1. SAILING
Efficacy and safety of dolutegravir (DTG) in treatment- experienced INI-naïve patients
UK/DLG/0083/14b(2)
Date of preparation: February 2017
Prescribing information is available at the end of this presentation

2. Declaration of interest
The presenter should complete this slide, declaring any conflicts of interest he/she may have.

3. DTG trials in treatment-EXPERIENCED ADULT subjects with hiv
Phase III, randomised, double-blind, active-controlled, parallel group, non-inferiority, multicentre study of:
DTG (50 mg QD) + BR
RAL (400 mg BID) + BR
SAILING1 INI-naïve
N=719
Phase IIb open-label, single-arm multicentre study (Cohort I) of:
DTG 50 mg QD + OBR (not incl. RAL)
VIKING2 (Cohort I) INI-resistant
N=27
Phase IIb open-label, single arm multicentre study (Cohort II) of:
DTG (50 mg BID) + OBR (not incl. RAL)
Subjects required to have ≥1 fully active ARV for Day 11 optimisation (not required for Cohort I)
VIKING2 (Cohort II) INI-resistant
N=24
Phase III, open-label, single-arm, multicentre study of:
DTG (50 mg BID) + OBR (not incl. RAL)
VIKING-33 INI-resistant
N=183
Phase III, open-label, placebo-controlled, multicentre study of:
DTG 50 mg BID vs placebo (both plus current failing regimen)
At Day 8, all subjects received DTG (50 mg BID) + OBR (containing ≥1 fully active ARV)
VIKING-44 INI-resistant
N=30
BID, twice daily; BR, background regimen; QD, once daily; OBR, optimised background regimen
1. Cahn P, et al. Lancet 2013;382:700–8; 2. Eron JJ, et al. J Infect Dis 2013;207:740–8; 3. Castagna A, et al. J Infect Dis 2014; 210: 740-8; 4. Akil B, et al. Antivir Ther 2015; 20:

4. Sailing: Study design
ARV-experienced, INI-naïve adults
HIV-1 RNA ≥400 c/mL*
Resistance to ≥2 ARVs (not incl. INIs)
Stratified by HIV-1 RNA (≤ or >50,000), DRV/r use and no. of fully active drugs in BR
DTG 50 mg QD plus BR [plus RAL placebo]
(n=354)
RAL 400 mg BID plus BR [plus DTG placebo]
(n=361)
Interim analysis Week 24
Week 48
Primary endpoint: proportion of patients with HIV-1 RNA <50 c/mL at Week 48, FDA Snapshot analysis (12% non-inferiority margin with pre-specified tests for superiority)
*With 2 consecutive HIV-1 RNA ≥400 c/mL, unless screening HIV-1 RNA >1,000 c/mL
Adapted from Cahn P, et al. Lancet 2013;382(9893):700-8

5. Baseline Characteristics
DTG 50 mg QD (n=354)
RAL 400 mg BID (n=361)
Age, median (years) 42 43
Gender, female (%) 30 34
Race
White (%) 49 48
African American or African heritage (%) 40 44
HIV-1 RNA, median (log10 c/mL)
4.17
4.21
>50,000 c/mL (%)
CD4+ count, median (cells/mm3)
205
193
HBV coinfection (%) 5 4
HCV coinfection (%) 9 13
Duration prior ART, median (months) 80 72
≥3 class resistance (%) 47 51
Most common background regimens, n (%)
DRV/r, TDF
62 (18)
73 (20)
LPV/r, TDF
40 (11)
DRV/r, ETR
33 (9)
LPV/r
36 (10)
35 (10)
ATV/r, TDF
37 (10)
DRV/r, MVC
23 (6)
19 (5)
Adapted from Cahn P, et al. Lancet 2013;382(9893):700-8

6. Proportion achieving HIV-1 RNA <50 c/mL (%)
In treatment-experienced, INI-naïve patients, DTG had statistically superior efficacy vs RAL AT 48 weeks
100 90
DTG 71% 80 70 60
Proportion achieving HIV-1 RNA <50 c/mL (%)
Favours RAL
Favours DTG 50
RAL 64% 40
0.7
7.4
14.2 30 20
–12% 0%
20%
DTG 50 mg QD (n=354)
RAL 400 mg BID (n=361) 10
† Test for superiority: p=0.03
Baseline 4 8 12 16 24 32 40 48
Week
Mean (SD) CD4+ change from baseline to Week 48 was similar between arms: DTG: +162 (151) cells/mm3; RAL: +153 (144) cells/mm3
Analysis based on all subjects randomised who received ≥1 dose of study drug, excluding four subjects at one site with violations of good clinical practice;
†Adjusted difference based on stratified analysis adjusting for BL HIV-1 RNA (≤50,000 c/mL vs >50,000 c/mL), DRV/r use without primary PI mutations and baseline PSS (2 vs <2)
Adapted from Cahn P, et al. Lancet 2013;382(9893):700-8

7. Fewer virologic non-responders for DTG vs RAL at 48 weeks (snapshot)
n/N (%)
DTG 50 mg QD
(n=354)
RAL 400 mg BID
(n=361)
HIV-1 RNA <50 c/mL, n (%)
251 (71)
230 (64)
Virologic non-respondera
71 (20)
100 (28)
No virologic data at Week 48b
32 (9)
31 (9)
Per protocol, HIV-1 RNA <50 c/mL
238/325 (73)
225/340 (66)
Adjusted difference, % (95% confidence interval)
7.5% (0.6, 14.3)*
Response <50 c/mL by baseline HIV-1 RNA
≤50,000 c/mL
186/249 (75)
180/254 (71)
>50,000 c/mL
65/105 (62)
50/107 (47)
Response <50 c/mL by background regimen phenotypic susceptibility scorec
<2
70/104 (67)
61/94 (65) 2
181/250 (72)
169/267 (63)
Use of DRV without primary PI mutations
Yes
50/72 (69)
54/77 (70) No
201/282 (71)
176/284 (62)
a HIV-1 RNA not <50 c/mL in window; discontinued for lack of efficacy; discontinued for other reason while not <50 c/mL; change in ART
b Discontinued due to AE, death or for other reasons unrelated to safety; missing data but still on study
c Two subjects with PSS=3 were included in the score=2 category
* Adjusted difference based on Cochran-Mantel-Haenszel stratified analysis adjusting for baseline HIV-1 RNA (≤50,000 c/mL vs >50,000 c/mL, DRV/r use without primary PI mutations (yes vs no) and baseline phenotypic susceptibility score (2 vs <2) to background regimen
Adapted from Cahn P, et al. Lancet 2013;382(9893):700-8

8. DTG was effective regardless of baseline viral load
RAL 400mg BID
DTG 50mg QD
Percentage with HIV-1 RNA <50 c/mL (%)
65 105
50 107
30% of patients had baseline viral load >50,000 copies/mL
Adapted from Cahn P, et al. Lancet 2013;382(9893):700-8

9. DTG had fewer resistance mutations than RAL At 48 weeks
The proportion of subjects with evidence of INI resistance was significantly lower in the DTG arm than in the RAL arm
DTG 50 mg QD + BR
(n=354)
RAL
400 mg BID + BR
(n=361)
Protocol-defined virologic failure, n (%)
21 (6)
45 (12)
INI mutations*, n (%)
4(1)†‡
17 (5) ‡
* Adjusted difference: -3.7% (95% CI:-6.1%,-1.2%); P=0.003
† Treatment-emergent INI mutations detected: R263K, R263R/K, V151V/I; one patient developed a T97A and E138T/A mutation, however this patient was subsequently found to have a Q148 mutation at baseline.
‡One patient in each group had INI resistance at baseline
Substitutions seen at positions R263 and V151 did not confer high levels of resistance to DTG (<2 fold change in IC50), or cross resistance to RAL.
Cahn P, et al. Lancet 2013;382(9893):700-8 and Supplementary Appendix

10. Dtg was generally well tolerated with few discontinuations
Adverse Events (AE), n (%)
at 48 weeks
DTG 50 mg QD
(n=357)
RAL 400 mg BID (n=362)
Subjects with AEs leading to discontinuation, n (%)
4 (1)
11 (3)
Serious drug-related AEs
2 (1)a
4 (1)b
Fatal AEs
3 (1)c
a DTG: 1 hepatotoxicity, 1 myositis and acute renal failure
b RAL: 1 oral mucosal blistering and rash pruritic, 1 pancreatitis, 1 hepatitis, 1 suicidal ideation
c 1 adenocarcinoma, 1 acute hepatic and renal failure, 1 cervical carcinoma
Low rate of discontinuation due to AEs through to 48 weeks (1% for DTG and 3% for RAL)
Cahn P, et al. Lancet 2013;382(9893):700-8; Cahn P, et al. IAS 2013; Oral WELBB03

11. DTG offered similar tolerability to RAL at 48 weeks
AEs, n (%)
DTG 50 mg QD (n=357)
RAL 400 mg BID (n=362)
AEs (≥5% in either arm)
Diarrhoea
71 (20)
64 (18)
Upper respiratory tract infection
38 (11)
29 (8)
Headache
33 (9)
31 (9)
Nausea
Cough
24 (7)
Influenza
26 (7)
Nasopharyngitis
23 (6)
22 (6)
Urinary tract infection
18 (5)
Vomiting
20 (6)
Fatigue
15 (4)
Rash
19 (5)
Arthralgia
10 (3)
Upper abdominal pain
17 (5)
5 (1)
Adapted from Cahn P, et al. Lancet 2013;382(9893):700-8

12. Dtg was generally well tolerated at 48 weeks1
DTG 50 mg QD (n=357)
RAL 400 mg BID (n=362)
Selected grade 3-4 laboratory abnormalities
ALT*
9 (3%)
7 (2%)
Cholesterol
6 (2%)
14 (4%)
Creatinine**
1 (<1%)
Hyperglycaemia
4 (1%)
Lipase
Total bilirubin†
21 (6%)
CPK
* 7 patients on DTG and 4 on RAL met protocol-defined stopping criteria for liver chemistry
** As previously described, small non-progressive increase in serum creatinine due to OCT2 inhibition2
† 16/21 subjects in the DTG arm and 11/14 in the RAL arm were receiving ATV1
ALT, alanine aminotransferase; CPK, creatine phosphokinase
1. Cahn P, et al. Lancet 2013;382(9893):700-8; 2. Koteff J et al. Br J Clin Pharmacol 2013;75(4):990-6

13. The effect of dtg on serum creatinine is not clinically relevant
Small increases in serum creatinine occurred initially and then remained stable through 48 weeks.1 These changes are not considered to be clinically relevant as the glomerular filtration rate is unchanged2
DTG 50 mg QD (n=357)
RAL 400 mg BID (n=362)
Renal laboratory values3
Change from baseline serum creatinine (μmol/L), mean (SD)
11.1 (15.53)*
(n=291)
5.1 (12.23)
(n=283)
Change from baseline urine albumin/creatinine ratio (mg/mmol), mean (SD)
-0.33 (27.51)
(n= 260)
-0.56 (31.81)
(n=253)
*As previously described, small non-progressive increase in serum creatinine due to OCT2 inhibition
ALT, alanine aminotransferase; CPK, creatine phosphokinase
Adapted from 1. Cahn P, et al. Lancet 2013;382(9893):700-8; 2. Koteff J et al. Br J Clin Pharmacol 2013;75(4):990-6; 3. Cahn P, et al. IAS Oral WELBB03

14. Summary
In the Week 48 primary analysis, DTG 50 mg QD was statistically superior to RAL BID in the proportion of subjects achieving HIV-1 RNA <50 c/mL
In treatment-experienced, INI-naïve subjects, DTG had statistically superior efficacy vs RAL at 48 weeks
71% vs 64% reached undetectability atWeek 48 (P=0.03)
DTG was effective regardless of baseline viral load
62% of treatment-experienced patients with HIV-1 RNA>50,000 copies/mL at baseline reached undetectability
Differences driven by lower rate of virologic failure in subjects on DTG vs RAL
Proportion of subjects with evidence of INI resistance was significantly lower in DTG arm vs RAL
Treatment-emergent resistance to optimised background regimen was also statistically lower in DTG arm vs RAL
DTG 50 mg QD was generally well tolerated and offered similar tolerability to RAL
1% vs 3% discontinued due to AEs
Cahn P, et al. Lancet 2013;382(9893):700-8

15. TIVICAY® (Dolutegravir) – Licensed indication
TIVICAY is indicated in combination with other anti-retroviral medicinal products for the treatment of Human Immunodeficiency Virus (HIV) infected adults and adolescents above 12 years of age
Population
Recommended dose
Patients without documented or clinically suspected resistance to the integrase class
50 mg once daily
Patients without documented or clinically suspected resistance to the integrase class, when co-administered with some medicines e.g. efavirenz, nevirapine, tipranavir/ritonavir, or rifampicin
50 mg twice daily
Patients with resistance to the integrase class (documented or clinically suspected)
In the presence of documented resistance including Q148 + ≥ 2 secondary mutations from G140A/C/S, E138A/K/T, L741, an increased dose may be considered for patients with limited treatment options (less than 2 active agents) due to advanced multi class resistance
100mg twice daily
Adolescents aged 12 and above and weighing at least 40 kg and without documented or suspected resistance to the integrase class
TIVICAY Summary of Product Characteristics, January 2017

16. TIVICAY SPECIAL WARNINGS AND PRECAUTIONS for use
Integrase class resistance with Q148 + ≥2 secondary mutations from G140A/C/S, E138A/K/T & L74I
Hypersensitivity reactions
Immune Reactivation Syndrome
Opportunistic infections
Drug interactions
Osteonecrosis
Please consult the Summary of Product Characteristics
for full prescribing information
TIVICAY Summary of Product Characteristics, January 2017

17. Abbreviations AE, adverse event HIV, Human immunodeficiency virus
ART, antiretroviral therapy
ARV, antiretroviral
ATV/r, atazanavir/ritonavir
BID, twice daily
BR, background regimen
c/mL, copies/mL
DRV/r, darunavir/ritonavir
DTG, dolutegravir
ETR, etravirine
HBV, hepatitis B virus
HCV, hepatitis C virus
HIV, Human immunodeficiency virus
INI, integrase inhibitor
LPV/r, lopinavir/ritonavir
MVC, maraviroc
OBR, optimised background regimen
PDVF, protocol-defined virologic failure
RAL, raltegravir
RNA, ribonucleic acid
TDF, tenofovir
QD, once daily

18. Prescribing Information
Tivicay® ▼ (dolutegravir 50mg tablets) (See Summary of Product Characteristics before prescribing)
Indication: HIV in >12 years and >40kg as part of combination therapy. Dosing: 50mg once daily with or without food if no proven/ suspected integrase resistance. 50mg twice daily with efavirenz, nevirapine, tipranavir/ritonavir, etravirine (without boosted PI), carbamazepine, oxcarbazepine, phenytoin, phenobarbital, St John’s Wort or rifampicin. Adults with proven/ suspected integrase resistance: 50mg twice daily preferably with food. Elderly: Limited data in 65+ yrs. Caution in severe hepatic impairment. Contraindications: Hypersensitivity to any ingredient. Co-administration with dofetilide. Warnings/precautions: Risk of hypersensitivity reactions. Discontinue dolutegravir and other suspect agents immediately if suspected. Risks of osteonecrosis, immune reactivation syndrome. Monitor LFTs in Hepatitis B/C co-infection and ensure effective Hepatitis B therapy. Caution with metformin: monitor renal function and consider metformin dose adjustment. Use with etravirine requires boosted PI or increased dose of dolutegravir. Use with Mg/Al-containing antacids, calcium, multivitamins or iron requires dosage separation.
Pregnancy/ lactation: Not recommended. Avoid breast-feeding. Side effects: See SPC for full details. Headache, GI disturbance, insomnia, abnormal dreams, depression, dizziness, rash, pruritus, fatigue, elevations of ALT, AST and CPK, arthralgia, myalgia, hypersensitivity, suicidal ideation or suicide attempt. Basic NHS costs: 30 tablets £ EU/1/13/892/001. MA holder: ViiV Healthcare UK Ltd, 980 Great West Road, Brentford, Middlesex TW8 9GS. Further information available from Customer Contact Centre, GlaxoSmithKline UK Ltd, Stockley Park West, Uxbridge, Middlesex UB11 1BT.
Tivicay is a registered trademark of the ViiV Healthcare Group of Companies
Date of approval: January Zinc code: UK/DLG/0055/13(9)
POM
S1A
Adverse events should be reported. For the UK, reporting forms and information can be found at Adverse events should also be reported to GlaxoSmithKline on  
  Adverse events should be reported. For Ireland, adverse events should be reported directly to the HPRA; Freepost, Pharmacovigilance Section, Health Products Regulatory Authority, Earlsfort Terrace, Dublin 2, Tel: , Adverse events should also be reported to GlaxoSmithKline on

19. Prescribing Information
TRIUMEQ® ▼ (DOLUTEGRAVIR 50MG/ABACAVIR 600MG/LAMIVUDINE 300MG TABLETS) (See Summary of Product Characteristics before prescribing)
Indication: HIV in over 12 years and > 40kg. Screen for HLA-B*5701 prior to use. Do not use if HLA-B*5701 positive. Dose: one tablet once daily with or without food. Elderly: Limited data in 65+ yrs. Creatinine clearance <50ml/min or moderate/severe hepatic impairment: Not recommended. Monitor closely in mild hepatic impairment. Contraindications: Hypersensitivity to any ingredient. Co-administration with dofetilide. Warnings/precautions: Both abacavir and dolutegravir are associated with risk of hypersensitivity reactions (HSR). Do not initiate in HLA-B*5701+ or previous suspected abacavir HSR. Stop Triumeq without delay if HSR suspected. Never reintroduce any dolutegravir- or abacavir-containing product after suspected HSR. Risks of immune reactivation syndrome, osteonecrosis, increased weight, lipids, glucose. Monitor LFTs in Hepatitis B/C co-infection. Inconclusive data on relationship between abacavir and MI; minimise all modifiable CV risk factors (e.g. smoking, hypertension, hyperlipidaemia). Not recommended if dolutegravir required b.d. (with etravirine [without boosted PI], efavirenz, nevirapine, rifampicin, boosted tipranavir, carbamazepine, oxcarbazepine, phenytoin, phenobarbital and St John’s Wort). Use with cladribine not recommended. Use
with Mg/Al-containing antacids, calcium, multivitamins or iron requires dosage separation. Caution with metformin: monitor renal function and consider metformin dose adjustment. Pregnancy/lactation: Not recommended. Avoid breast-feeding. Side effects: See SPC for details. Headache, insomnia, sleep/dream disorders, GI disturbance, fatigue, hypersensitivity, anorexia, depression, dizziness, somnolence, lethargy, malaise, cough, nasal symptoms, rash, pruritus, alopecia, arthralgia, myalgia, asthenia, fever, elevations of ALT, AST and CPK, blood dyscrasias, suicidal ideation or suicide attempt, rhabdomyolysis, lactic acidosis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis. Basic NHS costs: 30 tablets: £ EU/1/14/940/001. MA holder: ViiV Healthcare UK Ltd, 980 Great West Road, Brentford, Middlesex TW8 9GS. Further information is available from Customer Contact Centre, GlaxoSmithKline UK Ltd, Stockley Park West, Uxbridge, Middlesex UB11 1BT. 
S1A
Triumeq is a registered trademark of the ViiV Healthcare Group of Companies.
Date of approval: January Zinc code: UK/TRIM/0037/14(7)
POM
Adverse events should be reported. For the UK, reporting forms and information can be found at Adverse events should also be reported to GlaxoSmithKline on  
Adverse events should be reported. For Ireland, adverse events should be reported directly to the HPRA; Freepost, Pharmacovigilance Section, Health Products Regulatory Authority, Earlsfort Terrace, Dublin 2, Tel: , Adverse events should also be reported to GlaxoSmithKline on

20. Prescribing Information
Kivexa ® (abacavir 600mg/lamivudine 300mg tablets) (See Summary of Product Characteristics before prescribing)
Indications: HIV in adults, adolescents and children weighing at least 25 kg as part of combination therapy. Screen for HLA-B*5701 prior to use. Dose: one tablet daily with or without food. Elderly: No pharmacokinetic data in 65+ yrs. Renal impairment: Creatinine clearance <50ml/min: not recommended. Hepatic impairment: not recommended in moderate or severe hepatic impairment. Monitor closely in mild hepatic impairment. Contraindications: Hypersensitivity to any ingredient. Warnings/precautions: Risk of hypersensitivity reactions (HSR). Do not initiate in HLA-B*5701+ or previous suspected abacavir HSR. Stop Kivexa without delay if HSR suspected. Never re-introduce any abacavir-containing product after suspected HSR. Risks of virological failure, immune reactivation syndrome, osteonecrosis, increased weight, lipids, glucose. Monitor LFTs in Hepatitis B/C co-infection. Inconclusive data on relationship between abacavir and MI; minimise modifiable CV risk factors (e.g. smoking, hypertension, hyperlipidaemia). Use with cladribine, emtricitabine or high doses of co-trimoxazole
not recommended. Pregnancy/lactation: Not recommended. Avoid breast-feeding. Side effects: See SPC for full details. Hypersensitivity, GI disturbance, headache, anorexia, insomnia, rash, fever, lethargy, fatigue, malaise, arthralgia, muscle disorders, nasal symptoms, cough, alopecia, blood dyscrasias, rhabdomyolysis, lactic acidosis, erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis. Basic NHS costs: 30 tablets: £ EU/1/04/298/002. MA holder: ViiV Healthcare UK Ltd, 980 Great West Road, Brentford, Middlesex TW8 9GS. Further information is available from Customer Contact Centre, GlaxoSmithKline UK Ltd, Stockley Park West, Uxbridge, Middlesex UB11 1BT.
Kivexa is a registered trademark of the ViiV Healthcare Group of Companies
Date of approval: October Zinc code: UK/ABC3TC/0008/13(9)
POM
S1A
Adverse events should be reported. For the UK, reporting forms and information can be found at Adverse events should also be reported to GlaxoSmithKline on  
  Adverse events should be reported. For Ireland, adverse events should be reported directly to the HPRA; Freepost, Pharmacovigilance Section, Health Products Regulatory Authority, Earlsfort Terrace, Dublin 2, Tel: , Adverse events should also be reported to GlaxoSmithKline on