Key Principles and Recommended Regimens for First-line Antiretroviral Therapy

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 or lamivudine plus tenofovir DF or tenofovir AF, depending on the guideline) is a recommended first-line regimen in the DHHS guidelines^[1] and the European AIDS Clinical Society (EACS) guidelines.^[8] 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.^[13] 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.^[8]

Elvitegravir was initially approved for first-line therapy as part of the coformulated regimen cobicistat/elvitegravir/emtricitabine/tenofovir DF,^[14] and subsequently as part of the coformulated regimen cobicistat/elvitegravir/emtricitabine/tenofovir AF.^[15] 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.^[1,2,8] 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/min^[14] and cobicistat/elvitegravir/emtricitabine/tenofovir AF should be used only in patients with estimated glomerular filtration rates ≥ 30 mL/min.^[15] 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.^[8]

Dolutegravir, the third INSTI approved by the FDA, is administered once daily in treatment-naive patients and does not require a boosting agent. According to the DHHS^[1] and EACS^[8] guidelines, dolutegravir is a recommended agent for use in first-line regimens in combination with abacavir/lamivudine (with which there is a coformulated complete regimen) or with emtricitabine or lamivudine plus tenofovir DF or tenofovir AF. According to IAS-USA guidelines, dolutegravir in combination with abacavir/lamivudine or emtricitabine/tenofovir AF is recommended.^[2]

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]

In an updated analysis reported at the 2019 IAS Conference on HIV Science and published in the New England Journal of Medicine showed that as of March 2019, there has been 1 additional NTD case among 1257 additional births with dolutegravir exposure at conception, providing an updated NTD prevalence rate of 0.30% (5/1683; 95% CI: 0.13% to 0.69%) (Capsule Summary).^[4,5]  Although this rate is lower than previously indicated, this prevalence remains higher than the 0.10% prevalence of NTDs observed in women receiving non-dolutegravir ART during conception (15/14792; 95% CI: 0.06% to 0.17%).^[4,5] Based on these updated findings, the WHO reconfirmed the use of dolutegravir-based ART as preferred first-line and second-line therapy for all individuals living with HIV.^[7] The updated WHO guidelines state that for women of childbearing potential initiating ART, the benefits of dolutegravir—including better viral suppression, fewer maternal deaths, and fewer sexual and mother-to-child transmissions—likely outweigh the potential small increase in NTD risk associated with dolutegravir. The guidelines stress a woman-centered and rights-based approached, in which women are counseled on the benefits and risks to make an informed decision regarding dolutegravir use. The DHHS also revised their recommendations regarding dolutegravir-based ART to include the following for persons of childbearing potential based on the latest findings^[1]:

• A pregnancy test should be performed before initiating dolutegravir-based ART
• Providers should discuss the benefits and risks of dolutegravir around the time of conception, including the risk of NTDs
• Dolutegravir is recommended as an alternative rather than a preferred option for women trying to conceive or who are sexually active and not using effective contraception
• For women not trying to conceive and using effective contraception: dolutegravir-based ART is recommended

The EACS guidelines state that dolutegravir is not recommended in women who wish to conceive.^[8] The IAS-USA guidelines have yet to be updated to reflect the latest Tsepamo data. The guidelines currently recommend that dolutegravir should be avoided in individuals of childbearing age who wish to become pregnant, are trying to conceive, or who are sexually active and not using effective contraception.^[2]

It is important to note that in the Tsepamo study, there has been no evidence of increased NTDs among infants born to mothers who initiated dolutegravir-based ART during pregnancy.^[4,5] Therefore, dolutegravir is a recommended regimen in pregnancy by the DHHS, regardless of trimester, and is listed as a preferred regimen after the first 8 weeks of pregnancy in the EACS guidelines.^[6,8] The IAS-USA guidelines state that a negative pregnancy test should be documented prior to initiating dolutegravir in women of childbearing age.^[2]

DHHS guidelines also stress that it is not yet known whether other INSTIs taken at the time of conception also pose a risk of NTDs, and there are insufficient or limited data regarding the risks of bictegravir and raltegravir at the time of conception.^[1] Therefore, patients of childbearing potential should be made aware of the lack of information on these drugs at the time of conception during the informed decision-making process.^[1]

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.^[16] It is a recommended first-line regimen in the DHHS guidelines,^[1] the IAS-USA guidelines,^[2] and the EACS guidelines.^[8]

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.^[17,18] Dolutegravir was found to be superior to efavirenz at Week 48 in the SINGLE trial (primarily due to fewer discontinuations due to adverse events)^[19]; dolutegravir was also found to be noninferior to raltegravir in the SPRING-2 trial.^[20]

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.^[20] 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.^[21] 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.^[22] 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.^[23] In this trial, 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).^[24] In this trial, 629 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.^[1,8]

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.^[25] The other coformulated elvitegravir regimen contains tenofovir AF and is not recommended in patients with creatinine clearance < 30 mL/min.
  • Dolutegravir has been shown to be effective with NRTI backbones abacavir/lamivudine, emtricitabine/tenofovir DF, and emtricitabine/tenofovir AF. 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.^[21]
  • 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 ART^[26]
• 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 reported^[27]
  • When compared with efavirenz, more patients in the elvitegravir arm experienced nausea^[18]; 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
  • Observational studies have documented discontinuation of dolutegravir among certain populations of persons with HIV due to central nervous system adverse events^[28]
    • A retrospective analysis of clinical trials of dolutegravir found most psychiatric events were mild to moderate and discontinuation rate was low (Capsule Summary)^[29]
  • 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^[23,24]
  • Some studies have shown greater weight gain with INSTI-based regimens vs NNRTI-based or boosted PI–based regimens.^[30-33] Weight gain at Week 96 was similar with bictegravir- and dolutegravir-based regimens in a pooled analysis of 8 randomized, controlled trials.^[39]
• Baseline HIV-1 RNA and CD4+ cell count strata:
  • Raltegravir, elvitegravir, dolutegravir, bictegravir have been shown to be effective over a range of viral load and CD4+ cell count strata^{[17,18, 23,24,34]}; unlike efavirenz and atazanavir plus ritonavir, which appeared less effective when combined with abacavir/lamivudine in patients with high baseline viral load,^[35] raltegravir and dolutegravir^[19,36-38] have been shown to be similarly effective when combined with either emtricitabine/tenofovir DF or abacavir/lamivudine in patients with high viral load.^[20]
• 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. The FDA-approved raltegravir label notes an interaction with antacids containing polyvalent cations.^[27] 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 dofetilide plasma concentrations and associated serious and/or life-threatening events 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.^[40] 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.^[41] 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 elvitegravir.^[42]
    • 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.^{[19,20,36,38]}
    • 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.^[43,44]
  • In phase III clinical trials of bictegravir, no treatment-emergent resistance to any study drug was observed through Week 48.^[23,24]
• Pregnancy potential in women of childbearing age:
  • Interim results from the Tsepamo birth surveillance study in Botswana reported an increased risk of NTDs 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 receiving non-dolutegravir–based ART).^[3] An updated analysis reported at the 2019 IAS Conference on HIV Science and published in the New England Journal of Medicine showed that as of March 2019, there has been 1 additional NTD case among 1257 additional births with dolutegravir exposure at conception, providing an updated NTD prevalence rate of 0.30% (5/1683; 95% CI: 0.13% to 0.69%) (Capsule Summary).^[4,5]  Although this rate is lower than previously indicated, this prevalence remains higher than the 0.10% prevalence of NTDs observed in women receiving non-dolutegravir–based ART during conception (15/14792; 95% CI: 0.06% to 0.17%).^[4,5] Based on these updated findings, the WHO reconfirmed the use of dolutegravir-based ART as preferred first-line and second-line therapy for all individuals living with HIV.^[7] The updated WHO guidelines state that for women of childbearing potential initiating ART, the benefits of dolutegravir—including better viral suppression, fewer maternal deaths, and fewer sexual and mother-to-child transmissions—likely outweigh the potential small increase in NTD risk associated with dolutegravir. The guidelines stress a woman-centered and rights-based approached, in which women are counseled on the benefits and risks to make an informed decision regarding dolutegravir use. The DHHS also revised their recommendations regarding dolutegravir-based ART to include the following for persons of childbearing potential based on the latest findings^[1]:
    • A pregnancy test should be performed before initiating dolutegravir-based ART
    • Providers should discuss the benefits and risks of dolutegravir around the time of conception, including the risk of NTDs
    • Dolutegravir is recommended as an alternative rather than a preferred option for women trying to conceive or who are sexually active and not using effective contraception
    • For women not trying to conceive and using effective contraception: dolutegravir-based ART is recommended
  • The EACS guidelines state that dolutegravir is not recommended in women who wish to conceive.^[8] The IAS-USA guidelines have yet to be updated to reflect the latest Tsepamo data. The guidelines currently recommend that dolutegravir should be avoided in individuals of childbearing age who wish to become pregnant, are trying to conceive, or who are sexually active and not using effective contraception.^[2]
  • It is important to note that in the Tsepamo study, there has been no evidence of increased NTDs among infants born to mothers who initiated dolutegravir-based ART during pregnancy.^{[4; 5]} Therefore, dolutegravir is a recommended regimen in pregnancy by the DHHS, regardless of trimester, and is listed as a preferred regimen after the first 8 weeks of pregnancy in the EACS guidelines.^[6,8] The IAS-USA guidelines state that a negative pregnancy test should be documented prior to initiating dolutegravir in women of childbearing age.^[2]
  • DHHS guidelines also stress that it is not yet known whether other INSTIs taken at the time of conception also pose a risk of NTDs, and there are insufficient or limited data regarding the risks of bictegravir and raltegravir at the time of conception.^[1] Therefore, patients of childbearing potential should be made aware of the lack of information on these drugs at the time of conception during the informed decision-making process.^[1]