1. Why Dolutegravir? Daniel R. Kuritzkes, M.D.
Division of Infectious Diseases
Brigham and Women’s Hospital
Harvard Medical School

2. Disclosures
The speaker has received consulting honoraria, speaker fees or research grants from the following companies:
Gilead
GlaxoSmithKline
Janssen
Merck
ViiV

3. Why dolutegravir?
INSTI-based regimens now considered first line by ART guidelines worldwide
Increased prevalence of pre-existing NNRTI resistance requires alternative first-line ART
Favorable generic pricing of fixed-dose combination TLD makes this regimen cost-effective and cost-saving in many settings
Since 2016, WHO antiretroviral treatment guidelines have included DTG-based ART as an alternative first-line option

4. Potential advantages of dolutegravir
Similar efficacy to raltegravir
Superior to efavirenz and boosted darunavir
High barrier to resistance
No resistance observed to date in patients receiving DTG as first-line cART
Increasing resistance with accumulation of G140S/Q148H and additional RAL or EVG DRM
Caveat: DTG resistance may occur when used as monotherapy
Dolutegravir superior to LPV/r as second-line cART (DAWNING)
Data pending from ADVANCE
DTG/TAF/FTC vs DTG/TDF/FTC vs EFV/TDF/FTC

5. SINGLE study week 144 results
Walmsley S et al JAIDS 2015

6. SINGLE: Resistance at virologic failure
TDF/FTC/EFV
Walmsley et al ICAAC 2012
DRK

7. SPRING-2: Dolutegravir vs raltegravir
Proportion of patients with plasma HIV-1 RNA <50 c/mL
Raffi F et al Lancet Infect Dis 2013

8. Resistance in SPRING-2
Raffi F et al Lancet Infect Dis 2013

9. FLAMINGO: Primary result (proportion of patients with VL <50 c/mL)
N=242 per arm
Clotet B et al Lancet. 2014

10. Safety and tolerability of dolutegravir
Safe and well-tolerated in phase 3 trials
Fewer CNS side effects than EFV
Comparable to raltegravir, darunavir+ritonavir
Slight increase in serum Cr due to inhibition of tubular Cr secretion by DTG (no tubular or glomerular pathology)
One report from The Netherlands noted discontinuation of DTG-based cART in ~10% due to CNS toxicities1
Possible association with neural tube defects when taken during 1st trimester of pregnancy2
1de Boer et al AIDS 2016
2Zash R et al Intl AIDS Conf Amsterdam 2018

11. SPRING-2: Change in creatinine

12. DAWNING: DTG vs LPV/r as second-line ART
Aboud M et al 9th IAS Conf on HIV Science, Paris, 2017

13. INSPIRING: 48-week results
Dooley K et al Intl AIDS Conf, Amsterdam, 2018

14. GEMINI 1 and 2 Week 48 Results (Snapshot analysis)
No treatment-emergent INSTI mutations or NRTI mutations were observed among participants who met CVW (confirmed virologic failure) criteria
Cahn P et al Intl AIDS Conf, Amsterdam, 2018

15. Emergence of DTG resistance in monotherapy studies
Study name N
Efficacy
VF (N)
DRM/n
DRM/VFs
Mutations
ITALY 20
95% 1 -
DONOMO 86
88% 8
3/86 (3.5%)
3/8 (37.5%)
263K (1)
155H (1)
230R (1)
DOLAM 31
93.5% 2
2/31 (65%)
2/2 (100%)
155H, 147G, 148R (1)
138K, 155H, 140S (1)
REDOMO
122
91% 11
9/122 (7.4%)
9/11 (82%)
(various)
DOLUFRENCH 28
89% 3
3/28 (11%)
3/3 (100%)
138K, 140A, 148R (1), 74I, 92Q (1), 155H (1)
MONOCAY 78
93.6% 7
2/78 (2.6%)
2/7 (29%)
147G, 155H (1)
Adapted from Blanco JL et al Curr Opin Infect Dis 2018

16. Conclusions
Dolutegravir-based cART superior to current first- and second-line cART used in RLS
Higher barrier to resistance may provide advantages of current cART regimens
Twice-daily dosing permits use with rifampicin in patients who require treatment of TB
A switch to DTG as first-line ART more cost-effective than pre-ART resistance testing in LMIC
Despite high barrier to resistance, the drug is not foolproof—avoid monotherapy!
Potential embryotoxicity requires further study