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Nuevos fármacos
antiretrovirales
Pere Domingo
Malalties Infeccioses
Hospital de la Santa Creu i Sant Pau
Institut del Recerca del HSCSP
Universitat Autonòma de Barcelona
pdomingo@santpau.cat
Vacas flacas/lineales
INsTI
Bictegravir switch (Study 380-1844 ) #A022
Bictegravir swicth women (#500)
Bictegravir in adolescents (#844)
ITINAN
Switch a RPV/F/TAF (#504)
Doravirina, Drive-Ahead (#491)
ITIAN
EFdA (MK-8591)(#26, #89LB)
Anticuerpos monoclonales
Ibalizumab (# 561)
ARVs long acting
Implante SC (TAF, #486)
Nanoformulados
MVC, #48, #483
FTC, #484
CBV+RPV, #485
DRV/r, #480
3D (LPV, EFV, TFV) #487
4D (LPV/r, 3TC, TFV) #488
Vacas flacas/lineales
INsTI
Bictegravir switch (Study 380-1844 ) #A022
Bictegravir swicth women (#500)
Bictegravir in adolescents (#844)
ITINAN
Switch a RPV/F/TAF (#504)
Doravirina, Drive-Ahead (#491)
ITIAN
EFdA (MK-8591)(#26, #89LB)
Anticuerpos monoclonales
Ibalizumab (# 561)
ARVs long acting
Implante SC (TAF, #486)
Nanoformulados
MVC, #48, #483
FTC, #484
CBV+RPV, #485
DRV/r, #480
3D (LPV, EFV, TFV) #487
4D (LPV/r, 3TC, TFV) #488
Switch to Bictegravir/F/TAF From DTG and ABC/3TC
Jean-Michel Molina,1 Douglas Ward,2 Indira Brar,3 Anthony Mills,4 Hans Jürgen Stellbrink,5 Luis
López-Cortés,6 Peter Ruane,7 Daniel Podzamczer,8 Cynthia Brinson,9 Joseph Custodio,10 Hui Liu,10
Kristen Andreatta,10 Hal Martin,10 Andrew Cheng,10 Erin Quirk10
1Hôpital Saint Louis, Paris, France; 2Dupont Circle Physicians, Washington DC; 3Henry Ford Hospital, Detroit, MI; 4Southern
California Men’s Medical Group, Los Angeles, CA; 5ICH Study Center, Hamburg, Germany; 6Unidad Clínica de Enfermedades
Infecciosas, Microbiología y Medicina Preventiva, Hospital Universitario Virgen del Rocío/Instituto de Biomedicina de Sevilla,
Spain; 7Peter J. Ruane, MD Inc., Los Angeles, CA; 8Hospital Universitari de Bellvitge, Barcelona, Spain; 9Central Texas Clinical
Research, Austin, TX; 10Gilead Sciences, Inc., Foster City, CA
CROI 2018, Abstract 022 March 4–7, 2018 Boston, MA
Study 380-1844: Design
Phase 3, randomized, double-blind, multicenter, active-controlled study
(NCT02603120): North America, Europe, Australia
Primary endpoint: proportion with HIV-1 RNA ≥50 copies/mL at Week
48
– Noninferiority margin of 4% based on FDA snapshot algorithm
8 *Could be components of single-tablet regimen. OLE, open label extension.
Week 0 48
HIV-suppressed adults on regimen
containing DTG, ABC & 3TC*
HIV-1 RNA <50 copies/mL for ≥3 mo
eGFRCG ≥50 mL/min
No active HBV infection
No known resistance to study drugs
DTG/ABC/3TC placebo qd
B/F/TAF 50/200/25 mg qd
B/F/TAF Placebo qd
DTG/ABC/3TC 50/600/300 mg qd
n=282
n=281
Primary Endpoint
1:1
OLE B/F/TAF
OLE B/F/TAF
Baseline Characteristics Study 380-1844
B/F/TAF
n=282
DTG/ABC/3TC
n=281
Median age, years (range) 47 (21-71) 45 (20-70)
Male, % 88 90
Race, %
White 73 73
Black or African descent 21 22
Hispanic/Latino Ethnicity, % 16 19
Median CD4 cell count, cells/µL
(IQR) 732 (554,936) 661 (478,874)
Median eGFRCG, mL/min (IQR) 101(84,119) 101(85,122)
Virologic Outcome at Week 48 Study 380-1844
Switching to B/F/TAF was noninferior to remaining on DTG/ABC/3TC
10
Treatment Difference in RNA ≥50, % (95.002% CI)
-1.0 2.8
0.7
-4% 4%0
Favors
B/F/TAF
Favors
DTG/ABC/3TC
1.1
93.6
5.30.4
95.0
4.6
0
20
40
60
80
100
HIV-1 RNA
<50 c/mL
HIV-1 RNA
≥50 c/mL
No Virologic
Data
3
282
1
281
264
282
267
281
13
281
15
282
DTG/ABC/3TC (n=281)
B/F/TAF (n=282)
Virologic Outcome
Pa
tie
nts
, %
p=0.59
p=0.62
Virologic Outcome at Week 48 Study 380-1844
Switching to B/F/TAF was noninferior to remaining on DTG/ABC/3TC
No participant developed treatment-emergent resistance
11
Treatment Difference in RNA ≥50, % (95.002% CI)
-1.0 2.8
0.7
-4% 4%0
Favors
B/F/TAF
Favors
DTG/ABC/3TC
1.1
93.6
5.30.4
95.0
4.6
0
20
40
60
80
100
HIV-1 RNA
<50 c/mL
HIV-1 RNA
≥50 c/mL
No Virologic
Data
3
282
1
281
264
282
267
281
13
281
15
282
DTG/ABC/3TC (n=281)
B/F/TAF (n=282)
Virologic Outcome
Pa
tie
nts
, %
p=0.59
p=0.62
Adverse Events Leading to Study Drug Discontinuation Study 380-1844
2 deaths occurred in the B/F/TAF arm, unrelated to study medication:
– Male, 71 years old: sudden death, atherosclerotic CVD on autopsy
– Female, 46 years old: alcohol and opioid toxicity
12
*Not considered related to study treatment by investigator.
Patients, n (%)
B/F/TAF
n=282
DTG/ABC/3TC
n=281
Overall 6 (2) 2 (1)
Headache 2 1
Vomiting 1 0
Cerebrovascular
accident 1 0
Abnormal dreams 1 0
Suicidal ideation* 1 0
Pruritis 0 1
Most Common Adverse Events Through Week 48 Study 380-1844
Patients, n (%)
B/F/TAF
n=282
DTG/ABC/3T
C
n=281
Any AE (all grades) 225 (79.8) 225 (80.1)
AEs occurring in ≥5% of patients
Upper respiratory tract infection 29 (10) 27 (10)
Nasopharyngitis 20 (7) 22 (8)
Headache 19 (7) 21 (7)
Diarrhea 24 (9) 14 (5)
Arthralgia 19 (7) 10 (4)
Insomnia 8 (3) 14 (5)
13
Study Drug-Related AEs Through Week 48 Study 380-1844
14
All Grades
B/F/TAF
n=282
DTG/ABC/3
TC
n=281 p-Value
Any study drug-related AE,
n (%) 23 (8) 44 (16) 0.01
Study drug-related AE in
≥1%, n (%)
Headache 7 (3) 8 (3)
Abnormal dreams 1 (<1) 5 (2)
Flatulence 0 5 (2)
Nausea 0 5 (2)
Diarrhea 2 (<1) 4 (1)
Fatigue 1 (<1) 3 (1)
Insomnia 0 3 (1)
p-value from Fisher exact test
Laboratory Abnormalities Through Week 48 Study 380-1844
No cases of rhabdomyolysis
All amylase elevations were transient and not associated with pancreatitis; 4/7
cases had normal lipase
Grade 3 and 4 ALT abnormalities were not study treatment related, did not result
in study drug interruption, and were associated with other AEs: acute HCV
infection (n=3), acute HAV infection (n=1), alcohol abuse (n=1), and NASH (n=1) 15
Grade 3 or 4 Lab Abnormalities,
n (%)
B/F/TAF
n=282
DTG/ABC/3TC
n=281
Any 47 (17) 32 (11)
in ≥ 2% of patients
LDL elevation 14 (5) 13 (5)
Increased amylase 7 (2) 0
ALT elevation 6 (2) 0
CK elevation 6 (2) 6 (2)
Fasting hyperglycemia 6 (2) 2 (<1)
Change in eGFRCG Over Time Study 380-1844
No discontinuations due to renal AEs and no cases of renal tubulopathy in
either arm 16 *From 2-sided Wilcoxon rank-sum test.
1.0 mL/min
-1.8 mL/min
p <0.001*
Me
dia
n C
ha
ng
e F
rom
Ba
se
lin
e e
GF
RC
G,
mL
/min
(Q
1, Q
3)
Week
0
1 0
2 0
- 1 0
- 2 0
B / F / T A F
0 4 8 1 2 2 4 3 6 4 8
A B C / D T G / 3 T CB/F/TAF DTG/ABC/3TC
Changes in Quantitative Proteinuria at Week 48 Study 380-1844
17 *From 2-sided Wilcoxon rank-sum test for % change from baseline at Week 48 for each marker for treatment comparison.
14 20 21
9
29
17
-50
-25
0
25
50
75
100
-34
β2-microglobulin:CreatinineRetinol-Binding
Protein:Creatinine
Me
dia
n %
Ch
an
ge
Fro
m B
ase
lin
e (
Q1
, Q
3)
Albumin:Creatinine
B/F/TAF
DTG/ABC/3TC
6372
-6
-19-22 -20
66
-7
p=0.74*
Baseline 5.6 mg/g 5.4 mg/g
p=0.31* p=0.53*
8496
75
99 μg/g 96 μg/g 75 μg/g 77 μg/g
Changes in Spine and Hip BMD Through Week 48 Study 380-1844
18 *From ANOVA model for comparison of B/F/TAF vs DTG/ABC/3TC at Week 48.
B/F/TAF n=256
DTG/ABC/3TC n=262
244
253
233
244
256
265
246
253
229
242
-1
1
2
-2
0
0.30
0.16
0.69
0.42
HipSpine
-1
1
2
-2
0
Me
an
% C
ha
ng
e
Fro
m B
ase
lin
e(9
5%
CI)
WeekWeek
24 48 24 480 0
p=0.33*
p=0.47*
Fasting Lipid Changes at Week 48 Study 380-1844
19 *p-values from 2-sided Wilcoxon rank-sum test.
-1 0
-5
0
5
1 0
1 5
2 0
2 5
3 0
0
21
2
-1
-5
3
Total
Cholesterol
LDL
Cholesterol
TriglyceridesHDL
Cholesterol
B/F/TAF
DTG/ABC/3TC
113 118 49 48 111 111Baseline mg/dL 182 186
Media
n C
hange F
rom
Baseline, m
g/d
L*
0
p=0.77 p=0.42 p=0.13 p=0.028
3.7 3.8
0 0
Total
Cholesterol:HDL
p=0.56
Study 380-1844 Conclusions
Switching to B/F/TAF was non-inferior to remaining on
DTG/ABC/3TC
No treatment emergent resistance was observed in
either arm
B/F/TAF was well tolerated
– Adverse events were comparable between arms at Week
48
The lipid, bone and renal safety profiles of switching to
B/F/TAF were comparable to remaining on
DTG/ABC/3TC through 48 weeks of treatment
B/F/TAF offers an effective and safe alternative to
DTG/ABC/3TC
Study 380-1961: Switching to B/F/TAF in women (Kityo
et al. Poster 500)
20
Similar Efficacy and Safety By
Subgroup in DRIVE-AHEAD: DOR/3TC/TDF vs EFV/FTC/TDF
Orkin C, et al. #491
Proportion of Participants with HIV-1 RNA <50 copies/mL Over Time (FDA
Snapshot Approach)
Orkin C, et al. #491
Efficacy by Subgroup: Baseline Clinical Characteristics (Observed
Failure Approach)
Orkin C, et al. #491
Schematic representation of the mechanism of DNA polymerization
Sarafianos SG, et al. EMBO J. 2002
Step 1: Binding of DNA to free enzyme E [RT(apo)] with the
3′ primer end at the P site
Binding of dNTP to the N site to form an ‘open’ ternary
complex [open RT(ter)]
Formation of a ‘closed’ ternary complex
[closed RT(ter)] through conformational
change
Bond formation accompanied by release of
pyrophosphate to form the non‐translocated
complex N [RT(N)–dNMP]
Step 5: in processive synthesis, the primer translocates
from the N site to the P site
P = ‘priming’ site, N = nucleotide‐binding site
Schematic representation of the mechanism of DNA polymerization
Chain terminator
Sarafianos SG, et al. EMBO J. 2002
Step 1: binding of DNA to free enzyme E [RT(apo)] with the
3′ primer end at the P site
Binding of dNTP to the N site to form an ‘open’ ternary
complex [open RT(ter)]
Formation of a ‘closed’ ternary complex
[closed RT(ter)] through conformational
change
Bond formation accompanied by release of
pyrophosphate to form the non‐translocated
complex N [RT(N)–dNMP]
Step 5: in processive synthesis, the primer translocates
from the N site to the P site
P = ‘priming’ site, N = nucleotide‐binding site
Schematic representation of the mechanism of DNA polymerization
Sarafianos SG, et al. EMBO J. 2002
Step 1: binding of DNA to free enzyme E [RT(apo)] with the
3′ primer end at the P site
Binding of dNTP to the N site to form an ‘open’ ternary
complex [open RT(ter)]
Step 3: formation of a ‘closed’ ternary
complex [closed RT(ter)] through
conformational change
Step 4: bond formation accompanied by
release of pyrophosphate to form the
non‐translocated complex N [RT(N)–dNMP]
Step 5′: in non‐processive synthesis, DNA dissociates from
the enzyme
P = ‘priming’ site, N = nucleotide‐binding site
Multiple Daily Doses of MK-8591 as Low as 0.25 mg Are Expected to
Suppress HIV
Randolph P. Matthews1; Deanne Jackson Rudd1; Vanessa Lev'ine1; Sandra Zhang1; Laura Sterling2; Jay A. Grobler1; Ryan Vargo1; S. Aubrey Stoch1; Mar'ian
lwamoto1
Rhesus macaques treated with 3.9 mg/kg MK-859I weekly and challenged intrarectally with low dose SHIV 109CP3 weekly were completely protected
Recommended