Начало АРТ впервые.Наилучшая практика.best practices in...
TRANSCRIPT
Best Practices in Antiretroviral Therapy: Initiating First-line Therapy
This activity is supported by an independent educational grant from ViiV Healthcare
clinicaloptions.com/hivBest Practices in Antiretroviral Therapy: Initiating First-line Therapy
Faculty
Charles B. Hicks, MDProfessor of Clinical Medicine Director, Owen ClinicUniversity of California, San DiegoSan Diego, California
Program Director
Paul E. Sax, MDClinical Director HIV Program and Division of Infectious DiseasesBrigham and Women’s HospitalProfessor of MedicineHarvard Medical SchoolBoston, Massachusetts
clinicaloptions.com/hivBest Practices in Antiretroviral Therapy: Initiating First-line Therapy
Disclosures
Charles B. Hicks, MD, has disclosed that he has received consulting fees from Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck, and ViiV and royalties from UpToDate, Inc.
Paul E. Sax, MD, has disclosed that he has received consulting fees from AbbVie, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline/ViiV, Janssen, and Merck and funds for research support (paid to Brigham and Women’s Hospital) from Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline/ViiV, and Merck.
clinicaloptions.com/hivBest Practices in Antiretroviral Therapy: Initiating First-line Therapy
About These Slides Users are encouraged to use these slides in their own
noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent
These slides may not be published or posted online without permission from Clinical Care Options (email [email protected])
DisclaimerThe materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.
clinicaloptions.com/hivBest Practices in Antiretroviral Therapy: Initiating First-line Therapy
Overview Initiating ART in patients with newly diagnosed HIV
infection
Initiating ART in HIV-infected patients with comorbidities
Initiating ART in patients with advanced HIV infection
Initiating ART in Patients With Advanced HIV Infection
clinicaloptions.com/hivBest Practices in Antiretroviral Therapy: Initiating First-line Therapy
START: Immediate vs Deferred Therapy for Asymptomatic, ART-Naive Pts
Immediate ARTART initiated immediately
following randomization(n = 2326)
INSIGHT START Study Group. N Engl J Med. 2015;[Epub ahead of print]. Lundgren J, et al. IAS 2015. Abstract MOSY0302.
Deferred ARTDeferred 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 DSMBfollowing interim analysis
clinicaloptions.com/hivBest Practices in Antiretroviral Therapy: Initiating First-line Therapy
START: Time on ART and ART Use Follow-up time on ART:
– Immediate 94%
– Deferred 28%
Median time to ART initiation in deferred arm:– 3 yrs (IQR: 1.6-4.8;
projected 4 yrs)
ART use:– TDF: 89% in both arms
– EFV: immediate 73% vs deferred 51%
Immediate ART, % with HIV-1 RNA ≤ 200 c/mL
Deferred ART, % using ART
De ferr ed ART , % with HIV- 1 RNA ≤ 2 00 c/mL
Immediate ART, % using ART
INSIGHT START Study Group. N Engl J Med. 2015;373:195-807. Lundgren J, et al. IAS 2015. Abstract MOSY0302.
Mos
Pts
(%)
100
80
60
40
20
00 12 24 36 48 60
Time on ART
clinicaloptions.com/hivBest Practices in Antiretroviral Therapy: Initiating First-line Therapy
START: Primary Outcome
Primary Endpoint Immediate ART Deferred ARTNo. 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 patients with CD4+ cell counts > 500 cells/mm3
10
8
6
4
2
0
Cum
ulat
ive
Perc
ent
With
Eve
nt
0 6 12 18 24 30 36 42 48 54 60Mos
INSIGHT START Group. N Engl J Med. 2015;373:195-807. Lundgren J, et al. IAS 2015. Abstract MOSY0302.
2.5
5.3
Immediate ARTDeferred ART
clinicaloptions.com/hivBest Practices in Antiretroviral Therapy: Initiating First-line Therapy
START: Serious AIDS Events
72% reduced risk of serious AIDS events with immediate ARTINSIGHT START Study Group. N Engl J Med. 2015;373:195-807. Lundgren J, et al. IAS 2015. Abstract MOSY0302.
Serious AIDS Events Immediate ART Deferred ARTNo. with event (%) 14 50Rate/100 PY 0.20 0.72HR (immediate/deferred) 0.28 (95% CI: 0.15-0.50; P < .001)
0 6 12 18 24 30 36 42 48 54 60Mos
10
8
6
4
2
0
Cum
ulat
ive
Perc
ent
With
an
Even
t
Immediate ARTDeferred ART
clinicaloptions.com/hivBest Practices in Antiretroviral Therapy: Initiating First-line Therapy
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 60Mos
10
8
6
4
2
0
Cum
ulat
ive
Perc
ent
With
an
Even
t
INSIGHT START Study Group. N Engl J Med. 2015;373:195-807. Lundgren J, et al. IAS 2015. Abstract MOSY0302.
Serious Non-AIDS Events Immediate ART Deferred ARTNo. with event (%) 29 47Rate/100 PY 0.42 0.67HR (immediate/deferred) 0.61 (95% CI: 0.38-0.97; P = .04)
Immediate ARTDeferred ART
clinicaloptions.com/hivBest Practices in Antiretroviral Therapy: Initiating First-line Therapy
START: Types of Cancer
*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 ARTKaposi’s sarcoma 1 11Lymphoma, NHL + HL 3 10Prostate cancer 2 3
Lung cancer 2 2Anal cancer 1 2Cervical or testis cancer 1 2Other types* 4 9
Total 14 39
INSIGHT START Study Group. N Engl J Med. 2015;373:195-807. Lundgren J, et al. IAS 2015. Abstract MOSY0302.
clinicaloptions.com/hivBest Practices in Antiretroviral Therapy: Initiating First-line Therapy
START: Adverse Events
No difference in risk of selected adverse events[1]
TEMPRANO: immediate ART + 6 mos IPT reduced risk of severe illness vs deferred ART + no IPT in African pts with CD4+ > 500 cells/mm3[2]
1. INSIGHT START Group. N Engl J Med. 2015;373:195-807. Lundgren J, et al. IAS 2015. Abstract MOSY0302. 2. TEMPRANO ANRS 12136 Study Group. N Engl J Med. 2015;[Epub ahead of print].
Other Secondary Endpoints[1]
Immediate ART (n = 2326)
Deferred ART(n = 2359) HR
(95% CI) P Valuen 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
clinicaloptions.com/hivBest Practices in Antiretroviral Therapy: Initiating First-line Therapy
START Substudy: BMD Changes With Immediate vs Deferred ART Over 3 Yrs Substudy included 192 pts in
immediate ART arm and 204 pts in deferred ART arm
Greater BMD loss in hip and spine with immediate vs deferred ART
– Estimated mean difference for hip: -1.5% (95% CI: -2.3% to -0.8%; P < .001)
– Estimated mean difference for spine: -1.6% (95% CI: -2.2% to -1.0%; P < .001)
Osteoporosis and fracture incidence similar between arms
Hoy JF, et al. EACS 2015. Abstract ADRLH-62.
Cha
nge
From
BL
(%)
Cha
nge
From
BL
(%)
Total Hip BMD0
-1
-2
-3
-4
-50 12 24 36
Immediate ARTDeferred ART
Total Spine BMD0
-1
-2
-3
-4
-50 12 24 36
Mos From Randomization
clinicaloptions.com/hivBest Practices in Antiretroviral Therapy: Initiating First-line Therapy
HPTN 052: ART for Prevention of HIV Transmission in Serodiscordant Couples International, randomized, controlled trial
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
Stable, healthy, sexually active, HIV-discordant couples with CD4+ cell
count 350-550 cells/mm3 (N = 1763 couples)
Early ART ArmInitiate ART immediately
(n = 886 couples)
Delayed ART ArmInitiate ART at CD4+ count ≤ 250 cells/mm3 or at
development of AIDS-defining illness(n = 877 couples)
Cohen MS, et al. IAS 2015. Abstract MOAC0101LB.
clinicaloptions.com/hivBest Practices in Antiretroviral Therapy: Initiating First-line Therapy
HPTN 052: Reduced Risk of Partner Infection 8 linked HIV infections
diagnosed after seropositive patient started ART– All occurred soon after
initiation or after virologic failure
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.
clinicaloptions.com/hivBest Practices in Antiretroviral Therapy: Initiating First-line Therapy
DHHS and IAS-USA Guidelines: Recommended Regimens for First-line ART
1. DHHS Guidelines. April 2015. 2. Günthard HF, et al. JAMA. 2014;312:410-425.
Class DHHS[1] IAS-USA[2]
INSTI DTG/ABC/3TC* DTG + TDF/FTC EVG/COBI/TDF/FTC†
EVG/COBI/TAF/FTC‡
RAL + TDF/FTC
RAL + TDF/FTC EVG/COBI/TDF/FTC†
DTG + ABC/3TC*∫
DTG + TDF/FTC
Boosted PI DRV + RTV + TDF/FTC ATV + RTV + TDF/FTC or ATV + RTV + ABC/3TC*§
DRV + RTV + TDF/FTC
NNRTI EFV/TDF/FTC or EFV + ABC/3TC*§or RPV/TDF/FTC§
*Only for pts who are HLA-B*5701 negative. Only for pts with pre-ART CrCl > 70 mL/min.‡Only for pts with pre-ART CrCl ≥ 30 mL/min.∫Publication of these guidelines preceded the availability of DTG/ABC/3TC as a single-tablet regimen.§Not recommended in pts with baseline HIV-1 RNA > 100,000 copies/mL.Single-tablet regimens are in bold.
clinicaloptions.com/hivBest Practices in Antiretroviral Therapy: Initiating First-line Therapy
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 patient enrolled
clinicaloptions.com/hivBest Practices in Antiretroviral Therapy: Initiating First-line Therapy
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 RAL3.4% (-0.7 to 7.4)
DRV + RTV vs RAL5.6% (1.3-9.9)
ATV + RTV vs DRV + RTV-2.2% (-6.7 to 2.3)
ATV + RTV vs DRV + RTV9.2% (5.5-12.9)
0-10 10 20
ATV + RTV vs RAL12.7% (9.4-16.1)DRV + RTV vs RAL3.6% (1.4-5.8)
Favors RAL
Favors DRV + RTV
0-10 10 20
ATV + RTV vs RAL14.9% (10.2-19.6)
DRV + RTV vs RAL7.5% (3.2-11.8)
ATV + RTV vs DRV + RTV7.5% (2.3-12.7)
Favors RAL
Favors DRV + RTV
Favors RAL
*Pts were allowed to switch regimens and remain on study.
clinicaloptions.com/hivBest Practices in Antiretroviral Therapy: Initiating First-line Therapy
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
1. DeJesus E, et al. Lancet. 2012;379:2429-2438. 2. Rockstroh J, et al. J Acquir Immune Defic Syndr. 2013;62:483-486. 3. 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: 3.0% (-1.9 to 7.8) Δ: 1.1%
(-4.5 to 6.7)
Wk 48[1] Wk 144[3]
78 75
0
20
40
60
80
10090 87
Δ: 3.1% (-3.2 to 9.4)83
82
Wk 96[2]
clinicaloptions.com/hivBest Practices in Antiretroviral Therapy: Initiating First-line Therapy
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%
WAVES: EVG/COBI/TDF/FTC vs ATV + RTV + TDF/FTC in Tx-Naive Women
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
clinicaloptions.com/hivBest Practices in Antiretroviral Therapy: Initiating First-line Therapy
WAVES: EVG/COBI/FTC/TDF Superior to ATV + RTV + TDF/FTC At Wk 48
EVG/COBI/FTC/TDF superior to ATV + RTV + TDF/FTC
– Overall treatment difference 6.5% (95% CI: 0.4%-12.6%)
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.
Wk
48 H
IV-1
RN
A <
50
c/m
L (%
)
100
80
60
40
20
0Overall ≤ 100,000 > 100,000
HIV-1 RNA (copies/mL)
EVG/COBI/TDF/FTC ATV + RTV + TDF/FTC
8781 86 82
9078
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
clinicaloptions.com/hivBest Practices in Antiretroviral Therapy: Initiating First-line Therapy
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*
Virologic Nonresponse
No Virologic Data
Pts
(%)
FavorsEFV/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%
FavorsDTG+ABC/3TC
15%
Pappa K, et al. ICAAC 2014. Abstract H-647a.
8881 80
72 7163
5 6 7 8 10 7 713 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%
clinicaloptions.com/hivBest Practices in Antiretroviral Therapy: Initiating First-line Therapy
SPRING-2: DTG + NRTIs Noninferior to RAL + 2 NRTIs Through Wk 96
Outcomes at Wk 96[2] DTG + NRTIs RAL + NRTIs
Treatment-related d/c, % 2 2
Virologic nonresponse, % 5 10
Mean CD4+ cell count increase, cells/mm3
276 264
HIV
-1 R
NA
< 5
0 co
pies
/mL
(%) 88 85
DTG 50 mg QD (n = 411)
RAL 400 mg BID (n = 411)
0
20
40
60
80
100
8176
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%)
clinicaloptions.com/hivBest Practices in Antiretroviral Therapy: Initiating First-line Therapy
40
FLAMINGO: DTG Superior to DRV + RTV in ART-Naive Pts Through Wk 96
Virologic Success Virologic Nonresponse No Virologic Data
FavorsDRV + RTV
95% CI for Difference
0%-12%
Wk 48
Wk 96
Subj
ects
(%)
FavorsDTG
25%
DTG + 2 NRTIs (n = 242)
DRV + RTV + 2 NRTIs (n = 242)
Molina J-M, et al. HIV Drug Therapy Glasgow 2014. Abstract O153.
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
8390
80
68
6 7 812
410 12
21
clinicaloptions.com/hivBest Practices in Antiretroviral Therapy: Initiating First-line Therapy
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 at Wk 48
TAF/FTC/EVG/COBI*single-tablet regimen
(n = 866)
TDF/FTC/EVG/COBI†
single-tablet regimen(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 48Primary endpoint Wk 144
*10/200/150/150 mg once daily.†300/200/150/150 mg once daily.
Sax PE, et al. Lancet. 2015;385:2606-2615.
clinicaloptions.com/hivBest Practices in Antiretroviral Therapy: Initiating First-line Therapy
Studies 104/111: TAF Noninferior to TDF at Week 48
TAF/FTC/EVG/COBI was noninferior to TDF/FTC/EVG/COBI at Wk 48 in each study: 93% vs 92% (Study 104); 92% vs 89% (Study 111)
Declines in eGFR and in hip and spine BMD significantly less in TAF arm*HIV-1 RNA < 50 c/mL as defined by FDA Snapshot algorithmDiscontinued for AE, death, or missing data.
Sax PE, et al. Lancet. 2015;385:2606-2615.
No DataVirologic Success*
Virologic Failure
Pts
(%)
92 90TAF/FTC/EVG/COBI (n = 866)TDF/FTC/EVG/COBI (n = 867)
0
20
40
60
80
100
4 4 4 6n = 800 784
Favors TAF
0
4.7%-0.7%2.0%
Treatment Difference (95% CI)
-12% +12%
Favors TDF
Virologic Outcome
clinicaloptions.com/hivBest Practices in Antiretroviral Therapy: Initiating First-line Therapy
Potential Advantages and Disadvantages of Single-Tablet RegimensAdvantages 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
clinicaloptions.com/hivBest Practices in Antiretroviral Therapy: Initiating First-line Therapy
Available Single-Tablet Regimens
Agent Type Yr 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/tenofovir DF/emtricitabine (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.
A 48-Year-Old Man With HIV Infection and
Multiple Medical Problems
clinicaloptions.com/hivBest Practices in Antiretroviral Therapy: Initiating First-line Therapy
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
0All CV HTN DM Renal
2003 (n = 177; mean age 72.2 yrs)2013 (n = 436; mean age 72.9 yrs)
Pts
(%)
Medicaid100
80
60
40
20
0All CV HTN DM Renal
2003 (n = 3008; mean age 34.7 yrs)2013 (n = 1632; mean age 39.2 yrs)
clinicaloptions.com/hivBest Practices in Antiretroviral Therapy: Initiating First-line Therapy
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.
clinicaloptions.com/hivBest Practices in Antiretroviral Therapy: Initiating First-line Therapy
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/RTV TDF
On treatmentTDF censored
UnivariateMultivariate
clinicaloptions.com/hivBest Practices in Antiretroviral Therapy: Initiating First-line Therapy
NA-ACCORD: Recent ABC Use and Risk of MI
Several studies have reported an association between ABC use and MI risk; others found no association[2,3,4]
1. Palella F, et al. CROI 2015. Abstract 749LB. 2. Lundgren J, et al. CROI 2009. Abstract 44LB. 3. D:A:D Study Group. Lancet. 2008;371:1417-1426. 4. Bedimo RJ, et al. Clin Infect Dis. 2011;53:84-91.
0 2.001.00 4.003.00
Full Study
Restricted Study
D:A:DReplication
1.95
1.33
Adjusted HRs for MI in Pts With Recent ABC Use[1]
7 clinical cohorts from NA-ACCORD (~ 20%)
All ART users except pts on ABC at study entry
ART-naive pts who initiated ART in the cohort
clinicaloptions.com/hivBest Practices in Antiretroviral Therapy: Initiating First-line Therapy
Swiss HIV Cohort Study: Cumulative ABC Use and Risk of MI
Continued exposure to ABC during past 4 yrs increased risk of a CVD event (HR: 2.06; 95% CI: 1.43 to 2.98)
Young J, et al. J Acquir Immune Defic Syndr. 2015;69:413-421.
Effect of Exposure to Abacavir On the Risk of CVD Events0.04
0.03
0.02
0.01
0.00
-0.01
-0.02
Wei
ght
0
Marginal structural CoxConventional Cox
20 30 40 50 60Time Elapsed Since Exposure
to ABC (mos)
10
3.0
2.5
2.0
1.5
1.0
0.5
0.0H
R o
f Cum
ulat
ive
Expo
sure
to A
BC
0
Marginal structural CoxConventional Cox
20 30 40 50 60Length of Continuous Exposure
to ABC (mos)
10
clinicaloptions.com/hivBest Practices in Antiretroviral Therapy: Initiating First-line Therapy
Phase III Trial of EVG/COBI/TAF/FTC in Patients 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%
TAF/FTC/EVG/COBI (10/200/150/150 mg QD)single-tablet regimen
HIV-infected pts withHIV-1 RNA < 50 copies/mL
for ≥ 6 mos on ART, CD4+ cell count ≥ 50 cells/mm3, and
eGFR 30-69 mL/min(N = 242)
Wk 24Primary endpoint Wk 96
Gupta S, et al. IAS 2015. Abstract TUAB0103.
clinicaloptions.com/hivBest Practices in Antiretroviral Therapy: Initiating First-line Therapy
Change in Renal Function Following Switch to EVG/COBI/TAF/FTC
No change in actual GFR at Wk 48 In pts on TDF, tubular proteinuria improved after switch
Med
ian
Cha
nge
From
Bas
elin
e
eGFRCG
mL/mineGFRCKD-EPI Cr
mL/min/1.73m2
eGFRCKD-EPI cys C
mL/min/1.73m2
TDF at BL Non-TDF at BLAll pts
Baseline, n: 56 58 53 54 56 50 70 75 60
-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
clinicaloptions.com/hivBest Practices in Antiretroviral Therapy: Initiating First-line Therapy
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
BL HIV-1 RNA
< 100,000 c/mL
≥ 100,000 c/mL
n = 530
n = 275
BL CD4+ cell count
< 200/mm3
≥ 200/mm3
n = 123
n = 682
Primary Endpoint at Wk 96: Adjusted Difference in Proportion of Patients 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)
clinicaloptions.com/hivBest Practices in Antiretroviral Therapy: Initiating First-line Therapy
GARDEL: Dual Therapy Noninferior to Triple Therapy in Treatment-Naive Pts
Pts
(%)
Treatment difference: +4.6% (95% CI: -2.2% to 11.8%; P = .171)
Wk
HIV-1 RNA < 50 copies/mL (ITTe)
LPV/RTV + 3TC
LPV/RTV + 3TC or FTC + NRTI
100
80
60
40
20
0BL 4 8 12 24 36 48
88.3%83.7%
Cahn P, et al. Lancet Infect Dis. 2014;14:572-580.
clinicaloptions.com/hivBest Practices in Antiretroviral Therapy: Initiating First-line Therapy
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)
DHHS Guidelines. April 2015
A 43-Year-Old Woman With An Opportunistic Infection
clinicaloptions.com/hivBest Practices in Antiretroviral Therapy: Initiating First-line Therapy
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, OR (95% CI)
TotalPCP
Bacterial infectionOther OI
FungalCrypto
Mycobacterial> 1 OI
CD4+ < 50CD4+ ≥ 50
Events, n542811421288
303915
0 0.25 0.5 1.0 8.0 202.5Log OR of Death/AIDS Progression
Favors Early ART
clinicaloptions.com/hivBest Practices in Antiretroviral Therapy: Initiating First-line Therapy
Prevalence of Drug Resistance Mutations in Treatment-Naive Patients, 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 ≤ 0.2%
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 1.00
4.2
8.7
3.22.6 2.6
1.2
2.42.9
1.4
Margot NA, et al. CROI 2014. Abstract 578.
clinicaloptions.com/hivBest Practices in Antiretroviral Therapy: Initiating First-line Therapy
FLAMINGO: Virologic Outcomes by Baseline HIV-1 RNA and NRTI Use
Molina JM, et al. HIV Drug Therapy Glasgow 2014. Abstract O153.
TDF/FTC(n = 325)
ABC/3TC(n = 159)
Baseline NRTI
≤ 100,000(n = 362)
> 100,000(n = 122)
Baseline HIV-1 RNA (c/mL)
Pts With HIV-1 RNA < 50 c/mL at Wk 96DTG + 2 NRTIsDRV + RTV + 2 NRTIs
Overall(N = 484)
Pts
(%)
100
80
60
40
20
0
8068
8073
82
52
8275 79
64
clinicaloptions.com/hivBest Practices in Antiretroviral Therapy: Initiating First-line Therapy
Phase II Study of DRV/COBI/TAF/FTC vs DRV + COBI + TDF/FTC in Tx-Naive Pts
Randomized, double-blinded, placebo-controlled trial
Similar VL suppression at Wk 48
D/c for AEs: 2% (DRV/COBI/ TAF/FTC) vs 4% (DRV + COBI + TDF/FTC)
No emergent resistance
DRV/COBI/TAF/FTC associated with significantly greater increase in TC, LDL, HDL, and TG and with significantly less change in BMD at hip and spine
Mills A, et al. J Acquir Immune Defic Syndr. 2015;69:439-445.
Primary Endpoint: HIV-1 RNA < 50 c/mL at Wk 48 by FDA Snapshot
Analysis (ITT)100
80
60
40
20
0W48W24 W48W24 W48W24
Virologic Success
Virologic Failure
No Data
8 45 2
1612
2420
84777574
Weighted difference (95% Cl):Wk 24: 3.3 (-11.4 to 18.1)Wk 48: -6.2 (-19.9 to 7.4)DRV/COBI/TAF/FTC (n = 103)DRV + COBI + TDF/FTC (n = 50)
Pts
(%)
clinicaloptions.com/hivBest Practices in Antiretroviral Therapy: Initiating First-line Therapy
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 patient requirements, the evidence base, and practice guidance
Go Online for More CCO Educational Programming on
Antiretroviral TherapyDownloadable PowerPoint slideset for use as a self-study resource or in your own presentations
Additional CME-certified program on managing patients receiving antiretroviral therapy
clinicaloptions.com/ARTStart