2-Drug regimens in HIV Anton Pozniak MD FRCP

Transcription

1 2-Drug regimens in HIV Anton Pozniak MD FRCP

2 Advantages Cost Dual Therapy Toxicities of Nukes CV risk, bone, renal disease Smaller STRs Keep drugs for later etc.

3 Dual Therapy-Talking Points - What are the pros and cons of two drug combinations under development and products on the horizon? - How would dual therapy perform in the context of PW, TB cotreatment, Hepatitis B, adolescents, and children? What knowledge gaps must be addressed to prove dual therapy durability? - What are the pragmatic issues related to having patients on both three-drug and two-drug regimens? - How do we balance the financial impact of dual therapy with treatment durability in low-resource settings?

4 EACS (2017) 1 DHHS (2017) 2 IAS USA (2016) 3 GUIDELINES ARV First Line -Recommended and preferred regimens + ALTERNATIVE BHIVA (2016) 4 WHO (2016) 5 GUIDELINES NRTI BACKBONE NNRTI INSTI PI TAF/FTC TDF/FTC ABC/3TC* TAF/FTC TDF/FTC ABC/3TC* TAF/FTC ABC/3TC* TAF/FTC TDF/FTC ABC/3TC* TDF/XTC AZT/XTC AZT/XTC RPV* RPV* EFV EFV EFV RPV* EFV RPV EFV EFV 400 NVP DTG RAL EVG DTG RAL EVG DTG RAL EVG DTG RAL EVG DTG DRV/r or DRV/c DRV/r ATV/r ATV/r ATV/c ATV c/r DRV c/r DRV c/r 1. EACS Guidelines Version 9.0, October 2016; 2. DHHS Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents, Available from: Accessed October 2017; 3. Günthard HF, et al. JAMA 2016;316: ; 4. British HIV guidelines. Available from: Accessed October 2017; 5. WHO. Consolidated guidelines on the use of ARV drugs for treating and preventing HIV infection, Available from: /1/ _eng.pdf. Accessed October NRTI REDUCING DRV r/cr+ral LPV/r+ XTC DRV r/c+ral DRV r/c+ral DRV r/c+dtg DRV r/c+xtc DRV r/+ral

5 Dual therapy in ARV naïve? 5

6 ANRS TRILEGE Naïve patients Two drug regimen as initiation ART : A concept started..20 years ago Induction 12 weeks induction phase with AZT+3TC+IDV Then de-escalation for AZT+3TC vs AZT+IDV vs 3-DR Superiority of 3-DR But in those with baseline HIV-RNA < copies/ml, no significant difference between the 3 study arms Pialoux G, NEJM 1998 ACTG 343 Naïve patients AZT/3TC/IDV Then de-escalation to ZT+3TC vs IDV vs 3-DR Superiority of 3-DR But if high CD4 and using VS<200 cp/ml difference NS Although the results of this trial are somewhat disappointing, they should not discourage future attempts to simplify therapies for HIV Havlir DV, NEJM

7 What is needed Potency Once daily dosing High tolerability Favorable PK /long half life Virologic robustness Low primary resistance rates Dual ART : Which drugs to rely on? Potential drugs NRTI TDF/TAF - FTC PI Darunavir/r NNRTI Rilpivirine Integrase inhibitors RAL QD Dolutegravir Future drugs? Doravirine MK-8591

8 And Which combinations have been tested? Analysing the efficacy of 2-drug versus 3-drug treatments PI/r + raltegravir PI/r + maraviroc PI/r + NRTI (mainly 3TC) DTG + 3TC DTG + RPV CTV + RPV

9 LPV/r - EFV ATV/r - EFV LPV/r - NVP PIs+ NNRTIs Good virological response, but increased rate of side effects

10 MODERN: MVC QD + DRV/RTV Not-Noninferior to TDF/FTC + DRV/RTV in naïve patients Adjusted treatment difference: -9.5% (95%% CI: -14.8% to -4.2%) 86.8% TDF/FTC + DRV/RTV (n = 401) MVC + DRV/RTV (n = 396) 77.3% 0 BL Similar rates of HIV-1 RNA suppression at Wk 48 by screening assay type Assay Type Phenotypic Genotypic Δ (95% CI) MVC + DRV/RTV (n = 396) % (-1.3% to 15%) Wk IDMC, Sept 27th 2013 (Wk 48 preliminary review): Recommendation to terminate the trial, MVC has inferior efficacy compared to TDF/FTC 1. Stellbrink HJ, et al. AIDS 2014 Graphic used with permission. Abstract MOAB van Lunzen J, et al. AIDS Abstract LBPE19. TDF/FTC + DRV/RTV (n = 401) NR

11 ATV 300 mg BID + RAL in NAIVE SPARTAN Week 24 Results 100 NC = F 100 NC = M % 63.3% 20 0 ATV + RAL (n=63) ATV/RTV + TDF/FTC (n=30) 20 0 J J Weeks HIV-1 RNA <50 c/ml (%), CVR Weeks The overall profile did not appear optimal for further clinical development given high rate of resistance to RAL (4/6 VF) and higher rates of G4 hyperbilirubinemia with twice daily ATV compared with ATV/RTV (21% vs. 0%) KozalMJ, et al. HIV Clin Trial 2012;13: % 70.4%

12 2 Drugs in Naïve GARDEL: Dual ART With LPV/RTV + 3TC vs Triple ART With LPV/RTV + 2 NRTIs Randomized, open-label phase III noninferiority trial Primary endpoint: HIV-1 RNA < 50 c/ml (ITT-e, FDA snapshot analysis) Pts with virologic response at Wk 48 offered extension to Wk 96 Stratified by HIV-1 RNA ( vs > 100,000 c/ml) ART-naive pats with HIV-1 RNA > 1000 copies/ml; no NRTI/PI resistance; HBsAg negative (N = 426) Cahn P, et al. EACS Abstract 961. Wk 24 interim analysis Wk 48 primary analysis Lopinavir/Ritonavir 400/100 mg BID + Lamivudine 150 mg BID (n = 217) *ZDV/3TC: 54%; TDF/FTC: 37%; ABC/3TC: 9% Lopinavir/Ritonavir 400/100 mg BID + Investigator-Selected NRTIs in FDC* (n = 209) Wk 96 extension analysis

13 Pts (%) GARDEL: Dual ART Noninferior to Triple ART at Wk 48 and Wk 96 Safety and tolerability also similar between treatment arms Virologic Success Cahn P, et al. EACS Abstract Wk 48 difference: +4.6% (95% CI: -2.2 to 11.8; P =.171) Wk 96 difference: +5.9% (95% CI: -2.3 to 14.1; P =.165) Virologic Nonresponse D/C due to AE or Death Dual ART Triple ART Wk: D/C for Other Reasons

14 PI 3TC Dual DRV/r 800/100 +3TC vs TDF+FTC+DRV/r in naïve patients Phase 4, randomized, multicentric, open label study, Wk 48 Primary endpoint 145 ARV- naive patients 5 sites in Argentina 18 years 4.5 log HIV copies/ml 24% >5 log CD4 : 383 /mm3 No IAS-USA defined NRTI or PI resistance at screening* HB(s)Ag negative P. Cahn IAS 2017 MoAB0106LB Stratified at screening by HIV-1 RNA ( or > 100,000 copies/ml) Dual therapy DRV/r 800/100mg QD + 3TC 300 mg QD n= 75 Triple therapy : DRV/r 800/100mg QD + 3TC /TDF 300/300mg QD n=70 % HIV RNA < 400 cp/ml Wk 24 Interim analysis ITT snapshot 95% On Treatment 100% Discontinuations 4 Withdraw consent (1),SAE (1), LTFU (1), RASH (1) ITT snapshot 97% On Treatment 99 % Discontinuations 1 PDVF 1

15 PI/Ral 805 ART naive patients CD4 : 345/mm 3 CV : 4.76 log > 10 5 cp/ml : 35% NEAT 001/ANRS 143 DRV/r + RAL vs DRV/r + TDF/FTC % HIV RNA < 50 c/ml DRV/r + RAL, 89.4% (95% CI : ) DRV/r + TDF/FTC, 93.3% (95% CI : ) When CD4 are low or VL high prefer triple ART Raffi F. Lancet 2014;384:

16 Integrase-PADDLE Study: Efficacy-DTG and 3TC in Naïve patients # SCR BSL DAY 4 DAY 7 W.2 W.3 W.4 W.6 W.8 W.12 W.24 W.36 W <50 <50 <50 <50 <50 <50 <50 <50 < <50 <50 <50 <50 <50 <50 <50 <50 <50 < <50 <50 <50 <50 <50 <50 < <50 <50 <50 <50 <50 <50 < <50 <50 <50 <50 <50 <50 <50 < <50 <50 <50 <50 <50 <50 <50 <50 < <50 <50 <50 <50 <50 <50 <50 <50 < Not done 105 <50 <50 <50 <50 <50 <50 <50 < <50 <50 <50 <50 <50 <50 <50 SAE <50 <50 <50 <50 <50 <50 <50 <50 <50 < <50 <50 <50 <50 < <50 <50 <50 <50 <50 < <50 <50 <50 <50 <50 <50 <50 < < <50 <50 <50 <50 <50 < <50 <50 <50 Not done <50 <50 <50 <50 < <50 <50 <50 <50 <50 <50 <50 <50 < <50 <50 <50 <50 <50 <50 <50 < <50 <50 <50 <50 <50 <50 <50 < <50 <50 <50 <50 <50 PDVF <50 <50 <50 <50 <50 <50 <50 <50 <50 SAE = serious adverse event Cahn P, et al. AIDS 2016; Durban, South Africa; July 18-22, 2016; Abst. FARB0104LB. PDVF = protocol defined virologic failure

17 PADDLE Study: Efficacy-DTG and 3TC in Naïve patients # SCR BSL DAY 4 DAY 7 W.2 W.3 W.4 W.6 W.8 W.12 W.24 W.36 W <50 <50 <50 <50 <50 <50 <50 <50 < <50 <50 <50 <50 <50 <50 <50 <50 <50 < <50 <50 <50 <50 <50 <50 < <50 <50 <50 <50 <50 <50 < <50 <50 <50 <50 <50 <50 <50 < <50 <50 <50 <50 <50 <50 <50 <50 < <50 <50 <50 <50 <50 <50 <50 <50 < Not done 105 <50 <50 <50 <50 <50 <50 <50 < <50 <50 <50 <50 <50 <50 <50 SAE <50 <50 <50 <50 <50 <50 <50 <50 <50 < <50 <50 <50 <50 < <50 <50 <50 <50 <50 < <50 <50 <50 <50 <50 <50 <50 < < <50 <50 <50 <50 <50 < <50 <50 <50 Not done <50 <50 <50 <50 < <50 <50 <50 <50 <50 <50 <50 <50 < <50 <50 <50 <50 <50 <50 <50 < <50 <50 <50 <50 <50 <50 <50 < <50 <50 <50 <50 <50 PDVF <50 <50 <50 <50 <50 <50 <50 <50 <50 SAE = serious adverse event Cahn P, et al. AIDS 2016; Durban, South Africa; July 18-22, 2016; Abst. FARB0104LB. Large randomised phase 3 Studies being performed by ViiV. Gemini Data available Q PDVF = protocol defined virologic failure

18 Phase II, single-arm, 52- week, pilot study VL 1000 and <500,000 cpm Primary outcome Success VL < 50 cpm at W24 Non success VL>400 W16 or W20 VL>200 after W24 * Poor adherence; # Lost to follow-up, pregnancy ACTG 5353 Dolutegravir/3TC in naive pts % VL<50 cp/ml snapshot W24 Baseline HIV-1 RNA > 100,000 N=37 100,000 N=83 Total N=120 Virologic success 33 (89%) 75 (90%) 108 (90%) HIV-1 RNA < 50 cpm [95% CI] [75-97%] [82%,96%] [83%,95%] Virologic non-success 3 (8%) 2 (2%) 5 (4%) HIV-1 RNA 50 cpm Discontinued study Rx while HIV RNA 50* No virologic data in window 1 (3%) 6 (7%) 7 (6%) Discontinued study treatment for other reasons # On study but missing data in window [95% Confidence intervals] for proportion of participants with virologic success at Week 24 B.Taiwo et al IAS 2017

19 HIV-1 RNA (copies/ml) Taiwo BO, et al. IAS Abstract MOAB0107LB. And Resistance!! ACTG A5353: DTG/3TC in Naives Patient BL HIV-1 RNA 100,000 copies/ml Off DTG HIV-1 RNA < limit of detection No detectable DTG DTG Concentration (ng/ml)

20 DTG/3TC Other Disadvantages Health Warning! Not in countries without Hepatitis B screening and vaccination programs. Pregnancy? TB? High Viral Load? DDI with DTG

21 Prevalence of Hepatitis B in Africa Country HBsAg+ prevalence Zambia 6.5% Gabon 9.5% Cameroon 10.5% Mauritania 10.9% Ghana 13.5% Nigeria 13.6% Senegal 13.8% Burkina Faso 14.5% Zimbabwe 25.0% Zampino et al. WJG 2015, 21: 11941

22 AND Only Combinations with Reverse Transcriptase Inhibitors work!!

23 Advantages -Cost Vittoria JIAS 2016;19:20504

24 Girouard et al: CID 2016

25 SWITCH-Undetectable Dual therapy randomised studies Again 25

26 bpi+3tc for Maintenance of Virological Suppression: Individual Patient Meta-analysis At 48w, 4% of patients on DT vs. 3.04% on TT had HIV-RNA 50 cop/ml HIV-RNA 50 cop/ml at week 48 Dual therapy triple therapy (%) SALT ATLAS DUAL OLE POOLED Difference 0.9% (95%CI, -1.3% to 3.2%) Favours DT Treatment difference (DT vs. TT) was not affected by Sex, HCV infection status or type of PI Perez-Molina J, et al; 16th EACS, Milan, Italy, October 25-27, 2017; Abst. PD1/1. 0% 4% Absolute risk difference, (95% CI) Non-inferiority margin: 4% 1.40 (-2.80, 5.60) (-5.90, 4.40) 1.50 (-2.20, 5.30) 1.70 (-2.60, 6.00) 0.90 (-1.30, 3.20)

27 Baseline characteristics and primary outcome at W48 PI/r monotherapy N = 133 PI/r + 3TC N = 132 Median age, years Female, % HIV RNA < 50 c/ml, % CD4/mm 3, median Nadir CD4 < 100/mm 3, % PI/r = DRV, % Months on first-line cart, median Months on second-line cart, median M184V at first failure, % Resistance to one 2 nd line-drug, % Resistance to two 2 nd line-drug, % Failure, ITT, % (95% CI) Virological failure, N NRTI reintroduction, N Death, lost to follow-up, N ( ) 28 * 2 3 * All failure resuppressed to HIV RNA < 200 c/ml a median of 10 weeks after NRTI reintroduction MOBIDIP MOBIDIP Study: switch to PI/r + 3TC vs PI/r monotherapy in Stable patients with suppressed VL <200 copies/ml ( ) (p < 0.001) 3 * 0 1 Ciaffi L, Lancet HIV 2017, May 28, 2017 (Epub ahead of print)

28 Dual Therapy: Potential DTG-Based Regimens for Initial/Maintenance Therapy Regimen Treatment Setting Studies DTG + RPV DTG + 3TC Maintenance Initial DTG/RPV STR now FDA approved for maintenance therapy [1,2] GEMINI 1/2 (randomized phase III) [3,4] PADDLE* (open-label phase IV) [5] ACTG A5353* (phase II) [6] Maintenance ASPIRE* (randomized phase III) [7] DTG + DRV/RTV Maintenance DUALIS (randomized phase III) [8] DTG + ATV/RTV Maintenance DOLATAV (phase II) [9] DTG + MVC Maintenance HP (single-arm phase III) [10] *Available data.

29 Taiwo B, et al; 16th EACS, Milan, Italy, October 25-27, 2017; Abst. PE8/5. Dolutegravir Plus Lamivudine for Maintenance of Suppression (ASPIRE) Virologic Outcomes at Week 48 (FDA Snapshot) N On Study

30 Pts (%) Switch From Suppressive ART to DTG + RPV-SWORD Noninferior to Continued Baseline ART at Wk HIV-1 RNA < 50 c/ml Llibre JM, et al. CROI Abstract 44LB. DTG + RPV (n = 513) Baseline ART (n = 511) Treatment difference: -0.2% (95% CI: -3.0% to 2.5%) < 1 1 Virologic Nonresponse Wk No Data 1 pt with confirmed criteria for virologic withdrawal at Wk 36 in DTG + RPV arm had K101K/E (1.2-fold RPV change) Resuppressed with continued DTG + RPV No INSTI resistance AE rates generally similar between treatment arms through Wk 52 Numerically higher rate of drug-related grade 1/2 AEs with switch: 17% vs 2% Numerically higher rate of withdrawal for AEs with switch: 4% vs < 1%

31 DTG/RPV FDA Approved for Maintenance Therapy Once-daily single-tablet regimen of DTG and RPV First 2-drug STR FDA approved for use as a complete regimen in the US Indication Administration requirements Key DDIs Dose adjustments DTG/RPV [package insert]. November Key US Label Information For pts who have been virologically suppressed for 6 mos Pts must have no history of treatment failure and no resistance to DTG or RPV Must be taken with a meal Separate dose of DTG/RPV and antacid/polyvalent cation containing medications Avoid PPIs (eg, omeprazole, pantoprazole), dexamethasone None required for pts with mild/moderate renal impairment; in pts with CrCl < 30 ml/min, increase monitoring for AEs Slide credit: clinicaloptions.com

32 Switch to Long acting Injectables LATTE-2 HIV-1 RNA <50 c/ml at Week 48: ITT-ME (Snapshot) Both Q8W and Q4W comparable to Oral CAB at Week 48 a a Met prespecified threshold for concluding IM regimen is comparable to oral regimen (Bayesian Posterior Probability >90% that true IM response rate is no worse than -10% compared to the oral regimen). Observed Bayesian Probabilities: Q8W vs Oral = 99.7%; Q4W vs Oral = 99.4%. Margolis et al. AIDS 2016; Durban, South Africa. Abstract THAB0206LB.

33 Switch to Long acting Injectables LATTE-2 HIV-1 RNA <50 c/ml at Week 48: ITT-ME (Snapshot) Resistance to CAB has been found Detectable CAB can remain for up to one year? Impact on resistance long term and transmitted resistance Both Q8W and Q4W comparable to Oral CAB at Week 48 a a Met prespecified threshold for concluding IM regimen is comparable to oral regimen (Bayesian Posterior Probability >90% that true IM response rate is no worse than -10% compared to the oral regimen). Observed Bayesian Probabilities: Q8W vs Oral = 99.7%; Q4W vs Oral = 99.4%. Margolis et al. AIDS 2016; Durban, South Africa. Abstract THAB0206LB.

34 SWITCH-detectable Dual therapy randomised studies And Again 34

35 Has PI/r plus integrase a role in Treatment experience? In treatment-experienced patients, RAL+LPV/r was non-inferior to 2NRTI+LPV/r No efficacy advantage EARNEST and SECOND-LINE studies No significant difference in number of Grade 3 or 4 adverse events Costs of RAL+LPV/r significantly higher than 2NRTI+LPV/r in most countries

36 Switch to DTG + RPV in Suppressed Pts With Multiple Previous Treatment Failures Open-label cohort study based in clinical practice setting (N = 38) DTG 50 mg/day + RPV 25 mg/day for pts with long-term virologic suppression but virologic failure on > 1 previous ART regimens Baseline Characteristic, % Switch to DTG + RPV (N = 38) Regimen at time of switch Reasons for switch to DTG + RPV Pre-existing resistance mutations HIV-1 RNA suppressed to < 35 copies/ml in 92% (35/38) at Wk 48 No virologic failures; 3 pts d/c (GI toxicity, DDI, physician decision, n = 1) DTG + RPV associated with improved liver function tests, improved lipid profile, and stable kidney function at Wk 48 Díaz A, et al. AIDS Abstract TUPDB0106. NRTI + NNRTI + PI NRTI + NNRTI + PI + INSTI Drug drug interaction Toxicity Simplification NRTI: 65; NNRTI: 37; PI: 32; INSTI: NA

37 What are the Risks? Switching to Dual RX in LMICs What is the value? Is the cost differential going to save money when you may have VF and INSTI resistance at 1%? Is the toxicity argument a valid one?

38 Switching When Vl and resistance is NOT known CanYou switch to boosted PI and recycle nucleosides-yes -Earnest and Second Line But Can You switch to DTG and nucleosides without VL and resistance testing? What is the consequence of this??

39 Consequences of 100 patients with missing viral load What could happen if they switch to TDF/3TC/DTG? 80% RNA suppression 7% RNA+, >1 active NRTI 7% RNA+, poor adherence 6% RNA+, no active NRTIs

40 Dual Therapy-Conclusions -What are the pros and cons of two drug combinations under development and products on the horizon-cost, toxicity, smaller pills knowledge gaps TB co-infection, Hepatitis B, Pregnancy adolescents, and children? Awaiting -Large randomised studies in ART Naïve What are the pragmatic issues related to having patients on both three-drug and two-drug regimens-how to switch How do we balance the financial impact of dual therapy with treatment durability in low-resource settings careful if no VL or resistance testing