Previous investigational data using abacavir (ABC), lamuvidine (3TC), and zidovudine has suggested the possibility of triple nucleoside analogue reverse transcriptase inhibitors (NRTI) therapy as an option in the treatment of HIV infection. We performed a pilot study to assess the potency of once daily ABC+ 3TC+ tenofovir (TDF) in the treatment of HIV-infected naive patients. CD4 and HIV-viral load (VL) were followed monthly. Patients were considered to be nonresponder/failing if there was no reduction in VL by >/= 2 log(10) by week 8 and/or a rebound in VL after initial suppression. Resistance testing was then obtained. Nineteen patients naive to antiretroviral therapy (3 women and 16 men) were enrolled, of whom, 2 did not return (withdrew from study at week 2). Median VL and CD4 count at baseline were 147,167 copies per milliliter (5.16 log(10); [range, 7650->750,000]) and 277 cells/mm(3) (range, 59-598). Eight patients had VL > 100000 at baseline. Of 17 patients eligible for follow-up, 5 (27%) were responders (virologic success). Twelve patients (63%) were considered nonresponders and/or with virologic failure. The study was prematurely interrupted because of a high rate of treatment failure. Resistance testing available for 11 nonresponders (58%) showed: 2 patients with wild-type, 5 patients with M184V (reducing susceptibility to 3TC and ABC), 4 patients with M184V+K65R (K65R is responsible for reducing susceptibility to ABC, 3TC and TDF), and none with K65R alone. In conclusion, the combination of ABC, 3TC and TDF cannot be recommended for the initial regimen in HIV treatment-naive patients.