Dual therapy with

DTG/3TC or DTG/RPV

Dual therapy with

DTG/3TC or DTG/RPV

A new de-generation of HIV treatment

“Honeymoon phase”Drug just launched, Safety profile looks good

Phase 3 studies had strict inclusion and exclusion criteria

“Marriage blues”In the long-term, new evidence emerges…..

New patient populations, larger sample sizes, new methods to study

adverse events

Some couples can be a bit strange

SWORD and GEMINI trials

No improvement in efficacy

More discontinuations for adverse events on

dual therapy

…?????

All Grade 1-4 Adverse Events in switch

versus non-switch trials of DTG

Discontinuations due to Adverse Events

in switch vs non-switch trials of DTG

HIV RNA <50 copies/ml in switch

versus non-switch trials of DTG

Favours Control Favours DTG

Safety of unboosted TDF/FTC vs TAF/FTC

Meta-analysis of 5 treatment trials, n=3181

72.3%

16.3%

4.4% 5.2%

0.2% 0.0%

70%

20.7%

5% 4.8%

0.7% 0.1%0

10

20

30

40

50

60

70

80

1 2 3 4 5 6

Perc

en

t w

ith

ad

vers

e e

ven

ts

Grade 1-4

Clinical

Grade 3-4

Laboratory

Grade 3-4

Clinical

Serious

Adverse

Events

Bone

Fractures

Renal

D/C

Hill et al, J Virus Erad 2018, 4:72-78

p = n.s.

p = n.s.

p = n.s. p = n.s. p = n.s. p = n.s.

TDF/FTC TAF/FTC

Pilkington et al. J Vir. Erad 2018

Significant Increase in

Risk on PrEP? None None None None

17.4

9.4

3.7

0.1

4.3

16.8

10.1

3.3

0.12.3

0

2

4

6

8

10

12

14

16

18

20

%Ev

ent

s/To

tal People

Grade 3/4 Adverse Events

Serious Adverse Events

Fractures Creatinine Elevations (Grade 3+)

Creatinine Elevations (Grades 1-4)

p=0.04

PrEP: Safety of TDF/FTC vs placeboMeta-analysis of 13 PrEP trials, 22,730 person-years of follow up

p = n.s.

p = n.s.

p = n.s.

p = n.s.

p = 0.04

TDF/FTC placebo

Dual therapy approved!

BUT:

baseline resistance test.

Low baseline HIV RNA

Hepatitis C co-infection

Pregnant women?

Any experience in Africa / LMICs?

100 patients in Europe: what could happen if they switch to DTG/3TC?

Pregnant women NO DATA 7 PRIOR VF – NO DATA

HBV co-infection LFT FLARES? 6% NO BL RESISTANCE….???

100 patients in Africa: what could happen if they switch to DTG/3TC?

Pregnant women NO DATA 7 PRIOR VF – NO DATA

HBV co-infection LFT FLARES? 6% NO BL RESISTANCE….???

____________________________________________________________

Trial Design Outcomes

____________________________________________________________

NEAT 022 NRTIs + DTG +1kg rise in body weight to Week 48 (p=0.002)

(N=415, switch) NRTIs + PI/r

SPRING-1 TDF/FTC/EFV rises in body weight higher in DTG arms

N=204, naive TDF/FTC/DTG

Gilead 1490 TAF/FTC/DTG +3.9kg rise in body weight to Week 96

N=645, naïve TAF/FTC/BIC +3.5kg rise in body weight to Week 96

MONODO DTG mono +4.1kg rise in body weight to Week 24

N=8, naïve

____________________________________________________________

Randomised trials – effects of DTG and BIC on weight

DTG: DonuTaGravir

BIC: BIsCuitegravir

Weight gain on INSTI – women gain 2x more than men

Weight gain on INSTI – black people gain 2x more than whites

TDF = Tenofovir Diet Formula

TDF as PrEP: weight loss >5%

Odds Ratio = 1.32 (1.11 to 1.58)

P = 0.002

23

Change in body weight after switch from TDF to TAF – German cohort study

Gomez et al. Weight Gain switching TDF to TAF. Infection 2018

Only switch patients are shown, “TDF (TAF)—first/last weight measurement” denotes thefirst/last weight measured on TDF (TAF) treatment; results shown for weight in kg; NS not statistically significant

TAF = Tenofovir Added Fat

________________________________________

Drivers of weight gain / loss

25

Treatment

naive

Weight

gain

Weight

loss

________________________________________

Drivers of weight gain / loss

26

TDF

DTG

or BICTreatment

naive

Weight

gain

Weight

loss

PI

________________________________________

Drivers of weight gain / loss

27

TDF

DTG

or BIC

Women Black

Treatment

naive

Weight

gain

Weight

loss

PI

Some pairs will deny there are Any problems…..

Body weight: main ViiV Phase 3 trials

VIIV DTG

Randomised

clinical trials

n=6912

Integrated Safety Summary

SINGLE, n=833

SPRING-2, n=822

ARIA, n=495

FLAMINGO, n=484

GEMINI, n=1433

STRIIVING, n=551

SWORD 1+2, n=1024

DAWNING, n=551

SAILING, n=719

Sample size

= total enrolled

VIIV DTG

Randomised

clinical trials

n=6912

Integrated Safety Summary

SINGLE, n=833

SPRING-2, n=822

ARIA, n=495

FLAMINGO, n=484

GEMINI, n=1433

STRIIVING, n=551

SWORD 1+2, n=1024

DAWNING, n=551

SAILING, n=719

Sample size

= total enrolled

Weight not measured in any

trials, despite pre-clinical

signal on melanocortin

receptors suggesting

increased appetite

Dual therapy – a new de-

generation of HIV

treatment

No efficacy benefits

Safety the same or worse

Weight rises – watch this space

Cannot be used unless many tests have

been performed.