July 14, 2003
Once-daily therapies for the treatment of HIV infection have gained considerable popularity, particularly with the recent FDA-approval of the once-daily nucleoside reverse transcriptase inhibitors (NRTIs) tenofovir (TDF, Viread) and 3TC (lamivudine, Epivir) and the once-daily protease inhibitor (PI) atazanavir (ATV, Reyataz).
The basis for the once-daily use of abacavir (ABC, Ziagen)/3TC/tenofovir stems from several previous investigations of abacavir and 3TC.1, 2 Several of these studies explored the use of twice-daily abacavir/3TC as backbones of triple-drug therapy. The maker of abacavir and 3TC, GlaxoSmithKline, has studied twice-daily abacavir/3TC backbones, demonstrating comparable performance to the standard AZT (zidovudine, Retrovir)/3TC backbone in studies with efavirenz (EFV, Sustiva) (study CNA30024).3 Other studies have shown the abacavir/3TC backbone to be compatible (dosed twice daily) with the PI nelfinavir (NFV, Viracept) or the investigational PI 908 (studies APV3001 and APV30002).4, 5 Once-daily dosing of abacavir was suggested by pharmacokinetic studies that demonstrate a long intracellular half life (study CBD-TP).6, 7
Building on the previous successes of the twice-daily Trizivir (AZT/3TC/ABC)-triple-nucleoside therapy, Farthing studied a novel, once-daily, triple-nucleoside regimen of abacavir/3TC/tenofovir. The Farthing study was a small, open-label study (meaning that patients knew what medicines they were taking) of 19 patients. It was proposed that the substitution of the potent nucleoside tenofovir for the AZT in the Trizivir-triple-nuke regimen should have resulted in increased potency and even better tolerability. The average viral load of these patients was nearly 150,000 copies/mL and their average CD4 count was 277 cells/mm3. Unfortunately, it became clear early in the study that patients taking this regimen were not doing well, as 11 of the 19 patients either had virological rebound or non-response. Nine of these 11 patients also had new drug-resistance mutations.
How do we explain these unexpected results? Firstly, any inadequate response can be thought of as a situation in which there are inadequate drug levels to suppress viral replication and hence select for drug-resistant virus. It has been established recently that the use of tenofovir unexpectedly alters the drug levels of two other antiretroviral medications. When tenofovir is used with ddI (didanosine, Videx), the level of ddI goes up, whereas with atazanavir, the level goes down. Could it be that tenofovir alters the drug level or metabolism of abacavir too?
An alternative explanation (but not mutually exclusive) is that a single amino acid substitution (mutation) in the viral reverse transcriptase can result in significant loss of potency of both abacavir and tenofovir (and to a lesser extent, 3TC) -- perhaps this unfortunate mutational coincidence makes this particular triple-drug combination more vulnerable than others to drug resistance.
Recently, a very large, randomized clinical trial (sponsored by GlaxoSmithKline) called ESS30009 reached the same conclusions about the once-daily abacavir/3TC/tenofovir-triple-nuke combination -- namely, the premature treatment failure of this regimen and the common emergence of drug resistance mutations. Very significantly, the study subjects who took the other treatment regimen, once-daily abacavir/3TC/efavirenz, have done very well, implicating that the "problem" clearly does not lie with the once-daily characteristic of the abacavir/3TC nucleoside components of the regimen, but some other yet unexplained aspect of the triple-nucleoside regimen. Details of this study have not yet been publicly presented and will be anxiously awaited.
Combined with the well publicized ACTG 5095 clinical trial results (see The Body's conference coverage for details) demonstrating the relative under-performance of Trizivir compared to two- or three-nuke combinations with efavirenz, these data should raise caution regarding the use of triple nukes alone in the treatment of therapy-naive, HIV-infected individuals. This is not to say that Trizivir has done worse than before, but rather, that the standards for treatment effectiveness have increased over time.
These studies' most important conclusion is that forecasting the effectiveness of new drug regimens can be like forecasting the weather in Colorado -- usually, but not always correct. Seemingly reasonable combinations of new drugs don't always result in the expected efficacy. It is essential to understand this point. As we get more and more drugs to treat HIV, it becomes more difficult to test all possible drug combinations. Hence, both doctors and patients alike should look for drug combinations that have good clinical trials data that distinguishes them from more speculative regimens (even ones that seem to make good sense) which don't have such rigorous scientific backing.
For another report on this study, click here.
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