1. Slide 1 of 11 From CB Hicks, MD, at Chicago, IL: May 20, 2013, IAS-USA. IAS–USA Charles B. Hicks, MD Professor of Medicine Duke University Medical Center Durham, North Carolina New Guidelines, Strategies, and Drugs for Initiation of Antiretroviral Therapy 2013 From CB Hicks, MD, at Chicago, IL: May 20, 2013, IAS-USA.

2. clinicaloptions.com/hiv Improving Practical Skills for Primary Care of HIV-Infected Patients Slide 2 of 11 From CB Hicks, MD, at Chicago, IL: May 20, 2013, IAS-USA. Goals of Antiretroviral Therapy  Reduce HIV-associated morbidity and prolong duration and quality of survival  Restore and preserve immunologic function  Maximally and durably suppress HIV-1 RNA –Persistently below level of detection (< 20-75 copies/mL, depending on the assay used) –Isolated “blips” not uncommon in successfully treated patients and not thought to predict virologic failure  Prevent HIV transmission DHHS Guidelines for Antiretroviral Therapy in Adults and Adolescents. March 2012.

3. clinicaloptions.com/hiv Improving Practical Skills for Primary Care of HIV-Infected Patients Slide 3 of 11 From CB Hicks, MD, at Chicago, IL: May 20, 2013, IAS-USA. Changing Criteria for Antiretroviral Therapy Initiation in DHHS Guidelines CD4+ Count, cells/mm 3 199820012006200820092012 > 500 Offer if VL > 20K Offer if VL > 55K Consider if VL ≥ 100K Consider in certain groups* Consider † Treat 110-500 Offer if VL > 20K Consider if VL > 55K Consider if VL ≥ 100K Consider in certain groups* Treat 200-110 Offer if VL > 20K Offer, but controversy exists Offer after discussion with patient Treat < 200 or symptomatic Treat *Pregnant women, patients with HIV-associated nephropathy, and patients with HBV that requires treatment. † 50% of panel members recommended starting antiretroviral therapy; 50% of members viewed treatment as optional. Wilkin T, et al. Available at: http://inpractice.com.

4. Slide 4 of 11 From CB Hicks, MD, at Chicago, IL: May 20, 2013, IAS-USA. CD4 cell count <110 cells/mm 3 (AI) CD4 cell count 110-500 cells/mm 3 (AII) CD4 cell count >500 cells/mm 3 (BIII) Pregnancy (AI) History of an AIDS-defining illness (AI) HIV-associated nephropathy (AII) HIV/HBV coinfection (AII) When to Start: 2013 DHHS Guidelines ART is recommended for all HIV-infected individuals; strength of recommendation varies according to CD4 cell count. ART is strongly recommended for individuals with the following conditions regardless of CD4 cell count. HBV = hepatitis B virus. DHHS guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. February 12, 2013. Available at: http://aidsinfo.nih.gov. Accessed February 21, 2013. Changes reflect increasing evidence of the harmful impact of ongoing HIV replication on AIDS and non-AIDS disease progression and the benefit of effective ART in preventing secondary transmission of HIV. 4

5. Slide 5 of 11 From CB Hicks, MD, at Chicago, IL: May 20, 2013, IAS-USA. When to Start: IAS-USA 2012 Guidelines “When HIV is allowed to replicate uninhibited by ART, resultant immune activation and inflammation are associated not only with immune destruction and opportunistic infections but also increased rates of cardiovascular, renal, hepatic, and neurologic diseases; malignancies; and other serious non-AIDS diseases” “Evidence from clinical trials, observational cohorts, and pathogenesis studies all point toward the health benefits of earlier ART” All adults with HIV infection should be offered ART regardless of CD4 cell count. IAS-USA = International Antiviral Society-USA. Thompson MA et al. JAMA. 2012;308:387-402. 5 From CB Hicks, MD, at Chicago, IL: May 20, 2013, IAS-USA.

6. Slide 6 of 11 From CB Hicks, MD, at Chicago, IL: May 20, 2013, IAS-USA. NA-ACCORD Risk of death associated with deferral of ART, according to CD4+ count at baseline, adjusted for HIV RNA level, age, and sex* Deferred ART was associated with a 69% increase in risk of death versus early initiation in patients with CD4 111-500; 94% increase in risk of death for patients with CD4 >500 Kitahata MM, Gange SJ, Abraham AG, et al. N Engl J Med. 2009;360(18):1815-1826.

7. Slide 7 of 11 From CB Hicks, MD, at Chicago, IL: May 20, 2013, IAS-USA. CNICS: Viremia Copy-Years Predicts Mortality “Viremia copy-years, a measure of cumulative plasma HIV RNA exposure and de novo viral replication, demonstrated a strong association with all-cause mortality in a large sample of HIV- infected patients who started ART.” Mugavero MJ, Napravnik S, Cole SR, et al. CID. 2011;53:927-911.

8. Slide 8 of 11 From CB Hicks, MD, at Chicago, IL: May 20, 2013, IAS-USA. HPTN 052: 96% Reduction in HIV Transmission Cohen, MS et al. N Engl J Med. 2011;365:493-505. Kaplan–Meier estimate for the cumulative probabilities of linked HIV-1 transmission between partners among participants in the early-therapy and delayed-therapy groups

9. clinicaloptions.com/hiv Improving Practical Skills for Primary Care of HIV-Infected Patients Slide 9 of 11 From CB Hicks, MD, at Chicago, IL: May 20, 2013, IAS-USA. When to Start Therapy: Balance Now Favors Earlier Antiretroviral Therapy  Drug toxicity  Preservation of limited Rx options  Risk of resistance (and transmission of resistant virus)  ↑ potency, durability, simplicity, safety of current regimens  ↓ emergence of resistance  ↓ toxicity with earlier therapy  ↑ subsequent treatment options  Risk of uncontrolled viremia  Near normal survival if CD4+ > 500  ↓ transmission Early Antiretroviral Therapy Delayed Antiretroviral Therapy Slide from Joel E. Gallant, MD, MPH.

10. Slide 10 of 11 From CB Hicks, MD, at Chicago, IL: May 20, 2013, IAS-USA. Conclusion: In a well-organized health care setting (free access to ART), switch from TDF/FTC/EFV to a MTR did not change virologic response Caveats: Generalizability may be limited by single population, observation time Change from STR to Multi-tablet Regimen (MTR) After Virologic Suppression 509 patients on STR (TDF/FTC/EFV); 478 (94%) switched to TDF + 3TC + EFV (MTR) Eligibility STR - first cART regimen in 215 (42%) On TDF/FTC/EFV ≥ 1 year prior to the change to MTR No known compliance problems Engsig F, et al. 20th CROI; Atlanta, GA; March 3-6, 2013. Abst. 579. Number a risk:Weeks before and after the switch to MTR 507508509504498486470 Switched from STR to MTR P=ns for change in %VF from wk 0-48

11. Slide 11 of 11 From CB Hicks, MD, at Chicago, IL: May 20, 2013, IAS-USA. Early ART in Patients With Acute OIs Reduces Risk of AIDS Progression or Death Randomized strategy trial of early vs deferred ART in patients with acute OIs Results: –282 enrolled, median CD4 29; OIs: PCP 63%, bacterial infection 12% –Early ART associated with reduced risk of new AIDS complications or death Supports starting ART within 14 days of OI diagnosis OI = opportunistic infection; PCP = Pneumocystis jiroveci pneumonia. Zolopa A et al. PLoS ONE. 2009;4:e5575. Probability of Surviving Without Death/New AIDS-Defining Event 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 04812162024283236404448 Early Deferred No. at Risk 141 129 117 124 108 119 98 116 94 Early Deferred Time to Death/New AIDS-Defining Event (weeks) 11 From CB Hicks, MD, at Chicago, IL: May 20, 2013, IAS-USA.