Modern European Guidelines on HIV Treatment

Anna Maria Geretti

Institute of Infection & Global Health

University of Liverpool, United Kingdom

Themes

Updates on Factors to Consider:

• When deciding to start ART

• When selecting the first-line ART regimen

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*

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)

Incidence of New HIV Diagnoses Across Europe (per 100,000 residents)

WHO; eCDC

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

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

Cu

mu

lati

ve %

wit

h E

ven

t

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

START: Primary Endpoint Events by Latest CD4 Cell Count

Immediate ART Deferred ART

Pe

rce

nt

of

Follo

w-u

p T

ime

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

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 14

0.20 50

0.72 0.28 (0.15-0.50) <0.001

Serious non-AIDS event 29

0.42 47

0.67 0.61 (0.38-0.97) 0.04

All-cause death 12

0.17 21

0.30 0.58 (0.28-1.17) 0.13

Tuberculosis 6 0.09 20

0.28 0.29 (0.12-0.73) 0.008

Kaposi’s sarcoma 1 0.01 11

0.16 0.09 (0.01-0.71) 0.02

Malignant lymphoma 3 0.04 10

0.14 0.30 (0.08-1.10) 0.07

Non-AIDS defining cancer

9 0.13 18

0.26 0.50 (0.22-1.11) 0.09

Cardiovascular disease 12

0.17 14

0.20 0.84 (0.39-1.81) 0.65

INSIGHT START Study Group. N Engl J Med 2015

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 Cu

mu

lati

ve

% w

ith

Eve

nt

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

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

Factors to Consider When Selecting ART

Treatment-related

• Evidence of virological efficacy and safety

• Tolerability profile

• Barrier to resistance

• Drug interactions

• Convenience

• Cost

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

67 HEAT LPV/r (n=345)

HEAT LPV/r (n=343)

71 ASSERT EFV (n=193)

84

82 ECHO/THRIVE EFV (n=546)

76 ABT 730 LPV/r bid (n=331)

86

GS-102 STRIBILD (n=348)

90 GS-103 STRIBILD (n=353)

59 ASSERT EFV (n=192)

87 GS-103 ATV + RTV (n=355)

86

GS-102 ATRIPLA (n=352)

84 ARTEMIS DRV + RTV (n=343)

83 ECHO/THRIVE RPV (n=550)

76 GS-903 EFV (n=299)

82 STARTMRK EFV (n=282)

80 GS 934 EFV (n=244)

78 ARTEMIS 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

82 STaR EFV (n=392)

86 STaR RPV (n=394)

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

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

GS-1089: Renal Outcomes with Switch from TDF- to TAF-Containing ART

No proximal renal tubulopathy or Fanconi syndrome in either arm

Me

dia

n e

GFR

Ch

ange

(m

L/m

in)

Wk

8.4

2.8

P < .001

TAF

TAF

40

20

0

-20

-40

Me

dia

n %

Ch

ange

at

Wk

48

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

GS-1089: Bone Mineral Density (BMD) Changes with Switch from TDF- to TAF-Containing ART

Spine 4

2

0

Me

an %

ch

ange

in

BM

D (

95

% C

I)

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

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

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

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

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

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

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)

% w

ith

RA

Ms

Any

NRTI

NNRTI

PI

TDR = Transmitted drug resistance RAMs= Resistance-associated mutations

Baxter et al. HIV Med 2015

Virological or Tolerability Failure with RAL, ATV/r, or DRV/r + TDF/FTC in First-Line

Cu

mu

lati

ve In

cid

en

ce

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

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

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

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

Thank you