Title: TNFA genotype, patient height and age combine to predict risk of ATN in HIV patients receiving stavu
1TNFA genotype, patient height and age combine to
predict risk of ATN in HIV patients receiving
stavudine.
- CL Cherry, JS Affandi,
- E Yunihastuti , D Imran, P Price
2Background
- Sensory neuropathy (SN) is a common and disabling
complication of HIV and some HIV treatments - Stavudine (d4T) and didanosine (ddI) the dNRTIs
are independently associated with SN in
Melbourne
Smyth et al, HIV Medicine 2007
3Background
- d4T is used in 1st line HAART in many countries
- Relatively inexpensive
- Lower risk of anemia compared with AZT
- Two recent reports from Africa confirmed SN
rates gt35 in HAART clinics - Associated with d4T exposure
- Associated with isoniazid exposure
? Can SN be predicted among patients being
considered for treatment with d4T?
Forma et al and Kim et al, CROI 2006
4Pilot study in Australians exposed to dNRTIs
- AIM To determine risks for antiretroviral toxic
neuropathy (ATN) following exposure to dNRTIs - Case-control study
- ATN patients SN (symptoms and signs), symptom
onset within 6 months of dNRTI (n16) - ATN free patients neither symptoms nor signs of
SN despite 6 months of dNRTI exposure (n20) - Clinical factors and alleles of immune-related
genes considered as possible ATN risk factors
5Multivariate model for predicting ATN in
Australian patients
Overall model plt0.0001, R20.54
6HIV
Macrophage activation in DRG / nerve
HIV-SN
Neuronal /- mitochondrial injury
d4T / ddI
7HIV
Cytokine genotype
Macrophage activation in DRG / nerve
- Host vulnerabilities
- Nutritional
- Age
- Height
- Genetic
- Metabolic
- Other?
HIV-SN
Neuronal /- mitochondrial injury
d4T / ddI
8The Jakarta SN project
9Aims
- To determine risk factors associated with SN in
Indonesian patients exposed to d4T - Demographic
- Clinical
- Genetic
- To develop a model for predicting SN risk in
patients planned for treatment with d4T
10Methods
- Five week SN screening program in 2006
- Pokdisus HIV Care Clinic, Jakarta
- All consenting HIV patients exposed to d4T
- Clinical assessment for SN
- Demographic, medical and laboratory data
- Saliva for DNA ? selected alleles genotyped
- TNFA-308
- BAT1(intron 10)
- TNFA-1031
- IL1A4845
- IL12B(3UTR)
- Statistics performed in Stata 9.2 (StataCorp, USA)
11The ACTG brief SN screening tool
- Lower limb neuropathic symptoms
- Pain, aching or burning
- Pins and needles
- Numbness
- Lower limb neuropathic signs
- ? vibration sense (128Hz tuning fork at great toe
10 secs) - Absent ankle jerks
Neuropathy symptoms together with at least one
sign
12Results
- 96 patients participated
- 33 patients (34) had SN (symptoms signs)
- 7 patients had neuropathic symptoms but no signs
- 14 asymptomatic patients had neuropathic signs
- Only 41 patients had neither symptoms nor signs
- Mean duration of d4T use 17.3 (2-42) months
- Duration of d4T not associated with SN status
- 16.8 (SN) versus 18.5 (non-SN) months, p0.8
13Cohort Demographics
14Clinical neuropathy risks (Continuous variables,
univariate analysis)
unpaired t test
15Clinical neuropathy risks(dichotomous variables,
univariate analysis)
Chi2 test
16Multivariate analysis of clinical SN
risks(logistic regression modeling)
Overall model p 0.005
Factors included in the model gender, age,
height, BMI, months of HIV, months on d4T,
isoniazid use, HepC, initial CD4
17(No Transcript)
18Genotype as a neuropathy risk (univariate
analysis)
Chi2 test
19Multivariate model of SN risks overall
(logistic regression modeling)
Overall model p 0.0009
Factors included in the model genotype, gender,
age, height, BMI, months of HIV, months on d4T,
isoniazid use, HepC, initial CD4
20Conclusions
- SN prevalence is 34 in Jakarta HIV patients
exposed to d4T - Isoniazid exposure is not associated with an
increased risk of SN with d4T exposure.
NOTE all patients given isoniazid received
pyridoxine prophylaxis. - Independent risk factors for SN among patients
exposed to d4T are TNFA genotype, increasing age
and increasing height.
A simple algorithm based on TNFA genotype and a
patients height and age can predict SN risk
following d4T exposure
21Acknowledgements
University of Indonesia and Pokdisus Clinic
Patient volunteers Darma Imran Evy Yunihastuti
University of Western Australia Jacquita
Affandi Patricia Price
Burnet Institute Kate Cherry Steve Wesselingh
The Asia-Pacific neuroAIDS Consortium