HIV Treatment and Clinical Trials 2014

Eric S. Daar, M.D.Chief, Division of HIV MedicineHarbor-UCLA Medical Center

Professor of MedicineDavid Geffen School of Medicine at UCLA

DisclosuresGrants Bristol Myers Squibb, Gilead, Merck, ViiVConsultant Abbvie, Bristol Myers Squibb, Gilead, Janssen, Merck, Teva, ViiV

Overview

• Pathogenesis

• Treatment– When to start– What to start– When to switch

• Treatment as prevention

• Future

Viral DynamicsViral Dynamics

Productively Infected CD4+ Lymphocytes

Activated Uninfected CD4+ Lymphocytes

Long-lived Cells

Activated Uninfected CD4+ Lymphocytes

Antiretroviral Therapy

Infected Resting Memory CD4+ Lymphocytes

Perelson A, et al. 1995

Viral DynamicsProductively Infected CD4+ Lymphocytes

Activated Uninfected CD4+ Lymphocytes

Long-lived Cells

Activated Uninfected CD4+ Lymphocytes

>95%

T1/2~20 min.

T1/2~1 day

Antiretroviral Therapy

Weeks

Lo

g10

RN

A

Infected Resting Memory CD4+ Lymphocytes

Viral DynamicsProductively Infected CD4+ Lymphocytes

Activated Uninfected CD4+ Lymphocytes

Long-lived Cells

Activated Uninfected CD4+ Lymphocytes

>95%

<5%

T1/2~20 min.

T1/2~1 day

T1/2~2-4 weeksAntiretroviral Therapy

Weeks

Lo

g10

RN

A

Infected Resting Memory CD4+ Lymphocytes

Viral DynamicsProductively Infected CD4+ Lymphocytes

Activated Uninfected CD4+ Lymphocytes

Long-lived Cells

Activated Uninfected CD4+ Lymphocytes

>95%

<5%

<1%

T1/2~20 min.

T1/2~1 day

T1/2~6 months-years

Antiretroviral Therapy

Weeks --- Year

Lo

g10

RN

A

Infected Resting Memory CD4+ Lymphocytes

T1/2~2-4 weeks

Lessons From Pathogenesis

• High levels viral replication makes mutations (resistance) inevitable if detectable viremia

• Persistent cellular reservoirs of infection established early in course of infection– Source of archived virus throughout course of disease

• Viral rebound likely regardless of duration of viral suppression with current therapeutic options

Antiretroviral Activity:An Historical Perspective

HIV

RN

A c

han

ge

(lo

g10

c/m

L)

1994:Two-Drug Therapy

1997: HAART

1987: AZTMonotherapy

24-week response

0

-0.5

-1

-1.5

-2

-2.5

-3

0

-0.5

-1

-1.5

-2

-2.5

-3

0

-0.5

-1

-1.5

-2

-2.5

-3

Fischl, NEJM, 1987Katzenstein, NEJM, 1996

Eron, NEJM, 1995;Hammer, NEJM, 1996

Gulick, NEJM, 1997;Cameron, Lancet, 1998

24-week response 24-week response

Life Expectancy of HIV-Infected Patients

• Life expectancy of Athena cohort to general population (n=4,174)

• Expected life years remaining at age 25– 53.1 (44.9-59.5) for general

population

– 52.7 for asymptomatic HIV+ patients

van Sighem A, et al. AIDS 2010; 24:1527-1535

Age at time of death

Remaining life years

General populationAsymptomatic HIV+ patients

Awareness of Serostatus Among People with HIV and Estimates of

Transmission

~25% Unaware

ofInfection

~75% Aware

ofInfection

~46% New

Infections

~54% New

Infections

New Sexual InfectionsPeople Living with HIV

Accounting for:

Marks, et al, AIDS 2006;20:1447-50

Revised CDC Recommendations for HIV Testing in Healthcare Settings

• Routine voluntary testing for patients ages 13 to 64 years in healthcare settings– Not based on patient risk

• Opt-out testing • No separate consent for

HIV• Pretest counseling not

required• Repeat HIV testing left to

discretion of provider– Based on patient risk

Branson BM, et al. MMWR Recomm Rep. 2006;55(RR-14):1-17.

Rapid HIV Testing

HIV Cascade

When to Start?

Why not treat everyone?

• Not ready to commit to treatment• Short-term and long-term toxicity• Need for life long therapy• Risk of virologic failure, resistance and cross-

resistance• Limited evidence for earlier therapy being

associated with better outcomes than delayed therapy

Physical Manifestations of Fat Redistribution Syndromes

Case for earlier therapy

CIPRAHT001: Randomized Trial of When to Start ART in Haiti

Early Treatment(Immediate ZDV/3TC + EFV)

Standard Treatment(Delay until CD4+ <200 or AIDS

• Treatment-naive • No hx AIDS-defining illness• CD4 200-350

Primary endpoint: Survival

Randomized clinical endpoint study of when to start therapy

Baseline Characteristics Early (n=408) Standard (n=408)

Median age (years) 40 40

Male (%) 41% 44%

Median CD4+ (cells/mm3) 280 282

Body Mass Index (kg/m2) 21.4 21.0

Severe P, et al. NEJM 2010 363:257-265.

CIPRAHT001: Clinical Endpoints

Early Standard Hazards Ratio (p value)

Death 6 23 4.0(.0011 )

Incident Tuberculosis 18 36 2.0

(.0125 )

• Infectious causes of death– Early: 1 (gastroenteritis)– Standard: 17 (7 gastroenteritis, 5 TB, 4 pneumonia, 1 cholangitis/sepsis)

• More toxicity from ART and intensive need for lab f/u for deferred grp• WHO start guidelines now modified to <350 cells/uL

Clinical Endpoints

Severe P, et al. NEJM 2010 363:257-265.

May 2009: DSMB review stopped study due to excess deaths in Defer Treatment arm

NA-ACCORD: Risk of Death with ART Deferral

351-500 CD4+

RR 95% CI P

Deferral of ART 1.7 1.3, 2.3 <0.001

Female Sex 1.2 0.9, 1.6 0.24

Older Age (per 10 years)

1.7 1.5, 1.9 <0.001

Baseline CD4 count (per 100 cells/mm3)

1.1 0.7, 1.8 0.59

Kitahata M, et al. New Engl J Med 2009;360:1815-26.

>500 CD4+

RR 95% CI P

1.9 1.4, 2.8 <0.001

1.9 1.3, 2.6 <0.001

1.8 1.6, 2.1 <0.001

0.9 0.9, 1.0 0.03

Gras L, et al. J Acquir Immune Defic Syndr. 2007;45(2):183-192.

Ultimate CD4 Cell Count Depends on Where You Start

1000

800

600

400

200

0

0 48 96 144 192 240 288 336

ATHENA National Cohort2

Weeks From Starting ART

<50

50-200

200-350

350-500

≥500

Neurocognitive disorders associated with CD4 nadir

Odds Ratio for Cognitive Impairment by CD4 Nadir

Odds Ratios for NP Impairment

<50 50-199 200-349 ≥350

1.1

1

0.9

0.8

0.7

0.6

0.5

0.4

0.3

Odd

s R

atio

CD4 Nadir

Ellis R, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 429.

Consequences of stopping ARVs: SMART Trial

Continuous antiretroviral therapy throughout follow-up

(n = 2752)

ART stopped/deferred until CD4+ <250 cells/mm3 then started to

increase CD4+ to >350 cells/mm3

(n = 2720)

HIV-1-infected patients with

CD4+ cell count > 350 cells/mm3

(N = 5472)

95.4% treatment experienced

El-Sadr W et al. N Engl J Med. 2006; 355:2283-2296.

Favors VS ►

►

Favors DC

#Pts w/ EventsEndpoints Relative Risk (95% CI)

Progression of Disease or Death 164

Serious HIV Events 21 >

2.5

6.1Death 84

1.9

0.1 1 10

Severe Complications* 1141.5

*CVD, Renal, Hepatic Events (fatal/nonfatal)

El-Sadr W et al. N Engl J Med. 2006; 355:2283-2296.

SMART: Primary endpoint and components

*DC patients on ART at baseline with HIV RNA ≤400 copies/mL

≤400 401-10,000 10,000-50,000 >50,000

Month 1 HIV RNA Level (copies/mL)

∆ IL

-6 (p

g/m

L)P<.0001 for trend

∆ H

DL (μm

ol/L)

∆ IL-6 ∆ HDL

P=.0003 for trend

-0.4

-0.3

-0.2

-0.1

0

0.1

0.2

0.3

0.4

-0.4

-0.3

-0.2

-0.1

0

0.1

0.2

0.3

0.4

SMART: Changes in D-Dimer and IL-6 Levels

Change in Log IL-6 (pg/mL) and HDL (μmol/L) BL to 1 Month2*

1Kuller L, et al. PLoS 2008;10:1496-1508. 2SMART/INSIGHT: Duprez et al, CROI, 2009.

• Suggests HIV viremia effect on endothelium, leading to increased tissue factors and initiation of coagulation cascade

μg/m

L

≤400 401-10,000

10,000-50,000

>50,0000

0.1

0.2

0.3

00.04

0.11

0.28

Month 1 HIV RNA (c/mL)

Change in D-Dimer*, BL to 1 Month

P=.0005 for trend

HPTN 052: Immediate vs Delayed ART in Serodiscordant Couples

Cohen MS, et al. IAS 2011. Abstract MOAX0102. Cohen MS, et al. N Engl J Med. 2011 Jul 18. [Epub ahead of print]

Immediate ART Initiate ART at CD4+ cell count 350-550 cells/mm3

(n = 886 couples)

Delayed ARTInitiate ART at CD4+ cell count ≤ 250 cells/mm3*

(n = 877 couples)

HIV-infected, sexually active serodiscordant

couples; CD4+ cell count of the infected partner:

350-550 cells/mm3

(N = 1763 couples)

*Based on 2 consecutive values ≤ 250 cells/mm3.

• Primary efficacy endpoint: virologically linked HIV transmission• Primary clinical endpoints: WHO stage 4 events, pulmonary TB, severe

bacterial infection and/or death• Couples received intensive counseling on risk reduction and use of condoms

Cohen M, et al. NEJM July 18, 2011.

n=1; incidence rate0.1 per 100 p-y (95% CI 0.0, 0.4)

n=27; incidence rate1.7 per 100 p-y (95% CI 1.1, 2.5)

Linked HIV Transmission Events

Rationale for Recommending Therapy for Those with >350 CD4 cells/uL

• Recent cohort studies (4 for 350-500 cells/uL and 1 for >500 cells/uL)

• HIV replication associated with non-AIDS-defining diseases (e.g. cardiovascular, renal, liver, malignancy)

• Evidence that ARVs may reduce risk of transmission

US Department of Health and Human Services. Available at: http://aidsinfo.nih.gov/Guidelines.

• ARV more effective, convenient, better tolerated than in the past

When to Start Treatment

Clinical Category

CD4 Count (cells/mm3)

DHHS 2013

IAS-USA 2012

EACS 2012

BHIV 2012

WHO 2013

AIDS/Severe Sx Any value R R R R R

Asymptomatic ≤350 R R R R R

350 to ≤500 R R C D R

>500 R R D D D

Pregnant women

Any value R R R R R

HIV-associated nephropathy

Any value R R R R R

HIV/HBV Any value R R R R R

HIV-neg partner

Any value R R C C R

DHHS Mar 2013: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf;IAS-USA: Thompson MA, et al. JAMA. 2012; 308: 387-402;EACS Nov 2012. http://www.eacsociety.org/Portals/0/files/pdf%20files/EacsGuidelines-v6.1-2edition.pdf;BHIV 2012: http://www.bhiva.org/TreatmentofHIV1_2012.aspx;WHO June 2013: http://apps.who.int/iris/bitstream/10665/85321/1/9789241505727_eng.pdf

What to start?

HIV replication cycle and sites of drug activity

Capsidproteinsand viral

RNA

CD4Receptor

Viral RNA

New HIVparticles

Protease

Attachment Uncoating ReverseTranscription

Integration Transcription Translation

ReverseTranscriptase

Unintegrateddouble strandedViral DNA

Integratedviral DNA

ViralmRNA

Integrase

gag-polpolyprotein

1 2 3 4 56

Assembly andRelease

Protease InhibitorsIndinavir (Crixivan)Ritonavir (Norvir)

Saquinavir (Fortovase)Nelfinavir (Viracept)

Lopinavir/ritonavir (Kaletra)Atazanavir (Reyataz)

Fos Amprenavir (Lexiva)Tipranavir (Aptivus)Darunavir (Prezista)

NRTIsAZT (Zidovudine-Retrovir)

ddI (Didanosine-Videx)ddC (Zalcitabine-Hivid)d4T (Stavudine-Zerit)

3TC (Lamivudine-Epivir)ABC(Abacavir-Ziagen)

FTC (Emtricitabine, Emtriva)

NNRTIsEfavirenz (Sustiva)

Delavirdine (Rescriptor)Nevirapine (Viramune) (XR)

Etravirine (Intelense)Rilpivirine (Edurant)

Nucleus

Cellular DNA

HIV Virions

nRTITenofovir DF

(Viread)

Fusion InhibitorT-20

(Enfuvirtide, Fuzeon)

CCR5 AntagonistMaraviroc (Celsentri)

Integrase InhibitorRaltegravir (Isentress)

Elvitegravir /COBIDolutegravir (Tivicay)

Factors to consider in choosing first-line therapy

• Patients willingness to commit to therapy

• Baseline resistance

• Efficacy data

• Tolerability

• Convenience

• Comorbid conditions

• Consequences of failure (resistance)

• Since the introduction of potent ARV therapy preferred regimens all include NRTIs + third drug

Which Nucleoside Reverse Transcriptase Inhibitor?

A5202: Study Design

Stratified by screening HIV-1 RNA (< or ≥ 100,000 c/mL)

Enrolled 2005-2007

Followed through Sept 2009, 96 wks after last pt enrolled

HIV-1 RNA ≥1000 c/mL

Any CD4+ count

> 16 years of age

ART-naïve

N=1858

Randomized 1:1:1:1

TDF/FTC QD

ABC/3TC Placebo QD

EFV

QD

ABC/3TC QD

TDF/FTC Placebo QD

EFV

QD

TDF/FTC QD

ABC/3TC Placebo QD

ATV/rQD

ABC/3TC QD

TDF/FTC Placebo QD

ATV/r

QD

A

B

C

D

Arm

ART-naïve

1857 enrolled

Randomized 1:1:1:1

TDF/FTC QD EFV

QD

ABC/3TC QD

TDF/FTC Placebo QD

EFV

QD

TDF/FTC QD

ABC/3TC Placebo QD

ATV/rQD

ABC/3TC QD

TDF/FTC Placebo QD

ATV/r

QD

No. at Risk

ABC-3TC 398 363 313 267 222 188 137 87 49 20

TDF-FTC 399 361 321 284 236 204 160 104 65 23

A5202: Time to Virologic Failure in Patients with HIV RNA >100,000 c/mL

Sax PE, et al. NEJM 2009;361:2230-2240.

0

20

40

60

80

100

0 12 24 36 48 60 72 84 96 108

Pro

bab

ility

of

No

Vir

olo

gic

F

ailu

re (

%)

Weeks since Randomization

P<0.001, log-rank testHazard ratio, 2.33 (95% CI, 1.46-3.72)

TDF-FTC (26 events)

ABC-3TC (57 events)

Probability of No Virologic Failure

ABC/3TC vs. TDF/FTCTime to Virologic Failure

(End of Study: Low Viral Load Stratum)

Sax P, et al. JID 2011

Which third drug to combine with NRTIs?

Boosted-Protease Inhibitors

Adapted from: 1. Eron J, et al. Lancet 2006; 368:476-482; 2. Mills A, et al. AIDS May 29, 2009 3. Molina J-M, et al. 48th ICAAC/46th IDSA , Washington, DC, 2008. Abst. H-1250d

ARTEMIS2

(ITT, TLOVR)96 weeks

LPV/r QD or

BID

DRV/r 800/100

QD

79

71

n=343n=346

0

20

40

60

80

100

CASTLE3

(ITT, NC=F)96 weeks

ATV/r300/100

QD

LPV/r400/100

BID

6874

0

20

40

60

80

100

n=443 n=440

KLEAN1

(ITT-E, TLOVR)48 weeks

LPV/r400/100

BID

FPV/r 700/100

BID

66

65

N=444n=434

0

20

40

60

80

100

ATV/r vs. EFVPrimary Endpoint

Daar ES, et al. Ann Intern Med 2011

Percent of Failures with Emergence of Major Resistance Mutations*

ATV/r

ABC/3TC

ATV/rEFV EFV

TDF/FTC

*Major mutations defined by IAS-USA (2008) list plus T69D, L74I, G190C/E/Q/T/V for RT and L24I, F53L, I54V/A/T/S and G73C/S/T/A for PR

A5202: Overall ITT

p<0.0001

p=0.0003

p<0.0001

p=0.046

ANY

MAJOR

NRTI

NNRTI

PI

Viral failuresNo baseline resistance N=

p-values: ATV/r vs. EFV

(amongst failures)

76 63 54 48

ANY

MAJOR

NRTI

NNRTI

PI

ANY MAJOR

NRTI

NNRTI

PI

ANY MAJOR

NRTI

NNRTI

PI

Per

cent

Daar ES, et al. AIM 2011

STARTMRK: RAL vs. EFV

Rockstroh J, et al, 19th IAC; Washington, DC; July 22-27, 2012; Abst. LBPE19.

ITT, NC=F

281 278 279 280 281 281 277 280 281 281 277 279

282 282 282 281 282 282 281 281 282 282 282 279

Raltegravir 400 mg BID

Efavirenz 600 mg QHS

Number of Contributing Patients

0 12 24 48 72 96 120 144 168 192 216 240Weeks

0

20

40

60

80

100

P

erc

en

tag

e o

f P

ati

en

ts w

ith

HIV

RN

A L

ev

els

<5

0 C

op

ies

/mL

86

82

81

79

75

69

76

67

71

61

CD4 Change: RAL +374 vs. EFV +312

Twice per day vs. Once per dayBUT

Less side effects

ECHO and THRIVE: Rilpivirine

* Investigator’s choice: TDF/FTC; AZT/3TC; ABC/3TC

N=690 patientsN=690 patients

RPV 25 mg QD + TDF/FTC (n=346)RPV 25 mg QD + TDF/FTC (n=346)

EFV 600 mg QD + TDF/FTC (n=344)EFV 600 mg QD + TDF/FTC (n=344)

ECHO (TMC278-C209)1

1:1

RPV 25 mg QD + 2 NRTIs* (n=340)RPV 25 mg QD + 2 NRTIs* (n=340)

EFV 600 mg QD + 2 NRTIs* (n=338)EFV 600 mg QD + 2 NRTIs* (n=338)

THRIVE (TMC278-C215) 2

1:1N=678 patientsN=678 patients

Cohen C, et al. 18th IAC; Vienna, July 18-23, 2010. Abst. THLBB206. 1. Molina JM, et al. Lancet 2011; 378:238-46; 2. Cohen CJ, et al. Lancet 2011; 378:229-37,

Baseline parameterRPV

N=686 EFV

N=682

Median log10 VL, copies/mL (min–max) 5 (2–7) 5 (3–7)

Baseline VL >100,000 copies/mL 46% 52%

Median CD4 cells/mm3 (min–max) 249 (1–888) 260 (1–1,137)

Hepatitis B or C co-infection 7% 9%

ECHO and THRIVE Studies:HIV RNA <50 Copies/mL(ITT-TLOVR)

Rilpivirine

Efavirenz

Patie

nts

(%)

ECHO(n=346/344)

THRIVE(n=340/338)

Pooled Data(n=686/682)

83%

Cohen M, et al. 6th IAS Conference. Rome, 2011. Abstract TuLBPE032.Molina J-M, et al. Lancet. 2011;378:238-246.Cohen CJ, et al. Lancet. 2011;378:229-237.

83% 86%82% 78% 78%

Week 48

CD4+196

cells/µL

CD4+182

cells/µL

CD4+189

cells/µL

CD4+171

cells/µL

CD4+228

cells/µL

CD4+219

cells/µL

Week 96

Pooled ECHO/THRIVE (Week 96):Discontinuations and Virologic Failure

Cohen M, et al. 6th IAS Conference. Rome, 2011. Abstract TuLBPE032.

Pooled ECHO/THRIVE (Week 96):Safety

Cohen M, et al. 6th IAS Conference. Rome, 2011. Abstract TuLBPE032.*P<0.0001 and †P=0.0039 versus rilpivirine.

GS102 & GS103: EVG/COBI/TDF/FTC vs. EFV/TDF/FTC or ATV/RTV +

TDF/FTC

Sax P, et al, Lancet 2012: 379::2439-48; DeJesus E, et al, Lancet 2012; 379: 2429-38

Randomized, Phase III, Double-blind, Double Dummy, Active-controlled, International Studies

Treatment Naïve HIV-1 RNA ≥5,000 c/mL

Any CD4 cell counteGFR ≥70 mL/min

48 weeks 192 weeks

GS 102~89% men

33% >105 c/mLCD4= ~385 c/uL

GS 103~90% men

~41% >105 c/mLCD4= ~370 c/uL

Quad QDQuad QD

EFV/FTC/TDF Placebo QDEFV/FTC/TDF Placebo QD

EFV/FTC/TDF QDEFV/FTC/TDF QD

Quad Placebo QDQuad Placebo QD

Quad QDQuad QD

ATV/r +TDF/FTC Placebo QDATV/r +TDF/FTC Placebo QD

QUAD Placebo QDQUAD Placebo QD

ATV/r +TD/FTC QDATV/r +TD/FTC QD

Study 236-102: Primary Endpoint:HIV-1 RNA < 50 copies/mL

+3.6%, 95% CI 3.6 (-1.6% to +8.8%)+3.6%, 95% CI 3.6 (-1.6% to +8.8%)

CD4+ change: Quad +239 vs. EFV +206 c/mm3 (p=0.009)No difference by baseline characteristics

Sax P, et al, Lancet 2012: 379::2439-48

Study 236-102:Common Adverse Events

Quad(n=348)

EFV/FTC/TDF(n=352)

Treatment Emergent Adverse Events in ≥ 10% of subjects (%)

Diarrhea 23% 19%

Nausea * 21% 14%

Abnormal Dreams ^ 15% 27%Upper Respiratory Infection 14% 11%Headache 14% 9%

Fatigue 12% 13%

Insomnia * 9% 14%

Depression 9% 11%

Dizziness ^ 7% 24%

Rash # 6% 12%

* p<0.05; ^ p<0.001; # p=0.009

Sax P, et al, Lancet 2012: 379::2439-48

Study 236-102: Primary Endpoint:HIV-1 RNA < 50 copies/mL

+3.6%, 95% CI 3.6 (-1.6% to +8.8%)+3.6%, 95% CI 3.6 (-1.6% to +8.8%)

CD4+ change: Quad +239 vs. EFV +206 c/mm3 (p=0.009)No difference by baseline characteristics

Sax P, et al. 19th CROI; Seattle, WA; March 5-8, 2012. Abst. 101.

Study 236-102:Common Adverse Events

Quad(n=348)

EFV/FTC/TDF(n=352)

Treatment Emergent Adverse Events in ≥ 10% of subjects (%)

Diarrhea 23% 19%

Nausea * 21% 14%

Abnormal Dreams ^ 15% 27%Upper Respiratory Infection 14% 11%Headache 14% 9%

Fatigue 12% 13%

Insomnia * 9% 14%

Depression 9% 11%

Dizziness ^ 7% 24%

Rash # 6% 12%

* p<0.05; ^ p<0.001; # p=0.009

Sax P, et al, Lancet 2012: 379::2439-48

Dolutegravir vs Currently “Preferred” Regimens in Treatment-Naive Pts

• Randomized, noninferiority phase III studies

• Primary endpoint: HIV-1 RNA < 50 c/mL at Wk 48

ART-naive ptsVL ≥ 1000 c/mL

(N = 822)

DTG 50 mg QD + 2 NRTIs*(n = 411)

RAL 400 mg BID + 2 NRTIs*(n = 411)

*Investigator-selected NRTI backbone: either TDF/FTC or ABC/3TC.

ART-naive ptsVL ≥ 1000 c/mLHLA-B*5701-neg

CrCL > 50 mL/min(N = 833)

DTG 50 mg QD + ABC/3TC QD(n = 414)

EFV/TDF/FTC QD (n = 419)

SPRING-2[1]

(active controlled)

SINGLE[2]

(placebo controlled)

DTG 50 mg QD + 2 NRTIs*(n = 242)

DRV/RTV 800/100 mg QD + 2 NRTIs*(n = 242)

ART-naive ptsVL ≥ 1000 c/mL

(N = 484)

FLAMINGO[3]

(open label)

1. Raffi F, et al. Lancet. 2013;381:735-743. 2. Walmsley S, et al. ICAAC 2012. Abstract H-556b. 3. Feinberg J, et al. ICAAC 2013. Abstract H1464a.

SPRING-2: DTG vs RAL + 2 NRTIs in Naive Patients

• DTG noninferior to RAL at both Wk 48 primary endpoint[1] and Wk 96[2]

Treatment-related study d/c: 2% in each arm at Wk 96

• VF at Wk 96[2]: 5% (22/411) in DTG arm and 7% (29/411) in RAL arm

• CD4+ cell count increase at Wk 96 similar:

– +276 cells/mm3 (DTG) vs+264 cells/mm3 (RAL)

HIV

-1 R

NA

< 5

0 co

pie

s/m

L (

%)

88 85

DTG 50 mg QD (n = 411)

RAL 400 mg BID (n = 411)

0

20

40

60

80

100

8176

Wk 48 Wk 96

1. Raffi F, et al. Lancet. 2013;381:735-743. 2. Raffi F, et al. IAS 2013. Abstract TULBPE17.

361/411

351/411

333/411

314/411

Δ4.4%(-1.1% to 10.0%)

Δ2. 5% (-2.2% to 7.1%)

SINGLE: DTG + ABC/3TC vs EFV/TDF/FTC in Naive Pts at Wk 48

• DTG superior to EFV at Wk 48 primary efficacy endpoint

• Treatment-related study d/c: 2% in DTG vs 10% in EFV arm

• VF at Wk 48: 4% (18/414) in DTG arm and 4% (17/419) in EFV arm

• CD4+ cell count increase at Wk 48 greater with DTG: – +267 cells/mm3 (DTG) vs

– +208 cells/mm3 (EFV) (P < .001)

HIV

-1 R

NA

< 5

0 co

pie

s/m

L a

t W

k 48

(%

)

8881

Δ +7.4% 95% CI (+2.5% to +12.3%; P = .003)

Walmsley S, et al. NEJM 2013

DTG 50 mg + ABC/3TC QD

EFV/TDF/FTC QD

0

20

40

60

80

100

364/414

340/419

FLAMINGO: DTG vs DRV/RTV + 2 NRTIs in Naive Patients at Wk 48

• DTG superior to DRV/RTV at Wk 48 primary efficacy endpoint – Treatment-related study d/c:

2% in DTG arm vs 4% in DRV/RTV arm

• VF at Wk 48: < 1% (n = 2) in each arm

• CD4+ cell count increase at Wk 48 similar: – +210 cells/mm³ in each arm

HIV

-1 R

NA

< 5

0 co

pie

s/m

L a

t W

k 48

(%

)

9083

Δ +7.1%(95% CI: +0.9% to +13.2%; P = .025)

Feinberg J, et al. ICAAC 2013. Abstract H1464a.

DTG 50 mg QD + NRTIs

DRV/RTV 800/100 mg QD

+ NRTIs

217/242

200/242

0

20

40

60

80

100

Preferred Regimens

• EFV/TDF/FTC• ATV/r + TDF/FTC• DRV/r (once daily) + TDF/FTC• RAL + TDF/FTC•EVG/COBI/TDF/FTC•DTG + TDF/FTC•DTG + ABC/3TC[Pregnant Women Only: LPV/r (twice daily) + ZDV/3TC]

AlternativeRegimens

• EFV + ABC/3TC• RPV + (TDF or ABC)/(FTC or 3TC)• ATV/r or DRV/r + ABC/3TC• FPV/r or LPV/r (qd or bid) ABC/3TC or TDF/FTC• RAL + ABC/3TC

AcceptableRegimens

• EFV or RPV + ZDV/3TC• NVP + TDF/FTC or ZDV/3TC or ABC/3TC• ATV + (ABC or ZDV)/3TC• ATV/r, DRV/r, LPV/r, FPV/r , RAL + ZDV/3TC•MVC + ZDV or ABC/3TC•SQV/r + TDF/FTC or ABC/3TC or ZDV/3TC (with caution)

DHHS Guidelines: What to Start

DHHS Guidelines. Available at: http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf . Revision March 27, 2012.

October 30, 2013

Individualizing First-line Therapy: Specific Circumstances

Circumstance Agents No genotype Use boosted PI

High HIV-1 RNA Caution with ABC, RPV

Renal disease Caution with TDF, ATV/RTV; monitoring complicated with COBI and DTG

Dyslipidemia RAL, DTG, RPV most lipid neutral

CV risk factors Possible association with ABC, ddI, LPV/RTV No data for DRV/RTV, INSTIs, MVC

Pregnancy Preferred: ZDV/3TC + NVP, LPV/RTV, or ATV/RTV EFV can be used after first 5-6 wks

Chronic HBV Preferred TDF + 3TC or FTC Alternative is entecavir

Decreased BMD Caution with TDF

CNS effects Caution with EFV for at least first month

When to Consider ARV Switch

• ARV intolerance• Difficulty with adherence• Treatment failure

• Incomplete virologic response• Two consecutive HIV RNA>400 or >50

copies/mL after 24 and 48 weeks, respectively

• Virologic rebound• After virologic suppression HIV RNA

repeatedly above assay limit of detection

Adapted from US Department of Health and Human Services Guidelines; Revised January 10, 2011. Available at: http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf

Treatment-Experienced Patients: Full Virologic Suppression is Often

Achievable?

Availableactive agents

Assess abilityto adhere with future treat-ment options

Thorough assessmentof level of resistance

Treatmenthistory

Currentresistance testing

In general adding a single drug should

be avoided

Preferably at least two fully active agents needed

Genotypic Interpretation

Slide 62SUSCEPTIBILITY

BENCHMRK-1 & -2: Raltegravir in Treatment-Experienced Patients

HIV-infected patients with triple-class resistance and

HIV-1 RNA > 1000 copies/mL

(BENCHMRK-1: N = 352;BENCHMRK-2: N = 351) Placebo + OBR*

(BENCHMRK-1: n = 118;BENCHMRK-2: n = 119)

Raltegravir 400 mg twice daily + OBR*(BENCHMRK-1: n = 232;BENCHMRK-2: n = 230)

Planned follow-up:Week 156

*Investigator-selected OBR based on baseline resistance data and history; inclusion of darunavir and tipranavir permitted.

Current Analysis:Week 48

1. Cooper DA, et al. CROI 2008. Abstract 788. 2. Steigbigel R, et al. CROI 2008. Abstract 789.

BENCHMRK-1: Patients With HIV-1 RNA < 50 c/mL at Week 48

*P < .001 for RAL vs placebo, derived from a logistic regression model adjusted for baseline HIV-1 RNA level (log10), first ENF use in OBR, first DRV use in OBR, active PI in OBR.

0 2

Patie

nts

(%)

60

40

0

Weeks

100

80

20

8 12 16 24 32 40 484

118 118 118 118 117 118 118232 231 231 230 229 232 229

118230

118231

33%

62%*

31%

65%*

n =n =

Patie

nts

(%)

Placebo + OBR

RAL + OBRBENCHMRK-1[1]

1. Cooper DA, et al. CROI 2008. Abstract 788. 2. Steigbigel R, et al. CROI 2008. Abstract 789.

Antiretrovirals for prevention and future directions

HPTN 052: Immediate vs Delayed ART in Serodiscordant Couples

Cohen MS, et al. IAS 2011. Abstract MOAX0102. Cohen MS, et al. N Engl J Med. 2011 Jul 18. [Epub ahead of print]

Immediate ART Initiate ART at CD4+ cell count 350-550 cells/mm3

(n = 886 couples)

Delayed ARTInitiate ART at CD4+ cell count ≤ 250 cells/mm3*

(n = 877 couples)

HIV-infected, sexually active serodiscordant

couples; CD4+ cell count of the infected partner:

350-550 cells/mm3

(N = 1763 couples)

*Based on 2 consecutive values ≤ 250 cells/mm3.

• Primary efficacy endpoint: virologically linked HIV transmission• Primary clinical endpoints: WHO stage 4 events, pulmonary TB, severe

bacterial infection and/or death• Couples received intensive counseling on risk reduction and use of condoms

Cohen M, et al. NEJM July 18, 2011.

n=1; incidence rate0.1 per 100 p-y (95% CI 0.0, 0.4)

n=27; incidence rate1.7 per 100 p-y (95% CI 1.1, 2.5)

Linked HIV Transmission Events

68Scienceexpress, July 19th 2010.18th IAC 2010, Vienna, Austria, Abst. TUS505

69Scienceexpress, July 19th 2010.18th IAC 2010, Vienna, Austria, Abst. TUS505

(N=444)

(N=445)

High adherers (>80%) effectiveness = 54%

iPrEx Study (n=2499)

Grant R. et al. NEJM 2010; 363:2587-2599.

Cu

mu

lati

ve P

rob

abili

ty o

f H

IV In

fect

ion

Weeks

N=64

N=36

Risk Reduction 44% (95% CI: 15, 63) P=0.005

iPrEx Protection and Adherence

Overall >90% Adherence

Detectable Drug Levels

Grant R. et al. NEJM 2010; 363:2587-2599.

Efficacy Rates of Prevention Trials

Adapted from: Abdool Karim SS and Karim QA. Lancet 2011; 378(9809):e23-5 and Celum C and Baeten JM. Curr Opinion Infect Dis 2012; 25:51-57

Efficacy (Percent)

HIV vaccine;RV144, Thailand

Microbicide;CAPRISA 004, South Africa

Sexually transmitted diseases treatment; Mwanza, Tanzania

PrEP for MSMs; iPrEX, Americas, Thailand, South Africa

1000 20 40 60 80

Study

ART for prevention; HPTN 052, Africa, Asia, Americas

PrEP for discordant couples;Partners PrEP, Uganda, Kenya

PrEP for heterosexual men and women; TDF2, Botswana

Medical male circumcision; Orange Farm, Rakai, Kisumu

96 (73-99)

73 (49-85)

63 (21-84)

54 (38-66)

44 (15-63)

42 (21-58)

39 (6-60)

31 (1-51)

Effect Size, Percent (95% CI)

PrEP for women; FEM-PrEP, Kenya,SA, Tanzania 0 (-69-41)

Siliciano JD, et al. Nature Med 2003;9:727-8

Obstacle to cure: At least one….

Procedure and Events• Ablative chemotherapy• Total body XRT• Graft vs. host• Transplant with CCR5∆32

homozygous donor

Hutter G, et al. N Engl J Med 2009; 360:692-8.

Hypotheses:• Early treatment as PEP• Early treatment and

neonatal immune system prevented/limited reservoir and allowed for clearance

• Reservoir small and will take longer for rebound

• Child destined to be elite controller

• Other

Persaud D, et al. N Engl J Med 2013; 369: 1828-35

Thank You and

Questions