Современное лечение ВИЧ: когда начинать, чем начинать. Contemporary Management of HIV. When to Start, What to Start.2016

Contemporary Management of HIV:
When to Start, What to Start
This program is supported by an independent educational grant from
ViiV Healthcare

Slide credit: clinicaloptions.com
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Program Director and Core Faculty
Program Chair
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
Daniel R. Kuritzkes, MD
Chief, Division of Infectious
Diseases
Brigham and Women’s Hospital
Professor of Medicine
Harvard Medical School
Boston, Massachusetts

Faculty Disclosure Information
Eric S. Daar, MD, has disclosed that he has received
consulting fees from AbbVie, Bristol-Myers Squibb, Gilead
Sciences, Janssen, Merck, Teva, and ViiV and funds for
research support from Bristol-Myers Squibb, Gilead
Sciences, Merck, and ViiV.
Daniel R. Kuritzkes, MD, has disclosed that he has received
consulting fees from Gilead Sciences, Merck, and ViiV; fees
for non-CME/CE services received directly from a
commercial interest or their agents (eg, speaker bureaus)
from Gilead Sciences and Merck; and funds for research
support from Gilead Sciences and ViiV.

Case 1:
Patient Newly Diagnosed
With HIV Infection

Case 1: 22-Yr-Old Man Recently
Diagnosed With HIV
 22-yr-old black man presents with newly diagnosed HIV
infection, after testing positive on routine screening
 Tested HIV seronegative 6 mos ago
 No significant medical problems, no medication use
 Initial laboratory studies, including lipids, renal, and
hepatic function are normal
 CD4+ cell count 726 cells/mm3
(40%), HIV-1 RNA
2130 copies/mL
 HIV genotype WT, HBV immune, HCV negative, HLA-
B*5701 negative
 He is unsure if he should start antiretroviral therapy

Case 1: Current Presentation
 Pt expresses concern about having to take medicines
every day and is worried about adverse events
 He is a nonsmoker and has no family history of heart
disease
 He has multiple sex partners, but says he “almost
always” uses condoms when he has sex

Would you recommend antiretroviral
therapy for this pt?
A. Yes
B. No
C. Unsure
 22-yr-old black man with recent HIV seroconversion
 HIV-1 RNA 2130 copies/mL, CD4+ cell count 726 cells/mm3
 No medical problems
 Labs normal, HIV GT WT, HBV immune, HCV negative, HLA-B*5701 negative
 Multiple sex partners

START: Immediate vs Deferred Therapy
for Asymptomatic, ART-Naive Pts
Immediate ART
ART initiated immediately
following randomization
(n = 2326)
INSIGHT START Study Group. N Engl J Med. 2015;373:795-807.
Lundgren J, et al. IAS 2015. Abstract MOSY0302.
Deferred ART
Deferred until CD4+ cell count ≤ 350 cells/mm3
,
AIDS, or event requiring ART
(n = 2359)
HIV-positive, ART-naive
adults with CD4+ cell
count > 500 cells/mm3
(N = 4685)
Study closed by DSMB
following interim analysis

START: Primary Outcome
Primary Endpoint Immediate ART Deferred ART
No. with event (%) 42 (1.8) 96 (4.1)
Rate/100 PY 0.60 1.38
HR (immediate/deferred) 0.43 (95% CI: 0.30-0.62; P < .001)
 57% reduced risk of
serious events or
death with immediate
ART
 68% of primary
endpoints occurred in
pts with CD4+ cell
counts > 500 cells/mm3
10
8
6
4
2
0
CumulativePercent
WithEvent
0 6 12 18 24 30 36 42 48 54 60
Mos
INSIGHT START Group. N Engl J Med. 2015;373:795-807.
2.5
5.3
Immediate ART
Deferred ART

START: Serious AIDS Events
 72% reduced risk of serious AIDS events with immediate ART
Serious AIDS Events Immediate ART Deferred ART
No. with event (%) 14 50
Rate/100 PY 0.20 0.72
HR (immediate/deferred) 0.28 (95% CI: 0.15-0.50; P < .001)
0 6 12 18 24 30 36 42 48 54 60
Mos
10
8
6
4
2
0
CumulativePercent
WithanEvent
Immediate ART
Deferred ART

START: Serious Non-AIDS Events
 39% reduced risk of serious non-AIDS events with immediate ART
0 6 12 18 24 30 36 42 48 54 60
Mos
10
8
6
4
2
0
CumulativePercent
WithanEvent
Serious Non-AIDS Events Immediate ART Deferred ART
No. with event (%) 29 47
Rate/100 PY 0.42 0.67
HR (immediate/deferred) 0.61 (95% CI: 0.38-0.97; P = .04)
Immediate ART
Deferred ART

START: Reduced Risk of Cancers With
Immediate ART
*Immediate ART: squamous cell carcinoma, plasma cell myeloma, bladder cancer, fibrosarcoma.
Deferred ART: gastric adenocarcinoma, breast cancer, ureteric cancer, malignant melanoma, myeloid
leukemia, thyroid cancer, leiomyosarcoma, liver cancer, squamous cell carcinoma of head and neck.
Cancer Event Immediate ART Deferred ART
Kaposi’s sarcoma 1 11
Lymphoma, NHL + HL 3 10
Prostate cancer 2 3
Lung cancer 2 2
Anal cancer 1 2
Cervical or testis cancer 1 2
Other types* 4 9
Total 14 39
Lundgren J, et al. IAS 2015. Abstract MOSY0302. Slide credit: clinicaloptions.com

START: Adverse Events
 START: No difference in risk of selected adverse events[1,2]
1. INSIGHT START Group. N Engl J Med. 2015;373:795-807.
2. Lundgren J, et al. IAS 2015. Abstract MOSY0302..
Other Secondary
Endpoints[1,2]
Immediate ART
(n = 2326)
Deferred ART
(n = 2359) HR
(95% CI)
P Value
n n/100 PY n n/100 PY
Grade 4 event 73 1.06 73 1.05
1.01
(0.73-1.39)
.97
Unscheduled hospitalization 262 4.02 287 4.40
0.91
(0.77-1.08)
.28
Grade 4 event, unscheduled
hospitalization, or death
from any cause
283 4.36 311 4.78
0.91
(0.77-1.07)
.25

TEMPRANO: Immediate vs Deferred ART
Initiation and IPT Delivery for African Pts
TEMPRANO ANRS 12136 Study Group. N Engl J Med.
2015;373:808-822.
Mos From Randomization
CumulativeProbability
ofDeathorSevere
HIV-RelatedIllness(%)
25
20
15
10
5
0
0 6 12 18 24 30
Deferred ART
Deferred ART + IPT
Immediate ART
Immediate ART + IPT
30-Mo Probability, %
14.1
8.8
7.4
5.7

DHHS Recommendations for Early HIV
Infection
 ART recommended for early HIV infection
– Although no definitive data confirming whether this
approach has long-term virologic, immunologic, or
clinical benefits
 ART recommended for pregnant women with early
HIV infection
– To prevent perinatal transmission
 ART can start before drug resistance test results are
available
– Boosted PIs + 2 NRTIs recommended to prevent
resistance in this setting
DHHS Guidelines. November 2015 Slide credit: clinicaloptions.com

HPTN 052: ART for Prevention of HIV
Transmission in Serodiscordant Couples
 International, randomized, controlled trial
Stable, healthy, sexually
active, HIV-discordant
couples with CD4+ cell
count 350-550 cells/mm3
(N = 1763 couples)
Early ART Arm
Initiate ART immediately
(n = 886 couples)
Delayed ART Arm
Initiate ART at CD4+ cell count
≤ 250 cells/mm3
or at development of
AIDS-defining illness
(n = 877 couples)
Cohen MS, et al. IAS 2015. Abstract MOAC0101LB. Slide credit: clinicaloptions.com

HPTN 052: Reduced Risk of Partner
Infection
 ART offered to all index pts
in delayed ART arm from
May 2011 after interim
results
– 84% of pts in delayed ART
arm had initiated ART at
Yr 1 and 98% prior to study
closure
 No linked HIV transmissions
observed when index
participant stably suppressed
on ART
Partner
Infections, n
(rate/100 PY)
Overall
(April 2005 - May 2015)
Early
(4314 PY F/U)
Delayed
(4180 PY F/U)
All 19 (0.44) 59 (1.41)
Linked 3 (0.07) 43 (1.03)
Risk Reduction
With Early ART,
%
All infections 69 --
Linked infections 93 --
Cohen MS, et al. IAS 2015. Abstract MOAC0101LB. Slide credit: clinicaloptions.com

Which regimen would you recommend?
A. Dolutegravir/abacavir/
lamivudine
B. Elvitegravir/cobicistat/
tenofovir DF/emtricitabine
C. Elvitegravir/cobicistat/
tenofovir
alafenamide/emtricitabine
D. Efavirenz/
E. Rilpivirine/
F. Dolutegravir +
G. Raltegravir +
H. Darunavir + ritonavir +
I. I would recommend a
different regimen
 22-yr-old black man with recent HIV seroconversion, multiple sex partners
, no medical problems

Discussion Question: Would your choice
change if the pt . . .
 Was HLA-B*5701 positive?
 Was HBsAg positive?
 Had high viral load?
 Was a woman?
 22-yr-old black man with recent HIV seroconversion
 No medical problems
 Multiple sex partners

DHHS, IAS-USA, EACS Guidelines:
Recommended Regimens for First-line ART
 Recommendations may differ based on baseline viral load, CD4+ count, CrCl,
eGFR, HLA-B*5701 status, HBsAg status, and osteoporosis status
 Publication of these guidelines preceded the availability of DTG/ABC/3TC as a
single-tablet regimen
1. DHHS Guidelines. November 2015. 2. Günthard HF, et al. JAMA.
2014;312:410-425. 3. EACS Guidelines. October 2015.
Class DHHS[1]
IAS-USA[2]
EACS[3]
INSTI  DTG/ABC/3TC
 DTG + TDF/FTC
 EVG/COBI/TDF/FTC
 EVG/COBI/TAF/FTC
 RAL + TDF/FTC
 DTG + ABC/3TC
 DTG + TDF/FTC
 RAL + TDF/FTC
 DTG/ABC/3TC
 DTG + TDF/FTC
 RAL + TDF/FTC
Boosted
PI
 DRV + RTV +
TDF/FTC
 DRV + RTV + TDF/FTC
 ATV + RTV + TDF/FTC
 ATV + RTV + ABC/3TC
 DRV + RTV + TDF/FTC
NNRTI  EFV/TDF/FTC
 EFV + ABC/3TC
 RPV/TDF/FTC
 RPV/TDF/FTC

ACTG 5257: Open-Label ATV + RTV vs
RAL vs DRV + RTV in First-line ART
 Primary endpoints
– Virologic failure: time to HIV-1 RNA > 1000 copies/mL (at Wk 16 or before Wk 24) or
> 200 copies/mL (at or after Wk 24)
– Tolerability failure: time to discontinuation of randomized component for toxicity
 Composite endpoint: the earlier occurrence of either VF or TF in a given participant
 Switch of regimens allowed for tolerability
Lennox JL, et al. Ann Intern Med. 2014;161:461-471.
ART-naive pts with
HIV-1 RNA ≥ 1000
copies/mL
(N = 1809)
ATV + RTV 300 + 100 mg QD +
TDF/FTC
(n = 605)
RAL 400 mg BID +
TDF/FTC
(n = 603)
Stratified by HIV-1 RNA
< or ≥ 100,000 copies/mL, participation in
metabolic substudy, CV risk
DRV + RTV 800/100 mg QD +
TDF/FTC
(n = 601)
Wk 96 after last
pt enrolled

ACTG 5257: Primary Endpoint Analyses at
Wk 96
 Regimens equivalent
in time to VF
Lennox JL, et al. Ann Intern Med. 2014;161:461-471.
 Significantly greater
incidence of treatment
failure with ATV + RTV
vs RAL or DRV + RTV
– In part due to high
frequency of
hyperbilirubinemia*
 Considering both
efficacy and tolerability,
RAL superior to either
boosted PI
 DRV + RTV superior to
ATV + RTV
Virologic Failure Tolerability Failure Composite Endpoint
Difference in 96-Wk Cumulative Incidence (97.5% CI)
0-10 10 20
ATV + RTV vs RAL
3.4% (-0.7 to 7.4)
DRV + RTV vs RAL
5.6% (1.3-9.9)
ATV + RTV vs DRV + RTV
-2.2% (-6.7 to 2.3)
ATV + RTV vs DRV + RTV
9.2% (5.5-12.9)
0-10 10 20
ATV + RTV vs RAL
12.7% (9.4-16.1)
DRV + RTV vs RAL
3.6% (1.4-5.8)
Favors RAL
Favors DRV + RTV
0-10 10 20
ATV + RTV vs RAL
14.9% (10.2-19.6)
DRV + RTV vs RAL
7.5% (3.2-11.8)
ATV + RTV vs
DRV + RTV
7.5% (2.3-12.7)
Favors RAL
Favors DRV + RTV
Favors RAL
*Pts were allowed to switch regimens and remain on study.

Study 103: EVG/COBI/TDF/FTC
Noninferior to ATV + RTV + TDF/FTC
Through Wk 144
Outcomes at
Wk 144[3]
EVG/COBI/
TDF/FTC
ATV + RTV +
TDF/FTC
Treatment-
related d/c, %
6 9
Virologic
failure, %
8 7
Mean CD4+
cell count
increase,
cells/mm3
280 293
Clumeck N, et al. J Acquir Immune Defic Syndr. 2014;65:e121-124.
EVG/COBI/TDF/FTC
(n = 353)
ATV + RTV + TDF/FTC
(n = 355)
Δ: 2.7%
(-2.1 to 7.5)
Δ: 1.1%
(-4.5 to 6.7)
Wk 48 Wk 144
78
75
0
20
40
60
80
100
90 87
Δ: 3.1%
(-3.2 to 9.4)
83
82
Wk 96

WAVES: EVG/COBI/TDF/FTC vs ATV +
RTV + TDF/FTC in Tx-Naive Women
 International, randomized, double-blind phase III trial
 Pts generally well matched at baseline
– Pts with HIV-1 RNA > 100,000 copies/mL: EVG/COBI/TDF/FTC arm 24%;
ATV + RTV + TDF/FTC arm 25%
Squires K, et al. IAS 2015. Abstract MOLBPE08.
EVG/COBI/TDF/FTC QD +
Placebos for ATV, RTV, and TDF/FTC QD
(n = 289)
ATV + RTV + TDF/FTC QD +
Placebo for EVG/COBI/TDF/FTC QD
(n = 286)
HIV-infected women
with HIV-1 RNA
≥ 500 copies/mL;
no previous ART;
and eGFR ≥ 70 mL/min
(N = 575)
Wk 48
Open-label
extension
ATV 300 mg; RTV 100 mg; TDF/FTC 300/200 mg; EVG/COBI/TDF/FTC 150/150/300/200 mg

WAVES: EVG/COBI/TDF/FTC Superior to
ATV + RTV + TDF/FTC At Wk 48
 No significant differences
between arms in change
from BL for eGFR, spine
or hip BMD, LDL or HDL
cholesterol, total
cholesterol to HDL ratio,
or triglycerides
 Significantly greater
increase in total
cholesterol with
EVG/COBI/ TDF/FTC
 Lower rate of
discontinuations due to
AEs with EVG/COBI/
TDF/FTC vs ATV + RTV
+ TDF/FTC (2.4% vs
7.0%)
Squires K, et al. IAS 2015. Abstract MOLBPE08.
Wk48HIV-1RNA<50c/mL(%)
100
80
60
40
20
0
Overall ≤ 100,000 > 100,000
HIV-1 RNA (copies/mL)
EVG/COBI/TDF/FTC ATV + RTV + TDF/FTC
87
81
86
82
90
78
n = 289 286 220 214 69 72
Emergent Resistance
EVG/COBI/FTC/TDF
(n = 289)
ATV+RTV + TDF/FTC
(n = 286)
Resistance analysis
population 19 21
Developed resistance
mutations to study drugs 0 3

SINGLE: DTG + ABC/3TC Superior to
EFV/TDF/FTC in Tx-Naive Pts Through Wk 144
 Emergent resistance in those with VF: 0/39 (DTG) vs 7/33 (EFV)
Virologic
Success*[1]
Virologic
Nonresponse[2]
No Virologic
Data[2]
Pts(%)
Favors
EFV/TDF/FTC
95% CI for Difference†
0%
Wk 48
Wk 96
Wk 144
7.4%
8.0%
8.3%
2.5%
2.3
%
2% 14.6%
13.8%
12.3%
Favors
DTG+ABC/3TC
15%
1. Walmsley S, et al. J Acquir Immune Defic Syndr. 2015;70:515-519.
2. Pappa K, et al. ICAAC 2014. Abstract H-647a.
88
81 80
72 71
63
5 6 7 8 10
7 7
13 12
20
30
18
100
80
60
40
20
0
DTG + ABC/3TC QD (n = 414)
EFV/TDF/FTC QD (n = 419)
Wk 48 96 144 Wk 48 96 144 Wk 48 96 144
*HIV-1 RNA < 50 copies/mL as defined by FDA Snapshot algorithm.
†
-10% noninferiority margin.
-5%

SPRING-2: DTG + 2 NRTIs Noninferior to
RAL + 2 NRTIs Through Wk 96
Outcomes at
Wk 96[2] DTG + NRTIs RAL + NRTIs
D/c for AEs or
death, %
2 2
Virologic
nonresponse, %
5 10
Mean CD4+ cell
count increase,
cells/mm3
276 264
HIV-1RNA<50copies/mL(%)
88 85
DTG 50 mg QD
(n = 411)
RAL 400 mg BID
(n = 411)
0
20
40
60
80
100
81
76
Wk 48[1]
Wk 96[2]
1. Raffi F, et al. Lancet. 2013;381:735-743.
2. Raffi F, et al. Lancet Infect Dis. 2013;13:927-935.
361/
411
351/
411
332/
411
314/
411
Δ 4.5%
(-1.1% to 10.0%)
Δ 2.5%
(-2.2% to 7.1%)
n/N =

40
FLAMINGO: DTG Superior to DRV + RTV
in ART-Naive Pts Through Wk 96
Virologic Success Virologic Nonresponse No Virologic Data
Favors
DRV + RTV
95% CI for Difference
0%-12%
Wk 48
Wk 96
Subjects(%)
Favors
DTG
25%
DTG + 2 NRTIs (n = 242)
DRV + RTV + 2 NRTIs (n =
242)
Molina J-M, et al. Lancet HIV 2015;2:e127–36.
7.1%
12.4%
0.9%
4.7% 20.2%
13.2%
Wk 48 Wk 96 Wk 48 Wk 96 Wk 48 Wk 96
100
80
60
20
0
83
90
80
68
6 7 8
12
4
10 12
21
15 18 19 28 10 24 29 50217 200 194 164n =

Studies 104/111: Tenofovir Alafenamide
Fumarate vs TDF in Treatment-Naive Pts
 Parallel, randomized, double-blind, active-controlled phase III studies
 Primary endpoint: HIV-1 RNA < 50 c/mL at Wk 48, as defined by FDA
Snapshot algorithm
EVG/COBI/FTC/TAF*
(n = 866)
EVG/COBI/FTC/TDF†
(n = 867)
Treatment-naive
HIV-infected pts with
HIV-1 RNA ≥ 1000 copies/mL,
eGFR ≥ 50 mL/min
(N = 1733)
Stratified by HIV-1 RNA,
CD4+ cell count, geographic region
Wk 48
Primary endpoint Wk 144
*150/150/200/10 mg once daily.
†
150/150/200/300 mg once daily.
Sax PE, et al. Lancet. 2015;385:2606-2615. Slide credit: clinicaloptions.com

Studies 104/111: TAF Noninferior to TDF
at Wk 48
 EVG/COBI/FTC/TAF was noninferior to EVG/COBI/FTC/TDF at Wk 48 in each study:
93% vs 92% (Study 104); 92% vs 89% (Study 111)
– Race not significant predictor of virologic efficacy in multivariate analysis
 Declines in eGFR and in hip and spine BMD significantly less in TAF arm

Discontinued for AE, death, or missing data.
1. Sax PE, et al. Lancet. 2015;385:2606-2615.
2. Wohl D, et al. ID Week 2015. Abstract 1073.
No Data
Virologic
Success
Virologic
Failure
Pts(%)
92
90
EVG/COBI/FTC/TAF
(n = 866)
EVG/COBI/FTC/TDF
(n = 867)
0
20
40
60
80
100
4 4 4 6
n = 800 784
Favors TAF
0
4.7%-0.7%
2.0%
Treatment Difference (95% CI)
-12% +12%
Favors TDF
Virologic Outcome

Studies 104/111: Renal Outcomes With
TAF vs TDF in Black vs Nonblack Pts
 In black pts, decrease in median eGFR significantly smaller with
TAF vs TDF
 Less spine and hip BMD loss with TAF vs TDF both in black
and nonblack pts
Wohl D, et al. ID Week 2015. Abstract 1073.
Black Pts
EVG/COBI/FTC/TAF
Nonblack Pts
EVG/COBI/FTC/TDF
15
10
5
0
-5
-10
MeaneGFRChange(mL/min)
-15
-20
-25
-30
15
10
5
0
-5
-10
-15
-20
-25
-30
0 2 4 8 12 16 24 36 48
Wk
0 2 4 8 12 16 24 36 48
Wk

Potential Advantages and Disadvantages
of Single-Tablet Regimens
Advantages Disadvantages
 Simplicity
 Convenience
 Fewer copays
 Reduces selective nonadherence to
components of regimen
 Inability to adjust dosages of
components if needed due to drug–
drug interactions or tolerability
issues, eg, renal insufficiency
 Not available for all ART regimens
 Not available for all NRTI pairings

Available Single-Tablet Regimens
Agent Type Year of FDA
Approval
Efavirenz/tenofovir DF/
emtricitabine (EFV/TDF/FTC)
NNRTI + dual NRTI 2006
Rilpivirine/tenofovir DF/
emtricitabine (RPV/TDF/FTC)
NNRTI + dual NRTI 2011
Elvitegravir/cobicistat/
(EVG/COBI/TDF/FTC)*
INSTI + booster + dual NRTI 2012
Dolutegravir/abacavir/lamivudine
(DTG/ABC/3TC)*
INSTI + dual NRTI 2014
Elvitegravir/cobicistat/
tenofovir alafenamide/emtricitabine
(EVG/COBI/TAF/FTC)*
INSTI + booster + dual NRTI 2015
*DHHS recommended regimen for initial ART.

Take-Home Points
 Randomized trial data support ART initiation in pts
with CD4+ cell count > 500 cells/mm3
 ART guidelines recommend ART for all pts regardless
of CD4+ cell count
 Recommended regimens for ART initiation have been
revised
– NNRTIs removed from DHHS first-line options
– EVG/COBI/TAF/FTC added to DHHS first-line options,
safe in pts with CrCl ≥ 30 mL/min

Case 2:
HIV-Infected Patient
With Common Comorbidities

Case 2: 53-Yr-Old Man With HIV Infection
and Multiple Medical Problems
 53-yr-old man presents with newly diagnosed HIV
infection
 Tested for HIV infection by his PCP, who has been
treating him for hyperlipidemia and DM for 12 yrs
 Hospitalized 2 yrs earlier for chest pain and
diagnosed with NSTEMI
 Reports he has been better in the last yr at sticking to
his medical regimen and now rarely misses a dose of
his prescribed medications (metformin, glipizide,
aspirin, metoprolol, and atorvastatin)
 He is an exsmoker and denies use of illicit drugs

Case 2: Laboratory Analysis
 CD4+ count 423 cells/mm3
(27%), HIV-1 RNA 69,554
copies/mL
 HIV genotype K103N (resistant to EFV, NVP, DLV)
 HLA-B*5701 negative
 Cr/BUN 1.6/20, eGFRCG 53 mL/min
 ALT/AST normal, HBV immune, HCV negative
 Last recorded A1c 6.5; last LDL 105 mg/dL
 His hyperlipidemia and DM are relatively well
controlled
 He is interested in starting ART Slide credit: clinicaloptions.com

Which NRTI combination would you
recommend?
A. Abacavir/lamivudine
B. Tenofovir DF/emtricitabine
C. Tenofovir alafenamide/emtricitabine (as E/C/F/TAF)
D. I would use a different NRTI combination
E. I would use lamivudine or emtricitabine without other NRTIs
F. I would not use NRTIs in this pt
G. Unsure
 53-yr-old man recently diagnosed with HIV infection
 HIV-1 RNA 69,554 copies/mL, CD4+ count 423 cells/mm3
 Hyperlipidemia and DM controlled on medication, history of NSTEMI
 Cr/BUN 1.6/20, eGFR 53 mL/min, A1c 6.5, LDL 105 mg/dL
 HIV GT: K103N, HBV immune, HCV negative, HLA-B*5701 negative

Which other agents would you use in the
regimen?
A. Boosted PI
B. INSTI
C. Boosted PI + INSTI
D. Other
E. Unsure

Rising Rates of Comorbidities at HIV
Diagnosis in USA
Pts(%)
Meyer N, et al. IAS 2015. Abstract MOPEB157.
Medicare (> 65 Yrs)
100
80
60
40
20
0
All CV HTN DM Renal
2003 (n = 177; mean age: 72.2 yrs)
2013 (n = 436; mean age: 72.9 yrs)
Pts(%)
Medicaid
100
80
60
40
20
0
All CV HTN DM Renal
2003 (n = 3008; mean age: 34.7 yrs)
2013 (n = 1632; mean age: 39.2 yrs)

IAS-USA: Recommendations for Initial
ART in the Settings of Specific Conditions
 In pts with or at high risk of CVD, consider avoiding
ABC, LPV/RTV, or FPV + RTV
 In pts with reduced renal function, TDF should
generally be avoided, especially with a boosted PI
 In pts at elevated fracture risk (eg, HCV coinfection,
postmenopausal women, osteoporosis), it may be
prudent to avoid TDF, especially with a boosted PI
Günthard HF, et al. JAMA. 2014;312:410-425. Slide credit: clinicaloptions.com

1.80
1.60
1.40
1.20
1.00
0.00
D:A:D: Cumulative Exposure to ARVs
Associated With Increased CKD Risk
CKD Risk by Yrs of ARV Exposure, IRR
(95% CI)
Drug 1 Yr 2 Yrs 5 Yrs
TDF
1.12
(1.06-1.18)
1.25
(1.12-1.39)
1.74
(1.33-2.27)
ATV+
RTV
1.27
(1.18-1.36)
1.61
(1.40-1.84)
3.27
(2.32-4.61)
LPV/
RTV
1.16
(1.10-1.22)
1.35
(1.21-1.50)
2.11
(1.62-2.75)
Mocroft A, et al. CROI 2015. Abstract 142.
Relationship Between Increasing
Exposure to ARVs and CKD
ATV + RTV LPV/RTVTDF
Multivariate (on treatment)
Multivariate (TDF censored)
Univariate
Multivariate

Summary of Key Analyses Showing ABC
Associated With Risk of MI
Study
Study
Design
Age, Yrs
(Range)
Event
(n)
Pts,
N
TDF
CV
Effect
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 No 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 No Yes Current
4.3
(1.4-13.0)
STEAL[4]
RCT
45.7
±8.8
MI
(4)
357 No Yes 96
2.79*
(1.76-4.43)
QPHID[5]
CC
47
(22-67)
MI
(125)
7053 No Yes Any
1.79
(1.16-2.76)
Danish[6]
Cohort
39
(33-47)
MI
(67)
2952
No Yes > 6
2.00
(1.07-3.76)
VA (Choi)[7]
Cohort 46
CVD event
(501)
10,931 No Yes Recent
1.64
(0.88-3.08)
Swiss[8]
Cohort
Not
given
CVD event
(365)
11,856 No Yes Recent
4.06†
(2.24-7.34)
MAGNIFICENT[9]
CC
50
(22-85.5)
CVD event
(571)
1875 No Yes Current
1.56
(1.17-2.07)
NA-ACCORD[10]
Cohort
MI, validated
(301)
16,733 Yes ≤ 6 1.33
References in slidenotes Slide credit: clinicaloptions.com
*Risk for serious non-AIDS events (most common was CVD, 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.

Summary of Key Analyses Showing ABC
NOT Associated With Risk of MI
References in slidenotes
Study Study
Design
Age, Yrs
(Range)
Event
(n)
Pts,
N
TDF
CV
Effect
ABC
CV
Effect
Time
on ABC,
Mos
Adj Risk of
MI
(95% CI)
FHDH[1]
CC
47
(41-54)
MI
(289)
74,958 No No
< 12/
recent
1.27*
(0.64-2.49)
ALLRT/
ACTG[2] Cohort
37
(26-51)
MI
(36)
5056 No No 72
0.6
(0.3 -1.4)
VA[3]
Cohort 46
MI
(278) 19,424
No No Per 12
1.18
(0.92-1.50)
FDA[4]
Meta-
analysis
of RCTs
36-42
MI
(46)
9868 No No 19
1.02
(0.56-1.84)
NA-ACCORD[5]
Cohort
MI,
validated
(301)
16,733 No ≤ 6 1.33
*Without adjustment for cocaine use OR: 2.01 (1.11-3.64).

Subanalysis of 104/111: TAF Noninferior to
TDF at Wk 48 in Pts Aged 50 Yrs or Older
 Mean eGFR decline and mean % BMD decrease from baseline to Wk 48 significantly
lower with TAF vs TDF (eGFR: P = .01; spine: P = .01; hip: P < .001)
Daar ES, et al. ID Week 2015. Abstract 1074.
100
80
60
40
20
0
Virologic
Success
Virologic
Failure
No Data
EVG/COBI/FTC/TAF
(n = 89)
EVG/COBI/FTC/TDF
(n = 114)
94 91
3 4 2 4
-14 -10 -6 -2 2 6 10 14
-5.2
3.5
12.2
Favors TAFFavors TDF
Treatment Difference (95% CI)Virologic Outcome
Pts(%)

Phase III Trial of Stable Switch to
EVG/COBI/TAF/FTC in Pts With CKD
 Multicenter, single-arm, phase III switch study
 Primary safety endpoint: eGFR at Wk 24
 Baseline characteristics
– Median age 58 yrs, median eGFR 56 mL/min, clinically significant
albuminuria 49%, median CD4+ count 632 cells/mm3
, pre-switch TDF
65%, HTN 40%, DM 14%
EVG/COBI/TAF/FTC (150/150/10/200 mg QD)
HIV-infected pts with
HIV-1 RNA < 50 copies/mL
for ≥ 6 mos, CD4+ cell count
≥ 50 cells/mm3
, and
eGFR 30-69 mL/min
(N = 242)
Wk 24
Primary endpoint Wk 96
Gupta S, et al. IAS 2015. Abstract TUAB0103. Slide credit: clinicaloptions.com

Change in Renal Function Following
Switch to EVG/COBI/TAF/FTC
 No change in actual GFR at Wk 24
 In pts on TDF, tubular proteinuria improved after switch
MedianChangeFrom
Baseline
eGFRCG
mL/min
eGFRCKD-EPI Cr
mL/min/1.73m2
eGFRCKD-EPI cys C
mL/min/1.73m2
TDF at BL Non-TDF at BLAll pts
-0.6
+0.2
-1.8 -1.8* -1.5
-2.7*
+1.6*
-1.4
+2.7**P < .05
Gupta S, et al. IAS 2015. Abstract TUAB0103.
Change in eGFR From Baseline to Wk 48
10
0
-10

Considerations for Pts With Renal
Impairment
CrCl (mL/min) EVG/COBI/FTC/TAF[1]
EVG/COBI/FTC/TDF[2]
≥ 70 No adjustment needed No adjustment needed
50-70 No adjustment needed Initiation not recommended
30-49 No adjustment needed Initiation not recommended;
Discontinue if CrCl declines to this
level during treatment
< 30 Initiation not recommended Initiation not recommended
Discontinue if CrCl declines to this
level during treatment
1. EVG/COBI/FTC/TAF [package insert].
2. EVG/COBI/FTC/TDF [package insert]. Slide credit: clinicaloptions.com

If you were considering an ABC, TDF, and TAF–
sparing regimen, which would you most
strongly consider?
A. Boosted PI monotherapy
B. Boosted PI + INSTI ± 3TC (or FTC)
C. Boosted PI + 3TC (or FTC)
D. DTG + 3TC
E. I would not consider an ABC-, TDF-, and TAF-sparing regimen
in this type of pt
F. Other

< 100,000 c/mL
≥ 100,000 c/mL
n = 530
n = 275
BL HIV-1 RNA
NEAT: RAL + DRV/RTV Noninferior to
TDF/FTC + DRV/RTV in Naive Pts at 96 Wks
 Randomized, open-label phase III study of DRV/RTV + RAL vs
DRV/RTV + TDF/FTC in ART-naive pts
Raffi F, et al. Lancet. 2014;384:1942-1951.
Overall N = 805
Primary Endpoint at Wk 96: Adjusted Difference in Proportion
of Pts With Failure (RAL - TDF/FTC [95% CI])
-10 0 10 20 30
RAL TDF/FTC Adjusted Difference
Estimate (95% CI)
17.8 13.8 4.0 (-0.8 to 8.8)
7.4
36.8
7.3
27.3
0.1 (-3.8 to 4.0)
9.6 (-0.1 to 20.1)
43.2
13.7
20.9
12.3
22.3 (7.4 to 37.1)
1.4 (-3.5 to 6.3)
< 200/mm3
≥ 200/mm3
n = 123
n = 682
BL CD4+ cell count

GARDEL: Dual ART Noninferior to Triple
ART in Tx-Naive Pts at Wks 48 and 96
 Phase III, international, open-label, randomized study
 Safety and tolerability also similar between treatment arms
Virologic
Success
Virologic
Nonresponse
D/C due to AE
or Death
D/C for Other
Reasons
1. Cahn P, et al. EACS 2015. Abstract 961.
2. Cahn P, et al. Lancet Infect Dis. 2014;14:572-80.
Wk 48 difference: +4.6%
(95% CI: -2.2 to 11.8; P = .171)
Wk 96 difference: +5.9%
(95% CI: -2.3 to 14.1; P = .165)
100
80
60
40
20
0
Pts(%)
LPV/RTV + 3TC
LPV/RTV + 3TC
or FTC + NRTI
4.7 5.9 3 5 6 82.4 2.1
0.6
2.8 6.6 10.6
88.3
83.7
90.3
84.4
Wk: 96[1]
48[1]
96[1]
48[2]
96[1]
48[2]
96[1]
48[2]

PADDLE: Dolutegravir + Lamivudine in
Treatment-Naive Pts
 Open-label, single-arm phase IV exploratory trial
 BL RNA: median 24,128 copies/mL; IQR 11,686-36,794
copies/mL
 20 of 20 pts met primary endpoint of HIV-1 RNA < 50 copies/mL
at Wk 24 (ITT-e, FDA snapshot analysis)
– Including 4 pts with BL HIV-1 RNA > 100,000 copies/mL
– All pts virologically suppressed by Wk 8
Treatment-naive pts
with HIV-1 RNA
5000-100,000 copies/mL;
CD4+ ≥ 200 cells/mm3
;
HBsAg negative
(N = 20)
DTG 50 mg QD + 3TC 300 mg QD
(N = 20*)
*Pts enrolled in 2 cohorts of 10 pts. Second cohort enrolled following
confirmation of first cohort success at Wk 8.
Figueroa MI, et al. EACS 2015. Abstract 1066. Slide credit: clinicaloptions.com

Recommendations on the Use of NRTI-
Sparing Regimens in First-line ART
 Regimens using < 2 NRTIs should only be used in pts
who cannot take ABC or TDF
 These regimens can be considered when ABC or
TDF cannot be used:
– DRV + RTV + RAL (only for pts with HIV-1 RNA
< 100,000 copies/mL and CD4+ cell count > 200
cells/mm3
)
– LPV/RTV (BID) + 3TC (BID)

Case 3:
Patient With
Advanced HIV Disease

Case 3: 40-Yr-Old Woman With An OI
 A 40-yr-old woman presents to the ED with L arm
weakness, difficulty walking, and dysarthric speech
 Prior history of positive HIV serology, but she is
homeless and has neither entered into care for HIV
nor received ART
 CT scan shows R frontoparietal mass with extensive
edema; no hydrocephalus or midline shift
 Toxoplasma IgG is positive
 Pt is started on sulfadiazine, pyrimethamine and
folinic acid with improvement in her neurological
status

Case 3, Laboratory Analysis
(4%)
 HIV genotype is pending
 Coinfection with HCV (HCV RNA positive) and HBV
(HBsAg positive)
 HLA-B*5701 negative
 No known history of heart disease or renal insufficiency
 History of injection drug use
 She smokes 1 pack/day and uses methamphetamine and
opiates when she can get them

When would you recommend starting
antiretroviral therapy?
A. Start ART within 2-3 weeks
B. Defer ART until the pt completes treatment for
toxoplasmic encephalitis
C. Defer ART until the pt is in a stable living situation
D. Defer ART until the pt starts a drug treatment program
E. Unsure
 40-yr-old woman with untreated HIV infection and new dx of toxoplasmic encephalitis
 HIV-1 RNA 175,000 copies/mL, CD4+ cell count 65 cells/mm3
 HIV GT pending, HBsAg positive, HCV RNA positive, HLA-B*5701 negative
 Homeless

Favors Deferred ART
Zolopa AR, et al. PLoS ONE. 2009;4:e5575.
ACTG 5164: Immediate vs Deferred ART in
Pts With Acute Opportunistic Infections
Risk of AIDS Progression/Death by Entry Diagnoses, Log OR (95% CI)
Total
PCP
Bacterial infection
Other OI*
Fungal
Crypto
Mycobacterial
> 1 OI
CD4+ < 50
CD4+ ≥ 50
Events, n/N
54/282
28/181
11/41
42/194
12/52
8/41
8/18
30/148
39/196
15/86
0 0.25 0.5 1.0 8.0 202.5
Favors Early ART
*Includes 13 pts
with toxoplasmosis

Recommendations for ART in Pts With
Selected Opportunistic Infections
Opportunistic Infection DHHS Recommendation for ART
Pneumocystis pneumonia  Start ART within 2 wks of PCP diagnosis
Toxoplasma gondii encephalitis  Many clinicians start ART within 2-3 wks
 Based on A5164 study, in which the 282 pts
with OIs included 13 pts (5%) with
toxoplasmosis
Mycobacterium tuberculosis  Start ART within 2 wks if CD4+ < 50
cells/mm3
, by 8-12 wks for all others
 Consider DDIs, adherence support
Cryptosporidiosis  Start ART as part of OI management
Cryptococcal meningitis  Consider delaying ART until after
antifungal induction (2 wks) or
induction/consolidation (10 wks)

Which regimen would you recommend if
starting ART prior to discharge?
A. Dolutegravir/abacavir/lamivudine
B. Dolutegravir + tenofovir DF/emtricitabine
C. Elvitegravir/cobicistat/tenofovir DF/emtricitabine
D. Elvitegravir/cobicistat/tenofovir alafenamide/emtricitabine
E. Raltegravir + tenofovir DF/emtricitabine
F. Boosted darunavir + tenofovir DF/emtricitabine
G. NNRTI-based regimen
H. Something else
 40-yr-old woman with untreated HIV infection and new dx of toxoplasmic encephalitis
 HIV-1 RNA 175,000 copies/mL, CD4+ cell count 65 cells/mm3
 HIV GT pending, HBsAg positive, HCV RNA positive, HLA-B*5701 negative
 Homeless

Prevalence of Drug Resistance Mutations
in Treatment-Naive Pts, 2000-2013
 Baseline plasma samples from
4 phase III trials (GS 903, 934,
104, 111; N = 2531)
– 1617 samples analyzed for
integrase mutations
– 2531 analyzed for protease or
RT mutations
 Substantial ↑ in prevalence of
NNRTI resistance, modest ↑ in
PI resistance
 Stable prevalence of NRTI
resistance (mostly TAMs)
– M184V/I ≤ 0.2%; K65R ≤ 0.1%
 Little evidence of transmitted
INSTI resistance over period
– Mostly T97A polymorphism
2000 (GS-903)
2003 (GS-934)
2013 (GS-104/GS-
111)
0
2
NNRTI
10
4
6
8
NRTI PI INSTI
0.5 1.0
0
4.2
8.7
3.2
2.6 2.6
1.2
2.4
2.9
1.4
Margot NA, et al. CROI 2014. Abstract 578. Slide credit: clinicaloptions.com

Summary
 Randomized trial data support ART initiation in pts
with CD4+ cell count > 500 cells/mm3
 ART guidelines recommend ART for all pts regardless
of CD4+ cell count
 Recommended regimens for ART initiation have been
revised
 ART selection should be individualized according to
pt requirements, the evidence base, and practice
guidance

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