Antiretroviral Therapy: Current Recommendations, New Drugs, and Novel Strategies. Joel Gallant, MD, MPH Johns Hopkins University School of Medicine

Transcription

1 Antiretroviral Therapy: Current Recommendations, New Drugs, and Novel Strategies Joel Gallant, MD, MPH Johns Hopkins University School of Medicine

2 Initial Regimen: DHHS Guidelines 3/27/2012 Preferred Regimens Recent Changes: NRTI Component TDF/FTC + 3 rd Agent EFV ATV/r DRV/r RAL RPV + (TDF/FTC or ABC/3TC): new alternative regimen Acceptable agents: NVP AZT No longer recommended: Unboosted FPV ddi + 3TC DHHS Guidelines for Antiretroviral Therapy in Adults and Adolescents. October 14, 2011.

3 NNRTI vs. PI/r vs. RAL? PROS NNRTI Easiest regimens (1-2 pills/d) Minimal long-term toxicity PK forgiving of missed doses (EFV) CONS CNS side effects (EFV) Teratogenicity (EFV) Genetic barrier: resistance with interruption Poorer CD4 response than with other classes (EFV) PI/r RAL As effective as EFV (ATV/r in ACTG 5202) Less resistance with failure Preferred in pregnancy Non-inferior to EFV with better tolerability (superior at 192 wks in STARTMRK) Lipid neutral Greater pill burden GI side effects Twice-daily dosing Resistance with failure Expensive

4 NNRTIs

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

6 ECHO/THRIVE: Viral Load <50, 96 Week ITT-TLOVR Data RPV 25mg qd (N=686) RPV Cohen C, et al. J Acquir Immune Defic Syndr [Epub ahead of print]

7 ECHO/THRIVE: RPV vs EFV: 96 Week Results by Baseline VL Responders RPV -5.2 (-12, 1.5) EFV Non responders Discontinued due to other reasons Discontinued due to AE/death VF eff 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. 6th IAS; Rome, Italy; July 17-20, Abst. TULBPE032.

8 Which NNRTI? EFV NVP RPV PROS Coformulated with TDF/FTC Minimal long-term toxicity PK forgiving of missed doses Excellent tolerability Minimal long-term toxicity Lowest cost Safety data in pregnancy Better tolerated than EFV (CNS, rash) Fewer lipid effects than EFV Coformulated with TDF/FTC CNS side effects Teratogenicity CONS Genetic barrier: resistance with interruption Not as well studied as EFV High drop-out in studies with TDF Potential for serious liver/skin toxicity, especially at higher CD4 counts Less effective at high VL than EFV Less forgiving of non-adherence More resistance with failure, including ETR cross-resistance Food requirement No PPI, caution with H2 blockers

9 Integrase Inhibitors

10 STARMRK: RAL vs. EFV in naïve patients 192 week data % with VL< (RAL-EFV) [95% CI]=+9.0 [1.6, 16.4] Non-Inferiority p-value < Number of Contributing Patients Weeks RAL EFV DeJesus E, et al. 49 th IDSA, Boston, October 2011

11 QDMRK: Once-Daily vs Twice-Daily Raltegravir in Treatment-Naive Patients RAL QD not noninferior to RAL BID at Wk 48 (each with TDF/FTC) % vs 88.9% VL < 50 VL < 50 at Wk 48 (NC = F) B/L HIV RNA (copies/ml) > 100K 100K 200 > 200 B/L CD4+ count (cells/mm 3 ) Eron J, et al. Lancet Infect Dis. 2011;11: RAL 800 mg QD (n = 382) RAL 400 mg BID (n = 388) Lower RAL trough levels associated with higher risk of failure in QD arm but not in BID arm More resistance at failure in QD arm Parameter, n Patient with VF* and VL > 400 RAL QD (n = 382) RAL BID (n = 388) Integrase data available Signature InSTI resistance mutations N155H 4 0 Y143C/R 3 1 Failure included both failure to suppress and rebounders *Majority of patients with virologic failure and RAL resistance had 2 mutations associated with resistance to RAL.

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

13 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 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 88% 84% Virologic Success 7% 7% 9% 5% Virologic Non- Suppression No W48 Data -12% Favors EFV/FTC/TDF Favors Quad % Sax P, et al. CROI 2012 Quad EFV/FTC/TDF

14 GS 102: Quad vs. TDF/FTC/EFV Efficacy in Baseline VL and CD4 Subgroups Virologic Success (<50) Sax P, et al. CROI 2012

15 GS 102: Quad vs. TDF/FTC/EFV Integrase & NNRTI 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) 8 (2) Any Primary Integrase-R, n 7 E92Q 7 T66I 1 Q148R 1 N155H 1 Any Primary NNRTI-R n 8 K103N 7 V108I 2 Y188Y/F/H/L 1 G190A 1 Any Primary NRTI-R, n 8 2 M184V/I 8 2 K65R 3 2 *Subjects who experienced either suboptimal virologic response (two consecutive visits with HIV-1 RNA 50 c/ml and <1 log 10 Sax below P, et baseline al. CROI after 2012 Week 8), virologic rebound (two consecutive visits with HIV-1 RNA either 400 c/ml after achieving HIV- 1 RNA <50, or >1 log 10 increase from nadir), or had HIV-1 RNA 400 c/ml at their last visit.

16 GS 102: Quad vs. TDF/FTC/EFV Median Change in Serum Creatinine 0.35 Change from BL in Serum Creatinine (mg/dl) (IQR) BL Week Quad (n=): EFV/FTC/TDF (n=): Median change at Week 48: 0.14 mg/dl vs mg/dl (Quad vs. EFV/FTC/TDF group, p<0.001) Sax P, et al. CROI 2012

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

18 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 Favors ATV/r + FTC/TDF Favors Quad % 0 12% DeJesus E, et al. CROI 2012

19 GS 103: Quad vs. TDF/FTC + ATV/r Efficacy in Baseline VL and CD4 Subgroups Virologic Success (%) DeJesus E, et al. CROI 2012

20 GS 103: Quad vs. TDF/FTC + ATV/r Change in Serum Creatinine Change from Baseline in Serum Creatinine (mg/dl) BL Week QUAD (n=): ATV/r +FTC/TDF (n=): Median change W48: 0.12 mg/dl vs mg/dl (Quad vs. ATV/r + FTC/TDF group, p<0.001) DeJesus E, et al. CROI 2012

21 Quad Conclusions Quad non-inferior to TDF/FTC/EFV and TDF/FTC + ATV/r, overall and at all CD4 & 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 mg/dl due to inhibition of creatinine excretion Quad not recommended if egfr <70 Expected US approval August 2012

22 No integrase resistanceassociated mutations detected in pts failing DTG through Week 48 Grade 2-4 AEs numerically higher in EFV arm vs DTG arms DTG associated with lowlevel changes in serum creatinine Thought to be inhibition of renal transporter rather than true renal toxicity Lancet Infect Dis, 2011

23 PIs

24 Which Boosted PI? PI/r PROS CONS ATV/r Comparable to LPV/r at 96 wks (CASTLE) Lowest pill burden (2/d) Gastric acid requirement Food requirement Jaundice & scleral icterus DRV/r Comparable to LPV/r with better tolerability (ARTEMIS) Less hyperlipidemia (vs. LPV/r) No gastric acid issues (vs. ATV/r) LPV/r The only coformulated boosted PI Best safety data in pregnancy Food requirement Rash More GI side effects More lipid effects 200 mg of RTV required

25 D:A:D: No Association Between ATV and Increased Risk of MI or Stroke > 49,000 HIV-infected patients from 11 cohorts in Europe, US, and Australia 0.8 Any ATV (PYFU: 37,005) ATV with RTV (PYFU: 31,232) ATV without RTV (PYFU: 9611) None >0, <1 >1, < 2 >2, < 3 >3 None >0, <1 >1, < 2 >2, < 3 >3 Years of exposure None >0, <1 >1, < 2 >2, < 3 >3 Similar lack of association observed with ATV use and stroke Monforte Ad, et al. CROI Abstract 823.

26 NRTIs

27 ACTG 5202: Time to Virologic Failure by Baseline Viral Load and CD4 Count ABC/3TC TDF/FTC Probability of Remaining free of Virologic Failure 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) 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) Weeks from Randomization Weeks from Randomization Grant P, et al. CROI Abstract 535.

28 Abacavir and MI Risk: Recent published studies Reference Study Design Increased risk? Choi, AIDS 2011, VA Observational Yes Bedimo, CID 2011, VA Observational No Durand, J AIDS 2011, Montreal Observational Yes Ribaudo, CID 2011, ACTG Cohort from RCTs No Cruciani, AIDS 2011 Met-analysis No How difficult it is to find a consensus can be exemplifiedby the fact that even identical data sources (Veterans Health Administration) analyzed by different investigators can lead to conflicting results Georg Behrens, AIDS 2011; Paul Sax

29 Abacavir increases platelet activation in vitro Carbovir triphosphate (active metabolite of ABC) is competitive inhibitor of guanylyl cyclase, a negative regulator of platelet function Baum PD, et al. AIDS 2011;25:

30 Abacavir and hscrp ACTG 5224s: hscrp increases with ABC/3TC vs. TDF/FTC and with EFV vs. ATV/r Association remained after excluding pts with HSR Similar association seen in ACTG 5095, but not other studies Difference between EFV and ATV/r diminished at 96 vs. 24 weeks McComsey G, et al. 19th CROI, Seattle, Abst. 835

31 Abacavir and MI Risk Conflicting data from observational and prospective studies Proposed pathogenic models: Inflammation Increased platelet reactivity/adhesion Impaired flow-mediated dilatation Atherogenic lipid profile Guidelines: use with caution in patients with high CV risk DHHS Guidelines, October 14, 2011

32 VA Study: TDF and risk of kidney disease 10,841 HIV+ pts at VA Time to first occurrence of 1) proteinuria 2) rapid decline in kidney function and 3) CKD (egfr rate < 60 ) Each year of exposure to TDF associated with: 34% increased risk of proteinuria (p < ) 11% increased risk of rapid decline (p = ) 33% increased risk of CKD (p < ). Pre-existing renal risk factors did not appear to worsen the effects of tenofovir. Scherzer R, et al. AIDS 2012 [Epub ahead of print]

33 Aquitaine Cohort: TDF Use, Alone or With Concomitant PI, Associated With CKD 2693 HIV+ pts with baseline CrCl > 60 followed from cases of incident CKD during follow-up Among pts with CKD, 96% had baseline CrCl < 90 and 90% had 3 traditional risk factors* Association With CKD (Multivariate Analysis) Risk Ratio (95% CI)* TDF use (adjusted for other risk factors) 2.5 ( ) Without 6 mos of concomitant PI 1.8 ( ) With 6 mos of concomitant PI 3.5 ( ) *Other variables associated with increased CKD: female sex, older age, DM, hyperlipidemia, preexisting mild renal dysfunction (CrCl 61-89), and low CD4 count. PIs used: ATV/r 41%, LPV/r 35%, FPV 11%, SQV 4%. PI vs without PI: P =.02. Morlat P, et al. IAS Abstract WEPDB0104.

34 Switch to TDF increases bone turnover and reduces bone mineral density Subjects on AZT/3TC (n=54) randomized to continue or switch to TDF/FTC Continue AZT/3TC BMD Med. (IQR) Within group p-value Femoral neck 1.36 (-3.26, 1.63) Lumbar spine (-2.35, 1.85) Randomization group Switch to TDF/FTC Med. (IQR) (-3.04, 0.22) (03.28, -0.40) Within group p-value Between group p-value Markers of bone formation and bone resorption also increased in TDF/FTC group Cotter A, et al. Abstract 125LB, CROI 2012

35 Cumulative Use of TDF and/or Boosted PIs And Risk of Osteoporotic Fractures Retrospective analysis of 56,660 HIV+ male Veterans enrolled from Osteoporotic fractures assessed from ICD-9 codes Cumulative use of TDF and/or PI/r associated with higher risk in ART era, after controlling for risk factors Highest risk with concomitant use Cumulative use of LPV/r also associated with higher fracture risk PI association limited to LPV/r Cumulative use of ABC, thymidine analogs, NNRTIs not associated with higher risk Bedimo R, et al. AIDS [epub ahead of print]. HR for Fracture, HAART Era Limitations TDF Univariate analysis Controlled for effects of CKD, age, race, smoking, DM, BMI, and HCV. Controlled for covariates in Model 1 plus concomitant exposure to ARVs. Retrospective cohort study BMD data not available PI/r Fractures not verified to be osteoporotic

36 Tenofovir toxicity Renal Glomerular: decrease in GFR; monitor creatinine and egfr Tubular: proximal renal tubular dysfunction with phosphate wasting; monitor urinalysis Bone Greater loss in bone density with TDF than other agents Appears to be an early phenomenon and nonprogressive Avoid in patients with low bone density

37 GS-7340: Tenofovir pro-drug Greater antiviral activity vs TDF Dosing Placebo (n = 7) TDF 300 mg (n = 6) GS mg (n = 9) GS mg (n = 8) GS mg (n = 8) Day Higher intracellular tenofovir diphosphate levels and lower circulating plasma tenofovir levels with GS-7340 vs TDF Ruane PJ, et al. CROI Abstract 103.

38 NRTI-sparing regimens Study Regimen Efficacy/ Resistance Lipids Renal Bone Bilirubin A LPV/r + EFV Neutral Elevated Neutral Neutral - PROGRESS 4 LPV/r + RAL Neutral Elevated Neutral - - CCTG589 5 LPV/r + RAL Neutral SPARTAN 6 ATV + RAL More Resistance Neutral - - Elevated MVC Manufacturer 7 ATV/r + MVC Neutral Elevated MONET 8 DRV/r Not Non-Inferior Elevated A DRV/r + RAL Inferior TBD TBD TBD TBD 1. Riddler S, et al. New Engl J Med 2008;358: Huang J, et al. WAIDS Vienna. WEAB Goicoechea M, J et al. WAIDS Vienna. WEAB Reynes J, et al. WAIDS 2010; Vienna. MOAB Goicoechea M, J et al. WAIDS Vienna. THPE Kozal MJ, et al. WAIDS 2010; Vienna. THLBB Portsmouth S, et al. WAIDS 2010; Vienna. THLBB Rieger A, et al. WAIDS 2010; Vienna. THLBB Taiwo B, et al. CROI 2011; Boston. Poster 551

39 ACTG 5262: DRV/r + RAL 1.0 Time to Virologic Failure (VF) 1.0 Time to VF by Baseline HIV-1 RNA Probability of not having a VF Time (weeks) n with VF: n at risk: Taiwo B, et al. AIDS 2011,;25: Probability of not having a VF % failure by week 48 HIV-1 RNA 100,000 copies/ml HIV-1 RNA > 100,000 copies/ml Log Rank Test p= Time (weeks) VL 100,000 n with VF: n at risk: VL > 100,000 n with VF: n at risk:

40 Studies of NRTI-sparing regimens Features of most NRTI-sparing studies Use of a boosted PI Inclusion of 2 active agents Small sample sizes (not powered to establish efficacy) Inclusion of patients with low baseline VL Fully-powered comparative studies: DRV/r + RAL vs. DRV/r + TDF/FTC: ongoing DRV/r + MVC vs. DRV/r + TDF/FTC: planned

41 CCR5 Antagonists

42 MOTIVATE: Similar Efficacy of MVC QD vs BID + Boosted PI in ART-Exp Pts Post-hoc analysis of 448 patients in MOTIVATE studies who received MVC QD vs BID (plus a boosted PI*) vs placebo HIV-1 RNA < 50 c/ml, % *Patients on boosted FPV and boosted TPV excluded. Okoli C, et al. J Antimicrob Chemother. 2012;67: n/n = 85/187 84/176 14/85 MVC 150 mg QD MVC 150 mg BID Placebo Difference (97.5% CI): QD vs PBO: 27.8% (16.2 to 39.4) BID vs PBO: 30.6% (18.5 to 42.7) Difference (95% CI): QD vs BID: -2.4% (-12.5 to 7.7) 16.5

43 New Entry Inhibitors Cenicriviroc (TBR-652): CCR5 antagonist with anti-ccr2 properties (anti-inflammatory)

44 HIV Entry Inhibitors CD4 Binding Coreceptor Binding Virus-Cell Fusion BMS Ibalizumab CD4 gp41 gp120 V3 loop CCR5 antagonists Enfuvirtide Cell Membrane CCR5/CXCR4 (R5/X4)

45 New Entry Inhibitors Cenicriviroc (TBR-652): CCR5 antagonist with anti-ccr2 properties (anti-inflammatory) BMS : CD4 attachment inhibitor Ibalizumab (TNX-355): Anti-CD4 monoclonal antibody; once weekly IV dosing

46 ART: New and potential future options Single-tablet regimens TDF/FTC/RPV Quad regimens TDF/FTC/EVG/COBI GS7340/FTC/DRV/COBI DTG/ABC/3TC Other coformulations ATV/COBI DRV/COBI EVG/COBI GS7340/FTC NRTI sparing regimens CCR5 antagonists as initial therapy New entry inhibitors