The addition of enfuvirtide to an optimized antiretroviral regimen provided significant antiretroviral and immunologic benefit through 24 weeks in patients who had previously received multiple antiretroviral drugs and had multidrug-resistant HIV-1 infection.

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A multicenter, open-label study was performed to evaluate the safety, anti-hepatitis B virus (anti-HBV) activity, and pharmacokinetics of emtricitabine therapy administered once daily for 8 weeks to patients infected with HBV. Clinical and virologic evaluations were completed at the baseline; at 7, 14, 28, 42, and 56 days during treatment; and at 24, 48, and 28 days posttreatment. Forty-nine patients were enrolled in five dose cohorts (doses of 25, 50, 100, 200, and 300 mg, all of which were administered once daily [q.d.]). Peak plasma emtricitabine concentrations occurred within 1.5 h following dosing. Plasma emtricitabine concentrations (maximum concentrations of drug in plasma and areas under the concentration-time curves) increased nearly dose proportionally over the 25-to 300-mg dose range, with relatively small intersubject variabilities. The plasma half-life of emtricitabine ranged from 6 to 9 h. HBV DNA levels were measured by the Digene HBV Hybrid Capture II assay. Viral suppression (reduction in log 10 serum HBV DNA levels) occurred in all dose cohorts. All doses demonstrated potent and rapid antiviral activities, with a trend toward a greater suppression with daily doses of 100 mg or greater. At 2 months, the median change in the serum HBV DNA level from the baseline level ranged from ؊1.7 log 10 for the 25-mg dose administered q.d. to ؊3.3 log 10 for the 300 mg dose administered q.d. Emtricitabine was well tolerated over the 2-month dosing period. These results support further clinical development of emtricitabine for the treatment of chronic hepatitis B infection.Chronic hepatitis B virus (HBV) infection is a common and often severe form of liver disease that affects approximately 1 million Americans and 350 million people worldwide (4,8,14). In addition to treatment with alpha interferon, major therapeutic advances have occurred with the discovery of new antiviral compounds that inhibit the reverse transcriptase activity of HBV DNA polymerase. Recently, lamivudine (3TC) has been approved for use in the treatment of chronic HBV infection. However, prolonged monotherapy with 3TC selects for resistance mutations at rates varying from 16 to 32% at 1 year in immune competent patients (4,5,7,12,13). Therefore, there is a need to develop additional anti-HBV drugs that may be used alone or in combination to alleviate the problem of resistance.Emtricitabine (FTC) is a deoxycytidine analog reverse transcriptase inhibitor that has been demonstrated to have potent and selective inhibitory activities against HBV and human immunodeficiency virus (HIV) (the structure of FTC is illustrated in Fig. 1). FTC is readily anabolized by cellular enzymes stepwise to form its monophosphate, diphosphate, and finally, triphosphate forms. The triphosphate form is the active intracellular moiety that completely inhibits HBV DNA polymerase. The anti-HBV activity of FTC has been demonstrated in a chimeric mouse model and against woodchuck hepatitis virus in naturally infected woodchucks (1, 2).In in vitro assays with HIV, FTC is...

Antiretroviral monotherapy for initial drug characterization risks the selection of resistant virus, yet monotherapy is the only setting where many fundamental properties of a new drug can be reliably determined. Using data on viral replication kinetics and dynamics, we designed an accelerated (14 day) open-label study of single agent emtricitabine (formerly known as FTC)--a nucleoside reverse transcriptase inhibitor--to select a dosing regimen for further therapeutic study. Five regimens (25 mg bd, 100 mg od, 200 mg od, 100 mg bd and 200 mg bd) were evaluated in HIV-1-infected subjects over a 14 day dosing period to determine the optimal dose and pharmacokinetics. Serial blood samples for virological, pharmacokinetic and intracellular FTC-triphosphate measurements were drawn frequently. A dose-response relationship for the antiviral activity of emtricitabine was established, with total daily doses of 200 mg or more producing the greatest median HIV-1 viral load suppression: 1.72-1.92 log10. Based on virological outcomes, dose-response analysis and intracellular triphosphate levels, a once-daily dose of 200 mg was selected for further long-term clinical study. Adverse events possibly related to emtricitabine were unremarkable. The antiviral activity of emtricitabine correlated well with intracellular FTC-triphosphate concentrations. This study design is a safe, useful tool for early dose selection for drugs with potent antiretroviral activity and linear pharmacokinetics.