Manuel Battegay Div. Infectious Diseases & Hospital Epidemiology HIV complications and morbidity.

Manuel BattegayDiv. Infectious Diseases & Hospital Epidemiology

HIV complicationsand morbidity

Content• Introduction• Selected specific adverse events• ART and body shape changes • ART, HIV and metabolism

– Cardiovascular risk general remarks– ART and Lipids– ART, Insulin resistance and diabetes– HIV and cardiovascular risk– Therapeutic approaches, Guidelines

• Immune reconstitution inflammatary syndrome

cART dramatically improves life expectancy

Type of study Decrease Mortality %

1996 Delta RCT AZT vs dual ART

1996 ACTG 175 RCT AZT vs dual ART

1997 ACTG 320 RCT Dual vs HAART

1997 SHCS OS No HAART vs HAART

1998 HOPS OS No HAART vs HAART

2003 EUROSIDA OS 96/97 HAART vs 98-02 HAART

2005 SHCS OS No HAART vs HAART

2007 Danish Coh. OS HIV versus non HIV2008 20 year old: another 43 years years life prolongation with cART Normal life expectancy (?), The ART-Cohort Collaboration, The Lancet 2008

Hammer et al NEJM 1996; NEJM 1997; Gulick et al, NEJM 1998, Lancet 1996; Lancet 1997, Egger & Battegay et al, The SHCS, BMJ 1997; Palella et al, NEJM 1998; Jaggy et al, Lancet 2003; Mocroft et al, EuroSIDA, Lancet 2003; Sterne et al, The SHCS, Lancet, 2005, Lohse N et al, Ann Med, 2007

3050

70 - 80

86

HIV Complications1. HIV

diarrhea, dementia, wasting

2. Defined HIV related complicationopportunistic diseases

3. Drug - related complication ARTOI treatmentInteraction

4. IRIS

5. Concurrent unrelated complicationCatheter related infectionUrinary tract infection

6. Unrelated diseasesTumorsCardiovascular

Battegay et al, Antiviral Ther 2007

cART switch Swiss HIV Cohort Study 2000-2005

0 2 4 6 8 10 120.0

0.2

0.4

0.6

0.8

1.02000-20012002-20032004-2005

Logrank test p=0.17Test for trend p=0.15

Time since starting cART [months]

Pro

bab

ility

of

any

trea

tmen

t ch

ang

e

Vo et al., JID, Juni 2008

Reasons for switch

2000

-200

1

2002

-200

3

2004

-200

5

2000

-200

1

2002

-200

3

2004

-200

50

20

40

60

80

100

Failure

Intolerance

Patient'swish

Physician'sdecision

Otherreasons

Treatment inter-ruption >2 weeks

Treatment switch

Calendar period

Per

cen

t

NRTI->NRTI

NNRTI->PI

NNRTI->NNRTI

PI->NNRTI

PI->PI

Both c

lass

es

Other

0

20

40

60

80

100

Patterns of treatment switches(2-class regimen only)

Per

cen

t


Trends for specific side effects

0%

20%

40%

60%

80%

100%

2001 2002 2003 2004 2005 2006

Other

CVD concerns

Kidneys

Hypersensitivity

Nervous system

Lipodystrophy

Gastro-intestinal





Hammer, S. M. et al. IAS Guidelines JAMA 2008;300:555-570.

Recommended Components of Initial Antiretroviral Therapy and Considerations for Choosing a Regimen

Hammer, S. M. et al. IAS Guidelines JAMA 2008;300:555-570.

Recommended Components of Initial Antiretroviral Therapy and Considerations for Choosing a Regimen

Time to Onset of Abacavir HSRin Clinical Trials (n=206)

Data on file, GlaxoSmithKline.

Median time to onset 9 days

89% of cases occurred within 6 weeks of ABC initiation

Serious and sometimes fatal hypersensitivity

Symptoms worsen during continued therapy with abacavir and usually resolve upon discontinuation

Hypersensitivity to Abacavir

multi‑organ clinical syndrome usually characterized by a sign or symptom in 2 or more of the following groups:

• fever• rash• gastrointestinal (including nausea, vomiting,

diarrhea, or abdominal pain)• constitutional (including generalized malaise,

fatigue, or achiness)• respiratory (including dyspnea, cough, or

pharyngitis).

OR: 0.40P < .0001

(0/802)

OR: 0.03P < .0001

PREDICT-1: Clinically Suspected or Skin Patch–Defined HSR with abacavir treatment

Mallal S, et al. NEJM 2008

2.7

7.8

0%

3.4

0

1

2

3

4

5

6

7

8

9

Clinically Suspected HSR Skin Patch-Defined HSR

Inci

den

ce (

%)

Control arm

Prospective HLA-B*5701 screening arm

10

(66/847) (27/803) (23/842)




Lipoatrophy vs Wasting Syndrome

• Lipoatrophy: loss of subcutaneous fat in face, buttocks, abdomen, and limbs

• Lean tissue: (muscle) not lost• Wasting syndrome: both fat, lean tissue, and weight

diminish

Grinspoon S, Carr A. N Engl J Med. 2005;352:48; James J et al. Dermatol Surg. 2002;11:979–986.

Lipoatrophy: Risk Factors

• Almost certainly interrelated

– Antiretroviral therapy

• Thymidine analogue exposure (d4T >ZDV)

• Combinations of ART (eg, EFV + NRTIs, NFV + NRTIs)

– Host factors

• Age

– HIV disease factors

• Duration of illness

• Severity of illness: AIDS, low CD4+ cell count

Grinspoon S, Carr A. N Engl J Med. 2005;352:48; James J et al. Dermatol Surg. 2002;11:979–986.

Lipohypertrophy• increase in fat depots —

typically visceral, dorsocervical, and breast tissue fat

• Subcutaneous fat (pinch an inch fat) does not increase

• Difficult to distinguish from general “lipohypertrophy” associated with modern living

HIV+ patient with obesity. Subcutaneous fat is thick and fat in the abdomen is

scant.

HIV+ patient with visceral adiposity. Subcutaneous fat is scant and fat in the abdomen

is thick.

CT Scans of Two HIV+ Patients

Subcutaneous Fat

(pinch an inch fat)

Visceral Fat (dark shaded areas)

Images courtesy of D.A. Wohl.

Effect of NRTIs on Limb Fat

Gallant JE et al. JAMA. 2004;292:191-201; Pozniak AL et al. JAIDS. 2006;43:535-540.

128 115134 117

Week

Study 903

Week

Study 934

51 4949 44

*P<0.001

TDF + 3TC + EFV

d4T + 3TC + EFV

Mea

n L

imb

Fat

(kg

) 8.6*

4.5

0123456789

10

48 96 144

5.0

7.9*

8.1† ‡

0

2

4

6

8

0

*P=0.034†P<0.001 §P=0.001

0

2

4

6

8

0

2

4

6

8

TDF + FTC + EFV

ZDV/3TC + EFV

To

tal L

imb

Fat

(kg

)

48 96

10

12

6.0*†§5.5

7.4*

‡P=0.01

0

10

20

30

40

50

48 96Weeks on Study

d4T

ZDV

TDF

Lipoatrophy at Weeks 48 and 96(NRTI Arms Only)

16%

8%

26%27%

9%

42%

P Values at Week 96ZDV vs TDF: <0.001d4T vs TDF: <0.001d4T vs ZDV: 0.038

d4T 93 84TDF 133 117ZDV 153 136

Lip

oat

rop

hy

(% w

ith

>20

% l

oss

)

Haubrich R et al. 14th CROI 2007. Los Angeles, CA. Abstract 38.

Lipoatrophy (>20% loss of extremity fat) at Weeks 48 and 96

0

10

20

30

40

48 96Weeks on Study

Lip

oatr

op

hy

(% w

ith

>20%

loss)

EFV

LPV/r

LPV/r + EFV

P Values at Week 96 LPV/r + EFV vs LPV/r: 0.023LPV/r + EFV vs EFV: <0.001LPV/r vs EFV: 0.003

9%

17%

32%

7%10%

21%

EFV 188 171LPV/r 191 166LPV/r + EFV 197 173


Psychosocial Impact of body shape changes• Self-evaluated quality of relationships with friends, family, sexual

partner is inversely associated with self-perception of peripheral fat loss in HIV/AIDS outpatients (N=457)1

• A survey of HIV/AIDS patients with body fat changes (N=33)2 – Social withdrawal– Adversely affected sexual relationships – Forced disclosure of HIV status due to facial lipoatrophy– Depression – Poor body image– ART noncompliance– Economic impact of surgical interventions– more challenging than living with HIV

Santos CP et al. AIDS. 2005;19(suppl 4):S14-S21. Collins E et al. AIDS Reader. 2000;10:546-551.

Conclusions

• Body shape changes are multifactorial• Lipoatrophy and lipohypertrophy do not commonly

occur together• Newer NRTI have low- or non-existing potential for

body shape changes (abacavir, tenofovir)• Body shape changes are partly reversible• Abdominal fat increases are common to all ART

regimens studied so far• The psychosocial impact is strong




CHD risk ractors in HIV - infected population

HIV Infection

ART

CHD Risk --

Diabetes*Metabolic syndrome

Lipids*

Family History

Abdominal Obesity*

Hyper-tension*

Cigarette Smoking

Hyper-glycemiaInsulin

Resistance*

Inactivity, Diet

Age

Gender

Orange = Modifiable

Green = Nonmodifiable

Multiple Risk Factors: INTERHEART

1

2

4

8

16

32

64

128

256

512

Od

ds

Rat

io (

99%

CI)

2.9(2.6-3.2)

2.4(2.1-2.7)

1.9(1.7-2.1)

3.3(2.8-3.8)

13.0(10.7-15.8)

42.3(33.2-54.0)

68.5(53.0-88.6)

182.9(132.6-252.2)

333.7(230.2-483.9)

Smoke(1)

DM(2)

ApoB/A1(4)

1+2+3 All 4 +Obesity All RiskFactors

HTN(3)

Risk Factor (adjusted for all others)

+Psycho-social

Yusuf S et al. Lancet. 2004;364:937-952.

Multiple Traditional Risk Factors Confer Synergistic Increase in Risk of MI in General Population

Lipids and CVD Risk• Increasing plasma LDL increases relative risk of CHD• A 30 mg/dL ↑ in LDL is associated with ~30% ↑ CHD risk

Re

lati

ve

Ris

k o

f C

HD

(lo

g s

cal

e)

3.7

LDL Cholesterol (mg/dL)

40 70 100 130 160 190

2.9

2.2

1.7

1.3

1.0

Grundy SM et al. Circulation. 2004;110:227-239.

Higher HDL reduces cardiovascular and hypertriglyceridemia is independently associated with CVD

Study 934: ZDV/3TC vs TDF + FTC

Pozniak AL et al. JAIDS. 2006;43:535-540.

Mea

n C

han

ge

Fro

m B

asel

ine

(mg

/dL

)

0 4 16 24 32 48 60 72 84 96

-10

0

10

20

30

40

50

Study Week

TDF + FTC + EFV

ZDV/3TC + EFV

Triglycerides Fasting LDL

P =0.12

TDF + FTC + EFV

ZDV/3TC + EFV

P =0.067

Mean Change Lipid ProfileMean Change Lipid Profile

HEAT: Lipid Effects of ABC/3TC vs TDF/FTC at Week 48

32

13 8

64

23

11

-1

38

-20

0

20

40

60

80

TC HDL LDL TG

ABC/3TC + LPV/RTV (n = 343) TDF/FTC + LPV/RTV (n = 345)

Med

ian

Ch

ang

e F

rom

BL

(%

)

Smith K, et al. CROI 2008. Abstract 774.

Lipid effects comparable between arms

A5142: LPV/r + EFV vs LPV/r + 2 NRTIs vs EFV + 2 NRTIs

*

*

*

*

*Statistically significant difference with other 2 arms, P ≤0.01.

P =0.023

P ≤0.01

NS

NS

NS

By week 96, 10% and 12% of EFV and LPV subjects used a lipid-lowering agent.

Med

ian

Ch

ang

e F

rom

Bas

elin

e (m

g/d

L)


33

9

2219

32

8

26

46

57

16

44

62

0

10

20

30

40

50

60

70

TC HDL Non-HDL TG

EFV LPV/r LPV/r + EFV

Median Changes in Lipids From Baseline Median Changes in Lipids From Baseline –– Week 96 Week 96

CASTLE: Lipid Effects of ATV/RTV vs LPV/RTV at Week 48

• 2% of ATV/RTV vs 7% of LPV/RTV subjects initiated lipid-lowering therapy during study

TC LDL HDL Non-HDL TG

Med

ian

Ch

ang

e F

rom

BL

(%

)

*P < .0001

ATV/RTV + TDF/FTC (n = 440)LPV/RTV + TDF/FTC (n = 443)

Difference estimates (%) -9.5 -2.9 -3.8 -11.6 -25.2

0

10

20

30

40

50

60

**

*

Molina JM, et al. CROI 2008. Abstract 37.

Eron JJ, et al. Lancet. 2006;368:476-482.

KLEAN: Lipid Effects of FPV/RTV vs LPV/RTV at Week 48

39 39

29

60

3341

23

66

0

20

40

60

80

100

TC HDL LDL TG

FPV/RTV 700/100 mg BID +ABC/3TC (n = 434)

LPV/RTV SGC 400/100 mg BID +ABC/3TC (n = 444)

Med

ian

Ch

ang

e F

rom

BL

(%

)

Lipid effects comparable between arms

ARTEMIS: Mean Fasting Lipid Levels Over Time for DRV/RTV vs LPV/RTV

De Jesus E, et al. ICAAC 2007. Abstract 718b.

100

200

Mea

n T

G L

evel

( ±

SE

)

Time (Wks)343 320 306346 313 301

DRV/RTV n =LPV/RTV n =

LPV/RTV + TDF/FTC

Mea

n T

C:H

DL

Rat

io (

± S

E) 5.0

4.0

3.0

4.5

3.5

1.1

2.3

1.7

2.9

NCEP cutoff

mM ng/mL250

150

24 8 1216 24 36 48

DRV/RTV + TDF/FTC

24 8 1216 24 36 48

343 320 305346 313 301

Time (Wks)

TG TC:HDL Ratio

van Leth F, et al. PLoS Med. 2004;1:e19.

2NN: Lipid Effects of EFV vs NVP at Week 48• 48-week, multicenter, open-label,

randomized trial in treatment-naive patients (N = 1216)

– NVP 400 mg QD (n = 220)

– NVP 200 mg BID (n = 387)

– EFV 600 mg QD (n = 400)

– NVP 400 mg + EFV 800 mg QD (n = 209)

– All plus d4T + 3TC

• Similar efficacy with NVP BID and EFV but NVP did not meet equivalence criteria

• Greater lipid changes with EFV

*P < .05 vs NVP.†P < .001 vs NVP.

Mea

n C

ha

ng

e in

Lip

ids

Fro

m B

asel

ine

to W

eek

48 (

%)

*

†

†

-10

0

10

20

30

40

50

TC LDL HDL TG TC:HDL

EFV + 3TC/d4T Pooled NVP + 3TC/d4T

3127

40

35 34

43

49

20

5.9

-4.1

43

Insulin Resistance

Failure of target organs to respond

normally to the action of insulin

Ability of insulin to store exogenous glucose (muscle/fat)

Ability of insulin to suppress endogenous glucose production

(liver)

Impact of Various PIs on Glucose andGlucose Disposal Rate

PI2-Hour OGTT

IDV

LPV/r

ATV/r

d4T

3TC

1. Noor MA et al. AIDS. 2001;15:F11-F18; 2. Dubé MP et al. JAIDS. 2001;27:130-134; 3. Behrens G et al. AIDS. 1999;13:F63-F70; 4. Martinez E et al. AIDS. 1999;13:805-810; 5. Walli RK et al. Eur J Med Res. 2001;6:413-421; 6. Noor MA et al. AIDS. 2002;16:F1-F8; 7. Dubé MP et al. Clin Infect Dis. 2002;35:475-481; 8. Sension M et al. Antivir Ther. 2002;7:L26; 9. Noor MA et al. AIDS. 2004;18:2137-2144; 10. Lee GA et al. Clin Infect Dis. 2006;43:658-660.

Metabolic Syndrome in HIV-Infected vs HIV-Uninfected Patients

1. Mondy K, et al. Clin Infect Dis. 2007;44:726-734. 2. Sobieszczyk ME, et al. IAS 2006. Abstract WEPE0147. 3. Jerico C, et al. Diabetes Care. 2005;28:132-137.

Conflicting data on whether metabolic syndrome more prevalent in HIV-infected patients and whether associated with antiretroviral therapy

May also reflect background regional variations in risk

Study, %

Prevalence of Metabolic Syndrome

P ValueHIV-Infected Patients

HIV-Uninfected Controls

US; 471 men and women[1] 26 27 .77

US; 2394 women[2] 33 22 < .001

Spain; 710 men and women[3] 17 N/A --

NCEP ATP III, ≥ 3 of the following: Abdominal obesity (waist circumference > 102 cm for men; >88 cm for women), TG ≥ 150 mg/dL (≥ 1.70 mmol/L), HDL < 40 mg/dL (< 1.04 mmol/L) for men, < 50 mg/dL (< 1.30 mmol/L) for women, Blood pressure ≥ 130/≥ 85 mm Hg, Fasting glucose ≥ 110 mg/dL (≥ 5.55 mmol/L)

Friis-Møller N, et al. AIDS. 2003;17:1179-1193.

Prevalence of Traditional Cardiac Risk Factors at Baseline in the D:A:D Study

Large cohort of HIV-infected patients on HAART followed longitudinally (N = 23,468)

18,962 (80.8%) with previous ART exposure; 4506 (19.2%) antiretroviral naive

Family Historyof CHD

PreviousHistory of CHD

CurrentSmoking

BMI> 30

HTN Diabetes ↑ TotalCholesterol

↑ TG0

20

40

80

Per

cen

tag

e o

f C

oh

ort

Wit

h

Ris

k F

acto

r a

t B

asel

ine

11.43.5

8.52.51.4

51.5

33.8

22.2

100

60

D:A:D Study: Incidence of MI

Friis-Moller N et al. N Engl J Med. 2007;356:1723-1735.

A Small Increase in Incident CVD Is Associated WithDuration of Combination Antiretroviral Therapy

RR per Year of ART

Overall 1.16

Men 1.13

Women 1.36

Exposure to ART (y)

Inc

ide

nce

of

MI p

er

1000

PY

0

2

4

6

8

None

10

< 1 1-2 2-3 3-4 4-5 5-6 6-7 >7

D:A:D: Traditional Risk Factors for CHD in an HIV-Infected Population

Multivariable Poisson model adjusted for age, sex, BMI, HIV risk, cohort, calendar year, race, family history of CVD, smoking, previous CVD event, TC, HDL, hypertension, diabetes.

Relative Rate of MI (95% CI)

WorseBetter

0.1 0.5 1 5 10

RR: 1.86 (1.31-2.65)Diabetes (yes vs no)

RR: 1.30 (0.99-1.72)Hypertension (yes vs no)

Family history

Previous CVD

Male sex

Age per 5 yrs older

Smoking

RR: 1.40 (0.96-2.05)

RR: 2.92 (2.04-4.18)

RR: 2.13 (1.29-3.52)

RR: 4.64 (3.22-6.69)

RR: 1.32 (1.23-1.41)

Friis-Møller, et al. N Engl J Med. 2007;356:1723-1735.

Contribution of Dyslipidemia to MI Risk

*Adjusted for conventional risk factors (sex, cohort, HIV transmission group, ethnicity, age, BMI, family history of CVD, smoking, previous CVD events, lipids, diabetes, and hypertension).

†Unadjusted model.

Relative Rate of MI* (95% CI)

0.72 (0.52–0.99); P=0.05*

1.58 (1.43–1.75); P<0.001†

1.26 (1.19–1.35); P<0.001*

1.10 (1.01–1.18); P=0.002*

1.00 (0.93–1.09); P=0.92*

Total cholesterol(per mmol/L)

Triglycerides(per log2 mmol/L higher)

HDL cholesterol(per mmol/L)

PI exposure (per additional year)

NNRTI exposure(per additional year)

1 100.1

Friis-Moller N et al. N Engl J Med. 2007;356:1723-1735.

D:A:D – study results and abacavir• 1st Feb 2007, 33,347 patients, 157,912 person-years. • 517 MI (event rate 3.3 [95% CI 3.0-3.6] per 1,000 person-

years)• Abacavir and ddI associated with increased relative risk of

MI of 1.9# and 1.49 respectively• Associated with recent abacavir and ddI use (<6mths), not

cumulative exposure. Reversible on cessation of drug therapy

• Association remained after adjustment for HIV-RNA levels, CD4 count, dyslipidaemia, blood pressure, diabetes, fat loss/gain or latest glucose, Most pronounced in patients with a high underlying cardiovascular risk

• Insufficient data to assess TDF and FTC

D:A:D Study Group, The Lancet, 26 April, 2008

D:A:D – study results and abacavir• Analysis of 54 clinical trials involving 9,639

subjects exposed to ABC (7845 pyrs) and 5,044 subjects treated with non-ABC-containing regimens (4653 pyrs)

• Incidence of myocardial ischaemic events and MI similar regardless of therapy.

• no increased risk of coronary or myocardial events in any of the ABC-treated groups.

• Analysis of spontaneous reports submitted to GSK and the FDA found no signal of an increased risk of MI associated with use of ABC.

• 1 million patient years of abacavir experienceCutrell A et al, The Lancet, 26 April, 2008

Parameter HR (95% CI)

Death from any cause

Death from major cardiovascular, renal and hepatic events

1.8

1.7

1.0 5.00.1 Favors TI Favors CT

Risk o

f C

om

plicatio

ns

SMART: Treatment Interruption Associated With Increased CV Risk

2 HIV treatment strategies assessed for overall clinical benefit: CT or CD4-guided TI

TI associated with significantly greater disease progression or death, compared with CT: RR: 2.5 (95% CI: 1.8-3.6; P < .001)

El-Sadr W, et al. N Engl J Med. 2006;355:2283-2296.

Law MG, et al. HIV Med. 2006;7:218-230.Friis-Moller N, et al. CROI 2007. Abstract 808.

Framingham Underpredicts MI Risk in HIVAge, Sex, TC, HDL, Smoking, SBP, Medication for HBP

Observed and Predicted MI Rates According to ART Exposure(D:A:D Study)

0

1

2

3

4

5

6

7

8

Duration of cART Exposure (Yrs)

Rat

es p

er 1

000

Per

son

-Yrs

< 1 1-2 2-3 3-4 > 4

Observedrates

Best estimate

of predicted rates

None

Does not include HIV-specific factors; Immune status, Increased inflammatory markers, Insulin resistance

Conclusions• Strong correlation between LDL-C and CVD risk• HDL-C independent predictor of CVD• cART associated with increased risk of CVD, but

uncontrolled HIV infection also risk for CV events• Other traditional risks for CVD prevalent, including

those that can be modified (smoking)• NRTIs, NNRTIs, and PIs have varying effects on

lipids, insulin resistance, and fat distribution changes• Boosted PIs associated with increased prevalence of

dyslipidemia, although evidence suggests that RTV contributes substantially to lipid effects

Prevention of cardiovascular diseaseEACS guidelines 2007

Estimate risk of IHD (Ischaemic Heart Disease) in next 10 yrs

IHD risk <10% IHD risk 10-20%IHD risk >20%, prior CVD,

type II diabetes, type I diabetes with microalbuminuria

Encourage lifestyle changes (diet, exercise, cessation of smoking), reduce visceral fat, reduce insulin resistance and treat hypertension

LDL-c cut off level:3mmol/L(~115mg/dL) (3-2mmol/L

(~115- ~80mg/dL))


(~155- ~115mg/dL))


(~190- ~155mg/dL))

Consider modifying ART if:LDL-c is above cut off, i ART thought to contribute to ↑ LDL-c level, if possible without compromising HIV suppression



If lifestyle changes, with or without modification of ART, do not result in sufficient lowering of LDL-c to below target level, use of lipid-lowering medication should be considered

Accessed from http://www.eacs.eu/guide/index.htm

Dietary Prevention of Dyslipidemia

• Randomized trial of NCEP diet in adults initiating ART (N = 90)– 95% on ZDV/3TC

– 75% on EFV

• 15- to 30-minute session with a dietician every 3 months

• Other outcomes – Reduced fat, calorie intake

– Reduced BMI

– Increased dietary fiber intake

Lazzaretti F, et al. IAS 2007. Abstract WEAB303.

Diet Control

100

120

140

160

180

200

220

TC

(m

g/d

L)

406080

100120140160180200220240

6

TG

(m

g/d

L)

Smoking Cessation: Nonpharmacologic Therapy

• Interventions– Identify reasons for quitting

– Discuss options

– Set a quit date, chosen by the patient

– Set up a support system

– Identify rationalizations

– Identify alternatives for cravings

– Provide reliable sources of information

– Refer to local smoking cessation programs

Effective Smoking Cessation Strategies

• DHHS guidelines: pharmacotherapy for all patients attempting to quit smoking except those with medical contraindications – Approved pharmacotherapies: sustained-release bupropion, varenicline,

nicotine gum, inhaler, nasal spray, and patch

• More intensive intervention strategies significantly more effective than less intensive ones– Counseling sessions lasting > 3 minutes and > 10 minutes were 1.3-fold

and 2.3-fold, respectively, more likely to result in abstinence vs < 3 minutes

– 8 sessions were 2.3-fold more likely to result in abstinence vs 0-1 sessions

– Treatment by various clinician types, individualized counseling, and multiple intervention strategies associated with successful outcomes

Elzi L et al, Antiviral Therapy 2006, Fiore MC. Respir Care. 2000;45:1200-1262.

Interactions Between Antiretrovirals and Smoking Cessation Drugs

• Varenicline – No reported drug interactions with antiretroviral agents– minimal metabolism, 92% excreted unchanged in the urine

• Bupropion– Metabolized in liver by various CYP450 enzymes, predominantly

CYP2B6 – LPV/RTV and bupropion coadministration resulted in significantly

decreased concentrations of bupropion and hydroxybupropion[1] – Administration of ritonavir alone—most potent CYP3A4 inhibitor—

may slow buproprion metabolism[2]

– Patients receiving boosted PIs should be monitored carefully for bupropion lack of efficacy and adverse effects

1. Hogeland GW, et al. Clin Pharmacol Ther. 2007;81:69-75. 2. Hesse LM, et al. Drug Metab Dispos. 2001;29:100-102

Lipid-Lowering Therapy Overview

Nicotinic Acid

LDL , TG , HDL

Side effects: flushing, hyperglycemia, hyperuricemia, upper GI distress, hepatotoxicity

Statins

LDL , TG , HDL

Side effects: myopathy,

liver enzymes

Fibric Acids

LDL , TG , HDL

Side effects: dyspepsia, gallstones, myopathy

Ezetimibe LDL , TG , HDL Side effects: liver enzymes,

diarrhea

Omega-3 Fatty Acids

LDL , TG , HDL

Side effects: GI, taste

Bile Acid Sequestrants

LDL , TG , HDL

Side effects: GI distress/ constipation, absorption

of other drugs

Inhibit production of cholesterol

Augment lipoprotein lipase (VLDL)

Balancing ART and Lipid-Lowering Agents

FibratesFluvastatinPravastatin*Ezetimibe

Low InteractionPotential

Statin-FibratesAtorvastatinRosuvastatin

Lovastatin Simvastatin

UseCautiously

Contraindicated With PIs

Lipid Management With ART in HIV-Infected PatientsPotential Drug–Drug Interactions With PIs

Dubé M et al. Clin Infect Dis. 2003;37:613-627; Van Der Lee M et al. 13th CROI 2006. Denver, CO. Abstract 588; Prezista [package insert]. Raritan, NJ: Tibotec Therapeutics; 2006.

*Not recommended with darunavir/ritonavir.

Lipid-Lowering Therapy vs Switching PI

• 12-month, open-label study of 130 patients; 60% male; mean age: 39 years

• Stable on first HAART regimen randomized to

– PI EFV (n = 34)– PI NVP (n = 29)– Add bezafibrate (n = 31)– Add pravastatin (n = 36)

• Pravastatin or bezafibrate significantly more effective in management of hyperlipidemia than switching ART to an NNRTI

Calza L, et al. AIDS. 2005;19:1051-1058.

0 3 6 9 12Months

350300

250

200

150

100

50

00 3 6 9 12

Months

Me

an

Pla

sm

a T

Gs

(mg

/dL

)M

ea

n C

ho

les

tero

l(m

g/d

L)

350

300

250

200

150

100

50

0

Mallolas J, et al. IAS 2007. Abstract WEPEB117LB.

ATAZIP: Switch From LPV/RTV to ATV/RTV

TG LDL HDLTC

-60

-40

-20

0

20

P < .0001Ch

ang

e at

Wee

k 48

(m

g/d

L)

P < .0001

Continue LPV/RTV

Switch to ATV

Randomized trial of patients on LPV/RTV > 6 months randomized to continue LPV/RTV 400/100 mg BID (n = 127) or switch to ATV/RTV 300/100 mg QD (n = 121)

Strategies for Managing Hypertriglyceridemia

NCEP ATP III final report. Circulation. 2002;106:3143-3421.

Initial intervention: dietary modifications

Consider antiretroviral switch options

If TG > 500-1000 mg/mL (> 5.65-11.30 mmol/L) and antiretroviral switch not possible, consider fibrates

– Gemfibrozil 600 mg BID or fenofibrate 200 mg QD associated with 20% to 50% decrease in TG in general population

If hypertriglyceridemia remains uncontrolled

– Fish oil (up to 6 g/day) or niacin (0.5 to 2g twice-dialy) can be added

– Niacin associated with flushing and increased insulin resistance




IRIS = Inflammatory Immune Reconstitution Syndrome Incidence 3-25%

CD4 very low CD4 function and increase +++

Pathogen +++

Before ART

Advanced diseaseHigh pathogen endemicity

Battegay et al, JAC, 2008, Hirsch et al, CID 2004, French et al, AIDS 2004; Shelbourne et al, Med 2002

Threshold clinical disease

Pathogen (+)

After ART initiation

ART early initiationVL decrease, CD4 increaseInflammation

Pathogen specific immunity inflammation

A5164 Methods: Study Schema, n=282

Study day

Enrollment

OI/BI Treatment

Starts

Immediate Arm

Start ARTn=141

Deferred ArmStart ART

N=141

RecommendedStart window

48wks

48wks

-14 0 2 28 42 84 224

Immediate vs. Deferred ART in the Setting of Acute AIDS-Related OIs: Final Results of a Randomized Strategy TrialACTG A5164

Adapted from Andrew Zolopa. CROI 2008; abstract 142.

A5164: Safety outcomes over 48 weeks

Outcome P-Value Immediate Deferred

IRIS Reported 10 13

IRIS Confirmed 8 (5.7%) 12 (8.5%)

Outcome P-Value Immediate Deferred

Lab Adverse Events

Grades 2-3-40.77 31 – 39 – 20 36 – 45 – 21

Clinical Adverse Events

Grades 2-3-40.87 14 – 40 – 7 34 – 29 – 6


Immediate Deferred

CD4 (cells/mm3) Med (IQR) 31 (12 – 54) 28 (10 – 56)

Multiple OI/BI < 30 32% 33%

PCP n (%) 88 (62) 89 (63)

A5164: Time to AIDS progression or death

00.10.20.30.40.50.60.70.80.9

1

4 12 20 28 36 44

Immediate

Deferred

Pro

bab

ilit

y o

f S

urv

ivin

g W

ith

ou

t D

eath

/New

AID

S-D

efin

ing

Ill

nes

s

Time to Death/New AIDS-Defining Illness (Weeks)


HR=0.5399%CI (0.25, 1.09)

P = 0.023

116

94

Better CD4 increase, non significantly different VL results Less clinical progression

4 12 20 28 36 44

NEW NIH DHHS Guidelines„Some experts base the timing of initiation of antiretroviral therapy in treatment-naive patients with active TB disease on CD4 cell counts at the start of treatment, as shown below

• CD4 <100 ART after 2 weeks • CD4 =100–200 ART after 8 weeks • CD4 = 200–350 ART after 8 weeks* • CD4 >350 ART after 8-24 weeks or

after end of TB treatment*

* On case by case basis in clinician’s judgment.

A rifamycin should be included for pts receiving ART (dose adjustment) (AII). Rifabutin is the preferred rifamycin in HIV-infected pts with active TB disease due to its lower risk of substantial interactions with ART (AII).

Compiled from Benson et al at http://aidsinfo.nih.gov/guidelines/ 2008

Manuel Battegay Div. Infectious Diseases & Hospital Epidemiology HIV complications and morbidity.

Documents

haart vs haart

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