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FTC: 60 week study results
Reported by Jules Levin
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FTC was recently approved by the FDA in the USA. Gilead researchers reported that in 14-day FTC monotherapy studies of 100 patients HIV viral load is reduced by 1.5 to 1.9 log reduction in plasma viral load. In vitro (in the test tube) FTC has demonstrated more potency than 3TC. FTC is taken as a one 200 mg pill once daily. Gilead reports FTC has a long plasma half-life of about 10 hours resulting in steady state concentrations above the concentration needed to produce 90% inhibition (EC90) of HIV for up to 80 hours following dosing of 200 mg once daily. The steady state intracellular half-life, which may better reflect antiviral activity for nukes, is reported to be 39 hours compared to a reported 16 hours for 3TC. Unfortunately, the FTC mutation for resistance is the same as for 3TC, the M184V, meaning that if you have developed resistance to 3TC you will have resistance already to FTC.
FTC may be taken with or without food. FTC systemic exposure (AUC) was unaffected while Cmax (peak levels) decreased by 29% when FTC was administered with food (about 1000 kcal high-fat meal). Gilead reports that pharmacokinetics of FTC were similar in male and female patients and no PK differences due to race have been identified. The PK of FTC has not been fully evaluated in children or in the elderly.
Gilead reports that the PK of FTC are altered in patients with renal impairment. In patients with creatinine clearance <50 mL/min or with end-stage renal disease requiring dialysis, Cmax and AUC of FTC were increased due to a reduction in renal clearance. It is recommended that the dosing interval for FTC be modified in patients with creatinine clearance <50mL/min or in patients with end stage renal disease who require dialysis.
In drug interaction study Tenofovir increased FTC Cmin by 20% but had no effect on Cmax and AUC.
Gilead has reported data on cross-resistance. FTC resistant isolates (M184V) were cross-resistant to 3TC but retained sensitivity to abacavir, ddI, d4T, tenofovir, AZT, and NNRTIs. HIV isolates containing the K65R mutation, selected in vivo by abacavir, ddI, tenofovir, and ddC demonstrated reduced susceptibility to inhibition by FTC, Viruses harboring mutations conferring reduced susceptibility to d4T and AZT (M41L, D67N, K70R, T215Y/F, K219Q/E) or ddI (L74L) remained sensitive to FTC.
Francois Raffi of the Centre Hospitalier Universitaire de Nantes, France
described the 60-week results of Phase III Study 301 in an oral presentation today at the IAS Conference. Raffi concluded that once daily FTC demonstrated superior suppression of HIV viral load and was better tolerated compared to twice daily d4T. He also said that FTC/ddI/EFV was a convenient potent and well tolerated once daily regimen with durable suppression of HIV through 60 weeks in this study.
Previously week 48 viral response results from this study have been reported: 78% of patients receiving FTC arm vs 59% of patients in d4T group had <50 copies/ml. Viral failure rate was 11% in d4T group vs 3% in FTC group. Study discontinuation due to adverse event was 13% in d4T group vs 7% in the FTC group. CD4 increase was 168 cells for FTC group and 134 for d4T.
In previously reported study 303 patients were randomized to continue therapy with 3TC (150 mg bid) or to switch to FTC (200 mg QD). All patients were maintained on their stable background regimen. This was a 48-week open-label multi-center study comparing FTC to 3TC in combination with d4T or AZT and a PI or NNRTI in 440 patients who were on a 3TC containing regimen for at least 12 weeks prior to study entry and had HIV-RNA <400 copies/ml. Baseline mean CD4 count was 527, median HIV-RNA was 1.7 log. Median duration of ART was 27 months. After 48 weeks in study 67% in FTC group had <50 copies/ml vs 72% in 3TC group. Viral failure was 7% in FTC group and 8% in 3TC group. Study discontinuation due to adverse event was 4% in FTC group vs 0% in 3TC group.
The side effects and lab abnormality profiles for FTC & 3TC appear similar.
Study 301 enrolled 571 treatment-naive patients who at baseline had HIV RNA (viral load) of at least 5000 copies/mL. Patients were randomized (1:1) to receive once-daily Emtriva, or twice-daily stavudine, in combination with didanosine (ddl), another NRTI, and efavirenz, a non-nucleoside reverse transcriptase inhibitor (NNRTI). The median viral load at baseline was 4.9 log (just below 100,000 copies/ml) and the median CD4 cell count was 288 cells. Based on an interim analysis at 24 weeks when the median duration of follow-up was 42 weeks, the Data Safety Monitoring Board (DSMB) recommended that the trial be unblinded, and all patients offered open-label access to FTC. The d4T-treatment group discontinued.
Raffi presented the Kaplan-Meier curve for the probability of persistent virologic suppression <400 copies/ml and for <50 copies/ml after 60 weeks of study treatment: 79.4% for patients in the FTC arm vs 62.8% in the d4T arm; regarding <50 copies/ml: 75.6% for patients receiving FTC vs 53.7% for patients receiving d4T (p<0.0001). At the 60-week analysis 158 patients were on FTC and 124 on d4T.
The Kaplan-Meier probability of developing a treatment-limiting adverse event by week 60 leading to permanent discontinuation of the blinded study medication was 16.6% for patients taking d4T regimen and 7.4% for patients taking FTC regimen (log rank p=0.0028).
The Kaplan-Meier probability for virologic failure by week 60 was 14.5% for the d4T group vs 6.0% for the FTC group (log rank p-value=0.0008). Virologic failure was two consecutive plasma HIV-RNA measurements >400 copies/ml while on prescribed regimen.
Raffi reported the incidence of the most frequent or relevant adverse events (all grades): more prevalent in d4T group was diarrhea (34% vs 24%, p=0.005), nausea 24% vs 14%, p=0.001), neuropathy (13% vs 5%, p<0.001), SH/lactic acidosis (3% vs 0%, p=0.019), parasthesis (12% vs 6%, p=0.023), abnormal dreams (19% vs 11%, p=0.018). The incidence of most of the other adverse events were comparabe in the d4T and FTC groups.
The incidence of most frequent grade 3/4 lab abnormalities and clinical adverse events were: serum amylase 5% in FTC arm vs 10% in d4T group (p=0.02); CNS related events (1% in FTC group vs 4% in d4T group (p=0.03); the remaining events reported were not significantly different between the two treatment groups--triglycerides- about 8% in each group; AST 6-9%; creatinine kinase 11-12%; ALT 5-6%; serum glucose 2-3%; serum lipase 1-2%; neutrophils 5-7%.
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