Antiretroviral drug summaries: Efavirenz (EFV; Sustiva)
Last updated on Sep 22, 2007
Mutations at positions 103, 106, 188, and 190 are the most common mutations developing in viruses from patients with virological failure while receiving an EFV-containing treatment regimen (Bacheler et al. 2001; Gallant et al. 2004; Shafer et al. 2003). V106M occurs predominantly in non-subtype B viruses (Brenner et al. 2003; Deshpande et al. 2007; Grossman et al. 2004; Kantor et al. 2005).
K103N occurs in >50% of patients developing virologic failure while receiving EFV and reduces EFV susceptibility ~25-fold with the precise reduction in susceptibility depending on other NNRTI resistance mutations and several common polymorphic mutations that synergistically reduce susceptibility (Ceccherini-Silberstein et al. 2007; Rhee et al. 2006). Thymidine analog mutations which increase susceptibility but which do not appear likely to restore virological efficacy (Shulman et al. 2000; Tozzi et al. 2004).
The development of K103N is often accompanied by mutations at position 188 or 190 or followed by one of the accessory mutations described in the next section. K103R is a polymorphism that is not selected by NNRTIs; however, when present in combination with V179D it reduces NVP susceptibility about 15 fold (Parkin et al. 2006). K103S/T/H are rare mutations that also reduce EFV susceptibility (Harrigan et al. 2005).
V106M, Y188L, G190S, and V106M are each associated with >100-fold decreases in EFV susceptibility (Rhee et al. 2003). V106A, Y188H/C, and G190A are each associated with about 10-fold decreases in EFV susceptibility (Rhee et al. 2003).
L100I (Bacheler et al. 2001), K101P (Parkin et al. 2006), P225H (Bacheler et al. 2001; Pelemans et al. 1998), and K238T (Parkin et al. 2006) occur almost exclusively in combination with K103N (Rhee et al. 2003) and in combination with K103N each reduces EFV susceptibility >100 fold (Rhee et al. 2006).
Y181C occurs in <5% of patients developing virologic failure while receiving EFV nearly always in combination with other NNRTI-resistance mutations. Y181C/I/V reduce EFV susceptibility only ~2-fold. Nonetheless, EFV is often ineffective at treating patients with viruses containing Y181C because most patients failing a previous NNRTI-containing regimen harbor virus subpopulations with multiple different NNRTI-resistance mutations that are often not detectable by standard genotypic sequencing (Lecossier et al. 2005).
M230L reduces EFV susceptibility about 20-fold (Huang et al. 2000). V108I and V179D have been reported to emerge during in vitro passage experiments and synergistically reduce EFV susceptibility when combined with other NNRTI resistance mutations (Winslow et al. 1996). K101E reduces EFV susceptibility by 2-5 fold. It usually occurs in combination with G190S. A98G has little effect on EFV susceptibility but as an NNRTI-selected mutation it may indicate previous NNRTI selective pressure.
E138K is a rare mutations associated with ETR that appears to have little effect on EFV susceptibility (Brillant et al. 2004; Su et al. 2007).
V179F occurs almost exclusively in combination with Y181C and in this setting causes high-level resistance to NVP, DLV, and ETR but which has minimal effect on EFV (Rhee et al. 2003; Vingerhoets et al. 2005; Vingerhoets et al. 2004).
F227C is a rare ETR-associated mutation which based on preliminary data appears to also reduce NVP and EFV susceptibility (Andries et al. 2004; Su et al. 2007; Vingerhoets et al. 2004).
EFV is the preferred NNRTI for initial therapy combined with a TDF/FTC or ZDV/3TC (Hammer et al. 2006; US DHHS Panel 2006). ABC/3TC, ddI/3TC (or ddI/FTC), and d4T/3TC are alternative dual-NRTIs that have been combined successfully with EFV for initial therapy (Eron et al. 2006; Gallant et al. 2004; Saag et al. 2004).
EFV and a recommended dual-NRTI backbone is also highly effective for treatment simplification in patients with complete virologic suppression for > 6 months on a PI-based initial ARV regimen (Abgrall et al. 2006; Martinez et al. 2003).
In patients failing a PI-based regimen with viruses lacking NRTI-resistance mutations EFV and a recommended dual-NRTI combination may occasionally be effective at achieving and maintaining virologic suppression. However, in the presence of NRTI resistance, there will be a high risk of virologic failure. Therefore, if EFV is to be used, it should probably be used with a triple-NRTI regimen and/or change in PIs (Albrecht et al. 2001; Boyd et al. 2005; Falloon et al. 2002; Kempf et al. 2001).
In NNRTI-naïve patients with high-level resistance to multiple NRTIs and PIs, strong consideration should be given to delaying EFV use unless it is combined with a drug belonging to a previously unused drug class.
In NNRTI-experienced patients with virus containing a major EFV-resistance mutation (K103N, Y188L, G190S), there appears to be little benefit of including EFV in a salvage regimen (Deeks et al. 2005).
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