reducing drug regimens. what is the magic...
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Reducing drug regimens. What is the magic number?
Toxicity and co-morbidities perspective
José I BernardinoHIV Unit. Hospital La Paz
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Financial disclosures
Personal fees from Gilead, Janssen, ViiV healthcare, MSD
Kanters S. Lancet HIV 2016;3:e510-20
Kanters S. Lancet HIV 2016;3:e510-20
Network meta-analysis. Discontinuations due to AE and SAE
REAL life data on DTG Use, OLVG Hospital, Amsterdam.
De Boer. AIDS 2016;30:2832-4
Integrase Inhibitors. EMA SmPCRaltegravir. Special precautions of use. Section 4.4
Genvoya. Adverse effects. Section 4.8
Dolutegravir & Triumeq. Adverse effects. Section 4.8
http://www.ema.europa.eu/ema/index.jsp?curl=pages/home/Home_Page.jsp&mid=
Early D/Cany reason
IRR (95% CI)
Early D/Cdue to AE
IRR(95% CI)
RAL n(%) 71 (12.7) 1 20 (3.6) 1
EVG n(%) 26 (8.1) 0.62 (0.39-0.97) 16 (5) 1.35 (0.70-
2.61)
DTG n(%) 26 (12.3) 0.97 (0.62-1.52) 8 (3.8) 1.66 (0.47-
2.41)
Spanish cohort. RAL 557 EVG 322 DTG 212 German cohort. 1950 INSTI-based in 1704 patients
Peñafiel. JAC 2017. Hoffman. HIV medicine 2017
• Rate of D/C doubled when DTG was combined with ABC/3TC although NS
• Increasing age (4% per year) independent risk factor (aHR 1.04 (1.02-1.07)
• 17 Neuropsychiatric D/C: RAL 7 (35%), EVG 3 (19%), DTG 7 (88%)
D/C because Neuropsychiatric adverse events
• AE leading to D/C was observed in 122 (6.3%) • D/C due to any AE within 24 months:
RAL (3.9%), EVG (12.3%), DTG (9.3%)• Female and > 60 years increased risk for DTG
D/C
Hsu R. CROI Seattle 2017. Poster # 664
Psychiatric disorders. OPERA cohort.
History of psychiatric diagnoses at baseline
DTG (N=2180)EFV (N=1622)RAL (N=917)DRV (N=1759)RPV (N=1758)EVG (N=3303)
Hsu R. CROI Seattle 2017. Poster # 664
Psychiatric disorders. OPERA cohort.
Prevalent and incident psychiatric diagnoses
Smit M. Lancet Infect Dis 2015
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
2010 2012 2014 2016 2018 2020 2022 2024 2026 2028 2030
An individual-based model of an ageing HIV-population following patients on treatment as they age, develop NCDs and start co-administered medications
Clinical Implications of an Ageing HIV Population: ATHENA Cohort
Future Age Distribution of HIV Patientsin the Netherlands
Prop
ortio
n of
peo
ple
Year
>70 yr old
60 - 70 yr old
50 - 60 yr old
40 - 50 yr old
30 - 40 yr old
>30 yr old
In the ATHENA cohort, proportion of patients on ART aged ≥50 years old will increase from 28% to 73% between 2010 and 2030
Burden of NCDs mostly driven by larger increases in cardiovascular disease compared with increases in other comorbidities
In 2030 predictive models suggest: 84% 1 co-morbidity & 28% ≥ 3 co-morbidities
Changes in Relative Number of Patients with Specific NCDs
>30 yr old
CVDDiabetesMalignancy CVD
Diabetes
Malignancy
CVD
Diabetes
Malignancy
2010 2020
2030
Co-morbidities.CoRIS cohort (2004-2014)n = 9569
Alejos B. 21st IAC Durban 2016
Role of ART in co-morbidities
Haematology
Body composition
Cardiovascular disease Hypertension Lipids
Glucose
Pulmonary disease
Liver disease
Renal disease
Bone disease
Neurocognitive impairment Depression
Cancer
Lee H, et al. Biochemistry 2003; 42: 14711-9;Moyle G, et al. Drug Saf 2000; 23: 467-81;Lund, KC et al. AAC 2007, 51: 2531-9.;Carr A. Nat Rev Drug Discover2003; 2: 624-34.;Calmy A. Antivir Ther 2009;14: 165-179.
TOXICITYAGING
COSTSUSTAINABILITY
SIMPLICITYLESS-DRUGS
Reasons for reduced drug regimens
Mitochondrial toxicity (NRTI)
Lipodistrophy (EFV, d4T, ZDV, ddI)
Nephrotoxicity (TDF, ATV, LPV, IDV)
Bone toxicity (TDF, bPI)Cardiovascular toxicity (ABC, bPI)
Metabolic (ABC, bPI)
Neuropsychiatric (EFV, NRTI, INSTI?)
Telomerase inhibition (NRTI)
Study Type of Study N Regimen Results
GARDEL[1] Naive 426 LPV/RTV +3TC Similar efficacy as LPV/RTV + 2NRTIs
PADDLE[2] Naive 20 DTG + 3TC Small study. Encouraging results
NEAT001/ANRS143[3]
Naive 805 DRV/RTV + RAL Similar efficacy as DRV/RTV + TDF/FTC
OLE[4] Switch 250 LPV/RTV + 3TC Similar efficacy as standard ART
SALT[5] Switch 286 ATV/RTV + 3TC Similar efficacy as ATV/RTV + 2 NRTIs
ATLAS-M[6] Switch 266 ATV/RTV + 3TC Similar (improved in post hoc analysis) efficacy vs ATV/RTV + 2NRTIs
DUAL[7] Switch 260 DRV/RTV + 3TC Similar efficacy as DRV/RTV + 2NRTIs
LATTE[8] Switch 243 CAB + RPV Similar efficacy as cont. standard ART
LATTE-2[9] Induction-Maintenance
309 Induct:CAB + ABC/3TCMaint: LA CAB + LA RPV im
Similar efficacy as cont. oral CAB + ABC/3TC;
SWORD[10] Switch 1024 DTG + RPV Similar efficacy as cont standard ART
1.Cahn P et al, EACS 2015, Abstract 9512. Figueroa MI et al EACA 2015. Abstract 10663. Raffi F, et al Lancet 2014;384:1942-19514.Arribas JR et al Lancet Infec Dis 2015; 15:785-7925. Perez-Molina JA et al. Lancet Infect Dis 2015;15:775-784
6. Di Giambenedetto S, et al EACS 2015, Abstract 8677. Fulido F et al. Glasgow 2016 Abstract O 3318. Margolis DA et al. Lancet Infect Dis 2015; 15:1145-11559. Margolis DA et al CROI 2016 Abstract 31LB10. Llibre JM et al CROI 2017 Abstract 2421
Novel TDF-and ABC-Sparing ART Strategies
Renal and Bone safety in ATLAS-M Study
Di Giambenedetto. Glasgow 2016
No differences in Body mass changesNo differences in bone turnover markersSwitch to ATV/RTV +3TC increased cholesterol
Renal and Bone safety in NEAT 001/ANRS143
Creatinine clearance [Cockroft-Gault]Mean (95% CI) change from baseline
Lumbar spine BMDMean % (95% CI) change from baseline
No grade 2-4 creatinine elevation in either arm Although no statistically significant there was a trend for more fractures in the DRV/RTV + TDF/FTC
Raffi F, et al Lancet 2014;384:1942-1951 Bernardino JI, Lancet HIV 2015 11;e464-473
Llibre JM et al. CROI 2017 Abstract 2421
SWORD 1&2 Phase III Study design
Llibre JM et al. CROI 2017 Abstract 2421
Bone turnover markers in SWORD 1&2
GEMINI Studies
With newer and safer drugs as TAF,is there still room for less drug
regimens?
• At Week 24, median (Q1, Q3) change from baseline in eGFRCG was -0.4 (-4.8, 4.5) mL/min, and in eGFRCKD-EPI, cystatin C was 3.8 (-4.8, 11.2) mL/min/1.73 m2
• There was no significant change in eGFRCG or eGFRCKD-EPI, cystatin C to Week 48
0 4 8 12 16 24 36 48-10
-5
0
5
10
15
0.6-1.4
1.81.1
Primary Endpoint
-10
-5
0
5
10
15
Weeks
Primary EndpointChange in eGFR (CKD-EPI, Cystatin C)
Change in eGFR (Cockcroft-Gault)M
edia
n (Q
1,Q
3) e
GFR
Cha
nge
From
Bas
elin
e (m
L/m
in)
Med
ian
(Q1,
Q3)
eG
FRC
hang
eFr
om B
asel
ine
(mL/
min
/1.7
3 m
2 ))
<50 mL/minBaseline eGFRCG
0 4 8 12 16 24 36 48
Change in eGFR From Baseline to Week 48. Study GS 112
Pozniac A . CROI 2015 Poster 795
Median changes in eGFRCKD_EPI by Age. GS112 Sub analysis
Martorell C. HIV and Aging. Washington DC Poster 36
Tenofovir alafenamida. Study GS104 &111. 144 weeks
At Week 144, median change from baseline in eGFR CG was significantly lower with E/C/F/TAF vs E/C/F/TDF (1.6 vs 7.7 ml/min) p < 0.001
Arribas JR . CROI 2017 Poster 453
Goldstein D. HIV and Aging. Washington DC Poster 32
Mean change in BMD (%) by < 50 or ≥ 50 years. GS 109
Substudy GS109 &112
Brown T. CROI 2017 Poster 683
214 (19%) had a significant low BMD at baseline (T scores ≤ -2)
27% had > 5% increase in BMD at spine and 16% at total hipReversion from osteoporosis observed in 23%
Changes in BMD (%) through w96 Changes in T-score through w96
• TTAGGG• Shorten each mitotic
cycle• Senescence - apoptosis
TELOMERASE• Celular reverse
transcriptase- hTERT: Catalytic unit
(Reverse transcriptase)
Telomere & Telomerase
Stella-Ascariz N et al, JAIDS 2017
Montejano R et al, JAIDS 2017
Montejano R et al, JAIDS 2017
EPIGENETIC CLOCK METHOD
DNAm Age and telomere length on the same samples
Framingham Heart study. Brian Chen
HIV+ patients had a biological age advancement of 4.9 years on average (CI 95% 3.4-7.1years)Decreased HLA methylation is predictive of lower CD4+/CD8+ ratioAge advancement occurs early in the course of disease as a consequence of acute infection or reaction to drug treatment
Points for discussion• Are CNS effects related to integrase inhibitors really an issue?
• Overall data regarding long-term toxicity are lacking in less drug regimens
• With the safety profile of TAF, is there still room for less drugs regimens?
• Should all patients on TDF-based regimens be proactively switched to TAF-based regimens?
• The role of ART in the Aging process deserve further studies (Telomere length, DNA methylation changes…)