SELECTING THE BEST ART FOR EACH PATIENT

Transcription

1 SELECTING THE BEST ART FOR EACH PATIENT Corklin R Steinhart, MD, PhD Head, Global Medical Directors ViiV Healthcare CNVX/HIVP/0025/16 5th Asian Conference on Hepatitis & AIDS 第五届亚洲肝炎与艾滋病学术会议 May 2016, Nanjing, China 2016 年 5 月 28 至 29 日中国南京 1

2 DISCLAIMER I am a full time employee of ViiV Healthcare

3 ART DEVELOPMENT HAS TRANSFORMED THE PROGRESSION OF HIV AIDS-related mortality and/or morbidity Viral replication HIV-related morbidity ART initiated according to pre-treatment CD4 cell count criteria results in optimal reduction in mortality and/or morbidity Effective treatment with ART reduces viral replication, resulting in delayed disease progression ART can delay, prevent or reverse HIVassociated damage and complications including kidney and liver disease, various malignancies, cardiovascular disease and neurologic conditions Prevention of HIV transmission Convenience ART effectively suppresses HIV replication, therefore reducing likelihood of perinatal and/or sexual transmission ARTs offer better tolerability, dosing regimens and overall convenience and supports better adherence, making earlier treatment more realistic DHHS (2012) Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Available at:

4 ANTIRETROVIRALS IN 2016 NRTIs Abacavir (ABC) Didanosine (ddi) Emtricitabine (FTC) Lamivudine (3TC) Stavudine (d4t) Tenofovir (TDF) Zidovudine (ZDF) NNRTIs Delavirdine Efavirenz (EFV) Etravirine (ETR) Nevirapine (NVP) Nevirapine XR (NVP XR) Rilpivirine (RPV) PIs Atazanavir (ATV) Darunavir (DRV) Fosamprenavir (FPV) Indinavir (IDV) Lopinavir (LPV) Nelfinavir (NFV) Ritonavir (RTV) Saquinavir (SQV) Tipranavir (TPV) INIs Raltegravir (RAL) Dolutegravir (DTG) Elvitegravir (EVG) Fusion inhibitors Enfuvirtide (ENF) Entry inhibitors Maraviroc (MVC) Integrase Inhibitors INI, integrase Inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; PK, pharmacokinetic PK boosters Ritonavir (/r) Cobicistat (COBI) Single pill regimens Atripla (EFV/TDF/FTC) Eviplera (RPV/TDF/FTC) Stribild (EVG/COBI/ TDF/FTC) Triumeq (DTG/ABC/3TC) Genvoya (EVG/COBI/ TAF/FTC) Adapted from

5 ART CONSIDERATIONS IN THE ERA OF LIFE LONG THERAPY Because therapy is expected to be sustained indefinitely, regimen choice must consider patient convenience, potential toxicities, and tolerability that may affect adherence IAS guidelines 2012 IAS, International AIDS Society. Available at:

6 COMPARING PREFERRED AND ALTERNATIVE 1ST LINE ARV OPTIONS (DHHS, IAS, EACS AND WHO ART GUIDELINES) Guidelines IAS (2014) DHHS (2015) EACS (2015) WHO (2015) NRTI Backbone NNRTI INSTI PI TDF/FTC ABC/3T C AZT/3TC EFV NVP RIL DTG EVG RAL ATV DRV LPV Preferred Alternative Not recommended/special situations WHO Guidelines. EACS 2015; Barcelona, Spain.

7 COMPARING INTEGRASE INHIBITORS* Agent Advantages Disadvantages Raltegravir Longest experience Fewer drug interactions than EVG, DTG Elvitegravir Single-tablet regimen Once-daily dosing Dolutegravir Once-daily dosing Higher barrier to resistance Few drug interactions Active against some RALand EVG-resistant virus The only non-tdf containing single-tablet regimen Twice-daily dosing (for now) No coformulation Requires COBI boosting COBI drug interactions similar to RTV Coformulated with ABC/3TC only Increases metformin levels *Adapted from Evidence-Based Strategies for Individualizing ART Regimens clinicaloptions,com/hiv, 2015

8 OVERVIEW OF DTG STUDIES Exploring the breadth of data to support DTG

9 EXTENSIVE CLINICAL PROGRAM WITH 3,041 PATIENTS ACROSS 5 PHASE III TRIALS SINGLE 1 DTG + ABC/3TC vs Atripla (N=833) SPRING-2 2,3 DTG vs RAL* (N=822) * In combination with either TDF/FTC or ABC/3TC. In combination with an OBR. Patients received DTG + current failing regimen days 1-7. From day 8 on, patients received DTG in combination with an OBR. FLAMINGO 4 DTG vs DRV/r* (N=484) Treatment-naïve SAILING 5 DTG vs RAL (N=719) Treatment experienced VIKING-3 6 DTG BID (N=183) Heavily treatment experienced 1. Walmsley S, et al. N Engl J Med 2013; 369: Raffi F et al. Lancet 2013;381: Raffi F, et al. Lancet Infect Dis 2013; 13: Feinberg J et al. Slides presented at ICAAC Sept 10-13, 2013 Abstract H-1464a 5. Cahn P, et al. Lancet 2013;382(9893): Nichols G, et al. IAS Poster TULBPE19

10 VIIV/DLG/0003/13c (December 2013) Well. How efficacious is DTG in ARV-naïve pts?

11 SINGLE STUDY DESIGN 1,2 Treatment naïve, HIV-1 positive HLA-B*5701 negative HIV-1 RNA 1000 c/ml Creatinine clearance >50 ml/min Stratified by baseline viral load and CD4 cell count DTG 50 mg QD plus ABC/3TC FDC plus EFV/TDF/FTC placebo (N=414) EFV/TDF/FTC QD plus DTG + ABC/3TC FDC placebo (N=419) DTG 50 mg QD plus ABC/3TC FDC open label EFV/TDF/FTC QD open label DTG 50 mg QD plus ABC/3TC FDC open label Screening Visit (~Day 21) Randomisation (Day 1) Analysis Week 48 Analysis Week 96 Analysis Week 144 Screening period Randomised phase Open-label phase Continuation phase Primary endpoint: Proportion with HIV-1 RNA <50 c/ml at Week 48, FDA snapshot analysis (10% non-inferiority margin with pre-specified tests for superiority) Adapted from 1. Walmsley S, et al. N Engl J Med 2013;369: Walmsley S, et al. CROI Abstract 543

12 VIROLOGIC RESPONSE THROUGH TO WEEK 144 DTG + ABC/3TC remained statistically superior to EFV/TDF/FTC through to Weeks 96 1 and Proportion with HIV-1 RNA <50 c/ml % 81% 80% 72% Week 144 adjusted difference in response (95% CI): +8.3% (+2.0% to +14.6%); p= % 63% DTG 50 mg + ABC/3TC FDC QD EFV/TDF/FTC QD BL Week 1. Walmsley S, et al. CROI Abstract Adapted from Pappa K, et al. ICAAC Abstract H-647a

13 Virologic success* at week 144 (%) EFFICACY SNAPSHOT BY SUBGROUPS AT WEEK % 60% 40% 20% 0% 73% 69% 64% 61% 204/ / / / % 64% 60% 56% 262/ 230/ / 57 35/ 62 69% 46/ 67 48% 30/ 63 72% 72% 71% 71% 66% 250/ / 356 DTG 50 mg + ABC/3TC QD EFV/TDF/FTC QD 204/ 202/ / % 62/ 133 HIV-1 RNA (copies/ml) CD4 cell count (cells/mm 3 ) Gender Race Response rates were consistently higher for the DTG + ABC/3TC arm than the EFV/TDF/FTC arm, including among people with a high baseline VL, low baseline CD4 count, women and non-whites *HIV-1 RNA <50 c/ml Adapted from Pappa K, et al. ICAAC Abstract H-647a

14 300 Adjusted mean change from baseline CD4+ cell count (cells/mm 3 ) MEAN CHANGE IN CD4+ CELL COUNT AT WEEK 48, WEEK 96 AND WEEK 144 DTG+ABC/3TC cells/mm 3 EFV/TDF/FTC cells/mm 3 Week 48 difference in response (95% CI): 59 (33 to 84); P<0.001 DTG 50 mg + ABC/3TC FDC QD EFV/TDF/FTC QD Week At Week 96, mean change from baseline was cells/mm 3 versus cells/mm 3 ; p=0.004) 2 At Week 144, mean change from baseline was cells/mm 3 versus cells/mm 3 ; p=0.003) 3 Significant at pre-specified level of 4% 1. Walmsley S, et al. N Engl J Med 2013;369: Walmsley S, et al. CROI Abstract Pappa K, et al. ICAAC Abstract H-647a

15 SPRING-2 STUDY DESIGN Treatment naïve, HIV-1-infected adults HIV-1 RNA 1000 c/ml Stratified by NRTI and viral load DTG (50 mg QD) plus RAL placebo (BID) + 2 NRTIs* (N=411) RAL (400 mg BID) plus DTG placebo (QD) + 2 NRTIs* (N=411) DTG (50 mg QD) open label + 2 NRTIs Screening Visit (Day - 14) Randomisation (Day 1) Analysis Week 48 Analysis Week 96 Screening period Randomised phase Open-label phase Primary endpoint: proportion of subjects with HIV-1 RNA <50 c/ml at Week 48 (FDA Snapshot), with a 10% non-inferiority margin *Investigator s selection ABC/3TC or TDF/FTC FDA, Food and Drug Administration Raffi F, et al. Lancet 2013;381:735 43

16 IN TREATMENT-NAÏVE PATIENTS, DTG WAS NON- INFERIOR TO RAL AT 96 WEEKS Number of responders/ total assessed, n (%) Difference in proportion (95% CI) (DTG - RAL) Adjusted difference in proportion (95% CI) (DTG - RAL) Treatment DTG 50 mg QD 332/411 (81) 4.4% ( 1.2%, 10.0%) 4.5% ( 1.1%, 10.0%) RAL 400 mg BID 314/411 (76) DTG and RAL were associated with similar increases in CD4+ cell count from baseline over time. 1 3 Error bars indicate 95% CI 1. Adapted from Raffi F, et al. Lancet Infect Dis 2013; 13: Raffi F et al. IAS Poster TULBPE17 3. Raffi F et al. Lancet 2013;381:735 43

17 DTG EFFECTIVE REGARDLESS OF BASELINE VIRAL LOAD OR BACKGROUND REGIMEN (WEEK 96) Percent with HIV-1 RNA <50 c/ml ( 6.1, 6.3) ,000 >100,000 Baseline plasma HIV-1 RNA, c/ml ABC/3TC DTG 50 mg QD RAL 400 mg BID 15.1 (3.5, 26.8)* 1.6 ( 11.0,7.7) 8.6 (1.7, 15.5) TDF/FTC Background dual NRTI *P=0.026; P=0.083; p-values evaluated using a test for homogeneity Adapted Raffi F, et al. Lancet Infect Dis 2013; 13:927-35

18 FLAMINGO STUDY DESIGN 1,2 Treatment-naive HIV-1 RNA 1000 c/ml Stratified by baseline HIV-1 RNA (> or 100,000 c/ml) and background NRTIs* DTG 50 mg QD + 2 NRTIs* (N=242) DRV/r 800/100 mg QD + 2 NRTIs* (N=242) DTG 50 mg QD open label + ARVs Screening visit Screening period Randomisation (Day 1) Analysis Week 48 Open-label, randomised phase Analysis Week 96 Extension phase Primary endpoint: Proportion with HIV-1 RNA <50 c/ml at Week 48 (FDA Snapshot with a 12% non-inferiority margin and pre-specified tests for superiority) *Stratified by HIV-1 RNA >100,000 or 100,000 c/ml and ABC/3TC or TDF/FTC Adapted from 1. Clotet B, et al. Lancet 2014;383: Feinberg J, et al. ICAAC Abstract H-1464a

19 VIROLOGIC RESPONSE AT WEEK 96 Proportion with HIV-1 RNA <50 c/ml (%) % CI for difference Favours Favours DRV/r DTG % 0% 25% Test for superiority: p=0.002 DTG : 80% DRV/r : 68% B L Week 8 6 Differences largely driven by lower virologic failure rate and fewer withdrawals due to AEs in the DTG arm plus 2 NRTIs DTG 50 mg QD DRV/r 800/100 mg QD Molina JM, et al. HIV Drug Therapy Glasgow Abstract O153

20 VIROLOGIC RESPONSE BY BASELINE VIRAL LOAD AND DUAL NRTI THERAPY AT WEEK 96 Proportion with HIV-1 RNA <50 c/ml(%) DTG 50 mg QD DRV/r 800/100 mg QD 80% 80% 82% 82% 79% 73% 75% 68% 64% 52% N=484 n=362 n=122 n=159 n=325 Overall 100,000 c/ml >100,000 c/ml ABC/3TC TDF/FTC Baseline HIV-1 RNA Background NRTI Molina JM, et al. HIV Drug Therapy Glasgow Abstract O153

21 But how well tolerated and safe is DTG? VIIV/DLG/0003/13c (December 2013)

22 SUMMARY TOLERABILITY DATA FOR ARV NAÏVE PTS ART-naïve patients (n=833) 1,2 DTG + ABC/3TC was better tolerated vs Atripla with fewer discontinuations 13% vs 27% experienced drug-related AEs (Grades 2 to 4) 1 4% vs 14% discontinued due to AEs at 144 weeks 2 ART-naïve patients (n=822) 3,4 DTG offers similar tolerability to RAL 2% vs 2% discontinued due to AEs at 48 weeks 2% vs 2% discontinued due to AEs at 96 weeks ART-naïve patients (n=484) 5 DTG was well tolerated with lower rates of diarrhoea vs darunavir/r 2% vs 4% discontinued due to AEs at 48 weeks 1. Data on file. UK/DLG/0026/13,01/11/13 2. Walmsley S, et al. N Engl J Med 2013; 369: Raffi F et al. Lancet 2013;381: Raffi F, et al. Lancet Infect Dis 2013; 13: Feinberg J et al. Slides presented at ICAAC Sept 10-13, 2013 Abstract H-1464a

23 CHANGE FROM BASELINE TO 144 WEEKS IN RENAL PARAMETERS Mean change from baseline (SD) in serum creatinine, mg/dl 0,3 0,2 0,1 0-0,1-0,2 No. of patients DTG + ABC/3TC EFV/TDF/FTC BL Week DTG 50 mg + ABC/3TC QD EFV/TDF/FTC QD DTG + ABC/3TC QD EFV/TDF/FTC QD Parameter Week 48 Week 96 Week 144 Week 48 Week 96 Week 144 Urine albumin/creatinine ratio (mg/mmol) Median change (IQR) (-0.3, -0.3) (-0.3, 0.2) (-0.4, 0.2) (-0.2, 0.3) (-0.2, 0.3) (-0.2, 0.4) Adapted from Pappa K, et al. ICAAC Abstract H-647a

24 Is it convenient to take? VIIV/DLG/0003/13c (December 2013)

25 CONVENIENCE BEYOND ONCE-DAILY DOSING No boosting required Small tablet size Attributes of DTG No time-of-day restrictions Can be taken with or without food Few DDIs with commonly used medications TIVICAY (dolutegravir) Summary of Product Characteristics, 11/2013

26 DTG HAS FEW INTERACTIONS WITH COMMONLY USED MEDICATIONS 1,2,3 Commonly used medications Oral contraceptives Proton pump inhibitors H 2 antagonists (including cimetidine, famotidine, nizatidine, ranitidine) Methadone Hepatitis B transcriptase inhibitor (adefovir) Hepatitis C protease inhibitors (telaprevir, boceprevir) Antidepressants Statins Rifampicin Magnesium/aluminium-containing antacids Calcium and iron supplements Multivitamins EFV, NVP, and TPV/r ETV Dose adjustment required No No No No No* No No* No* Dose DTG 50 mg BID Avoid in INI-class resistance Dose separate DTG 2 hours before or 6 hours after these medicines Dose DTG 50 mg BID Avoid in INI-class resistance Must only be used in combination with ATV/r, DRV/r or LPV/r at a dose of 50 mg QD DTG and dofetilide coadministration contraindicated due to potential life-threatening toxicity caused by high dofetilide concentration DTG is not primarily metabolised via the CYP450 pathway List is not complete, and for further information the TIVICAY SmPC should be consulted * Based on results from other drug interaction trials, DTG is not expected to affect the pharmacokinetics of these drugs DTG is metabolised by the UGT1A1 pathway 1. TIVICAY (dolutegravir) Summary of Product Characteristics, 11/ Fantauzzi A et al. HIV/AIDS (Auckl) 2013;5: Teixeira R et al. Braz J Infect Dis 2013;17(2): )

27 VIIV/DLG/0003/13c (December 2013) What about DTG s barrier to resistance?

28 N (%) SUMMARY OF EMERGENT MUTATIONS IN DTG PHASE III CLINICAL TRIALS IN TREATMENT-NAIVE SUBJECTS SPRING-2 1 (to Week 96)* DTG 50 mg QD (N=411) RAL 400 mg BID (N=411) DTG 50 mg +ABC/3TC QD (N=414) SINGLE 2,3 (to Week 144)* EFV/TDF/FTC QD (N=419) FLAMINGO 4,5 (to Week 96) DTG 50 mg QD (N=242) DRV/r 800/100 mg QD (N=242) Subjects with PDVF 22 (5) 29 (7) 39 (9) 33 (8) 2 (<1) 4 (2) Integrase genotypic results at baseline and time of PDVF INI-resistant mutations 0 1 (6) RT genotypic results at baseline and time of PDVF NRTI-resistant mutations 0 4 (21) 0 1 (K65R) 0 0 NNRTI-resistant mutations 0 6 (K101E, K103N, K103K/N G190G/A) PI-resistant mutations *PDVF defined as two consecutive plasma HIV-1 RNA values 50 c/ml between Weeks 24 and 96 PDVF defined as two consecutive plasma HIV-1 RNA values >200 c/ml on or after Week 24 Adapted from: 1. Raffi F, et al. Lancet Infect Dis 2013;13: One subject had INI-resistance mutations and NRTI-resistance mutations 2. Pappa K, et al. ICAAC Abstract H-647a E157Q/P polymorphism detected with no significant change in phenotypic susceptibility 3. ViiV data on file (SINGLE 144-week Clinical Study Report) One subject had phenotypic resistance to nelfinavir 4. Clotet B, et al. Lancet 2014;383: PDVF, protocol defined virologic failure; PI, protease inhibitor; RT, reverse transcriptase 5. Molina JM, et al. HIV Drug Therapy Glasgow Abstract O153 28

29 OVERALL CONCLUSIONS: RESISTANCE PROFILE OF DTG In-vitro studies suggest DTG has a high barrier to resistance 1,2 In treatment-naïve subjects, no evidence of treatment-emergent resistance observed with DTG to date 3,4 In treatment-experienced, INI-naïve subjects, development of INI resistance was lower with DTG than with RAL, and was associated with low fold change in IC 50 5 In treatment-experienced, INI-resistant subjects previously treated with RAL or EVG, a number of INI resistance mutations were required to confer reduced susceptibility to DTG 6,7 No in-vivo evidence of emergence of novel mutations that result in a substantial decrease in DTG susceptibility to date 5 7 The slower dissociation of DTG and the need for accumulation of multiple RALassociated mutations contribute to its distinct resistance profile and potential to have a higher barrier to resistance 8 1. Sato A, et al. IAS Abstract WEPEA097; Seki T, et al. CROI Poster J Raffi F, et al. Lancet 2013;381:735 43; 4 Walmsley S, et al. N Engl J Med 2013; 369: Co-administration of Tivicay with some medicines should be avoided in this population (e.g. efavirenz, nevirapine, tipranavir/ritonavir, or rifampicin). Separate formulations of DTG, ABC and 3TC are available 5. Cahn P, et al. Lancet 2013;382(9893): ; 6. Eron J, et al. J Infect Dis 2013;207: Nichols G, et al. IAS Poster TULBPE19; 8. Hightower KE, et al. Antimicrob Agents Chemother 2011;55: Triumeq & Tivicay Summary of Product Characteristics accessed 01/05/2015

30 SUMMARY Highly potent antiviral activity 1 Once daily administration without a PK enhancer 2 Low PK variability and predictable exposureresponse relationship 1,2 Distinct in-vitro resistance profile, with an apparent high barrier to resistance 3 Attributes of DTG Low potential for drug interactions 2 (favourable drug interaction profile) Can be taken without regard to meals, no significant food effect 4 Generally well tolerated 1,2 PK, pharmacokinetics 1. Min, S. et al. AIDS 2011;25: Min, S. et al. Antimicrob Agents Chemother. 2010;54: Kobayashi, M. et al. Antimicrob Agents Chemother 2011;55: Song, I. et al. Antimicrob Agents Chemother 2012;56:1627 9

31 SUMMARY HIV treatment guidelines and regimens have evolved considerably since early HAART HIV clinicians face many challenges when treating their HIV-positive patients As a result of advancements in ART, people with HIV are living longer, so there is a need for a well-tolerated, effective, lifelong therapy with few DDIs DTG is recommended as part of an initial treatment regimen in major international guidelines The use of DTG is supported by data from extensive clinical studies DTG has demonstrated a high barrier to resistance to date DTG is a suitable therapy option for patients in a variety of treatment situations, such as a treatment-naïve shift worker, a patient who switches therapy because of depression and then needs PPIs and antacids, and a patient co-infected with tuberculosis