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First-line ART
Key Principles and Recommended Regimens for First-line Antiretroviral Therapy

Released: May 22, 2019

Expiration: May 20, 2020

Joseph J. Eron
Joseph J. Eron, Jr., MD
Daniel R. Kuritzkes
Daniel R. Kuritzkes, 医学博士
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When discussing comparisons of INSTIs with NNRTIs, the comparison is with efavirenz, the standard-of-care NNRTI at the time when INSTIs were in development. In all comparisons with INSTIs, one of the primary considerations affecting the outcomes of the clinical trials was the difference in drug-related adverse events between the INSTI and efavirenz; this was particularly true in the trials comparing raltegravir and dolutegravir with efavirenz. In addition, none of the patients receiving dolutegravir developed resistance to INSTIs or NRTIs at virologic failure, an important feature of this drug that is also shared with bictegravir.

At the current time, there are no large clinical trials comparing rilpivirine with any of the INSTIs.

Raltegravir vs Efavirenz in Treatment-Naive Patients
Use of the integrase strand transfer inhibitor raltegravir as part of an initial regimen is supported by the phase III STARTMRK study, which compared the safety and efficacy of raltegravir with those of efavirenz, each combined with emtricitabine/tenofovir DF, in 563 treatment-naive patients.15 At Week 48, the efficacy of raltegravir was shown to be noninferior to that of efavirenz, with 86% and 82% of patients, respectively, achieving HIV-1 RNA < 50 copies/mL by intent-to-treat, noncompleter-equals-failure analysis. The noninferiority of raltegravir compared with efavirenz continued blinded through the Year 5 final analysis with 71% and 61% of patients, respectively, achieving HIV-1 RNA < 50 copies/mL using an intent-to-treat, noncompleter-equals-failure analysis specified by the trial protocol (difference: 9.5; 95% CI: 1.7-17.3; P < .001 for noninferiority); in fact, from Week 192, raltegravir was superior in efficacy to efavirenz.75,76 Over the entire study, fewer patients experienced neuropsychiatric and other drug-related adverse events in the raltegravir group than in the efavirenz group. HIV-1 RNA declined more rapidly in the raltegravir arm, an effect also observed in other studies of integrase inhibitors in first-line therapy, although the clinical significance of this finding (if any) is unclear. Mean changes in CD4+ cell count after 5 years were 374 and 312 cells/mm³ in the raltegravir vs efavirenz groups, respectively, significantly favoring raltegravir.

Despite these favorable issues in efficacy and tolerability, there are some drawbacks to consider regarding raltegravir as first-line therapy. The primary consideration is the rapid emergence of resistance at virologic failure.34 Until recently, there has been limited information about use of raltegravir with NRTI combinations other than emtricitabine/tenofovir DF; the phase III SPRING-2 trial has documented the efficacy of raltegravir combined with abacavir/lamivudine.18,20

Elvitegravir/Cobicistat/Emtricitabine/Tenofovir DF Coformulated Regimen vs Efavirenz in Treatment-Naive Patients
The coformulated regimen cobicistat/elvitegravir/emtricitabine/tenofovir DF has been shown to be noninferior to both efavirenz/emtricitabine/tenofovir DF16 and atazanavir/ritonavir plus emtricitabine/tenofovir DF in separate phase III trials.28

Study 102, which compared cobicistat/elvitegravir/emtricitabine/tenofovir DF with efavirenz/emtricitabine/tenofovir DF in a double-blind fashion in 700 treatment-naive patients with baseline estimated glomerular filtration rate (eGFR) ≥ 70 mL/min, found the elvitegravir/cobicistat regimen to be noninferior to the efavirenz regimen at Week 48 with 84% of the efavirenz arm vs 88% of the elvitegravir/cobicistat arm achieving virologic suppression to HIV-1 RNA < 50 copies/mL by FDA snapshot analysis.16 The analysis of this trial will continue to Week 192. At Week 96, cobicistat/elvitegravir/emtricitabine/tenofovir DF remained noninferior to efavirenz/emtricitabine/tenofovir DF with 84% of patients receiving the elvitegravir/cobicistat regimen and 82% of patients receiving the efavirenz regimen maintaining HIV-1 RNA < 50 copies/mL, based on the FDA snapshot algorithm.77 Noninferiority was also observed at Week 144, with 80% vs 75% of patients maintaining virologic suppression.78 An analysis by baseline characteristics showed that the elvitegravir/cobicistat regimen and the efavirenz regimen were similar in efficacy over a wide range of baseline HIV-1 RNA and CD4+ cell count strata.16

Through Week 144, there was a similar rate of toxicity-driven discontinuation between arms (6% vs 7%).78 The elvitegravir/cobicistat regimen was associated with an increased risk of nausea, whereas the efavirenz regimen was associated with an increased risk of sleep disturbance, dizziness, and rash. There were greater changes in total cholesterol, low density lipoprotein cholesterol, and high density lipoprotein cholesterol with efavirenz, but the total cholesterol:high density lipoprotein cholesterol ratio was similar between arms.

There was a significantly greater median increase in serum creatinine with the elvitegravir/cobicistat regimen vs the efavirenz regimen (0.14 vs 0.01 mg/dL, respectively; P < .001). This is caused by a documented effect of cobicistat on creatinine transport and does not reflect an adverse impact on renal function.23 This change in creatinine stabilized by Week 4 and did not increase thereafter.11

Virologic failure had occurred in 7% of patients in the elvitegravir/cobicistat arm at Week 144 and in 10% of the efavirenz recipients. A total of 10 patients had developed resistance in the elvitegravir/cobicistat arm and 14 in the efavirenz arm. Of the 10 in the elvitegravir/cobicistat arm, 9 had INSTI resistance mutations and all 10 had NRTI mutations. Of the 14 in the efavirenz arm, all 14 had NNRTI mutations, but only 4 had NRTI mutations.

A parallel trial compared cobicistat/elvitegravir/emtricitabine/tenofovir DF with atazanavir plus ritonavir plus emtricitabine/tenofovir DF.28

Dolutegravir vs Efavirenz in Treatment-Naive Patients
The phase III SINGLE trial compared dolutegravir plus abacavir/lamivudine with efavirenz/emtricitabine/tenofovir DF in a double-blind fashion in 830 treatment-naive patients.17 At Week 48, the dolutegravir regimen was statistically superior to efavirenz, with 88% vs 81% of patients, respectively, achieving HIV-1 RNA < 50 copies/mL by the FDA snapshot analysis (difference: 7.4; 95% CI: 2.5-12.3; P = .003). The difference was driven primarily by adverse events: More patients in the efavirenz arm vs the dolutegravir arm discontinued therapy for adverse events (10% vs 2%, respectively). The adverse events seen with efavirenz were primarily neuropsychiatric events and rash. The dolutegravir regimen remained statistically superior to the efavirenz regimen at Week 144 with 71% vs 63% of patients with HIV-1 RNA < 50 copies/mL (P = .01).50 No change in urine protein/creatinine ratio was observed over 144 weeks. The protocol-defined virologic failure rate was low in both arms (9% and 8%, respectively) and no treatment-emergent integrase or NRTI-resistance mutations were identified in the dolutegravir arm, but in the efavirenz arm, 6 patients developed NNRTI resistance and 1 patient developed NRTI resistance. Overall, a higher proportion of patients experienced adverse events leading to treatment withdrawal with the efavirenz regimen vs the dolutegravir regimen (14% vs 4%).

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 No patients withdrew because of renal events.17

Dolutegravir was also compared with raltegravir in the phase III SPRING-2 study and to darunavir plus ritonavir in the open-label FLAMINGO study.

Considerations for Choosing Efavirenz vs INSTI-based Therapy
When choosing between INSTIs and efavirenz, the following considerations might be taken into account:

  • Dosing
    • Efavirenz is given once daily at bedtime and is part of a complete coformulated regimen with emtricitabine/tenofovir DF
  • Renal function
    •  Efavirenz does not have a significant effect on renal function
  • Lipids: 3 of the 4 INSTIs, raltegravir, elvitegravir, and dolutegravir, were directly compared and found to have less effect on lipids than efavirenz50,75,76,78
  • Adverse events (other than renal)
    • Efavirenz is well known to be associated with neuropsychiatric adverse events that resolve in most patients within 4 weeks79
    • A more important adverse event is the potential increased risk of suicidality in patients receiving efavirenz. This was observed in a retrospective analysis of 4 randomized clinical trials comparing efavirenz- to non-efavirenz–containing regimens80
    • In the clinical trials of INSTIs vs efavirenz, an important factor related to the outcome of the trials was the proportion of patients who discontinued therapy due to drug-related adverse events. This was also true for the STARTMRK trial of raltegravir vs efavirenz and for the SINGLE trial of dolutegravir vs efavirenz15,50
  • Baseline HIV-1 RNA and CD4+ cell count strata
    • With emtricitabine/tenofovir DF, efavirenz is effective at all baseline HIV-1 RNA levels and CD4+ cell counts29
    • Efavirenz appeared less effective when combined with abacavir/lamivudine in patients with high baseline HIV-1 RNA29
  • Drug–drug interactions
    • Efavirenz is an inducer of the CYP system. Significant interactions occur with efavirenz and drugs in many classes
  • Virologic failure
    • Upon virologic failure of efavirenz, resistance is generally seen both to efavirenz and to NRTIs in the regimen. In trials of raltegravir or cobicistat/elvitegravir vs efavirenz, a greater proportion of patients receiving the INSTI developed NRTI mutations than in those receiving efavirenz
    • On the other hand, development of resistance mutations either to INSTIs or NRTIs at virologic failure of first-line dolutegravir-based or bictegravir-based combination regimens has not yet been documented in trials of dolutegravir or bictegravir in treatment-naive patients14,17,18,30,32
  • Rapid decline in HIV-1 RNA with INSTIs
    • One of the hallmarks of INSTI therapy is the rapid decline in HIV-1 RNA levels after start of therapy. The clinical significance of this is currently still unknown, but this feature of INSTI therapy may be important in treating acute HIV infection. Some evidence has suggested that the incidence of immune reconstitution inflammatory syndrome (IRIS) was more common with INSTI-based therapy, possibly related to this faster decline in HIV-1 RNA.81 However, subsequent studies, including 2 randomized controlled trials, reported no difference in IRIS event risk between patients who initiated INSTI-containing vs non-INSTI regimens, and including among patients with low CD4+ cell counts (< 100 or < 200 cells/mm3).82-84
  • Pregnancy potential in women of childbearing age:
    • 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 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.

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