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Early Virologic Non-response to Once Daily Combination of Lamivudine, Tenofovir, and Nevirapine in ART-naive HIV-infected Patients: Preliminary Results of the DAUFIN Study
David Rey*1, M P Schmitt1, G Hoizey2, P Meyer1, P Chavanet3, C Allavena4, M Diemer5, T May6, B Hoen7, and J M Lang1
1Univ Hosp, Strasbourg, France; 2Univ Hosp, Reims, France; 3Univ Hosp, Dijon, France; 4Univ Hosp, Nantes, France; 5Lariboisiere Univ Hosp, Paris, France; 6Univ Hosp, Nancy, France; and 7Univ Hosp, Besançon, France
Background: Combination of an non-nucleoside
reverse transcriptase inhibitor (NNRTI) with 2 NRTI is 1 of the validated
options for first-line ART. The once-daily combination of lamivudine
(3TC), tenofovir (TDF), and nevirapine
(NVP) has not been evaluated in a prospective clinical trial.
Methods: This randomized, open-label, multicenter non-inferiority trial compared 3TC 300 mg, TDF
245 mg, and NVP 400 mg once daily (group 1) with zidovudine
(ZDV)/3TC 300/150 mg and NVP 200 mg twice daily (group 2), in ART-naïve HIV-1-infected
patients whose CD4 count <350/mm3. The primary end-point was the proportion
with undetectable viral load at 96 weeks of treatment.
Results: As of May 2006, we had enrolled 71 patients (36 in group 1 and 35 in group 2). The 2 groups were
comparable for baseline parameters: median
CD4 cell count 207/mm3 and 209/mm3 and median plasma
viral load 4.85 log and 4.94 log, respectively, in groups 1 and 2. We observed
7 early non-responses, defined as either a <2.0 log10 copies/mL decrease in plasma viral load by week 12, or a rebound
>1 log of plasma viral load at week 12 after an initial decrease, all in
group 1 (19% early non-response rate). Viral genotypes for these 7 non-responders
showed the following mutations: M184M/V/I
(n = 4), K65R/K (n = 4), and 1 or more NNRTI-resistance mutations in all cases
(Y181Y/C, 7; G190A/G, 4; K101E, 2; K103N, 1). In 1 subject, the K101E mutation
was present at baseline; 6 patients were infected with B subtype and 1 with CRF06.
Trough NVP plasma concentrations were at or above the expected level in all
patients. At baseline, the 7 group-1 early non-responders had higher median plasma
viral load (5.35 log) and lower median CD4 cell count (110/mm3) than
the other group 1 patients (4.73 log, p
= 0.007 and 217/mm3, p =
0.0007, respectively). The trial steering committee decided to stop the trial
and recommended that all group 1 patients be switched to another ART regimen.
Conclusions: In ART-naïve HIV-infected patients, the once-daily
3TC, TDF, and NVP regimen resulted in an unexpectedly high rate of early non-response
with a high incidence of K65R and M184V. The reasons for these failures are
unclear.
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