Comparison of INSTI vs PI  FLAMINGO  GS  ACTG A5257

Lennox JL. Ann Intern Med 2014;161: ACTG A5257  Design  Objective –Evaluate regimen equivalence regarding virologic efficacy and tolerability over 96 weeks, by intention-to-treat analysis. Equivalence = 2-sided 97.5% CI on the pairwise difference in 96-week cumulative incidence of each individual or composite endpoint falling between - 10% and 10%, 90% power. If equivalence was not shown, superiority was defined as exclusion of 0 from the 97.5% CI Randomisation* 1 : 1 : 1 Open label *Randomisation was stratified by HIV RNA ( 100,000 c/mL) at screening, participation in cardiovascular sub-study, and 10-year Framingham risk score ACTG A5257 Study: (ATV/r vs DRV/r vs RAL) + TDF/FTC N = 603 N = 605 W96 N = 601 > 18 years ARV-naïve (< 10 days of ART) HIV RNA > 1,000 c/mL Any CD4 cell count No resistance to NRTI or PI ATV/r 300/100 mg QD + TDF/FTC RAL 400 mg BID + TDF/FTC DRV/r 800/100 mg QD + TDF/FTC

 Endpoints –Virologic failure: confirmed HIV-1 RNA > 1,000 c/mL at or after W16, or > 200 c/mL at or after W24 –Tolerability failure: time from randomisation to discontinuation of the randomised regimen component for toxicity (substitution of TDF or FTC not considered as tolerability failure) –Composite endpoint: virologic or tolerability failure, whichever occurred first –ITT-TLOVR, with HIV-1 RNA threshold of 200 c/mL –HIV-1 RNA < 50 c/mL at W96 by ITT, snapshot –Sensitivity analysis: as-treated (virologic failure including treatment discontinuation as a competing event) –Key toxicity secondary endpoint: time from initiation of treatment to the first grade 2, 3, or 4 sign or symptom (grade 3 or 4 if after week 48) or any grade 3 or 4 laboratory abnormality while the patient was receiving the randomized treatment (as-treated) Prespecified sensitivity analysis excluded hyperbilirubinemia and elevated CK levels Further sensitivity analysis included all qualifying adverse events regardless of status on randomized treatment (ITT analysis) Lennox JL. Ann Intern Med 2014;161: ACTG A5257 ACTG A5257 Study: (ATV/r vs DRV/r vs RAL) + TDF/FTC

ATV/r + TDF/FTC N = 605 DRV/r + TDF/FTC N = 601 RAL + TDF/FTC N = 603 Median age, years37 36 Female24% 25% HIV RNA (log 10 c/mL), median HIV RNA > 100,000 c/mL32%27.8%32% HIV RNA > 500,000 c/mL6.9%6.0%8.3% CD4 cell count (/mm 3 ), mean CD4 < 200 per mm %29%31% Hepatitis B / hepatitis C coinfection2.5% / 7.8%3% / 7.5%2.7% / 8.1% Never started ART, n544 Discontinuation by W968.1%9.1%7.1% Death10136 Lost to follow-up Baseline characteristics and patient disposition Lennox JL. Ann Intern Med 2014;161: ACTG A5257 ACTG A5257 Study: (ATV/r vs DRV/r vs RAL) + TDF/FTC

Lennox JL. Ann Intern Med 2014;161: ACTG A5257 ACTG A5257 Study: (ATV/r vs DRV/r vs RAL) + TDF/FTC Cumulative incidence of virologic failure (primary end point) ATV/r (12.6%) vs. RAL (9.0%) 3.4% (-0.7% to 7.4%) DRV/r (14.9%) vs. RAL (9.0%) 5.6% (1.3% to 9.9%) ATV/r (12.6%) vs. DRV/r (14.9%) -2.2% (-6.7% to 2.3%) Week ATV/r RAL DRV/r ATV/r (10.7%) vs. RAL (8.0%) 2.4% (-1.4% to 6.2%) DRV/r (13.1%) vs. RAL (8.0%) 4.7% (0.7% to 8.7%) ATV/r (10.7%) vs. DRV/r (13.1%) -2.3% (-6.5% to 2.0%) Week ATV/r RAL DRV/r Virologic failure (ITT)Virologic failure (as-treated) Equivalence of the 3 regimens ATV/r RAL DRV/r Cumulative probability of virologic failure by W96 –ATV/r: 12.6% –DRV/r: 14.9% –RAL: 9.0% ≠ (97.5% CI)

Lennox JL. Ann Intern Med 2014;161: ACTG A5257 ACTG A5257 Study: (ATV/r vs DRV/r vs RAL) + TDF/FTC  Greater tolerability benefit of –RAL vs ATV/r in patients with baseline HIV RNA < 100,000 c/mL –RAL vs DRV/r in women  RAL equivalent to DRV/r  RAL superior to ATV/r  DRV/r superior to ATV/r Favors RAL Favors DRV/r Week ATV/r RAL DRV/r ATV/r (13.9%) vs. RAL (0.9%) 12.7% (9.4% ; 16.1%) DRV/r (4.7%) vs. RAL (0.9%) 3.6% (1.4% ; 5.8%) ATV/r (13.9%) vs. DRV/r (4.7%) 9.2% (5.5% ; 12.9%) ATV/r RAL DRV/r Cumulative incidence of tolerability failure (primary end point) ≠ (97.5% CI)

Lennox JL. Ann Intern Med 2014;161: ACTG A5257 ACTG A5257 Study: (ATV/r vs DRV/r vs RAL) + TDF/FTC ATV/r + TDF/FTC N = 605 DRV/r + TDF/FTC N = 601 RAL + TDF/FTC N = 603 Any toxicity/discontinuations95 (15.7%)32 (5.3%)8 (1.3%) Jaundice or hyperbilirubinemia4700 Nausea or other gastrointestinal toxicities25142 Hepatic toxicity451 Skin toxicity7 5 (1 Stevens-Johnson) 2 Metabolic toxicity620 Renal toxicity400 Abnormal chemistry/hematology findings020 Other243 Discontinuations of randomised antiretroviral therapy for toxicity

Lennox JL. Ann Intern Med 2014;161: ACTG A5257 ACTG A5257 Study: (ATV/r vs DRV/r vs RAL) + TDF/FTC  ATV/r inferior to DRV/r and to RAL  DRV/r inferior to RAL Week ATV/r RAL DRV/r Participants in the risk set, n Favors RAL Favors DRV/r Favors RAL ATV/r (24.1%) vs. RAL (8.6%) 14.9% (10.2% ; 19.6%) DRV/r (16.6%) vs. RAL (8.6%) 7.5% (3.2% ; 11.8%) ATV/r (24.1%) vs. DRV/r (16.6%) 7.5% (2.3% ; 12.7%) ATV/r RAL DRV/r Cumulative incidence of virologic or tolerability failure (preplanned composite failure) ≠ (97.5% CI)

Lennox JL. Ann Intern Med 2014;161: ACTG A5257 ACTG A5257 Study: (ATV/r vs DRV/r vs RAL) + TDF/FTC ATV/r RAL DRV/r Participants contributing data, n ATV/r RAL DRV/r Participants contributing data, n ATV/r RAL DRV/r Week HIV-1 RNA level ≤ 50 copies/mL, regardless of ART change (ITT analysis) HIV-1 RNA level ≤ 50 copies/mL and receiving randomized ART (ITT, snapshot analysis) 79.8% 72.7% 62.6% 93.9% 89.4% 88.3%

Lennox JL. Ann Intern Med 2014;161: ACTG A5257 ACTG A5257 Study: (ATV/r vs DRV/r vs RAL) + TDF/FTC Genotypic analysis for resistance at virologic failure ATV/r + TDF/FTC N = 605 DRV/r + TDF/FTC N = 601 RAL + TDF/FTC N = 603 Virologic failure Genotype available Any resistance detected9418 PI resistance000 NRTI-only resistance837 - FTC - TDF - FTC and TDF INI-only resistance111 NRTI and INI resistance FTC and RAL - FTC, TDF and RAL 7373 Patients may not have been on their randomised treatment at time of failure

Lennox JL. Ann Intern Med 2014;161: ACTG A5257 ACTG A5257 Study: (ATV/r vs DRV/r vs RAL) + TDF/FTC Grade 2 or higher adverse events in ≥ 5% of participants in either group ATV/r + TDF/FTC N = 605 DRV/r + TDF/FTC N = 601 RAL + TDF/FTC N = 603 Grade, nTotalGrade, nTotalGrade, nTotal Diarrhea (7.6) (8.6) (6.0) Nausea (7.4) (6.8) (5.5) Vomiting (5.0) (5.3) (4.0) Abdominal pain (5.1) (4.8) (2.8) Headache (5.8) (7.3) (7.0) Pain in extremity (6.9) (5.3) (7.5) Arthralgia (4.1) (4.7) (3.6) Back pain (3.0) (3.5) (5.1) Fatigue (6.4) (5.5) (5.1) Cough (6.9) (6.0) (6.6) Dyspepsia (4.3) (3.8) (4.6) Pyrexia (4.3) (4.5) (5.8) Hyperbilirubinemia (47.3)0404 (< 1)0505 (< 1) Hypophosphatemia (5.6) (6.2) (4.8) Hyperglycemia (4.3) (4.5) (4.3)

Lennox JL. Ann Intern Med 2014;161: ACTG A5257 ACTG A5257 Study: (ATV/r vs DRV/r vs RAL) + TDF/FTC Other safety data ATV/r + TDF/FTC N = 605 DRV/r + TDF/FTC N = 601 RAL + TDF/FTC N = week cumulative incidence of the 1st clinical or laboratory AE Any AE80.3%64.9%59.5% Excluding bilirubin and CK62.3%64.9%59.3% Fasting LDL-cholesterol increasep ≤ 0.001* - Fasting triglycerides increasep ≤ 0.001* - Grade 3-4 elevation in creatinineN = 7N = 12N = 4 Substitution of TDF and/or FTCN = 20N = 23 N = 9 * vs RAL

 Conclusion –ATV/r, RAL, and DRV/r were equivalent for virologic efficacy, when given with TDF/FTC –ATV/r + TDF/FTC was less-well tolerated than DRV/r + TDF/FTC or RAL + TDF/FTC –A composite assessment of virologic efficacy and tolerability found that RAL + TDF/FTC was superior to both PI-containing regimens DRV/r + TDF/FTC was superior to ATV/r + TDF/FTC –Tolerability result was caused primarily by jaundice for ATV/r and gastrointestinal toxicity for both PI/r ATV/r was less tolerated than DRV/r and RAL across all sub-groups RAL tolerability benefit over DRV/r was greater in women –Limitations: open-label design, switch to another arm for tolerability or toxicity allowed –When tolerability and virologic response are considered together, RAL + TDF/FTC was superior overall to both PI-based therapies and DRV/r was superior to ATV/r. An advantage of PI/r over RAL is the reduced likelihood of drug resistance if virologic failure occurs Lennox JL. Ann Intern Med 2014;161: ACTG A5257 ACTG A5257 Study: (ATV/r vs DRV/r vs RAL) + TDF/FTC