1. March 3-6, 2014 Boston, Massachusetts HIV/AIDS Update From Boston 2014 CCO Independent Conference Coverage of the 2014 Annual Conference on Retroviruses and Opportunistic Infections * *CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs. This program is supported by an educational grant from This program is supported by educational grants from

2. Antiretroviral Therapy

3. clinicaloptions.com/hiv HIV/AIDS Update From Boston 2014 ACTG 5257: Open-Label ATV/RTV vs RAL vs DRV/RTV in First-line ART  Primary endpoints –Virologic failure: time to HIV-1 RNA > 1000 c/mL (at Wk 16 or before Wk 24) or > 200 c/mL (at or after Wk 24) –Tolerability failure: time to discontinuation of randomized component for toxicity  Composite endpoint: the earlier occurrence of either VF or TF in a given participant  Switch of regimens allowed for tolerability Landovitz R, et al. CROI 2014. Abstract 85. ART-naive patients with HIV-1 RNA ≥ 1000 c/mL (N = 1809) ATV/RTV 300/100 mg QD + TDF/FTC (n = 605) RAL 400 mg BID + TDF/FTC (n = 603) Stratified by HIV-1 RNA < or ≥ 100,000 c/mL, participation in metabolic substudy, CV risk DRV/RTV 800/100 mg QD + TDF/FTC (n = 601) Wk 96 after last patient enrolled

4. clinicaloptions.com/hiv HIV/AIDS Update From Boston 2014 ACTG 5257: Primary Endpoint Analyses at Wk 96  Regimens equivalent in time to VF Landovitz R, et al. CROI 2014. Abstract 85. Reproduced with permission.  Significantly greater incidence of treatment failure with ATV/RTV vs RAL or DRV/RTV –In part due to high proportion of pts with hyperbilirubinemia  Considering both efficacy and tolerability, RAL superior to either boosted PI  DRV/RTV superior to ATV/RTV Virologic FailureTolerability FailureComposite Endpoint Difference in 96-Wk Cumulative Incidence (97.5% CI) 0-10 1020 ATV/RTV vs RAL 3.4% (-0.7 to 7.4) DRV/RTV vs RAL 5.6% (1.3 -9.9) ATV/RTV vs DRV/RTV -2.2% (-6.7 to 2.3) 0-10 1020 ATVRTV vs RAL 15% (10-20) DRV/RTV vs RAL 7.5% (3.2-12.0) ATV/RTV vs DRV/RTV 7.5% (2.3-13.0) Favors RAL Favors DRV/RTV Favors RAL 0-10 1020 ATV/RTV vs RAL 13% (9.4-16.0) DRV/RTV vs RAL 3.6% (1.4-5.8) ATV/RTV vs DRV/RTV 9.2% (5.5-13.0) Favors RAL Favors DRV/RTV

5. clinicaloptions.com/hiv HIV/AIDS Update From Boston 2014 89% ACTG 5257: Virologic Efficacy  In ITT analysis with ART changes allowed (per protocol), regimens similar in virologic efficacy at Wk 96 and through Wk 144  In ITT analysis when change = failure (Snapshot), RAL superior to both boosted PIs at Wk 96 and DRV/RTV superior to ATV/RTV at Wks 96 and 144  Similar mean change in CD4+ count across arms –ATV/RTV (+284); RAL (+288) DRV/RTV (+256) cells/mm 3 Landovitz R, et al. CROI 2014. Abstract 85. Reproduced with permission. 1.0 Proportion With HIV-1 RNA ≤ 50 c/mL 0.8 0.6 0.4 0.2 0 ITT, Regardless of ART Change 0 24 48 64 80 96 120144 1.0 0.8 0.6 0.4 0.2 0 ITT, NC = Failure (Snapshot) RAL DRV/RTV ATV/RTV Study Wk 0 24 4864 80 96 120 144 88% 94% 63% 73% 80% RAL DRV/RTV ATV/RTV

6. clinicaloptions.com/hiv HIV/AIDS Update From Boston 2014 ACTG 5257: Resistance and Lipids  VF with drug resistance occurred more often in pts initially assigned to RAL [1] –3% of those randomized to RAL had ≥ 1 resistance mutation and 1.8% had INSTI mutations –1.5% randomized to ATV/RTV and < 1% randomized to DRV/RTV developed resistance –No major PI mutations observed  PI-containing regimens associated with significantly greater increases in TC, LDL-C, TGs vs RAL at Wk 96 [2] –Lipids remained stable or decreased in RAL arm –Lipids changes in boosted PI arms similar 1. Landovitz R, et al. CROI 2014. Abstract 85. 2. Ofotokun I, et al. CROI 2014. Abstract 746.

7. clinicaloptions.com/hiv HIV/AIDS Update From Boston 2014 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.

8. clinicaloptions.com/hiv HIV/AIDS Update From Boston 2014 STRATEGY Trials: Switch to EVG/COBI/TDF/FTC in Suppressed Pts  Randomized, open-label switch studies in pts virologically suppressed on an NNRTI- or boosted PI–based regimen (both with TDF/FTC) for ≥ 6 mos  Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 48 HIV-1 RNA < 50 c/mL,  2 previous regimens, no resistance to FTC or TDF and CrCl ≥ 70 mL/min STRATEGY-NNRTI [1] (N = 434) STRATEGY-PI [2]* (N = 433) Switch to EVG/COBI/TDF/FTC QD (n = 291) Remain on NNRTI + TDF/FTC (n = 143) Switch to EVG/COBI/TDF/FTC QD (n = 293) Remain on Boosted PI + TDF/FTC (n = 140) 1. Pozniak A, et al. CROI 2014. Abstract 553LB. 2. Arribas J, et al. CROI 2014. Abstract 551LB. *Pts with previous VF ineligible.

9. clinicaloptions.com/hiv HIV/AIDS Update From Boston 2014 STRATEGY-NNRTI: Change to EVG/COBI Noninferior to Stable NNRTIs at Wk 48  Regimens: EFV, 78%; NVP, 17%; RPV, 4%; ETR, < 1%; 74% on EFV/TDF/FTC; 91% on first regimen  Results similar across all baseline virologic and demographic subgroups  3 pts with VF in EVG/COBI arm and 1 in NNRTI arm –No pts with resistance in either arm  5 in the switch arm and 1 in the NNRTI arm discontinued due to adverse event Patients (%) 93 88 Δ +5.3% (95% CI: -0.5 to +12) EVG/COBI/TDF/FTC (n = 290) Stable NNRTIs (n = 143) 0 20 40 60 80 100 1313 < 1 1 6 11 Virologic Success* Virologic Nonresponse No Data  n = *HIV-1 RNA < 50 c/mL as defined by FDA Snapshot algorithm  Discontinued for AE, death, or missing data. Pozniak A, et al. CROI 2014. Abstract 553LB. Reproduced with permission. 27112616

10. clinicaloptions.com/hiv HIV/AIDS Update From Boston 2014 STRATEGY-PI: Change to EVG/COBI Better Than Maintaining bPIs at Wk 48  Regimens: ATV, 40%; DRV, 40%; LPV, 17%; FPV, 3%; SQV, < 1%; 79% on first regimen  Results similar across all baseline virologic and demographic subgroups  2 pts with VF in each arm but no pts with resistance in either arm  5 in the switch arm and 2 in the boosted PI arm discontinued due to adverse event  Lipids in switch pts –  TGs vs all bPIs –  TC, TG, HDL-C vs LPV/RTV –  HDL-C vs DRV/RTV Patients, % 94 87 Δ +6.7% (95% CI: 0.4-13.7) EVG/COBI/TDF/FTC (n = 290) Stable boosted PIs (n = 139) 0 20 40 60 80 100 < 1 2 1212 6 12 Virologic Success* Virologic Nonresponse No Data  n = *HIV-1 RNA < 50 c/mL as defined by FDA Snapshot algorithm  Discontinued for AE, death, or missing data. Arribas J, et al. CROI 2014. Abstract 551LB. 27212116

11. clinicaloptions.com/hiv HIV/AIDS Update From Boston 2014 SINGLE: Dolutegravir + ABC/3TC vs EFV/TDF/FTC in Naive Pts: 96-Wk Report  Randomized, noninferiority phase III studies  Primary endpoint: HIV-1 RNA < 50 c/mL at Wk 48 ART-naive pts VL ≥ 1000 c/mL HLA-B*5701 neg CrCL > 50 mL/min (N = 822) DTG 50 mg QD + 2 NRTIs* (n = 411) RAL 400 mg BID + 2 NRTIs* (n = 411) *Investigator-selected NRTI backbone: either TDF/FTC or ABC/3TC. ART-naive pts VL ≥ 1000 c/mL HLA-B*5701 neg CrCL > 50 mL/min (N = 833) DTG 50 mg QD + ABC/3TC QD (n = 414) EFV/TDF/FTC QD (n = 419) SPRING-2 [1] (placebo controlled) SINGLE [2] (placebo controlled) DTG 50 mg QD + 2 NRTIs* (n = 242) DRV/RTV 800/100 mg QD + 2 NRTIs* (n = 242) ART-naive pts VL ≥ 1000 c/mL (N = 484) FLAMINGO [3] (open label) 1. Raffi F, et al. Lancet. 2013;381:735-743. 2. Walmsley S, et al. N Engl J Med. 2013;369:1807-1818. 3. Feinberg J, et al. ICAAC 2013. Abstract H1464a.

12. clinicaloptions.com/hiv HIV/AIDS Update From Boston 2014 SINGLE: DTG + ABC/3TC Superior to EFV/TDF/FTC at Both Wk 48 and 96  Treatment-related study d/c: 3% in DTG vs 11% in EFV arm –No new treatment-related AEs in either arm btwn Wks 48-96  VF at Wk 96: 25 (6%) in each arm  0 pts with resistance in DTG arm; 1 pt with NRTI and 6 pts with NNRTI resistance in EFV arm  CD4+ count increase at Wk 96 greater with DTG: +325 vs +281 cells/mm 3 (P =.004) HIV-1 RNA < 50 copies/mL (%) 88 81 DTG + ABC/3TC (n = 414) EFV/TDF/FTC (n = 419) 0 20 40 60 80 100 80 72 Wk 48 [1] Wk 96 [2] 364/ 414 338/ 419 331/ 414 302/ 419 Δ 8.0% (2.3-13.8; P =.006) Δ 7% (2-12; P =.003) 1.Walmsley S, et al. N Engl J Med. 2013;369:1807-1818. 2.Walmsley S, et al. CROI 2014. Abstract 543. n/N =

13. clinicaloptions.com/hiv HIV/AIDS Update From Boston 2014 Snapshot, Wk 96 Overall Baseline HIV-1 RNA ≤ 100,000 c/mL Baseline HIV-1 RNA > 100,000 c/mL Protocol-Defined Virologic Failure Overall Baseline HIV-1 RNA ≤ 100,000 c/mL Baseline HIV-1 RNA > 100,000 c/mL Treatment-Related Discontinuation = Failure Overall Baseline HIV-1 RNA ≤ 100,000 c/mL Baseline HIV-1 RNA > 100,000 c/mL SINGLE: HIV-1 RNA < 50 c/mL at Wk 96 by Baseline HIV-1 RNA Difference in Proportion (DTG + ABC/3TC - EFV/TDF/FTC) Favors EFV/TDF/FTC QD Favors DTG + ABC/3TC QD Walmsley S, et al. CROI 2014. Abstract 543. Reproduced with permission. -20-15-10-50510201525

14. clinicaloptions.com/hiv HIV/AIDS Update From Boston 2014 NEAT-001/ANRS 143: DRV/RTV + RAL vs DRV/RTV + TDF/FTC in Naive Pts  Randomized, open-label phase III study  Primary endpoint –Virologic: change of treatment before Wk 32 because of insufficient response or HIV-1 RNA ≥ 50 c/mL at Wk 32 or beyond –Clinical: death, any new AIDS-defining event, any new non-AIDS event Raffi F, et al. CROI 2014. Abstract 84LB. ART-naive pts with HIV-1 RNA > 1000 c/mL CD4+ cell count ≤ 500 cells/mm 3 (N = 805)  DRV/RTV 800/100 mg QD + RAL 400 mg BID (n = 401) Wk 96 DRV/RTV 800/100mg QD + TDF/FTC 300/200 mg QD (n = 404) Stratified by country of origin and participation in virology/immunology substudy

15. clinicaloptions.com/hiv HIV/AIDS Update From Boston 2014 NEAT: RAL + DRV/RTV Noninferior to TDF/FTC + DRV/RTV at 96 Weeks  Overall, regimens noninferior by % reaching composite primary endpoint of 6 virologic and clinical endpoints at Wk 96 –RAL: 17.4%; TDF/FTC: 13.7% –Inferior response in pts with BL CD4 < 200 and a trend toward more primary endpoints in pts with BL VL ≥ 100K  S imilar numbers of pts with PDVF (RAL: n = 66; TDF/FTC: n = 52)  No pts with resistance in TDF/FTC arm vs 5 with integrase mutations and 1 with K65R in RAL arm Raffi F, et al. CROI 2014. Abstract 84LB. Reproduced with permission. OverallN = 805 BL HIV-1 RNA < 100,000 c/mL ≥ 100,000 c/mL n = 530 n = 275 BL CD4+ cell count < 200/mm 3 ≥ 200/mm 3 n = 123 n = 682 Primary Endpoint at Wk 96: Adjusted Difference Estimate (95% CI) RAL - TDF/FTC -100102030 RALTDF/FTC 17.413.7 7 36 7 27 (P =.09) 39.0 13.6 21.3 12.2 (P =.02)  Significantly greater mean increases in fasting lipids in RAL arm

16. clinicaloptions.com/hiv HIV/AIDS Update From Boston 2014 LATTE: GSK1265744 as Part of ART in Naive Pts: Results of 24-Wk Induction  GSK1265744 (744), DTG analogue with long half-life, oral or injectable formulations  Randomized, dose-ranging phase IIb study of oral formulation  Primary endpoint: HIV-1 RNA < 50 c/mL at Wk 48 744 10 mg QD + RPV 25 mg QD 744 30 mg QD + RPV 25 mg QD *Pts with HIV-1 RNA < 50 c/mL at Wk 24 continued to maintenance phase.  TDF/FTC or ABC/3TC. ART-naive pts, HIV-1 RNA > 1000 c/mL (N = 243) 744 60 mg QD + RPV 25 mg QD EFV 600 mg QD + 2 NRTIs QD (n = 62) Margolis D, et al. EACS 2013. Abstract PS7/1. Margolis D, et al. CROI 2014. Abstract 91LB. 744 10 mg QD + 2 NRTIs  (n = 60) 744 30 mg QD + 2 NRTIs  (n = 60) 744 60 mg QD + 2 NRTIs  (n = 61) Wk 48 primary analysis Stratified by HIV-1 RNA (≤ vs > 100,000 c/mL) and NRTI Wk 24 Induction Phase*Maintenance Phase

17. clinicaloptions.com/hiv HIV/AIDS Update From Boston 2014 LATTE: Virologic Success During Induction and Maintenance Phases  2 pts with PDVF during maintenance; both with INSTI mutations at BL Margolis D, et al. EACS 2013. Abstract PS7/1. Margolis D, et al. CROI 2014. Abstract 91LB HIV-1 RNA < 50 c/mL by Snapshot Algorithm (%) 100 80 60 40 20 0 BL248121624 Wks 92% 94% 96% 91% GSK1265744 10 mg (n = 60) GSK1265744 30 mg (n = 60) GSK1265744 60 mg (n = 61) EFV 600 mg (n = 62) Induction PhaseMaintenance Phase 262832364048

18. Cure Research

19. clinicaloptions.com/hiv HIV/AIDS Update From Boston 2014 Possible Second Case of Early Triple ART and “Functional Cure” in HIV+ Child  Mississippi HIV+ infant treated at 31 hrs of age with ZDV/3TC + NVP until 7 days and then with ZDV/3TC + LPV/RTV to 18 mos, after which ART was suspended [1] –At 39 mos of age, remains in remission with undetectable plasma HIV-1 RNA < 20 copies/mL and normal CD4+ and CD8+ cell counts [2]  Second case: A different child with high-risk HIV exposure started on triple- ART at 4 hrs of age [2] –HIV infection confirmed by positive peripheral blood HIV-1 DNA at 4 hrs and HIV-1 RNA (217 copies/mL) at 36 hrs of age –Plasma HIV-1 RNA undetectable by 11 days through 8 mos of age and no replication-competent HIV recovered from resting CD4+ cells at 1 and 3 mos of age –At 3 mos of age, HIV antibody is indeterminate and CD4+ cell percentages remain normal for age –Pt remains on ART 1. Persaud D, et al. CROI 2013. Abstract 48LB. 2. Persaud D, et al. CROI 2014. Abstract 75LB.

20. clinicaloptions.com/hiv HIV/AIDS Update From Boston 2014 HIV-1 Reservoirs Reduced in HIV-Positive Children With Early ART and Viral Control  Cross-sectional study of 144 perinatally HIV-infected pts with long-term (median: 10.2 yrs) virologic suppression on ART  Higher proviral burden with increasing age at virologic suppression [1]  In perinatally infected baby treated early (at 4 hrs of age) with triple ART, noninduced proviral genomes detected by PCR at 1 mo but not at 3 mos of age [2] 1. Persaud D, et al. CROI 2014. Abstract 72. 2. Persaud D, et al. CROI 2013. Abstract 48LB. Proviral Reservoir Size by Age of Virologic Control [1] Age, yrMedian copies HIV DNA/ 10 6 PBMCs (IQR) < 1 (n = 14) 4.2 (2.6-8.6) 1-5 (n = 53) 19.4 (5.5-99.8) > 5 (n =77) 70.7 (23.2-70.7)* *P <.001 compared with < 1 yr

21. clinicaloptions.com/hiv HIV/AIDS Update From Boston 2014 Lack of Detectable HIV DNA in Subject With Acute Infection on PrEP  Pt on PrEP Demo Project, HIV negative at screening but HIV positive at BL  Received 7 days of oral TDF/FTC PrEP but switched to ART immediately when test results returned and remains on ART  Plasma HIV-1 RNA levels: 220 c/mL at PrEP BL; 120 c/mL at 7 days of PrEP; “detected < 40 c/mL” at ~ 32 days after infection –All subsequent HIV-1 RNA tests negative  Single occurrence of low-level cell-associated HIV-1 RNA (4.7 c/million CD4+ T cells) ~ 32 days after infection –All other HIV-1 RNA and DNA tests have been negative, including those performed in a colorectal biopsy  Total CD4+ T cells and CD4+ T-cell subsets also negative for HIV-1 RNA and DNA Hatano H, et al. CROI 2014. Abstract 397LB..

22. clinicaloptions.com/hiv HIV/AIDS Update From Boston 2014 Prevention of HIV Transmission by Early ART After Infected Blood Transfusion  12-y/o girl with sickle cell crisis received unit of packed RBCs from donor later found to be HIV+ –Donor HIV-1 RNA 9740 c/mL (not on ART)  1 day after transfusion, pt had positive HIV ELISA and confirmatory Western blot (WB), but negative for HIV DNA by PCR –Reactive bands on Western blot identical to donor  ART initiated with TDF/FTC + RAL + DRV/RTV (later changed to LPV/RTV) ~24h after transfusion –No signs of acute infection  Pt received 13 weeks of ART under DOT  HIV-1 DNA, HIV-1 RNA negative by commercial and sensitive research assays during and 3 mos after stopping ART  HIV antibody undetectable 7 mos after exposure Hajjar S, et al. CROI 2014. Abstract 960.

23. clinicaloptions.com/hiv HIV/AIDS Update From Boston 2014 HIV Rebound After Treatment Interruption in 2 BMT Pts  2 HIV+ persons treated with allogeneic hematopoietic stem cell transplantation from CCR5 wild-type donors  HIV-1 remained undetectable in blood and rectal tissue while pts on ART  ART withdrawn and pts followed with weekly or biweekly monitoring of viral load (VL) and proviral DNA by clinical assays  Pt A: no detectable plasma HIV-1 RNA or cell-associated HIV-1 DNA for 3 mos after ART cessation, then rebound  Pt B: no detectable virus (including negative PBMC HIV DNA and HIV-1 RNA by ultrasensitive assays) for 8 mos after ART cessation, then rebound  Both pts developed symptoms of acute retroviral syndrome, including aseptic meningitis  Symptoms rapidly resolved with ART initiation and viral suppression in both pts Heinrich TJ, et al. CROI 2014. Abstract 144LB.

24. Prevention

25. clinicaloptions.com/hiv HIV/AIDS Update From Boston 2014 PARTNER: Risk of HIV Transmission With Condomless Sex on Suppressive ART  Observational study of rate of HIV transmission in heterosexual and MSM serodiscordant couples (N = 767 couples) –HIV+ partner on suppressive ART –Condoms not used  Analyses: 6-monthly risk behavior questionnaire, HIV-1 RNA (HIV+ persons), HIV test (HIV-negative persons)  Endpoint: phylogenetically linked transmissions  No linked transmissions recorded in any couple during study period Rodger A, et al. CROI 2014. Abstract 153LB. Reproduced with permission. 0204060 80100 Risk Behaviors, % Vaginal sex with ejaculation Vaginal sex Receptive anal sex Receptive anal sex with ejaculation Only insertive anal sex MSM HT♀ HT♂ 0123 4 Rate of Within-Couple Transmission Events Per 100 CYFU, % (95% CI) HT♀ Vaginal sex with ejaculation (CYFU = 192) HT♂Vaginal sex (CYFU = 272) Receptive anal sex with ejaculation (CYFU = 93) Receptive anal sex without ejaculation (CYFU = 157) Insertive anal sex (CYFU = 262) MSM Estimated rate95% CI

26. clinicaloptions.com/hiv HIV/AIDS Update From Boston 2014 PROMOTE: EFV vs LPV/RTV in HIV+ Pregnant or Breastfeeding Women  PROMOTE: open-label randomized comparison in HIV+ women between 12-28 wks of gestation in Uganda –EFV + ZDV/3TC (n = 195) –LPV/RTV* + ZDV/3TC (n = 194)  Analyses of maternal and infant efficacy and safety, including: –Maternal VL suppression (HIV-1 RNA < 400) at delivery and postpartum Wk 24 –HIV-free infant survival  HIV transmission in 2 LPV/RTV-treated infants (in utero, n = 1; breastfeeding, n = 1)  HIV-free survival: 97.2% in EFV arm vs 92.9% in LPV/RTV arm (P =.1)  Similar grade 3/4 AEs between arms; more nausea and vomiting in LPV/RTV arm Cohan D, et al. CROI 2014. Abstract 69. Reproduced with permission. VL Suppression in HIV+ Women *LPV/RTV dose: 400/100 mg until gestation Wk 30; then 600/150 mg until delivery. EFV LPV/RTV 79 HIV-1 RNA < 400 c/mL (%) 100 80 60 40 20 0 Wk 8 on ARTDeliveryWk 24 PP 70 72 858485 166/ 195 162/ 194 166/ 195 153/ 194 140/ 194 137/ 195 P <.001 n/N =

27. clinicaloptions.com/hiv HIV/AIDS Update From Boston 2014 VOICE: Injectable Contraception and HIV Transmission in South African Women  VOICE (MTN-003): multisite placebo-controlled trial of oral and vaginal TDF, TDF/FTC as PrEP –Failed to show efficacy of PrEP, attributed to low rates of adherence [1]  Comparison of 2 types of contraception and HIV acquisition in South African women [2] –DMPA (depot medroxyprogesterone) vs NET-EN (norethisterone enanthate)  Overall increased risk of HIV acquisition with use of DMPA vs NET-EN –Incidence (per 100 PYs): 7.96 vs 5.36 (adjusted HR: 1.43; 95% CI, 1.04- 1.97, P =.026)  No control group of women not using injectable contraception prevents estimation of overall risk 1. Marrazzo J, et al. CROI 2013. Abstract 26LB. 2. Noguchi L, et al. CROI 2014. Abstract 847.

28. clinicaloptions.com/hiv HIV/AIDS Update From Boston 2014 GSK1265744 Long-Acting Injections and Vaginal and Rectal Exposure in Macaques Vaginal study [1]  GSK1265744 LA 50 mg/kg IM (n = 6 females) vs placebo (n = 6 females) at Wks 0, 4, 8  Biweekly intravaginal challenge with CCR5-tropic SHIV 162p3 through Wk 12 (up to 22 challenges)  GSK1265744 LA–treated animals remained aviremic and seronegative throughout 28 wks of follow-up  Animals protected throughout multiple menstrual cycles Rectal study [2]  Single injection of GSK1265744 LA 50 mg/kg IM (n = 12 males) vs placebo (n = 4 males) 1 wk before first challenge  Weekly intrarectal challenge with CCR5-tropic SHIV 162p3 until infection occurred  1 dose of GSK744 LA delayed infection by 5 to 10 (median: 8) challenges (~2 months)  0/59 challenges resulted in infection when GSK1265744 LA plasma levels > 3 x protein- adjusted IC 90 1. Radzio J, et al. CROI 2014. Abstract 40LB. 2. Andrews CD, et al. CROI 2014. Abstract 39.

29. Comorbidity

30. clinicaloptions.com/hiv HIV/AIDS Update From Boston 2014 D:A:D: Abacavir Remains Associated With Elevated Risk of MI  Update of analysis of ABC and risk of acute MI in pts with low, medium, and high CVD risk  After initial D:A:D report in March 2008, decline in ABC initiations in pts with higher CVD risk Framingham Risk Group ABC Use as Proportion of All ART Initiations, % Before March 2008  Low/unknown CVD risk13.6  Moderate/high CVD risk17.1 After March 2008  Low/unknown CVD risk7.6  Moderate/high CVD risk5.3 Sabin C, et al. CROI 2014. Abstract 747LB. Reproduced with permission. 35 30 25 20 15 10 5 0 Low CVD risk Moderate CVD risk High CVD risk CVD risk unknown Total cohort 2000 200120022003200420052006200720082009201020112012 Patients on ABC by CVD Risk Patients (%)

31. clinicaloptions.com/hiv HIV/AIDS Update From Boston 2014 D:A:D: Current Abacavir Use Associated With 98% Increase in Acute MI Risk  Current ABC use remained associated with increased risk of acute MI –Similar RR in post-3/08 group vs pre-3/08 group, despite decrease in ABC use in pts with high CVD risk –Absolute risk in the post 2008 small: 6 cases /2000 PY vs 3 cases/2000 PY or absolute risk  0.15%  Overall cohort: 941 MI events during 367,599 PYs –0.47/100 PYs (95% CI: 0.42-0.52) with current ABC –0.21 (95% CI: 0.19-0.22) with no current ABC No Current ABC Events/PYs600/295,642425/169,417175/126,225 Rate/100 PYs 0.20 (0.19-0.22) 0.25 (0.23-0.28) 0.14 (0.12-0.16) Current ABC Events/PYs341/71917247/4083394/31084 Rate/100 PYs 0.47 (0.42-0.52) 0.61 (0.53-0.68) 0.30 (0.24-0.36) Sabin C, et al. CROI 2014. Abstract 747LB. Reproduced with permission. 5 4 3 2 1 0.7 Overall Pre-3/08Post-3/08 Adjusted Relative Rate of MI in Pts Currently Receiving ABC 1.98 (1.72-2.29) 1.97 (1.68-2.33) 1.97 (1.43-2.72)

32. clinicaloptions.com/hiv HIV/AIDS Update From Boston 2014 Incidence of MI in HIV+ vs HIV- Subjects in Kaiser Cohort  Retrospective analysis of Kaiser cohort EMRs during 1996-2011 for inpatient MI diagnosis  HIV-/HIV+ pts matched 10:1  MI rates in HIV+ and HIV- converged over time –40% increased risk of MI in HIV+ pts overall, but difference no longer observed in most recent yrs Klein D, et al. CROI 2014. Abstract 737. Reproduced with permission. Framingham Risk Score Components, 2010-11 HIV+HIV- P Value Mean Framingham score, 10-yr risk of MI, % 9.29.6<.001 Male, % 90.790.4.42 Mean age, yrs 47.948.5<.001 TC > 200 mg/dL, % 30.039.6<.001 HDL-C < 40 mg/dL, % 39.426.2<.001 Hx of hypertension, % 28.526.2<.001 Hx of smoking, % 48.734.9<.001 400 300 200 100 0 1996-992000-032004-072008-092010-11 MIs per 100,000 PY HIV+ HIV-

33. clinicaloptions.com/hiv HIV/AIDS Update From Boston 2014 ACTG 5280: High-Dose Vitamin D and Calcium Attenuate Bone Loss in EFV Pts  Randomized, double-blind trial in pts initiating TDF/FTC/EFV with baseline vitamin D 10-75 ng/mL –Vitamin D3 4000 IU/day plus –Calcium carbonate 1000 IU/day  Significant, 50% reduction in loss of hip BMD at Wk 48 in treated pts  Smaller nonsignificant difference in spine BMD in treated pts  Smaller increase in markers of bone turnover in treated pts Overton ET, et al. CROI 2014. Abstract 133. Reproduced with permission. 5 0 -5 -10 -15 Total Hip Lumbar Spine -1.46 -3.19 -1.41 -2.91 P <.001 P =.085 Placebo Decline in BMD From Baseline to Wk 48 Lower and upper edges of box indicate 25th and 75th percentiles; lines inside box indicate median. Change in BMD (%) Vitamin D/calcium

34. clinicaloptions.com/hiv HIV/AIDS Update From Boston 2014 Risk of New Onset Depression in CHARTER Cohort  Longitudinal follow-up of 223 participants in CHARTER cohort taking ART from 2004-2009 –No depression at BL –≥ 3 LPs per subject –2496 person-mos follow-up  Higher incidence of new-onset depression with detectable HIV-1 RNA in CSF  Detectable VL in CSF, but not plasma, at any previous visit associated with 4.7-fold increased risk of new-onset depression Hammond E, et al. CROI 2014. Abstract 33. Incidence of Depression in CHARTER Cohort Incidence/100 Person-Mos All subjects 9.2 CSF HIV-1 RNA  50 c/mL 8.2 CSF HIV-1 RNA > 50 c/mL 19.6

35. clinicaloptions.com/hiv HIV/AIDS Update From Boston 2014 Cumulative Viral Load Predicts Mortality in ART-Treated Patients  Estimated cumulative VL (viremia copy-yrs) assessed in 33,563 pts at 17 sites of ART Cohort Collaboration  After adjusting for age, sex, risk group, BL and time- related VL, and cohort, viremia copy-yrs stratum predicted –All-cause mortality –AIDS-related mortality Mugavero M, et al. CROI 2014. Abstract 565. Reproduced with permission. 2.50 2.25 2.00 1.75 1.50 1.25 1.00 0.75 0.5 0 0-3.0 3.0-3.5 3.5-4.04.0-4.5 4.5-4.754.75-5.05.0-5.255.25-5.55.5-5.75 > 5.75 HR Log 10 Viremia Copy-Yrs Hazard of All-Cause Mortality by Viremia Copy-Yrs Deciles (Controlling for Cross-sectional VL)

36. clinicaloptions.com/hiv HIV/AIDS Update From Boston 2014 Normalization of CD4/CD8 Ratio and Non-AIDS Events in ICONA Cohort  Analysis of 3236 pts with virologic suppression on ART and CD4/CD8 ratio  0.8 –458 pts reached CD4/CD8 ≥ 1 –Median time to normalization: 10.1 yrs –Younger pts, those starting ART in recent yrs, and those with higher CD4+ counts more likely to normalize  Current CD4/CD8 ratio predicted incidence of clinical progression (serious non-AIDS36–related events or all-cause death) –Remained predictive after adjusting for current CD4+ cell count Mussini C, et al. CROI 2014. Abstract 753. Reproduced with permission. Time Probability of CD4/CD8 Normalization (95% CI) 1 yr4.4 (3.7-5.2) 2 yrs11.5 (10.2-13.0) 5 yrs29.4 (26.7-32.4) Current CD4/CD8 Ratio Incidence of Clinical Progression (95% CI) < 0.304.8 (3.9-5.9) 0.30-0.452.4 (1.9-3.1) > 0.452.0 (1.7-2.3)

37. Resistance

38. clinicaloptions.com/hiv HIV/AIDS Update From Boston 2014 Prevalence of Drug Resistance Mutations in Treatment-Naive Patients, 2000-2013  Baseline plasma samples from 4 phase III trials (GS 903, 934, 104, 111) –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.

39. clinicaloptions.com/hiv HIV/AIDS Update From Boston 2014 Bulk vs Sensitive Genotyping for Detection of Transmitted Drug Resistance  Re-examination of 1070 de-identified samples in CDC Variant Atypical Resistance HIV Surveillance database of ART-naive pts in 2009-2011  Use of sensitive testing increased total prevalence of transmitted resistance from 7.9% to 13.6% (P <.0001)  Analysis of 5 mutations as sentinel markers of transmitted resistance 0.8 1.1 Specimens (%) 3.0 2.4 1.8 1.2 0.6 0 K65RY181CM184V 0.3 1.4 0 1.7 2.7 1.4 M41L 10 8 6 4 2 K103N 7.0 8.4 P <.0001 Li J, et al. CROI 2014. Abstract 87. Bulk Sensitive 0 Transmitted Resistance Mutations 1892931512157590 n =

40. New HCV Treatments

41. clinicaloptions.com/hiv HIV/AIDS Update From Boston 2014 PHOTON-1: Sofosbuvir + Ribavirin in GT1-3 HCV Pts Coinfected With HIV  Ongoing, nonrandomized, open-label phase III study  Stable ART (HIV-1 RNA 8 wks before enrollment) –95% on ART: TDF/FTC, 100%: EFV: 35%; ATV/RTV: 17%; DRV/RTV: 15%; RAL: 16% RPV: 6%  10% of pts with cirrhosis  Primary endpoint: SVR12 Naggie S, et al. CROI 2014. Abstract 26. Wk 24 Sofosbuvir + Ribavirin (n = 114) Sofosbuvir + Ribavirin (n = 41) Sofosbuvir + Ribavirin (n = 68) Wk 12 Tx-naive GT1 Tx-naive GT2/3 Tx-expd GT2/3 SVR12, % (n/N) 76 (87/114) GT2: 88 (23/26) GT3: 67 (28/42) GT2: 92 (22/24) GT3: 94 (16/17) Sofosbuvir 400 mg QD; weight-based ribavirin 1000 or 1200 mg/day

42. clinicaloptions.com/hiv HIV/AIDS Update From Boston 2014 SYNERGY: Sofosbuvir/Ledipasvir FDC ± GS-9669 or GS-9451 in GT1 HCV Patients  NIAID nonrandomized, parallel-arm phase II trial –HCV-monoinfected patients –Sofosbuvir (nucleotide polymerase inhibitor) coformulated with ledipasvir (NS5A inhibitor) + either GS-9669 (nonnucleoside polymerase inhibitor) or GS-9451 (PI)  Primary endpoint: SVR12 Tx naive GT1, F0-F4 SOF/LDV FDC + GS-9669 (n = 20) SOF/LDV FDC (n = 20) Tx naive GT1, F0-F3 SOF/LDV FDC + GS-9451 (n = 20) Wk 12 Sofosbuvir/ledipasvir 400/90 mg QD; GS-9669 500 mg QD; GS-9451 80 mg QD. Wk 6 Tx naive GT1, F0-F3 Kohli A, et al. CROI 2014. Abstract 27LB. SVR12, % (n/N) 100 (20/20) 95 (19/20) 100 (20/20)

43. clinicaloptions.com/hiv HIV/AIDS Update From Boston 2014 PEARL-III: ABT-450/RTV/ABT-267 + ABT-333 ± RBV in Noncirrhotic GT1b HCV Pts  Randomized, placebo-controlled phase III study –HCV-monoinfected patients –ABT-450 (RTV-boosted PI) coformulated with ABT-267 (NS5A inhibitor) + ABT-333 (nonnucleoside polymerase inhibitor) + RBV  Primary endpoint: SVR12 Ferenci P, et al. CROI 2014. Abstract 29LB. HCV Tx-naive noncirrhotic pts with GT1b HCV (N = 419) ABT-450/RTV/ABT-267 + ABT-333 + RBV (n = 210) Wk 12 ABT-450/RTV/ABT-267 + ABT-333 (n = 209) ABT-450/RTV/ABT-267 150/100/25 mg QD; ABT-333 250 mg BID; weight-based RBV 1000 or 1200 mg/day SVR12, % (n/) 99.5 (209/210) 99.0 (207/209)

44. References

45. Go Online for More CCO Coverage of the 2014 Retrovirus Meeting! Capsule Summaries of key data Expert Analysis of key studies with expert faculty commentary clinicaloptions.com/boston2014