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Combination Therapy With Telaprevir for Chronic Hepatitis C Virus Genotype 1 Infection in Patients With HIV: A Randomized Trial
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Ann Intern Med. July 16 2013
Mark S. Sulkowski, MD; Kenneth E. Sherman, MD, PhD; Douglas T. Dieterich, MD; Mohammad Bsharat, PhD; Lisa Mahnke, MD, PhD; Jurgen K. Rockstroh, MD; Shahin Gharakhanian, MD, DPH; Scott McCallister, MD; Joshua Henshaw, PhD; Pierre-Marie Girard, MD, PhD; Bambang Adiwijaya, PhD; Varun Garg, PhD; Raymond A. Rubin, MD; Nathalie Adda, MD; and Vincent Soriano, MD, PhD
Background: Telaprevir (TVR) plus peginterferon-α2a (PEG-IFN-α2a) and ribavirin substantially increases treatment efficacy for genotype 1 chronic hepatitis C virus (HCV) infection versus PEG-IFN-α2a-ribavirin alone. Its safety and efficacy in patients with HCV and HIV-1 are unknown.
Objective: To assess the safety and efficacy of TVR plus PEG-IFN-α2a-ribavirin in patients with genotype 1 HCV and HIV-1 and to evaluate pharmacokinetics of TVR and antiretrovirals during coadministration.
Design: Phase 2a, randomized, double-blind, placebo-controlled study.
(ClinicalTrials.gov: NCT00983853)
Setting: 16 international multicenter sites.
Patients: 62 patients with HCV genotype 1 and HIV-1 who were HCV treatment-naive and receiving 0 or 1 of 2 antiretroviral regimens were randomly assigned to TVR plus PEG-IFN-α2a-ribavirin or placebo plus PEG-IFN-α2a-ribavirin for 12 weeks, plus 36 weeks of PEG-IFN-α2a-ribavirin.
Measurements: HCV RNA concentrations.
Results: Pruritus, headache, nausea, rash, and dizziness were higher with TVR plus PEG-IFN-α2a-ribavirin during the first 12 weeks. During this period, serious adverse events occurred in 5% (2 in 38) of those receiving TVR plus PEG-IFN-α2a-ribavirin and 0% (0 in 22) of those receiving placebo plus PEG-IFN-α2a-ribavirin; the same number in both groups discontinued treatment due to adverse events. Sustained virologic response occurred in 74% (28 in 38) of patients receiving TVR plus PEG-IFN-α2a-ribavirin and 45% (10 in 22) of patients receiving placebo plus PEG-IFN-α2a-ribavirin. Rapid HCV suppression was seen with TVR plus PEG-IFN-α2a-ribavirin (68% [26 in 38 patients] vs. 0% [0 in 22 patients] undetectable HCV RNA levels by week 4). Two patients had on-treatment HCV breakthrough with TVR-resistant variants. Patients treated with antiretroviral drugs had no HIV breakthroughs; antiretroviral exposure was not substantially modified by TVR.
Among black patients, SVR was achieved in 8 of 9 persons who received TVR and 3 of 7 who received placebo.
Limitation: Small sample size and appreciable dropout rate.
Conclusion: In patients with HCV and HIV-1, more adverse events occurred with TVR versus placebo plus PEG-IFN-α2a-ribavirin; these were similar in nature and severity to those in patients with HCV treated with TVR. With or without concomitant antiretrovirals, sustained virologic response rates were higher in patients treated with TVR versus placebo plus PEG-IFN-α2a-ribavirin.
Primary Funding Source: Vertex Pharmaceuticals and Janssen Pharmaceuticals.
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Editors' Notes
Context
· In patients with genotype 1 hepatitis C virus (HCV), adding telaprevir to peginterferon-α2a (PEG-IFN-α2a) and ribavirin produces a greater sustained virologic response than with PEG-IFN-α2a-ribavirin alone. Patients with HCV often also have HIV.
Contribution
· In a small, randomized trial of patients with both genotype 1 HCV and HIV, treatment with telaprevir plus PEG-IFN-α2a-ribavirin achieved a greater sustained virologic response than PEG-IFN-α2a-ribavirin alone and with a magnitude similar to that seen in patients with only HCV. No HIV breakthroughs took place.
Caution
· The number of withdrawals was appreciable. Adverse events were more common in groups receiving treatment with telaprevir plus PEG-IFN-α2a-ribavirin than with PEG-IFN-α2a-ribavirin alone. Only certain HIV antiretroviral regimens were permitted.
Implication
· The role of direct-acting antivirals in the treatment of HCV and HIV warrants further study.
-The Editors
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With the development of effective therapies against HIV, hepatitis C virus (HCV) infection has emerged as a major cause of morbidity and mortality among patients with HIV (1). In patients with only HCV and those with both HCV and HIV, HCV treatment resulting in sustained virologic response (SVR) has been associated with decreased likelihood of end-stage liver disease, hepatocellular carcinoma, and death (2-4). Accordingly, practice guidelines recommend that HCV treatment should be given to patients with both HCV and HIV in whom the likelihood of serious liver disease and achieving SVR is judged to outweigh the risk for adverse events (AEs) (5-9).
The efficacy of peginterferon-α2a (PEG-IFN-α2a) and ribavirin is low for patients with both HCV and HIV compared with patients with genotype 1 HCV alone, ranging from 14% to 29% (10-11). In patients with HCV genotype 1 alone, the addition of an HCV NS3/4A protease inhibitor, either telaprevir (TVR) or boceprevir, to PEG-IFN-α2a-ribavirin substantially increased the SVR rate (12-16), leading to the recommendation for routine use of these agents in patients with HCV (17). Despite the potential benefit of HCV protease inhibitor-based therapy in the treatment of HCV in patients with HIV, potential concerns for patients with both HCV and HIV include increased AEs (such as anemia, gastrointestinal symptoms, and rash); antiviral drug resistance; and the demonstration, in healthy volunteers, of potentially clinically significant drug interactions with antiretrovirals through inhibition of cytochrome P450 3A4 (CYP3A4) (18). To date, very few case reports on the use of HCV protease inhibitors in patients with HIV have been published (19-20).
The objectives of this study were to assess the safety, tolerability, and efficacy of TVR plus PEG-IFN-α2a-ribavirin in patients with both HCV genotype 1 and HIV and to evaluate the pharmacokinetics of TVR and selected antiretroviral medications during coadministration.
Methods
Design Overview
This study (VX08-950-110) was a phase 2a, randomized, double-blind (through week 24), placebo-controlled, multicenter study. Patients were required to be receiving no antiretrovirals (part A) or 1 of 2 specified antiretroviral regimens (part B), including either efavirenz or ritonavir-boosted atazanavir. Patients in part A were randomly assigned in a 1:1 ratio and patients in part B were randomly assigned in a 2:1 ratio to receive TVR or placebo, both in combination with PEG-IFN-α2a-ribavirin. Randomization was done using an interactive Web response system and was blocked and stratified to optimize balance among the treatment groups with regard to baseline viral load (HCV RNA levels <800 000 IU/mL or ≥800 000 IU/mL). In part B, randomization was also stratified to optimize balance between the protocol-specified antiretroviral regimens. A blinded statistician from Vertex Pharmaceuticals (Cambridge, Massachusetts) created the randomization code, which was kept on a protected server. Telaprevir or placebo was administered orally every 8 hours with food, 180 μg of PEG-INF-α2a (Pegasys, Hoffmann-La Roche, Nutley, New Jersey) was injected subcutaneously once weekly, and ribavirin (Copegus, Hoffmann-La Roche, Nutley, New Jersey) was administered by mouth twice daily for the first 12 weeks, followed by an additional 36 weeks of PEG-IFN-α2a-ribavirin. On the basis of drug interaction studies in healthy volunteers, patients receiving efavirenz-based antiretroviral therapy received 1125 mg of TVR every 8 hours, whereas all others received 750 mg every 8 hours (18). Ribavirin was administered at 800 mg daily according to the recommendations for dosing in patients with both HIV and HCV in the United States and Canada (21-22), which are based on a large, randomized, controlled trial that showed similar SVR and lower incidence of anemia with this dose compared with higher, weight-based doses (23). In France and Germany, ribavirin was administered at 1200 mg daily for patients weighing 75 kg or greater and 1000 mg daily for those weighing less than 75 kg (24); country-specific amendments were made based on local practice guidelines (25).
Setting and Participants
Patients with both HCV and HIV (n = 62) were enrolled at 16 investigational sites in 4 countries (United States [n = 48], Spain [n = 9], Germany [n = 3], and France [n = 2]). Key inclusion criteria included age of 18 to 65 years, genotype 1 chronic HCV infection, chronic HIV-1 infection, no previous HCV treatment, and hemoglobin levels of 120 g/L or greater in women and 130 g/L or greater in men. Patients were required to have stable HIV disease defined as follows: Part A (no antiretroviral therapy) participants had CD4 counts of 0.500 x 109 cells/L or greater and HIV RNA levels of 100 000 copies/mL or less, and part B (antiretroviral therapy for >12 weeks) participants had CD4 counts of 0.300 x 109 cells/L or greater and HIV RNA levels less than 50 copies/mL. For part B, permissible antiretroviral regimens were efavirenz, tenofovir, and emtricitabine, or ritonavir-boosted atazanavir, tenofovir, and either emtricitabine or lamivudine. Exclusion criteria for patients in all parts included hepatic decompensation; other causes of significant liver disease, cancer within 5 years, significant cardiac dysrhythmia, and active AIDS-related conditions within 6 months. All patients had liver biopsies within 1 year unless previous biopsies indicated cirrhosis; histologic assessment according to the METAVIR scoring system was done by a local pathologist.
Outcomes and Follow-up
Safety
Adverse events were recorded for all patients who received at least 1 dose of a study drug through 30 days after the last dose. Except for rash, the severity of all AEs was graded according to the Division of AIDS Table 1 for Grading the Severity of Adult and Pediatric Adverse Events, version 1.0. Planned safety reviews were conducted by independent statistical and data monitoring committees. Patient-specific HCV RNA response was monitored by an unblinded independent reviewer until week 24 and then by the study site investigators (Appendix 1) after HCV RNA unblinding (from week 24 onward). The results of HCV RNA data before week 24 and treatment assignments were unblinded only after all patients completed week 24. Virologic breakthrough was defined as an increase greater than 1 log10 in HCV RNA above nadir or greater than 100 IU/mL if previously undetected. Patients with HCV RNA levels greater than 1000 IU/mL at week 4 were required to discontinue treatment with TVR and continue PEG-IFN-α2a-ribavirin. All study medications were discontinued in patients with virologic breakthrough or at treatment week 12 in patients with a decrease less than 2 log10 in HCV RNA from baseline or at weeks 24 or 36 in patients with quantifiable HCV RNA. No placebo was administered to patients once study medications were discontinued.
Efficacy
Hepatitis C virus RNA levels were assessed using the Cobas TaqMan HCV Test, version 2.0 (Roche Molecular Systems, Branchburg, New Jersey), which has a lower limit of quantitation (LLOQ) of 25 IU/mL and a lower limit of detection of 15 IU/mL. The LLOQ was used to define SVR, and the lower limit of detection was used to assess on-treatment response. A patient was defined as achieving SVR if HCV RNA levels were less than the LLOQ at posttreatment weeks 12 (SVR12) or 24 (SVR24). Relapse was defined as HCV RNA levels less than the LLOQ at the actual end-of-treatment window but subsequent HCV RNA levels greater than or equal to the LLOQ. To be eligible for relapse, a patient's HCV RNA levels had to be less than the LLOQ at the actual end of treatment or during the next treatment visit window (Appendix 2). The primary efficacy end point was HCV RNA level at week 12. Secondary end points were HCV RNA levels at week 4, proportion of patients with undetectable HCV RNA levels at weeks 4 and 12, and unquantifiable HCV RNA levels at end of treatment and at posttreatment weeks 12 (SVR12) and 24 (SVR24). For patients with no HCV RNA assessment at posttreatment week 24, the SVR12 assessment was imputed for SVR24. For all end-of-treatment, relapse, and SVR windows, the last available HCV RNA assessment in the study treatment window was used (Appendix 2).
Pharmacokinetics
Antiretrovirals
Ratios of mean predose concentrations (Ctrough) during HCV treatment (weeks 1, 2, 4, and 12) to the Ctrough before HCV treatment (day -1) were calculated within individual patients; the median (25th to 75th percentiles) was calculated for all patients in a treatment group.
Telaprevir
Week-4 intensive TVR concentration-time profiles were collected before and at 1, 2, 3, 4, 6, and 8 hours after dose. Steady-state pharmacokinetic parameters of TVR minimum, average, and maximum concentrations (Cmin, Cavg, and Cmax, respectively) were determined through standard noncompartmental analysis (WinNonlin, version 5.3, Pharsight, Mountain View, California).
Interim Analysis
Four interim analyses were conducted. The first 2 were protocol-specified by the independent statistical and data monitoring committee and were conducted after 20 and 40 patients (enrolled in parts A or B) completed 8 weeks of dosing with study treatment (or discontinued treatment earlier). These first 2 interim analyses were blinded at the individual-patient level and were unblinded by overall treatment group to the study sponsor for regulatory purposes only after the interim analysis was completed. A third interim analysis was warranted to evaluate the efficacy and safety and information for a phase 3 study and regulatory purposes. It included all data in the clinical database at the time of the data cutoff, including data collected through week 24 and safety data for the 62 patients who were randomly assigned. A fourth interim analysis included data through 12 weeks after the last dose of a study drug. The third and fourth analyses were unblinded because all patients had reached protocol treatment week 24, at which time the study was no longer blinded.
Statistical Analysis
Sample size was selected to provide data regarding the safety, pharmacokinetic, and antiviral activity of TVR plus PEG-IFN-α2a-ribavirin to inform the design of subsequent studies; no formal sample size calculation was done in this pilot study.
All patients who were administered at least 1 dose of placebo or TVR were included in safety and efficacy summaries. No formal hypothesis testing was conducted. Patients with missing on-treatment HCV RNA assessments in the specific study visit window were counted as being nonrespondent even if they ultimately achieved SVR.
Role of the Funding Source
This study was funded by Vertex Pharmaceuticals and Janssen Pharmaceuticals. The protocol was approved by the institutional review boards of all study centers and was done in accordance with Good Clinical Practice guidelines, as described in the International Conference on Harmonisation Guideline E6 and the Declaration of Helsinki. All patients provided written informed consent. The protocol was designed by the pharmaceutical sponsors in collaboration with the principal investigator, who is not employed by Vertex Pharmaceuticals, had unrestricted access to the data, and wrote the first draft of the manuscript. Subsequent drafts of the manuscript reflect comments from all coauthors. The study and data analysis were conducted and the decision to submit the manuscript was made by the pharmaceutical sponsors in collaboration with the principal investigator. All authors reviewed and approved the final manuscript and assume responsibility for the accuracy and completeness of the data reported. The National Institutes of Health had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, and approval of the manuscript.
Results
Baseline Characteristics
Of 113 patients screened, 60 were randomly assigned and received at least 1 dose of TVR (n = 38) or placebo (n = 22). Thirteen patients did not receive antiretroviral therapy, and 47 patients received efavirenz-containing (n = 24) or ritonavir-boosted, atazanavir-containing (n = 23) antiretroviral therapy (Figure 1). Most patients were men (88%); were white (70%); had HCV genotype 1, subtype a (68%); had high levels of HCV RNA (≥800 000 IU/mL [85%]); and were enrolled in the United States (77%) (Table 1). Overall, 7 patients (12%) had bridging fibrosis or cirrhosis. Among patients not taking antiretrovirals, the median HIV RNA level was 1495 copies/mL and CD4 cell count was 0.652 x 109 cells/L. Among patients taking antiretrovirals, HIV RNA levels were less than 50 copies/mL and the median CD4 cell count was 0.518 x 109 cells/L.
Adverse Events and Tolerability
During the TVR versus placebo phase (weeks 1 through 12), patients treated with TVR had a higher incidence (difference of >10 percentage points compared with placebo) of pruritus, headache, nausea, rash, and dizziness (Table 2). During this phase, rash was seen in 11 of 38 (29%) and 4 of 22 (18%) patients treated with TVR and placebo, respectively; no patients had severe or life-threatening rash or discontinued treatment with TVR due to rash. Topical corticosteroids were used to manage rash; no patients received systemic corticosteroids.
Anorectal symptoms were reported in 5 of 38 (13%) and 1 of 22 (5%) patients treated with TVR and placebo, respectively. Abdominal pain occurred more frequently in the TVR plus PEG-IFN-α2a-ribavirin groups (≥10-percentage point difference) compared with PEG-IFN-α2a-ribavirin, but occurred in fewer than 15% of patients.
During the overall treatment phase (weeks 1 through 48), AEs were consistent with those seen during the first 12 weeks (Appendix Table 1). Although most AEs were mild to moderate in severity, 9 patients had serious AEs (TVR, n = 7; placebo, n = 2); 2 AEs occurred during the initial 12 weeks of treatment (both in the TVR group). Three patients in the TVR group discontinued all study medications because of an AE (vomiting, n = 1; anemia, n = 1; and cholelithiasis, n = 1), and 1 patient taking ritonavir-boosted atazanavir discontinued TVR because of jaundice. Among patients taking ritonavir-boosted atazanavir, grade 3 and 4 hyperbilirubinemia (predominantly indirect bilirubin) occurred in 13 of 15 (87%) TVR recipients and 5 of 8 (63%) placebo recipients during the first 12 weeks of therapy; such increases were not seen in patients who did not receive antiretroviral therapy or in those receiving efavirenz. Anemia was common, with a decrease in hemoglobin levels to less than 100 g/L in 12 of 38 (32%) TVR recipients and 5 of 22 (23%) placebo recipients. Anemia was managed with blood transfusion in 5 patients (TVR, n = 4; and placebo, n = 1) and administration of epoetin-α in 4 patients (TVR, n = 3; and placebo, n = 1). Grade 3 or greater neutropenia was seen in 6 of 38 (16%) and 6 of 22 (27%) patients treated with TVR and placebo, respectively. As in previous studies of patients with both HCV and HIV treated with PEG-IFN-α2a-ribavirin (11), absolute CD4 cell count decreased in all patients; however, the percentage of the CD4+ lymphocytes was unchanged during treatment. No deaths or AIDS-defining illnesses were seen during the study.
Efficacy
Of the 60 patients who received study medications, 35 (58%) completed 48 weeks of treatment and 25 (42%) discontinued treatment early because of protocol-defined virologic failure (TVR, n = 2, weeks 4 or 8; placebo, n = 7, weeks 12 or 24), AEs (TVR, n = 3, at or before weeks 4, 24, or 36; placebo, n = 0), loss to follow-up (TVR, n = 2, at or before weeks 36 or 48; placebo, n = 1, at or before week 24), withdrawal of consent (TVR, n = 1, at or before week 4; placebo, n = 0), or other reasons (nonadherence, n = 4; lack of response, n = 1; thought they completed therapy, n = 1; moved, n = 1; patient decision, n = 2) (Figure 1). The decreases in HCV RNA levels from baseline were more rapid in TVR recipients than in placebo recipients (Figure 2), with mean changes in log10 HCV RNA levels from baseline to week 12 of -5.8 IU/mL and -3.8 IU/mL, respectively (Table 3). By week 4, HCV RNA levels were not detected in 26 of 38 (68%) patients in the TVR group and 0 of 22 (0%) patients in the placebo group (difference, 68 percentage points [95% CI, 54 to 83 percentage points]). By week 12, HCV RNA levels were undetectable in 30 of 38 (79%) TVR recipients and 6 of 22 (27%) placebo recipients (difference, 52 percentage points [CI, 29 to 74 percentage points]) (Table 3). Sustained virologic response at posttreatment weeks 12 and 24 was higher in patients treated with TVR plus PEG-IFN-α2a-ribavirin (28 of 38 patients [74%]) than in those treated with PEG-IFN-α2a-ribavirin alone (10 of 22 patients [45%]) (difference, 29 percentage points [CI, 3 to 53 percentage points]). Among black patients, SVR was achieved in 8 of 9 persons who received TVR and 3 of 7 who received placebo. Evaluation of SVR according to genotype 1 subtype and interleukin-28B genotype was limited by small numbers of patients (subtype 1b) and incomplete data (interleukin-28B) (Appendix Table 2). After treatment discontinuation, HCV viral relapse occurred in 1 of 32 (3%) TVR recipients and 2 of 13 (15%) placebo recipients; HCV viremia was detected at posttreatment week 4 in all 3 patients.
Virology
At baseline, TVR-resistant variants were not seen in patients who received TVR. Two patients with HCV subtype 1a had virologic breakthrough while receiving TVR (1 receiving ritonavir-boosted atazanavir at week 4; 1 receiving efavirenz at week 12); both had variants with the combination of TVR-resistant amino acid substitutions at NS3 positions 36 (V36M) and 155 (R155K). No substitutions were detected in the 2 patients who discontinued treatment with TVR prematurely. In the 1 TVR recipient with posttreatment HCV relapse, the resistant variant V36M was detected at relapse but not at subsequent testing 14 weeks later. Among patients not receiving antiretroviral therapy, HIV RNA level decreased in both TVR (-1.16 log10 at week 4) and placebo (-0.91 log10 at week 4) recipients. Among patients taking antiretroviral therapy, HIV breakthrough was not seen.
Pharmacokinetics of TVR and Antiretroviral Drugs
Plasma concentrations were available for 36 of 38 TVR recipients and all patients who received efavirenz (n = 24), atazanavir (n = 23), or tenofovir (n = 47). The median ratios of antiretroviral trough concentrations during and before TVR treatment were 6% lower for efavirenz and 16% higher for atazanavir (Table 4). The median ratios of tenofovir concentrations during and before TVR treatment varied according to concurrent administration of atazanavir (25% lower) or efavirenz (6% higher), but the median trough concentrations of tenofovir were similar in the TVR (116 ng/mL; range, 63.7 to 233 ng/mL) and placebo (98.8 ng/mL; range, 38.5 to 257 ng/mL) groups. Telaprevir concentrations with and without concurrent antiretroviral therapy were similar with the exception that the minimum TVR concentration was 31% higher in patients taking ritonavir-boosted atazanavir; however, no corresponding increase in the average or maximum TVR concentration was seen in this group.
Discussion
Treatment with HCV protease inhibitors in combination with PEG-IFN-α2a-ribavirin is recommended for patients with only genotype 1 chronic HCV infection (17). However, the use of these regimens in patients with both HCV and HIV has been limited by the absence of data about the safety and efficacy of HCV protease inhibitors and their effect on the metabolism of antiretroviral drugs (16, 26-27). In this preliminary study, TVR plus PEG-IFN-α2a-ribavirin in patients with HCV genotype 1 and HIV was associated with a higher virologic response and more AEs than PEG-IFN-α2a-ribavirin alone.
The nature and severity of AEs were similar to those seen in larger studies of patients with only HCV, including skin rash, gastrointestinal symptoms, and anemia (13, 15). Compared with those treated with placebo, patients with both HCV and HIV treated with TVR were more likely to have mild and moderate rashes or pruritus. Although serious cutaneous adverse reactions, including fatal outcomes, have been reported with TVR combination therapy (26), severe or treatment-limiting rash was not seen in the 38 patients treated with TVR in this small study. Anemia has also been seen in patients treated with TVR plus PEG-IFN-α2a-ribavirin. Although the incidence of anemia in this study was similar in patients treated with TVR and placebo, management of treatment-related anemia with epoetin-α or blood transfusion was more common in patients treated with TVR. Nonetheless, only 1 patient treated with TVR discontinued therapy because of anemia. Compared with previous studies, the severity of anemia in this study may have been alleviated by the administration of low fixed-dose ribavirin (800 mg/d) to most patients, which was associated with similar SVR and less anemia compared with higher, weight-based ribavirin in the study by Rodriguez-Torres and colleagues (23) and by the exclusion of the patients taking the antiretroviral drug zidovudine, which worsens anemia related to PEG-IFN-α2a-ribavirin therapy (28-30). Although we did not detect a difference in safety or tolerability of TVR compared with previous studies of patients with only HCV (26), larger studies of TVR plus PEG-IFN-α2a-ribavirin are needed to fully characterize the profile of TVR in patients with both HCV and HIV.
In this small preliminary study, 74% of patients with both genotype 1 HCV and HIV treated with TVR plus PEG-IFN-α2a-ribavirin achieved SVR compared with 45% of those treated with PEG-IFN-α2a-ribavirin alone. The observed safety and tolerability of TVR in this small preliminary study were consistent with that previously reported in patients with only HCV (26, 31). It is important to note that no adverse effect on HIV infection or its treatment with antiretroviral drugs was detected. The addition of TVR to PEG-IFN-α2a-ribavirin led to robust and rapid HCV suppression, with two thirds of patients achieving undetectable HCV RNA levels after 4 weeks compared with none of the patients treated with placebo. This is consistent with the viral kinetics seen in larger studies of patients with only HCV (13, 15-16). For most patients with both HCV and HIV treated with TVR, this early HCV suppression was sustained during and after treatment. Although interpretation is limited by the small sample size and appreciable dropout rate, there was a 29-percentage point difference in SVR in patients treated with TVR compared with those treated with placebo, and virologic breakthrough with TVR-resistant variants was uncommon, occurring in only 2 patients. The increase in efficacy with TVR compared with placebo was similar to that seen in clinical trials of patients with only HCV (13, 15). This finding was not expected because the efficacy of HCV treatment with PEG-IFN-α2a-ribavirin has been markedly lower in patients with both HCV and HIV compared with patients with only HCV in previous studies (10-11, 23), suggesting blunted interferon responsiveness in patients with HIV. Although preliminary, our data suggest that drugs directly targeting HCV may overcome the effect of HIV infection on treatment response and support larger, ongoing confirmatory studies of TVR plus PEG-IFN-α2a-ribavirin in patients with both HCV and HIV.
Because TVR is metabolized by and is a strong inhibitor of CYP3A4 (18), interactions with antiretroviral drugs that inhibit or induce, or are metabolized by, CYP3A4 were anticipated. On the basis of the results of interaction studies completed in healthy volunteers (18, 26), antiretroviral regimens were limited to ritonavir-boosted atazanavir with a standard dose of TVR or efavirenz with a higher dose of TVR to overcome induction of CYP3A4. In this study of patients with both HCV and HIV, the pharmacokinetics of TVR and antiretroviral drugs was carefully assessed to determine the applicability of the data derived from healthy volunteers. Considering the high degree of variability of antiretroviral drug exposure, the coadministration of TVR did not have a clinically meaningful effect on the antiretroviral drugs studied. The lack of HIV breakthrough provides additional support for coadministration of TVR with the selected antiretroviral regimens. Similarly, compared with patients with both HCV and HIV who were not taking antiretrovirals, concurrent antiretroviral therapy did not seem to alter the HCV response during TVR administration. Finally, as predicted from healthy volunteer studies, the higher dose of TVR (1125 mg every 8 hours) seemed to compensate for the induction effect of efavirenz on TVR metabolism (18). Taken together, these data underscore the value of conducting interaction studies with novel anti-HCV and antiretroviral drugs before treating patients with both HCV and HIV in clinical trials or practice.
This study has several important limitations. It was small, limiting the interpretation of safety and efficacy findings. In addition, because we enrolled patients who had not been previously treated for HCV and those who had stable HIV disease and high CD4 cell counts; as such, these results are not generalizable to patients with both HCV and HIV who had previous HCV treatment failure or those with more advanced HIV infection. Similarly, because we included only patients taking specific antiretroviral drugs for which interactions with TVR were predicted to be acceptable, these results cannot be extended to patients receiving other antiretroviral regimens. However, the pharmacokinetic data from this study were consistent with predications derived from interaction studies in healthy volunteers, indicating that interaction data derived from such studies are informative.
In conclusion, the addition of TVR to PEG-IFN-α2a-ribavirin led to a higher virologic response in this preliminary study in patients with both genotype 1 HCV and HIV. The observed safety and tolerability of TVR was consistent with the profile seen in patients with only HCV. Although drug interactions between TVR and antiretroviral drugs metabolized by CYP3A4 limited the antiretroviral therapy regimens that were studied, no adverse effect on HIV disease or its treatment was seen. These findings support the conduct of larger, ongoing, confirmatory phase 3 studies of TVR plus PEG-IFN-α2a-ribavirin in patients with both genotype 1 HCV and HIV.
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