DISCOVER Study: Efficacy and Safety of F/TAF with F/TDF for the Prevention of HIV Among Cisgender MSM and Transgender Women Who Have Sex with Men

26 Oct, 20

Introduction

Tenofovir alafenamide shows high antiviral efficacy and improved renal and bone safety compared with tenofovir disoproxil fumarate when used for HIV treatment

To compare the efficacy and safety of emtricitabine and tenofovir alafenamide (F/TAF) with emtricitabine and tenofovir disoproxil fumarate(F/TDF) for the prevention of HIV among cisgender men who have sex with men (MSM) and transgender women who have sex with men

Patients Profile

Adult cisgender MSM
Transgender women who have sex with men
Tested HIV negative at baseline and with a high risk of acquiring HIV on the basis of their self-reported sexual behaviour

Methods

DISCOVER study is an ongoing, randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial

Study Design

¹24 participants were excluded for not having undergone a post-baseline HIV test

²28 participants were excluded for not having undergone a post-baseline HIV test

Study Drugs

F/TAF group: Once daily tablets of F/TAF FDC (emtricitabine (200 mg) and tenofovir alafenamide (25 mg)) and placebo.

F/TDF group: Once daily tablets of F/TDF FDC (emtricitabine (200 mg) and tenofovir alafenamide (300 mg)) and placebo.

Study Endpoints

The primary efficacy outcome was incident HIV infection, diagnosed by:
- serological evidence of seroconversion
- virological evidence of HIV infection
- evidence of acute HIV infection
Secondary safety outcomes, measured as percentage changes from baseline to week 48, included:
- hip bone mineral density
- spine bone mineral density
- urine ?₂-microglobulin to creatinine ratio
- retinol-binding protein to creatinine ratio
- changes in the distribution of urine protein to creatine ratio above the clinically significant threshold of 22?6 mg/mmol at 48 weeks)
- change in serum creatinine from baseline
Additional outcomes
- incidence of treatment-emergent adverse events
- other laboratory abnormalities (changes in blood lipids from baseline; changes in weight from baseline)
- HIV antiretroviral drug resistance in participants who acquired HIV infection.

Results

Baseline demographic characteristics, clinical characteristics, and risk factors were well balanced between the two groups

Table 1: Baseline characteristics

	Emtricitabine and tenofovir alafenamide group (n=2694)	Emtricitabine and tenofovir disoproxil fumarate group (n=2693)
Demographics
Age, years	34 (28–43)	34 (28–44)
Gender or sexual orientation
Transgender women who have sex with men	45 (2%)	29 (1%)
Cisgender men who have sex with men	2649 (98%)	2664 (99%)
Sexual orientation
Gay	2461 (92%)	2434 (91%)
Straight	21 (1%)	16 (1%)
Bisexual	171 (6%)	214 (8%)
Other	23 (1%)	13 (<1%)
Median body-mass index, kg/m²	25 (23–29)	25 (23–28)
Sexually transmitted infections by laboratory test at baseline visit
Rectal gonorrhoea	123/2668 (5%)	113/2669 (4%)
Rectal chlamydia	199/2669 (7%)	189/2670 (7%)
Syphilis	7 (<1%)	4 (<1%)
Self-reported HIV risk factors
Two or more of receptive condomless anal sex partners in the past 12 weeks‡	1616/2602 (62%)	1569/2597 (60%)
History of rectal gonorrhoea in the past 24 weeks	274 (10%)	262 (10%)
History of rectal chlamydia in the past 24 weeks	342 (13%)	333 (12%)
History of syphilis in the past 24 weeks	230 (9%)	263 (10%)
Recreational drug use in the past 12 weeks^‡	1785/2680 (67%)	1786/2677 (67%)
Binge drinking^‡§	618/2657 (23%)	599/2680 (22%)
Taking emtricitabine and tenofovir disoproxil fumarate for pre-exposure prophylaxis at baseline	465 (17%)	440 (16%)

^‡As reported by use of a computer-assisted self-interview.

^§Defined as the consumption of six or more drinks on one or more occasion occurring at least once per month.

F/TAF was non-inferior to F/TDF for HIV prevention
- Incidence rate ratio (IRR) was less than the prespecified non-inferiority margin of 1·62 (IRR 0·47)
After 8756 person-years of follow-up, 22 participants were diagnosed with HIV

Figure1: Incidence on F/TAF versus F/TDF at the primary efficacy analysis

F/TAF=emtricitabine and tenofovir alafenamide

F/TDF=emtricitabine and tenofovir disoproxil fumarate

F/TAF was superior to F/TDF in all six prespecified secondary safety endpoints

Table 2: Secondary outcomes

	Baseline	F/TAF	Baseline	F/TDF	P
Bone Mineral density (mean % change from Baseline)
Hip BMD		0.18		-0.99	P<0.0001^*
Spine BMD		0.50		-1.12	P<0.0001^*
? microglobulin to creatinine ratio (Change between baseline and 48 week)	9·51 µg/mmol	10.7% reduction	9·67 µg/mmol	15.2%increase	P<0.0001
RBP to creatinine ratio	11·40 µg/mmol	0.2% increase	11·72 µg/mmol	19.9%increase
Quantitative proteinuria at 48 weeks Proportion of participants (%)		1		2	P=0.005^‡
UPCR elevation >22·6 mg/mmol (Number of participants)	25	25	25	45
Serum creatinine (µmol/L)	83·10 µmol/L	83·10 +0.88	83·10 µmol/L	83·10 - 0.88
Creatinine clearance (eGFRCG) (mL/min)	123	123+1.8	121	121 -2.3	p<0·0001^†

BMD=bone mineral density. RBP=retinol-binding protein. UPCR=urine protein to creatinine ratio. eGFRCG=estimated glomerular filtration rate by Cockcroft-Gault

Both regimens were well tolerated, with a low number of participants reporting adverse events that led to discontinuation of the study drug
- F/TAF group = 36 [1%] of 2694 participants
- F/TDF group = 49 [2%] of 2693 participants

Conclusions

F/TAF has non-inferior efficacy to F/TDF for HIV prevention
F/TAF had more favourable effects on bone mineral density and biomarkers of renal safety than F/TDF
The number of adverse events for both regimens were low
Both F/TAF and F/TDF were safe and well-tolerated.
Daily F/TAF therefore, offers a new option for HIV prevention in these populations