Emtricitabine

Emtricitabine (Emtriva®) is an orally administered nucleoside reverse transcriptase inhibitor (NRTI) that is indicated in combination with other antiretroviral agents in the treatment of HIV infection in adults. As a component of antiretroviral therapy (ART), emtricitabine effectively reduces and/or maintains suppression of viral load in ART-naive adults or ART-experienced adults switching from stable combination regimens, and is generally well tolerated. Emtricitabine is a component of preferred initial HIV combination therapy regimens; it can be used in place of lamivudine as part of the dual NRTI backbone in non-nucleoside reverse transcriptase inhibitor (NNRTI)- and protease inhibitor (PI)-based regimens. Moreover, preliminary data from a randomised, open-label study suggest that emtricitabine plus tenofovir DF, a preferred dual-NRTI combination, is better tolerated than co-formulated lamivudine/zidovudine, another preferred dual-NRTI combination, resulting in a higher persistent virological response rate, as analysed using the US FDA time to loss of virological response (TLOVR) algorithm. With the convenience of once-daily (single pill) administration, no dietary restrictions and a favourable drug interaction and tolerability profile, emtricitabine should facilitate patient adherence to treatment, which, in turn, is central to the success of antiretroviral therapy. Similarly, emtricitabine is attractive as an option for ART-experienced stable adults requiring regimen simplification.

Incorporation of emtricitabine 5′-triphosphate, the active metabolite of emtricitabine, into the HIV-1 DNA chain results in chain termination. Compared with lamivudine, emtricitabine was more active against HIV in the majority of in vitro studies, and in HIV-infected patients. It also showed additive-to-synergistic activity in combination with certain other antiretroviral drugs (e.g. tenofovir, zidovudine, efavirenz, nevirapine and ritonavir) in vitro.

The pharmacokinetics of oral emtricitabine allow for once-daily administration. It is rapidly absorbed from the gastrointestinal tract and both the oral bioavailability (93%) of, and systemic exposure to, the drug are unaffected by food. At the recommended dosage in adults (200mg once daily), emtricitabine has a plasma half-life of ≈8–10 hours and emtricitabine 5′-triphosphate has an intracellular half-life of 39 hours. Emtricitabine penetrates semen, and is primarily eliminated in the urine, mainly as unchanged drug. Adjustment of the dosage interval is necessary in patients with renal impairment (baseline creatinine clearance <50 mL/min [3 L/h]).

Emtricitabine is neither metabolised by, nor is an inhibitor of, cytochrome P450 enzymes and, thus, has limited potential to interact with coadministered agents that are metabolised by these enzymes.

In clinical trials in HIV-infected adults, emtricitabine-containing triple combination therapies, including two completely once-daily regimens, were effective in achieving and/or maintaining suppression of viral loads to undetectable levels in ART-naive patients or ART-experienced patients switching from stable combination regimens. Viral suppression was accompanied by increases in CD4+ cell counts. Although plasma HIV-RNA levels were typically assessed after 24 and/or 48 weeks of therapy, there is evidence of the continuing effectiveness of the drug as part of combination therapy after 3–4 years of follow-up in ART-naive or -experienced patients.

In the pivotal, randomised, double-blind FTC-301A study in ART-naive adults, emtricitabine once daily was superior to stavudine twice-daily (each administered with once-daily didanosine and efavirenz), based on an analysis of persistent virological responses using the TLOVR algorithm, as suggested by the US FDA. The greater virological efficacy of emtricitabine was confirmed in an astreated analysis. Preliminary data from a randomised, open-label, noninferiority trial (Study 934) in ART-naive adults also suggested that once-daily emtricitabine plus tenofovir disoproxil fumarate (DF) was superior to twice-daily co-formulated lamivudine/zidovudine (each used in combination with once-daily efavirenz), based on persistent virological response using the TLOVR algorithm, but not in an as-treated analysis.

In the pivotal, randomised, open-label, equivalence FTC-303 trial in ART-experienced stable adults, switching to once-daily emtricitabine was as effective as continuing on twice-daily lamivudine (each administered with twice-daily stavudine or zidovudine plus an NNRTI or PI), based on the rate of virological failure using the TLOVR algorithm. Similarly, in a randomised, open-label, non-inferiority trial (ANRS 099-ALIZE) in ART-experienced stable adults, switching to a once-daily regimen of emtricitabine, didanosine and efavirenz was no less effective than continuing on a Pi-based regimen, based on sustained viral suppression.

A once-daily dose of emtricitabine 200mg, as part of combination therapy, was generally well tolerated in clinical trials of adults infected with HIV. The most common treatment-emergent adverse events in ART-naive or -experienced patients who received emtricitabine in two pivotal studies included headache, diarrhoea, nausea, rash, rhinitis, increased cough and asthenia of generally mild-to-moderate intensity. There were no reports of symptomatic hyperlactataemia/lactic acidosis in these trials, while grade 3/4 hepatic transaminase elevations occurred in 5–6% of patients. Some patients, mostly Black patients, experienced skin discolouration, although this does not appear to be a treatment-limiting adverse event.

The tolerability profile of emtricitabine-containing triple combination therapy was similar to that of lamivudine-containing triple combination therapy and a PI-based regimen in studies of HIV-infected, ART-experienced patients. With regard to treatment-limiting adverse events in HIV-infected, ART-naive patients, however, emtricitabine was better tolerated than stavudine (both administered with didanosine plus efavirenz). Preliminary data indicate that emtricitabine andtenofovir DF, administered as individual formulations, were likewise better tolerated than co-formulated lamivudine/zidovudine (both used with efavirenz). Emtricitabine-containing triple combination therapy continued to be well tolerated after 3–4 years of treatment in adults with HIV infection.