Модификация схем АРТ у пациентов с вирусной...

Best Practices in Antiretroviral Therapy: Switching ART in Virologically Suppressed Patients and After Virologic Failure

This activity is supported by an independent educational grant from ViiV Healthcare

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Faculty

Joseph J. Eron, Jr., MDProfessor of Medicine and EpidemiologyUniversity of North Carolina School of MedicineDirector, AIDS Clinical Trials UnitUniversity of North CarolinaChapel Hill, North Carolina

Program Director

Paul E. Sax, MDClinical Director HIV Program and Division of Infectious DiseasesBrigham and Women’s HospitalProfessor of MedicineHarvard Medical SchoolBoston, Massachusetts


Disclosures

Joseph J. Eron, Jr., MD, has disclosed that he has received funds for research support paid to the University of North Carolina from GlaxoSmithKline/ViiV and Janssen and consulting fees from AbbVie, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline/ ViiV, Merck, Tibotec/Janssen, and Tobira.

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

Switching ART in virologically suppressed patients to improve tolerability

Switching ART in virologically suppressed patients with comorbid conditions

Switching ART after virologic failure

Switching ART in Virologically Suppressed Patients

to Improve Tolerability


Reasons to Consider Regimen Switching in Virologically Suppressed Pts Simplification

Avoid toxicity

Improve tolerability or convenience

Manage drug–drug or drug–food interactions

Pregnancy

Cost

DHHS Guidelines. May 2015.


Principles of Regimen Switching in Virologically Suppressed Pts Review ART history for intolerance or possible virologic failure

Review all available drug resistance testing results

If prior resistance uncertain, only consider switch if new regimen likely to maintain suppression of resistant virus

– Care needed when switching from PI/RTV to another class if full treatment or resistance history is not known

Consult an expert when switching a pt with resistance to ≥ 1 class

Within class switches usually maintain virologic suppression if no resistance to drugs in that class are present

Increase monitoring during first 3 mos after switch



Study 102: Persistence of EFV-Related Symptoms Over Time

Wohl D, et al. ICAAC 2013. Abstract H-672a.

Incidence of Common Neuropsychiatric AEs Through Wk 144

Most events were grade 1– Abnormal dreams (EVG 96% vs EFV 86%); dizziness (EVG 93% vs EFV 87%)

25

20

15

10

5

0

25

20

15

10

5

0

DizzinessAbnormal Dreams

WksWks1449648

14%

14496480

1%

14%

8%

15%

8% 5%1%4%

1%5%

EVG/COBI/TDF/FTC (n = 348)

Incidence (bar): Pts with new onset AEs at each 4-wk window.Prevalence (line): Pts with AEs at each 4-wk window.

Patie

nts

With

AE

(%)

9%

0

EFV/TDF/FTC (n = 352)


Risk of Suicidality in Pts Treated With EFV-Containing Regimens in ACTG Trials Treatment with EFV associated

with increased risk of suicidality– Absolute risk is small

Trend towards higher incidence of attempted or completed suicide with EFV use (HR: 2.58; 95% CI: 0.94-7.06; P = .065)

EFV also associated with increased risk of death from injury, substance use, or unknown causes

HR: 2.28 (95% CI 1.27-4.10; P = .006)

47 events/5817 PY (8.08/1000 PY)

15 events/4099 PY (3.66/1000 PY)

Mollan K, et al. Ann Intern Med. 2014;161:1-10.

Multivariate Analysis of Factors Associated With Suicidality in ACTG Clinical Trials

Variable HR (95% CI) P Value

Randomly assigned EFV 1.94 (1.17-3.23) .011

Age category, yrs < 30 vs ≥ 45 30-44 vs ≥ 45

3.58 (1.71-7.48) 1.81 (0.90-3.63)

.001NA

Hx IDU 2.70 (1.50 -4.88) < .001

Psychiatric hx or psychoactive rx 3.75 (2.33 -6.03) < .001

EFVEFV free

0.05

0.04

0.03

0.02

0.01

0

Prob

abili

ty

1920 24 48 72 96 120 144 168Wks to Suicidality


UK Multicenter Study: Switch From EFV/FTC/TDF to RPV/FTC/TDF for CNS Toxicity

All 40 pts (100%) maintained virologic suppression following switch; median CD4+ cell count at Wk 12 was 584 cells/mm3 (P = .156 vs BL)

Grade 2-4 CNS AEs significantly decreased at Wks 4 and 12 (P < .001 vs BL)

Each CNS AE, except headache, showed statistically significant improvement (P < .05)

Nelson M, et al. ICAAC 2013. Abstract H-672b.

100

80

60

40

20

0

P = .008

P = .029P = .001

P = .021

P = .005

P = .008 P = .003

P = .034

P < .001

P = .564

Individual Grade 2-4 CNS AEs Through Wk 12 Following Switch

Baseline Wk 4 Wk12

Pts

(%)

Dizziness Depression Insomnia Anxiety/Nervousness

Confusion ImpairedConcentration

HeadacheSomnolence AbnormalDreams

AggressiveMood


STRATEGY-NNRTI: Switch From NNRTI + TDF/FTC to EVG/COBI/TDF/FTC Randomized, open-label switch study in pts virologically suppressed on an

NNRTI-based regimen (with TDF/FTC) for ≥ 6 mos

Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 48

HIV-1 RNA < 50 copies/mL, 2 previous regimens,

no resistance to study drugs or prior INSTI use, and

eGFR ≥ 70 mL/min(N = 439)

Switch to EVG/COBI/TDF/FTC QD(n = 290)

Remain on NNRTI + TDF/FTC(n = 143)

Pozniak A, et al. Lancet Infect Dis. 2014;14:590-599.

Wk 96Wk 48


STRATEGY-NNRTI: Outcomes at Wk 48 Switch to EVG/COBI noninferior to

stable NNRTIs at Wk 48

Regimens: EFV 78%; NVP 17%; RPV 4%; ETR < 1%; 74% on EFV/TDF/FTC; 91% on first regimen

Results similar across all baseline virologic and demographic subgroups

3 pts with VF in EVG/COBI arm and 1 in NNRTI arm

– No pts with resistance in either arm

5 in the switch arm and 1 in the NNRTI arm discontinued due to AE

Pts

(%)

93 88

Δ +5.3%(95% CI: -0.5 to +12)

EVG/COBI/TDF/FTC (n = 290)

Stable NNRTIs (n = 143)

0

20

40

60

80

100

13

11

611

Virologic Success*

Virologic Nonresponse

No Data

n =

*HIV-1 RNA < 50 c/mL as defined by FDA Snapshot algorithm.Discontinued for AE, death, or missing data.


271 126 16 16


*P < .001 †P < .01 (comparison with baseline within treatment group)

Subj

ect R

epor

ting

Sym

ptom

s (%

)

HIV Symptom Index

Vivid Dreams Insomnia Anxiety Dizziness

100

136224

75212

65101

5687

119224

84209

48100

4187

103222

71208

40100

3487

90225

49211

3799

3287

BL W48 BL W48 BL W48 BL W48 BL W48 BL W48 BL W48 BL W48


STRATEGY-NNRTI: Outcomes in Pts Switching From EFV-Based Therapy

70605040302010

0

61

35*

64 64

53

40†48 47 46

34†40 39 40 37 37

23*

EVG/COBI/TDF/FTC NNRTI + TDF/FTC


STRIIVING: Switch From Suppressive ART to Fixed-Dose DTG/ABC/3TC Ongoing randomized, open-label phase IIIB study

– Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 24

HIV-1 RNA < 50 copies/mL on stable ART ≥ 6 mos;

no previous virologic failure; HLA-B*5701 negative

(N = 551)

DTG/ABC/3TC(n = 274)

Wk 48Wk 24

Trottier B, et al. ICAAC 2015.

*Containing 2 NRTIs plus NNRTI, PI, or INSTI.

Baseline ART*(n = 277)

DTG/ABC/3TC(n = 277)

Baseline ART use: PI 42%; NNRTI 31%; INSTI 26%; TDF/FTC 77%


STRIIVING: Study Disposition at Wk 24


13% of subjects withdrawn (n = 35)

Adverse event 10 (4%)

Lack of efficacy (virologic failure)

0

Protocol deviation 15 (5%)

Stopping criteria met 0

Lost to follow-up 3 (1%)

Investigator discretion 3 (1%)

Withdrew consent 4 (1%)

Randomized and treated DTG/ABC/3TC

(n = 274)

87% completed (n = 239)

Screened (N = 841)

12% of subjects withdrawn (n = 32)

Adverse event 0

Lack of efficacy (virologic failure)

0

Protocol deviation 17 (6%)

Stopping criteria met 0

Lost to follow-up 3 (1%)

Investigator discretion 3 (1%)

Withdrew consent 9 (3%)

Randomized and treated Baseline ART

(n = 277)

88% completed (n = 244)

1 with missing information


52

STRIIVING: Outcomes at Wk 24

Switch to DTG/ABC/3TC noninferior to maintaining baseline ART

No pt met criteria for protocol-defined virologic failure; 3 pts in DTG/ABC/3TC arm (1%) and 4 pts in BL ART arm (1%) had HIV-1 RNA > 50 copies/mL but < 100 copies/mL through Wk 24

10 pts d/c for AEs in DTG/ABC/3TC arm vs 0 in baseline ART arm


Primary Efficacy Analysis: ITT-Exposed and Per Protocol Populations100

80

60

40

20

0 VirologicSuccess

VirologicNonresponse

No Virologic Data

HIV

-1 R

NA

<50

c/m

L (%

)

DTG/ABC/3TC (ITT-E, n = 274)Baseline ART (ITT-E, n = 277)DTG/ABC/3TC (PP, n = 220)Baseline ART (PP, n = 215)

858893 93

1410 61 1 < 1

12-12 -8 -4 0 4 8

12-12 -8 -4 0 4 8

-4.9-0.3

4.4

2.3-9.1

ITT-E Population

PP Population

-3.4

DTG/ABC/3TCBaseline ART


Drugs That Should Not Be Used With Antiretroviral AgentsARV Drugs That Should Not Be Used ConcomitantlyDTG[1] Dofetilide, rifapentine, St. John’s wort

EFV[1] Rifapentine, St. John’s wort, boceprevir, dasabuvir, ombitasvir, paritaprevir, simeprevir.

EVG/COBI/TDF/FTC[1]

Ranolazine, lovastatin, simvastatin, rifampin, rifapentine, lurasidone, pimozide, midazolam, triazolam, St. John’s wort, boceprevir, dasabuvir, ledipasvir, ombitasvir, paritaprevir, simeprevir, alfuzosin, cisapride, ergot derivatives, salmeterol, sildenafil for PAH.

EVG/COBI/TAF/FTC[2]

Lovastatin, simvastatin, rifampin, rifapentine, pimozide, midazolam, triazolam, St. John’s wort, phenobarbital, phenytoin, alfuzosin, carbamazepine, cisapride, ergot derivatives, salmeterol, sildenafil for PAH.

RPV[1] Rifampin, rifapentine, carbamazepine, oxcarbazepine, phenobarbital, phenytoin, St. John’s wort, dasabuvir, ombitasvir, paritaprevir, proton pump inhibitors (eg, omeprazole)

1. DHHS Guidelines. April 2015. 2. EVG/COBI/TAF/FTC Prescribing Information. November 2015.


Randomized, active-controlled, open-label study

Primary endpoint: proportion of pts with HIV-1 RNA < 50 copies/mL after 48 wks of treatment

Switching From TDF- to TAF-Based Regimens in Virologically Suppressed Pts

Mills A, et al. IAS 2015. Abstract TUAB0102.

Pts with HIV-1 RNA < 50 copies/mL (≥ 96 wks) and eGFR > 50

mL/min on stable TDF-based regimen for ≥ 48

wks(N = 1436)

Switch to EVG/COBI/FTC/TAF QD*(n = 959)

Continue previous TDF-based regimen†

(n = 477)

Primary EndpointWk 48

*EVG/COBI/FTC/TAF (150/150/200/10 mg). †Previous TDF-based regimens: EVG/COBI/FTC/TDF (n = 459), EFV/TDF/FTC (n = 376), ATV/(COBI or RTV) + TDF/FTC (n = 601).

Continue through Wk 96


Switching From TDF- to TAF-Based Regimens

Mills A, et al. IAS 2015. Abstract TUAB0102.

100

80

60

40

20

0

Wk

48 H

IV-1

RN

A <

50

c/m

L (%

)

All Prior Regimens

Prior EFV/TDF/FTC

Prior Boosted

ATV + TDF/FTC

Prior EVG/COBI/FTC/TDF

EVG/COBI/FTC/TAF TDF-based regimenPrimary Endpoint

P < .001 P = .02 P = .02 P = NS97 93 96

9097

9298 97

932/959

444/477

241/251

112/125

390/402

183/199

301/306

149/153n/N =

Switching ART in Virologically Suppressed Patients

With Comorbid Conditions


D:A:D: Cumulative Exposure to ARVs Associated With Increased CKD RiskCKD Risk by Yrs of ARV Exposure, Incidence

Rate Ratio (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.

1.80

1.60

1.40

1.20

1.00

0

Relationship Between Increasing Exposure to ARVs and CKD

ATV + RTV LPV/RTV TDF

On treatmentTDF censored

UnivariateMultivariate


STRATEGY-PI Trial: Switch From PI + RTV + TDF/FTC to EVG/COBI/TDF/FTC Randomized, open-label switch study in pts virologically suppressed

on PI + RTV + TDF/FTC for ≥ 6 mos

Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 48

HIV-1 RNA < 50 copies/mL, 2 previous regimens, no resistance to study drugs

and CrCl ≥ 70 mL/min(N = 433)

Switch to EVG/COBI/TDF/FTC QD(n = 293)

Remain on Boosted PI + TDF/FTC(n = 140)

Arribas JR, et al. Lancet Infect Dis. 2014;14:581-589.

*Pts with previous VF ineligible.

Wk 96Wk 48


STRATEGY-PI: Outcomes at Wk 48 Switch to EVG/COBI/TDF/FTC noninferior to stable PI + RTV + TDF/FTC 2 pts with VF in each arm but no pts with resistance in either arm 5 pts in switch arm and 2 pts in boosted PI arm discontinued due to AEs

Pts

(%) EVG/COBI/TDF/FTC (n = 290)

PI + RTV + TDF/FTC (n = 139)

*HIV-1 RNA < 50 c/mL as defined by FDA Snapshot algorithm. Discontinued for AE, death, or missing data.Arribas JR, et al. Lancet Infect Dis. 2014;14:581-589.

9487

Δ +6.7% (95% CI: 0.4-13.7)

0

20

40

60

80

100

1 1 6 12

Virologic Success* Virologic Nonresponse No Data

n = 272 121 16 162 2


SPIRIT: Switch to RPV/TDF/FTC From PI + RTV in Suppressed Pts, No Prior Failure Multicenter, randomized, open-label switch study

– Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 24

Pts with HIV-1 RNA < 50 copies/mL on

stable RTV-boosted PI + 2 NRTIs for

≥ 6 mos, no prior VL failure or resistance

to study drugs (N = 476)

Switch to RPV/TDF/FTC(n = 317)

Continue RTV-Boosted PI* +

2 NRTIs(n = 159)

Wk 48Wk 24

Switch to RPV/TDF/FTC(n = 159)

Palella F, et al. AIDS. 2014;28:335-344.

*ATV/RTV 34%; LPV/RTV 37%; DRV/RTV 21%; FPV/RTV 8%; SQV/RTV 1%.

Continue RPV/TDF/FTC(n = 317)


RPV/TDF/FTC(immediate switch, Day 1 - Wk 24)

bPI + 2 NRTIs(continued, Day 1 - Wk 24)

RPV/TDF/FTC (delayed switch, Wk 24 - Wk 48)

SPIRIT: Virologic Suppression at Wk 24 and Wk 48 Switch to RPV/TDF/FTC noninferior to continuing boosted PI regimen at Wk 24

17/18 pts with preexisting K103N in immediate switch arm maintained virologic suppression at Wk 48

Palella F, et al. AIDS. 2014;28:335-344.

Pts

(%)

0

20

40

60

80

100

Virologic Suppression

Virologic Failure

No Data

FDA Snapshot at Wk 24

93.7 89.9 92.1

0.9 5 1.3 5.4 5 6.60

20

40

60

80

100

Virologic Suppression

Virologic Failure

No Data

FDA Snapshot at Wk 48

89.3

2.5 8.2

RPV/TDF/FTC(immediate switch, Day 1 - Wk 48)


Simplification to NRTI-Sparing or NRTI-Limiting Regimens

Study N Switch Regimen ResultsASSURE[1] 296 ATV + ABC/3TC Similar efficacy as continued standard ART;

decline in urine β2-microglobulin creatinine ratio

MONET[2] 256 DRV/RTV Similar efficacy as continued standard ART

SALT[3] 286 ATV/RTV + 3TC Similar efficacy as continued standard ART

OLE[4] 250 LPV/RTV + 3TC or FTC

Similar efficacy as continued standard ART

NA[5] 48 DRV/RTV + 3TC Small study; encouraging efficacy

HARNESS[6] 109 ATV/RTV + RAL Less effective than standard ART

LATTE[7] 243 CAB + RPV Similar efficacy as continued standard ART

1. Wohl DA, et al. HIV Med. 2015;[Epub ahead of print]. 2. Arribas JR, et al. AIDS. 2010;24:223-230. 3. Perez-Molina JA, et al. Lancet Infect Dis. 2015;15:775-784. 4. Arribas JR, et al. Lancet Infect Dis. 2015;15:785-792. 5. Casado JL, et al. J Antimicrob Chemother. 2015;70:630-632. 6. Van Lunzen J, et al. AIDS 2014. Abstract LBPE19. 7. Margolis DA, et al. Lancet Infect Dis. 2015;[Epub ahead of print].


SALT: Simplification to Dual ART With ATV + RTV + 3TC in Suppressed Pts Randomized, open-label phase IV noninferiority trial

Primary endpoint: free of VF at Wk 48

HIV-infected pts with HIV-1 RNA < 50 copies/mL;

on triple ART for 6 mos; no prior treatment failure or

resistance(N = 286)

Atazanavir + Ritonavir 300/100 mg QD +3TC QD(n = 143)

Atazanavir + Ritonavir 300/100 mg QD +2 Investigator-Selected NRTIs

(n = 143)

Wk 48primary analysis

Perez-Molina JA, et al. Lancet Infect Dis. 2015;15:775-784.


SALT: Outcomes at Wk 48

ATV + RTV + 3TC noninferior to continued ATV + RTV + NRTIsPerez-Molina JA, et al. Lancet Infect Dis. 2015;15:775-784.

0%

Treatment Difference (95% CI)

Favors ATV + RTV + 3TC

Favors ATV + RTV + 2 NRTIs

-5% 6% 16%

-12% 12%

Pts

(%)

ATV + RTV + 3TC (n = 133)ATV + RTV + NRTIs (n = 135)

8478

0

20

40

60

80

n = 112 105

100

HIV-1 RNA < 50 copies/mL at Wk 48 (Per Protocol)


LATTE: : Cabotegravir (GSK1265744) + RPV as Maintenance ART: Wk 96 Results

Median CD4+ count increase vs BL: +296 cells/mm3 (CAB) vs +289 cells/mm3 (EFV)

Margolis D, et al. Lancet Infect Dis. 2015;15:1145-1155.

HIV

-1 R

NA

< 5

0 c/

mL

by

Snap

shot

Alg

orith

m (%

)

100

80

60

40

20

0BL 4 12 24 28 36 48 72 96

Induction Phase* Maintenance Phase*

CAB 10 mg (n = 60)CAB 30 mg (n = 60)CAB 60 mg (n = 61)EFV 600 mg (n = 62)

68%63%

84%75%

Wks*CAB given with 2 NRTIs in induction phase and with RPV in maintenance phase. EFV given with 2 NRTIs throughout.


Multicenter, open-label phase III trial

GS-112: Switching to a TAF-Based Regimen in Pts With Renal Impairment

Gupta S, et al. IAS 2015. Abstract TUAB0103.

Virologically suppressed, HIV-positive pts with mild-moderate renal impairment (stable

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 CCR5Antag. TDF ABC Other

NRTINo

NRTIART use, % 44 42 24 3 65 22 7 5

Wk 48Wk 24


TDF TDF

GS-112: Key Results at Wk 48Change in eGFR From Baseline to Wk

48 Changes in Spinal BMD From Baseline to Wk 48

Gupta S, et al. IAS 2015. Abstract TUAB0103.

Non-TDF

Med

ian

Cha

nge

From

Bas

elin

e

10

0

-10

+0.2

-1.8 -1.5 -2.7*

Baseline: 58 53 56 50eGFRCG

mL/mineGFRCKD-EPI Cr

mL/min/1.73 m2*P < .05

Non-TDF

*P < .05

4

2

0

-2M

ean

% C

hang

e Sp

ine

BM

D

2.95*

0.99

Baseline Wk 24 Wk 48 HIV suppression maintained No change in actual GFR at Wk 48 in subset analysis In pts on TDF, tubular proteinuria improved after switch

Switching ART After Virologic Failure


DHHS Guidelines for Virologic Failure Assess adherence, drug–drug or drug–food interactions,

tolerability, HIV-1 RNA and CD4+ count trends, treatment history, and prior and current resistance data

Perform resistance test while the patient is on failing ART, or within 4 wks of discontinuation; testing after this point may still provide useful information

Goal of treatment for ART-experienced pts with drug resistance and virologic failure is to suppress HIV-1 RNA

New regimen should include ≥ 2, and preferably 3, fully active agents, ie, agents with uncompromised activity based on treatment and resistance, and/or novel action



LPV/RTV + RAL(n = 270)

LPV/RTV + 2-3 NRTIs*(n = 271)

HIV-infected patients with confirmed VF

on NNRTI + 2 NRTIswith no previous PI

or INSTI use(N = 541)

Wk 96

*NRTIs selected by genotypic resistance test or by algorithm.

SECOND-LINE: Study Design Randomized, open-label, multicenter trial

Amin J, et al. PLoS One. 2015;10:e0118228

Wk 48


LPV/RTV + RAL(n = 433)

LPV/RTV + 2-3 NRTIs*(n = 426)

HIV-infected patients with confirmed VF

on NNRTI + 2 NRTIswith no previous PI

use(N = 1277)

Wk 96

*NRTIs selected by clinician.

EARNEST: Study Design Randomized, open-label, multicenter trial

Paton NI, et al. N Engl J Med. 2014; 371:234-247.

Wk 12

LPV/RTV Monotherapy(n = 418)

LPV/RTV+ RAL

(n = 418)


First-line NNRTI Failure: Boosted PI + NRTIs Noninferior to Boosted PI + RAL

1. Amin J, et al. PLoS One. 2015;10:e0118228. 2. Paton NI, et al. N Engl J Med. 2014; 371:234-247.

EARNEST: Efficacy Outcomes At Wk 96[2]SECOND-LINE: HIV-1 RNA < 200 c/mL and < 50 c/mL at Wk 96 (ITT)[1]

81%

83%

Pts

(%)

Treatment difference (< 200 c/mL): 4.4% (95% CI: -2.6 to 11.3); (< 50 c/mL) : 2.5% (95% CI: -5.3 to 10.3).

80 7670 68

VL < 200 c/mL VL < 50 c/mL

100

80

60

40

20

0

LPV/RTV + RAL (n = 270)LPV/RTV + 2/3 NRTIs (n = 271) 100

80

60

40

20

0

Pts

(%)

Good HIV Disease Control†

HIV-1 RNA < 50 copies/mL

LPV/RTV + RAL (n = 433)LPV/RTV + 2/3 NRTIs (n = 426)LPV/RTV monotherapy* (n = 418)

6460 55

74‡73‡

44

*Monotherapy given following LPV/RTV + RAL induction phase.†Alive with no new stage 4 events, CD4+ count > 250 cells/mm3, and HIV-1 RNA < 10,000 c/mL or no PI mutations.‡P < .0001 vs LPV/RTV monotherapy.


LPV/RTV + RALLPV/RTV + 2/3 NRTIs

50

40

30

20

SECOND-LINE Resistance Substudy:Predictors of Virologic Failure

Boyd M, et al. AIDS 2014. Abstract TUAB0105LB.

Variable Multivariate OR (95% CI)

P Value

Black race(ref: Asian)

3.49 (1.68-7.28) .007

BL VL > 100,000 c/mL (ref: ≤ 100,000)

3.43 (1.70-6.94)

< .001

Adherence (Wk 4)* 2.18 (1.07-4.47)

.032

Adherence (Wk 48)* 3.43 (1.09-5.69)

.03

Low resistance by gGSS (ref: high resistance)

4.73 (1.04-11.46) .002

*< All ART taken in last 7 days (ref: all ART taken).

Predictors of Virologic Failure at Wk 96

10

0

Pts

(%)

914 1312

4338

Wk 96 Virologic Failureby Baseline gGSS

117134 7786 2116High Moderate Low

Level of Resistance

n =


DHHS Guidelines: Management of First-line ARV FailureFailing Regimen Comments

NNRTI + NRTI Even pts with NRTI resistance can often be treated with a boosted PI + NRTIs or RAL

Boosted PI + NRTI A systematic review of multiple randomized studies of first-line boosted PI therapy showed that maintaining the same regimen, presumably with efforts to enhance adherence is as effective as changing to new regimens

INSTI + NRTI Pts should respond to a boosted PI + NRTIs A boosted PI + INSTI may also be a viable option if there is no

INSTI resistance If RAL or EVG resistance detected, DTG + a boosted PI “can be

used”



VIKING-3: Dolutegravir After Failure of Integrase Inhibitor–Based Regimen Mutlicenter, open-label, single-arm phase III trial

Wk 24 population (n = 183) includes the total number recruited

Wk 48 population (n = 114) includes those subjects who had the opportunity to reach Wk 48 at time of data cutoff

Castagna A, et al. J Infect Dis. 2014;210:354-362.

Pts with HIV-1 RNA ≥ 500 c/mL, RAL and/or

EVG resistance, and resistance to ≥ 2 other antiretroviral classes*

(N = 183)

Dolutegravir 50 mg BID +

Continue Failing

Regimen

Dolutegravir 50 mg BID +Optimized Background Regimen

With Overall Susceptibility Score ≥ 1 (ie, ≥ 1 active drug)

Day 8 Wk 24 Wk 48

*Detected at screening or based on historical evidence.

Functional monotherapy

Optimized therapy


HIV

-1 R

NA

< 5

0 c/

mL*

Baseline INSTI Mutations

n = 183 126 36 21

69

24

79

58

Overall No Q148 Q148 + 1* Q148 + ≥ 2*

100

80

60

40

20

0

*Key secondary mutations were G140A/C/S, L74I and E138A/K/T. Vavro CL, et al. EUDRW 2014. Abstract O_10.

VIKING-3: DTG BID in Previously Treated Pts With RAL and EVG Resistance

4 of 33 pts with N155 mutation at baseline had protocol-defined virologic failure

HIV-1 RNA < 50 c/mL At Wks 24 and 48 (ITT-E)

63

183 126

71

36

56

21

29

Wk 24 DTG 50 mg BID + OBR

Wk 48 DTG 50 mg BID + OBR


Summary Switching ART in pts with virologic suppression can improve

tolerability and maintain virologic efficacy

– Consider previous ART intolerance, failure, resistance history, and comorbidities when selecting a new ART regimen for virologically suppressed pts

Goal of treatment for ART-experienced pts with drug resistance and virologic failure is to suppress HIV-1 RNA

– Assess adherence, DDIs, tolerability, HIV-1 RNA and CD4+ cell count trends, treatment and resistance history

– Select a new regimen that includes ≥ 2, and preferably 3, fully active agents

– First-line failure with limited resistance may not require 3 fully active agents

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/ARTSwitch

http://www.clinicaloptions.com/hiv

Модификация схем АРТ у пациентов с вирусной...

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