Современное лечение ВИЧ.Усилить или не усилить : преимущества и недостатки бустированных режимов АРТ / Contemporary Management of HIV.To Boost or Not to Boost-Advantages and Disadvantages of Boosted ART.2017

Contemporary Management of HIV
To Boost or Not to Boost: Advantages and
Disadvantages of Boosted ART
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About These Slides

Program Director and Core Faculty
Program Director
Joseph J. Eron, Jr., MD
Professor of Medicine and
Epidemiology
University of North Carolina
School of Medicine
Director, AIDS Clinical Trials Unit
University of North Carolina
Chapel Hill, North Carolina
Core Faculty
Eric S. Daar, MD
Chief, Division of HIV Medicine
Harbor-UCLA Medical Center
Professor of Medicine
David Geffen School of Medicine
at UCLA
Los Angeles, California

Faculty Disclosure Information
Joseph J. Eron, Jr., MD, has disclosed that he has received
consulting fees from Gilead Sciences, Janssen, Merck, and ViiV
and funds for research support from AbbVie, Gilead Sciences,
Janssen, and ViiV.
Eric S. Daar, MD, has disclosed that he has received consulting
fees from Bristol-Myers Squibb, Gilead Sciences, Merck, Teva, and
ViiV and funds for research support from Gilead Sciences, Merck,
and ViiV.

Where Boosted Regimens Fit in the First-line HIV
Treatment Armamentarium: DHHS Guidance
 Recommendations may differ based on baseline HIV-1 RNA or CD4+ cell
count, CrCl, eGFR, HLA-B*5701 status, HBsAg status, osteoporosis status,
and cardiovascular risk
Slide credit: clinicaloptions.comDHHS Guidelines.
Agent NRTI Backbone DHHS Recommendation
INSTI-Based Regimens
DTG ABC/3TC or FTC/TAF or FTC/TDF Recommended
EVG/COBI FTC/TAF or FTC/TDF Recommended
RAL FTC/TAF or FTC/TDF Recommended
PI-Based Regimen
DRV/RTV FTC/TAF or FTC/TDF Recommended
DRV/COBI FTC/TAF or FTC/TDF Alternative
DRV/RTV or COBI ABC/3TC Alternative
ATV/RTV or COBI FTC/TAF or FTC/TDF Alternative
NNRTI-Based Regimen
RPV FTC/TAF or FTC/TDF Alternative
EFV FTC/TAF or FTC/TDF Alternative

Boosted ART Regimens: Advantages
Boosted Protease Inhibitors EVG/COBI/FTC/TAF (or TDF)
Efficacy Efficacy
Tolerability Tolerability
Long history of use Extensive comparative trial data
ATV and DRV available as FDC with
COBI;
can be used in novel combinations
(eg, with 3TC or INSTI alone)
INSTI STR
High barrier to resistance
Active in those with partially active
backbone regimens

 Randomized, open-label, multicenter phase III trial
ACTG 5257: DRV/RTV vs ATV/RTV vs RAL in
Treatment-Naive Pts
 Primary endpoints:
– Virologic failure: HIV-1 RNA > 1000 copies/mL (at or after Wk 16 and before Wk 24) or
> 200 copies/mL (at or after Wk 24)
– Tolerability failure: time to discontinuation of ATV, RAL, or DRV for toxicity
 Secondary composite endpoint: earlier occurrence of either virologic or tolerability failure
ART-naive pts with
HIV-1 RNA ≥ 1000 copies/mL
and no NRTI or PI resistance
(N = 1809)
ATV/RTV 300/100 mg QD + FTC/TDF
(n = 605)
RAL 400 mg BID + FTC/TDF
(n = 603)
DRV/RTV 800/100 mg QD + FTC/TDF
(n = 601)
Wk 96
Slide credit: clinicaloptions.comLennox JL, et al. Ann Intern Med. 2014;161:461-471.
Regimen switch allowed for tolerability.

ATV/RTV vs RAL
(favors RAL)
14.9% (10.2 to 19.6)
DRV/RTV vs RAL
(favors RAL)
7.5% (3.2 to 11.8)
ATV/RTV vs DRV/RTV
(favors DRV/RTV)
7.5% (2.3 to 12.7)
ACTG 5257: Wk 96 Endpoint Analyses
 Regimens equivalent
in probability of VF by
Wk 96
 Greater incidence of d/c for
tolerability with ATV/RTV vs
RAL or DRV/RTV, in part due
to high frequency of
hyperbilirubinemia
 RAL superior to both
boosted PIs
 DRV/RTV superior to
ATV/RTV
Virologic Failure Tolerability Failure Composite Endpoint
Difference in 96-Wk Cumulative Incidence (97.5% CI)
ATV/RTV vs RAL
3.4% (-0.7 to 7.4)
DRV/RTV vs RAL
5.6% (1.3 to 9.9)
ATV/RTV vs DRV/RTV
-2.2% (-6.7 to 2.3)
0-10 10 20
ATV/RTV vs DRV/RTV
(favors DRV/RTV)
9.2% (5.5 to 12.9)
ATV/RTV vs RAL
(favors RAL)
12.7% (9.4 to 16.1)
DRV/RTV vs RAL
3.6% (1.4 to 5.8)
0-10 10 20 0-10 10 20
Slide credit: clinicaloptions.comLennox JL, et al. Ann Intern Med. 2014;161:461-471.

ACTG A5257: Genotypic Analysis for Resistance
at Virologic Failure
 VF with resistance rare but
more frequent with RAL
 RAL arm: 3.0%
– Intermediate-level resistance
to DTG, n = 2
 Boosted PI arms: ≤ 1.5%
– RAL resistance without
known INSTI exposure, n = 2
All patients received TDF/FTC.
*Tested in 27 pts on PIs: ATV/RTV, n = 15; DRV/RTV, n = 12.
Virologic Failure at Week 96
Characteristic, n ATV/RTV
(n = 95)
RAL
(n = 85)
DRV/RTV
(n = 115)
Genotypic testing 75 65 99
Any resistance 9 18 4
PI only 0 0 0
NRTI only
 FTC
 TDF
 FTC and TDF
8
5
2
1
7
7
0
0
3
3
0
0
INSTI only 1* 1 1*
NRTI and INSTI
 FTC and RAL
 FTC, TDF, RAL
0
0
0
10
7
3
0
0
0
Lennox JL, et al. Ann Intern Med. 2014;161:461-471.

Efficacy of ATV or DRV + COBI + NRTIs in
Treatment-Naive Pts
 GS-0114: multicenter, randomized, double-
blind, active-controlled phase III trial in
treatment-naive adults (N = 692)[1]
 ATV 300 mg + (COBI 150 mg vs RTV 100 mg)
+ TDF/FTC
 GS-0130: multicenter, single-arm, open-label
phase IIIb trial (N = 313); 94% treatmen -
naive[2]
 DRV 800 mg + COBI 150 mg + 2 NRTIs
Slide credit: clinicaloptions.com1. Gallant JE, et al. J Infect Dis. 2013;208:32-39. 2. Tashima K, et al. AIDS Res Ther. 2014;11:39.
HIV-1RNA<50c/mL(%)
WksWks
HIV-1RNA<50c/mL(%)
87%
85%
(P = .4)
100
80
60
40
20
0
0 12 24 36 48
COBI (n = 344)
RTV (n = 348)
100
80
60
40
20
0
0 16 24 32 48408
81%

Boosted EVG-Based Regimens Noninferior in
Treatment-Naive Pts at Wk 48
1. Sax PE, et al. Lancet. 2012;379:2439-2448.
2. DeJesus E, et al. Lancet. 2012;379:2429-2438.
3. Sax PE, et al. Lancet. 2015;385:2606-2615.
Study Regimens Wk 48 HIV-1 RNA
< 50 c/mL, %
Adjusted Treatment
Difference, % (95% CI)
GS-102[1]  EVG/COBI/FTC/TDF (n = 348)
 EFV/FTC/TDF (n = 352)
87.6
84.1
3.6 (-1.6 to 8.8)
GS-103[2]  EVG/COBI/FTC/TDF (n = 353)
 ATV/RTV + FTC/TDF (n = 355)
89.5
86.8
3.0 (-1.9 to 7.8)
GS-104/111[3]  EVG/COBI/FTC/TAF (n = 866)
 EVG/COBI/FTC/TDF (n = 867)
92.4
90.4
2.0 (-0.7 to 4.7)

Boosted ART Regimens: Disadvantages
Boosted Protease Inhibitors EVG/COBI/FTC/TAF (or TDF)
DDIs DDIs
GI adverse events, hyperbilirubinemia
(ATV), and lipid abnormalities
Limited flexibility in NRTI choice
Lack of current STR Relatively low barrier to resistance
Possible CV risk for DRV

Potential Interactions With COBI and RTV
 Both inhibit CYP3A and P-gp; RTV also an inducer of CYP1A2,
CYP2B6, CYP2C8, CYP2C9, CYP2C19, or UGT1A1
Marzolini C, et al. J Antimicrob Chemother. 2016;71:1755-1758.
COBI [package insert]. RTV [package insert].
Agents That Have Interactions With RTV and/or COBI
 Analgesics  Contraceptives
 Antiarrhythmics  Digoxin
 Anticancer agents  Glucocorticoids
 Anticoagulants  Methamphetamine
 Anticonvulsants  PDE5 inhibitors
 Antidepressants  Rifabutin
 Beta-blockers  Sedatives/hypnotics
 Clarithromycin  Statins

D:A:D: Cumulative Exposure to DRV/RTV
Increases CVD Risk
 Prospective analysis of pts followed from 2009 to earliest CVD, last visit + 6 mos, or
February 2016 (N = 35,711)
Slide credit: clinicaloptions.comRyom L, et al. CROI 2017. Abstract 128LB.
CVD
 Cumulative exposure to DRV/RTV, but not ATV/RTV, associated with increased
CVD risk in multivariate analysis: 59% risk increase per 5-yrs’ DRV/RTV
CVDIncidenceRate/
1000PYFU(95%CI)
5
4
3
2
1
0
0 0-1 1-2 2-3 3-4
10
15
20
4-5 5-6 > 6 0 0-1 1-2 2-3 3-4 4-5 5-6 > 6
Events 824 75 49 41 26 46 34 62 909 52 51 44 39 17 18 27
Cumulative Yrs of Exposure
ATV/RTV DRV/RTV
5.03
(4.69-5.37)
6.68
(5.02-8.35)
4.91
(4.59-5.23)
13.67
(8.51-18.82)

Case 1:
Pt With OI Requiring First-line ART
Before Resistance Results Available

Case 1: Presentation
 32-yr-old woman presents with fever, chills, nonproductive cough,
and increasing dyspnea on exertion with rapid HIV test positive
Characteristic Finding
HIV-1 RNA  Viral load pending
Genotype  Pending
CD4+ cell count  21 cells/mm3
Chest x-ray  Diffuse interstitial infiltrates
Laboratory findings
 Metabolic panel: normal
 Arterial blood gas assessment: pH
7.50, pCO2 22 mm Hg, pO2 61 mm Hg
 Hemoglobin: 10.1 g/dL
 White blood count:
4.3 x 109/L
Bronchoalveolar lavage  Positive for P jirovecci

Case 1: Treatment and Follow-up Labs
 Pt started on trimethoprim-sulfamethoxazole plus prednisone
– Good clinical response/tolerability through 7 days; begins
prednisone taper
 Patient is anxious to start ART
Follow-up Laboratory Values Finding
HIV-1 RNA  221,000 copies/mL
Genotype  Pending
HLA-B*5701  Positive

What would you recommend for this pt?
A. Start ART when P jirovecci infection stable and follows up in clinic
B. Start ARVs after genotype results return
C. Start boosted PI + 2 NRTIs immediately
D. Start DTG + 2 NRTIs immediately
E. Start EVG/COBI/FTC/TAF immediately
F. Start RAL + 2 NRTIs immediately
G. Something else
 32-yr-old woman newly diagnosed with HIV and P jirovecci pneumonia
 CD4+ cell count 21 cells/mm3, HIV-1 RNA 221,000 copies/mL, HLA-B*5701 positive
 HIV genotype pending
 Pt anxious to initiate ART immediately

ACTG 5164: Immediate vs Deferred ART During
Acute OI Therapy
 Multicenter, open-
label, randomized
phase IV strategy trial
 ART given within 14
days of starting or
after completion of
treatment for acute
AIDS-related OIs or
serious bacterial
infections (N = 282)
Slide credit: clinicaloptions.comZolopa AR, et al. PLoS ONE. 2009;4:e5575.
Favors Deferred ART
Risk of AIDS Progression/Death by Entry Diagnoses
Total
PCP
Bacterial infection
Other OI
Fungal
Crypto
Mycobacterial
> 1 OI
CD4+ < 50
CD4+ ≥ 50
# Events
54
28
11
42
12
8
8
30
39
15
0 0.25 0.5 1.0 8.0 202.5
Log OR of Death/AIDS Progression (95% CI)
Favors Early ART

DHHS Guidance on Initial ART in Pts Needing Tx
Before Receipt of Drug Resistance Results
 For pts with most AIDS-associated OI, ART should be initiated as
soon as possible to improve immune function
Slide credit: clinicaloptions.comDHHS Guidelines.
Consideration Rationale
Avoid NNRTI-based regimens
 Transmitted mutations conferring NNRTI resistance
more likely vs PI or INSTI resistance mutations
Recommended regimens:
 DRV/RTV + FTC/TAF or FTC/TDF
 DTG + FTC/TAF or FTC/TDF
 Resistance to DRV/RTV and DTG emerges slowly
 Transmitted resistance to DRV rare, to DTG not yet
reported

INSTI Resistance in the United States
 Analyzed 14,468 sequences
from National HIV Surveillance
System in 9 US jurisdictions
 INSTI genotypic testing
increased over time (2010-2014)
 Prevalence of INSTI
resistance: 65/14,468 (0.4%)
 Pre-ART prevalence of INSTI
resistance (ie, transmitted):
2/4631 (0.04%)
Slide credit: clinicaloptions.comHernandez AL, et al. CROI 2017. Abstract 478.
Pts(%)
Prevalence of Specific INSTI Mutations
in Pts With Any INSTI Mutations
0
10
20
30
40
50

Barrier to Resistance With Recommended INSTI-
Based Regimens
Regimen
Barrier to
Resistance
Comments
Mutations Highly
Reducing
Susceptibility[2]*
DTG/3TC/ABC
DTG + FTC/TDF or FTC/TAF
High
 Resistance to DTG emerges slowly; multiple
mutations required for resistance[1,2]
 DTG + FTC/TDF or FTC/TAF recommended
by DHHS if must treat before resistance
results available[1]
--
EVG/COBI/FTC/TDF
EVG/COBI/FTC/TAF
Low/Moderate  Few EVG mutations required for resistance[2]
T66I/A/K
E92Q
S147G
Q148H/R/K
N155H
RAL + FTC/TDF or FTC/TAF Low/Moderate  Few RAL mutations required for resistance[2]
Y143C/R/H
Q148H/R/K
N155H
*NRTI backbone mutations not shown in column: FTC/TDF, M184V/I, K65R, T69ins; ABC/3TC, M184V/I, K65R, L74V/I,
T69ins, Y115F, Q151M.
Slide credit: clinicaloptions.comReferences in slidenotes.

DTG + NRTIs: High Barrier to Resistance in
Treatment-Naive Pts
HIV-1 RNA < 50 c/mL by Snapshot Analysis: 95% CI for Treatment Difference
No emergent resistance in any recipients of DTG-based regimens
Wk 48
Wk 96
Wk 144
-5% 15%0
Favors
EFV/TDF/FTC
Favors
DTG+ABC/3TC
2% 14.6%
8.3%
7.4%
12.3%
8.0%
13.8%
2.5%
2.3%
SINGLE[1]
-12% 25%0
Favors
DRV/RTV
Favors
DTG
7.1%
13.2%
12.4%
20.2%
0.9%
4.7%
FLAMINGO[2]
-12% 12%0
Favors
RAL
Favors
DTG
2.5%
7.1%
4.5%
10%
-2.2%
-1.1%
SPRING-2[3,4]
-5% 20%0
Favors
ATV/RTV + TDF/FTC
Favors
DTG/ABC/3TC
10.5%
17.8%3.1%
ARIA[5]
1. Walmsley S, et al. J Acquir Immune Defic Syndr. 2015;70:515-519. 2. Molina JM, et al. Lancet HIV. 2015;2:e127-
e136. 3. Raffi F, et al. Lancet. 2013;381:735-743. 4. Raffi F, et al. Lancet Infect Dis. 2013;13:927-935.
5. Orrell C, et al. AIDS 2016. Abstract THAB0205LB.

 Randomized, open-label, multicenter phase III trial in sub-Saharan Africa
LPV/RTV + RAL
(n = 433)
LPV/RTV + 2-3 NRTIs*
(n = 426)
HIV-infected pts
> 12 yrs of age with
confirmed treatment failure
on NNRTI + 2 NRTIs
and no prior PIs
(N = 1277)
Wk 96
LPV/RTV 400/100 mg and RAL 400 mg dosed BID.
*New or recycled NRTIs chosen WITHOUT genotype by clinician.
EARNEST: Boosted PIs Effective Even With
Partially Active Background Regimen
Wk 12
LPV/RTV Monotherapy
(n = 418)
LPV/RTV + RAL
(n = 418)
Stratified by study center,
CD4+ cell count (< 200 vs
≥ 200 cells/mm3)
Paton NI, et al. N Engl J Med. 2014;371:234-247.

EARNEST: Boosted PI + RAL Comparable to
Boosted PI + NRTIs
 SECOND-LINE[3] and ACTG 5273[4,5] showed similar results
LPV/RTV + RAL
(n = 433)
LPV/RTV + 2/3 NRTIs
(n = 426)
LPV/RTV monotherapy
(n = 418)
100
80
60
40
20
0
Pts(%)
HIV-1 RNA < 50 copies/mL, Wk 96[1]
7473
44
P < .001
HIV-1 RNA < 400 copies/mL, Wk 144[2]
0
20
40
60
80
100
LPV/RTV + NRTI
(Number of Active NRTIs)
Pts(%)
88
0 LPV/
RTV +
RAL
77 8185
61
1 2-3 LPV/
RTV
References in slidenotes.

Take-home Points
 DHHS guidelines recommend either boosted DRV or DTG plus
FTC/TAF or FTC/TDF for pt who need ART prior to resistance
testing results
– Most pts presenting with OI should be begin ART within 2 wks
 Substantial experience with boosted PIs in pts with OI
 Boosted PI plus NRTI likely to have activity against most viruses
with transmitted drug resistance
 Transmitted integrase inhibitor resistance remains very
uncommon

Case 2: Pt With Adherence Issues and
Toxicity With PI-Based Regimen

Case 2: History
 54-yr-old man diagnosed with HIV 5 yrs ago
 Put on first-line regimen of EFV + FTC/TDF
– After initial suppression, started using drugs/missed ARV doses
– Virologic failure with M184V and K103N mutations 2 yrs ago
 Switched to DRV/RTV + FTC/TDF
– Good suppression but GI intolerance that persisted with PI switch to
ATV/COBI
– Pt desires another switch to address toxicity

What would you recommend for this pt?
A. Maintain current regimen with symptomatic treatment; it is too
risky to consider a regimen that does not include a boosted PI
B. Switch to DTG + 2 NRTIs
C. Switch to DTG + RPV
D. Switch to EVG/COBI/FTC/TAF
E. Switch to RAL + 2 NRTIs
F. Something else
 54-yr-old man with prior VF and M184V, K103N mutations
 Suppressed on DRV/RTV + TDF/FTC with GI intolerance to DRV/RTV and ATV/COBI
 Pt wants to remove boosted PI from regimen to address GI issues

SWITCHMRK: Reduced Virologic Efficacy
Following Switch From Boosted PI to RAL
 Underlying resistance matters: percent with HIV-1 RNA < 50 c/mL for RAL vs LPV/RTV
by investigator report of previous virologic failure: No, 89% vs 90%; Yes, 77% vs 92%
Switch to RAL
Continue LPV/RTV
50
60
70
80
90
100
0 4
Wks
HIV-1RNA<50c/mL(%)
8 12 24
87%
81%
∆: -6.6 (95% CI: -14.4 to 1.2)
SWITCHMRK-1 SWITCHMRK-2
50
60
70
80
90
100
0 4
Wks
8 12 24
∆: -5.8 (95% CI: -12.2 to 0.2)
94%
88%
Slide credit: clinicaloptions.comEron JJ, et al. Lancet. 2010;375:396-407.
HIV-1RNA<50c/mL(%)
Prespecified noninferiority margin: -12%.
 Randomized, double-blind, active-controlled trials in which virologically suppressed pts
continued LPV/RTV-based regimen or switched to RAL-based regimen (N = 702)

DTG + Partially Active NRTI Backbone
 No resistance to DTG or NRTIs
emerged in treatment-naive pts in
clinical trials
 First case report of possible
treatment-emergent INSTI
resistance in pt with VF on first-line
DTG + NRTIs[1]
 Limited INSTI resistance in
treatment-experienced pts who are
INSTI naive
– SAILING: 1% (4/354) with DTG vs
5% (17/361) with RAL at Wk 48[2]
*In pts receiving NRTI-only background regimens; activity
based on phenotype.
1. Fulcher JA, et al. CROI 2017. Abstract 500LB.
2. Cahn P, et al. Lancet. 2013;382:700-708.
3. Demarest, et al. AIDS 2014. Abstract TUAB0104.
PDVF by Number
of NRTIs,* n/N[3]
DTG
(n = 32)
RAL
(n = 32)
2 fully active NRTIs 0/16 3/19
1 fully active NRTI 0/12 4/13
0 fully active NRTIs 0/1 -
Missing phenotype 0/3 -

SWORD 1 & 2: Switch From Suppressive ART to
DTG + RPV in Pts With No Previous VF
 Randomized, open-label, multicenter phase III trials
 70% to 73% of pts receiving TDF at baseline
Llibre JM, et al. CROI 2017. Abstract 44LB.
Adult pts on
stable ART* ≥ 6 mos with
HIV-1 RNA < 50 copies/mL at BL;
no previous virologic failure
or HBV infection
(N = 1024)
DTG 50 mg QD +
RPV 25 mg QD
(n = 513)
Wk 52
Baseline ART
(n = 511)
Wk 48
Primary Endpoint
Pts continued or
switched to DTG + RPV
through Wk 148
*Comprising an INSTI, NNRTI, or PI plus 2 NRTIs.

SWORD 1 & 2: Key Dual Therapy Efficacy
Results
 1 pt receiving DTG + RPV
with confirmed criteria for
virologic withdrawal at Wk 36
had K101K/E
– Documented nonadherence
at virologic failure
– Resuppressed with
continued DTG + RPV
– No INSTI resistance
Llibre JM, et al. CROI 2017. Abstract 44LB.
Virologic
Nonresponse
Wk 48
HIV-1 RNA
< 50 c/mL
No Data
100
80
60
40
20
0
Pts(%)
95 95
< 1 1
5 4
Treatment difference: -0.2%
(95% CI: -3.0% to 2.5%)
DTG + RPV (n = 513)
Baseline ART (n = 511)

Take-home Points
 Switch from a suppressive boosted PI regimen to another class
should be done with caution
 All previous resistance data should be carefully considered
 Data are limited for switching pts on boosted PI therapy who
have known resistance mutations
 Integrase inhibitor–based therapy may be appropriate in a given
clinical setting with careful monitoring

Case 3: Treatment-Naive Pt With
Multiple Comorbidities and
Potential Adherence Concerns

Case 3: History
 48-yr-old treatment-naive man with HIV diagnosed in 2014
 Intermittent substance abuse; DM, HTN, and chronic kidney disease
– Frequently misses appointments, is poorly adherent to comorbidity
medications despite multiple interventions from psychologist, social
worker, and case manager
 Has been resisting initiation of ART
– Gradual decline in CD4+ cell count from 400 to 190 cells/mm3
– HIV-1 RNA recently between 120,000 and 180,000 copies/mL
– Wild-type HIV genotype
– HLA-B*5701 negative

Case 3: Current Presentation
 At most recent visit
– Acknowledges that he is medically in trouble
– Willing to increase adherence to visits and HTN and DM
medications
 Follow-up labs
– Cr 2.4 mg/dL, eGFR 35 mL/min
– UA with 3+ proteinuria
– A1C 10.9%
 Ready to start ART; strongly desires a single-tablet regimen

What would you recommend for this patient?
A. Pt is not ready to start ART until clinic visit adherence improves
B. EFV/FTC/TDF
C. EVG/COBI/FTC/TAF
D. DTG/ABC/3TC
E. RPV/FTC/TAF
F. I would not recommend an STR for this pt
 48-yr-old treatment-naive man with substance abuse, missed appointments
 DM (A1C 10.9%), HTN, CKD (eGFR 35 mL/min)
 CD4+ cell count 190 cell/mm3, HIV-1 RNA 180,000 c/mL, HLA-B*5701 negative, wild-type HIV genotype
 Wants STR

Case 3: Key Issues for Consideration
 Concerns for poor adherence and emerging resistance
 Chronic kidney disease
 Cardiovascular disease
 Desires STR

Class DHHS[1] IAS-USA[2] EACS[3]
INSTI
based
 DTG/ABC/3TC
 DTG + FTC/TDF or
FTC/TAF
 EVG/COBI/FTC/TDF or
EVG/COBI/FTC/TAF
 RAL + FTC/TDF or FTC/TAF
 DTG/ABC/3TC
 DTG + FTC/TAF
 EVG/COBI/FTC/TAF
 RAL + FTC/TAF
 DTG/ABC/3TC
 DTG + FTC/TDF or
FTC/TAF
 EVG/COBI/FTC/TDF or
EVG/COBI/FTC/TAF
 RAL + FTC/TDF or FTC/TAF
PI
based
 DRV/RTV + FTC/TDF or
FTC/TAF
 DRV/(RTV or COBI) +
FTC /TDF or FTC/TAF
NNRTI
based
 RPV/FTC/TDF* or
RPV/FTC/TAF*
Recommended First-line Regimens: STRs
 Recommendations may differ based on baseline HIV-1 RNA or CD4+ cell count, CrCl,
HLA-B*5701 status, HBsAg status, osteoporosis status, and cardiovascular risk
Bolding indicates single-tablet regimen. *Avoid if HIV-1 RNA ≥ 100,000 c/mL or CD4+ cell count ≤ 200 cells/mm3.
1. DHHS Guidelines. 2. Günthard HF, et al. JAMA. 2016;316:191-210. 3. EACS Guidelines. January 2017.

Emergent PI Resistance Rare: Rationale for PI
Use in Pts at Risk for Poor Adherence
Trial Name
F/U,
Wks
Treatment Arm
Virologic
Failure, n (%)
Treatment-Emergent
Primary Mutations, n
CASTLE[1] 96
ATV/RTV + TDF/FTC (n = 440) 28 (6) 1 (PI), 7 (NRTI)
LPV/RTV + TDF/FTC (n = 443) 29 (7) 10 (NRTI)
ACTG A5202[2] 96
ATV/RTV + NRTIs (n = 928) 140 (15) 1 (NNRTI), 1 (PI), 16 (NRTI)
EFV + NRTIs (n = 929) 129 (14) 68 (NNRTI), 36 (NRTI)
GS-103[3] 144
ATV/RTV + TDF/FTC (n = 355) NR (7) 2 (NRTI)
EVG/COBI/TDF/FTC (n = 353) NR (8) 8 (INSTI), 8 (NRTI)
ARTEMIS[4] 96
DRV/RTV + TDF/FTC (n = 343) NR (12) 2 (NRTI)
LPV/RTV + TDF/FTC (n = 346) NR (17) 5 (NRTI)
FLAMINGO[5] 96
DRV/RTV + NRTIs (n = 242) 4 (2) 0
DTG + NRTIs (n = 242) 2 (< 1) 0
ACTG A5257[6] 96
ATV/RTV + TDF/FTC (n = 605) 95 (16) 1 (INSTI), 8 (NRTI)
DRV/RTV + TDF/FTC (n = 601) 115 (19) 1 (INSTI), 3 (NRTI)
RAL + TDF/FTC (n = 603) 85 (14) 1 (INSTI), 7 (NRTI), 10 (INSTI + NRTI)

DRV/COBI/FTC/TAF STR Currently in
Development
 Randomized, double-blind, active-controlled phase II trial[1]
 Wk 48 pts with VF/no data (ITT): TAF group, 16%/8%; TDF group, 12%/4%; no
resistance in pts with VF
 TAF regimen associated with less deleterious effects on renal biomarkers and BMD
 Phase III EMERALD and AMBER studies ongoing[2,3]
1. Mills A, et al. J Acquir Immune Defic Syndr. 2015;69:439-445. 2. ClinicalTrials.gov. NCT02269917.
3. ClinicalTrials.gov. NCT02431247.
Wk 48
DRV/COBI/FTC/TAF QD +
4 Placebos
(n = 103)
DRV + COBI + FTC/TDF QD +
1 Placebo
(n = 50)
Wk 24
Primary Endpoint
ART-naive pts with
HIV-1 RNA ≥ 5000 copies/mL;
CD4+ cell count > 50 cells/mm3;
eGFRCG ≥ 70 mL/min;
DRV/TDF/FTC sensitive
(N = 153)
HIV-1 RNA
< 50 copies/mL, % (ITT)
Wk 24 Wk 48
75 77
74 84

Choosing an Integrase Inhibitor
Agent Advantages Disadvantages
RAL  Longest experience
 Fewer DDIs vs EVG, DTG
 No coformulation
 Relatively low barrier to resistance
EVG  STR with TAF
 Once-daily dosing
 EVG/COBI/FTC/TAF STR approved
for use in pts with CrCl > 30 mL/min
 Requires COBI boosting with associated
DDIs
 Relatively low barrier to resistance
DTG  Only non-tenofovir–containing STR
 Once-daily dosing
 Higher barrier to resistance
 Few DDIs
 Active against some RAL- and EVG-
resistant virus
 Only coformulated with ABC/3TC
 Increases metformin levels
 DTG/ABC/3TC STR not recommended
for pts with CrCl < 50 mL/min
EVG/COBI/FTC/TAF [package insert]. DTG/ABC/3TC [package insert]. RAL [package insert].
Clutter DS, et al. Infect Genet Evol. 2016;[Epub ahead of print].

Virologic Failure and Treatment-Emergent
Resistance With DTG and EVG
Trial Name F/U,
Wks
Treatment Arm Virologic Failure, n (%) Treatment-Emergent
Primary Mutations, n
SPRING-2[1] 96
DTG + 2 NRTIs (n = 411) 22 (5) 0
RAL + 2 NRTIs (n = 411) 29 (7) 1 (INSTI), 4 (NRTI)
SINGLE[2] 144
DTG + ABC/3TC (n = 414) 39 (9) 0
EFV/TDF/FTC (n = 419) 33 (8) 1 (NRTI), 6 (NNRTI)
FLAMINGO[3] 96
DTG + 2 NRTIs (n = 242) 2 (< 1) 0
DRV/RTV + 2 NRTIs (n = 242) 4 (2) 0
GS-102[4]
144
EFV/TDF/FTC (n = 352) NR (10) 14 (NRTI)
GS-103[5]
144
ATV/RTV + TDF/FTC (n = 355) NR (7) 2 (NRTI)
1. Raffi F, et al. Lancet Infect Dis. 2013;13:927-935. 2. Walmsley S, et al. J Acquir Immune Defic Syndr.
2015;70:515-519. 3. Molina JM, et al. Lancet HIV. 2015;2:e127-e136. 4. Wohl DA, et al. J Acquir Immune
Defic Syndr. 2014;65:e118-e120. 5. Clumeck N, et al. J Acquir Immune Defic Syndr. 2014;65:e121-e124.

 Multicenter, single-arm, open-label phase III trial
GS-112: Switching to a TAF-Based Regimen in
Pts With Renal Impairment
Virologically suppressed pts with
mild to moderate renal impairment
(eGFRCG 30-69 mL/min)
(N = 242)
TDF-Based ART
(n = 158)
Non-TDF–Based ART
(n = 84)
EVG/COBI/FTC/TAF
(N = 242)
Wk 96
PI NNRTI INSTI
CCR5
Antag.
TDF ABC
Other
NRTI
No
NRTI
BL ART use,% 44 42 24 3 65 22 7 5
Slide credit: clinicaloptions.comPozniak A, et al. J Acquir Immune Defic Syndr. 2016;71:530-537.

GS-112: Key Results
Change in eGFR From BL to Wk 48 Measured GFR by Iohexol Clearance
From BL to Wk 24
TDF Non-TDF
MedianChangeFrom
Baseline
10
0
-10
+0.2
-1.8 -1.5
-2.7*
Baseline: 58 53 56 50
eGFRCG
mL/min
eGFRCKD-EPI Cr
mL/min/1.73 m2*P < .05
mGFR(mL/min)
BL Wk
2/4/8
Wk
24
63
50
62
48
63
49
0
20
40
60
80 Non-TDFTDF
BL Wk
2/4/8
Wk
24
GLSM Ratio vs
BL, % (90% CI)):
98
(94-102)
100
(96-105)
96
(86-108)
98
(87-111)
Gupta S, et al. IAS 2015. Abstract TUAB0103.
Pozniak A, et al. J Acquir Immune Defic Syndr. 2016;71:530-537.

Important Caveats Regarding TAF for Pts With
CKD
 Data limited in pts with advanced renal disease
 GS-112 study enrolled only pts with stable CKD and included no
control group
 No data with TAF 25 mg (dose in FTC/TAF FDC) when given with
boosted PIs in pts with CKD
Slide credit: clinicaloptions.comPozniak A, et al. J Acquir Immune Defic Syndr. 2016;71:530-537.

Summary of Key Analyses Addressing Risk of MI
With ABC
Study Study
Design
Age, Yrs
(Range)
Event (n) Pts, N ABC
CV Effect
Time on
ABC, Mos
Risk of MI
(95% CI)
D:A:D[1] Cohort 40 (35-47) MI, validated (387) 22,625 Yes ≥ 6 2.04 (1.66-2.51)
D:A:D 2015[2] Cohort 39 (33-46) MI (493) 32,663 Yes Current 1.47 (1.26-1.71)
SMART[3] RCT 45 (39-51) MI, validated (19) 2752 Yes Current 4.3 (1.4-13.0)
STEAL[4] RCT 45.7 ± 8.8 MI (4) 357 Yes 96 2.79* (1.76-4.43)
QPHID[5] CC 47 (22-67) MI (125) 7053 Yes Any 1.79 (1.16-2.76)
Danish[6] Cohort 39 (33-47) MI (67) 2952 Yes > 6 2.00 (1.07-3.76)
VA (Choi)[7] Cohort 46 CVD event (501) 10,931 Yes Recent 1.64 (0.88-3.08)
Swiss[8] Cohort NR CVD event (365) 11,856 Yes Recent 4.06† (2.24-7.34)
MAGNIFICENT[9] CC 50 (22-85.5) CVD event (571) 1875 Yes Current 1.56 (1.17-2.07)
NA-ACCORD[10] Cohort NR MI, validated (301) 16,733 Yes Recent 1.33
FHDH[11] CC 47 (41-54) MI (289) 74,958 No < 12/recent 1.27‡ (0.64-2.49)
ALLRT/ACTG[12] Cohort 37 (26-51) MI (36) 5056 No 72 0.6 (0.3-1.4)
VA[13] Cohort 46 MI (278) 19,424 No Per 12 1.18 (0.92-1.50)
FDA[14] MA of
RCTs
36-42 MI (46) 9868 No 19 1.02 (0.56-1.84)
NA-ACCORD[10] Cohort NR MI, validated (301) 16,733 No Recent 1.33
*Risk for serious non-AIDS events (CVD most common, including MI); HR for CVD with TDF vs ABC: 0.12 (95% CI: 0.02-0.98; P = .048).
†Risk for CVD event, including MI, invasive CV procedure, or CV-related death.
‡Without adjustment for cocaine use OR: 2.01 (1.11-3.64).

A Select List of Novel, Simplified First-line
Regimens Not Containing TAF, TDF, or ABC
Regimen Limitations
Boosted PI + 3TC[1]  ≥ 2 pills
 Limited data with first-line PIs
Boosted PI + INSTI[2]  ≥ 2 pills
 Limited data with first-line PIs and INSTIs
 Concern in pts with low CD4+ cell counts or high HIV-1
RNA
DTG + 3TC[3]  2 pills
 Very limited data, including in pts with high HIV-1 RNA
References in slidenotes.

Take-home Points
 In pts at high risk for poor adherence consider choosing an initial
regimen with a high barrier to resistance
– Balancing resistance barrier with regimen simplicity is a challenge
 In pts with comorbid conditions, DDIs, dose adjustments, and
increasing risk of comorbid outcomes (eg, MI, progression of
renal dysfunction) need to be considered

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Современное лечение ВИЧ.Усилить или не усилить : преимущества и недостатки бустированных режимов АРТ / Contemporary Management of HIV.To Boost or Not to Boost-Advantages and Disadvantages of Boosted ART.2017

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Современное лечение ВИЧ.Усилить или не усилить : преимущества и недостатки бустированных режимов АРТ / Contemporary Management of HIV.To Boost or Not to Boost-Advantages and Disadvantages of Boosted ART.2017