highlights of aids 2014 .cco official conference coverage of the 20th international aids conference

July 20-25, 2014Melbourne, Australia

Highlights of AIDS 2014 CCO Official Conference Coverageof the 20th International AIDS Conference

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Faculty

David A. Cooper, MD, DScDirector, Kirby InstituteUniversity of New South WalesSydney, Australia

Joel E. Gallant, MD, MPHAssociate Medical Director of Specialty ServicesSouthwest CARE CenterSanta Fe, New MexicoAdjunct Professor of MedicineDivision of Infectious DiseasesJohns Hopkins University School of MedicineBaltimore, Maryland


Disclosures

David A. Cooper, MD, DSc, has disclosed that he has received consulting fees from Gilead Sciences, Janssen, Merck, and ViiV and funds for research support from AbbVie, Gilead Sciences, and Merck.

Joel E. Gallant, MD, MPH, has disclosed that he has received consulting fees from Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck, and Takara Bio and funds for research support from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Merck, Sangamo Biosciences, Vertex, and ViiV.

Antiretroviral Therapy


IAS-USA: 2014 Recommended Regimens for First-line ART

Günthard HF, et al. JAMA. 2014;312:410-425.

Class Recommended Regimens*

NNRTI EFV/TDF/FTC EFV + ABC/3TC RPV/TDF/FTC

Boosted PI ATV/RTV + TDF/FTC ATV/RTV + ABC/3TC DRV/RTV + TDF/FTC

INSTI

DTG + ABC/3TC DTG + TDF/FTC EVG/COBI/TDF/FTC RAL + TDF/FTC

*Please see notes section of slide for important caveats regarding certain agents and regimens.


Randomized, double-blind, international phase III trial

Primary endpoint: HIV-RNA < 50 c/mL at Wk 48

TDF/FTC QD + DRV/RTV QD

MVC 150 mg QD + DRV/RTV QD

Treatment-naive HIV-infected

patients

Wk 48primary analysis

Stellbrink HJ, et al. AIDS 2014. Abstract MOAB0101.

MODERN: Maraviroc QD + Darunavir/RTV as First-line ART

TDF/FTC QD + DRV/RTV QD

MVC 150 mg QD + DRV/RTV QD

Phenotypic tropism assay

Genotypic tropism assay

Randomization of pts with CCR5-tropic HIV


MODERN: MVC QD + DRV/RTV Not Noninferior to TDF/FTC + DRV/RTV

HARNESS: suppressed pts switched from any ART to ATV/RTV + RAL had higher rates of virologic rebound vs those switched to ATV/RTV + TDF/FTC[2]

Similar rates of HIV-1 RNA suppression at Wk 48 by screening assay type

1. Stellbrink HJ, et al. AIDS 2014 Graphic used with permission. Abstract MOAB0101. 2. van Lunzen J, et al. AIDS 2014. Abstract LBPE19.

MVC + DRV/RTV (n = 396)

TDF/FTC + DRV/RTV (n = 401)

100

80

60

40

20

0

Wk

Pts

Wit

h H

IV-1

RN

A <

50

co

pie

s/m

L[1

]

BL 4 8 12 16 20 24 36 48

77.3%

86.8%

Adjusted treatment difference: -9.5% (95%% CI: -14.8% to -4.2%)

Assay Type

MVC + DRV/RTV(n = 396)

TDF/FTC + DRV/RTV(n = 401)

Phenotypic 74.4 87.0

Genotypic 80.7 86.5

Δ (95% CI) 6.9% (-1.3% to 15%)

NR


OLE: Simplification to Dual ART With LPV/RTV + 3TC or FTC in Suppressed Pts Randomized, open-label phase III noninferiority trial

Primary endpoint: free of VF at Wk 48

HIV-infected patients with HIV-1 RNA < 50 c/mL;

on triple ART with LPV/RTV + 3TC or FTC + NRTI for 6 mos; no resistance to LPV/RTV or 3TC or FTC

(N = 239)

Lopinavir/Ritonavir 400/100 mg BID +Lamivudine or Emtricitabine

(n = 118)

Lopinavir/Ritonavir 400/100 mg BID +Lamivudine or Emtricitabine +

Investigator-selected NRTIs in FDC* (n = 121)

Wk 48primary analysis

Gatell J, et al. AIDS 2014. Abstract LBPE17.

*TDF/FTC: 60%; ABC/3TC: 28%; Other: 12%


OLE: Switching Suppressed Pts to Dual ART Noninferior to Triple ART at Wk 48

New grade 3/4 AEs in 9 pts in each arm

Significantly greater increases in TC (P = .02), numerically greater increases in TG (P = .09) in dual-ART arm

Numerically greater decreases in creatinine in triple-ART arm

New lab abnormalities similar

VF in 3 pts in each arm

– 1 pt (dual-ART) tested for resistance; had K103N and M184V

SALT trial of switches in suppressed pts showed switch to ATV/RTV + 3TC noninferior to switch to ATV/RTV + 2 NRTIs[2]

Pat

ien

ts (

%)[1

]

91.5 90.9

Δ -0.6%(95% CI: -6.9% to 8.1%)

Dual ART (n = 118)

Triple ART (n = 121)

0

20

40

60

80

100

2.5 2.5 0.83.3

n =

Therapeutic Response*

VF D/C Due to AE

D/C for Other

Reasons

5.1 3.3

*HIV-1 RNA < 50 c/mL at Wk 48 (mITT).

1. Gatell J, et al. AIDS 2014. Abstract LBPE17. Graphic used with permission. 2. Perez-Molina JA, et al. AIDS 2014. Abstract LBPE18.


SAILING Subanalysis: Activity of DTG in INSTI-Naive Pts With NRTI Resistance Post hoc analysis of SAILING: randomized, double-blind, active-

controlled phase III noninferiority trial

Treatment-experienced, INSTI-naive patients with

HIV-1 RNA ≥ 400 copies/mL and ≥ 2 class

resistance(N = 715)

Dolutegravir 50 mg QD +background regimen*

(n = 354)

Raltegravir 400 mg BID +background regimen*

(n = 361)

Wk 96

Stratified by number of fully active background agents, use of DRV,

screening HIV-1 RNA ≤ vs > 50,000 c/mL

*Background regimen contains 1-2 agents, at least 1 of which is fully active.

Current Analysis: Wk 48

Demarest J, et al. AIDS 2014. Abstract TUAB0104.


SAILING: No Virologic Failure With DTG + NRTIs, Even If No Fully Active NRTIsPts With Protocol-Defined Virologic Failure at Wk 48, n/N (%)

DTG 50 mg QD(n = 354)

RAL 400 mg BID(n = 361)

Overall 21/354 (6) 45/361 (12)

Type of background regimenPI containingNRTI onlyOther

18/300 (6)0/32

3/22 (14)

36/305 (12)7/32 (22)22/24 (8)

Fully active NRTIs* in background regimen210Missing phenotype

0/160/120/10/3

3/194/13

----

Demarest J, et al. AIDS 2014. Abstract TUAB0104.

*Fully active based on PhenoSense assay.


Canadian National Cohort: Switching After Suppression Associated With Risk of VF Retrospective analysis of correlates

of VF among suppressed pts who switched ART for reasons other than VF (N = 2807)

– Initiated first-line ART with ≥ 3 agents between 1/1/2005 and 6/30/2012

In multivariate model

– Switching ART associated with increased risk of VF (P < .001)

– Females and patients with IDU history at increased risk of VF with switch (P < .001)

Authors advocate closer follow-up of pts switching for nonvirologic reasons

– Switching may serve as marker for problems with adherence or tolerance of ART agents

Hull M, et al. AIDS 2014. Abstract TUAB0103. Table used with permission.

Factor Adj OR(95% CI)

P Value

ART switch 1.35 (1.18-1.53) < .001

Male sex 0.35 (0.21-0.58) < .001

IDU 2.85 (1.70-4.80) < .001

Age (per 10 yrs) 0.98 (0.71-1.35) .884

BL CD4+ count, per 100 cells/mm3 1.08 (0.93-1.26) .30

Initiated ART before vs after 2008

1.17 (0.70-1.93) .55

Province (ref. British Columbia) .260

Ontario Quebec

1.11 (0.63-1.95)1.33 (0.78-2.26)


Resistance analysis of randomized, open-label, multicenter trial

LPV/RTV + RAL

(n = 270)

LPV/RTV + 2-3 NRTIs*(n = 271)

HIV-infected patients with confirmed VF

on NNRTI + 2 NRTIswith no previous PI

or INSTI use(N = 541)

Wk 96

*NRTIs selected by genotypic resistance test or by algorithm.

SECOND-LINE Subanalysis: Resistance to NRTIs and Risk of Virologic Failure

Primary analysis: LPV/RTV + RAL noninferior to LPV/RTV + 2-3 NRTIs after VF of initial NNRTI regimen

46% with high-level NRTI resistance at baseline by global genotypic sensitivity score

Risk of VF at Wk 96 in both treatment arms higher among pts with lower levels of NRTI resistance by gGSS

Boyd M, et al. AIDS 2014. Abstract TUAB0105LB. Graphic used with permission.

VF at Wk 96 by BL Resistance Level, %

LPV/RTV +2-3 NRTIs

LPV/RTV + RAL

High 9 14

Moderate 13 12

Low 43 38


SECOND-LINE: Predictors of Virologic Failure at Wk 96 by Multivariate Analysis Risk of VF at Wk 96 higher among pts with lower levels of NRTI resistance by gGSS

Predictors of VF at Wk 96 Multivariate OR (95% CI) P Value

Race Asian White Hispanic Black

1 (ref)2.28 (0.65-8.02) 3.13 (1.21-9.13) 3.49 (1.68-7.28)

NR.007

Baseline VL, copies/mL ≤ 100,000 > 100,000

1 (ref) 3.43 (1.70-6.94) < .001

Adherence (Wk 4) All ART in last 7 days < All ART in last 7 days

1 (ref) 2.18 (1.07-4.47) .032

Adherence (Wk 48) All ART in last 7 days < All ART in last 7 days

1 (ref)3.43 (1.09-5.69) .03

Resistance by gGSS High Moderate Low

1 (ref) 1.03 (0.52-2.03) 4.73 (1.04-11.46) .002

Boyd M, et al. AIDS 2014. Abstract TUAB0105LB. Table used with permission.


In modified analysis, no difference in rate of VF among those with consistent HIV-1 RNA < 20 vs those HIV-1 RNA < 20 c/mL and transient increases to 50 c/mL

– Transient HIV-1 RNA increases to > 200 significantly associated with VF (P = .0157)

– Trend toward increased risk of VF with blips between 50-200 copies/mL (P = .09)

VACH Cohort: HIV-1 RNA 20-50 c/mL Not Predictive of VF After Suppression to < 20 Retrospective analysis of Spanish

VACH cohort (N = 21,480 on ART)

Compared risk of virologic failure in

– Pts maintaining HIV-1 RNA < 20 c/mL vs

– Pts with transient increases (“blips”) of HIV-1 RNA to 20-50 c/mL

Analysis included pts with HIV-1 RNA < 50 c/mL on 2 determinations and HIV-1 RNA < 20 c/mL at least once

VF: one HIV-1 RNA > 200 followed by one of the following

– Second HIV-1 RNA > 200, censoring, change of treatment, or loss to follow-up

Teira R, et al. AIDS 2014. Abstract TUAB0102. Table used with permission.

Factors Predictive of VF

Variable RH 95% CI

Transient VL 20-50 vs consistent VL < 20

0.588 0.399-0.899

Nadir CD4+ count 0.998 0.997-0.999

MSM vs IDU 0.577 0.337-0.989

Time receiving effective ART (per yr)

0.916 0.853-0.983

Pre-Exposure Prophylaxis(PrEP)


iPrEX OLE: Oral PrEP Reduces Incidence of HIV in MSM Open-label extension of iPrEX trial of daily TDF/FTC oral PrEP in MSM and

transgender women (N = 1603)

– Started PrEP at enrollment: 72%

– Started PrEP later: 6%

– Never started PrEP: 23%

PrEP uptake significantly higher among those reporting receptive anal intercourse without condoms (P = .003) or HSV coinfection (P = .03)

Evaluated HIV acquisition according to PrEP use, adherence, and risk behavior

HIV incidence decreased in those starting PrEP

– HR adjusted for sexual behavior: 0.51 (95% CI: 0.26-1.01)

Grant R, et al. AIDS 2014. Abstract TUAC0105LB.


iPrEX OLE: 100% Adherence With Daily PrEP Not Required to Attain Full Benefit

TFV-DP: tenofovir diphosphate (measurable tenofovir in dried blood spots)

Grant R, et al. AIDS 2014. Abstract TUAC0105LB. Graphic used with permission.

HIV Incidence and Drug Concentrations5

4

3

2

1

0

150012501000700500350LLOQ0

Off PrEP

On PrEP

TFV-DP in fmol/punch

7 Tablets/Wk4-6 Tablets/Wk< 2 Tablets/Wk 2-3 Tablets/Wk

HIV

Inci

den

ce p

er

100

Per

son

-Yrs

Follow-up,%Risk Reduction,%95% Cl, %

2644

-31 to 77

21100

12100

86 to 100 (combined)

1284

21 to 99


iPrEX OLE: HIV Infection Occurred During Periods of Nonadherence

Grant R, et al. AIDS 2014. Abstract TUAC0105LB. Graphic used with permission.

1.0

0.8

0.6

0.4

0.2

072 60 48 36 24 12 0 12 24 36 48 60

Control

ControlCase

Case

Wks PostinfectionWks Preinfection

3808

130622

164722

139624

148924

144126

133828

7687

386 266 171 44Control, n:Case, n:

Pro

po

rtio

n W

ith

TF

V-D

P

Det

ecte

d i

n D

ried

Blo

od

Sp

ots

First evidence of HIV infection

TFV-DP LLOQ TFV-DP ≥ 350 fmol/punch


ANRS Ipergay: Detection of TFV in Plasma After On-Demand PrEP ANRS Ipergay: planned randomized,

placebo-controlled trial of event-driven PrEP vs placebo in MSM engaging in high-risk sex

Planned study population: 950 per arm

Event-driven PrEP:

2 tablets (TDF/FTC or placebo) 2-24 hrs before sex

1 tablet 24 hrs later

1 tablet 48 hrs later

Proof-of-concept of 129 pts measuring TFV and FTC in plasma after intermittent PrEP

Overall, TFV was detected in plasma in 86% of samples from pts in the TDF/FTC arm vs 4% from those in placebo arm

0

20

40

60

80

100

113 0

1071

1012

864

776

488

1610

56 57 51 56 49 52 42 44 37 40 22 26 8 8

100

8883

918582

4 6 5 50 02

52333404446 22323 8

Par

tici

pa

nts

(%

)

Fonsart J, et al. AIDS 2014. Abstract TUAC0103. Graphic used with permission.

Arm ns:N:

Month:

Comorbidities


All time-updated variables

D:A:D: BMI Gain After ART Initiation and Increased Risk of Diabetes, CVD Analysis of D:A:D cohort including pts starting ART with BMI data and no DM or CVD

1 yr before starting ART (N = 9321)

– 70% with normal or low BMI (< 25) before starting ART

Diabetes risk ↑ by ~ 10%/BMI unit gain after ART initiation regardless of pre-ART BMI

Post-ART BMI gain associated with ↑ risk of CVD in middle 2 pre-ART BMI quartiles

1.6

1.4

1.0

0.8

1.2

0.6BMI Q1< 20.9

BMI Q220.9-23.0

BMI Q323.0-25.5

BMI Q4> 25.5

IRR

*P for effect modification in adjusted models: .011

Adjusted IRR for CVD per Unit Gain in BMI

1.6

1.4

1.0

0.8

1.2IR

R

All Patients*

Underweight< 18.5

Normal18.5-25

Obese> 30

Overweight25-30

Pre-ART BMIPre-ART BMI*P for effect modification in adjusted models: > .05

Adjusted IRR for DM per Unit Gain in BMI

Achhra AC, et al. AIDS 2014. Abstract WEAB0103. Graphics used with permission.

*

*

*

Adjusted for demographics All time-updated variablesAdjusted for demographics

HCV Treatment in HIV/HCV-Coinfected Patients


TURQUOISE-I: ABT-450/RTV/Ombitasvir + Dasabuvir + RBV in GT1 HCV/HIV Pts Open-label phase II/III trial

Inclusion criteria: GT1; compensated cirrhosis (Child-Pugh A) allowed; DAA naive but pegIFN naive or experienced; HIV-1 RNA < 40 c/mL on ATV or RAL regimen; CD4+ count ≥ 200 or %CD4+ ≥ 14%

52% on ATV, 49% on RAL in 12-wk arm; 38% on ATV, 63% on RAL in 24-wk arm; 19% with cirrhosis

Primary endpoint: SVR12

ABT-450/RTV/Ombitasvir + Dasabuvir + RBV(n = 32)

ABT-450/RTV/Ombitasvir + Dasabuvir + RBV

(n = 31)

Wk 24

Sulkowski M, et al. AIDS 2014. Abstract MOAB0104LB.

ABT-450/RTV/ombitasvir 150/100/25 mg once daily; dasabuvir 250 mg twice daily; RBV 1000-1200 mg/day.

DAA-naive HIV-infected pts with GT1 HCV infection

(N = 63)

Wk 12


TURQUOISE-I: Efficacy Results

Anemia in 12.9% of 12-wk arm and 9.4% of 24-wk arm; hyperbilirubinemia in 35.5% of 12-wk arm and 18.8% of 24-wk arm

12 wks (n = 31)24 wks (n = 32)

Pat

ien

ts (

%)

100 100

31/31 32/320

20

40

60

80

100 96.8 96.9 93.5 96.9

n = 31/3230/31 29/31

RVR (Wk 4) EOTR (Wk 12 or 24)

SVR4 SVR12

93.5

29/31 31/32

Sulkowski M, et al. AIDS 2014. Abstract MOAB0104LB. Graphic used with permission.


PHOTON-2: Sofosbuvir + Ribavirin in GT1-4 HCV Pts Coinfected With HIV Ongoing, nonrandomized, open-label phase III study

Stable ART (HIV-1 RNA < 50 copies/mL for ≥ 8 wks before enrollment); CD4: > 200 cells/mm3 if ART treated; > 500 cells/mm3 if ART naive

– 97% on ART: TDF/FTC, 100%; EFV: 25%; ATV/RTV: 17%; DRV/RTV: 21%; RAL: 23%; RPV: 5%

20% of pts with compensated cirrhosis

Primary endpoint: SVR12

Molina JM, et al. AIDS 2014. Abstract MOAB0105LB.

Wk 24

Sofosbuvir + Ribavirin(n = 200)

Sofosbuvir + Ribavirin (n = 55)

Sofosbuvir + Ribavirin(n = 19)

Wk 12

Tx-naive GT1, 3, 4

Tx-naive GT2

Tx-exp’d GT2, 3

Sofosbuvir 400 mg QD; weight-based ribavirin 1000 or 1200 mg/day


PHOTON-2: SVR12 by Genotype and Cirrhosis

Absolute CD4+ cell count—but not CD4%—decreased, consistent with effect of RBV on lymphocytes

Molina J-M, et al. AIDS 2014. Abstract MOAB0105LB. Graphic used with permission.

24 wks, noncirrhotic24 wks, cirrhotic

12 wks, noncirrhotic

12 wks, cirrhotic

0

20

40

60

80

100

Total GT1a GT1b Naive

GT1 Naive

Pat

ien

ts W

ith

SV

R (

%)

Exp’d Naive Exp’d Naive

GT2 GT3 GT4

89100 100 100

78

9291

7583

8888

65

87

62

100

75

84/95

11/17

76/87

8/13

7/7

3/4

16/18

3/4

49/54

1/1

2/2

3/3

24/26

18/23

19/23

7/8

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