September 16, 2003
Among the HIV medications currently approved for use, several are already approved as once-daily medications (tenofovir [TDF, Viread], ddI [didanosine, Videx], 3TC [lamivudine, Epivir], efavirenz [EFV, Susitva], atazanavir [ATV, Reyataz] and ritonavir [RTV or r, Norvir]-boosted amprenavir [APV, Agenerase] -- a once-daily version of d4T [stavudine, Zerit] is nearly available); several additional medications currently dosed twice daily are being investigated for their once-daily potential -- these include abacavir (ABC, Ziagen), nevirapine (NVP, Viramune) and a number of boosted protease inhibitors.
These abacavir studies extend previous observations and form the basis for the development of once-daily abacavir and the anticipated clinical trials of a once-daily fixed dose combination pill of abacavir/3TC.
The first study by Piliero measured how long the active part of abacavir (called carbovir-TP) remains in the body -- if this period is lengthy, then once-daily dosing might be reasonable; if too short, then the drug levels might not be high enough to suppress HIV. The study looked at the abacavir levels in blood and inside of blood mononuclear cells in HIV-infected persons already taking an abacavir-containing regimen. This means that the drug levels were at "steady-state" -- or at equilibrium, in a way. The Piliero study confirmed previous observations that the levels of abacavir in blood plasma last a relatively short period -- seemingly bad news for once-a-day usage. This experiment, however, showed that the active drug metabolite (carbovir-TP) stayed in the body a long time (50 percent of the drug level remained over 20 hours after the previous dose) -- important because it is enough time to lend credence to the once-daily dosing of abacavir.
Now, the Piliero study is reassuring, but this evidence alone is definitely not enough to prescribe once-daily abacavir. What we really would like is a study that compares abacavir dosed QD to BID (the conventional dose) in a real three-drug combination. This is what the ZODIAC study did.
In the ZODIAC study, presented by the colorful Professor Brian Gazzard from London, 770 therapy-naive persons received HIV treatment with 3TC and efavirenz (dosed QD) and were randomly assigned to take abacavir either once daily or twice daily. There was an abacavir placebo in both cases, so that neither the patient nor the doctors knew if the drug was dosed QD or BID. After 48 weeks of medication, the two groups of study patients performed nearly identically with about two thirds of patients achieving viral loads less than 50 copies at 48 weeks. There were no differences in performance between persons who started with high viral loads compared with low viral loads and the CD4 cell increases were very similar (about 200 cells). The treatments were generally well tolerated, though about 7-9 percent were thought to experience abacavir allergic reactions ("hypersensitivity") and there was no difference between the side effects that the two groups reported.
Together, these data seem to provide extremely strong evidence for the once-daily dosing of abacavir. Given the approval of once-daily 3TC, it is obvious that an entirely once-daily regimen that includes abacavir/3TC is just around the corner. Since both abacavir and 3TC are manufactured by the same company (GlaxoSmithKline), it is expected that we will soon see the results of studies using the abacavir/3TC FDC pill -- an attractive one-pill/two-drug once-daily combination.
An important but as yet unanswered question is which of the newer once-daily options is best. Tenofovir with 3TC has been extensively analyzed in a study called Gilead 903 (for a summary of this study, click here) and we have the recent approval of FTC (emtricitabine, Emtriva) -- another once-daily drug which adds yet another permutation, since 3TC and FTC seem extremely similar. We will likely see a tenofovir/FTC FDC pill (also one pill a day) in the next couple of years.
Overall, these data are important for doctors and patients alike for the future. For today, in certain difficult adherence cases, these studies will support dosing simplification for persons whose HIV treatment contains twice-daily abacavir. Clearly, the prospect of a potent three-drug, two-pill, once-daily HAART regimen is exciting and represents the ever improving options for HIV therapies.
Read the poster of abstract A-1797.
Abstract: A Study Examining the Pharmacokinetics of Abacavir and the Intracellular Carbovir Triphosphate (GSK Protocol CNA10905) (Poster A-1797)
Authored by: P. Piliero, A. D. Shachoy-Clark, M. Para, S. Preston, Y. Lou, G. Drusano, D. Stein, G. J. Yuen
Affiliations: Albany Medical College, Albany, NY; GlaxoSmithKline, Research Triangle Park, NC; Ohio State University Medical College, Columbus, OH
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