Queen’s Anniversary Award 2018

Global HIV Clinical Forum

What is the Pharmacological support for

reduced drug regimens?

David Back

University of Liverpool, UK

Disclosures

• Honoraria received for advisory boards and

lectures from AbbVie, BMS, Gilead, Merck, ViiV,

Janssen.

• Educational grants from AbbVie, BMS, Gilead,

Janssen, Merck, ViiV for:

Key Considerations for Reduced Drug Regimens1

Overview

Balanced Half-Lives2

Tissue Penetration3

DDIs: The Interaction with TB Therapy4

Pregnancy5

Long Acting Preparations6

Key Considerations for Reduced Drug Regimens1

What makes the Ideal Antiretroviral?

❑Efficacy/potency

❑Tolerability/Lack of toxicity

❑Convenience

❑Resistance profile

❑Use in Coinfections and comorbidities

❑Use in Pregnancy

❑Cost

Note: This is not an exhaustive listing.

Why consider 2-Drug Regimens (2DR)?

AE, adverse event; ARV, antiretroviral; DDI, drug-drug interaction;

HCP, healthcare professional; SoC, standard of care; 2DR, two-drug regimen;

Reduce impact of long-term

exposure to multiple ARVs

Less potential for AEs?

Why take 3 (or 4) drugs, when

2 can do?

Why 2DR?

Fewer drugs - Potential to reduce

DDIs Important with Aging patients

and Comorbidities

Potential preservation of

future treatment options Less API

Cost?

Establish new treatment

paradigms and evolve SoC.

Slide courtesy of Viiv Healthcare

Which 2DR?

❑PI/r + 3TC

❑DTG + 3TC

❑DTG/RPV (FDC)

❑CAB + RPV

❑ DRV/r + RPV

❑ DRV/c +3TC

❑ DRV/c + DTG

❑ DRV/c + RPV

Taken from: Quercia MD et al JAIDS 2018; 78: 125-135; CCO: Contemporary Management of HIV – Current Controversies

in HIV. June 2018.

PK-PD and IQ of Key ARVs:

Parameter DRV LPV DTG RPV CAB

*IC90/95PA

ng/ml

55 80 64 12 164

EC90 ng/ml 324

Ctrough (ng/ml) 2100 5500 1090 70 4100

IQ (Ctrough

/IC90/95PA)

~40 ~70 ~17 ~6 ~25

*IC90/95PAprotein binding adjusted conc inhibiting viral replication by 90/95%

Higher IQ and relationship to higher genetic barrier to resistance

Note: 3TC not shown due to the complex interrelationship between 3TC and 3TC-TPPodany AT et al Clin Pharmacokin 2017; 56: 25-40; Custodio J CROI 2018; Margolis et al AIDS 2016; Molto J Spanish

Integrase Forum 2017; www.hiv-druginteractions.org

Why consider DTG as an important component

of 2DRs?

ATV; atazanavir; DDI, drug–drug interaction; DRV, darunavir; EFV, efavirenz; EVG, elvitegravir; INI, integrase inhibitor; RAL, raltegravir; tx, treatment; QD, once daily; WT, wild-type

1. Min S et al. AIDS 2011;25:1737–1745; 2. Walmsley S et al. N Engl J Med 2013;369:1807–1818; 3. Clotet B et al. Lancet 2014;383:2222–2231; 4. Orrell C et al. ARIA Study.

Int AIDS Conference (IAC), July 2016, Durban, SA. Abstract #10215; 5. Cahn P et al. Lancet 2013;382:700–708; 6. Raffi F et al. Lancet 2013;381:735–743; 7. Kobayashi M et

al. AAC 2011;55:813–821; 8. Hightower KE et al. AAC 2011;5:4552–4559; 9. van Lunzen J et al. Lancet Infect Dis 2012;12:111–118; 10. Elliot E et al. IWCPHIV 2015. Abs 13.

High IQ; Long half-life;

• Ctrough 17-fold above IC909

• Long ‘tail’10

Rapid and potent antiviral

activity1

Clinical trial data2–5

• Numeous trials in tx-naïve and

tx-experienced subjects.

Generally well tolerated

• Few discontinuations due to

AEs in clinical trials2–6

High barrier to resistance5,7

• In vitro and Phase III data

Long binding to WT INI8

• Slow dissociation from INI–DNA

complexes

DDIs

• Relatively few clinically significant

DDIs

✓

✓

✓✓

✓✓Dolutegravir

Slide modified from Viiv Healthcare

Why 3TC or RPV in combination with DTG?

▪ Present in major Guidelines1-4

▪ Well tolerated; Low discontinuations due to AEs

in pivotal clinical trials5-8

▪ Long Intracellular half-life (22h)9

▪ Low potential for DDIs9

▪ Clinical data for 2DR emerging10

▪ LATTE studies proof of principle for

maintenance therapy11,12.

▪ Long half-life (~50h) and relatively low DDI

profile9

▪ RPV associated with fewer CNS AEs than EFV

in tx-naïve patients13

3TC RPV

Slide modified from Viiv Healthcare

1. DHHS. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. 2016; 2. Günthard HF, et al. JAMA 2016;316:191–210; 3. EACS guidelines,

Version 8.2 January 2017; 4. World Health Organization. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. Updated 2016; 5.

Eron JJ, et al. AIDS 1996;5:S11–9; 6. Bartlett JA, et al. Ann Intern Med 1996;125:161−72; 7. Result summary for NUCB3001, ViiV Healthcare 2005; 8. Result summary for

NUCB3002, ViiV Healthcare 2005; 9. www.hiv-druginteractions.org. 10. Cahn P, et al. Lancet Infect Dis 2014;14:572–80; 11. Margolis DA, et al. Lancet Infect Dis

2015;15:1145–55; 12. Margolis DA, et al. CROI 2016. Abstract 31LB; 13. 13. Gunthard H, et al. JAMA 2016;316:191–210;;

Characteristic DRV/r + 3TC LPV/r + 3TC DTG + 3TC DTG/RPV CAB + RPV

Half lives; Balance

& Forgiveness

Tissue Penetration

DDI profile

Use in Pregnancy

Use in Renal

Impairment

Use in Chronic HBV

Initial therapy; High

VLs?

Past NRTi failures?

Key Pharmacological Considerations for 2DR

Balanced Half Lives2

2 Drug Regimens (oral)Characteristic DRV/r + 3TC LPV/r + 3TC DTG + 3TC DTG + RPV CAB + RPV

Half lives DRV/r: 15h

3TC-TP:

15-21h

LPV/r: 6h

3TC-TP:

15-21h

DTG: 14h

3TC-TP:

15-21h

DTG: 14h

RPV: 50h

CAB: 40h

RPV: 50h

Balanced(Based on t½)

Yes ? Yes ? Yes

www.hiv-druginteractions.org; Moore KH et al AIDS 1999; 13: 2239-2250; Else LJ et al AAC 2012; 56: 1`427-

1433. Juluca SmPC, May 2018; Landovitz RJ et al. Curr Opinion HIV AIDS 2016; 11: 122-128

Dolutegravir and Rilpivirine Plasma

Concentrations: ‘Tail’ when Stopping Drug Intake

Dolutegravir

Rilpivirine

PAIC90 64ng/ml

EC90 324 ng/ml

PAIC90

12ng/ml

‘Target’50 ng/ml

Dickinson L et al AAC 2015; 59: 6080-6086; Elliot E et al JAC 2016; 71: 1031-1036; Dickinson L et al Glasgow 2016

DTG below EC90 target: 48-60h

RPV below target: 48-60h

‘True’ terminal t½ ~ 60h*

SWORD (DTG + RPV) PK Analysis

Adkinson K et al CROI 2017

DTG Disassociates Very Slowly from WT IN-

DNA Complex at 37oC

Adapted from: Hightower KE et al AAC, 2011; 55: 4552-4559

Tissue Penetration3

Clin Transl Sci 2017; 10: 133-142.

Inadequate ART Penetration into Tissues

may Contribute to Residual Viraemia

Oral Drug

Dose

Gut PlasmaLymphoid

Tissue

Elimination

KptKa

CL/V

Drug

▪ Molecular size

▪ Lipophilicity

▪ Protein binding

▪ Ionization

Tissue

▪ Blood perfusion

▪ Transporters

▪ LN fibrosis

▪ Mucosal

inflammation

Patient

▪ Host genetics

▪ Body wt

▪ Renal function

▪ Hepatic function

Modified from Lee S CROI 2017

PNAS 2014; 111: 2307–2312

Fletcher CV CROI 2018; Abs 27

INSTIs in PBMCs, LN, Ileal and

Rectal MNCs: Clinical Study

▪ HIV-infected person receiving dolutegravir (n=11),

elvitegravir/cobi (n=17) or raltegravir (n=6) with NRTIs.

▪ PBMCs and mononuclear cells from LN, ileum and

rectum obtained and intracellular concentrations of

INSTIs quantified.

DTG EVG RAL

IC90/95

(ng/ml)

64 44.9 14.7

Ctrough

(ng/ml)

1100 450 124

IQ 17 10 8

IQ based on plasma data

Fletcher CV CROI 2018; Abs 27

Inhibitory Quotients for INSTIs: PBMCs & LNs

IQ based on PBMC data IQ based on LN MNC data

Summary of Inhibitory Quotient Values

Fletcher CV CROI 2018; Abs 27; Weber MD et al AVT 2018 (ahead of print)

❑Do these conditions allow persistent viral replication?

❑ Median rectal tissue:plasma ratio was 11.25 (RAL; n=10) and 0.44 (DTG; n=10).

Important Considerations

❑The physicochemical, pharmacologic and virologic

characteristics of ARV regimens in lymphoid tissues

need to be established.

❑Impact of an ARV regimen where concentrations in LN ≤

PBMCs is not known. Implications for 2-drug regimens?

❑Full suppression of viral replication in reservoirs

necessary to the success of any eradication strategy.

❑Can LT penetration be improved ie nanoformulations,

trageting of tissue; pro-drugs (eg TAF v TDF)

25

Protein

binding

CSF/

plasma

Semen/

plasma

Rectum/

plasma

Vagina/

plasma

Darunavir 95.0% 0.005 – 0.01 0.17 - 0.2 2.7 0.1 - 1.5

Lopinavir >98% 0.004 0.07 n/a 0.03 – 0.2

Lamivudine 36.0% 0.12 9.1 67 (FTC) 1.0 - 9.0

Dolutegravir 98.9% 0.02 - 0.05 0.07 0.2 0.06 - 0.1

Rilpivirine 99.7% 0.02 0.1 1.5-2.5 0.65

Cabotegravir 99.0% n/a n/a 0.08 0.2

Adapted from Molte J Spanish Integrase Forum 2017

Penetration into Compartments

Tivicay SmPC; Adams Jl et al AVT 2013; 18: 1005-1014; Greener BN et al. JAIDS 2013; 64:39-44; Calcagno A et al CID 2015; 60: 311-317; Else LJ et al AVT 2011; 16; 1149-

1167; Trezza CR & Kashuba AD 2014; Clin Pharmacokinet 53: 611-624.www.hiv-druginteractions.org

* Note: Ratio’s can vary due to sampling times

DDIs: The Interaction with TB Therapy4

2 Drug Regimens and anti-TB Therapy

TB Drug DRV/r +

3TC

LPV/r +

3TC

DTG + 3TC DTG/RPV CAB + RPV

Rifampicin Large decrease

in PI exposure

Contra

indicated

Large decrease

in PI exposure

Not

recommended

↓DTG Cmin

72%;

Add additional

dose of DTG in

absence of

integrase

resistance.

↓DTG Cmin 54%;

↓RPV Cmin 80%;

Contra

indicated

↓RPV Cmin 80%;

↓CAB Cmin

~40%*;

Contra

indicated

Rifabutin

RFB 3 times

per week

RFB AUC: ↑

5.7-fold

RFB 3 times

per week

↓DTG Cmin 30%;

No dose

adjustment

necessary

↓DTG Cmin 30%;

↓RPV Cmin 48%;

Add additional

RPV 25mg

↓CAB Cmin 26%;

↓RPV Cmin ‘X’%;

Add additional

RPV 25mg ?

Prezista SmPC 03/18; Tivicay SmPc 03/18.; Kaletra SmPC 02/18; Juluca SmPC; 05/18; *PBPK modelling – Rajoli RFR et al CROI 2018;

Ford SL et al AAC; 2017: 61: e00487-17

Conclusion:

❑ DTG 50 mg BID during concomitant RIF-based TB therapy demonstrated

high efficacy and good immunological response through week 24.

❑ DTG Ctau was similar to DTG 50 mg QD without RIF

‘Adjusting the dolutegravir dose might be challenging in public sector programmes and would negate the benefits of a once-daily regimen,meaning that further work is needed to assess the clinical effect of rifampicin co-administered with once daily dolutegravir’.

www.thelancet.com/hiv Vol 5 July 2018

Although there were substantial reductions in the DTG key PK

parameter C24h (↓ 76%) when co-administered with RIF,

concentrations of DTG 100mg OD with RIF were still above the

protein binding-adjusted IC of 64 ng/ml, suggesting the need for

further study of this dose.

Antiviral PK Workshop May 2018

❑ Giving BFTAF BD does not overcome the RIF effect. The Ctrough is still

markedly reduced (by 80%).

Custodio J et al; CROI 2018; Abs 34.

Pregnancy5

Third Trimester Exposure (vs PP) of HIV Drugs

Stek et al JAIDS 2015; 70: 33; Colbers et al AIDS 2013; 27: 739; Moodley et al JID 1998; 178: 1327; Le et al AVT;

2015: 20: 507; Mirochnik et al CPK; 2004; 43: 1071; Blonk et al CID; 2015; 61: 809; Colbers et al CID; 2015; 61:

1582; Else et al AAC; 2012; 56: 816; Best et al HIV Med 2015; 16: 502; Mulligan et al CROI 2016; Best CROI 2017;

* Dolutegravir exposure is decreased in pregnancy compared with postpartum, but remains at therapeutic concentrations

during pregnancy with standard once-daily dosing (Mulligan N et al AIDS 2018; 32: 729-737)

** FDA/EMEA May 2018

2 Drug Regimens and Pregnancy

DRV/r +

3TC

LPV/r + 3TC DTG + 3TC DTG/RPV CAB + RPV

Pregnancy No specific

study of

regimen

Lower DRV

exposure

during

pregnancy cf

PP.

DRV must be

used twice daily

in pregnancy

(DHHS).

Twice daily may

be considered if

initiating

(BHIVA)

No specific study

of regimen

Lower LPV

exposure during

pregnancy cf

PP.

Long term data

on LPV/r.

LPV/r bd as

alternative

(DHHS).

Some experts

recommend

dose increase

No specific study

of regimen.

Lower DTG

exposure during

T3 vs PP*

Safety issue of

DTG in

pregnancy**

No specific study

of regimen

Lower exposures

of DTG & RPV

have been

observed.

Currently not

recommended

No specific study

of regimen

Currently no

data on CAB in

pregnancy.

Prezista SmPC 03/18; Tivicay SmPc 03/18.; Kaletra SmPC 02/18; Juluca SmPC; 05/18*

TUES 16.30 – 18.00

WED 16.30- 18.00

Long Acting6

Long Acting – What’s the attraction?

❑Infrequent dosing

❑Lower overall drug dose

❑Prevents poor adherence

❑Use in patients with pill fatigue (possibly

temporarily?)

❑Potential of directly observed therapy

❑Target tissues?

❑Better protects health privacy and treatment-

related stigma

– CAB Oral 30 mg (t½, ~40 hours)

– CAB LA nano 200 mg/mL (t½, ~20-40 days)

– RPV Oral 25 mg (t½, ~50 hours)

– RPV LA nano 300 mg/mL (t½, ~30-90 days)

• Oral 2-drug CAB + RPV proof of efficacy

through Week 96 in LATTE-1

• im 2-drug CAB + RPV maintained VL < 50 in LATTE-2*

Long Acting im

- Cabotegravir and Rilpivirine

Margolis et al. Lancet Infect Dis. 2015;15:1145-1155. Margolis et al. AIDS 2016; Durban, South Africa. Abstract THAB0206LB; Slide modified from Viiv Healthcare.

CAB, cabotegravir; LA, long-acting; RPV, rilpivirine; t½, half-life.

Long Acting Injectables: Some Key Issues

➢ What drugs can be combined?

➢ Injection volume for im?

➢ What to do about missed doses

➢ Long term low drug levels at end of dosing interval

➢ Management of adverse events – non-reversible

❑ Need for oral lead-in

➢ How much long term safety and efficacy data required?

➢ DDIs different?

Long Acting Implants

❑Potential advantages over injectables▪ Removable

▪ More consistent drug release

▪ Could remain in place for years.

❑Potential disadvantages over injectables.▪ Specialised device required for insertion

▪ Removal?

▪ Regulated as both a drug and device.

▪ Generic marketplace?Schlesinger E et al Pharm Res 2016; 33: 1649-1656; Gunawardana M et al; AAC; 2015; 59: 3913-3919

Yearly intake of ARV by regimen

Regimen Daily Dose (mg) Yearly dose (g)

3-Drug Regimens:

DRV/r + FTC/TDF

RAL + F/TAF

DTG/ABC/3TC

EVG/c/FTC/TAF

800/100 + 200/300

800 + 200/10

50/600/300

150/150/200/10

511.0

368.7

346.8

186.2

2-Drug Regimens:

DTG + 3TC

DTG + RPV

CABoral + RPVoral

CABim + RPVim

50 + 300

50 + 25

30 + 25

400 + 600 (every 2 mo)

127.8

27.4

20.1

6g

50 years of tx

Acknowledgments