comparison of nrti combinations

Comparison of NRTI combinations

ZDV/3TC vs TDF + FTC– Study 934

ABC/3TC vs TDF/FTC– HEAT Study– ACTG A5202 Study– ASSERT Study

FTC/TDF vs FTC/TAF– Studies GS-US-292-0104 and GS-US-292-0111

Sax PE. JAIDS 2014;67:52-82920102/TAF phase 2

Design

Primary objective– Determine virologic efficacy of EVG/c/FTC/TAF

– 150 patients provide 76% power to detect a 1.5% (SD of 3.3%) difference in hip bone mineral density in the EVG/c/FTC/TAF arm relative to the EVG/c/FTC/TDF arm

EVG/c/FTC/TAF 150/150/200/10 mg QD STREVG/c/FTC/TDF placebo

EVG/c/FTC/TDF 150/150/200/300 mg QD STREVG/c/FTC/TAF placebo

Randomisation*2 : 1

Double-blind

Randomisation*2 : 1

Double-blind

> 18 yearsARV-naïve

HIV RNA > 5,000 c/mLCD4 cell count > 50/mm3

eGFR > 70 mL/min

> 18 yearsARV-naïve

HIV RNA > 5,000 c/mLCD4 cell count > 50/mm3

eGFR > 70 mL/min

*Randomisation was stratified by HIV RNA (< or > 100,000 c/mL) at screening

Study 292-0102: EVG/c/FTC/TAF QD vs EVG/c/FTC/TDF QD (Phase 2)

N =58

N = 112

W24W24 W48W48

Baseline characteristics– Median viral load at baseline : 4.6 log10 c/mL (21% > 100,000 c/mL),

median CD4+ cell count : 391 cells/mm3 (15% > 200/mm3)

Main results– Discontinuation due to adverse events by W48 : 4 in TAF arm vs 0 in TDF arm

– HIV RNA < 50 c/mL at W24 : 87.5% E/c/F/TAF vs 89.7% E/c/F/TDF

– 3 patients in each arm met criteria for resistance testing (virologic failure [2 consecutive HIV RNA > 50 c/mL] with HIV RNA > 400 c/mL). Genotype was performed on confirmatory sample

• E/c/F/TAF : no resistance detected

• E/c/F/TDF : 2 patients developed resistance, 1 to NRTI, 1 to INSTI + NRTI

– PK substudy : plasma TFV exposure was 91% lower with E/c/F/TAF than with E/c/F/TDF, as measured by AUCtau. Conversely, intracellular TFV-DP levels in PBMCs were 5.3-fold higher with E/c/F/TAF



Safety– Significantly less change in the E/c/F/TAF arm in BMD at hip

(-0.62% vs -2.39%, p < 0.001) and lumbar spine (-1.0% vs -3.37%, p < 0.001) at W48, which were also significant at week 24

– In the E/c/F/TAF arm, 32% of patients had no decrease in hip BMD vs 7% in the E/c/F/TDF arm (p < 0.001)

– Median change in eGFR by Cockcroft–Gault = -5.5 mL/min for E/c/F/TAF vs -10.1 mL/min for E/c/F/TDF (p = 0.041)

– Renal tubular proteinuria [urine retinol-binding protein/creatinine ratio and urine -2 microglobulin/creatinine ratio] was significantly lower in patients who received E/c/F/TAF : no cases of proximal tubulopathy

– Grade 3-4 adverse events : 9.8% TAF vs 5.2% TDF– Most common treatment-emergent adverse events : nausea (21% vs 12%),

diarrhea (16% in each arm)– Higher elevations in lipids with TAF



E/C/F/TAF E/C/F/TDFAny 25% 17%

LDL-cholesterol 9% 3%

Creatine phosphokinase 6% 3%

Neutropenia 5% 2%

Amylase 3% 3%

Urine red blood cells 2% 0

Total cholesterol 2% 0

ALT / AST 1% / 1% 2% / 0

Gamma glutamyl transferase 1% 2%

White blood cells 1% 0

Hypophosphatemia 1% 0

Urine protein 1% 0

Glucose 1% 2%

Triglycerides 1% 2%

Grade 3 or 4 laboratory abnormalities



Summary of week 48 results– In this phase 2, randomised clinical trial, HIV-positive treatment-naive adults

received STRs of E/c/F/TAF or E/c/F/TDF. Both STRs demonstrated high and comparable rates of virologic suppression through 48 weeks of therapy

– Both regimens were well tolerated, with few discontinuations due to adverse events. Nausea occurred more frequently with E/c/F/TAF

– Plasma concentrations of TFV were substantially (91%) lower with E/c/F/TAF than with E/c/ F/TDF, and the TAF regimen delivered 5.3 times the intracellular, physiologically active metabolite, TFV-DP, to PBMCs, which could translate into less end-organ toxicity and/or improved virologic control

– Significant smaller decreases in bone mineral density through 48 with E/c/F/TAF than with E/c/F/TDF

– Urinary RBP/creatinine and -2 microglobulin/creatinine ratios were significantly lower in the E/c/F/TAF arm, which suggests that TAF has a lesser effect than TDF on the proximal renal tubular cell



comparison of nrti combinations

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