1. Joseph J. Eron, Jr., MD University of North Carolina School of Medicine Director, AIDS Clinical Trials Unit University of North Carolina Chapel Hill, North Carolina Current Controversies in Managing HIV-Infected Patients Supported by educational grants from multiple commercial supporters.

2. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium About These Slides  Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent  These slides may not be published or posted online without permission from Clinical Care Options (email permissions@clinicaloptions.com) Disclaimer The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

3. Controversy: Should virtually all naive patients be started on an integrase inhibitor regimen?

4. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium Key INSTI Trials in Treatment-Naive Pts  STARTMRK: RAL noninferior to EFV in HIV-1 RNA < 50 c/mL at Wk 48 primary endpoint (ITT, NC = F analysis); superior from Wk 192 [1]  Study 102: EVG/COBI noninferior to EFV at Wk 48 primary endpoint [2] and through Wk 144 [3,4]  Study 103: EVG/COBI arm noninferior to ATV/RTV at Wk 48 primary endpoint [5] and through Wk 144 [6,7]  SINGLE: DTG superior to EFV at Wk 48 primary efficacy endpoint [7] and through Wk 96 [8]  FLAMINGO: DTG superior to DRV/RTV at Wk 48 primary efficacy endpoint [9]  ACTG 5257: Considering both efficacy and tolerability, RAL superior to both ATV/RTV and DRV/RTV [10] 1. Rockstroh J, et al. J Acquir Immune Defic Syndr. 2013;63:77-85. 2. Sax PE, et al. Lancet. 2012;379:2439-2448. 3. Zolopa A, et al. J Acquir Immune Defic Syndr. 2013;63:96-100. 4. Wohl D, et al. ICAAC 2013. Abstract H-672a. 5. De Jesus E, et al. Lancet. 2012;379:2429-2438. 6. Rockstroh J, et al. J Acquir Immune Defic Syndr. 2013;62:483-486. 7. Clumeck N, et al. EACS 2013. Abstract LBPS7/2. 8. Walmsley S, et al. N Engl J Med. 2013;369:1807-1818. 9. Walmsley S, et al. CROI 2014. Abstract 543. 10. Landovitz R, et al. CROI 2014. Abstract 85.

5. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium Prevalence of Drug Resistance Mutations in Treatment-Naive Patients, 2000-2013  Baseline plasma samples from 4 phase III trials (GS 903, 934, 104, 111, N = 2531) –1617 samples analyzed for integrase mutations –2531 analyzed for protease or RT mutations  Substantial  in prevalence of NNRTI resistance, modest  in PI resistance  Stable prevalence of NRTI resistance (mostly TAMs) –M184V/I ≤ 0.2%; K65R ≤ 0.2%  Little evidence of transmitted INSTI resistance over period –Mostly T97A polymorphism 2000 (GS-903) 2003 (GS-934) 2013 (GS-104/GS-111) 0 Pts With Mutations at BL (%) 2 NNRTI 10 4 6 8 NRTIPIINSTI 0.5 1.0 0 4.2 8.7 3.2 2.6 1.2 2.4 2.9 1.4 Margot NA, et al. CROI 2014. Abstract 578.

6. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium Expert Panel Discussion  Multiple studies demonstrating noninferior or superior outcomes with INSTI-based regimens in naive pts (see slide 4)  Recent data have shown that once-daily dolutegravir has a high barrier to resistance and good tolerability [1,2] –Real world clinical data are currently lacking  ACTG 5257 showed superiority of raltegravir vs boosted PI regimens [3] –Current twice-daily dosing of raltegravir is one drawback –Boosted PI regimens may be a good choice for patients at risk for nonadherence due to lower risk of resistance 1. Walmsley S, et al. CROI 2014. Abstract 543. 2. Pozniak A, et al. CROI 2013. Abstract 179LB. 3. Landovitz RJ, et al. CROI 2014. Abstract 85.

7. Controversy: Should anal Pap smears be performed routinely on all HIV+ MSM?

8. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium NYS Department of Health Guidelines: Recommendations for Anal Pap Smears  At baseline and as part of the annual physical examination for all HIV-infected adults, regardless of age, clinicians should: –Inquire about anal symptoms, such as itching, bleeding, diarrhea, or pain –Perform a visual inspection of the perianal region –Perform a digital rectal examination  Clinicians should refer women with cervical HSIL and any patient with abnormal anal physical findings for high-resolution anoscopy and/or examination with biopsy of abnormal tissue  Clinicians should obtain anal cytology at baseline and annually in the following HIV-infected populations –Men who have sex with men –Any patient with a history of anogenital condylomas –Women with abnormal cervical and/or vulvar histology New York State Dept Health AIDS Institute. Anal Dysplasia and Cancer, July 2007.

9. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium HIVMA/IDSA Primary Care Guidelines  MSM, women with a history of receptive anal intercourse or abnormal cervical Pap test results, and all HIV-infected persons with genital warts should have anal Pap tests (weak recommendation, moderate quality evidence)  If abnormal findings, then high-resolution anoscopy should be performed with biopsy of abnormal areas and appropriate therapy based on biopsy results Aberg, et al. HIVMA/IDSA. Primary Care Guidelines. 2013.

10. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium Suggested Paradigm for Screening and Follow-up Chin-Hong PV, et al. Clin Infect Dis. 2002;35:1127-1134.  Repeat in 12 mos (HIV+)  Repeat in 2-3 yrs (HIV−) High-resolution anoscopy with biopsy No lesion seen Follow up every 6 mos AIN II or III AIN I Treat Anal cytology screening NormalASCUS HSIL LSIL

11. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium Premalignant Lesions of the Anus  Squamous intraepithelial lesion (SIL) –Typically used for cytology –Atypical cells of undetermined significance (ASCUS) –Low-grade squamous intraepithelial lesion (LSIL) –High-grade squamous intraepithelial lesion (HSIL)  Anal intraepithelial neoplasia (AIN) –Typically used for histology –AIN1, AIN2, AIN3 –AIN1 = low grade –AIN2 and 3 = high grade

12. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium Expert Panel Discussion  Recommendations on anal Pap smears are controversial –No evidence to support efficacy in preventing anal cancer –CDC guidelines do not recommend annual anal Pap smears [1]  Screening on patients < 30 yrs of age not recommended  Access to experienced professionals is critical for follow- up management of patients with positive Pap smears  Digital rectal exam should be performed as part of routine anal cancer screening 1. CDC. Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents. 2013.

13. Controversy: Should all HIV+ patients 50 yrs of age or older be evaluated with a DXA scan?

14. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium Both Osteopenia and Osteoporosis Are Common in the HIV+ Population Brown T, et al. AIDS. 2006;20:2165-2174. Odds of Osteoporosis in HIV-Infected Patients Compared With HIV-Uninfected Controls Study Amiel (2004) Brown (2004) Bruera (2003) Dolan (2004) Huang (2002 Knobel (2001) Loiseau-Peres (2002) Madeddu (2004) Tebas (2000) Teichman (2003) Yin (2005) Overall (95% Cl) Odds Ratio (95% Cl) 5.03 (1.47-17.27) 4.26 (0.22-82.64) 4.51 (0.26-79.27) 2.11 (0.54-8.28) 3.52 (0.15-81.92) 5.13 (1.80-14.60) 4.28 (0.46-39.81) 29.84 (1.80-494.92) 3.40 (0.19-61.67) 17.41 (0.97-313.73) 2.37 (1.09-5.16) 3.68 (2.31-5.84) Odds Ratio 0.011100

15. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium Recommendations for DXA Screening in HIV+ Persons  HIVMA/IDSA Guidelines [1] : baseline bone densitometry (DXA) screening for osteoporosis in HIV-infected patients should be performed in postmenopausal women and men aged 50 yrs or older (strong recommendation, moderate quality evidence)  McComsey et al [2] : we recommend a DXA scan for all HIV-infected postmenopausal women and men aged 50 yrs or older 1. Aberg, et al. HIVMA/IDSA. Primary Care Guidelines. 2013. 2. McComsey G, et al. Clin Infect Dis. 2010;51:937-946..

16. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium EACS: Recommendations for DXA  EACS: consider DXA in any patient with ≥ 1 characteristic –Postmenopausal women –Men ≥ 50 yrs of age –History of low-impact fx or high risk for falls –Clinical hypogonadism –Oral glucocorticoid use (minimum 5 mg prednisone equivalent for > 3 mos)  Preferably perform DXA in those with above risk factors prior to ART initiation  Assess fracture risk by including DXA results in the FRAX score –Only use if patient is older than 40 yrs of age –May underestimate risk in HIV patients –Consider using HIV as secondary cause of osteoporosis EACS v. 6.1. November 2012.

17. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium Management of Bone Disease in HIV McComsey G, et al. Clin Infect Dis. 2010;51:937-946. ≥ 50 yrs ♂, postmenopausal ♀, AND/OR hx of fracture? Measure BMD by DXA HIV-Infected Individual Assess Risk Factors Age, sex, weight/height, hx of fractures, secondary causes Lifestyle Advice Smoking cessation, vitamin D/calcium intake, weight-bearing exercise, sun exposure Secondary cause Calculate FRAX score T-score > -2.5 and ≤ -1 NO fragility fracture Monitor DXA in 2-5 yrsMonitor DXA in 1-2 yrs Evaluate potential secondary causes identified in history < 50 yrs ♂, premenopausal ♀, AND NO hx of fracture? Lifestyle Advice Continue ART T-score > -1 NO fragility fracture Lifestyle Advice Continue ART WAIT T-score ≤ -2.5 OR fragility fracture Consider bisphosphonate or other treatment Treat secondary cause YES Consider Initial Approach Indications for DXA Workup Phase Treatment Phase Follow-up Phase YES NO 10-yr fracture risk (USA) ≥ 20% major osteoporotic AND/OR ≥ 3% hip

18. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium NRTI Component Primary Analysis NNRTI/PI Component Secondary Analysis NNRTI/PI Component Secondary Analysis Loss of Bone With Initiation of ART in ACTG 5224 (5202 Substudy)  Change in spine (left) and hip (right) BMD with ART  Top panels: ABC vs TDF  Bottom: EFV vs ATV/RTV McComsey G, et al. J Infect Dis. 2011;203:1791-1801. 0 -2 -3 -4 -5 0 244896144192 128 130 111 122 105 106 97 101 87 80 53 Patients, n TDF/FTC ABC/3TC *2-sample T-test. Wk From Randomization NRTI Component Primary Analysis P =. 004 * Spine BMD Change From Wk 0 (%) 0 -2 -3 -4 -5 0244896144192 126 128 109 119 104 96 99 85 79 53 54 Patients, n TDF/FTC ABC/3TC *2-sample T-test. Wk From Randomization P =.024* Hip BMD Change From Wk 0 (%) TDF/FTC ABC/3TC Patients, n EFV ATV/RTV *2-sample T-test. 0 -2 -3 -4 -5 0244896144 133 125 117 116 109 102 107 91 86 81 58 48 Wk From Randomization P =.035* 192 0 -2 -3 -4 -5 0244896144192 131 123 114 107 101 105 90 84 80 59 48 Patients, n EFV ATV/RTV *2-sample T-test. Wk From Randomization P =.61* EFV ATV/RTV Hip BMD Change From Wk 0 (%)

19. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium P =.004 ACTG 5257: Loss of BMD With First-line Boosted PI vs RAL  All arms associated with significant loss of BMD through Wk 96 (P <.001)  Total body BMD loss significantly greater with ATV/RTV than either DRV/RTV or RAL  At hip and spine, similar loss of BMD in the PI arms –Significantly greater loss in the combined PI arms than in the RAL arm ATV/RTV RAL DRV/RTV Combined PI arms -5 Loss of BMD (%) -4 0 -3 -2 -3.9 -1.7 -3.4 -2.9 -3.7 -2.4 -1.8 -4.0 -3.8 -3.6 -1.6 P =.36 Total HipTotal SpineTotal Body P =.005 P =.42 P <.001 P =.001 P =.72 Brown T, et al. CROI 2014. Abstract 779LB. Reproduced with permission.

20. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium Factors Associated With Incident Fracture in the SUN and HOPS Cohorts Battalora L, et al. CROI 2014. Abstract 781.

21. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium Expert Panel Discussion  DXA scans are relatively inexpensive, painless, and easily interpreted  There is great potential to improve outcomes for patients with abnormal DXA results –Explore secondary causes of osteoporosis  Measuring vitamin D levels is an important complementary screening measure for bone loss, though data are lacking on the ideal levels and mode of supplementation

22. Controversy: Should all HIV+ patients be treated with a statin regardless of their lipid levels?

23. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium ACC/AHA: Patient Groups in Whom a Statin Should Be Recommended  Individuals with atherosclerotic cardiovascular disease (coronary heart disease, stroke, or peripheral arterial disease)  Individuals with LDL ≥ 190 mg/dL  Individuals 40-75 yrs of age with diabetes and LDL between 70-189 mg/dL  Individuals without atherosclerotic cardiovascular disease or diabetes 40-75 yrs of age with LDL between 80-189 mg/dL and with an estimated 10-yr cardiac risk of atherosclerotic cardiovascular disease of 7.5% or higher using a pooled cohort risk assessment equation Stone NJ, et al. J Am Coll Cardiol. 2013;[Epub ahead of print].

24. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium D:A:D: Framingham Model Underestimates CVD Risk in HIV+ Patients  Classic CVD risk factors important in HIV+ pts  Framingham appears to underestimate risk compared with D:A:D models Framingham model D:A:D reduced model D:A:D full model Observed Kaplan-Meier 5-Yr CVD Risk by Age and Diabetes Status DM No DM 50+ yr 40-49 yr 30-39 yr < 30 yr Estimated 5-Yr Risk (%) 12 10 8 6 4 2 0 Friis-Møller N, et al. EACS 2013. Abstract PS1/3. Reproduced with permission.

25. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium Atorvastatin and Immune Activation in HIV+ Patients  In randomized, double-blind, placebo-controlled trial of atorvastatin 80 mg vs placebo in 24 HIV+ pts not on ART –HIV-1 RNA level unaffected –Atorvastatin resulted in reductions in circulating proportions –CD4+/HLA-DR+ cells (-2.5%; P =.02) –CD8+/HLA-DR+ cells (-5%; P =.006) –CD8+/HLA-DR+/CD38+ cells (-3%; P =.03) Ganesan J, et al. J Infect Dis. 2011;203:756-764.

26. clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium clinicaloptions.com 24th Annual CCO HIV and Hepatitis C Symposium Expert Panel Discussion  In practice, statins are generally prescribed only to HIV- infected patients with elevated lipids  HIV infection is associated with high levels of inflammation regardless of viral suppression by ART –HIV infection could potentially be considered a risk factor for cardiovascular disease  Recent data indicate that statin use results in lower levels of inflammatory biomarkers [1] and greater improvement in CD4+ cell counts [2] in HIV-infected patients on stable ART 1. Funderburg N, et al. CROI 2014. Abstract 335. 2. Drechsler HJ, et al. CROI 2014. Abstract 308.