toxoplasmosis, malaria, and hiv: impact of latent co-infection on hiv disease

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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

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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

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T. gondii Life Cycle

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Epidemiology

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LT Prevalence in USA

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Increasing Prevalence with Age

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LT Prevalence in France

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LT and HIV Co-infection

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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

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• 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%)

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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%

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Impact of LT on Brain

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Animal Studies

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Morris water maze 19

Human Studies

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• 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)

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• 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

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• 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

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• 758 women in 16th week of gestation

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

• Cumulative effect

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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

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Mechanism behind impact of LT on brain

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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

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• 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

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Our Findings

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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

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Objectives

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

• To evaluate its impact on neurocognitive functioning

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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

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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

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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)

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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)

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Toxo titers and CD4+ count

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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)

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Toxo Titers and GDS

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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)

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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

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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

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Malaria

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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

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Life Cycle

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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

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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

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Our Findings

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Study Objective

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

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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

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Results

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

• PCR negative

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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

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Future Directions

• Alternate site with high malaria prevalence – Nigeria

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

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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

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Questions?

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