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Cases from the Clinic(ians):
Case-Based, Panel Discussion
Michael S. Saag, MD
Professor of Medicine
Associate Dean for Global Health
University of Alabama at Birmingham
Birmingham, Alabama
FORMATTED 04/05/2016
Washington, DC: April 15, 2016
From MS Saag, MD, at Washington, DC: April 15, 2016, IAS-USA.
Learning Objectives
After attending this presentation, participants will
be able to:
 Select antiretroviral treatment in patients who
are:
– Hepatitis
B virus (HBV) coinfected
– Pregnant
– Partners
of seropositive patients
– Dealing with chronic kidney disease
Slide 2 of 18
From MS Saag, MD, at Washington, DC: April 15, 2016, IAS-USA.
DHHS Guidelines, January 2016
What to Start
Recommended regimens
Boosted PI-based
 DRV/r + FTC/TDF
INSTI-based
 RAL + FTCTDF
 EVG/COBI/FTC/TDF
 DTG + FTC/TDF
 DTG/3TC/ABC
 EVG/COBI/FTC/TAF
Alternative regimens
NNRTI-based
 EFV/FTC/TDF
 RPV/FTC/TDF (VL <100,000; CD4 >200)
PI-based
 ATV/c + FTC/TDF (CrCl >70)
 ATV/r + FTC/TDF
 (DRV/c or DRV/r) + 3TC/ABC
 DRV/c + FTC/TDF (CrCl >70)
Slide 3 of 18
DHHS Guidelines
forMS
Antiretroviral
in Adults and
January
2016
From
Saag, MD,Therapy
at Washington,
DC:Adolescents,
April 15, 2016,
IAS-USA.
The 5 initial regimens we’ll probably be using soon
INSTI-based
 EVG/COBI/FTC/TAF
 DTG + FTC/TAF
 DTG/3TC/ABC
PI-based
 DRV/c + FTC/TAF
NNRTI-based
 RPV/FTC/TAF
Slide 4 of 18
From MS Saag, MD, at Washington, DC: April 15, 2016, IAS-USA.
SINGLE: Dolutegravir + ABC/3TC vs. EFV/TDF/FTC
100
DTG+ABC/3TC: 88%
Proportion (%) with <50 c/mL
90
80
EFV/TDF/FTC: 81%
70
WK 48 difference in response (95% CI):
+7.4% (+2.5% to +12.3%); p=0.003
60
50
40
30
20
10
DTG 50 mg + ABC/3TC QD
EFV/TDF/FTC QD
0
BL
2
4
8
12
16
24
Week
32
40
48
● DTG + ABC/3TC QD superior to EFV/TDF/FTC at Wk 48 (1o endpoint)
Walmsley S, et al. N Engl J Med 2013;369:1807-18
Slide 5 of 18
From MS Saag, MD, at Washington, DC: April 15, 2016, IAS-USA.
TAF vs. TDF: Mechanism of Action
GI TRACT
PLASMA
RENAL
TUBULAR
CELL
LYMPHOCYTE
TFV
TDF
(tenofovir
disoproxil
fumarate)
300 mg
TFV
TAF
(tenofovir
alafenamide)
HIV
91% lower
plasma TFV
25 mg
RENAL
TUBULAR
CELL
Slide 6 of 18

1. Lee W et al. Antimicr Agents Chemo 2005;49:1898-906; 2. Birkus G, et al. Antimicr Agents Chemo 2007;51:543-50; 3. Babusis D, et al. Mol Pharm 2013;10:459-66; 4.
Ruane P, et al. JAIDS 2013;63:449-5; 5. Sax P, et al. JAIDS 2014;67:52-8; 6. Sax P, et al. Lancet 2015;385:2606-15.
GS 1089: Switch from F/TDF to F/TAF
 Randomized, double-blind, double-dummy, active-controlled study
F/TAF (200/10 or 200/25 mg)* QD
n=333
F/TDF Placebo QD
Continue Third Agent
VL <50 on F/TDF + Third Agent
eGFR ≥50 mL/min
F/TDF (200/300 mg) QD
F/TAF* Placebo QD
n=330
Continue Third Agent
BL
*F/TAF
•
•
Dose:
200/10 mg with boosted PIs
200/25 mg with unboosted third agents
Wk 48
Wk 96
Primary Endpoint
HIV-1 RNA <50 c/mL
Secondary
Endpoint
Gallant J, et al. CROI 2016
Slide 7 of 18
From MS Saag, MD, at Washington, DC: April 15, 2016, IAS-USA.
GS 1089: Efficacy at Week 48 (Snapshot)
Virologic Outcome
Treatment Difference (95% CI)
F/TAF
VL <50, %
F/TDF
1.3
-2.5
‒10%
Non-success
Slide 8 of 18
5.1
0
+10%
Gallant J, et al. CROI 2016
From MS Saag, MD, at Washington, DC: April 15, 2016, IAS-USA.
GS 1089: Switch from F/TDF to F/TAF
Changes in eGFR
F /T A F ( n = 3 3 3 )
20
10
8.4 mL/min
p <0.001
2.8 mL/min
*
e G F R (m L /m in )
M e d ia n (Q 1 , Q 3 ) c h a n g e
F /T D F ( n = 3 3 0 )
0
-1 0
0
12
24
W eeks
*eGFR
36
48
Gallant J, et al. CROI 2016
calculated with Cockcroft-Gault equation
Slide 9 of 18
From MS Saag, MD, at Washington, DC: April 15, 2016, IAS-USA.
Reasons to consider switching therapy in
suppressed patients
 Older PIs:
– Reduce pill burden
– Decrease metabolic effects
– Decrease GI side effects
 Older NRTIs:
– d4T, ddI: SWITCH! (toxicity)
– AZT: consider switch (toxicity, side effects,
simplification)
 Nevirapine:
– Reduce pill burden
– Not toxicity (most toxicity occurs with
initiation)
 Efavirenz:
– CNS side effects
– No TAF-based coformulation
 TDF:
– If price the same, no advantage of TDF over
TAF
From MS Saag, MD, at Washington, DC: April 15, 2016, IAS-USA.
Minimum Costs of ARV treatments
______________________________________________________________
Combination
Estimated price / year
______________________________________________________________
TDF/3TC/ATV/r
$279
TDF/FTC/ELV/c
$184
ABC/3TC/DTG
$179
TDF/FTC/EFV600
$144
TDF/3TC/EFV600
$130
TDF/3TC/EFV400
$100
TAF/3TC/DTG
$60
DTG/3TC
$46
GREEN – FULLY GENERIC
WORLDWIDE IN 2017
RED –
STILL PATENTED TO 2025+ :
VOLUNTARY LICENSES
_______________________________________________________
Slide 11 of 18
From MS Saag, MD, at Washington, DC: April 15, 2016, IAS-USA.
Dolutegravir in pregnancy: Background
 No fetal toxicity or teratogenicity in animal studies described
in manufacturer’s submission for regulatory approval1
 High placental transfer of DTG relative to other ARVs in an
ex vivo study2
 “Unexpected placental transfer of DTG with fetal
accumulation and then slow neonatal clearance”3
1. European Medicines Agency. Tivicay, INN-dolutegravir. Annex I: Summary of Product Characteristics.
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002753/WC500160680.pdf
2. Schalkwijk S, Greupink R, Colbers AP, Wouterse AC, Verweij VGM, van Drongelen J, et al. Placental transfer of the HIV integrase inhibitor dolutegravir in an ex
vivo human cotyledon perfusion model. J Antimicrob Chemother. 2015 Nov 3 pii: dkv358. [Epub ahead of print] Available from:
http://www.jac.oxfordjournals.org/lookup/doi/10.1093/jac/dkv358
3. Pain JB, Lê MP, Caseris M, Amiel C, Lassel L, Charpentier C, et al. Pharmacokinetics of Dolutegravir in a Premature Neonate after HIV Treatment Intensification
during Pregnancy: FIG 1. Antimicrob Agents Chemother [Internet]. 2015 Jun;59(6):3660–2. Available from: http://aac.asm.org/lookup/doi/10.1128/AAC.00173-15
Slide 12 of 18
From MS Saag, MD, at Washington, DC: April 15, 2016, IAS-USA.
Dolutegravir PK IMPAACT P1026s
Mulligan N et al. CROI 2016. Poster abstract 398
 DTG AUC 25-30% lower in 2nd/3rd trimester vs paired postpartum (PP)
data. Differences not significant.
 DTG Cmax significantly lower in 3rd trimester vs postpartum. C24 41%
lower in 2nd/3rd trimester – not significant.
 6/9 (67%) women in 2nd trimester, 12/15 (80%) in 3rd and 8/9
postpartum had AUC above 10th percentile (37.5 mcg*hr/mL) of nonpregnant adults.
 “AUC and trough exposures appeared to be lower in pregnancy
compared to postpartum. But antepartum AUC and trough values still
similar to those seen in non-pregnant adults.”
Slide 13 of 18
From MS Saag, MD, at Washington, DC: April 15, 2016, IAS-USA.
Slide 14 of 18
Hunt, et al. CROI 2016 Abs 671
From MS Saag, MD, at Washington, DC: April 15, 2016, IAS-USA.
Slide 15 of 18
From MS Saag, MD, at Washington, DC: April 15, 2016, IAS-USA.
Slide 16 of 18
From MS Saag, MD, at Washington, DC: April 15, 2016, IAS-USA.
Change in eGFR (Cockcroft-Gault) with TAF vs TDF
Studies 104 and 111: Week 48 Combined Analysis
(SD) Change
Mean Mean
(SD) change
from baseline
Baseline eGFR*
from
eGFR
Cockroft-Gault
(mL/min)
20
E/C/F/TAF
E/C/F/TDF
10
0
-6.6
p <0.001
-10
-11.2
-20
0
12
24
Time
(Weeks)
Time (Weeks)
36
48
*Cockroft-Gault (mL/min).
Slide 17 of 18
From MS Saag, MD, at Washington, DC: April 15, 2016, IAS-USA.
0.70
ART
 Crude 1.29 (0.68-2.43)
 Adjusted 1.30 (0.66-2.55)
0.60
 Hazard Ratios (95% CI) for deferred vs early
Regime A (early ART)
Regime B (deferred ART)
0.50
% still alive
 84% male, median age at CM 38 years.
0.80
0.90
 235 patients from 28 cohorts
 Death rate at 6 months: 42/235 (18%)
Kaplan-Meier survival estimates
1.00
Results:
0
Number at risk
Regime A 235
Regime B 235
2
4
Time (months) since CM diagnosis
58
66
56
63
6
55
60
Conclusions:
• Early ART does not seem to be associated with higher mortality in resource rich settings, in contrast
to data from resource limited settings
• Underpowered to provide robust evidence
• Limitation: lack of data on CM treatment and disease management. We aim to obtain this in the future.
Slide 18 of 18
From MS Saag, MD, at Washington, DC: April 15, 2016, IAS-USA.