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What ’ s New in Antiretroviral Therapy??

What ’ s New in Antiretroviral Therapy??. Joe Eron UNC School of Medicine. DHHS Guidelines, March 2012: What to Start. DHHS Guidelines for Antiretroviral Therapy in Adults and Adolescents. March 27, 2012. IAS-USA Guidelines, July 2012: What to Start.

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What ’ s New in Antiretroviral Therapy??

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

  2. DHHS Guidelines, March 2012: What to Start DHHS Guidelines for Antiretroviral Therapy in Adults and Adolescents. March 27, 2012

  3. IAS-USA Guidelines, July 2012: What to Start *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. Thompson MA, et al. JAMA. 2012;308:387-402

  4. 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

  5. ECHO/THRIVE: RPV vs EFV: 96 Week Results by Baseline VL Responders RPV -5.2 (-12, 1.5) EFV 4.0 (–1.7, 9.7) 70 75 Non responders 84 80 Discontinued due to other reasons† Discontinued due to AE/death VFeff >100K ≤100K • 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

  6. 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 (1o endpoint) • No events leading to discontinuation after switch • RPV mean Ctrough within target range by 2 weeks Plasma Concentrations of RPV (Ctrough) or EFV (any time) 2000 EFV concentrationRPV CtroughRPV mean Ctrough in ECHO/THRIVE 1600 1200 800 Mean Concentration (ng/mL) 400 120 80 40 0 0 2 4 6 8 10 12 Weeks After Switch Mills A, et al. ICAAC 2011. Abstract H2-794c.

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

  8. 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/FTC Boosted PI Δ3.8% (-1.6 to 9.1) Δ5.9%(-1.4 to 12.9) Δ3.2% (-4.8 to 11.3) 95.5 93.7 95.0 100 92.3 89.9 89.2 80 60 Pts With VL < 50 c/mL (%) 40 20 152/160 83/ 93 128/134 48/52 n = 317 159 0 Overall < 100K ≥ 100K Baseline VL (When Naive)* *Excludes 23 RPV and 14 boosted PI pts lacking baseline VL while ARV naive . Palella F, et al. AIDS 2012. Abstract TUAB0104.

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

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

  11. GS 102: “Quad” vs. TDF/FTC/EFV1o Endpoint: VL <50 at 48 weeks Quad non-inferior to EFV/FTC/TDF at Week 48 95% CI for Difference Favors EFV/FTC/TDF Favors Quad 3.6 -1.6 8.8 -12% 0 12% Sax P, et al. CROI 2012

  12. GS 103: “Quad” vs. TDF/FTC + ATV/r1o Endpoint: VL < 50 at 48 weeks QUAD non-inferior to ATV/r + FTC/TDF 95% CI for Difference Favors ATV/r + FTC/TDF Favors Quad 3.0 -1.9 7.8 -12% 0 12% DeJesus E, et al. CROI 2012

  13. GS 102: “Quad” vs. TDF/FTC/EFV Drug resistance through week 48 *Subjects who experienced either suboptimal virologic response (two consecutive visits with HIV-1 RNA ≥50 c/mL and <1 log10 below baseline after Week 8), virologic rebound (two consecutive visits with HIV-1 RNA either ≥400 c/mL after achieving HIV-1 RNA <50, or >1 log10 increase from nadir), or had HIV-1 RNA ≥400 c/mL at their last visit. Sax P, et al. CROI 2012

  14. GS 103: “Quad” vs. TDF/FTC + ATV/r:Drug resistance through week 48 DeJesus E, et al. CROI 2012

  15. 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) 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) BL 2 4 8 12 16 24 32 40 48 Week Quad (n=): 348 341 345 345 337 335 328 323 320 320EFV/FTC/TDF (n=): 352 340 340 336 327 323 317 313 309 307 Sax P, et al. CROI 2012

  16. “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

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

  18. 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) ATV/COBI ATV/r Δ-2.2% (-7.4 to 3.0) P = NS P = NS P = NS P = NS 100 90 90 88 87 86 86 85 85 84 81 80 60 Patients (%) 40 20 179/212 181/205 114/132 123/143 156/174 164/183 137/170 140/165 n = 344 348 0 Overall Baseline VL ≤ 100K BaselineVL > 100K BaselineCD4+ ≤ 350 Baseline CD4+ > 350 Gallant J, et al. IAC 2012. Abstract TUAB0103.

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

  20. 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 Δ1.6% (95% CI: -2.7% to 5.9%) 100 88% 80 85% Δ2.5% (95% CI: -2.2% to 7.1%) DTG 50 mg QD (n = 411)RAL 400 mg BID (n = 411) 60 Pts With VL < 50 c/mL (%) 40 20 0 BL 4 8 12 16 24 32 40 48 Wk Raffi F, et al. IAC 2012. Abstract THLBB04.

  21. SPRING-2: Safety and Resistance • Less confirmed virologic failure at or after Wk 24 with DTG vs RAL (5% vs 7%) • 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 1. Raffi F, et al. IAC 2012. Abstract THLBB04. 2. Koteff J, et al. ICAAC 2011. Abstract A1-1728.

  22. SINGLE: Study Design 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 DTG 50 mg plus ABC/3TC FDC QD + Atripla (ATR) placebo Atripla QD + DTG plus ABC/3TC FDC placebo Randomization Week 96 Week 48 primary analysis • 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 Walmsley S, et al. ICAAC 2012. Oral Abstract H-556b

  23. Proportion (95% CI) of Subjects<50 c/mL (FDA Snapshot) 100 DTG + ABC/3TC: 88% 90 80 70 ATR: 81% 60 Week 48 difference in response (95% CI): +7.4% (+2.5% to +12.3%); P=0.003 Proportion of Subjects <50 c/mL HIV-1 RNA, % 50 40 30 20 DTG 50 mg + ABC/3TC QD 10 Atripla (ATR) QD 0 BL 4 8 12 24 32 40 2 16 48 Week • 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 Walmsley S, et al. ICAAC 2012. Oral Abstract H-556b

  24. Supportive Efficacy Analyses 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

  25. Snapshot of Primary Outcomeat Week 48 by Strata * 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

  26. Absolute Change From Baseline in CD4+ Cell Count: Repeated Measures Mixed Model Analysis DTG + ABC/3TC 267 cells/mm3 300 250 200 Adjusted Mean Change From Baseline CD4+ Cell Count (cells/mm3) ATR 208 cells/mm3 150 Week 48 difference in response (95% CI): 59 (33-84); P<0.001 100 50 Atripla QD DTG 50 mg + ABC/3TC QD 0 4 8 12 24 32 40 16 48 Week Significant at prespecified level of 4% Walmsley S, et al. ICAAC 2012. Oral Abstract H-556b

  27. Virology: Resistance * 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

  28. 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

  29. Single tablet regimens

  30. Single tablet regimens

  31. 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 + 3rd agent: • Patients with kidney disease

  32. Choice of ART:Special populations and scenarios • Pregnancy or likelihood of pregnancy • Avoid EFV (1st 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

  33. 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

  34. 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

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