What is the Magic Number? Clinical Pharmacology of Non ... · Clinical Pharmacology of Non Conventional regimens Ospedale Amedeo di Savoia. ... • Pharmacokinetics ... STRATEGY -

Gianni Di Perri

Clinica di Malattie InfettiveUniversità degli Studi di Torino

Ospedale Amedeo di Savoia

What is the Magic Number? Clinical Pharmacology of Non Conventional

regimens

Ospedale Amedeo di Savoia

To answer the question (…..the magic number?) several recognized key factors that contribute to define the pharmacological profile of a drug/regimen and its therapeutic efficacy should be taken into consideration…..

• Intrinsic potency

• Mechanism of action / Pharmacodynamics

• Adherence

• Pharmacokinetics

• Forgiveness

• Genetic barrier

…and their interrelationship

FLAMINGO: DTG vs DRV/RTV + 2 NRTIs in

Naive Patients at Wk 48

• DTG superior to DRV/RTV

at Wk 48 primary efficacy

endpoint

– Treatment-related study

d/c: 2% in DTG arm vs 4%

in DRV/RTV arm

• VF at Wk 48: < 1% (n = 2)

in each arm

• Similar CD4+ cell count

increase at Wk 48:

– +210 cells/mm³ in each

arm

HIV

-1 R

NA

< 5

0 c

/mL

at

Wk 4

8 (

%)

9083

Δ +7.1%

(95% CI: +0.9% to +13.2%; P = .025)

Feinberg J, et al. ICAAC 2013. Abstract H1464a.

DTG 50 mg

QD + NRTIs

DRV/RTV

800/100 mg QD

+ NRTIs

217/242

200/

2420

20

40

60

80

100


DTG 50 mg

QD + NRTIs

217/242

HIV

-1 R

NA

< 5

0 c

/mL

at

Wk 4

8 (

%)

0

20

40

60

80

100

90

25/242 (10%) Patients underwent virological failure

Why ?

RELATIONSHIP BETWEEN DTG TROUGH CONCENTRATION AND VIRAL LOAD REDUCTION

DTG is associated with a well characterised, predictable exposure-response relationship

Phase IIa, dose-ranging, placebo-controlled, 10-day monotherapy study

Placebo

2 mg QD

10 mg QD

50 mg QD

Model fit: Emax = –2.6, IC50 – 0.036 µg/mL

C (µg/mL)

Day

11

log 1

0vi

ral l

oad

ch

ange

fro

m

bas

elin

e

–3.5

–3.0

–2.5

–2.0

–1.5

–1.0

–0.5

0

0.5

1.0

0 0.4 0.6 0.8 1.0 1.4

c/mL, copies/mL; Emax, maximum effect; RNA, ribonucleic acid

Subjects with

HIV-1 RNA <50 c/mL

are represented by

orange-bordered

circles

Open circles with lines

denote mean standard

deviation

Adapted from Min S, et al. AIDS 2011; 25:1737–45

0.2 1.2

A patient taking the 2 mg dose underwent virologic suppression in 10 days !!!

Integrase Inhibitors (IIs): main clinical trials

Superiority: at week 48; * at week 156; ** > 100.000 c/mL at baseline; not non-inf.

Treatment-naïve pts

Treatment-exp. patients

Switch studies

Dolutegravir (DGV)

SPRING 1, 2 (vs RAL &

EFV)

SINGLE (vs

EFV/FTC/TDF [atripla])

VIKING I, II, III (RAL-R)

SAILING (vs RAL, IIs-

naïve pts)

FLAMINGO (vs DRV/r)

***96 w

Elvitegravir (ELV)

Study 102 (vs

EFV/FTC/TDF [atripla])

Study 103 (vs ATV/r)

STRATEGY - PI

STRATEGY - NNRTI

Study 109 vs F/TDF + 3rd drug

Raltegravir (RAL)

BENCHMRK

SWITCHMRK

STARTMRK

ARDENT (ACTG 5257)

QDMRK (QD vs bid)

*

ONCEMRK (vs bid)

1. In these patients (possibly with baseline unfavourablefactors, e.g. very high VL, very low CD4+ cell counts) the potency of the regimen is insufficient;

1. Incomplete drug/s absorption;

2. Pre-existing drug-resistance;

1. They stopped drug intake soon after enrollment (for whatever reason);

2. They were not fully adherent (for whatever reason);

1. Other…..

1. In these patients (possibly with baseline unfavourablefactors, e.g. very high VL, very low CD4+ cell counts) the potency of the regimen is insufficient;

1. Incomplete drug/s absorption;

2. Pre-existing drug-resistance;

1. They stopped drug intake soon after enrollment (for whatever reason);

2. They were not fully adherent (for whatever reason);

1. Other…..

Unlikely as sole factor

Rare, & drug potency usually compensates

Rare, easy to rule out

Yes, few Patients do so

Yes, a sizeable % of Patients adhere subotimally?


DTG 50 mg

QD + NRTIs

217/242

HIV

-1 R

NA

< 5

0 c

/mL

at

Wk 4

8 (

%)

0

20

40

60

80

100

90

25/242 (10%) Patients underwent virological failure

Few Patients stop to take drug/s soon after enrollment and fail

Some Patients adhere suboptimally, and a proportion of them fail

In this subgroup, further to specific regimen properties (e.g. intrinsic

potency, forgiveness…), the probability of failure might also

depend upon some co-factors (e.g. high BL HIV-RNA, low CD4+ cell

counts, HCV co-infection)

3TC, PIs & NNRTIsNaïve ptsPrimary endpoint:% of pts. With HIV-RNA < 400 copies/mL

1. EFV + IDV2. EFV + AZT + 3TC3. IDV + AZT + 3TC

Efavirenz plus Zidovudine and Lamivudine, Efavirenz plus Indinavir, and Indinavir plus Zidovudine and Lamivudine in the Treatment of HIV-1 Infection in Adults. SchlomoStaszewski, et al.

Volume 341:1865-1873December 16, 1999

100 %

75%

50 %

25 %

0 %

EFVAZT3TC

EFVIDV

IDVAZT3TC

Efavirenz plus Zidovudine and Lamivudine, Efavirenz plus Indinavir, and Indinavir plus Zidovudine and Lamivudine in the Treatment of HIV-1 Infection in Adults. SchlomoStaszewski, et al.

Volume 341:1865-1873December 16, 1999

100 %

75%

50 %

25 %

0 %

EFVAZT3TC

EFVIDV

IDVAZT3TC

?

% <

40

0 c

. HIV

-RN

A/m

L

Very poor adherence

Suboptimal adherence

INTRINSIC

POTENCY




• Adherence


• Forgiveness

• Genetic barrier


Intrinsic potency of antivirals may allow for some reduction in overall exposure to drugs, in terms of:

- n. of drugs required to achieve the desired level of efficacy- duration of treatment required to achieve the desired level of

efficacy.

The latter does not fully apply to antiretrovirals, as a permanent treatment is necessary to avoid resumption of viral replication, but It might be interpreted as the time required to reduce the viral burden below a given molecular threshold (e.g. < 50 copies HIV-RNA/mL)

The case of the fast evolution of DAAs-based anti-HCV treatment clearly shows as more potent drugs may actually allow for lesser exposure.

Compound

Replicon cell line EC50 (pM)

1a 1b 2a 2b 3a 4a 5a 6a

Pibrentasvir1 2 4 2 2 2 2 1 3

Ombitasvir1 14 5 12 4 19 2 3 366

Daclatasvir2 22 3 13,000 530 13 5 74

Ledipasvir3 31 4 21,000 16,000 168,000 390 150 1,100

Elbasvir4 4 3 3 3,000 20 3

Velpatasvir5 12 15 9 8 12 9 75 6

Odalasvir6 14 12 ~150

Samatasvir7 8 3 24 17 2 37

Compound

Replicon cell line EC50 (nM)

1a 1b 2a 3a 4a 5a 6a

Glecaprevir 0.85 0.94 2.7 1.6 2.8 0.12 0.86

Paritaprevir 1.0 0.21 5.3 19 0.09 0.42 0.68

Grazoprevir 0.4 0.5 1.2 35 1.2 0.9 0.89

Simeprevir 13 9.4 15 472 36

Asunaprevir 4 1.2 230 1162 52

Voxilaprevir 3.9 3.3 3.7 6.1 2.9 1.9 1.5

Inhibitors of NS3/4A

Inhibitors of NS5A

Comparative “in vitro” potency of DAAs

1

2

3

5

6

NRTI monotherapy

P24 Antigen

1987 - 1994

1

2

3

5

6

NRTI dual therapy

HIV-RNA/mL Log10

1994 - 1996

1

2

3

5

6

HIV-RNA/mL Log10

HAART

2NRTIs + NNRTI or PI/r or II

1996 - now

HAART

2NRTIs + PI (single)

1996 - 2000/1

HIV RNA copies/mL

Di Perri. G.teaching material, 2015

PI/

rC

on

centr

atio

n (

µg/m

l)

Spontaneous mutants withreduced drug-sensitivity

Unboosted PI

RTV-boosted PI

In case of a WT HIV viral population Pk exposure of boosted-PIsis such that even the least drug-sensitive variant is inhibited by

the drug

Time

MUTANT SELECTION WINDOW


50

HIV RNA /mL

[c]

90%

[c]

90%

50

HIV RNA /mL

[c] range

unboosted PIs

[c] range

RTV-boosted PIs


Emax Model (phase II, dose-ranging studies)

Short-term monotherapy study

100%

50%

20%

10%

0

A B C D E

With all validated triple regimens and most investigational non-

conventional options being used we are well here,

provided patients take their drugs


Van Lunzen J, et al. Once daily dolutegravir (S/GSK1349572) in combination therapy in antiretroviral-naive adults with HIV: planned interim 48 week results from SPRING-1, a dose-ranging, randomised, phase 2b trial. Lancet Infect Dis. 2012 Feb;12(2):111-8.

Haubrich RH, et al. AIDS 2011; 25: 2269-2278.

Min S, et al.

Markowitz M, et al.

bid

Gallant JE, et al. J Acquir Immune Defic Syndr. 2017 May 1; 75(1): 61–66.

Antiviral Activity, Safety, and Pharmacokinetics of Bictegravir as 10-Day Monotherapy in HIV-1–Infected Adults

BIC 75 mg?

Murphy RL, et al.

3TC and d4T added after 3 weeks

Ruane PJ, et al.

ACTG 5202 interim results:

time to first safety event

(High viral load stratum at

DSMB action)

As-treated analysis of patients receiving first NRTI backboneP

rob

ab

ilit

y (

co

mb

ined

to

xic

ity

-fre

e)

0 4 16 24 36 48 60 72 84 96 108

Weeks from treatment dispensation

ABC/3TC (130 events) log rank test p value: 0.0001TDF/FTC (78 events) HR (95% CI) 1.89 (1.43, 2.50)

Number at risk

397397

311333

219272

177233

148188

118156

82112

4971

2735

512

ABC/3TCTDF/FTC

8

258299

1.0

0.8

0.6

0.4

0.2

0.0Sax et al. NEJM

2009;361:2230

Hazard Ratio

1 5-

4

Favors

TDF/FTC

Favors

ABC/3TC

ABC/3TC vs. TDF/FTC with

EFV

ATV/r HR 2.22 (95% CI, 1.19,

4.14)

HR 2.46 (95% CI 1.20,

5.25)

ABC/3TC vs.

TDF/FTC: primary

virologic endpoint

(High viral load

stratum at DSMB

action)

Darr, E. et al. 17th CROI, San Francisco, CA, 2010, presentation 59LB.

Similar Efficacy of INSTIs (RAL or DTG) +

ABC/3TC or TDF/FTC, Even for High BL VL

• In SPRING-2, similar efficacy with ABC/3TC or TDF/FTC + RAL or

DTG, including with high BL HIV-1 RNA*

Eron J, et al. Glasgow 2012. Abstract P204.

< 100k 100K - < 250K 250K - 500K > 500K0

20

40

60

80

100

HIV

-1 R

NA

< 5

0 c

/mL

at W

k 4

8 b

y FD

A

Snap

sho

t A

nal

ysis

(%

)

86

n/N =

88

225/257

91

306/335

36/42

82

72/88

81

13/16

76

29/38

72

13/18

64

18/28

Baseline HIV-1 RNA (c/mL)

TDF/FTC

ABC/3TC

*Pooled data from both INSTIs.




• Adherence


• Forgiveness

• Genetic barrier


….invading the pocket natively occupied by the pro-viral DNA extemity…..

…chelating the metallic cations indispensable for the integrase catalytic activity…

• The inhibition of pro-viral DNA integration by INSTIs depends upon the drug residence time inside the complex formed by INTEGRASE, VIRAL DNA and the drug.

• Removal of RAL from cell medium until 72 h post-infection leads to viral regrowth due to new integration events. The viral resumption resulted from the cleavage of LTR-LTR junction followed by their integration in the host cell genome, thus indicating that 2-LTRc accumulated under INSTIs treatment may work as substrate for the integration process.

• Stability of the INSTI on the complex depends on the individual drug being tested, as different discordant half-lives have been described for RAL, EVG and DGV (8.8, 2.7 and 71 h respectively – Hightower et al. AAC 2011; 55: 4552-4559)

Dolutegravir Raltegravir Elvitegravir

Hightower KE, et al.

Diss. Time (T/2)

FC EC50

DGV

71 h 1

RAL 8.8 h 1

ELV 2.7 h 1

Diss. Time (T/2)

FC EC50

DGV

42 h 1.4

RAL 1.1 h 16

ELV 1.7 h 1.8

Diss. Time (T/2)

FC EC50

DGV

5.2 h 0.97

RAL 0.2 h 13

ELV 0.2 h 7.3

Diss. Time (T/2)

FC EC50

DGV

9.6 h 0.99

RAL 0.6 h 8.4

ELV 0.4 h 25




• Adherence


• Forgiveness

• Genetic barrier


0 6 12 18 24 30 36 42 46 .... ….. …

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

10000

11000

12000

13000

[c](ng/mL)

Time (h)

Lopinavir half-life: 5-6 hours

Efavirenz half-life: 45 hours


Treatment interruption

Time of residual effective Pkexposure

In ITT analysis of clinical trials, there seems to be a

tendency to better virological outcome in case of drugs

with longer elimination half-life?

* Intracellular triphosphate active moiety

Study Virological response

(< 50 copies/mL)

Half-life

(T/2, hours)

ACTG 5142

(144 weeks)

EFV + 2N/NtRTIs 76%

LPV/r + 2N/NtRTIs 63%

EFV: 45

LPV: 5-6

ARTEMIS

(96 weeks)

DRV/r + TDF/FTC 79%

LPV/r + TDF/FTC 71%

DRV: 10-15

LPV: 5-6

CASTLE

(96 weeks)

ATV/r + TDF/FTC 74%

LPV/r + TDF/FTC 68%

ATV: 8.6-15

LPV: 5-6

ARTEN

(48 weeks)

NVP + TDF/FTC 67%

ATV/r + TDF/FTC 65%

NVP: 25-30

ATV: 8.6-15

ACTG 5202

(48 weeks)

TDF/FTC + EFV or ATV/r 80%

ABV/3TC + EFV or ATV/r 75%

TDF/FTC: 150/39*

ABV/3TC: 20/25*

STARTMRK

(156 weeks)

RAL + TDF/FTC 75%

EFV + TDF/FTC 68%

RAL: 9

EFV: 45

T/2 – related forgiveness


0

10

20

30

40

50

60

70

80

90

100

Adherent Sub-optimally Adherent Sub-optimally

adherent adherent

82%

(n=269) 76%

(n=55)

78%

(n=252)

53%

(n=70)

Pati

en

ts w

ith

<50 c

op

ies/m

L a

t

Week 9

6

p=0.3312 p<0.0001

DRV/r LPV/r

82% 78%76%

53%

[c]

Time

MEC

Treatment not taken

Residual pharmacokinetic

coverage once a dose is not taken

• Integrase Inhibitors (IIs) have a rather short elimination half-life (T/2), such as values in the same order of magnitude as those of RTV-boosted protease inhibitors (PIs/RTV)

• As a consequence IIs should have the same limitations in terms of “forgiveness” when compared to drugs with a long T/2 (e.g. NNRTIs)….. But …… >>


The reason why, inspite of similar or much shorter T/2, INSTIs tend to overcome other “third drugs” in terms of forgiveness is likely to be multifactorial:

- Better tolerability leading to better adherence;

- Faster viral load reduction (possibly associated to longer time to viral regrowth); at any time point, any episode of missing drug intake takes place with a lower viral load and the chance of a measureable viral regrowth is less likely with INSTIs, particularly in the first weeks of therapy (provided that treatment is resumed);

- Longer residency time on target (Pk lesser predictive of PD as a variable associated to antiretroviral activity);

- Due to the magnitude of the IQ (inhibitory quotient), even with relatively short T/2, the residual drug concentration is still enough to guarantee anti-HIV activity for a relatively long time (e.g. DGV).




• Adherence


• Forgiveness

• Genetic barrier


PI/

rC

on

centr

atio

n (

µg/m

l)

Spontaneous mutants withreduced drug-sensitivity

Unboosted PI

RTV-boosted PI

In case of a WT HIV viral population Pk exposure of boosted-PIsis such that even the least drug-sensitive variant is inhibited by

the drug

Time

MUTANT SELECTION WINDOW

fosAmprenavir vs fosAmprenavir/RTV:

Mutations with boosted vs unboosted PIs: NEAT vs SOLO

Resistance-associated

mutations emerging

during therapy

1° or 2° PR

mutations

3TC (M184I/V)

3TC or ABC (M184I/V,

K65R, L74V)

908 - NEAT 908/RTV - SOLO

908§

n = 29

28%

55%

55%

NFV

n = 26

31%

77%

77%

p

1.000

0.157

0.157

908/r QD

n = 32

0%

13%

13%

NFV bid

n = 54

50%

56%

57%

p

<0.001

<0.001

<0.001

Common natural polymorphism in the absence of any other RT or PR mutations are excluded (NFV n = 3: [M36mI,

K20km, L10I] 908/r n = 1: [V77v/i]

Macmanus S, et al. !0th CROI, Boston 2003 #598 §908 = GW433908, fos-amprenavir

Stanford Resistance Database, Dec 2010

Resistance with Single Mutation (PIs/r)

Increased Fold Change to LPV with Mutation V82A

Increased Fold Change to LPV with Mutation I84V

Increased Fold Change to DRV with Mutation I84V

Resistance with Single Mutation (NNRTIs)

NVP with Mutation K103N

Stanford Resistance Database, Dec 2010

EFV with Mutation K103N

PI/

rC

once

ntr

atio

n

(µg/m

l)

RTV-boosted PI

In case of missed PI/rdose….

Time

Although with some differences, PIs/r have

all a relatively short half-life, so that the

time with drug [c] within the mutantselection window

(MSW) is minimal and no R is selected

What about poor adherencewith PI/r?

MSW

0.5 - 2 h

Graphic simulation of boosted PI pharmacokinetics according to information provided by: www.hiv-druginteractions.org

• The genetic barrier of antiretrovirals is usually defined as the number of mutations required to make the virus resistant at Pkexposure commonly achievable in humans

• Such a definition is fully appropriate when a comparative evaluation is made between PIs/r and NNRTIs.

• As anticipated, differences in elimination half-life (T/2) also contribute in real life to the different probability of selecting resistance-associated mutations in case of virological failure with PIs/r or NNRTIs.

• In case of INSTIs, however, at least two additional factors should also be considered:

✓Very fast viral clearance ✓ Long residency time on the target

1 1. Regimen providing only transient reduction of the

basic reproduction number R0

< 1

2

2. Regimen providing reduction of the basic

reproduction number R0 < 133. Regimen providing fast reduction of the basic reproduction

number R0 < 1

The area between 2 and 3 quantifies the total residual viral replication during treatment and thus the risk of drug resistance evolution

Below the limit of detection

TIME

HIV RNA

Measurement at this time point

alone would not distinguish

between 2 and 3…

Estimated risk of

resistance

selection

Low

High

Low

Ferguson NM, Fraser C, & Anderson R. TRENDS in

Pharmacological Sciences 2001; 22: 97-100

Antituberculous drugs display a barely measurable synergy

The main reason why they are given together is that of

establishing a “genetic barrier”

This particularly applies when high bacillary loads are

present, since the likelihood of selecting those

spontaneous resistant mutants basically depends upon

three factors:

a) Their spontaneous frequency in the population

b) The size of the population

c) The duration of exposure to the selecting agent

From: “Tuberculosis”, ROM WN, Garay SM, Bloom BR Eds. Lippincott Williams & Wilkins, Philadelphia, 2004. 2nd ed.

Infections with a high bacterial density at the initiation of antibiotic therapy maypresent a therapeutic problem, including a higher risk for the emergence of resistancedue to the larger number of bacteria present and the higher probability of having atleast one resistant bacterial cell within a large initial inoculum (CFUo)

Johnson, C. C.,et al. Activity of cefepime against ceftazidime-resistant gram-negative bacilli using low and high inocula. J. Antimicrob. Chemother 1995. 35:765-773.

1 in 106

10 in 107100 in 108

1000 in 109

1 in 106

10 in 107100 in 108

1000 in 109

1 in 10610 in 107

100 in 1081000 in 109

Duration of exposure to the selecting agent


Emerging Infectious Diseases 2009; 9: 10-16.

% with undetectable HIV-RNA

0 %

20 %

40 %

60 %

80 %

100 %0 4 16 24 48 weeks

DGV (all)

EFV 600 mg


MONOI: Switch to DRV/r ± NRTIs

Valantin M-A, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 534.

Randomized study of DRV/r or DRV/r + NRTIs in Patients with HIV

RNA <50 c/mL on ART and No Prior PI Failure and Naïve to DRV

Proportion with HIV RNA < 50 copies/ml (ITT)

88%

84%

P=NS

Variables associated with rebound at week 96

OR (95% CI) p OR (95% CI) p

Duration of prior ART (per 5 year decrease)

1.74 (1.11, 2.73) 0.013 2.11 (1.23, 3.8) 0.009

Difficulty in Adherence (<100% vs 100%)

2.36 (0.94, 5.92) 0.07 3.84 (1.29, 12.49) 0.02

HIV-1 DNA at D0 (per 1 log10 copies/106 cells increase)

2.45 (1.07, 5.61) 0.03 2.66 (1.11, 7.48) 0.04

DRV/r monotherapy (112 pts.)

DRV/r + 2 N/NtRTIs (113 pts.)

Response Predictors:

Univariate analysis Multivariate analysis

Selected Previous Trials of Dual Therapy Regimens for Initial Therapy

Study N Regimen Results

PI-Based Dual Therapy

NEAT001[1] 805DRV/RTV +

RAL

Similar efficacy as DRV/RTV +

FTC/TDF; poor efficacy in pts with

high HIV-1 RNA, low CD4+ cell

counts

GARDEL[2] 426LPV/RTV +

3TC

Similar efficacy as LPV/RTV + 2

NRTIs

DTG-Based Dual Therapy

PADDLE[3] 20 DTG + 3TC

18/20 pts achieved virologic

suppression; n = 1 experienced

PDVF (BL HIV-1 RNA > 100,000

c/mL); resuppressed HIV-1 RNA

without ART change by

discontinuation visit1. Raffi F, et al. Lancet. 2014;384:1942-1951. 2. Cahn P, et al. EACS 2015.

Abstract 961. 3. Cahn P, et al. IAC 2016. Abstract FRAB0104LB.

ANDES: DRV/RTV + 3TC vs DRV/RTV + 3TC/TDF for ART-Naive Pts

• Randomized, open-label phase IV study in Argentina

• Baseline: 24% HIV-1 RNA > 100,000 copies/mL

Sued O, et al. IAS 2017. Abstract MOAB0106LB.

HIV-1 RNA < 400 c/mL (ITT) at Wk 24,

n/N (%)DRV/RTV + 3TC DRV/RTV + 3TC/TDF

Overall 71/75 (95) 68/70 (97)

BL HIV-1 RNA > 100,000 copies/mL 20/20 (100) 15/15 (100)

▪ 1 virologic failure with DRV/RTV + 3TC/TDF

Interim Analysis

Wk 24

DRV/RTV + 3TC QD

(n = 75)

DRV/RTV + 3TC/TDF QD(n = 70)

ART-naive pts with

HIV-1 RNA > 1000 copies/mL

(N = 145)

Primary Endpoint

Wk 48

Dosing: DRV/RTV, 800/100 mg; 3TC, 300 mg;

3TC/TDF, 300/300 mg.

ACTG A5353: DTG + 3TC for ART-Naive Pts

• Single-arm phase II study[1]

• Baseline: 31% HIV-1 RNA > 100,000 c/mL

1. Taiwo BO, et al. IAS 2017. Abstract MOAB0107LB.

2. ClinicalTrials.gov. NCT02831673. 3. ClinicalTrials.gov. NCT02831764.

Virologic

Outcome at

Wk 24, n

(%)

Baseline HIV-1 RNA,

copies/mL Total

(N = 120)> 100,000

(n = 37)

≤ 100,000

(n = 83)

Success* 33 (89) 75 (90) 108 (90)

Nonsuccess 3 (8) 2 (2) 5 (4)

No data 1 (3) 6 (7) 7 (6)

▪ n = 3 with PDVF; n = 1 with emergent M184V and R263R/K mixture

– All 3 pts had DTG levels reflective of suboptimal adherence

▪ GEMINI 1/2 randomized phase III trials of DTG + 3TC ongoing[2,3]

*HIV-1 RNA < 50

copies/mL.

ART-naive pts with

HIV-1 RNA ≥ 1000 and < 500,000

copies/mL;

no RT, INSTI, major PI resistance

mutations

(N = 120)

DTG 50 mg + 3TC 300 mg

Primary

Endpoint

Wk 24

ACTG A5353: HIV-1 RNA Levels and DTG Concentration in Pts Experiencing PDVF

Taiwo BO, et al. IAS 2017. Abstract MOAB0107LB. Reproduced with permission.

Pt 1

BL HIV-1 RNA > 100,000

copies/mL

Pt 2

BL HIV-1 RNA ≤ 100,000

copies/mL

Pt 3

BL HIV-1 RNA ≤ 100,000

copies/mL

HIV-1 RNA < limit of detection

No detectable DTG

HIV

-1 R

NA

(co

pie

s/m

L)

0

100

1000

10,000

100,000

1,000,000

Study Wk

0

1000

2000

3000

4000

50

024 8 12162024 32

None

0

100

1000

10,000

100,000

1,000,000

Study Wk

0

1000

2000

3000

4000

50

024 8 12162024 32

DT

G C

on

cen

tratio

n (n

g/m

L)0

100

1000

10,000

100,000

1,000,000

Study Wk

0

1000

2000

3000

4000

50

024 8 12162024 32

Off DTG

None M184VM184V

R263RK

Off DTG

V1061

HIV-1 RNA (copies/mL)

DTG concentration (ng/mL)

SWORD 1 & 2: Switch From Suppressive

ART to DTG + RPV Dual Therapy

• Randomized, open-label, multicenter phase III trials

• HIV-1 RNA < 50 c/mL at Wk 48 (primary endpoint; ITT-E snapshot)

– 95% in both arms; Wk 48 treatment difference showed

noninferiority of switch: -0.2% (95% CI: -3.0% to 2.5%)

• Significantly greater improvement in bone turnover markers from

baseline to Wk 48 in switch arm

Switch to DTG + RPV(n = 513)

Continue Baseline ART

(n = 511)

Pts with HIV-1 RNA < 50 c/mL for ≥ 12 mos while receiving first or second ART regimen

with 2 NRTIs + INSTI, NNRTI, or PI; no previous VF; HBV

negative(N = 1024)

Wk 52

Switch to DTG + RPV

Continue DTG + RPV

Walmsley S, et al. IDWeek 2017. Abstract 1382. Llibre JM, et al. CROI 2017. Abstract 44LB.

SWORD 1 & 2: Efficacy and Safety in

Pooled Subgroup Analysis

Walmsley S, et al. IDWeek 2017. Abstract 1382.

HIV-1 RNA < 50

c/mL at Wk 48, %

(n/N)

DTG + RPV

(n = 513)

Continue

BL ART

(n = 511)

Age

▪ < 50 yrs 96 (350/366) 94 (348/369)

▪ ≥ 50 yrs 93 (136/147) 96 (137/142)

Sex

▪ Male 95 (375/393) 96 (387/403)

▪ Female 93 (111/120) 91 (98/108)

Race

▪ White 94 (395/421) 95 (378/398)

▪ African heritage 97 (36/37) 94 (44/47)

▪ Asian 100 (38/38) 98 (49/50)

▪ Other 100 (17/17) 88 (14/16)

AEs Leading to

Withdrawal, %

(n/N)

DTG +

RPV

(n = 513)

Continue

BL ART

(n = 511)

Age

▪ < 50 yrs 3 (12/366) < 1 (2/369)

▪ ≥ 50 yrs 3 (5/147) < 1 (1/142)

Sex

▪ Male 2 (12/393) < 1 (1/403)

▪ Female 4 (5/120) 2 (2/108)

Race

▪ White 4 (17/421) < 1 (2/398)

▪ Nonwhite 0 (0/17) 6 (1/16)

• Randomized, open-label, multicenter phase III trials demonstrated that switch to DTG + RPV noninferior to remaining on baseline ART at Wk 48 in virologically suppressed pts[1]

• Current analysis assessed BMD in pts who continued on TDF-containing triple ART regimen or switched from TDF-containing triple ART to DTG + RPV (N = 102)[2]

SWORD 1 & 2 Substudy: BMD Impact of Switch From TDF-Based ART to DTG + RPV

1. Llibre JM, et al. CROI 2017. Abstract 44LB. 2. McComsey G, et al. IAS 2017. Abstract

TUPDB0205LB.

Change From BL in BMD at Wk 48

Total Hip* Lumbar Spine

Mea

n A

dju

sted

Ch

ange

in

BM

D F

rom

BL

(%)

2.5

1.5

0.5

-0.5

-1.5

-2.5 BL 48 Wks

P = .014

1.34

0.05

DTG + RPV (n = 46)

Continued TDF-based ART (n = 35)

BL 48 Wks

P = .0391.46

0.15

*Primary

endpoint.

• A series of studies on < 3 drug-regimens (LDRs) have shown some potential benefit of treating HIV infection with fewer antiretrovirals

• A synergistic mix of potency and genetic barrier seems to be able to confer adequate antiretroviral performance to a two-drug regimen

• As a result of the various therapeutic attempts to treat HIV infection with LDRs, some criteria for appropriate patients’ selection are now part of the knowledge and experience of most HIV prescribers

• The “induction – maintenance” strategy might allow for a greater proportion of patients to be included on a long-term perspective

• More potent drugs are today available and new ones (e.g. EfdA) are being developed, possibly increasing the possibility to treat HIV infection with <3 drugs

• The development of injectable, long-acting (LA) drugs and regimens might actually minimizes the impact of adherence

• Cost saving

PROs

• No registration trials have yet fully validated any ARV regimens with less than 3 drugs, although this might soon change (e.g. GEMINI 1 & 2 studies)

• We actually evaluate the performance of LDRs with the same parameters we relying upon for conventional regimens (e.g. plasma HIV-RNA, CD4+ T-cell count, side effects, metabolic impact, etc….), and we cannot exclude that some hidden higher HIV activity takes place with LDRs as compared to conventional regimens

• Following initial enthusiasm on the measurement of proviral DNA as complementary parameter of HIV “quantitation” (e.g. MONOI study on DRV/r monotherapy), no relevant improvements have followed in the validation of such parameter, and other ancillary parameters (e.g. activation markers) are yet to be fully validated as monitoring and/or prognostic indicators

• New studies on lymphonode histology and physiology in the long run of HIV infection actually suggest that the brilliant immunovirological picture we see in plasma might not be the same in the lymphatic compartment

• Proviral DNA dynamics in fully virologically controlled patients seems to be less dormant than expected, with drug-specific reshaping taking place

CONs

Santoro et al., Antivir ther 2013

Are we happy with this ?

Acknowledgments

THE UNIVERSITY

of LIVERPOOL

TORINO:

Stefano Bonora

Antonio D’Avolio

Mauro Sciandra

Marco Siccardi

Lorena Baietto

Cristina Tettoni

Sabrina Audagnotto

Letizia Marinaro

Jessica Cusato

Margherita Bracchi

Laura Trentini

Andrea Calcagno

Marco Simiele

Amedeo De Nicolò

Anna Lucchini

Filippo Lipani

Roberto Bertucci

Agostino Maiello

Bernardino Salassa

Francesco G. De Rosa

Chiara Montrucchio

Chiara Alcantarini

Chiara Cardellino

LIVERPOOL:

David Back

Saye Khoo

Andy Owen

Marco Siccardi

Anna Maria Geretti

LONDON:

Marta Boffito

Margherita Bracchi

Nicole Pagani

ROMA:

Andrea Antinori

Adriana Ammassari

Giuseppe Ippolito

Alessandra Arialdo

Micol Ferrara

Alice Trentalange

Nicole Pagani

Lucio Boglione

Sarah Allegra

Marino Bonasso

Alessandro Turchi

Debora Pensi

Pino Cariti

Paolo Bigliano

Ilaria Motta

Silvia Corcione

Ambra Barco

Maria Laura Stella

Giancarlo Orofino

Valeria Ghisetti

Documents

What is the Magic Number? Clinical Pharmacology of Non ... · Clinical Pharmacology of Non Conventional regimens Ospedale Amedeo di Savoia. ... • Pharmacokinetics ... STRATEGY -