The UC San Diego AntiViral Research Center sponsors weekly presentations by infectious disease clinicians, physicians and researchers. The goal of these presentations is to provide the most current research, clinical practices and trends in HIV, HBV, HCV, TB and other infectious diseases of global significance. The slides from the AIDS Clinical Rounds presentation that you are about to view are intended for the educational purposes of our audience. They may not be used for other purposes without the presenter’s express permission.

AIDS CLINICAL ROUNDS

Toxoplasmosis, malaria, and HIV: Impact of latent co-infection on HIV

disease Ajay R. Bharti, MD Assistant Professor

Division of Infectious Diseases

1

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

T. gondii Life Cycle

3

Epidemiology

4

LT Prevalence in USA

5

Increasing Prevalence with Age

6

7

LT Prevalence in France

8

9

LT and HIV Co-infection

10

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

LT seroprevalence among HIV+ population in southern Alberta, Canada

12

• 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

A=31% B=68% C=28%

JPM, 1997 14

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

15

Impact of LT on Brain

16

Animal Studies

17

18

Morris water maze 19

Human Studies

20

• Case control study – 54 suicide attempters and 30 controls

• Self-directed violence assessed by SUAS-S score

J Clin Psy, Aug 2012 21

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

22

• 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

24

• 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

• 758 women in 16th week of gestation

• LT+ women had a lower body weight (p = 0.02)

• Cumulative effect

26

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

28

Mechanism behind impact of LT on brain

29

TH within cysts

PC12 cell culture 30

• 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

• 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

Our Findings

33

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

Objectives

• To determine the prevalence of LT in our HIV+ cohort

• To evaluate its impact on neurocognitive functioning

35

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

Neuropsychological Test Battery

Verbal Fluency Sound Animals Action

Attn/Working Memory PASAT-50 WMS-III Spatial Span

Processing Speed WAIS-III Digit Symbol WAIS-III Symbol Search Trails A Color Trails 1

Executive Functioning Category Test WCST-64 Color Trails II

Learning/Memory Verbal (Hopkins Verbal Learning

Test - Revised) Visual (Brief Visuospatial

Memory Test - Revised) Motor

Grooved Pegboard

37

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

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) • 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

Toxo titers and CD4+ count

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)

42

Toxo Titers and GDS

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)

44

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

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

Malaria

47

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

Life Cycle

49

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

51

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

Our Findings

53

Study Objective

• To retrospectively determine the prevalence of malaria co-infection in a cohort of HIV-infected individuals in southern India

54

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

Results

• Malaria co-infection rate 9.8% (45/460)

• PCR negative

56

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

Future Directions

• Alternate site with high malaria prevalence – Nigeria

• Use of more suitable specimens – Whole blood or Dried blood spots

58

59

Acknowledgements

• United States – Scott Letendre – Davey Smith – Tom Marcotte – Ron Ellis – Connie Benson – Chip Schooley – Igor Grant – Allen McCutchan

– Cris Achim – D. J. Perkins – Walter Royal

• India – N. Kumarasamy – Jabin

• Nigeria

– Kanayo Okwuasaba – Ndidi Agala

• Funding

– NIMH 1 K23 MH085512-01A2 – CFAR International Pilot Project Grant

• Study participants

60

Questions?

61