ADVANCE Trial: DTG Combined with TAF or TDF, Noninferior to the Standard -of- care Regimen at Week 48

15 Jun, 20

Introduction

Dolutegravir (DTG) has potency, resistance, and side-effect benefits over EFV, and there are widespread plans to expand its use in low- and middle-income countries rapidly.

To evaluate the efficacy and safety of two antiretroviral therapy (ART) combinations tenofovir alafenamide fumarate (TAF)/emtricitabine (FTC)/dolutegravir (DTG) (TAF/FTC/DTG) and tenofovir disoproxil fumarate (TDF)/FTC/DTG, as compared with the current first-line regimen of TDF–FTC (or 3TC)– efavirenz (EFV) used in the majority of patients in low- and middle-income countries

Patient Profile

Patients with HIV type 1 (HIV-1) infection starting ART
Age of 12 years or older
Weight of 40 kg or more
Viral load of 500 copies or more per millilitre
Creatinine clearance of more than 60 ml per minute (Cockcroft–Gault formula) in patients 19 years of age or older or more than 80 ml per minute (modified Cockcroft–Gault formula) in those younger than 19 years of age

Methods

The ADVANCE trial is randomized, open-label, noninferiority, 96-week, phase 3 trial
Patients were randomly assigned (in a 1:1:1 ratio) to receive TAF–FTC–DTG, as two tablets daily (TAF-based group); TDF–FTC–DTG, as two tablets daily (TDF-based group); or TDF–FTC–EFV as a single tablet daily (standard-care group).

Figure 1: Study Design

Study Outcomes

The primary endpoint was the percentage of patients with an HIV-1 RNA level of less than 50 copies per millilitre at week 48.
Secondary Outcomes: Additional viral-load thresholds, CD4 count changes, and side-effect profile and safety, including findings on physical examination, laboratory analyses, and dual-energy x-ray absorptiometry (DXA) scans

Results

A total of 59% of the patients were female, more than 99% were black, and 62% were from South Africa
Mean CD4 count was 337 cells per cubic millimetre
78% of the patients had a baseline HIV-1 RNA level of less than 100,000 copies per millilitre

Table 1: Baseline characteristics

Characteristic	TAF-Based Group (N = 351)	TDF-Based Group (N = 351)	Standard-Care Group (N = 351)
Female sex — no. (%)	214 (61)	208 (59)	201 (57)
Age — yr	33±7.8	32±8.1	32±7.4
Body weight — kg
Male patients	67.9±10.9	67.1±11.2	67.3±11.9
Female patients	68.8±14.8	69.5±16.2	70.2±16.5
Body-mass index
Male patients	21.7±3.7	21.6±3.3	21.8±3.6
Female patients	25.6±5.0	26.1±6.1	26.1±6.2
Categories of body-mass index — no./total no. (%)
<18.5: underweight	42/350 (12)	35/351 (10)	37/351 (11)
18.5 to <25: normal	177/350 (51)	190/351 (54)	193/351 (55)
25 to <30: overweight	96/350 (27)	78/351 (22)	77/351 (22)
≥30: obese	35/350 (10)	48/351 (14)	44/351 (13)
CD4 count — cells/mm³	349±225.3	323±234.3	337±221.6
HIV-1 RNA level — no. (%)
≤100,000 copies/ml	274 (78)	280 (80)	271 (77)
100,001–500,000 copies/ml	66 (19)	62 (18)	72 (21)
>500,000 copies/ml	11 (3)	9 (3)	8 (2)

* Plus–minus values are means + SD. Patients were randomly assigned to receive tenofovir alafenamide fumarate (TAF)–emtricitabine (FTC)–dolutegravir (DTG) (TAF-based group), tenofovir disoproxil fumarate (TDF)–FTC–DTG (TDF-based group), or TDF–FTC–efavirenz (standard-care group). Percentages may not total 100 owing to rounding. HIV-1 denotes human immunodeficiency virus type 1.

Efficacy outcomes at week 48

DTG-containing regimens were noninferior to the standard-care regimen

Figure 1: Primary Endpoint: Percentage of patients with an HIV-1 RNA level of less than 50 copies per millilitre at week 48

The difference between the prevalence of HIV-1 RNA suppression at week 48
- TAF-based group and the standard-care group was 5.1 percentage points (P = 0.08)
- TDF-based group and the standard-care group was 6.3 percentage points (P = 0.03)
- TAF-based group and the TDF-based group was −1.1 percentage points (P = 0.68)
The time to viral suppression at an HIV-1 RNA level of less than 50 copies per millilitre was longer in the standard-care group than in the other two groups
No resistance to integrase inhibitors was observed in patients receiving the DTG-containing regimens

In a multivariate analysis of response, younger age (≤32 years) and unemployment were significant predictors of treatment failure at week 48 (P<0.01 for both comparisons)

Safety Outcomes At week 48

The standard-care group had more discontinuations because of adverse events and a higher incidence of loss to follow-up than the other two groups

Weight gain was associated with DTG.
In the TAF-based group, weight increase (both lean and fat mass) was greatest among female patients and patients with lower CD4 counts and higher viral loads.
- TAF -based group mean increase was 64 kg
- TDF-based group was 3.2 kg
- Standard -care group was 1.7 kg
The TDF-containing regimens had a greater effect on lumbar and hip DXA-assessed bone density and renal tubular markers than the TAF-based regimen
There were slightly more reported cases of grade 3 or 4 insomnia in the TAF-based group than in the other groups but no discontinuations of the trial regimen due to insomnia

Table 2: Adverse Events and Laboratory Abnormalities That Emerged during Treatment ^*

Adverse Events	TAF-Based Group (N = 351)	TDF-Based Group (N = 351	Standard-Care Group (N = 351)
Adverse event leading to discontinuation of trial regimen — no. of patients^†	1	0	10
Elevated liver enzymes	1	0	5
Rash	0	0	2
Renal disorder	0	0	2
Adverse event of grade 2–4 — no. of patients	21	19	26
Hypertension^‡	11	13	4
Dizziness	0	0	12
Neutropenia	4	4	9
Insomnia	6	2	1
Most common grade 3 or 4 laboratory abnormalities — no. of patients^§	26	37	83
Elevated ?-glutamyl transferase	4	6	35
Elevated alanine aminotransferase	10	7	18
Elevated aspartate aminotransferase	6	6	14
Abnormal creatinine clearance	3	11	6
Low hemoglobin	3	7	10
DXA of bone
New osteopenia — (%)
Whole body	1	2	1
Spine	18	23	22
Hip	7	16	18
New osteoporosis — (%)
Spine	4	7	8
Hip	1	1	5
DXA of body composition — kg^¶
Mean change in truncal fat
Male patients 0.6 0.1 −0.4
Female patients	1.7	0.7	0.1
Mean change in truncal lean mass
Male patients	1.8	1.2	0.7
Female patients	1.1	1.0	0.6
Mean change in limb fat
Male patients	0.5	0.1	−0.4
Female patients	1.9	0.6	0.2
Mean change in limb lean mass
Male patients	2.2	1.5	0.7
Female patients	1.8	1.2	0.7
New obesity —(%)^?
Male patients	7	3	3
Female patients	20	11	9

* DXA denotes dual-energy x-ray absorptiometry.

† All discontinuations were for presumed DTG or efavirenz toxicity, except for two discontinuations due to renal disorders,

both of which involved clinical conditions that resulted in discontinuation of TDF.

‡ Despite the higher number of patients reporting hypertension in the groups receiving the DTG-containing regimens than in the standard-care group, there were no substantial differences among the three groups with regard to systolic or diastolic blood pressure.

§ Shown are grade 3 or 4 laboratory abnormalities that occurred in at least 5% of the patients. Grading of laboratory abnormalities was done according to criteria of the Division of AIDS, National Institute of Allergy and Infectious Diseases.

¶ Shown is the mean change from baseline to week 48.

? New obesity was measured from baseline to week 48. All patients with paired data were included in the analysis, except for patients who were obese at baseline.

** New underweight was measured from baseline to week 48. All patients with paired data were included in the analysis, except for patients who were underweight at baseline and female patients who were pregnant.

Conclusion

The ADVANCE trial demonstrated that treatment with DTG combined with either of two tenofovir prodrugs (TAF and TDF) was noninferior to the standard of- care regimen with respect to the percentage of patients with HIV-1 RNA suppression at week 48
There was significantly more weight gain with the DTG-containing regimens, especially in combination with TAF than with the standard-care regimen