Abstract
INSIGHT (ClinicalTrials.gov NCT01513941) evaluated the efficacy, safety and pharmacokinetics of telaprevir-based therapy and specific antiretroviral agents in hepatitis C virus genotype 1 (HCV-1)/HIV-1-coinfected patients.
Open-label, Phase IIIb, multicentre study of telaprevir with pegylated-IFN (Peg-IFN) α2a and ribavirin in treatment-naive or -experienced HCV-1/HIV-1-coinfected patients on stable HIV HAART comprising efavirenz, atazanavir/ritonavir, darunavir/ritonavir, raltegravir, etravirine or rilpivirine with two nucleos(t)ide analogues. Patients received 750 mg telaprevir (1125 mg, if on efavirenz) every 8 h plus 180 μg/week Peg-IFNα2a and 800 mg/day ribavirin for 12 weeks, followed by Peg-IFNα2a and ribavirin alone for 12 weeks (HCV treatment naive and relapsers without cirrhosis, with extended rapid virological response) or 36 weeks (all others).
Overall, 162 patients (median age of 46 years, 78% male, 92% Caucasian and mean CD4 count of 687 cells/mm3) were treated; 13% had cirrhosis. One-hundred-and-thirty-two patients (81%) completed telaprevir; 14 (9%) discontinued due to an adverse event (AE). Sustained virological response (SVR) 12 rates (<25 IU/mL HCV RNA 12 weeks after the last planned treatment dose) in treatment-naive patients, relapsers and non-responders were 64% (41 of 64), 62% (18 of 29) and 49% (34 of 69), respectively. SVR12 rates ranged from 51% (33 of 65) (patients receiving efavirenz) to 77% (13 of 17) (patients receiving raltegravir). Most frequently reported AEs during telaprevir treatment were pruritus (43%) and rash (34%) special search categories. Anaemia special search category occurred in 15% of patients; 6% of patients reported a serious AE.
In treatment-naive/-experienced HCV-1/HIV-1 patients there were significantly higher SVR rates with telaprevir-based therapy compared with pre-specified historical controls, and safety comparable to that in HCV-monoinfected patients.
Introduction
Hepatitis C virus (HCV) infection is a major cause of morbidity and mortality in HIV-infected patients.1 Historically, in HCV/HIV-coinfected patients treated with pegylated-IFN (Peg-IFN) α2a or α2b plus ribavirin, sustained virological response (SVR) rates were lower than in treated HCV-monoinfected patients (14%–38% versus 55%, respectively).2–5 However, with the introduction of direct-acting antivirals (DAAs), reported SVR rates in HCV/HIV-coinfected patients are comparable to monoinfected patients,6,7 and indications for treatment of HCV/HIV-coinfected patients are identical to those with HCV monoinfection.8,9
Telaprevir was one of the first DAAs available.10 Although other DAA-based treatments have been developed, in many settings these new agents are unavailable, meaning the triple combination of telaprevir with Peg-IFN/ribavirin remains an appropriate option.8
A Phase II study in HCV/HIV-coinfected patients showed the SVR24 rate (24 weeks after the last planned treatment dose) was higher in patients receiving telaprevir-based triple therapy (74%) than in those taking telaprevir-matched placebo in combination with Peg-IFN/ribavirin, followed by 36 weeks of Peg-IFN/ribavirin alone (45%) (NCT00983853).11 INSIGHT is a Phase IIIb, confirmatory study investigating use of telaprevir with Peg-IFN/ribavirin in HCV/HIV-coinfected patients receiving a broader range of antiretroviral (ARV) agents.
Patients and methods
Participants
INSIGHT (ClinicalTrials.gov NCT01513941) enrolled patients (18–70 years) coinfected with HCV genotype 1 (HCV-1)/HIV type 1 at 39 international sites. Eligible patients had chronic HCV infection and were HCV treatment naive or experienced [including relapsers and prior non-responders (partial responders and null responders)] with >1000 IU/mL HCV RNA and <50 copies/mL HIV-1 RNA. Chronic HCV infection was confirmed by detectable HCV RNA >6 months before screening or by liver biopsy.
Other inclusion criteria were: HIV-1 infection >6 months; screening CD4 count >300 cells/mm3; receiving ART continuously ≥12 weeks before screening, without the expectation to switch ARV regimen up to at least week 14 (lamivudine could be substituted for emtricitabine and vice versa). Permitted ARV agents were efavirenz, darunavir/ritonavir, atazanavir/ritonavir, raltegravir, etravirine or rilpivirine, each with lamivudine or emtricitabine with either tenofovir disoproxil fumarate or abacavir. Patients were excluded if they had evidence of decompensated liver disease. The study protocol was approved by the appropriate institutional ethics committees and health authorities, and the study was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice guidelines and applicable regulatory requirements. Written informed consent was obtained from all participants.
Study design
All patients received 750 mg telaprevir every 8 h with food plus 180 µg/week Peg-IFN and 800 mg/day ribavirin for 12 weeks. Patients receiving efavirenz as part of the ARV regimen received 1125 mg telaprevir every 8 h.12,13 Following telaprevir-based therapy, patients received either 12 or 36 weeks of Peg-IFN/ribavirin alone.
HCV treatment-naive patients and prior relapsers without cirrhosis received treatment for a total of 24 weeks if they achieved an extended rapid virological response (eRVR; patients with <25 IU/mL HCV RNA, target not detected at weeks 4 and 12). All other patients received treatment for a total of 48 weeks.
Stopping rules were applied: all HCV treatment was discontinued if >1000 IU/mL HCV RNA at weeks 4, 8 or 12, or if detectable at weeks 24 or 36.12,13
Objectives
The primary objective was to assess the efficacy and safety of telaprevir in combination with Peg-IFN/ribavirin. Secondary objectives included comparing the SVR rate with a pre-specified historical control for HCV/HIV-coinfected patients treated with Peg-IFN/ribavirin.
Safety and tolerability were also assessed as were the pharmacokinetics of telaprevir and specific ARV agents during co-administration.
Study evaluations
Blood samples for HCV RNA quantification were taken at screening, baseline (day 1 pre-dose), weeks 4, 8, 12, 24, 36 or 48, or discontinuation of treatment, and during follow-up using the High Pure System (HPS, HCV COBAS® TaqMan® assay version 2.0; lower limit of quantification of 25 IU/mL and limit of detection of 15 IU/mL).
Plasma HIV RNA values were measured at the above timepoints using the COBAS® AmpliPrep/COBAS® Taqman® HIV-1 RNA (v2.0; Roche) assay. HIV protease/RT sequencing was performed if the HIV-1 RNA result was ≥200 copies/mL (HIV viral breakthrough) and a confirmatory HIV-1 RNA result >50 copies/mL was observed.
HCV NS3•4A sequencing analyses were performed on all baseline samples and in the case of on-treatment virological failure or relapse using the list of telaprevir-resistant variants previously identified.14
Safety and tolerability were assessed throughout the treatment period and during the safety follow-up visit. All AEs were coded using the Medical Dictionary for Regulatory Activities Version 14.1. Sparse plasma samples were to be collected in all patients for estimation of telaprevir pharmacokinetic parameters (Bayesian estimation), and measurement of selected ARV concentrations. A small subset of patients at selected sites was enrolled in a darunavir/ritonavir pharmacokinetic substudy (available as Supplementary data at JAC Online).
Total concentrations of selected HIV ARVs were analysed using validated, specific and sensitive liquid chromatography–MS/MS.
Statistical methods
The ITT population, used for the efficacy and safety analyses, included all patients who received at least one dose of telaprevir. The primary endpoint was the proportion of patients achieving SVR12 (<25 IU/mL HCV RNA 12 weeks after the last planned HCV medication intake).
On-treatment virological failure was defined as meeting a virological stopping rule and/or viral breakthrough (increase >1 log in HCV RNA from the lowest level reached, or >100 IU/mL HCV RNA in patients whose HCV RNA was <25 IU/mL during treatment). Relapse was defined as having detectable HCV RNA during the follow-up period after <25 IU/mL HCV RNA at the planned end of HCV treatment.
A sample size of ∼150 patients was considered adequate for estimation of SVR with a two-sided 95% CI, as well as for comparison with a historical SVR rate. Historical comparators used were SVR data in treatment-naive HCV-1/HIV-coinfected patients receiving Peg-IFN/ribavirin5 (29%), and SVR rates from the monoinfection studies (with a scaling factor of 75%, as no direct data on HCV/HIV-coinfected HCV treatment-experienced patients were available).15,16 If the lower boundary of the two-sided 95% CI of SVR excluded the pre-specified historical control rates then the null hypothesis that telaprevir plus Peg-IFN/ribavirin had an SVR equal to the historical control SVR rate was rejected.
Results
Patient disposition and baseline characteristics
Of the 162 patients enrolled (Table 1), 98 (60%) were HCV treatment experienced. At baseline, 13% of patients had cirrhosis. Most patients received efavirenz or atazanavir/ritonavir (Table 1).
Baseline demographics and disease characteristics
| Treatment naive (n = 64) | Treatment experiencedb (n = 98) | All patients (n = 162) | |
|---|---|---|---|
| Male, n (%) | 51 (80) | 76 (78) | 127 (78) |
| Caucasian, n (%) | 61 (95) | 88 (90) | 149 (92) |
| Age (years), median | 43 | 48 | 46 |
| HCV RNA ≥800 000 IU/mL, n (%) | 49 (77) | 92 (94) | 141 (87) |
| BMI (kg/m2), median (range) | 24.4 (18.5–36.5) | 23.7 (18.9–31.8) | 24.0 (18.5–36.5) |
| HCV genotype, n (%)a | |||
| 1a | 35 (55) | 68 (69) | 103 (64) |
| 1b | 29 (45) | 30 (31) | 59 (36) |
| IL28B subtype, n/N (%) | |||
| CC | 22/63 (35) | 22/97 (23) | 44/160 (28) |
| CT | 29/63 (46) | 58/97 (60) | 87/160 (54) |
| TT | 12/63 (19) | 17/97 (18) | 29/160 (18) |
| Cirrhosis, n/N (%) | 6/64 (9) | 15/98 (15) | 21/162 (13) |
| HIV RNA <50 copies/mL, n (%) | 62 (97) | 97 (99) | 159 (98) |
| CD4 cell count (×109/L), median (range) | 0.6 (0.3–1.4) | 0.7 (0.3–1.6) | 0.7 (0.3–1.6) |
| ARV agent, n (%) | |||
| EFV | 23 (36) | 42 (43) | 65 (40) |
| ATV/r | 27 (42) | 32 (33) | 59 (36) |
| DRV/r | 8 (13) | 9 (9) | 17 (10) |
| RTG | 5 (8) | 12 (12) | 17 (10) |
| ETR | 1 (2) | 3 (3) | 4 (2) |
| ARV background regimen, n (%) | |||
| TDF/FTC or 3TC | 53 (83) | 75 (77) | 128 (79) |
| ABC/FTC or 3TC | 11 (17) | 23 (23) | 34 (21) |
| Laboratory measurements, mean (SEM) | |||
| platelet count (109/L) | 218.0 (8.9) | 203.6 (6.9) | 209.3 (5.5) |
| haemoglobin (g/L) | 149.4 (1.5) | 152.7 (1.2) | 151.4 (0.94) |
| LDL-cholesterol (mmol/L) | 2.4 (0.1) | 2.3 (0.08) | 2.3 (0.06) |
| Treatment naive (n = 64) | Treatment experiencedb (n = 98) | All patients (n = 162) | |
|---|---|---|---|
| Male, n (%) | 51 (80) | 76 (78) | 127 (78) |
| Caucasian, n (%) | 61 (95) | 88 (90) | 149 (92) |
| Age (years), median | 43 | 48 | 46 |
| HCV RNA ≥800 000 IU/mL, n (%) | 49 (77) | 92 (94) | 141 (87) |
| BMI (kg/m2), median (range) | 24.4 (18.5–36.5) | 23.7 (18.9–31.8) | 24.0 (18.5–36.5) |
| HCV genotype, n (%)a | |||
| 1a | 35 (55) | 68 (69) | 103 (64) |
| 1b | 29 (45) | 30 (31) | 59 (36) |
| IL28B subtype, n/N (%) | |||
| CC | 22/63 (35) | 22/97 (23) | 44/160 (28) |
| CT | 29/63 (46) | 58/97 (60) | 87/160 (54) |
| TT | 12/63 (19) | 17/97 (18) | 29/160 (18) |
| Cirrhosis, n/N (%) | 6/64 (9) | 15/98 (15) | 21/162 (13) |
| HIV RNA <50 copies/mL, n (%) | 62 (97) | 97 (99) | 159 (98) |
| CD4 cell count (×109/L), median (range) | 0.6 (0.3–1.4) | 0.7 (0.3–1.6) | 0.7 (0.3–1.6) |
| ARV agent, n (%) | |||
| EFV | 23 (36) | 42 (43) | 65 (40) |
| ATV/r | 27 (42) | 32 (33) | 59 (36) |
| DRV/r | 8 (13) | 9 (9) | 17 (10) |
| RTG | 5 (8) | 12 (12) | 17 (10) |
| ETR | 1 (2) | 3 (3) | 4 (2) |
| ARV background regimen, n (%) | |||
| TDF/FTC or 3TC | 53 (83) | 75 (77) | 128 (79) |
| ABC/FTC or 3TC | 11 (17) | 23 (23) | 34 (21) |
| Laboratory measurements, mean (SEM) | |||
| platelet count (109/L) | 218.0 (8.9) | 203.6 (6.9) | 209.3 (5.5) |
| haemoglobin (g/L) | 149.4 (1.5) | 152.7 (1.2) | 151.4 (0.94) |
| LDL-cholesterol (mmol/L) | 2.4 (0.1) | 2.3 (0.08) | 2.3 (0.06) |
3TC, lamivudine; ABC, abacavir; ATV/r, atazanavir/ritonavir; DRV/r, darunavir/ritonavir; EFV, efavirenz; ETR, etravirine; FTC, emtricitabine; RTG, raltegravir; TDF, tenofovir disoproxil fumarate; FTC, emtricitabine.
aDetermined by 5′NC-genotyping.
bIncludes 29 prior relapsers, 18 prior partial responders and 51 prior null responders.
Baseline demographics and disease characteristics
| Treatment naive (n = 64) | Treatment experiencedb (n = 98) | All patients (n = 162) | |
|---|---|---|---|
| Male, n (%) | 51 (80) | 76 (78) | 127 (78) |
| Caucasian, n (%) | 61 (95) | 88 (90) | 149 (92) |
| Age (years), median | 43 | 48 | 46 |
| HCV RNA ≥800 000 IU/mL, n (%) | 49 (77) | 92 (94) | 141 (87) |
| BMI (kg/m2), median (range) | 24.4 (18.5–36.5) | 23.7 (18.9–31.8) | 24.0 (18.5–36.5) |
| HCV genotype, n (%)a | |||
| 1a | 35 (55) | 68 (69) | 103 (64) |
| 1b | 29 (45) | 30 (31) | 59 (36) |
| IL28B subtype, n/N (%) | |||
| CC | 22/63 (35) | 22/97 (23) | 44/160 (28) |
| CT | 29/63 (46) | 58/97 (60) | 87/160 (54) |
| TT | 12/63 (19) | 17/97 (18) | 29/160 (18) |
| Cirrhosis, n/N (%) | 6/64 (9) | 15/98 (15) | 21/162 (13) |
| HIV RNA <50 copies/mL, n (%) | 62 (97) | 97 (99) | 159 (98) |
| CD4 cell count (×109/L), median (range) | 0.6 (0.3–1.4) | 0.7 (0.3–1.6) | 0.7 (0.3–1.6) |
| ARV agent, n (%) | |||
| EFV | 23 (36) | 42 (43) | 65 (40) |
| ATV/r | 27 (42) | 32 (33) | 59 (36) |
| DRV/r | 8 (13) | 9 (9) | 17 (10) |
| RTG | 5 (8) | 12 (12) | 17 (10) |
| ETR | 1 (2) | 3 (3) | 4 (2) |
| ARV background regimen, n (%) | |||
| TDF/FTC or 3TC | 53 (83) | 75 (77) | 128 (79) |
| ABC/FTC or 3TC | 11 (17) | 23 (23) | 34 (21) |
| Laboratory measurements, mean (SEM) | |||
| platelet count (109/L) | 218.0 (8.9) | 203.6 (6.9) | 209.3 (5.5) |
| haemoglobin (g/L) | 149.4 (1.5) | 152.7 (1.2) | 151.4 (0.94) |
| LDL-cholesterol (mmol/L) | 2.4 (0.1) | 2.3 (0.08) | 2.3 (0.06) |
| Treatment naive (n = 64) | Treatment experiencedb (n = 98) | All patients (n = 162) | |
|---|---|---|---|
| Male, n (%) | 51 (80) | 76 (78) | 127 (78) |
| Caucasian, n (%) | 61 (95) | 88 (90) | 149 (92) |
| Age (years), median | 43 | 48 | 46 |
| HCV RNA ≥800 000 IU/mL, n (%) | 49 (77) | 92 (94) | 141 (87) |
| BMI (kg/m2), median (range) | 24.4 (18.5–36.5) | 23.7 (18.9–31.8) | 24.0 (18.5–36.5) |
| HCV genotype, n (%)a | |||
| 1a | 35 (55) | 68 (69) | 103 (64) |
| 1b | 29 (45) | 30 (31) | 59 (36) |
| IL28B subtype, n/N (%) | |||
| CC | 22/63 (35) | 22/97 (23) | 44/160 (28) |
| CT | 29/63 (46) | 58/97 (60) | 87/160 (54) |
| TT | 12/63 (19) | 17/97 (18) | 29/160 (18) |
| Cirrhosis, n/N (%) | 6/64 (9) | 15/98 (15) | 21/162 (13) |
| HIV RNA <50 copies/mL, n (%) | 62 (97) | 97 (99) | 159 (98) |
| CD4 cell count (×109/L), median (range) | 0.6 (0.3–1.4) | 0.7 (0.3–1.6) | 0.7 (0.3–1.6) |
| ARV agent, n (%) | |||
| EFV | 23 (36) | 42 (43) | 65 (40) |
| ATV/r | 27 (42) | 32 (33) | 59 (36) |
| DRV/r | 8 (13) | 9 (9) | 17 (10) |
| RTG | 5 (8) | 12 (12) | 17 (10) |
| ETR | 1 (2) | 3 (3) | 4 (2) |
| ARV background regimen, n (%) | |||
| TDF/FTC or 3TC | 53 (83) | 75 (77) | 128 (79) |
| ABC/FTC or 3TC | 11 (17) | 23 (23) | 34 (21) |
| Laboratory measurements, mean (SEM) | |||
| platelet count (109/L) | 218.0 (8.9) | 203.6 (6.9) | 209.3 (5.5) |
| haemoglobin (g/L) | 149.4 (1.5) | 152.7 (1.2) | 151.4 (0.94) |
| LDL-cholesterol (mmol/L) | 2.4 (0.1) | 2.3 (0.08) | 2.3 (0.06) |
3TC, lamivudine; ABC, abacavir; ATV/r, atazanavir/ritonavir; DRV/r, darunavir/ritonavir; EFV, efavirenz; ETR, etravirine; FTC, emtricitabine; RTG, raltegravir; TDF, tenofovir disoproxil fumarate; FTC, emtricitabine.
aDetermined by 5′NC-genotyping.
bIncludes 29 prior relapsers, 18 prior partial responders and 51 prior null responders.
Patient disposition by prior HCV treatment status is summarized in Figure 1.
Patient disposition (final analysis), showing completion and discontinuation of telaprevir, Peg-IFNα2a and ribavirin. RBV, ribavirin; TVR, telaprevir.
Efficacy outcomes
Overall, 57% of patients achieved SVR12 (92 of 162 patients; 95% CI = 49%–65%). SVR12 rates were 64% (41 of 64; 95% CI = 51.1%–75.7%) in treatment-naive patients, 62% (18 of 29; 95% CI = 42.3%–79.3%) in relapsers and 49% (34 of 69; CI = 37.0%–61.6%) in non-responders: prior partial responders (72%; 95% CI = 46.5%–90.3%) and prior null responders (41%; 95% CI = 27.6%–55.8%). All patients who achieved SVR12 also achieved SVR24. One patient who missed the SVR12 assessment achieved SVR24. In all prior treatment groups, the lower boundary of the two-sided 95% CI of SVR exceeded the pre-specified historical control SVR rates, thus rejecting the null hypothesis. SVR12 rates by ARV ranged from 50.8% (efavirenz) to 76.5% (raltegravir) (Figure 2). SVR12 rates were higher in IL28B CC patients (77%, 95% CI = 62%–89%) compared with CT (49%, 95% CI = 39%–60%) and TT (48%, 95% CI = 29%–68%). The SVR12 rate in patients with cirrhosis was 43% (9 of 21 patients; 95% CI = 22%–66%). As >75% of patients received a ribavirin dose of 800 mg/day or higher, it was not possible to ascertain any relationship between ribavirin dose and SVR.
HCV virological response by selected ARVs used in concomitant HAART. Dashed reference line = SVR rate of the overall population (57.4%). ATV/r, atazanavir/ritonavir; DRV/r, darunavir/ritonavir; EFV, efavirenz; ETR, etravirine; LCL, lower confidence limit; RTG, raltegravir; UCL, upper confidence limit.
Overall, RVR (<25 IU/mL plasma HCV RNA target not detected at week 4) was achieved by 85 of 162 (52%) patients; eRVR by 80 of 162 (49%) patients. The proportion of patients achieving eRVR who achieved SVR12 was 88% compared with 28% for those who did not achieve eRVR.
Forty-one patients (25%) experienced on-treatment virological failure (19 during the telaprevir phase; 22 during the post-telaprevir phase). Of these, 39 patients met a virological stopping rule and two experienced viral breakthrough. The main reason for treatment-naive patients and prior non-responders not achieving SVR12 was on-treatment virological failure, i.e. 14 of 64 (22%) and 26 of 69 (38%), respectively; in prior relapsers, this was 3% (1 of 29).
Virology
Of the 41 patients with on-treatment virological failure and sequencing data, most (63%; 26 of 41) had higher-level telaprevir-resistant variants at time of failure, 24% (10 of 41) had lower-level telaprevir-resistant variants and 12% (five patients) had WT virus. Most relapsers (six of eight patients; 75%) had lower-level telaprevir-resistant variants at time of failure.
Safety and tolerability
Incidences of AEs were generally comparable between overall and telaprevir treatment phases, with the exception of serious AEs and AEs of at least grade 3, where incidence was higher in the overall treatment phase (14% and 44%, respectively) than in the telaprevir treatment phase (6% and 33%, respectively).
Overall, 157 (97%) patients reported at least one AE during the telaprevir treatment phase, mostly grade 1 or 2. The most frequently reported AEs in the telaprevir phase were pruritus special search category (SSC) and rash SSC. Rash SSC of at least grade 3 was reported in four (2%) patients, leading to permanent discontinuation of telaprevir in three patients.
Incidences of SSC AEs were similar in both treatment phases except for anaemia SSC [reported more often in the overall treatment phase (21%) than the telaprevir treatment phase (15%)]. Three per cent of patients experienced at least grade 3 anaemia during the telaprevir treatment phase.
For 19 of 24 patients who reported anaemia SSC in the telaprevir treatment phase, the ribavirin dose was either reduced (n = 12), temporarily discontinued (n = 6) or permanently discontinued (n = 1). Six patients received erythropoietin or blood transfusion.
Thirty-seven patients (23%) reported a treatment-emergent grade 3 (n = 24) or 4 (n = 13) hyperbilirubinaemia. Of these, 36 patients received atazanavir as part of their ART. In the subgroup of patients not taking atazanavir, the reported hyperbilirubinaemia rate was <1%. No patient discontinued Peg-IFN/ribavirin or telaprevir due to hyperbilirubinaemia.
Increases in creatinine occurred in seven patients (4%) during the telaprevir treatment phase, but returned to baseline values by week 16. There were no renal events or increases in creatinine that led to telaprevir discontinuation. No clinically relevant changes in other laboratory parameters were seen.
HIV outcome
HIV virological response was maintained for all patients during the telaprevir treatment phase. During follow-up, three patients had a viral load increase ≥200 copies/mL HIV-1 RNA at their last viral load (HIV viral breakthrough). All were receiving atazanavir/ritonavir and had at least one IAS-USA HIV protease inhibitor resistance mutation related to their ARV regimen at the time of breakthrough. There were no AIDS-defining illnesses reported.
Pharmacokinetics
Sparse plasma samples were obtained from 147 patients. Mean (SD) trough concentration at steady-state (C0h,ss) and maximum plasma concentration at steady-state (Cmax,ss) for telaprevir (sparse sampling) was 2510 (846) ng/mL and 3430 (1020) ng/mL, respectively. Mean AUC from 0 to 24 h (AUC0–24) was 74 200 (22 700) ng·h/mL. Population pharmacokinetic parameter estimates for telaprevir at steady-state were broadly similar, irrespective of the ARV agent in the patients' regimens (Supplementary Data).
Plasma concentrations of abacavir, etravirine, raltegravir and ritonavir remained generally constant during the weeks of sparse sampling for ARVs (Supplementary Data). However, a trend was observed towards higher darunavir plasma concentrations in the absence of telaprevir (baseline and week 24) (Supplementary Data). Investigation of the relationship between drug exposure and SVR12 indicated no clinically relevant differences in either the range of AUC24,ss or C0h,ss values between patients who did and those who did not achieve SVR12 (data not shown).
Supplementary Data shows the baseline characteristics of the 17 patients included within the darunavir substudy. Total and unbound (free) concentrations of telaprevir and darunavir are shown in Supplementary Data.
Discussion
INSIGHT, the first known Phase III clinical study to investigate the antiviral efficacy of telaprevir in combination with Peg-IFN/ribavirin in patients with HCV/HIV coinfection, demonstrated efficacy (overall SVR 57%) in a relatively difficult-to-treat population. Overall, attainment of eRVR was a good predictor of SVR.
Previously, in Phase IIa Study 110, the SVR24 rate (74%) was higher than achieved here.11 The higher response rate may be accounted for by baseline characteristics of the patients: all patients in Study 110 were treatment naive, whereas 60% were treatment experienced in INSIGHT; also, fewer patients in Study 110 had cirrhosis (2 of 38 patients; 5%) than in INSIGHT (21 of 162; 13%). In addition, a higher percentage of patients had genotype 1a in Study 110 than INSIGHT (27 of 38 patients; 71%) versus 103 of 162 patients (64%). In all treatment groups the null hypothesis was rejected. SVR12 rates by prior treatment status were 64%, 62% and 49% in treatment-naive patients, prior relapsers and prior non-responders, respectively.
INSIGHT demonstrated that the resistance profile observed in HCV/HIV-1-coinfected patients was similar to the resistance profile in HCV-monoinfected patients.15,16
INSIGHT explored a large number of ARV regimens. Efficacy was demonstrated across this range and, although there were small differences in SVR12 rates, no obvious trends were seen in telaprevir pharmacokinetic estimates at steady-state. These findings suggest the variability in response rates is a result of the heterogeneous patient population and may be the result of the low sample size in these subgroups. In Study 110, only specific ARV regimens were permitted (efavirenz, tenofovir disoproxil fumarate and emtricitabine, or atazanavir/ritonavir, tenofovir disoproxil fumarate and either emtricitabine or lamivudine).
In HCV/HIV-coinfected patients, weight-based ribavirin (1000–1200 mg/day) has not shown significantly higher SVR rates than fixed-dose ribavirin (800 mg/day), yet it is associated with greater haemoglobin reduction.17 INSIGHT showed lower rates of anaemia (including grade 3 or 4) using 800 mg/day ribavirin than previously observed in monoinfected studies with weight-based dosing (21% versus 33%–39%, respectively).15,16,18
As was observed in Study 110, and as expected, most patients who received atazanavir experienced grade 3 and 4 hyperbilirubinaemia.19 However, no patient discontinued study medication due to hyperbilirubinaemia. In INSIGHT, there was a low proportion of serious rash; serious rash SSC events were reported in only one (0.6%) patient during the telaprevir treatment phase.
Telaprevir and darunavir total concentrations were generally similar to the lowest quartiles observed for patients in earlier studies of telaprevir or darunavir,20,21 and there were no incidences of HIV-1 viral breakthrough.
One important limitation of this study is that the findings may not be applicable to patients with more advanced HIV infection, as only patients with stable HIV disease and high CD4 cell counts were recruited. In addition, although the sample size was sufficient to meet the study objectives, low numbers and heterogeneous population prevented reliable interpretation of some subgroups.
In conclusion, telaprevir with Peg-IFN/ribavirin showed higher SVR rates than historical controls, with a range of ARV regimens, regardless of prior HCV treatment experience. A similar safety and tolerability profile to previous telaprevir studies was seen, but with reduced incidence of anaemia. Therefore, findings confirm those of the earlier Phase II study indicating the potential for telaprevir-containing triple therapy as a treatment for HCV/HIV-coinfected patients.
Funding
This work was supported by Janssen Pharmaceuticals. In addition, the editorial support (see below) was funded by Janssen Pharmaceuticals.
Transparency declarations
M. L. M. has received consulting fees from Abbott Pharmaceuticals, Boehringer Ingelheim, Janssen Pharmaceuticals, Gilead Sciences and ViiV Healthcare, and has received payment for lectures from Abbott Pharmaceuticals, Bristol-Myers Squibb and Roche. M. N. has served on advisory boards for and received honoraria and research grants from Janssen Pharmaceuticals, Merck Sharp and Dohme, Boehringer Ingelheim, Bristol-Myers Squibb, Abbott Pharmaceuticals and Gilead Sciences. P.-M. G. has received grant/research support from Abbott Pharmaceuticals and has served on advisory boards for Boehringer Ingelheim, Bristol-Myers Squibb, Merck, Roche, Tibotec/Janssen, ViiV Healthcare and Gilead Sciences. J. S. has received honoraria and research grants from Gilead Sciences, Bristol-Myers Squibb, Roche, Merck Sharp and Dohme, and Janssen Pharmaceuticals. A. R. has served on advisory boards for and received honoraria and research grants from Janssen Pharmaceuticals, Merck Sharp and Dohme, Boehringer Ingelheim, Bristol-Myers Squibb, Roche, Abbott Pharmaceuticals and Gilead Sciences. J. D. has received grant/research support from Abbott Pharmaceuticals and has served on advisory boards for Bristol-Myers Squibb. E. O.-G. has received support for the organization of refresher courses and served on advisory boards for Bristol-Myers Squibb, Gilead Sciences, ViiV Healthcare and Janssen Pharmaceuticals. E. L., K. J., S. O.-M. and J. W. are employees of Janssen Pharmaceuticals. J. G.-G. has served on advisory boards, received grant/research support and honoraria for lectures from Abbott Pharmaceuticals, Bristol-Myers Squibb, Gilead Sciences, Janssen Pharmaceuticals, Merck Sharp and Dohme, Roche and ViiV Healthcare. A. H., B. G. and N. Z. have no conflicts of interest to declare.
Editorial support for this manuscript was provided by Sally Gray (Senior Medical Writer of Zoetic Science, an Ashfield Company, part of UDG Healthcare plc, Macclesfield, UK.
Author contributions
M. L. M., M. N., P.-M. G., J. S., A. H., B. G., N. Z., A. R., J. G.-G., E. O.-G. and J. D. were involved in the recruitment of patients into the study and participated in data collection and data analysis. E. L., K. J., S. O.-M. and J. W. contributed to data analysis. All authors critically reviewed the article for important intellectual content and approved the final draft for submission.
Acknowledgements
Data in this manuscript were presented at the Twelfth Glasgow Congress on HIV Therapy, Glasgow, UK, 2014 (Poster P094).
We are grateful to patients in the Phase III study for their participation and support. We would also like to thank all the investigators: Australia, Drs Matthews, Russell; Brazil: Drs Madruga, Munhoz Leite, Furtado, Mendes Corrêa, Lima, Brandao Mello; Spain, Drs Gutiérrez, de Los Santos, Pineda, Tural, Von Wichmann, Reus; France, Drs Lacombe, Bollens, Sebire, Poizot-Martin, Teicher; UK, Drs Mutimer, Orkin, Agarwal, Fox, Cooke, Bhagani; Poland, Drs Halota, Janczewska; Russia, Drs Voronin, Dushkina, Kulagin, Tsybakova, Khafizov; and Sweden, Drs Blaxhult, Falconer.
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