MAJOR MUTATIONS: Mutations that cause high-levels of decreased susceptibility of strong clinical evidence for contributing to virological failure. 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. Although G140SA do not decrease INI susceptibility, they occur almost uniformly in combination with the highly potent Q148 INI-resistance mutations. The major mutations shown here have been selected in persons receiving RAL (Cooper 2008, Malet 2008, Sichtig 2009, Wittkp 2009, Canducci 2009, Baldanti 2010, Reuman 2010, Hatano 2010), or EVG (McColl HIVDRW 2007, Zolopa JID 2010) and characterized for in vitro susceptibility (Shimura 2007, Goethals 2008, Kobayashi 2008, Fransen 2009, Jones 2009, da Silva 2009, Reuman 2010, Goethals 2010, Kobayashi 2011). Mutations in bold red are associated with >5-10 fold decreased susceptibility. Although E138 and G140 mutations alone do not decrease INI susceptibility that greatly contributed to decreased susceptibility in combinationion with Q148 mutations.

NONPOLYMORPHIC ACCESSORY MUTATIONS: These mutations rarely develop in the absence of selective INI pressure. They are among the most common INI-resistance mutations occurring in vivo and are responsible both for increasing the fitness of viruses containing major INI-resistance mutations and for increasing the levels of resistance associated with the major mutations. The most commonly occurring mutations in this category are skewed towards those developing in patients receiving RAL. They include T97A (which is highly synergistic with Y143RC), E138AK (which although it does not reduce INI susceptibility by itself may be almost as important for G140AS particularly for DTG resistance), H51Y, L74MR, Q65K, V151I, G163RK, and S230R, and R263K. S153Y appears to be associated with slightly reduced susceptibility to EVG and DTG.

HIGHLY UNUSUAL MUTATIONS: F121Y decreases RAL and EVG susceptibility >10-fold but has not been reported in vivo. P145S and Q146P have been selected in vitro by EVG and markedly reduce its susceptbility. E92V and I151AL have been selected in vitro by other INIs and decrease RAL and EVG susceptibility by >5-fold. G140C and N155S are rare mutations at common INI-resistance positions.

DOLUTEGRAVIR (DTG): is less well studied than RAL or EVG (reviewed in Blanco 2011). Although most individual RAL-associated mutations have little effect on DTG susceptibility, combinations of Q148HKR ± G140SA ± E138KA are associated with 10-20 fold reduced susceptibility (http://hivdb.stanford.edu/pages/geno_clinical_review/NRTI.html). G118R, a mutation that has not yet been reported in vivo, reduces DRG susceptibility several-fold (Kobayashi 2011).

INVESTIGATIONAL INIs: EVG is in advance phase III trials as part of the once daily QUAD pill (EVG/cobicistat/TDF/FTC). It is likely to be available in 2012. Phase II studies of DTG for first-line and salvage therapy have been completed. Clinical investigation of this compound is progressing rapidly.