Central nervous system tuberculosis and HIV

1
Central nervous system tuberculosis and HIV

• Guy Thwaites
• Oxford University Clinical Research Unit, Vietnam
• And
• Imperial College, London

2
HIV and tuberculosis

• Acquired immune deficiency in Haitians
  opportunistic infections in previously healthy
  Haitian immigrants. NEJM. 1983308(3)125-9. 6/10
  had tuberculosis
• Tuberculosis, atypical mycobacteriosis, and the
  acquired immunodeficiency syndrome among Haitian
  and non-Haitian patients in south Florida.Ann
  Intern Med. 1984101(5)641-5. 27/45 Haitians
  had TB vs 1/37 non-Haitians 19/27 had
  disseminated TB
• Central nervous system tuberculosis with the
  acquired immunodeficiency syndrome and its
  related complex.Ann Intern Med.
  1986105(2)210-3. Described manifestations of
  CNS tuberculosis in 10 patients with acquired
  immune deficiency syndrome in the USA
• Tuberculous meningitis in patients infected with
  the human immunodeficiency virus.N Engl J Med.
  1992326(10)668-72. HIV-infected patients
  with tuberculosis are at increased risk for
  meningitis, but infection with HIV does not
  appear to change the clinical manifestations or
  the outcome of tuberculous meningitis.

3
Questions

• Does HIV influence the clinical features and
  diagnosis of tuberculous meningitis?
• Does HIV co-infection change the treatment and
  prognosis of tuberculous meningitis?
• What further studies are required?

4
Normal clinical features of TBM(143 adults
with TBM vs 108 adults with pyogenic bacterial
meningitis)
Lancet.360 2002
5
Influence of HIV on presentationof TBM (96 HIV,
432 HIV-)

• HIV does not influence neurological presentation
  of TBM
• Extremes of CSF WCC reported
• Disseminated extra-pulmonary disease common in
  HIV infected

J Infect Dis. 2005 Dec 15192(12)2134-41.
6
Radiological features TBM
Paed Infect Dis J. 2006 25 (1) 65-9
7
Does HIV influence the performance of other
diagnostic tests?

• Conventional bacteriology HIV increases
  likelihood of positive CSF smear and culture (42
  vs 29, Vietnam series)
• NAAT/PCR no good data
• The ?-interferon assays blood and CSF

J Immunol. 2006176(3)2007-14
8
Does HIV influence outcome and response to
treatment?
J Infect Dis. 2005 Dec 15192(12)2134-41.
9
AIDS. 2007 Jan 3021(3)373-4.
Identification of independent variables
associated with death during hospitalization in
101 HIV-infected patients with tuberculous
meningitis.

• Death also associated with high CSF
  concentrations of ?-IFN, IL-10, and IL-8
• J Immunol. 2006 Feb176(3)2007-14

10
Relapse and response to treatment
J Infect Dis. 2005 Dec 15192(12)2134-41.
11
Are corticosteroids effective?

• 545 adults with TBM randomised to placebo or
  dexamethasone
• RR death 0.69 (0.52-0.92)
• 98 HIV infected (no HAART)
• Stratified relative risk of death across HIV
  infected 0.78 (0.59 to 1.04) P0.08

NEJM. 2004. 3511741-1751
12
Bacterial genotype and drug resistance

• Beijing genotype of Mycobacterium tuberculosis
  is significantly associated with human
  immunodeficiency virus infection and multidrug
  resistance in cases of tuberculous meningitis. J
  Clin Micro. 2006 Nov44(11)3934-9.
• Beijing genotype responsible for outbreaks of
  drug resistant TB in various populations (e.g New
  York in 1990s)
• Animal models suggest it is hypervirulent
  (causing rapidly lethal disease)
• May also acquire resistance determinants more
  easily than other strains
• We compared bacterial genotypes of CSF isolates
  from 35 HIV infected adults with 187 HIV
  uninfected adults
• Beijing genotype significantly associated with
  HIV status (OR 2.95 95 CI, 1.38 to 6.44 P
  0.016), resistance to any drug (OR 3.34 95
  CI, 1.87 to 5.95 P lt 0.001) and multidrug
  resistance (P 0.001).
• The association of the Beijing genotype with drug
  resistance was independent of HIV status.

Variation in M. tuberculosis bacterial genotype
may be more important than previously thought it
may influence transmission (high risk grps), and
likelihood of drug resistance and successful
treatment.
13
Questions

• Does HIV influence the clinical features and
  diagnosis of tuberculous meningitis?
• Similar neurological features other organ
  involvement common bacteriological diagnosis
  easier
• Does HIV co-infection change the treatment and
  prognosis of tuberculous meningitis?
• Yes, prognosis much worse corticosteroids may
  be less effective drug resistant bacteria may be
  more common in some populations
• What further studies are required?

14
Further studies

• Rapid diagnosis of drug resistant TBM molecular
  methods, Microscopic observational drug
  susceptibility assay
• Timing of HAART immediate or deferred? RCT
  on-going in Vietnam. Results in 18/12.
• Clinical importance of bacterial genotype on
  disease transmission, clinical phenotype, and
  treatment outcome.

15
Acknowledgments
HTD/ OUCRU TTH Chau PP Mai NT Dung TT Hien DX
Sinh NH Phu Cam Simmons Max Caws Jeremy
Farrar Nick White
PNT TT Bang TH Tuan NV Hiep NN Thoa TN Hoa DS
Hien HH Hai NT Phuong NT Lan HT Quy