Anne-Marie Quinson

Efficacy and safety of nevirapine extended-release once daily versus nevirapine immediate-release twice-daily in treatment-naive HIV-1-infected patients.

BACKGROUND This study (VERxVE) compared the efficacy and safety of the new nevirapine extended-release (NVP XR) formulation dosed once daily with NVP immediate release (IR) twice daily in treatment-naive patients. METHODS Randomized, double-blind, double-dummy, parallel group study of HIV-1-infected adult patients with baseline viral load (VL) ≥ 1,000 copies/ml and CD4(+) T-cell count of >50-<400 (males) and >50-<250 cells/mm(3) (females). Patients stratified by baseline VL (≤ 100,000/>100,000 copies/ml) were randomized 1:1 to NVP XR 400 mg once daily (plus placebo) or NVP IR 200 mg twice daily (plus placebo), both combined with tenofovir disoproxil fumarate (TDF) 300 mg and emtricitabine 200 mg once daily. Primary endpoint was sustained virological response (<50 copies/ml) through week 48 using the time to loss of virological response algorithm. Non-inferiority of NVP XR to NVP IR was tested using Cochrans statistic incorporating baseline VL stratum with pre-specified, non-inferiority margin of -10%. RESULTS Among 1,011 patients randomized and treated, virological response at week 48 was 81.0% (409/505) for NVP XR and 75.9% (384/506) for NVP IR with adjusted difference of 4.9% in favour of NVP XR (95% CI -0.1-10.0%), demonstrating non-inferiority of NVP XR to NVP IR. This finding was supported by secondary endpoints. The safety profile of NVP XR was similar to NVP IR, but showed numerically fewer treatment-related adverse events. CONCLUSIONS NVP XR in combination with TDF and emtricitabine was shown to be non-inferior in efficacy to NVP IR with a similar safety and adverse event profile, with the potential for the added convenience of once-daily dosing. TRIAL REGISTRATION ClinicalTrials (NCT): NCT00561925.

STARTVerso1: A randomized trial of faldaprevir plus pegylated interferon/ribavirin for chronic HCV genotype-1 infection

BACKGROUND & AIMS The efficacy and tolerability of faldaprevir, a potent hepatitis C virus (HCV) NS3/4A protease inhibitor, plus peginterferon (PegIFN) and ribavirin (RBV) was assessed in a double-blind, placebo-controlled phase 3 study of treatment-naïve patients with HCV genotype-1 infection. METHODS Patients were randomly assigned (1:2:2) to PegIFN/RBV plus: placebo (arm 1, n = 132) for 24 weeks; faldaprevir (120 mg, once daily) for 12 or 24 weeks (arm 2, n = 259); or faldaprevir (240 mg, once daily) for 12 weeks (arm 3, n = 261). In arms 2 and 3, patients with early treatment success (HCV-RNA <25 IU/ml at week 4 and undetectable at week 8) stopped all treatment at week 24. Other patients received PegIFN/RBV until week 48 unless they met futility criteria. The primary endpoint was sustained virologic response 12 weeks post-treatment (SVR12). RESULTS SVR12 was achieved by 52%, 79%, and 80% of patients in arms 1, 2, and 3, respectively (estimated difference for arms 2 and 3 vs. arm 1: 27%, 95% confidence interval 17%-36%; and 29%, 95% confidence interval, 19%-38%, respectively; p < 0.0001 for both). Early treatment success was achieved by 87% (arm 2) and 89% (arm 3) of patients, of whom 86% and 89% achieved SVR12. Adverse event rates were similar among groups; few adverse events led to discontinuation of all regimen components. CONCLUSIONS Faldaprevir plus PegIFN/RBV significantly increased SVR12, compared with PegIFN/RBV, in treatment-naïve patients with HCV genotype-1 infection. No differences were seen in responses of patients given faldaprevir once daily at 120 or 240 mg.

Assessment of Nevirapine Bioavailability From Targeted Sites in the Human Gastrointestinal Tract

This study investigated absorption of nevirapine (NVP) from targeted sites of the gastrointestinal tract using remotely activated capsules and gamma scintigraphy. A total of 24 participants were randomized to receive 50 mg NVP orally as a suspension or via remotely activated capsules for release into the ascending colon. The 24 participants were then rerandomized into parallel groups of n = 8 for drug release into the ileum, jejunum, or descending colon. The mean gastric emptying time of capsules ranged from 0.88 to 3.35 hours. The small intestinal and colon transit time ranged from 4.08 to 7.76 hours and 17.6 to 21.2 hours, respectively, and capsule recovery time ranged from 27.6 to 34.4 hours. The relative bioavailability ratio of NVP in the jejunum was 1.06 (90% confidence interval [CI]: 1.00–1.12) compared to suspension. In the ileum, ascending colon, and descending colon, bioavailability decreased to 0.89 (0.80–0.99), 0.82 (0.71–0.95), and 0.58 (0.22–1.53), respectively. The absorption rate decreased by ∼10‐fold from the jejunum (3.83 h−1) to the descending colon (0.338 h−1), and tmax increased from 2.42 hours (jejunum) to 16.3 hours (descending colon). Overall, NVP is absorbed from all 4 sites of the gastrointestinal tract, and the rate of absorption decreased from the jejunum to the descending colon. Relative bioavailability of NVP was in the order of jejunum > ileum > ascending colon > descending colon.

Bioavailability of Extended-Release Nevirapine 400 and 300 mg in HIV-1: A Multicenter, Open-Label Study

BACKGROUND Nevirapine (NVP) is a widely used non-nucleoside reverse transcriptase inhibitor. A once-daily extended-release (XR) formulation would potentially increase adherence and thus efficacy. OBJECTIVE The aim of this study was to investigate the steady-state bioavailability of 2 once-daily tablet formulations of NVP XR (containing 25% or 20% hypromellose; NVP XR25 and NVP XR20, respectively) in 400- or 300-mg tablets compared with twice-daily immediate-release (IR) NVP 200-mg tablets. METHODS This Phase Ib multinational, multicenter, open-label trial was conducted in patients aged 18 to 60 years, infected with HIV-1 (viral load, ≤50 copies/mL), and treated for ≥12 weeks with twice-daily NVP IR 200 mg. Patients were switched to NVP XR25 400 or 300 mg or NVP XR20 400 or 300 mg for 19 days. Plasma samples were collected over 24-hour periods at steady state. Primary end points were AUC(0-24,ss), C(max,ss), and C(min,ss), analyzed using an ANOVA statistical model on the logarithmic scale and 2-sided 90% CI. Sample size was determined assuming an intrasubject %CV of 20% for C(max). Adverse events (AEs) and viral loads were monitored. RESULTS Ninety-two patients were enrolled (NVP XR25 400 mg, 24 patients; NVP XR20 400 mg, 24; NVP XR25 300 mg, 21; NVP XR20 300 mg, 23). Compared with NVP IR, the AUC(0-24,ss) values of the NVP XR formulations were lower (test/reference ratios: 79.5% [90% CI, 73.0-86.7; P = 0.544], 71.0% [90% CI, 63.3-79.7; P = 0.956], 90.3% [90% CI, 80.4-101.4; P = 0.044], and 83.7% [90% CI, 77.9-89.9; P = 0.148] with NVP XR25 400 mg, NVP XR20 400 mg, NVP XR25 300 mg, and NVP XR20 300 mg, respectively). The relative bioavailability of NVP XR25 was greater compared with that of NVP XR20. C(max,ss) values were lower with all NVP XR formulations compared with NVP IR. For C(min,ss), NVP XR25 400 and 300 mg were not significantly different from NVP IR, with 90% CIs within the range of 80% to 125% (P = 0.039 and P = 0.017, respectively). All AEs were mild or moderate, with no significant differences between treatment groups. No virologic failures (viral load, >50 copies/mL over 2 consecutive readings) were observed. CONCLUSIONS Extent of bioavailability was lower and t(max,ss) was delayed with all NVP XR formulations compared with NVP IR. The bioavailability of the NVP XR25 formulations was greater than that of the NVP XR20 formulations. C(min,ss) with NVP XR25 was similar to that with NVP IR. All of the NVP XR formulations were well tolerated. The 400-mg NVP XR25 formulation was selected for further development.

Su1049 Faldaprevir Plus Pegylated Interferon Alfa-2A and Ribavirin in Treatment-Naïve Patients With Chronic Hepatitis C Genotype-1 Infection: A Pooled Analysis of Two Randomized, Double-Blind Placebo-Controlled Phase III Trials (Startverso1&2)

A S L D A b st ra ct s Retrospective cohort study using data from Kaiser Permanente Southern California. Study participants were ≥18 years old with a diagnosis and/or a positive lab result for HCV RNA and ≥6 months continuous membership plus drug benefit prior to HCV treatment. Baseline demographics and comorbid illnesses representing absolute or relative contraindications to treatment with peginterferon, ribavirin, boceprevir, or telaprevir were determined. Multivariate logistic regression was used to determine predictors of treatment. Results: From Jan 2002 through Dec 2012, 51,984 HCV patients were identified and 7,945 (15.3%) of this population received treatment. After applying exclusion criteria, 32,283 patients were identified, of which 26,750 received no treatment and 5,533 received treatment. Factors significantly associated with receipt of treatment were age 45-65, male gender, cirrhosis, HIV, non-alcoholic fatty liver disease (NAFLD), depression, and prior liver transplant. Factors significantly associatedwith receiving no treatment are seen in Table 1. Conclusion: Treatment of HCV with peginterferon-based regimens is significantly limited by numerous comorbid conditions. Future treatment may be better tolerated and with fewer contraindications, thus increasing treatment effectiveness and thereby reducing future morbidity and mortality of liver disease.

Steady-state Pharmacokinetics of Nevirapine Extended-release Tablets in Hiv-1–infected Children and Adolescents: An Open-label, Multiple-dose, Cross-over Study

Background: To compare steady-state (ss) pharmacokinetic targets of nevirapine extended-release (NVP-XR) tablets once-daily (QD) with immediate-release (NVP-IR) tablet or oral suspension twice-daily in HIV-1–infected children and adolescents. Methods: Phase I, open-label, multidose, cross-over study with optional extension phase, in 85 patients 3 to <18 years of age, previously on an NVP-IR–based regimen for ≥18 weeks with baseline viral load <50 copies/mL. Patients were stratified by age, treated with NVP-IR twice-daily for 11 days, then NVP-XR QD for 10 days. Cpre,ss (steady-state, predose concentrations) was obtained from all, and 12-hour NVP-IR and 24-hour NVP-XR steady-state pharmacokinetic profiles were obtained in the pharmacokinetic substudy. Viral loads, CD4 counts and adverse events (AEs) were monitored. Results: Eighty patients completed the trial. Adjusted geometric mean (gMean) Cpre,ss for NVP-XR and NVP-IR exceeded the target of 3000 ng/mL, and the adjusted gMean NVP-XR:NVP-IR ratio (90% confidence interval) for QD normalized and un-normalized Cpre,ss were 91.2% (83.5–99.6%) and 91.8% (83.7–100.7%). gMean 24-hour area under the curve at steady-state NVP-XR:NVP-IR for un-normalized dose was 90.4% and un-normalized Cpre,ss NVP-XR:NVP-IR were 91.0%, 81.9% and 103.7% for the 3 age groups, 3 to <6, 6 to <12 and 12 to <18 years, respectively. gMean values indicated no exposure to subtherapeutic NVP concentrations and viral suppression was adequate and maintained in all QD groups. Most AEs were mild and similar between age groups. No serious or Division of AIDS Grade 4 AEs or AE related treatment discontinuations occurred. Conclusions: NVP-XR exhibited adequate trough concentrations with equivalent area under the curve at steady-state relative to NVP-IR. NVP-XR was well-tolerated and is a valuable treatment option for HIV-infected children and adolescents.

Effect of Steady-State Faldaprevir on Pharmacokinetics of Atorvastatin or Rosuvastatin in Healthy Volunteers: A Prospective Open-Label, Fixed-Sequence Crossover Study

Faldaprevir (FDV) is a potent, orally administered inhibitor of hepatitis C virus protease. It inhibits multiple cytochrome P‐450 enzymes and multiple membrane transporters. The objective of this study was to evaluate the effect of steady‐state faldaprevir on the pharmacokinetics (PK) of a single dose of atorvastatin or rosuvastatin. In this single‐center, open‐label, fixed‐sequence crossover study, 33 healthy adult male and female volunteers were given either atorvastatin 10 mg (n = 16) or rosuvastatin 10 mg (n = 17) on day 1. Subjects subsequently received 240 mg twice daily of faldaprevir (loading dose) on day 5, followed by 240 mg faldaprevir once daily from day 6 to day 10, with an additional single dose of atorvastatin (10 mg) or rosuvastatin (10 mg) given on day 10. PK samples for the statins were collected on days 1–3 and days 10–12. Concomitant administration with faldaprevir led to approximately 9‐fold and 34‐fold increases in AUC0–∞ and Cmax, respectively, of atorvastatin and approximately 15‐fold and 33‐fold increases in AUC0–∞ and Cmax, respectively, of rosuvastatin, compared with the statins given alone. Exposure to the major metabolites (ortho‐hydroxyatorvastatin and N‐desmethylrosuvastatin) was increased to a similar magnitude as that of the parent compounds. The marked drug–drug interaction observed is most likely related to the inhibitory effects of faldaprevir on transporters, particularly hepatic uptake transporters such as OTAP1B1 and OATP1B3. Given the significant increase in exposure to statins in healthy volunteers, coadministration of faldaprevir with statins should be avoided.

Pharmacokinetic analysis of nevirapine extended release 400 mg once daily vs nevirapine immediate release 200 mg twice daily formulation in treatment-naïve patients with HIV-1 infection

Background: VERxVE data showed non-inferior virologic efficacy with extended release nevirapine (NVP-XR) dosed 400 mg once daily (QD) versus immediate release nevirapine (NVP-IR) 200 mg twice daily in a double-blind, non-inferiority study in treatment-naïve HIV-1-positive patients. Objective: To study the pharmacokinetics (PK) of the NVP formulations and identify possible associations with demographic factors. Methods: Patients with viral load ≥1000 copies/mL and CD4+ count > 50– <400 cells/mm3 (males) and >50– <250 cells/mm3 (females) at screening received NVP-IR 200 mg QD during a 14-day lead-in and were then stratified by baseline viral load and randomized to NVP-XR or -IR. NVP trough concentrations at steady state (SS) (Cpre,ss,N) were measured up to week 48 for all participating patients. In a PK sub-study, SS parameters – AUC0–24, Cmax, Cmin, and peak-to-trough fluctuation were obtained and analyzed with relative bioavailability assessed at week 4 by plasma collection over 24 h. Results: Trough concentrations were stable from week 4 to week 48 for all patients (n = 1011) with both formulations, with NVP-XR/IR ratios of 0.77–0.82. Overall, 49 patients completed the PK sub-study: 24 XR and 25 IR. NVP-XR showed less peak-to-trough fluctuation (34.5%) than IR (55.2%), and lower AUC0–24, Cmin, Cmax, and trough concentrations than IR. However, no effect of SS trough concentrations was found on the virologic response proportion at least up to 1000 ng/mL. No significant association was found between NVP PK and gender, race, and viral load. Conclusion: These data suggest NVP-XR achieves lower but effective NVP exposure compared with NVP-IR.

Su1053 Virological Response in Treatment-Naïve Patients With Chronic HCV Genotype-1 Infection Receiving Faldaprevir Plus Pegylated Interferon α-2A and Ribavirin Is Unaffected by Ribavirin Dose Reduction

Background: Optimal duration of interferon-free HCV treatment continues to be examined in clinical trials. The SOUND-C2 and -C3 studies assessed the efficacy and safety of 16, 24, 28 and 40 weeks (W) of the interferon-free combination of faldaprevir, deleobuvir ± ribavirin in treatment-naive patients infected with HCV genotype (GT)-1. Relapse was higher in HCV GT-1a-infected patients treated for 16W with this regimen compared with GT-1b. We examined the relationship between duration of undetectable HCV RNA and virological response in SOUND-C2 and -C3. Methods: Patients received faldaprevir 120 mg QD plus deleobuvir 600 mg BID or TID. A ribavirin-free arm was investigated in SOUND-C2. The relationship between duration of undetectable HCV RNA to the end of treatment and SVR12 was assessed. Results: SVR rates among patients with undetectable HCV RNA at the last ontreatment visit, based on duration of undetectable HCV RNA, are shown (Table). GT-1binfected patients may require less time at undetectable HCV RNA (8-12W) compared with GT-1a patients (>16W) in order to achieve SVR. Regression analysis indicated that duration of undetectable HCV RNA was significantly associated with SVR. Conclusions: Duration of undetectable HCV RNA to end of treatment with this two DAA regimen was associated with SVR. These data suggest that the optimal treatment duration in GT-1b-infected patients is between 8W and 12W plus the time required to reach undetectable HCV RNA. There were

Safety and efficacy of faldaprevir in combination with pegylated interferon α‐2b and ribavirin in Japanese patients with genotype‐1 chronic hepatitis C virus infection

We evaluated the safety and efficacy of the hepatitis C virus (HCV) NS3/4A A protease inhibitor faldaprevir plus pegylated interferon α‐2b and ribavirin (PegIFNα‐2b/RBV) in Japanese patients with HCV genotype‐1 infection.