Modern European Guidelines on HIV Treatment 2016. Key Updates

1. Modern European Guidelines
on HIV Treatment
Anna Maria Geretti
Institute of Infection & Global Health
University of Liverpool, United Kingdom

2. Themes
Updates on Factors to Consider:
• When deciding to start ART
• When selecting the first-line ART regimen

3. HIV Treatment Guidelines: When to Start?
EACS 2015
Symptomatic Asymptomatic
Any CD4 Count CD4 <350 CD4 ≥350
Strongly
recommend
Strongly
recommend
Recommend
EACS 2016*
All patients
*EACS 2016 Guidelines in preparation
DHSS 2016
All patients*

4. HIV Treatment Guidelines: When to Start?
EACS 2016*
All patients
*EACS 2016 Guidelines in preparation
 ART prevents HIV-related disease and mortality
(AI-level evidence)
 ART prevents HIV transmission
(AI-level evidence)

5. Incidence of New HIV Diagnoses Across Europe
(per 100,000 residents)
WHO; eCDC

6. START: Immediate vs. Deferred Therapy
for Asymptomatic, ART-Naive Patients
• International, randomized trial
• Composite primary endpoint: any serious AIDS or non-AIDS* event or death
• Follow-up mean 3 years
• Median baseline CD4 count 651 cells, plasma HIV-1 RNA 12,759 cps
• Median CD4 count at ART initiation for deferred group: 408 cells
Immediate ART
ART initiated immediately
following randomization (n= 2326)
INSIGHT START Study Group. N Engl J Med 2015
Deferred ART
Deferred until CD4 count ≤350 cells,
AIDS, or event requiring ART (n= 2359)
ART-naïve adults
CD4 count >500 cells
(N= 4685)
Study closed by DSMB
following interim analysis
*Non-AIDS event: Cardiovascular disease, end-stage renal disease, decompensated liver disease,
non-AIDS cancer

7. START: 57% Reduced Risk of Serious Events
or Death With Immediate ART
 Serious AIDS or non-AIDS event or death: 4.1% vs. 1.8% in
deferred vs. immediate ART (HR 0.43; 95% CI 0.30-0.62; P<0.001)
10
8
6
4
2
0
Cumulative%withEvent
0 6 12 18 24 30 36 42 48 54 60
Months
Deferred ART
Immediate ART
INSIGHT START Study Group. N Engl J Med 2015

8. START: Primary Endpoint Events by Latest
CD4 Cell Count
Immediate ART Deferred ART
PercentofFollow-upTime
Latest CD4 Count (cells/mm3)
60
50
40
30
20
10
0
2
(4.7)
No. of Pts With Events
(Rates/100 PY)
No. of Pts With Events
(Rates/100 PY)
3
(0.8)
6
(0.4)
11
(0.6)
20
(0.6)
5
(1.8)
34
(2.0)
34
(1.5)
9
(0.6)
14
(1.1)
INSIGHT START Study Group. N Engl J Med 2015

9. START: Primary Endpoint Components
With Immediate vs. Deferred ART
Endpoint
Immediate ART
(n= 2326)
Deferred ART
(n= 2359) HR
(95% CI)
P
Value
N Rate/100 PY N Rate/100 PY
Serious AIDS event
1
4
0.20
5
0
0.72 0.28 (0.15-0.50) <0.001
Serious non-AIDS event
2
9
0.42
4
7
0.67 0.61 (0.38-0.97) 0.04
All-cause death
1
2
0.17
2
1
0.30 0.58 (0.28-1.17) 0.13
Tuberculosis 6 0.09
2
0
0.28 0.29 (0.12-0.73) 0.008
Kaposi’s sarcoma 1 0.01
1
1
0.16 0.09 (0.01-0.71) 0.02
Malignant lymphoma 3 0.04
1
0
0.14 0.30 (0.08-1.10) 0.07INSIGHT START Study Group. N Engl J Med 2015

10. START: Cancer Events With Immediate vs.
Deferred ART
Cancer
Event, n
Immediate
ART
(n= 2326)
Deferred
ART
(n=
2359)
Total 14 39
Kaposi’s sarcoma 1 11
Lymphoma NHL + HL 3 10
Prostate 2 3
Lung 2 2
Anal 1 2
Cervical or testis 1 2
Other types* 4 9
*Immediate ART: squamous cell carcinoma,
plasma cell myeloma, bladder cancer, fibrosarcoma
*Deferred ART: gastric adenocarcinoma, breast cancer,
ureteric cancer, malignant melanoma, myeloid
leukemia, thyroid cancer, leiomyosarcoma,
liver cancer, squamous cell carcinoma of head and neck
Time to Cancer Event
10
8
6
4
2
0
Cumulative%withEvent
0 12 24 36 48 60
Months
Deferred ART
Immediate ART
Rate/100 PY:
Immediate 0.20; deferred 0.56
(HR: 0.36; 95% CI 0.19-0.66; P = .001)
INSIGHT START Study Group. N Engl J Med 2015

11. Factors to Consider When Selecting ART
Patient-related
• CD4 count, Viral Load, Resistance, HLA-B*5701 status
• Preferences & Life-style; Anticipated adherence;
Psyco-social dimension
• Cardiovascular, renal, or neurological disease;
Metabolic disorders; Osteoporosis; Hepatitis B or C; TB
• Psychiatric illness; Drug abuse or dependency;
Narcotic replacement therapy
• Pregnancy and pregnancy potential

12. Factors to Consider When Selecting ART
Treatment-related
• Evidence of virological efficacy and safety
• Tolerability profile
• Barrier to resistance
• Drug interactions
• Convenience
• Cost

13. Registrational Treatment-Naive Clinical Trials
HIV-1 RNA <50 copies/mL at Week 48
*This slide depicts data from multiple studies ( 2004-2013). Not all regimens have been compared head-to-head in a clinical trial
78
77
76
0 10 20 30 40 50 60 70 80 90 100
STARTMRK RAL (n=281)
CASTLE ATV + RTV (n=440)
ABT 730 LPV/r qd (n=333)
CASTLE LPV/r (n=443)
68
67HEAT LPV/r (n=345)
HEAT LPV/r (n=343)
71ASSERT EFV (n=193)
84
82ECHO/THRIVE EFV (n=546)
76ABT 730 LPV/r bid (n=331)
86
GS-102 STRIBILD (n=348)
90GS-103 STRIBILD (n=353)
59ASSERT EFV (n=192)
87GS-103 ATV + RTV (n=355)
86
GS-102 ATRIPLA (n=352)
84ARTEMIS DRV + RTV (n=343)
83ECHO/THRIVE RPV (n=550)
76GS-903 EFV (n=299)
82STARTMRK EFV (n=282)
80GS 934 EFV (n=244)
78ARTEMIS LPV/r (n=346)
SPRING-2 DTG (n=242) 89
SINGLE DTG (n=414) 88
SPRING-2 DTG (n=169)
88
NRTI Backbone
FTC/TDF
3TC/ABC
TDF/3TC
82STaR EFV (n=392)
86STaR RPV (n=394)

14. HIV Treatment Guidelines
• When to start? Now
• What to start? A preferred regimen
EACS 2015 DHSS 2016
ABC 3TC DTG
TDF FTC DTG
TDF FTC RAL Preferred with anti-TB therapy
TDF FTC EVG/c* Pre-treatment estimated CrCl ≥70 mL/min
In 2016 TAF FTC EVG/c* Pre-treatment estimated CrCl ≥30 mL/min
TDF FTC DRV/r*
TDF FTC RPV* CD4 count >200 cells and VL <100,000 cps (BI-level)
ABC only if HLA-B*5701 negative; 3TC may substitute FTC
*With food
ABC= Abacavir; 3TC= Lamivudine; DTG= Dolutegravir; TDF= Tenofovir DF;
FTC= Emtricitabine; RAL= Raltegravir; EVG/c= Elvitegravir/cobicistat
TAF= Tenofovir AF; DRV/r= Darunavir + ritonavir; RPV= Rilpivirine

15. TAF in Clinical Trials
Study Design Follow-up Outcomes in TAF arm
1089 Randomised
(1:1)
DB (n=663)
Continue suppressive
TDF/FTC + 3rd agent
Or Switch TDF to TAF
Wk 48
(primary)
Through wk 96
Wk 48: virologically
non-inferior; better
renal & bone measures
104/
111
Randomised
(1:1)
DB (n=1733)
Naïve adults
TDF/FTC/EVG/c vs.
TAF/FTC/ EVG/c (1:1)
Wk 48
(primary)
Through wk 144
Wk 96: virologically
non-inferior; better
renal measures
109 Randomised
(1:2)
Open label
(n=1426)
Continue suppressive
TDF/FTC + 3rd agent
or Switch to
TDF/FTC/EVG/c
Wk 48
(primary)
Through wk 96
Wk 48: virologically
statistically superior;
better renal & bone
measures
112 Single arm
Open label
(n=242)
Suppressed adults with
renal Impairment
(eGFR 30-69 mL/min)
Switch to TAF/FTC/EVG/c
Wk 24
(primary)
Through wk 144
Wk 96: 2% virological
failure; improved
renal & bone measures
106 Single arm
Open label
(n=50)
Naïve adolescents
TAF/FTC/EVG/c
Wk 48
(primary)
Wk 48: 6% virological
failure; improved
bone measures

16. GS-1089: Renal Outcomes with Switch from
TDF- to TAF-Containing ART
 No proximal renal tubulopathy or Fanconi syndrome in either arm
MedianeGFRChange(mL/min)
Wk
8.4
2.8
P < .001
TAF
TAF
40
20
0
-20
-40
Median%ChangeatWk48
Protein Albumin RBP β2-M
Urine Protein-to-Creatinine Ratio
7.7
-14.6
-7.7
-16.3
-39.6
12.3
18.2 22.0
TDF
TDF
P < .001
P < .001
P < .001
P < .001
Gallant et al. CROI 2016
20
10
0
-10
0 12 24 36 48

17. GS-1089: Bone Mineral Density (BMD) Changes
with Switch from TDF- to TAF-Containing ART
Spine
4
2
0
Mean%changein
BMD(95%CI)
1.5
-0.2
P < .001
BL 24 48
Wks
FTC/TAF, n
FTC/TDF, n
321
320
310
310
300
306
Hip
4
2
0
1.1
-0.2
BL 24 48
Wks
321
317
309
305
300
303
P < .001
≥ 3% BMD Increase at Wk 48 FTC/TAF FTC/TDF P Value
Spine 30% 14% <0.001
Hip 17% 9% 0.003
Gallant et al. CROI 2016

18. Alternative & Other First-Line Regimens
EACS 2015 DHSS 2016
TDF FTC RPV* CD4 count >200 cells and VL <100,000 cps
TDF FTC EFV Preferred with anti-TB therapy
TDF FTC ATV/r*
TDF FTC ATV/c* Pre-treatment estimated CrCl ≥70 mL/min
ABC 3TC DRV/r or DRV/c* Pre-treatment estimated CrCl ≥70 mL/min
TDF FTC DRV/c* Pre-treatment estimated CrCl ≥70 mL/min
ABC only if HLA-B*5701 negative; 3TC may substitute FTC
*With food
TDF= Tenofovir DF; FTC= Emtricitabine; RPV= Rilpivirine; EFV= efavirenz
ATV/r= Atazanavir + ritonavir; ATV/c= Atazanavir/cobicistat
ABC= Abacavir; 3TC= Lamivudine; DRV/r= Darunavir + ritonavir
DRV/c= Darunavir/cobicistat

19. Alternative & Other First-Line Regimens
EACS 2015 DHSS 2016
ABC 3TC RAL
ABC 3TC EFV VL <100,000 cps
ABC 3TC ATV/r or ATV/c* VL <100,000 cps
ABC 3TC LPV/r*
TDF FTC LPV/r* Caution if high cardiovascular risk
DRV/r RALa* CD4 count >200 cells and VL <100,000 cps
3TC LPV/ra*
aIf ABC and TDF/TAF cannot be used
ABC only if HLA-B*5701 negative; 3TC may substitute FTC
*With food ABC= Abacavir; 3TC= Lamivudine; RAL= Raltegravir
EFV= Efavirenz; ATV/r Atazanavir + ritonavir
ATV/c= Atazanavir/cobicistat; LPV/r= Lopinavir/ritonavir
DRV/r= Darunavir + ritonavir

20. Common Reasons for Starting a PI
• Concerns about adherence – protective effect of high
barrier to emergence of resistance
• Need to start ART immediately and resistance test
result not yet available – e.g., PHI
• Perceptions about potency in late presenters
with low CD4 cells counts and high viral load
• Hospitalised patients undergoing diagnostic
investigations
PI= Protease Inhibitor
PHI = Primary HIV Infection

21. Proportion with HIV-1 RNA <50 copies/ml through 48 weeks
FLAMINGO: DTG vs. DRV/r in First-Line ART
Clotet et al. Lancet 2014
Virological success
DTG DRV
90% 83%
DTG DRV

22. FLAMINGO: Responses by Baseline Viral
Load & NRTI Backbone
DTG DRV Difference (95%
CI)
P-value
Baseline VL
≤100,000 160/181 (88%) 157/181 (87%) 1.7 (-5.1 to 8.5)
>100,000 57/61 (93%) 43/61 (70%) 23 (9.9 to 36) 0.005
Backbone
ABC 3TC 71/79 (90%) 68/80 (85%) 4.9 (-5.4 to 15.1)
TDF FTC 146/163 (90%) 132/162 (81%) 8.1 (0.5 to 15.7) 0.624
Proportions with HIV-1 RNA <50 copies
Clotet et al. Lancet 2014

23. START: TDR Rates by ARV Class
10,1
13
8,8
10,6
13
4,4
0
2
4
6
8
10
12
14
Total
(n=1781)
USA
(n=392)
Europe
(n=1219)
Germany
(n=263)
Spain
(n=184)
UK
(n=295)
%withRAMs
Any
NRTI
NNRTI
PI
TDR = Transmitted drug resistance
RAMs= Resistance-associated mutations
Baxter et al. HIV Med 2015

24. Virological or Tolerability Failure with
RAL, ATV/r, or DRV/r + TDF/FTC in First-Line
CumulativeIncidence
1.00
0.75
0.50
0.25
0.00
ATV/r
RAL
DRV/r
Lennox et al. Ann Intern Med 2014
Difference in 96 wk cumulative incidence (97.5% CI)
605 536 494 427 317
603 574 545 511
307
601 559 520 470 358
ATV/r
RAL
DRV/r

25. Food
requirements
Determinants of ART Success
Potency of the
ART regimen
Pill burden and
dosing schedules
Drug
interactions
Convenience of the
ART regimen
Drug
resistance Drug PK
Psyco-social factors
Pre-ART CD4 Count
and Viral Load
Tolerability of the ART
regimen Retention
Adherence

26. Summary: Starting ART
• All patients will benefit from starting ART soon after diagnosis
– Use the correct language in patients who are reluctant
– Consider transmission risk
• Mental illness, substance abuse, psychosocial challenges
are not reasons to withhold ART
– Select the ART regimen accordingly and use additional
interventions to support adherence and retention

27. When: Annually in September
Where: Aix en Provence, France
For: Healthcare practitioners and clinical researchers
Structure:
Morning: Research and clinical plenaries for all
Afternoon: Research (A) and clinical (B) tracks
HIV Summer School Residential Course
Clinical Management of HIV Online Course
Main topics
• Epidemiology and surveillance of HIV
• Opportunistic infections and co-morbidities
• Antiretroviral therapy and complications of ART
• Continuum of HIV Care
• Key affected populations
• Treatment as prevention of HIV Russian translation available

28. Thank you