Infektion und Infektion und Dyslipoproteinämie Dyslipoproteinämie Mechanismus und Bedeutung Mechanismus und Bedeutung für die für die Atherosklerose Atherosklerose Prof. Dr. Dr. h.c. W.F. Riesen Institut für Klinische Chemie und Hämatologie Kantonsspital, St. Gallen IKCH
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Scientific background for Scientific background for global risk assessmentglobal risk assessment
•• In predicting the occurrence of myocardial infarctions, risk algIn predicting the occurrence of myocardial infarctions, risk algorithms are orithms are superior to individual risk factors.superior to individual risk factors.
•• The better an algorithm is able to detect a risk patient, the moThe better an algorithm is able to detect a risk patient, the more effectivere effectiveresources can be applied. resources can be applied.
Strukturelle Verwandtschaft vonStrukturelle Verwandtschaft vonLpLp(a) und (a) und PlasminogenPlasminogen
I II III IV V
V ProteaseIV
ProteasePlasminogen
Apo (a)
1 2 - 29 30 31 32 33 34 35 36 3728
Incidence of Coronary EventsIncidence of Coronary Events(per 1'000 in 10 years)(per 1'000 in 10 years)
Data from PROCAMData from PROCAM
II
300300
00
100100
200200
4646
IVIV VVIIIIII
26262323000000 00
IIII
LpLp(a)(a) 0.2 g/l0.2 g/l
LpLp(a)(a) < 0.2 g/l< 0.2 g/l
135135 127127
257257
Quintiles of estimated CHD riskQuintiles of estimated CHD riskVonVon EckardsteinEckardstein;; JACC,JACC, 20012001
Infektion/Inflammation sind mit einer Zunahme der HMGInfektion/Inflammation sind mit einer Zunahme der HMG--CoACoA ReduktaseReduktase assoziiert.assoziiert.Allerdings ist die Expression der übrigen Enzyme mitAllerdings ist die Expression der übrigen Enzyme mit MevalonatmetabolismusMevalonatmetabolismus vermindert.vermindert.
MMäässige Zunahme der ssige Zunahme der hepatischenhepatischen Cholesterinsynthese und andere Cholesterinsynthese und andere MevalonatmetaMevalonatmeta--bolitenboliten werden Nonwerden Non--SterolSterol--Wegen zugefWegen zugefüührt.hrt.
PotentialPotential ProatherogenicProatherogenic Changes and Effects ofChanges and Effects ofLipoprotein during Infection and InflammationLipoprotein during Infection and Inflammation
Changes Effects
VLDLIncreased VLDL levels Provides lipid substrates for macrophage uptakeDecreased LPL and HL Decreases clearance of triglyceride-rich lipoproteinsDecreased tissue Decreases lipoprotein clearance apo E expression
LDLIncreased small Increases susceptibility to oxidation; increases LDL penetration throughdense LDL endothelium; increases interaction with arterial wall proteoglycans and
LDL retention in arterial wallIncreased sphingo- Facilitates LDL aggregation and uptake into macrophageslipid contentIncreased Increases LDL oxidation ceruloplasmin
HDLDecreased HDL Impairs apolipoprotein-mediated cholesterol removal from cellsand apo A-IDecreased LCAT Impairs cholesterol removal from cells by diffusion mechanismDecreased CETP Impairs cholesterol transfer to triglyceride-rich lipoproteinsDecreased HL Reduces pre- HDL generationDecreased PLTP Reduces pre- HDL generation; decreases HDL phospholipid content and
impairs cholesterol removal by increasing cholesterol flux from HDL into cells
Colagreco: J of Ass Nurses in AIDS Care 2004; 15: 30-41
Reported Changes of Lipids during InfectionReported Changes of Lipids during Infection
ClinClin ChemChem 32, 198632, 1986
Study Species Infecting agent TC TG HDL-C -LP -LP pre -LP1 Hu Gram +2 Hu Gram + and –3 Hu Gram –4 Ra Gram +5 Hu Gram + N
Gram – NViral hepatitis
6 Ra Gram +7 Mo Gram +
Gram –8 Hu Virus N N–9 Ra Gram +
10 Hu Gram – 011 Ha Virus12 Mo Gram + N N
Gram – N13 Hu Virus14 Hu Viral hepatitis 0 015 Hu P. vivax 0 016 Hu Virus –N17 Hu P. vivax18 Hu Cytomegalovirus19 Hu Gram + and –
Concentrations of Lipids in Serum of the Reference NormalConcentrations of Lipids in Serum of the Reference NormalPopulation, Patients with Sepsis, and Patients with Population, Patients with Sepsis, and Patients with Similar Pathologies but without Infections (Controls)Similar Pathologies but without Infections (Controls)
ClinClin ChemChem 32, 198632, 1986
TC HDL-C TG Albumin Apo-A Apo-Bmmol/l mmol/l mmol/l g/L
Significantly (p <0.05) different from Significantly (p <0.05) different from aathethe reference normal population or reference normal population or bbthethe controls.controls.
Mean Values for Serum Lipids, Mean Values for Serum Lipids, ApoproteinsApoproteins, and, andAlbumin in Patients who died (Albumin in Patients who died ( ) or recovered () or recovered (o)o)
BarsBars indicateindicate meanmean and SD. and SD. ShadedShaded areasareas indicateindicate normalnormal rangerange..
Incidence of Myocardial Infarction According to the Incidence of Myocardial Infarction According to the Duration of Exposure to Combination Antiretroviral TherapyDuration of Exposure to Combination Antiretroviral Therapy
The Data Collection on Adverse Events of Anti-HIV Drugs (DAD) Study Group, N Engl J Med 2003;349:1993
Plasma Levels of LipidsPlasma Levels of LipidsChange
1Group includes 37 subjects receiving ritonavir + saquinavir and 9 subjects receiving ritonavir alone
2Group includes 11 subjects receiving nelfinavir + saquinavir and 10 subjects receiving nelfinavir alone
3P 0.001 vs change in PI-naive group4 P 0.05 vs change in PI-naive group5 P 0.01 vs change in PI-naive group
Périard et al: Circulation 1999; 100: 700-705
Incidence of Abnormalities of Serum Lipid LevelsIncidence of Abnormalities of Serum Lipid Levelsat the End of 1 Year Followat the End of 1 Year Follow--up in 212 HIVup in 212 HIV--infectedinfected
treated Patients who received different PItreated Patients who received different PI
20
70
Inc
ide
nc
e (
%)
RTV0
10
30
40
50
60
SQV IDV NFV APV
Protease inhibitors
Hypertriglyceridemia
Hypercholesterolemia
LPV/RTV
Calza et al: JAC 2004; 53: 10-14
ConclusionConclusion
Use of HIV PIs is associated withUse of HIV PIs is associated with
atherogenicatherogenic lipoprotein changes and lipoprotein changes and
endothelial dysfunction. Because these endothelial dysfunction. Because these
metabolic and vascular changes predispose metabolic and vascular changes predispose
toto atherosclerosisatherosclerosis, monitoring and treatment , monitoring and treatment
ofof dyslipidemiadyslipidemia in patients taking these in patients taking these
medications is warranted.medications is warranted.
Circulation 2001; 104: 257-262
Association of Combination Antiretroviral Therapy andAssociation of Combination Antiretroviral Therapy andOther Cardiovascular Risk Factors with the Rate of Other Cardiovascular Risk Factors with the Rate of
Mode of HIV-1 transmission 0.32 0.28Homosexual 1.00 1.00Heterosexual 0.69 (0.44-1.08) 1.13 (0.69-1.88)Intravenous drug use 0.76 (0.47-1.23) 1.49 (0.88-2.55)Other 0.32 (0.04-2.31) 0.30 (0.04-2.19)Unknown 0.98 (0.50-1.90) 1.40 (0.68-2.86)
The Data Collection on Adverse Events of Anti-HIV Drugs (DAD) Study Group, N Engl J Med 2003; 349: 1993-2003
Association of Combination Antiretroviral Therapy andAssociation of Combination Antiretroviral Therapy andOther Cardiovascular Risk Factors with the Rate of Other Cardiovascular Risk Factors with the Rate of
Myocardial Infarction (23’468 Patients) cont.Myocardial Infarction (23’468 Patients) cont.Variable Univariable Model Multivariable Model
Relative Rate Relative Rate(95% CI) P Value (95% CI) P Value
The Data Collection on Adverse Events of Anti-HIV Drugs (DAD) Study Group, N Engl J Med 2003; 349: 1993-2003
Changing Rates of Use of Antiretroviral Drugs Changing Rates of Use of Antiretroviral Drugs (Panel A) and Vascular Events and Death (Panel B)(Panel A) and Vascular Events and Death (Panel B)
DyslipoproteinämieDyslipoproteinämie bei Infektionbei Infektion
HIV und HIV und LipideLipide
Behandlung der Behandlung der DyslipoproteinämieDyslipoproteinämie beibeiHIVHIV--PatientenPatienten
LipidLipid--lowering Response in lowering Response in DyslipidemicDyslipidemic HAARTHAART--treated HIVtreated HIV--infected Patientsinfected Patients
Drug regimens No. of % Change mean (median)patientsa
Triglycerides Total cholesterol HDL-cholesterolmg/dl mg/dl mg/dl
First line LLD regimenb 103 -26 (-32) -19 (-17) +9 (+5)(median follow-up 44 weeks) p<0.002 p<0.003 p=NS
Second line LLD regimenc 33 -44 (-40) -25 (-26 +0.5 (+0.4)(median follow-up 25 weeks) p<0.02
Third line LLD regimend 15 -25 (-30) -9 (-10) +7 (+5)(median follow-up 20 weeks) p = NS
Pooled lipid lowering effect stratified by drug class:Fibrates 77 -11 (-40)e -9 (-7)e +24 (+1)Fibrates + statinsf 20 -32 (-42)g -23 (-22)e +5 (+5)Statinsf 38 -1 (-21) -11 (-14)g +2 (0)a More than one drug and drug class were used for a single patientbFirst line LLD regimen: 71% treated with fibrates, 28% with statins and 1% with fibrates + statins;median follow-up of 44 weeks
c Second line LLD regimen: 15% treated with fibrates, 39% with statins and 45% with fibrates + statins;median follow-up of 30 weeks
dThird line LLD regimen: 13% treated with fibrates, 40% with statins and 47% with fibrates + statins;median follow-up of 20 weeks.
e = p<0.001f Statins used were: atorvastatin 49%, pravastatin 20%, simvastatin 19%, lovastatin 12%g= p<0.05 Visnegarwala et al: J of Infection 2004; 49: 283-290
Overall Response to LipidOverall Response to Lipid--lowering Drugs among lowering Drugs among DyslipidemicDyslipidemic HAARTHAART--treated HIVtreated HIV--infected Patients (N=103)infected Patients (N=103)
Cholesterol
-100
-50
0
50
100
Pre
cen
tag
ech
an
ge f
rom
baselin
e
TriglyceridesHDL-C Non HDL-C
Visnegarwala et al: J of Infection 2004; 49: 283-290
AntiretroviralsAntiretrovirals and Lipidand Lipid--Lowering TherapyLowering Therapy
PIs and PIs and NNRTIsNNRTIs areare metabolizedmetabolized by or affect theby or affect thefunction of various CYP function of various CYP isoformsisoforms
The primary route of metabolism for most The primary route of metabolism for most statinsstatinsis via oxidation using CYP3A4is via oxidation using CYP3A4
Inhibitors of CYP3A4 (Inhibitors of CYP3A4 (egeg PIs) can increase thePIs) can increase theconcentration of certain concentration of certain statinsstatins
DrugDrug--drug interactions with drug interactions with statinsstatins andand NNTIsNNTIsare possible, but data are not availableare possible, but data are not available
Certain PIs may have little (Certain PIs may have little (IndinavirIndinavir,, SequinavirSequinavir),),if any (if any (AtazanavirAtazanavir) effect on possible plasma lipid ) effect on possible plasma lipid concentrationsconcentrations
Current Strategies for Management ofCurrent Strategies for Management ofDyslipidemiaDyslipidemia in the Setting of HIV Therapyin the Setting of HIV Therapy
Nursing Intervention
General Monitor patient fasting lipid profilesconsiderations Counsel patient on nonpharmacologic and pharmacologic lipid-lowering interventions
Monitor medication adherence and adherence to follow-up (laboratories andscheduled appointments)Monitor for expected outcome (e.g. improved lipid levels)Educate patient about disease process and health promotion
Use Monitor prescribed medications for PI-statin drug-drug interactionsof Recommend use of pravastatin (or atorvastatin) when total and LDL cholesterol levels
statins are increasedReview signs and symptoms of common and adverse drug reactions(e.g. signs and symptoms of Myopathy)
Replace statins Recommend that fibrates replace statins when the primary lipid abnormality iswith fibrates hypertriglyceridemia
Recommend that fibrates be considered as therapy for mixed dyslipidemiaReview medication administration regimen (review drug-food interactions)Review signs and symptoms of common and adverse drug reactions
Use non-PI- Monitor antiretroviral drug history and resistance profilesbased strategies Recommend possible use of non-PI-based regimens in presence of
hypercholesterolemiaSubstitute new Recommend consideration of atazanavir in presence of hypercholesterolemia
PIs such as and/or hypertriglyceridemiaatazanavir thathave no effect onlipid metabolism
Modif.afterColagreco: J of Ass Nurses in AIDS Care 2004; 15: 30-41
Choice of Initial Drug Therapy forChoice of Initial Drug Therapy forDyslipidemiaDyslipidemia in Patients with HIV onin Patients with HIV on
Antiretroviral TherapyAntiretroviral Therapy
Therapy
Lipid Abnormality First Choice Alternative(s)
Elevated LDL-C with Statin FibrateTG 1.7 – 4.5 mmol/L or
Niacin
Triglyceride > 4.5 mmol/L Fibrate Niacinor
Fish oils
StatinsStatins Inhibit in vitro and in vivo Inhibit in vitro and in vivo HIVHIV--1 Infection of Human 1 Infection of Human PBMCsPBMCs
Infection of untreated ( ), Lov- ( ), or Love plus Mev-treated ( ) PHA activated human PBMCs by X4 or R5 HIV-1 viral strains.Data are mean SD of triplicate points (n=3).
8
p24 (
ng
/ml)
6
4
2
0
6
4
2
00 3 6 9 12 0 3 6 9 12
Time (days)
NL4-3 (X4) BaL (R5)
del Real et al: J Exp Med 2004; 4: 541-547
StatinsStatins Inhibit HIVInhibit HIV--11--Entry and ExitEntry and Exit
120
80
40
0Untr.
Infe
cti
vit
y(%
)
**HIV-pseudotyped
VSV-G-pseudotyped
Lov. Lov. +Mev.
Single-round infections were performed in untreated, Lov-, and Lov plus Mev-treated MT2-CCR5 cells using a replication-defective NL4-3 virus bearing the luciferase reporterpseudotyped withHIV-1Ada or VSV-G envelopes.Cell infection was nor-malized using untrea-ted cells as 100%.
del Real et al: J Exp Med 2004; 4: 541-547
StatinsStatins Inhibit HIVInhibit HIV--11--Entry and ExitEntry and Exit
0HIV-1
5
10
15
20
25
RL
U (
x 1
03)
*
Untreated
Lovastatin
Lov. + Mev.
VSV
Virus production was measured by titration of viral stocks produced in untreated Lov-, and Lovplus Mev-treated HEK-293T cells transfectedwith replication-defective NL4-3 virus. Relative luciferase units were calculated after normalization with luciferase activity from extracts of stock-producing cells.
del Real et al: J Exp Med 2004; 4: 541-547
0000
1010
2020
3030
4040
Fo
ldo
f in
du
cti
on
Untreated
Lov.
Lov. + GGPP
5050
3030 6060 9090 120120
Time (min)
StatinsStatins InhibitInhibit
HIVHIV--1 Infection 1 Infection
byby
DownDown--regulatingregulating
RhoRho ActivationActivation
del Real et al: J Exp Med 2004; 4: 541-547
StatinsStatins Inhibit HIVInhibit HIV--1 Infection by 1 Infection by DownDown--regulatingregulating RhoRho ActivationActivation
Time (min):0 30 45 60 120 Time (min) 0 30 45 60 120
Time (min):
Rho
Rho-GTP
Rac
Rac-GTP
0 30 45 60 120 0 30 45 60 120 0 30 45 60 120
Rho-GTP
Total Rho
B
A
Untreated Lovastatin Lovastatin + GGPP
del Real et al: J Exp Med 2004; 4: 541-547
Cholesterol Metabolism during the APRCholesterol Metabolism during the APR
Infektion/Inflammation sind mit einer Zunahme der Infektion/Inflammation sind mit einer Zunahme der HMGHMG--CoACoA ReduktaseReduktase assoziiert.assoziiert.Allerdings ist die Expression der übrigen Enzyme mitAllerdings ist die Expression der übrigen Enzyme mit MevalonatmetabolismusMevalonatmetabolismus vermindert.vermindert.
MMäässige Zunahme der ssige Zunahme der hepatischenhepatischen Cholesterinsynthese und andere Cholesterinsynthese und andere MevalonatmetaMevalonatmeta--bolitenboliten werdenwerden NonNon--SterolSterol--WegenWegen zugefzugefüührt.hrt.
ZusammenfassungZusammenfassung
Infektionen gehen mit Veränderungen der Infektionen gehen mit Veränderungen der SerumlipideSerumlipide undundSerumlipoproteineSerumlipoproteine einher.einher.
1)1) ErhöhteErhöhte VLDLVLDL--SyntheseSynthese und verminderter und verminderter VLDLVLDL--AbbauAbbauerhöhteerhöhte TriglycerideTriglyceride
2)2) Infektionen/Inflammationen erniedrigen sowohl LDL als Infektionen/Inflammationen erniedrigen sowohl LDL als auch HDL auch HDL erniedrigter „erniedrigter „cholesterolcholesterol reversereverse transporttransport““und vermehrte Cholesterinabgabe an Immunzellen. und vermehrte Cholesterinabgabe an Immunzellen.
3)3) Die Oxidation von LDL und VLDL nimmt zu, HDL wird ein Die Oxidation von LDL und VLDL nimmt zu, HDL wird ein propro--iflammatorischesiflammatorisches MolekülMolekül
4)4) Unter Therapie mit Unter Therapie mit ProteaseinhibitorenProteaseinhibitoren werden diese werden diese Veränderungen bei HIVVeränderungen bei HIV--Patienten noch verstärkt. Diese Patienten noch verstärkt. Diese Medikamente gehen mit einer veränderten Fettverteilung Medikamente gehen mit einer veränderten Fettverteilung und Insulinresistenz einher und Insulinresistenz einher vorzeitige Atherosklerose vorzeitige Atherosklerose und Pankreatitisund Pankreatitis
5)5) Der Einsatz von Der Einsatz von PIsPIs sollte wenn sollte wenn möglich vermieden werden, möglich vermieden werden, bzwbzwsolltensollten PIsPIs, die keinen Einfluss auf , die keinen Einfluss auf denden LipoproteinstoffwechselLipoproteinstoffwechsel haben,haben,eingesetzt werden (eingesetzt werden (AtazanavirAtazanavir),),insbesoinsbeso beibei HypercholHyperchol././HypertriglycHypertriglyc..
6)6) Zur Behandlung der Zur Behandlung der PIPI--induzierteninduziertenDyslipoproteinämieDyslipoproteinämie werden als erste werden als erste WahlWahl StatineStatine eingesetzt (bei eingesetzt (bei vorwiegender Cholesterinerhöhung), vorwiegender Cholesterinerhöhung), bzwbzw FibrateFibrate (bei vorwiegender (bei vorwiegender TriglyceriderhöhungTriglyceriderhöhung).).
Bei der Bei der StatinbehandlungStatinbehandlung solltesolltepotentiellen Interaktionen mit anderen potentiellen Interaktionen mit anderen Medikamenten (Abbau über CYP450) Medikamenten (Abbau über CYP450) Aufmerksamkeit geschenkt werden.Aufmerksamkeit geschenkt werden.