FTC is a once-daily (QD) thiacytidine nucleoside analogue developed by Triangle Pharmaceuticals. The compound, 2'-3'-dideoxy-5-fluoro-3'-thiacytidine, was licensed from Emory University in 1996. It comes in 200 mg capsules and should be stored at room temperature. There are no food restrictions with FTC administration. FTC has been developed quite slowly. What may have been the most interesting thing about this drug (i.e., once daily dosing) is less interesting now that 3TC is licensed as such.
People with the M184I/V mutation associated with 3TC (Epivir) will not benefit from FTC, given that the M184 mutation confers high-level resistance to FTC. For this reason, it is important that persons with detectable viral loads who plan to switch from 3TC to FTC have genotypic testing performed to determine whether the M184V mutation is present. (Of course, a patient's treatment history is also extremely important.) If 3TC has failed in the past, the 184 mutation is archived, thus rendering FTC ineffective.
Five hundred and seventy-one people were randomized and received at least one dose of randomized study medication. At baseline, the median viral load was 4.9 log copies/mL and the median CD4 count was 288 cells/mm3. The proportion of people having viral failure through Week 48 was 5.3% in the FTC group and 12.7% in the d4T group (p<0.01). The mean increase from baseline to Week 48 in CD4 was significantly greater in the FTC group (+153 cells/mm3) than the d4T group (+120 cells) (p<0.05).
Also measured was efficacy failure -- defined as virologic failure, death, progression to CDC class C event, or loss to follow-up -- which occurred in 18% of people in the d4T group and 9% of people in the FTC group through Week 48 (p<0.01). In terms of the proportion of people with undetectable viral loads at Week 48 using an intent-to-treat analysis (non-completer equals failure): 80% in the FTC group and 67% in the d4T group had viral loads below 400 copies/mL (p<0.001), and for plasma viral load <50 copies/mL, 74% FTC, compared to 58% d4T, got there after 48 weeks of treatment (p<0.0001).
Genotypic analysis was performed on all of the 49 individuals with confirmed virologic failure through Week 48 (35 d4T, 14 FTC). Of the 35 genotypic evaluable volunteers failing d4T, 34 (97%) had mutations in the HIV polymerase gene as compared to 71% (10/14) from the FTC subgroup (p=0.019). The M184V mutation was observed only in the FTC subset, 43% (6/14), while the thymidine analogue mutations ("TAMs") were observed in 7% (1/14) of the FTC group and 20% (7/35) of the d4T group. Although these results show that FTC was statistically superior to d4T, it is worth reminding that the combination ddI + d4T is not regularly recommended.
In another "non-inferiority" study, the French ANRS 099 or ALIZE, people receiving a protease inhibitor-based regimen with plasma HIV-RNA level <400 copies/mL were randomized to continue their regimen (C) or to switch to once-daily combination (5 pills per day) of FTC, ddI, and efavirenz (once daily). Intent-to-treat on available data, on treatment on available data and intent-to-treat with (missing=failure) analyses were conducted.
A total of 355 people were randomized; 86% were male with a median age of 41, a median duration of PI use of 35 months, and a median CD4 count of 540 cells/mm3. Of course, today, at 540 CD4s, these people would probably be offered a treatment interruption of some sort instead of rolled into another new treatment protocol of 48 weeks. The proportion (98%) of people with virologic success at Week 48 was 92% for the "C" group (continue) and 94% for the FTC group (ITT).
There was a statistically significant difference in the proportion of people having plasma HIV-1 RNA <50 at Week 48 (95% on once daily vs. 87% on C, p=0.01). Median CD4 count increase was similar between groups. Rates of treatment discontinuations were "low" (12.4% and 10.1%, no statistical difference). A significant increase in median fasting HDL cholesterol levels was observed in the QD group as compared to the C group. Other metabolic parameters remained similar between groups throughout the 48 weeks of the study. People who simplified to this once-daily regimen had an improved outcome compared to subjects remaining on more the complex protease inhibitor-based regimens.
FTC-303 was a randomized, 48-week, open label equivalence trial in which people with HIV-1 RNA <400 copies/mL either continued their 3TC regimen or switched 3TC 150 mg twice daily to FTC 200 mg once daily while continuing the other medications in their regimen. People with plasma HIV-1 RNA <400 copies/mL at Week 48 were offered FTC as part of their HAART regimen in protocol FTC-350.
Out of 294 people originally randomized to FTC in study 303, 227 (77%) had HIV-1 RNA <400 copies/mL at Week 48. Of these, 215 continued in rollover study FTC-350; 152 of 294 (51%) maintained suppression of HIV-1 RNA <400 copies/mL and 139 (47%) <50 copies/mL through Week 120 (2.3 years). Through a median follow-up of four years, the probability of virologic failure (>400 copies/mL) was 11% while prescribed FTC.
FTC was well tolerated throughout the study. The probability of treatment limiting adverse events was <13% at year 4 of follow-up. The annualized rate of the most common treatment-emergent Grade 3 or Grade 4 laboratory abnormalities was 7% for creatine kinase and 5% for hypertriglyceridemia, with the annualized rate of all other laboratory abnormalities <2% after 4 years of follow-up. Asymptomatic and transient elevations in CPK accounted for more than 2/3 of the overall Grade 4 adverse events. Everyone continued on the background regimen that was part of the stable 3TC regimen at the start of FTC-303. This regimen included AZT or d4T as well as an NNRTI or PI.
The author would like to thank Francois Houyez for his collaboration on this paper.
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