Transcript Cohen-AIDS-2014-PPT

ART Initiation: PrEP and
Treatment-naïve Patients
Calvin Cohen, MD, MSc
Clinical Instructor, Harvard Medical School
Director of Research, CRI New England
Vice Chair, INSIGHT Scientific Steering Committee
Boston, USA
Disclosures
• Grants/Research Support: Gilead, Viiv, Merck, Janssen, BMS
• Advisory Boards: Gilead, Viiv, Merck, Janssen, BMS, Splicos,
Oncolys
• Speakers Bureau: none
• Stock Shareholder: none
• Other Support: Expert Testimony - Gilead
When to Start? The SMART Study:
Predictors of Clinical Illness/Death
• For every 100-cell increase in CD4:
– 22% decreased risk (CI 13%-30%)
• Risk of OI/death after controlling for CD4:
Most recent viral load
HR for OI/Death
<400 c/mL vs 401-10,000
2.3 (1.1-4.9)
<400 c/mL vs >10,000
4.1 (1.8-9.3)
• Age – per decade: 1.6 (1.3-1.8)
SMART Study Group. J Infect Dis. 2008:197:1145-1155.
The START Study: Design
ART-naïve HIV-infected individuals
Confirmed CD4 count >500 cells/mm3
Early ART group
Initiate ART immediately
following randomization
n=2,300
•
•
Deferred ART group
Defer ART until the CD4 count
declines to <350 cells/mm3 or
AIDS develops
n=2,300
Fully enrolled Dec. 2013
Hypothesis: early ART reduces rate of primary endpoint by 28.8%
–
43% for AIDS events, 24% for non-AIDS events
www.clinicaltrials.gov Accessed Feb 04, 2014
When to Start ART:
Global Consensus and Diversity
CD4 Count (cells/mm3)
AIDS or
HIV-related
Symptoms
<350
350-500
>500
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
British HIV Association (2013)
Yes
Yes
Consider
Defer
European AIDS Society (2013)
Yes
Yes
Consider
Consider
WHO (2013)
Yes
Yes
Yes
Defer
United States
DHHS (2014)
IAS-USA (2012)
DHHS. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision May, 2014.
IAS-USA. Thompson MA, et al. JAMA. 2012;308:387-402.
EACS. Available at: http://www.europeanaidsclinicalsociety.org. Version 7.0 October 2013.
BHIVA. Available at: www.bhiva.org.
WHO. Available at: http://www.who.int/publications/guidelines/hiv_aids/en/index.html.
HPTN 052: Treatment as Prevention
Randomized, Placebo-controlled Efficacy and Safety Study
13 Sites in Africa, Asia, Americas
• n=1,763 HIV-positive
patients in
relationship with
HIV-negative partner
n=886
immediate
HAART
• 97% Heterosexual
• CD4 350-550
n=1
transmission
96% risk reduction
n=877 Delayed
HAART until
CD4<250
(or AIDS)
•
Study stopped 4 years early by DSMB (May 2011)
•
All received ongoing safe sex education/condoms
Available at: http://www.hptn.org/web%20documents/PressReleases/HPTN052PressReleaseFINAL5_12_118am.pdf
Accessed May 12, 2011.
n=27
transmissions
PrEP Efficacy and the iPrEx Study:
HIV Dx by Group and Drug Detection
Group
Drug
detection
HIV infections
Incidence
Placebo
No
64
3.86
No
33
4.04
Yes
3
0.35
FTC/TDF
Relative rate reduction by use of FTC/TDF
Grant R, et al. N Engl J Med. 2010;30:2587-2599.
91%
iPrEx: Intracellular Tenofovir Drug Levels and
HIV Infection
• Drug levels measured for all active arm
participants in iPrEX
• Model estimated HIV incidence
• Drug levels compared to those in STRAND
– PK study of oral TDF in 23 HIV volunteers
Model estimates for HIV risk reduction (95% CI)
2 doses/wk
76% (56% - 96%)
4 doses/wk
96% (90% - >99%)
7 doses/wk
99% (96% - >99%)
Anderson PL, et al. 19th CROI; Seattle, WA; March 5-8, 2012. Abst. 31LB.
Summary of Investigational
ARVs for PrEP
Mechanism
Dosing route
Dosing
frequency
Current stage
Maraviroc
CCR5
antagonist
oral
once daily
Phase 2 enrolling
Rilpivirine-LA
NNRTI
injectable, IM
once monthly
Phase 1 pilot;
Phase 2 planned
Dapivirine
NNRTI
ring
monthly
Phase 3 enrolling
Ibalizumab
CD4
attachment
inhibitor
injectable, SC
once weekly
Phase 1 pilot
‘744-LAP
integrase
inhibitor
injectable, IM
once quarterly
Phase 1 pilot;
Phase 2 enrolling
Gulick R. 7th IAS Conference on Pathogenesis, Treatment, and Prevention, Kuala Lumpur, Malaysia, June 30 – July 3, 2013,
Abs MOBS0204.
US DHHS Guidelines April 2014:
Seven Preferred Regimens
NNRTI
PI
Efavirenz1/emtricitabine2/tenofovir DF3
Atazanavir4 + ritonavir + emtricitabine2/tenofovir DF3
Darunavir + ritonavir (qd) + emtricitabine2/tenofovir DF3
INSTI
Raltegravir + emtricitabine2/tenofovir DF3
Elvitegravir/cobicistat/emtricitabine/tenofovir DF5
Dolutegravir + abacavir/lamivudine6
Dolutegravir + emtricitabine/tenofovir DF
INSTI: Integrase strand transfer inhibitors.
1Efavirenz should not be used during the first trimester of pregnancy or in women trying to conceive or not using effective and consistent contraception.
2Lamivudine may substitute for emtricitabine or visa versa.
3Tenofovir DF should be used with caution in patients with renal insufficiency.
4Atazanavir + RTV should not be used in patients who require >20 mg omeprazole equivalent/day.
5Patients
6Patients
with creatinine clearance >70 mL/min.
who are HLA-B*5701 negative.
DHHS. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.
Revision February 12, 2013.
DHHS. Available at: http://aidsinfo.nih.gov/contentfiles/AdultARV_INSTIRecommendations.pdf.
Update October 30,2013.
US DHHS Guidelines May 2014:
Ten Recommended Regimens
NNRTI
PI
Efavirenz1/emtricitabine2/tenofovir DF3
Atazanavir4 + ritonavir + emtricitabine2/tenofovir DF3
Darunavir + ritonavir (qd) + emtricitabine2/tenofovir DF3
INSTI
Additional
options if the
VL < 5 log:
Raltegravir + emtricitabine2/tenofovir DF3
Elvitegravir/cobicistat/emtricitabine/tenofovir DF5
Dolutegravir + abacavir/lamivudine6
Dolutegravir + emtricitabine/tenofovir DF
Efavirenz + abacavir/lamivudine6
Atazanavir + ritonavir + abacavir/lamivudine6
Rilpivirine / tenofovir DF / emtricitabine (if CD4 count > 200/mm3)
INSTI: Integrase strand transfer inhibitors.
1Efavirenz should not be used during the first trimester of pregnancy or in women trying to conceive or not using effective and
consistent contraception.
2Lamivudine may substitute for emtricitabine or visa versa.
3Tenofovir DF should be used with caution in patients with renal insufficiency.
4Atazanavir + RTV should not be used in patients who require >20 mg omeprazole equivalent/day.
5Patients
6Patients
with creatinine clearance >70 mL/min.
who are HLA-B*5701 negative.
DHHS. Available at: http://aidsinfo.nih.gov/contentfiles/AdultARV_INSTIRecommendations.pdf.
Update May 2014
Current EACS Guidelines:
Ten Initial Recommended Regimens
One from A
& one from B
A
B
• EFV/TDF/FTC
coformulated
• RPV/TDF/FTC
coformulated
• RPV only for VL<5 log
NNRTI
• EFV
• RPV
Recommended
Ritonavirboosted PI
• ATV/r
• DRV/r
Integrase
Inhibitor
• RAL
Remarks
ABC/3TC or
TDF/FTC
Caution: ABC in
those with high
CVD risk and
persons with a
VL>5 log
• ATV/r: 300/100 mg QD
• DRV/r: 800/100 mg QD
• RAL: 400 mg BID
WHO 2013 Guidelines: What to Start
First-line ART
Preferred (FDC) regimen(s)
Adults and adolescents
(including pregnant women,
TB coinfection and HBV coinfection)
TDF + 3TC (or FTC) + EFV
AZT + 3TC + EFV (or NVP)
Alternative regimens
TDF + 3TC (or FTC) + NVP
ABC + 3TC + EFV (or NVP)
Special situations
AZT (or ABC) + 3TC + LPV/r (or ATV/r)
How Do We Choose from Among These Options?
Drug characteristics:
– Twice-daily vs once-daily dosing
– Food requirements
– Number of pills per day (range 1-3)
 Role of coformulation vs multi-tablet regimens
– Pharmacologic “forgiveness” for missed doses
– Barrier to resistance if viremic
– Potential for drug-drug interactions
– Duration of experience
How Do We Choose from Among
These Options?
Patient characteristics:
– Risk of pretreatment virus resistance
– Risk of adverse events
 Rate, type, strength of evidence of adverse events
– Other medical comorbidities
 CV, diabetes, renal, bone, psychological, etc.
– Cost, access, and payment factors
Other criteria you use?
ARV Development:
More FDCs & STRs
Nonnucleoside RTIs
Protease Inhibitors
• EFV/TDF/FTC
• RPV/TDF/FTC
•
•
•
•
ATV/COBI
ATV/RTV
DRV/COBI
DRV/COBI/FTC/TAF
Integrase Inhibitors
•
•
•
•
EVG/COBI/FTC/TDF
EVG/COBI/FTC/TAF
DTG/ABC/3TC
DTG/RPV
FDC – Fixed dose combinations; STR – Single tablet regimens
Summary and Conclusions
• When to Start – What to do until the START study results
– No controversy about treatment for prevention
• Which Regimen to Choose
– Matching drug attributes to patient needs
• The increasing support for PrEP
– How best do we implement this