Stanford University HIV Drug Resistance Database - A curated public database designed to represent, store, and analyze the divergent forms of data underlying HIV drug resistance.

Antiretroviral drug summary: Tenofovir (TDF; Viread)

Last updated on Sep 11, 2007
Key Mutations
K65R is selected in vitro when HIV-1 is cultured in the presence of increasing TDF concentrations (Wainberg et al. 1999). It reduces TDF susceptibility about 2-fold as measured by the PhenoSense assay (Rhee et al. 2006; Whitcomb et al. 2003). The clinical significance of K65R-mediated TDF resistance was demonstrated by the rapid virological failure associated with the emergence of M184V + K65R in patients receiving TDF/3TC/ABC and TDF/3TC/ddI for initial HAART (Delaunay et al. 2005; Gallant et al. 2005).

K65R occurs less commonly in patients receiving TDF/FTC + NVP or EFV partly because virological failure is rarer in these patients, and partly because virological failure is often detected at an earlier stage in association with M184V and NNRTI associated mutations but not K65R. Although there have been no direct comparative trials, K65R has occurred less commonly with TDF/FTC/EFV than with TDF/3TC/EFV (Gallant et al. 2006; Gallant et al. 2004) possibly because the TDF/FTC coformulation and the longer and comparable half-lives of TDF aand FTC redice the risk for functional mono or dual therapy should adherence be suboptimal.

K65R rarely occurs in combination with Type I TAMs because of a mutual antagonism among themse mutations (McColl et al. 2004; Parikh et al. 2006a; Parikh et al. 2006b; Parikh et al. 2005; Trotta et al. 2006; White et al. 2005; Wirden et al. 2005). K65N is an rare mutation that has an effect on NRTI susceptibility similar to K65R (Margot et al. 2006; Ross et al. 2006).
K70E is selected in patients with virological failure on a TDF containing regimen (Delaugerre et al. 2005; Delaunay et al. 2005; Mulato et al. 1998; Ross et al. 2005; Van Houtte et al. 2006). Like K65R, this mutation usually occurs in viruses lacking TAMs and decreases susceptibility to TDF, ABC and 3TC (Sluis-Cremer et al. 2006; Van Houtte et al. 2006).
Thymidine analog mutations (TAMs)
TAMs are selected when TDF is added to a regimen containing ZDV or d4T or when used for treating viruses that already contain TAMs (Margot et al. 2003). The combination of M41L, L210W, and T215Y reduces TDF susceptibility ~4 fold and is associated with a marked decrease in TDF activity when TDF is added to a failing regimen or used as part of a new salvage therapy regimen (Masquelier et al. 2004b; Miller et al. 2004; Squires et al. 2003). Viruses containing only one or two of these three mutations retain partial TDF susceptibility (Barrios et al. 2003).

The Type II TAMs D67N, K70R, T215F, K219Q/E reduce TDF susceptibility less than the Type I TAMs (Barrios et al. 2003; Miller et al. 2004).
T215 revertants:
T215 revertants are back mutations that are usually detected in patients primarily infected with a virus containing T215Y or F (Chappey et al. 2003; de Ronde et al. 2001; Garcia-Lerma et al. 2001; Goudsmit et al. 1997; Yerly et al. 1998). They do not reduce NRTI susceptibility, but suggest that T215Y/F may be present (Garcia-Lerma et al. 2001). Preliminary data suggest that some first line regimens may be less effective in patients with virus containing a T215 revertant (Van Laethem et al. 2007; Violin et al. 2004).
T69 insertion mutations
T69 insertions occur in ~1% of treated patients, nearly always in combination with multiple TAMs. Together these mutations cause high-level resistance to each of the NRTIs including 3TC, FTC, and TDF (Cases-Gonzalez et al. 2006; Clevenbergh et al. 2002; de Jong et al. 1999; Eggink et al. 2007; Gallego et al. 2003; Kew et al. 1998; Larder et al. 1999; Masquelier et al. 2001; Matamoros et al. 2004; Meyer et al. 2003; Rakik et al. 1999; Tamalet et al. 1998; Tamalet et al. 2000; Van Vaerenbergh et al. 2000; White et al. 2004; Winters et al. 1998).
Q151M complex
Usually in combination with V75I, F77L, F116Y
Q151M confers low-level resistance to TDF, 3TC, and FTC, and high -level resistance to each of the remaining NRTIs. In combination with mutations at positions 75, 77, and 116, Q151M confers intermediate resistance to 3TC, FTC, and TDF, and higher levels resistance to the remaining NRTIs(Clevenbergh et al. 2002; Deval et al. 2002; Feng et al. 2006; Gallego et al. 2003; Garcia-Lerma et al. 2000; Iversen et al. 1996; Matsumi et al. 2003; Schmit et al. 1998; Shafer et al. 1995; Shafer et al. 1994; Shirasaka et al. 1995; Van Vaerenbergh et al. 2000; Zaccarelli et al. 2004)
M184V increases phenotypic susceptibility to TDF by ~2-fold and partially restores phenotypic resistance caused by K65R (Naeger et al. 2001; Whitcomb et al. 2003; Wolf et al. 2003).
L74V increases phenotypic susceptibility to TDF (Parkin et al. 2003; Rhee et al. 2006). However, L74V has been associated with decreased TDF clinical activity suggesting that L74V may often be a marker for the presence of other drug-resistance mutations such as K65R or possibly multiple TAMs with which it often occurs (Masquelier et al. 2004a; Svarovskaia et al. 2007).
Y115F is rarely selected by TDF in vitro in vivo and is associated with decreased TDF susceptibility (Margot et al. 2006; Rey et al. 2006; Rhee et al. 2006; Wirden et al. 2005).
E44D +/- V118I
E44D and V118I are accessory mutations that usually occur with multiple TAMs. In this setting they contribute some degree of resistance to each of the NRTIs including 3TC and FTC (Delaugerre et al. 2001; Gianotti et al. 2006; Girouard et al. 2003; Hertogs et al. 2000; Lin et al. 1999; Montes and Segondy 2002; Romano et al. 2002).
Clinical Uses
Initial therapy
TDF/3TC and TDF/FTC are preferred dual NRTI backbones. TDF/FTC containing regimens have been associated with a remarkably low failure rates (Bartlett et al. 2007; Gallant et al. 2006) possibly because of the convenient co-formulation of TDF with FTC in Truvada and with FTC and EFV in Atripla and possibly because the similar intracellular half-lives of TDF, FTC, and EFV mean that functional monotherapy rarely occurs even in persons who undergo brief treatment interruptions.

In an open-label noncomparative trial, ZDV/3TC/TDF appeared as effective as ZDV/3TC/ABC but less effective than currently recommended NNRTI- or PI-containing HAART regimens (DART Virology Group and Trial Team 2006; Masquelier et al. 2006; Rey et al. 2006). TDF/ddI is not recommended because of an increased failure rate, even when combined with EFV (Leon et al. 2005; Podzamczer et al. 2005; Torti et al. 2005).
Salvage therapy
Other than K65R most genetic mechanisms of TDF resistance require multiple mutations. Therefore, unless K65R is present, TDF is likely to retain significant efficacy in patients with few previous virologic failures. However, even in patients developing virologic failure with K65R, TDF/FTC in combination with ZDV may retain antiretroviral activity because K65R increases ZDV susceptibility (Landman et al. 2005; Staszewski et al. 2006).
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