ART Update 2015

Joel E. Gallant, MD, MPHMedical Director of Specialty Services Southwest CARE CenterSanta Fe, New MexicoAdjunct Professor of MedicineDivision of Infectious DiseasesJohns Hopkins University School of MedicineBaltimore, Maryland

ART Update 2015

Supported by educational grants from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Janssen Therapeutics, Merck and ViiV.

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Disclosures

Joel E. Gallant, MD, MPH, has disclosed that he has received consulting fees from Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck, and ViiV and funds for research support from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck, Sangamo, and ViiV.


START: Immediate vs Deferred ART

International, randomized phase IV study

– 215 sites in 35 countries

Study stopped by data and safety monitoring board following results of interim analysis

– Risk of serious illness or death reduced by 53% with immediate ART

– Rates of serious AIDS-related and non–AIDS-related events lower in immediate ART arm

ART-naive adults with CD4+ cell count > 500 cells/mm3

(N = 4685)

Immediate ART*

Delayed ART* (until CD4+ cell count

≤ 350 cells/mm3)

Randomized 1:1Interim results:

serious AIDS and non-AIDS events, n

41

86

*Any licensed ART allowed, according to national guidelines.

ClinicalTrials.gov. NCT00867048. NIH Press Release, May 27, 2015.


When to Start Therapy:Balance Now Favors Early ART

Drug toxicity Preservation of limited Rx

options Risk of resistance (and

transmission of resistant virus)

↑ potency, durability, simplicity, safety of current regimens

↓ emergence of resistance ↓ toxicity with earlier therapy ↑ subsequent treatment options Risk of uncontrolled viremia at all CD4

levels ↓ transmission

Delayed ART Early ART


DHHS Guidelines, April 2015: What to Start

NNRTIs and ATV/r, previously classified as “recommended,” are now “alternative regimens”

DHHS Guidelines. April 2015.

*Only for pts who are HLA-B*5701 negative. †Only for pts with pre-ART CrCl ≥ 70 mL/min.

Recommended Regimens

INSTI based DTG/ABC/3TC*DTG + TDF/FTC

EVG/COBI/TDF/FTC†

RAL + TDF/FTC

PI based DRV/r + TDF/FTC


DHHS Guidelines, April 2015: What to Start


*Only for pts with pre-ART HIV-1 RNA < 100,000 copies/mL and CD4+ > 200 cells mm3.†Only for pts with pre-ART CrCl ≥ 70 mL/min.‡Only for pts who are HLA-B*5701 negative.

Alternative Regimens

NNRTI based EFV/TDF/FTCRPV/TDF/FTC*

PI based ATV/COBI + TDF/FTC†

ATV/r + TDF/FTC DRV/COBI + ABC/3TC‡

DRV/r + ABC/3TC‡

DRV/COBI + TDF/FTC†

An alternative regimen may be the preferred regimen for some pts


Integrase Inhibitors


Difference in 96-wk cumulative incidence (97.5% CI)

-20 0-10 10 20

15% (10% to 20%)

7.5% (3.2% to 12%)

7.5% (2.3% to 13%)

ATV/r vs RAL

DRV/r vs RAL

ATV/r vs DRV/r

Favors RAL

Favors RAL

Favors DRV/r

Lennox JL, et al. Ann Intern Med. 2014;161:461-471.

*Plus TDF/FTC.

ATV/r*RAL*DRV/r*

ACTG 5257: Cumulative Incidence of Virologic or Tolerability Failure

1.00

0.75

0.50

0.25

0.00

Cu

mu

lati

ve In

cid

ence

Wks Since Study Entry

0 24 48 64 80 96 112 128 144


Toxicities Associated With Discontinuation, n (%)

ATV/r†

(n = 605)RAL†

(n = 603)DRV/r†

(n = 601)

Any 95 (16%) 8 (1%) 32 (5%)

Gastrointestinal toxicity 25 2 14

Jaundice/hyperbilirubinemia 47 0 0

Other hepatic toxicity 4 1 5

Skin toxicity 7 2 5

Metabolic toxicity 6 0 2

Renal toxicity (all nephrolithiasis) 4 0 0

Abnormal chem/heme (excl. LFTs) 0 0 2

Other toxicity 2 3 4

*Participants allowed to switch therapy for intolerable toxicity.†Plus TDF/FTC.


ACTG 5257: Tolerability FailureToxicity-Associated Discontinuation of Randomized ART*


GS 102: EVG/COBI/TDF/FTC Noninferior to EFV/TDF/FTC Through Wk 144

1. Sax PE, et al. Lancet. 2012;379:2439-2448. 2. Zolopa A, et al. J Acquir Immune Defic Syndr. 2013;63:96-100. 3. Wohl D, et al. J Acquir Immune Defic Syndr. 2014;65:e118-e120.

Wk 48

Wk 144

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

EFV/TDF/FTC (n = 352)

8075

8884 8482

Wk 96

7 7 6 8 7 105

9 9 11 12 15

Wk 48

Wk 144

Wk 96

Wk 48

Wk 144

Wk 96

Virologic Success Virologic Failure No Data

95% CI for Difference

Wk 48[1]

Wk 96[2]

Wk 144[3]

-12% 12%0

Favors EFV

Favors EVG/COBI

-1.3% 11.1%

4.9%

3.6%

8.8%

2.7%

-1.6%

-2.9%

0

20

40

60

80

100

8.3%


GS 103: EVG/COBI/TDF/FTC Noninferior to ATV/r + TDF/FTC Through Wk 144

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-e124.

EVG/COBI/TDF/FTC (n = 353)

ATV/RTV + TDF/FTC (n = 355)

7875

9087

Wk 48

Wk 144

0

20

40

60

80

100

Wk 96

Wk 48

Wk 144

Wk 96

Wk 48

Wk 144

Wk 96

Virologic Success Virologic Failure No Data

8382

5 5 57 7 78 8 101014

18

-12% 12%0

Favors ATV/RTV

Favors EVG/COBI

-3.2% 9.4%

3.1%

2.7%

7.5%1.1%

6.7%

-2.1%

-4.5%

Wk 48[1]

Wk 96[2]

Wk 144[3]



SINGLE: DTG + ABC/3TC Superior to EFV/TDF/FTC in ART-Naive Pts to Wk 144 Open-label extension, excluding pts with HBV Emergent resistance in those with VF: 0/39 (DTG) vs 7/33 (EFV)

Virologic Success*

Virologic Nonresponse

No Virologic Data

Pts

(%

)

FavorsEFV/TDF/FTC


0

Wk 48

Wk 96

Wk 144

7.4%

8.0%

8.3%

2.5%

2.3%

2.0% 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 8 107 7

13 1220

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.

-15%


FLAMINGO: DTG Superior to DRV/r in ART-Naive Pts to Wk 96

Virologic Success Virologic Nonresponse No Virologic Data

FavorsDRV/r


0%-12%

Wk 48

Wk 96

7.1%

12.4%

0.9%

4.7% 20.2%

13.2%

Su

bje

cts

(%

)

FavorsDTG

25%

DTG 50 mg QD + 2 NRTIs (n = 242)

DRV/r 800 mg/100 mg QD + 2 NRTIs (n = 242)

Molina et al. HIV Drug Therapy Glasgow 2014; Glasgow, UK. Slides O153.

0

20

40

60

80

100

W48 W48 W48W96 W96 W96

9083

80

68

6 7 812

410 12

21


Comparing the Integrase Inhibitors

Agent Advantages Disadvantages

Raltegravir Longest experience Fewer drug interactions than

EVG, DTG

Twice daily dosing (for now) No coformulation

Elvitegravir Single-tablet regimen (STR) Once-daily dosing

Requires COBI boosting COBI drug interactions similar to

RTV

Dolutegravir The only non-TDF–containing STR

Once-daily dosing Higher barrier to resistance Few drug interactions Active against some RAL- and

EVG-resistant virus

Coformulated with ABC/3TC only

Together, the results of STARTMRK, GS 102 and 103, SINGLE, FLAMINGO, and ACTG 5257 suggest that integrase inhibitor–based regimens are the preferred starting

regimens in the majority of pts


PIs


Difference in 96-wk cumulative incidence (97.5% CI)

-20 0-10 10 20

15% (10% to 20%)

7.5% (3.2% to 12%)

7.5% (2.3% to 13%)

ATV/r vs RAL

DRV/r vs RAL

ATV/r vs DRV/r

Favors RAL

Favors RAL

Favors DRV/r


*Plus TDF/FTC.

ATV/r*RAL*DRV/r*

ACTG 5257: Cumulative Incidence of Virologic or Tolerability Failure

1.00

0.75

0.50

0.25

0.00

Cu

mu

lati

ve In

cid

ence

Wks Since Study Entry

0 24 48 64 80 96 112 128 144


GS 114: ATV/COBI vs ATV/r With TDF/FTC Snapshot Wks 48, 96, 144 (ITT)

*No data include: DC study drug due to AE/death; DC study drug (other reasons) and last available HIV-1 RNA < 50 c/mL; missing data during window.

Per

cen

tag

e o

f S

ub

ject

s (%

)

Virologic SuccessVirologic Success Virologic FailureVirologic Failure No Data*No Data*


-7.4 3.0

FavorsATV + RTV

-2.2

FavorsATV + COBI

Wk 48Wk 48

-7.6 4.7

-1.4Wk 96Wk 96

4.5-8.7

-2.1Wk 144Wk 144

Mean CD4 cell increase (cells/mm3) was 310 (COBI) vs 332 (RTV)

12% 0 -12%

Gallant JE, et al. ICAAC 2014. Abstract H-647.

100

80

60

40

20

0Wk48 Wk96 Wk144 Wk48 Wk96 W144 Wk48 Wk96 Wk144

85 8778 79

72 74

6 4 7 5 8 5 9 915 16 20 21

COBI + TDF/FTC (n = 344)

RTV + TDF/FTC (n = 348)


Now Approved: New Boosted PI Fixed-Dose Combinations ATV/COBI 300/150 mg once daily[1]

DRV/COBI 800/150 mg once daily[2]

– Only for pts with no DRV resistance mutations

Both FDCs added as “alternative regimen” options in DHHS guidelines[3]

1. Atazanavir/cobicistat prescribing information 2015.2. Darunavir/cobicistat prescribing information 2015.3. DHHS Guidelines. April 2015.


NRTIs


Study Association? Description

D:A:D[1] Cohort collaboration (prospective)

Danish HIV Cohort[2] Cohort (linked with registries)

Montreal study[3] Nested case-control study

SMART[4] Post-hoc subgroup analysis of RCT (use of ABC not randomised)

STEAL[5] Preplanned secondary analysis of RCT (use of ABC randomised)

Desai et al[6] Cohort (retrospective)

Swiss HIV Cohort[7] Cohort (retrospective)

FHDH ANRS CO4[8] ? Nested case-control study

NA-ACCORD[9] ? Cohort (retrospective)

VA Clinical Case Registry[10] Cohort (retrospective)

Brothers et al. analysis[11] Post-hoc meta-analysis of RCTs

ACTG A5001/ALLRT[12] Post-hoc meta-analysis of RCTs

FDA meta-analysis[13] Post-hoc meta-analysis of RCTs

1. Friis-Møller N, et al. N Engl J Med. 2003;349:1993-2003. 2. Obel N, et al. HIV Med. 2010;11:130-136. 3. Durand M, et al. J Acquir Immune Defic Syndr. 2011;57:245-253. 4. Phillips AN, et al. Antiv Ther. 2008;13:177-187. 5. Martin A, et al. AIDS. 2010;24:2657-2663. 6. Desai M, et al. Clin Infect Dis. 2015;[Epub ahead of print]. 7. Young J, et al. J Acquir Immune Defic Syndr. 2015;[Epub ahead of print]. 8. Lang S, et al. AIDS. 2010;24:1228-1230. 9. Palella F, et al. CROI 2015. Abstract 749LB. 10. Bedimo RJ, et al. Clin Infect Dis. 2011;53:84-91. 11. Brothers CH, et al. J Acquir Immune Defic Syndr. 2009;51:20-28. 12. Ribaudo HJ, et al. Clin Infect Dis. 2011;52:929-940. 13. Ding X, et al. J Acquir Immune Defic Syndr. 2012;61:441-447.

Studies Addressing Abacavir and MI


Nuke-Sparing and “Nuke-Lite” Regimens

Regimen Results

DRV/r + RAL (ACTG 5262)[1] Poor performance at high VL

DRV/r + RAL (NEAT)[2] Less effective at high VL, low CD4

DRV/r + MVC (MODERN)[3] Less effective than standard ART

ATV/r + RAL (HARNESS – switch)[4] Less effective than standard ART

LPV/r + RAL (PROGRESS)[5] Small study; few pts with high VL

LPV/r + EFV (ACTG 5142)[6] Poorly tolerated but effective

LPV/r + 3TC (GARDEL)[7] As effective as standard ART

LPV/r + 3TC or FTC (OLE – switch)[8] As effective as standard ART

ATV/r + 3TC (SALT – switch)[9] As effective as standard ART

1. Taiwo B, et al. AIDS. 2011;25:2113-2122. 2. Raffi, et al. CROI 2014. Abstract 84LB. 3. Stellbrink HJ, et al. IAD 2014. Abstract MOAB0101. 4. Van Lunzen J, et al. IAC 2014. Abstract A-641-0126-11307. 5. Reynes J, et al. AIDS Res Hum Retroviruses. 2013;29:256-265. 6. Daar ES, et al. Ann Intern Med. 2011;154:445-456. 7. Cahn P, et al. Lancet Infect Dis. 2014;14:572-580. 8. Gatell J, et al. AIDS 2014. Abstract LBPE17. 9. Perez-Molina JA, et al. IAC 2014. Abstract LBPE18.


How to Select a Nuke-Sparing Regimen When You Need One? All NRTI-sparing regimens should include a boosted PI . . .

for now

– LPV/r + EFV was effective but poorly tolerated, but other PI/NNRTI combinations could be considered

– Boosted PI + INSTI may not be enough

My choices:

– DRV/c + DTG + (3TC or FTC)

– DRV/c + ETR (+/- 3TC or FTC)

– DRV/c + (3TC or FTC)?


LATTE: NRTI-Sparing Maintenance With Cabotegravir + Rilpivirine

6 pts in CAB arms with PDVF at Wk 96; 4 additional pts since Wk 48

Margolis D, et al. CROI 2015. Abstract 554LB.

VL

< 5

0 c/

mL

by

Sn

apsh

ot

Alg

ori

thm

(%

)

100

80

60

40

20

0BL 4 12 24 28 36 48 72 96

Induction Phase Maintenance Phase (NRTI Sparing)

CAB 10 mg + 2 NRTIs* CAB + RPV (n = 60) CAB 30 mg + 2 NRTIs* CAB + RPV (n = 60)†

CAB 60 mg + 2 NRTIs* CAB + RPV (n = 61)EFV 600 mg + 2 NRTIs* (n = 62)

68%63%

84%

75%

Wks

*TDF/FTC or ABC/3TC.†Cabotegravir 30 mg selected for future development.

Induction Regimen Maintenance Regimen


Virologic Success*

Virologic Failure

No Data

Studies 104/111: TAF Noninferior to TDF at Wk 48

TAF also noninferior to TDF at Wk 48 in each study (104 and 111)

Results similar across all baseline virologic and demographic subgroups

7 pts in TAF arm and 5 pts in TDF arm with NRTI resistance at VF

– 1 in TAF arm and 2 in TDF arm with combined M184V/I + K65R

5 pts in TAF arm and 3 pts in TDF arm with INSTI resistance at VF

0.9% in TAF arm and 1.5% in TDF arm discontinued due to AE

CD4+ increases greater in TAF arm: 211 vs 181 (P = .024)

Pts

(%

)

9290

Δ +2.0%(95% CI: -0.7% to +4.7)

EVG/COBI/FTC/TAF (n = 866)EVG/COBI/FTC/TDF (n = 867)

0

20

40

60

80

100

4 4 4 6

n =

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

800 784

Wohl DA, et al. CROI 2015. Abstract 113LB.


TAF vs TDF: Renal Safety

EVG/COBI/FTC/TAF(n = 866)

EVG/COBI/FTC/TDF(n = 867)

Events, n (%)Renal adverse events leading to discontinuation 0 4 (0.5)

Tubulopathy/Fanconi syndrome 0 0

-6.6P < .001

-11.2

Sax P, et al. CROI 2015. Abstract. 143LB.

20

10

0

-10

-20Mea

n (

SD

) C

han

ge

Fro

m B

asel

ine

eGF

R*

0Time (Wks)

12 24 36 48

EVG/COBI/FTC/TAF

EVG/COBI/FTC/TDF


TAF vs TDF: Quantitative Proteinuria

Med

ian

% C

han

ge

Fro

m B

asel

ine

(Q1

, Q

3)

β2- microglobulin

P < .001for all

Baseline44

mg/g44

mg/g5

mg/g5

mg/g64

μg/g 67

μg/g 101

μg/g 103

μg/g

Protein (UPCR)

Albumin (UACR)

Retinol-binding protein

Sax P, et al. CROI 2015. Abstract. 143LB.

76* 133* 168*

-57*

*Upper or lower limit of error bar.

EVG/COBI/FTC/TAFEVG/COBI/FTC/TAF

EVG/COBI/FTC/TDFEVG/COBI/FTC/TDF

75

50

25

0

-25

-50

-3

20

-5

7 9

51

-32

24


Switch to EVG/COBI/FTC/TAF in Renal Impairment

Change in eGFR (Cockcroft-Gault)

0 4 8 12 16 24 36 48-10

-5

0

5

10

15

0.6-1.4

Primary Endpoint

Me

dia

n (

Q1

, Q

3)

eG

FR

C

ha

ng

e F

rom

B

as

eli

ne

(m

L/m

in)

Baseline eGFR < 50 mL/min (n = 80) ≥ 50 mL/min (n = 162)

Retinol Binding Protein/Creatinine RatioWks

-40

-20

0

Me

dia

n %

Ch

an

ge

in

RB

P/C

rea

tin

ine

Ra

tio

(µ

g/g

)

P < .001 at all time points (for all pts combined)

-80

-60

-100

01 4 12 24 482

β2-Microglobulin/Creatinine Ratio

-40

-20

0

Me

dia

n %

Ch

an

ge

in

ß2-

M/C

rea

tin

ine

Ra

tio

(µ

g/g

)

-80

-60

-100 P < .001 at all time points (for all pts combined)

Wks01 4 12 24 482

Pozniak A, et al. CROI 2015. Abstract 795.

Baseline eGFRCG

< 50 mL/min ≥ 50 mL/min

65% receiving TDF at baseline


EVG/COBI/TAF/FTC

TAF/FTC

RPV/TAF/FTC


In the Pipeline

DRV/COBI/TAF/FTC: STR

Doravirine[1]: NNRTI

– Active against K103N, Y181C

Ibalizumab[2]: entry inhibitor

– Monoclonal antibody binds CD4

– Being studied for treatment and prevention

BMS-663068[3]: entry inhibitor

– Blocks attachment by binding to gp120

BMS 955176[4]: maturation inhibitor

– Disrupts processing of gag protein

– Trial in naive pts planned

1. Morales-Ramirez J, et al. CROI 2014. Abstract 92LB 2. Ernst J, et al. ICAAC 2014. Abstract H-995. 3. Lalezari J, et al. CROI 2014. Abstract 86. 4. Hwang C, et al. CROI 2015. Abstract 114LB.


What to Start?(My personal recommendations) No comorbidities or interacting medications

– DTG/ABC/3TC

– EVG/COBI/FTC/TDF

High cardiac risk

– DTG + TDF/FTC

– EVG/COBI/FTC/TDF

Kidney disease (low cardiac risk)

– DTG/ABC/3TC (expect fall in eGFR)

– RAL + ABC/3TC

RTV or COBI interactions

– DTG/ABC/3TC

– DTG + TDF/FTC

– RAL + TDF/FTC


How to Choose?(My personal recommendations) Adverse effects or desire for simplification

on a suppressive regimen

– DTG/ABC/3TC (no switch data yet, but why not?)

– EVG/COBI/TDF/FTC

– RPV/TDF/FTC

Known or predicted nonadherence

– DRV/COBI + TDF/FTC (compare with DHHS)

– DTG/ABC/3TC (?)

Likelihood of pregnancy

– ATV/r + TDF/FTC

HCV coinfection

– DTG/ABC/3TC (or TDF/FTC)

– RAL + TDF/FTC

Switching and Simplifying Therapy in Suppressed Patients


Switching Regimens

Rationale for switching in setting of virologic suppressionTo simplify therapy (reduce pill burden, dosing frequency, improve adherence)To enhance tolerability, decrease short- and long-term toxicityTo change food or fluid requirementsTo avoid parenteral administration (enfuvirtide)To minimize or address drug interactionsTo allow for optimal use of ART during or in event of pregnancyTo reduce cost

Other reasons (mine)To avoid embarrassmentTo prevent boredom



Recent Switch Studies: Suppressed

Trial From To Outcome

GS-123 [1] RAL + TDF/FTC EVG/TDF/FTC/COBI ✔

GS-264[2] EFV/TDF/FTC TDF/FTC/RPV ✔

Strategy-NNRTI[3] NNRTI + TDF/FTC EVG/TDF/FTC/COBI ✔

Strategy-PI[4] PI/r + TDF/FTC EVG/TDF/FTC/COBI ✔

SPIRIT[5] PI/r + 2 NRTI RPV/TDF/FTC ✔

SPIRAL[6] PI/r + 2 NRTI RAL + 2 NRTI ✔

SALT[7] ATV/r + 2 NRTI ATV/r + 3TC ✔

OLE[8] LPV/r + 2 NRTIs LPV/r + 3TC ✔

SWITCHMRK[9] LPV/r + 2 NRTI RAL + 2 NRTI ✗

HARNESS[10] 3rd agent + 2 NRTI RAL+ ATV/r ✗

1. Mills A, et al. HIV Clin Trials. 2014;15:51-56. 2. Mills A, et al. HIV Clin Trials. 2013;14:216-223. 3. Pozniak A, et al. Lancet Infect Dis. 2014;14:590-599. 4. Arribas JR, et al. Lancet Infect Dis. 2014;14:581-589. 5. Brunetta J, et al. Patient. 2015;[Epub ahead of print]. 6. Martínez E, et al. AIDS. 2010;24:1697-1707. 7. Perez-Molina JA, et al. AIDS 2014. Abstract LBPE18. 8. Gatell J, et al. AIDS 2014. Abstract LBPE17. 9. Eron JJ, et al. Lancet. 2010;375:396-407. 10. van Lunzen J, et al. AIDS 2014. Abstract LBPE19.


Switching: Caveats

Know the treatment and resistance history

Avoid switching from high barrier to lower barrier agents when you don’t


Switching and Simplifying Therapy: “Horizontal” vs “Vertical” SwitchesVertical Switches: switch to drug with lower resistance barrierMost drug discontinuations

Boosted PI → NNRTI

Boosted PI → INSTI

Boosted PI → any STR

DRV/r twice daily → once daily

Horizontal Switches: switch to drug with equal or higher resistance barrierRTV → COBI (boosters)

Switches within INSTI class in previously INSTI-naive pts

EFV or NVP → RPV or ETR

LPV/r or ATV/r → DRV/r

ABC or AZT → TDF

TDF → TAF


Conclusions

Initial therapy

– Due to a combination of efficacy, safety, and tolerability, 4 of the 5 DHHS recommended regimens are now INSTI-based combinations

– DRV/r is the only recommended PI

– ATV/r, ETR, and RPV are now alternative agents

Some pts still need “nuke-sparing” or “nuke-lite” regimens

– DHHS guidelines list no NRTI-sparing regimen as “Recommended” or “Alternative”

– TAF may make this less necessary in the near future

Switching therapy in virologically suppressed pts is appropriate and safe, provided resistance profile and resistance barrier are considered

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