Major Integrase Inhibitor (INSTI) Resistance Mutations
The table lists the most common clinically significant INSTI-resistance mutations. Mutations in bold red are associated with the highest levels of reduced susceptibility or virological response to the indicated INSTI. Mutations in bold reduce INSTI susceptibility or virological response. Mutations in plain text contribute to reduced suceptibility in combination with other INSTI-resistance mutations.
H51Y is a rare nonpolymorphic accessory mutation. It is selected in vitro by EVG (1,2,3) and DTG (4) and in patients receiving RAL (5,6) and EVG (7,8). It reduces EVG susceptibility by ~2-3-fold (1,3,4,9,10) but alone does not appear to reduce RAL, DTG, or BIC susceptibility (3,4,11,12).
T66A is a nonpolymorphic mutation selected in patients receiving EVG (5,13,8,14) and RAL (15,16,5). It reduces EVG susceptibility ~5-fold but has minimal effect on RAL, DTG or BIC susceptibility (17,3,18,19,20,10).
T66I is a nonpolymorphic mutation frequently selected in vitro (2,1,21,3,22) and in patients receiving EVG (2,1,21,7,8). It has also been reported in patients receiving RAL (23) and DTG (24). T66I reduces EVG susceptibility ~10-fold (17,3,25,18,19) but does not reduce RAL (17,25,3,18,20), DTG, (19,26,10), or BIC (12) susceptibility.
T66K is a nonpolymorphic mutation selected in vitro by EVG (3). It has also been selected in patients receiving EVG (13,19) and RAL (23). It is associated with >40-fold reduced EVG susceptibility (17,3,19), >10-fold reduced RAL susceptibility (17,3,19,10) and 2-3-fold reduced DTG susceptibility (17,19,10).
L74M occurs in nearly 10% of CRF02_AG viruses from ARV-naïve patients but is otherwise minimally polymorphic with an ARV-naive prevalence ranging between 0.3% to 3% in other subtypes (27). It is selected in patients receiving RAL (28,29,30,31,23) and EVG (5,8), and in RAL-experienced patients receiving DTG salvage therapy (32,33). By itself, it has minimal if any effect on INSTI susceptibility (25,34,10). However, it reduces RAL susceptibility in combination with other INSTI-resistance mutations (22,25,6). In combination with mutations at positions 140 and 148, it reduces DTG susceptibility (17) and the clinical response to DTG-salvage therapy regimens (32,32).
L74I is highly polymorphic, occurring in 3% to 30% of viruses from ARV-naïve patients depending on subtype (27). It may be weakly selected by INSTI therapy. It does not appear to be associated with reduced INSTI susceptibility.
L74F is an extremely rare mutation reported in one RAL-treated patient (35). Alone, it minimally reduces RAL and EVG susceptibility. In combination with G140S and Q148H it contributes to reduced DTG susceptibility (35).
E92Q is a nonpolymorphic mutation selected in patients receiving RAL (28,5,7,8) and EVG (5,13,36,7). It reduces RAL susceptibility ~5-fold (17,25,18,19) and EVG susceptibility ~30-fold (1,17,25,18,19). It is often the primary mutation associated with VF on an EVG-containing regimen (7,8). It is selected in vitro by DTG and reduces DTG susceptibility ~1.5-fold (17,19,37,38). It does not appear to reduce BIC susceptibility (39).
E92G is a nonpolymorphic mutation selected in vitro by EVG (3) and in patients receiving RAL and EVG (8,19). It reduces EVG susceptibility ~10-fold (3,19) but does not reduce RAL, or DTG susceptibility (3,19).
E92V has been reported to emerge during in vitro passage with an investigational INSTI and to reduce EVG and possibly RAL but not DTG susceptibility (25,17). It has rarely been reported in patients receiving INSTIs (23).
T97A is a polymorphic accessory INSTI-resistance mutation occurring in 1% to 4% of viruses from untreated persons depending on subtype (27). (40,41)(; ) It is selected in patients receiving RAL (42,43,6,8), EVG (8), and DTG (32,33). It reduces EVG susceptibility by ~3-fold (10), but has not been shown to reduce the efficacy of first-line EVG-containing regimens (44). Alone, it has minimal if any effect on RAL or DTG susceptibility but it contributes to markedly reduced RAL (32,45) and DTG susceptibility when combined with other INSTI-resistance mutations (33,46).
G118R is an extremely rare nonpolymorphic accessory mutation selected in vitro by DTG (11,47). It has also been selected in one patient receiving RAL (48) and two patients receiving DTG monotherapy (47,49,50). Overall reductions in susceptibility are ~5-10-fold for RAL and EVG, ~3-5-fold for DTG, and ~2-3-fold for BIC (22,48,9,47,51,11,52,53,12). G118R is also commonly observed in sequences with G-to-A hypermutation and in this setting it should not be considered an indicator of drug resistance (54).
F121Y is a nonpolymorphic mutation that is selected in vitro by RAL (55,37) and EVG (1) and rarely in vivo by RAL (56) It reduces susceptibility to RAL and EVG ~5 and >10-fold, respectively (1,22,9,10). It has been shown to have minimal if any effect on DTG susceptibility (57,10,39,17,52,53,39).
E138K/A are nonpolymorphic accessory resistance mutations selected in patients receiving RAL (28,58,54,23), EVG (13), and DTG (32,33) usually in combination with Q148 mutations. Alone they do not reduce INSTI susceptibility (2,25,17,10). In combination with Q148 mutations they reduce RAL and EVG susceptibility >100-fold (45,59,10) and DTG susceptibility up to 10-fold (32,60,17,10). E138T is a less common INSTI-selected nonpolymorphic accessory resistance mutation (54,38,33).
G140S is a nonpolymorphic mutation that usually occurs with Q148H/R/K in patients receiving RAL (28,61,5,30,43,15) and EVG (13,7,8). Alone, it reduces EVG susceptibility 3-5-fold but does not reduce RAL or DTG susceptibility (17,10). In combination with Q148H/R/K, it reduces RAL and EVG susceptibility >100-fold and DTG up to 10-fold (60). G140A/C are less well-studied nonpolymorphic variants that appear to have effects similar to G140S (62,63,64).
P142T is a rare nonpolymorphic mutation selected in vitro (65,37) and in vivo by RAL (33,54). It usually occurs in combination with other INSTI-resistance mutations. Its effect on susceptibility has not been studied.
Y143C/R are nonpolymorphic mutations selected by RAL (61,28,66,43,9,61,67,30). Alone, Y143C and Y143R reduce RAL susceptibility by ~5 and 20-fold respectively (28,9,59,61,30) but with T97A or other accessory mutations, they reduce RAL susceptibility >100-fold (45,61,28,9). Y143H is a less common mutation at this position, which is likely a transitional mutation between the wildtype Y and the 2-base pair mutation R. Alone, Y143C/R mutations have minimal effects on EVG susceptibility (17,19,30,18). However, in combination with multiple additional accessory INSTI-resistance mutations including L74M, T97A, G163R, and S230R they reduce EVG susceptibility up to 10-20 fold (32). Y143 mutations do not reduce DTG or BIC susceptibility (30,20,18,17,39).
S147G is a nonpolymorphic mutation selected in patients receiving EVG (13,8). It reduces EVG susceptibility about 5-fold but has minimal if any effect on RAL, or DTG susceptibility (3,1,18,19,10). It has also been selected in patients receiving DTG monotherapy (70) and DTG salvage therapy (33).
Q148H/K/R are nonpolymorphic mutations selected in patients receiving RAL and EVG, (29,61,8,5,45,43,30,71,31,15). Q148H/R has been reported in patients with VF during DTG mono- (72,50,70) or salvage therapy (33).
By itself, Q148H reduces RAL and EVG susceptibility about 5-10 fold and Q148R/K reduce RAL and EVG susceptibility 30-100 fold (45,17,19,21,34,30,59). With G140S/A, Q148H/R/K reduce RAL and EVG susceptibility >100-fold. (45,17,19,21,34,30,59). By themselves, Q148H/K/R alone have minimal effects on DTG and BIC susceptibility (17,73,19,39,12). However, in combination with E138K ± G140SA, Q148 mutations (and particularly Q148K) reduce DTG and BIC susceptibility up to 10-fold (17,32,73,19,39,64,12). The combination of Q148H/R/K + (E138K ± G140S/A) + one or two additional mutations such as N155H or the accessory mutations L74M and T97A, cause even higher levels of reduced DTG and BIC susceptibility (33,46,64,12).
Q148N is a rare INSTI-selected mutation that causes reduces EVG susceptibility ~3-fold. It may represent a Q148H or Q148K revertant (74).
In subtype B viruses G140 is encoded primarily by GGT or GGC whereas for most other subtypes, G140 is encoded primarily by GGG or GGA. Therefore, a single G to A change at the first position of the G140 codon results in a serine in subtype B viruses. G140S is an important compensatory mutation for Q148 mutations and this may explain why Q148 mutations occur significantly more commonly in subtype B viruses compared to non-B viruses from patients with RAL VF (75,76,77).
G149A selected in vivo by DTG in RAL experienced patients (33) and selected in vitro by CAB (78). It appears to have no effect by itself but in combination with mutations at positions 140 and 148, it reduces DTG and CAB susceptibility (78).
V151I is a polymorphic accessory INSTI-selected mutation occurring in 1% to 6% of viruses depending on subtype (27). It is selected in vitro by EVG (22) and in vivo by RAL (28). It appears to have little or no effect on INSTI susceptibility (79). V151L is an extremely rare nonpolymorphic mutation selected in vitro by early investigational INSTIs but it has not been reported in patients receiving INSTIs. It reduces susceptibility to RAL, EVG, and DTG by 10-15, 20-30, and 2-3-fold, respectively (17,10). V151A is an extremely rare nonpolymorphic mutation that has been selected in vitro by an investigational INSTI and it has been associated with ~3-fold reduced EVG susceptibility (25,10).
S153Y/F are extremely rare nonpolymorphic mutations selected in vitro by EVG (3,1), DTG (17,17), and BIC (64). S153F is also selected in vitro by DTG (17). Each mutation reduces EVG, DTG, and BIC susceptibility ~2-3-fold respectively (17,38,10,64,39).
N155H is a nonpolymorphic mutation selected in patients receiving RAL and EVG (29,61,8,5,45,43,30,71,31,15,13,7,8,63). By itself, it reduces RAL and EVG susceptibility ~10 and 30-fold, respectively (17,3,25,61,18,45). N155H has been selected by DTG in INSTI-naïve (80,81,70) and RAL-experienced patients (32). N155S/T are extremely rare nonpolymorphic mutations that reduce RAL and EVG susceptibility less than N155H (17,25,20,17). N155D is a rare nonpolymorphic INSTI-selected mutation that has not been well-characterized (54).
E157Q occurs in ~2-5% of viruses from ARV-naïve patients depending on subtype (27). It is commonly selected during INSTI therapy (27). It has minimal if any effect on RAL, EVG, or DTG susceptibility () (34,9,84,85,86) and alone it does not appear to influence the response to INSTI therapy (86).
G163RK are nonpolymorphic in all subtypes except subtype F (54). They have been shown to be selected in subtype B patients receiving RAL. They appear to be accessory mutations as they usually occur in combination with other INI-resistance mutations particularly N155H (28,16,29). G163E is a polymorphic mutation that does not appear to be selected by INSTIs.
S230R is a nonpolymorphic mutation selected in vitro and in vivo by RAL and in vitro by EVG (21). It has also been selected in patients receiving an incompletely suppressive DTG-containing regimen (80,81). Alone, it reduces DTG susceptibility ~3-fold but does not appear to reduce RAL or EVG susceptibility (87).
R263K is a nonpolymorphic mutation selected in vitro by EVG (3), DTG (4,88) and BIC (39,64). It occurs in a high proportion of patients developing VF on an incompletely suppressive DTG-containing regimen (60,24,89,90,81) and rarely in patients receiving RAL (27). It reduces DTG and BIC susceptibility ~2-fold and reduces EVG susceptibility somewhat more. (4,88,30,3,10,12,64). It usually does not occur in combination with other INSTI-associated DRMs (91).
V54I is a relatively non-polymorphic mutation selected rarely in patients receiving RAL and EVG (54).
S119R is a polymorphic mutation that is weakly selected by INSTIs usually in combination with several major INSTI-associated DRMs (94). Alone, it has little, if any effect, on INSTI susceptibility (10).
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