Complications Toxicity Case 5: Francis

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Complications ToxicityCase 5 Francis

• Christine KATLAMA
• Hôpital Pitié Salpêtrière
• Université Pierre et Marie Curie Paris VI
• Unité INSERM 204
• 6TH Advanced HIV course Montpellier 2008

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Complications ToxicityCase 5 Francis

• Francis 37 ans, French gay male , clerk
• HIV Primary infection in 1992
• April 1996
• CD4 HIV RNA
• 300/mm3 4000 copies/ml
• 1ARV therapy DDI / D4T
• September 2001 
• CD4 450/mm3 HIV RNAlt 400 cp/ml
• Retinal lesion with scotoma and severe visual
  impairment

6th Advanced HIV Course 2008 Complications
Toxicity
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Complications ToxicityCase 5 Francis

• What is your hypothesis to explain these
  symptoms ?
• CMV retinitis ?
• Toxoplasma retinitis ?
• Drug toxicity ?
• Others
• What do you do with regards to ARV therapy ?

6th Advanced HIV Course 2008 Complications
Toxicity
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Complications ToxicityCase 5 Francis

• September 2001 
• CD 450/mm3 HIV RNAlt 400 cp/ml
• Retinal lesion with scotoma and severe visual
  impairment
• Hypothesis Mitochondrial toxicity
• STOP ARV lesions improvement

6th Advanced HIV Course 2008 Complications
Toxicity
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Complications ToxicityCase 5 Francis
Peripheral Neuropathy and NRTI
Moore RD et coll J Acq Immune Defic Syndr
200014273-8
SUITE
6th Advanced HIV Course 2008 Complications
Toxicity
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Complications ToxicityCase 5 Francis
Mitochondrial toxicity index of NRTI
Toxicity index (Log)
Correlation with kinetics incorporated by
mitochondrial polymerase DNA
RETOUR
6th Advanced HIV Course 2008 Complications
Toxicity
Lee H et coll. Biochemistry 200342(50)14711-9
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Effect of NRTIs on mtDNA (in vitro)
Complications ToxicityCase 5 Francis
Effect of NRTIs on Hep G2 Cell Mitochondrial DNA
Content
140 120 100 80 60 40 20 0
3TC
TDF
ABC
ZDV
Mitochondrial DNA content ()
d4T
ddC
ddI
0.1 1 10
100 1000 Log drug
concentration (µM)
6th Advanced HIV Course 2008 Complications
Toxicity
Birkus G et al. Antimicrob Agents Chemother.
200246716-723.
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Mitochondrial Toxicity Does Not Immediately
Translate into Symptoms
Complications ToxicityCase 5 Francis
Threshold effect
? mtDNA
Relative units ()
? lactate
symptoms
100
90
80
70
?-polymerase activity
oxidative capacity
clinical manifestations
60
50
40
30
20
10
0
Relative time
Harmful event
Hypothetical Example
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Lipid Abnormalities and Mitochondrial Dysfunction
Complications ToxicityCase 5 Francis
cytoplasm
glucose
lactate NAD
pyruvate NADH
FFA
TG
ATP
CIII
CII
CIV
CI
CV
Respiratory chain
ADP
Acethyl CoA
pyruvate
Krebs cycle
CO2 H2O
NADH
mitochondrion
NAD
Ketonic bodies
NAD
Brinkman K et al. AIDS Rev. 19991140-146
6th Advanced HIV Course 2008 Complications
Toxicity
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Complications ToxicityCase 5 Francis
Comparative effects of NRTI on the DNA of hepatic
cellular cultures and striated muscle
Cellules du muscle Strié
Cellules hépatiques HepG2
In vitro
Birkus G, et al. Antimicrob Agents Chemother.
200246716.
6th Advanced HIV Course 2008 Complications
Toxicity
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Lipid Changes Differ Among PIs
Complications ToxicityCase 5 Francis
350
Naïve patients receiving PI-based first-line
regimen
All measurements following ?4 weeks of treatment
change from baseline
APV 1
NFV 2
ATV 2
SQV 3
RTV 4
IDV 5
LPV/r 6
1. Drug Facts and Comparisons. April 2001. 2.
Cahn P, et al. IAS. July 2001. 3. Moyle,
Baldwin. 1999.
4. Danner, et al. 1995.5. Rockstroh, et al.
2000.6. MicroMedEx-DrugDex.
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Lipid Changes Differ Among NRTIsd4T vs ABC
Complications ToxicityCase 5 Francis
ABCDE study
1.4
1.22
1.2
1.12
ABC
plt0.05
d4T
1
0.81
0.8
0.8
Change in mmol/L
0.6
0.49
0.49
0.4
0.38
0.4


0.27
0.24
0.2
0
Lactate
Total chol
HDL
LDL
Triglycerides
plus 3TCEFV. Podzamczer, et al. 11th CROI.
2004 Abstract 716.
6th Advanced HIV Course 2008 Complications
Toxicity
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Lipid Changes Differ Among NRTIsd4T vs TDF
Complications ToxicityCase 5 Francis
Study 903
160
plt0.001
140
TDF
120
d4T
100
Mean change from baseline value(mg/dL)
80
plt0.001
60
plt0.001
40
p0.003
20
0
TG
TC
LDL-C
HDL-C
plus 3TCEFV. Gallant JE et al. JAMA.
2004292191-201.
6th Advanced HIV Course 2008 Complications
Toxicity
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Complications ToxicityCase 5 Francis

• What is your attitude regarding ARV ?
• - restart therapy ? Why ?
• - delay resumption of therapy ? Why ?

6th Advanced HIV Course 2008 Complications
Toxicity
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Complications ToxicityCase 5 Francis

• No treatment until September 2004
• Thrombopenia (5000 plaquettes / mm3)
• CD4 Charge virale
• 400/mm3 2 500 copies/ml
• Does thrombopenia require a specific therapy ?
  
• - corticosteroids ?
• - splenectomy ?
• - ARV therapy ?
• - other ?
• What drugs ARV strategy would you choose
  in 2006 ?
• - TDF3TC NNRTI
• - ABC3TC NNRTI
• - Boosted PI monotherapy
• - Dual PI monotherapy

6th Advanced HIV Course 2008 Complications
Toxicity
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Complications ToxicityCase 5 Francis

• September 2004
• CD4 Viral load
• 400/mm3 2 500 copies/ml 
• Restart ARV therapy AZT/ 3TC / NVP
• November 2004
• patient complains about diffuse myalgias and
  intense fatigability
• CD4 Viral load
• 422/mm3 lt 50 copies/ml

• What do you propose ?

6th Advanced HIV Course 2008 Complications
Toxicity
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?
Complications ToxicityCase 5 Francis
Dossier médical

• November 2004
• Switch to TDF / FTC / NVP
• January 2005
• Decrease in visual acuity and scotomas patient
  needs lens to read
• Patient is tired of therapy and stops ARV
• April 2005 no ocular symptoms
• CD4 Viral load
• 220 /mm3 55 000 copies / ml
• Do you perform a resistance test ?
• What do you expect in terms of resistance
  mutations?.

6th Advanced HIV Course 2008 Complications
Toxicity
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Complications ToxicityCase 5 Francis

• What drugs ARV strategy would you choose in
  2006 ?
• - TDF3TC NNRTI
• - ABC3TC NNRTI
• - Boosted PI monotherapy
• - Dual PI monotherapy
• -

6th Advanced HIV Course 2008 Complications
Toxicity
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Complications ToxicityCase 5 Francis

• What is your attitude regarding ARV ?
• - do you ask for genotypic resistance test ?
• - What do you expext ?
• No resistance mutations expected only M63I

6th Advanced HIV Course 2008 Complications
Toxicity
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?
Complications ToxicityCase 5 Francis

• Aout 2005
• CD4 Charge virale
• 257/mm3 3851 copies/ml
• Genotype semblable à celui davril (pas de
  résistance)
• Dosages lopinavir infra limite détectable

6th Advanced HIV Course 2008 Complications
Toxicity