Genotypic and phenotypic predictors of the magnitude of response to tenofovir disoproxil fumarate treatment in antiretroviral-experienced patients

Results from 2 placebo-controlled intensification trials of tenofovir disoproxil fumarate (DF) in treatment-experienced human immunodeficiency type 1 (HIV-1)-infected patients (n=332) were integrated to determine the effects of resistance at baseline on HIV-1 RNA response. In these trials, there was a high prevalence of HIV-1 resistance mutations, with 94% of patients having nucleoside-associated mutations and 71% having thymidine analogue-associated mutations (TAMs). Statistically significant HIV-1 RNA reductions associated with tenofovir DF treatment, relative to placebo (P<.001), were observed for patients without TAMs (n=97) or for patients with 1-2 (n=88) or >or=3 TAMs (n=147). Response to tenofovir DF was reduced among patients with HIV-1 with >or=3 TAMs inclusive of either the M41L or L210W mutation (n=86) or patients who had a preexisting K65R mutation (n=6). Slightly increased treatment responses were observed when the M184V mutation was present. Phenotypic cutoffs were established at 1.4-fold and 4-fold, respectively, for the beginning of reduced response to tenofovir DF and for a strongly reduced response. The results from these controlled clinical trials provide guidance for the use of tenofovir DF for treatment-experienced patients.     

Tenofovir, adefovir, and zidovudine susceptibilities of primary human immunodeficiency virus type 1 isolates with non-B subtypes or nucleoside resistance

New antiretroviral drugs with activity against strains of human immunodeficiency virus type 1 (HIV-1) with non-B subtypes and with resistance to current antiretroviral drugs are needed. The activity of two nucleotide analogs, tenofovir and adefovir (PMPA and PMEA, respectively), against non-B subtypes and nucleoside-resistant primary HIV-1 isolates was assessed. Tenofovir and adefovir were fully active against a panel of subtypes A, C, D, E, F, G, and group O primary HIV-1 isolates as compared with their respective activity against subtype B isolates. Moreover, the susceptibility of a panel of 10 primary HIV-1 isolates with >10-fold mean resistance to zidovudine, lamivudine, and abacavir was within 2.2-fold of wild-type tenofovir susceptibility for each isolate. An oral prodrug of tenofovir, tenofovir disoproxil fumarate (DF), is currently in phase III clinical trials for the treatment of HIV-1 infection. These in vitro susceptibility results suggest that tenofovir DF may be active in vivo against HIV-1 with nucleoside resistance as well as against HIV-1 with non-B subtypes.     

Tenofovir DF in antiretroviral-experienced patients: results from a 48-week,randomized, double-blind study

OBJECTIVE: To evaluate the safety and efficacy of once daily doses of tenofovir DF (TDF) administered in combination with other antiretroviral therapy (ART) in treatment-experienced HIV-1-infected patients with incomplete virological suppression. DESIGN: One-hundred and eighty-nine subjects with plasma HIV-1 RNA levels between 400 and 100,000 copies/ml and stable ART (> or = 8 weeks) were randomized (2 : 2 : 2 : 1 ratio) to add TDF 75 mg, 150 mg, or 300 mg or placebo to existing ART in a double-blinded manner. After 24 weeks, patients initially randomized to placebo received blinded TDF 300 mg. METHODS: Efficacy was analyzed by the mean changes HIV-1 RNA levels (log10 copies/ml plasma; DAVG(xx)) from week 0 to weeks 4, 24, and 48. Safety was analyzed by incidence of grade 3 or 4 clinical and laboratory adverse events. RESULTS: At baseline, patients had mean 4.6 years prior ART use with 94% having HIV-1 with nucleoside-associated resistance mutations. There were statistically significant decreases in DAVG(4) and DAVG(24) for all doses of TDF compared with placebo, with the greatest effect seen with TDF 300 mg (DAVG(4), -0.62, P < 0.001; DAVG(24), -0.58; P < 0.001; DAVG(48), -0.62). The incidence of adverse events was similar among the TDF groups and placebo through week 24. Throughout the 48-week study, no significant changes in renal function were observed. CONCLUSIONS: In treatment-experienced patients with baseline nucleoside resistance mutations, TDF provided dose-related, durable reductions in HIV-1 RNA. Through 24 weeks, the safety profile of TDF was similar to that of placebo.