Tenofovir (Viread)

Published October 02, 2001; Updated February 2013
Susa Coffey, MD
http://hivinsite.ucsf.edu/InSite?page=ar-01-07
Selected Reference
24. Margot  NA, Isaacson  E, McGowan  I, Cheng  A, Miller  MD.
Extended treatment with tenofovir disoproxil fumarate in treatment-experienced HIV-1-infected patients: genotypic, phenotypic, and rebound analyses. J Acquir Immune Defic Syndr. 2003 May;33(1):15-21
[PubMed ID: 12792350]
Abstract:
OBJECTIVE: To study the potential development of genotypic and phenotypic resistance to tenofovir disoproxil fumarate (tenofovir DF) when used as a part of a 96-week HIV-1 treatment regimen for antiretroviral treatment-experienced HIV-infected patients. DESIGN AND METHODS: Clinical trial GS-98-902 was a placebo-controlled, 48-week phase 2 study of three doses of tenofovir DF when added to stable antiretroviral therapy for 189 treatment-experienced HIV-infected patients (mean of 4.6 years of prior antiretroviral treatment; 94% had nucleoside reverse transcriptase [RT] inhibitor [NRTI]-associated mutations). There was a statistically significant reduction in the mean HIV-1 RNA level at week 24 (average change in HIV-1 RNA level of -0.58 log(10) through week 24) with 300 mg of tenofovir DF once daily that was durable through week 48 (average change in HIV-1 RNA level of -0.62 log(10) through week 48). At week 48, 135 patients enrolled in an open-label, 48-week extension phase with 300 mg of tenofovir DF once daily added to their antiretroviral therapy. Genotypic analysis of plasma HIV-1 was performed for all patients after 96 weeks of study or upon early termination. Phenotypic analyses were performed at week 96 for patients with increases in HIV-1 RNA levels of > or =0.5 log(10) from week 48 to week 96. RESULTS: Genotypic results were obtained for 96 of 135 patients. NRTI-associated mutations developed in 41 (30%) of 135 patients from week 48 to week 96. Those mutations were primarily thymidine analog-associated mutations (33/41 patients) and developed while patients were receiving either stavudine or zidovudine. Two patients (1.5%) developed the K65R RT mutation (selected by tenofovir in vitro) but maintained HIV-1 suppression (-0.39 log(10)). These 96-week results were analogous to the 48-week results, in which 33% (n = 63) and 2.1% (n = 4) of patients developed thymidine analog-associated mutations or the K65R mutation, respectively. Although most patients maintained HIV-1 RNA suppression, an analysis of patients with increases in HIV-1 RNA levels of > or =0.5 log(10) (n = 21) from week 48 to week 96 was performed. For eight of 21 patients, development of primary protease inhibitor-associated or non-NRTI-associated resistance mutations was likely responsible for the HIV-1 RNA rebound. The remaining patients developed either no mutation (n = 3) or a new NRTI-associated mutation (n = 10) and were analyzed phenotypically. No phenotypic changes for tenofovir were observed in these analyses. In addition, no new mutations potentially associated with tenofovir DF therapy were identified. Overall, patients had a similar reduction in HIV-1 RNA levels at week 96 and at week 48 compared with baseline (-0.55 and -0.60 log(10), respectively). CONCLUSIONS: Adding tenofovir DF (300 mg) to existing antiretroviral therapy for highly treatment-experienced patients with preexisting resistance mutations showed significant and durable reductions in HIV-1 RNA levels through week 96. Through 96 weeks of tenofovir DF therapy, 48 weeks of which included suboptimal doses of tenofovir DF, there was infrequent development of RT mutations associated with tenofovir DF therapy (K65R mutation, 3%), consistent with the durability of the observed HIV-1 RNA responses.