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: Abacavir (ABC; Ziagen)

Last updated on Sep 11, 2007
Key Mutations
L74V/I
L74V is selected when HIV-1 is cultured with increasing ABC concentrations (Tisdale et al. 1997). It also occurs commonly in patients failing ABC and ABC/3TC usually in combination with M184V (Bartlett et al. 2006; Descamps et al. 2006; Moyle et al. 2005). By itself, L74V reduces ABC susceptibility ~2-fold; with M184V, ABC susceptibility is reduced 5-6 fold and has diminished in vivo activity (Brun-Vezinet et al. 2003). L74I occurs less commonly than L74V; its phenotypic and clinical significance is believed to be similar to L74V (Berkhout et al. 2006).
 
K65R/N
K65R is selected when HIV-1 is cultured with increasing ABC concentrations (Harrigan et al. 2000; Tisdale et al. 1997{Saag, 1998 #2179) and occurs commonly in patients failing ABC, ABC/3TC, ABC/TDF/3TC and ABC/d4T/ddI (Delaunay et al. 2005; Gallant et al. 2005; Lanier et al. 2004b; Roge et al. 2003). By itself, K65R reduces ABC susceptibility ~3-fold. In combination with M184V, it reduces ABC susceptibility ~6-8 fold. K65N is an rare mutation that has an effect on NRTI susceptibility similar to K65R (Margot et al. 2006; Ross et al. 2006).
 
TAMs
M41L
D67N/G
L210W
T215F/Y
K219E/Q/N/R
TAMs occur in patients developing virological failure while receiving ZDV/3TC/ABC (Ait-Khaled et al. 2002). T215Y/F alone has little effect on ABC susceptibility. However, M41L + T215F/Y ± L210W reduces ABC susceptibility 2-3 fold. The addition of M184V and other TAMs to this set of mutations reduces ABC susceptibility 6-8 fold and decreases the virologic response to ABC intensification and salvage therapy (Brun-Vezinet et al. 2003; Lanier et al. 2004a).
 
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
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 even high-levels of 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).
 
Q151M complex
Usually in combination with V75I, F77L, F116Y
Q151M confers low-level resistance to TDF, 3TC, and FTC, and high lintermediate-to-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 high-level 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).
 
Y115F
Y115F occurs in ~10% if patients receiving ABC alone and in ~1% of heavily treated patients. It reduces ABC susceptibility ~3-fold (Tisdale et al. 1997). Because ABC is the NRTI that is most affected by Y115F, ABC is unlikely to be a good choice for treating viruses with this mutation.
 
K70E
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).
 
E44D +/- V118I
E44D and V118I are accessory mutations that usually occur with multiple TAMs. 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
The U.S. DHHS lists ABC/3TC as an alternative first line dual NRTI backbone behind TDF/FTC and ZDV/3TC. The IAS-USA Guidelines list ABC/3TC as a preferred first line dual NRTI backbone along with TDF/FTC and AZT/3TC. ABC/3TC has been shown to be as effective as ZDV/3TC when combined with EFV (DeJesus et al. 2004; Eron et al. 2006; Moyle et al. 2005). A study comparing ABC/3TC with TDF/FTC in combination with either EFV or ATV/r is ongoing.

ABC/3TC/ZDV is not recommended for initial treatment (Gulick et al. 2004; Sturmer et al. 2007). 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).
 
Salvage therapy
ABC retains activity against viruses that emerge after initial HAART failure with M184V alone or M184V and one or two TAMs. Therefore, once-daily 3TC/ABC or twice-daily 3TC/ABC/ZDV are often useful NRTI backbones for patients with an initial virologic failure. Anecdotal data suggests that 4-drug NRTI regimers including ZDV/ABC/TDF in combination with 3TC or FTC may be highly effective salvage therapy options in some patients (Balestre et al. 2006; Latham et al. 2005; Moyle et al. 2006; Rodriguez et al. 2006).
 
References
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