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