July 13, 2004
At the 2nd International AIDS Society Conference in Paris in the summer of 2003, we first learned of the unexpected weakness of the triple-nucleoside regimen consisting of tenofovir (TDF, Viread) plus lamivudine (3TC, Epivir) plus abacavir (ABC, Ziagen). This surprised everyone because this combination is only a slight modification of zidovudine/lamivudine/abacavir (AZT/3TC/ABC, Trizivir), which is a pretty good regimen. It substitutes the zidovudine (AZT, Retrovir) for tenofovir, which is more potent based on initial response in monotherapy. The finding was also disappointing because tenofovir plus lamivudine/abacavir is a well-tolerated once-a-day regimen.
But fail it did and in a major way. Tenofovir plus once-a-day, coformulated lamivudine/abacavir was one arm of GlaxoSmithKline's ESS30009 comparison study with the combination of efavirenz (EFV, Sustiva, Stocrin) plus lamivudine/abacavir.
In the study, within 12 weeks, 74% of the patients randomized to tenofovir plus lamivudine/abacavir experienced virological failure (either failure to experience a 2-log drop in viral load by 12 weeks, or an increase in viral load by at least 1 log) (see Ben Young's report on this study). Virtually all of the HIV isolates from patients with failing regimens had the signature tenofovir mutation, K65R, at the time of failure or soon thereafter. This mutation occasionally occurs in abacavir-treated patients, and also confers lamivudine resistance.
In the last year, a great deal of effort has been expended in trying to explain why once-a-day tenofovir plus lamivudine/abacavir underperforms so badly. It has since been established that there is no pharmacologic interaction either at the plasma level or in the intracellular levels of triphosphorylated drug. Once-a-day lamivudine/abacavir has been verified as effective by intracellular pharmacologic studies and clinical trials. It seems likely that the issue is one of understanding why the K65R mutation confers resistance to all 3 of the drugs in this now-forbidden regimen.
The failure of tenofovir plus lamivudine/abacavir has called into question triple-nucleoside regimens in general, and even the validity of coformulated lamivudine/abacavir as a nucleoside backbone.
Details of This Study
This study reviews 8 GlaxoSmithKline trials that combined lamivudine/abacavir with zidovudine, stavudine (d4T, Zerit) or efavirenz. A reanalysis of the 12-week status was carried out using the same 12 virological failure criteria that the forbidden tenofovir regimen failed so badly in the ESS30009 trial (either failure to experience a 2-log drop in viral load by 12 weeks, or an increase in viral load by at least 1 log).
The 12-week virological failure rates ranged from 0 to 24%. Only 1 trial exceeded 14%. The lamivudine/abacavir arms did well when the 12-week outcomes were examined within 3 baseline viral load strata (<30,000 copies/mL; 30,000-100,000 copies/mL; and >100,000 copies/mL).
Significance for Patients and Clinicians
This study provided considerable confidence that the failure of tenofovir plus once-a-day, coformulated lamivudine/abacavir does not undermine lamivudine/abacavir as a dual nucleoside backbone. It is still a contender with twice-a-day, coformulated zidovudine/lamivudine (AZT/3TC, Combivir) and the soon-to-be-coformulated tenofovir and emtricitabine (FTC, Emtriva) as the backbone of choice in initial regimens.
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