El Futuro del Tratamiento Antirretroviral · 2018-12-10 · El Futuro del Tratamiento...

Dr. José M. Miró Servicio de Enfermedades Infecciosas

Hospital Clínic - IDIBAPSUniversidad de Barcelona

Barcelona

Dr. José M. Miró Servicio de Enfermedades Infecciosas

Hospital Clínic - IDIBAPSUniversidad de Barcelona

BarcelonaCorreo electrónico: [email protected] electrónico: [email protected]

El Futuro del Tratamiento Antirretroviral

XXII Jornadas Internacionales sobre TB - 2018Mesa Redonda: Guías de Práctica Clínica en TB/VIH

26 de Noviembre del 2018

XXII Jornadas Internacionales sobre TB - 2018Mesa Redonda: Guías de Práctica Clínica en TB/VIH

26 de Noviembre del 2018

Potential conflict of interestPotential conflict of interestDr. José M Miró has received honoraria for speaking or

participating in Advisory Boards and/or research grants from the following Pharmaceutical Companies:

Dr. José M Miró has received honoraria for speaking or participating in Advisory Boards and/or research grants from

the following Pharmaceutical Companies:

MerckNovartisPfizerRoche TheravanceViiV Healthcare

MerckNovartisPfizerRoche TheravanceViiV Healthcare

Abbvie Contrafect CubistGenentechGilead Sciences Jansen-Cilag

Abbvie Contrafect CubistGenentechGilead Sciences Jansen-Cilag

The Future of Antiretroviral Treatment


Where we come from: 1 - 2 - 3Where we are now: TT regimens New regimens: 2D oral New regimens: 2D long-acting Monotherapy Take home messages


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

1984 2018

Retrovir 100 mg capsule

<50 cop./mLInSTI

STR

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

Hospital Clinic of BarcelonaHIV cohort (1983-2018)8,500 patients (historical cohort)

5,300 active patients5,100 (95%) on ART (>95% VL BDL)

Number of new and accumulated HIV-infected patients and patients on ART at the H. Clinic of Barcelona (1986-2017)

5267 patients98% on

ART

PrEP !!!

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

Annual mortality rates in the cohort of HIV-infected patients of the H. Clinic of Barcelona (1986-2017)

20%

<1%

The Constant Evolution of Initial ART at the Hospital Clinic of Barcelona, Spain (1990-2017)

InSTI = 60%

/r/c

Fast Track Targets by 2020

73%of all people living

with HIV

VIRALLY SUPPRESSED

=

Target 1 Target 2 Target 3 Overall target

diagnosed with HIV

ON ART

living with HIV

DIAGNOSED

on ART

VIRALLY SUPPRESSED

75% 79% 81%= 49%UNAIDS 2018

Progress toward achieving the 1st 9090% of all PLHIV who know their status (n=39)

Source: ECDC. Dublin Declaration monitoring 2018; validated unpublished data.Latest available data reported, ranging from 2014‐2017.

Target reached Above regional average Below regional average

Global target 90%

Europe and Central Asia 80%80%

Global target 90%

Europe and Central Asia 64%


Progress toward achieving the 2nd 9090% of those diagnosed on ART (n=39)

Target reached Above regional average Below regional average95%

Progress toward achieving the 3rd 9090% of those on ART virally suppressed (n=33)

Global target 90%

Europe and Central Asia 84%


Target reached Above regional average Below regional average

@ECDC_HIVAIDS

88%

NRTIZidovudine (AZT)Didanosine (ddI)Zalcitabine (ddC)Lamivudine (3TC)*Stavudine (d4T)Abacavir (ABV)*Emtricitavine (FTC)*

NRTIZidovudine (AZT)Didanosine (ddI)Zalcitabine (ddC)Lamivudine (3TC)*Stavudine (d4T)Abacavir (ABV)*Emtricitavine (FTC)*

PROTEASA INHIBITORS (PI)Saquinavir / Indinavir / Nelfinavir Ritonavir (rtv) Fosamprenavir/rtvLopinavir/rtv*Atazanavir/r/c*Tipranavir/rDarunavir/r/c*

PROTEASA INHIBITORS (PI)Saquinavir / Indinavir / Nelfinavir Ritonavir (rtv) Fosamprenavir/rtvLopinavir/rtv*Atazanavir/r/c*Tipranavir/rDarunavir/r/c*

NNRTIEfavirenz* NevirapineEtravirineRilpivirine*Doravirine*

NNRTIEfavirenz* NevirapineEtravirineRilpivirine*Doravirine*

NtRTITenofovir (TDF/TAF)*NtRTITenofovir (TDF/TAF)*

ENTRY INHIBITORS- Fusion inhibitor: Enfuvirtide (T-20)- CCR5 inhibitor: Maraviroc

ENTRY INHIBITORS- Fusion inhibitor: Enfuvirtide (T-20)- CCR5 inhibitor: Maraviroc

Antiretroviral Drugs Marketed in Spain (2018)Antiretroviral Drugs Marketed in Spain (2018)

INTEGRASE INHIBITORSRaltegravirElvitegravir/cobicistat*Dolutegravir*Cabotegravir*

INTEGRASE INHIBITORSRaltegravirElvitegravir/cobicistat*Dolutegravir*Cabotegravir* *STRs

http://www.biology.arizona.edu/immunology/tutorials/AIDS/treatment.html

Targets of antiretroviral drugs

NRTINNRTINtTI

Protease inhibitors

Entryinhibitors

IntegraseInhibitors

Maturationinhibitors

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

Recommended Initial ART Regimens for Treating HIV Infection in 2018Saag MS et al. JAMA. 2018;320:379-396.

Alternative ART Regimens for Treating HIV Infection in 2018

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

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 2018


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

No R mutationsAE 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

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

23

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 QDB/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

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)

24

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

FavorsDTG + F/TAF

FavorsB/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 VirologicData

DTG + F/TAF (n=325)

B/F/TAF (n=320)

Prop

ortio

n of

par

ticip

ants

, %

Virologic Outcome

269320

281325

14320

9325

35325

37320

No R mutationsAE D/C = 6/5

89% vs. 93% at W48B/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

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

plus TAF/FTCPros- 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)

Evolution of ART regimens over time1984-2018 Future of ART

/r/c

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

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

bPI-based 2DC: Trial Designs

Study Follow Up Week Dual 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

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%

Percen

tage of p

atients w

ho achieved

endp

oint ( %)

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

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 2DCNaïve (+ 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)

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

Week48

Primary endpoint at Week 48:

participants withHIV-1 RNA <50 c/mL

(ITT-E snapshot)a

Double-blind phase

Open-labelphase

Continuation phase

CountriesArgentina Australia BelgiumCanada France GermanyItaly Republic of Korea Mexico Netherlands Peru PolandPortugal Romania Russian Federation South Africa Spain Switzerland Taiwan United Kingdom United States

Week144

Week 24

Week96

• 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).


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

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

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

• No treatment-emergent INSTI mutations or NRTI mutations

-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)


TRDF Analysis

566576

>100,000≤100,000 >200 ≤200Baseline HIV-1

RNA, c/mLBaseline 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 ≤200Baseline HIV-1

RNA, c/mLBaseline CD4+

cell count, cell/mm3

553564

138140

149153

642653

647662

6263

5555

526576

531564

129140

138153

605653

618662

5063

5155

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

SWORD-1 and -2: Phase III Study Design

*8% non-inferiority margin for pooled data. -10% non-inferiority margin for individual studiesHBV, 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 52Primary endpoint

at 48 weeks: subjects withVL <50 c/mL

(ITT-E snapshot)*

Early-switch phase Late-switch phase Continuation phase

Countries:Argentina Australia Belgium CanadaFrance Germany Italy NetherlandsRussia Spain Taiwan United KingdomUnited States

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

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

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

*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)*

• No INI resistance-associated mutations were identified

Evolution of ART regimens over time

2D or not 2Dthat is the question

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

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

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

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.

4343Spreen W et al. JAIDS 2014;67:487-92.

Cabotegravir (CAB) LA Single Injection Provides Detectable Drugin Plasma for 48 Weeks

T im e (weeks)0 4 8 12 16 20 24 28 32 36 40 44 48

Plas

ma

CAB

(g/

mL)

0 .1

1

100m g IM200m g IM400m g IM800m g IM (split)100m g SC200m g SC400m g 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 !

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

Prop

ortio

n, %

(95%

CI)

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%)

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

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.

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

Virologic outcomes Treatment differences (95% CI)

Oral IMQ8W 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*

Evolution of ART regimens over time

LA or not LAthat is the question

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

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- Avoid TB-HIV

Long-Acting (LA) ART

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

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

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)Randomization

1:1

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

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%

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-MonotherapyNaïve- 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.

Study (n) 24 weeksProportion (95% CI)

48 weeksProportion (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 failure0% 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 failure0% 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)

→ On DTG monotherapy, 50% of virological failures develop a new resistance to integrase inhibitors

Evolution of ART regimens over time1984-2018 Future of ART

/r/c

Take Home MessagesTake 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.

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.

J.R. ArribasA. CalmyE. LazzariJ.M. LlibreE. Martinez

G. MoraJ. Perez-Molina

Acknowledgements

A. Pharris

JansenGilead

ViiV Healthcare

El Futuro del Tratamiento Antirretroviral · 2018-12-10 · El Futuro del Tratamiento...

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