Clinical considerations in switching antiretroviral therapy
David JilichDepartment of Infctious Diseases, 1st Faculty of Medicine,
Charles University in Prague and Na Bulovce Hospital
4th CEE Meeting on Viral Hepatitis and HIV
October 11, 2018
Dislosures
• DJ has recieved honoraria for Advisory Board participation by GileadSciences, GSK ViiV and travel grants by Gilead Sciences
http://www.eacsociety.org/files/guidelines_9.0-english.pdf
Reasons for switching
• toxicity
• intolerance
• DDI´s
• comorbidities (e.g. liver or renal failure)
• aging/risk factors (cardiovascular, diabetes, etc.)
• incovenience/simplification (pill burden, bid)
• patient´s wish/preference (STR)
• specific populations (drug users, pregnant women, etc.)
Reasons for switching (DORIVIR Study)
42,3
27,8
17,3
12,5
toxicity inconvenience DDI´s other
n=104
Palacios et al. 2018
%
%
%
%
TDF vs. TAF
† T1/2 based on in-vitro plasma data1. Lee W, et al. Antimicr Agents Chemo 2005;49(5):1898–906; 2. Birkus G, et al. Antimicr Agents Chemo 2007;51(2):543–50; 3. Babusis
D, et al. Mol Pharm 2013;10(2):459–66; 4. Ruane P, et al. J Acquir Immune Defic Syndr 2013; 63:449–5; 5. Sax P, et al. JAIDS 2014;67(1):52–8; 6. Sax P, et al. Lancet 2015 [Epub
ahead of print]
HIV TARGET CELL
AMIDATE
ESTER
DIANION
GI TRACT
Tenofovir
alafenamide
(TAF)
Tenofovir
disoproxil
fumarate
(TDF)
Tenofovir
(TFV) Parent
Nucleotide
T1/2 = 90 min†
T1/2 = 0.4 min†
PLASMA
TAF10mg
TDF 300 mg
TFV
TFV
TFV
91% lower TFV levels minimize renal and bone effects while maintaining high potency for suppressing HIV
TFV HIV
Studies 104 & 111 (w144)
* p-values calculated using 2-sided Wilcoxon rank-sum test to compare treatment groups.
Arribas J et al. CROI 2017. Seattle, WA. Poster #453;
-24
-20
-16
-12
-8
-4
0
4
8
Week
Me
dia
n (I
QR
) ch
ange
fr
om
BL
(mL/
min
)
eGFR
-1.6
-7.7
-2.0
-7.7
-6.2
-11.2
-6.0
-10.5
0 12 24 48 96 144
E/C/F/TDFE/C/F/TAFBL, mL/min117.0113.9
p <0.001
Intolerance
Raffi F et al. J Antimicrob Chemother 2014; 69: 1742–1747
Intolerance
Raffi F et al. J Antimicrob Chemother 2014; 69: 1742–1747
Lipid profiles in 48w (DOR vs. DRV/r) 30.8.2018
Molina et al. CROI 2017 Abstract 45LB
DDI´s
● ▪ ◊
RAL 0 26 630
DTG 4 38 614
EVG/c 12 262 382
www.hiv-druginteractions.org
Cobicistat vs. RitonavirCobicistat Ritonavir
Chemical structure
Enzymatic inhibition CYP3A4CYP2D6 (slabá)
P-gp
CYP3A4CYP2C8CYP2C9CYP2D6
P-gp
Enzymatic induction None CYP2B6CYP2C9
CYP2C19UGT1A4
P-gp
Anti-HIV activity No Yes
Co-administration withother antiretrovirals
Yes Yes with limitations
Influence of lab markers Increases serum creatinine concentration without decreasing renal function, increases lipids
Increases serum lipids
CYP = cytochrome P450; P-gp = P-glycoprotein; UGT = uridine 5’-diphosphoglucuronosyltransferase.
Shah B, et al. Pharmacotherapy. 2013;33(10):1107-1016.
Non-boosted agents
13
BIC
RAL EVG
DTG
DDI´s in HIV/HCV co-infected persons
www-hep-druginteractions.org
Study 1717 (Platelet Substudy)
Phase 3, randomised, double-blinded, active-controlled study
Week 0 9648
n=280
n=276
1:1
ABC/3TC + Third Agent
• HIV-1 RNA <50 c/mL for ≥6 months
• No CD4 criteria
• Estimated CrCL ≥50 mL/min
• No single-tablet regimen allowed
TAF/FTC QD
Continue Third Agent
ABC/3TC QD
Continue Third Agent
Platelet Substudy (n=61)
From 4 sites in Dublin and London
120 4
12
Objectives of platelet substudy and gGPVI analysis:• Measure platelet reactivity using aggregometry at baseline, Week 4, Week 121
• Collagen, TRAP, ADP, epinephrine, arachidonic acid• Measure platelet surface markers at baseline and Week 121
• GPVI, CD42b [GP1bA], P-selectin [CD62P]• Measure soluble GPVI through Week 48 (whole Study 1717 population, n=545)2
ADP, adenosine diphosphate; GPVI, glycoprotein VI; TRAP, thrombin receptor-activating peptide
1. Mallon P, et al. CROI 2018. Boston, MA. Oral 802. Mallon P, et al. CROI 2018. Boston, MA. Poster 677LB
sGPVI (n=545)
Solubile GPVI (Study 1717)
In TAF/FTC arm , solubile GPVI significantly increases within 48 weeks
0
1 0
2 0
3 0
4 0
5 0
4 1 2 2 4 4 80
Prů
měr
ná
% z
měn
aso
lub
ilníh
oG
PV
I
Week
TAF/FTC ABC/3TC
Mallon P, et al. CROI 2018. Boston, MA. Poster 677LB
268 261 259 252 229TAF/FTC, n=267 259 259 255 243ABC/3TC, n=
Pill burden (past vs. present)
Pill size (plays a role…)
E/C/F/TAF (1082 mg)
DTG/ABC/3TC (1750 mg)
B/F/TAF (721 mg)
Dual therapy (in Europe)
0
2
4
6
8
10
12
14
16
18
EU5 France Germany Italy Spain UK
Chart Title
2013 2017
IPSOS, HIV Heathy Living 2018, poster 006
Female populations specifics
www.hiv-druginteractions.org
Female populations specifics
www.hiv-druginteractions.org
Female population specifics
https://aidsinfo.nih.gov/news/2109/recommendations-regarding-the-use-of-dolutegravir-in-adults-and-adolescents-with-hiv-who-are-pregnant-or-of-child-bearing-potential
http://www.eacsociety.org/files/guidelines_9.0-english.pdf
Summary
Switch strategy should be:
• individualized
• optimalized
