HIV Update Allegra CPD Day Program Port Elizabeth Dr L E Nojoko

Transcription

1 HIV Update 2014 Allegra CPD Day Program Port Elizabeth Dr L E Nojoko

2 Global estimates for adults and children 2011 People living with HIV 34.0 million [31.4 million 35.9 million] New HIV infections in 2011 Deaths due to AIDS in million [2.2 million 2.8 million] 1.7 million [1.5 million 1.9 million]

3 The Global Picture (2011) On ART: 8 million Number needing ART: 15 million New infections: 2 million People were waiting to become treatment-eligible, sicken, or die: ~24 million Estimated coverage of ART in low- and middle-income countries: 36% Granich R, et al. Curr Opin HIV AIDS. 2013;8:41-49.

4 No Single, Stand-Alone HIV Prevention Intervention Will Halt the HIV Pandemic Over the past 30 years, existing prevention strategies have had limited to no success Education about risks Behavioral interventions to decrease risk Harm reduction Circumcision ART Vaccines

5 Simultaneous Use of Different Classes of Prevention Strategies

6 Potential Therapeutic Targets CCR5 Inhibitors Fusion Inhibitors Cytoplasm Reverse Transcriptase Inhibitors Protease Inhibitors Integrase Inhibitors Nucleus

7 HIV Attachment, Co-receptor Binding, and Fusion Targets for Inhibition CD4 Attachment Co-receptor Binding Virus Cell Fusion CD4 attachment inhibitors gp41 gp120 CCR5 antagonists Fusion inhibitors V3 loop CD4 Cell membrane CCR5 or CXCR4 Adapted from Moore JP, et al. Proc Natl Acad Sci USA 2003;100:

8 When to Start Treatment Clinical Category AIDS-defining illness or severe symptoms CD4 Count (cells/mm 3 ) HIV RNA (copies/ml) 2/2013 DHHS Guidelines Any value Any value Treat 2012 IAS-USA Guidelines Asymptomatic <500 Any value Treat >500 Any value Treat Pregnant women Any value Any value Treat HIV-associated nephropathy Any value Any value Treat HIV/HBV coinfection when HBV treatment is indicated Any value Any value Treat The IAS-USA guidelines also recommends initiating antiretroviral therapy in HIV-infected patients with active hepatitis C virus infection, active or high risk for cardiovascular disease, and symptomatic primary HIV infection. DHHS. Available at: Revision February 12, 2013; Thompson MA, et al. JAMA. 2012;308:

9 CIPRA HT 001

10 Early versus Standard Antiretroviral Therapy for HIV-Infected Adults in Haiti with a CD4 Count of cells/mm 3 Study Features N = 816 persons enrolled 18 years of age or older Randomized, open label, controlled Conducted in Haiti Antiretroviral naïve CD4 count: cells/mm 3 HIV RNA > 10,000 copies/ml Absence of AIDS diagnosis Early-Treatment Group (initiated *antiretroviral therapy within 2 weeks after enrollment) (n = 408) Standard-Treatment Group (initiated *antiretroviral therapy when single CD4 < 200 cells/mm 3 or when AIDS-defining illness) (n = 408) *Antiretroviral therapy = zidovudine + lamivudine + efavirenz Source: Severe P, et al. N Eng J Med 2010; 363:

11 Probability of Survival Early versus Standard Antiretroviral Therapy for HIV-Infected Adults in Haiti with a CD4 T cell count of cells/mm 3 Kaplan Meier Estimates of Survival in Treatment Groups 1.00 Early antiretroviral treatment P=0.001 Standard antiretroviral treatment No. at Risk Early treatment 408 Standard treatment Source: Severe P, et al. N Eng J Med 2010; 363: Months

12 ANTIRETROVIRAL THERAPY Strategic Timing of Antiretroviral Therapy (START) Randomized Controlled Trial: INSIGHT* START 001 Study Features CD4 count >500 cells/mm 3 N = 4,000 planned persons enrolled N = 900 for pilot phase Age 18 years of age or older Randomized, open label, controlled Antiretroviral naïve Absence of AIDS diagnosis Setting: 22 countries Early Antiretroviral Therapy (initiate antiretroviral therapy immediately after enrollment) Deferred Antiretroviral Therapy (initiate antiretroviral therapy when two values of CD4 < 350 cells/mm 3 or AIDS develops) *INSIGHT = International Network for Strategic Initiatives in Global HIV Trials Source:

13 Newer ART regimens The Shift Towards Earlier Initiation of Antiretroviral Therapy - Generally better tolerated, more convenient, and more potent than older regimens Survival benefit - Randomized controlled trials - Observational cohort data Untreated HIV - Maybe associated with the development of non-aids-defining illness Biologic rationale Effective ART reduces HIV transmission

14 Summary and Implications New ARV Guidelines Recommendations for earlier initiation Guideline have major influence on clinical practice

15 DHHS and IAS-USA Guidelines: What to Start DHHS Preferred Regimens [1] IAS-USA Recommended Regimens [2] NNRTI Boosted PI EFV/TDF/FTC ATV/RTV + TDF/FTC DRV/RTV + TDF/FTC EFV/TDF/FTC or EFV + ABC/3TC* INSTI RAL + TDF/FTC RAL + TDF/FTC ATV/RTV + (TDF/FTC or ABC/3TC* ) DRV/RTV + TDF/FTC DHHS Alternative Regimens [1] IAS-USA Alternative Regimens [2] NNRTI Boosted PI based INSTI based EFV + ABC/3TC* RPV/TDF/FTC or RPV + ABC/3TC* ATV/RTV + ABC/3TC DRV/RTV + ABC/3TC FPV/RTV + (TDF/FTC or ABC/3TC) LPV/RTV + (TDF/FTC or ABC/3TC ) RAL + ABC/3TC* EVG/COBI/TDF/FTC NVP + (TDF/FTC or ABC/3TC* ) RPV/TDF/FTC or RPV + ABC/3TC* DRV/RTV + ABC/3TC LPV/RTV + (TDF/FTC or ABC/3TC* ) RAL + ABC/3TC* EVG/COBI/TDF/FTC *In HLA-B*5701 negative patients with baseline HIV-1 RNA < 100,000 copies/ml. Avoiding the use of ABC or LPV/RTV might be considered for patients with or at high risk of cardiovascular disease. 1. DHHS Guidelines. February Thompson MA, et al. JAMA. 2012;308:

16 DHHS Guidelines: October 2013 Update on Integrase Inhibitors NNRTI Boosted PI INSTI Preferred Regimens EFV/TDF/FTC ATV/RTV + TDF/FTC DRV/RTV + TDF/FTC RAL + TDF/FTC EVG/COBI/TDF/FTC DTG + ABC/3TC DTG + TDF/FTC Alternative Regimens EFV + ABC/3TC RPV/TDF/FTC or RPV + ABC/3TC ATV/RTV + ABC/3TC DRV/RTV + ABC/3TC FPV/RTV + (TDF/FTC or ABC/3TC) LPV/RTV + (TDF/FTC or ABC/3TC) RAL + ABC/3TC All 3 integrase inhibitors are now part of preferred first-line regimens DHHS Guidelines, February DHHS Recommendation on INSTIs, October 2013.

17 2013 Update: EACS Guidelines for Treatment of HIV-Infected Pts in Europe Recommendation for ART initiation remains at CD4+ cell counts < 350 cells/mm 3 ART can be considered at higher CD4+ counts, depending on patient readiness Guideline AIDS or HIV-Related Symptoms CD4+ Cell Count < > 500 EACS [1] Yes Yes Consider Consider US DHHS [2] Yes Yes Yes Yes IAS-USA [3] Yes Yes Yes Yes WHO [4] Yes Yes Yes Not addressed* *ART may be recommended for the HIV+ partner in serodiscordant couples as prevention of transmission. 1. EACS Guidelines, February DHHS Guidelines, February IAS-USA Guidelines, July WHO ART Guidelines, June 2013.

18 Factors to Consider in Choosing First-line Therapy Patient s willingness to commit to therapy/concerns regarding adherence Baseline characteristics (eg, CD4+ cell count, HIV-1 RNA, resistance) Efficacy data Tolerability Convenience Drug drug or drug food interactions Comorbid conditions (eg, HBV, CV risk, renal, bone) Consequences of failure (resistance) Since the introduction of potent ARV therapy, preferred regimens all include 2 NRTIs + third drug

19 Readiness for Therapy: A Key Decision Point Potential options PI-based therapy: lower risk of resistance at treatment failure with boosted PIs vs NNRTI- and RAL-based strategies Simple regimen (1 pill, once daily): adherence more likely Regimens to avoid Complicated regimens: frequent dosing, food requirements Regimens with more adverse events: may affect adherence Regimens with higher risk of resistance at failure

20 Selection of NRTIs for First-line Therapy

21 ACTG 5202: First-line Therapy With ABC/3TC vs TDF/FTC + EFV vs ATV/RTV Stratified by HIV-1 RNA < or 100,000 copies/ml Wk 96 TDF/FTC* 300/200 mg QD + EFV 600 mg QD (n = 464) Antiretroviral-naive patients with HIV-1 RNA 1000 copies/ml and any CD4+ cell count (N = 1857) *Double blind. Open label. ABC/3TC* 600/300 mg QD + EFV 600 mg QD (n = 465) TDF/FTC* 300/200 QD + ATV/RTV 300/100 mg QD (n = 465) ABC/3TC* 600/300 mg QD + ATV/RTV 300/100 mg QD (n = 463) Sax PE, et al. N Engl J Med. 2009;361: Daar ES, et al. Ann Intern Med. 2011;154:

22 Probability of No Virologic Failure (%) A5202: Time to Virologic Failure in Patients With HIV-1 RNA 100,000 c/ml HR: 2.33 (95% CI: ; P <.001, log-rank test) TDF/FTC (26 events) ABC/3TC (57 events) Pts at Risk, n ABC/3TC TDF/FTC Sax PE, et al. N Engl J Med. 2009;361: Wks Since Randomization

23 Probability (Remaining Free of Virologic Failure) A5202: Time to Virologic Failure in Patients With HIV-1 RNA < 100,000 c/ml EFV + TDF/FTC (33 events) EFV + ABC/3TC (39 events) ATV/RTV + TDF/FTC (29 events) ATV/RTV + ABC/3TC (35 events) Pts at Risk, n EFV + TDF/FTC EFV + ABC/3TC ATV/RTV + TDF/FTC ATV/RTV + ABC/3TC Wks From Randomization Sax PE, et al. J Infect Dis. 2011:204;

24 HIV-1 RNA < 50 c/ml at Wk 48 (%) SINGLE Study: First-line Therapy With Dolutegravir/ABC/3TC vs EFV/TDF/FTC Difference (%): +7.4 (+2.5, +12.3; P =.003) DTG noninferior and superior to EFV at Wk 48 primary efficacy endpoint Time to HIV-1 RNA < 50 copies/ml days with DTG vs 84 days with EFV (P <.0001) 20 0 DTG 50 mg + ABC/3TC QD (n = 414) EFV/TDF/ FTC QD (n = 419) CD4+ cell change +267 with DTG vs +208 with EFV (P <.001) Walmsley S, et al. ICAAC Abstract H-556b.

25 Dolutegravir Effective With ABC/3TC or TDF/FTC, Regardless of BL HIV-1 RNA HIV-1 RNA < 50 c/ml at Wk 48 by Subgroup (FDA Snapshot Analysis), % BL HIV-1 RNA 100,000 c/ml ABC/3TC TDF/FTC BL HIV-1 RNA > 100,000 c/ml ABC/3TC TDF/FTC DTG + NRTIs SPRING-2 RAL + NRTIs DTG + ABC/3TC SINGLE EFV/TDF/ FTC DTG well tolerated with similar renal safety with either ABC/3TC or TDF/FTC Eron J, et al. Glasgow Abstract P204.

26 Concerns Regarding NRTIs ABC TDF Decreased potency compared with TDF in those with high HIV-1 RNA levels (> 100,000 copies/ml) when combined with EFV and ATV + RTV Variable results regarding relationship with CV events Avoid in patients with positive HLA-B*5701 test Associated with greater decline in bone mineral density than ABC Associated with variable decline in renal function compared with other NRTIs

27 Selecting the Third Drug in a First-line Regimen

28 What s Available as Fixed-Dose Combinations, and What s Coming? Available Now Efavirenz/tenofovir DF/ emtricitabine Rilpivirine/tenofovir DF/ emtricitabine Elvitegravir/cobicistat/ tenofovir DF/emtricitabine Future Options Darunavir/cobicistat Darunavir/cobicistat/ emtricitabine/tenofovir alafenamide (GS- 7340) Atazanavir/cobicistat Dolutegravir/abacavir/ lamivudine Dolutegravir will be initially available as single tablet, not fixed-

29 HIV-1 RNA < 50 c/ml (%) HIV-1 RNA < 50 c/ml (%) Efficacy Comparison of Boosted PIs 100 ARTEMIS [1] (ITT, TLOVR) 96 Wks 100 CASTLE [2] (ITT, NC = F) 96 Wks LPV/RTV 800/200 QD or BID 343 DRV/RTV 800/100 QD 1. Mills A, et al. AIDS. 2009;23: Molina JM, et al. J Acquir Immune Defic Syndr. 2010;53: LPV/RTV 400/100 BID ATV/RTV 300/100 QD

30 Probability (Remaining Free of Virologic Failure) A5202: Efficacy With ATV/RTV vs EFV Pts at Risk, n 0 EFV + TDF/FTC EFV + ABC/3TC ATV/RTV + TDF/FTC ATV/RTV + ABC/3TC EFV + TDF/FTC (57 events) EFV + ABC/3TC (72 events) ATV/RTV + TDF/FTC (57 events) ATV/RTV + ABC/3TC (83 events) Wks From Randomization Daar ES, et al. Ann Intern Med. 2011;154: Sax PE, et al. J Infect Dis. 2011;204:

31 HIV-1 RNA < 50 c/ml (%) STARTMRK: Efficacy of RAL vs EFV RAL is BID vs QD (EFV) but fewer adverse events (52% vs 80%) CD4+ gain: ITT, NC = F Pts at Risk, n RAL 400 mg BID EFV 600 mg QHS Wks Rockstroh JK, et al. J Acquir Immune Dis Syndr. 2013;63:77-85.

32 ECHO and THRIVE: HIV-1 RNA < 50 c/ml With EFV vs RPV ECHO Wk 48 Wk 96 Favors EFV -3.2% -0.4% Favors RPV P =.0055 P <.0001 THRIVE Wk 48 Wk % 2.4% P <.0001 P <.0001 Pooled Wk % P <.0001 ITT-TLOVR Percent Difference (Noninferiority at 12% Margin) Cohen CJ, et al. AIDS. 2013;27: Molina JM, et al. Lancet. 2011;378: Cohen CJ, et al. Lancet. 2011;378: All patients received TDF/FTC.

33 Investigational Rilpivirine (formerly TMC-278) Rilpivirine-3D Structure NNRTI compound with potent activity Once daily dose: 25 mg Planned co-formulation with Tenofovir-Emtricitabine Less CNS disturbances than efavirenz and non-teratogenic From: Azijn H, et al. AAC. 2010:54; Active against most nevirapine and efavirenz-resistant clinical isolates Unfavorable interactions with acid suppressant medications From: Garvey L, et al. Expert Opin Investig Drugs. 2009;18:

34 Investigational Rilpivirine (TMC-278) vs. Efavirenz in ARV-Naive ECHO and THRIVE: Results 48 Week Data: Virologic Response ( ITT-TLOVR) All regimens included 2 NRTIs Source: Cohen C, et al. 17 th International AIDS Conference. 2010:THLBB206.

35 Investigational Rilpivirine (TMC-278) vs. Efavirenz in ARV-Naive ECHO and THRIVE: Results 48 Week Data: Virologic Failure All regimens included 2 NRTIs Source: Cohen C, et al. 17 th International AIDS Conference. 2010:THLBB206.

36 Investigational Rilpivirine (TMC-278) vs. Efavirenz in ARV-Naive ECHO and THRIVE: Results 48 Week Data: Discontinuation Due to Adverse Effects All regimens included 2 NRTIs Source: Cohen C, et al. 17 th International AIDS Conference. 2010:THLBB206.

37 Summary and Implications Rilpivirine ECHO and Thrive Studies Overall similar results as efavirenz Well-tolerated, convenient NNRTI Unexpected higher virologic failure rate than with efavirenz

38 RPV/TDF/FTC Indications [1] RPV/TDF/FTC DHHS guidelines 2013 [2] RPV is not recommended in patients with pretreatment HIV-1 RNA > 100,000 copies/ml Higher rate of virologic failures reported in patients with pre-art CD4+ count < 200 cells/mm 3 who were treated with RPV + 2 NRTIs 1. RPV/TDF/FTC [package insert]. June DHHS Guidelines. February 2013.

39 What s Available as Fixed-Dose Combinations, and What s Coming? Available Now Efavirenz/tenofovir DF/ emtricitabine Rilpivirine/tenofovir DF/ emtricitabine Elvitegravir/cobicistat/ tenofovir DF/emtricitabine Future Options Darunavir/cobicistat Darunavir/cobicistat/ emtricitabine/tenofovir alafenamide (GS-7340) Atazanavir/cobicistat Dolutegravir/abacavir/ lamivudine Dolutegravir will be initially available as single tablet, not fixed-dose combination

40 Quad Pill Tenofovir + Emtricitabine + Cobicistat + Elvitegravir Booster INSTI

41 Cobicistat: A New Boosting Agent Small molecule with no HIV activity No concern of drug resistance in pts with suboptimal virologic response Similar from BL in fasting TC and TGs compared with RTV when boosting same agent [1] Inhibitor of CYP3A4; many drug drug interactions [2,3] Modest, rapid increase in serum Cr due to inhibition of tubular secretion [3] Not associated with any change in actual GFR Other drugs (including ARVs) have similar effect [4,5] Availability of cobicistat has allowed for development of new coformulated agents and regimens 1. Gallant JE, et al. J Infect Dis. 2013;208: DHHS Guidelines February TDF/FTC/EVG/COBI [package insert]. 4. RPV [package insert]. 5. DTG [package insert].

42 Study 102: QUAD Versus Efavirenz/Emtricitabine/Tenofovir DF Single-Tablet, Once-Daily Regimens Phase 3 study (192 weeks) Treatment-naïve Double-blind HIV RNA >5000 copies/ml Any CD4 count Non-inferiority (12% margin) Randomization 1:1 Elvitegravir 150 mg/cobicistat 150 mg/ Emtricitabine/Tenofovir DF (n=348) Efavirenz 600 mg/ Emtricitabine/Tenofovir DF (n=352) Primary Endpoint Week 48 HIV RNA <50 Copies/mL Sax PE, et al. Lancet. 2012;379: Zolopa A, et al. J Int AIDS Soc. 2012;15(suppl 4): Abstract O424a.

43 Patients (%) CD4 Gain (cells/mm 3 ) Study 102: Virologic and Immunologic Outcomes HIV RNA <50 Copies/mL CD4 Cell Gain EVG/COBI/FTC/TDF EFV/FTC/TDF EVG/COBI/FTC/TDF EFV/FTC/TDF Difference (%): 3.6 (-1.6, 8.8) 88% 84% Difference (%): 2.7 (-2.9, 8.3) 84% 82% 239* (n=348/352) Week 96 (n=348/352) *P= (n=325/315) Week Sax PE, et al. Lancet. 2012;379: Zolopa A, et al. J Int AIDS Soc. 2012;15(suppl 4): Abstract O424a. 96 (n=307/302)

44 Patients (%) Patients (%) Study 102: Virologic Outcomes by Baseline HIV RNA Baseline HIV RNA <100K Copies/mL Baseline HIV RNA >100K Copies/mL EVG/COBI/FTC/TDF EFV/FTC/TDF EVG/COBI/FTC/TDF EFV/FTC/TDF 90% 85% 86% 81% 84% 82% 81% 83% 48 (n=348/352) Week 96 (n=230/236) Sax PE, et al. Lancet. 2012;379: Zolopa A, et al. J Int AIDS Soc. 2012;15(suppl 4): Abstract O424a. 48 (n=348/352) Week 96 (n=230/236)

45 Study 103: QUAD Versus Atazanavir/r + Emtricitabine/Tenofovir DF Once-Daily Regimens Phase 3 study (192 weeks) Treatment-naïve Double-blind HIV RNA >5000 copies/ml Any CD4 count Non-inferiority (12% margin) Randomization 1:1 Elvitegravir/Cobicistat/ Emtricitabine/Tenofovir DF (n=353) Atazanavir/r + Emtricitabine/Tenofovir DF (n=355) Primary Endpoint Week 48 HIV RNA <50 Copies/mL DeJesus E, et al. Lancet. 2012;379: Rockstroh J, et al. J Int AIDS Soc. 2012;15(suppl 4): Abstract O424b.

46 Elvitegravir/Cobicistat vs EFV or ATV/RTV + TDF/FTC in Treatment-Naive Pts Randomized, double-blind, active-controlled phase III studies Primary endpoint: HIV-1 RNA < 50 copies/ml at Wk 48 Study 102 [1] (N = 700) Treatment naive HIV-1 RNA 5000 copies/ml Any CD4+ cell count Susceptible to TDF, FTC, and EFV, or ATV egfr 70 ml/min Study 103 [2] (N = 708) EVG/COBI/TDF/FTC QD (n = 348) EFV/FTC/TDF QD (n = 352) EVG/COBI/TDF/FTC QD (n = 353) ATV/RTV + TDF/FTC QD (n = 355) 1. Sax P, et al. Lancet. 2012;379: DeJesus E, et al. Lancet. 2012;379:

47 Patients (%) EVG/COBI/TDF/FTC Noninferior to EFV/TDF/FTC Through Wk EVG/COBI/TDF/FTC (n = 348) EFV/TDF/FTC (n = 352) 95% CI for Difference Favors EFV Favors EVG/COBI Wk Wk Wk Wk Wk Wk Wk Wk Wk Virologic Success* Virologic Failure No Data *HIV-1 RNA < 50 c/ml as defined by FDA Snapshot algorithm. Discontinued for AE, death, or missing data. Wk 48 [1] Wk 96 [2] Wk 144 [3] 3.6% -1.6% 2.7% -2.9% 4.9% 8.8% -1.3% 11.1% -12% 12% 0 1. Sax PE, et al. Lancet. 2012;379: Zolopa A, et al. J Acquir Immune Defic Syndr. 2013;63: Wohl D, et al. ICAAC Abstract H-672a. Graphic reproduced with permission.

48 Considerations for Patients Without Other Medical Concerns Adherence Patient preference (ie, simple regimen) Efficacy Baseline HIV-1 RNA > 100,000 copies/ml Use abacavir with caution Rilpivirine not recommended Concerns about specific adverse events

49 Switch Strategy

50 Mean Concentration (ng/ml) Switching From EFV/TDF/FTC to RPV/TDF/FTC in Suppressed Patients Single-arm study of 50 patients virologically suppressed on EFV/TDF/FTC as first regimen for 3 mos No known resistance mutations to study meds Desiring to switch for intolerance of regimen 100% maintained HIV-1 RNA < 50 c/ml at Wk 12 after switch to RPV/TDF/FTC (primary endpoint) No events leading to discontinuation after switch RPV mean C trough within target range by 2 wks Plasma Concentrations of RPV (C trough ) or EFV (Any Time) EFV concentration RPV C trough RPV mean C trough in ECHO/THRIVE Mills A, et al. ICAAC Abstract H2-794c. Wks After Switch

51 TAF (tenofovir alafenamide)

52 48-Wk Results of TAF vs Tenofovir DF in ART- Naive Pts TAF (GS-7340), investigational prodrug of tenofovir with lower TFV plasma concentrations, increased delivery to hepatocytes, lymphoid cells Randomized, placebo-controlled, phase II trial of TAF vs TDF, each coformulated with FTC/EVG/COBI, in ART-naive patients Gut TFV TDF TAF Plasma TDF/TFV TAF Lymphoid Cells TAF Cathepsin A TFV TFV-MP ART-naive patients, CD4+ cell count > 50 cells/mm 3, egfr 70 ml/min (N = 170) Wk 24 TAF/FTC/EVG/COBI (n = 112) TDF/FTC/EVG/COBI (n = 58) Wk 48 TFV-DP Zolopa A, et al. CROI Abstract 99LB. Sax P, et al. ICAAC Abstract H-1464d. Reproduced with permission.

53 Patients (%) TAF/FTC/EVG/COBI Noninferior to TDF/FTC/EVG/COBI Through Wk Δ 1.0% (95% CI: to +10.0; P =.84) n = Virologic Success* 6.3 TAF/FTC/EVG/COBI TDF/FTC/EVG/COBI Virologic Nonresponse No Data *HIV-1 RNA < 50 c/ml as defined by FDA Snapshot algorithm. Discontinued for AE, death, or missing data. Noninferiority at Wk 24 primary endpoint analysis [1] 89.7% vs 87.5 % with HIV- 1 RNA < 50 c/ml, respectively 6 pts (3 per arm) eligible for resistance analysis at Wk 48 [2] No pts with resistance in TAF arm 1 pt with NRTI and INSTI resistance in TDF arm (M184V, E92Q) 1. Zolopa A, et al. CROI Abstract 99LB. 2. Sax P, et al. ICAAC Abstract H-1464d.

54 Median (Q1, Q3) Change in BMD Median (Q1, Q0) Change in BMD Change in egfr and BMD With TAF vs TDF at Wk 48 Patients on TAF had smaller decrease in egfr 2 TAF/FTC/EVG/COBI (n = 112) TDF/DTC/EVG/COBI (n = 58) -5.5 vs ml/min with TDF (P =.041) No renal discontinuations and no tubulopathy in either arm Less change in renal tubular proteins with TAF Spine P <.001 Smaller change in both spine and hip BMD (by DXA) over 48 wks with TAF vs TDF Sax P, et al. ICAAC Abstract H-1464d. Reproduced with permission Hip Wks P <.001

55 HIV Entry DHS/P P

56

57 CD4 Co-receptors: CCR5 and CXCR4

58 Clinical Trials Tx-naïve (MERIT Trial) Tx-experience (MOTIVATE I-II)

59 FDA Approves First Drug for Reducing the Risk of Sexually Acquired HIV Infection (July 16, 2012) Available at:

60 CDC Interim Guidance for Healthcare Providers: Beginning PrEP Medication Regimen Prescribe emtricitabine/tenofovir DF (200/300 mg) 1 tablet daily In general, prescribe no more than a 90-day supply Renew only after confirming patient remains HIV uninfected If HBV infected Consider emtricitabine/tenofovir DF for HBV and HIV prevention Provide risk-reduction and PrEP medication adherence counseling and condoms CDC. MMWR Morb Mortal Wkly Rep. 2011;60: CDC. MMWR Morb Mortal Wkly Rep. 2012;61:

61 CDC Interim Guidance for Healthcare Providers: Follow-Up While on PrEP Evaluate and support PrEP medication adherence at each follow-up visit (more often if needed) For women, conduct pregnancy test Every 2 to 3 months HIV antibody test (document negative result) Assess Risk behaviors and provide risk-reduction counseling and condoms STI symptoms (if present, test and treat as needed) Every 6 months Test for STI regardless of symptomatology (treat as needed) Every 3 months after initiation, then yearly while on PrEP Blood urea nitrogen Serum creatinine CDC. MMWR Morb Mortal Wkly Rep. 2011;60: CDC. MMWR Morb Mortal Wkly Rep. 2012;61:

62 Conclusions Currently many simple and easy-to-administer Co-formulations of first-line antiretroviral regimens The decision as to which regimen to select first is based upon efficacy, safety, Cost, and select characteristics Adherence Virologic characteristic (eg, baseline HIV-1 RNA, drug resistance) Comorbid conditions Cobicistat new pharmacologic booster Effective in increasing exposure of these drugs with no HIV activity However, effects on serum creatinine and need for renal monitoring important for use with this drug