tratamiento antirretroviral: 30 años de historia · ias 2015 • 8th ias conference on hiv...

Dr. Jose M. Miro Infectious Diseases Service

Hospital Clínic - IDIBAPSUniversity of Barcelona

Barcelona, Spain

Dr. Jose M. Miro Infectious Diseases Service

Hospital Clínic - IDIBAPSUniversity of Barcelona

Barcelona, Spain

E-mail address: [email protected] address: [email protected]

Tratamiento Antirretroviral: 30 años de historia

XXI Jornadas Internacionales sobre TBMesa Redonda de VIH/Sida

XXI Jornadas Internacionales sobre TBMesa Redonda de VIH/Sida

Antiretroviral treatment: 30 years of history


� Introduction� The Dark period (1980-1995)� The age of Hope (1996-2006)� The current Splendor (2007-2017)� An even better future � Take home messages


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

Hospital Clinic of BarcelonaHIV cohort (1983-2017)8,500 patients (historical cohort)

5,500 active patients5,000 (91%) on ART (>90% VL BDL)

Number of new and accumulated HIV-infected patients and patients on ART at the H. Clinic of Barcelona (1986-2016)

>5,000>95%

on ART

Percentage of patients with undetectable HIV RNA viral load on ART at the H. Clinic of Barcelona (1995-2016)

50%

95%

0%

Annual mortality rates in the cohort of HIV-infected patients of the H. Clinic of Barcelona (1986-2016)

20%

<1%

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

THE EVOLUTION OF TB THERAPY 12 DRUGS

0

20

40

60

80

100

%

1990

1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

2014

2015

2016

2NRTI+1InSTI 2NRTI+1PI/r,c 2NRTI+1PI2NRTI+1NNRTI MONO DUALTRIPLE >=4 ART OTHER

The constant evolution of ART at the Hospital Clinic of Barcelona, Spain (1990-2016)

Discovery, Evolution and Future of Antiretroviral Therapy




First cases in 1981AIDS defining diseases- Prophylaxis- Diagnosis- TreatmentDeadly disease(1-1.5 yr. survival)

Zidovudine (AZT, ZDV, NRTI)Zidovudine (AZT, ZDV, NRTI)

Retrovir 100mg capsule

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

1984 AZT suppresses HIV replication in vitro (NCI)

AZT NRTI

1986, Phase II Trial of AZT stopped by DSMB because of patients treated with AZT had a significant survival than the placebo (p<.001)




Deaths at 6 mo.- PCB, 19/137 (14%)- AZT, 1/145 (0.5%)

(p<0.001)

The Dark period (1980-1995): pre-HAARTThe Dark period (1980-1995): pre-HAART

AZT (1987), DDI, DDC, D4T.- Mono/Dual NRTI RCT- Too much toxicity- Do not prevent HIV progression

nor NRTI resistance→ No long-term effect on survival

The “Goods News” of the late Dark periodThe “Goods News” of the late Dark period• First phase I/II trials of HIV protease inhibitors (PIs) presented in

Berlin (1993).• Demonstration of the possibility to reduce mother-to-child

transmission through antiretroviral treatment of HIV-infected mothers.• Double nucleoside combinations (2NUCs) proven more efficacious

over monotherapy (ACTG 175 and Delta trials).• Demonstration that quantity of HIV-RNA in plasma predicts

progression of the disease.• Better understanding of HIV pathogenesis: rapid viral turnover and

mechanisms of HIV resistance to antiretroviral drugs.• Discovery of latently infected long-lived HIV cellular reservoirs

• First phase I/II trials of HIV protease inhibitors (PIs) presented in Berlin (1993).

• Demonstration of the possibility to reduce mother-to-child transmission through antiretroviral treatment of HIV-infected mothers.

• Double nucleoside combinations (2NUCs) proven more efficacious over monotherapy (ACTG 175 and Delta trials).

• Demonstration that quantity of HIV-RNA in plasma predicts progression of the disease.

• Better understanding of HIV pathogenesis: rapid viral turnover and mechanisms of HIV resistance to antiretroviral drugs.

• Discovery of latently infected long-lived HIV cellular reservoirsVella S et al. AIDS 2012, 26:1231–1241Vella S et al. AIDS 2012, 26:1231–1241

Connor EM et al. NEJM. 1994; 331:1173-80.

Reduction of MTCT of HIV with Zidovudine

XI International Conference on AIDS 7-12 July 1996, Vancouver, Canada

XI International Conference on AIDS 7-12 July 1996, Vancouver, Canada



� Introduction� The Dark period (1980-1995)� The age of Hope (1996-2006)� The current Splendor (2007-2017)� An even better Future � Take home messages

� Introduction� The Dark period (1980-1995)� The age of Hope (1996-2006)� The current Splendor (2007-2017)� An even better Future � Take home messages


1996: US FDA approved two new ART families

NRTIProtease inhibitors

NNRTI

Triple Therapy (HAART) better tan Dual NUC TherapyNo viral replication – No mutations – No resistance

<50 cop./mL

First RCT using triple drug combinations, showing a sustained decrease in plasma HIV viral load: Merck 035 and INCAS trialsFirst RCT using triple drug combinations, showing a sustained decrease in plasma HIV viral load: Merck 035 and INCAS trials

Triple Therapy with Indinavir vs. Dual Therapy: Mean Change from Base Line in the Plasma HIV-1 RNA Viral Load

Triple Therapy with Indinavir vs. Dual Therapy: Mean Change from Base Line in the Plasma HIV-1 RNA Viral Load

Hammer SM et al NEJM 1997;337:725-33

First RCT using triple drug combinations, showing a sustained decrease in plasma HIV viral load: Merck 035 and INCAS trialsFirst RCT using triple drug combinations, showing a sustained decrease in plasma HIV viral load: Merck 035 and INCAS trials

Montaner JSG et al. JAMA. 1998; 279:930-7.

Triple therapy with nevirapine vs. Dual therapy: Mean Change from Base Line in the Plasma HIV-1 RNA Viral Load

Triple therapy with nevirapine vs. Dual therapy: Mean Change from Base Line in the Plasma HIV-1 RNA Viral Load

Montaner JSG et al. JAMA. 1998; 279:930-7

The age of Hope (1996-2006): HAART periodThe age of Hope (1996-2006): HAART periodTwo new families: PI/NNRTI3TC (1997)1996 IAS-USA = Triple Therapy- Improving survival but …… Metabolic toxicities… Lipodystrophy

2nd generation boosted PI/rFusion inhibitors (2003) FTC (2003) TDF (2004) →1st Single Tablet Regimen (STR): Atripla® (2006)SMART Trial: Never stop ARTMDR HIV = VL<50 cop./mL

Dramatic decline in morbidity and mortality with the introduction of triple combination antiretroviral therapy

Dramatic decline in morbidity and mortality with the introduction of triple combination antiretroviral therapy

Palella FJ et al. NEJM. 1998;338:853-60

Mortality and Frequency of Use of Combination ART Including a Protease Inhibitor among HIV-Infected Patients with <100 CD4

Courtesy of Esteban Martinez, Spain

The Lipodystrophy Period

SMART study group. NEJM. 2006; 355:2283-96.

SMART Trial: Never stop ART


New targets of antiretroviral drugs: InSTI, Entry and Maturation inhibidors

NRTINNRTINtTI

Protease inhibitors

Entryinhibitors

IntegraseInhibitors

Maturationinhibitors

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 (Kaletra®)Atazanavir/r/cTipranavir/rDarunavir/r/c

PROTEASA INHIBITORS (PI)Saquinavir / Indinavir / Nelfinavir Ritonavir (rtv) Fosamprenavir/rtvLopinavir/rtv (Kaletra®)Atazanavir/r/cTipranavir/rDarunavir/r/c

NNRTIEfavirenz* NevirapineEtravirineRilpivirine*

NNRTIEfavirenz* NevirapineEtravirineRilpivirine*

NtRTITenofovir (TDF)NtRTITenofovir (TDF)

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

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

Antiretroviral drugs marketed in Spain (2017)Antiretroviral drugs marketed in Spain (2017)

INTEGRASE INHIBITORSRaltegravirElvitigravir/cobicistat*Dolutegravir*Cabotegravir

INTEGRASE INHIBITORSRaltegravirElvitigravir/cobicistat*Dolutegravir*Cabotegravir

*STR: Atripla®, Eviplera®, Triumec®, Stribild®, Genvoya®

TDF x TAF

RTV x Cobicistat

↑↑↑ Integrase inhibitors

The current Splendor (2007-2017)The current Splendor (2007-2017)More ART families: InSTI, Maturation & Entry Inhibitors2nd & 3rd generation of PI/NNRTI/NRTI More STRs→ Higher efficacy & safety- ART recommended to all patients regardless CD4 T cell count- TasP and PrEP concepts- HIV as a chronic disease, with similar survival to HIV negative persons - Aging- Increase non-AIDS defining events - Cascade of Care: 90-90-90- Global ART coverage: 15 M. x 2015

ART Trials: Virologic Responses from 1997 to 2012114 studies through 2012, up to 3 years of f/u: ITT analyses

Lee FJ et al PLoS One 2014;9:e97482

40%

80%

ART Trials: D/C for Adverse Events from 1997 to 2012114 studies through 2012, up to 3 years of f/u: ITT analyses

Lee FJ et al PLoS One 2014;9:e97482

14% 4%

Walmsley SL et al. NEJM. 2013;369:1807-18.

Dolutegravir superior to Efavirenz (SINGLE trial)

Copyright © 2008 Merck & Co., Inc., Whitehouse Station, New Jersey, USA. All rights reserved.

Results were confirmed in per protocol analysis: 91% DTG versus 84% DRV/r, ∆ (CI): 7.4 (-1.4 - 13.3)

Proportion (95% CI) of Individuals With HIV-1 RNA <50 c/mL Over Time – Snapshot

DTG: 90%

DRV/r: 83%

WeekBL

4 8 12 16 3624 48

Prop

ortio

n (%

)

Dolutegravir superior to Darunavir/rtv (FLAMINGO trial)

Clotet B et al. Lancet. 2014; 383:2222-31

The Integrase Inhibitors Era: VL<50 → 85-90%

ART: Convenience – 1 STR

2015 Aug 27;373:795-807

2015 Aug 27;373:808-22

IAS 2015 • 8th IAS Conference on HIV Pathogenesis, Treatment and Prevention • 19 - 22 July 2015 • Vancouver, Canada

TasP = TAR as HIV prevention

Efficacy of PreP in HIV negative persons → Strong Evidence from RCT!!!Population Trials Reduction in

HIV incidenceDrug, delivery, regimen

Gaps inevidence

MSM and transgender

• iPrEX• PROUD• IPERGAY

44%86%86%

TDF/FTCOralDaily/on demand

TDFTopical

Heterosexual men and women

• Partners PrEP

• TDF2

63 - 84%

62%

TDF +/- FTCOralDaily On demand

Women • CAPRISA• FACTS• FEM-PREP• VOICE

39%0%6%

-49% - 15%

TDF +/- FTCGel/Oral Daily/on demand

Adherence

People who inject drugs

• BTS 49% TDFOralDaily

Route of transmission

Günthard HF et al. JAMA. 2016; 316:191-210

Recommendations for When to Start ARTGünthard HF et al. JAMA. 2016; 316:191-210

Recommended Initial ART RegimensGünthard HF et al. JAMA. 2016; 316:191-210

Triumec®; Tivicay® + Descovy®; Genvoya®; Isentress® + Descovy®

“For the first time in global health history, the world has reached a global numerical treatment target prior to the agreed deadline: providing antiretroviral therapy to 15 million people by 2015”

EACS, 2015

Global ART Coverage with the New WHO guidelines (2015)

CD4 < 200CD4 < 2001

CD4 < 3502

CD4 < 5003

at any CD4

1. At CD4 < 350: active TB disease and HIV+ pregnant women 2. At any CD4: active TB disease and HBV co-infection requiring HBV treatment”3. At any CD4: active TB disease, HBV co-infection with severe liver disease, HIV+ pregnant women and HIV serodiscordant couples

Source WHO rand UNAIDS reports

1% 5%21%

41%36%

PLH

IV

Incidence of New HIV infections from 1980 to 2015GBD 2015 HIV Collaborators. Lancet HIV 2016; 3: e361–87

New HIV Infections in 2015 = 2.1 million

The Cascade to End AIDS

• “Modelling by UNAIDS indicates that the world has a brief, five-year window of opportunity to lay the foundation to end the AIDS epidemic as a public health threat.”

EACS, 2015

Future challenges: Looking at 2030Future challenges: Looking at 2030

� Increasing global ART coverage� New forms of healthcare� New ART drugs and new regimens� Eradication / Functional cure� Preventive strategies & HIV Vaccine

→ Moving to the end of AIDS

� Increasing global ART coverage� New forms of healthcare� New ART drugs and new regimens� Eradication / Functional cure� Preventive strategies & HIV Vaccine

→ Moving to the end of AIDS

Moving towards end of AIDS: main results and new ambitious targets…

Key parameters 2005 2015 2020 2030New HIV infections 3 million 2 million 500,000 200,000

AIDS‐associateddeaths

2.4 million 1.2 million 500,000 400,000

PLHIV accessing ART 1.5 million 15 million 30 million ALL

Investments for globalHIV response (US$)

7 billion 20 billion 32 billion 29 billion

Vitoria M. WHO & UNAIDS reports , 2014 & 2015

[È 35%]

[È 50%]

[Ç 10x]

[Ç 3x]

58

• NRTIs– MK-8591 (eFDA)– LA TAF

• NNRTIs– Doravirine (MK1439)– MK1439A (TDF/3TC/DOR)– LA Rilpivirine

• PIs– TAF/FTC/DRV/c STR

• InSTI– Bictegravir (B/F/TAF)– LA Cabotegravir– QD Raltegravir– NCINIs

• ENTRY INHIBITORS– Fostemsavir (BMS 663068)– Ibalizumab (TNX-355)– UB-421– PRO140– Albuvirtide / Combinectin

• MATURATION INHIBITORS• CAPSID INHIBITORS• BROADLY NEUTRALIZING Antibodies

New ART drugs and Combinations (2018-22)

• NEW ART STRATEGIES– DUAL: 3TC + PI/r or DTG– Oral NRTI-sparing regimens: DTG+RPV– Parenteral long-acting NRTI-sparing

regimens: LA CBT + LA RPV

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-2 RCT

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

Margolis et al. Lancet Infect Dis. 2015;15:1145-1155.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)

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

LATTE-2: IM CAB+RPV EVERY 4/8 WEEKS HIV-1 RNA <50 c/mL by Snapshot (32 weeks)

*Met pre-specified threshold for concluding IM regimen is comparable to oral regimen (Bayesian posterior probability >90% that true IM response rate is no worse than -10% compared with the oral regimen).

Both Q8W and Q4W comparable to oral CAB at Week 32

Virologic outcomes Treatment differences (95% CI)

Oral

-4.8 12.2

Q8W

-5.8 11.5

Q4W

* * IM

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

Examples of strategies currently in human studies

SHOCKReactivating latently-

infected cellsInhibit histone deacetylase (HDACi)Inhibit bromodomain extraterminal

Activate toll-like receptors Activate protein kinase C

KILLViral clearance by the immune system

Broadly neutralizing antibodiesTherapeutic HIV vaccines

Anti programmed cell death (PD)1

Anti PD ligand 1

HIV RESISTANT CELLSTransfusing cells without CCR5 gene

Gene-editing therapyBone marrow or cord blood transplantation (Berlin patient!)

HIV RESISTANT CELLSTransfusing cells without CCR5 gene

Gene-editing therapyBone marrow or cord blood transplantation (Berlin patient!)

MINIMIZE RESERVOIRLimit reservoir starting very early

antiretroviral therapy in PHI !!!Broadly neutralizing antibodies

Combination Cure

Take Home MessagesTake Home Messages� Over the past 30 years there has been a steady development of antiretroviral

drugs that have converted a short-term fatal infection into a chronic disease with a life expectancy similar to that of the general population.

� Current ART has important clinical, immunological, virological benefits, lowers the HIV reservoir but does not eradicate HIV infection and therefore ART should be taken for ever.

� Global ART coverage is a challenge and is the only way to reduce new infections and mortality. The 90-90-90 must be achieved worldwide !

� In the coming years governments must invest more money and researchers work as a team to achieve the functional cure / eradication of HIV and a preventive vaccine.

� Over the past 30 years there has been a steady development of antiretroviral drugs that have converted a short-term fatal infection into a chronic disease with a life expectancy similar to that of the general population.

� Current ART has important clinical, immunological, virological benefits, lowers the HIV reservoir but does not eradicate HIV infection and therefore ART should be taken for ever.

� Global ART coverage is a challenge and is the only way to reduce new infections and mortality. The 90-90-90 must be achieved worldwide !

� In the coming years governments must invest more money and researchers work as a team to achieve the functional cure / eradication of HIV and a preventive vaccine.

J.R. ArribasE. LazzariJ.M. LlibreG. Mora

Acknowledgements

H. Clinic HIV TeamJ.M. GatellJ. MallolasF. García

E. MartínezJ.L. Blanco

tratamiento antirretroviral: 30 años de historia · ias 2015 • 8th ias conference on hiv...

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