Effets secondaires des ARV

1
Effets secondaires des ARV

• Cours IMEA
• Roland Landman

2
Reasons for Discontinuation of the First HAART
Regimen

• 862 ART-naïve patients initiated HAART
• 727 (84.3) took 2 NRTIs and 1 PI
• 312 patients (36.2) discontinued tx over a
  median of 45 weeks most due to toxicity or
  nonadherence

Virologic Failure
Toxicity
Nonadherence
Other
d'Arminio Monforte A et al. AIDS. 200014499-507.
3
Reasons Patients Reported for Missing
Antiretrovirals
60
(59)
50
40
(36)
30
Patient Percent
(26)
(26)
20
(16)
(17)
(14)
(15)
(13)
(11)
10
0
Rash
Gas or bloating
Fatigue/ tiredness
Change In taste
Diarrhea
Nausea/ upset stomach
Body shape change
Headache
Vomiting
Neuropathy /tingling
1POZ, 6(2), May, 1998
4
Inhibiteurs analogues nucléosidiques de la
transcriptase inverse 
5
(No Transcript)
6
Inhibiteur nucléotidique de la transcriptase
inverse 
7
Small Reductions in Renal Function With Tenofovir
vs Other NRTIs

• Small but statistically significant decrease in
  CLCr with TDF
• Clinical significance unclear
• Not grounds to exclude TDF use for pts at risk
  for renal dysfunction (but dose-adjust in renal
  insufficiency)
• Other studies
• Glomerular filtration (GFR) detects more patients
  with mild renal impairment than serum
  creatinine2
• 10 of TDF pts w. grade 3 GFR
• MACS TDF associated with lower GFR3

120



100
Normal range 80-120 mL/min
80
CLCr
60
40
P lt .05 change from baseline for TDF vs NRTI
20
0
0
90
180
270
360
Days
Last CLCr on treatment carried forward if
treatment stopped
1. Gallant J, et al. Abstract 820. 2. Becker S,
et al. Abstract 819. 3. Reisler R, et al.
Abstract 818.
8
Inhibiteurs non-nucléosidiques de la
transcriptase inverse 
9
Inhibiteurs de protéase 
10
(No Transcript)
11
Metabolic and MorphologicComplications
Associated with ARV Therapy

• Metabolic
• Glucose disorders
• insulin resistance
• impaired glucose tolerance
• hyperglycemia / diabetes
• Lipid elevations
• increased triglycerides
• increased cholesterol
• Hyperlactatemia
• lactic acidosis
• Bone disease
• osteopenia
• osteoporosis
• avascular necrosis

• Morphologic
• Fat loss
• extremities
• face
• Buttocks
• Fat accumulation
• abdominal obesity
• buffalo hump
• lipomatosis
• breast enlargement
• Mixed Syndrome

12
Selected PI Side Effects
Abbott Study 418 Risk of moderate/severe
diarrhea 17 QD LPV/r vs. 5 BID LPV/r (p0.014)
Includes abdominal pain/discomfort, abnormal
stools and dyspepsia Diarrhea only reported 1.
Data from NV15355 (FTV 1200mg TID 2 NAs) and
FOCUS study (SQV/r 1600/200 mg QD 2 NAs) 2.
Data from Abbott Study 863 (NA d4T 3TC) 3.
Data from 2 trials with APV/r 1200/200 mg QD 4.
Data from NEAT and SOLO trials (NA ABC 3TC)
5. Data from BMS 034 (NA ZDV 3TC) and 045
(ATV/r 300/100 mg TDF NA)
13
Most Common Adverse Events and Laboratory
Abnormalities with LPV/r
M97-720
Most commonoccurring in gt10 of patients. All
patients received lamivudine stavudine.
Eron J, et al. 43rd ICCAC. Chicago, 2003.
Abstract H-844.
14
Metabolic and MorphologicComplications
Associated with ARV Therapy

• Metabolic
• Glucose disorders
• insulin resistance
• impaired glucose tolerance
• hyperglycemia / diabetes
• Lipid elevations
• increased triglycerides
• increased cholesterol
• Hyperlactatemia
• lactic acidosis
• Bone disease
• osteopenia
• osteoporosis
• avascular necrosis

• Morphologic
• Fat loss
• extremities
• face
• Buttocks
• Fat accumulation
• abdominal obesity
• buffalo hump
• lipomatosis
• breast enlargement
• Mixed Syndrome

15
(No Transcript)
16
(No Transcript)
17
(No Transcript)
18
Tolerability/Toxicity PI
LPV/r SQV/r
NFV IDV/r
ATV FPV/r ATV/r DRV/r
19
Ease/Convenience PI
LPV/r
NFV SQV/r IDV/r
ATV ATV/r FPV/r DRV/r
20
DADProlonged Antiretroviral Exposure and
Myocardial Infarction

• Updated analysis shows continuing increase in
  risk with longer duration1
• Increased risk partially but not completely
  explained by dyslipidemia
• However, trend for decreasing MI incidence from
  2000-2003 after adjusting for ? smoking, ?
  lipid-lowering therapy2

Adjusted RR, 1.17 (95 Cl, 1.081.26)
HAART per addl year
Age per 5 yrs older
Male sex
Previous CVD
Smoking
Family history
1
0
10
Relative rate of MI (95 Cl) Multivariate model
adjusted for family history, BMI, HIV risk,
cohort, year and race
1. El-Sadr W, et al. Abstract 42. 2. Sabin C, et
al. Abstract 866.
21
Akileswaran c, CID 2006 (28 articles consultés)

• Effets secondaires 8 études sur 17
  (14,3-80,2)
• -vertiges
• -anémie
• -rash
• -neutropénie
• -neuropathies périphériques

22
Effets secondaires précoces
23
Drug discontinuation second-line regimen, by
first-line regimen
All patients who started the given first line
regimen gt 1 month before July 31st 2006
Source Aconda/ISPED/EGPAF August 2006 report
24
Drug discontinuation Reasons
All patients who started the first line regimen
gt 1 month before July 31st 2006 Mainly
tuberculosis
Source Aconda/ISPED/EGPAF August 2006 report
25
Incidence et facteurs prédictifs de lanémie
sévère dans un régime ARV contenant de la
ZDVEssai DART (N3314)AZT 3TC TDF (74) ou
ABC (9) ou NVP (17)

• Incidence de lanémie à S48 (épisodes)
• - Grade 4 (lt 6.5 g/dl) 219
  (6.6)
• - Grade 3 (6.5-lt7.0 g/dl) 259 (7.8)
• - Grade 2 (7.0-lt8.0 g/dl) 393
  (11.8)
• - Grade 1 (8.0-lt9.5 g/dl) 789 (23.8)

Facteurs de risque Sexe F, Hb, CD4, BMI bas à
linitiation ART
Ssali F, Antiviral Therapy 2006
26
Tolérance traitement de première ligne(AZT 3TC
EFV), Afrique du Sud N67

• AZT 3TC EFV (n65/67) ( ES à 2 semaines)
• -vertiges (58)
• -troubles du sommeil (37)
• -somnolence(24)
• -rash 1 cas
• -pas d ? transaminases gt 5 VN
• -3 cas darrêt dEFV à S2

Whetman J XV AIDS Conference, Toronto 2006
27
Tolérance traitement de première ligne(AZT
3TC EFV), Côte dIvoire N740
37 ES grade 3-4? arrêt TTT, 0,9/100
personnes/mois

• AZT 28 ES
• 25 anémie sévère
• 2 neutropénies
• 1 cardiomyopathie non
• obstructive
• Arrêt 0,6/100 pers/ mois

• EFAVIRENZ (9)
• 4 vertiges sévères
• 1 délire aigu
• 3 ES cutanés
• - 2 rash fébriles
• - 1 prurit féroce
• cytolyse hépatique (G3)
• Arrêt 0,1/100 pers/mois

Source Danel JAIDS 2006
28
Symptomes déclarés par les patients sous
AZT-3TC-EFV, par mois de traitement(essai
Trivacan ANRS 1269, Abidjan)
Source Danel JAIDS 2006
29
Tolérance neuropsychique de lefavirenz Étude
sur la qualité de vie et la dépression N200
(Sénégal)
Source Poupard M, HIV Medecine, sous presse
30

• D4T 3TC NVP Triomune
• MSF (12 centres ) 6861 patients 5175(75,4)
  Afrique, durée my 4.1 mois
• 30 (5) arrêts TTT grades 3-4
• Drug N 30
  Reasons (N)
• Nevirapine 23
  Skin toxicity, 12 (40)
• 
  Liver toxicity, 11
  (36.7)
• 
  
• Stavudine 7
  Neuropathy, 5 (16.7)
• 
  Lipodystrophy, 2
  (6.7)

Source, Calmy A, AIDS 2006
31
Tolérance traitement de première ligne(D4T 3TC
NVP, Triomune), Cameroun N60

• 5 ES grade 3 (8.3), 17.8/100 pers/année
• 1 cas durticaire généralisé
• 4 cas de cytolyse hépatique gt 5N
• 1 switcth NVP indinavir (urticaire
  cytolyse)

Source, Laurent C, Lancet 2006
32
CBV ABC vs CBV NVP en traitement de 1ère
ligne chez des patients africains essai NORA
Evènements indésirables (EI) de grade 4 ABC,
78 (26 )chez 64 patients vs NVP, 109 (36.4)
chez 91 patients Incidence (pour 100
années-patient) - ABC, n 59 vs NVP, n 88,
p 0,008 majorité ES hématologiques
Neutropénie ABC, n 46, NVP, n 71, Anémie
ABC, n 17, NVP, n 16, Elevation grade 4
transa chez 8 patients (2,7), tous sous NVP
Munderi P., CROI 2006 Abs. 109LB