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State-of-the-ART in Antiretroviral Therapy:
Optimal Initial Regimens in 2016
Rajesh T. Gandhi, MD
Director, HIV Clinical Services and Education
Massachusetts General Hospital
Boston, Massachusetts
Thanks to Alice Pau, Roger Bedimo and Marilyn
Shi for assistance with slides
Washington, DC: August 23, 2016
Financial Relationships With Commercial Entities
 Dr Gandhi has received grants paid to his
institution from Gilead Sciences, Inc, EBSCO,
Merck & Co, Inc, and ViiV Healthcare. (Updated
08/15/16)
Slide 2 of 44
Learning Objectives
After attending this presentation, participants will
be able to:
 Identify optimal antiretroviral regimens for
HIV-infected persons
 Customize antiretroviral regimens for
persons with specific comorbidities
Slide 3 of 44
HIV: What to Start in 2016
• Choosing an Initial Regimen
• Treatment Guidelines and Recent Changes
• Four Controversies
Slide 4 of 44
Reproductive Cycle of HIV and Sites of Action of Major
Classes of Antiretroviral Medications
Slide 5 of 44
Gandhi M, Gandhi RT. N Engl J Med 2014;371:248-259.
Reproductive Cycle of HIV and Sites of Action of Major
Classes of Antiretroviral Medications
Fusion Inhibitors
CCR5 Antagonists
Reverse Transcriptase
Inhibitors (RTI)
Nucleoside RTI (NRTIs) –
tenofovir, abacavir, 3TC, FTC
Nonnucleoside RTI (NNRTIs)
– efavirenz, rilpivirine
Slide 6 of 44
Gandhi M, Gandhi RT. N Engl J Med 2014;371:248-259.
Protease inhibitors (PI) –
darunavir/ritonavir or cobi;
atazanavir/ritonavir or cobi
Integrase strand transfer
inhibitors (INSTI) –
dolutegravir, raltegravir,
elvitegravir/cobicistat
Antiretroviral Therapy 2016: >25 Options
Nucleoside and nucleotide RTIs (NRTI)
Non nucleoside NRTIs: (NNRTI)
• Zidovudine, AZT
• Delavirdine (DLV)
• Abacavir, ABC
• Nevirapine, NVP
• Lamivudine, 3TC
• Efavirenz, EFV
• Didanosine, ddI
• Etravirine
• Stavudine, d4T
• Rilpivirine
• Tenofovir, TDF
• Emtricitabine, FTC
Fusion inhibitors:
• AZT/3TC
• Enfuvirtide, ENF or T20
• AZT/3TC/ABC
• ABC/3TC
• TDF/FTC
Red – combination agents
• TAF/FTC
Single pill regimens
CCR5 receptor blocker
• EFV/FTC/TDF
• Maraviroc
• RPV/FTC/TDF
Integrase inhibitor (INSTI)
• EVG/cobi/FTC/TDF
• Raltegravir, RAL
• DTG/ABC/3TC
• Elvitegravir, EVG
• Dolutegravir, DTG
Protease inhibitors (PIs):
• Indinavir, IDV
• Saquinavir, SQV
• Nelfinavir, NFV
• Amprenavir, APV
• Atazanavir, ATV
• Fosamprenavir, FPV
• Lopinavir/ritonavir
• Tipranavir
• Darunavir
• Darunavir/cobicistat
• Atazanavir/cobicistat
• EVG/cobi/FTC/TAF
• Rilpivirine/FTC/TAF
Commonly Used Medications for HIV
NRTIs
• Abacavir (ABC)/3TC
• Tenofovir*/FTC
* Tenofovir disoproxil fumarate
(TDF) or tenofovir alafenamide
(TAF)
Slide 8 of 44
NNRTI:
Rilpivirine (RPV)** (if VL <100K, CD4>200)
Efavirenz (EFV)+
Boosted PI: ritonavir or cobicistat plus
Darunavir (DRV/r or DRV/c)
Atazanavir (ATV/r or ATV/c)
Integrase inhibitor:
Raltegravir (RAL)
Elvitegravir (EVG)/cobicistat**
Dolutegravir (DTG)++
**Coformulated with TDF/FTC and TAF/FTC; +Coformulated with TDF/FTC; ++Coformulated with ABC/3TC
Choosing An Initial Regimen
EFV
DTG
RPV
EVG/cobi
RAL
DTG
EFV
EFV
EVG/cobi
DTG
ATV/r
DRV/r
DRV/r
RAL
ATV/r
ATV/r
Slide 9 of 44
Updated July 14, 2016
Recommended Regimens
Integrase inhibitor + 2
Nucleoside RTI
Dolutegravir/abacavir/3TC
Dolutegravir+TDF/FTC or TAF/FTC
Elvitegravir/cobi/TDF (or TAF)/FTC
Raltegravir +TDF/FTC or TAF/FTC
Protease inhibitor + 2
Nucleoside RTI
Darunavir/r +TDF/FTC or TAF/FTC
Slide 10 of 44
http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf
What’s New in the DHHS Treatment Guidelines
• TAF/FTC added as 2-NRTI option in several Recommended and
Alternative Regimens
• Guidance on choosing between ABC, TAF and TDF-containing
regimens added
• LPV/r plus 2-NRTI regimen removed from list of Other Regimens
• TAF added as an option for HIV/HBV coinfected patients
• TAF should be avoided in patients on rifamycins, e.g. those
receiving rifampin-containing TB therapy
Slide 11 of 44
July 12, 2016
Recommended Initial Antiretroviral Therapy Regimens
Regimen
DTG/ABC/3TC
DTG + TAF/FTC
EVG/cobi/TAF/FTC
RAL + TAF/FTC
Rating
Ala
Ala
Ala
Alll
If TAF not available, TDF remains an effective and generally well-tolerated
option . . . . Some clinicians may prefer to continue using TDF pending
broader experience with TAF in clinical practice
Slide 12 of 44
HIV: What to Start in 2016
• Four controversies:
– Should all HIV-infected patients be treated, including elite
controllers?
– Should all newly-diagnosed HIV-infected patients be
started on an integrase inhibitor (INSTI)-based regimen?
– Should TAF replace TDF for all patients?
– How should an ART regimen be chosen in patients with
specific comorbidities or conditions?
Slide 13 of 44
Controversy 1:
Should all HIV-infected patients be treated,
including elite controllers?
Slide 14 of 44
When to START?
HIV-infected adults
CD4 count >500
N=4685
Immediate ART (n=2326)
Deferred ART (n=2359)
(CD4 Declined to <350 or AIDS-related event)
• Primary endpoint: serious AIDS-related event, serious non–AIDS-related
event, or death
• May 2015: DSMB recommended offering ART to all participants
• Median baseline CD4 count 651. Deferred group: median CD4 count at ART
initiation, 408
• Median HIV RNA: ≈13,000 (IQR ≈ 3,000, 43,000)
Slide 15 of 44
Immediate ART Prevents AIDS- and
Non-AIDS Related Events
Number of Serious Events
Number of Events
100
96
80
60
50
42
40
72%
Reduction
(P<0.001)
47
39%
Reduction
(P=0.04)
29
20
0
Deferred ART (n=2359)
Immediate ART (n=2326)
57%
Reduction
(P<0.001)
14
Composite
Endpoint
AIDSRelated
Components
(Serious Events)
Non-AIDS
Related
• TB, KS, lymphoma —
most common AIDSrelated events — all less
frequent in immediateART group1
• Cancer rates (combining
AIDS/non-AIDS) lower in
immediate-ART group2
• Greatest benefit:
age >50, VL >50,000,
CD4:CD8 <0.5,
Framingham score >10%3
Slide 16 of 44 1Lundgren J, et al. INSIGHT START Study Group. N Engl J Med. 2015. 2Borges et al, CROI 2016, #160; 3Molina J et al, International AIDS Conference 2016, Abstract THAB0201
DHHS and IAS–USA:
ART recommended for all HIV+ individuals,
regardless of CD4 cell count
CD4 Cell Count
Recommendation
≤ 350
350-500
>500
AI
AI
AI
AI: strong recommendation, data from randomized clinical trials
WHO on Sept 30, 2015: “Treat-all”
US DHHS Guidelines, January 2011.
Slide 17 of 44
Earlier and earlier . . . .
Data Supporting “Same Day” ART Initiation:
San Francisco (Pilcher CD, JAIDS 2016);
South Africa (Rosen S, PLoS Medicine, 2016);
Haiti (Koenig S, International AIDS Conf., July 2016, WEA0202)
US DHHS Guidelines, January 2011.
Slide 18 of 44
What about Elite Controllers (EC)?
Reasons to not start ART
• Drug toxicities
• Risk of drug resistance if
patient non-adherent
• Cost of ARVs
• No proof that ART prevents
complications
Slide 19 of 44
What about Elite Controllers (EC)?
Reasons to not start ART
• Drug toxicities
• Risk of drug resistance if
patient non-adherent
• Cost of ARVs
• No proof that ART prevents
complications
Landay A, AIDS 2014; Dinoso JB, CID 2008; Chun TW,
JID 2013; Pereyra F AIDS 2012; Crowell TA, JID, 2015
Hatano H, PLoS Pathogens, 2013; Kim CJ JAIDS,
2014
Slide 20 of 44
Reasons to start ART
• EC have higher HIV RNA levels, immune
activation and inflammation than ARTtreated patients – ongoing replication
• EC have high rates of subclinical
atherosclerosis
• EC have higher hospitalization rates for
CVD than ART-treated patients
• EC may develop low CD4 counts , low
CD4/CD8 ratio
• Treating EC increases CD4 counts and
CD4/CD8 ratio; decreases T cell
activation
Should all EC be treated?
• Some EC have “quiescent” phenotype
– Higher CD4 count
– Lower HIV RNA (ultrasensitive assays)
– Different transcriptional profile of
immune activation & cytokine genes
• Other EC have more “active” phenotype
– Decreased CD4 counts; elevated CD8
counts; decreased CD4:CD8 ratio
– Elevated CRP
– Intermittently detectable virus
Slide 21 of 44
Transcriptional profiling reveals
distinct subgroups of EC
• I recommend treatment to latter
group, citing theoretic rationale,
acknowledging uncertainty
• More data needed on EC
Controversy 2:
Should all newly diagnosed patients be
started on an integrase inhibitor?
Slide 22 of 44
What to Start
Recommended Regimens
Randomized controlled
trials indicate INSTI-based
Dolutegravir/abacavir/3TC
regimens are optimal for most patients with newlyIntegrase inhibitor + 2 Dolutegravir+TDF/FTC or TAF/FTC
diagnosed HIV
Nucleoside RTI
Elvitegravir/cobi/TDF (or TAF)/FTC
Raltegravir +TDF/FTC or TAF/FTC
Protease inhibitor + 2
Nucleoside RTI
Slide 23 of 44
Darunavir/r +TDF/FTC or TAF/FTC
http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf
Randomized controlled trials:
INSTI vs. NNRTI
• Dolutegravir + ABC/3TC superior to EFV/TDF/FTC
(SINGLE)
• More discontinuations in EFV group (10% vs. 2%)
Slide 24 of 44
Walmsley S et al, NEJM, 2013
Randomized controlled trials: INSTIs vs. PI
• RAL superior to ATV/r & DRV/r
(ACTG A5257)1
• Dolutegravir superior to DRV/r
(FLAMINGO)2
• EVG/cobi superior to ATV/r in
women (WAVES)3
• DTG/ABC/3TC superior to ATV/r
+ TDF/FTC in women (ARIA)4
1 Lennox
Slide 25 of 44
ARIA: Wk 48 VL <50
J et al, Ann Int Med, 2014; 2Clotet B et al, Lancet, 2014; 3Squires K, et al. Lancet HIV, 2016; 4C. Orell et al. International AIDS
Conference, July 2016, Durban, South Africa. TUAC1021
Which INSTI?
• EVG vs. RAL
− Treatment-experienced: both drugs comparable1
• DTG vs. RAL
− Treatment naïve (SPRING-2): both drugs
comparable2
− Treatment-experienced (SAILING): DTG superior
to RAL3
Slide 26 of 44
1.Elion
R et al, JAIDS, 2013. 2Raffi F et al, Lancet, 2013. 3Cahn P et al, Lancet, 2013
INSTI
PROS
• Longest-track record
• Fewest drug interactions
• Twice daily (once daily formulation
coming – ONCEMRK trial)
• Not coformulated as part of single-pill
regimen
• Available in single-pill regimen
with TDF/FTC, TAF/FTC
• Most drug interactions (because of cobi)
• Food requirement
• Available in single-pill regimen
with ABC/3TC
• High genetic barrier to
resistance
• Not coformulated with tenofovir
• Largest pill size of single pill regimens
• Drug interaction with metformin
RAL
EVG/c
DTG
Slide 27 of 44
CONS
ONCEMRK
• 802 pts randomized (2:1)
– RAL 1200 mg QD + TDF/FTC
– RAL 400 mg BID + TDF/FTC
Wk 48 VL<40 (Snapshot)
• RAL QD non-inferior to RAL BID
– VL <40: 88.9% vs. 88.3%
• Resistance
– QD arm: 5 pts (0.9%): RAL, FTC
– BID arm: 3 pts had testing (2
no resistance, 1 failed testing)
Slide 28 of 44
Cahn P et al, International AIDS Conference, 18-22 July 2016,
Durban, South Africa. Abstract FRAB0103LB
INSTIs: Limitations
• In some trials, INSTIs comparable to (not better than) other
agents: e.g. studies 102 & 103, EVG/cobi similar to EFV and ATV/r
• Cations affect INSTI absorption (need to stagger dosing)
• Adverse events: rhabdo with RAL; insomnia with DTG
• Only INSTI single-pill regimen that contains tenofovir is with
EVG/c, which has multiple drug interactions
− New unboosted INSTI, GS-9883 (bictegravir), being developed
for use in TAF/FTC-containing single-pill regimen1,2
1Tsiang
Slide 29 of 44
M, ASM Microbe 2016, PW-031;
2Gallant
J, ASM Microbe 2016, PW-030
Scenarios in which Alternative to INSTI Might be
Chosen
• Patient with uncertain adherence or need to start ART before
resistance test available:
– Boosted PI (DRV/r or DRV/c): high genetic barrier to resistance
• Patient with low HIV RNA, high CD4 count:
– RPV/TDF/FTC, RPV/TAF/FTC: small pill, well-tolerated
– RPV/TDF/FTC superior to EFV/TDF/FTC if VL <100,0001
– Don’t use RPV if VL >100,000, CD4 <200
– Food requirement; avoid PPI; stagger H2 blocker
Slide 30 of 44
1Cohen
C et al, AIDS 2014
Scenarios in which Alternative to INSTI Might be
Chosen
• Patient with TB on rifampin-based regimen:
– Most data with EFV/TDF/FTC
– Rifampin has less effect on EFV concentrations
than other ARVs
– RAL, DTG can also be used (but at increased dose)
Slide 31 of 44
Controversy 3:
Should TAF replace TDF for all patients?
Slide 32 of 44
Tenofovir alafenamide (TAF)
• TAF: pro-drug of tenofovir that concentrates in cells, converted to
tenofovir (TFV)
• TAF: 90% lower plasma TFV levels compared to TDF (tenofovir
disoproxil fumarate)
• EVG/cobi/FTC/TAF compared to EVG/cobi/FTC/TDF for initial therapy:
n=1733
Slide 33 of 44
Sax P et al, Lancet, 2015
TAF vs. TDF
HIV-1 RNA <50 %
• Virologic efficacy: E/C/F/TAF non-inferior
92 90
to E/C/F/TDF1
100
E/C/F/TAF
• TAF associated with:
80
E/C/F/TDF
− Smaller decrease in eGFR
60
(-6.4 vs. -11 mL/min)
40
− Less proteinuria
20
4 4
4 6
− Smaller decrease in bone mineral
0
Success
Failure
No Data
density (BMD)
− But greater increase in cholesterol,
LDL, HDL, TGs
• EVG/c/FTC/TAF approved for patients
 D TC: +29 mg/dL
with CrCL down to 302
 D LDL: + 14 mg/dL
 D TC:HDL: same
1
2
Slide 34 of 44
Sax P et al, Lancet, 2015; Pozniak A et al, JAIDS, 2016
TAF/FTC Switch Study
HIV RNA <50 at wk 48
• 663 patients with virologic suppression on
TDF/FTC + 3rd agent randomized to continue
94 93
TDF/FTC or switch to TAF/FTC (plus 3rd agent)
• TAF non-inferior to TDF in maintaining
virologic suppression
EVG/c/FTC/TAF – Nov. 2015
• TAF group:
(initial therapy & switch studies)
– increased eGFR (+8.4 vs. 2.8 ml/min)
RPV/FTC/TAF – Mar. 2016
– improved proteinuria
(bioequivalence study)
– increased BMD (1.1-1.5%)
FTC/TAF (25 mg) – April 2016
– But: increased cholesterol, LDL, TG; no
(switch studies)
difference in TC:HDL
Darunavir/c/FTC/TAF – phase III
F/TAF (n=333)
100
94.3
F/TDF (n=330)
93.0
80
60
40
20
0.3
1.5
5.4
5.5
0
Success
Slide 35 of 44
Failure
No Data
Gallant J et al, Lancet HIV, 2016
Should TAF replace TDF?
Reasons to choose TAF
Reasons to choose TDF
• TAF is virologically as effective as
TDF.
• Compared with TDF, TAF has more
favorable effects on renal and bone
markers.
− Particularly important in
patients who already have
renal or bone disease or who
are at high risk of these
complications.
• Compared with TAF, more and
longer-term data with TDF,
particularly in studies in treatment
naïve patients.
• More favorable lipid effects.
• Renal and bone marker advantages
of TAF not yet known to translate
into better clinical outcomes.
• TDF-regimens likely to be cheaper
than TAF when TDF goes generic.
• Cost of TAF- and TDF-regimens
currently similar.
Slide 36 of 44
TAF or TDF
• When should you definitely use TAF over TDF?
– Patient with osteoporosis or osteopenia
– Patient with renal disease (eGFR >30) or evidence for
proximal tubular dysfunction (e.g. proteinuria)
– Growing proportion of patients: “graying of the epidemic”
• When should you definitely not use TAF?
– Patient on rifamycin (may decrease TAF levels)
– Pregnant women
– For pre-exposure prophylaxis (PrEP)
Slide 37 of 44
Controversy 4:
How should an ART regimen be chosen in
patients with specific conditions?
ABC/3TC
DTG
TDF/FTC
TDF/FTC
RAL
DTG
TAF/FTC
DRV/r
ABC/3TC
EVG/cobi
TAF/FTC
TDF/FTC
ATV/r
EVG/cobi
ABC/3TC
EFV
NRTI
ABC/3TC
PROS
• Not nephrotoxic
• Single pill regimen with DTG
(unboosted INSTI)
CONS
• Must confirm HLA-B5701
negative
• Some studies, but not all, show
association with cardiac events
• Greater nephrotoxicity than ABC
and TAF
• Larger decline in bone mineral
density than with ABC or TAF
TDF/FTC
• Single pill regimens with EFV, RPV,
EVG/c
• Lowers lipids
• Active vs. HBV
TAF/FTC
• More favorable effects on renal and • Less long-term data, particularly
bone markers than TDF
for initial therapy
• Single pill regimens with EVG/c, RPV
• Active vs. HBV
Slide 39 of 44
Customizing ART
Scenario
Preferred Therapy
Kidney Disease
(eGFR < 60)
ABC + 3TC or TAF/FTC (if CrCl >30)
(Avoid TDF, ATV/r, LPV/r: associated with kidney disease1)
High cardiac risk
HBV
Favor TDF or TAF
TDF/FTC or TAF/FTC
(Less data with TAF; HBV indication not yet included in its
label)
Pregnancy
Osteoporosis/
osteopenia
Slide 40 of 44
ABC/3TC, TDF/FTC or AZT/3TC
plus RAL or ATV/r, DRV/r or EFV*
*after first 8 wks
Avoid TDF
1Mocroft
A et al, Lancet, 2016
ACTG A5224s: Spine BMD: TDF vs. ABC
(in combination with EFV or ATV/r)1
TDF
2
ABC
0
-1.3%
-2
-3.3%
-4
-6
0
48
Weeks
96
Median change from baseline, %
Median change from baseline, %
ABC and TAF Cause Less BMD Loss Than TDF
GS studies: Spine BMD: TDF vs. TAF
(in combination with EVG/cobi/FTC)2
TDF
2
TAF
0
-0.96%
-2
-2.8%
-4
-6
0
48
96
Weeks
• Which causes more bone loss – ABC or TAF? No head to head trials yet
• Randomized trial comparing ABC/3TC/DTG to TAF/FTC/GS-9883 (ongoing)
• In patients with osteoporosis or osteopenia: avoid TDF – use ABC or TAF
Slide 41 of 44
1McComsey GA,
JID, 2011; 2Wohl D, JAIDS, 2016
Customizing ART: Drug Interactions
Scenario
Preferred Therapy
HCV Therapy Anticipated
Often use raltegravir, dolutegravir: fewer
drug interactions
Acid-lowering therapy
Avoid or caution with rilpivirine,
atazanavir
Stagger dosing of integrase inhibitors
Cations
CYP3A4 metabolized
medications
Avoid or caution with PIs, cobi
Useful site: http://www.hiv-druginteractions.org
Slide 42 of 44
Drug Interactions: Exogenous Steroids
• Injectable steroids: levels increased by PI, cobi
– 10% of patients on PIs who received steroid injection
developed clinical evidence of steroid excess or adrenal
insufficiency1
• Inhaled fluticasone2 & budesonide3: systemic levels
increased by PI, cobi
– Beclomethasone is safer alternative4
1Hyle
2DHHS
E et al, JAIDS, 2013
guidelines for use of antiretroviral agents in HIV-1-infected adults and adolescents. http://AIDSinfo.nih.gov
3http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm336367.htm
Slide 43 of 44
4Boyd
S et al, JAIDS, 2013
HIV: What to Start in 2016
• Should all HIV-infected patients be treated?  Yes. Data
supporting same-day initiation. Case can be made for also
treating elite controllers.
• Should all HIV-infected patients be started on an INSTI-based
regimen?  Most should receive INSTI. Certain scenarios where
other regimens may be preferred.
• Should TAF replace TDF for all patients?  In patients with bone
or renal disease, TAF is particularly advantageous.
• Choosing ART in pt with comorbidities?  Customize based on
effects on bone, kidney, CV disease, HBV/HCV; drug interactions.
Slide 44 of 44
State-of-the-ART in Antiretroviral Therapy:
Optimal Initial Regimens in 2016
Rajesh T. Gandhi, MD
Director, HIV Clinical Services and Education
Massachusetts General Hospital
Boston, Massachusetts
Thanks to Alice Pau, Roger Bedimo and Marilyn
Shi for assistance with slides
Washington, DC: August 23, 2016