Antiretroviral drug summary: Stavudine (d4T; Zerit)
Last updated on Sep 11, 2007
TAMs were once the most common mutations occurring in patients receiving d4T-containing regimens (Ross et al. 2001; Shulman et al. 2001)}(Calvez et al. 2002) Kempf, 2004 #1231}. The effect of TAMs on in vitro susceptibility is subtle with two or more TAMs (generally M41L + T215Y) required before reductions (>1.5-fold) in d4T susceptibility are detected. Nonetheless, the TAMs are generally considered to be as determinental to the virological success of d4T-containing regimens as they are for ZDV-containing regimens (Ross et al. 2001; Shulman et al. 2001)}(Calvez et al. 2002).
In high income countries, TAMs are now decreasing in frequency because ZDV and d4T are used less frequently as part of initial HAART and because even when these NRTIs are used, virological failure is usually diagnosed early at which time M184V (in response to 3TC or FTC) and an NNRTI-resistance mutation (in response to NNRTI-containing regimens) may be present but before TAMs appear (Eron et al. 2006; Gallant et al. 2006; Shafer et al. 2003).
However, TAMs remain common following first virological failure in low-income countries in which virological monitoring is less frequent and patients typically receive their initial HAART regimen (which is more likely to obtain ZDV or d4T) for a longer time before the diagnosis of treatment failure is made (Chaix et al. 2005; Ferradini et al. 2006; Idigbe et al. 2007; Wallis et al. 2007).
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).
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 susceptibility to d4T by an amount that clinically appears to be similar to its effect on ZDV. M184V is not prevented in patients receiving d4T/3TC; but the emergence of M184V slows the development of high-level d4T resistance.
K65R has been selected in vitro in viruses cultured with increasing d4T concentrations (Garcia-Lerma et al. 2003). K65R has not been reported in patients receiving d4T monotherapy but occurs in patients receiving d4T/ddI and d4T/3TC at rates significantly higher than that observed with ZDV/ddI or ZDV/3TC (Shafer et al. 2003) particularly in subtype C isolates (Doualla-Bell et al. 2006).
V75T has been selected in vitro in viruses cultured with increasing d4T concentrations (Lacey and Larder 1994). It occurs in 1% of patients receiving NRTIs, particularly d4T, and it reduces d4T susceptibility by ~2-fold (Lennerstrand et al. 2000; Selmi et al. 2001). V75M occurs in about 2% of patients receiving NRTIs and appears to have the same effect on d4T susceptibility (Lin et al. 1999; Rhee et al. 2006).
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).
Because of the higher short and long-term potentially irreversible mitochondrial toxicity associated with d4T, d4T/3TC is considered by the U.S. DHHS and IAS-USA Guidelines as an acceptable alternative dual NRTI option that is inferior to TDF/FTC, ZDV/3TC, and ABC/3TC.
The role of d4T in both early and late virologic failure is similar to that of ZDV. d4T is less active than ZDV against variants containing K65R, but otherwise the impact of these drugs on resistant viruses is comparable. If d4T is used for late virologic failure, it should (like ZDV) be combined with 3TC or FTC, drugs with which it is synergistic.
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