Genotypic and phenotypic analyses of HIV-1 in antiretroviral-experienced patients treated with tenofovir DF.
OBJECTIVE
To evaluate the virologic responses and mutational profiles in antiretroviral-experienced patients adding tenofovir DF once-daily to their existing regimens.


METHODS
Resistance analyses were performed for patients in a phase II placebo-controlled clinical trial of tenofovir DF.


METHODS
HIV-1 reverse transcriptase and protease genes from plasma samples were analyzed genotypically and phenotypically at baseline, week 24, and week 48.


RESULTS
Of 184 patients, 173 (94%) had baseline HIV-1 expressing one or more nucleoside reverse transcriptase inhibitor-associated resistance mutation. Protease inhibitor and non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance mutations were observed in 57% and 32% of patients, respectively. Compared to placebo, significant reductions in HIV-1 RNA were observed for tenofovir DF-treated patients who had thymidine analog- (TAM), lamivudine- (M184V), NNRTI- or protease inhibitor-associated mutations. Patients with phenotypic susceptibility to tenofovir within 4-fold of wild-type responded durably to tenofovir DF 300 mg therapy with a decline in plasma HIV-1 RNA of > or = 0.5 log10 copies/ml; few patients had a more than 4-fold reduced susceptibility to tenofovir at baseline. Four patients (2%) developed the K65R mutation (selected by tenofovir in vitro) and showed 3- to 4-fold reductions in tenofovir susceptibility but no evidence of rebound viremia. Thirty-four percent of patients developed additional TAMs, coincident with concurrent zidovudine or stavudine therapy, but also showed durable HIV-1 reductions. There was no evidence of novel resistance to tenofovir.


CONCLUSIONS
Adding tenofovir DF 300 mg to an existing regimen in patients with ongoing viral replication and a wide range of genotypic resistance patterns resulted in significant and durable HIV-1 RNA reductions. In addition, there was a low incidence of genotypic or phenotypic resistance to tenofovir DF arising during 48 weeks of therapy.
Margot
Nicolas A
NA
Gilead Sciences, Inc., Foster City, California 94404, USA.
Isaacson
Erica
E
McGowan
Ian
I
Cheng
Andrew K
AK
Schooley
Robert T
RT
Miller
Michael D
MD
D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use*; D004311:Double-Blind Method; D024882:Drug Resistance, Viral / Q000235:genetics; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology*; D054303:HIV Reverse Transcriptase / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics* / Q000502:physiology; D006801:Humans; D009154:Mutation / Q000187:drug effects* / Q000235:genetics; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D010641:Phenotype; D012367:RNA, Viral / Q000032:analysis / Q000235:genetics; D000068698:Tenofovir; D013997:Time Factors
D063065:Organophosphonates; D009943:Organophosphorus Compounds; D012367:RNA, Viral; D000068698:Tenofovir; D054303:HIV Reverse Transcriptase; D000225:Adenine