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…)