CNScomplications in AIDS patients in Japan

1
CNS-complications in AIDS patients in Japan

• Shinichi Oka, MD
• AIDS Clinical Center (ACC)
• International Medical Center of Japan (IMCJ)

2
Survival rate of HIV patients on ART in Japan
Survival rate
(n3370)
- HRD data -
3
Annual change of incidence of opp. infections
Patients per 100 HIV
Year
4
No of opp. events in ACC (1997-2005)
1,680 patients
person
5
Mortality of opp. events in AIDS patients
()
6
Treatment of CNS-complications
Improvement following
7
CNS-complications observed in ACC

• Primary infection
• - Meningoencephalitis, Peripheral neuropathy,
  Guillain-Barre synd., Acute myeloradiculoneuritis
  (AMRN)
• Asymptomatic carrier
• - Neurosyphilis
• AIDS
• - PML, Toxoplasma encephalitis, Cryptococcus
  meningitis, Herpes encephalitis, CNS-lymphoma,
  AIDS dementia
• Disease progression of some of these
  complications are very rapid and clinical
  features are sometimes atypical

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What is your diagnosis?
27yrs male CCs fever, headache CCs had started
since early April MRI was performed on May
1st Lesions were enhanced by Gd CD4459/ml Lumba
r puncture Initial pressure22 cmH2O Cell 492/3
(NL44448) Pro 92 mg/ml, Glu 30 mg/dl
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Syphilitic gummas serum IgG 2750 mg/dl STS
x64, TPHA x10240 CSF IgG 31.7 mg/dl STS x16,
TPHA x5120 ITPA index 43
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What is your diagnosis?
41yrs male CCs fever, somnolence, tetraplegia
(U/E flaccidic, L/E spastic) Nuchal rigidy
(-), CD439/ml CSFcell 2.6/ml, glu 31 mg/dl
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Brain cryptococcoma (Gelatinous pseudocysts)
Gatanaga Oka et al. Clin Infect Dis, 2003
(photo quiz)
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CSF of advanced AIDS patients with cryptococcus
meningitis
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What is your diagnosis?
35yrs female CC headache CD4lt50/ml Dx by a
radiologist was brain infarction I thought
infarction?, CNS-ML(-), PML (-), ----,??Then, I
started treatment
14
Toxoplasma encephalitis
2 weeks after Toxoplasma Tx
At diagnosis
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A new medico-social problem of PML
In HAART era, PML is not progressive but stable
if on HAART. However, neurological sequela
remain. A number of bedridden patients is
Increasing.
16
Improvement of PML after HAART
Before HAART
19 months after HAART
17
2002.09.25
A case of PML deteriorated after HAART
In September, he complained rt-hemiplegia
(paresis) HAART was started on Oct 4th He was
in total aphasia and had tetraplegia in Nov His
clinical symptoms were fixed and stable
thereafter
MRI at diagnosis JCV in CSF ()
18
2002.09.25
Change of MRI along with clinical course
At diagnosis rt-hemiplegia (paresis)
3 wks after HAART clinical symptoms progress
8 wks after HAART total aphasia tetraplegia
12 wks after HAART stable
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Summary 1

• In Japan, frequencies of CNS-complications in
  AIDS patients are low.
• However, mortalities of the CNS-complications are
  still very high
• Especially in advanced AIDS patients, clinical
  features are sometimes atypical
• In HAART era, increasing number of bedridden
  patients due to PML is a new medico-social problem

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- A case of early failure -
A 36y female treated with EFV EFV was stopped
because of psychiatric problem (She became
violent and hit her son) 13 days after EFV
initiation.
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EFV Concentration (600mg 10-14hr)
- ACC data -
CYP2B6 genotype
Tsuchiya Oka et al. BBRC 2004
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Dose Reduction of EFV in CYP2B6 6/6 Holders
CNS symptoms improved? HIV-1 load suppressed
enough?
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EFV conc. 10-14 hr (nM)
EFV dose reduction
Viral Load (copies/ml)
EFV 600mg
40,000
400mg
200mg
105
pleasant dream
30,000
104
nightmare
20,000
no dream
103
10,000
102
lt50
v
0
40
44
52 months
48
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- A case of early failure -
A 36y female with CYP2B6 6/6 EFV was stopped
because of psychiatric problem (She became
violent and hit her son) 13 days after EFV
initiation. pEFV(600mg, po, 24hr)
40520nM (normal range 10-14hr, 5000-15000nM)
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Reduction of Efavirenz Dose in HIV-1Infected
Patients with CYP2B66/6

• Objective Whether EFV dose can be reduced safely
  in
• patients harboring
  CYP2B66/6
• Design Prospective, observational, multicenter,
• clinical trial
• No of case 20 cases (screening of CYP2B6 500
  cases)

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EFV concentration and CYP2B6 genotype in Japanese
50,000
EFV(nM)
40,000
30,000
20,000
10,000
0
GG non-6 (n 67)
GT 6-heterozygote (n 28)
TT 6/6 (n 16)
CYP2B6 G516T genotype allele type
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EFV conc. (10-14hr) of CYP2B6 6/6 holders
50,000
EFV(nM)
40,000
30,000
20,000
10,000
3,170
0
600mg (n 12)
200mg (n 10)
400mg (n 16)
EFV dosage
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Changes in CNS-related symptoms following
reduction of EFV dose (n14)
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Summary 2
CNS symptoms improved? Yes. HIV-1 suppressed
enough? Yes.

• Dose reduction of EFV in CYP2B6 6/6 holders was
  successful
• The first step of the Tailor-Made therapy of
  HIV-1 infection

Gatanaga Oka et al. Clin Infect Dis (in press)