1. ART: When to Start? – Case Discussion Roy M. Gulick, MD, MPH Professor of Medicine Chief, Division of Infectious Diseases Weill Medical College of Cornell University New York City, USA

2. Case: NR NR is a 32 year old accountant referred to to discuss HIV treatment options. Past History: –gonorrhea 1 year ago that responded to rx –tested HIV negative “every year since 2000” Meds: none Social History: Sexually active gay man, not currently in a committed relationship; has health insurance through work.

3. Case: NR (continued) Physical Exam: normal Labs: –CBC, chemistries, liver function tests normal –HIV antibody + –HIV RNA 47,000 –CD4 count 635/µL He understands the requirements of ART and is willing to start if you recommend it.

4. Question Asymptomatic, VL 47,000; CD4 635 Do you recommend ART now? 1.Yes 2.No 3.It depends

5. When to Start? AIDS/ symptoms CD4 <200 CD4 200-350 CD4 >350-500 CD4 >500 US DHHS 2013 www.aidsinfo.nih.gov YES IAS-USA 2012 JAMA 2012;308:387 YES UK 2012 HIV Med 2012; www.bhiva.org YES certain patients EACS 2012 www.europeanaidsclinic alsociety.org/ YES certain patients WHO 2010 www.who.int/hiv/pub/arv/ adult2010/en YES NO 3 YES

6. ART for “Certain Patients” with CD4 >350 BHIVA Guidelines 2012: AIDS (e.g., KS) HIVAN ITP Neurocognitive HBV HCV (CD4 <500) Non-AIDS malignancies requiring rx EACS Guidelines 2012: AIDS, including TB HIVAN Neurocognitive HBV HCV (CD4 <500) Hodgkin’s lymphoma HPV-associated cancer

7. Case NR (continued) He says he’ll think about it and schedules an appointment for additional labs and a follow-up visit in 3 months. At the 3 month visit: –Asymptomatic with normal physical exam –Hepatitis B surface Ag -, Ab +; Hep C Ab - –HIV RNA 53,000; CD4 642 Met a new partner 2 months ago who is “the love of his life” and is HIV-negative. He knows “all about” safe sex but also wants to do “everything he can” to protect his partner.

8. Question Asymptomatic, VL 53,000; CD4 642; HIV-negative partner Do you recommend ART now? 1.Yes 2.No 3.Maybe

9. HPTN 052 1,763 discordant couples (97% heterosexual) in Africa, Asia, Americas with HIV+ with CD4 350-550 HIV+ partner randomized to start cART immediately or deferred until CD4 <250 DSMB Interim analysis: 90% on ART had HIV RNA <400 40 incident cases of HIV 29 linked genetically to partner 96% reduction in transmission! Cohen #MOAX0102 and NEJM 2011;365:493 years probability New HIV infections (all) 28 cases 1 case

10. ART + Serodiscordant Couples BHIVA Guidelines 2012: “…if a patient with a CD4 >350 wishes to start ART to reduce the risk of transmission to partners, this decision is respected and ART is started.” EACS Guidelines 2012: “…should be strongly considered and actively discussed.”

11. Case NR (continued) He agrees to start ART. He also understands he should continue to practice safe sex with his partner. At his routine visit 3 months later, he has not missed an ART dose and is VL is 2,350. He says he’s heard something about giving HIV- uninfected people HIV drugs to protect them and asks what you would recommend for his partner?

12. Question HIV+ MSM on ART At 3 months, VL ↓ 2,350 cps/ml HIV- partner Do you recommend PrEP? 1.Yes 2.No 3.Maybe

13. Question HIV+ MSM on ART At 6 months, VL <20 cps/ml HIV- partner Do you recommend PrEP? 1.Yes 2.No 3.Maybe

14. Oral PrEP Studies Study (reference)f Study population Design Results: Reduction in HIV Infection IPREX Grant NEJM 2010;363:2587 2499 gay menTDF/FTC vs. placebo TDF/FTC: 45% (92% if TFV detected) CDC – TDF-2 Thigpen NEJM 2012;367:423 1200 Botswana adults (45% women) TDF/FTC vs. placebo TDF/FTC: 63% (84% if TFV detected) Partners PREP Baeten NEJM 2012;367:399 4758 discordant African couples TDF vs. TDF/FTC vs. placebo TDF: 67% TDF/FTC: 75% (86-90% if TFV detected)

15. Oral PrEP Studies Study (reference) Study population Design Results: Reduction in HIV Infection FEM-PREP Van Damme NEJM 2012;367:411 2120 women in Kenya, South Africa, Tanzania TDF/FTC vs. placebo TDF/FTC: 6% (adherence < 40%) VOICE Marrazzo CROI 2013 #26LB 5029 women in South Africa, Uganda, Zimbabwe 1% TDF gel vs. placebo gel; oral TDF vs. TDF/FTC vs. placebo No study drugs effective (adherence < 30%)

16. DeCock and El-Sadr NEJM 2013;368:886 When to start ART? 2013

17. Acknowledgments Cornell HIV Clinical Trials Unit (CCTU) Division of Infectious Diseases Weill Medical College of Cornell University AIDS Clinical Trials Group (ACTG) Division of AIDS, NIAID, NIH The patient volunteers!