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Key Principles and Recommended Regimens for First-line Antiretroviral Therapy

Joseph J. Eron, Jr., MD
Program Director
Daniel R. Kuritzkes, MD
Program Director
Paul E. Sax, MD
Released: June 11, 2020

Clinical Trials of NNRTI-Based vs INSTI-Based Therapy

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 INSTI 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.[17] 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.[81,82] 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.[41] 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.[20,22]

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 DF[18] and atazanavir plus ritonavir plus emtricitabine/tenofovir DF in separate phase III trials.[34]

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.[18] 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.[83] Noninferiority was also observed at Week 144, with 80% vs 75% of patients maintaining virologic suppression.[84] 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.[18]

Through Week 144, there was a similar rate of toxicity-driven discontinuation between arms (6% vs 7%).[84] 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.[25] This change in creatinine stabilized by Week 4 and did not increase thereafter.[14]

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.[34]

Dolutegravir vs Efavirenz in Treatment-Naive Patients
The phase III SINGLE trial compared dolutegravir plus abacavir/lamivudine with efavirenz/emtricitabine/tenofovir in a double-blind fashion in 830 treatment-naive patients.[19] 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).[57] 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.[21] No patients withdrew because of renal events.[19]

The IMPAACT 2010 study was a randomized, open-label phase III trial that examined the safety and efficacy of dolutegravir vs efavirenz and tenofovir DF vs tenofovir AF in treatment-naive pregnant women initiating ART at 14 to 28 weeks of gestation (Capsule Summary).[85] The study found that neonatal death was more frequent with efavirenz/emtricitabine/tenofovir DF vs either dolutegravir plus emtricitabine/tenofovir AF or dolutegravir plus emtricitabine/tenofovir DF. Two infants were diagnosed with HIV in the dolutegravir plus emtricitabine/tenofovir AF arm, while 1 infant was diagnosed with HIV in the dolutegravir plus emtricitabine/tenofovir DF arm. Regarding virologic efficacy, significantly more women had HIV-1 RNA < 200 copies/mL at the time of delivery in the dolutegravir-based arms vs the efavirenz-based arm in the intent to treat population: 97.5% vs 91% (P = .005). This was also true for the per protocol population, with 97.5% and 91.4% (P = .008) of women achieving this endpoint, respectively. Regarding adverse pregnancy outcomes, there was a significantly lower risk of any adverse pregnancy outcome and stillbirth in the dolutegravir plus emtricitabine/tenofovir AF group vs the other 2 treatment groups. There was also a significantly lower risk of preterm delivery with dolutegravir plus emtricitabine/tenofovir AF vs efavirenz/emtricitabine/tenofovir DF.

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 complete coformulated regimens with emtricitabine/tenofovir DF or lamivudine/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 efavirenz[57,81,82,84]
  • Adverse events (other than renal)
    • Efavirenz is well known to be associated with neuropsychiatric adverse events that resolve in most patients within 4 weeks[86]
    • 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 regimens[87]
    • 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 efavirenz[17,57]
  • 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 counts[35]
    • Efavirenz appeared less effective when combined with abacavir/lamivudine in patients with high baseline HIV-1 RNA[35]
  • 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 patients[16,19,20,36,38]
  • 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.[88] However, subsequent studies, including 2 randomized 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).[89-91]
    • 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]

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