medical perspective on hiv/aids and the importance of treatment

Medical Perspective on HIV/AIDS and the Importance of Treatment

Corklin R. Steinhart, MD, PhD

Global Medical Lead, “TRII”

Executive Director Medical Strategy, North America

ViiV Healthcare

August 4, 2014

Thanks to Clinical Care Options (Dr. Paul Sax) and to Dr.

Andrew Carr for the use of some slides

Take Home Messages

• The HIV virus “sets up shop” in the human body within hours of infection

• HIV is a chronic viral infection• Question: why would you want a viral infection to

cause relentless damage to your body before beginning effective cART?

•All guidelines are changing to begin therapy regardless of CD4 count: it’s about time!•HIV therapy is needed for life at this time•Is there a place for newer and better ARVs and strategies?• Yes, because currently there are no perfect ARVs or

strategies!•If you take the medicines, they work: ADHERENCE is the key to success!

“OK. I’m done! Any

questions?”

Fig. 1 Age and sex-adjusted (European population was used as standard) AIDS mortality rates (per 100,000 person-years) in population aged 20–49 years. Region of Madrid (Spain), 1990–2003.

Social Science & Medicine, Volume 68, Issue 3, 2009, 419 - 426

http://dx.doi.org/10.1016/j.socscimed.2008.10.039

Major reduction in AIDS-mortality inequalities after HAART:

JAMA. 2014; 312 (4): 410-425

Paul E. Sax, MDClinical DirectorDivision of Infectious DiseasesBrigham and Women’s HospitalProfessor of MedicineHarvard Medical SchoolBoston, Massachusetts

Antiretroviral Therapy Update 2014

Supported by educational grants from multiple commercial supporters.

CHOICE OF INITIAL 3RD ART DRUGART guidelines

1. DHHS Guidelines for the Use of Antiretroviral Agents inHIV-1-Infected Adults and Adolescents, May 2014

2. EACS Guidelines Version 7.02, June 20143. Günthard HF, et al. JAMA 2014;312:410-425

4. WHO guidelines for the use of antiretroviral drugsfor treating and preventing HIV infection, June 2013

DHHS, 20141 EACS, 20142 IAS-USA, 20143 WHO, 20134

TDF/FTC EFV TDF/FTC EFVRPV* TDF/FTC EFV

RPV*TDF/FTC TDF/3TC EFV

ABC/3TC EFVRPV ABC/3TC EFV

TDF/FTC ATV/rDRV/r TDF/FTC ATV/r

DRV/r TDF/FTC ATV/rDRV/r

ABC/3TC ATV/rDRV/r ABC/3TC ATV/r

TDF/FTC DTG

EVG/cRAL

TDF/FTC RALEVG/c TDF/FTC

DTGEVG/cRAL

ABC/3TC DTG ABC/3TC DTG

NRTIs NNRTI PI/r INI*For patients with HIV-1 RNA <100,000 c/mLDHHS, Department of Health and Human Services; EACS, European AIDS Clinical Society; IAS-USA, International Antiviral Society USA Panel; WHO, World Health Organization; TDF/FTC tenofovir/emtricitabine; EFV, efavirenz; ABC/3TC abacavir/lamivudine; RPV, rilpivirine; ATV/r, atazanavir/ritonavir; DRV/r, darunavir/ritonavir; DTG, dolutegravir; EVG/c, elvitegravir/cobicistat; RAL, raltegravir; NRTIs, nucleoside reverse transcriptase inhibitors; NNRTI, non-nucleoside reverse transcriptase inhibitor; PI/r, boosted protease inhibitor; INI, integrase inhibitor

DESIRABLE ATTRIBUTES OF NEW AGENTS AS PART OF A FIRST-LINE TREATMENT REGIMEN

ARV

Highly potent antiviral activity

No food requirements Favourable resistance

profile

Once-daily administration without

a PK enhancer

Low PK variability and predictable exposure-response relationship

Simple regimen Safe and generally well tolerated

DHHS Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents, May 2014ARV, antiretroviral; PK, pharmacokinetic

clinicaloptions.com24th Annual CCO HIV and Hepatitis C Symposium

Extensive New Data on Integrase-Based First-line Therapy

The following DTG studies all presented and/or published in past yr

– SPRING-2

– SINGLE

– FLAMINGO

TDF/FTC/EVG/COBI: no new cases of renal tubulopathy in long-term f/u

ACTG 5257: raltegravir vs boosted PIs


Dolutegravir Clinical Trials 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 negCrCl > 50 mL/min

(N = 833)

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

EFV/TDF/FTC QD (n = 419)

SPRING-2[1]

(placebo 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. N Engl J Med. 2013;369:1807-1818. 3. Clotet B, et al. Lancet. 2014;[Epub ahead of print].


1. Walmsley S, et al. N Engl J Med. 2013;369:1807-1818. 2. Walmsley S, et al. CROI 2014. Abstract 543.

24 32 40 48 60 8472 96161284

Wk 96 adjusted difference in response (95% CI): +8.0% (+2.3% to +13.8%); P = .006

TreatmentWk 96 ∆ From BL Adjusted Mean SE

Difference in Response (95% CI)

DTG + ABC/3TC QD (n = 414) 325.3 10.5 44.0 (14.3, 73.6)P = .004EFV/TDF/FTC QD (n = 419) 281.4 10.9

DTG: 80%

EFV: 72%

CD4 ∆ from BL

SINGLE: Dolutegravir + ABC/3TC vs Efavirenz/TDF/FTC in Tx-Naive Pts

DTG superior to EFV at Wk 48[1] and Wk 96[2]

Treatment-related study d/c: 3% in DTG vs 11% in EFV arm at Wk 96; comparable rates of virologic failure (6% in each arm at Wk 96)

No resistance in DTG arm through Wk 9

Pro

port

ion

of P

atie

nts

(%) 100

80

60

40

20

00

Wk

DTG + ABC/3TC EFV/TDF/FTC


1. Lennox J, et al. Lancet. 2009;374:796-806. 2. Sax PE, et al. Lancet. 2012;379:2439-2448. 3. De Jesus E, et al. Lancet. 2012;379:2429-2438. 4. Brinson C, et al. CROI 2013. Abstract 554. 5. Feinberg J, et al. ICAAC 2013. Abstract 1464a.

≤ 100,000 c/mL> 100,000 c/mL

SPRING-2[4]

3020100-20 -10

Difference, % (DTG-RAL) and 95% CI

In favor of RAL In favor of DTG

≤ 100,000 c/mL> 100,000 c/mL

SINGLE[4]

3020100-20 -10

Difference, % (DTG-EFV) and 95% CI

In favor of DTGIn favor of EFV

Study 102[2]

FLAMINGO[5]

≤ 100,000 c/mL> 100,000 c/mL

3020100-20 -10

Difference , % (DTG-DRV/RTV) and 95% CI

In favor of DTGIn favor of DRV/RTV

40

≤ 100,000 c/mL> 100,000 c/mL

Difference, % (EVG/COBI-EFV) and 95% CI

In favor of EFV In favor of EVG/COBI

Study 103[3]

-15 -10 -5 5 10 150

≤ 100,000 c/mL > 100,000 c/mL

Difference, % (EVG/COBI-ATV/RTV) and 95% CI

In favor of ATV/RTV In favor of EVG/COBI

≤ 100,000 c/mL> 100,000 c/mL

STARTMRK[1]

3020100-20 -10

Difference, % (RAL-EFV) and 95% CI

In favor of EFV In favor of RAL

-15 -10 -5 5 10 150

Activity of Integrase-Based Therapies Maintained at High HIV-1 RNA


Increased Risk of Suicidality Associated With EFV

Mollan K, et al. IDWeek 2013. Abstract 40032.

*Person-years, sum of at-risk follow-up.

As-treated HR 2.16 (1.16-4.00)

HR (95% CI)2.28 (1.27-4.10), P = .006

47 events/5817 PY* (8.08/1000 PY)

15 events/4099 PY* (3.66/1000 PY)

5%EfavirenzEfavirenz-free

Pro

bab

ility

.05

.04

.03

.02

.01

00 24 48 72 96 120 144 168 192

Wks to Suicidality


ACTG 5257: Open-Label ATV/RTV vs RAL vs DRV/RTV in First-line ART

Primary endpoints– Virologic failure: time to HIV-1 RNA > 1000 c/mL (at Wk 16 or before Wk 24) or > 200 c/mL

(at or after Wk 24)– Tolerability failure: time to discontinuation of randomized component for toxicity

– Composite endpoint: the earlier occurrence of either VF or TF in a given participant– Switch of regimens allowed for tolerability

Landovitz R, et al. CROI 2014. Abstract 85.

ART-naive patients with HIV-1 RNA

≥ 1000 c/mL (N = 1809)

ATV/RTV 300/100 mg QD +TDF/FTC(n = 605)

RAL 400 mg BID +TDF/FTC(n = 603)

Stratified by HIV-1 RNA < or ≥ 100,000 c/mL, participation in metabolic

substudy, CV risk

DRV/RTV 800/100 mg QD +TDF/FTC(n = 601)

Wk 96 after last patient enrolled


ACTG 5257: Primary Endpoint Analyses at Wk 96

Regimens equivalent in time to VF

Landovitz R, et al. CROI 2014. Abstract 85. Reproduced with permission.

Significantly greater incidence of treatment failure with ATV/RTV vs RAL or DRV/RTV

– In part due to high proportion of pts with hyperbilirubinemia

Considering both efficacy and tolerability, RAL superior to either boosted PI

DRV/RTV superior to ATV/RTV

Virologic Failure Tolerability Failure Composite Endpoint

Difference in 96-Wk Cumulative Incidence (97.5% CI)

0-10 10 20

ATV/RTV vs RAL3.4% (-0.7 to 7.4)

DRV/RTV vs RAL5.6% (1.3 -9.9)

ATV/RTV vs DRV/RTV-2.2% (-6.7 to 2.3)

0-10 10 20

ATV/RTV vs RAL15% (10-20)

DRV/RTV vs RAL7.5% (3.2-12.0)

ATV/RTV vs DRV/RTV7.5% (2.3-13.0)

Favors RAL

Favors DRV/RTV

Favors RAL

0-10 10 20

ATV/RTV vs RAL13% (9.4-16.0)

DRV/RTV vs RAL3.6% (1.4-5.8)

ATV/RTV vs DRV/RTV9.2% (5.5-13.0)

Favors RAL

Favors DRV/RTV

Novel Strategies for Treatment


3 Active Drugs—Not 2, Not 4—Have Been the Sweet Spot for Initial HIV TreatmentStudies With 2-Drug Strategies

DMP-066

ACTG 5142

SPARTAN

ACTG 5162

RADAR

PROGRESS

A4001078

Studies With 4-Drug Strategies

ACTG 5095

ACTG 5173

COL40263

None to date offers compelling evidence to move from 3-drug approach.


LATTE: Study Design

Phase IIb, randomized, multicenter, partially blind, dose-ranging study comparing S/GSK744 plus RPV to EFV plus NRTIs

*ABC/3TC or TDF/FTC.

Patients on 744 + NRTI: If Wk 20 VL < 50 c/mL, simplify to 744/RPV at Wk 24.

HIV-1 ART-naiveHIV-1 RNA > 1000

c/mL1:1:1:1 randomization

Stratified by VL and NRTI

744 30 mg + 2 NRTIs*

744 10 mg + 2 NRTIs*

Oral Induction Phase

744 60 mg + 2 NRTIs*

Oral Maintenance Phase

744 10 mg + RPV 25 mg

744 30 mg + RPV 25 mg

744 60 mg + RPV 25 mg

2416 20 48 9672

EFV 600 mg + 2 NRTIs*

WkD1

Margolis D, et al. EACS 2013. Abstract PS7/1.


744 + RPV Regimen Maintained Suppression Comparable to EFV-Based Therapy

Wk

744 OR Wk 4882%

EFV response Wk 4871%

744 OR Wk 2487%

EFV response Wk 2474%

Median (IQR) Change From BL CD4+ Cell Count (Cells/mm3)

Wk 48744 overall +219 (141,343)

EFV +227 (134,369)

242 4 8 12 16 4032 48362628BL

Induction Phase Maintenance Phase

Margolis D, et al. CROI 2014. Abstract 91LB.

Pro

por

tion,

%

0

20

40

60

80

100

744 10 mg (N = 60) 744 30 mg (N = 60) 744 60 mg (N = 61) EFV 600 mg (N = 62)

Investigational Drugs


Tenofovir Alafenamide: Summary and What’s Coming

Phase II and preclinical data suggest the following potential benefits

– Reduced renal and bone toxicity

– Lower dose allows smaller pill, novel coformulations

– Possible activity vs some TDF-resistant strains

Phase III studies of “ECF-TAF” or “Quad-II” fully enrolled

Development of TAF/FTC and TAF/FTC/DRV/COBI planned


MK-1439 all doses combined: 76.4%

32/40 32/41 27/42

Doravirine vs EFV Phase II: 24-Wk Results

Morales-Ramirez J, et al. CROI 2014. Abstract 92LB.

HIV

-1 R

NA

< 4

0 C

opie

s/m

L (%

)

0

20

40

60

80

100

MK-143925 mg

MK-143950 mg

MK-1439100 mg

MK-1439200 mg

Efavirenz600 mg

80.0 76.271.4

78.0

64.3

32/42 30/40

1. Müller et al. Eur J Pharm Biopharm. 2011;78:1-9. 2. Spreen et al. IAS 2013; Kuala Lumpur, Malaysia. Abstract WEAB0103.3. Min et al. ICAAC 2009; San Francisco, CA. Abstract H-1228. 4. Taoda et al. International Congress on Drug Therapy in HIV Infection 2012; Glasgow, Scotland. Abstract P206.

GSK744 LA Is Formulated as a 200 mg/mL Nanosuspension

Andrews et al. CROI 2014; Boston, MA. Abstract 39.

GSK1265744(GSK744)

NN

O

OOH O

NH

O

F

HF

Dolutegravir

NN

OOH O

NH

O

F

F

OH

Adapted from Spreen et al. IAC 2012; Washington, DC. Abstract TUPE040.

Pharmacokinetic Evaluation of a Single Intramuscular GSK744 LA Injection in Human Volunteers

Andrews et al. CROI 2014; Boston, MA. Abstract 39.

4X PAIC90

1X PAIC90


Drugs With Novel Mechanisms for Pan-Resistant HIV in Phase II or Later

BMS-663068 (attachment inhibitor)

It is therefore critical that patients with highly resistant virus preserve virologic suppression through excellent adherence!

Lalezari J, et al. CROI 2014. Abstract 86.

Adherence as a Driver for Treatment Success

MSD Satellite Symposium EACS Belgrade, Oct 12 2011

cART 4 life – the patient marathon

• Long-term adherence is difficult: Toxicities, side

effects, co-morbidities, mental health

• Non-adherence is dangerous: Resistance risk

• Individual adherence barriers: Drug or alcohol use,

Problems at work or in relationships, readiness relapse

• System related barriers: Insurance coverage, stock-

outs, stigmatisation

ADHERENCE“The bottom line is this: if patients take their meds they will

do well!”

Assuming they are all available….


Antiretroviral Therapy: What to Expect in the Next 12 Mos

Coformulated ABC/3TC/DTG

Coformulated DRV/COBI

Coformulated ATV/COBI

Phase III data of TAF/FTC/EVG/COBI

Additional data on long acting parenteral formulations

Other key data?


Antiretroviral Therapy in 2014: Conclusions

Treatment has become the cornerstone of HIV prevention

Data on integrase inhibitor–based initial therapies are increasingly favorable

2-drug strategies should generally be avoided pending further data

Drugs in development may offer improvements in safety, tolerability, convenience

Take Home Messages

• The HIV virus “sets up shop” in the human body within hours of infection

• HIV is a Chronic Viral Infection• Question: why would you want a viral infection to

cause relentless damage to your body before beginning effective cART?

•All guidelines are changing to begin therapy regardless of CD4 count: it’s about time!•HIV therapy is needed for life at this time•Is there a place for newer and better ARVs and strategies?• Yes, because currently there are no perfect ARVs or

strategies!•If you take the medicines, they work: ADHERENCE is the key to success!

Thanks very much

medical perspective on hiv/aids and the importance of treatment

Documents