Saye Khoo

University of Liverpool, UK

Future directions of ARVs

A Pharmacology Perspective

Declaration of Interestswww.hiv-druginteractions.org & www.hep-druginteractions.org

Receives sponsorship from AbbVie, Merck, BMS, Janssen, Gilead, ViiV.Editorial content remains independent.

Research funding, travel grants, speakers bureau from Gilead, AbbVie, ViiV, Merck, Janssen

See https://www.liverpool.ac.uk/translational-medicine/staff/saye-khoo/external-engagement/

A Pharmacology Perspective

Smit et al. Lancet ID 2015;15:810-18

▪ >= 50% patients aged over 50

▪ Multiple co-morbidities the norm

▪ Geriatric syndromes

A Pharmacology Perspective

• Liver• Renal• Bone• Metabolic syndrome• Other

Toxicities

• Cardio/cerebrovascular• T2 Diabetes• NAFLD• CKD• Malignancy• Neuropsychiatric

Multiple Morbidities

• Driven by polypharmacy• Not ‘designed out’

DDIs

• Better drugs & formulations• Fewer pills (2DRs? 1DR ??)• LA oral & parenteral• Adjuvant therapies

Burden of Treatment • Dosing Tolerant• Home monitoring • Blips, LLV & sanctuaries• ‘Special’ populations• DDI management

Delivery of Care

Monotherapy

▪ bPI monotherapy (DRVr or LPVr)

virologically inferior, but resistance is unusual, and resuppression expected after re-introduction of NRTIs

may be useful to bridge acute events, eg overdose, post-operatively, ICU (NG feeding), drug toxicity, etc

▪ DTG monotherapy

increased failure WITH high risk of resistance

DOMONO, REDOMO

avoid

2 Drug Regimens

• Pill Size

• Pill number (but FDCs)

• Toxicity (TFV-sparing)

• Interactions (depends)

• Cost saving (depends)

• Preserving options

Why ?

• Less tolerance for missed doses

• Less tolerance for DDI

• More likely to fail with resistance (?)

• Sanctuaries and sterilisation of compartments

Why Not ?

Initiating ART Suppressed Switch

bPI + 3TC

INSTI + 3TC

bPI + INSTI

other

GARDEL (416) LPVr+3TCANDES (145) DRVr+3TC

PROGRESS (206) LPVr+RALNEAT001 (805) DRVr+RAL

PADDLE (20) DTG+3TCACTG5353 (120) DTG+3TCGEMINI (700) DTG+3TC

LATTE-2 (286) CAB+RPVMODERN (804) DRVr+MVC

ATLAS-M (266) ATVr+3TCSALT (273) ATVr+3TCOLE (250) LPVr+3TCDUAL (257) DRVr+3TCMOBIDIP (265) DRVr/LPVr+3TC***

KITE (60) LPVr+RALHARNESS (108) ATVr+RALSPARE (59) DRVr+RAL

LAMIDOL/ANRS167 (104) DTG+3TCDOLULAM (27) DTG+3TC(TANGO DTG+3TC)

SWORD (1024) DTG+RPVLATTE (243) CAB+RPVPROBE (60) DRVr+RPVMultineka (67) LPVr+NVPGUSTA (133) DRVr+MVCMARCH (395) bPI+MVC

What makes a successful 2DR ?

M184V- 92.5% (95% CI 87.2; 97.8)M184V+ 92.5% (95% CI 85.0; 99.9)

p=0.824

Estimated probability of remaining free from VF with dual therapy at 3 years

Gagliardini R 15th EU HIV & Hep Conference, Rome 2017 Abstr 13

ARCA – Virological outcome on dual therapies

Patients suppressed, switch to 2DR (bPI or INI + 3TC) (N=454) vs bPI monotherapy (N=216)Median follow-up: 1.2 years (IQR 0.6-2.4)Overall incidence of VF: 2.35 per 100 PYFU

Dual M184V+ vs monotherapy

Estimated probability of remaining free of VF at 3 yearsDT M184V+ 92.5% (95% CI 85.0; 99.9)

Mono 81.5% (95% CI 73.1; 89.9)p=0.049

Overall dual vs monotherapy

Estimated probability of remaining free of VF at 3 yearsDT 92.5% (95% CI 87.9; 97.0)

Mono 81.5% (95% CI 73.1; 89.9)p<0.001

Initiating ART Suppressed Switch

bPI + 3TC

INSTI + 3TC

bPI + INSTI

other

GARDEL (416) LPVr+3TCANDES (145) DRVr+3TC

PROGRESS (206) LPVr+RALNEAT001 (805) DRVr+RAL

PADDLE (20) DTG+3TCACTG5353 (120) DTG+3TCGEMINI (700) DTG+3TC

LATTE-2 (286) CAB+RPVMODERN (804) DRVr+MVC

ATLAS-M (266) ATVr+3TCSALT (273) ATVr+3TCOLE (250) LPVr+3TCDUAL (257) DRVr+3TCMOBIDIP (265) DRVr/LPVr+3TC***

KITE (60) LPVr+RALHARNESS (108) ATVr+RALSPARE (59) DRVr+RAL

LAMIDOL/ANRS167 (104) DTG+3TCDOLULAM (27) DTG+3TC(TANGO DTG+3TC)

SWORD (1024) DTG+RPVLATTE (243) CAB+RPVPROBE (60) DRVr+RPVMultineka (67) LPVr+NVPGUSTA (133) DRVr+MVCMARCH (395) bPI+MVC

What makes a successful 2DR ?

-3.00

-2.50

-2.00

-1.50

-1.00

-0.50

0.00

DTGRALEVGrETRT20LPVrMVC3TCZDV

- 1.70

- 2.46

- 2.03- 1.99- 1.96- 1.85

- 1.42

- 1.19

- 0.52

ΔV

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from J Arribas CROI 2017

Lalezari IAS 2009 abst TUAB105;

DeJesus JAIDS 2006;43:1-5;

Markowitz JAIDS 2006;43:509

Sankatsing AIDS 2003;17:2623

Kilby AIDS Res Hum Retroviruses 2002:18:685

Murphy AIDS 2001;15:F1-9

Fatkenhuer Nat Med 2005;11:1170

Eron NEJM 1995;333:1662

Potency of Individual ARVs as Initial Therapy

Rosenbloom et al. Nat Med 2012;18:1378 Laskey & Siliciano. Nat Rev (Microbiol) 2014;12:772

In-vitro, Empirical Assessment of ARVs

Genetic Barrier Synergy/Additivity

• CPE scores do not seem to predict HAND or CSF viral escape

CNS Safety of 2DR

• ATLAS-M (ATVr/3TC)Neurocognitive assessment (N=151)

increase in Global Deficit Score over study

No difference between arms

• Switch to ATVr/3TC (single arm)open label, uncontrolled (N=40)

No change in neurocognitive performance

• SALT (ATVr/3TC)Effect over 96w (N=92)

No difference between 2DR and 3DR

• bPI monotherapy not conclusively shown CNS viral escape

eg LPVr (N=40) monotherapy

Ciccarelli et al CROI 2016

DeLuca et al. IAS 2011

Perez-Valero et al. CROI 2016

Santos et al PLoS ONE 8(7): e70201.

2DRs – Conclusions

• 2DR regimens Not all the same

Need to be individually assessed

Best data for bPI+3TC

Role of 3TC ?

• Reduced covering fire e.g. low adherence, DDIs

… but excluded from trials !

• Compartments Theoretical concern

No actual evidence of harm/benefit

• Not for everyone Special Populations:• Hep B co-infection

• Treatment-experienced ?

• Persistent blips / LLV

• Pregnancy

• DDIs which compromise one/both

Induction period

LATTE-2 Study Design

Week 32

Primary analysis

Dosing regimen

selection

Day 1

Randomization

2:2:1

Week 48

Analysis

Dosing regimen

confirmation

CAB 400 mg IM + RPV 600 mg IM Q4W (n=115)

CAB 600 mg IM + RPV 900 mg IM Q8W (n=115)

Week 96b

CAB loading dose at Day 1

CAB loading doses at Day 1 and Week 4

CAB 30 mg +

ABC/3TC for

20 weeks

CAB 30 mg + ABC/3TC PO QD (n=56)

Maintenance perioda

Add RPV

PO QD4 weeks

Margolis et al. AIDS 2016; Durban, South Africa. Abstract THAB0206LB.

ABC/3TC, abacavir/lamivudine; ALT, alanine aminotransferase; IM, intramuscular; PO, orally; QD, once daily; Q4W, every 4 weeks;

Q8W, every 8 weeks; ULN, upper limit of normal. aSubjects who withdrew after at least 1 IM dose entered the long-term follow-up period. bSubjects can elect to enter Q4W and Q8W LA Extension Phase beyond Week 96.

LATTE-2 Week 48 Results: HIV-1 RNA <50 c/mL by Snapshot (ITT-ME)

Snapshot success

D1 W32

Q4W 99% 94%

Q8W 95% 95%

Oral 98% 91%

Pro

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vir

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BL W-16 W-12 W-8 D1 W4 W8 W12 W16 W20 W24 W28 W32

Study visit

Induction period Maintenance period

W-4 W36 W40 W44 W48

Oral CAB induction (ME population) Oral CAB (n=56) Q4W IM (n=115) Q8W IM (n=115)

High potency underpins the LA approach

CAB – PK Characteristics

Spreen et al. JAIDS 2014, Aug 21

Spreen. 16th Hep-HIV PK Workshop 2015

• 200mg/mL suspension

• PK linear & dose proportional

• Putative MEC 4 x PA-IC 90 (0.664μg/mL)

• Drug still detectable a year after a single IM dose

Real-life Challenges - injectables

▪ Injection relatedISR, needle fatigue

consistency & reproducibility of injections

children, low BMI

gender-based differences

▪ Pharmaceuticalformulations and co-formulations

variability – BMI, gender, pharmacogenetic

cold chain

scalability, affordability

implementation and health system capacity

alignment with allied interventions (LA contraceptives)

Real-life Challenges - injectables

▪ ClinicalPatient selection

Lead-in, lead-out, bridging scenarios

Missed dosing

Managing DDIs

Managing Incident Clinical Events

- Pregnancy

- epilepsy, TB (Rif - CAB 59%, RPV 80% after oral dosing)

- liver/renal failure,

- cardiac event, cancer, surgery, etc, etc

▪ PrePwhat is the prevention target ?

stopping PreP

Drug-Drug Interactions

• Recognition Take full medication history

Ask about recreational, OTC, herbals

Just too many to remember !

www.hiv-druginteractions.org

www.hep-druginteractions.org

HIV iCharts

Hep iCharts

HIV and Hepatitis DDI Websites

Drug-Drug Interactions

• Recognition Take full medication history

Ask about recreational, OTC, herbals

Just too many to remember !

• Risk assessment Not all DDIs lead to harm

How bad is the harm ? (Therapeutic index)

How likely in this patient ?

• Response Assessing need for drugs

Alternative options ?

Dose modification possible ?

Monitoring safety ?

Discuss with patient and accept risk ?

Guidelines often do not consider Co-morbidities

▪ Survey of NICE Guidelines for T2 Diabetes, Depression, Heart Failure

▪ Compared with recommendations from 12 common co-morbidities

▪ DDI liability assessed

Dumbreck et al. BMJ 2015;350:bmj.h949

Summary

▪ DDIs are frequent and unavoidable

▪ Generally manageable, but only with complete medication recording

▪ Fragmented care - information is lost between teams

▪ Lack of awareness

Increases risk of harm

▪ Good communication and training

▪ Patient involvement

▪ Exploit digital resources for patient safety

Protects against harm

▪ New therapies unlikely to eliminate DDIs (especially with muli-morbidities)

▪ Not all 2DRs are the same

▪ Not all people will benefit from 2DRs

▪ Not all HIV morbidities will be eliminated by virological suppression

Acknowledgements

University of LiverpoolDavid Back

Laura Else

Andrew Hill

Adeneyi Olagunju

Catriona Waitt

Andrew Owen

Marco Siccardi

Kay Seden

Alieu Amara

Sara Gibbons

Sujan Dilly Penchala

Laura Dickinson

Alessandro Schipani

Henry Pertinez

Katie McAllister

St Stephens AIDS TrustMarta Boffito

Infectious Disease Institute, Kampala Mohamed Lamorde