ADVANCE Trial: 96-week Efficacy and Safety of DTG Combined with FTC and TAF or TDF versus EFV Combined with FTC and TDF

Table of Content

Introduction

The ADVANCE study is an ongoing randomised, open-label, non-inferiority phase 3 trial that evaluates safety and efficacy of dolutegravir (DTG) or efavirenz (EFV), both combined with tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC), or a third regimen of dolutegravir combined with tenofovir alafenamide and emtricitabine (TAF). Previous 48-week virological efficacy and safety data showed more weight gain in the dolutegravir groups than in the efavirenz group, especially when dolutegravir was combined with tenofovir alafenamide.

Aim

To compare the efficacy and safety, with additional metabolic markers, including an analysis of visceral adipose tissue using dual-energy x-ray absorptiometry (DXA),  of two antiretroviral first-line combinations (dolutegravir combined with emtricitabine and either tenofovir disoproxil fumarate or tenofovir alafenamide), with a third regimen (efavirenz combined with emtricitabine and tenofovir disoproxil fumarate)

Patient Profile

  • Patients with HIV type 1 (HIV-1) infection and had no antiretroviral exposure in the previous 6 months
  • Age: 12 years or older
  • Weight: 40 kg or more
  • Plasma HIV-1 viral load: 500 copies/mL or higher
  • Creatinine clearance of more than 60 mL/min (Cockcroft–Gault formula) in patients 19 years of age or older or more than 80 mL/ minute (modified Cockcroft–Gault formula) in those younger than 19 years of age

Methods

Study Design

Study Regimens

  • Once-daily oral fixed-dose combination tenofovir alafenamide 25 mg and emtricitabine 200 mg, and once-daily oral dolutegravir 50 mg
  • Once-daily oral fixed-dose combination tenofovir disoproxil fumarate 300 mg and emtricitabine 200 mg, and once-daily oral dolutegravir 50 mg
  • Once-daily oral fixed-dose combination of tenofovir disoproxil fumarate 300 mg, emtricitabine 200 mg, and efavirenz 600 mg

Study Outcomes

  • The proportion of participants who had a plasma HIV-1 RNA concentration of less than 50 copies per mL at the week 96 visit
  • Secondary safety analyses included physical examination and measurement of vital signs, laboratory analyses, dual-energy x-ray absorptiometry (DXA) scans, and monitoring of adverse events and concomitant medications during the study
  • Genotyping was done in participants who had ongoing virological failure

Results

  • Baseline demographics were similar between treatment groups, with a mean age of 32 years
  • 623 (59%) of 1053 participants were women, 1051 (99%) were black, and 398 (38%) were from outside South Africa
  • The mean CD4 count was 337 cells/μL (range 1–1721)
  • Baseline plasma HIV-1 RNA concentration of more than 100 000 copies per mL was measured in 228 (22%) participants
  • 10% participants had hypertension, 2% had diabetes and 5% had metabolic syndrome.

Efficacy outcomes at week 96

  • Non-inferiority was established in all three comparisons, and no significant treatment effects were observed. 
Figure 1: Percentage of patients with an HIV-1 RNA level of less than 50 copies/mL and HIV RNA concentration of 50 copies/mL or higher at week 96

  • Protocol -defined virological failure was reported in
    • tenofovir alafenamide, emtricitabine, and dolutegravir group =18%
    • tenofovir disoproxil fumarate, emtricitabine, and dolutegravir group=19%
    • tenofovir disoproxil fumarate, emtricitabine, and efavirenz group =14%

Safety

  • All three regimens were well tolerated, with more discontinuations observed in the efavirenz-containing group within first 48 weeks than the two other treatment groups
  • The only grade 3 or 4 differences between groups were associated with dizziness or elevated ɣ.-glutamyl transferase, with more events in the tenofovir disoproxil fumarate, emtricitabine, and efavirenz group than the other groups
  • Dolutegravir-containing regimen group reported higher weight gain than the group given the efavirenz-containing regimen and was significantly higher when combined with tenofovir alafenamide at week 96
    • Tenofovir alafenamide, emtricitabine, and dolutegravir group mean increase was 7.1 kg
    • Tenofovir disoproxil fumarate, emtricitabine, and dolutegravir group was 4.3 kg
    • Tenofovir disoproxil fumarate, emtricitabine, and efavirenz group was 2.3 kg
  • Increases in fat mass (combined trunk and limbs) was significantly higher in women than men (p<0·001)
  • Increases in visceral adipose tissue between baseline and week 96 were higher in women than men, although these differences were not statistically significant, and were higher in the tenofovir alafenamide, emtricitabine, and dolutegravir group
Table 1: Body composition and obesity outcomes at week 96

 

Tenofovir

alafenamide,

emtricitabine,

and

dolutegravir

group (n=351)

Tenofovir

disoproxil

fumarate,

emtricitabine,

and dolutegravir

group (n=351)

Tenofovir

disoproxil

fumarate,

emtricitabine,

and efavirenz

group (n=351)

Mean change in body composition from baseline to week 96*

Participants with available data, n

 

 

Men

102

117

108

Women

157

151

142

Trunk fat, kg

 

 

 

Men

1·8 (2·2)

1·4 (2·1)

0·6 (2·0)

Women

2·8 (2·7)

1·8 (2·5)

1·3 (2·5)

Trunk lean mass, kg

 

 

 

Men

1·1 (1·6)

0·4 (1·5)

0·1 (1·3)

Women

0·7 (1·3)

0·4 (1·3)

0·1 (1·4)

Limb fat, kg

 

 

 

Men

1·4 (2·0)

1·0 (1·7)

0·5 (1·7)

Women

2·5 (2·8)

1·5 (2·5)

1·2 (2·5)

Limb lean mass, kg

 

 

 

Men

1·5 (1·7)

0·8 (1·6)

–0·1 (1·5)

Women

1·4 (1·4)

0·9 (1·5)

0·3 (1·5)

Mean change in visceral adipose tissue from baseline to week 96

Participants with available data, n

 

 

Men

96

120

108

Women

154

143

129

Mass, kg

 

 

 

Men

0·11 (0·11)

0·06 (0·13)

0·05 (0·12)

Women

0·14 (0·15)

0·08 (0·13)

0·07 (0·14)

Mass, percentage change

 

 

Men

35·8% (38·3)

22·7% (37·7)

17·8% (34·8)

Women

51·4% (57·9)

33·8% (66·7)

27·8% (61·1)

Volume, cm3

 

 

 

Men

117·1 (124·2)

62·4 (140·8)

48·9 (124·4)

Women

151·2 (166·8)

88·2 (141·1)

80·8 (153·8)

Visceral adipose tissue to subcutaneous adipose tissue mass ratio

Men

–0·06 (0·12)

–0·04 (0·11)

–0·02 (0·11)

Women

0·02 (0·07)

0·01 (0·05)

0·02 (0·06)

Treatment-emergent obesity at week 96†

 

Men

5/108 (5%)

5/120 (4%)

3/112 (3%)

Women

42/151 (28%)

23/129 (18%)

15/125 (12%)

Data are n, n/N (%) or mean (SD). On-treatment findings for all individuals with results at week 96. Individuals with obesity at baseline were excluded; obesity was defined as body-mass index of higher than 30 kg/m². DXA=dual-energy x-ray absorptiometry. *Assessed by DXA. †p=0·0012 for tenofovir alafenamide, emtricitabine, and dolutegravir group vs tenofovir disoproxil fumarate, emtricitabine, and efavirenz group; p=0·1928 for tenofovir disoproxil fumarate, emtricitabine, and dolutegravir group vs tenofovir disoproxil fumarate, emtricitabine, and efavirenz group; and p=0·0049 for tenofovir alafenamide, emtricitabine, and dolutegravir group vs tenofovir disoproxil fumarate, emtricitabine, and dolutegravir group.

  • No differences were identified in total bone density. However, greater bone density in the hip and lumbar area were observed in the tenofovir alafenamide group when compared with the two other groups.
  • A positive correlation between percentage change in weight and percentage change in hip bone mineral density for all three groups
  • No association was observed between changes in weight and spine bone mineral density
  • 88 pregnancies occurred among 82 women, during the 96-week follow-up period
    • Three congenital anomalies were reported, including one child each with umbilical hernia, polydactyly, and micropenis
    • No neural tube defects were recorded

Conclusion

  • This study identified higher weight gain in the groups given the dolutegravir-containing regimens than the group given the efavirenz-containing regimen, which was significantly higher when combined with tenofovir alafenamide
  • Medium-term and long-term metabolic and clinical consequences of the considerable increase in body weight were observed in participants given these antiretroviral regimens
  • Future research is required to investigate whether weight gain would plateau and the effect of weight gain on cardiovascular risk markers over longer periods, and to assess switch strategies for those affected
  • Currently, the only practical alternative to dolutegravir is efavirenz in low-income and middle-income countries, and addressing improved first-line regimens, including investigation of other potential replacements for dolute- gravir and efavirenz, is urgently needed

Reference

 Lancet HIV 2020; 7: e666–76