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Telaprevir, peginterferon alfa-2a, and ribavirin for 28 days in chronic hepatitis C patients EDITORIAL
 
 
  Journal of Hepatlogy
May 22, 2008
Article in Press
 
Stefan Zeuzem
 
published online 22 May 2008.
Uncorrected Proof
 
Associate Editor: M.P. Manns
 
"the question needs to be answered, whether selected HCV strains in non-responders will persist and impair the chances for patients to be cured in the future with the development of antiviral combination therapies of, e.g., protease and polymerase inhibitors.....Representatives from the industry developing these new compounds together with those from academic centers performing phase 1-3 clinical trials and regulatory agencies must carefully balance the urgent need for these new drugs on one hand with the responsibilities and requirements of a thoughtful and comprehensive clinical development program on the other hand [11] that should answer most of the questions raised above.
 
Article Outline

 
The first potent and specific inhibitor of the NS3/4A serine protease to be tested in a randomized, placebo-controlled pilot study in patients with chronic hepatitis C was ciluprevir (BILN 2061). In previously untreated patients with genotype 1 infection, treatment with ciluprevir for 2 days resulted in HCV RNA reductions of 2-3log10 copies/mL in most of the patients, thus providing proof-of-concept that HCV NS3/4A protease inhibitors are a therapeutic option for patients with chronic hepatitis C [1]. However, further clinical development of ciluprevir was suspended following reports of cardiotoxicity in animal studies [1].
 
The NS3/4A protease inhibitors telaprevir and boceprevir have been shown to reduce serum HCV RNA levels when used alone [2], [3] and to produce additive reductions in levels when administered with peginterferon (PEG-IFN) [3], [4]. Telaprevir monotherapy for 2 weeks was associated with a more than 4log10 median reduction of HCV RNA in patients with chronic hepatitis C genotype 1 infection [2]. When used as monotherapy, current protease inhibitors show a low barrier to genetic resistance, a potential problem for antivirals given the high rate and error-prone nature of HCV replication [5].
 
The study by Lawitz et al. [6] in the current issue of this Journal assessed the safety and antiviral effects of telaprevir (750mg q8h) in combination with peginterferon alfa-2a and ribavirin (RBV). Previously untreated patients infected with HCV genotype 1 received triple therapy for 28 days and could then start off-study treatment with PEG-IFN alfa-2a and RBV for up to 44 weeks at the discretion of the investigator and patient. All patients had undetectable HCV RNA levels by day 28, indicating that the addition of PEG-IFN and RBV may be able to inhibit the rapid selection of resistant strains as observed in the telaprevir monotherapy trials. Eight patients completed 44 weeks of off-study standard of care combination therapy. Eight patients achieved a sustained virologic response, including one patient who received only 22 weeks of treatment. In general, triple therapy was well tolerated, however, rash or pruritus occurred in 5 of the 12 patients [6].
 
Based on these data, larger phase II clinical trials have been initiated and very recently completed [7], [8]. The PROVE 1 trial in the US enrolled patients into 4 treatment groups: (i) group 1: telaprevir 750mg q8h, with PEG-IFN and RBV for 12 weeks; (ii) groups 2 and 3: patients received the same triple combination for 12 weeks, followed by treatment with PEG-IFN plus RBV alone for 12 or 36 weeks, respectively; (iii) group 4: 48 weeks of PEG-IFN plus RBV (controls). The PROVE 2 trial was conducted in Europe and had a similar design as PROVE 1, with an extra arm evaluating the PEG-IFN/telaprevir combination without RBV.
 
In PROVE 2 HCV RNA was undetectable at week 4 in 122/163 (75%) and 124/163 patients (76%) receiving triple therapy [8]. Thus, compared to the 12 patients of the study of Lawitz et al. (100% RVR), the RVR in the PROVE 2 study was apparently lower. Certainly, patients in the first pilot study of triple therapy were under very careful surveillance. Compliance with drug doses and intervals may have been less stringent in larger patient cohorts of the PROVE studies. Other factors may comprise adverse events leading to premature discontinuation, the development of viral resistance and breakthrough, perhaps due to different PEG-IFN and/or RBV sensitivities in the respective patient populations.
 
With the addition of direct antivirals to PEG-IFN/RBV several questions must be addressed in the future:
 
(i) Will every HCV-1 infected patient need the addition of a protease inhibitor to improve changes for SVR?
 
Probably not because patients with a low baseline viral load and a rapid virologic response comprising approximately 15% of the overall HCV-1 infected population already have SVR rates around 90% with only 24 weeks of PEG-IFN and RBV combination therapy [9].
 
(ii) What is the minimum Peg-IFN and RBV sensitivity to avoid functional monotherapy?
 
An "ideal" direct antiviral drug or drug combination which does not select for resistant strains may not require combination with PEG-IFN and RBV. However, drugs with a low genetic barrier such as protease inhibitors currently require the combination with PEG-IFN and RBV to eradicate the mutant viral strains. Whether substantial reduction of HCV RNA replication can restore innate immunity and IFN sensitivity in vivo (as it has been shown in vitro [10]) remains to be proven. Such effects would most likely enhance SVR rates.
 
[10]. [10]Foy E, Li K, Wang C, Sumpter R, Ikeda M, Lemon SM, et al.. Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease. Science. 2003;300:1145-1148
 
(iii) Is RBV needed? Is PEG-IFN needed?
 
The RBV sparing arm of PROVE 2 clearly shows that RBV is required in particular to reduce virologic relapse rates after the end of therapy. Furthermore, preliminary data from the SPRINT1 trial [10] suggest that RBV doses cannot even be reduced to 400-800mg without reducing the chances to achieve a virologic response. The question whether (peg)interferon is ultimately required cannot be answered at present. However, proof-of-concept pilot trials using potent protease and polymerase inhibitors in combination with RBV may provide an answer in the near future.
 
(iv) Is there a potential value of a PEG-IFN/RBV lead-in phase?
 
Hypothetically, achieving steady-state levels for peginterferon and ribavirin may (quantitatively) reduce the selection and expansion of resistant strains after the addition of a protease inhibitor. However, SVR-12 rates in patients treated for 24-28 weeks with peginterferon alfa-2b, ribavirin and boceprevir were similar but independent of a 4-week lead-in phase with PEG-IFN/RBV (57% vs. 55%) [10]. The benefit of lead-in phase remains to identify patients who do not require the addition of a protease inhibitor (low baseline viral load and RVR) and those who do not respond at all to PEG-IFN/RBV and would be exposed to functional monotherapy by addition of a protease inhibitor.
 
(v) How long must a potent direct antiviral be given and how long should be the overall treatment duration?
 
Direct antiviral agents may eradicate the sensitive wild-type population rapidly, perhaps within 8-12 weeks, which is reflected in the design of forthcoming phase III trial with telaprevir. So far, in patients with virologic breakthrough or relapse treated with telaprevir only resistant but not wild-type variants were identified supporting the concept that approximately 8-12 weeks may suffice to eradicate the resistant viral population. The question of how long PEG-IFN/RBV therapy must be continued to eradicate the mutant variants is quite unclear. Data suggest that overall PEG-IFN/RBV should be continued longer in patients not achieving a RVR (e.g. 36 vs. 12 additional weeks). On the other hand, in PROVE 2 62% and 68% of HCV-1 infected patients achieved an SVR with 12-week triple therapy and 12-week triple therapy followed by another 12 weeks of PEG-IFN/RBV combination, respectively. This implies that more than 90% of patients achieving an SVR in the latter group were apparently overtreated. The crucial question how patients who require more than 12-week triple therapy can be identified will need further attention. Possibly, pretreatment and on-treatment predictors of SVR may differ with triple therapy compared to PEG-IFN/RBV standard combination therapy.
 
(vi) How important is the pharmacokinetic profile of an antiviral drug?
 
Several HCV NS3/4A protease inhibitors are currently dosed every 8h. Experience from the treatment of HIV shows that compliance and adherence to such dosing intervals is impaired and affects antiviral responses. A major difference between HIV and HCV, however, is the overall duration of combination therapy. Patients should be able to adhere to strict dosing intervals for a limited period of time which is better than if treatment is required indefinitely. Nevertheless, there is no doubt that antiviral drugs which require only once (qd) or twice (bid) a day dosing will be preferred. Pharmacokinetics may also affect the emergence of resistant strains. So far, little information is published and more combined data on pharmacokinetics, pharmacodynamics, and the emergence of resistant strains are required.
 
(vii) Will the improvement in SVR rates be the only parameter to consider?
 
In the past, progress in the treatment of chronic hepatitis C was defined by improvement of SVR rates. Patients who failed PEG-IFN and RBV treatment were generally not considered to have endured any harm beyond the side effects they suffered during therapy. However, in the era of drugs rapidly selecting for resistance, the question needs to be answered, whether selected HCV strains in non-responders will persist and impair the chances for patients to be cured in the future with the development of antiviral combination therapies of, e.g., protease and polymerase inhibitors. Data for how long resistant strains can persist and whether these mutants can improve viral fitness by compensatory mutations are largely lacking.
 
(viii) What are the short and long-term side effects of the new direct antiviral drugs?
 
Relevant clinical and laboratory side effects of protease inhibitors comprise rash (telaprevir), anemia (telaprevir, boceprevir) and gastrointestinal side effects. Cardiotoxicity - as described for ciluprevir in monkeys - has yet not been observed in clinical trials in patients with chronic hepatitis C. All adverse events so far described were fully reversible after drug discontinuation. The safety data base, however, is still too small to definitely exclude the risk of life-threatening or irreversible side effects.
 
The data of the study by Lawitz et al. [6] as well as the recently presented data for telaprevir from the PROVE studies [7], [8] clearly show the tremendous potential of new direct antiviral drugs. Many patients are desperately waiting for improved treatment modalities for chronic hepatitis C. Representatives from the industry developing these new compounds together with those from academic centers performing phase 1-3 clinical trials and regulatory agencies must carefully balance the urgent need for these new drugs on one hand with the responsibilities and requirements of a thoughtful and comprehensive clinical development program on the other hand [11] that should answer most of the questions raised above.
 
Antiviral effects and safety of telaprevir, peginterferon alfa-2a, and ribavirin for 28 days in hepatitis C patients

 
Journal of Hepatology
May 22, 2008
Articles in Press
 
Eric Lawitz1, Maribel Rodriguez-Torres2, Andrew J. Muir3, Tara L. Kieffer4, Lindsay McNair4, Ariya Khunvichai4, John G. McHutchison3
 
Received 25 August 2007; received in revised form 23 February 2008; accepted 13 March 2008. published online 29 April 2008. Corrected Proof
 
ABSTRACT
Background/Aims

 
This study assessed the safety and antiviral effects of telaprevir (VX-950) in combination with peginterferon alfa-2a and ribavirin.
 
Methods
 
Twelve treatment-naive patients with chronic genotype 1 hepatitis C virus infection received telaprevir (750mg q8h), peginterferon alfa-2a (180μg/week), and ribavirin (1000 or 1200mg/day) for 28 days. Patients could then start off-study treatment with peginterferon alfa-2a and ribavirin for up to 44 weeks, at the discretion of the investigator and patient.
 
Results
 
The combination of telaprevir, peginterferon alfa-2a, and ribavirin was well tolerated, with no serious adverse events or treatment discontinuations. Rash or pruritus occurred in 5 of the 12 patients; all cases resolved either during or after the end of telaprevir treatment. All 12 patients had undetectable HCV RNA levels by day 28 (rapid viral response, RVR). Eight patients completed 44 weeks of off-study peginterferon alfa-2a and ribavirin treatment. Eight patients achieved a sustained viral response (SVR), including one patient who received only 22 weeks of treatment.
 
Conclusions
 
The combination of telaprevir, peginterferon alfa-2a, and ribavirin was generally well tolerated. Events of pruritus and rash resolved during or after end of telaprevir dosing. All 12 patients achieved an RVR.
 
Associate Editor: M.P. Manns
 
1. Introduction
 
Approximately 170 million people are infected with hepatitis C virus (HCV), and 3-4 million people are newly infected each year [1]. Of those infected, 55% to 85% develop chronic HCV infection [2]. The prevalence of chronic HCV infection in the United States from 1999 through 2002 was 1.3% (3.2 million people) [3]. The current treatment for patients infected with HCV genotype 1 is the combination of peginterferon alfa and ribavirin for 48 weeks [2]. However, this treatment results in a sustained viral response (SVR) in only about 45% of patients with genotype 1 HCV infection [4], [5]. Thus, there is a need for a treatment regimen with higher SVR rates than that currently available.
 
The HCV-encoded serine protease NS34A is essential for viral replication and is therefore an attractive target for anti-HCV therapy [6]. Telaprevir (VX-950) is a reversible, selective inhibitor of the HCV NS34A protease. In trials in which patients with genotype 1, chronic HCV infection were treated with telaprevir [7], [8], the 16 patients treated with telaprevir had a median decrease in plasma HCV RNA of approximately 4_log10 [7], [8]. The combination of telaprevir and peginterferon alfa-2a had a greater antiviral effect than telaprevir alone: in the eight patients who received telaprevir and peginterferon alfa-2a, the median decrease in HCV RNA was 5.5_log10 [8].
 
The primary objective of the present study was to assess the safety of 28 days of dosing of telaprevir in combination with peginterferon alfa-2a and ribavirin. We also evaluated antiviral effects and HCV NS34A sequence evolution. After the 28-day dosing period, subjects were offered off-study treatment with peginterferon alfa-2a and ribavirin and were evaluated for treatment outcomes.
 
2. Materials and methods
2.1. Study design and organization
 
This single-arm, open-label study was conducted between December 2005 and April 2006 at Alamo Medical Research, San Antonio, TX, USA, and Fundacion de Investigacion de Diego, San Juan, Puerto Rico. The study was conducted in compliance with Good Clinical Practice guidelines and the Declaration of Helsinki. Before the study, the protocol and informed consent form were approved by an institutional review board. All patients provided written informed consent.
 
All 12 patients received telaprevir, peginterferon alfa-2a (Pegasys, Roche Pharmaceuticals, Nutley, NJ), and ribavirin (Copegus, Roche Pharmaceuticals, Nutley, NJ) for 28 days. The first telaprevir dose was a 1250-mg loading dose (to shorten time required to reach a previously determined target telaprevir trough concentration); subsequent doses were 750mg every 8h. Peginterferon alfa-2a was given by subcutaneous injection at a dosage of 180μg/week. Ribavirin was given at a dosage of 1000mg/day (<75kg body weight) or 1200mg/day (_75kg body weight). Patients returned for follow-up visits 2 and 12 weeks after the end of the study drug dosing period.
 
After the 28-day study dosing period, all patients were offered an additional 44 weeks of peginterferon alfa-2a and ribavirin, so that they could complete standard therapy. This treatment was off-study but overlapped with the post-study follow-up visits noted above. The study investigators continued to follow these patients during the off-study treatment, and treatment outcomes are reported in this manuscript.
 
2.2. Study population
 
Patients enrolled in this study were men and women between 18 and 65 years of age with chronic HCV genotype 1 infection and detectable HCV RNA. Patients were judged to be in good health based on medical history and physical examination, and agreed to use two methods of contraception. Patients were excluded from the study if they had prior approved or investigational therapy for hepatitis C; contraindications to peginterferon alfa-2a or ribavirin; decompensated liver disease or any other cause of significant liver disease; histologic evidence of cirrhosis; excessive use of alcohol in the previous 12 months; hepatitis B or human immunodeficiency virus infection; or abnormal urine screen for illegal or illicit drugs.
 
2.3. Pharmacokinetics
 
Blood samples were collected for analysis of telaprevir, peginterferon-alfa-2a, and ribavirin concentrations. Multiple timepoints were assessed on days 1 and 28; single samples were drawn on days 2, 3, 8, 15, and 22. Plasma concentrations of telaprevir and ribavirin were determined using high performance liquid chromatography with tandem mass spectroscopic detection. Serum concentrations of peginterferon alfa-2a were determined by an enzyme-linked immunosorbent assay. A nonlinear mixed-effect modeling approach implemented in NONMEM software (Pharsight Corporation, Mountain View, CA) was used to determine the pharmacokinetic model that best described telaprevir pharmacokinetics. Peginterferon alfa-2a and ribavirin trough concentrations on day 28 were summarized.
 
2.4. HCV RNA measurements
 
HCV genotype and subtype were determined by sequence analysis of the 5_ noncoding region of HCV (TRUGENE 5_NC HCV Genotyping Kit, Bayer HealthCare, Diagnostics Division, Tarrytown, NY, USA). Plasma HCV RNA levels were determined using the Roche COBAS TaqMan HCV/HPS assay (Roche Molecular Systems Inc., Branchburg, NJ, USA). The linear dynamic range of the assay was 30IU/mL to 2.0_108IU/mL. The lower limit of quantitation of the assay was 30IU/mL, and the limit of detection (LOD) was 10IU/mL. HCV RNA levels were measured on days 1 through 3 and on days 8, 15, 22, and 28 of the study drug dosing period and 2 weeks and 12 weeks after the end of study drug dosing. Investigators and patients were blinded to HCV RNA results during the study drug dosing period.
 
2.5. HCV NS3 sequence analysis
 
HCV RNA was isolated from plasma samples collected on day 1 before the first dose of study drug, on days 2, 8, 15, 22, and 28 of the study drug dosing period and at the 2-week and 12-week follow-up visits. During off-study treatment, additional samples were obtained from 2 subjects who had viral breakthrough (patient 3 at weeks 16 and 24 and patient 8 at week 24). The full 534bp NS3 protease catalytic domain was amplified by semi-nested RT-PCR, cloned, and sequenced. The sequencing assay LOD was 100IU/mL. Enzymatic phenotypic studies of all variants were performed to determine whether the mutations decreased the sensitivity of the virus to telaprevir [8].
 
2.6. Safety assessments
 
During the on-study period, patients were monitored for safety at regular intervals from the start of dosing through a follow-up visit 2 weeks after completion of study drug dosing. Safety assessments included physical examinations, clinical laboratory tests, ECGs, and adverse events. During off-study therapy, patients were monitored for safety per investigator standard practice.
 
2.7. Statistical analysis
 
No prospective calculations of statistical power were made. The sample size was selected to provide information on the safety, tolerability, pharmacokinetics, and pharmacodynamics of telaprevir in combination with peginterferon alfa-2a and ribavirin during 28 days of dosing. For HCV RNA levels and clinical laboratory assessments, baseline was defined as the median of all pre-dose values. HCV RNA values were summarized using descriptive statistics. Descriptive statistics were reported for clinical laboratory and vital sign data. Categorical presentation was used for adverse events.
 
3. Results
 
3.1. Patient characteristics

 
Twelve patients (6 men and 6 women) were enrolled in the study and completed the study drug dosing period and follow-up visits (Fig. 1). Patient baseline characteristics are shown in Table 1. Data for all 12 patients were included in the analyses.
 
3.2. Pharmacokinetics
 
Telaprevir absorption was characterized by an initial slow phase followed by a second rapid phase. Absorption was preceded by an average lag time of 0.21h. Telaprevir exposure, as measured by the population-predicted telaprevir median AUC0-8 value at steady-state, was 26.4mgh/mL. The predicted median trough concentration of telaprevir from the final population pharmacokinetic model was 2568ng/mL. The observed median trough concentrations on day 28 were 17ng/mL for peginterferon alfa-2a and 2580ng/mL for ribavirin.
 
3.3. HCV RNA levels
 
Between baseline and day 28, all 12 patients had a decrease from baseline of at least 4_log10 (10,000-fold), and 10 patients had a decrease greater than 5_log10. No patient had any evidence of viral breakthrough during the dosing period (Fig. 2). Two patients had undetectable levels of plasma HCV RNA (<10IU/mL) within 8 days of the start of dosing, and all patients had undetectable HCV RNA levels at the end of the 28-day dosing period.
 
All patients started off-study standard peginterferon alfa-2a and ribavirin treatment within 1 day of the end of study drug dosing. Table 1 shows the treatment outcomes. Eight patients achieved an SVR, including one patient who discontinued after 22 weeks of treatment because of fatigue. Two patients discontinued treatment because of viral breakthrough.
 
3.4. HCV NS3 sequence analysis
 
All 12 patients were sequenced at baseline, and only wild-type virus (virus with no previously-identified telaprevir-resistance mutations) was detected. On day 2 of treatment, only wild-type virus was detected in 11 patients. One patient (1, Fig. 3) had a small amount (5%) of the V36M variant, which has a lower-level of telaprevir resistance; this variant was reduced to undetectable levels at the next timepoint in this patient (day 8). Because of the rapid and substantial response to treatment (Fig. 2), HCV RNA levels on day 8 were below the LOD of the sequencing assay (100IU/mL) in 10 patients. Therefore, day 8 sequence data are only available for two patients. One of the patients had only wild-type virus detected. The other patient (4, Fig. 3) had a mixture of lower-level (77% V36M) and higher-level telaprevir-resistant variants (A156T, 11%; 36/156, 5%) and wild-type virus (7%).
 

WT-1.gif

As described in the previous section, two patients had viral breakthrough during off-study treatment with peginterferon alfa-2a and ribavirin. Patient 3 (Fig. 3) had detectable HCV RNA (<30IU/mL) at the 12-week follow-up and was retested 10 days later and found to have a viral load of 350IU/mL. No sequencing sample was obtained at this time point. To determine the sequence of the rebounding virus, a sample was obtained at Week 16 of follow-up. The HCV RNA level was 490IU/mL and consisted of 90% R155K, a low-level resistant variant, and 10% wild-type virus. A second sample taken at the 24-week follow-up revealed that the R155K variant had begun to be replaced by wild-type virus (60% wild-type virus; 40% R155K). A second patient (8, Fig. 3) had detectable HCV RNA at 24 weeks after the end of study drug dosing, and virus at this timepoint consisted of predominantly wild-type virus (86% wild-type virus; 14% R155K variant).
 
3.5. Serum ALT and AST levels
 
The median decrease from baseline to day 28 was _18IU/mL for ALT and _17IU/mL for AST. In seven patients, ALT and AST levels were above the normal range at baseline and within the normal range at day 28. Five patients had ALT levels within the normal range at baseline and at day 28; ALT decreased during the dosing period in four of these patients (decreases of 6-19IU/mL) and remained stable in one patient (decrease of 2IU/mL). Four patients had normal AST levels at baseline and at day 28; AST decreased during the dosing period in two of these patients (decreases of 6 and 15IU/mL) and remained stable in two patients (decreases of 2 and 3IU/mL). One patient had high AST levels at baseline and at day 28.
 
3.6. Safety
 
All patients had at least one adverse event. The most frequent events were influenza-like illness, fatigue, headache, nausea, anemia, depression, and pruritus (Table 2). The dose of ribavirin was reduced from 1000mg/day to 600mg/day for one patient because of clinically significant anemia. There were no other dose reductions, and no serious adverse events or premature discontinuations. One patient had a severe headache, and six patients had moderate adverse events (influenza-like illness, fatigue, pruritic rash, constipation, abdominal pain, gastroesophageal reflux disease, nausea, vomiting, headache, acute otitis media, and seasonal allergy). All other adverse events were of mild intensity.
 
Two patients had mild erythematous rash, and two patients had moderate pruritic rash. In one patient, the erythematous rash began on day 4, was treated with a topical steroid, and was ongoing at the 2-week follow-up visit. In the second patient, the erythematous rash began on day 15, was treated with topical clotrimazole, and resolved on day 26. In the two patients with moderate pruritic rash, the events resolved following administration of topical corticosteroids and physiologic or lower doses of oral corticosteroids as first-line treatment. The rashes in these patients were maculo-papular; localized to discrete areas of arms, chest, and neck; and without desquamation, fever, or mucosal involvement. In one patient, the rash began on day 4, was improved and of mild severity on day 15, and resolved on day 26. In the second patient, the rash began on day 7 and resolved on day 12. Mild pruritus occurred in two patients, including one of the patients with pruritic rash. The pruritus resolved after two days in one patient and after three days in the second patient.
 
Decreases in hemoglobin, total white blood cell count, neutrophils, and platelets occurred during the study drug dosing period; median changes from baseline to day 28 were _2.8g/dL for hemoglobin (range: _6.2 to _0.8), _3.75_109/L for white blood cell count (range: _6.45 to _1.26), _2.39_109/L for absolute neutrophil count (range: _3.94 to _0.17), and _86_109/L for platelet count (range: _125 to 21). The only clinically significant hematology abnormalities were anemia in four patients and mild neutropenia in one patient.
 
During the off-study dosing period, the safety profile was as expected with peginterferon alfa-2a and ribavirin treatment.
 
4. Discussion
 
This was the first clinical study in which telaprevir was administered in combination with peginterferon alfa-2a and ribavirin. All 12 treatment-naive patients with genotype 1 chronic hepatitis C completed the 28-day study drug dosing period and then began off-study treatment with peginterferon alfa-2a and ribavirin.
 
The combination of telaprevir, peginterferon alfa-2a, and ribavirin substantially and rapidly decreased HCV RNA levels in all 12 patients. All 12 patients had a rapid viral response (RVR, defined as undetectable HCV RNA 4 weeks after the start of treatment). The 100% RVR rate in the present study was achieved despite the high baseline HCV RNA levels of the patients: 10 of the 12 patients had baseline HCV RNA levels greater than 800,000IU/mL. The RVR rate in the present study contrasts with the RVR rates reported for treatment-naive patients with genotype 1 hepatitis C treated with standard peginterferon alfa-2a and ribavirin. In one recent study, 23% (88/389) of patients treated with standard peginterferon alfa-2a and ribavirin dosages had an RVR [9]. Week 4 response rates were even lower for genotype 1 infected patients with higher baseline HCV RNA levels (>600,000IU/mL [9] or >800,000IU/mL [10]).
 
As in a prior study of telaprevir and peginterferon alfa-2a [8], all patients in the present study had continual viral decline during the study drug dosing period. Viral sequencing analysis showed no evidence of previously-identified telaprevir-resistant mutations in 10 patients during study drug dosing. In two patients, variants with telaprevir resistance were detected early during the dosing period, as wild-type virus was cleared, but HCV RNA continued to decline to undetectable levels in both of these patients by day 22. This is consistent with results of an earlier study that showed that telaprevir-resistant variants remained sensitive to peginterferon alfa-2a and ribavirin [11].
 
Two patients had viral breakthrough during off-study treatment with peginterferon alfa-2a and ribavirin. In both patients, viral breakthrough was due to the telaprevir-resistant variant R155K. Although telaprevir-resistant variants are sensitive to IFN and RBV in vitro [12], patients with chronic hepatitis C have variable responses to peginterferon alfa-2a and ribavirin. Both patients were compliant during both the 28-day dosing period and the off-study treatment period. Breakthrough in these patients may have been due to a poor intrinsic response to peginterferon alfa-2a and ribavirin; both patients had characteristics that are associated with a decreased likelihood of achieving SVR with standard peginterferon alfa and RBV therapy (high baseline viral load [5], [13]; body weight >75kg [4], [14], BMI >30kg/m2 [15], and Latino ethnicity [16], [17], [18], [19]). In one of the patients with breakthrough (3), a second analysis performed 8 weeks after the initial detection of R155K revealed that wild-type virus had begun to become predominant, consistent with previous findings [20].
 
The safety results in this study were generally consistent with those commonly seen with peginterferon and ribavirin treatment [2], [4], except for the rash events. Rash or pruritus occurred in 5 of the 12 patients; the events showed no patterns in time of onset, and all cases resolved either during or after the end of telaprevir treatment. Rash was also observed in later studies of telaprevir [21], [22]. At the time the present study was conducted, it was difficult to determine if the events represented an increased frequency, because of the small sample size and lack of a control group. It is unknown if the rash events were secondary to telaprevir or if telaprevir worsened ribavirin-associated skin reactions. Future trials with larger populations and a control group are needed to further evaluate rash in patients treated with telaprevir, peginterferon alfa-2a, and ribavirin.
 
In this small study, patients who achieved RVR and continued to be undetectable for the duration of therapy achieved higher SVR rates than were expected based on their baseline characteristics. The findings of this study suggest that the addition of telaprevir to peginterferon alfa-2a and ribavirin treatment can increase the RVR rate and subsequently may improve SVR rates in treatment-naive patients with genotype 1 hepatitis C.
 
In conclusion, this small pilot study in 12 patients showed that the combination of telaprevir with peginterferon alfa-2a and ribavirin rapidly and substantially decreased HCV RNA levels. All patients achieved RVR. Telaprevir, peginterferon alfa-2a, and ribavirin were generally well tolerated, without serious adverse events or premature discontinuations. Rash will need to be evaluated further in larger controlled trials. Currently, larger studies are evaluating whether telaprevir, in combination with peginterferon alfa-2a and ribavirin, will increase SVR rates and possibly allow for shorter treatment durations.
 
 
 
 
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