Pharmacology Update
Tenofovir Disoproxil Fumarate Tablets—Viread (Gilead)
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD
The FDA has approved the first nucleotide (nucleoside phosphonate) analog for the treatment of HIV-1 infections. Gilead’s tenofovir disoproxil fumarate (Viread) is similar to nucleoside analogs and should be used as part of a drug cocktail. Tenofovir appears to be well tolerated and is conveniently dosed once a day.
Indications
Tenofovir is indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infections.1
Dosage
The recommended dose of tenofovir is 300 mg once daily taken with meals. If the drug is used in combination with didanosine, tenofovir should be taken 2 hours before or 1 hour after didanosine. Tenofovir should not be administered to patients with renal impairment (creatinine clearance < 60 mL/min).1
Tenofovir is supplied as 300 mg tablets.
Potential Advantages
Tenofovir is dosed as 1 tablet once daily and has a low potential for drug-drug interactions involving the cytochrome P450 system.1 It is also less susceptible to pyrophosphorolysis and degradation by nucleotide-dependent chain-terminator removal than zidovudine or stavudine. This may contribute to improved durability of the antiretroviral response of tenofovir.2 Tenofovir appears to be generally well tolerated.
Potential Disadvantages
Lactic acidosis and severe hepatomegaly with steatosis have been reported with other nucleoside analogs. The same warning is issued for tenofovir, which is a nucleoside phosphonate. These conditions could be fatal. Potential risk factors are female gender, obesity, prolonged nucleoside exposure, and liver disease. Cases have been reported in patients with no known risk factors.1 Common side effects include mild-to-moderate gastrointestinal side effects such as diarrhea, nausea, vomiting, and flatulence. The frequency varied from 4-11%.1 The clinical experience with tenofovir is limited.
Comments
Tenofovir is an acyclic nucleoside phosphonate analog of adenosine-5-monophosphate. It is administered as the disoproxil fumarate, a prodrug form, and converted to its active form by diester hydrolysis. It is the first nucleotide analog to be approved as others have been nucleoside analogs. The optimal dose appears to be 300 mg daily as no increase in antiretroviral activity has been reported with doses between 300 and 600 mg.1,3 The clinical experience of tenofovir is limited. The FDA approval was based on 2 clinical trials involving about 700 patients who had been previously treated with antiretroviral drugs, but showed signs of continued viral replication. One was a placebo-controlled 24-week study and the other a dose-ranging 48-week study with placebo patients receiving tenofovir 300 mg daily at 24 weeks. Patients in the 24-week study (n = 550, 368 on tenofovir) had a mean baseline CD4 cell count of 426 cells/mm3 (range, 23-1385), a median baseline plasma HIV RNA of 2340 copies/mL (range, 50-75,900), and a mean duration of prior treatment of 5.4 years. The addition of tenofovir to a standard background regimen compared to the addition of placebo resulted in a mean change in plasma HIV RNA of -0.6 log through week 24. There was a greater percentage of patients who achieved plasma HIV RNA < 50, 19% for tenofovir, and 1% for placebo. Mean change in CD4 counts were not significant, +11 cell/mm3 and -5 cells/mm3 for tenofovir and placebo, respectively.1 Results from the dose-ranging study (n =186) were similar to the results from the 24-week study and suggested that viral response (-0.6 log) for the 300-mg dose was maintained over 48 weeks.
The wholesale cost for tenofovir is $4135 per year.
Clinical Implications
Tenofovir provides another antiretroviral agent against HIV-1 infections. It offers some advantages in terms of tablet burden, once daily dosing, and low potential for drug-drug interactions involving the cytochrome P450 enzyme system. Simplified regimens have been reported to improve adherence.4 However, the clinical experience with this drug is extremely limited in terms of the population in which it has been tested and the long-term benefits or risks.
Dr. Elliott, Chair, Formulary Committee, Northern California Kaiser Permanente; Asst. Clinical Professor of Medicine, University of California-San Francisco; and Dr. Chan, Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA, are Associate Editors of Internal Medicine Alert.
References
1. Viread Product Information. Gilead Sciences, Inc. October 2001.
2. Naeger LK, et al. Nucleosides Nucleotides Nucleic Acids. 2001;20:635-639.
3. Barditch-Crovo P, et al. Antimicrob Agents Chemother. 2001;45(10):2733-2739.
4. Stone V, et al. J Acquir Immune Defic Syndr. 2001; 28:124-131.
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