MAJOR MUTATIONS: Mutations that are associated with high levels of phenotpyic resistance or clinical evidence for reduced virological response. Those in bold red are associated with the highest levels of phenotypic resistance or with the strongest clinical evidence for reduced virological response. Mutations in bold grey are intermediate to those in bold red vs. those in plain text. The mutations shown at positions 103, 106, 181, 188, and 190 are generally primary because they generally occur before the mutations L100I and K101EP (Bacheler 2000, Koval 2006, Reuman 2010). M230L is uncommon and may occur alone or with other mutations (Huang 2000, Vingerhoets 2005, RPV Prescribing Information) Position 138 is included because E138K is the most commonly occurring mutation to develop in patients receiving RPV (Rimsky 2011). V106M is more common than V106A in subtype C viruses. In contrast to V106A, V106M causes high-level EFV resistance (Brenner 2003, Grossman 2004, Cane 2004)

NONPOLYMORPHIC ACCESSORY MUTATIONS: These mutations rarely develop in the absence of selective NNRTI pressure. They are among the most common NNRTI-resistance mutations. V90I, A98G, V108I, V179DEF, H221Y are selected by some or each of the NNRTIs and decrease NNRTI susceptibility by 1-5-fold. (Tambuyzer 2009, Zhang 2011) V90I, V108I, and V179D are somewhat polymorphic occurring in about 1% to 2% of untreated persons. P225H contributes to EFV resistance in combination with K103N (Bacheler 2001, Reuman 2010). F227L contributes to NVP resistance in combination with V106A (Balzarini 1998, Huang 2007, Reuman 2010) . K238T is an uncommon mutation that reduces NVP and EFV susceptibiity alone and in combination with K103N (Parkin 2006, Vermeiren 2007), it may also reduce ETR susceptibility (Haddad 2010). Y318F reduces NVP susceptbility about 10-fold (Harrigan 2002). N348I reduces susceptibility to NVP and EFV about 3-fold (Yep 2007, Hachiya 2008). Its effect on ETR is less certain (Sluis-Cremer 2010, Gupta 2011).

HIGHLY UNUSUAL MUTATIONS: K103TH are rare mutations selected by NVP and EFV that decrease susceptibility to a lesser extent than K103N (Harrigan2005, Tambuyzer2009). G190QCTV markedly reduce NVP and EFV susceptibility, although only G190QC have consistently been reported in vivo (Huang 2006, Shahriar 2009). F227C is an extraorindarily rare mutation selected in vitro by ETR, which causes >10-fold decreased susceptibility to each of the NNRTIs (Andries 2004, Tambuyzer 2009).

E138 MUTATIONS: E138K is the most commonly emerging NNRTI-resistance mutation in patients receiving RPV (Rimsky 2011). E138KAQG also emerge frequently in patients receiving ETR (Tambuyzer 2011, Asahchop 2011). In patients receiving RPV, E138K usually occurs with M184I (not M184V) and decreases RPV susceptibility >5-fold (Rimsky 2011, Tambuyzer 2011 Xu 2011, Hu 2011). E138AQG decrease ETR and RPV susceptibility primarily when they occur with other ETR/RPV-associated mutations. E138A is polymorphic occurring in 2% of viruses from untreated persons. NVP and EFV rarely select for E138KQAG. Preliminary data, however, suggests that E138KQAG may confer some degree of cross-resistance to NVP and EFV (Tambuyzer 2009, Tambuyzer 2011, Rimsky 2011).

MUTATIONAL INTERACTIONS: Mutational interactions are particularly important for ETR: Y181C decreases ETR and RPV susceptibility about 3-5-fold, whereas V179F increases ETR and RPV. However, the combination of Y181C + V179F reduces ETR and RPV susceptibility >50-fold (Vingerhoets 2010, Azin 2011). Alone G190AS do not decrease ETR or RPV susceptibility; however, they are synergistic with Y181C at reducing ETR susceptibility (Vinegerhoets 2010, Azjin 2011). K103R has no effect on NNRTI susceptibility; V179D decreases NVP and EFV susceptibility about 2-fold. However, the combination of K103R + V179D decreases NVP and EFV susceptibility >10-fold (Parkin 2006). V106I + V179D are also synergistic at reducing NVP and EFV susceptibility (Gatanaga 2010). Many polymorphic and relatively minor nonpolymorphic mutations that have little or no effect on ETR susceptibility alone contribute to resistance when they occur with multiple additional ETR resistance mutations. These mutations include V90I, A98G, V106I, E138A, V179DET, and H221Y.

TIBOTEC 2010 WEIGHTED ETR GENOTYPIC SUSCEPTIBILITY SCORE: Y181IV (3.0); L100I, K101P, Y181C, M230L (2.5); V90I, E138A, V179F, G190S (1.5); A98G, K101EH, V179DT, G190A (1.0). (Ruxrungtham 2008, Vingerhoets 2010) E138GKQR have been added to this score but not yet assigned weights.

OTHER NNRTIS: DLV is rarely used because of its poor pharmacokinetics. Its susceptibility pattern is similar to that of NVP with the following exceptions: NVP often selects for P236L, which increases NVP susceptibility. G190AS (but not EQ) increase DLV susceptibility. Lersivirine is an investigational NNRTI in phase II studies that appears to have a unique resistance profile (Corbau 2010).