Virologic outcome after switching from a nucleoside reverse transcriptase inhibitor to tenofovir in patients with undetectable HIV-1 RNA plasma level.

To the Editor: Tenofovir disoproxil fumarate (TDF), a prodrug of the nucleotide reverse transcriptase inhibitor tenofovir, has been approved for use in combination therapy for HIV-1 infection, based on its activity in treatment-naive and drug-experienced subjects. However, recent studies reported early virologic failures in a very high proportion of patients after the initiation of a once-daily regimen of TDF, lamivudine (3TC), and abacavir (ABC) in treatment-naive patients. Therefore, this regimen cannot be recommended for the initiation of antiretroviral treatment in HIV-1-infected patients with a detectable HIV-1 viral load in plasma. Moreover, switching to this particular combination (ABC/3TC/TDF) in patients with well-controlled viremia was also recently associated with virologic failures. However, little is known about the efficacy of TDF as a component of other regimens used for switching treatment in patients with undetectable viral load. Thus, we do not know if another triplenucleoside/nucleotide combination (excluding ABC) might still be considered as a possible alternative in HIV-1 treatment, or if TDF must imperatively be associated with at least one compound of the 2 other antiretroviral classes: nonnucleoside reverse transcriptase inhibitors (NNRTIs) and the protease inhibitors (PIs). The aim of this study was to compare the virologic outcome after switching to TDF in a context of combinations of various antiretroviral classes and a baseline suppressed HIV-1 RNA in plasma. In this retrospective study, we selected from our database all HIV-1infected patients who have undergone a switch from a nucleoside reverse transcriptase inhibitor (NRTI) to TDF. We then only kept the patients who had no other change in their antiretroviral treatment and who had an undetectable viral load in plasma at the time of switch (<200 copies/mL; Roche Amplicor (Roche Diagnostic, Neylan, France) HIV-1 Monitor assay 1.5). Virologic failure was defined as at least one measurement of plasma HIV-1 RNA >200 copies/mL in the 6 months following the switch without a return below this threshold. A genotypic resistance testing (automated population-based-full sequence analysis) was performed on the sample whose viral load rebounded. Forty-one patients met criteria. Their baseline treatments were switched for TDF to simplify the regimen (oncedaily regimen) or to avoid or reverse adverse effects (such as clinical lipoatrophy). Before switching, the 41 combinations were as follows: 11 patients received one PI plus 2 or 3 NRTIs (n = 9 and 2, respectively); 19 patients received one NNRTI plus 2 NRTIs; and 11 patients received 3 NRTIs. Thus, after switching to TDF, 11 patients received TDF with PI-based regimen; 19 were on an NNRTI-based regimen; and 11 patients were on triple-nucleoside/nucleotide therapy. The NRTIs switched for TDF were zidovudine (ZDV, n = 8), stavudine (d4T, n = 17), didanosine (ddI, n = 13), and ABC (n = 3). After a follow-up of at least 6 months, virologic failures occurred in 17% of patients (7/41). All the failures were observed with triple-nucleoside/nucleotide therapy. In contrast, no failure was observed in the patients on TDF plus a PIor NNRTI-based regimen. Viral load and patterns of resistance mutations at the time of failure are summarized in Table 1 with details of treatment before and after switching. According to contingency tables and the Fisher exact test, there were significantly more failures in the patients receiving triple-nucleoside/nucleotide therapy as compared with those receiving one PI or NNRTI in their regimen (64 vs. 0%, P < 0.0001). As all the patients had maintained a well-suppressed HIV-1 viral load for a long time before switching, it can be assumed that they were compliant. The high rate of failure observed on this combination therapy is in agreement with the 2 previous studies concerning virologic outcome after initiation of ABC/TDF/3TC therapy. Interestingly, our study raises the question of other triple-nucleoside/nucleotide combinations mostly as concerns oncedaily ddI/3TC/TDF. These results suggest that when a TDF-based switch is envisaged, the choice will not involve a triple-nucleoside/nucleotide combination. Some hypotheses can be advanced to explain these results, such as pharmacokinetic problems using ABC or ddI once daily. However, recent results showed that clinical and pharmacokinetic data were in favor of once-daily ABC as well as once-daily 250-mg ddI-EC plus TDF with food. Previous studies have shown that virologic failure after switching from PI to triple-NRTI therapy can be explained by prior suboptimal NRTI regimen that selected some mutations to this class. In these previous studies, the number of nucleoside-associated mutations shown at the time of failure was in support of this idea. In our study, 6 of the 7 patients who experienced a failure had no detectable viral load at any time during prior NRTI therapies, and the resistance profiles observed at the time of rebound were in agreement with this fact (Table 1). Patient 5, who harbored a resistance profile that could be related to previous antiretroviral regimens, was the only subject who had had NRTI suboptimal therapy. The genotype of the 6 other patients, in line with the observation of Supported by Sidaction and ANRS (Agence Nationale de Recherche sur le SIDA).