current controversies in managing hiv-infected patients.2014

Joseph J. Eron, Jr., MDUniversity of North Carolina School of MedicineDirector, AIDS Clinical Trials UnitUniversity of North CarolinaChapel Hill, North Carolina

Current Controversies in Managing HIV-Infected Patients

Supported by educational grants from multiple commercial supporters.

clinicaloptions.com24th Annual CCO HIV and Hepatitis C Symposium


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Controversy:Should virtually all naive patients

be started on an integrase inhibitor regimen?



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.



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 1.00

4.2

8.7

3.22.6 2.6

1.2

2.4

2.9

1.4

Margot NA, et al. CROI 2014. Abstract 578.



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.

Controversy: Should anal Pap smears be

performed routinely on all HIV+ MSM?



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.



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.



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



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




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.

Controversy: Should all HIV+ patients 50 yrs of age or older be evaluated with a

DXA scan?



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 Ratio0.01 1 100



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..



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.



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 FactorsAge, sex, weight/height, hx of fractures, secondary causes

Lifestyle AdviceSmoking 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

WorkupPhase

TreatmentPhase

Follow-upPhase

YES NO NO

10-yr fracture risk (USA) ≥ 20% major osteoporotic

AND/OR ≥ 3% hip



NRTI Component Primary Analysis

NNRTI/PI ComponentSecondary Analysis

NNRTI/PI ComponentSecondary 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

-50 24 48 96 144 192

128130

111122

105106

97101

8780

5353

Patients, nTDF/FTCABC/3TC*2-sample T-test.

Wk From Randomization

NRTI ComponentPrimary Analysis

P = .004*

Sp

ine

BM

D C

han

ge

Fro

m W

k 0

(%)

0

-1

-2

-3

-4

-50 2448 96 144 192

126128

109119

104104

9699

8579

5354

Patients, nTDF/FTCABC/3TC*2-sample T-test.


P = .024*

Hip

BM

D C

han

ge

Fro

m W

k 0

(%)

TDF/FTCABC/3TC

Patients, nEFVATV/RTV*2-sample T-test.

0

-1

-2

-3

-4

-50 24 48 96 144

133125

117116

109102

10791

8681

5848


P = .035*

192

0

-1

-2

-3

-4

-50 24 48 96 144 192

131123

114114

107101

10590

8480

5948

Patients, nEFVATV/RTV*2-sample T-test.


P = .61*

EFVATV/RTV

Hip

BM

D C

han

ge

Fro

m W

k 0

(%)



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 RALDRV/RTVCombined 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 < .001P = .001

P = .72

Brown T, et al. CROI 2014. Abstract 779LB. Reproduced with permission.



Factors Associated With Incident Fracture in the SUN and HOPS Cohorts

Battalora L, et al. CROI 2014. Abstract 781.




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

Controversy: Should all HIV+ patients be

treated with a statin regardless of their lipid levels?



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].



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 modelObserved Kaplan-Meier

5-Yr CVD Risk byAge and Diabetes Status

DM

No

DM

50+

yr

40-4

9 yr

30-3

9 yr

< 30

yr

Est

ima

ted

5-Y

r R

isk

(%)

12

10

8

6

4

2

0

Friis-Møller N, et al. EACS 2013. Abstract PS1/3. Reproduced with permission.



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.




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.

current controversies in managing hiv-infected patients.2014

Health & Medicine