Safety Information of PREZISTA: Effect on Lipids in Treatment-Naive Adults

Summary

• The METABOLIK study compared changes in triglycerides (TG), total cholesterol (TC), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) in treatment-naïve patients receiving PREZISTA/ritonavir (r) or atazanavir/r (ATV/r).  At week 48, patients had a mean increase from baseline in TG of 26.1 mg/dL in the PREZISTA/r arm and 9.6 mg/dL in the ATV/r arm.¹
• The ACTG A5257 study evaluated the metabolic profiles of PREZISTA/r, ATV/r, and raltegravir (RAL) in treatment naïve patients. Both boosted protease inhibitors (bPI) had greater increases in all lipid values, excluding HDL, relative to RAL at week 96 (P≤0.001).²
• In the ATADAR study, patients in the ATV/r arm had increased TG relative to the PREZISTA/r arm, however TC and HDL increases were comparable in the two arms.³
• In the ARTEMIS study, patients in the lopinavir (LPV)/r group compared with the PREZISTA/r 800/100 mg QD group had a higher incidence of grade 2-4 increases in TC (32.7% vs. 24.3%; P=0.018) and TG (16% vs 5.9%; P<0.001) at week 192.⁴
• In the DRIVE-FORWARD study, patients in the PREZISTA/r group compared to the doravirine (DOR) group had higher increases in TC (21.9 mg/dL vs 4.1 mg/dL), LDL (14.0 mg/dL vs -0.4 mg/dL), and TG (22.5 mg/dL vs -1.1 mg/dL), and similar increases in HDL (4.2 mg/dL vs 4.5 mg/dL) at week 96.⁵

STUDIES EVALUATING THE EFFECT OF PREZISTA/R ON LIPID PARAMETERS

METABOLIK Study

The METABOLIK (Metabolic Evaluation in Treatment-naïves Assessing the impact of two BOosted protease inhibitors on LIpids and other marKers) study evaluated the metabolic effects of PREZISTA/r compared to ATV/r in treatment-naïve, HIV-1–infected patients.¹

Study Design/Methods

• Phase 4, randomized, open-label, multicenter, 48-week study (N=65).
• Patients were randomized (1:1) to either PREZISTA/r 800/100 mg QD (n=34) or ATV/r 300/100 mg QD (n=31). All patients received a fixed-dose background regimen of emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) 200/300 mg QD.
• Select inclusion criteria: treatment-naïve HIV-1 infected adults (≥18 years), VL ≥1,000 copies/mL, HIV-1 sensitive to ATV, DRV, FTC, and tenofovir (TFV) upon baseline resistance testing.
• Select exclusion criteria: LDL >130 mg/dL, TG >200 mg/dL, fasting glucose >110 mg/dL, body mass index (BMI) >30 kg/m², acute/chronic hepatitis A, B, or C.
• Lipid-lowering agents were not allowed from 28 days prior to baseline through week 12 and then allowed after week 12.
• Primary endpoint: change in TG levels from baseline to week 12
• Secondary endpoints to week 48 included changes in:
  • TG, TC, HDL, measured LDL, and apolipoproteins (apo) A1 and B
  • Glucose levels, insulin levels, and insulin sensitivity (measured by homeostasis model assessment of insulin resistance [HOMA-IR] method)
  • Inflammatory biomarkers: interleukin (IL)-1, IL-6, tumor necrosis factor-alpha (TNF-RII), and high sensitivity C-reactive protein (hs-CRP)
  • Coagulation biomarkers: fibrinogen and d-dimer
  • Bacterial translocation marker: lipopolysaccharide (LPS)
  • VL and CD4+ cell count
  • Fat redistribution, which was evaluated using computed tomography (CT) scans performed at L4-L5 and mid-thigh at baseline and week 48 and centrally analyzed for total (TAT), subcutaneous (SAT), visceral (VAT), and peripheral (PAT) adipose tissue.
    • In addition, the self-reported Assessment of Body Change and Distress (ABCD) questionnaire was administered at baseline and at weeks 12 and 48.

Results

Patient Characteristics

• At baseline, patients in the PREZISTA/r arm had higher viral loads, lower median CD4+ counts, and lower TC and LDL levels than patients in the ATV/r arm.

Lipid Evaluations

• Lipid parameters were evaluated in 28 patients in the PREZISTA/r group and 27 patients in the ATV/r group.
• There were no lipid-lowering agents started after week 12.
• Primary endpoint: from baseline to week 12, patients receiving PREZISTA/r had a mean increase in TG of 22.0 mg/dL and patients receiving ATV/r had a mean increase of 8.1 mg/dL (difference 13.8, 95% CI: -25.8 to 53.4).
• By week 48, the mean increase in TG from baseline was 26.1 mg/dL in the PREZISTA/r arm and 9.6 mg/dL in the ATV/r arm (difference 16.5, 95% CI: -25.0 to 58.0) (Table: Lipid Parameters at Baseline, Week 12, and Week 48, Mean [SD]).
• Differences between arms in other fasting lipid parameters were small and similar at week 48.

ACTG A5257 Study

The ACTG A5257 study aimed to evaluate the metabolic profiles of PREZISTA/r, ATV/r, and RAL in randomized treatment naïve patients with a VL >1000 copies/mL.²

Study Design/Methods

• Phase 3, randomized, open label, 96-week study.
• Patients were randomized 1:1:1 to receive PREZISTA/r 800mg/100mg once daily (n=601), ATV/r 300mg/100mg once daily (n=605), or RAL 400mg twice daily (n=603), each in combination with FTC/TDF 200mg/300mg once daily and were stratified by baseline VL (< or ≥100,000 copies/mL), cardiovascular risk, and metabolic for substudy participation.⁶
• Metabolic endpoints: change from baseline in fasting TC, HDL-C, TG, non-HDL-C, calculated LDL-C, plasma glucose, waist:height ratio, and prevalence of metabolic syndrome
• An association between plasma ritonavir C₂₄ at steady state and fasting plasma lipid levels were also evaluated from baseline to 48 weeks between the bPI groups.

Results

Patient Characteristics

• Baseline characteristics were similar among groups.
• Overall population: median age 37 years; 76% male; 34% white/42% black/22% Hispanic; median VL 4.6 (log₁₀) copies/mL; VL ≥100,000: 30.6%; median CD4+ <200: 29.6%.

Lipid Evaluations

• 1797 patients with confirmed baseline fasting samples and clinical measures were included in the metabolic analyses: PREZISTA/r (n=595); ATV/r (n=602); RAL (n=600).

• There were no differences between the ATV/r and PREZISTA/r arms (all P >0.05) in all lipid measures from baseline to weeks 24, 48, and 96.
• There were greater increases in each of bPI arms compared to the RAL arm in TC, TG, non-HDL-C, and LDL-C (all P ≤0.001).
• All treatment arms had an increase in HDL-C (an average increase of 6 mg/dL over 96 weeks), with no significant differences between the three arms (all P >0.06).
• Each arm had an increase in lipid-lowering agents from baseline to week 96: ATV/r: 5% to 11%, RAL: 6% to 9%, PREZISTA/r: 6% to 14%.
• There was no association between ritonavir troughs and lipid parameters for PREZISTA/r and ATV/r.

ATADAR Study

The ATADAR study compared the effects of PREZISTA/r and ATV/r on metabolism, body composition, overall tolerability, and efficacy in treatment-naïve, HIV-1 infected patients (N=178).³

Study Design/Methods

• Phase 4, randomized, open-label, multicenter, 96-week study.
• ARV-naïve adults with VL ≥1000 copies/mL were randomized (1:1) to receive either PREZISTA/r 800/100 mg QD (n=88) or ATV/r 300/100 mg QD (n=90). All patients received a fixed-dose background regimen of FTC/TDF QD.
• Primary endpoint: change in TC levels from baseline to week 24.
• Secondary endpoints included:
  • Proportion of patients free of treatment failure or virologic failure (VF; VL ≥50 copies/mL) at week 96.
  • Proportion of patients with study drug discontinuation due to AEs at week 96.
  • Changes in lipids, total bilirubin, and CD4+ counts at weeks 48 and 96.
  • Changes in dual-X absorptiometry (DXA)- and computed tomography (CT)-derived body composition parameters at weeks 48 and 96.

Results

Patient Characteristics

• Baseline characteristics were similar between groups except for CD4+ count.
  • PREZISTA/r: mean age 37 years; 89% male; mean (SD) VL: 4.8 (0.8) log₁₀ copies/mL; VL ≥100,000 copies/mL: 33%; CD4+ <200 cells/mm³ 14.1%.
  • ATV/r: mean age 35 years; 87% male; mean (SD) VL: 4.8 (0.7) log₁₀ copies/mL; VL ≥100,000 copies/mL: 36%; CD4+ <200 cells/mm³ 27.8%.
• No patients received lipid-lowering therapy at baseline or during the study.

Lipid Evaluations

• At week 24, TC increased by 11.5 mg/dL and 7.2 mg/dL and HDL increased by 3.9 mg/dL and 5.5 mg/dL in the PREZISTA/r and ATV/r arms, respectively.
• Increases in TG were higher in the ATV/r arm than in the PREZISTA/r arm at week 96 (difference 21.5 mg/dL, 95% CI: -0.7 to 43.8; P=0.058).

DATA FROM OTHER CLINICAL TRIALS

ARTEMIS Study

The ARTEMIS study is a randomized, controlled, open-label, 192-week phase 3 study comparing PREZISTA/r 800/100 mg QD versus either lopinavir/ritonavir (LPV/r) 800/200 mg QD or LPV/r 400/100 mg twice daily (BID) in treatment-naïve patients. All patients received a fixed-dose background regimen of FTC/TDF 200/300 mg QD (N=689).⁷

Lipid Results

• Patients in the LPV/r group compared with PREZISTA/r group experienced greater median increases in TG and TC.
• Median TG, TC, and LDL-C levels were below the National Cholesterol Education Program (NCEP) cut-offs for patients that received PREZISTA/r.

DRIVE-FORWARD

Molina et al (2018)⁵ conducted a phase 3, randomized, controlled, double-blind, parallel-group, multicenter, 96-week noninferiority study to compare PREZISTA/r 800/100 mg QD and DOR 100 mg QD, given with 2 investigator-selected NRTIs (FTC/TDF or abacavir [ABC]/lamivudine [3TC]) for previously untreated HIV-1 infection (N=769).

Lipid Results

• Mean change from baseline to week 96 in fasting lipids, PREZISTA/r vs DOR (95% CI):
  • LDL cholesterol: 14.0 (11.0 to 17.0) vs -0.4 (-2.8 to 1.9) mg/dL
  • Non-HDL cholesterol: 17.7 (14.3 to 21.0) vs -0.5 (-3.3 to 2.3) mg/dL
  • Total cholesterol: 21.9 (18.3 to 25.5) vs 4.1 (1.0 to 7.1) mg/dL
  • Triglycerides: 22.5 (13.6 to 31.4) vs -1.1 (-8.9 to 6.6) mg/dL
  • HDL cholesterol: 4.2 (2.3 to 5.5) vs 4.5 (3.3 to 5.8) mg/dL
• Few patients modified their lipid-lowering therapy during the study (PREZISTA/r, n=11; DOR, n=10).

LITERATURE SEARCH

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 20 November 2025.