IAS 2015: Return to Vancouver · Favors ATV+ RTV Favors STB 12.6%-12% +12% 0.4% 0 Treatment Difference (95% CI) 6.5% Mean CD4 Cell Increase (cells/mm3) was 196 (EVG/COBI/FTC/TDF &

IAS 2015: Return to Vancouver

Paul E. Sax, M.D.Clinical Director, Division of Infectious Diseases

Brigham and Women’s HospitalProfessor of Medicine

Harvard Medical SchoolNEAETC

Memories from 1996 …

• First realization for many that combination ART could suppress viral replication … indefinitely?

• Panel of HIV researchers “drenched in blood” by ACT-UP activists; Marty Hirsch’s new suit ruined

• Hospital installed “high-speed” internet access for all

• Elsewhere: Atlanta Olympics (and bombing), Clinton vsDole, Fargo, Alanis Morissette…

Gulick R, et al. NEJM 1997;337:734

“Kicking over chairs, throwing microphones, smashing glasses and overturning conference tables, protesters demanded an immediate end to the practice of treating AIDS patients with dangerous chemotherapeutic agents.

The activists asserted that the therapies hyped during the week-long conference such as AZT, ddI, ddC and protease inhibitors impair the immune system's natural ability to fight HIV and control the opportunistic infections that kill people with AIDS.”

http://www.virusmyth.com/aids/news/actupsfpr2.htm

December 30, 1996

IAS Vancouver 2015: Outline

• START: A landmark study

• Antiretroviral therapy

The biggest news out of Vancouver IAS 2015 was:

1 2 3 4 5

0% 0% 0%0%0%

1. Teenager “cured” of HIV.

2. Results of the START study.

3. A clinical trial of ART with 100% of the participants women.

4. Largest switch study ever in stably suppressed patients.

5. Marty Hirsch got a new suit.

START Study: Study Design

Lundgren J, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. MOSY0301.

HIV-infected individuals who are ART-naïve with CD4+ count >500 cells/mm3

Immediate ART Group

Initiated ART immediatelyFollowing randomization

N=2,326

Deferred ART Group

Defer ART until the CD4+ count declines to <350 cells/mm3

N=2,359

Primary Composite Endpoint, Target =213

Serious AIDS or death from AIDS

Serious Non-AIDS Events and death not attributable to AIDS

CVD, ESRD, decompensated live disease, & non-AIDS defining cancers

DSMB Stopped Study on May 27, 2015

START Study: Baseline Characteristics

CharacteristicsImmediate-Initiation

Group(N=2326)

Deferred-InitiationGroup

(N=2359)

All Patients(N=4685)

Median Age (IRQ)-yr 36 (29-44) 36 (29-44) 36 (29-44)

Female Sex – no. (%) 624 (26.8) 633 (26.8) 1,257 (26.8)

Mode of Infection with HIV – no. (%)

Sexual Contact

Men Having Sex with Men 1,300 (55.9) 1,286 (54.5) 2,586 (55.2)

With Person of Opposite Sex 873 (37.5) 917 (38.9) 1,790 (38.2)

Injection-drug Use 37 (1.6) 27 (1.1) 37 (1.6)

Blood Products, Other, or Unknown 116 (5.0) 129 (5.5) 116 (5.0)

Median Time Since HIV Diagnosis (IQR) – yr 1.0 (0.4-3.0) 1.1 (0.4-3.1) 1.0 (0.4-3.0)

Median CD4+ count (IQR) – cells/mm 651 (585-765) 651 (582-764) 651 (585-765)

Median HIV RNA (IQR) – copies/ml13,000

(3133-43,808)12,550

(2963-42,567)13,000

(3133-43,808)

Median CHD Risk at 10yr (IQR) - % 1.9 (0.5-5.0) 1.9 (0.5-5.3) 1.9 (0.5-5.0)

Lundgren J, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. MOSY0301.No significant differences between groups

START Study: CD4 Cell Counts


450

500

550

600

650

700

750

800

850

900

950

1000

12 24 36 48 60

Me

an C

D4

+Co

un

t (c

ells

/mm

3)

Months

B CD4+ Count

Immediate Initiation

Deferred Initiation

CD4 at the start of ART in deferred. Median 408

Estimated difference 194 cells

START Study: Initial ART Combinations


Deferred

TDF/FTC/EFV

TDF/FTC/ATV/r

ZDV/3TC/EFV

TDF/FTC/DRV/r

TDF/FTC/RPV

TDF/FTC/RAL

Other

Immediate

N=2287 (98%) N=1134 (48%)

EFV: 73% vs 51%TDF: 89% in both groups

START Study: Primary Endpoint

Immediate ART Deferred ART

No. with Event (%) 42 (1.8%) 96 (4.1%)

Rate/100PY 0.60 1.38

HR (Imm/Def) 0.43 (95% CI: 0.30 to 0.62, p<0.001)


0

2

4

6

8

10

0 6 12 18 24 30 36 42 48 54 60

Cu

mu

lati

ve P

erc

en

t w

ith

an

Eve

nt

Months

Immediate ART

Deferred ART

5.3

2.5

0

2

4

6

8

10

0 6 12 18 24 30 36 42 48 54 60

Cu

mu

lati

ve P

erc

en

t w

ith

an

Eve

nt

Months

Immediate ART

Deferred ART

START Study: Serious AIDS Events


No. with Event (%) 14 50

Rate/100PY 0.20 0.72

HR (Imm/Def) 0.28 (95% CI: 0.15 to 0.50, p<0.001)


START Study: Serious NON-AIDS Events


No. with Event (%) 29 47

Rate/100PY 0.42 0.67

HR (Imm/Def) 0.61 (95% CI: 0.38 to 0.97, p=0.04)


0

2

4

6

8

10

0 6 12 18 24 30 36 42 48 54 60

Cu

mu

lati

ve P

erc

en

t w

ith

an

Eve

nt

Months

Immediate ART

Deferred ART

START Study:Primary and Secondary Endpoints

End Point

Immediate-Initiation

Group(N=2326)

Deferred-Initiation

Group(N=2359)

Hazard Ratio(95% CI)

P Value

No. No. /100 person-yr

No.No. /100 person-yr

Composite Primary End Point 42 0.60 96 1.38 0.43 (0.30-0.62) <0.001

Components of the Primary End Point

Serious AIDS-Related Event 14 0.20 50 0.72 0.28 (0.15-0.50) <0.001

Serious Non-AIDS-Related Event 29 0.42 47 0.67 0.61 (0.38-0.97) 0.04

Death From Any Cause 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

Cancer Not Related to AIDS 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


Primary Endpoint Subgroup Analysis


SubgroupPercentage in

GroupImmediate Initiation

Deferred Initiation

Hazard Ratio (95% CI)P Value for Interaction

no. of patients with event (rote per 100 person-yr)

Age 0.98

≤35yr 48.8 I5 (0.43) 31 (0.91) 0.47

>35yr 51.2 27 (0.78) 65 (1.85) 0.42

Sex 0.38

Male 73.2 35 (0.66) 74 (1.40) 0.47

Female 26.8 7 (0.42) 22 (1.34) 0.31

Race 0.65

Black 30.1 I5 (0.82) 28 (1.52) 0.57

White 44.5 21 (0.63) 53 (1.54) 0.40

Other 25.4 6 (0.34) 15 (0.91) 0.37

Geographic region 0.55

High income 46.0 20 (0.56) 51 (1.42) 0.39

Low or moderate income 54.0 22 (0.65) 45 (1.35) 0.48

Baseline CD4+ 0.71

<600 cells/mm3 31.5 10 (0.44) 35 (1.54) 0.28

600-800 cells/mm3 48.6 24 (0.70) 46 (1.38) 0.50

>800 cells/mm3 19.9 8 (0.63) 15 (1.14) 0.56

Baseline HIV RNA 0.25

<5000 copies/ml 31.8 12 (0.56) 18 (0.83) 0.66

5000-30,000 copies/ml 35.5 13 (0.53) 36 (1.41) 0.38

>30.000 copies/ml 32.5 17 (0.72) 42 (1.92) 0.37

Smoker 0.93

Yes 31.9 18 (0.78) 43 (1.81) 0.43

No 68.1 24 (0.52) 53 (1.16) 0.44

Framingham 10-yr CHD risk 0.56

<0.8 32.7 8 (0.35) 17 (0.77) 0.46

0.8-3.6 32.3 11 (0.48) 27 (1.23) 0.39

>3.6 33.5 23 (1.00) 50 (2.05) 0.50

0.25 0.50 1.00 2.00

Immediate Initiation Better

Deferred Initiation Better

0

10

20

30

40

50

60

Pe

rce

nt

of

Follo

w-u

p T

ime

Latest CD4+ Count (Cells per Cubic Millimeter)

START Study: CD4 at Event


2 3 6 11 20

(4.7) (0.8) (0.4) (0.6) (0.6)

5 34 34 9 14

(1.8) (2.0) (1.5) (0.6) (1.1)

<350 350-499

500-649

650-799

≥ 800 <350 350-499

500-649

650-799

≥ 800


Immediate DeferPercent 88% 59%Rate (/100 PY) 0.6 1.1

No. of Participants with Events (Rates per 100 PY)

Primary Events at Latest CD4 count >500 c/mm3

The START study results will profoundly influence clinical practice.

1 2

0%0%

1. True – now it is proven that HIV treatment is beneficial for all.

2. False – we have been treating everyone regardless of CD4 for years anyway.

“ART is recommended for all HIV-infected individuals.”

--DHHS Guidelines, 2012https://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL003093.pdf

IAS Vancouver 2015: Outline

• START: A landmark study

• Antiretroviral therapy

Week 48

ATV+RTV+FTC/TDF Placebo QD

EVG/COBI/FTC/TDF QD

EVG/COBI/FTC/TDF Placebo QD

ATV+RTV+FTC/TDF QD(n=575)

WAVES 1:1

Key Eligibility Criteria: HIV infected womem HIV-1 RNA ≥ 500 copies/mL Estimated GFR ≥ 70 mL/min No history of prior antiretroviral therapy Sensitivity to FTC, TDF, and ATV Stratification:

HIV-1 RNA (<=100,000, >100,000-<=400,000, >400,000 copies/mL)

Race (Black or non-Black)

Baseline

Open Label Extension

WAVES : Initial ART in Women

Squires K, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. MOLBPE08.

WAVES: Study Enrollment

Squires K, et al. IAS 2015, #MOLBPE08 21

STB(n=289)

ATV+RTV+TVD(n=286)

Age (years), median (Q1,Q3) 34 (28,43) 35 (29,42)

RaceWhiteBlackAsian

44%49%3%

42%47%6%

Mode of InfectionHeterosexual 96% 94%

HIV DiseaseAsymptomaticAIDS

81%4.2%

75%4.5%

Body Mass Index (BMI), Mean (SD) 26 (7.02) 26 (5.69)

Positive HBsAg 3.1% 2.4%

Positive HCV Antibody 7.6% 8.7%

HIV-1 RNA (log10 copies/mL), Median (Q1,Q3)< 100,000 c/mL

>100,000-400,000 c/mL> 400,000 c/mL

4.46 (4.09,4.97) 76%15%9%

4.56 (4.02,5.00)75%17%8%

CD4 cell count (cells/mm3), Median (Q1,Q3)<200 cells/mm3

344 (246,466)17%

370 (244,489)18%

WAVES Study: Baseline Characteristics


HIV

-1 R

NA

< 5

0 c

/mL,

%

ATV+ RTV + FTC/TDF (n=286)

EVG/COBI/FTC/TDF (n=289)

Favors ATV+ RTV Favors STB

12.6%

-12%+12%

0.4%

0

Treatment Difference(95% CI)

6.5%

Mean CD4 Cell Increase (cells/mm3) was 196 (EVG/COBI/FTC/TDF & ATV/RTV + FTC/TDF)

WAVES Study: Primary Endpoint

RESISTANCESTB: Only on pt with emergent D67D/N

ATV/r: 3 with M184V/I


87

94

81

127

0

20

40

60

80

100

Virologic Success Virologic Failure No Virologic Data

87 86 90 88 8681 82

7882 79

0

20

40

60

80

100

Overall VL≤ 100,000

VL> 100,000

CD4≤ 350

CD4> 350

EVG/COBI/FTC/TDF ATV+RTV+FTC/TDF

Vir

olo

gic

Succ

ess

(%)

HIV-1 RNA (c/mL) CD4 Cell Count (/µL)

WAVES Study: Efficacy by Baseline HIV-1 RNA & CD4 Count


N 289 286 220 214 69 72 146 131 143 154

AERs leading to d/c: E/C/F/T - 7 vs ATV/r - 20

Integrase-Based First-Line Therapy: It’s Better

• WAVES: EVG/COBI/TDF/FTC better than ATV/r

• SPRING-2: DTG better than EFV

• FLAMINGO: DTG better than DRV/r

• ACTG 5257: RAL better than DRV/r and ATV/r

ACTG: Risk of EFV Suicidality May Be Associated with CYP2B6 and 2A6 Metabolizer Genotypes

Weeks Since EFV Initiation

Pro

bab

ility

of

Suic

idal

ity

0 48 96 144 192

0.0

00

.01

0.0

20

.03

0.0

40

.05

Extensive (levels: 1-2)

Intermediate (3-7)

Slow (8-12)

UnweightedNo. at risk:

Extensive 623 506 435 233 52Mid 838 659 566 276 45

Slow 195 152 124 62 8

9 events

18 events

7 events*

Mollan K, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. TUPEB273.

* Hazard ratio (95% CI): 1.85 (1.05, 3.26), P= 0.03

83.392.4

60.5

92.185.7 92.1

65.8

94.7

0

20

40

60

80

100

% <40 c/mL % <200 c/mL % <40 c/mL % <200 c/mL

Doravirine 100 mg q.d. Efavirenz 600 mg q.d.

≤100,000 c/mL >100,000 c/mL

n/N: 55/66 54/63

TDF/FTC + Doravirine vs EFV: Results by Baseline HIV RNA

Gatell J, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. TUAB04.

25: 51/66 58/63 11: 23/38 25/38 35/38 36/38

Virologic failures: DRV 17, EFV 11 -- mostly due to low-level viremia at week 24 (no resistance detected)

1 or more CNS adverse events: DRV 27%, EFV 46% -- difference -19.4% (95% CI -31.7, -6.6)

Three ECF-TAF Switch Studies

1. From first regimens – TDF/FTC/EFV, TDF/FTC + ATV/r or ATV/c, or TDF/FTC/EVG/c

2. In chronic renal insufficiency

3. In hepatitis B/HIV co-infection

Tenofovir Alafenamide (TAF)

† T1/2 based on in vitro plasma data.1. Lee W et. Antimicr Agents Chemo 2005;49(5):1898-1906. 2. Birkus G et al. Antimicr Agents Chemo 2007;51(2):543-550. 3. Babusis D, et al. Mol Pharm 2013;10(2):459-66. 4. Ruane P, et al. J Acquir Immune Defic Syndr 2013; 63:449-5. 5. Sax P, et al. JAIDS 2014. 2014;67(1):52-8. 6. Sax P, et al. Lancet 2015;385:2606-15.

HIV TARGET CELL

AMIDATE

ESTER

DIANION

GI TRACT

Tenofovir

alafenamide

(TAF)

Tenofovir

disoproxil

fumarate

(TDF)

Tenofovir

(TFV) Parent

Nucleotide

T1/2 = 90 min†

T1/2 = 0.4 min†

PLASMA

TAF25 mg

TDF 300 mg

TFV

TFV

TFV

• 91% lower plasma TFV levels minimize renal and bone effects while maintaining

high potency for suppressing HIV

TFV HIV

Switch to E/C/F/TAF from First RegimenPrimary Endpoint

HIV-1 RNA <50 c/mL

Week 0

Switch to E/C/F/TAF

Continue TDF-Based

Regimen

9

64

8

Virologically

Suppressed

Adults

E/C/F/TDF

(n=459)

EFV/FTC/TDF

(n=376)

Boosted ATV +

FTC/TDF

(n=601)

Randomized (2:1), active-controlled, open-label study

n=959

n=477

Mills A, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. TUAB0102.

Baseline Characteristics E/C/F/TAFn=959

TDF-Based Regimenn=477

Median age, years 41 40

Female, % 11 11

Race, %

White 68 66

Black or African descent 18 21

Hispanic/Latino ethnicity 26 17

Median CD4 count, cells/mm3 675 662

Patients with <200 cells/mm3, % 0.5 0.8

Median estimated GFR, mL/min* 106 108

Dipstick proteinuria, %

Grade 1 8.5 9.2

Grade 2 0.4 0.6

97

1 2

93

16

0

20

40

60

80

100

Success Failure No Virologic Data

E/C/F/TAF… TDF-Based Regimen n=477

Virologic Outcome

TDF Based E/C/F/TAF

0

HIV

-1 R

NA

<50

c/m

L, %

‒12% +12%

6.71.6

4.1

Switch to E/C/F/TAF from First Regimen: Results

31

932 444 10 6 17 27n=

Treatment Difference (95% CI)


97 96 97 9893

90 9297

0

20

40

60

80

100

All Prior Regimens PriorEFV/FTC/TDF

PriorBoosted

ATV + FTC/TDF

PriorE/C/F/TDF

Virologic Outcome By Prior Treatment

32

Pa

tie

nts

Wit

h H

IV-1

RN

A <

50

c/m

L, %

p <0.001 p=NSp=0.02 p=0.02

932959

444477

301306

149153

241251

112125

390402

183199

0.5—12.3 0.9—9.2 -1.9—3.91.6—6.7 95% CI =

TDF-Based RegimenE/C/F/TAF


Primary Endpoint

Switch to E/C/F/TAF in Suppressed Adults: Effect on Tubular Proteinuria

• Switch to E/C/F/TAF associated with:– Improvement in spine and hip BMD– Reduction in proportion classified as osteopenia or osteoporosis– Reduction in tubular proteinuria; no change in eGFR– Increase in fasting lipids

-21-18

-33

-52

10 9

18 19

-60

-50

-40

-30

-20

-10

0

10

20

30UPCR UACR RBP: Cr Ratio B2MG: Cr Ratio

Me

dia

n %

Ch

ange

E/C/F/TAF

TDF-Based Regimen


Urine Protein:Creatinine

UrineAlbumin:Creatinine

Urine Beta 2 Microglobulin:Creatinine

Urine Retinol Binding Protein:Creat

Study 112: Switch to E/C/F/TAF in Patients With Renal Impairment

Gupta S, et al. J Int AIDS Soc. 2015;18(suppl 4):35-36. Abstract TUAB0103..

Phase 3 study(96 weeks)

Treatment-experienced

Open-label

HIV RNA <50 copies/mL

eGFR 30-69 mL/min

Switch to E/C/F/TAF(n=242)

Primary EndpointWeek 24

Change FromBaseline in eGFR

E/C/F/TAF: elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide.TAF 25 mg.Pre-switch ART regimens:• NRTI: tenofovir DF (65%), abacavir (22%), other (7%), none (5%).• Third agent (some regimens included >1 third agent): PI (44%), NNRTI (42%), INSTI (24%), CCR5 antagonist (3%).

Baseline characteristics:Median age: 58 years.Hypertension/diabetes: 40%/14%.Median CD4: 632 cells/mm3.Median eGFR: 56 mL/min (<60 mL/min: 66%).Dipstick proteinuria grade 1/2/3-4: 23%/10%/0%.

Study 112: Change in GFR After Switch to E/C/F/TAF in Patients With Renal Impairment


Mean Change in eGFR at Week 48(Cockcroft-Gault)

-6

-4

-2

0

2

4

6

-0.6

AllPatients

Yes

Ch

an

ge

in

eG

FR

(m

L/m

in)

No

0.2

-1.8

TDF in Previous Regimen

Actual GFR at Week 24(Iohexol Clearance)

0

10

20

30

40

50

60

70

80

59

AllPatients

Yes

Ac

tua

l G

FR

(m

l/m

in)

No

TDF in Previous Regimen

58

63 63

50 49

Baseline

Week 24

56 58 53

Baseline eGFR (mL/min):

Study 112: Change in GFR and Other Outcomes After Switch to E/C/F/TAF

• Actual GFR was unaffected by E/C/F/TAF switch, regardless of previous regimen– eGFR remained unchanged through week 48

• Significant improvements after E/C/F/TAF switch (P<0.05)– Spine and hip bone mineral density– Urinary tubular proteins and fractional excretion of

uric acid– Albuminuria and proteinuria– Cholesterol fractions in patients not on a TDF-based

regimen at time of switch


HIV-1 “Remission” for >12 Years After Early ART

• Mother at delivery

– ddC since 13 weeks gestation

– HIV RNA 4.63 log10 copies/mL and CD4 81 cells/mm3

• Infant (delivery 37 weeks, 5 days of gestation)

– At birth

• Zidovudine prophylaxis, HIV RNA undetectable at day 3

• HIV DNA undetectable at days 3 and 14, detected at week 4

– Week 6: zidovudine interrupted, HIV RNA rose sharply to 2.17 million copies/mL

– Month 3: initiate ART (zidovudine, didanosine, abacavir, ritonavir)

– Loss to follow-up between 5.8 and 6.8 years

• ART interrupted by mother at approximately year 6.5

– Remains HIV RNA undetectable after returning to care

• Unknown if HIV-1 remission in this infant represents early treatment translating into long-term control or if long-term control is related to other factors

Frange P, et al. J Int AIDS Soc. 2015;18(suppl 4):3-4. Abstract MOAA0105LB.

February 12, 1996

Thank you!

IAS 2015: Return to Vancouver · Favors ATV+ RTV Favors STB 12.6%-12% +12% 0.4% 0 Treatment Difference (95% CI) 6.5% Mean CD4 Cell Increase (cells/mm3) was 196 (EVG/COBI/FTC/TDF &

Documents