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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 INSTI-Based vs Boosted PI-Based Therapy

There have been clinical trials comparing atazanavir plus ritonavir and darunavir plus ritonavir with 3 INSTIs, raltegravir, dolutegravir, and bictegravir. As with efavirenz-based initial therapy, one of the primary considerations of boosted PI–based therapy is the difference in tolerability between the PIs and the INSTIs, particularly raltegravir, dolutegravir, and bictegravir. Rate of adverse events and bone and lipid changes are more similar between cobicistat/elvitegravir/emtricitabine/tenofovir DF and the boosted PIs.

Raltegravir vs Boosted PIs in Treatment-Naive Patients
The phase III ACTG A5257 trial undertook a randomized, open-label comparison of atazanavir plus ritonavir, darunavir plus ritonavir, and raltegravir, each in combination with emtricitabine/tenofovir DF, in 1809 treatment-naive patients.[92] The primary endpoint, time to virologic failure (defined as confirmed HIV-1 RNA > 1000 copies/mL any time from 16-24 weeks or > 200 copies/mL at or after 24 weeks), was equivalent with all 3 regimens, with the cumulative incidence of virologic failure by Week 96 ranging from 9% to 15% across treatment arms.[ 92] Analysis of a preplanned composite endpoint accounting for the first occurrence of either virologic failure or treatment failure, defined as the discontinuation of an assigned treatment component because of toxicity, revealed that the raltegravir arm was superior to both the atazanavir plus ritonavir and darunavir plus ritonavir arms, and the darunavir plus ritonavir arm was superior to the atazanavir plus ritonavir arm. This outcome resulted largely from tolerability differences between the regimens, with patients in the atazanavir plus ritonavir arm experiencing significantly more toxicity-related discontinuations by Week 96 (13.9% vs 4.7% with darunavir plus ritonavir and 0.9% with raltegravir). The difference in toxicity-related discontinuations was largely driven by hyperbilirubinemia/jaundice in the atazanavir plus ritonavir arm. In an intent-to-treat analysis in which ART changes were allowed according to the protocol, all 3 arms showed equivalent virologic efficacy, defined as HIV-1 RNA ≤ 50 copies/mL, at Week 96 (88.3% for atazanavir plus ritonavir, 93.9% for raltegravir, and 89.4% for darunavir plus ritonavir). In a separate intent-to-treat “snapshot” analysis in which ART changes were counted as failures, the raltegravir regimen was superior to each of the other arms at Week 96, with 79.8% of patients having HIV-1 RNA ≤ 50 copies/mL vs 72.7% in the darunavir plus ritonavir arm and 62.6% in the atazanavir plus ritonavir arm. In the same analysis, the darunavir plus ritonavir regimen was superior to the atazanavir plus ritonavir regimen at Week 96 and Week 144. All 3 regimens exhibited comparable increases in mean CD4+ cell counts, and the incidence of virologic failure with drug resistance was rare, although it was more frequent among patients in the raltegravir arm (3% vs ≤ 1.5% in the other arms). A subanalysis of lipid outcomes in ACTG A5257 demonstrated significantly lower increases in low density lipoprotein cholesterol levels in the raltegravir-containing arm vs the PI-containing arms (P £ .001).[92,93] Ritonavir exposure was not associated with changes in levels of triglycerides, calculated low density lipoprotein cholesterol, and non–high density lipoprotein cholesterol through Week 96. In a separate substudy of bone outcomes, all 3 regimens were associated with significant bone mineral density loss at Week 96 (P < .001) at all evaluated sites (total hip, lumbar spine, and total body).[94] When the 3 regimens were compared, bone mineral density losses at the hip and spine were significantly greater with the 2 PI-based regimens vs the raltegravir-based regimen (P = .005 for total hip and P < .001 for lumbar spine), whereas total body bone mineral density loss was greater in the atazanavir plus ritonavir–containing arm vs either the darunavir plus ritonavir–containing arm (P = .001) or the raltegravir-containing arm (P = .004).

Elvitegravir/Cobicistat/Emtricitabine/Tenofovir DF Coformulated Regimen vs Boosted PIs in Treatment-Naive Patients
Study 103, the parallel trial to Study 102 compared cobicistat/elvitegravir/emtricitabine/tenofovir DF (n = 353) with atazanavir plus ritonavir plus emtricitabine/tenofovir DF (n = 355) in a double-blind fashion, and found the elvitegravir/cobicistat regimen to be noninferior to the atazanavir plus ritonavir regimen at Week 48 with 90% of the elvitegravir/cobicistat arm vs 87% of the boosted PI arm achieving virologic suppression to HIV-1 RNA < 50 copies/mL by FDA snapshot analysis.[34] The overall rate of adverse events was also similar between arms, except for the anticipated higher rate of hyperbilirubinemia (58% vs 1%) and sclera icterus (14% vs 1%) in the atazanavir plus ritonavir arm. Elvitegravir/cobicistat was associated with a significantly greater median increase in serum creatinine (0.12 vs 0.08 mg/dL; 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]

Atazanavir plus ritonavir was associated with a greater increase in triglycerides at Week 48 (23 vs 8 mg/dL [0.26 vs 0.90 mmol/L]; P = .006). As in the other study, there were no significant differences between the arms when stratified by baseline HIV-1 RNA and CD4+ cell count levels.

At Week 96, cobicistat/elvitegravir/emtricitabine/tenofovir DF remained noninferior to atazanavir plus ritonavir plus emtricitabine/tenofovir DF with 83% of elvitegravir/cobicistat patients and 82% of atazanavir plus ritonavir recipients maintaining HIV-1 RNA < 50 copies/mL, based on the FDA snapshot algorithm.[95] Noninferiority was also observed at Week 144, with 78% vs 75% of patients maintaining virologic suppression.[96]

As in Study 102, there was a similar low rate of toxicity-driven discontinuation between arms through Week 144 (6% in the elvitegravir/cobicistat arm vs 8.5% in the atazanavir plus ritonavir arm). Virologic failure occurred in 8% of elvitegravir/cobicistat patients and 7% of atazanavir plus ritonavir patients by Week 144. A total of 8 patients in the elvitegravir/cobicistat arm developed resistance-associated mutations, whereas 2 of the patients in the boosted PI arm developed resistance mutations. Both of these patients developed the M184V NRTI mutation; no patients developed primary PI resistance.

Women with HIV are generally underrepresented in HIV treatment trials, and this was the case for Study 103 with women representing only 8% to 11% of the overall study population. To address this discrepancy, the double-blind phase III WAVES trial enrolled and randomized 575 women to cobicistat/elvitegravir/emtricitabine/tenofovir DF (n = 289) or atazanavir plus ritonavir plus emtricitabine/tenofovir DF (n = 286). The results demonstrated that the elvitegravir/cobicistat regimen was superior to the atazanavir plus ritonavir regimen at Week 48 with 87% vs 81%, respectively, achieving virologic suppression to HIV-1 RNA < 50 copies/mL by FDA snapshot analysis.[97] Cobicistat/elvitegravir/emtricitabine/tenofovir DF was associated with decreased frequency of discontinuation for adverse events, decreased frequency of jaundice and scleral icterus, and decreased risk of grade 3/4 hyperbilirubinemia vs atazanavir plus ritonavir plus emtricitabine/tenofovir DF. In this trial, there was no significant difference between treatment arms in the change from baseline to Week 48 for the following parameters: estimated glomerular filtration rate, spine or hip bone mineral density, low or high density lipoprotein cholesterol, total to high density lipoprotein cholesterol ratio, or triglycerides. However, the increase in total cholesterol was significantly greater with cobicistat/elvitegravir/emtricitabine/tenofovir DF vs atazanavir plus ritonavir plus emtricitabine/tenofovir DF (P = .02). The M184V/I resistance mutation was identified in 3 patients treated with atazanavir plus ritonavir but was not observed in any patient treated with the elvitegravir regimen. No patients developed primary PI resistance, integrase inhibitor resistance, or K65R.

Dolutegravir vs Boosted PIs in Treatment-Naive Patients
The phase III FLAMINGO trial compared dolutegravir with darunavir plus ritonavir (n = 242 in each arm), each combined with either abacavir/lamivudine or emtricitabine/tenofovir DF in treatment-naive patients.[37]

At the Week 48 primary endpoint, dolutegravir-based therapy was superior to the boosted PI regimen with 90% vs 83%, respectively, reaching HIV-1 RNA < 50 copies/mL, based on the FDA snapshot analysis (difference: 7.1; 95% CI: 0.9-13.2; P = .025).[37] Protocol-defined virologic failure occurred in only 2 patients (< 1%) of each arm. Among those who experienced virologic failure, no resistance mutations were seen. Tolerability was good in both arms; patients on darunavir plus ritonavir experienced more diarrhea; those on dolutegravir experienced more headache. Only 2% of patients receiving dolutegravir and 4% of patients receiving darunavir plus ritonavir discontinued due to adverse events. At Week 96, the dolutegravir-based regimen continued to be superior to the boosted PI regimen with 80% vs 68% of patients with HIV-1 RNA < 50 copies/mL (P = .002).[38] Fewer patients receiving the dolutegravir-based regimen compared with the boosted PI regimen had overall virologic nonresponse (8% vs 12%) and nonresponse for other reasons (12% vs 21%). Patients with high baseline HIV-1 RNA showed a more pronounced response to the dolutegravir-based regimen (82% vs 52%). Protocol-defined virologic failure defined as HIV-1 RNA > 200 copies/mL on or after Week 24 occurred in 2 patients receiving the dolutegravir-based regimen (both prior to Week 48) and 4 patients receiving the boosted PI regimen (2 prior to Week 48; 2 after). A significantly higher proportion of patients receiving the boosted PI regimen experienced grade ≥ 2 fasting low density lipoprotein cholesterol abnormalities (22% vs 7%; P < .001).

The open-label phase IIIb ARIA trial enrolled and randomized 495 treatment-naive HLA-B*5701–negative women to abacavir/dolutegravir/lamivudine (n = 248) or atazanavir plus ritonavir plus emtricitabine/tenofovir DF (n = 247). The results demonstrated that the dolutegravir regimen was superior to the atazanavir plus ritonavir regimen at Week 48 with 82% vs 71%, respectively, achieving virologic suppression to HIV-1 RNA < 50 copies/mL by intent-to-treat exposed analysis (Capsule Summary).[98] Abacavir/dolutegravir/lamivudine was associated with a numerically lower rate of discontinuation for adverse events and of jaundice and scleral icterus vs atazanavir plus ritonavir plus emtricitabine/tenofovir DF. The M184V resistance mutation was identified in 1 patient treated with atazanavir plus ritonavir but was not observed in any patient treated with the dolutegravir regimen. There were no treatment-emergent resistance mutations to the regimen components among patients in the dolutegravir arm with confirmed virologic withdrawal.

Dolutegravir has also been compared with raltegravir in the phase III SPRING-2 study and to efavirenz in the SINGLE study.

Considerations for Choosing Boosted PI vs INSTI-Based Therapy
When choosing between INSTI-based and boosted PI–based therapy, the following considerations might be taken into account:

  • Dosing
    • There is now 1 boosted PI–based coformulated single-tablet regimen, cobicistat/darunavir/emtricitabine/tenofovir AF. The boosted PIs atazanavir/cobicistat and cobicistat/darunavir are also coformulated, but the NRTI pair must be given separately
  • Renal function
    • Atazanavir plus ritonavir is associated with nephrolithiasis[99] and the development of chronic kidney disease[100]
    • A study of 1430 patients in the UK CHIC HIV cohort showed improved renal function in virologically suppressed patients switched from atazanavir plus ritonavir or lopinavir/ritonavir to darunavir plus ritonavir[101]
  • Lipids
    • Both atazanavir plus ritonavir and darunavir plus ritonavir had greater effects on lipids than raltegravir in ACTG 5257[92]
    • Darunavir plus ritonavir had greater effects on lipids than dolutegravir in FLAMINGO[37]
    • In WAVES, changes in fasting total cholesterol were greater with cobicistat/elvitegravir/emtricitabine/tenofovir DF than with atazanavir plus ritonavir plus emtricitabine/tenofovir DF[97]
  • Bone
    • In ACTG 5257, the raltegravir-based regimen was associated with significantly smaller bone mineral density loss at the hip and spine than with the 2 PI-based regimens. In WAVES, there was no difference in bone mineral density changes with cobicistat/elvitegravir/emtricitabine/tenofovir DF vs atazanavir plus ritonavir plus emtricitabine/tenofovir DF[92]
  • Other adverse events
    • Atazanavir plus ritonavir is associated with hyperbilirubinemia and sclera icterus[99]
    • In D:A:D, 5-year cumulative exposure to darunavir plus ritonavir was associated with increased risk of cardiovascular disease, defined as myocardial infarction, sudden cardiac death, or use of invasive cardiovascular procedures[102]
      • Several studies have exonerated atazanavir plus ritonavir from an association with cardiovascular disease risk[67,103,104]
  • Drug–drug interactions
    • Ritonavir and cobicistat are inhibitors of the CYP system. Significant interactions occur between these boosters and drugs in many classes
    • Atazanavir has significant interactions with proton pump inhibitors and gastric acid inhibitors that affect dosing
  • Virologic failure
    • With virologic failure of first-line PI therapy, primary PI resistance is very rarely seen. With virologic failure of atazanavir plus ritonavir, a small percentage of patients may develop NRTI resistance[98]

      As such, many physicians believe that boosted PI first-line therapy may be the best choice for patients for whom they have adherence concerns

  • 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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