Background:   High rates of early virological failure have been reported in naïve patients who received the triple nucleoside/nucleotide once daily regimen of abacavir (ABC), lamivudine (3TC), and tenofovir (TDF). Several explanations are being considered, including low genetic barrier to resistance and negative pharmacokinetic interactions (intracellular or plasma). We reported similar unexpected results of early virological failures.

Methods:  Pilot study, HIV1⁺ patients, were included to receive ABC/3TC/TDF once daily for 12 months. Trough plasma concentrations (Cmin) at M1, CD4 cells count, and plasma viral load (pVL) at months 1, 3. and 6 were performed. Virological failure was defined as patients who never reached undetectable pVL below 400 copies/mL or a rebound above 0.7 log₁₀ copies/mL after decrease. RT gene sequencing was performed at month 3 or 6. The trial was prematurely interrupted after an unplanned interim analysis.

Results:  38 antiretroviral naïve patients were included. At baseline median CD4 cells count was 221 cells/mm³ (61 to 348) and median pVL was 4.9 log₁₀ copies/mL (2.0 to  5.9):  30 and 8 patients with pVL above and below 4 log₁₀ copies/mL, respectively. Virological failures were observed in 12/36 patients:  12/28 and 0/8 patients with baseline pVL above and below 4 log₁₀ copies/mL, respectively (p = 0.03). Achievement of viral replication below 50 copies/mL was observed in 12/34 patients and 17/26  patients at month 3 and 6, respectively. At month 3, 5/26 (19%) and 7/8 (88%) of patients with baseline pVL above and below 4 log₁₀ c/mL, respectively, were below 50 copies/mL (p <0.001); similar results were found at month 6 (9/18 vs 8/8 (p = 0.02). In specimens available from 12 patients with virological failures between month 3 and month 6, 11/12 had both K65R and M184V mutations and 1 had the M184V mutation alone. At month 1, 32/37 patients had Cmin considered as adequate for all the 3 drugs and 5 had at least 1 Cmin below LOQ for TDF (5), ABC (3), and 3TC (3).

Conclusions:  The association of adequate expected plasma Cmin of the 3 drugs, high proportion of early virological failures, and high rate of rapid selection of both K65R and M184V mutations in patients with pVL above 4 log copies/mL at baseline support the hypothesis of low genetic barrier to resistance as the major cause of failure of this triple nucleoside/nucleotide once daily regimen.  From the preliminary results of the first series of 14 samples, major intracellular interaction between ABC, 3TC, and TDF is unlikely.

Keywords: triple NRTI; once daily regimen; resistance to antiretroviral therapy