The US Food and Drug Administration (FDA) announced yesterday (Wednesday, July 2) that it has approved FTC (emtricitabine), a new nucleoside reverse transcriptase inhibitor (NRTI). FTC will be marketed by Gilead as Emtriva. Approval in the European Union is likely in the early part of 2004.
FTC is a once daily nucleoside analogue, with a similar structure and resistance profile to 3TC (lamivudine). However, resistance to FTC is less likely to emerge when compared to 3TC, even though the two drugs share the same resistance pathway. This is because FTC remains in the blood for much longer than 3TC - its half-life is 39 hours.
FTC is also active against hepatitis B, but has not yet been approved for hepatitis treatment. The FDA warned that removal of FTC in hepatitis B-infected individuals could result in flare-ups of hepatitis B, as with 3TC removal. Manufacturer Gilead plans to combine FTC in one tablet with its other antiretroviral tenofovir (Viread); this coformulation could be marketed by 2005. Gilead is also running a study comparing this coformulation to Glaxo Smith Kline’s Combivir (AZT/3TC), using efavirenz as the third drug for all patients. Gilead hopes that this 48 week study will show superiority of its product, or at least a lower rate of treatment failure caused by the M184V mutation (the common site of resistance to 3TC and FTC).
Gilead is also looking at whether FTC can be used in children as part of a once daily regimen. Yesterday's approval did not extend to paediatric treatment.
The FDA based its approval on data from two 48 week clinical trials. The first trial (Study 301A) was a double-blind, active-controlled multicenter study comparing Emtriva (200 mg once daily) administered in combination with didanosine and efavirenz versus stavudine, didanosine and efavirenz in 571 antiretroviral naïve patients. The proportion of patients who achieved and maintained confirmed HIV RNA Emtriva, didanosine and efavirenz group vs 61% (59%) for the stavudine, didanosine and efavirenz group, respectively. The mean increase from baseline in CD4 cell count was 168 cells/mm3 for the Emtriva arm compared to 134 cells/mm3 for the control arm.
The second trial (Study 303) was an open-label, active-controlled multicenter study comparing Emtriva to lamivudine, in combination with stavudine or zidovudine and a protease inhibitor or NNRTI in 440 treatment experienced patients who were on lamivudine-containing triple-antiretroviral drug regimen for at least 12 weeks prior to study entry, and had HIV-1 RNA Emtriva group vs 82% (72%) for the lamivudine group. The mean increase from baseline in CD4 cell count was 29 cells/mm3 for the Emtriva arm compared to 61 cells/mm3 for the lamivudine arm.
The most common adverse events that occurred in patients receiving Emtriva with other antiretroviral agents in clinical trials were headache, diarrhea, nausea, and rash, which were generally of mild to moderate severity. Approximately 1% of patients discontinued participation in the clinical studies due to these events. With the exception of skin discoloration, which was reported with higher frequency in the Emtriva treated group all other adverse events were reported with similar frequency in Emtriva and control treatment groups.
Skin discoloration, manifested by hyperpigmentation (excess pigmentation) on the palms and/or soles, was predominantly observed in non-Caucasian patients. The mechanism and clinical significance are unknown.
It is recommended that all patients with HIV be tested for the presence of chronic hepatitis B virus (HBV) before initiating antiretroviral therapy. Emtriva is not indicated for the treatment of chronic HBV infection and the safety and efficacy of Emtriva have not been established in patients co-infected with HBV and HIV. "Flare-ups" of hepatitis B, where the illness can return in a worse way than before, have been reported in patients after the discontinuation of Emtriva. Patients co-infected with HIV and HBV should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment.
As with other NRTIs, Emtriva may cause lactic acidosis (buildup of an acid in the blood), serious liver problems called hepatotoxicity, with liver enlargement (hepatomegaly) and fat in the liver (steatosis).