ART Initiation: PrEP and Treatment-naïve Patients

Clinical Instructor, Harvard Medical School

Director of Research, CRI New England

Vice Chair, INSIGHT Scientific Steering Committee

Boston, 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 orHIV-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/TDF

No 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 routeDosing

frequency Current stage

MaravirocCCR5 antagonist oral once daily Phase 2 enrolling

Rilpivirine-LA NNRTI injectable, IM once monthlyPhase 1 pilot; Phase 2 planned

Dapivirine NNRTI ring monthly Phase 3 enrolling

IbalizumabCD4 attachment inhibitor

injectable, SC once weekly Phase 1 pilot

‘744-LAPintegrase 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