US approval of FTC (emtricitabine)

On 2 July, the US Food and Drug Administration (FDA) announced the approval of FTC (emtricitabine, trade name Emtriva), a new nucleoside reverse transcriptase inhibitor (NRTI) to be used in combination with other antiretroviral agents for the treatment of patients with HIV infection.

The FDA based its approval on data from two 48 week clinical trials. The first trial was a double-blind, active-controlled multicentre study comparing FTC (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 < 400 copies/mL (< 50 copies/mL) through week 48 was 81% (78%) for the FTC, didanosine and efavirenz group versus 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 FTC arm compared to 134 cells/mm3 for the control arm.

The second trial was an open-label, active-controlled multicentre study comparing FTC 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 < 400 copies/mL. The proportion of patients who achieved confirmed HIV RNA < 400 copies/mL (< 50 copies/mL) through week 48 was 77% (67%) for the FTC group versus 82% (72%) for the lamivudine group. The mean increase from baseline in CD4 cell count was 29 cells/mm3 for the FTC arm compared to 61 cells/mm3 for the lamivudine arm.

The most common adverse events that occurred in patients receiving FTC with other antiretroviral agents in clinical trials were headache, diarrhoea, 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 FTC treated group all other adverse events were reported with similar frequency in FTC and control treatment groups.

Skin discoloration, manifested by hyperpigmentation (excess pigmentation) on the palms and/or soles, was predominantly observed in non-Caucasian patients.

It is recommended that all patients with HIV be tested for the presence of chronic hepatitis B virus (HBV) before initiating antiretroviral therapy.

FTC is not indicated for the treatment of chronic HBV infection and the safety and efficacy of FTC 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 FTC. 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, FTC 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).

Comment

FTC has had such a long development programme that its final approval has taken many people by surprise. This one-tablet-a-day drug has a very long plasma and intracellular half-life that may provide protective dosing even in the event of missing a single daily dose. It can be taken with or without food.

On 24 July, the CPMP (the scientific committee of the European Medicines Evaluation Agency) recommended granting marketing authorisation for FTC in Europe and full approval usually takes an additional four months.

This is a drug that should therefore be available in the UK later this year.