Advances in HIV Treatment: When to Start Treatment Which Antivirals to Use

Advances in HIV Treatment: When to Start Treatment Which Antivirals to Use Calvin Cohen MD Harvard Vanguard Medical Associates CRI New England Vice Chair, Science Steering Cmte, INSIGHT Boston MA

Learning Objectives Upon completion of this presentation, learners should be better able to: Apply HIV treatment guidelines to the practice of HIV medicine. Assess the remaining challenges to optimal health in HIV positive patients and the ongoing research related to these challenges.

Faculty and Planning Committee Disclosures Please consult your program book. Off-Label Disclosure There will be no off-label/investigational uses discussed in this presentation.

When to start HIV treatment Late clinical stages Early clinical stages < 200 > 500 High viral load 200 350 Any viral load CD4 Adapted from Schechter M, JID 2004;190:1043-1045

Mr. WTS He is a 35 year old male Has been seeing you for the past few years for his HIV No other medical concerns or issues CD4 counts consistently >500/mm 3 Viral load consistently < 5000 c/ml Has a steady partner who is HIV+ on meds Is willing to start treatment Wants your advice Are the possible medication side effects are worth it?

Mr. WTS 1. Yes he is ready and HIV treatment is appropriate 2. No need to start yet with this low viral load and high CD4, and his concern for possible medication side effects 3. I d refer him to the START study 4. I don t know what to recommend 5. Other?

Four Questions for Deciding When to Start Is there damage done by waiting to start treatment for patients with high T4 counts e.g., >500/mm 3? If yes, is the damage done by delaying HIV treatment completely reversible? At what CD4 count does the damage become irreversible? Are HIV treatments sufficiently ideal to treat everyone who is willing even those at very low risk of HIV-related illness?

Current Life Expectancy of HIV-Positive Patients Comparison of life expectancy of Athena cohort patients (n=4,174) to general population Years of Life Remaining Age at time of death Years lived Remaining Life Years General Population Asymptomatic HIV+ Patients Age at 24 weeks (years) van Sighem A, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 526.

CIPRAHT001: Randomized Trial of When to Start ART: Haiti Randomized clinical endpoint study of when to start therapy Treatment-naive No hx AIDS-defining illness CD4 200-350 (n=816) Immediate start with CD4 200-350 on ZDV/3TC + EFV Standard Treatment (Delay until CD4+ <200 or AIDS Primary endpoint: Survival Baseline Characteristics Early (n=408) Standard (n=408) Median age (years) 40 40 Male (%) 41% 44% Median CD4+ (cells/mm 3 ) 280 282 May 2009: DSMB review stopped study due to excess deaths in Standard Treatment arm Severe P, et al. 49 th ICAAC; San Francisco, CA; Sept. 12-15, 2009; Abst. H-1230c.

CIPRAHT001: Clinical Endpoints Clinical Endpoints Early Rx Standard Hazard Ratio (p value) Death 6 23 4.0 (.0011 ) Incident Tuberculosis 18 36 2.0 (.0125 ) Infectious causes of death Early: 1 (gastroenteritis) Standard: 17 (7 gastroenteritis, 5 TB, 4 pneumonia, 1 cholangitis/sepsis) Severe P, et al. 49 th ICAAC; San Francisco, CA; Sept. 12-15, 2009; Abst. H-1230c.

EACS Guidelines: When to Start ARV Therapy Condition Current CD4 + lymphocyte count C = CONSIDER. D = DEFER. R = RECOMMENDED 350-500 >500 Asymptomatic HIV infection Consider Defer Symptomatic HIV disease (CDC B or C conditions) incl. tuberculosis Primary HIV infection C C Conditions (likely or possibly) associated with HIV, other than CDC stage B or C disease: HIV-associated kidney disease R R HIV-associated neurocognitive impairment R R Hodgkin's lymphoma R R HPV-associated cancers R R High risk for CVD (>20% estimated 10 yr risk) or history of CVD C C R R In serodiscordant couples early initiation of ART as one aspect of the overall strategy to reduce HIV transmission to the seronegative partner should be considered and actively discussed www.eacs.eu (October, 2011)

IAS-USA 2010: Guidelines for When to Start ARV Therapy Specific conditions Measure Symptomatic HIV disease Pregnancy High HIV-1 RNA Level (>100,000 copies/ml) Rapid CD4 count decline (>100 cells/mm 3 per year) Active hepatitis B or C* virus co-infection Active or high risk for cardiovascular disease* HIV-associated nephropathy Symptomatic primary HIV infection* Age > 60* Recommendation ART recommended regardless of CD4 cell count Risk for secondary HIV transmission is high* CD4 cell count 500 cells/mm 3 ART recommended CD4 cell count >500 cells/mm 3 ART should be considered * Differs from 2009 DHHS guidelines Unless patient is an elite controller (HIV-1 RNA <50 copies/ml) or has stable CD4 cell count and low-level viremia in the absence of ART Thompson MA, et al. JAMA 2010;304(3):321-333; US Department of Health and Human Services Guidelines; Revised December 1, 2009. Available at: http://aidsinfo.nih.gov/contentfiles/adultandadolescentgl.pdf.

2012 DHHS Guidelines: Recommendations for Initiation of ART in Naïve Patients Clinical Category CD4 Cell Count (cells/mm 3 ) 2012 DHHS Guidelines Strength-Quality AIDS-defining illness Pregnancy HIV-associated nephropathy HIV/HBV coinfection Persons at risk of transmitting to sexual partners Age > 50 years old Any value Treat AI AI AII AII AI/AIII BIII <350 Treat AI Asymptomatic 350 to 500 Treat AII >500 Treat BIII Strength of Recommendation: A = Strong; B = Moderate; C = Optional Quality of Evidence for Recommendation: I = data from randomized controlled trials; II = data from well-designed nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = expert opinion Available at: http://www.aidsinfo.nih.gov/contentfiles/adultandadolescentgl.pdf. Revision March 29, 2012.

Results of Three Large Observational Cohorts At what CD4 count does evidence of clinical harm (incr. risk of AIDS and/or death) begin when deferring starting Antiretroviral Therapy? ART-CC: < 350/mm 3 Cascade: < 500/mm 3 NA-ACCORD: Any delay, including > 500/mm 3 Sterne J, at al. 16th CROI; 2009; Montreal. Abstract 72LB., Funk MJ, et al. 18th IAC; Vienna, July 18-23, 2010; Abst. THLBB201., Kitahata M, et al. New Engl J Med 2009;360:1815-26

Rodger A, et al. 19th CROI; Seattle, WA; March 5-8, 2012. Abst. 638. SMART and ESPRIT: Mortality Risk of Patients on Suppressive ART vs. HIV negative population 3280 Non-IDU Patients from SMART and ESPRIT Most Recent Eligible Observed Death Rates and Overall SMRs Standardized by CD4 Age Count and Sex Cells/µL and Country 350-499 >500 Person-years of follow-up Proportion 12357 3729 30% 8628 70% Observed deaths 28 34 Expected deaths 15.86 33.96 SMR (95% CI) 1.77 (1.17-2.55) 1.00 (0.69-1.40) SMR: Standardized Mortality Ratio

SMART Naïve/Off Treatment Sub-study: Clinical Outcomes of (re-)starting ARVs Cum. Probability (X100) 25 20 15 10 5 Opportunistic disease and death Hazard Ratio = 4.38 (95%.CI: 1.45-13.2) p=0.009 Deferred ART Immediate ART No. at Risk Deferred ART 228 Immediate ART 249 192 210 162 179 130 144 0 0 4 8 12 16 20 24 28 32 36 Months 95 124 73 104 58 80 37 58 26 44 21 35 per 100 person years Emery S, et al. JID 2008; 197: 1133 1144.

SMART Naïve/Off Treatment Sub-study: Clinical Outcomes of (re-)starting ARVs 25 Opportunistic disease and death 25 Composite endpoint Cum. Probability (X100) 20 15 10 5 Hazard Ratio = 4.38 (95%.CI: 1.45-13.2) p=0.009 Deferred ART Immediate ART 20 15 10 5 Hazard Ratio = 5.08 (95% CI: 1.91-13.5) p=0.001 No. at Risk Deferred ART 228 Immediate ART 249 0 0 4 8 12 16 20 24 28 32 36 192 210 Continuous ART Intermittent ART 162 179 130 144 Months 95 124 73 104 58 80 37 58 26 44 21 35 0 0 4 8 12 16 20 24 28 32 36 No. at Risk Months 228 249 188 210 157 179 125 144 90 124 Last CD4+ cell count (cells/ml) < 250 250-349 350-499 > 500 Overall Event Rate * 10.4 6.7 1.8 0.0 1.3 Event Rate * 16.0 9.2 7.6 3.1 7.0 per 100 person years Emery S, et al. JID 2008; 197: 1133 1144. 69 104 55 79 33 57 24 43 20 35

SMART: Non-AIDS event rates with Continuous vs. Intermittent ART Endpoint Continuous (n=2752) Intermittent (n=2720) HR (95% CI) P Value Any cause death 30 55 1.8 (1.2-2.9).007 Major CV, renal, or hepatic disease Fatal/nonfatal CV disease Fatal/nonfatal renal disease Fatal/nonfatal liver disease 39 65 1.7 (1.1-2.5).009 1.1% 1.8% 1.6 (1.0-2.5).05 0.07% 0.3% 4.5 (1.0-20.9).05 0.25% 0.4% 1.4 (0.6-3.8).46 Adapted from El-Sadr WM, et al. N Engl J Med 2006;355:2283-96.

HPTN 052: Treatment as Prevention Randomized, placebo-controlled efficacy and safety study 13 sites in Africa, Asia, Americas: N=1763 HIV-positive patients in relationship with HIVnegative partner 97% Heterosexual CD4 350-550 N= 886 immediate HAART N=877 Delayed HAART until CD4<250 (or AIDS) N=1 transmission 96% risk reduction N=27 transmissions All received ongoing safe sex education/condoms Study stopped four years early by DSMB (May 2011) All 28 transmissions genetically linked to the positive partner All on delayed arm now offered HAART Available at: http://www.hptn.org/web%20documents/pressreleases/hptn052pressreleasefinal5_12_118am.pdf Accessed May 12, 2011.

Oral sex? The HOT study Cohort study of MSM Unprotected RAI** Protected RAI** Exclusively fellatio N = 439 6 mo follow up 6 5 3.5 Oral sex: No HIV infections observed despite lack of condom use (94%) Conclusions: Percent 4 3 2 1 1.7 0 Rate of transmission via oral sex is low; 0 Unprotected RAI** Protected RAI** Exclusively fellatio Not zero: <0.8%. * HIV incidence determined in repeat testers ** RAI = receptive anal intercourse Page-Shafer K, et al. XIV Int AIDS Conference, Barcelona 2002, #4872; Balls et al We PpC2072, Bangkok 2004

START Study: Design HIV-infected individuals who are ART-naïve with CD4+ count > 500 cells/mm 3 Early ART group Initiate ART immediately following randomization N=2,000 Deferred ART group Defer ART until the CD4+ count declines to < 350 cells/mm 3 or AIDS develops N=2,000 Rate of primary endpoint in deferred group: 2.8 per 100 PY Non-AIDS : AIDS events = 4:1 Early ART reduces rate of primary endpoint by 28.8% 43% for AIDS and 24% for non-aids www.clinicaltrials.gov

What to Start?

Which Antiretrovirals: 2012 Currently Available (US) NRTIs Abacavir Didanosine NNRTIs Delavirdine Efavirenz PIs Atazanavir Darunavir Fusion Inhibitors Enfuvirtide Emtricitabine Etravirine Fos-Amprenavir Lamivudine Nevirapine (XR) Indinavir Stavudine Rilpivirine Lopinavir Entry inhibitors Tenofovir Nelfinavir Maraviroc Zidovudine Ritonavir Saquinavir Tipranavir Integrase inhibitors Raltegravir

EACS Guidelines: Ten Initial Combination Regimens 1 drug in column A 1 NRTI combination A B REMARKS Recommended EFV NVP NNRTI Ritonavirboosted PI ATV/r DRV/r LPV/r Integrase Inhibitor RAL C = CONSIDER. D = DEFER. R = RECOMMENDED www.eacs.eu. (October 2011) ABC/3TC or TDF/FTC TDF/FTC ABC/3TC or TDF/FTC TDF/FTC TDF/FTC co-formulated ABC/3TC co-formulated EFV/TDF/FTC co-formulated ATV/r: 300/100 mg qd DRV/r: 800/100 mg qd LPV/r: 400/100 mg bid or 800/200 mg qd RAL: 400 mg bid

EACS Guidelines: 9 Alternative Initial Combination Regimen 1 drug in column A 1 NRTI combination A B REMARKS Alternative SQV/r FPV/r MVC ZDV/3TC ddl/3tc or FTC SQV/r: start with 500/100 mg then change to 1000/100 mg bid after one week FPV/r: 700/100 mg bid or 1400/200 mg qd ZDV/3TC co-formulated C = CONSIDER. D = DEFER. R = RECOMMENDED www.eacs.eu. (October 2011)

2012 DHHS Guidelines: What to Start: Four Preferred Preferred Regimens: Regimens with optimal and durable efficacy, favorable tolerability and toxicity profile, and ease of use NNRTI: EFV/TDF/FTC EFV caution for women given risk of birth defects when EFV used in first trimester PI: ATV/r + TDF/FTC DRV/r (once daily) + TDF/FTC Int: RAL + TDF/FTC ATV/r should not be used in patient who require >20mg omeprazole equivalent per day RAL dosing BID Comments: TDF should be used with caution in patients with renal insufficiency Available at: http://www.aidsinfo.nih.gov/contentfiles/adultandadolescentgl.pdf. Revision March 29, 2012.

2012 DHHS Guidelines: What to Start: Four Preferred Preferred Regimens: Regimens with optimal and durable efficacy, favorable tolerability and toxicity profile, and ease of use NNRTI: EFV/TDF/FTC EFV caution for women given risk of birth defects when EFV used in first trimester PI: ATV/r + TDF/FTC DRV/r (once daily) + TDF/FTC Int: RAL + TDF/FTC Preferred Regimen for Pregnant Women LPV/r (twice daily) +ZDV/3TC ATV/r should not be used in patient who require >20mg omeprazole equivalent per day RAL dosing BID Once-daily LPV/r is not recommended in pregnant women Comments: TDF should be used with caution in patients with renal insufficiency Available at: http://www.aidsinfo.nih.gov/contentfiles/adultandadolescentgl.pdf. Revision March 29, 2012.

2012 DHHS Guidelines: What to Start: 14 Alternatives Alternative Regimens - that are effective and tolerable but have potential disadvantages compared with preferred regimens. An alternative regimen may be the preferred regimen for some patients. NNRTI Based Regimens: EFV + ABC/3TC (BI) PI Based Regimens (alphabetically) ATV/r + ABC/3TC (BI) DRV/r + ABC/3TC (BIII) INSTI Based Regimen RAL + ABC/3TC (BIII) RAL dosed twice daily Comments for abacavir: Should not be used in patients who test positive for HLA-B5701 Use with caution in patients with known high risk of cardiovascular disease or with pretreatment HIV RNA >100,000 copies/ml Available at: http://www.aidsinfo.nih.gov/contentfiles/adultandadolescentgl.pdf. Revision March 29, 2012.

2012 DHHS Guidelines: What to Start: 14 Alternatives Alternative Regimens - that are effective and tolerable but have potential disadvantages compared with preferred regimens. An alternative regimen may be the preferred regimen for some patients. NNRTI Based Regimens: EFV + ABC/3TC (BI) RPV/TDF/FTC (BI) RPV + ABC/3TC (BIII) Use RPV with caution in patients with pretreatment HIV RNA >100,000 copies/ml Use of proton pump inhibitors is contraindicated with RPV PI Based Regimens (alphabetically) ATV/r + ABC/3TC (BI) DRV/r + ABC/3TC (BIII) FPV/r (QD or BID) + ABC/3TC or TDF/FTC (BI) LPV/r (QD or BID) + ABC/3TC or TDF/FTC (BI) INSTI Based Regimen RAL + ABC/3TC (BIII) RAL dosed twice daily Comments for abacavir: Should not be used in patients who test positive for HLA-B5701 Use with caution in patients with known high risk of cardiovascular disease or with pretreatment HIV RNA >100,000 copies/ml Available at: http://www.aidsinfo.nih.gov/contentfiles/adultandadolescentgl.pdf. Revision March 29, 2012.

What to Start: The Basis for These Rankings There is no single perfect regimen Each regimen has Pros and Cons If there was, this would be a much shorter talk What data justifies these rankings?

ACTG 5142: EFV with better response vs. LPV/r for VL > 5 log Screening viral load 100,000 copies/ml Patients at Risk (n) 121 123 122 108 105 102 96 90 86 90 81 81 76 67 66 40 32 35 11 6 9 Riddler SA, et al. N Engl J Med 2008;358:2095 106.

DRV/r and ATV/r in ARV-Naïve Patients: Higher Response Rates than LPV/r Patient Percent <50 copies/ml 100 80 60 40 20 0 ARTEMIS 1 (ITT, TLOVR)* 96 weeks 71 n=346 LPV/r QD or BID 79 n=343 DRV/r 800/100 QD 100 80 60 40 20 0 CASTLE 2 (ITT, NC=F) 96 weeks 68 LPV/r 400/100 BID 74 n=443 n=440 ATV/r 300/100 QD *Estimated difference in response vs LPV/r for superiority: ITT = 8.3% (95% CI 1.8;14.7, P=0.012) Adapted from: 1. Mills A, et al. AIDS May 29, 2009 [Epub ahead of print]; 2. Molina J-M, et al. 48th ICAAC/46th IDSA, Washington, DC, 2008.Abst. H-1250d

ACTG 5202: ATV/r vs. EFV Week 96 % with Virologic Suppression HR 1.26 (0.76,2.05) Percent without Virologic Failure 83.4% 85.3% 89% 89.8% HR 1.13 (0.82,1.56) ABC/3TC HR 1.01 (0.70,1.46) TDF/FTC CD4 Change (cells/mm 3 ) P= 250 251 252 221 0.89 0.002 Daar E, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 59LB.

STARTMRK: Design and Outcomes at Week 192 Randomized 1:1 To RAL:EFV Plus TDF/FTC Double Blind design N=281 RAL + TDF/FTC N=282 EFV + TDF/FTC Discontinuation: N=58 (20.6%) 5 lack of efficacy 13 AEs 8 lost to follow-up 32 miscellaneous Discontinuation: N=85 (29.9%) 8 lack of efficacy 26 AEs 17 lost to follow-up 34 miscellaneous 223 (79.4%) Completed 197 (69.9%) Completed DeJesus E, et al. IDSA 2011, 405;

STARTMRK: RAL vs. EFV + TDF/FTC % with HIV RNA <50 c/ml (NC=F) Percent of Patients with HIV RNA <50 Copies/mL 100 80 60 40 20 86 82 81 75 79 69 Δ (RAL-EFV) [95% CI]=+9.0 [1.6, 16.4] Non-Inferiority p-value <0.001 76 67 0 0 16 48 72 96 120 156 192 Number of Contributing Patients Weeks Raltegravir group Efavirenz group 281 281 280 281 281 277 281 281 282 281 281 282 282 281 282 282 DeJesus E, et al. IDSA 2011, 405; Rockstroh J, et al. EACS 2011, PS1/1.

STARTMRK: Four Year Follow Up Rates of Failure Proportion of Patients (%) with: CD4 Cell Count, Change from BL (cells/mm 3 ) Observed VF AE Related DC Both Trt Related DC=Failure NC=F Obs Failure RAL (N=281) 9% 5% 14% 24% 360.7 EFV (N=282) 15% 9% 24% 33% 300.9 RAL - EFV 6.0* (0.1, 12.2) 4.0 (NA) 10.1* (3.3, 17.0) 9.0* (1.6,16.4) 59.8 (24.1, 95.4) Observed Failure (OF): Patients who discontinued tx due to lack of efficacy were considered as failures thereafter Tx-Related Discontinuation=Failure: Patients who discontinued tx due to lack of efficacy or AE were considered as failures thereafter. Non-Completer=Failure (NC=F): Patients who discontinued tx regardless of reason were considered as failures thereafter DeJesus E, et al. IDSA 2011, 405; Rockstroh J, et al. EACS 2011, PS1/1. * p-value for non-inferiority <0.001

Absence of Primary Protease Mutations in First-Line Therapy With PI/r Study n NRTI backbone PI/r Week Genotypes Primary PI mutations 720 1 100 d4t + 3TC LPV 312 17 0 863 2 653 d4t + 3TC LPV 108 51 0 940 3 44 d4t + 3TC LPV 72 13 0 056 4 38 d4t + 3TC LPV 72 5 0 418 5 190 TDF + 3TC LPV 96 15 0 Solo 6 649 ABC + 3TC FPV 64 32 0 Staccato 7 258 ddi + d4t SQV 19 48 10 0 BMS 089 8 95 d4t-xr + 3TC ATV 48 2 0 ARTEMIS 9 689 TDF + FTC LPV or DRV 96 NA 0 CASTLE 10 881 TDF + FTC LPV or ATV 96 52 1* *in ATV/r arm 1. Gulick R, et al. 7th ICDTHI, 2004; Abstract P28. 2. Kempf D, et al. J InfDis 2004;189:51; 3. Cahn P, et al. 1st IAS, 2001; Abstract 779. 4. Feinberg J, et al. 14th IAC, 2002; Abstract TuPeB4445. 5. Molina JM, et al. 15th IAC, 2004; Abstract WePeB570. 6. MacManus S, et al. AIDS 2004;18:65; 7. Ananworanich J, et al. 3rd IAS, 2005; Abstract WePe4.4C12; 8. Malan N, et al. CROI 2006; Abstract 107LB. 9. Mills T, et al. 48th ICAAC/46th IDSA, 2008; Abstract H-1250c. 10. Molina J-M, et al. 48th ICAAC/46th IDSA, 2008; Abstract H-1250d.

Adherence: On time Pharmacy Refills by Number of Tablets per Day Single Tablet Regimen Multi-Tablet Regimen p<0.01 11% better adherence to STR: 70% vs.59% Percentage of Patients p<0.01 p<0.01 p<0.01 N = 122 690 427 1686 824 2454 465 1044 <60% >60-79% 80-94% 95-100% Cohen CJ et al. ESPACOMP Nov 2011, Utrecht. Oral 315 Adherence to Antiretroviral Therapy

A5202: Two NRTIs plus EFV / ATV/r: Impact of baseline viral load and CD4 count ABC/3TC TDF/FTC 1 HIV RNA 100,000 c/ml HIV RNA < 100,000 c/ml Probability of remaining free of virologic failure n=98 35 VF n=78 23 VF n=80 19 VF n=153 10 VF n=39 6 VF n=273 28 VF n=23 5 VF n=184 29 VF 0.8 0.6 0.4 0.2 n=80 6 VF n=83 17 VF n=70 9 VF n=158 19 VF n=55 8 VF n=289 29 VF n=20 2 VF n=173 24 VF 0 CD4 (cells/mm 3 ) Adapted from Grant P, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 535. <50 50 to <200 200 to <350 350

Comparisons of Safety and Adverse Events

D:A:D Study: The Controversy about NRTI MI risk Recent Exposure*: yes/no Relative risk (95% CI) 1.9 1.5 1.2 1 0.8 Similar concern raised about LPV/r 0.6 ZDV ddi d4t 3TC ABC TDF #PYFU: 138,109 74,407 95,320 152,009 53,300 39,157 #MI: 523 331 405 554 221 139 * Recent use=current or within the last 6 months. Adapted from Lundgren JD, et al. 16th CROI; Montreal, Canada; February 8-11, 2009. Abst. 42LB.

ACTG 5202: TDF/FTC vs. ABC/3TC with Atazanavir/r vs. EFV: Change in Creatinine Clearance 10 Wk 48, p=0.17 Wk 96, p=0.33 Wk 48 Wk 96 Wk 48, p=0.001 Wk 96, p<0.001 Median Change in Calculated Creatinine Clearance, (ml/min) 8 6 4 2 0-2 3.1 6.1 ATV/r 4.3 EFV 7.8 ATV/r -0.9-2.6 4.1 p-values: ATV/r vs. EFV EFV 4.9-4 ABC/3TC TDF/FTC N= 377 330 338 287 394 352 360 327 Backbone Daar E, et al. CROI 2010, 59LB

A5224s: Mean Percent Change in Lumbar Spine Bone Mineral Density NRTI Component: Primary Analysis NNRTI/PI Component: Secondary Analysis Lumbar Spine Percent BMD Change from Week 0 to 192 ABC/3TC TDF/FTC EFV ATV/r P=0.004 P=0.035 Hip BMD: Significantly greater percent decline with TDF/FTC than ABC/3TC; not significant for NNRTI/PI No significant difference in fracture rate between arms McComsey, G, et al. CROI 2010, 106LB.

A5224s: Change in Visceral Adipose Tissue VAT change from week 0 (%) CT Results: Mean percent change in VAT (ITT) NRTI Component Secondary Analysis P = 0.55 NNRTI/PI Component Secondary Analysis P = 0.018 ATV/r average gain 1.8 kg trunk fat; EFV average gain 0.7 kg trunk fat. McComsey, G, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 77.

STARTMRK Metabolic Study: RAL vs. EFV at Week 96 Lipid Changes p <0.001 * P =0.025 * No sig diff in total/hdl ratio Mean Percent Change in Appendicular Fat Dexa substudy (n=111) Week 96, >20% loss of limb fat 3/37 (8%) on RAL 2/38 (5%) on EFV 18.1 17.7 18.2 17.0 DeJesus E, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 720.

Rilpivirine: ECHO and THRIVE Wk 48 Outcome by Adherence and Viral Load Adherent Suboptimally Adherent BL VL <100K BL VL >100K BL VL <100K BL VL >100K RPV EFV RPV EFV RPV EFV RPV EFV Virologic Responder 95% 92% 87% 92% 47% 39% 31% 37% Virologic Failure 3% 4% 10% 4% 21% 11% 50% 17% Other D/C 2% 5% 2% 4% 31% 50% 19% 46% Adapted from Rimsky L, et al. 50th ICAAC; Boston, MA; September 12-15, 2010; Abst. H-1810.

Mr. WTS Mr. S transfers to your practice He tested positive a year ago Ready to start treatment but didn t feel his other clinician really knew HIV Says he hears you really do CD4 is 290, Viral load 75,163 c/ml Genotype showed no resistance mutations

Mr WTS What do you recommend? 1. TDF/FTC/EFV 2. TDF/FTC/ATV/r 3. TDF/FTC/DRV/r 4. TDF/FTC/RAL 5. TDF/FTC/RPV 6. Other 7. I don t know

Summary When to Start: Consensus to start when CD4 count >350/mm 3 How high above 350 an ongoing discussion Which to Start: Multiple Randomized trials identify several regimens with: Efficacy: Durablevirologic suppression Safety: Fewer side effects vs. prior ARVs Which one an ongoing discussion