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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 PI-Based Therapy

Large-scale clinical trials have compared efavirenz to lopinavir/ritonavir[104] and to atazanavir plus ritonavir.[35,54] There are as yet no large-scale clinical trials comparing efavirenz with darunavir plus ritonavir or comparing rilpivirine with any boosted PI.

Efavirenz vs Boosted PIs in Treatment-Naive Patients
The first large-scale clinical trial comparing efavirenz with a boosted PI was ACTG 5142.[104] In this randomized, open-label phase III trial, 753 patients began treatment with either efavirenz or lopinavir/ritonavir soft-gel capsules twice daily, each combined with 2 NRTIs, or with an NRTI-sparing regimen comprising efavirenz plus lopinavir/ritonavir.[104] At 96 weeks, efavirenz plus 2 NRTIs was found to be superior to lopinavir/ritonavir plus 2 NRTIs by the coprimary endpoint of time to virologic failure (P = .006) but was not different from the NRTI-sparing regimen of lopinavir/ritonavir plus efavirenz by this measure (P = .49). There was no statistically significant difference between the 2 NRTI-containing regimens by the coprimary endpoint of time to regimen completion (ie, virologic failure of toxicity-related discontinuation of any regimen component). At Week 96, the rate of virologic suppression was also significantly higher in the efavirenz plus 2 NRTIs arm vs the lopinavir/ritonavir plus 2 NRTIs arm (HIV-1 RNA < 50 copies/mL in 89% vs 77%, respectively; P = .003) and not significantly different from the NRTI-sparing arm. However, CD4+ cell count increases were significantly higher in the lopinavir/ritonavir-containing arms and in patients with virologic failure; efavirenz-containing regimens were associated with a significantly higher rate of drug resistance. In addition, there was a lower rate of protocol-specified lipoatrophy, although the rate was low overall in all patients who received tenofovir DF–containing regimens.[106] Time to treatment-limiting toxicity was similar between arms. The virologic efficacy of efavirenz plus lopinavir/ritonavir was similar to that of efavirenz plus 2 NRTIs, but this regimen was associated with excess risk of grade 3/4 laboratory events, predominantly lipid elevations.

ACTG A5202 was a randomized blinded phase IIIb comparison between abacavir/lamivudine and emtricitabine/tenofovir DF, which also provided an open-label randomized comparison of efavirenz with atazanavir plus ritonavir.[54] At the Week 96 primary endpoint analysis, there was a similar time to virologic failure with atazanavir plus ritonavir vs efavirenz when combined with either abacavir/lamivudine (HR: 1.13; 95% CI: 0.82-1.56) or emtricitabine/tenofovir DF (HR: 1.01; 95% CI: 0.70-1.46). This was the first large, prospective clinical trial demonstrating comparable antiviral activity of a boosted PI to efavirenz.

There were significant differences between the 2 agents, however, related to safety, tolerability, and resistance.

  • There was a significantly longer time to grade 3/4 safety event with atazanavir plus ritonavir vs efavirenz when combined with abacavir/lamivudine (HR: 0.81; 95% CI: 0.66-1.00; P = .05) but no difference when combined with emtricitabine/tenofovir DF (HR: 0.91; 95% CI: 0.72-1.15; P = .44).
  • There was a significantly longer time to treatment modification with atazanavir plus ritonavir vs efavirenz when combined with abacavir/lamivudine (HR: 0.69; 95% CI: 0.55-0.86; P = .0008), but no difference when combined with emtricitabine/tenofovir DF (HR: 0.84; 95% CI: 0.66-1.07; P = .17).
  • There were also significantly greater increases in total cholesterol, low density lipoprotein cholesterol, and high density lipoprotein cholesterol with efavirenz vs atazanavir plus ritonavir. However, there was no significant difference in total cholesterol:high density lipoprotein cholesterol ratio between any of the arms. There was also a significantly greater increase in triglycerides in the atazanavir plus ritonavir vs efavirenz arm when paired with abacavir/lamivudine in the stratum of patients with HIV-1 RNA < 100,000 copies/mL at baseline.
  • In ACTG 5224, the metabolic substudy of ACTG 5202, there were greater absolute and percentage increases in limb and trunk fat with atazanavir plus ritonavir vs efavirenz in both the intent-to-treat and as-treated analyses (P < .05). Atazanavir plus ritonavir led to significant losses in spine but not hip bone mineral density vs efavirenz.[61]
  • The emergence of major ARV resistance mutations at virologic failure was significantly more frequent with efavirenz vs atazanavir plus ritonavir when combined with either abacavir/lamivudine or emtricitabine/tenofovir DF.

Doravirine vs Boosted PIs in Treatment-Naive Patients
The most recently approved NNRTI doravirine was compared with a boosted PI–based regimen in the large-scale DRIVE-FORWARD clinical trial.[107] In this randomized, double-blind, international phase III noninferiority trial, 769 treatment-naive adults were randomized to either doravirine or ritonavir-boosted darunavir, each in combination with the investigator’s choice of 2 NRTIs. At 48 weeks, doravirine plus 2 NRTIs was found to be noninferior to ritonavir-boosted darunavir plus 2 NRTIs by the primary endpoint of the proportion of patients achieving HIV-1 RNA levels < 50 copies/mL according to the FDA snapshot algorithm. In the doravirine arm, 84% of patients achieved virologic suppression compared with 80% in the darunavir arm (treatment difference: 3.9%; 95% CI: -1.6% to 9.4%). Similar rates were observed in subgroups with high baseline HIV-1 RNA levels and low baseline CD4+ cell counts. At Week 48, the rates of protocol-defined virologic failure (PDVF) were 5% in the doravirine arm vs 6% in the darunavir arm. Resistance testing of a subset of doravirine-treated patients with PDVF found neither phenotypic resistance nor genotypic mutations associated with doravirine resistance; in a subset of darunavir-treated patients with PDVF, mutations in the viral protease gene that were not associated with phenotypic resistance to darunavir were identified in 3 out of 8 patients. The rates of adverse events and drug-related adverse events were comparable between arms, with a slightly lower rate of drug-related diarrhea in the doravirine arm vs darunavir arm (5% vs 13%, respectively). Regarding lipid effects, doravirine was associated with more favorable changes from baseline to Week 48 vs ritonavir-boosted darunavir. Although mean fasting concentrations of low density lipoprotein cholesterol, non–high density lipoprotein cholesterol, total cholesterol, and triglycerides slightly decreased among patients in the doravirine arm, these values all increased among patients in the darunavir arm.

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