Mericitabine and ritonavir-boosted danoprevir with or without ribavirin in treatment-naive HCV genotype 1 patients: INFORM-SVR study.

BACKGROUND & AIMS: Safety and tolerability of peginterferon-based hepatitis C virus (HCV) infection therapy remains suboptimal, even when direct-acting antiviral agents are added. This study assessed the efficacy, safety and tolerability of mericitabine combined with ritonavir-boosted danoprevir (danoprevir/r) ± ribavirin for up to 24 weeks in treatment-naïve HCV genotype (G)1 infected patients. METHODS: Patients received twice daily mericitabine (1000 mg) and danoprevir/r (100 mg/100 mg) plus either ribavirin (1000/1200 mg/day; Arm A) or placebo (Arm B) for 12 or 24 weeks. Patients with HCV RNA <43 IU/ml between Weeks 2 and 8 and HCV RNA <15 IU/ml at Week 10 were rerandomized (1:1) at Week 12 to discontinue/continue assigned regimens until Week 24. Because of unacceptable relapse rates in both 12-week arms and in ribavirin-free Arm B, treatment was extended to 24 weeks and patients in Arm B received peginterferon alfa-2a/ribavirin. The primary outcome was sustained virological response 24 weeks after end of treatment (SVR24). RESULTS: In Arm A, the SVR24 rate in patients receiving 24 weeks of therapy was 37.9% (25/66); 63.6% (14/22) in G1b and 25.0% (11/44) in G1a patients. Virologic breakthrough and relapse were associated with danoprevir-resistant virus in most cases. The mericitabine-resistance mutation (NS5BS282T) was detected in two patients bearing dual resistant virus NS3 R155K/NS5B S282T and dual resistance mutation L159F/L320F in one patient. Treatment was safe and well tolerated. CONCLUSIONS: Mericitabine, danoprevir/r plus ribavirin for 24 weeks were safe and well tolerated. However, SVR rates were poor, achieving rates of only 25.0% in G1a and 63.6% in G1b patients.

Efficacy and safety of 48 weeks of enfuvirtide 180 mg once-daily dosing versus 90 mg twice-daily dosing in HIV-infected patients.

PURPOSE: To evaluate the safety and antiviral activity of once-daily (qd) enfuvirtide (ENF) compared with twice daily (bid) ENF. METHOD: T20-401 was a phase 2, open-label, randomized, 48-week pilot study comparing ENF 180 mg qd versus ENF 90 mg bid, added to an optimized background (OB) regimen. Patients were randomized 1:1 to receive ENF 180 mg qd given as two 90-mg injections (n = 30) or one 90-mg injection bid (n = 31), plus OB. The primary efficacy endpoint was the proportion of patients achieving a HIV-1 RNA viral load <400 copies/mL. Adherence, pharmacokinetics, safety, and tolerability parameters, including injection site reactions (ISRs), were compared between treatment arms. RESULTS: At Week 48, 23.3% of patients on once daily versus 22.6% on twice daily (p = .969) reached <400 copies/mL and 13.3% and 22.6% (p = .323), respectively, reached <50 copies/mL. The proportion reporting 1 adverse event or ISRs was comparable between arms, despite an increased incidence of grade 4 erythema (13% vs. 0%), induration (33% vs. 12%), and ecchymosis (7% vs. 0%) on twice daily versus once daily. ENF adherence (95% of prescribed doses) was higher on once daily (80.0%) versus twice daily (58.1%). CONCLUSION: The antiviral efficacy, safety, and tolerability of 180 mg ENF qd appeared comparable with that of 90 mg ENF bid at Week 48, although the study was not powered to demonstrate the noninferiority of once daily versus twice daily.

Adherence to enfuvirtide and its impact on treatment efficacy.

High adherence rates to antiretroviral (ARV) therapy are associated with increased durability of viral suppression and decreased rates of drug resistance. The requirement of twice-daily subcutaneous self-administration of enfuvirtide (ENF) has raised concerns about adherence. This study assesses adherence to ENF and an optimized background (OB) of ARVs and its impact on virological and immunological responses during the TORO trials. Eighty-eight percent of patients in the OB arm reported > or = 85% adherence versus 87% of patients in the ENF + OB arm. Higher overall adherence was associated with improved virological and immunological response in both treatment arms at 48 weeks. In patients with > or = 85% adherence, 33% of patients in the ENF + OB arm achieved HIV-1 RNA < 400 copies/ml, versus 13% in the OB arm (p < 0.0001). Similarly, patients with > or = 85% adherence in the ENF + OB arm achieved a mean increase in CD4 cell count of 104 cells/mm(3) compared with 58 cells/mm(3) for patients in the OB arm (p < 0.001). None of the demographic factors explored (age, gender, race) or baseline characteristics (CD4 count, viral load, or baseline sensitivity score) was significant in predicting adherence to ENF when analyzed by multiple regression. Importantly, a history of intravenous drug use (IDU) was not associated with a significant decrease in adherence (mean adherence for IDU 96% versus mean adherence for non-IDU 96%; p = 0.825). Adherence was high in patients receiving the self-injectable ARV enfuvirtide. In addition, the inclusion of ENF did not negatively impact adherence to the ARV regimen as a whole.

Safety of enfuvirtide in combination with an optimized background of antiretrovirals in treatment-experienced HIV-1-infected adults over 48 weeks.

BACKGROUND: Antiretroviral tolerability is a critical factor contributing to treatment outcome. The T-20 Versus Optimized Background Regimen Only (TORO) studies assessed the safety and efficacy of enfuvirtide in treatment-experienced HIV-1-infected patients. METHODS: A total of 997 patients were randomized at a 2:1 ratio to an optimized background antiretroviral regimen plus enfuvirtide (n = 663) or an optimized background regimen alone (control group; n = 334). Control patients could switch to enfuvirtide on virologic failure. RESULTS: In total, 26.5% of patients randomized to enfuvirtide and 36.6% to the control group discontinued study treatment before week 48; the percentage of patients withdrawn for safety reasons (including adverse events [AEs], deaths, and laboratory abnormalities) was 14.0% in the enfuvirtide group and 11.6% in the control group. Injection site reactions (ISRs) occurred in 98% of enfuvirtide patients and led to treatment discontinuation in 4.4%. Treatment-related (defined as possibly, probably, or remotely) AE rates per 100 patient-years were lower with enfuvirtide (96.2) than in the control group (149.9); diarrhea, nausea, and fatigue, the most frequently reported AEs, were significantly less frequent with enfuvirtide than in the control group. Pneumonia was significantly more frequent in patients treated with enfuvirtide (6.7 vs. 0.6 events per 100 patient-years), although the incidence was within expected ranges for this population. Lymphadenopathy was also higher in enfuvirtide-treated patients (7.1 vs. 1.2 events per 100 patient-years) for control patients. CONCLUSION: The addition of enfuvirtide to an optimized background regimen does not exacerbate AEs commonly associated with antiretrovirals. ISRs limited treatment in <5% of patients.