La formación continuada en la infección VIH. Toxicidad del tratamiento antirretroviral

Mar MasiáHospital General Universitario de Elche

Caso clínico: presentación

Varón, 45 años Infección VIH diagnosticada en

1986 Sarcoma de Kaposi Hipertrigliceridemia

Caso clínico: tratamientos previos AZT monoterapia (1993) AZT + ddC d4T + 3TC d4T + 3TC + indinavir (Ene-97) d4T + ddI + saquinavir/r (Dic- 97)

Julio 98: CD4=81 cel/mm3; CV >106 c/ml

Estudio resistencias: TI: M41L, D67N, L210W, T215YPR: L10I, L24I, M36I, M46I, I54V, V82A, I84V

Caso clínico: tratamientos

Ago-98: d4T+ ddI + NFV/SQV + NVP Seguimiento: CV= 3100; CD4=200 Nuevas resistencias:

TI: M41L, D67N, L74V, Y181C, L210W, T215Y

PR: L10I, L24I, M36I, M46I, I54V, V82A, I84V

Ene-00: d4T+3TC+ ABC+ EFV+NFV+SQV

Caso clínico: síntomas

24-36 h tras inicio nueva pauta: Exantema macular tronco y

extremidades Febrícula 37.7ºC Quebrantamiento general, lumbalgia Dolor faríngeo y tos seca

Reacción de hipersensibilidad sistémica/rash cutáneo

Antirretrovirales asociados con mayor frecuencia:

NNRTIs NVP 15-17% DLV 18% EFV 10%

PI Amprenavir 15-20%

NRTIs Abacavir 3-8%

Hipersensibilidad a abacavir

Incidencia: 3-8% Síntomas:

Inicio 4-6 semanas tras comienzo tratamiento: Fiebre, rash cutáneo, fatiga, Síntomas GI (náusea, vómitos, diarrea, dolor abdominal) Síntomas tracto respiratorio (odinofagia, disnea, tos)

Tratamiento: Discontinuar abacavir NUNCA REINICIAR: recurrencia de síntomas

graves en horas, incluidas hipotensión grave y muerte

Abacavir Hypersensitivity

Association with HLA-B*5701, HLA-DR7 HLA-DQ3

(Mallal S, et al., Lancet 2002)

PREDICT-1: HLA-B*5701 Allele Screening to Reduce ABC-HSR

6-week observation period

Screen for HLA-B*5701(n = 859)

No Screening Control(ABC regimen + standard

monitoring for HSR)(n = 913) HLA-B*5701 positive

subjects excluded from ABC treatment

HLA-B*5701 negative subjects* treated with ABC +standard monitoring for HSR

HIV-infectedabacavir-naive

patients

(N = 1772)

*Physicians not informed of screening status.

Mallal S, et al. IAS 2007. Abstract WESS101.

Incidence of ABC HSRScreened for HLA-B*5701,

% (n/N)

Not Screened, % (n/N)

OR (95% CI) P Value

Clinically suspected 3.4 (27/802) 7.8 (66/847) 0.4 (0.25-0.62) < .0001

Skin patch test positive 0 (0/802) 2.7 (23/842) 0.03 (0-0.18) < .0001

CASES CONTROLS

Black and white subjects with clinically suspected

ABC HSR (CS-HSR)

SHAPE: Retrospective Case-Control Study

White: n = 130Black: n = 69

White: n = 42Black: n = 5

White: n = 85Black: n = 63

White: n = 202Black: n = 206

Black and white subjects enrolled in KLEAN, ALOHA,

CNA30027, CNA30032

ABCskin patch test

and HLA-B*5701

Identify ABC-tolerantsubjects

Skin patch test positive

Skin patch test negative

Saag M, et al. IAS 2007. Abstract WEAB305.

SHAPE: Sensitivity and Specificity of HLA-B*5701

0

30

60

100

Sen

siti

vity

/Sp

ecif

icit

y o

f H

LA

-B*5

701

, %

CS-HSR Skin Test Positive

44%

96%100%

10

20

40

50

70

80

90

White

CS-HSR

14%

99%100%

Black

Control Control

57/130 42/42 194/202 10/69 5/5 204/206

Skin Test Positive

Saag M, et al. IAS 2007. Abstract WEAB305.

CS-HSR confirmed by HLA-B*5701 Sensitivity of HLA-B*5701 Specificity of HLA-B*5701

Summary of HLA-B*5701 Screening and ABC-HSR In white and black patients, screening for HLA-B*5701

significantly reduced clinically and immunologically confirmed ABC-HSR[1]

– 100% sensitivity

– Consistent with PREDICT-1 and other ABC-HSR trial results[2,3]

Sensitivity more important than specificity in screening test to predict toxicity

1. Saag M, et al. IAS 2007. Abstract WEAB305.2. Mallal S, et al. IAS 2007. Abstract WESS101. 3. Philips E, et al. IAS 2007. Abstract MOPEB001.

Caso clínico

Se SUSPENDE abacavir 5 días después suspensión: resolución

exantema, no fiebre. Inicia EFAVIRENZ, sin abacavir:

d4T+3TC+ EFV+NFV+SQV 2 meses después:

Ataxia matutina Cefalea frontal Pesadillas, insomnio Disminución capacidad intelectual

Adverse Effect Associated Antiretroviral Drug(s)

Peripheral neuropathy

ddId4TddCPIs

MyopathyZDVTDF

Neuromuscular weakness syndrome d4T

Neuropsychiatric symptoms (eg, dizziness, headache, confusion, stupor, impaired concentration, agitation, amnesia, insomnia, abnormal or vivid dreams, depersonalization, hallucinations)

EFV

Common Neurologic and Psychiatric Complications of Antiretrovirals

Neurotoxicidad efavirenz

Neurotoxicidad EFV: 50% Somatización, ansiedad, conducta obsesivo-

compulsiva, mareo, irritabilidad, somnolencia, dificultad concentración…

Mayor 6 primeros meses y en descenso a los 2 años

(EFV vs PIs al menos 4 semanas, 152 pacientes)

Hawkins, HIV Clin Trials 05:

Treatment-naive patients,

VL > 400 copies/mL

(N = 303)

EFV-containing regimen(EFV plus either ZDV/3TC or ZDV/3TC/ABC)

(n = 200)

Non-EFV–containing regimen(ZDV/3TC/ABC)

(n = 103)

Week 1 Week 4 Week 12 Week 24

Neuropsychometric assessments, blood samples taken to determine EFV trough concentrations in plasma

Clifford DB, et al. Ann Intern Med. 2005;143:714-721.

ACTG 5097s: CNS Adverse Effects of EFV Usually Mild and Transient

Clifford DB, et al. Ann Intern Med. 2005;143:714-721.

Outcomes in ACTG 5097s

Efectos de EFV sobre SNC más frecuentes el día 7 Autolimitados generalmente a semana 4 Mayores niveles séricos EFV → peores tests

neuropsicológicos en semanas 4, 12 Niveles plasmáticos EFV no asociados con cambios del

humor Limitaciones del estudio:

– Bajo número pacientes con antecedentes psiquiátricos

– Baja frecuencia de abuso tóxicos a nivel basal (10%)

– Bajo porcentaje de mujeres en el estudio

Clifford D, et al. 2005 CROI. Abstract 773.

Long-term Effects of EFV in Study 5097s

117 patients treated with EFV-based therapy for 184 weeks

Median change in overall symptom scores unchanged (median: 0; P = .42)– Symptoms associated with EFV increased (median: +1; P = .03)

Median score of neuropsychological function improved from baseline by +0.56 (P < .001) – Median score changes in components

– Trailmaking A test: +0.81

– Trailmaking B test: +0.39

– Digit symbol test: +0.49 (all P < .001 compared with baseline)

Bad dream sleep scores (P = .0002) and anxiety scores (P = .03) increased

Global depression and global sleep scores unchanged

Neurotoxicidad efavirenz: FACTORES DE RIESGO

Características basales: menor nivel educativo, mejor nivel psicológico basal, ansiedad (Blanch J JAIDS 01)

Depresión previa (Boly L, JAIDS 06)

Niveles plasmáticos (Gutiérrez 05, Clifford 05)

Predisposición genética: CYP2B6 (Haas D, AIDS 04; Hasse, CID 05; Rodríguez-Novoa, CID 05; rotger, Pharmacogenetics 05; Tsuchiya, Biochem Biophys Res Comm 04)

(Gutiérrez F, CID 05)

Haas DW, et al. AIDS.2004;18:2391-2400.

Pharmacogenetic Analysis of Patients in Study 5097s

CYP2B6 T/T genotype at position 516 (Gln → His substitution) more common in blacks (20%) than in whites (3%)

– Associated with greater EFV plasma exposure (P < .0001) and decreased clearance of EFV

CYP2B6 G516T genotype also associated with increased CNS symptoms at Week 1 (P = .036)

Caso clínico

Dic-00: LPV/r+SQV (ft)+d4T+3TC+NVP

2 meses después: CD4 231 cel/mm3 CV 8000 c/ml Colesterol total 260 mg/dl Triglicéridos: 1076 mg/d

Lipids and HIV Infection

HIV infection causes dyslipidemia

– Decreased cholesterol

– Decrease in total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), and high density lipoprotein cholesterol (HDL-C)

– Increased triglycerides (TG)

Treatment of HIV increases TC and LDL-C

– Does not increase HDL-C as predictably

Specific antiretroviral drugs (and drug classes) have differing effects on lipids

Lipid ChangesLipid Changes

-40

-30

-20

-10

0

10

20

30

HIV+ ART Naive

7 Years

MACS: 10-Year Prospective Assessment of Lipid Levels

Patients With Abnormal Lipids at Baseline, %

Lipid Levels, mmol/L (mg/dL)

TC > 6.2 (> 240)

HDL-C < 0.9 (< 35)

TG > 2.3 (> 200)

ART naive 7.7 25.5 15.2

NRTIs only 9.8 24.8 22.7

NRTI + PI 27.0 27.1 40.0

NRTI + NNRTI 22.8 19.1 31.8

NRTI + PI + NNRTI 44.1 23.8 54.3

Stable levels after 3-6 months of antiretroviral therapy

↑ TC also associated with higher CD4+ cell count, lower viral load, lipodystrophy, longer exposure to NNRTI and PI, and older age

Association Between Dyslipidemia and ART Experience: D:A:D Baseline Data

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

Hypercholesterolemia* Increased Triglycerides†

Fasting lipids available from 36% of patients, 24% non-fasting, and 40% missing information.*Defined as TC ≥ 6.2 mmol/L (240 mg/dL). †Defined as TG ≥ 2.3 mmol/L (200 mg/dL).

D:A:D: Prevalence of CVD Risk Factors in a Cohort of HIV-Infected Patients

0

5

10

15

20

25

30

35

% o

f C

oh

ort

Wit

h R

isk

Fac

tor

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

*Adjusted for conventional risk factors (age, sex, prior/family history of CVD, smoking) not influenced by CART.

Contribution of Dyslipidemia to MI Risk

El-Sadr W, et al. CROI 2005. Abstract 745.

Relative Rate of MI* (95% CI)

Total cholesterol(per mmol/L)

Triglycerides(per log2 mmol/L higher)

HDL cholesterol(per mmol/L)

CART exposure (per additional year)

0.60 (0.42-0.88); P = .008

1.64 (0.98-2.74); P = .06

1.15 (1.06-1.25); P = .001

1.10 (1.01-1.19); P = .03

1 100.1

Metabolic Effects of Non-PIs

*NVP has more of an effect on HDL than EFV and less effect on TG.

Agent Lipids Glucose

NRTIs TC + TG with d4T ± ddI insulin resistance with lipoatrophy

EFV TC + HDL, TG No insulin sensitivity

NVP* TC + HDL, TG ? no ENF No No

GS 934: 96-Week Extension[1]

ZDV/3TC + EFV vs TDF + FTC + EFVGS 903: Week 144 DataGS 903: Week 144 Data[2][2]

d4T + 3TC + EFV vs TDF + 3TC + EFVd4T + 3TC + EFV vs TDF + 3TC + EFV

Mea

n C

ha

ng

e F

rom

B

asel

ine

(mg

/dL

)

P < .001

P = .067

P = .022

P = .115

ZDV/3TC

TDF + FTC

d4T

TDF

P < .001

P < .001P = .003

P < .001

Lipid Effects of NRTIs: Increased Dyslipidemia With d4T or ZDV vs TDF

1. Pozniak AL, et al. J Acquir Immune Defic Syndr. 2006 Oct 12; Epub ahead of print.2. Gallant JE, et al. JAMA. 2004;292:191-201.

0

20

40

60

80

100

120

140

160

TC LDL-C HDL-C TGTC LDL-C HDL-C TG0

5

10

15

20

25

30

35

40

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

2NN Study

– Randomized 4-arm study in treatment-naive patients

– EFV vs NVP QD vs NVP BD vs dual NNRTI

– All patients received 3TC + d4T

Treatment allocation

– EFV (n = 289)

– NVP (n = 417)

*P < .05 vs nevirapine.†P < .001 vs nevirapine.

Lipid Changes at Week 48

†

†

*

-10

0

10

20

30

40

50

60

TC LDL-C HDL-C TG TC:HDL-C Ratio

Mea

n C

ha

ng

e F

rom

Bas

eli

ne

(%

) EFV

NVP

Lipid Effects of NNRTIs:Efavirenz vs Nevirapine

Metabolic Effects of PIs

Agent Lipids Glucose

RTV (full dose) TC/TG insulin resistance

LPV/RTV TC/TG insulin resistance

IDV/RTV TC/TG insulin resistance

NFV LDL/TG, HDL(?) No insulin sensitivity

APV/RTV or FPV/RTV TC/TG No insulin sensitivity

TPV/RTV TC/TG ?

SQV/RTV Little No insulin sensitivity

ATV No No insulin sensitivity

ATV/RTV Little No insulin sensitivity

DRV/RTV ? ?

RTV associated with more pronounced effect on lipids than other PIs

Gutiérrez F, Padilla S, JAIDS 03

Metabolic Effects of PIs: LPV/RTV vs NFV Phase III, randomized trial of treatment-naive patients

125

47 5348

Ch

ang

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rom

Bas

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W

eek

48 (

mg

/dL

)

0

10

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100

TG TC

0

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mg

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)

0

0.11

0.23

0.34

0.45

0.56

0.68

0.79

0.90

1.02

1.13 Ch

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e F

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Week 24 (m

mo

l/L)

0

0.26

0.52

0.78

1.03

1.29

1.55

1.81

2.07

2.33

2.59 Ch

ang

e F

rom

Baselin

e to

Week 24 (m

mo

l/L)

LPV/RTV NFV

Walmsley S, et al. N Engl J Med. 2002;346:2039-2046.

P=0.17P<0.001

BMS-045: randomized trial of patients with 2 HAART failures

TC HDL-CLDL-C* TG*

*Fasting values.†P < .0001 vs LPV/RTV.† † P<0.005

-8†

6

-7

2

-10

1

-4* † †

30

-15

-5

5

15

25

35

Mea

n C

han

ge

Fro

m

Bas

elin

e to

Wk

48 (

%)

ATV/RTV LPV/RTV

Metabolic Effects of PIs:LPV/RTV vs ATV/RTV

Johnson M, et al. AIDS. 2005;19-685-694.

Individual susceptibility is the missing factor in ARV efficacy and tolerability

Polymorphisms also affected pretreatment lipid levels in these studies

Polymorphism Association

Resistin gene Predicted metabolic toxicity with greater relative risk in

homozygotes compared with heterozygotes[1]

Lipid-metabolizing enzyme Treatment-related changes in TG, TC, and HDL-C [2]

MDR-1 gene (affects p-glycoprotein concentration)

Treatment-related fat accumulation and HDL-C[3,4]

Apolipoproteins Treatment-related changes in TG and TC[5]

APOE, APOC3 Treatment-related risk of severe hypertriglyceridemia[6]

Genetic Polymorphisms and Metabolic Complications

1. Ranade K, et al. CROI 2006. Abstract 763. 2. Arnedo M, et al. CROI 2006. Abstract 764. 3. DeLuca A, et al. CROI 2006. Abstract 766. 4. Cossarizza A, et al. CROI 2006. Abstract 767. 5. Gometz E, et al. CROI 2006. Abstract 768. 6. Tarr PE, et al. J Infect Dis. 2005;191:1397-1400.

Caso clínico LPV/r+SQV (ft)+d4T+3TC+NVP Fenofibrato: 2 meses después:

CD4 331 cel/mm3

CV 160.000 c/ml Colesterol total 189 mg/dl Triglicéridos: 432 mg/dl

2002-2003: Aumento perímetro abdominal y lipoatrofia facial

Lipodystrophy Illustrations

“Buffalo hump”

“Crix belly”

“Facial wasting”

Lipoatrophy: Lipohypertrophy: Antiretroviral therapy

– Thymidine analogue exposure (d4T > ZDV)

– ? PI use

Host factors

– Age

HIV disease factors

– Duration of illness

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

Antiretroviral therapy

– Protease inhibitors use

HIV disease factors

– Markers of disease severity

– Duration of therapy

Risk Factors

Lichtenstein, JAIDS 05

*P < .001

n = 128 115n = 134 117

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*

Week

Study 903

8.1†‡

0

2

4

6

8

0

*P = .034†P < .001 §P = .001

0

2

4

6

8

Week

0

2

4

6

8

TDF + FTC + EFV

ZDV/3TC + EFV

To

tal L

imb

Fat

(kg

)

Study 934

GS 903 and GS 934: Differential Effect of NRTIs on Total Limb Fat

Gallant JE, et al. JAMA. 2004;292:191-201.Pozniak AL, et al. J Acquir Immun Defic Syndr. 2006 Epub.

n = 51 49n = 49 44

48 96

10

12

6.0*†§5.5

7.4*

‡P = .01

Dubé, JAIDS 2007

P=0.03

P=0.03

Dubé, JAIDS 2007

P<0.0001

ACTG 5142: Efavirenz Versus ACTG 5142: Efavirenz Versus Lopinavir/Ritonavir RegimensLopinavir/Ritonavir Regimens

Treatment-naïve patients (n=753)– Baseline characteristics similar across all groups

Randomized arms– Lopinavir/ritonavir (400/100 mg twice-daily, SGC)

+ 2 NRTIs– Efavirenz (600 mg once-daily) + 2 NRTIs– Efavirenz (600 mg once-daily) + lopinavir/ ritonavir

(533/133 mg twice-daily, SGC)– Selected NRTIs in combination with lamivudine:

zidovudine (42%), stavudine XR (24%), tenofovir DF (34%)

Haubrich R, et al. 14th CROI. Los Angeles, 2007. Abstract 38SGC=soft-gel capsules.

ACTG 5142:ACTG 5142:Incidence of Lipoatrophy at Week 96Incidence of Lipoatrophy at Week 96

0

10

20

30

40

50

60

Overall

Pat

ient

s (%

)

32%*

Stavudine Zidovudine Tenofovir DF

Stratified by NRTI

17%

51%*

33%

40%*

16%

6%

12%

EfavirenzLopinavir/ritonavir

*P<0.01 versus lopinavir/ritonavir.

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

ACTG 5142:ACTG 5142:Limb Fat and Lipid Changes at Week 96Limb Fat and Lipid Changes at Week 96

Lopinavir/r+ 2 NRTIs(n=253)

Efavirenz +2 NRTIs(n=250)

Efavirenz + Lopinavir/r

(n=250)

Lipoatrophy (%) 17* 32 9†

Extremity fat (%) 9.8‡ 1.4 18§

Total cholesterol (mg/dL) 32 33 57║

HDL-C (mg/dL) 8 9 16║

Non-HDL-C (mg/dL) 26 22 44║

Triglycerides (mg/dL) 46¶ 19 62#

Median changes from baseline.*P=0.003 versus efavirenz + 2 NRTIs.†P<0.001 versus efavirenz + 2 NRTIs and P=0.023 versus lopinavir/r +2 NRTIs.‡P=0.007 versus efavirenz + 2 NRTIs.§P<0.001 versus efavirenz + 2 NRTIs and P=0.013 versus lopinavir/r + 2 NRTIs.║P<0.001 versus efavirenz + 2 NRTIs and lopinavir/r + 2 NRTIs.¶P=0.006 versus efavirenz + 2 NRTIs.#P<0.001 versus efavirenz + 2 NRTIs and P=0.03 versus lopinavir/r + 2 NRTIs.

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

Week 96 Outcomes

Cameron W, et al. 14th CROI. Los Angeles, 2007. Abstract 44LB.

ConclusionsLopinavir/ritonavir monotherapy was significantly associated with less lipoatrophy, greater limb fat gain, and increased triglyceride levels than efavirenz + ZDV/3TC

Randomized open-label study in treatment-naïve

Caso clínico

(Mutaciones TI: 41L, 67N, 184V, 181C, 190A, 210W, 215Y, 219R; IP: 24I, 46I, 54V, 82A)

Junio 04: TDF + ddI + ATV/r + T20 (+ fenofibrato) 28 semanas después:

CV<50 c/ml CD4 430 cel/mm3

1 año más tarde: CV=250 c/ml CD4 380 cel/mm3

(Mutaciones TI: 41L, 67N, 74V, 184V, 190A, 210W, 215Y; IP: 24I, 46I, 54V, 82A)

Junio 2006: TMC114/r TDF+AZT/3TC (+fenofibrato) Enero 2007:

CV<50 c/ml CD4=280 cel/mm3

CT=154 mg/dlTG=327 mg/dl

CT=251 mg/dlTG=924 mg/dl

CT=189 mg/dlTG=332 mg/dl