Ajay R. Bharti, MD of UC San Diego presents "Toxoplasmosis, Malaria, and HIV: Impact of Latent Co-infection on HIV Disease"

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2. Toxoplasmosis, malaria, and HIV:
Impact of latent co-infection on HIV
disease
Ajay R. Bharti, MD
Assistant Professor
Division of Infectious Diseases
1

3. Toxoplasmosis
• Toxoplasma gondii
• Acute infection
– Flu-like symptoms that resolve in a few weeks
– CMI controls but does not eradicate the parasite
– May cause congenital infection
• Latent infection
– Life long
– Dormant in tissue
• Brain: neurons and astrocytes
• Muscle: skeletal, heart, and smooth muscle
– Reactivation disease after loss of CMI
– Encephalitis and chorioretinitis
2

4. T. gondii Life Cycle
3

5. Epidemiology
4

6. LT Prevalence in USA
5

7. Increasing Prevalence with Age
6

8. 7

9. LT Prevalence in France
8

10. 9

11. LT and HIV Co-infection
10

12. Toxoplasma seroprevalence among HIV-infected
patients
• Mathews, WC and Fullerton, SC
• July 1, 1986 to March 31, 1990
• Laboratory database of 1599 HIV+ patients
• 344 had Toxo IgG results
• LT seroprevalence of 16%
Arch Pathol Lab Med. 1994 Aug;118(8):807-10. 11

13. LT seroprevalence among HIV+ population in southern Alberta,
Canada
12

14. • St. Paul hospital, Addis Ababa
• Tested 330 samples (165 HIV+, 165 HIV-)
• Overall seroprevalence 90%
• High but similar in both groups
– HIV+ (93.3%) vs. HIV- (86.7%)
13

15. A=31%
B=68%
C=28%
14
JPM, 1997

16. • Prospective study
• Recruited 79 subjects
• LT seroprevalence similar in HIV+ and HIV-
• Overall prevalence of 64%
15

17. Impact of LT on Brain
16

18. Animal Studies
17

19. 18

20. 19
Morris water maze

21. Human Studies
20

22. • Case control study
– 54 suicide attempters and 30 controls
• Self-directed violence assessed by SUAS-S
score
J Clin Psy, Aug 2012
21

23. • Violent suicide attempts, RR=1.81 (95% CI, 1.13-2.84)
• Suicide, RR=2.05 (95% CI, 0.78-5.20)
22

24. • First study to investigate the effect of LT in
humans
• Significant delay in reaction time in those with
LT
• Positive correlation between length of
infection and mean reaction time
23

25. 24

26. • Prospective study of 3,890 male subjects
• LT increased the chance of traffic accidents
– (OR 2.43, CI95: 1.11–5.35, P = 0.027)
• RhD positivity reduced the risk of traffic
accidents in LT+ subjects
– (OR 0.35, CI95: 0.136–0.902, P= 0.028)
• RhD+ people are protected against LT-induced
impaired reaction time
25

27. • 758 women in 16th
week of gestation
• LT+ women had a
lower body weight
(p = 0.02)
• Cumulative effect
26

28. Other Effects of LTI
• Alzheimer’s disease
• Parkinson’s disease
• Schizophrenia
• OCD
• Increases probability of birth of male offspring
• Effect on personality
– High intelligence, guilt proneness, radicalism, and
high ergic tension
27

29. 28

30. Mechanism behind impact of LT on
brain
29

31. TH within cysts
30
PC12 cell culture

32. • Cysts widely distributed in brain
• Cerebral cortex had higher cyst density than
subcortical region
• Cerebellum consistently had low cysts
• Myelinated fiber tracts devoid of cysts
• No tropism towards dopaminergic or
hypothalamic systems
31

33. • Men with LT had decreased leukocyte, NK-cell
and monocyte counts
• Women had increased counts
• B-cell counts were reduced in both men and
women
• The difference between LT+ and LT- subjects
declined with decline in Toxo IgG titers
32

34. Our Findings
33

35. Background
• Prevalence of LT is similar or higher in HIV+
compared with HIV- individuals
• ARVs do not affect LT
• HIV-associated neurocognitive disorders
persist despite adequate ART
– Co-infections like LT may contribute to NCI
• Impact of LT on neurocognitive impairment in
HIV+ individuals has not been studied
34

36. Objectives
• To determine the prevalence of LT in our HIV+
cohort
• To evaluate its impact on neurocognitive
functioning
35

37. Methods
• Randomly selected 120 HIV+ participants from an NIH-
funded cohort project
• Toxoplasma IgG was measured in serum by commercial
immunoassay
• HNRC neurocognitive test battery was used
– Tests 7 ability areas
• Performance was summarized as the validated global
deficit score (GDS)
– GDS ≥ 0.5 defined neurocognitive impairment
• Data were analyzed by routine statistical methods,
including Pearson’s correlations and linear regression
36

38. Neuropsychological Test Battery
Verbal Fluency Executive Functioning
Sound Category Test
Animals WCST-64
Action Color Trails II
Attn/Working Memory Learning/Memory
PASAT-50 Verbal (Hopkins Verbal Learning
WMS-III Spatial Span Test - Revised)
Processing Speed Visual (Brief Visuospatial
Memory Test - Revised)
WAIS-III Digit Symbol
WAIS-III Symbol Search
Motor
Trails A Grooved Pegboard
Color Trails 1
37

39. Results
• LT was detected in 12 (10%) participants
• LT+ subjects were similar to LT- subjects
except that they were significantly older
• LT+ subjects were more likely to have
neurocognitive impairment (although not
statistically significant)
– This difference was greater among subjects who
were older than the median age of 44 years (60%
vs. 33%, p = 0.11)
38

40. 39

41. Results
• LT was detected in 12 (10%) participants
• LT+ subjects were similar to LT- subjects except that they
were significantly older
• LT+ subjects were more likely to have neurocognitive
impairment (although not statistically significant)
– This difference was greater among subjects who were older
than the median age of 44 years (60% vs. 33%, p = 0.11)
• Among LT+ subjects, higher IgG titers titers were
associated with
– higher CD4+ T-cell counts (r=0.74, p=0.05, Fig. 1)
– worse GDS (r=0.31, p=0.33, Fig. 2)
– On excluding the 2 outliers, worse GDS (r=0.88, p=0.0007, Fig. 2)
– Higher memory deficit (p=0.01)
40

42. Toxo titers and CD4+ count
41

43. Results
• LT was detected in 12 (10%) participants
• LT+ subjects were similar to LT- subjects except that they
were significantly older
• LT+ subjects were more likely to have neurocognitive
impairment (although not statistically significant)
– This difference was greater among subjects who were older
than the median age of 44 years (60% vs. 33%, p = 0.11)
• Among LT+ subjects, higher IgG titers titers were
associated with
– higher CD4+ T-cell counts (r=0.74, p=0.05, Fig. 1)
– worse GDS (r=0.31, p=0.33, Fig. 2)
– On excluding the 2 outliers, worse GDS (r=0.88, p=0.0007, Fig. 2)
– Higher memory deficit (p=0.01)
42

44. Toxo Titers and GDS
43

45. Results
• LT was detected in 12 (10%) participants
• LT+ subjects were similar to LT- subjects except that they
were significantly older
• LT+ subjects were more likely to have neurocognitive
impairment (although not statistically significant)
– This difference was greater among subjects who were older
than the median age of 44 years (60% vs. 33%, p = 0.11)
• Among LT+ subjects, higher IgG titers titers were
associated with
– higher CD4+ T-cell counts (r=0.74, p=0.05, Fig. 1)
– worse GDS (r=0.31, p=0.33, Fig. 2)
– On excluding the 2 outliers, worse GDS (r=0.88, p=0.0007, Fig. 2)
– Higher memory deficit (p=0.01)
44

46. Conclusions
• Prevalence of LT in our HIV+ cohort was 10%
– Similar to the general population (10.8%)
– Not generalizable as our cohort consisted of drug
abusers
• LT+ older subjects trended towards worse
neurocognitive functioning and higher anti-Toxo
IgG titers were associated with worse functioning
• Studies with a larger number of LT+ individuals
are needed to validate this finding
45

47. Future Directions
• Identify a larger HIV and LT co-infected cohort
– Owen clinic and HNRC
• Investigate the impact on driving in more
detail
– Driving simulator studies
• Mechanistic studies
– Role of inflammation: plasma and CSF
– In vitro brain model
46

48. Malaria
47

49. Malaria
• Mosquito-borne infectious disease
• Plasmodium spp.
– P. falciparum, P. vivax
– P. ovale, P. malariae
• 300-500 million episodes of acute illness
• > 1 million deaths/year worldwide
48

50. Life Cycle
49

51. Malaria and HIV Interactions
• HIV+ patients are twice as likely to get malaria*
• ↑HIV RNA and ↓CD4 counts
• Malaria doubles HIV-1-RNA with 0.25 log ↑**
• HIV RNA ↑ (0.82 log ↑) greatest when
• Febrile patient
• Parasite density >2,000/µL
• CD4 >300/µL
• Mathematical model
• Village of ~200,000 had excess 8,500 HIV infections and
980,000 malaria episodes***
*Patnaik et al J Infect Dis 2005; **Kublin et al Lancet 2005; ***Kublin Science 2006
50

52. 51

53. Asymptomatic Malaria
• Seen in areas of high transmission
• Also reported in low edemicity regions
• Clinical immunity that controls parasitemia but does
not completely eliminate it
• Described for both P. falciparum & P. vivax malaria
• Few studies on HIV and asymptomatic malaria co-
infections
• Since malaria prevalence is not homogenous, sites
need to be tested individually
52

54. Our Findings
53

55. Study Objective
• To retrospectively determine the prevalence
of malaria co-infection in a cohort of HIV-
infected individuals in southern India
54

56. Methods
• Individuals presenting to YRG CARE, Chennai,
India between Jan 1, 2008 and Dec 31, 2008
• Stored serum samples randomly selected from
HIV+ individuals
• Retrospectively diagnosed malaria by antibody
testing and PCR
55

57. Results
• Malaria co-infection
rate 9.8% (45/460)
• PCR negative
56

58. Discussion
• Considerable burden of malaria co-infection
• Predominently due to P. vivax
• Rate of P. falciparum 6-fold higher than in the
general population
• Co-infected subjects not more likely to be
immunosupressed than HIV mono-infected
• Negative PCR
– Possibly due to parasitemia below detection limit
– Parasite DNA degradation unlikely
• Our strategy may be used for identifying co-
infections in areas with unstable malaria
transmission
57

59. Future Directions
• Alternate site with high malaria prevalence
– Nigeria
• Use of more suitable specimens
– Whole blood or Dried blood spots
58

60. 59

61. Acknowledgements
• United States • India
– Scott Letendre – N. Kumarasamy
– Davey Smith – Jabin
– Tom Marcotte
– Ron Ellis • Nigeria
– Connie Benson – Kanayo Okwuasaba
– Chip Schooley – Ndidi Agala
– Igor Grant
– Allen McCutchan
• Funding
– Cris Achim – NIMH 1 K23 MH085512-01A2
– D. J. Perkins – CFAR International Pilot Project Grant
– Walter Royal
• Study participants
60

62. Questions?
61