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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


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.


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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


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


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


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


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



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


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)



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



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


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


Total Spine BMD0

-1

-2

-3

-4

-50 12 24 36

Mos From Randomization


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.


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.


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.


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


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.


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]


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


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


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%


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%)


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


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.


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


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


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


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)


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.


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


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


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


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.


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


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)


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.


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


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


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.


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


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

(%)


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

http://www.clinicaloptions.com/hiv

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