hiv alert :updating your practice based on new guideline recommendations.2016

HIV Alert: Updating Your Practice Based on New Guideline Recommendations

This program is supported by independent educational grants from Gilead Sciences and ViiV Healthcare.

Slide credit: clinicaloptions.com

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Faculty

Eric S. Daar, MDChief, Division of HIV MedicineHarbor-UCLA Medical Center Professor of Medicine David Geffen School of Medicine at UCLA Los Angeles, California

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

Faculty Disclosure Information

Eric S. Daar, MD, has disclosed that he has received consulting fees from Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck, Teva, and ViiV and funds for research support from Gilead Sciences, Merck, and ViiV.

Paul E. Sax, MD, has disclosed that he has received consulting fees from AbbVie, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Janssen, Merck, and ViiV and funds for research support from Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, and ViiV.


Program Overview

Updated Initial Therapy Recommendations Recommendations on Switching ART in Virologically

Suppressed Patients Expert Perspective

– Applying the Guidelines in Clinical Practice

Other Key Guideline Updates


Updated Initial Therapy Recommendations

Updated DHHS Guidelines: Recommendations for Initial ART

Recommendations may differ based on baseline HIV-1 RNA, CD4+ count, CrCl, eGFR, HLA-B*5701 status, HBsAg status, and osteoporosis status

ClassFirst-line ART Regimens

Recommended AlternativeINSTI DTG/ABC/3TC

DTG + FTC/TDF or FTC/TAF EVG/COBI/FTC/TDF EVG/COBI/FTC/TAF RAL + FTC/TDF or FTC/TAF

Boosted PI

DRV + RTV + FTC/TDF or FTC/TAF ATV/(COBI or RTV) + FTC/TDF or FTC/TAF

DRV/(COBI or RTV) + ABC/3TC DRV/COBI + FTC/TDF or FTC/TAF

NNRTI EFV/FTC/TDF EFV + FTC/TAF RPV/FTC/TDF or RPV/FTC/TAF

Slide credit: clinicaloptions.comDHHS Guidelines. July 2016.

Bolding indicates single-tablet regimen.



Updated IAS-USA Guidelines: Recommendations for Initial ART Key difference from DHHS: recommended regimens include only

INSTIs + FTC/TAF or ABC/3TC (ie, no TDF)– Panel notes that if FTC/TAF is unavailable, TDF + FTC or 3TC remains

effective and in general well tolerated

Günthard HF, et al. JAMA. 2016;316:191-210.

ClassFirst-line ART Regimens

Recommended Alternative (If INSTI Not an Option)INSTI DTG/ABC/3TC

DTG + FTC/TAF EVG/COBI/FTC/TAF RAL + FTC/TAF

Boosted PI

DRV/(COBI or RTV) + ABC/3TC DRV/(COBI or RTV) + FTC/TDF or FTC/TAF

NNRTI EFV/FTC/TDF RPV/FTC/TDF or RPV/FTC/TAF

Recommendations may differ based on baseline HIV-1 RNA, CD4+ count, CrCl, eGFR, HLA-B*5701 status, HBsAg status, and osteoporosis status


Clinical Trials Supporting FTC/TAF Use

TAF noninferior to TDF as initial therapy in GS-104/111

– Wk 48 virologic success: 92% with EVG/COBI/FTC/TAF vs 90% with EVG/COBI/FTC/TDF (difference: 2%; 95% CI:-0.7% to 4.7)

Study Pt Population Treatment

GS-104/111[1] Treatment naive (N = 1733) EVG/COBI/FTC/TAF vs EVG/COBI/FTC/TDF

GS-109[2] Virologically suppressed on TDF-based regimen (N = 1436)

Switch to EVG/COBI/FTC/TAF vs remain on TDF-based regimen

GS-1089[3] Virologically suppressed on FTC/TDF + third ARV (N = 663)

Switch to FTC/TAF + continue third ARV vs remain on FTC/TDF + third ARV

GS-112[4]Virologically suppressed on

varied regimens; stable eGFRCG 30-69 mL/min (N = 242)

Switch to EVG/COBI/FTC/TAF


1. Sax PE, et al. Lancet. 2015;385:2606-2615. 2. Mills A, et al. Lancet Infect Dis. 2016;16:43-52. 3. Gallant JE, et al. Lancet HIV. 2016;3:e158-e165. 4. Pozniak A, et al. J Acquir Immune Defic Syndr. 2016;71:530-537.


TAF Associated With More Favorable Renal and Bone Marker Changes vs TDF In both initial therapy and switch studies, TAF-based ART associated

with the following (vs TDF-based ART) at Wk 48:

– Higher eGFRCG

– Less proteinuria (urinary protein, albumin, RBP, and β2-M to urine Cr ratio)

No proximal renal tubulopathy or Fanconi syndrome has been observed with TAF-based treatment

In initial therapy studies: smaller declines in spine and hip BMD with TAF-based ART vs TDF-based ART at Wk 48 (P < .001)

In switch studies: TAF-based treatment improved spine and hip BMD vs remaining on TDF-based treatment at Wk 48

TAF lipid neutral, lacks lipid lowering effects observed with TDF


Sax PE, et al. Lancet. 2015;385:2606-2615. Mills A, et al. Lancet Infect Dis. 2016;16:43-52. Gallant JE, et al. Lancet HIV. 2016;3:e158-e165. Wohl D, et al. J Acquir Immune Defic Syndr. 2016;72:58-64.


GS-112: Switching to EVG/COBI/FTC/TAF in Pts With Renal Impairment Multicenter, single-arm, open-label phase III trial in which virologically suppressed pts

with stable eGFRCG 30-69 mL/min switched to EVG/COBI/FTC/TAF (N = 242)

– Varied preswitch regimens: 65% received TDF

Pozniak A, et al. J Acquir Immune Defic Syndr. 2016;71:530-537. Slide credit: clinicaloptions.com

Clinically Relevant ProteinuriaMeasured GFR by Iohexol Clearance

100

80

60

40

20

0

mG

FR(m

L/m

in)

BL < 50 mL/min BL ≥ 50 mL/min

BL Wk 2/4/8

Wk24

47 43 44

65 65 67

BL Wk 2/4/8

Wk24

100

80

60

40

20

0

Pts

(%)

Proteinuria (UPCR) ≤ 200 mg/g

BL Wk 48 BL Wk 48

> 200 mg/g

56

75 65

91

44

2535

9

BL < 50 mL/min BL ≥ 50 mL/min


Recommendations on Switching ART in Virologically Suppressed

Patients

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



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

Review resistance testing results

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

– Care needed when switching from pharmacologically-boosted PI to another class if full treatment or resistance history is unknown

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

Increase monitoring during first 3 mos after switch

Don’t forget about HBV



Updated DHHS Guidelines: Switching ART in Virologically Suppressed Pts

Switch Strategies With Good Supporting Evidence

Switch Strategies under Evaluation

(Not Yet Recommended)

Switch Strategies Not Recommended

Within-class switch• EFV to RPV• TDF to TAF• RAL to DTG or EVG/COBI• PI/RTV to PI/COBI

Between-class switch, provided no resistance to other regimen components

• Boosted PI to RPV• NNRTI to INSTI• Boosted PI to INSTI

PI/RTV + 3TC, if no baseline resistance and pt has had sustained virologic suppression

Switch to PI/RTV + INSTI

Switch to EVG/COBI/FTC/TDF + DRV

Switch to DTG + 3TC or FTC

Switch to RTV-boosted PI monotherapy

Switching 1 component to MVC



Expert Perspective: Applying the Guidelines in

Clinical Practice

How to Choose Among Recommended First-line Regimens: Comparison of INSTIs

Günthard HF, et al. JAMA. 2016;316:191-210. Orrell C, et al. AIDS 2016. Abstract THAB0205LB. Slide credit: clinicaloptions.com

INSTI Advantages Disadvantages

DTG

QD dosing Available as STR Highest barrier to resistance No food requirement Superior to EFV and DRV/RTV Superior to RAL in tx-exp’d pts Superior to ATV/RTV in women

Only coformulated with ABC/3TC Serum Cr increases (inhibits tubular

secretion) Insomnia and headache more frequent in

some studies Largest pill size of STRs

EVG

QD dosing Available as STR Superior to ATV/RTV in women

Requires PK boosting (COBI) Only coformulated with FTC/(TDF or TAF) Most drug-drug interactions Serum Cr increases because cobicistat

inhibits tubular secretion Requires food with dosing

RAL

Longest safety record Fewest drug-drug interactions No food requirement Superior to ATV/RTV and

DRV/RTV

Currently BID Not available as STR


When to Use Alternative Regimens for Initial ART: When INSTIs Not an Option When you cannot use an INSTI

– For EVG/COBI, if potential DDIs exist

– Eg, in combination with rifampin or rifapentine, lovastatin, simvastatin, corticosteroids, etc.

– For DTG, in combination with dofetilide or rifapentine

– If pt experiences neuropsychiatric adverse events with INSTI

Previously, INSTIs avoided in absence of drug resistance testing, but latest DHHS guidance recommends the following regimens in this setting:

– (DRV/RTV or DTG) + (FTC/TAF or FTC/TDF)



Do not use EVG/COBI/FTC/TAF

– If severe hepatic impairment

– If potential COBI DDIs

– Eg, lovastatin, simvastatin, corticosteroids

When to Use Alternative Regimens for Initial ART: When TAF Not an Option Do not use TAF

– If CrCl < 30 mL/min

– With rifabutin, rifampin, or rifapentine (rifamycins are potent P-gp inducers and TAF is P-gp substrate)

– In pregnancy (pending data in this setting)

– As PrEP



Recommended TDF and TAF Co-formulations in Pts With Renal Impairment CrCl (mL/min)

EVG/COBI/FTC/TAF[1]

or FTC/TAF[2]FTC/TDF[3] EVG/COBI/FTC/TDF[4]

≥ 70 No adjustment needed No adjustment needed

No adjustment needed

50-70 No adjustment needed No adjustment needed*

Initiation not recommended

30-49 No adjustment needed Adjust dosing interval

Initiation not recommended;discontinue EVG/COBI/FTC/TDFif CrCl declines to this level during

treatment

< 30 Initiation not recommended Initiation not recommended

Initiation not recommended;discontinue EVG/COBI/FTC/TDFif CrCl declines to this level during

treatment

1. EVG/COBI/FTC/TAF [package insert]. 2. FTC/TAF [package insert]. 3. FTC/TDF [package insert]. 4. EVG/COBI/FTC/TDF [package insert]. 5. Lucas GM, et al. Clin Infect Dis. 2014;59:e96-e138. Slide credit: clinicaloptions.com

*IDSA recommends against use of TDF if CrCl < 60 mL/min.[5]

Do not use DTG/ABC/3TC

– If moderate or severe hepatic impairment

– If patient is also receiving dofetilide or rifapentine

– If CrCl < 50 mL/min

When to Use Alternative Regimens for Initial ART: When ABC Not an Option Do not use ABC

– If patient is HLA-B*5701 positive

– If patient is HBsAg positive and the regimen does not include 2 other drugs active against HBV

Use ABC with caution– If patient has or is at

high risk for cardiovascular disease


When to Use Alternative Regimens for Initial ART: When DRV/RTV Not an Option Do not use DRV/RTV

– If severe hepatic impairment

– If potential DDIs present

– Eg, lovastatin, simvastatin, rifampin, rifapentine, corticosteroids

Use DRV/RTV with caution– If patient has history of severe sulfonamide reaction


Other Key Guideline Updates

Updated IAS-USA Guidelines: Opportunistic Infection Prophylaxis “Primary Mycobacterium avium complex prophylaxis

is not recommended if effective ART is initiated immediately and viral suppression achieved”[1]

“Primary Pneumocystis pneumonia prophylaxis is recommended for patients who meet CD4 cell count criteria, even if taking ART”[1]

– CD4+ cell count threshold: < 200 cells/mm3[2]

1. Günthard HF, et al. JAMA. 2016;316:191-210. 2. DHHS Adult OI Guidelines. August 2016. Slide credit: clinicaloptions.com

Updated Recommendations for HBV/HIV Coinfection FTC/TAF now recommended as NRTI backbone in

pts with HBV/HIV coinfection in both DHHS and IAS-USA guidelines even though not yet FDA approved for this indication

Both recommend TDF or TAF plus 3TC or FTC as backbone in suppressive ART regimen

DHHS Guidelines. July 2016.Günthard HF, et al. JAMA. 2016;316:191-210. Slide credit: clinicaloptions.com

Key Take-Home Points

Updated DHHS and IAS-USA Guidelines include INSTIs as part of all recommended first-line regimens

– Exception: DRV/RTV also recommended in DHHS

FTC/TAF has been added as an NRTI pair of choice for all recommended regimens

Additional guidance provided on switching ART in patients with virologic suppression

Primary MAC prophylaxis no longer recommended if patients are to start ART promptly


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