La formacin continuada en la infeccin VIH' Toxicidad del tratamiento antirretroviral

1
La formación continuada en la infección VIH.
Toxicidad del tratamiento antirretroviral

• Mar Masiá
• Hospital General Universitario de Elche

2
Caso clínico presentación

• Varón, 45 años
• Infección VIH diagnosticada en 1986
• Sarcoma de Kaposi
• Hipertrigliceridemia

3
Caso clínico tratamientos previos

• AZT monoterapia (1993)
• AZT ddC
• d4T 3TC
• d4T 3TC indinavir (Ene-97)
• d4T ddI saquinavir/r (Dic- 97)
• Julio 98 CD481 cel/mm3 CV gt106 c/ml
• Estudio resistencias
• TI M41L, D67N, L210W, T215Y
• PR L10I, L24I, M36I, M46I, I54V, V82A, I84V

4
Caso clínico tratamientos

• Ago-98 d4T ddI NFV/SQV NVP
• Seguimiento CV 3100 CD4200
• Nuevas resistencias
• TI M41L, D67N, L74V, Y181C, L210W, T215Y
• PR L10I, L24I, M36I, M46I, I54V, V82A, I84V
• Ene-00 d4T3TC ABC EFVNFV SQV

5
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

6
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

7
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

8
Abacavir Hypersensitivity

• Association with HLA-B5701,
• HLA-DR7
• HLA-DQ3

(Mallal S, et al., Lancet 2002)
9
PREDICT-1 HLA-B5701 Allele Screening to Reduce
ABC-HSR
6-week observation period
No Screening Control (ABC regimen
standard monitoring for HSR) (n 913)
HIV-infected abacavir-naive patients (N 1772)
HLA-B5701 positive subjects excluded from ABC
treatment
Screen for HLA-B5701 (n 859)
HLA-B5701 negative subjects treated with ABC
standard monitoring for HSR
Physicians not informed of screening status.
Mallal S, et al. IAS 2007. Abstract WESS101.
10
SHAPE Retrospective Case-Control Study
CASES
CONTROLS
Black and white subjects with clinically
suspectedABC HSR (CS-HSR)
Black and white subjects enrolled in KLEAN,
ALOHA,CNA30027, CNA30032
ABCskin patch test and HLA-B5701
Identify ABC-tolerantsubjects
White n 130 Black n 69
White n 202 Black n 206
Skin patch test positive
Skin patch test negative
White n 42 Black n 5
White n 85 Black n 63
Saag M, et al. IAS 2007. Abstract WEAB305.
11
SHAPE Sensitivity and Specificity of HLA-B5701
CS-HSR confirmed by HLA-B5701
Sensitivity of HLA-B5701
Specificity of HLA-B5701
100
99
100
96
100
90
80
70
44
60
Sensitivity/Specificity of HLA-B5701,
50
40
14
30
20
10
57/130
42/42
194/202
10/69
5/5
204/206
0
Skin Test Positive
CS-HSR
Skin Test Positive
CS-HSR
Control
Control
White
Black
Saag M, et al. IAS 2007. Abstract WEAB305.
12
Summary of HLA-B5701 Screening and ABC-HSR

• In white and black patients, screening for
  HLA-B5701 significantly reduced clinically and
  immunologically confirmed ABC-HSR1
• 100 sensitivity
• Consistent with PREDICT-1 and other ABC-HSR trial
  results2,3
• 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.
13
Caso clínico

• Se SUSPENDE abacavir
• 5 días después suspensión resolución exantema,
  no fiebre.
• Inicia EFAVIRENZ, sin abacavir d4T3TC
  EFVNFVSQV
• 2 meses después
• Ataxia matutina
• Cefalea frontal
• Pesadillas, insomnio
• Disminución capacidad intelectual

14
Common Neurologic and Psychiatric Complications
of Antiretrovirals
15
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
16
ACTG 5097s CNS Adverse Effects of EFV Usually
Mild and Transient
Neuropsychometric assessments, blood samples
taken to determine EFV trough concentrations in
plasma
Week 24
Week 1
Week 4
Week 12
EFV-containing regimen (EFV plus either ZDV/3TC
or ZDV/3TC/ABC) (n 200)
Treatment-naive patients, VL gt 400 copies/mL (N
303)
Non-EFVcontaining regimen (ZDV/3TC/ABC) (n 103)
Clifford DB, et al. Ann Intern Med.
2005143714-721.
17
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 DB, et al. Ann Intern Med.
2005143714-721.
18
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 lt .001)
• Median score changes in components
• Trailmaking A test 0.81
• Trailmaking B test 0.39
• Digit symbol test 0.49 (all P lt .001 compared
  with baseline)
• Bad dream sleep scores (P .0002) and anxiety
  scores (P .03) increased
• Global depression and global sleep scores
  unchanged

Clifford D, et al. 2005 CROI. Abstract 773.
19
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)

20
(Gutiérrez F, CID 05)
21
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 lt
  .0001) and decreased clearance of EFV
• CYP2B6 G516T genotype also associated with
  increased CNS symptoms at Week 1 (P .036)

Haas DW, et al. AIDS.2004182391-2400.
22
Caso clínico

• Dic-00 LPV/rSQV (ft)d4T3TCNVP
• 2 meses después
• CD4 231 cel/mm3
• CV 8000 c/ml
• Colesterol total 260 mg/dl
• Triglicéridos 1076 mg/d

23
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

24
MACS 10-Year Prospective Assessment of Lipid
Levels
Lipid Changes
30
20
10
0
-10
-20
-30
-40
HIV ART Naive 7 Years
25
Association Between Dyslipidemia and ART
Experience DAD Baseline Data

• 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

Friis-Moller N, et al. AIDS. 2003171179-1193.
26
DAD Prevalence of CVD Risk Factors in a Cohort
of HIV-Infected Patients
35
30
25
20
of Cohort With Risk Factor
15
10
5
0
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).
Friis-Moller N, et al. AIDS. 2003171179-1193.
27
Contribution of Dyslipidemia to MI Risk
Adjusted for conventional risk factors (age,
sex, prior/family history of CVD, smoking) not
influenced by CART.
El-Sadr W, et al. CROI 2005. Abstract 745.
28
Metabolic Effects of Non-PIs
NVP has more of an effect on HDL than EFV and
less effect on TG.
29
Lipid Effects of NRTIs Increased Dyslipidemia
With d4T or ZDV vs TDF
GS 934 96-Week Extension1 ZDV/3TC EFV vs TDF
FTC EFV
GS 903 Week 144 Data2 d4T 3TC EFV vs TDF
3TC EFV
ZDV/3TC
d4T
TDF FTC
TDF
P lt .001
P lt .001
160
40
P .115
140
35
P .067
120
30
100
25
P lt .001
Mean Change From Baseline (mg/dL)
P .022
80
20
P lt .001
60
15
P .003
40
10
20
5
0
0
TC
LDL-C
HDL-C
TG
TC
LDL-C
HDL-C
TG
1. Pozniak AL, et al. J Acquir Immune Defic
Syndr. 2006 Oct 12 Epub ahead of print.2.
Gallant JE, et al. JAMA. 2004292191-201.
30
Lipid Effects of NNRTIsEfavirenz vs Nevirapine
Lipid Changes at Week 48

• 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)

60
EFV

50
NVP
40

30
Mean Change From Baseline ()
20
10

0
-10
TC
LDL-C
HDL-C
TG
TCHDL-C Ratio
P lt .05 vs nevirapine. P lt .001 vs nevirapine.
van Leth F, et al. PLoS Med. 20041e19.
31
Metabolic Effects of PIs

• RTV associated with more pronounced effect on
  lipids than other PIs

32
Gutiérrez F, Padilla S, JAIDS 03
33
Metabolic Effects of PIs LPV/RTV vs NFV

• Phase III, randomized trial of treatment-naive
  patients

LPV/RTV
NFV
TG
TC
125
P0.17
100
100
1.13
2.59
Plt0.001
90
90
1.02
2.33
80
80
0.90
2.07
70
70
0.79
1.81
47
53
Change From Baseline to Week 48 (mg/dL)
Change From Baseline to Week 48 (mg/dL)
Change From Baseline to Week 24 (mmol/L)
Change From Baseline to Week 24 (mmol/L)
48
60
60
0.68
1.55
50
50
0.56
1.29
40
40
0.45
1.03
30
30
0.34
0.78
20
20
0.23
0.52
10
10
0.11
0.26
0
0
0
0
Walmsley S, et al. N Engl J Med.
20023462039-2046.
34
Metabolic Effects of PIsLPV/RTV vs ATV/RTV

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

ATV/RTV
LPV/RTV
TC
HDL-C
LDL-C
TG
35
30
25
15
Mean Change From Baseline to Wk 48 ()
6
2
5
1
-5
-4
-8
-7
-10
-15
Fasting values. P lt .0001 vs LPV/RTV.
Plt0.005
Johnson M, et al. AIDS. 200519-685-694.
35
Genetic Polymorphisms and Metabolic Complications

• Individual susceptibility is the missing factor
  in ARV efficacy and tolerability
• Polymorphisms also affected pretreatment lipid
  levels in these studies

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. 20051911397-1400.
36
Caso clínico

• LPV/rSQV (ft)d4T3TCNVP
• 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

37
Lipodystrophy Illustrations
Buffalo hump
Facial wasting
Crix belly
38
Lipoatrophy Lipohypertrophy
Risk Factors

• Antiretroviral therapy
• Thymidine analogue exposure (d4T gt 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

Lichtenstein, JAIDS 05
39
GS 903 and GS 934 Differential Effect of NRTIs
on Total Limb Fat
Study 903
Study 934
TDF 3TC EFV
TDF FTC EFV
d4T 3TC EFV
ZDV/3TC EFV
10
12
9
8.6
7.9
8
10
7
8
8
8
7.4
6
5.0
Mean Limb Fat (kg)
5
Total Limb Fat (kg)
6
6
6
4.5
5.5


6.0
4
4
4
4
3
P .01
P .034
2
P lt .001
2
2
2
1
P .001
0
0
0
0
48
96
144
48
96
0
Week
Week
n 128 115 n 134 117
n 51 49 n 49 44
Gallant JE, et al. JAMA. 2004292191-201. Pozniak
AL, et al. J Acquir Immun Defic Syndr. 2006 Epub.
40
P0.03
P0.03
Dubé, JAIDS 2007
41
Plt0.0001
Dubé, JAIDS 2007
42
ACTG 5142 Efavirenz Versus Lopinavir/Ritonavir
Regimens

• Treatment-naïve patients (n753)
• 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 38
SGCsoft-gel capsules.
43
ACTG 5142Incidence of Lipoatrophy at Week 96
Efavirenz Lopinavir/ritonavir
51
40
33
32
Patients ()
17
16
12
6
Overall
Stavudine
Zidovudine
Tenofovir DF
Stratified by NRTI
Plt0.01 versus lopinavir/ritonavir.
Haubrich R, et al. 14th CROI. Los Angeles, 2007.
Abstract 38
44
ACTG 5142Limb Fat and Lipid Changes at Week 96
Median changes from baseline. P0.003 versus
efavirenz 2 NRTIs. Plt0.001 versus efavirenz
2 NRTIs and P0.023 versus lopinavir/r 2
NRTIs. P0.007 versus efavirenz 2
NRTIs. Plt0.001 versus efavirenz 2 NRTIs and
P0.013 versus lopinavir/r 2 NRTIs. Plt0.001
versus efavirenz 2 NRTIs and lopinavir/r 2
NRTIs. P0.006 versus efavirenz 2
NRTIs. Plt0.001 versus efavirenz 2 NRTIs and
P0.03 versus lopinavir/r 2 NRTIs.
Haubrich R, et al. 14th CROI. Los Angeles, 2007.
Abstract 38
45

• Randomized open-label study in treatment-naïve

Week 96 Outcomes
Conclusions Lopinavir/ritonavir monotherapy was
significantly associated with less lipoatrophy,
greater limb fat gain, and increased triglyceride
levels than efavirenz ZDV/3TC
Cameron W, et al. 14th CROI. Los Angeles, 2007.
Abstract 44LB.
46
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
• CVlt50 c/ml
• CD4 430 cel/mm3
• 1 año más tarde
• CV250 c/ml
• CD4 380 cel/mm3
• (Mutaciones TI 41L, 67N, 74V, 184V, 190A, 210W,
  215Y IP 24I, 46I, 54V, 82A)
• Junio 2006 TMC114/r TDFAZT/3TC (fenofibrato)
• Enero 2007
• CVlt50 c/ml
• CD4280 cel/mm3

• CT154 mg/dl
• TG327 mg/dl

• CT189 mg/dl
• TG332 mg/dl

• CT251 mg/dl
• TG924 mg/dl