Terapia Antirretroviral en la Infección por el VIH (problemas, retos y soluciones) Dr. Jose R

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1 Terapia Antirretroviral en la Infección por el VIH (problemas, retos y soluciones) Dr. Jose R

2 Disclosures Speaker s Bureau: Gilead Board Member/Advisory Panel: MSD, Gilead, Janssen, ViiV 2

3 2020 Challenge Source: 3

4 HIV testing and care continuum (2016) Source: 4

5 ATHENA: Older Patients Becoming More Prevalent in the HIV+ Population Proportion of HIV+ People ATHENA: Observational cohort of HIV+ pts in the Netherlands Modeling study projections: Proportion of HIV+ pts 50 yrs to increase from 28% in 2010 to 73% in 2030 Median age of HIV+ pts on combination ART to increase from 43.9 yrs in 2010 to 56.6 yrs in

6 Participants, % Prevalence of COMORBIDITIES. The AGEhIV Cohort Study Subjects 45 years with age-associated non-communicable comorbidities, by HIV serostatus (AGEhIV Study, ) 2 50 P< HIV-negative individuals (n=349) HIV-infected individuals (n=381) P=0.010 P=0.017 P=0.015 P=0.043 P< P= Hypertension Non-AIDS cancer Angina pectoris Myocardial infarction Peripheral artery disease Age-associated non-communicable comorbidity Chronic Cardiovascular liver disease disease Source: Schouten J et al. Clinical Infectious Diseases 2014; 59:

7 People (n) ATHENA and Swiss HIV Cohort Studies: Polypharmacy Among HIV+ Pts on ART Participants (%) 16,000 14,000 12,000 10, ATHENA Modeling Study [1] 3 or more comedications 2 comedications 1 comedication No comedication Predicts that 20% of pts will be taking 3 meds other than ART in Swiss HIV Cohort Study (N = 8444) [2] Prospective Observational study 0 n = 5761 n = 2233 n = 450 < 50 Yrs Yrs 65 Yrs No comedication 1 comedication 2 comedication 3 comedications 4 or more comedications 115 (5.2%) of 2233 participants yrs of age and 64 (14.2%) of 450 participants 65 yrs of age received 4 meds other than ART Source: Smit M, et al. Lancet Infect Dis. 2015;15: Hasse B, et al. Clin Inf Dis. 2011:

8 Remaining challenges: ART optimization Worsening of comorbidities Bone Renal Cardiovascular Liver CNS Interactions Polypharmacy Recreational drugs 8

9 Impact of TDF and some PIs on the risk of renal complications Prospective cohort of 22,603 PLWHIV with a normal baseline renal function * from the D:A:D study at clinics in Europe, the USA and Australia 1 ARV exposure and rates of cegfr 70 ml/min from egfr>90 ml/min, adjusted analysis 1 cegfr 70mL/min, adjusted IRR (95% CI) TDF ATV/r LPV/r 0.25 Never exposed < >36 Current ART exposure (months) TDF and some PIs are associated with an exacerbated decline of renal function over time 1,2 * Defined as egfr >90 ml/min/1.73m 2 ; adjusted for baseline egfr, age, gender, race, HIV risk group, enrolment cohort, CD4 nadir and baseline date, AIDS, HBV/HCV status, smoking status, hypertension, diabetes, CVE, CD4, viral load, and cumulative exposure to ART ART, antiretroviral therapy; ARV, antiretroviral; ATV, atazanavir; CI, confidence interval; CVE, cardiovascular event; cegfr, Cockroft-Gault estimated glomerular filtration rate; D:A:D, Data collection on Adverse events of Anti-HIV Drugs; egfr, estimated glomerular filtration rate; HBV, hepatitis B virus; HCV, hepatitis C virus; IRR, incidence rate ratio; LPV, lopinavir; PI, protease inhibitor; PLWHIV, people living with HIV; /r, ritonavir-boosted; TDF, tenofovir disoproxil fumarate 1. Ryom L et al. CROI Seattle, WA. #865; 2. Nishijima T et al. AIDS 2014;28:

10 Incidence/1,000 PYFU (95% CI) Risk of fracture for TDF and PIs EuroSIDA participants (n=11,820) across Europe, Israel and Argentina were prospectively followed until last visit or death, to assess fractures and femoral osteonecrosis, from 2004 onwards, resulting in 86,118 PYFU1,2 14 Crude incidence of new fracture and TDF use Never Ever Off On >5 Exposure to TDF Cumulative exposure to TDF (years) Adapted from Borges A et al. CROI Boston, MA. #46 Current or past TDF exposure was independently associated with a higher incidence of any fracture, but was not significant for osteoporotic fractures 1,2 PIs have also been associated with an increased risk of fracture in some studies 3 CI, confidence interval; PI, protease inhibitor; PYFU, person-years of follow-up; TDF, tenofovir disoproxil fumarate 1. Borges A et al. CROI Boston, MA. #46; 2. Borges AH et al. Clin Infect Dis 2017;64: ; 3. Bedimo R et al. AIDS 2012;26:

11 RR (95% CI) CVD incidence rate ratio (95% CI) Link between the risk of MI with ABC and some antiretrovirals D:A:D study population of 33,308 PLWHIV, followed up from enrolment until the first MI event, 1st February 2008, or 6 months after the last clinic visit 1 Relative risk (RR) of MI for different ART 1 D:A:D study population of 35,711 PLWHIV evaluating the association between CVD and PIs from 2009 to Association between CVD IRR and cumulative use of DRV + RTV NRTI PI #PYFU: ddi ABC IDV LPV/r 74,407 53,300 68,469 37,136 Never exposed Univariate/ 5 years exp Multivariate/ 5 years exp RR of recent * exposure RR of cumulative exposure/year DRV + RTV Recent exposure to ABC or ddi, and cumulative exposure to IDV, LPV/r or DRV + RTV was associated with increased risk of MI 1,2 * Current or within last 6 months; approximate test for heterogeneity: p=0.02; myocardial infarction, stroke, sudden cardiac death, invasive cardiovascular procedures; primary model; baseline adjustment only for variables on the potential causal pathway between PI/r use and CVD ABC, abacavir; ART, antiretroviral therapy; ATV, atazanavir; CI, confidence interval; CKD, chronic kidney disease; CVD, cardiovascular disease; D:A:D, Data collection on Adverse events of Anti-HIV Drugs; ddi, didanosine; DRV, darunavir; IDV, indinavir; IRR, incidence rate ratio; LPV, lopinavir; MI, myocardial infarction; PI, protease inhibitor; PLWHIV, people living with HIV; PYFU, person-years of follow-up; /r, boosted ritonavir; RR, relative risk; RTV, ritonavir 1. Lundgren JD et al. CROI Montreal, Canada. #44LB; 2. Ryom L et al. CROI Seattle, WA. Oral #128LB 11

12 Probability Risk of Suicidality in Pts Treated With EFV-Containing Regimens in ACTG Trials Treatment with EFV associated with increased risk of suicidality Absolute risk is small EFV EFV free HR: 2.28 (95% CI ; P =.006) Trend toward higher incidence of attempted or completed suicide with EFV use (HR: 2.58; 95% CI: ; P =.065) EFV also associated with increased risk of death from substance abuse, homicide, or accident Multivariable Analysis of Factors Associated With Suicidality in ACTG Clinical Trials events/5817 PY (8.08/1000 PY) 15 events/4099 PY (3.66/1000 PY) Wks to Suicidality 192 Variable HR (95% CI) P Value Randomly assigned EFV 2.08 ( ).014 Weight category, kg < 60 vs vs ( ) 1.21 ( ).022 Hx IDU 2.26 ( ).019 Psychiatric Hx or psychoactive Rx 4.07 ( ) <.001 Source: Mollan K, et al. Ann Intern Med. 2014;161:

13 Better Triple Drug Combinations? TAF/FTC/DRV/c vs TDF/FTC-DRV/c naïve: AMBER TAF/FTC/DRV/c vs TDF/FTC-bPI suppressed: EMERALD TDF/FTC or ABC/3TC- DOR vs TDF/FTC or ABC/3TC- DRV naïve: MK DOR/3TC/TDF vs 2NRTIs-bPI supppressed: MK B/F/TAF naïve: 1489, 1490 B/F/TAF suppressed: 1844,

14 Better Triple Drug Combinations? TAF/FTC/DRV/c vs TDF/FTC-DRV/c naïve: AMBER TAF/FTC/DRV/c vs TDF/FTC-bPI suppressed: EMERALD TDF/FTC or ABC/3TC- DOR vs TDF/FTC or ABC/3TC- DRV naïve: MK DOR/3TC/TDF vs 2NRTIs-bPI supppressed: MK B/F/TAF naïve: 1489, 1490 B/F/TAF suppressed: 1844,

15 TAF A novel prodrug of Tenofovir DIANION GI TRACT TFV (tenofovir) TDF (tenofovir disoproxil fumarate) RENAL TUBULAR CELL PLASMA SHORT PLASMA HALF-LIFE TFV TFV TFV OAT 1 & 3 LYMPHOCYTE ESTER PRO DRUG LONGER PLASMA HALF-LIFE - GREATER PLASMA STABILITY HIV AMIDAT E TAF (tenofovir alafenamide) RENAL TUBULAR CELL OAT 1 & 3 TFV TAF results in 90% lower TFV plasma levels 15

16 HIV-1 RNA <50 Copies/mL, % TAF vs TDF (FTC/EVG/c) in Naïves: 144 Weeks E/C/F/TAF (n=866) E/C/F/TDF (n=867) Wk Virologic Success Virologic Failure No Virologic Data At Week 144, E/C/F/TAF was superior to E/C/F/TDF in efficacy difference at both <50 copies/ml; 4.2% (95% CI 0.6%, 7.8%; p=0.02) and <20 copies/ml: 5.4% (95% CI 1.5%, 9.2%; p=0.01) Source: Arribas J, et al. 24th CROI; Seattle, WA; February 13-16, Abst

17 Mean % Change (95% CI) TAF vs TDF (FTC/EVG/c) in Naïves: Bone and Renal Endpoints 2 0 Spine 2.0-1,0-0,9-1,3 Renal AE D/C, n E/C/F/TAF n=866 E/C/F/TDF n=867 Total 0 12 Proximal renal tubulopathy 0 4 Increased creatinine/decreased efgr ,8-2,8-3,0 Renal failure 0 2 Nephropathy Week Proteinuria 0 1 Bladder spasm patients discontinued due to decrease in BMD Source: Arribas J, et al. 24th CROI; Seattle, WA; February 13-16, Abst

18 Doravirine (MK-1439) Next generation NNRTI QD, no food effect Low rates of CNS toxicity Does not inhibit or significantly induce drug-metabolizing CYP enzymes Active against K103N, Y181C, G190A. Selects different mutations than EFV, RPV Single tablet doravirine/lamivudine/tdf Close to clinic. Phase III ongoing 18

19 Percentage of Participants (95% CI) Doravirine. Drive-Ahead Study 100 DOR/3TC/TDF EFV/FTC/TDF DOR/3TC/TDF is non-inferior to EFV/FTC/TDF at Week Difference (95% CI): 3.5 (-2.0, 9.0) Low rate of resistance, with only 1.6% of participants developing resistance to any study drug through Week 48 Significantly less CNS AEs with Doravirine Treatment Week Source: Squires K, et al; 9th IAS, Paris, France, July 23-26, 2017; Abst. TUAB0104LB. 19

20 ONCEMRK: RAL 1200 mg QD Noninferior to 400 mg BID at Wk 48 in ART-Naive Pts Pts With HIV-1 RNA < 40 copies/ml (%) Multinational, double-blind phase III trial in ART-naive pts with HIV-1 RNA 1000 c/ml Pts randomized to RAL 1200 mg QD vs RAL 400 mg BID + FTC/TDF (N = 802) Noninferior Wk 48 HIV-1 RNA < 40 copies/ml in pts with BL HIV-1 RNA > 100,000 copies/ml RAL QD: 86.7%; RAL BID: 83.8% ( 2.9; 95% CI: -6.5 to 14.1) RAL QD associated with overall safety profile similar to RAL BID Treatment Wk 88.7 RAL 1200 mg QD + FTC/TDF RAL 400 mg BID + FTC/TDF Source: Cahn P, et al. AIDS Abstract FRAB0103LB. 20

21 D/C/F/TAF. EMERALD: Study Design Screening Phase Treatment Phase Extension Phase Roll-Over Phase 30 days prior to baseline Randomisation 2:1 N=1149 D/C/F/TAF Continue bpi + F/TDF D/C/F/TAF D/C/F/TAF Baseline Week 24 Week 48 Week 96 Interim analysis Primary endpoint Previous ART VF allowed Absence of history of VF on DRV, and if historical genotype available, absence of DRV RAMs Viral load (VL) <50 c/ml for 2 months before screening; one VL 50 and <200 c/ml within 12 months prior to screening allowed Creatinine clearance (by Cockcroft-Gault) 50 ml/min Source: Molina JM, et al; 9th IAS, Paris, France, July 23-26, 2017; Abst. TUAB

22 Proportion of Patients (%) Proportion of Patients (%) EMERALD Study: Efficacy % Confirmed Virologic Rebound Cumulative through Week % (95% CI: 1.7%, 3.3%) 96.3% 95.5% % Response and Virologic Failure at Week 24 (FDA Snapshot) % (95% CI: 2.0%, 1.5%) 1.8% (n=14) DCFTAF (N=763) 2.1% (n=8) Control (N=378) 20 0 (n=735) Virologic success (n=361) 0.5% (n=4) Virologic failure 0.8% (n=3) 3.1% (n=24) 3.7% (n=14) No virologic data VF (50c/mL) at W24 defined as last VL in W24 window 50c/mL, or premature discontinuations ( AE/death), with last (single) VL 50c/mL Most rebounders (10/14 D/C/F/TAF and 5/8 control) resuppressed (<50c/mL) by Week 24 No confirmed rebounds 200 c/ml No discontinuations for VF No DRV/primary PI or NRTI RAMs were observed (2 patients genotyped in each group Source: Molina JM, et al; 9th IAS, Paris, France, July 23-26, 2017; Abst. TUAB

23 BICTEGRAVIR Bictegravir is a novel specific inhibitor of HIV-1 integrase strand transfer activity 1 Structurally related to Dolutegravir. Unboosted Active against diverse subtypes of wild-type HIV-1 clinical isolates and HIV-2 2 Low cytotoxicity in multiple non-target human cell lines and in primary human hepatocyte 2 Average human T1/2 of ~19 hours, allowing for once daily dosing 3 Close to clinic. Phase III ongoing Source: 1. Lazerwith S, et al. ASM 2016; Boston, MA. Poster # Tsiang M, et al. ASM 2016; Boston, MA. Poster # Gallant J, et al. ASM Boston, MA. Poster #415 23

24 HIV-1 RNA <50 c/ml, % GS-1489 STUDY (BICTEGRAVIR): Results Virologic Outcome % Treatment Difference (95% CI) ,4 93 B/F/TAF (n=314) DTG/ABC/3TC (n=315) Favors DTG/ABC/3TC Favors B/F/TAF HIV-1 RNA <50 copies/ml HIV-1 RNA 50 copies/ml ,7 2,5 4,4 No Virologic Data BF-TAF non-inferior to DTG/ABC/3TC No resistance in either study arm Lipids not significantly different No drug-related renal events Significantly less nausea and minor adverse events with BF-TAF Source: Gallant J, et al; 9th IAS, Paris, France, July 23-26, 2017; Abst. MOAB0105LB. 24

25 Why still Triple? DTG-3TC Naïve ACTG 5353, GEMINI DTG-3TC Suppressed ASPIRE, TANGO DTG-RPV Suppressed SWORD CBT-RPV (LA) early switch: FLAIR CBT-RPV (LA) stable switch : ATLAS 25

26 PADDLE: DTG + 3TC (naïve) # 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 Source: Cahn P, et al. AIDS 2016; Durban, South Africa; July 18-22, 2016; Abst. FARB0104LB. 26

27 Dual therapy with DTG+ 3TC in naïve & suppressed NAÏVE DTG + 3TC (Paddle) DTG + 3TC (ACTG 5353) vs DTG + TDF/FTC (GEMINI9) SUPPRESSED DTG + 3TC (LAMIDOL #458) 97% 48 DTG + 3TC vs 2NRTIs + 3rd drug (ASPIRE) vs TAF-based regimens (TANGO) DTG + 3TC Source: Cahn P, et al. AIDS 2016; Durban, South Africa; July 18-22, 2016; Abst. FARB0104LB. Joly I CROI 2017 #458. NCT NCT NCT NCT

28 DUAL THERAPY IN SUPPRESSED. SIMPLICITY 2.0 Difference in rates of supression at 48 weeks (reduced regimen minus triple regimen) ORAL CAB + RPV vs 2NRTIs + EFV (LATTE) -1% DTG + RPV vs 2NRTIs + 3 rd drug (SWORD, #44LB) LONG ACTING CAB + RPV vs CAB + ABC/3TC (LATTE-2) 8w: +2.9% 4w: +2.0% CAB + RPV 4w vs ABC/3TC/DTG (FLAIR) 2NRTIs + 3 rd drug (ATLAS) ISTI + RPV Margolis DA et al. The Lancet Infectious Diseases 2015; 15: Margolis DA et al. AIDS 2016; Durban, South Africa. Abstract THAB0206LB. NCT NCT

29 SWORD-1 and SWORD-2 Phase III Study Design Identically designed, randomized, multicenter, open-label, parallel-group, non-inferiority studies Screening VL <50 c/ml on INI, NNRTI, or PI + 2 NRTIs 1:1 Early switch phase Late switch phase Continuation phase DTG + RPV (N=513) DTG + RPV DTG + RPV CAR (N=511) Day 1 Inclusion criteria On stable CAR >6 months before screening 1st or 2nd ART with no change in prior regimen due to VF Confirmed HIV-1 RNA <50 c/ml during the 12 months before screening HBV negative Week 52 Primary endpoint at 48 weeks: subjects with VL <50 c/ml (ITT-E snapshot) a Week 148 Countries Argentina Australia Belgium Canada France Germany Italy Netherlands Russia Spain Taiwan United Kingdom United States a -8% non-inferiority margin for pooled data. -10% non-inferiority margin for individual studies Source: Llibre et al. CROI 2017; Seattle, WA. Abstract

30 HIV-1 RNA <50 c/ml, % Snapshot outcomes at week 48 (SWORD-1&2) Virologic outcomes Adjusted treatment differences (95% CI) a CAR DTG + RPV 80 SWORD SWORD Virologic success <1 <1 <1 2 Virologic non-response No virologic data Percentage-point difference DTG + RPV is non-inferior to CAR with respect to snapshot in the ITT-E population (<50 c/ml) at Week 48 in both studies a Adjusted for age and baseline 3 rd agent. Source: Llibre JM CROI 2017 #44LB 30

31 CAB & RPV LA Nanosuspensions CAB is an HIV-1 integrase inhibitor Oral 30 mg tablet (t ½, ~40 hours) LA nanosuspension 200 mg/ml (t ½, ~20-40 days) RPV is an HIV-1 NNRTI Oral 25 mg tablet (t ½, ~50 hours) LA nanosuspension 300 mg/ml (t ½, ~30-90 days) Source: Margolis et al. AIDS 2016; Durban, South Africa. Abstract THAB0206LB. 31

32 HIV-1 RNA <50c/mL, % LATTE-2 Study: Efficacy Virologic Outcomes Treatment Differences (95% CI) CAB + RPV LA Q8W (n=115) CAB + RPV LA Q4W (n=115) CAB + NRTIs PO (n=56) Oral Q8W IM IM % Q4W IM 20 0 Virologic Success Virologic Non-Response No Virologic Data -8.4 [VALOR X].0% Source: Eron J, et al; 9th IAS, Paris, France, July 23-26, 2017; Abst. MOAX0205LB 32

33 Terapia Antirretroviral en la Infección por el VIH (problemas, retos y soluciones) TAF/FTC/DRV/c vs TDF/FTC-DRV/c naïve: AMBER TAF/FTC/DRV/c vs TDF/FTC-bPI suppressed: EMERALD TDF/FTC or ABC/3TC- DOR vs TDF/FTC or ABC/3TC- DRV naïve: MK DOR/3TC/TDF vs 2NRTIs-bPI supppressed: MK B/F/TAF naïve: 1489, 1490 B/F/TAF suppressed: 1844, 1878 DTG-3TC Naïve ACTG 5353, GEMINI DTG-3TC Suppressed ASPIRE, TANGO DTG-RPV Suppressed SWORD CBT-RPV (LA) early switch: FLAIR CBT-RPV (LA) stable switch : ATLAS PRO-140 suppressed Vedolizumad suppressed VRC01 suppressed VRC01-LS + CAB LA suppressed (ACTG 5357) Virologic control Forgiveness Residual viremia Persistent inflammation Immunoactivation Penetration in reservorirs Inmmunotherapy 33

34 Aknowledgments HIV Unit at La Paz Hospital 34