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
e F
rom
Bas
elin
e to
W
eek
48 (
mg
/dL
)
0
10
20
30
40
50
60
70
80
90
100
TG TC
0
10
20
30
40
50
60
70
80
90
100
Ch
ang
e F
rom
Bas
elin
e to
W
eek
48 (
mg
/dL
)
0
0.11
0.23
0.34
0.45
0.56
0.68
0.79
0.90
1.02
1.13 Ch
ang
e F
rom
Baselin
e to
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