Virologic and Immunologic Efficacy of the Tenofovir/Didanosine/Lamivudine Regimen

Abstract

To the Editor: Antiretroviral regimens combining the nucleotide/nucleoside reverse transcriptase inhibitors (NRTIs) tenofovir (TDF), lamivudine (3TC), and abacavir or didanosine (ddI) have recently been linked to unexpectedly high rates of virologic failure, raising serious concerns about NRTI-only strategies. The European Agency for Evaluation of Medicinal Products recommended that the TDF/ddI/3TC combination should not be used, particularly as a once-a-day (OAD) regimen.1 This combination is frequently associated with the emergence of the K65R and M184V/I mutations.2 However, there is evidence that thymidine-associated mutations (TAMs) may protect against virologic failure and K65R selection during this treatment.3-6 The combination of TDF, 3TC, and abacavir or ddI therefore appears to provide a low genetic barrier to resistance, especially in previously untreated patients, as suggested by the results of in vitro studies and retrospective cohorts.7-11 Coadministration of TDF and a ddI dose of 400 mg/day appears to have a deleterious effect on the CD4 cell count, despite complete viral suppression. An imbalance in adenosine metabolites resulting from TDF inhibition of purine nucleoside phosphorylase in CD4 cells may explain this phenomenon.12-14 We reviewed the files of all consecutive patients who had been prescribed TDF 300 mg, didanosine 250 mg (reduced dose), and 3TC 300 mg daily, in an OAD schedule, between January 2002 and December 2004 in our center unit. Changes in the CD4 T-cell count and plasma viral load (pVL) were analyzed, together with the results of genotypic testing at baseline and during treatment. The patients were stratified by the baseline pVL (< or >500 copies/mL). Kaplan-Meier analysis was used to compare the outcomes in the 2 strata. Forty-two patients were enrolled, of whom 64% were men. The median age was 39.0 years (range, 24.7-58.2 years). The median duration of previous antiretroviral therapy was 6.3 years (range, 0-14.2 years), and the patients had received a median of 4 lines (range, 0-24 lines) of antiretroviral therapy. Three patients (7%) were antiretroviral-naive. The median duration of the OAD regimen was 16.8 months (range, 10.6-29.8 months). The median baseline CD4 cell count was 429.5 cells/mm3 (range, 9.3-1578 cells/mm3), and the baseline pVL was 3.25 log10 copies/mL (range, 1.7-5.7 log10 copies/mL). Genotyping showed that 31% of the patients had at least 3 TAMs at baseline. None of the antiretroviral-experienced patients developed the K65R mutation during the OAD regimen. In contrast, all 3 antiretroviral-naive patients developed both K65R and M184V mutations and had virologic failure. Overall, the slope of the CD4 cell count during the study period was -18.1/year (range, -594.3-1041.8/year). The median CD4 cell count did not differ significantly between baseline and the end of follow-up (P = 0.56). Overall, 52% of patients had a sustained pVL of less than 500 copies/mL (47.4% <50 copies/mL) after 96 weeks of follow-up. Nineteen patients had a baseline pVL of less than 500 copies/mL. Kaplan-Meier analysis showed a significant difference in pVL kinetics between the 2 strata (Fig. 1), whereas the CD4 cell count kinetics were similar (median, -29/year [range, -362-1042/year], P = 0.32 vs 13/year [range, -170-594], P = 0.47). Overall, the median CD4 cell count did not fall relative to baseline.FIGURE 1: Kaplan-Meier analysis: time on treatment (3TC-ddI-TDF).Experienced patients who switched to the OAD regimen when they already had undetectable plasma viremia continued to have a sustained virologic response, despite the presence of TAMs, such as T215Y, or the 3TC-associated mutation M184V at baseline. No resistance mutations specific for TDF were present at baseline in experienced patients. The results of this observational cohort study show the efficacy of the triple NRTI regimen consisting of TDF, ddI, and 3TC. The results are less worrisome than those of previous studies of triple NRTI regimens in naive patients and/or with ddI standard dosing. Indeed, low-dose ddI plus TDF and 3TC provided sustained virologic control and CD4 cell count stability. Romina Quercia, MD* Corinne Amiel, MD† Elisete Da Silva Marechal, MS* Marie-Gisèle Lebrette, MD* Sandrine Thevenet, CRA* Stéphanie Renaud, PD‡ Veéronique Schneider, MD† Ali Kara, MD† Sabine Guessant, DP‡ Gilles Pialoux, MD, PhD* *Infectious Disease Unit †Virology, ‡Pharmacy Tenon Hospital, Paris, France [email protected]