Available Integrase Inhibitors
There are currently 4 INSTIs that have been approved by the FDA for treatment of ARV-naive patients. They are listed in order of development.

Raltegravir in combination with 2 NRTIs (emtricitabine/tenofovir DF or emtricitabine/tenofovir AF, depending on the guideline) is one of the recommended first-line regimens in the DHHS guidelines¹ and the EACS guidelines.⁴ The FDA-approved dose of raltegravir is 400 mg twice daily, with or without food, or 2 tablets of the newer 600-mg formulation (1200 mg total dose) once daily, with or without food. Once-daily raltegravir 1200-mg dosing using the recently approved 600-mg formulation was shown to have noninferior efficacy at both Weeks 48 and 96 as initial therapy vs twice-daily raltegravir 400 mg in the phase III ONCEMRK trial.¹⁰ All other comparative raltegravir trials discussed in this module used 400-mg twice daily dosing. Raltegravir does not require a boosting agent when used once daily or twice daily. There are no coformulated regimens containing raltegravir.

Raltegravir has also been investigated as part of an NRTI-sparing regimen. In the DHHS and IAS-USA guidelines, raltegravir is included as part of a nontraditional 2-drug regimen with darunavir plus ritonavir (both twice daily) for persons with baseline HIV-1 RNA < 100,000 copies/mL and CD4+ cell count > 200 cells/mm³ who require first-line therapy and cannot receive tenofovir DF, tenofovir AF, or abacavir.^1,2 In the EACS guidelines, raltegravir is included as part of a 2-drug regimen with darunavir plus ritonavir or cobicistat/darunavir only if CD4+ cell count is > 200 cells/mm³ and HIV-1 RNA < 100,000 copies/mL.⁴

Elvitegravir was initially approved for first-line therapy as part of the coformulated regimen cobicistat/elvitegravir/emtricitabine/tenofovir DF,¹¹ and subsequently as part of the coformulated regimen cobicistat/elvitegravir/emtricitabine/tenofovir AF.¹² Cobicistat/elvitegravir/emtricitabine/tenofovir DF and cobicistat/elvitegravir/emtricitabine/tenofovir AF are considered alternative regimens in all current treatment guidelines due to the increased likelihood of drug–drug interactions with cobicistat and the fact that elvitegravir has a lower barrier to resistance than dolutegravir or bictegravir.^1,2,4 These coformulated regimens are both administered once daily but differ in renal function thresholds for use: cobicistat/elvitegravir/emtricitabine/tenofovir DF should be reserved for those with estimated glomerular filtration rates ≥ 70 mL/min¹¹ and cobicistat/elvitegravir/emtricitabine/tenofovir AF should be used only in patients with estimated glomerular filtration rates ≥ 30 mL/min.¹² The EACS guidelines further recommend that cobicistat/elvitegravir/emtricitabine/tenofovir DF not be given to patients with estimated glomerular filtration rates < 90 mL/min unless this is the preferred treatment.⁴ It should be noted that many physicians (including this author) prefer the tenofovir AF–containing regimen due to improved renal and bone safety when compared with the tenofovir DF–containing regimen. In the opinion of this author, clinicians should use the tenofovir AF–containing formulation in all settings where the single-tablet elvitegravir-based regimens are selected.

Dolutegravir, the third INSTI approved by the FDA, is administered once daily in treatment-naive patients and does not require a boosting agent. It is a recommended agent for use in first-line regimens in combination with abacavir/lamivudine (with which there is a coformulated complete regimen), emtricitabine/tenofovir DF, or emtricitabine/tenofovir AF, according to the DHHS¹ and EACS⁴ guidelines and in combination with abacavir/lamivudine or emtricitabine/tenofovir AF according to IAS-USA guidelines.² In April 2019, the coformulated 2-drug regimen dolutegravir/lamivudine became the first 2-drug combination to be approved by the FDA as a complete regimen for the treatment of HIV infection in adults who are ARV naive and have no known substitutions associated with resistance to the individual components.¹³ This simplified regimen is included as part of “First-line Regimens to Be Used in Certain Clinical Situations,” specifically when abacavir, tenofovir DF, and tenofovir AF cannot be used, in the DHHS guidelines and is included among the alternative regimen recommendations in the EACS guidelines.⁴

However, it is important to note that interim results from the Tsepamo birth surveillance study in Botswana reported an increased risk of NTD in infants whose mothers became pregnant while receiving dolutegravir-based ART (0.94% of 426 births in women receiving dolutegravir-based ART vs 0.12% of 11,300 births in women in women receiving non-dolutegravir–based ART),³ prompting the DHHS and the IAS-USA to provide interim recommendations for dolutegravir use in women of childbearing age.^1,2 It is currently recommended by the DHHS, IAS-USA, and EACS that dolutegravir should not be initiated during the first trimester of pregnancy.^1,2,4 In addition, a documented negative pregnancy test is recommended by the DHHS and IAS-USA panels before starting dolutegravir in women of childbearing potential and use of dolutegravir in women should be accompanied by counseling about the potential risks of NTDs if dolutegravir is taken during/near the time of conception and during the first 12 weeks of pregnancy.^1,2

The coformulated regimen bictegravir/emtricitabine/tenofovir AF was approved by the FDA in 2018 as a complete regimen for the treatment of HIV infection in adults who are ARV naive or as a switch regimen in those who are virologically suppressed (HIV-1 RNA < 50 copies/mL) on a stable ARV regimen for ≥ 3 months with no history of treatment failure and no known substitutions associated with resistance to the individual components.¹⁴ It is a recommended first-line regimen in the DHHS guidelines,¹ the IAS-USA guidelines,² and the EACS guidelines.⁴

Clinical Trials Comparing Integrase Inhibitors
There are no large-scale head-to-head trials comparing raltegravir and elvitegravir or comparing elvitegravir and dolutegravir in treatment-naive patients. Both raltegravir and elvitegravir were found to be noninferior to efavirenz at the primary endpoints of their respective trials.^15,16 Dolutegravir was found to be superior to efavirenz at Week 48 in the SINGLE trial (primarily due to fewer discontinuations due to adverse events)¹⁷; dolutegravir was also found to be noninferior to raltegravir in the SPRING-2 trial.¹⁸

The phase III SPRING-2 trial compared once-daily dolutegravir with twice-daily raltegravir, each with 2 NRTIs (investigator-selected abacavir/lamivudine or emtricitabine/tenofovir DF) in 822 treatment-naive patients.¹⁸ At the Week 48 primary efficacy analysis, dolutegravir was noninferior to raltegravir with 88% vs 85% of patients, respectively, with HIV-1 RNA < 50 copies/mL based on the FDA snapshot analysis. Both arms were associated with a CD4+ cell count increase of 230 cells/mm³. There were no significant differences in virologic response between the arms at Week 48 according to baseline HIV-1 RNA level or NRTI backbone. The rate of protocol-defined virologic failure was lower with dolutegravir vs raltegravir (5% vs 7%, respectively). No integrase or NRTI resistance was identified among patients in the dolutegravir arm, but integrase and NRTI resistance were identified in 1 and 4 patients, respectively, among those in the raltegravir arm.

No clinically significant changes were noted in the fasting lipid profile in either group. Dolutegravir was associated with a small increase in creatinine resulting from the anticipated inhibition of creatinine secretion of dolutegravir without affecting actual glomerular filtration rate.¹⁹ These Increases in serum creatinine were evident in both groups by Week 2, but remained stable through Week 48. The mean change in estimated creatinine clearance at Week 48 was -16.5 mL/min in the dolutegravir group and -5.4 mL/min in the raltegravir group. No patients had grade 3 or 4 increases in creatinine, and no patients in either group discontinued because of renal events.

Noninferiority was maintained at Week 96 with 81% vs 76% of patients with HIV-1 RNA < 50 copies/mL.²⁰ Median CD4+ cell count increases were similar between arms through Week 96: +276 cells/mm³ with dolutegravir and +264 cells/mm³ with raltegravir. At Week 96, the rate of withdrawal from the trial was very low in both arms: 10 patients (2%) of each group. No further increase in serum creatinine was observed between Weeks 48 and 96.

The FDA approval of bictegravir/emtricitabine/tenofovir AF was as a result of the phase III GS-1490 trial in which coformulated bictegravir/emtricitabine/tenofovir AF was found to be noninferior to dolutegravir plus emtricitabine/tenofovir AF at the primary endpoint Week 48 analysis.²¹ In this trial, HIV-infected treatment-naive adults with HIV-1 RNA ≥ 500 copies/mL and estimated glomerular filtration rate ≥ 30 mL/min were randomly assigned to receive fixed-dose combination bictegravir/emtricitabine/tenofovir AF (n = 320) or dolutegravir plus emtricitabine/tenofovir AF (n = 325) once daily for 144 weeks. The primary endpoint was the proportion of participants with plasma HIV-1 RNA < 50 copies/mL at Week 48 by the FDA snapshot algorithm, with a prespecified noninferiority margin of -12%. At Week 48, 286 (89%) of those in the bictegravir arm and 302 (93%) of those in the dolutegravir arm achieved HIV-1 RNA < 50 copies/mL (difference -3.5%; 95% CI: -7.9% to 1.0%; P = .12), demonstrating noninferiority of the bictegravir regimen to the dolutegravir regimen. No treatment-emergent resistance to any study drug was observed. Incidence and severity of adverse events were similar between groups, and only 5 patients (2%) in the bictegravir group and 1 patient (< 1%) in the dolutegravir group discontinued treatment due to adverse events. Study drug–related adverse events were significantly less common in the bictegravir group than in the dolutegravir group (57 18% vs 83 26%, respectively; P = .022).

The phase III GS-1489 trial compared the 2 coformulated regimens bictegravir/emtricitabine/tenofovir AF and abacavir/dolutegravir/lamivudine for initial ART (Capsule Summary).²² In this trial, 629 HIV-infected, HLA-B*5701–negative, treatment-naive adults with HIV-1 RNA ≥ 500 copies/mL and estimated glomerular filtration rate ≥ 50 mL/min were randomly assigned to receive the oral fixed-dose combination bictegravir/emtricitabine/tenofovir AF (n = 314) or oral fixed-dose abacavir/dolutegravir/lamivudine (n = 315) once daily for 144 weeks. (In this study, patients with chronic hepatitis B virus coinfection were excluded; they were eligible for GS-1490.) At Week 48, 92.4% of patients in the bictegravir arm vs 93.0% of those in the dolutegravir arm achieved HIV-1 RNA < 50 copies/mL (difference: 0.6%; 95% CI: -4.8% to 3.6%), demonstrating noninferiority of the coformulated bictegravir regimen to the coformulated dolutegravir regimen. Similar to GS-1490, few patients discontinued treatment for adverse events related to the study drugs: 0 patients receiving bictegravir/emtricitabine/tenofovir AF vs 4 (1.3%) patients receiving abacavir/dolutegravir/lamivudine. Nausea (all grades) was more common with use of abacavir/dolutegravir/lamivudine (P < .001). No treatment-emergent resistance to any study drug was observed. Treatment assignment had no significant impact on change in renal markers, bone mineral density at spine or hip, or lipid levels at Week 48.

Bictegravir/emtricitabine/tenofovir AF is not recommended for patients with estimated creatinine clearance < 30 mL/min or in patients with severe hepatic impairment.

Choosing Among Integrase Inhibitors
When choosing among the 4 INSTIs, the following considerations might be taken into account:

• Dosing:
  • Raltegravir can be given as 400 mg twice daily or 1200 mg (using 2 tablets of a newer 600-mg formulation) once daily
  • The elvitegravir regimen is given once daily. Elvitegravir must be given with a pharmacologic booster; that function in first-line regimens is supplied by cobicistat, a drug with no anti-HIV activity; consequently, there are more drug–drug interactions with this regimen (see below)
  • Dolutegravir is given once daily in treatment-naive patients with no pharmacologic booster
  • Bictegravir is given once daily without boosting
• Renal function:
  • Although recommended as part of a regimen with emtricitabine/tenofovir DF, raltegravir can be prescribed with other NRTIs in patients with reduced renal function. Raltegravir itself has minimal effect on renal function. The SINGLE trial also showed that raltegravir is effective with an NRTI backbone of abacavir/lamivudine, an option for patients with impaired renal function (although this combination is recommended only for those who are negative for HLA-B*5701 and have a baseline HIV-1 RNA < 100,000 copies/mL)¹
  • One of the coformulated elvitegravir regimens contains tenofovir DF and is not recommended in patients with creatinine clearance < 70 mL/min (ie, the dose of tenofovir DF cannot be adjusted with the coformulated elvitegravir regimen). Cobicistat may also modestly increase creatinine levels by inhibiting tubular creatinine secretion; this happens early in treatment and persists throughout therapy with this agent.²³ The other coformulated elvitegravir regimen contains tenofovir AF and is not recommended in patients with creatinine clearance < 30 mL/min. Now that cobicistat is available as a single agent, it also can be combined with a modified tenofovir DF dose if needed to reduce the risk of renal changes
    • Given the improved renal and bone safety of tenofovir AF, this author recommends the tenofovir AF coformulation over the tenofovir DF coformulation whenever elvitegravir-containing first-line regimens are chosen
  • Dolutegravir has been shown to be effective with an NRTI backbone of either abacavir/lamivudine, emtricitabine/tenofovir DF, or lamivudine alone in a 2-drug NRTI-limiting first-line regimen (FDA approved for initial ART in 2019). Like cobicistat, dolutegravir has a documented effect on creatinine excretion that modestly increases creatinine levels but does not reflect an adverse impact on renal function.¹⁹
  • Bictegravir/emtricitabine/tenofovir AF is not recommended for patients with estimated creatinine clearance < 30 mL/min. There are no data on the use of bictegravir with other NRTI backbones than emtricitabine/tenofovir AF.
• Lipids: Raltegravir, elvitegravir, and dolutegravir have been found to have less effect on lipids than efavirenz. In the phase III GS-1878 study, which evaluated the efficacy and safety of switching virologically suppressed adult patients with HIV infection from a multitablet regimen containing a boosted PI to fixed-dose bictegravir/emtricitabine/tenofovir AF, lipid parameters significantly improved with the switch to bictegravir/emtricitabine/tenofovir AF vs continued baseline PI-based ART²⁴
• Adverse events (other than renal): All 4 INSTIs are well tolerated:
  • The most common adverse events seen in clinical trials of raltegravir were insomnia and headache; isolated cases of myopathy and rhabdomyolysis have been reported²⁵
  • When compared with efavirenz, more patients in the elvitegravir arm experienced nausea¹⁶; other adverse events were seen in similarly low numbers with the exception of neuropsychiatric events, which were greater in the efavirenz group
  • Elvitegravir is also associated with documented increase in serum creatinine
  • Adverse events seen in clinical trials of dolutegravir include headache and the documented increase in serum creatinine
  • Raltegravir, elvitegravir, and dolutegravir may be associated with weight gain
  • Observational studies have documented discontinuation of dolutegravir among certain populations of persons with HIV due to central nervous system (CNS) adverse events²⁶
    • A retrospective analysis of clinical trials of dolutegravir found most psychiatric events were mild to moderate and discontinuation rate was low (Capsule Summary)²⁷ 
  • In phase III clinical trials, incidence and severity of adverse events were similar between patients receiving the bictegravir regimen and those receiving dolutegravir-based regimens^21,22
• Baseline HIV-1 RNA and CD4+ cell count strata:
  • Raltegravir, elvitegravir, and dolutegravir have been shown to be effective over a range of viral load and CD4+ cell count strata^15,16,28; unlike efavirenz and atazanavir plus ritonavir, which appeared less effective when combined with abacavir/lamivudine in patients with high baseline viral load,²⁹ raltegravir and dolutegravir^17,30-32 have been shown to be similarly effective when combined with either emtricitabine/tenofovir DF or abacavir/lamivudine in patients with high viral load¹⁸
    • It should be noted, however, that current DHHS guidelines recommend raltegravir plus abacavir/lamivudine as a first-line regimen only in certain clinical situations and only for patients with baseline HIV-1 RNA < 100,000 copies/mL¹ as SPRING-2 has been the only trial that has studied this combination as first-line therapy in patients with HIV-1 RNA > 100,000 copies/mL (n = 115)
• Drug–drug interactions:
  • Raltegravir is not an inhibitor or inducer of the CYP system. Similarly, raltegravir is not an inhibitor of UDP-glucuronosyltransferases or P-glycoprotein–mediated transport. Therefore, raltegravir does not have significant interactions with drugs metabolized by these systems, including hormonal contraceptives, methadone, or other ARV agents. An update to the FDA-approved raltegravir label notes an interaction with antacids containing polyvalent cations.²⁵ There is also an interaction with rifampin seen with all INSTIs
  • Coadministration of cobicistat/elvitegravir/emtricitabine/tenofovir DF or cobicistat/elvitegravir/emtricitabine/tenofovir AF is contraindicated with drugs that are highly dependent on CYP3A for clearance, including the antituberculosis drug rifampin, the statins lovastatin and simvastatin, and erectile dysfunction agents
  • Dolutegravir has few drug–drug interactions. Like raltegravir, dolutegravir should not be dosed in combination with laxatives or antacids containing polyvalent cations; dolutegravir also has an interaction with metformin increasing levels of metformin. There is also an interaction with rifampin seen with all INSTIs and with the NNRTIs efavirenz and etravirine and with the PIs fosamprenavir and tipranavir
  • Bictegravir is contraindicated with dofetilide due to the potential for increased and rifampin due to decreased bictegravir plasma concentrations, which may result in the loss of therapeutic effect and development of resistance to this drug and other components of the regimen
• Virologic failure:
  • Upon virologic failure of either raltegravir or elvitegravir/cobicistat, resistance occurs in one third to one half of patients. Resistance to the INSTIs is associated with mutations in the integrase gene that take 1 of at least 3 distinct genetic pathways. With raltegravir, these are defined by the presence of 2 or more mutations including a signature mutation at Q148H/K/R, N155H, or Y143R/H/C plus 1 or more addi­tional minor mutations in the Q148H/K/R pathway. Failure of elvitegravir may include mutations T66I/A/K and E92Q/G.³³ Patients who remain on INSTI-based therapy while experiencing virologic failure typically experience ongoing evolution of resistance mutations, with more mutations and greater loss of susceptibility accumulating with longer time on the failing regimen.³⁴ There appears to be extensive cross-resistance between elvitegravir and raltegravir, such that patients who develop resistance to raltegravir are not anticipated to benefit from elvitegravir³⁵  
    • Failure of either of these drugs is also often associated with development of resistance to 1 or both NRTIs in the background regimen as well
  • On the other hand, development of resistance mutations either to INSTIs or NRTIs at virologic failure of first-line dolutegravir-based combination regimens has not yet been documented in trials of dolutegravir in treatment-naive patients^17,18,30,32
    • Two reports of potential emergence of resistance in individuals treated with dolutegravir in first-line therapy have recently appeared; in one case, baseline integrase was not sequenced^36,37
  • In phase III clinical trials of bictegravir, no treatment-emergent resistance to any study drug was observed through Week 48^21,22
• Pregnancy potential in women of childbearing age:
  • Initial results from the Tsepamo birth surveillance study in Botswana reported an increased risk of NTD in infants whose mothers became pregnant while receiving dolutegravir-based ART (0.94% of 426 births in women receiving dolutegravir-based ART vs 0.12% of 11,300 births in women in women receiving non-dolutegravir–based ART),³ prompting the DHHS and the IAS-USA to provide interim recommendations for dolutegravir use in women of childbearing age.^1,2 It is currently recommended by the DHHS, IAS-USA, and EACS not to start dolutegravir during the first trimester of pregnancy,^1,2,4 and use of dolutegravir in women should be accompanied by counseling about the potential risks of NTDs if dolutegravir is taken during/near the time of conception and during the first 12 weeks of pregnancy.^1,2 It is also recommended by the DHHS and IAS-USA panels to have a documented negative pregnancy test result before initiating dolutegravir in women of childbearing potential. The interim guidance notes that it is unclear if this potential effect could be specific to dolutegravir or if it could be a potential class effect of INSTIs