hiv alert :updating your practice based on new guideline recommendations.2016
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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.
Slide credit: clinicaloptions.com
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.
Slide credit: clinicaloptions.com
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
Slide credit: clinicaloptions.com
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
Slide credit: clinicaloptions.com
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
Slide credit: clinicaloptions.comDHHS Guidelines. July 2016.
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
Slide credit: clinicaloptions.comDHHS Guidelines. July 2016.
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
Slide credit: clinicaloptions.comDHHS Guidelines. July 2016.
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)
Slide credit: clinicaloptions.comDHHS Guidelines. July 2016.
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
Slide credit: clinicaloptions.com
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
Slide credit: clinicaloptions.com
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
Slide credit: clinicaloptions.com
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
Slide credit: clinicaloptions.com
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