Didactic Series. CROI Update - II. Christian B. Ramers, MD, MPH Family Health Centers of San Diego Ciaccio Memorial Clinic 5/28/15

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1 Didactic Series CROI Update - II Christian B. Ramers, MD, MPH Family Health Centers of San Diego Ciaccio Memorial Clinic 5/28/15 ACCREDITATION STATEMENT: University of California, San Diego School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The University of California, San Diego School of Medicine designates this educational activity for a maximum of one credit per hour AMA PRA Category 1 Credits. Physicians should only claim credit commensurate with the extent of their participation in the activity. 1

2 Disclosures Speaker s Bureau: Janssen Therapeutics (HIV), ViiV (HIV), Gilead Sciences (HIV, HCV), AbbVie (HCV) Scientific Advisor: Gilead Sciences (HIV, HIV/HCV), Janssen Therapeutics (HCV) Grant/Research Support: CDC/HRSA, Northwest AETC, Pacific AETC, HealthHIV

3 Learning Objectives 1) Review newly discovered HIV therapeutics 2) Discuss clinical trials of HCV treatment in HIV patients

4 Discussion Question What is the most important challenge in HIV therapeutics? A. Discovering New ART classes B. Making ART more potent C. Making ART more convenient D. Making ART less toxic E. Developing long-acting ART (e.g. depo shots)

5 Tenofovir Alafenamide (TAF) TFV tenofovir Gut Plasma Lymphoid Cells TDF tenofovir disoproxil fumarate TFV TDF TDF TFV TAF TFV TFV-mP TAF tenofovir alafenamide TAF TAF TFV-dP TAF more stable in plasma than TDF TAF is transported into target cells, then activated to TFV-DP TAF at 25 mg (or 1 mg if boosted) has 9% lower plasma TFV compared to TDF 3 mg

6 GS-734 Dose-Ranging Study 14: Lower Plasma TFV and Higher Intracellular TFV-DP Plasma Concentrations Intracellular PBMC Concentrations TFV Plasma Concentration (ng/ml) TDF 3 mg GS mg GS mg GS mg AUC Cmax reference 79% 89% 86% 94% 96% 98% Intracellular TFV-DP (µm*h) 1 5 Ref TDF >2X ~7X ~1X GS-734 GS-734 GS-734 Time (hour) 3 mg 8 mg 25 mg 4 mg TAF 25 mg has 9% lower plasma TFV compared to TDF 3 mg Ruane P, et al. CROI

7 TAF: Clinical Applications ECF/TDF Stribild F/TDF Truvada R/F/TDF Complera DRV/c+FTC/TDF Prezcobix + Truvada TDF Hepatitis B F/TDF Truvada PrEP ECF/TAF Elvitegravir/Cobicistat/Emtricitabine AF F/TAF Emtricitabine/TAF R/F/TAF Rilpivirine/Emtricitabine DCF/TAF Darunavir/Cobicistat/Emtricitabine/ F TAF Hepatitis B F/TAF PrEP

8 GS 14/111: Tenofovir alafenamide fumarate (TAF) vs TDF in ART-naïve patients Parallel, randomized, double-blind, active-controlled phase III studies Primary endpoint: VL at Week 48 Stratified by VL CD4 count, geographic region Wk 48 Primary endpoint Wk 144 ART-naïve HIV+ pts With VL 1 c/ml, egfr 5 ml/min (N = 1733) *25/2/15/15 mg once daily. 3/2/15/15 mg once daily. TAF/FTC/EVG/COBI* single-tablet regimen (n = 866) TDF/FTC/EVG/COBI single-tablet regimen (n = 867) Wohl DA, et al. CROI LB.

9 GS 14/111: ECF/TAF non-inferior to ECF/TDF at week 48 Patients, % Δ +2.% (95% CI: -.7% to +4.7) TAF/FTC/EVG/COBI (n = 866) 8 TDF/FTC/EVG/COBI(n = 867) n = Virologic Success* Virologic Failure Wohl DA, et al. CROI LB No Data *VL < 5 c/ml as defined by FDA Snapshot algorithm Discontinued for AE, death, or missing data. 6 Results similar across all baseline virologic and demographic subgroups.9% in TAF arm and 1.5% in TDF arm discontinued due to AE CD4 increases greater in TAF arm: 211 vs 181 (P =.24)

10 TAF vs. TDF: Resistance E/C/F/TAF n=866 E/C/F/TDF n=867 Patients analyzed for resistance, n (%) 16 (1.8) 19 (2.2) Primary Genotypic Resistance NRTI Resistance, n INSTI Resistance, n Wohl D, et al. CROI LB. Any, n (%) 7 (.8) 5 (.6) Study 14, n 3 3 Study 111, n 4 2 Any 7 5 M184V/I 6 3 M184V/I + K65R 1 2 Any 5 3 T66A 1 E92Q 2 1 Q148R 1 Q148R + T66I/A 1 Q148R + E92Q 1 N155H 1

11 GS14/111: Significantly smaller decline in hip and spine BMD with ECF/TAF Smaller decline in hip and spine BMD with TAF TAF/FTC/EVG/COBI (n = 866) TDF/FTC/EVG/COBI (n = 867) Mean % Change From BL n n =845 =85 P <.1 P <.1 2 Wk Higher fasting lipids with TAF; TC:HDL ratio same [1] Wk Sax P, et al. CROI

12 GS14/111: Renal Safety 2 E/C/F/TAF E/C/F/TDF 1 Mean (SD) Change from Baseline egfr* p < Time (Weeks) n (%) E/C/F/TAF n=866 E/C/F/TDF n=867 Events Renal adverse events leading to discontinuation 4 (.5) Tubulopathy/Fanconi syndrome Sax P, et al. CROI LB.

13 GS14/111: Quantitative Proteinuria Urine [protein]:creatinine Ratio Median % Change from Baseline (Q1, Q3) Protein (UPCR) Albumin (UACR) 7 9 RBP 51 Beta2- microglobulin E/C/F/TAF E/C/F/TDF p <.1 for all Baseline 44 mg/g 44 mg/g 5 mg/g 5 mg/g 64 μg/g 67 μg/g 11 μg/g 13 μg/g Sax P, et al. CROI LB.

14 Safety of Tenofovir Alafenamide in Renal Impairment: Switch to E/C/F/TAF Virologically suppressed patients on or off tenofovir DF-containing regimens (n=242) - egfr 3-6 ml/min Mean age: 68 years - On TDF-containing ART: 65% - Median egfr: 56 ml/min - Diabetes: 14%; hypertension: 39% egfr unchanged through week 48 Significant improvement (P<.1) - Urinary tubular proteins and fractional excretion of uric acid - Bone mineral density - Lipids (in those switching from non-tdf regimens) Pozniak A, et al. CROI Mean Change (ml/min) E/C/F/TAF: elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide. 1-5 Mean Change in egfr (C-G) 5 Baseline egfr (ml/min) <5 (n=8) >5 (n=162) Primary Endpoint Treatment Week

15 Safety of Tenofovir Alafenamide in Renal Impairment: Switch to E/C/F/TAF Median (Q1,Q3) egfr Change From Baseline (ml/min) Change in egfr (Cockcroft-Gault) Primary Endpoint Baseline egfr CG <5 ml/min 5 ml/min Median % Change in RBP/Creatinine Ratio (µg/g) -2-4 Retinol Binding Protein/Creatinine Ratio Weeks p <.1 at all time points (for all patients combined) Median % Change in ß2MG/Creatinine Ratio (µg/g) Beta-2 Microglobulin/Creatinine Ratio Weeks p <.1 at all time points (for all patients combined) Pozniak, A, et al. CROI Baseline egfr <5 ml/min (n=8) 5 ml/min (n=162)

16 TAF - Summary Highest 48 wk virologic success rate ever reported (92.4%) in an HIV clinical trial Wide applicability to most modern regimens - (ECF/TAF, F/TAF, RF/TAF, DCF/TAF, TAF) Non-inferior efficacy with some significant improvements in renal/bone safety over TDF May result in approval down to egfr >3

17 Discussion Question #2 Do we need more HIV drug classes? A. No, there are no more targets in HIV life cycle B. No, current ART is good enough C. Yes, resistance is on the rise D. Yes, we can always use more

18 Anti-retroviral drug targets Entry Inhibitors Nucleoside RTI Integrase Inhibitors HIV Nucleus CCR5 CD4 HIV HIV RNA HIV DNA mrna Myr Non-Nucleoside RTI Host Cell Gag-Pol Gag Protease Inhibitors Maturation Inhibitors Source: David Spach, MD

19 BMS : HIV RNA Decline at Day 11 With a Second- Generation HIV-1 Maturation Inhibitor Disrupts final step in processing of gag protein Binds gag, not protease. Greater potency and coverage of gag polymorphs than 1 st -generation maturation inhibitors Phase 2a, dose-finding study - Treatment-naïve or -experienced patients - Baseline HIV RNA >5 copies/ml and CD4 >2 cells/µl Once-daily dosing for 1 days Key results log 1 decline in HIV RNA 4 to 12 mg QD - Similar effectiveness against HIV-1 with Gag polymorphisms not responsive to first-generation maturation inhibitors - Generally safe and well tolerated Maximum Median Change (log 1 copies/ml) Placebo (n=12) -.38 Change in HIV RNA 5 mg (n=8) mg (n=12) mg (n=8) mg (n=8) mg (n=12) mg (n=8) Hwang C, et al. CROI LB.

20 BMS Novel Attachment Inhibitor: Study Design Treatment experienced patients, sensitive to all study drugs BMS mg BID + RAL + TDF N = 5 BMS mg BID + RAL + TDF N = 5 BMS mg QD + RAL + TDF N = 5 BMS mg QD + RAL + TDF N = 5 ATV/r 3 mg QD + RAL + TDF N = 5 BMS Monotherapy Substudy: 1 pts Per Study Arm Partial Blind Day 1 Week 8 Week 24 Primary Study Start of Combination Therapy Data Monitoring Committee Assessment Primary Endpoint Week 48 Long-term Follow-up Through Week 48 (Secondary Endpoint) Week 96 Long-term Follow-up Through Week 96 Thompson M, et al. CROI,

21 BMS-66368: Results Proportion of Subjects Achieving HIV-1 <5 c/ml (% with 95% CI) Treatment experienced patients, sensitive to all study drugs 1% 9% 8% 7% 6% 5% 4% 3% 2% 1% % X X X X X On Treatment Analysis Week X X X X X X Proportion <5 c/ml BMS mg BID 91% BMS mg BID 73% BMS mg QD 69% BMS mgqd 79% ATV/r 3/ 1 mg QD 88% Thompson M, et al. CROI

22 Discussion Question #3 Why might one prescribe an NRTI-sparing regimen? A. Serious prior NRTI toxicity B. Extensive NRTI resistance C. ABC-hypersensitivity + TDF toxicity D. A, B, and C E. There is never a reason to prescribe an NRTI-sparing regimen

23 LATTE: Cabotegravir + rilpirivine as maintenance ART: wk 96 results Cabotegravir (CAB): DTG analog with long half-life, oral or injectable formulations Randomized, dose-ranging phase IIb study of oral formulation Stratified by VL ( vs > 1, c/ml) and NRTI Wk 24 Induction Phase* CAB 1 mg QD + 2 NRTIs (n = 6) Wk 48 primary analysis Maintenance Phase CAB 1 mg QD + RPV 25 mg QD ART-naive pts, VL 1 c/ml (N = 243) CAB 3 mg QD + 2 NRTIs (n = 6) CAB 6 mg QD + 2 NRTIs (n = 61) CAB 3 mg QD + RPV 25 mg QD CAB 6 mg QD + RPV 25 mg QD Wk 96 *Pts with VL < 5 c/ml at Wk 24 continued to maintenance phase. Margolis D, et al. CROI 215; 554LB. EFV 6 mg QD + 2 NRTIs QD (n = 62)

24 LATTE: Virologic success through maintenance week 96 6 pts in CAB arms with PDVF at Wk 96; 4 additional pts since Wk 48 VL < 5 c/ml by Snapshot Algorithm (%) Induction Phase Maintenance Phase 4 CAB 1 mg (n = 6) CAB 3 mg (n = 6)* 2 CAB 6 mg (n = 61) EFV 6 mg (n = 62) BL Wks 84% 75% 68% 63% *DAB 3 mg selected for future development Margolis D, et al. CROI LB.

25 Discussion Question #4 Why are HIV/HCV-infected patients a special population? A. Lower SVR12 rates with the new DAA s than monoinfected HCV patients B. Faster progression of liver fibrosis than monoinfected HCV patients C. HIV/HCV patients are not a special population

26 1. Lawitz E, et al. EASL 211, poster 1219; 2. Cheng G, et al. EASL 212, poster 1172 Sofosbuvir/Ledipasvir: A Single Tablet Regimen (STR) Ledipasvir - Picomolar potency against HCV GT 1a and 1b 1 - Effective against NS5B RAV S282T 2 - Once-daily, oral, 9 mg LDV NS5A inhibitor O H O N O N N N H F F H N H N N O N O H O Sofosbuvir Potent antiviral activity against HCV GT 1 6 High barrier to resistance Once-daily, oral, 4-mg tablet H 3 C H 3 C O O CH 3 O HN P O O O O N NH O CH 3 HO F SOF - NS5B nucleotide polymerase inhibitor Ledipasvir/Sofosbuvir STR - Once-daily, oral fixed-dose (9/4 mg) combination tablet - No food effect - >2 patients treated LDV NS5A inhibitor SOF - NS5B nucleotide polymerase inhibitor Priority Review and Breakthrough Status Granted - Approved: Oct 1, 214

27 Sofosbuvir/Ledipasvir: ION Trials ION-1 12 wks +/- Ribavirin ION-2 Rx-Experienced 12 vs. 24 weeks ION-3 Rx-naïve 8 vs. 12 weeks LDV/SOF LDV/SOF+RBV SVR12 (%) / / / Weeks 24 Weeks 12 Weeks 24 Weeks ION-1 GT-1 Treatment-naïve Including Cirrhotics 215/ / / / Weeks 12 Weeks ION-3 GT-1 Treatment-naïve Non-cirrhotic 12/ 19 17/ / 19 11/ 111 ION-2 GT-1 treatment-experienced Including Cirrhotics and PI Failures

28 ION-4 - Sofosbuvlr/Ledipasvir in HIV/HCV GT1/4 Phase III open-label study in HIV virologically suppressed HIV/HCV coinfected pts (N = 335) - 2% with compensated cirrhosis - n = 8 with HCV GT4 ART regimens - TDF/FTC/EFV (n = 16) - TDF/FTC + RAL (n = 146) - TDF/FTC/RPV (n = 29) HCV treatment experienced, 55% - Previous HCV PI therapy: 29% - n = 13 previously failed SOF + RBV SVR12, % High rate of SVR n/n = No difference in SVR rates based on HCV treatment experience or cirrhosis status SVR Rates According to BL Characteristics / 335 Overall No Yes / / / 268 No 63/ 67 Yes Previous HCV Tx Cirrhosis Naggie S, et al. CROI 215; 152LB.

29 ION-4: LDV/SOF effective across all patient demographic and disease subgroups Overall Race HCV Genotype Baseline HCV RNA (IU/mL) aseline BMI (kg/m 2 ) IL28B Black Non-Black 1a 1b 4 < 8, 8, < 3 3 CC CT TT SVR12, % (95% CI) Statistically significant in multivariate analysis 1 relapses, all in black pts No HIV virologic rebound No discontinuation due to adverse events 4 pts had increase in creatinine >.4 mg/dl - 2 completed treatment without change in ART - 1 pt changed TDF to new NRTI - TDF dose reduced in 1 pt ARV Regimen TDF/FTC/EFV TDF/FTC + RAL TDF/FTC/RPV Baseline CD4 (cells/mm³) < Naggie S, et al. CROI LB.

30 ION-4: Drug-drug interactions with bpis Drug-drug interaction studies with LDV/SOF and boosted PIs and TDF - LDV/SOF increases ATV, RTV, and TFV exposure - ATV/r + TDF/FTC increases LDV - DRV/r + TDF/FTC decreases SOF Staggered administration did not mitigate interactions, but interactions not deemed clinically relevant German P, et al. CROI 215. Abstract 82.

31 ALLY-2: SOF + DCV in GT 1-6 HCV/HIV-coinfected Pts Phase III open-label study - Non GT1 < 2% in each cohort; compensated cirrhosis < 5% overall; VL < 5 and CD4 1 in pts on ART; CD4 35 in pts not on ART - ART allowed: PI/r, NRTIs, NNRTIs, INSTIs, MVC, ENF Primary endpoint: SVR12 in GT1 naive pts treated for 12 wks Wk 8 Wk 12 ART-naive pts (N = 151) ART-experienced pts (N = 52) SOF 4 mg QD + DCV 3/6/9* mg QD (n = 11) SOF 4 mg QD + DCV 3/6/9* mg QD (n = 5) SOF 4 mg QD + DCV 3/6/9* mg QD (n = 52) Pts followed to Wk 36 *Standard dose of 6 mg adjusted for ART: 3 mg with RTV; 9 mg with NNRTIs except RPV. Wyles DL, et al. CROI LB.

32 ALLY-2: Virologic outcomes with SOF + DCV High SVR12 rates with 12 wks SOF + DCV SVR12, % - Large decline in SVR rate with shortening to 8 wks n/n = 96 8/ Wk GT Overall / 43/ 98/ 38/ 51/ Wk 12-Wk 12-Wk 8-Wk 12-Wk Naive Exp d Naive Exp d In 12-wk groups analyzed by GT, 1% with SVR12 except GT1a GT1a naive: 96%; Exp d: 97% Similar SVR12 rates in pts with or without baseline NS5A RAVs 12 pts with relapse, 1 in 8-wk arm 1 relapse in 8-wk arm had emergent NS5A RAVs No NS5B RAVs at BL or time of failure No discontinuation due to AEs 1 pts with VL > 5 at EOT 8 with repeat testing; 7 with suppression without change in ART; 1 with VL of 59; 2 LTFU 2 with HIV VF = VL 4 c/ml Wyles DL, et al. CROI 215. Abstract 151LB.

33 Summary TAF is coming soon and make take over the DHHS preferred regimen list because TDF so prevalent ART pipeline is not completely dry! New agents and long-acting forms coming soon HCV is easily curable, even in HIV/co-infection. Even better oral regimens on their way soon!