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Terapia Antirretroviral en la Infección por el VIH (problemas, retos y soluciones)
Dr. Jose R Arribas
@jrarribas
2
Disclosures
Speaker’s Bureau: Gilead Board Member/Advisory Panel: MSD, Gilead, Janssen, ViiV
Terapia Antirretroviral en la infección por el VIH
3
2020 Challenge
Terapia Antirretroviral en la infección por el VIH
Source:
4
HIV testing and care continuum (2016)
Terapia Antirretroviral en la infección por el VIH
Source:
5
ATHENA: Older Patients Becoming More Prevalent in the HIV+ Population
• ATHENA: Observational cohort of 10278 HIV+ pts in the Netherlands
• Modeling study projections:
– Proportion of HIV+ pts ≥ 50 yrs to increase from 28% in 2010 to 73% in 2030
– Median age of HIV+ pts on combination ART to increase from 43.9 yrs in 2010 to 56.6 yrs in 2030
Pro
po
rtio
n o
f H
IV+
Peo
ple
Terapia Antirretroviral en la infección por el VIH
6
Prevalence of COMORBIDITIES. The AGEhIV Cohort Study
Source: Schouten J et al. Clinical Infectious Diseases 2014; 59:1787–1797.
Age-associated non-communicable comorbidity
P<0.0001
Hypertension Non-AIDS cancer
Angina pectoris
Myocardial infarction
Peripheral artery disease
Chronic liver disease
Cardiovascular disease
Par
tici
pan
ts, %
0
20
30
40
50
10
P<0.0001
P=0.010
P=0.017 P=0.015
P=0.043 P=0.034
HIV-negative individuals (n=349)
HIV-infected individuals (n=381)
Subjects ≥45 years with age-associated non-communicable comorbidities, by HIV serostatus (AGEhIV Study, 2010–2012)2
Terapia Antirretroviral en la infección por el VIH
7
ATHENA and Swiss HIV Cohort Studies: Polypharmacy Among HIV+ Pts on ART
Source: Smit M, et al. Lancet Infect Dis. 2015;15:810-818. 2. Hasse B, et al. Clin Inf Dis. 2011:1130-1139
Terapia Antirretroviral en la infección por el VIH
• Predicts that 20% of pts will be taking ≥ 3 meds other than ART in 2030
• 115 (5.2%) of 2233 participants 50-64 yrs of age and 64 (14.2%) of 450 participants ≥ 65 yrs of age received ≥ 4 meds other than ART
< 50 Yrs 50-64 Yrs ≥ 65 Yrs
Swiss HIV Cohort Study (N = 8444)[2]
Prospective Observational study
ATHENA Modeling Study[1]
100
80
60
40
20
0
Par
tici
pan
ts (
%)
n = 5761 n = 2233 n = 450
No comedication 1 comedication 2 comedication 3 comedications 4 or more comedications
16,000
14,000
12,000
10,000
8000
6000
4000
2000
0
Pe
op
le (
n)
3 or more comedications 2 comedications 1 comedication No comedication
2010 2015 2020 2025 2030
8
Remaining challenges: ART optimization
• Worsening of comorbidities – Bone
– Renal
– Cardiovascular
– Liver
– CNS
• Interactions – Polypharmacy
– Recreational drugs
Terapia Antirretroviral en la infección por el VIH
9
Impact of TDF and some PIs on the risk of renal complications
Terapia Antirretroviral en la infección por el VIH
Prospective cohort of 22,603 PLWHIV with a normal baseline renal function* from the D:A:D study at clinics in Europe, the USA and Australia1
ARV exposure and rates of ceGFR≤70 mL/min
from eGFR>90 mL/min, adjusted analysis1
TDF
ATV/r
LPV/r
ceG
FR ≤
70m
L/m
in, a
dju
sted
†
IRR
(95%
CI)
Current ART exposure (months)
Never exposed
4
2
0.5
0.25
1
12–24 <12 24–36 >36
TDF and some PIs are associated with an exacerbated decline of renal function over time1,2
* Defined as eGFR >90 mL/min/1.73m2; † adjusted for baseline eGFR, age, gender, race, HIV risk group, enrolment cohort, CD4 nadir and baseline date, AIDS, HBV/HCV status, smoking status, hypertension, diabetes, CVE, CD4, viral load, and cumulative exposure to ART ART, antiretroviral therapy; ARV, antiretroviral; ATV, atazanavir; CI, confidence interval; CVE, cardiovascular event; ceGFR, Cockroft-Gault estimated glomerular filtration rate; D:A:D, Data collection on Adverse events of Anti-HIV Drugs; eGFR, estimated glomerular filtration rate; HBV, hepatitis B virus; HCV, hepatitis C virus; IRR, incidence rate ratio; LPV, lopinavir; PI, protease inhibitor; PLWHIV, people living with HIV; /r, ritonavir-boosted; TDF, tenofovir disoproxil fumarate 1. Ryom L et al. CROI 2012. Seattle, WA. #865; 2. Nishijima T et al. AIDS 2014;28:1903–1910
10
Risk of fracture for TDF and PIs
Terapia Antirretroviral en la infección por el VIH
CI, confidence interval; PI, protease inhibitor; PYFU, person-years of follow-up; TDF, tenofovir disoproxil fumarate 1. Borges A et al. CROI 2016. Boston, MA. #46; 2. Borges AH et al. Clin Infect Dis 2017;64:1413–1421; 3. Bedimo R et al. AIDS 2012;26:825–831
EuroSIDA participants (n=11,820) across Europe, Israel and Argentina were prospectively followed until last visit or death, to assess fractures and femoral osteonecrosis, from 2004 onwards, resulting in 86,118 PYFU1,2
Crude incidence of new fracture and TDF use1
Cumulative exposure to TDF (years)
14
12
10
8
6
4
2
0
Never Ever Off On 0 1 2 3 4 5 >5
Inci
de
nce
/1,0
00
PY
FU (
95
% C
I)
7.5
10.6
9.1
6.1
8.5 8.1
4.7
7.8
5.6
8.1
4.7
Exposure to TDF
Adapted from Borges A et al. CROI 2016. Boston, MA. #46
Current or past TDF exposure was independently associated with a higher incidence of any fracture, but was not significant for osteoporotic fractures1,2
PIs have also been associated with an increased risk of fracture in some studies3
11
Link between the risk of MI with ABC and some antiretrovirals
Terapia Antirretroviral en la infección por el VIH
* Current or within last 6 months; † approximate test for heterogeneity: p=0.02; ‡ myocardial infarction, stroke, sudden cardiac death, invasive cardiovascular procedures; § primary model; baseline adjustment only for variables on the potential causal pathway between PI/r use and CVD ABC, abacavir; ART, antiretroviral therapy; ATV, atazanavir; CI, confidence interval; CKD, chronic kidney disease; CVD, cardiovascular disease; D:A:D, Data collection on Adverse events of Anti-HIV Drugs; ddI, didanosine; DRV, darunavir; IDV, indinavir; IRR, incidence rate ratio; LPV, lopinavir; MI, myocardial infarction; PI, protease inhibitor; PLWHIV, people living with HIV; PYFU, person-years of follow-up; /r, boosted ritonavir; RR, relative risk; RTV, ritonavir 1. Lundgren JD et al. CROI 2009. Montreal, Canada. #44LB; 2. Ryom L et al. CROI 2017. Seattle, WA. Oral #128LB
Recent exposure to ABC or ddI, and cumulative exposure to IDV, LPV/r or DRV + RTV was associated with increased risk of MI1,2
Relative risk (RR) of MI for different ART1
74,407 53,300 68,469 37,136 #PYFU:
RR of recent* exposure RR of cumulative exposure/year DRV + RTV
NRTI PI†
ddI ABC
Association between CVD IRR and cumulative use of DRV + RTV2§
RR
(9
5%
CI)
IDV LPV/r
2.5
2.0
1.5
1.0
0.5
0.0
Never exposed
Multivariate/ 5 years exp
Univariate/ 5 years exp
CV
D in
cid
en
ce r
ate
rat
io (
95
% C
I) 2.5
2.0
1.5
1.0
0.5
0.0
D:A:D study population of 33,308 PLWHIV, followed up from enrolment until the first MI event, 1st
February 2008, or 6 months after the last clinic visit1
D:A:D study population of 35,711 PLWHIV evaluating the association between CVD‡ and PIs from
2009 to 20162
12
Risk of Suicidality in Pts Treated With EFV-Containing Regimens in ACTG Trials
• Treatment with EFV associated with increased risk of suicidality
– Absolute risk is small
HR: 2.28 (95% CI 1.27-4.10; P = .006)
47 events/5817 PY (8.08/1000 PY)
15 events/4099 PY (3.66/1000 PY)
EFV EFV free
0.05
0.04
0.03
0.02
0.01
0
Pro
bab
ility
192 0 24 48 72 96 120 144 168
Wks to Suicidality
• Trend toward higher incidence of attempted or completed suicide with EFV use (HR: 2.58; 95% CI: 0.94-7.06; P = .065)
• EFV also associated with increased risk of death from substance abuse, homicide, or accident
Multivariable Analysis of Factors Associated With Suicidality in ACTG Clinical Trials
Variable HR (95% CI) P Value
Randomly assigned EFV 2.08 (1.16-3.75) .014
Weight category, kg < 60 vs ≥ 80 60-79 vs ≥ 80
2.69 (1.25-5.79) 1.21 (0.64-2.29)
.022
Hx IDU 2.26 (1.15-4.46) .019
Psychiatric Hx or psychoactive Rx
4.07 (2.32-7.13)
< .001
Source: Mollan K, et al. Ann Intern Med. 2014;161:1-10
Terapia Antirretroviral en la infección por el VIH
13
Better Triple Drug Combinations?
• TAF/FTC/DRV/c vs TDF/FTC-DRV/c naïve: AMBER
• TAF/FTC/DRV/c vs TDF/FTC-bPI suppressed: EMERALD
• TDF/FTC or ABC/3TC- DOR vs TDF/FTC or ABC/3TC- DRV naïve: MK1439-018
• DOR/3TC/TDF vs 2NRTIs-bPI supppressed: MK1439-024
• B/F/TAF naïve: 1489, 1490
• B/F/TAF suppressed: 1844, 1878
Terapia Antirretroviral en la infección por el VIH
14
Better Triple Drug Combinations?
• TAF/FTC/DRV/c vs TDF/FTC-DRV/c naïve: AMBER
• TAF/FTC/DRV/c vs TDF/FTC-bPI suppressed: EMERALD
• TDF/FTC or ABC/3TC- DOR vs TDF/FTC or ABC/3TC- DRV naïve: MK1439-018
• DOR/3TC/TDF vs 2NRTIs-bPI supppressed: MK1439-024
• B/F/TAF naïve: 1489, 1490
• B/F/TAF suppressed: 1844, 1878
Terapia Antirretroviral en la infección por el VIH
15
TAF – A novel prodrug of Tenofovir
Terapia Antirretroviral en la infección por el VIH
TAF results in 90% lower TFV plasma levels
LYMPHOCYTE
TFV
OAT 1 & 3
OAT 1 & 3
RENAL TUBULAR
CELL
TFV
RENAL TUBULAR
CELL
PLASMA
TFV
ESTER
AMIDATE
DIANION
TDF (tenofovir disoproxil fumarate)
TAF (tenofovir
alafenamide)
TFV (tenofovir)
PRO DRUG
LONGER PLASMA HALF-LIFE † - GREATER PLASMA STABILITY
SHORT PLASMA HALF-LIFE†
TFV HIV
GI TRACT
16
TAF vs TDF (FTC/EVG/c) in Naïves: 144 Weeks
Source: Arribas J, et al. 24th CROI; Seattle, WA; February 13-16, 2017. Abst. 453.
At Week 144, E/C/F/TAF was superior to E/C/F/TDF in efficacy difference at both <50 copies/mL; 4.2% (95% CI 0.6%, 7.8%; p=0.02) and <20 copies/mL: 5.4% (95% CI 1.5%, 9.2%; p=0.01)
92 87
84 90
85 80
0
20
40
60
80
100
48 96 144
HIV
-1 R
NA
<5
0 C
op
ies/
mL,
%
Virologic Success
4 5 5 4 4 4
48 96 144
Virologic Failure
4 9 11
6 11
16
48 96 144
No Virologic Data
E/C/F/TAF (n=866)
E/C/F/TDF (n=867)
Wk
Terapia Antirretroviral en la infección por el VIH
17
TAF vs TDF (FTC/EVG/c) in Naïves: Bone and Renal Endpoints
Source: Arribas J, et al. 24th CROI; Seattle, WA; February 13-16, 2017. Abst. 453.
Renal AE D/C, n E/C/F/TAF
n=866
E/C/F/TDF n=867
Total 0 12
Proximal renal tubulopathy 0 4
Increased creatinine/decreased eFGR 0 3
Renal failure 0 2
Nephropathy 0 1
Proteinuria 0 1
Bladder spasm 0 1
-1,3 -1,0 -0,9
-2,8 -2,8 -3,0
-4
-2
0
2
0 48 96 144
Me
an %
Ch
ange
(9
5%
CI)
Week
Spine
∆ 2.0
6 patients discontinued due to decrease in BMD
Terapia Antirretroviral en la infección por el VIH
18
Doravirine (MK-1439)
• Next generation NNRTI
• QD, no food effect
• Low rates of CNS toxicity
• Does not inhibit or significantly induce drug-metabolizing CYP enzymes
• Active against K103N, Y181C, G190A. Selects different mutations than EFV, RPV
• Single tablet doravirine/lamivudine/TDF
• Close to clinic. Phase III ongoing
Terapia Antirretroviral en la infección por el VIH
19
Doravirine. Drive-Ahead Study
Source: Squires K, et al; 9th IAS, Paris, France, July 23-26, 2017; Abst. TUAB0104LB.
23
49
77
87 89 84
20
46
73
81 85
81
0
20
40
60
80
100
0 4 8 12 16 20 24 28 32 36 40 44 48
DOR/3TC/TDF EFV/FTC/TDF
Pe
rce
nta
ge o
f P
arti
cip
ants
(9
5%
CI)
Treatment Week
Difference (95% CI): 3.5 (-2.0, 9.0)
DOR/3TC/TDF is non-inferior to EFV/FTC/TDF at Week 48
Low rate of resistance, with only 1.6% of participants developing resistance to any study drug through Week 48 Significantly less CNS AEs with Doravirine
Terapia Antirretroviral en la infección por el VIH
20
ONCEMRK: RAL 1200 mg QD Noninferior to 400 mg BID at Wk 48 in ART-Naive Pts
Source: Cahn P, et al. AIDS 2016. Abstract FRAB0103LB.
• Multinational, double-blind phase III trial in ART-naive pts with HIV-1 RNA ≥ 1000 c/mL
– Pts randomized to RAL 1200 mg QD vs RAL 400 mg BID + FTC/TDF (N = 802)
• Noninferior Wk 48 HIV-1 RNA < 40 copies/mL in pts with BL HIV-1 RNA > 100,000 copies/mL
– RAL QD: 86.7%; RAL BID: 83.8% (∆ 2.9; 95% CI: -6.5 to 14.1)
• RAL QD associated with overall safety profile similar to RAL BID
100
80
60
40
20
0 Pts
Wit
h H
IV-1
RN
A <
40
co
pie
s/m
L (
%)
0 4 8 12 16 20 24 28 32 36 40 44 48
Treatment Wk
RAL 1200 mg QD +
FTC/TDF
RAL 400 mg BID + FTC/TDF
88.3 88.7 86.5 83.5
78.2
51.9
53.5
76.3
82.1 87.4 87.2
88.9
Terapia Antirretroviral en la infección por el VIH
21
D/C/F/TAF. EMERALD: Study Design
Source: Molina JM, et al; 9th IAS, Paris, France, July 23-26, 2017; Abst. TUAB0101.
Baseline Week 96
Randomisation 2:1
N=1149
Week 48 Primary endpoint
Screening Phase
Treatment Phase
D/C/F/TAF
Extension Phase
≤30 days prior to baseline
Week 24 Interim analysis
D/C/F/TAF
Continue bPI + F/TDF
D/C/F/TAF
Roll-Over Phase
• Previous ART VF allowed
• Absence of history of VF on DRV, and if historical genotype available, absence of DRV RAMs
• Viral load (VL) <50 c/mL for ≥2 months before screening; one VL ≥50 and <200 c/mL within 12 months prior to screening allowed
• Creatinine clearance (by Cockcroft-Gault) ≥50 mL/min
Terapia Antirretroviral en la infección por el VIH
22
EMERALD Study: Efficacy
Source: Molina JM, et al; 9th IAS, Paris, France, July 23-26, 2017; Abst. TUAB0101.
1.8% (n=14)
2.1% (n=8)
0
20
40
60
80
100
DCFTAF(N=763)
Control(N=378)
Pro
po
rtio
n o
f P
atie
nts
(%
)
% Confirmed Virologic Rebound Cumulative
through Week 24
96.3%
0.5% (n=4)
3.1% (n=24)
95.5%
0.8% (n=3)
3.7% (n=14)
0
20
40
60
80
100
Virologicsuccess
Virologicfailure
No virologic data
Pro
po
rtio
n o
f P
atie
nts
(%
)
% Response and Virologic Failure at Week 24 (FDA Snapshot)
VF (50c/mL) at W24 defined as last VL in W24 window ≥50c/mL, or premature discontinuations (≠ AE/death), with last (single) VL ≥50c/mL
(n=735) (n=361)
∆ –0.3% (95% CI: –2.0%, 1.5%)
∆ 0.8% (95% CI: –1.7%, 3.3%)
• Most rebounders (10/14 D/C/F/TAF and 5/8 control) resuppressed (<50c/mL) by Week 24
• No confirmed rebounds ≥200 c/mL
• No discontinuations for VF
• No DRV/primary PI or NRTI RAMs were observed (2 patients genotyped in each group
Terapia Antirretroviral en la infección por el VIH
23
BICTEGRAVIR
• Bictegravir is a novel specific inhibitor of HIV-1 integrase strand transfer activity1
• Structurally related to Dolutegravir. Unboosted
• Active against diverse subtypes of wild-type HIV-1 clinical isolates and HIV-22
• Low cytotoxicity in multiple non-target human cell lines and in primary human hepatocyte2
• Average human T1/2 of ~19 hours, allowing for once daily dosing3
• Close to clinic. Phase III ongoing
Source: 1. Lazerwith S, et al. ASM 2016; Boston, MA. Poster #414 2. Tsiang M, et al. ASM 2016; Boston, MA. Poster #416 3. Gallant J, et al. ASM 2016. Boston, MA. Poster #415
Terapia Antirretroviral en la infección por el VIH
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GS-1489 STUDY (BICTEGRAVIR): Results
Source: Gallant J, et al; 9th IAS, Paris, France, July 23-26, 2017; Abst. MOAB0105LB.
% Treatment Difference (95% CI)
290 314
293 315
3 314
8 315
14 315
21 314
92,4
1 6,7
93
2,5 4,4
0
20
40
60
80
100
HIV-1 RNA<50 copies/mL
HIV-1 RNA ≥50 copies/mL
No VirologicData
HIV
-1 R
NA
<5
0 c
/mL,
% B/F/TAF (n=314)
DTG/ABC/3TC (n=315)
Virologic Outcome
-12 12 0 -4 -8 4 8
Favors B/F/TAF
Favors DTG/ABC/3TC
- 4.8 3.6
- 0.6
• BF-TAF non-inferior to DTG/ABC/3TC
– No resistance in either study arm
• Lipids not significantly different
• No drug-related renal events
• Significantly less nausea and minor adverse events with BF-TAF
Terapia Antirretroviral en la infección por el VIH
25
Why still Triple?
• DTG-3TC Naïve ACTG 5353, GEMINI
• DTG-3TC Suppressed ASPIRE, TANGO
• DTG-RPV Suppressed SWORD
• CBT-RPV (LA) early switch: FLAIR
• CBT-RPV (LA) stable switch : ATLAS
Terapia Antirretroviral en la infección por el VIH
26
PADDLE: DTG + 3TC (naïve)
# SCR BSL DAY 4 DAY 7 W.2 W.3 W.4 W.6 W.8 W.12 W.24 W.36 W.48
1 5.584 10.909 383 101 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50
2 8.887 10.233 318 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50
3 67.335 151.569 1.565 1.178 97 53 < 50 < 50 < 50 < 50 < 50 < 50 < 50
4 99.291 148.370 3.303 432 178 55 < 50 < 50 < 50 < 50 < 50 < 50 < 50
5 34.362 20.544 1.292 570 107 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50
6 16.024 14.499 1.634 162 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50
7 37.604 18.597 819 61 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50
8 25.071 24.368 1.377 Not done 105 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50
9 14.707 10.832 516 202 < 50 < 50 < 50 < 50 < 50 < 50 < 50 SAE
10 10.679 7.978 318 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50
11 50.089 273.676 68.129 3.880 784 290 288 147 < 50 < 50 < 50 < 50 < 50
12 13.508 64.103 3.296 135 351 84 67 < 50 < 50 < 50 < 50 < 50 < 50
13 28.093 33.829 26.343 539 61 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50
14 15.348 15.151 791 198 < 50 61 64 < 50 < 50 < 50 < 50 < 50 < 50
15 23.185 23.500 4.217 192 < 50 < 50 < 50 Not done < 50 < 50 < 50 < 50 < 50
16 11.377 3.910 97 143 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50
17 39.100 25.828 1.970 460 52 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50
18 60.771 73.069 2.174 692 156 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50
19 82.803 106.320 2.902 897 168 76 < 50 < 50 < 50 < 50 < 50 PDVF
20 5.190 7.368 147 56 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50
Source: Cahn P, et al. AIDS 2016; Durban, South Africa; July 18-22, 2016; Abst. FARB0104LB.
Terapia Antirretroviral en la infección por el VIH
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Dual therapy with DTG+ 3TC in naïve & suppressed
Source: Cahn P, et al. AIDS 2016; Durban, South Africa; July 18-22, 2016; Abst. FARB0104LB. Joly I CROI 2017 #458. NCT02582684. NCT02263326. NCT02831673. NCT02831764.
2016
2017
…
DTG + 3TC (ACTG 5353) vs DTG + TDF/FTC (GEMINI9)
2015
DTG + 3TC (Paddle)
DTG + 3TC (LAMIDOL #458) 97% <50 @wk 48
NAÏVE
SUPPRESSED
DTG + 3TC vs 2NRTIs + 3rd drug (ASPIRE) vs TAF-based regimens (TANGO)
DTG + 3TC
Terapia Antirretroviral en la infección por el VIH
28
ISTI + RPV
2016
2017
CAB + RPV vs CAB + ABC/3TC (LATTE-2) 8w: +2.9% 4w: +2.0%
CAB + RPV 4w vs ABC/3TC/DTG
(FLAIR) 2NRTIs + 3rd drug
(ATLAS)
… 2014
2015
CAB + RPV vs 2NRTIs + EFV (LATTE)
-1%
DUAL THERAPY IN SUPPRESSED. SIMPLICITY 2.0 Difference in rates of
supression at 48 weeks (reduced regimen minus triple regimen)
Margolis DA et al. The Lancet Infectious Diseases 2015; 15:1145–1155. Margolis DA et al. AIDS 2016; Durban, South Africa. Abstract THAB0206LB. NCT02938520. NCT02951052
DTG + RPV vs 2NRTIs + 3rd drug
(SWORD, #44LB)
ORAL
LONG ACTING
Terapia Antirretroviral en la infección por el VIH
29
SWORD-1 and SWORD-2 Phase III Study Design
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, randomized, multicenter, 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 52
Primary endpoint at 48 weeks: subjects with VL <50 c/mL
(ITT-E snapshot)a
Early switch phase Late switch phase Continuation phase
• a-8% non-inferiority margin for pooled data. -10% non-inferiority margin for individual studies
Countries Argentina Australia Belgium Canada France Germany Italy Netherlands Russia Spain Taiwan United Kingdom United States
Source: Llibre et al. CROI 2017; Seattle, WA. Abstract 2421.
Terapia Antirretroviral en la infección por el VIH
30
Snapshot outcomes at week 48 (SWORD-1&2)
Source: Llibre JM CROI 2017 #44LB
0
20
40
60
80
100
Virologicsuccess
Virologicnon-response
No virologicdata
HIV
-1 R
NA
<5
0 c
/mL,
%
Virologic outcomes Adjusted treatment differences (95% CI)a
CAR DTG + RPV
-10 -8 -6 -4 -2 0 2 4 6 8 10
-4.3 3.0
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
-3.9 4.2
SWORD-1
SWORD-2
95 96 94 94
<1 <1 <1 2 4 4 5 4
0.2
-0.6
aAdjusted for age and baseline 3rd agent.
Terapia Antirretroviral en la infección por el VIH
31
CAB & RPV LA Nanosuspensions
Terapia Antirretroviral en la infección por el VIH
• 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)
Source: Margolis et al. AIDS 2016; Durban, South Africa. Abstract THAB0206LB.
32
LATTE-2 Study: Efficacy
Terapia Antirretroviral en la infección por el VIH
Virologic Outcomes Treatment Differences (95% CI)
Oral IM
10.0%
-12 -9 -6 -3 0 3 6 9 12 15
20.5 -0.6
Q8W IM
[VALOR X].0%
-12 -9 -6 -3 0 3 6 9 12 15
14.4 -8.4
Q4W IM
94
4 2
87
0
13
84
2
14
0
20
40
60
80
100
VirologicSuccess
VirologicNon-Response
No VirologicData
HIV
-1 R
NA
<5
0c/
mL,
%
CAB + RPV LA Q8W (n=115)
CAB + RPV LA Q4W (n=115)
CAB + NRTIs PO (n=56)
Source: Eron J, et al; 9th IAS, Paris, France, July 23-26, 2017; Abst. MOAX0205LB
• TAF/FTC/DRV/c vs TDF/FTC-DRV/c naïve: AMBER
• TAF/FTC/DRV/c vs TDF/FTC-bPI suppressed: EMERALD
• TDF/FTC or ABC/3TC- DOR vs TDF/FTC or ABC/3TC- DRV naïve: MK1439-018
• DOR/3TC/TDF vs 2NRTIs-bPI supppressed: MK1439-024
• B/F/TAF naïve: 1489, 1490
• B/F/TAF suppressed: 1844, 1878
• DTG-3TC Naïve ACTG 5353, GEMINI
• DTG-3TC Suppressed ASPIRE, TANGO
• DTG-RPV Suppressed SWORD
• CBT-RPV (LA) early switch: FLAIR
• CBT-RPV (LA) stable switch : ATLAS
• PRO-140 suppressed
• Vedolizumad suppressed
• VRC01 suppressed
• VRC01-LS + CAB LA suppressed (ACTG 5357)
33
Terapia Antirretroviral en la Infección por el VIH (problemas, retos y soluciones)
Virologic control Forgiveness Residual viremia Persistent inflammation Immunoactivation Penetration in reservorirs Inmmunotherapy
Terapia Antirretroviral en la infección por el VIH
34
Aknowledgments
HIV Unit at La Paz Hospital
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