considerations…. from the - virology...

A case, and some

pharmacological

considerations…. from the

perspective of a virologist

Anna Maria Geretti

University of Liverpool, United Kingdom

1

Case History: Mr RS

• 53-year-old male

• Diagnosed HIV positive in 1999

• Baseline CD4 count 46 cells

• Baseline viral load 83,000 cps

• Subtype C

• Past hepatitis B infection

• Hepatitis C negative

• Oct 1999 starts AZT/3TC + IDV

Medical and ART historyDate started

Date stopped

ART Viral load CD4 Resistance

Oct 1999 Oct 2000 AZT/3TC IDV 442 83

Oct 2000 Nov 2001 ABC/3TC EFV 31,500 127

RT: 67N 215Y 184V 74V 100I 103N

Nov 2001 Jul 2004TDF d4T 3TC

LPV/r<50 280

Jul 2004 Jul 2008 TDF ATV FPV/r 771 399RT:

NonePR: 32I

Jul 2008 Nov 2011TDF RAL DRV/r (600/100 bid)

<50 to 175 447

Mr RS Which is your preferred strategy?

1. Do nothing as long as the viral load is <200 cps

2. Address patient-related psyco-social issues &

adherence

3. Address sample- and/or lab-related technical issues

4. Request more tests – which?

5. Change or intensify the ART regimen

Management strategies

Review:

• Technical issues of viral load testing

• Adherence, tolerability, psycho-social issues

• Expected potency of the regimen

• Drug-drug interactions (DDIs) and food requirements

• Reasonable to perform a drug resistance test

• Reasonable to check drug levels

• CD4 nadir and pre-ART viral load inform

Size of HIV DNA reservoir

Likelihood of compartmentalised virus replication

Plasma HIV-1 RNA during ART

Spivak et al. Trends Mol Med 2016

Cellular HIV-1 DNA load during suppressive ART

Geretti et al. Int. Workshop HIV & Hepatitis Viruses Drug Resistance 2013; Ruggiero et al. EBioMed 2015

HIV

-1 D

NA

log 1

0 c

ps

pe

r 1

06

CD

4 T

-ce

lls

Years of suppressive ART

Cohort started 2 NRTIs + EFV or NVP, achieved VL <50 cps within 6 months, and during subsequent follow-up had VL consistently <50 cps (no blips or interruptions) while remaining on the initial NNRTI (n=104)

Mean change integrated HIV-1 DNA for 10 yrs of ART (log10 cps/106 PBMC)

+0.2 [95% CI -0.2, +0.6; p 0.28]

Virus replication in sanctuary compartments due to poor drug penetration or activity

Virus reactivation in latently infected cells, with presence

of ART ensuring that new cells cannot be productively

infected

Untimed drug levels & resistance test at LLV predict viral load rebound >1000 cps

• First LLV plasma sample: PI/NNRTI concentration and resistance test (n=328)

• Concentrations classed as ‘therapeutic' or ‘suboptimal' based on target Ctrough

• Genotypic sensitivity score (GSS) of regimen by Stanford algorithm

Independent predictors of

VL rebound >1000 cps (adjOR)

o Suboptimal drug levels = 2.53

(95% CI 1.72-3.72; p<0.001)

o GSS <3 = 1.55

(95% CI 1.02-2.34; p=0.04)

o LLV (cps):

250-499 = 2.48 (95% CI 0.99-6.22)

500-749 = 2.36 (95% CI 0.91-6.11)

750-999 = 3.65 (95% CI 1.42-

9.39)(p<0.001)

Gonzalez-Serna et al. CROI 2015

Low drug levels predict faster resistance

Gonzalez-Serna et al. CROI 2015

Case History: Mr RS

• DRV plasma concentration in range

• Plasma resistance test (RT, PR, IN) wild-type X 3

• CSF HIV RNA 3128 cps/ml

• CSF resistance testRT: 67N 215Y 184V 100I 103NPR: wild-typeIN: RT 155H

Nightingale et al. J NeuroVirol 2016

HIV-1 RNA Detection in CSF according to LLV

• HIV-1 RNA measured in paired plasma and CSF of 43 subjects with plasma VL <50 cps over ≥12 months of ART and in 40 subjects with a history of LLV

• HIV-1 RNA detected in CSF in 0/43 vs. 9/40 (22%) respectively

• Detection of HIV-1 RNA in CSF associated with low nadir CD4 count (p=0.030) and black heterosexual exposure group (p=0.007) but not with drug concentration or CPE score

• ART-experienced, INI-naïve

• TDF FTC + DTG 50 mg OD

PDVF= Protocol-defined virological failure;

FC = Fold change; RC = Replication capacity

Underwood et al. European HIV & Hepatitis Workshop 2015

10

100

1000

10000

0 12 24 36 48 60 72 84 96 108 120 132 144

PDVF

Wk 120

622 cps/mL

Confirm

Wk 132

1054 cps/mL

Day 1 PDVF Confirm.

HIV-1 RNA 733 622 1054

INI

mutation

- A49G,

S230R,

R263K

A49G,

S230R,

R263K

DTG FC 0.73 3.82 5.77

RAL FC 0.54 2.39 2.62

INI RC 20% 7.1% 12%

No NRTI resistance at any time point

386 cps/mL

HIV

-1 R

NA

cp

s/m

LSAILING Case-1

• ART-experienced, INI-naïve

• ABC 3TC + DTG 50 mg OD

10

100

1000

10000

100000

0 12 24 36 48 60 72 84 96 108 120

PDVF

Wk 108

3895 cps/mL

Confirm

Wk 108 retest

407 cps/mL

Day 1 PDVF

HIV-1 RNA 25105 3895

IN mutation - N155H

DTG FC 0.97 1.8

RAL FC 1.18 12

IN RC NRb NR

PDVF BR: No emergent resistance, loss of M184M/V

Week

HIV

-1 R

NA

cp

s/m

L

Underwood et al. European HIV & Hepatitis Workshop 2015

PDVF= Protocol-defined virological failure;

FC = Fold change; RC = Replication capacity

SAILING Case-2

You plan to modify the ART regimen Which is your preferred strategy?

1. DRV/b + DTG

2. DRV/b + DTG + ETR

3. DRV/b + DTG + MVC

4. DRV/b + MVC + ETR

5. DRV/b + DTG + MVC + ETR

Add TDF or TAF to any of the above, +/- FTC?

Which dose of DTG?

Pharmacology of integrase inhibitors

DTG EVG RALDose 50mg od

(50-100mg bd)150mg od(boosted)

400mg bd

• Potent inhibitors of integrase enzyme

• Protein binding-adjusted IC90/95 values in the low ng/ml range - High inhibitory quotient (IQ) - DTG > EVG > RAL

• Each INI has unique PK/PD properties

• PK variability highest for RAL and lowest for DTG

• Different hepatic metabolism: RAL and DTG minimal cytochrome P450 (CYP) involvement; EVG primarily thorugh CYP3A4

• RAL and DTG have minimal DDI profiles

• EVG requires boosting to be amenable to OD dosing and has greater DDI potential – manageable as with RTV


Podany et al. 2016



(bd if INI experienced)150mg od(boosted)

400mg bd

Food effect on drug exposure

Take with food if possibility of INI

resistance

Low (33%), moderate (41%), and high (33%) fat

meals increased AUC

Take with food

Light (36%), and high (91%) fat meals

increased AUC

Take without regard to food

High fat doubles AUC, food increases variability

• Absorption affected by divalent / trivalent cations, such as those found in multivitamins and antacids

DT

G m

ean

plas

ma

conc

entr

atio

n (n

g/m

L)

Effect of food on DTG exposure - healthy volunteers

*50 mg formulation

Song et al. Antimicrob Agents Chemother 2012

Low, moderate, and high fat meals increase DTG AUC by 33%, 41%, and 66%, respectively. In INI-naive patients, dose with or without food.

In INI-resistant patients, dose with food.

Low fatFasting

Moderate fatHigh fat

PA-IC90 0.064 µg/mL

Time (hours)

0 10 20 30 40 50 60

4500

4000

3500

3000

2500

2000

1500

1000

500

0

Dolutegravir + antacid 2h later

Dolutegravir alone

0 10 20 30 40 50 8060 70

2.0

1.8

1.6

1.4

1.2

1.0

0.8

0.6

0.4

0.2

0Mea

n D

TG

con

cent

ratio

n (µ

g/m

L)

26%

74%

Time (hrs)

Dolutegravir +antacid

Patel et al. JAC 2011; Pommier et al. Nat Rev 2005; Stribild SmPC June 23rd 2015; Tivicay SmPc Oct 1st 2015

INI chelation with cations

Mg2+

Mg2+

Binding of integrase inhibitors

Mg

Mg

EVG AUC EVG Cmin

Al/Mg containing antacid takentogether

Decreased 45%

Decreased 41%

Antacid +/- 2h after EVG

↔ ↔

Not recommended – RAL Separate – DTG and EVG/c

Impact of acid-reducing agents and multivitamins on DTG exposure

1. Tivicay SmPC January 2014

2. Patel et al. J Antimicrob Chemother 2011

Co-administered drug

DTG C or C24

Geometric mean change Recommendation

Antacids and supplements≠

Magnesium / aluminium-

containing antacid

AUC*↓74%

Take antacids and supplements a minimum of

2 hours after or 6 hours before DTG1Calcium supplements ↓39%

Iron supplements ↓56%

Multivitamins ↓32%

Acid-lowering agents

Omeprazole ↓5% No significant effect observed2

C: Trough concentration



(bd if INI experienced)150mg od(boosted)

400mg bd

Food effect Take with food if possibility of INI

resistance

Low (33%), moderate (41%), and high (33%) fat

meals increased AUC

Take with food

Light (36%), and high (91%) fat meals

increased AUC

Take without regard to food

High fat doubles AUC, food increases variability

MetabolismUGT1A1

(CYP3A 10-15%)CYP3A / UGT1A1/3 UGT1A1

Protein binding >99% 99% 76-83%

Half life 11-12h 9h 9h

Dose-exposure Dose proportional up to 100mg

Less than dose-proportional

Nearly dose-proportional

DTG distribution and CSF penetration

Plasma protein binding: >99%1

Blood:plasma ratio: 0.44–0.54 → minimal association with blood cellular components1

A Phase IIIb study assessed the distribution of DTG in CSF2

DTG concentrations observed in CSF at both Week 2 and Week 16 averaged 18 ng/ml (comparable to unbound concentration) and exceeded the in vitro IC50 against wild-type viruses (0.2 ng/mL)2 for all subjects, suggesting that DTG was able to achieve therapeutic concentrations in the CSF

1. Tivicay SmPC, January 2014;

2. Letendre et al. CROI 2013

Special groups

DTG EVG RALSwallowing Granule being

developed( bioavailability)

Cannot be chewed or crushed

Chewable tablets, granules

(bioavailability)

Children Not licensed <12y Not licensed <18y, avoid <6y

Licensed from 4 weeks

Pregnancy No dataFDA Cat B

Limited dataFDA Cat B

Some data FDA Cat C

Renal impairment

No adjustmentDTG exposure reduced in severe renal disease

FDC with TDF not <70, stop <50

FDC with TAF >30

No adjustment

Cirrhosis CP-A

CP C

No adjustment

Caution

No adjustment

Not recommended

No adjustment

Caution

Dose-exposure relationship for DTG

*PA-IC90 is the protein-adjusted 90% inhibitory concentration †Inhibitory quotient is defined as C/PA–IC90

1. van Lunzen et al. Lancet Infect Dis 2012;

2. Rockstroh et al. HIV10 2010

DTG PK parameters at Week 2 by dose in the SPRING-1 Phase IIb trial1,2

QD dose

Cmax

(μg/mL)

AUC0–

(µg·h/mL)

C

(µg/mL) IQ†

10 mg1,2 1.10 (37) 16.0 (40) 0.30 (71) 4.7

25 mg1,2 1.71 (43) 23.1 (48) 0.54 (67) 8.4

50 mg1,2 3.40 (27) 48.1 (40) 1.20 (62) 19

●DTG shows low to moderate PK variability1,2

●All drug levels well above the in-vitro PA-IC90 of 0.064 μg/mL1,2

Values shown are geometric means (CV%)

0 5

Post-dose time (hours)

10.0

1.0

Mea

n D

TG

con

cent

ratio

n (µ

g/m

L)

0.1

10 15 20 25

10 mg QD2

25 mg QD2

50 mg QD2

PA-IC90 0.064 µg/mL*

SAILING: Response rates by quartile of DTG c0_avg

The average plasma concentration of DTG was a significant predictor of virological response: subjects in the lowest quartile had a lower response

SAILING: Phase III study in ART-experienced, INI-naïve subjects

Song et al. ICAAC 2013

100

80

60

40

20

0 0–25

0.304 μg/mL

(0.000–0.555)

Response rate

63.5%

25–50

0.805 μg/mL

(0.557–1.069)

Response rate

72.9%

50–75

1.347 μg/mL

(1.072–1.793)

Response rate

82.4%

75–100

2.665 μg/mL

(1.805–8.673)

Response rate

75.3%

C0_avg quartile

Res

po

nd

ers,

%

Responders Non-responders

DDI liability

DTG EVG RAL

Metabolism UGT1A1

(CYP3A 10-15%)

CYP3A

UGT1A1/3

UGT1A1

Perpetrator of

DDIs

No effect on CYPs,

UGTs.

Inhibits OCT2

Cobicistat – potent

CYP3A, mod CYP2D6

and MATE1

EVG – mod inducer

of CYP2C9

No effect on CYPs,

UGT or PgP

Divalent cations Al/Mg/Ca/Fe/Multivit

amins

Separate -6 or +2h

Al/Mg antacids ±2h

Multivitamins ±4h

Al/ Mg contraindicated

Ca: not clinically

meaningful

Gastric pH No significant

interaction

No significant

interaction

RAL absorption with

OMP (39%) / FAM

(45%); no adjustment

needed

DTG interactions

Commonly used medications Interactions

Oral contraceptives1 No dose adjustment necessary

H2-receptor antagonists (e.g.,ranitidine, cimetidine)2 No dose adjustment necessary

Prednisone1, Methadone1, Rifabutin1 No dose adjustment necessary

Metformin1 Limit the total daily dose of metformin to 1,000 mg. When stopping DTG, the

metformin dose may require an adjustment. Monitoring of blood glucose when initiating

concomitant use and after withdrawal of DTG recommended

Multivitamins, calcium supplements, iron supplements1 DTG to be administered 2 hours before or 6 hours after taking these agents

Magnesium/aluminium-containing antacids1 DTG to be administered 2 hours before or 6 hours after taking these agents

Carbamazepine, rifampicin, efavirenz; nevirapine andtipranavir/r1

The recommended dose of DTG is 50 mg twice daily when co-administered with these

agents. In the presence of INI resistance, combination with these agents should be

avoided Note: Co-administration of dofetilide and dolutegravir is contraindicated.1,2

1. TIVICAY Summary of Product Characteristics. September 20152. TRIUMEQ Summary of Product Characteristics. September 2015

Co-administered drug

DTG C or C24

Geometric mean change Recommendation1

Protease inhibitors

DRV/r 600/100 mg BID* ↓38% No DTG dose adjustment required

ATV 400 mg OD*¥ ↑180% No DTG dose adjustment required

ATV/r 300/100 mg OD* ↑121% No DTG dose adjustment required

NNRTIs

RPV 25 mg OD ↑22% No DTG dose adjustment required

EFV 600 mg OD ↓75% DTG 50 mg BID should be given‡

ETR 200 mg BD ↓88% DTG should not be given with ETR without

co-administration of ATV/r, DRV/r or LPV/r

NRTIs

TDF 300 mg OD ↓8% No DTG dose adjustment required

Impact of ARVs on DTG exposure

*DTG 30 mg OD studied; ¥ Unboosted ATV is not licensed in the EU; ‡INI-

naive patients; alternative combinations should be considered where possible

for INI-experienced patients with certain

INI-associated resistance substitutions or clinically suspected INI resistance1.Tivicay SmPC January 2014

C: Trough concentration

DTG AUC 70%

DTG 50mg qd

+ ETR 200mg bd

+ LPVr 400/100 bd

+ DRVr 600/100 bd

DTG AUC ↔

DTG AUC 25%

DTG + ETR without bPI DTG + ETR with bPI twice daily

Song et al. AAC 2011

DTG with ETR

VIIV EUROPEAN SCIENTIFIC REVIEW FORUM ON DOLUTEGRAVIR

ETR + MVC = MVC (600mg or 150 bd without/with PI/b) RTV + MVC = MVC (150mg bd)RTV + DTG = potentially DTG ETR + DTG = DTG

You plan to modify the ART regimen Which is your preferred strategy?

1. DRV/b + DTG

2. DRV/b + DTG + ETR

3. DRV/b + DTG + MVC

4. DRV/b + MVC + ETR

5. DRV/b + DTG + MVC + ETR

Added TAF/FTC

DTG 100mg bd

Thanks to

Saye Khoo (UoL)

David Back (UoL)

Romina Quercia (ViiV)

34

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