Antiretroviral drug summary: Didanosine (ddI; Videx)
Last updated on September 07, 2007
L74V is the most common mutation occurring in patients receiving ddI monotherapy (Kozal et al. 1994; Shafer et al. 1994; St. Clair et al. 1991). It also occurs commonly in viruses from persons receiving ddI/3TC, ddI/FTC, or ddI/TDF. Although L74V reduces ddI susceptibility by only ~1.8 fold, it predicts a poor virologic response (Molina et al. 2005). L74I occurs less commonly than L74V, appearing more often in viruses containing multiple TAMs. Its phenotypic and clinical significance appears similar to that of L74V (Berkhout et al. 2006; Rhee et al. 2006).
K65R occurs in patients receiving ddI monotherapy (Winters et al. 1997), ddI/d4T, (Shafer et al. 2003), ddI/TDF, and ddI/TDF/3TC. It reduces ddI susceptibility ~2.0 fold. ddI is likely to be inactive at treating patients with viruses containing K65R. K65N is an rare mutation that has an effect on NRTI susceptibility similar to K65R (Margot et al. 2006; Ross et al. 2006).
TAMs are the primary mutations associated with virologic failure in patients receiving ddI/ZDV (Montaner et al. 1998; Shafer et al. 1995) and ddI/d4T (Coakley et al. 2000; Pellegrin et al. 1999). TAMs have a subtle effect on in vitro ddI susceptibility, with three or more TAMs (particularly M41L, L210W, and T215Y) required to reduce susceptibility by ~1.5 fold. However, despite the minimal effect on in vitro susceptibility, the presence of M41L, L210W, and T215Y is associated with a greatly drediced virological response to ddI intensification (Marcelin et al. 2005; Molina et al. 2005).
M184V occurs in a small proportion of patients receiving ddI monotherapy (usually after development of L74V) but does not occur in patients receiving ddI with ZDV or d4T (Shafer et al. 1994). M184V reduces ddI susceptibility slightly <1.5 fold. In combination with multiple TAMs, M184V contributes to greater reductions in susceptibility (Whitcomb et al. 2003). However, M184V does not appear to reduce the virologic response to ddI, possibly because the M184V-associated decreased RC and the accompanying increased susceptibility to TDF, ZDV, and d4T associated with M184V counter the decrease in ddI susceptibility.
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 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).
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 (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).
T69D has minimal, if any, effect on ddI susceptibility in vitro. However, in combination with multiple TAMs, these mutations are associated with a decreased virologic response to ddI in vivo (Naugler et al. 2002).
V75T and V75M have each been shown to reduce ddI susceptibility in vitro (Lacey and Larder 1994; Rhee 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).
ddI + 3TC or FTC in combination with an NNRTI have been highly effective first line therapies in several small clinical trials (Saag et al. 2004) and therefore this combination has been classified as alternative NRTI backbone of initial regimens by the US DHHS Guidelines. ddI/d4T is not recommended because of decreased efficacy and increased toxicity. ddI/TDF is not recommended because it has been associated with early virologic failures in patients with high plasma HIV-1 RNA levels (Leon et al. 2005; Podzamczer et al. 2005; Torti et al. 2005). ddI/ZDV has not been widely studied as part of an initial HAART regimen.
In patients harboring viruses with M184V and TAMs, ddI has a high genetic barrier to resistance. However, the optimal NRTIs to be used in combination with ddI are not known. ddI/TDF coadministration has been associated with a blunted CD4 response, particularly but not exclusively when ddI is not administered at the appropriately reduced dosage of 250 mg per day for TDF co-administration (Barrios et al. 2005; Clotet et al. 2007; Karrer et al. 2005; Negredo et al. 2005). There are also too few data on the use of ddI in combination with ZDV, 3TC, or ABC, although the latter is not likely to be useful because similar mutations cause resistance to both drugs.
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