art initiation: prep and treatment-naïve patients
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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. - PowerPoint PPT PresentationTRANSCRIPT
ART Initiation: PrEP and Treatment-naïve Patients
Clinical Instructor, Harvard Medical SchoolDirector of Research, CRI New EnglandVice Chair, INSIGHT Scientific Steering CommitteeBoston, USA
Calvin Cohen, MD, MSc
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:
• Age – per decade: 1.6 (1.3-1.8)
SMART Study Group. J Infect Dis. 2008:197:1145-1155.
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)
The START Study: Design
• 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
Early ART groupInitiate ART immediately following randomization
n=2,300
Deferred ART groupDefer ART until the CD4 countdeclines to <350 cells/mm3 or
AIDS developsn=2,300
ART-naïve HIV-infected individuals Confirmed CD4 count >500 cells/mm3
CD4 Count (cells/mm3)AIDS or
HIV-related Symptoms <350 350-500 >500
United States DHHS (2014) Yes Yes Yes Yes
IAS-USA (2012) 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
When to Start ART:Global Consensus and Diversity
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.
• n=1,763 HIV-positive patients in relationship with HIV-negative partner
• 97% Heterosexual• CD4 350-550
n=877 Delayed HAART until
CD4<250 (or AIDS)
n=886 immediate
HAART
Randomized, Placebo-controlled Efficacy and Safety Study 13 Sites in Africa, Asia, Americas
HPTN 052: Treatment as Prevention
• Study stopped 4 years early by DSMB (May 2011)
n=1 transmission
n=27 transmissions
96% risk reduction
Available at: http://www.hptn.org/web%20documents/PressReleases/HPTN052PressReleaseFINAL5_12_118am.pdfAccessed May 12, 2011.
• All received ongoing safe sex education/condoms
PrEP Efficacy and the iPrEx Study: HIV Dx by Group and Drug Detection
Grant R, et al. N Engl J Med. 2010;30:2587-2599.
Group Drug detection HIV infections Incidence
Placebo No 64 3.86
FTC/TDFNo 33 4.04
Yes 3 0.35
Relative rate reduction by use of FTC/TDF 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
Anderson PL, et al. 19th CROI; Seattle, WA; March 5-8, 2012. Abst. 31LB.
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%)
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
IbalizumabCD4 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
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.
NNRTI Efavirenz1/emtricitabine2/tenofovir DF3
PI 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 with creatinine clearance >70 mL/min.6Patients who are HLA-B*5701 negative.
US DHHS Guidelines May 2014: Ten Recommended Regimens
NNRTI Efavirenz1/emtricitabine2/tenofovir DF3
PI 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
Additional options if the
VL < 5 log:
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 with creatinine clearance >70 mL/min.6Patients 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 Remarks
Recommended
NNRTI• EFV • RPV
ABC/3TC or TDF/FTC
• EFV/TDF/FTC coformulated
• RPV/TDF/FTCcoformulated
• RPV only for VL<5 log
Ritonavir-boosted PI• ATV/r • DRV/r
• ATV/r: 300/100 mg QD• DRV/r: 800/100 mg QD
IntegraseInhibitor• RAL
• RAL: 400 mg BID
Caution: ABC in those with high CVD risk and
persons with a VL>5 log
WHO 2013 Guidelines: What to Start
First-line ART
Adults and adolescents (including pregnant women,
TB coinfection and HBV coinfection)
Preferred (FDC) regimen(s) TDF + 3TC (or FTC) + EFV
Alternative regimensAZT + 3TC + EFV (or NVP)
TDF + 3TC (or FTC) + NVP
Special situationsABC + 3TC + EFV (or NVP)
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?
Nonnucleoside RTIs• EFV/TDF/FTC• RPV/TDF/FTC
ARV Development: More FDCs & STRs
Protease Inhibitors• 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