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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
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!
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:
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
clinicaloptions.com24th Annual CCO HIV and Hepatitis C Symposium
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].
clinicaloptions.com24th Annual CCO HIV and Hepatitis C Symposium
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
clinicaloptions.com24th Annual CCO HIV and Hepatitis C Symposium
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
clinicaloptions.com24th Annual CCO HIV and Hepatitis C Symposium
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
clinicaloptions.com24th Annual CCO HIV and Hepatitis C Symposium
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
clinicaloptions.com24th Annual CCO HIV and Hepatitis C Symposium
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
clinicaloptions.com24th Annual CCO HIV and Hepatitis C Symposium
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.
clinicaloptions.com24th Annual CCO HIV and Hepatitis C Symposium
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.
clinicaloptions.com24th Annual CCO HIV and Hepatitis C Symposium
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)
clinicaloptions.com24th Annual CCO HIV and Hepatitis C Symposium
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
clinicaloptions.com24th Annual CCO HIV and Hepatitis C Symposium
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
clinicaloptions.com24th Annual CCO HIV and Hepatitis C Symposium
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.
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
clinicaloptions.com24th Annual CCO HIV and Hepatitis C Symposium
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?
clinicaloptions.com24th Annual CCO HIV and Hepatitis C Symposium
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!