Download - 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
Vo et al., JID, Juni 2008
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
Vo et al., JID, Juni 2008
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
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)
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
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
Haubrich R et al. 14th CROI 2007. Los Angeles, CA. Abstract 38.
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
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
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)
Haubrich R et al. 14th CROI 2007. Los Angeles, CA. Abstract 38.
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))
LDL-c cut off level:4mmol/L(~155mg/dL) (4-3mmol/L
(~155- ~115mg/dL))
LDL-c cut off level:5mmol/L(~190mg/dL) (5-4mmol/L
(~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
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
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
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
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
Adapted from Andrew Zolopa. CROI 2008; abstract 142.
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)
Adapted from Andrew Zolopa. CROI 2008; abstract 142.
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