR or T12PR). Patients who attained undetectable HCV RNA at both weeks 4 and 12 were defined as having had extended rapid virological response (eRVR), and were assigned to stop after total treatment of 24 weeks. In contrast, patients who failed to attain eRVR were treated for up to 48 weeks.
Stopping rules included discontinuation of telaprevir alone after 4 weeks if HCV RNA was over 1000 IU/ml, discontinuation of all treatment for < 2 log decline in HCV RNA at week 12, and discontinuation of all therapy for detectability of HCV RNA at 24 weeks or any time thereafter.
Sustained virological response rates of 75 and 69% for T12PR and T8PR, respectively, compared with 44% in controls confirmed the superiority of telaprevir combination therapy over the current standard of care (P < 0.001 for T12PR or T8PR vs. PR). Relapse rates were 9% in each of the telaprevir groups and 28% in the control patients. Patients in T12PR and T8PR had RVR rates of 68 and 67%, respectively, and eRVR rates of 58 and 57% vs. only 9 and 8% of controls. The patients with eRVR were those assigned to 24 weeks of treatment; these patients had SVR rates of 89% (T12PR) and 83% (T8PR). Of the small number of patients who received PR for 48 weeks after attaining eRVR, 97% had SVR. Patients who failed eRVR had SVR rates of 54, 50 and 39% in T12PR, T8PR and PR. Subset analyses showed that African Americans who received PR had SVR of 25% vs. 62% with T12PR, and patients with advanced fibrosis had an increase in SVR from 33 to 62%.
The rate of virological failure, defined by the meeting of one of the stopping rules or having an HCV RNA >1000 IU/ml at week 12 even if HCV RNA declined by 2 log10) during the first 12 weeks, was 3% in both the T12 and T8 groups and was associated with the emergence of variants with a high level of resistance to telaprevir. After week 12, during PEG-IFN/RBV, treatment failure was somewhat higher in T8/PR (10%) compared with T12/PR (5%) and associated with wild-type and lower level TVR-resistant variants. The rate of virological failure with PR was 32%. These observations suggest that the main benefit of T12 compared with T8, reflected in the slightly higher rate of SVR of T12 (the study was not powered to demonstrate a statistical difference between T12 and T8), was more efficient clearance of wild-type and low-level-resistant variants with the additional 4 weeks of telaprevir in T12 .
Overall rates of treatment discontinuation for adverse events occurred in 10, 10 and 7% of patients in T12PR, T8PR and PR. During the first 12 weeks of therapy, telaprevir/placebo alone was stopped in 11, 7 and 1% for adverse events overall. Telaprevir was associated with an increase in rash and anaemia, as well as diarrhoea, pruritus, and nausea. Grade 3 rash occurred in 6, 3, and 1% of patients. The rash was primarily eczematous clinically and histologically. Severe rash was managed by sequentially discontinuing telaprevir, followed by RBV 7 days later if considered necessary and then PEG-IFN for continued progression. Severe rash events led to discontinuation of telaprevir/placebo in 7, 5 and 1%. In contrast, discontinuation of all study drugs for rash events seldom occurred: 1.4, 0.5, and 0%. The rash resolved upon discontinuation . The rash management plan was credited with a lower rate of overall treatment discontinuation for rash than occurred in the phase 2 programme.
A nadir haemoglobin of < 10 gm/dl occurred in 38% of telaprevir patients and 14% of controls, while nadir haemoglobin < 8.5 gm occurred in 9% of telaprevir patients and 2% of controls. As per the protocol, anaemia was managed with RBV dose modifications and erythropoiesis-stimulating agents were not allowed. Discontinuation of all drugs because of anaemia events occurred in 1, 3 and 1% of patients in T12PR, T8PR and PR. Four per cent, 2 and 0% of patients respectively discontinued telaprevir/placebo only. By 24 weeks of therapy, haemoglobin levels were comparable among patients who had initially received telaprevir and controls. Retreatment with only 8 weeks of telaprevir was not associated with less discontinuation of the entire treatment regimen because of adverse events than 12 weeks (8% vs. 7%) .
The ADVANCE study strongly suggested that 24 weeks of total therapy was sufficient in patients with eRVR, an inference derived from the high rates of SVR and low rates of relapse in patients with eRVR treated for 24 weeks. To support this concept, the ILLUMINATE trial was undertaken . It was a phase 3 open label multicentre (74) study. HCV G1 treatment-naïve subjects treated with 12 weeks of triple therapy (telaprevir, PEG-IFN and RBV) and those who achieved an extended rapid viral response (eRVR) were randomized at week 20 to receive either 24 or 48 weeks of total PEG-IFN/RBV therapy to show non-inferiority of the 24 week treatment course. Patients who did not achieve eRVR continued 48 weeks of therapy. The study population included cirrhotics (11%).
Non-inferiority of the 24 week treatment regimen among subjects who achieved eRVR was established by SVR rates of 92% for 24 weeks vs. 88% for 48 weeks of therapy. Overall SVR in the intention-to-treat analysis was 72%. Permanent discontinuation of therapy because of adverse events occurred in 17.4% of subjects and was more common the in 48 week treatment group. ILLUMINATE affirmed the foundation for response-guided therapy in telaprevir-containing combination treatment of HCV .
The REALIZE Trial (Re-treatment of Patients with Telaprevir-based Regimen to Optimize Outcomes) was conducted to further define telaprevir-based therapy in subjects who have previously failed a course of PEG-IFN and RBV . There were 3 treatment arms: (i) telaprevir dosed at 750 mg q8h for 12 weeks in combination with standard doses of PEG-IFN and RBV, followed by 36 weeks of treatment with PEG-IFN and RBV alone; (ii) A delayed start arm, comprised of 4 weeks of treatment with PEG-IFN and RBV, followed by telaprevir dosed at 750 mg q8h for 12 weeks in combination with standard doses of PEG-IFN and RBV, followed by another 32 weeks of PEG-IFN and RBV alone; and (iii) A control arm with standard doses of PEG-IFN and RBV dosed for 48 weeks.
Overall, SVR occurred in 65% of telaprevir recipients and 17% of controls. There was no significant difference in SVR rates between patients in the delayed start arm and those who started all three drugs simultaneously. As expected, a gradient of SVR occurred such that patients with the highest degree of intrinsic responsiveness to interferon, i.e. relapsers, had the highest rate of SVR (86%). Partial responders, those with a > 2 log reduction in HCV RNA at week 12 previously, had SVR in 57%, and null responders, who had a < 2 log decline in HCV RNA at week 12 previously, had SVR in 31%.
An important subanalysis of this trial demonstrated that, among relapsers, cirrhosis did not adversely affect SVR rates. However, in prior partial responders with cirrhosis, the SVR rate was reduced to 34% and, even more impactfully, prior null responders with cirrhosis had an SVR rate of only 14%.
Analysis of the lead-in arm of the REALIZE trial evaluated the association between degree of HCV RNA decline after the 4-week lead-in period of PEG-IFN/RBV and the subsequent likelihood of SVR . In relapsers, SVR rates were 62% in those who had less than 1 log10 decline in HCV RNA at week 4 compared to 94% in those with a decline of 1 log10 or greater. In partial responders, SVR rates were 56 and 50% respectively. The greatest impact was observed in prior null responders, with SVR rates of 15 and 54% respectively.
The capacity of HCV to become resistant to DAAs in general, including protease inhibitors, manifests itself in the resistant variants, which are usually detectable in patients with virological failure or virological breakthrough on therapy with telaprevir. There has been considerable concern about the long-term fate and clinical impact of these resistant variants. If such variants are persistent, they could theoretically have an adverse impact on treatment outcomes if patients who have failed a prior course of therapy with a protease inhibitor are being considered for retreatment with the same or similar drugs in future regimens of which they are a component. The EXTEND trial was conducted as a 3-year virology follow-up study on subjects from the phase 2 and 3 telaprevir trials. In an interim analysis of the patients in the phase 2 studies, and hence followed up for a longer period of time as of late 2010, SVR was shown to be durable (99%) with telaprevir-based therapy, and that there is reversion to wild-type virus in subjects who had developed telaprevir resistance on therapy. Subjects who had viral variants (AA positions 36, 54, 155, 156) associated with decreased telaprevir susceptibility at time of treatment failure were evaluated and at a median of 25 months after treatment, the resistant variants had cleared in 89% of subjects as determined by population sequencing, which requires that at least 20% of the viral population consist of a given variant . In a subset of patients evaluated by more sensitive clonal sequencing, these results were verified. This analysis is planned to continue, and such long-term monitoring studies should be considered important components of trials of new direct-acting antiviral agents (Figs 4 and 5).
Building on the results of the studies above using telaprevir-based therapy in treatment-experienced patients, investigators in the PROVE studies selected 117 patients in the placebo arms who were either nonresponders or relapsers to PEG-IFN/RBV and rolled them over into treatment with telaprevir-containing regimens . The initial protocol was 12 weeks of telaprevir/PEG-IFN/RBV followed by an additional 12 weeks of PEG-IFN/RBV. The protocol was changed during the study so that prior null responders had PEG-IFN extended to week 48, whereas all other patients received either 24 total weeks of therapy if HCV RNA was undetectable at weeks 4 and 12 or 48 weeks of therapy if HCV RNA was detectable at weeks 4 or 12. The overall SVR rate was 59%. SVR was achieved in 37% (19/51) of prior null responders, 55% (16/29) of prior partial responders, 75% (6/8) in prior breakthroughs and 97% (28/29) of prior relapsers.
The observations in relapsers helped to establish the basis for the recommendation in the product label for truncation of total therapy to 24 weeks in the event of an eRVR, even though only 48 weeks of therapy was evaluated in the phase 3 REALIZE study.
Effect of ribavirin dose reduction
Retrospective analysis was performed on the treatment-naïve patients in the ADVANCE and ILLUMINATE trials as well as treatment-experienced patients in the REALIZE trial who received the telaprevir-containing regimen to assess the effect of RBV dose reduction on SVR rates . Of the treatment-naïve patients, 50% required RBV dose reduction, including 45% with reduction to 600 mg daily or lower. In these patients, 75% of those reduced to 800–1000 mg RBV and 74% of those reduced to 600 mg or less RBV daily achieved SVR, compared to 79% who did not require RBV dose reduction. In the treatment-experienced patients, RBV dose reduction was required in 39% of the prior relapsers, 31% of the prior partial responders, and 18% of the prior null responders in the telaprevir arms. Of the prior relapsers, SVR was achieved in 90% who had RBV dose reduction to 600 mg daily or lower and in 84% who had RBV dose reduction to 800–1000 mg daily as opposed to 82% in those who did not require RBV dose reduction. In prior partial responders, 62% of those who had RBV dose reduction to 600 mg daily or lower achieved SVR compared to 50% who had reduction to 800–1000 mg daily and 62% who did not require dose reduction. Finally, SVR rates in prior null responders were 22% in those who had reduction to 600 mg or less RBV daily, 50% in those reduced to 800–1000 mg daily, and 31% who did not require dose reduction. Collectively, these observations have been interpreted as providing reassurance to clinicians that ribavirin dose reductions for anaemia do not substantially compromise the chance of SVR.
Safety of use in cirrhosis
Given the small number of cirrhotics included in the aforementioned Phase 3 trials, further study has been performed on the safety of treating cirrhotic patients with a telaprevir-containing regimen . In the French Early Access Program (ANRS C020-CUPIC), 169 patients with compensated Child's A genotype 1 HCV cirrhosis were treated with telaprevir in combination with PEG-IFN-alfa2a and RBV. Patients were treated for a median of 16 weeks prior to abstract publication. Overall, 51% of patients experienced a serious adverse event. Discontinuation of treatment medications occurred in 12% of patients. Grade 2 anaemia was observed in 32% of patients, while Grade 3 to 4 anaemia was observed in 14%. With the proviso that ribavirin dose reductions were seldom implemented in these patients, more than half required erythropoietin administration for anaemia and 19% required blood transfusions. Grade 3 to 4 anaemia was observed in 12% of patients, while Grade 3 to 4 thrombocytopenia was observed in 22%. Finally, 7% experienced Grade 3 rash while 2% died while being treated.
Dosing frequency and interferon preparation considerations
A recent study investigated the safety, tolerability, and pharmacokinetics of telaprevir dosed in the usual 750 mg q8h interval as well as 1125 mg q12h in combination with either PEG-IFN alfa-2a or PEG-IFN alfa-2b . In this study, 161 treatment-naïve patients were randomized to receive one of the two telaprevir dosing regimens above combined with either PEG-IFN 2a or 2b and RBV. All patients received triple therapy for 12 weeks followed by either 12 or 36 additional weeks PEG-IFN/RBV based on viral response. There was no significant difference in SVR rates among the groups (81–85%), leading investigators to conclude that either telaprevir dosing frequency or type of PEG-IFN alpha was acceptable. Twice daily telaprevir dosing is being evaluated in a larger trial.
Use in HIV/HCV coinfection
Telaprevir in combination with PEG-IFN/RBV is also being studied in the treatment of HIV/HCV genotype 1 co-infected individuals, a patient population with historically low response rates to treatment with PEG-IFN/ribavirin alone . In a phase 2 trial, 13 co-infected patients with CD4 T-cell counts greater than 500 cells/mm3 not currently on antiretroviral therapy (ART) and 47 co-infected patients on ARTs (24 on efavirenz, tenofovir, and emtricitabine and 23 on ritonavir-boosted atazanavir, tenofovir, and emtricitabine) were randomized to receive either telaprevir with PEG-IFN alpha− 2a/RBV or placebo with PEG-IFN alpha-2a/RBV. Triple therapy was given for 12 weeks, with PEG-IFN/RBV continued through week 48. Patients taking efavirenz had their dose of telaprevir increased to 1125 mg three times daily to compensate for a known drug interaction that lowers the level of telaprevir. Patients on atazanavir were given the standard dose of telaprevir, 750 mg three times daily.
Overall, 74% of patients taking the telaprevir-containing regimen achieved SVR12, compared with 45% of those taking PEG-IFN/RBV alone. In the patients not taking ARTs, the SVR12 rates were 71 and 33% respectively. In patients taking efavirenz, SVR12 was seen in 69% of those treated with telaprevir compared with 50% of those in the PEG-IFN/ribavirin–alone arm. In patients taking atazanavir, SVR12 was seen in 80% of those in the telaprevir group compared with 50% of those in the placebo group. No HIV viral rebound was observed during the study. Three patients taking telaprevir discontinued treatment because of adverse events compared with none in the PEG-IFN/ribavirin-alone groups. These early data suggest that the efficacy and safety of HIV/HCV-co-infected patients may parallel those seen in HCV-monoinfected patients.
Efficacy in genotype 2 and 3 HCV
The antiviral activity or telaprevir alone or in combination with PEG-IFN/RBV has recently been studied in genotypes 2 and 3 HCV . In this randomized, multicentre trial, 23 patients with genotype 2 HCV and 26 patients with genotype 3 HCV were enrolled. Levels of HCV RNA were observed to decrease in all patients with genotype 2 HCV, including those who received telaprevir monotherapy. In genotype 2 patients, SVR rates were 56% in those treated with telaprevir monotherapy followed by PEG-IFN/RBV for 24 weeks, 89% in those treated with PEG-IFN/RBV alone, and 100% in those treated with the three-drug combination. In genotype 3 patients, telaprevir monotherapy had limited activity in terms of viral response and addition of telaprevir did not increase the SVR rates above that of PEG-IFN/RBV alone.
Current prescribing guidelines and considerations
The use of a protease inhibitor in conjunction with PEG-IFN and ribavirin can be considered the new standard of care in genotype 1 HCV-infected patients. Telaprevir was approved by the FDA in May 2011 for the treatment of chronic HCV genotype 1 infection. The medication is available in oral tablet form and is to be given at a dose of 750 mg to be taken three times daily every 7–9 h with a 20 g fat-containing meal or snack, in combination with PEG-IFN/RBV therapy . Patients must receive the three-drug regimen for 12 weeks, followed by response-guided therapy (RGT) of either 12 or 36 additional weeks of PEG-IFN/RBV, depending on viral response and prior response. For treatment-naïve patients and prior relapsers, those with undetectable HCV RNA at weeks 4 and 12 (eRVR) are instructed to undergo therapy with 12 additional weeks of PEG-IFN/RBV. The exception to this guideline is for treatment-naïve patients with cirrhosis and undetectable HCV RNA at weeks 4 and 12 where 36 additional weeks of PEG-IFN/RBV is suggested. Many clinicians, including the authors, also recommend 48 weeks of total therapy in prior relapsers even when eRVR has been attained. For prior partial and null responders, all patients should receive 12 weeks of the three-drug regimen, followed by 36 weeks of PEG-IFN/RBV. Discontinuation is recommended for patients with HCV RNA greater than 1000 IU/ml at week 4 or 12, or detectable HCV RNA at week 24. Retrospective analysis of the ADVANCE, ILLUMINATE and REALIZE trials has now clearly demonstrated that those patients with greater than 1000 IU/ml at week 4 accurately predicted treatment failure, with 24/25 of these patients already experiencing viral breakthrough , and none going on to SVR despite continuation of PEG-IFN/RBV past week 4 in these studies.
Patients should be monitored during therapy with follow-up visits and lab testing including complete blood count, chemistry, liver function tests and thyroid-stimulating hormone as per current standard of care. A greater mean level of haemoglobin decline than traditionally seen with PEG-IFN and RBV should be anticipated [14, 17]. Anaemia should be managed with RBV dose reductions prior to discontinuation of therapy. Although erythropoiesis-stimulating agents were not allowed in development programmes and are not FDA-approved, they can be considered in patients on an individualized basis.
An eczematous rash may occur. Severe rash, e.g. rash involving over 50% of body surface area or any evidence of mucosal ulceration, should be managed with sequential discontinuation of drug therapy as necessary by first discontinuing telaprevir, followed by RBV 7 days later as necessary and PEG-IFN if there is continued progression. Therapy need not be stopped all at once unless necessary in the clinician's judgement . Although 12 weeks of telaprevir therapy is preferred, telaprevir may be discontinued at week 8 with only a slight impact on the chance for SVR .
Because telaprevir is a potent inhibitor of the cytochrome enzyme CYP3A, it is contraindicated for concurrent use with medications that are highly dependent on CYP3A for clearance. Medications of note include lovastatin, simvastatin and atorvastatin. Similarly, concurrent use of medications that strongly induce CYP3A should be avoided as they lead to reduced efficacy. Because exposure to ethinyl estradiol may be reduced when telaprevir is coadministered, hormonal contraceptives should not used as 1 of the 2 required methods of contraception for PEG-IFN/RBV therapy while telaprevir is being given and for 2 weeks after telaprevir is discontinued. Clinicians should consult the list of contraindicated drugs and the more extensive list of drugs with potential interactions available in the telaprevir package insert. Dose reduction and telaprevir monotherapy are strictly prohibited to minimize the emergence of viral resistance.
The treatment of prior null responders with telaprevir deserves particular mention. The success rates reported in such patients represent a more efficacious option than any prior treatment regimen. However, it must be understood that the price of treatment failure with telaprevir (or any protease inhibitor) is a high likelihood that the patient will be left with resistant variants. This is particularly notable in prior null responders, in whom the SVR rates of just over 30% must be balanced against the high chance of leaving those patients who fail such treatment, representing the majority of the this subpopulation, with resistant variants. In the benefit–risk assessment pertaining to these patients, those with advanced fibrosis would seem to comprise the prior null responders in whom the most compelling argument for retreatment exists. As with all patients in the new treatment era, the concept of resistance, and the basic aspects of what we understand about its potential implications, must be conveyed to patients in a manner understandable to the patient.
This article was published in Clinics in Liver Disease, Copyright Elsevier, 2012.