Tenofovir: The First Nucleotide for HIV Infection
By Jay F. Dobkin, MD; Columbia University College of Physicians and Surgeons, New York
Originally published in Infections in Medicine 19(1):11, 38, 2002
Introduction
Driving to work recently, I heard a radio report of a study showing equivalent efficacy among the 3 most widely prescribed antidepressants in the multibillion-dollar US market. Some listeners might wonder what the need is for these "me too" drugs. Although the costs and benefits to society of developing close variants once a new drug class is established remain debatable, there is no doubt about the business logic: better a small chunk of a big market than a monopoly in a tiny one. Early in the AIDS epidemic, there was a distinct lack of interest on the part of the pharmaceutical industry. Now, there is lots of money to be made and lots of competition. Someday, the "me too" syndrome will arise in HIV treatment, but not yet. For instance, tenofovir (Viread), the 17th antiretroviral, which was approved by the FDA in October 2001, has several distinctive characteristics and brings significant new possibilities to our therapeutic arsenal.
Formally known as tenofovir disoproxil fumarate, this agent also marks the introduction of a new class or subclass of antiretrovirals. It is the first nucleotide analogue reverse transcriptase inhibitor (RTI) to be released for general use. Adefovir, a previous nucleotide analogue from the same manufacturer, was denied approval for HIV treatment because of renal toxicity, which seems to be absent with tenofovir. The general profile for this new drug appears to be good activity for an RTI inhibitor, limited cross-resistance with nucleoside RTIs, and limited toxicity and side effects. Clinical trials have focused mostly on heavily experienced patients, with encouraging results. Potential use as a first-line agent has been largely unexplored.
The chemical distinction (and, potentially, a clinical one as well) between tenofovir and its cousins in the nucleoside analogue class of RTIs is in the phosphorylation status of the tenofovir molecule. Compared with the traditional "nukes," which are really pro-drugs and require activation by intracellular phosphorylation, tenofovir is already activated and thus may be effective in a wider array of body cells than the activated CD4 cells, where the nukes presumably act. This could make tenofovir a very important drug with the capacity to purge HIV from a variety of resting cells, but this benefit remains to be proved. In addition, the drug's structure may be responsible for its broad range of activity against many more viruses than HIV-1. Of most interest, tenofovir, like adefovir, shows potent activity against hepatitis B virus. It is also active against simian immunodeficiency virus.
Pharmacologically, the most notable aspect of tenofovir is its long half-life and once-daily 300-mg dosing.
Bioavailability is increased when the drug is taken with food, especially a high-fat meal.
It is not subject to cytochrome metabolism, so drug-interaction issues seem minimal, although there are data indicating that levels of didanosine (Videx) may be increased when coadministered with tenofovir. Since tenofovir is metabolized by the kidney, dose reduction may be needed for renal insufficiency.
Two trials have reported results with tenofovir in patients receiving failing regimens. In GS 902, patients with detectable virus after 8 weeks of other treatment were randomized to 1 of 3 doses of tenofovir or placebo. At 48 weeks, the highest dose (300 mg) produced the best response: about 0.6 log decrease of viral load. In GS 907, 552 patients whose earlier treatment was failing received tenofovir or placebo. Median viral load at baseline was about 2400 copies/mL. At 6 months, 19% in the tenofovir group had undetectable viral loads (below 50 copies/mL) compared with 1% in the placebo arm. Tenofovir was well tolerated in these trials, but animal toxicities involving kidney and bone mandate careful long-term monitoring.
High-level resistance to tenofovir has been described, but generally cross-resistance with the nucleoside analogues appears limited. In a large in vitro study, about 85% of strains with high-level phenotypic resistance to zidovudine remained susceptible to tenofovir. However, a cross-study genotypic analysis showed average viral load decreases of only 0.21 logs after 6 months of tenofovir if there were at least 3 thymidine analogue mutations (including M41L or L210W) at baseline, compared with 0.8 logs if there were no mutations of this type. The 184 mutation selected by lamivudine seems to enhance susceptibility to tenofovir, while the K65R mutation is often associated with decreased tenofovir activity.
While potential use as a first-line agent remains to be defined, tenofovir—unlike any previous new antiretroviral—enters clinical use with a good deal of resistance and salvage data. A welcome difference.
Dr. Dobkin is associate professor of clinical medicine, Columbia University College of Physicians and Surgeons, and medical director, Presbyterian Hospital AIDS Center, New York.
