Gustavo LopardoFUNCEI

Hospital Bernardo HoussayUniversidad de Buenos Aires

Simposio Fundación Huésped

Agosto 2019

TOXICIDAD DE LOS INHIBIDORES DE INTEGRASA

Conflictos de interés

Disertante: GADOR_Gilead, Janssen-Cilag, ViiV

Grants investigación: NIH, MSD, ViiV

Características de los Inhibidores de Integrasa

• La toxicidad observada con NRTI, NNRTI e IP se produce en parte porque son inhibidores de polimerasas o de proteasas, enzimas abundantes en las células eucariotas

• Las células humanas no poseen integrasa y, por tanto, la presunta interferencia causada por un INSTI debe ser mínima

• DTG superior to EFV at Wk 48 primary efficacy endpoint

• Treatment-related study d/c: 2% in DTG vs 10% in EFV arm

• VF at Wk 48: 4% (18/414) in DTG arm and 4% (17/419) in EFV arm

• CD4+ cell count increase at Wk 48 greater with DTG:

– +267 cells/mm3 (DTG) vs

– +208 cells/mm3 (EFV) (P < .001)

HIV

-1 R

NA

< 5

0 c

op

ies/m

L a

t W

k 4

8 (

%)

88

81

Δ +7.4%

95% CI (+2.5% to +12.3%; P = .003)

Walmsley S, et al. NEJM 2013

DTG 50 mg +

ABC/3TC QD

EFV/TDF/

FTC QD

0

20

40

60

80

100

364/

414

340/

419

La diferencia de eficacia

determinada por menos eventos

adversos y discontinuaciones

con DTG

SINGLE: DTG + ABC/3TC vs EFV/TDF/FTC en pacientes naive semana 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

• CD4+ cell count increase at Wk 48 similar:

– +210 cells/mm³ in each arm

HIV

-1 R

NA

< 5

0 c

op

ies/m

L a

t W

k 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

Mayor eficacia por menos suspensiones

con DTG, mayor eficacia virológica

especialmente con CV > 100.000 cop/mL

FLAMINGO: DTG vs DRV/RTV + 2 NRTIs en pacientes naïve semana 48

6

Favorece RAL

Favorece DRV/RTV

Lennox JL, et al. Ann Intern Med. 2014;161:461-471

ACTG 5257: Incidencia acumulada de fallo portolerabilidad a la semana 96

Diferencia en Incidencia Acumulada a la

Semana 96 (97.5% CI)

-20 0-10 10 20

ATV/RTV vs RAL

12.7% (9.4% a 16.1%)

DRV/RTV vs RAL

3.6% (1.4% a 5.8%)

ATV/RTV vs DRV/RTV

9.2% (5.5% a 12.9%)

1.00

0.75

0.50

0.25

0

Incid

en

cia

Acu

mu

lad

a

0

Semanas desde enrolamiento

24 48 64 80 96 112 128 144

ATV/RTV

RAL

DRV/RTV

INSTI drogas de elección en la mayoría de las recomendaciones de inicio de TARV

1. Saag M, et al. JAMA 2018;320(4):379-396. https://www.iasusa.org/guidelines2. DHHS. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents, 2018

7

DHHS 20192

RECOMMENDED REGIMENS FOR MOST PEOPLE WITIH HIV*

BIC/FTC/TAF† (AI)

DTG/3TC‡/ABC** (AI)

DTG+ FTC/TAF† (AI) or FTC‡/TDF† (AI)

RAL§+ FTC/TAF† (AII) or FTC‡/TDF† (AI)

* eGFR cut-offs based on NRTIs: FTC/TAF 30 mL/min, FTC/TDF and 3TC/ABC 50 mL/min

† TAF and TDF are two forms of tenofovir approved by FDA. TAF has fewer bone and kidney

toxicities than TDF, while TDF is associated with lower lipid levels. Safety, cost and access are

among the factors to consider when choosing between these drugs.

‡ 3TC may substitute for FTC or vice versa

** Only for HLA-B*5701 negative

§ RAL can be given as 400 mg BID or 1200 mg (two 600-mg tablets) once daily

IAS-USA 20181

GENERALLY RECOMMENDED INITIAL REGIMENS

BIC/FTC/TAF

DTG/3TC/ABC

DTG + FTC/TAF

All US guideline-recommended initial regimens are integrase inhibitor-based, triple therapy regimens

INSTI drogas de elección en la mayoría de las recomendaciones de inicio de TARV

8

* eGFR cut-offs based on NRTIs: FTC/TAF 30 mL/min, FTC/TDF and 3TC/ABC 50 mL/min

† TAF and TDF are two forms of tenofovir approved by FDA. TAF has fewer bone and kidney

toxicities than TDF, while TDF is associated with lower lipid levels. Safety, cost and access are

among the factors to consider when choosing between these drugs.

‡ 3TC may substitute for FTC or vice versa

** Only for HLA-B*5701 negative

§ RAL can be given as 400 mg BID or 1200 mg (two 600-mg tablets) once daily

IAS-USA 20181

GENERALLY RECOMMENDED INITIAL REGIMENS

BIC/FTC/TAF

DTG/3TC/ABC

DTG + FTC/TAF

http://www.eacsociety.org/files/2018_guidelines-9.1-english.pdf

Regímenes de inicio – SADI 2018-19

https://www.sadi.org.ar/guias-recomendaciones-y-consensos/item/771-vii-consenso-argentino-de-terapia-antirretroviral-2018-2019 9

Tolerabilidad de INSTI-STR-RCT Domingo P et al. AIDS Review 2018; 20: 141-149

Experiencia con DTG en la Práctica clínica

ClinicNo. of

patients

Discontinuation

due to AEs

Mean Time to

Discontinuation

Main Reason for

Discontinuation

OLVG6 387 62 (16%) 78 d Sleeping, gastro-intestinal, neurological

Brighton7 128 16 (13%) 120 d Sleep

Foch8 105 11 (10.4%) 80 d Vertigo, headache, insomnia, malaise

Cardiff9 63 6 (10%) 87 d Sleep

Cochin10 279 26 (9.3%) n/aArthralgia, myalgia, nausea, vomiting,

vertigo, rash, digestive troubles

Manchester11 178 15 (8.4%) 91 d CNS, malaise and joint pain

St Thomas12 181 9 (5%) n/a Insomnia, malaise/myalgia

Imperial13 138 3 (2%) n/a Sleep dizziness

Wohl D, et al. ID Week 2017. San Diego, CA. Oral # 1687

▪ Higher incidence rates of neuropsychiatric events, including sleep disturbances, depression and suicidal

ideation, have been reported with DTG vs. other INSTIs− In 2 blinded trials (SINGLE & B/F/TAF Study 1489) – higher insomnia rates1,2

• Although not in other trials (SAILING, FLAMINGO, SPRING 2)3-5

− In clinical cohorts6-13

• Limitations of relatively small samples, bias due to confounding and channeling

Cohortes alemanas con alta tasa de eventos

adversos y discontinuciones con DTG ▪ Retrospective study of therapy discontinuation data extracted from 2

German HIV treatment clinics

– All HIV-positive pts (N = 1704) initiating INSTI-based treatment (N = 1950 exposures) January 2007 - April 2016

– Excluded clinical trial participants

Sabranski M, et al. HIV Glasgow 2016. Abstract O214. Slide credit: clinicaloptions.com

Discontinuation Reason

Drug (Exposures)

Dolutegravir

(n = 985)

Elvitegravir

(n = 287)

Raltegravir

(n = 678)

Any AE, n (%) 67 (6.8) 27 (9.4) 28 (4.1)

Neuropsychiatric AE,* n (%)

▪ Insomnia/sleep disturbances

▪ Poor concentration/slow thinking

▪ Dizziness

▪ Headache/paresthesia

▪ Depression

49 (5.0)

36 (3.7)

8 (0.8)

13 (1.3)

16 (1.6)

7 (0.7)

3 (1.0)

2 (0.7)

0 (0)

1 (0.3)

1 (0.3)

0 (0)

14 (2.1)

4 (0.6)

0 (0)

3 (0.4)

6 (0.9)

1 (0.1)

*Can include ≥ 1 symptom.

Factores de riesgo para discontinuaciones

por trastornos neuropsiquiátricos asociadas

al uso de DTG▪ 86% of pts who discontinued DTG tolerated subsequent ART

▪ Several risk factors identified to be associated with neuropsychiatric event-related DTG discontinuation

– RH for female vs male sex: 2.64 (95% CI: 1.23-5.65; P = .0122)

– RH for age > 60 vs < 60 yrs: 2.86 (95% CI: 1.42-5.77; P = .0033)

– RH for concurrent ABC initiation vs none: 2.42 (95% CI: 1.38-4.24; P = .002)

– RH for DTG initiation in 2016 vs 2014-15: 11.36 (95% CI: 4.31-9.41; P < .0001)

▪ Neuropsychiatric symptoms in pts receiving DTG rapidly resolved without hospitalization after DTG discontinuation

Slide credit: clinicaloptions.comSabranski M, et al. Glasgow 2016. Abstract O214.

Eventos adversos psiquiátricos en ensayos

fase III/IIb con DTG

▪ Analysis of treatment-naive pts (N = 2634) in phase III/IIbtrials comparing dolutegravir (n = 1315) vs other INSTI/NNRTI/PIs

▪ AEs reported at study visits coded with Medical Dictionary for Regulatory Activities into 5 categories

– Anxiety

– Insomnia

– Depression

– Suicidality

– Nightmares/abnormal dreams

Quercia R, et al. HIV Glasgow 2016. Abstract P210. Slide credit: clinicaloptions.com

Eventos adversos psiquiátricos en

ensayos fase III/IIb con DTG▪ Low neuropsychiatric AE rates with DTG 50 mg QD in tx-naive pts; most events

mild/moderate, improved/resolved with continued DTG

– Higher rates in SINGLE trial potentially result of proactive CNS questionnaire use and double-blind comparison with EFV

– Discontinuation 1.2 to 2.5%

Slide credit: clinicaloptions.comQuercia R, et al. HIV Glasgow 2016. Abstract P210.

Psychiatric AE, %

SPRING-2 FLAMINGO SINGLE ARIA

DTG RAL DTGDRV/

RTVDTG EFV DTG

ATV/

RTV

Insomnia 6 5 8 7 17 12 4 3

Anxiety 4 6 5 4 7 7 2 3

Depression 7 5 7 5 8 11 4 4

Suicidality < 1 1 2 < 1 < 1 2 1 2

Nightmares/

abnormal dreams5 2 2 1 10 21 1 < 1

Incidencia de discontinuaciones en elprimer 1 año de TARV por EA en sujetos recibiendo INSTI (Cohorte PISCIS)

Llibre JM et al. HIV Medicine 2019

Discontinuaciones por toda causa

Discontinuaciones por Neuropsiquiátrico

Factores asociados

Incidencia de discontinuaciones en el primer 1 año de TARV por EA en sujetos recibiendo INSTI (Cohorte PISCIS)

• Las discontinuaciones fueron similares para los 3 INSTI

• Pocas discontinuaciones por efectos neuropsiquiátricos, más frecuentes con dolutegravir

• No encontraron asociación con edad, sexo o uso de abacavir

• Gran variabilidad en discontinuaciones en los diferentes centros

Llibre JM et al. HIV Medicine 2019

Metaanálisis (FDA) comparando eventos neuropsiquiátricos con INSTI vs IP vs EFV- RCT fase III, semana 96: no se observaron diferencias

Yombi J. AIDS Review 2018; 20:13-25

Metaanálisis (FDA) comparando eventos neuropsiquiátricos con INSTI vs IP vs EFV- RCT fase III, semana 96: no se observaron diferencias

Yombi J. AIDS Review 2018; 20:13-25

Resumen de los trastornos neuropsiquiátricos

• Ocurren con todos los INSTI (en menor grado que con EFV)

• Algunas cohortes discontinuaciones por trastornos neuropsiquiátricos más frecuentes con DTG

• El uso concomitante de abacavir podría incrementar el riesgo (abacavir sin INSTI no asociado a trastornos neuropsiquiátricos)

• Tolerancia a DTG

• En RCT 1.2 a 2.5% de discontinuaciones, generalmente durante el 1er año de tratamiento

• En cohortes 4 a 10% de discontinuaciones, generalmente durante el 1er año de tratamiento (media 3 a 6 meses)

• Factores de riesgo mayor edad, inicio de DTG reciente, ¿Género? ¿Abacavir?

Tsepamo Study Preliminary NTD Results: May 2018

0.94

0.050.12

0.000.09

0

0.5

1

1.5

2

2.5

DTG-CONCEPTION ANYNON-DTGART-CONCEPTION

EFV-CONCEPTION DTGSTARTEDDURING

PREGNANCY

HIV-NEG

PERCE

NTA

GE(95%

CI)W

ITHNEU

RALTU

BEDEFEC

T

NTDs/Exposures 4/426 14/11,300 3/5,787 0/2,812 61/66,057

% with NTD (95% CI)

0.94%(0.37%, 2.4%)

0.12%(0.07%, 0.21%)

0.05%(0.02%, 0.15%)

0%(0%, 0.13%)

0.09%(0.07%, 0.12%)

Prevalence Difference (95% CI) ref

0.82%(0.24%, 2.3%)

0.89% (0.31%, 2.3%)

0.94% ( 0.35%, 2.4%)

0.85% (0.27%, 2.3%)

Zash R et al. N Engl J Med 2018

In April 2018, we were asked by WHO to provide any preliminary data available for upcoming HIV guidelines committee meeting for women on DTG from conception

0.30

0.10

0.04 0.030.08

0

0.5

1

D T G - C O N C E P T I O N A N Y N O N - D T G A R T -C O N C E P T I O N

E F V - C O N C E P T I O N D T G - P R E G N A N C Y H I V - N E G

Per

cen

tage

wit

h N

eu

ral T

ub

e D

efec

t

%

%

Since May 20181 NTD/1275 additional exposures to DTG at conception

0.94

NTDs/Exposures 5/1683 15/14792 3/7959 1/3840 70/89372

% with NTD (95% CI)

0.30%(0.13, 0.69)

0.10%(0.06, 0.17)

0.04%(0.01, 0.11)

0.03%(0.0, 0.15)

0.08%(0.06, 0.10)

Prevalence Difference

(95% CI)ref

0.20%(0.01, 0.59)

0.26%(0.07, 0.66)

0.27% (0.06, 0.67)

0.22% (0.05, 0.62)

NTD Prevalence by Exposure

0.090.080.030.04

Tsepamo: NTD Prevalence by ARV Exposure

▪ As of March 2019, rate of NTDs with DTG at conception lower than initially signaled[1,2]

▪ No significant difference in major external structural malformations with DTG vs non-DTG ART[1,2]

▪ WHO released updated recommendations reconfirming use of DTG-based ART as preferred first-line and second-line therapy[3]

Slide credit: clinicaloptions.com

OutcomeAt Conception DTG in

Pregnancy(n = 3840)

HIV Negative(n = 89,372)

DTG(n = 1683)

Non-DTG(n = 14,792)

EFV (n = 7959)

NTDs per exposures, n/N 5/1683 15/14792 3/7959 1/3840 70/89372

▪ Prevalence difference, % (95% CI) Reference0.20

(0.01-0.59)0.26

(0.07-0.66)0.27

(0.06-0.67)0.22

(0.05-0.62)

NTDs per exposures since May 2018, n/N 1/1275 1/3492 0/2172 1/1028 9/23,315

1. Zash. IAS 2019. Abstr MOAX0105LB. 2. Zash. NEJM. 2019;[Epub]. 3. WHO ARV Policy Update. July 2019.

Pre-May 2018Current analysis

DTG Any Non-DTG ART

EFV HIV Negative

Pregnancy

NTD

s, %

(9

5%

CI)

DTG

Conception

0.30

0.10 0.05 0.00

0.5

1

0

0.94

0.12

No DTG (N=1068) Any DTG (N=384) P value

NTD 0 (0) 0 (0) -

Live birth

Stillbirth

Abortion

1025 (96.0)

15 (1.4)

28 (2.6)

359 (93.5)

2 (0.5)

23 (6.0)

<0.01

• Of the total 1452 birth outcomes, there were no NTD observed

• No occurrences of NTD in this national cohort study.

• Folic acid supplementation in Brazil: Enriched flour and high prevalence of

prenatal supplementation in this study

• Pharmacovigilance is a priority for the Ministry of Health in Brazil

• Results of this study do not conclusively indicate increased or decreased risk

of stillbirth and/or abortion associated with periconception DTG exposure.

Conclusions

Cambio de peso a lo largo de la historia del VIH

NA-ACCORD 1998-2010A los 3 años de inicio de

TARV22% sobrepeso18% obesidad

Era Pre-INSTI

¿Qué genera el aumento de peso en la era actual?

Impacto del incremento de peso en PcVIH

Ganancia de peso: estudio retrospectivo US

2013-2017: 3468

sujetos con

supresión viral que

hicieron switch a un

nuevo régimen

GA McComsey. CROI 2019. #671.

Efectos de raltegravir, dolutegravir y bictegravir en el peso en RCT pacientes naive

Evidencia del aumento de peso proveniente de estudios de switch

NA-ACCORD: Weight Gain Among 24,001 ART-Naive Patients Initiating Treatment

• Multivariate analysis of weight gain following ART initiation (January 2007 - December 2016)

• INSTI-based regimens: n = 4740• EVG: n = 2124; RAL: n = 1681; DTG: n = 935

• PI-based regimens: n = 7436

• NNRTI-based regimens: n = 11,825

Bourgi. CROI 2019. Abstr 670.

NA-ACCORD: Weight Gain by Class or Specific INSTIP

red

icte

d W

eigh

t (k

g)

Yrs Since ART Initiation

86

84

82

80

0 1 2 3 4 5

Yr 2

Yr 5

INSTI

PI

NNRTI

+4.9

+4.4

+3.3

+6.0

+5.1

+4.3

Pre

dic

ted

Wei

ght

(kg)

86

84

82

80

Yrs Since ART Initiation0 0.5 1.0 1.5 2.0

Yr 2

DTG

RAL

EVG

+6.0

+4.9

+3.8

PI

NNRTI

Bourgi. CROI 2019. Abstr 670.

Conclusiones del NA-ACCORD

• Mayor ganancia de peso con regímenes conteniendo INSTI vs NNRTI

• Mayor ganancia de peso con DTG o RAL vs EVG

• La ganancia de peso con INSTI no varió según sexo o edad

Bourgi. CROI 2019. Abstr 670.

Rol de los NRTIRol del TAF

• AMBER mayor incremento de peso con tenofovir

AF/emtricitabine/darunavir/c (+1.8 kg) versus

tenofovir DF/emtricitabine/darunavir/c (0.8 kg)

• Cohorte alemana muestra aumento de 2.3 kg tras

switch de tenofovir DF a tenofovir AF

• En el estudio STEAL el switch a abacavir o

tenofovir, se asoció a incremento de 1 kg en la

rama abacavir

• Mecanismo: Tratamiento con tenofovir DFdisminuye los niveles de colestrerol, y estopodría contribuir a la reducción de peso

Hill A et al. Journal of Virus Eradication 2019; 5: 41–43

Cabotegravir no asociado a incremento de peso en estudio de PrEP

Ganancia de peso con antirretrovirales

Dolutegravir inhibe la unión de la hormona

estimulante de los melanocitos al receptor

melanocortin 4 (MC4R)

MC4R participa en la regulación de la ingesta de

alimentos y su déficit se asocia con obesidad

Hill A et al. Journal of Virus Eradication 2019; 5: 41–43

Déficit MC4R

obesidad

NAMSAL and ADVANCE: Study Design

▪ Multicenter, randomized, open-label phase III trials[1-3]

DTG 50 mg + 3TC/TDF QD(n = 310)

EFV 400 mg + 3TC/TDF QD(n = 303)

ART-naive patients (≥ 12 yrs) with HIV-1 RNA ≥ 500 c/mL

(N = 1053)

ADVANCE: South Africa

Wk 96

DTG 50 mg + FTC/TAF QD(n = 351)

DTG 50 mg + FTC/TDF QD(n = 351)

EFV 600 mg/FTC/TDF QD(n = 351)

1. Hill. IAS 2019. Abstr MOAX0102LB. 2. NCT02777229. 3. NCT03122262. 4. NAMSAL ANRS 12313 Study Group. NEJM. 2019:[Epub]. 5. Venter. NEJM. 2019:[Epub].

ART-naive adults with HIV-1 RNA > 1000 c/mL

(N = 613)

NAMSAL: Cameroon

Primary Endpoint (Both Trials)HIV-1 RNA < 50 c/mL at Wk 48 by FDA Snapshot in ITT population (noninferiority margin: -10%)[4,5]

NAMSAL and ADVANCE: Progressive Weight Gain and Clinical Obesity

Slide credit: clinicaloptions.com

Outcome

NAMSAL ADVANCE

DTG + 3TC/TDF(n = 293)

EFV + 3TC/TDF(n = 278)

P ValueDTG +

FTC/TAFDTG +

FTC/TDFEFV/

FTC/TDFP Value

Mean Δ in weight, kg▪ Wk 48▪ Wk 96

+5NA

+3NA

< .001 +6+8

+3+5

+1+2

< .001

Mean Δ in BMI at Wk 48 +1.7 +1.2 < .001 NR NR NR

Treatment-emergent overweight (BMI 25-29.9), %▪ Wk 48▪ Wk 96

16NA

17NA

NS 2325

1413

911

NS

Treatment-emergent obesity (BMI ≥ 30), %▪ Wk 48▪ Wk 96

12NA

5NA

< .01 1419

78

64

< .01

Hill. IAS 2019. Abstr MOAX0102LB.

▪ Significantly greater weight increase* with DTG vs EFV, with TAF vs TDF; plateauing in weight gain after Wk 48 observed in men but not in women

ADVANCE: Mean Change in Weight to Wk 96 by Sex

Slide credit: clinicaloptions.com

Wk

Women

Hill. IAS 2019. Abstr MOAX0102LB. Reproduced with permission.

Me

an W

eig

ht

Ch

ange

(kg

)

Men

4

2

0

0 4 12 24 36

10

8

6

12

48 60 72 84 96

14

n = 430 418 402 387 376 374 366 292 232 140

+5 kg+4 kg

+1 kg

NS

*Wilcoxon rank-sum comparison at Wk 96.

WkM

ean

We

igh

t C

han

ge (

kg)

4

2

0

0 4 12 24 36

10

8

6

12

48 60 72 84 96

DTG + FTC/TAF

DTG + FTC/TDFEFV + FTC/TDF

14

n = 549 531 514 488 474 459 441 359 276 175

+10 kg

+5 kg

+3 kg

P< .0

5P

< .00

1

P< .0

1

P< .0

01

P< .0

1

DTG + TAF

• El aumento de peso tras el inicio de TARV se ha

considerado como “retorno al estado de salud”

• Evidencias crecientes que el uso de inhibidores de

integrasa, en particular DTG genera incremento en

el peso

• No resulta claro si el uso de inhibidores de

integrasa se asocia a incremento de peso

clínicamente relevante. Generalmente el

incremento es <5% del peso corporal

• El rol de los NRTI no es claro, uso de TAF

probablemente asociado

Conclusiones ganancia de peso con antirretrovirales