What I Use and Why: Expert Strategies for Selecting the Best ART Regimen for Each Patient.2015

What I Use and Why:
Expert Strategies for Selecting the
Best ART Regimen for Each Patient
This activity is supported by an independent educational grant
from ViiV.

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Evidence-Based Strategies for Individualizing ART Regimens
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Faculty and Disclosure Information
Joseph J. Eron, Jr., MD
Professor of Medicine and Epidemiology
University of North Carolina School of Medicine
Director, AIDS Clinical Trials Unit
University of North Carolina
Chapel Hill, North Carolina
Joseph J. Eron, Jr., MD, has disclosed that he has received
funds for research support from GlaxoSmithKline/ViiV and
Janssen and consulting fees from AbbVie, Bristol-Myers Squibb,
GlaxoSmithKline/ViiV, Gilead Sciences, Merck, Tibotec/Janssen,
and Tobira.

Other Faculty Who Contributed to This
Program
David A. Cooper, MD, DSc
Director, Kirby Institute
University of New South Wales
Sydney, Australia
Eric S. Daar, MD
Chief, Division of HIV Medicine
Harbor-UCLA Medical Center
Professor of Medicine
David Geffen School of Medicine at
UCLA
Los Angeles, California
Sally Hodder, MD
Director, Clinical Translation Science
Institute
West Virginia University
Morgantown, West Virginia
Daniel R. Kuritzkes, MD
Chief, Division of Infectious Diseases
Brigham and Women’s Hospital
Harvard Medical School
Boston, Massachusetts
Anton L. Pozniak, MD, FRCP
Consultant Physician
Director of HIV Services Department of
HIV and Genitourinary Medicine
Chelsea and Westminster Hospital
NHS Foundation Trust
London, United Kingdom
Mark A. Wainberg, PhD
Director, McGill AIDS Centre
McGill University
Montreal, Quebec, Canada

Program Overview
 What I Use and Why – Series of case scenarios discussed
at recent IAS and ICAAC satellite symposia
– Patient cases addressing the following topics:
– When to start
– What to start
– Switching

Case 1: Young patient
hesitant to start therapy

Patient History
 HH is a 34-year-old woman diagnosed with HIV 3 yrs ago
– Not ready to start treatment at that time
– Baseline CD4+ count: 1175 cells/mm3
; HIV-1 RNA: 6125 c/mL
 Current disease parameters:
– CD4+ count: 995 cells/mm3
, HIV-1 RNA: 17,525 c/mL
– No transmitted drug resistance
– HLA-B*5701: negative
– CBC, urea and electrolytes, liver function tests: normal
– HBV immune; HCV Ab negative
 No significant medical history

Social History
 Husband died in South America 4 years ago of MDR TB
 No children, no regular partner
– No sexual activity since HIV diagnosis
 Has a sister living nearby, but the rest of her family resides
in South America
 She has missed several previous appointments, saying it
is hard to get time off work, and she feels well anyway

What I Would Do
 On balance, I would initiate ART in this patient
 Considerations that support the decision to start:
– Clear data on benefits of early ART
– Labs suggest her HIV disease has progressed since time of
diagnosis
– Potential for prevention of MDR-TB
– Prevention of onward HIV transmission
 Considerations that support waiting to start ART:
– Low event rate at high CD4+ cell counts
– Potential adherence concerns

START: Immediate vs Deferred ART
 International, randomized phase IV study: 215 sites in 35 countries
 Study stopped by DSMB following results of interim analysis
– Overall HR: 0.43 (P < .001)
– HR for serious AIDS-related events: 0.28 (P < .001)
– HR for non-AIDS–related events: 0.61 (P = .04)
Serious AIDS and
Non-AIDS Events, n
42
96
Lundgren JD, et al. IAS 2015. Abstract MOSY0301. Lundgren JD, et al. N Engl J Med. 2015;[Epub ahead of print].
Immediate ART
Delayed ART
(until CD4+ cell count
≤ 350 cells/mm³)
Treatment-naive
pts with CD4+ cell count
> 500 cells/mm³
(N = 4685)

START: Serious AIDS and Non-AIDS
Events
Components of the
Primary Endpoint
Immediate ART
(n = 2326)
Deferred ART
(n = 2359)
HR (95% CI) P Value
n n/100 PY n n/100 PY
Serious AIDS-related event 14 0.2 50 0.72 0.28 (0.15-0.50) < .001
Serious non-AIDS–related
event
29 0.42 47 0.67 0.61 (0.38-0.97) .04
Death from any cause 12 0.17 21 0.3 0.58 (0.28-1.17) .13
Tuberculosis 6 0.09 20 0.28 0.29 (0.12-0.73) .008
Kaposi’s sarcoma 1 0.01 11 0.16 0.09 (0.01-0.71) .02
Malignant lymphoma 3 0.04 10 0.14 0.3 (0.08-1.10) .07
Cancer not related to AIDS 9 0.13 18 0.26 0.5 (0.22-1.11) .09
Cardiovascular disease 12 0.17 14 0.2 0.84 (0.39-1.81) .65
Lundgren JD, et al. IAS 2015. Abstract MOSY0301.
Lundgren JD, et al. N Engl J Med. 2015;[Epub ahead of print].
 68% of serious AIDS-related and non-AIDS–related events occurred in pts
with CD4+ cell count > 500 cells/mm3

HPTN 052: Immediate vs Delayed ART in
Serodiscordant Couples
 HIV transmission reduced by 93% with immediate ART (10-yr
analysis) Total HIV-1 Transmission Events: 78
(19 in immediate arm and
59 in delayed arm)
Linked
Transmissions: 46
Unlinked
Transmissions: 32
P < .001
Immediate
Arm: 3
Delayed
Arm: 43
Cohen MS, et al. IAS 2015. Abstract MOAC0101LB.
No linked HIV transmission (from
index participant to partner) occurred
while index participant was receiving
ART and had stable virologic
suppression

HPTN 052: Decrease in AIDS-Related
Events in Immediate vs Delayed ART Arms
Subjects Experiencing
≥ 1 AIDS-Related Event Delayed Immediate
Tuberculosis, n (%) 34 (4) 17 (2)
Severe bacterial infection, n (%) 13 (1) 20 (2)
WHO stage 4 event*, n (%) 19 (2) 9 (1)
Esophageal candidiasis, n 2 2
Cervical carcinoma, n 2 0
Extrapulmonary cryptococcosis, n 0 1
HIV-related encephalopathy, n 1 0
Herpes simplex (chronic), n 8 2
Kaposi’s sarcoma, n 1 1
Primary CNS lymphoma, n 1 0
Pneumocystis pneumonia, n 1 0
Recurrent septicemia, n 0 2
HIV wasting, n 2 0
Recurrent severe bacterial
pneumonia, n
1 2
 Non-AIDS events infrequent, with
similar numbers of events in each arm
Grinsztejn B, et al. Lancet Infect Dis. 2014;14:281-290.
Time to First AIDS-Defining Disease
Logrank P = .031
FailureProbability
Yrs Since Randomization
0 51 2 3 4
.25
.20
.15
.10
.05
0
886
875
829
822
454
435
169
165
35
31
35
29
Immediate ART
Delayed ART
Pts at Risk, n
*Excluding tuberculosis.

When To Start Guideline Updates Reflect
Latest Data
 ART now recommended for all HIV-infected pts worldwide,
regardless of CD4+ cell count
– Updated WHO guidance released September 2015[1]
 DHHS ART guidance panel statement released July 2015,
strengthening recommendation for initiating ART at any CD4+
cell count[2]
– “With the availability of the START and TEMPRANO trial results,
the Panel’s overall recommendation remains the same: ART is
recommended for all HIV-infected patients regardless of pre-
treatment CD4 count. However, the strength of the
recommendation will be changed to AI (strong recommendation
based on data from randomized controlled trials) for all patients.”
1. WHO. Sept 2015. http://www.who.int/hiv/pub/guidelines/earlyrelease-arv/en/.
2. DHHS ART Panel Statement. July 2015.

Case 2: Young, asymptomatic
patient with no comorbidities

Patient History
 SH, a 28-year-old MSM who works as a lawyer for a bank
 Diagnosed with HIV in 2012
 Baseline disease parameters:
– CD4+ cell count: 895 cells/mm3
– HIV-1 RNA: 48,750 copies/mL

Current Presentation
 Current visit (September 2015):
– Complete blood count, urea and electrolytes, liver function
tests: all normal
– Sexual health screen: negative; prior syphilis treated
 You advise SH that he should start ART

Social History
 Compliant with regular 6 monthly visits and attends all of
his appointments
 No current partner
 Occasional cannabis, alcohol, nothing else recreational
 Takes over-the-counter vitamins, minerals
 No other medications
 Has no preferences regarding type of ART regimen

What I Would Do
 Eligible for any of recommended regimens. Most would offer simplicity of
single-tablet regimen
– DTG/ABC/3TC
– EVG/COBI/TDF/FTC
– RPV/TDF/FTC
– I also keep DTG plus TDF/FTC on the list I discuss
 Both ABC and TDF would be appropriate because he has no cardiovascular
or bone/renal issues and he is HLA-B*5701 negative
 My approach for this patient would be to have a discussion with him
regarding his lifestyle and specific features of each of the regimens above
(pill size, food requirements, potential future drug-drug interactions, etc.)
to determine his preferences
– If he is unable to decide based on that discussion, I would recommend either
DTG/ABC/3TC or DTG plus TDF/FTC

Comparison of Current International
Guidelines for Treatment-Naive Pts
Regimen DHHS[1]
IAS-USA[2]
EACS[3]
BHIVA[4]
WHO[5]
EFV/TDF/FTC
RPV/TDF/FTC
ATV/RTV + TDF/FTC
DRV/RTV + TDF/FTC
DTG/ABC/3TC
DTG + TDF/FTC
EVG/COBI/TDF/FTC
RAL + TDF/FTC
1. DHHS Guidelines. April 2015. 2. Günthard H, et al. JAMA. 2014;312:410-425. 3. EACS HIV Guidelines.
V 8. October 2015. 4. BHIVA Guidelines. 2015. 5. WHO Guidelines. June 2013.
Preferred/recommended Alternative Not listed

Efficacy of Coformulated Regimens at
Wk 48 Primary Endpoint
Single-Tablet
Regimen
HIV-1 RNA < 50 c/mL at
Wk 48, %
Trials Considered
EFV/TDF/FTC 81-90 ACTG 5202[1]
; GS 102[2]
;
STARTMRK[3]
; SINGLE[4]
;
ECHO/THRIVE[5]
; STaR[6]
RPV/TDF/FTC 84-86 ECHO/THRIVE[5]
; STaR[6]
EVG/COBI/TDF/FTC 88-90 GS102[2]
; GS103[7]
;
GS104/111[8]
DTG/ABC/3TC 86-90 SINGLE[4]
; SPRING[9]
;
FLAMINGO[10]
1. Daar ES, et al. Ann Intern Med. 2011;154:445-456. 2. Sax PE, et al. Lancet. 2012;379:2439-2448.
3. Lennox JL, et al. Lancet. 2009;374:796-806. 4. Walmsley S, et al. N Engl J Med. 2013;369:1807-1818.
5. Cohen C, et al. Lancet. 2011;378:238-246. 6. Cohen C, et al. AIDS. 2014;28:989-997.
7. De Jesus E, et al. Lancet. 2012;379:2429-2438. 8. Wohl DA, et al. CROI 2015. Abstract 113LB.
9. Raffi F, et al. Lancet. 2013;381:735-743. 10. Clotet B, et al. Lancet. 2014;383:2222-2231.

Most Widely Recommended Single-Tablet
Regimens: Advantages & Disadvantages
Regimen Advantages Disadvantages
RPV/TDF/FTC[1,2]  Compared with EFV
– Better tolerated
– Reduced risk of
rash
– Lipid neutral
 Switch data available
 Lower virologic efficacy for
VL > 100K c/mL, CD4+ < 200 cells/mm3
 Must be taken with food
 DDIs (including acid-reducing agents)
 DHHS: no longer among recommended first-
line therapies
EVG/COBI/TDF/FTC[3]  Virologic efficacy
 Tolerability
 More clinical experience
than DTG/ABC/3TC
 Switch data available
 Drug interactions
 Early Cr increase
 Cannot be used in pts with CrCl < 70 mL/min
 Must be taken with food
 Caution with divalent cations
DTG/ABC/3TC[4]  Virologic efficacy
 Tolerability > EFV,
DRV/RTV
 Few drug interactions
 Lipid neutral
 Less resistance
 No meal restrictions
 Mixed data on CVD risk with ABC
 Cannot be used in
HLA-B*5701–positive pts
 Early Cr increase
 Least experience in clinical practice
 Not sufficient for HBV
 Caution with divalent cations
1. RPV/TDF/FTC [package insert]. 2. DHHS Guidelines 2015. 3. EVG/COBI/TDF/FTC [package insert].
4. DTG/ABC/3TC [package insert].

Drug-Drug Interaction and Food
Considerations
 INSTIs
– Polyvalent cations should not be taken at the same time
– Exceptions: RAL can be taken with calcium carbonate
antacids; DTG can be taken with calcium or iron supplements
with food, or if separated 2 hrs before or 6 hrs after
 Rilpivirine
– Must be taken with food
– Contraindicated in combination with proton pump inhibitors
(eg, omeprazole)
– Caution and separate timing required for antacid or
H2-receptor antagonist coadministration

Case 3: Older asymptomatic
patient with diabetes and
hypertension

Patient History
 TM is a 58-year-old man with newly diagnosed
asymptomatic HIV infection
 He has reasonably well-controlled hypertension and
diabetes while taking the following medications:
– Metformin
– Sulfonylurea
– ACE inhibitor
 Nonsmoker, occasional alcohol use
 His father had MI at 62 years of age

Laboratory Parameters
 Baseline laboratories are as follows:
– Calculated creatinine clearance: 80 mL/min
– Urinalysis: 2+ proteinuria

What I Would Do
 The following regimens would be reasonable options:
– RAL + TDF/FTC
– DTG*/ABC/3TC or DTG + TDF/FTC
– Note DTG may increase metformin levels when coadministered
– EVG/COBI*/TDF/FTC
– Note COBI would likely increase DDI potential in an older patient with
comorbidities such as this
– DRV/RTV* or COBI* + TDF/FTC
 Based upon overall tolerability, convenience, and efficacy of
preferred options, I would use DTG + TDF/FTC with careful
monitoring of renal function and dose reduction of metformin
*COBI, DTG, and to lesser extent RTV associated with reduced active secretion of creatinine in renal
tubules leading to initial increases in creatinine levels after starting treatment.

Why I Eliminated Other Options
 Other INSTIs
– EVG and RAL both viable options which I would have strongly
considered
 NNRTIs
– EFV has inferior tolerability and RPV is not an option for patients
with HIV-1 RNA > 100,000 copies/mL
 Boosted PI + TDF/FTC
– Potential for increased TDF toxicity with boosted PI and potentially
not as well tolerated as DTG
 ABC-containing options
– I try to avoid ABC in patients with elevated CVD risk
 ABC- and TDF-sparing regimens
– Data limited

Studies Addressing Abacavir and MI
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
randomized)
STEAL[5]  Preplanned secondary analysis of RCT (use of ABC
randomized)
Swiss HIV Cohort[6]  Cohort (prospective)
FHDH ANRS CO4[7]
? Nested case-control study
NA-ACCORD[8]
? Cohort (retrospective)
VA Clinical Case Registry[9]
X Cohort (retrospective)
Brothers et al analysis[10]
X Post hoc meta-analysis of RCTs
ACTG A5001/ALLRT[11]
FDA meta-analysis[12]
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. Antiviral Ther. 2008;13:177-187.
5. Martin A, et al. AIDS. 2010;24:2657-2663. 6. Young J, et al. J Acquir Immune Defic Syndr. 2015;[Epub ahead of print].
7. Lang S, et al. AIDS. 2010;24:1228-1230. 8. Palella F, et al. CROI 2015. Abstract 749LB.
9. Bedimo RJ, et al. Clin Infect Dis. 2011;53:84-91. 10. Brothers CH, et al. J Acquir Immune Defic Syndr. 2009;51:20-28.
11. Ribaudo HJ, et al. Clin Infect Dis. 2011;52:929-940. 12. Ding X, et al. J Acquir Immune Defic Syndr. 2012;61:441-447.

Tenofovir DF and Chronic Kidney Disease
 TDF has been associated with renal tubulopathy and
requires dose adjustment in patients with renal impairment
 EVG/COBI/TDF/FTC should not be administered to
patients with eGFR < 70 mL/min
TDF [package insert]. EVG/COBI/TDF/FTC [package insert].

TDF + Boosted PI and CKD
 Higher incidence of CKD among patients receiving TDF
+ PI vs TDF without a PI (IRR: 3.1 vs 1.3; P < .001)[1]
 Greater decline in renal function among patients
receiving TDF + PI vs TDF + NNRTI[2,3]
 Higher incidence of renal events among women
receiving TDF + LPV/r vs TDF + NVP (OR: 3.12;
P = .019)[4]
1. Morlat P, et al. PLoS One. 2013;8:e66223. 2. Goicoechea M, et al. J Infect Dis. 2008;197:102-
108. 3. Gallant JE, et al. AIDS. 2009;23:1971-1975. 4. Mwafongo A, et al. AIDS. 2014;28:1135-1142.

Comparing 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
 Once-daily dosing
 Requires COBI boosting
 COBI drug interactions
similar to RTV
Dolutegravir  The only non-TDF–
containing single-tablet
regimen
 Once-daily dosing
 Higher barrier to resistance
 Few drug interactions
 Active against some RAL-
and EVG-resistant virus
 Coformulated with ABC/3TC
only
 Increases metformin levels

Wk 48
Wk 96
Wk 144
-5% 15%0
Favors
EFV/TDF/FTC
Favors
DTG+ABC/3TC
2% 14.6%
8.3%
7.4%
12.3%
8.0%
13.8%
2.5%
2.3%
-12% 25%0
Favors
DRV/RTV
Favors
DTG
7.1%
13.2%
12.4%
20.2%
0.9%
4.7%
-12% 12%0
Favors
RAL
Favors
DTG
2.4%
7.1%
4.5%
10%
-2.2%
-1.1%
HIV-1 RNA < 50 c/mL by Snapshot Analysis: 95% CI for Treatment Difference
SINGLE[1]
FLAMINGO[2]
SPRING-2[3]
1. Walmsley S, et al. J Acquir Immune Defic Syndr. 2015;[Epub ahead of print]. 2. Molina JM,
et al. Glasgow HIV 2014. Abstract O153. 3. Raffi F, et al. Lancet. 2013;381:735-743.
Dolutegravir Phase III Trials in Treatment-
Naive Patients

What if… he experienced progressive
renal dysfunction during ART?
 TM was started on DTG + TDF/FTC with good tolerability
and viral suppression for the last 18 mos
 Although DM and HTN remained controlled, he has
experienced progressive decline in CrCl to 40-50 mL/min
with stable 2+ proteinuria

What if… he experienced progressive
renal dysfunction during ART?
 Switch to ABC + dose-adjusted 3TC + DTG
– Concern about ABC in patient with multiple cardiovascular
risk factors
 Switch to ABC- and TDF-sparing regimen
– Data for suppressed and treatment-naive patients with
boosted PI alone and with 3TC
– Data for treatment-naive patients with boosted PI + INSTI
– Limited data in suppressed patients using INSTI + NNRTI

 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
CCR5
Antag.
TDF ABC
Other
NRTI
No
NRTI
ART use,% 44 42 24 3 65 22 7 5
Wk 48Wk 24

GS-112: Key Results
Change in eGFR From
Baseline to Wk 48
Actual GFR by Iohexol Clearance
From Baseline to Wk 24
Gupta S, et al. IAS 2015. Abstract TUAB0103.
TDF Non-TDF
MedianChange
FromBaseline
10
0
-10
+0.2
-1.8 -1.5
-2.7*
Baseline: 58 53 56 50
eGFRCG
mL/min
eGFRCKD-EPI Cr
mL/min/1.73 m2
*P < .05
IohexolClearance(mL/min)
BL Wk
2/4/8
Wk
24
63
50
62
48
63
49
0
20
40
60
80 Non-TDFTDF
BL Wk
2/4/8
Wk
24
GLSM Ratio vs
BL (% [90% CI]):
98
(94-102)
100
(96-105)
96
(86-108)
98
(87-111)

Case 4: Woman with PCP and
no available HIV resistance data

Patient History
 LW, a 32-year-old black woman presenting to the
emergency department
 No past medical history except for 3 wks of tactile fevers,
nonproductive cough, and increasing dyspnea on exertion
– Also reports 20-lb weight loss over the last 3 months
 Physical exam shows oral thrush
 Arterial blood gases show PO2 of 64 mmHg
 Diagnosis of PCP confirmed

HIV Laboratory Parameters
 Rapid HIV test is positive and confirmed
 HIV genotype is sent and pending
 CD4+ cell count: 31 cells/mm3
 HIV-1 RNA: 210,000 copies/mL
 HLA-B*5701: negative
 HBV immune

Clinical Course
 Patient is started on trimethoprim/sulfamethoxazole +
prednisone
 During the first 5 days of hospitalization, the patient
becomes afebrile and has decreasing shortness of breath
 The patient is switched to oral medications, and after 7
days of hospitalization is prepared for discharge
– HIV genotype pending

What I Would Do
 I would start ART immediately with boosted DRV + NRTIs because:
– Randomized controlled ACTG 5164 trial showed reduced risk of new AIDS
events or death in patients with PCP who received ART within 2 wks of
diagnosis
– Very little evidence of transmitted resistance to boosted PIs with little risk
of resistance even if there is transmitted NRTI resistance
– Once suppressed and genotype is back can always switch to simpler
regimen
 Alternative option would be DTG + TDF/FTC
– Transmitted INSTI resistance has been rarely reported
– Available data suggest higher genetic barrier to resistance with DTG than
other INSTIs
– DTG generally better tolerated than boosted PIs

ACTG A5164: Reduced Risk of AIDS/Death
With Immediate ART During Acute OI
 Median duration from start of
OI treatment to initiation of
ART
– Immediate group: 12 days
– Deferred group: 45 days
 92% treatment naive
– Median CD4+ count:
29 cells/mm3
– Median VL: 5.07 log10 c/mL
 Safety and incidence of IRIS
similar between groups
PatientsProgressingto
AIDSorDeathatWk48(%)
100
80
60
40
20
0
14.2
24.1
Immediate Deferred
P = .035
Zolopa AR, et al. PLoS One. 2009;4:e5575.

Prevalence of Drug-Resistance Mutations
in Treatment-Naive Patients
 Baseline plasma samples
from 4 phase III trials 2000-
2013 (N = 2531)[1]
– 1617 samples analyzed for
integrase mutations
– 2531 analyzed for protease
or RT mutations
– Little evidence of transmitted
INSTI resistance
– Mostly T97A polymorphism
 No transmitted INSTI resistance among 339 genotypic
resistance tests from treatment-naive pts at 13 CA AIDS
Healthcare Foundation sites Mar 2013 to Jun 2015[2]
1. Margot NA, et al. CROI 2014. Abstract 578. 2. Volpe JM, et al. ICAAC 2015. Abstract.
2000 (GS-903)
2003 (GS-934)
2013 (GS-104/GS-111)
0
2
NNRTI
10
4
6
8
NRTI PI INSTI
0.5 1.0
0
4.2
8.7
3.2
2.6 2.6
1.2
2.4
2.9
1.4

Low Virologic Failure and Treatment-
Emergent Resistance With Boosted PIs
Trial Name F/u,
Wks
Treatment Arm Virologic
Failure, n (%)
Treatment-Emergent
Primary Mutations, n
CASTLE[1]
96
ATV/RTV + TDF/FTC (n = 440) 28 (6) 1 (PI), 7 (NRTI)
LPV/RTV + TDF/FTC (n = 443) 29 (7) 10 (NRTI)
ACTG 5202[2]
96
ATV/RTV + NRTIs (n = 928) 140 (15) 1 (PI), 16 (NRTI)
EFV + NRTIs (n = 929) 129 (14) 68 (NNRTI), 36 (NRTI)
Study 103[3]
144
ATV/RTV + TDF/FTC (n = 355) NR (7) 2 (NRTI)
EVG/COBI/TDF/FTC (n = 353) NR (8) 8 (INSTI), 8 (NRTI)
ARTEMIS[4]
96
DRV/RTV + TDF/FTC (n = 343) NR (12) 2 (NRTI)
LPV/RTV + TDF/FTC (n = 346) NR (17) 5 (NRTI)
FLAMINGO[5]
96
DRV/RTV + 2 NRTI (n = 242) 4 (2) 0
DTG + 2 NRTI (n = 242) 2 (< 1) 0
ACTG 5257[6]
96
ATV/RTV + TDF/FTC (n = 605) 95 (16) 1 (INSTI), 8 (NRTI)
DRV/RTV + TDF/FTC (n = 601) 115 (19) 1 (INSTI), 3 (NRTI)
RAL + TDF/FTC (n = 603) 85 (14)
1 (INSTI), 7 (NRTI),
10 (INSTI + NRTI)
1. Molina JM, et al. J Acquir Immune Defic Syndr. 2010;53:323-332. 2. Daar ES, et al. Ann Intern Med. 2011;154:445-456.
3. Clumeck N, et al. J Acquir Immune Defic Syndr. 2014;65:e121-e124. 4. Mills A, et al. AIDS. 2009;23:1679-1688.
5. Molina JM, et al. Glasgow HIV 2014. Abstract O153. 6. Lennox JL, et al. Ann Intern Med. 2014;161:461-471.

Low Virologic Failure and Lack of
Treatment-Emergent Resistance With DTG
Trial Name
F/u,
Wks
Treatment Arm
Virologic
Failure, n (%)
Treatment-Emergent
Primary Mutations, n
SPRING-2[1]
96
DTG + 2 NRTI (n = 411) 22 (5) 0
RAL + 2 NRTIs (n = 411) 29 (7) 1 (INSTI), 4 (NRTI)
SINGLE[2]
144
DTG + ABC/3TC (n = 414) 39 (9) 0
EFV/TDF/FTC (n = 419) 33 (8) 1 (NRTI), 6 (NNRTI)
FLAMINGO[3]
96
DTG + 2 NRTI (n = 242) 2 (< 1) 0
DRV/RTV + 2 NRTI (n = 242) 4 (2) 0
Study 102[4]
144
EFV/TDF/FTC (n = 352) NR (10) 4 (NRTI), 14 (NNRTI)
Study 103[5]
144
ATV/RTV + TDF/FTC (n = 355) NR (7) 2 (NRTI)
1. Raffi F, et al. Lancet Infect Dis. 2013;13:927-935. 2. Pappa K, et al. ICAAC 2014. Abstract H-647a.
3. Molina JM, et al. Glasgow HIV 2014. Abstract O153. 4. Wohl DA, et al. J Acquir Immune Defic Syndr.
2014;65:e118-e120. 5. Clumeck N, et al. J Acquir Immune Defic Syndr. 2014;65:e121-e124.

Case 5: Suppressed on efavirenz,
considering switch

Patient History
 MZ, 38-year-old male mental health nurse living in Los
Angeles
 Receiving EFV/TDF/FTC for 1 year with viral suppression,
but still struggles with dizziness, abnormal dreams, and
chronic depression
 Aware of new US and UK ART guidelines
– With more options now available, expresses interest in
switching to another newer single-tablet regimen

Patient History (continued)
 Occasional alcohol, no other recreational substances
 No other drugs/medicines

Disease and Lab Parameters
 Current disease and laboratory parameters:
– HIV-1 RNA: < 50 copies/mL
– Baseline drug resistance: not done
– Complete blood count, urea and electrolytes, liver function
tests, chest x-ray: all normal
– HBV immune; HCV ab negative
– Sexual health screen: negative

What I Would Do
 I would switch this patient’s regimen to either EVG/COBI/TDF/FTC or
DTG/ABC/3TC
 Concerns regarding long-term CNS effects of EFV
– Clinical trial data suggest association between EFV and suicidality but not
confirmed to date in cohort analyses
 Unlikely this patient will want to increase his pill burden
 Studies of switch from EFV/TDF/FTC to RPV/TDF/FTC,
EVG/COBI/TDF/FTC, or DTG/ABC/3TC have shown good
maintenance of virologic suppression
 Other potential switch option: coformulated DRV/COBI + 2 NRTIs, but
no supporting data yet

2014-2015 Guidelines on Efavirenz for
Treatment-Naive Pts
 DHHS[1]
: Alternative
 IAS-USA[2]
: Recommended
 WHO[3]
: Recommended
 EACS[4]
: Alternative
 BHIVA[5]
: Alternative
1. DHHS Guidelines. April 2015. 2. Günthard H, et al. JAMA. 2014;312:410-425. 3. WHO Guidelines.
June 2013. 4. EACS HIV Guidelines. V 8.0 October 2015. 5. BHIVA Guidelines. 2015.

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
 Risk of attempted or completed suicide
also associated with EFV (HR: 2.58;
95% CI: 0.94 to 7.06; P = .065)
 EFV also associated with increased risk
of death from injury, substance use, or
unknown causes
– Careful attention should be paid to
cause of death in all clinical trials
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 2.15 (1.20-3.87) .01
Age category, yrs
< 30
30-44
≥ 45
2.82 (1.25-6.34)
1.69 (0.81-3.55)
1.00 (reference)
.04
Hx IDU 2.18 (1.11 -4.30) .02
Psychiatric hx or
psychoactive rx 3.90 (2.23 -6.82) < .001
EFV
EFV-free
0.05
0.04
0.03
0.02
0.01
0
Probability
1920 24 48 72 96 120 144 168
Wks to Suicidality

 Insurance claims data obtained from commercial insurance database and
multistate Medicaid database
 Suicidality determined by medical coding
 Primary outcome: suicidality (coded as suicidal ideation or suicide attempt)
 Secondary outcomes
– Suicide attempt (coded as suicide and self-inflicted injury)
– Injuries consistent with suicide attempt (coded as poisoning, open wounds,
asphyxiation)
 Adjusted HR for primary outcome of suicidality (vs EFV-free regimens)
– Commercial database: 1.03 (95% CI: 0.64-1.67)
– Medicaid database: 0.90 (95% CI: 0.62-1.32)
Nkhoma E, et al. IDWeek 2014. Abstract 646.
Real-World Assessment of Suicidality Risk
Among Pts Initiating EFV

Principles of ART Switch
 Maintain viral suppression (do no harm or don’t mess up)
 Need to know beforehand:
– Previous ART history
– Previously demonstrated or possible/probable ARV resistance
based on history
– Drug-resistant virus remains archived in latently infected cells and
does not disappear even if not detected by resistance tests
– Likelihood of patient adherence to new regimen and its
requirements
– Patient acceptance of any new potential adverse effects
– Other medications for potential DDIs
– Affordability
 Use available evidence to guide switch decisions

*P < .001
†
P < .01 (comparison with baseline within treatment group)
SubjectReportingSymptoms(%)
HIV Symptom Index
Vivid Dreams Insomnia Anxiety Dizziness
100
136
224
75
212
65
101
56
87
119
224
84
209
48
100
41
87
103
222
71
208
40
100
34
87
90
225
49
211
37
99
32
87
BL Wk48 BLWk48 BL Wk48 BLWk48 BLWk48 BLWk48 BL Wk48 BL Wk48
Pozniak A, et al. Lancet Infect Dis. 2014;14:590-599.
STRATEGY-NNRTI: Outcomes in Pts
Switching From EFV-Based Therapy
70
60
50
40
30
20
10
0
61
35*
64 64
53
40†
48 47 46
34†
40 39 40 37 37
23*
EVG/COBI/TDF/FTC
NNRTI + TDF/FTC
 Switch noninferior to continued NNRTI regimen
– Wk 48 HIV-1 RNA < 50 c/mL: 93% vs 88% (P = .
066)

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 c/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. Abstract.
*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: Switch to DTG/ABC/3TC
Noninferior to Maintaining Baseline ART
 No pt met criteria for protocol-defined virologic failure
 D/c for AEs: 4% DTG/ABC/3TC vs 0 BL ART; grade 3/4 AEs: 3%
DTG/ABC/3TC vs 2% BL ART; serious AEs: 2% in each arm
 Small, nonprogressive serum Cr ↑ in DTG/ABC/3TC arm due to known DTG
inhib. of tubular Cr secretion; no significant lipid changes in either arm
 Significantly greater improvement in treatment satisfaction score with switch to
DTG/ABC/3TC vs continuing BL ART
Trottier B, et al. ICAAC 2015. Abstract.
Outcomes at Wk 24, %
ITT-Exposed Population Per Protocol Population
DTG/ABC/3TC
(n = 274)
Baseline ART
(n = 277)
DTG/ABC/3TC
(n = 220)
Baseline ART
(n = 215)
Virologic success 85 88 93 93
Virologic nonresponse 1 1 < 1 2
No virologic data 14 10 6 5
Treatment difference (95% CI) -3.4 (-9.1 to 2.3) -0.3 (-4.9 to 4.4)

Take-Home Points on First-line ART and
Switch Strategies
 National/international guidelines on first-line ART changing
– Shifting away from NNRTIs
– Shifting toward INSTIs
– Still include some PIs
 Key principles for selecting among the available choices
– Convenience
– NRTI backbone
– Efficacy/safety/drug–drug interactions
 Primary focus when switching ART is maintaining viral
suppression

Go Online for More From CCO
on Selecting Initial and Switch ART
Regimens!
ClinicalThought™ commentaries by expert faculty focusing on the
practical application of new data, guidelines and regulatory developments
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What I Use and Why: Expert Strategies for Selecting the Best ART Regimen for Each Patient.2015

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