144-week Efficacy and Safety of Fixed-dose Combination Bictegravir, Emtricitabine, and Tenofovir alafenamide versus Dolutegravir-containing Regimens for Initial Treatment of HIV-1 Infection

13 Jan, 21

Introduction

Bictegravir is the most recent addition to the integrase strand-transfer inhibitor class. Bictegravir, coformulated with emtricitabine and tenofovir alafenamide, when compared with either co-formulated dolutegravir, abacavir, and lamivudine or dolutegravir plus emtricitabine and tenofovir alafenamide was non-inferior to either dolutegravir-containing regimen for up to 96 weeks

Aim

To evaluate 144-week efficacy and safety outcomes of bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir-containing regimens in treatment-naive individuals initiating HIV therapy

Patient Profile

Study1

Treatment-naive adults living with HIV, with plasma HIV-1 RNA levels of at least 500 copies/mL, HLA-B*5701 negative, did not have hepatitis B virus infection, and who had an estimated glomerular filtration rate (eGFR) 50 mL/min (Cockcroft–Gault equation).

Study 2

Treatment-naive adults living with HIV with an eGFR 30 mL/min; participants with chronic hepatitis B infection were allowed to participate.

Methods

Randomised, double-blind, multicentre, phase 3, non-inferiority trials

Study Design

Study Drugs

A once-daily regimen of coformulated bictegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg; or, either dolutegravir 50 mg, abacavir 600 mg, and lamivudine 300 mg (Study 1); or dolutegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg (Study 2)

Study Duration

144 week

Study Outcome

The proportion of participants with plasma HIV-1 RNA less than 50 copies per mL at week 144, as defined by the US Food and Drug Administration Snapshot algorithm

the proportion of participants with HIV-1 RNA less than 20 copies per mL at week 144 by the Snapshot algorithm
Change in CD4 cell count from baseline at week 144
The percentage changes from baseline in hip and lumbar spine bone mineral density were assessed as a secondary outcome at week 144
Renal safety assessments included the change from baseline in serum creatinine and eGFR at week 144
Adverse event incident rates through week 144 and changes in fasting lipids at week 144 were assessed by treatment group.

Results

At week 144, bictegravir, emtricitabine, and tenofovir alafenamide was non-inferior to both dolutegravir-containing regimens for efficacy.
No participant had treatment-emergent resistance to study drugs in both studies up to week 144.
Results across other efficacy outcomes consistently showed the durable efficacy of both regimens.

Figure 1: Virological outcomes at week 144

Table 1: Virological outcomes at week 144

	Study 1		Study 2
	Bictegravir, emtricitabine, and tenofovir alafenamide (n=314)	Dolutegravir, abacavir, and lamivudine (n=315)	Bictegravir, emtricitabine, and tenofovir alafenamide (n=320)	Dolutegravir plus emtricitabine, and tenofovir alafenamide (n=325)
HIV-1 RNA <50 copies per mL (full analysis set)	256 (82%)	265 (84%)	262 (81%)	273 (84%)
Difference in percentages (95% CI)	–2·6% (–8·5% to 3·4%)		–1·9% (–7·8% to 3·9%)
HIV-1 RNA ≥50 copies per mL	2 (<1%)	9 (3%)	15 (5%)	10 (3%)
HIV1 RNA ≥50 copies per mL at week 144	1 (<1%)	2 (<1%)	1 (<1%)	4 (1%)
Discontinued because of lack of efficacy	0	0	0	0
Discontinued for other reasons and last available HIV-1 RNA ≥50 copies per mL	1(<1%)	7 (0<1%)	14(4%)	6(2%)
No virological data	56(18%)	41(13%)	43(13%)	42(13%)
Discontinued because of adverse event or death	2(<1%)	6(2%)	8(3%)	9(3%)
Discontinued for other reasons and last available HIV-1 RNA <50 copies per mL	50(16%)	34(11%)	35(11%)	29(9%)
Missing data but on treatment	(1%)	(<1%)	0	(1%)
HIV-1 RNA <50 copies per mL (per-protocol set)	256/257 (99%)	260/262 (99%)	257/258 (99%)	270/273 (99%)
Difference in percentages	0·4% (–1·6% to 2·4%)		0·7% (–1·4% to 2·7%)
HIV-1 RNA <50 copies per mL by missing as failure	259/314 (83%)	267/315 (85%)	268/320 (84%)	276/325 (85%)
Difference in percentages	–2·3% (–8·1% to 3·6%)		–0·9% (–6·6% to 4·7%)
HIV-1 RNA <50 copies per mL by missing as excluded	259/260 (99%)	267/269 (99%)	268/270 (99%)	276/280 (99%)
Difference in percentages	0·4% (–1·6% to 2·3%)		0·7% (–1·6% to 2·9%)
HIV-1 RNA <20 copies per mL (full analysis set)	245(78%)	259(82%)	248(78%)	257(79%)
Difference in percentages	–4·2% (–10·5% to 2·1%)		–1·1% (–7·4% to 5·3%)

Safety

All treatment regimens were well tolerated with additional exposure
Less nausea and fewer drug-related adverse effects were reported in those treated with co-formulated bictegravir, emtricitabine, and tenofovir alafenamide compared with those who received dolutegravir, abacavir, and lamivudine

Table 2: Adverse events until week 144

	Study 1			Study 2
	Bictegravir, emtricitabine, and tenofovir alafenamide (n=314)	Dolutegravir, abacavir, and lamivudine (n=315)	p value*	Bictegravir, emtricitabine, and tenofovir alafenamide (n=320)	Dolutegravir plus emtricitabine, and tenofovir alafenamide (n=325)
Any adverse event	300 (96%)	304(97%)	··	291 (91%)	300 (92%)
Adverse event ≥10%
Nausea	38 (12%)	76 (24%)	0·0001	31 (10%)	42 (13%)
Diarrhoea	54 (17%)	57 (18%)	··	66 (21%)	52 (16%)
Upper respiratory tract infection	43 (14%)	59 (19%)	··	43 (13%)	52 (16%)
Headache	44 (14%)	56 (18%)	··	56 (18%)	57 (18%)
Nasopharyngitis	40 (13%)	52 (17%)	··	50 (16%)	62 (19%)
Syphilis	39 (12%)	49 (16%)	··	33 (10%)	31 (10%)
Back pain	34 (11%)	38 (12%)	··	28 (9%)	38 (12%)
Fatigue	33 (11%)	38 (12%)	··	28 (9%)	36 (11%)
Insomnia	25 (8%)	35 (11%)	··	29 (9%)	24 (7%)
Oropharyngeal pain	21 (7%)	35 (11%)	··	20 (6%)	18(6%)
Cough	34 (11%)	20 (6%)	··	25 (8%)	29 (9%)
Grade 3 or 4 adverse event	50 (16%)	50 (16%)	··	54 (17%)	43 (13%)
Serious adverse event	41 (13%)	53 (17%)	··	63 (20%)	40(12%)
Study drug-related adverse event	94 (30%)	132 (42%)	0·0021	71 (22%)	95(29%)
Study drug-related adverse event ≥5%
Nausea	18 (6%)	56 (18%)	<0·0001	10 (3%)	17(5%)
Diarrhoea	19 (6%)	13 (4%)	··	10 (3%)	10 (3%)
Headache	16 (5%)	16(5%)	··	14 (4%)	10 (3%)
Study drug-related serious adverse event	2 (<1%)	1 (<1%)	··	3 (<1%)	3 (<1%)
Any adverse event leading to study drug discontinuation†	0	5 (2%)	··	6 (2%)	6 (2%)
Death‡	2 (<1%)	1 (<1%)	··	4 (1%)	4 (1%)

Bone mineral density, glomerular filtration rate, and biomarkers of renal tubular function were similar between bictegravir, emtricitabine, and tenofovir alafenamide and dolutegravir, abacavir, and lamivudine
Weight gain was seen across all treatment groups in both studies, with no differences in median changes from baseline in weight at week 144 for either study

Table 3: Changes in Bone mineral density total cholesterol and weight gain at week 144

	Study 1(Bictegravir, emtricitabine, and tenofovir alafenamide vs Dolutegravir, abacavir, and Lamivudine) (p-value)	Study 2 (Bictegravir, emtricitabine, and tenofovir alafenamide vs Dolutegravir, abacavir, and Lamivudine) (p-value)
Changes from baseline in hip and lumbar spine bone mineral density
Hip BMD	−1·02% versus −1·29%
Lumbar BMD	−0·37% versus 0·04%
Median changes from baseline in lipids
fasting total cholesterol	14 mg/dL vs 10 mg/dL; p=0.034
direct LDL	21 mg/dL vs 14 mg/dL; p=0·004
total cholesterol to HDL ratio	–0·1 vs –0·3; p=0·007
Median change in weight from baseline	+4·1 kg vs +3·5 kg (p=0·196)	+4.4 kg vs +5·0 kg (p=0·649)

Conclusion

The 144-week data showed that bictegravir, emtricitabine, and tenofovir alafenamide continued to be non-inferior to dolutegravir-containing regimens
There was no emergent drug resistance or proximal renal tubulopathy detected, but with a better gastrointestinal tolerability profile
Co-formulated bictegravir, emtricitabine, and tenofovir alafenamide can be administered once daily, does not require HLA B*5701 testing, and provides guideline-recommended therapy for people with HIV and with HIV–hepatitis B virus co-infection.

Reference

Lancet HIV 2020; 7: e389–400