Current Controversies in Managing HIV-Infected Patients.2014

1. Joseph J. Eron, Jr., MD
University of North Carolina School
of Medicine
Director, AIDS Clinical Trials Unit
University of North Carolina
Chapel Hill, North Carolina
Current Controversies in
Managing HIV-Infected Patients
Supported by educational grants from multiple commercial supporters.

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3. Controversy:
Should virtually all naive patients
be started on an integrase
inhibitor regimen?

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Key INSTI Trials in Treatment-Naive Pts
 STARTMRK: RAL noninferior to EFV in HIV-1 RNA < 50 c/mL at Wk 48
primary endpoint (ITT, NC = F analysis); superior from Wk 192[1]
 Study 102: EVG/COBI noninferior to EFV at Wk 48 primary endpoint[2]
and
through Wk 144[3,4]
 Study 103: EVG/COBI arm noninferior to ATV/RTV at Wk 48 primary
endpoint[5]
and through Wk 144[6,7]
 SINGLE: DTG superior to EFV at Wk 48 primary efficacy endpoint[7]
and
through Wk 96[8]
 FLAMINGO: DTG superior to DRV/RTV at Wk 48 primary efficacy endpoint[9]
 ACTG 5257: Considering both efficacy and tolerability, RAL superior to both
ATV/RTV and DRV/RTV[10]
1. Rockstroh J, et al. J Acquir Immune Defic Syndr. 2013;63:77-85. 2. Sax PE, et al. Lancet. 2012;379:2439-2448.
3. Zolopa A, et al. J Acquir Immune Defic Syndr. 2013;63:96-100. 4. Wohl D, et al. ICAAC 2013. Abstract H-672a.
5. De Jesus E, et al. Lancet. 2012;379:2429-2438. 6. Rockstroh J, et al. J Acquir Immune Defic Syndr. 2013;62:483-486.
7. Clumeck N, et al. EACS 2013. Abstract LBPS7/2. 8. Walmsley S, et al. N Engl J Med. 2013;369:1807-1818.
9. Walmsley S, et al. CROI 2014. Abstract 543. 10. Landovitz R, et al. CROI 2014. Abstract 85.

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Prevalence of Drug Resistance Mutations
in Treatment-Naive Patients, 2000-2013
 Baseline plasma samples from
4 phase III trials (GS 903, 934,
104, 111, N = 2531)
– 1617 samples analyzed for
integrase mutations
– 2531 analyzed for protease or
RT mutations
 Substantial ↑ in prevalence of
NNRTI resistance, modest ↑ in
PI resistance
 Stable prevalence of NRTI
resistance (mostly TAMs)
– M184V/I ≤ 0.2%; K65R ≤ 0.2%
 Little evidence of transmitted
INSTI resistance over period
– Mostly T97A polymorphism
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
Margot NA, et al. CROI 2014. Abstract 578.

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Expert Panel Discussion
 Multiple studies demonstrating noninferior or superior outcomes
with INSTI-based regimens in naive pts (see slide 4)
 Recent data have shown that once-daily dolutegravir has a high
barrier to resistance and good tolerability[1,2]
– Real world clinical data are currently lacking
 ACTG 5257 showed superiority of raltegravir vs boosted PI
regimens[3]
– Current twice-daily dosing of raltegravir is one drawback
– Boosted PI regimens may be a good choice for patients at risk for
nonadherence due to lower risk of resistance
1. Walmsley S, et al. CROI 2014. Abstract 543. 2. Pozniak A, et al. CROI 2013. Abstract 179LB.
3. Landovitz RJ, et al. CROI 2014. Abstract 85.

7. Controversy:
Should anal Pap smears be
performed routinely
on all HIV+ MSM?

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NYS Department of Health Guidelines:
Recommendations for Anal Pap Smears
 At baseline and as part of the annual physical examination for all HIV-infected
adults, regardless of age, clinicians should:
– Inquire about anal symptoms, such as itching, bleeding, diarrhea, or pain
– Perform a visual inspection of the perianal region
– Perform a digital rectal examination
 Clinicians should refer women with cervical HSIL and any patient with
abnormal anal physical findings for high-resolution anoscopy and/or
examination with biopsy of abnormal tissue
 Clinicians should obtain anal cytology at baseline and annually in the following
HIV-infected populations
– Men who have sex with men
– Any patient with a history of anogenital condylomas
– Women with abnormal cervical and/or vulvar histology
New York State Dept Health AIDS Institute. Anal Dysplasia and Cancer, July 2007.

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HIVMA/IDSA Primary Care Guidelines
 MSM, women with a history of receptive anal intercourse
or abnormal cervical Pap test results, and all HIV-infected
persons with genital warts should have anal Pap tests
(weak recommendation, moderate quality evidence)
 If abnormal findings, then high-resolution anoscopy should
be performed with biopsy of abnormal areas and
appropriate therapy based on biopsy results
Aberg, et al. HIVMA/IDSA. Primary Care Guidelines. 2013.

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Suggested Paradigm for Screening and
Follow-up
Chin-Hong PV, et al. Clin Infect Dis. 2002;35:1127-1134.
 Repeat in 12 mos (HIV+)
 Repeat in 2-3 yrs (HIV−)
High-resolution anoscopy
with biopsy
No lesion seen
Follow up every 6 mos
AIN II or IIIAIN I
Treat
Anal cytology screening
Normal ASCUS HSILLSIL

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Premalignant Lesions of the Anus
 Squamous intraepithelial lesion (SIL)
– Typically used for cytology
– Atypical cells of undetermined significance (ASCUS)
– Low-grade squamous intraepithelial lesion (LSIL)
– High-grade squamous intraepithelial lesion (HSIL)
 Anal intraepithelial neoplasia (AIN)
– Typically used for histology
– AIN1, AIN2, AIN3
– AIN1 = low grade
– AIN2 and 3 = high grade

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Expert Panel Discussion
 Recommendations on anal Pap smears are controversial
– No evidence to support efficacy in preventing anal cancer
– CDC guidelines do not recommend annual anal Pap
smears[1]
 Screening on patients < 30 yrs of age not recommended
 Access to experienced professionals is critical for follow-
up management of patients with positive Pap smears
 Digital rectal exam should be performed as part of routine
anal cancer screening
1. CDC. Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and
Adolescents. 2013.

13. Controversy:
Should all HIV+ patients 50 yrs of
age or older be evaluated with a
DXA scan?

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Both Osteopenia and Osteoporosis Are
Common in the HIV+ Population
Brown T, et al. AIDS. 2006;20:2165-2174.
Odds of Osteoporosis in HIV-Infected Patients Compared With HIV-Uninfected Controls
Study
Amiel (2004)
Brown (2004)
Bruera (2003)
Dolan (2004)
Huang (2002
Knobel (2001)
Loiseau-Peres (2002)
Madeddu (2004)
Tebas (2000)
Teichman (2003)
Yin (2005)
Overall (95% Cl)
Odds Ratio (95% Cl)
5.03 (1.47-17.27)
4.26 (0.22-82.64)
4.51 (0.26-79.27)
2.11 (0.54-8.28)
3.52 (0.15-81.92)
5.13 (1.80-14.60)
4.28 (0.46-39.81)
29.84 (1.80-494.92)
3.40 (0.19-61.67)
17.41 (0.97-313.73)
2.37 (1.09-5.16)
3.68 (2.31-5.84)
Odds Ratio
0.01 1 100

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Recommendations for DXA Screening in
HIV+ Persons
 HIVMA/IDSA Guidelines[1]
: baseline bone densitometry
(DXA) screening for osteoporosis in HIV-infected patients
should be performed in postmenopausal women and men
aged 50 yrs or older (strong recommendation, moderate
quality evidence)
 McComsey et al[2]
: we recommend a DXA scan for all
HIV-infected postmenopausal women and men aged 50
yrs or older
1. Aberg, et al. HIVMA/IDSA. Primary Care Guidelines. 2013.
2. McComsey G, et al. Clin Infect Dis. 2010;51:937-946..

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EACS: Recommendations for DXA
 EACS: consider DXA in any
patient with ≥ 1 characteristic
– Postmenopausal women
– Men ≥ 50 yrs of age
– History of low-impact fx or high
risk for falls
– Clinical hypogonadism
– Oral glucocorticoid use
(minimum 5 mg prednisone
equivalent for > 3 mos)
 Preferably perform DXA in
those with above risk factors
prior to ART initiation
 Assess fracture risk by
including DXA results in the
FRAX score
– Only use if patient is older than
40 yrs of age
– May underestimate risk in HIV
patients
– Consider using HIV as
secondary cause of
osteoporosis
EACS v. 6.1. November 2012.

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Management of Bone Disease in HIV
McComsey G, et al. Clin Infect Dis. 2010;51:937-946.
≥ 50 yrs ♂, postmenopausal ♀,
AND/OR hx of fracture?
Measure BMD by DXA
HIV-Infected Individual
Assess Risk Factors
Age, sex, weight/height, hx of
fractures, secondary causes
Lifestyle Advice
Smoking cessation, vitamin D/calcium
intake, weight-bearing exercise, sun
exposure
Secondary cause
Calculate FRAX score
T-score > -2.5 and ≤ -1
NO fragility fracture
Monitor DXA in 2-5 yrsMonitor DXA in 1-2 yrs
Evaluate potential secondary
causes identified in history
< 50 yrs ♂, premenopausal ♀,
AND NO hx of fracture?
Lifestyle Advice
Continue ART
T-score > -1
NO fragility fracture
Lifestyle Advice
Continue ART
WAIT
T-score ≤ -2.5 OR fragility
fracture
Consider bisphosphonate or
other treatment
Treat secondary cause
YES
Consider
Initial
Approach
Indications
for DXA
Workup
Phase
Treatment
Phase
Follow-up
Phase
YES NO NO
10-yr fracture risk (USA)
≥ 20% major osteoporotic
AND/OR ≥ 3% hip

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NRTI Component
Primary Analysis
NNRTI/PI Component
Secondary Analysis
NNRTI/PI Component
Secondary Analysis
Loss of Bone With Initiation of ART in
ACTG 5224 (5202 Substudy)
 Change in spine (left) and hip
(right) BMD with ART
 Top panels: ABC vs TDF
 Bottom: EFV vs ATV/RTV
McComsey G, et al. J Infect Dis. 2011;203:1791-1801.
0
-1
-2
-3
-4
-5
0 24 48 96 144 192
128
130
111
122
105
106
97
101
87
80
53
53
Patients, n
TDF/FTC
ABC/3TC
*2-sample T-test.
Wk From Randomization
NRTI Component
Primary Analysis
P = .004*
SpineBMDChange
FromWk0(%)
0
-1
-2
-3
-4
-5
0 2448 96 144 192
126
128
109
119
104
104
96
99
85
79
53
54
Patients, n
TDF/FTC
ABC/3TC
*2-sample T-test.
Wk From Randomization
P = .024*
HipBMDChange
FromWk0(%)
TDF/FTC
ABC/3TC
Patients, n
EFV
ATV/RTV
*2-sample T-test.
0
-1
-2
-3
-4
-5
0 24 48 96 144
133
125
117
116
109
102
107
91
86
81
58
48
Wk From Randomization
P = .035*
192
0
-1
-2
-3
-4
-5
0 24 48 96 144 192
131
123
114
114
107
101
105
90
84
80
59
48
Patients, n
EFV
ATV/RTV
*2-sample T-test.
Wk From Randomization
P = .61*
EFV
ATV/RTV
HipBMDChange
FromWk0(%)

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P = .004
ACTG 5257: Loss of BMD With First-line
Boosted PI vs RAL
 All arms associated with
significant loss of BMD
through Wk 96 (P < .001)
 Total body BMD loss
significantly greater with
ATV/RTV than either
DRV/RTV or RAL
 At hip and spine, similar
loss of BMD in the PI arms
– Significantly greater loss
in the combined PI arms
than in the RAL arm
ATV/RTV
RAL
DRV/RTV
Combined PI arms
-5
-4
0
-3
-2
-1
-3.9
-1.7
-3.4
-2.9
-3.7
-2.4
-1.8
-4.0
-3.8
-3.6
-1.6
P = .36
Total Hip Total Spine Total Body
P = .005
P = .42
P < .001
P = .001
P = .72
Brown T, et al. CROI 2014. Abstract 779LB. Reproduced with permission.

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Factors Associated With Incident Fracture
in the SUN and HOPS Cohorts
Battalora L, et al. CROI 2014. Abstract 781.

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Expert Panel Discussion
 DXA scans are relatively inexpensive, painless, and easily
interpreted
 There is great potential to improve outcomes for patients
with abnormal DXA results
– Explore secondary causes of osteoporosis
 Measuring vitamin D levels is an important complementary
screening measure for bone loss, though data are lacking
on the ideal levels and mode of supplementation

22. Controversy:
Should all HIV+ patients be
treated with a statin regardless
of their lipid levels?

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ACC/AHA: Patient Groups in Whom a
Statin Should Be Recommended
 Individuals with atherosclerotic cardiovascular disease
(coronary heart disease, stroke, or peripheral arterial
disease)
 Individuals with LDL ≥ 190 mg/dL
 Individuals 40-75 yrs of age with diabetes and LDL
between 70-189 mg/dL
 Individuals without atherosclerotic cardiovascular disease
or diabetes 40-75 yrs of age with LDL between 80-189
mg/dL and with an estimated 10-yr cardiac risk of
atherosclerotic cardiovascular disease of 7.5% or higher
using a pooled cohort risk assessment equation
Stone NJ, et al. J Am Coll Cardiol. 2013;[Epub ahead of print].

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D:A:D: Framingham Model
Underestimates CVD Risk in HIV+ Patients
 Classic CVD risk factors
important in HIV+ pts
 Framingham appears to
underestimate risk
compared with D:A:D
models
Framingham
modelD:A:D reduced
modelD:A:D full model
Observed Kaplan-Meier
5-Yr CVD Risk by
Age and Diabetes Status
DMNo
DM
50+
yr40-49
yr30-39
yr<
30
yr
Estimated5-YrRisk(%)
12
10
8
6
4
2
0
Friis-Møller N, et al. EACS 2013. Abstract PS1/3. Reproduced with permission.

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Atorvastatin and Immune Activation in
HIV+ Patients
 In randomized, double-blind, placebo-controlled trial of
atorvastatin 80 mg vs placebo in 24 HIV+ pts not on ART
– HIV-1 RNA level unaffected
– Atorvastatin resulted in reductions in circulating proportions
– CD4+/HLA-DR+ cells (-2.5%; P = .02)
– CD8+/HLA-DR+ cells (-5%; P = .006)
– CD8+/HLA-DR+/CD38+ cells (-3%; P = .03)
Ganesan J, et al. J Infect Dis. 2011;203:756-764.

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Expert Panel Discussion
 In practice, statins are generally prescribed only to HIV-
infected patients with elevated lipids
 HIV infection is associated with high levels of inflammation
regardless of viral suppression by ART
– HIV infection could potentially be considered a risk factor for
cardiovascular disease
 Recent data indicate that statin use results in lower levels
of inflammatory biomarkers[1]
and greater improvement in
CD4+ cell counts[2]
in HIV-infected patients on stable ART
1. Funderburg N, et al. CROI 2014. Abstract 335. 2. Drechsler HJ, et al. CROI 2014. Abstract 308.