Major Integrase Inhibitor (INI) Resistance Mutations
The table lists the most common clinically significant INI-resistance mutations. Mutations in bold red are associated with the highest levels of reduced susceptibility or virological response to the indicated INI. Mutations in bold reduce INI susceptibility or virological response. Mutations in plain text contribute to reduced suceptibility in combination with other INI-resistance mutations.
Major Primary Resistance Mutations
T66I is a nonpolymorphic mutation selected in vitro (1,2,3,4,5) and in patients receiving EVG (1,2,3,6,7) T66I reduces EVG susceptibility by ~10-fold (8,4,9,10,11) but does not reduce RAL (8,9,4,10,12) or DTG susceptibility (11,13).
T66K is a nonpolymorphic mutation selected in vitro (4) and in vivo (14) by EVG. It is associated with 40-80-fold reduced EVG susceptibility (8,4,11), 10-20-fold reduced RAL susceptibility (8,4,11) and 2-to-3-fold reduced DTG susceptibility (8,11).
T66A is a nonpolymorphic mutation selected in vivo by EVG (15,14,7) and RAL (16,17,15) usually in combination with other INSTI-resistance mutations. It reduces EVG susceptibility ~5-fold but has minimal if any effect on RAL or DTG susceptibility (8,4,10,11,12).
E92Q is a nonpolymorphic mutation selected in patients receiving RAL (18,15,6,7) and EVG (15,14,19,6). It reduces RAL susceptibility >5-fold (8,9,10,11) and EVG susceptibility >30-fold depending on the assay and genetic context (2,8,9,10,11,20). It is often the primary mutation associated with virological failure on an EVG-containing regimen (6,7). It is selected in vitro by DTG and reduces DTG susceptibility ~1.5-fold (8,11,20).
E92G is a rare nonpolymorphic mutation selected in vitro (4) and in vivo by EVG (7,11). It reduces EVG susceptibility ~10-fold (4,11) but does not reduce RAL or DTG susceptibility (4,11). E92V has been selected in vitro by an investigational INSTI and reported to reduce RAL and EVG susceptibility by 10 and 40-fold, respectively (9). It has not been reported in patients receiving RAL, EVG, or DTG.
E138K/A are nonpolymorphic accessory resistance mutations selected in patients receiving RAL (18,21,22), EVG (14), and DTG (23). They usually occur in combination with Q148 mutations. Alone they do not reduce INSTI susceptibility (1,9), however, they are associated with >100-fold reduced RAL and EVG susceptibility and up to 10-fold reduced DTG susceptibility when they occur with Q148 mutations (24,25,23,26,20). E138T is a less common nonpolymorphic INSTI-selected mutation that appears to have effects similar to E138K/A (22,27).
E138D is a polymorphism that occurs in 1% to 2% of viruses from INSTI-naive patients and does not appear to be selected by INSTIs or to reduce INSTI susceptibility (22).
G140S is a nonpolymorphic mutation that usually occurs in combination with Q148H/R/K in patients receiving RAL (18,28,15,29,30,16) and EVG (14,6). Alone it does not reduce INSTI susceptibility. However, in combination with Q148 mutations, it is associated with a >100-fold reduced RAL and EVG susceptibility and up to 10-fold reduced DTG susceptibility. (24,25,26,20). G140A/C are less well-studied INSTI-selected nonpolymorphic mutations that appear to have effects similar to G140S (31,32,20).
Y143C/R are nonpolymorphic mutations selected by RAL (28,18,33,30,34,28,35,29). Alone, Y143C and Y143R reduce RAL susceptibility by ~5 and 20-fold respectively (18,34,25,28,29) but in combination with T97A or other accessory mutations, they reduce RAL susceptibility >100-fold (24,28,18,34). Y143H is a less common mutation at this position. It is likely a transitional mutation between the wildtype Y and the 2-base pair mutant R.
Alone, Y143C/R mutations have minimal effects on EVG susceptibility (8,11,29,10). However, in combination with accessory INSTI-resistance mutations particularly T97A, they are associated with a 10 to 20-fold reduction in EVG susceptibility (36). Y143 mutations do not reduce DTG susceptibility (29,12,10).
Q148H/K/R are nonpolymorphic mutations selected in patients receiving RAL and EVG (37,28,7,15,24,30,29,38,39,16). Alone Q148H reduces RAL and EVG susceptibility about 5-10 fold and Q148R/K reduce RAL and EVG susceptibility 30-100 fold (24,8,11,3,40,29,25). In combination with G140S/A, Q148H/R/K reduce RAL and EVG susceptibility >100-fold. (24,8,11,3,40,29,25). Alone Q148H/K/R have minimal effects on DTG susceptibility (8,26,11). However, in combination with E138K/A/T or G140S/A, they cause >10-fold reduced DTG susceptibility (8,23,26,11). Q148N is a rare INSTI-selected mutation that causes low-level EVG resistance. It may represent a Q148H or Q148K revertant (41).
In subtype B viruses G140 is encoded primarily by GGT or GGC whereas for nearly all 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 in patients with RAL VF (42,43,44).
N155H is a nonpolymorphic mutation selected in patients receiving RAL and EVG (37,28,7,15,24,30,29,38,39,16,14,6,7,32). Alone, it reduces RAL susceptibility >10-fold and EVG susceptibility >30-fold (8,4,9,28,10,24,20).
N155H is selected by DTG in RAL-experienced patients (23). There have also been several reports of VF on DTG in patients who had N155H at baseline and developed additional INSTI-resistance mutations (45,46).
N155ST are extremely rare nonpolymorphic INSTI-resistance mutations that reduce RAL and EVG susceptibility somewhat less than that of N155H (8,9,12,8). N155D is a nonpolymorphic RAL-selected mutation that has not been studied.
Major Accessory Resistance Mutations
H51Y is a rare nonpolymorphic accessory mutation selected in vitro by EVG (2,1,4) and DTG (47) and in patients receiving RAL (15,48) and EVG (6). It reduces EVG susceptibility by 2-3-fold (2,4,47,34) but alone does not appear to reduce RAL or DTG susceptibility (4,47). In combination with R263K, it has been reported to reduce DTG susceptibility 7-fold (47).
L74M/I are highly polymorphic accessory INSTI-resistance mutation selected in patients receiving RAL (18,37,29,39) and EVG (15). In ARV-naive patients, L74M occurs in 0.5% to 10% of patients and L74I occurs in 3% to 20% of patients, depending on subtype. L74M/I are also selected by DTG in patients previously treated with RAL who have primary DTG-associated mutations (23,49,27). Alone, these mutations have minimal if any effect on INSTI susceptibility (9,40). However, in combination with other primary resistance mutations they appear to contribute to reduced susceptibility to each of the INSITs (5,9,48,49,27).
T97A is a polymorphic accessory INSTI-resistance mutation that occurs in 1% to 4% of viruses from untreated persons depending on subtype (50). It is selected by RAL (51,30,7) and EVG (7). In site-directed mutagenesis studies, it has minimal if any effect on INSTI susceptibility. However, in a recent analysis of clinical isolates from the U.S., it was associated with 5 to 10-fold reduced susceptibility to RAL and EVG, possibly because many of these isolates may have been from INSTI-treated patients whose viruses had other accessory resistance mutations or minority variant primary resistance mutations (20). T97A synergistically reduces RAL and EVG susceptibility in combination with Y143CR (36,24,20). T97A is selected by DTG in RAL-experienced patients with primary DTG-associated mutations (23,49,27).
V151I occurs in 5% of subtype B viruses from ARV-naive patients but is nonpolymorphic in most other subtypes. It is selected in patients receiving RAL (18) and in vitro by EVG (5). It appears to have little or no effect on INSTI susceptibility (53). V151L is an extremely rare nonpolymorphic mutation selected in vitro by early investigational INSTIs but not in patients receiving currently approved INSTIs. It reduces susceptibility to RAL, EVG, and DTG by ~10, ~40, and 3.6-fold, respectively (8). V151A is also an extremely rare nonpolymorphic mutation selected in vitro by an investigational INSTI. It reduces susceptibility to RAL by 4-fold and to EVG by 12-fold (9).
E157Q is a polymorphic mutation selected in patients receiving RAL (51) and in vitro by EVG (2). It has also been reported in a patient with virological failure on a DTG-containing regimen (55). It appears to reduce RAL and EVG susceptibility by 2- to 3-fold (40,34) and to increase DTG susceptibility (56).
G163R/K are nonpolymorphic in all subtypes except subtype F (50,22). G163R/K are selected in subtype B viruses from RAL-experienced patients. They are accessory mutations that usually occur in combination with other INSTI-resistance mutations particularly N155H (18,17,37).
Rare Primary INSTI-Resistance Mutations
Its reported effects on in vitro susceptibility have been highly variable. In combination with L74M the virus was found to be associated with ~10-fold reduced RAL susceptibility and lower levels of reduced EVG susceptibility (5,57,34). In site directed mutants, it has been found in one study to have no effect on INSTI susceptibility (58). However, in other studies, it has been reported to cause 5 to 20-fold reduced susceptibility to each of the INSTIs (60,59,61,62).
G118R is also commonly observed in sequences with G-to-A hypermutation and in this setting it should be considered a result of lethal APOBEC-mediated virus editing and not an indicator of drug resistance (22).
F121Y is a nonpolymorphic mutation that is selected in vitro by RAL (63) and EVG (2) and rarely in vivo by RAL (64) It reduces susceptibility to RAL and EVG by about 10 and 30-fold, respectively (2,5,20). Most studies suggest that it does not reduce DTG susceptibility (65,61,62,20).
R263K is a rare nonpolymorphic mutation selected in vitro by EVG (4) and DTG (47,67). R263K is extremely rare in patients receiving RAL occurring in 6 of 893 patients in HIVDB and in 0/502 in another study (42). However, R263K did develop in two clinical trial patients receiving DTG plus an optimized background regimen (68). R263K rarely occurs with other DRMs and also appears to have reduced replication (69). It reduces DTG and EVG susceptibility ~2-fold and 6-fold, respectively but has minimal if any effect on RAL susceptibility (47,67,29,4).
Miscellaneous INSTI-Associated Mutations
V54I is a minimally polymorphic mutation (50) selected in vitro (40) and rarely in vivo by RAL (22). L68V is a polymorphic accessory mutation selected in vivo by EVG (15,1,6). In combination with E92Q, it contributes reduced EVG susceptibility (1). H114Y is an extremely rare nonpolymorphic mutation (50) selected in vitro by EVG (3). A128T is a nonpolymorphic mutation selected in vitro by EVG, but which does not appear to reduce INSTI susceptibility (3,53).
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