Update on acute/recent HIV-1 Infection

Dr. José M. Miró Servicio de Enfermedades Infecciosas

Hospital Clínic - IDIBAPSUniversidad de Barcelona

Barcelona

Correo electrónico: [email protected]

Nuevas Modalidades de Tratamiento Antirretroviral

X Congreso Nacional de GESIDA

Sesión PlenariaGESIDA 2018

Potential conflict of interest

Dr. José M Miró has received honoraria for speaking or

participating in Advisory Boards and/or research grants from

the following Pharmaceutical Companies:

Merck

Novartis

Pfizer

Roche

Theravance

ViiV Healthcare

Abbvie

Contrafect

Cubist

Genentech

Gilead Sciences

Jansen-Cilag

GESIDA 2018

New Modalities of Antiretroviral Treatment

Where we come from: 1 - 2 - 3

Where we are now: TT regimens

New regimens: 2D oral

New regimens: 2D long-acting

Monotherapy

Take home messages

GESIDA 2018

THE EVOLUTION OF HIV THERAPY >30 ARTS

FDA. Antiretroviral drugs used in the treatment of HIV infection http://www.fda.gov/ForPatients/Illness/HIVAIDS/Treatment/ucm118915.htm Accessed August 2015

FDA news release November 2015 http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm471300.htm Accessed November 2015

1984 2018

Retrovir 100 mg capsule

<50 cop./mL

InSTI

STR

GESIDA 2018

Hosp. Clinic-IDIBAPS-Univ. of Barcelona, Barcelona, Spain

Hospital Clinic of Barcelona

HIV cohort (1983-2018)8,500 patients (historical cohort)

5,300 active patients

5,100 (95%) on ART (>95% VL BDL)

GESIDA 2018

Number of new and accumulated HIV-infected patients and

patients on ART at the H. Clinic of Barcelona (1986-2017)

5267 patients

98% on

ART

PrEP !!!

GESIDA 2018

Percentage of patients with undetectable HIV RNA viral load

(<400 c/mL) on ART at the H. Clinic of Barcelona (1995-2017)

50%

97%

0%

80-90%

Lee FJ et al PLoS One 2014;9:e97482; Carr A et al. Glasgow 2018 P#51

GESIDA 2018

Annual mortality rates in the cohort of HIV-infected

patients of the H. Clinic of Barcelona (1986-2017)

20%

<1%

GESIDA 2018

The Constant Evolution of Initial ART at the

Hospital Clinic of Barcelona, Spain (1990-2017)

InSTI = 60%12/r/c

GESIDA 2018






Monotherapy

Take home messages

GESIDA 2018

Saag MS et al. JAMA. 2018; 320:379-396

GESIDA 2018

Recommended Initial ART Regimens for

Treating HIV Infection in 2018Saag MS et al. JAMA. 2018;320:379-396.GESIDA 2018

Alternative ART Regimens for Treating

HIV Infection in 2018 Saag MS et al. JAMA. 2018;320:379-396.GESIDA 2018

B/F/TAF vs. DTG/3TC/ABC

B/F/TAF vs. DTG

plus TAF/FTC

96 wk. Results Presented at the IDWeek

and HIV Glasgow Meetings in 2018GESIDA 2018


Gallant J, et al. Lancet. 2017;390:2063-2072 & Wohl D et al. IDWeek. October 3-7, 2018

GESIDA 2018

No R mutations

AE D/C = 0/5

92% vs. 93% at W48


Gallant J, et al. Lancet. 2017;390:2063-2072 & Wohl D et al. IDWeek. October 3-7, 2018

GESIDA 2018

GS-US-380-1490 Study Design

Phase 3, randomized, double-blind, active-controlled study

– Stratified by HIV-1 RNA, CD4 cell count, geographic region (USA vs non-USA)

– North America, Europe, Australia, and Latin America

– Chronic hepatitis B and/or C virus (HBV/HCV) infection allowed

Primary endpoint: proportion with HIV-1 RNA <50 copies/mL at Week 48

– B/F/TAF 89.4% vs DTG + F/TAF 92.9% with HIV-1 RNA <50 c/mL (p=0.12)1

Secondary endpoint: proportion with HIV-1 RNA <50 copies/mL at Week 96

– Noninferiority margin of 12% based on FDA Snapshot algorithm

18

ClinicalTrials.gov NCT02607956. c, copies; eGFRCG, estimated glomerular filtration rate by Cockcroft-Gault equation.

1. Sax et al. Lancet 2017; 390:2073-82.

48Week 0 144

Treatment-Naïve Adults

HIV-1 RNA ≥500 c/mL

eGFRCG ≥30 mL/min

n=320

n=325

1 Endpoint

96

DTG + F/TAF Placebo QD

B/F/TAF QD

B/F/TAF Placebo QD

DTG + F/TAF QD

1:1

2º Endpoint

B/F/TAF vs. DTG plus TAF/FTC

Stellbrink HJ et al. HIV Glasgow. October 28-31, 2018

GESIDA 2018

Baseline Characteristics

19

c, copies; eGFRCG, estimated glomerular filtration rate by Cockcroft-Gault; IQR, interquartile range.

* Positive HBV surface antigen; isolated positive HBV core antigen, with quantifiable HBV DNA (ie, ≥20 IU/mL) on or prior to 1st dose.† Positive HCV antibody and quantifiable HCV RNA (ie, ≥15 IU/mL) prior to 1st dose of study drug.

B/F/TAF

n=320

DTG + F/TAF

n=325

Median age, y (range) 33 (18–71) 34 (18–77)

Male, % 88 89

Race/ethnicity, %

Black or African descent 30 31

White 57 60

Hispanic/Latino 26 25

Median HIV-1 RNA, log10 copies/mL (Q1, Q3) 4.43 (3.95, 4.90) 4.45 (4.03, 4.84)

HIV-1 RNA >100,000 copies/mL, % 21 17

Median CD4 cell count, cells/µL (Q1, Q3) 440 (289, 591) 441 (297, 597)

CD4 count <200 cells/µL, % 14 10

HBV*/HCV† coinfection, % 3/2 2/2

Median eGFRCG, mL/min (Q1, Q3) 120 (101, 142) 121 (103, 145)

Sax PE, et al. Lancet. 2017;390:2073-2082 & Stellbrink HJ et al. HIV Glasgow. October 28-31, 2018

B/F/TAF vs. DTG plus TAF/FTCGESIDA 2018

Virologic Outcome at Week 96Snapshot analysis

At Week 96, B/F/TAF was noninferior to DTG + F/TAF by FDA Snapshot analysis

– Per protocol analysis: B/F/TAF 100% vs DTG + F/TAF 98%

Mean CD4 increase from baseline at Week 96:

– B/F/TAF +237 cells/µL vs DTG + F/TAF +281 cells/µL (p=0.008)

– Mean CD4 % change B/F/TAF 11% vs DTG + F/TAF 11% (p=0.37)

– Mean absolute CD4 B/F/TAF 693 vs DTG + F/TAF 733 (p=0.13)

20

P-value was from analysis of variance (ANOVA) model adjusted by the baseline HIV-1 RNA and region stratum.

% Treatment Difference (95% CI)

-7.9 3.2

-2.3

-12 120-6 6

Favors

DTG + F/TAF

Favors

B/F/TAF

84

412

86

311

0

20

40

60

80

100

HIV-1 RNA

<50 copies/mL

HIV-1 RNA

≥50 copies/mL

No Virologic

Data

DTG + F/TAF (n=325)

B/F/TAF (n=320)

Pro

po

rtio

n o

f p

art

icip

ants

, %

Virologic Outcome

269

320

281

325

14

320

9

325

35

325

37

320

No R mutations

AE D/C = 6/5

89% vs. 93% at W48

B/F/TAF vs. DTG plus TAF/FTC

Sax PE, et al. Lancet. 2017;390:2073-2082 & Stellbrink HJ et al. HIV Glasgow. October 28-31, 2018

GESIDA 2018


vs. DTG

plus TAF/FTC

Pros- Same day T&T w/STR

- HBV

Cons- Acute infection

- Advanced Infection

- Avoid in TB/HIV

- Less long-term data

Pros- More long-term data

- TB/HIV

Cons- HLA-B*5701 testing

- Same day T&T w/TAF/FTC

- HBV w/TAF/FTC

- Advanced Infection

- NRC (DTG) and CVD (ABC) issues

- Teratogenicity (e.g. NTD)

GESIDA 2018

Evolution of ART regimens over time

2

1984-2018 Future

112/r/c

GESIDA 2018






Monotherapy

Take home messages

GESIDA 2018

What are the reasons to start/switch to 2DC

• To avoid potential NRTI-related toxicity

- Bone

- Kidney

- Cardiovascular

- Other

• Less exposure to ART drugs throughout life

• Economic cost

• Naïve or virologically suppressed patients

• No antiretroviral-resistance mutations

• Never do it in HBV/HIV coinfected patients

GESIDA 2018

2D vs. TT RCT

Naïve

- GARDEL (LPV/r + 3TC)

- KALEA (LPV/r + TDF)

- NEAT001/ANRS143 (DRV/r + RAL)*

- ANDES (DRV/r + 3TC)

Switching

- OLE (LPV/r + 3TC)

- ATLAS-M (ATV/r + 3TC)

- SALT (ATV/r + 3TC)

- DUAL-GESIDA (DRV/r + 3TC)

r/PI-based 2DC

*Not recommended if plasma HIV RNA VL

>100.000 copies/mL and CD4 < 200/mm3

GESIDA 2018

bPI-based 2DC: Trial Designs

StudyFollow Up

WeekDual Triple Treatment History

GARDEL (n=306) 96 LPV/r + 3TC LPV/r + 2 NRTI Naïve

KALEAD (n=152) 24 LPV/r + TDF LPV/r + 2 NRTI Naïve

ANDES (n=145) 48 DRV/r + 3TC DRV/r + 3TC/TDF Naïve

OLE (n=250) 48 LPV/r + 3TC LPV/r + 2 NRTI Switch

ATLAS-M (n=266) 96 ATV/r + 3TC ATV/r + 2 NRTI Switch

SALT (n=267) 96 ATV/r + 3TC ATV/r + 2 NRTI Switch

DUAL-GESIDA (n=249) 48 DRV/r + 3TC DRV/r + 2 NRTI Switch

Total (n=1635)

Liev Z et al. HIV Glasgow. October 28-31, 2018

GESIDA 2018

bPI-based 2DC: HIV-RNA <50 copies/mL

StudyFollow Up

WeekDual Triple

RD, 95% Confidence Interval

GARDEL (n=306) 96 90.3% 84.4% +6% (-2%, +13%)

KALEAD (n=152) 24 69.4% 70.0% -1% (-15%, +14%)

ANDES (n=145) 48 93.3% 94.2% -1% (-9%, +7%)

OLE (n=250) 48 87.8% 86.6% +1% (-7%, +9%)

ATLAS-M (n=266) 96 77.4% 65.4% +12% (1 %, +23%)

SALT (n=267) 96 74.4% 73.4% +1% (-10%, +11%)

DUAL-GESIDA (n=249) 48 88.9% 92.7% -4% (-11% , +3%)

Total (n=1635) p=0.40 83.6% 80.6% +2% (-2%, +6%)


GESIDA 2018

bPI-based 2DC: Virological failure (PDVF)

StudyFollow Up

WeekDual Triple


GARDEL (n=306) 96 7.3% 6.4% +1% (5%, +7%)

KALEAD (n=152) 24 15.3% 8.8% -7% (-4%, +17%)

ANDES (n=145) 48 0.0% 1.4% -1% (-5%, +2%)

OLE (n=250) 48 2.4% 2.4% 0% (-4%, +4%)

ATLAS-M (n=266) 96 1.5% 6.8% -5% (-10%, - 1%)

SALT (n=267) 96 6.8% 3.7% +3% (-2%, +8%)

DUAL-GESIDA (n=249) 48 3.2% 1.6% +2% (-2%, +8%)

Total (n=1635) p=0.98 5.0% 4.5% 0% (-2%,+2%)


GESIDA 2018

Treatment Emergent Resistance Mutations

StudyFollow Up

WeekDual Triple


GARDEL (n=306) 96 2.4% 2.1% -1% (-5%, +2%)

KALEAD (n=152) 24 0.0% 1.3% -1% (-5%, +2%)

OLE (n=250) 48 0.8% 0.0% +1% (-1%, +1%)

ATLAS-M (n=266) 96 0.0% 0.0% 0% (-1%, +1%)

SALT (n=267) 96 0.0% 0.7% -1% (-3%, +1%)

DUAL-GESIDA (n=249) 48 0.0% 0.0% -1% (-1%, +1%)

Total (n=1490) p=0.89 0.7% 0.7% 0% (-1%, +1%)

Only few NRTI mutations in 2D and TT arms (M184V). No major PI mutations.


GESIDA 2018

Discontinuations due to Adverse Events

StudyFollow Up

WeekDual Triple


KALEAD (n=152) 24 11.1% 7.5% +4% (-6%, +13%)

TDF (n=152) p=0.45 11.1% 7.5% +4% (-6%, 13%)

GARDEL (n=306) 96 0.6% 2.8% -2% (-5%, +1%)

OLE (n=250) 48 0.8% 3.1% -2% (-6%, +1%)

ATLAS-M (n=266) 96 1.5% 2.3% -1% (-4%, +3%)

SALT (n=281) 96 5.0% 7.1% -2% (-8%, +3%)

DUAL-GESIDA (n=249) 48 0.8% 1.6% -1% (-4%, +2%)

3TC (n=1352) p=0.04 1.7% 3.5% -2% (-3%, 0%)

GESIDA 2018

0

20

40

60

80

100

<50cp/ml PDVF Resistance D/AE

bPI-based 2DC: Summary Findings

HIV-RNA <50 copies/mL

Protocol Defined Virological Failure

Resistance Mutations

Discontinuations due to adverse

events

Dual

DualDual

Dual

Triple

TripleTriple

Triple

83.6% 80.6%

5.0% 4.5%0.7% 0.7%

2.7% 3.9%

Perc

enta

ge o

f p

atie

nts

wh

o a

chie

ved

en

dp

oin

t (

%)

GESIDA 2018

2D vs. TT RCT

Naïve

- GARDEL (LPV/r + 3TC)

- KALEA (LPV/r + TDF)

- NEAT001/ANRS143 (DRV/r + RAL)

- ANDES (DRV/r + 3TC)

Switching

- OLE (LPV/r + 3TC)

- ATLAS-M (ATV/r + 3TC)

- SALT (ATV/r + 3TC)

- DUAL-GESIDA (DRV/r + 3TC)

r/PI-based 2DC DTG-based 2DC

Naïve (+ 3TC)

- PADDLE (single arm)

- ACTG A5353 (single arm)

- GEMINI 1+2 (DTG + 3TC)

Switching

- SWORD 1+2 (DTG + RPV)

- ASPIRE (DTG + 3TC)

- ANRS 167 LAMIDOL

(single arm DTG + 3TC)

GESIDA 2018

22nd International AIDS Conference; July 23-27, 2018; Amsterdam, the Netherlands

a−10% noninferiority margin for individual studies.

GEMINI-1 and -2 Phase III Study Design

Cahn P et al. AIDS 2018; Amsterdam, the Netherlands. Slides TUAB0106LB.

DTG + 3TC (N=716)

Day

1

Screening

(28 d)

Identically designed, randomized, double-blind, parallel-group,

multicenter, noninferiority studies

DTG + TDF/FTC (N=717)

DTG + 3TC

Week

48

Primary endpoint

at Week 48:

participants with

HIV-1 RNA <50 c/mL

(ITT-E snapshot)a

Double-blind

phase

Open-label

phase

Continuation

phase

CountriesArgentina Australia Belgium

Canada France Germany

Italy Republic of Korea Mexico

Netherlands Peru Poland

Portugal Romania Russian Federation

South Africa Spain Switzerland

Taiwan United Kingdom United States

Week

144

Week

24

Week

96

• ART-naive adults

• VL 1000-500,000 c/mL

1:1

Eligibility criteria

•≤10 days of prior ART

•No evidence of pre-existing viral resistance

based on presence of any major resistance-

associated mutation

•No HBV infection or need for HCV therapy

Baseline stratification factors: plasma HIV-1 RNA (≤100,000 c/mL vs >100,000 c/mL) CD4+ cell count (≤200 cells/mm3 vs >200 cells/mm3).

GESIDA 2018


Demographic and Baseline Characteristics for the

Pooled GEMINI-1 and -2 Population

Characteristic

DTG + 3TC

(N=716)

DTG + TDF/FTC

(N=717)

Age, median (range), y

≥50 y, n (%)

32.0 (18-72)

65 (9)

33.0 (18-70)

80 (11)

Female, n (%) 113 (16) 98 (14)

Race, n (%)

African American/African heritage

Asian

White

Other

Ethnicity, n (%)

Hispanic or Latino

Not Hispanic or Latino

99 (14)

71 (10)

480 (67)

66 (9)

215 (30)

501 (70)

76 (11)

72 (10)

497 (69)

72 (10)

232 (32)

485 (68)

HIV-1 RNA, median (range), log10 c/mL

≤100,000

>100,000a

4.43 (1.59-6.27)

576 (80)

140 (20)

4.46 (2.11-6.37)

564 (79)

153 (21)

CD4+ cell count, median (range), cells/mm3

>200

≤200

427.0 (19-1399)

653 (91)

63 (9)

438.0 (19-1497)

662 (92)

55 (8)

a2% of participants in each arm had baseline HIV-1 RNA >500,000 c/mL


up to 500,000

GESIDA 2018


Pooled Snapshot Outcomes at Week 48: ITT-E and Per Protocol Populations


aBased on Cochran-Mantel-Haenszel stratified analysis adjusting for the following baseline stratification factors: plasma HIV-1 RNA

(≤100,000 c/mL vs >100,000 c/mL), CD4+ cell count (≤200 cells/mm3 vs >200 cells/mm3), and study (GEMINI-1 vs GEMINI-2). bPP, per

protocol: population consisted of participants in the ITT-E population except for significant protocol violators, which could potentially

affect efficacy outcomes as determined by the medical monitor prior to database lock.

Virologic outcome Adjusted treatment difference (95% CI)a

DTG + TDF/FTC DTG + 3TC

-4.4 1.1

-1.7

Percentage-point difference

DTG + 3TC is non-inferior to DTG + TDF/FTC

with respect to proportion <50 c/mL at Week 48

(snapshot, ITT-E population) in both studies

-1.3

-3.9 1.2

ITT-E

PP

ITT-E DTG + 3TC (N=716) DTG + TDF/FTC (N=717)

PPb DTG + 3TC (N=694) DTG + TDF/FTC (N=693)

GESIDA 2018


TRDF Analysis

566

576

>100,000≤100,000 >200 ≤200

Baseline HIV-1

RNA, c/mL

Baseline CD4+

cell count, cell/mm3

Pooled Outcomes at Week 48 Stratified by Baseline HIV-1 RNA and

CD4+ Cell Count: Snapshot and TRDF Analysis

Snapshot Analysis

• 2% of participants in each arm had baseline HIV-1 RNA >500,000 c/mL. Treatment related discontinuation = failure (TRDF) population accounts for

confirmed virologic withdrawal (CVW), withdrawal due to lack of efficacy, withdrawal due to treatment-related AE, and participants who met protocol-defined

stopping criteria. DTG + 3TC CD4 <200 Snapshot non-response (n=13): 1 CVW, 3 with VL >50 in window (2 of 3 re-suppressed), 2 discontinued due to

AE (TB, Chagas disease), 2 protocol violations, 2 lost to follow-up, 1 withdrew consent, 1 withdrew to start HCV treatment, 1 change in ART (incarcerated).

DTG + TDF/FTC < 200 Snapshot non-response (n=4):1 investigator discretion, 1 withdrew consent, 1 lost to follow-up, 1 VL >50 (re-suppressed).

DTG + 3TC DTG + TDF/FTC

>100,000≤100,000 >200 ≤200

Baseline HIV-1

RNA, c/mL

Baseline CD4+

cell count, cell/mm3

553

564

138

140

149

153

642

653

647

662

62

63

55

55

526

576

531

564

129

140

138

153

605

653

618

662

50

63

51

55

Cahn et al. AIDS 2018; Amsterdam, the Netherlands. Slides TUAB0106LB.

GESIDA 2018


Confirmed Virologic Withdrawals Through Week 48: ITT-E Population

GEMINI 1 GEMINI 2 Pooled

Variable, n (%)

DTG + 3TC

(N=356)

DTG +

TDF/FTC

(N=358)

DTG + 3TC

(N=360)

DTG +

TDF/FTC

(N=359)

DTG + 3TC

(N=716)

DTG +

TDF/FTC

(N=717)

CVW 4 (1) 2 (<1) 2 (<1) 2 (<1) 6 (<1) 4 (<1)

Treatment-emergent

resistance

0 0 0 0 0 0

• Low rates of virologic withdrawals were observed at Week 48

Cahn et al. AIDS 2018; Amsterdam, the Netherlands. Slides TUAB0106LB.

• No treatment-emergent INSTI mutations or NRTI mutations were observed

among participants who met CVW (confirmed virologic failure) criteria

Confirmed virologic withdrawal criteria is defined as a second and consecutive HIV-1 RNA value meeting virologic non-response or rebound. Virologic non-response is defined as either a decrease in

plasma HIV-1 RNA of less than 1 log10 c/mL by Week 12 with subsequent confirmation unless plasma HIV-1 RNA is <200 c/mL, or confirmed plasma HIV-1 RNA levels ≥200 c/mL on or after Week 24.

Virologic rebound is defined as confirmed rebound in plasma HIV-1 RNA levels to ≥200 c/mL after prior confirmed suppression to <200 c/mL.

.

GESIDA 2018

SWORD-1 and -2: Phase III Study Design

*8% non-inferiority margin for pooled data. -10% non-inferiority margin for individual studies

HBV, hepatitis B virus; ITT(-E), intent to treat (- exposed); NRTI, nucleoside reverse transcriptase inhibitor

Inclusion criteria

• On stable CAR 6 months before

screening

• 1st or 2nd ART with no change in prior

regimen due to VF

• Confirmed HIV-1 RNA <50 c/mL during

the 12 months before screening

• HBV-negative

DTG + RPV (N=513)

Day 1

Screening

Week 148

Identically designed, randomised, multicentre, open-label,

parallel-group, non-inferiority studies

CAR (N=511) DTG + RPV

VL <50 c/mL on INI, NNRTI,or PI + 2 NRTIs

1:1

DTG + RPV

Week 52

Primary endpoint

at 48 weeks:

subjects with

VL <50 c/mL

(ITT-E snapshot)*

Early-switch phase Late-switch phase Continuation phase

Countries:

Argentina Australia Belgium Canada

France Germany Italy Netherlands

Russia Spain Taiwan United Kingdom

United States

Llibre JM, et al. CROI 2017. Oral Presentation 44LB

GESIDA 2018

SWORD-1 and -2: Demographics and

Baseline Characteristics


Data pooled across SWORD-1 and -2

DTG + RPV

(n=513)

n (%)

CAR

(n=511)

n (%)

Age, mean (SD)

≥50 years

43 (11)

147 (29)

43 (10)

142 (28)

Female 120 (23) 108 (21)

Race, non-white 92 (18) 111 (22)

CD4+ cell count, cells/mm3 (median)

≤500

>500

611

165 (32)

348 (68)

638

149 (29)

362 (71)

Baseline third-agent class

PI

NNRTI

INI

133 (26)

275 (54)

105 (20)

136 (27)

278 (54)

97 (19)

Baseline TDF use 374 (73) 359 (70)

Median duration of ART prior to Day 1, months 51 53

GESIDA 2018

SWORD-1 and -2: Snapshot Outcomes at Week 48


*Adjusted for age and baseline third agent

CAR DTG + RPV

–4.3 3.0

SWORD-1

SWORD-2

–3.9 4.2

SWORD-1

SWORD-2

95 96 94 94

<1 <1 <1 2 4 4 5 4

0.2

–0.6

Percentage-point difference

DTG + RPV is non-inferior to CAR with

respect to snapshot in the ITT-E population

(<50 c/mL) at Week 48 in both studies

0

Virologic outcomes

Adjusted treatment

difference (95% CI)*

GESIDA 2018

SWORD-1 and -2: Confirmed Virologic Withdrawals


• One subject on DTG + RPV meeting virologic withdrawal criteria had an NNRTI

resistance-associated mutation (K101K/E) identified

• No INI resistance-associated mutations were identified

Data pooled across SWORD-1 and -2

*CVW defined as current ‘retest’ HIV-1 RNA ≥200 c/mL, prior ≥50 c/mL

CVW, confirmed virologic withdrawal

Early-switch phase

DTG + RPV

n=513

n (%)

CAR

n=511

n (%)

CVW* 2 (<1) 2 (<1)

GESIDA 2018


2D or not 2Dthat is the question

Hamlet, Act III, Scene I. Sir William Shakespeare, 1564 - 1616.

GESIDA 2018

Uptake and effectiveness of 2D compared to TT ART

regimens in Europe

Pelchen-Matthews A et al. EuroSida. IAS. Amsterdam, 2018 Poster No. THPEB052

2D ART regimens ART response at 48 wk.

Switching ART in >80% of cases

GESIDA 2018

Pros- Excellent efficacy & safety data

- More long-term data

- No bPI mutations

- bPI can be used in CKD

Cons- DDIs

- No STRs

- “b/PI-side effects”

Pros- Excellent efficacy & safety data

- STRs (DTG+RPV, DTG+3TC soon)

- No DDIs

- No DTG mutations

- DTG + RPV can be used in CKD

Cons- Limited data in acute/recent infection

- Limited data in advanced patients

- “DTG-side effects”

- RPV must be taken with food, avoid

PPIs and separated from antiacids.

2D vs. TT RCTr/PI-based 2DC DTG-based 2DC

Potential 2DC RCTs in naïve patients

• DTG+3TC vs. bDRV+3TC

• BIC+3TC vs. DTG+3TC or bDRV+3TC

• DTG+3TC in Acute-Recent/Advanced Patients

GESIDA 2018






Monotherapy

Take home messages

GESIDA 2018

What are the reasons to use long-acting (LA)

antiretrovirals for treating HIV-infection

Adherence to oral

antiretrovirals can be variable

Special populations

- Drug and alcohol abuse

- Psychiatric illness

Antiretroviral stigma

Patients´ preference

Monroe M et al. Bioengineering & Translational Medicine 2018;3:102–123

GESIDA 2018

Requirements Infrequent dosing (~ 2-3 months)

Practical injection volume (≤ 4mL)

Minimal PK tail

High genetic barrier to resistance

Minimal injection associated

adverse events

Stable formulation ideally without

cold chain requirements

LA ARV drugs LA Rilpivirine

LA Cabotegravir

MK-8591 (EFdA)*

GS-CA1 (Capsid inhibitor)**

Broadly Neutralizing

Monoclonal antibodies (PRO140; UB-421; VRC01; VRC01-

LS; 3BNC117; 10-1074)

Main Characteristics of LA ARV drugs

*Nucleoside reverse transcriptase translocation inhibitor” – inhibits reverse transcriptase by two different mechanisms. Implant

Formulations Release Effective Drug Levels for >180 days; ** Capsid inhibitor. It is the most potent antiretroviral agent.

GESIDA 2018

4848Spreen W et al. JAIDS 2014;67:487-92.

Cabotegravir (CAB) LA Single Injection Provides Detectable Drug

in Plasma for 48 Weeks

Time (weeks)

0 4 8 12 16 20 24 28 32 36 40 44 48

Pla

sma C

AB

(

g/m

L)

0.1

1

100mg IM

200mg IM

400mg IM

800mg IM (split)

100mg SC

200mg SC

400mg SC (split)

4*PA-IC90

PA-IC90

Mean Concentration-Time Profile (n=6/cohort)

CAB 5mg/day p.o.

Ctau = 0.6 ug/mL

(0.67 ug/mL)

CAB LA apparent half-life ~40days

versus CAB oral ~40hr half-life

Very very

long PK tail !

GESIDA 2018

23rd Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, MA

• CAB is an HIV-1 integrase inhibitor– Oral 30 mg tablet (t½, ~40 hours)

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

• RPV is an HIV-1 NNRTI– Oral 25 mg tablet (t½, ~50 hours)

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

• Oral 2-drug CAB + RPV proof of efficacy

through Week 96 in LATTE-1

Parenteral Cabotegravir + Rilpivirine as Long-Acting Maintenance Therapy: LATTE-1 RCT

Margolis et al. Lancet ID. 2015; 15:1145-55.

BL, baseline; CAB, cabotegravir; CI, confidence interval; EFV, efavirenz; LA, long-acting; NNRTI, non-nucleoside reverse

transcriptase inhibitor; RPV, rilpivirine; t1/2, half-life.

0

20

40

60

80

100

CAB 10 mg (n=60) CAB 30 mg (n=60)CAB 60 mg (n=61) EFV 600 mg (n=62)

12 1684BL 2 242628 32 36 40 48 60 72 84 96

Pro

po

rtio

n,

% (

95

% C

I)

GESIDA 2018

21st International AIDS Conference; July 18-22, 2016; Durban, South Africa

Induction period

LATTE-2 Study Design (Phase 2)

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)

CAB 30 mg + ABC/3TC PO QD

for 20 weeks

(N=309)

Maintenance perioda

Add RPV

PO QD

4 weeks

Inclusion

criteria

• >18 years old• Naive to antiretroviral therapy• CD4+ >200 cells/mm3

Exclusion

criteria

• Positive for hepatitis B• ALT ≥5 × ULN• Creatinine clearance <50

mL/min

Qualification

for

maintenance

• HIV-1 RNA <50 c/mL between Week -4 and Day 1

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.

286/309 (92,5%)

GESIDA 2018


LATTE 2. HIV-1 RNA <50 c/mL at 48 wk. ITT-ME (Snapshot)

Abstract THAB0206LB.

Oral IM

Virologic outcomes Treatment differences (95% CI)

-6.6 12.4

Q8W IM (CAB 600 + RPV 900 mg)

-7.6 11.6

Q4W IM (CAB 400 + RPV 600 mg)

ITT-e (286 out of 309)

Margolis et al. Lancet ID 2015; 15:1145-55.

GESIDA 2018

9th IAS Conference on HIV Science; July 23-26, 2017; Paris, France

Virologic outcomes Treatment differences (95% CI)

Oral IM

Q8W IM

−8.4% 14.4%

Q4W IM

− 0.6% 20.5%

Eron et al. IAS 2017; Paris, France. MOAX0205LB; * Margolis DA et al. HIV Glasgow, UK, October 28-31, 2018

ITT-ME, intent-to-treat maintenance exposed; LA, long acting; Q4W, every 4 weeks; Q8W, every 8 weeks.

LATTE 2. HIV-1 RNA <50 c/mL at 96 wk. ITT-ME (Snapshot)

90% Q8W vs. 83% Q4W

at W160*GESIDA 2018


01 4 8 12 16 20 24 28 32 36 40 44 48

10

100

1000

Me

an

pla

sm

a R

PV

±S

D, n

g/m

L

Week

Q4W

Q8W

PA-IC90

25 mg PO Cτ

LATTE 2. PK of CAB + RPV Q4W and Q8W.

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

01 4 8 12 16 20 24 28 32 36 40 44 48

0.1

1

10

100

Me

an

pla

sm

a C

AB

±S

D,

μg/m

L

Week

Q4WQ8WPA-IC9010 mg PO Cτ30 mg PO Cτ

Cτ, trough concentration; PA-IC90, protein binding–adjusted 90% inhibitory concentration; SD, standard deviation.

• Both Q4W and Q8W steady state exposures approximate once-daily oral dosing

• Phase 3 FLAIR (NCT02938520), n=570. CAB-LA + RPV-LA Q4 wk. vs. DTG/ABC/3TC

in Naives. Fully recruited.

• Phase 3 ATLAS (NCT02951052), n=570. Switch from any triple ART (2NRTIs + 3rd

drug) to CAB LA + RPV LA Q4 wk. Fully recruited.

• Phase 3 ATLAS 2M, n=1020. Switch from any triple ART to CAB LA +RPV LA Q4 or

Q8 wk. Fully recruited.

GESIDA 2018


LA or not LAthat is the question

Hamlet, Act III, Scene I. Sir William Shakespeare, 1564 - 1616.

GESIDA 2018

Pros- Innovative approach

- Excellent efficacy data

- Safety (except ISR)

- Useful for non-adherent target

populations

- Also useful for PrEP

Cons- No data in VS patients with

CD4<200/mm3

- Lead-in oral phase duration not

well defined

- Best schedule not defined yet

- Drug toxicity management

- Resistance concern

- Limited PK data in sanctuaries

- Stopping rules not defined (long

PK tail)

- Logistics outside RCT

Long-Acting (LA) ARTGESIDA 2018






Monotherapy

Take home messages

GESIDA 2018

Monotherapy

Naïve

- MONARK (LPV/r)*

- IMANI I, II (LPV/r)*

Switching

- OK / OK04 (LPV/r)

- KALMO / IMANI III (LPV/r)

- ACTG5201 (ATV/r)*

- ATARIMO / OREY (ATV/r)*

- MONET / MONOI / MONARCH (DRV/r)

PI/r-Monotherapy

*Hight rates of treatment failures

GESIDA 2018

PI/r monotherapy

• Not recommended in naïve patients

• LPV/r and DRV/r demonstrated the

non-inferiority in switching trials

• Strict adherence is necessary

• VF not associated with PI R mutations

• Most patients resupressed with TT

• EACS Guidelines considered this

option for selected patients

GESIDA 2018

SEMINARIO VIH: ACTUALIZACIÓN EN TRATAMIENTO ANTIRRETROVIRAL TRIPLE Y DUAL

MOBIDIP/ANRS286 RCT in sub-Saharan Africa

The patients came from a

prospective cohort generated after

the 2LADY study

PI/r* monotherapy (n=133)

Randomization1:1

Basal Week 24 Week 96

- HIV-1 VL <200 c/mL ≥ 6 mo.

- CD4> 100 cels / mm3

- Adherence ≥ 90% last control

- No ART changes in last 3 mo.2 NRTI + 1 boosted PI PI/r* + 3TC (n=132)

PI/r Mono PI/r + 3TC Total

Ciaffi L, et al. Lancet HIV 2017;4:e384-e392

GESIDA 2018

SEMINARIO VIH: ACTUALIZACIÓN EN TRATAMIENTO ANTIRRETROVIRAL TRIPLE Y DUAL

Ciaffi L, et al. Lancet HIV 2017;4:e384-e392

The monotherapy arm was

stopped by recommendation

of the DSMB

Treatment Failure (ITT análisis)

Efficacy of the PI/r + 3TC arm at W96 was 92%

7/8 VF were genotyped: without R to PIs or NRTI

MOBIDIP/ANRS286 RCT in sub-Saharan Africa

2%

21%

GESIDA 2018

Monotherapy

Naïve

- MONARK (LPV/r)

- IMANI I, II (LPV/r)

Switching

- OK / OK04 (LPV/r)

- KALMO / IMANI III (LPV/r)

- ACTG5201 (ATV/r)

- ATARIMO / OREY (ATV/r)

- MONET / MONOI / MONARCH (DRV/r)

PI/r-Monotherapy DTG-Monotherapy

Naïve

- No studies

Switching

- DOLAM (TT vs. 2D vs. M)

- DOMONO (TT vs. M)

- Several cohort studies

- Recent HIV Infection (TT vs. M)*

*Only study without any case of VF. Braun DL et al. IAS Amsterdam, July 2018.

GESIDA 2018

Study (n)24 weeks

Proportion (95% CI)48 weeks

Proportion (95% CI)

Gubavu et al. (21) 0.00% (0.00-16.1) –

Katlama et al. (28) 10.7% (2.27-28.2) –

Lecompte et al. (8) 0.00% (0.00-36.9) –

Oldenbüttel et al. (31) 3.23% (0.08-16.7) –

Rojas et al. (31) 3.23% (0.08-16.7) –

Rokx et al. (5) 0.00% (0.00-52.2) 20.0% (0.51-71.6)

Wijting et al. (96) 2.08% (0.25-7.32) 8.33% (3.67-15.8)

Borghetti et al. (36) 0.00% (0.00-9.74) –

Gantner et al. (116) 0.86% (0.02-4.71) –

Joly et al. (104) 0.96% (0.02-5.24) 0.96% (0.02-5.24)

Llibre et al. (513) 0.19% (0.00-1.08) 0.39% (0.05-1.40)

Maggiolo et al. (94) 0.00% (0.00-3.85) 0.00% (0.00-3.85)

Reynes et al. (27) 0.00% (0.00-12.8) 0.00% (0.00-12.8)

Riva et al. (61) 0.00% (0.00-5.87) –

SUMMARY 0.8% (0.29-2.19) 1.14% (0.22-5.61)

DTG-

Mono

DTG-

Dual

Virological failure

0% 5% 10% 15% 20% 25%

24 weeks 48 weeks

Meta-analysis DTG+3TC and DTG monotherapyProportion of virologic failures

Buzzi et al. EACS 2017; Milan, Italy. Oral PS1/2.

Mono

Dual

Virological failure

0% 5% 10% 15% 20% 25%

3.18% (1.52-6.52) 8.91% (4.70-16.2)

0.32% (0.10-0.97) 0.41% (0.13-1.25)

GESIDA 2018

Types of

therapy

Subjects

exposed, n

Virological

failureAmplified, n

New

resistancesTypes of resistance

DTG-mono 220 14 12 7

E138K + G140A +

Q148R

E92Q

N155H

S230R

R263K

N155H

Q148H + G140S

DTG-RPV 629 3 2 1 K101K/E

DTG-3TC 261 1 0 - /

DTG-ATZ 61 0 - - /

→ On DTG monotherapy, 50% of virological failures

develop a new resistance to integrase inhibitors

Meta-analysis DTG+3TC and DTG monotherapyResistances

Buzzi et al. EACS 2017; Milan, Italy. Oral PS1/2.

GESIDA 2018


1984-2018 Future

112/r/c

GESIDA 2018






Monotherapy

Take home messages

GESIDA 2018

Take Home Messages Current IAS ART guidelines recommend for initial therapy an integrase strand

transfer inhibitor (InSTI) (bictegravir or dolutegravir) plus 2 nucleoside reverse

transcriptase inhibitors (NRTIs).

Dual-therapy regimens that include boosted darunavir or dolutegravir plus

lamivudine might be considered for initial therapy in selected non-advanced chronic

HIV-infected patients.

Dual-therapy regimens that include a boosted protease inhibitor (lopinavir/darunavir)

plus lamivudine or dolutegravir plus rilpivirine can be considered for switching

therapy in selected virologically suppressed chronic HIV-infected patients.

Monotherapy with PIs or dolutegravir as a maintenance strategy is not

recommended because of higher rates of treatment failure, often with resistant virus

in patients taken dolutegravir monotherapy.

GESIDA 2018

J.R. Arribas

A. Calmy

E. Lazzari

J.M. Llibre

E. Martinez

G. Mora

J. Perez-Molina

Acknowledgements

A. Pharris

Jansen

Gilead

ViiV Healthcare

GESIDA 2018

In Memoriam

Teresa Gallart Gallart (1942-2018)

Servei d‘Inmunologia

Hospital Clínic de Barcelona

GESIDA 2018

Update on acute/recent HIV-1 Infection

Documents

Transcript of Update on acute/recent HIV-1 Infection