Antiretroviral drug summary: Zidovudine (ZDV; Retrovir)
Last updated on Sep 11, 2007
Thymidine analog mutations (TAMs)
TAMs were once the most common mutations occurring in patients receiving ZDV- or d4T-containing regimens. K70R and T215Y/F reduced ZDV susceptibility ~4-fold and ~10-fold, respectively. However, combinations of 4 or more TAMs reduced ZDV susceptibility several hundred fold.
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 quite common 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 can be 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).
K65R, K70E, L74V/I, M184V
Each of these mutations causes ZDV hypersusceptibility. K65R and L74V rarely occur in viruses from patients receiving ZDV-containing regimens. M184V is not prevented in patients receiving ZDV/3TC; but the emergence of M184V slows the development of high-level ZDV resistance. Few data are available on the clinical significance of K70E mediated ZDV hypersusceptibility.
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).
ZDV/3TC is a preferred NRTI backbone for initial therapy in combination with an NNRTI or boosted PI. It has a high genetic barrier to resistance but has performed less well than TDF/FTC in a recent clinical trial presumably because of its requirement for twice daily dosing and its higher frequency of intolerance (Gallant et al. 2006).
ZDV/3TC/ABC alone should not be for initial HAART because it is inferior to ZDV/3TC/EFV (Gulick et al. 2004). ABC/3TC/ZDV may have a role for simplifying therapy but onlly in previously untreated patients who have maintained complete virologic suppression for more than six months on an initial ARV regimen (Katlama et al. 2003; Markowitz et al. 2005; Martinez et al. 2003).
An open label trial of ZDV/3TC/TDF suggested that it may be superior to ZDV/3TC/ABC but inferior to a dual NRTI / NNRTI containing regimen (DART Virology Group and Trial Team 2006). In short pilot studies, quadruple NRTI containing regimens consisting of ZDV/TDF/ABC in combination with 3TC or FTC have had fewer virological failures but higher rates of adverse treactions than triple NRTI-containing regimens (Elion et al. 2006; Moyle et al. 2006).
A ZDV-containing NRTI backbone is particularly useful in patients failing an initial ARV regimen with viruses containing K65R, L74V, or M184V, but would be suboptimal for viruses containing multiple TAMs. ZDV should be combined with 3TC or FTC as these NRTIs select for M184V, which decreases virus RC and increases ZDV susceptibility. Ongoing studies are evaluating the potential role of triple and quadruple ZDV-containing NRTI combinations for salvage therapy.
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