1. Joe Eron UNC School of Medicine What’s New in Antiretroviral Therapy??

2. DHHS Guidelines, March 2012: What to Start Preferred Regimens NNRTI based  EFV/TDF/FTC Boosted PI based  ATV/r + TDF/FTC  DRV/r + TDF/FTC INSTI based  RAL + TDF/FTC Alternative Regimens NNRTI based  EFV + ABC/3TC  RPV/TDF/FTC or RPV + ABC/3TC Boosted PI based  ATV/r + ABC/3TC  DRV/r + ABC/3TC  FPV/r + (ABC/3TC or TDF/FTC)  LPV/r + (ABC/3TC or TDF/FTC) INSTI based  RAL + ABC/3TC DHHS Guidelines for Antiretroviral Therapy in Adults and Adolescents. March 27, 2012

3. IAS-USA Guidelines, July 2012: What to Start Recommended Regimens NNRTI based  EFV/TDF/FTC or EFV + ABC/3TC*  Boosted PI based  ATV/r + (TDF/FTC or ABC/3TC*  )  DRV/r + TDF/FTC INSTI based  RAL + TDF/FTC Alternative Regimens ‡ NNRTI based  NVP + (TDF/FTC or ABC/3TC*  )  RPV/TDF/FTC or RPV + ABC/3TC*  Boosted PI based  DRV/r + ABC/3TC  LPV/r  + (TDF/FTC or ABC/3TC*  ) INSTI based  RAL + ABC/3TC*   EVG/COBI/TDF/FTC Thompson MA, et al. JAMA. 2012;308:387-402 *HLA-B*5701 screening recommended before ABC administration to reduce risk of HSR..  Consider avoiding use of ABC or LPV/r for pts with or at high risk of CV disease. ‡ ZDV/3TC is alternative NRTI component of NNRTI-, PI/r-, and RAL-based regimens, but toxicity profile of ZDV reduces its utility.

4. RPV + TDF/FTC (n = 346) EFV + TDF/FTC (n = 344) *THRIVE only. † Selected by investigator from ABC/3TC, TDF/FTC, ZDV/3TC. Stratification by BL VL < 100,000 vs ≥ 100,000, NRTI use* Wk 96 final analysis Wk 48 primary analysis RPV 25 mg QD + 2 NRTIs † (n = 340) EFV + 2 NRTIs † (n = 338) ECHO, THRIVE: Rilpivirine vs EFV in ART-Naïve Patients Randomized, double-blind phase III trials Cohen C, et al. J Acquir Immune Defic Syndr. 2012 ECHO (N = 690) THRIVE (N = 678) Treatment-naive, VL ≥ 5000 no NNRTI RAMs, susceptible to NRTIs

5. ECHO, THRIVE: Rilpivirine vs EFV in ART-Naïve Patients : Viral Load <50, 96 Week ITT-TLOVR Data RPV 25mg qd (N=686) RPV Cohen C, et al. J Acquir Immune Defic Syndr. 2012

6. ECHO/THRIVE: RPV vs EFV: 96 Week Results by Baseline VL ≤100K >100K 75 8480 4.0 (–1.7, 9.7) -5.2 (-12, 1.5) 70 RPV Responders Discontinued due to other reasons † VF eff Discontinued due to AE/death EFV Non responders RPV: More virologic failures and NNRTI/NRTI resistance; cross-resistance with ETR (138K mutation) EFV: More adverse effects (rash, CNS side effects), greater increase in lipids RPV: More virologic failures and NNRTI/NRTI resistance; cross-resistance with ETR (138K mutation) EFV: More adverse effects (rash, CNS side effects), greater increase in lipids Cohen C, et al. J Acquir Immune Defic Syndr. 2012

7. Switching From TDF/FTC/EFV to TDF/FTC/RPV in Suppressed Pts Single-arm study of 50 pts virologically suppressed on TDF/FTC/EFV as first regimen for ≥ 3 mos –No known resistance mutations to study meds –Desiring to switch to TDF/FTC/RPV for intolerance of regimen 100% maintained VL < 50 at Wk 12 after switch (1 o endpoint) No events leading to discontinuation after switch RPV mean C trough within target range by 2 weeks Mills A, et al. ICAAC 2011. Abstract H2-794c. Plasma Concentrations of RPV (C trough ) or EFV (any time) Mean Concentration (ng/mL) Weeks After Switch 2000 1600 1200 800 400 120 80 40 0 024681012 EFV concentration RPV C trough RPV mean C trough in ECHO/THRIVE

8. Multicenter, randomized, open-label switch study –1 o endpoint: maintenance of VL < 50 c/mL at Wk 24 (FDA snapshot analysis) Pts with VL < 50 on stable PI/r + 2 NRTIs for ≥ 6 mos, no previous NNRTI use (N = 476) RPV/TDF/FTC (n = 317) PI/r* + 2 NRTIs (n = 159) Wk 48 Randomized 2:1 Wk 24 Primary endpoint (n = 159) RPV/TDF/FTC SPIRIT: Switch to RPV/TDF/FTC From Boosted-PI Regimens in Suppressed Pts Palella F, et al. AIDS 2012. Abstract TUAB0104. *PIs: ATV/r, 37%; LPV/r, 33%; DRV/r, 20%; FPV/r, 8%; SQV/r, 2%.

9. SPIRIT: Switch to RPV/TDF/FTC From Boosted-PI Regimens in Suppressed Pts Switch to RPV/TDF/FTC noninferior to maintaining boosted-PI regimen at Wk 24 –93.7% vs 89.9% with VL < 50 –Noninferior regardless of pretreatment VL stratum 17/17 with baseline K103N maintained suppression after switch Sig. reductions in TC, LDL, TG, HDL, TC:HDL ratio (P <.001) and in 10-yr Framingham score (P =.001) at Wk 24 with switch VL< 50 at Wk 24 RPV/TDF/FTCBoosted PI 40 0 100 20 80 89.2 95.0 60 83/ 93 152/ 160 n = ≥ 100K Pts With VL < 50 c/mL (%) 92.3 95.5 128/ 134 48/ 52 < 100K 89.9 93.7 Overall Δ 3.8% (-1.6 to 9.1) Δ 3.2% (-4.8 to 11.3) Δ 5.9% (-1.4 to 12.9) *Excludes 23 RPV and 14 boosted PI pts lacking baseline VL while ARV naive. Palella F, et al. AIDS 2012. Abstract TUAB0104. 317159 Baseline VL (When Naive)*

10. GS 102: TDF/FTC/EVG/COBI (“Quad”) vs. TDF/FTC/EFV: Study Design ART- naive Any CD4 count (N = 700 planned) Quad QD EFV/FTC/TDF QHS Placebo EFV/FTC/TDF QHS Quad Placebo QD Randomized 1:1 Stratification by VL (>100,000) Conducted in US n=350 1 o Endpoint: Proportion with VL< 50 at Week 48 –FDA snapshot analysis (ITT), 12% noninferiority margin Week 48 Week 192 Sax P, et al. CROI 2012

11. GS 103: TDF/FTC/EVG/COBI (“Quad”) vs. TDF/FTC + ATV/r: Study Design ART naive (N = 700 planned) Quad QD ATV/r + FTC/TDF Placebo QD ATV/r + FTC/TDF QD Quad Placebo QD International Randomized 1:1 Stratification by VL (>100,000) (n=350) 1 o Endpoint: Proportion with VL < 50 at Week 48 –FDA snapshot analysis, 12% non-inferiority margin Week 48 Week 192 DeJesus E, et al. CROI 2012

12. GS 102: “Quad” vs. TDF/FTC/EFV 1 o Endpoint: VL <50 at 48 weeks Quad non-inferior to EFV/FTC/TDF at Week 48 95% CI for Difference 12% -1.68.8 Favors EFV/FTC/TDF 3.6 Favors Quad 0 -12% Sax P, et al. CROI 2012

13. GS 103: “Quad” vs. TDF/FTC + ATV/r 1 o Endpoint: VL < 50 at 48 weeks QUAD non-inferior to ATV/r + FTC/TDF 95% CI for Difference 12% -1.97.8 Favors ATV/r + FTC/TDF 3.0 Favors Quad 0 -12% DeJesus E, et al. CROI 2012

14. GS 102: “Quad” vs. TDF/FTC/EFV Drug resistance through week 48 Quad (n=348) EFV/FTC/TDF (n=352) Subjects Analyzed for Resistance*, n (%)14 (4)17 (5) Subjects with Resistance to ARV Regimen, n (%)8 (2) Any Primary Integrase-R, n7 E92Q7 T66I1 Q148R1 N155H1 Any Primary NNRTI-R n 8 K103N7 V108I2 Y188Y/F/H/L1 G190A1 Any Primary NRTI-R, n82 M184V/I82 K65R32 *Subjects who experienced either suboptimal virologic response (two consecutive visits with HIV-1 RNA ≥50 c/mL and 1 log 10 increase from nadir), or had HIV-1 RNA ≥400 c/mL at their last visit. Sax P, et al. CROI 2012

15. GS 103: “Quad” vs. TDF/FTC + ATV/r: Drug resistance through week 48 Quad (n=353) ATV/r + FTC/TDF (n=355) Subjects Analyzed for Resistance a, n (%)12 (3)8 (2) Subjects with Resistance to ARV Regimen, n (%)5 (1)0 Any Primary Integrase-R, n4- E92Q1- T66I1- Q148R2- N155H2- Any Primary PI-R, n-0 Any Primary NRTI-R, n40 M184V/I4 K65R1 DeJesus E, et al. CROI 2012

16. GS 102: “Quad” vs. TDF/FTC/EFV Median Change in Serum Creatinine Median change at Week 48: 0.14 mg/dL vs. 0.01 mg/dL (Quad vs. EFV/FTC/TDF group, p<0.001) Quad (n=): 348341345345337335328323320320 EFV/FTC/TDF (n=):352340340336327323317313309307 BL248121624324048 0.35 0.30 0.25 0.20 0.15 0.10 0.05 0.00 -0.05 -0.10 Change from BL in Serum Creatinine (mg/dL) (IQR) Week Sax P, et al. CROI 2012

17. “Quad” Conclusions Non-inferior to TDF/FTC/EFV and TDF/FTC + ATV/r, overall and at all CD4 and VL strata More nausea than EFV; same as ATV/r Less CNS effects than EFV; less jaundice than ATV/r Better lipid profiles than comparators (esp. TG) Better CD4 response than EFV; more rapid VL response than comparators Cobicistat increases serum creatinine by ~0.12-0.14 mg/dL due to inhibition of creatinine excretion –Quad not recommended if creatinine clearance <70 –Discontinue if creatinine clearance <50

18. GS 114: Cobicistat-Boosted vs RTV- Boosted ATV in ART-Naïve Patients Randomized, multicenter, placebo-controlled phase III trial –1 o endpoint: VL < 50 c/mL at Wk 48 (FDA snapshot analysis) ART-naïve pts, VL ≥ 5000, eGFR ≥ 70 mL/min (N = 692) ATV/COBI* + TDF/FTC (n = 344) ATV/r  + TDF/FTC (n = 348) Wk 48 Primary endpoint Stratification by VL ≤ vs > 100,000 copies/mL Gallant J, et al. IAC 2012. Abstract TUAB0103. Wk 96

19. GS 114: Cobicistat-Boosted vs RTV- Boosted ATV in ART-Naïve Patients CD4 count gain: +213 with ATV/COBI vs +219 with ATV/r Among 24 pts with suboptimal virologic response and genotype: no primary PI or TDF resistance; M184V/I in 2 pts in COBI arm, 0 in RTV arm VL < 50 at Wk 48 (Snapshot Analysis) Gallant J, et al. IAC 2012. Abstract TUAB0103. ATV/COBIATV/r 40 0 100 20 80 87 85 60 348344n = Baseline VL ≤ 100K Baseline VL > 100K Overall Patients (%) 88 84 86 179/ 212 181/ 205 114/ 132 123/ 143 Δ-2.2% (-7.4 to 3.0) P = NS Baseline CD4+ ≤ 350 Baseline CD4+ > 350 90 85 81 156/ 174 164/ 183 137/ 170 140/ 165 P = NS

20. Randomized, double-blind, placebo-controlled phase III trial –1 o endpoint: VL < 50 at Wk 48 (FDA snapshot analysis) ART-naive pts, VL ≥ 1000 (N = 822) DTG 50 mg QD + 2 NRTIs* (n = 411) RAL 400 mg BID + 2 NRTIs* (n = 411) Wk 96 Stratified by screening VL (≤ vs > 100,000) and NRTI backbone *Investigator-selected NRTI backbone: either TDF/FTC or ABC/3TC. Wk 48 Primary endpoint SPRING-2: Dolutegravir vs Raltegravir in ART-Naive Pts at 48 Wks Raffi F, et al. IAC 2012. Abstract THLBB04.

21. SPRING-2: Dolutegravir Noninferior to Raltegravir at 48 Wks CD4 gain of +230 from BL in both arms No significant differences by baseline VL or NRTI backbone  Per protocol response: 90% (DTG) vs 88% (RAL) by snapshot analysis Δ 1.6% (95% CI: -2.7% to 5.9%) 88% 85% 100 80 60 40 20 0 BL48121624324048 Wk Pts With VL < 50 c/mL (%) DTG 50 mg QD (n = 411) RAL 400 mg BID (n = 411) Δ 2.5% (95% CI: -2.2% to 7.1%) Raffi F, et al. IAC 2012. Abstract THLBB04.

22. SPRING-2: Safety and Resistance Less confirmed virologic failure at or after Wk 24 with DTG vs RAL (5% vs 7%) 1. Raffi F, et al. IAC 2012. Abstract THLBB04. 2. Koteff J, et al. ICAAC 2011. Abstract A1-1728.  DTG had favorable safety profile, comparable to RAL –Few AEs necessitating discontinuation (2% in each arm) –Greater increase in creatinine with DTG vs RAL (+0.139 vs +0.053 mg/dL) –DTG increases serum creatinine by inhibiting renal creatinine secretion but does not affect actual GFR [2] –No premature discontinuation for renal events PatientsDTG 50 mg QD (n = 411) RAL 400 mg BID (n = 411) Subjects with virologic failure, n2028 Resistance, n/N  INSTI resistance mutations  NRTI resistance mutations 0/8 0/12 1/18 4/19

23. SINGLE: Study Design DTG 50 mg plus ABC/3TC FDC QD + ATRIPLA (ATR) placebo ATRIPLA QD + DTG plus ABC/3TC FDC placebo HIV + ART-naive VL ≥1000 c/mL HLA-B*5701 negative Creatinine clearance >50 mL/min Stratified by: Baseline plasma HIV-1 RNA and CD4 cell count Primary endpoint: Proportion with HIV-1 RNA <50 c/mL at Week 48, FDA snapshot analysis – 10% noninferiority margin with prespecified tests for superiority Secondary endpoints: – Tolerability, long-term safety, immunologic, health outcome, and viral resistance Randomization Week 48 primary analysis Week 96 Walmsley S, et al. ICAAC 2012. Oral Abstract H-556b 23

24. Baseline Characteristics DTG 50 mg + ABC/3TC QD (n=414) Atripla QD (n=419) Total (n=833) Age (years), median3635 Female, %16%15%16% African American/African heritage24% CDC class C, %4% HIV-1 RNA (log 10 c/mL), median4.674.704.68 >100,00032%31%32% CD4+ (cells/mm 3 ) median335339338 <20014% 200 to <35039%38%39% 350 to <50032%31% ≥50015%17%16% Walmsley S, et al. ICAAC 2012. Oral Abstract H-556b 24

25. Subject Disposition Randomized DTG + ABC/3TC 50 mg QD (n=422) Randomized ATRIPLA QD (n=422) Screened (N=1090) Adverse event10 (2%) Suspected HSR 2 (<1%) Lack of efficacy14 (3%) (virologic failure) Protocol deviation 7 (2%) Lost to follow-up14 (3%) Investigator discretion 1 (<1%) Withdrew consent 5 (1%) Randomized and treated (n=419) 88% continued (n=363) 12% subjects withdrawn (n=51) 80% continued (n=335) Randomized and treated (n=414) 20% subjects withdrawn (n=84) Adverse event42 (10%) Suspected HSR 4 (<1%) Lack of efficacy13 (3%) (virologic failure) Protocol deviation 7 (2%) Lost to follow-up 9 (2%) Investigator discretion 2 (<1%) Withdrew consent 11 (3%) Walmsley S, et al. ICAAC 2012. Oral Abstract H-556b 25

26. Proportion (95% CI) of Subjects <50 c/mL (FDA Snapshot) Week Proportion of Subjects <50 c/mL HIV-1 RNA, % DTG 50 mg + ABC/3TC QD was statistically superior to ATRIPLA at Week 48 (primary endpoint) Subjects receiving DTG + ABC/3TC achieved virologic suppression faster than ATRIPLA, median time to HIV-1 RNA <50 c/mL of 28 days (DTG + ABC/3TC) vs 84 days (ATRIPLA), P<0.0001 ATRIPLA (ATR) QD DTG 50 mg + ABC/3TC QD Week 48 difference in response (95% CI): +7.4% (+2.5% to +12.3%); P=0.003 DTG + ABC/3TC: 88% ATR: 81% 4032 1648 12824 2 0 20 40 60 80 100 BL4 90 70 50 30 10 Walmsley S, et al. ICAAC 2012. Oral Abstract H-556b 26

27. Proportion <50 c/mL: Snapshot Outcomes Outcome (snapshot) at Week 48 DTG 50 mg + ABC/3TC QD n=411 n (%) ATRIPLA QD (n=419) n (%) Virologic success364 (88)338 (81) Virologic nonresponse21 (5)26 (6) Data in window not <50 c/mL6 (1)5 (1) Discontinued for lack of efficacy7 (2)9 (2) Discontinued for other reason while not <50 c/mL8 (2)12 (3) No virologic data at Week 4829 (7)55 (13) Discontinued because of AE or death*9 (2)40 (10) Discontinued for other reasons20 (5)14 (3) Missing data during window but on study01 (<1) * Deaths: n=2, both on ATRIPLA; n=1, primary cause of death (sepsis) judged unrelated to study drug but complicated by renal failure judged possibly related to ATRIPLA; n=1, not related to ATRIPLA (pneumonia). Walmsley S, et al. ICAAC 2012. Oral Abstract H-556b 27

28. Supportive Efficacy Analyses DTG 50 mg + ABC/3TC QD (n=414) Atripla QD (n=419) Difference in proportion (95% CI) (DTG–Atripla) Proportion of responders Per protocol analysis (<50 c/mL; “snapshot”) 90%81%8.7 (3.9, 13.4) Estimated proportion without failure by Week 48 Treatment-related discontinuation=failure (TRDF) 94%87%7.7 (3.6, 11.7) Efficacy-related discontinuation=failure (ERDF) 95% 0.2 (-2.9, 3.3) TRDF=PDVF or withdrawal due to drug-related adverse event, safety stopping criteria, or lack of efficacy. ERDF=PDVF or withdrawal due to lack of efficacy. Walmsley S, et al. ICAAC 2012. Oral Abstract H-556b 28

29. Snapshot of Primary Outcome at Week 48 by Strata DTG 50 mg + ABC/3TC QD (n=414) (%) Atripla QD (n=419) (%) Difference in proportion (95% CI) (DTG–ATR) Number of responders/ total assessed Baseline plasma HIV-1 RNA ≤100,000 c/mL253/280 (90)238/288 (83)7.7 (2.1, 13.3) >100,000 c/mL111/134 (83)100/131 (76)6.5 (-3.2, 16.2) P=0.831* CD4 Cell Count >200 cells/mm 3 319/357 (89)290/357 (81)8.1 (3.0, 13.3) ≤200 cells/mm 3 45/57 (79)48/62 (77)1.5 (-13.3, 16.4) P=0.414* * Test for homogeneity: P value confirms that there is no evidence of heterogeneity in treatment difference across the baseline stratification factors. Walmsley S, et al. ICAAC 2012. Oral Abstract H-556b 29

30. Absolute Change From Baseline in CD4+ Cell Count: Repeated Measures Mixed Model Analysis Week Adjusted Mean Change From Baseline CD4+ Cell Count (cells/mm 3 ) Significant at prespecified level of 4% ATRIPLA QD DTG 50 mg + ABC/3TC QD Week 48 difference in response (95% CI): 59 (33-84); P<0.001 DTG + ABC/3TC 267 cells/mm 3 ATR 208 cells/mm 3 4032 1648 12824 0 50 100 150 200 300 4 250 Walmsley S, et al. ICAAC 2012. Oral Abstract H-556b 30

31. Protocol-Defined Virologic Failure DTG 50 mg + ABC/3TC QD (n=414) (%) Atripla QD (n=419) (%) Subjects with PDVF18 (4)17 (4) VL at confirmed failure (c/mL) 50 to <40016 (89)14 (82) 400 to <100001 (6) 1000 to ≤100,0002 (11)1 (6) >100,00001 (6) All PDVFs had attempted phenotype/genotype testing for Day 1 and at time of failure samples (including those with <400 c/mL). Protocol-defined virologic failure (PDVF) Confirmed HIV-1 RNA ≥50 c/mL at or after Week 24 PDVF before Week 48 required withdrawal Walmsley S, et al. ICAAC 2012. Oral Abstract H-556b 31

32. Virology: Resistance DTG 50 mg + ABC/3TC QD (n=414) ATRIPLA QD (n=419) Subjects with PDVF18 (4%)17 (4%) PDVF genotypic population119 PDVF genotypic (RT results at baseline and PDVF)99 NRTI tmt-emergent major mutations01 (K65R) NNRTI tmt-emergent major mutations0 4 (K101E, K103N, G190A)* PDVF genotypic (IN results at baseline and PDVF)77 INI-r tmt-emergent major substitution0**0 * n=1 with K101E; n=1 with K103N; n=1 with G190A; n=1 with K103N+G190A. ** E157Q/P polymorphism detected with no significant change in IN phenotypic susceptibility. Walmsley S, et al. ICAAC 2012. Oral Abstract H-556b 32

33. PI News Coming soon: –DRV 800 mg tab –DRV/COBI and ATV/COBI coformulations Coming later: –DRV/COBI/GS7340/COBI coformulation Fully enrolled: –ACTG ARENT: DRV/r vs. ATV/r vs. RAL comparison

34. ACTG 5202: Time to Virologic Failure by Baseline Viral Load and CD4 Count CD4<50, RNA≥100K (n=98, 35 VF) CD4<50, RNA<100K (n=78, 23 VF) CD4 50 to <200, RNA≥100K (n=80, 19 VF) CD4 50 to <200, RNA<100K (n=153, 10 VF) CD4 200 to <350, RNA≥100K (n=39, 6 VF) CD4 200 to <350, RNA<100K (n=273, 28 VF) CD4≥350, RNA≥100K (n=23, 5 VF) CD4≥350, RNA<100K (n=184, 29 VF) ABC/3TCTDF/FTC 1.0 0.8 0.6 0.4 0.2 0.0 0 24 48 72 96 120 144 168 192 216 Weeks from Randomization Probability of Remaining free of Virologic Failure 1.0 0.8 0.6 0.4 0.2 0.0 0 24 48 72 96 120 144 168 192 216 Weeks from Randomization Probability of Remaining free of Virologic Failure CD4<50, RNA≥100K (n=80, 6 VF) CD4<50, RNA<100K (n=83, 17 VF) CD4 50 to <200, RNA≥100K (n=70, 9 VF) CD4 50 to <200, RNA<100K (n=158, 19 VF) CD4 200 to <350, RNA≥100K (n=55, 8 VF) CD4 200 to <350, RNA<100K (n=289, 29 VF) CD4≥350, RNA≥100K (n=20, 2 VF) CD4≥350, RNA<100K (n=173, 24 VF) Grant P, et al. CROI 2011. Abstract 535.

35. Single tablet regimens PROSCONS TDF/FTC/EFV PK forgiving of missed doses CNS side effects Teratogenicity Resistance with interruption Rash More lipid effects than others TDF/FTC/RPV Better tolerated than EFV Less effective at high VL? Less forgiving of non-adherence More resistance with failure, including ETR cross-resistance Food requirement No PPI, caution with H2 blockers TDF/FTC/ EVG/COBI Non-inferior to TDF/FTC/ EFV Better tolerated than EFV COBI drug interactions COBI effect on eGFR

36. Single tablet regimens PROSCONS TDF/FTC/EFV PK forgiving of missed doses CNS side effects Teratogenicity Resistance with interruption Rash More lipid effects than others TDF/FTC/RPV Better tolerated than EFV Less effective at high VL? Less forgiving of non-adherence More resistance with failure, including ETR cross-resistance Food requirement No PPI, caution with H2 blockers TDF/FTC/ EVG/COBI Non-inferior to TDF/FTC/ EFV Better tolerated than EFV COBI drug interactions COBI effect on eGFR ABC/3TC/DTG Only non-TDF-based STR Superior to TDF/FTC/EFV due to better tolerability ABC issues

37. Why use multiple tablet regimens?  Boosted PI + 2 NRTIs: –Lack of resistance with failure. Ideal for patients with unreliable adherence. –Preferred in pregnancy  RAL + 2 NRTIs: –Superior to EFV at 4 & 5 years. –Few drug interactions. Ideal for patients needing HCV therapy  ABC/3TC + 3 rd agent: –Patients with kidney disease

38. Choice of ART: Special populations and scenarios Pregnancy or likelihood of pregnancy Avoid EFV (1 st trimester) No data on newer agents (RPV, EVG/COBI) NRTIs: AZT/3TC, TDF/FTC PIs: LPV/r, ATV/r HCV coinfection RAL: can be used with telaprevir, boceprevir ATV: can be used with telaprevir EFV: requires higher dose telaprevir HBV coinfection TDF/FTC-based regimen if possible

39. Choice of ART: Special populations and scenarios Chronic kidney disease Avoid TDF (and ATV, LPV/r?) Pre-existing osteoporosis/osteopenia Avoid TDF Need for urgent ART without resistance data (primary HIV, acute OI) Boosted PI-based regimen Transmitted resistance Depends on mutations PI-based regimen preferred for NRTI resistance

40. ART: New formulations  3 single-tablet regimens now available; 2 more in development: –DTG/ABC/3TC –DRV/COBI/GS7340/FTC/  Other new formulations planned: –DRV 800 mg tab –ATV/COBI –DRV/COBI –EVG/COBI –GS7340/FTC