HIV / HTLV Coinfection:preliminary results in a cohort from

Rio de Janeiro, Brazil

Instituto de Pesquisa Clínica Evandro Chagas Fundação Oswaldo Cruz (FIOCRUZ)

Rio de Janeiro, Brazil

www.ipec.fiocruz.br / www.fiocruz.brmarcus@ipec.fiocruz.br

Talk structure

Some aspects of HTLV infection

HIV infection and the nervous system

• Risk for neurological diseases in

HIV/HTLV coinfection

Preliminary results in a cohort from

Rio de Janeiro

Background

HIV-1 & HTLV• common tropism for T cells

HTLV-1:CD4+

HTLV-2:CD8+

• modes of transmission

• affect nervous system

• long latency period

• regulatory genes

Detection and isolation of HTLV-1 from cultured lymphocytes. Courtesy of Dra Maria José de Andrada-Serpa, IPEC/FIOCRUZ

Background

HTLV• cell proliferatives

• poor replicatives

• genetically stables

A Araújo, MT Silva. Neurologic Manifestations of HTLV-I Infection. In: ROSS, Karen. (Ed). Neurologic Infectious Diseases - Principles and Practice, 2005, p. 137-149

HTLV-1 - epidemiology

3%-6%30%

1.8%

A Araújo, MT Silva. Neurologic Manifestations of HTLV-I Infection. In: ROSS, Karen. (Ed). Neurologic Infectious Diseases - Principles and Practice, 2005, p. 137-149

HTLV-2 - epidemiology

HTLV

Neoplastic

ATL

Inflammatory

Arthritis

HAM/TSP

Polymyositis

Uveitis

Human T-lymphotropic virus 1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP)

Silva MT, Araújo A. Arch Neurol, 2004;61:1134-5

Peripheral neuropathy

Amyotrophic lateral sclerosis syndrome

A B

C D

Hand atrophy, miofasciculations

Pathogenesis

2% to 5% → Neurological disease(HAM/TSP)

• Viral genotypes?

• High HTLV-1 antibodies

• Female

• High HTLV-1 proviral load

HIV and neurological diseases

Frequent and disabling (Price, 1988)

• HIV clinics - more than 1/3 patients

• Autopsy studies - more than 80% patients

Brazil – 26% to 94% (Cerebral toxoplasmosis)

Silva MT, Araújo A. J Neurovirol, 2005

HIV/HTLV coinfection - neurological diseases

Risk for neurological diseases

• Brazil - M Schechter (1997): myelopathy

11/15 HIV/HTLV vs 10/62 HIV single infection (OR 13)

• USA – M Beilke (2005): myelopathy

2339 HIV-infected patients

172 coinfected (prevalence of 7.4%)

• 41 (35.7%) HTLV-1: Myelopathy in 4

HIV/HTLV coinfection – laboratorial parameters

HIV/HTLV coinfection

• Higher CD4+ counts (Schechter, 1994)

• Does not affect

HIV viral load (Schechter, 1997)

HTLV-1 proviral load (Césaire, 2001)

Objectives

What is the prevalence of HIV/HTLV

coinfection in a big cohort of HIV-

infected people from Rio de Janeiro?

Objectives

Does HIV/HTLV coinfection render

additional risk for neurological

diseases?

Objectives

Are HTLV-1 proviral load, HIV viral

load, and CD4+/CD8+ counts affected

by HIV/HTLV-1 coinfection in the era

post-HAART?

Methods

Evandro Chagas Clinical Research Institute

(www.ipec.fiocruz.br)

• 2738 HIV-1-infected individuals

Random selection of 484 stored samples

HTLV-1/2 serological study

• 713 HTLV-infected individuals

Random selection of 89 individuals

Methods

HTLV 1/2 serological study

• ELISA

• Western Blot

HTLV Proviral load

• real time PCR (TaqMan system) number of copies/100 cells = [tax copies/(β-globin copies/2)]100

Methods

Neurological assessment

• Myelopathy

HAM/TSP - WHO criteria (1990)

• Peripheral neuropathy

Clinical

Electrophysiological

Preliminary results

General group

51 10,5 10,5 10,5433 89,5 89,5 100,0484 100,0 100,0

CoinfectedHIV-1 single infectionTotal

ValidFrequency Percent Valid Percent

CumulativePercent

Overview

Virological group

36 70,6 70,6 70,63 5,9 5,9 76,55 9,8 9,8 86,37 13,7 13,7 100,0

51 100,0 100,0

HIV/HTLV-1HIV/HTLV-2HIV/HTLV-1/2IndeterminateTotal

ValidFrequency Percent Valid Percent

CumulativePercent

Overview

Demographic data

HIV single infection (N 433)• Age:41 (18-73)• Sex: 167 female (38%)

HTLV single infection (N 89)• Age:52 (20-88)• Sex: 51 female (57%)

HIV/HTLV coinfection (N 51)• Age:46 (30-71)• Sex: 17 female (33%)

Laboratorial data

CD4+ count• HIV single infection

• HIV/HTLV coinfection

Test Statisticsa

7241,00081932,000

-,894,371

Mann-Whitney UWilcoxon WZAsymp. Sig. (2-tailed)

CD4 count

Grouping Variable: HIV/HTLV coinfectiona. HIV/HTLV coinfection

NoYes

CD

4+ ly

mph

ocite

cou

nt

4000

3000

2000

1000

0

-1000

5354445369710112520868400255157

323

4

204

Laboratorial data

CD8+ count• HIV single infection

• HIV/HTLV coinfection

Test Statisticsa

7407,50081327,500

-,369,712

Mann-Whitney UWilcoxon WZAsymp. Sig. (2-tailed)

CD8 count

Grouping Variable: HIV/HTLV coinfectiona.

HIV/HTLV coinfection

NoYes

CD

8+ ly

mph

ocite

cou

nt

4000

3000

2000

1000

0

-1000

12770113101

469

204139

Laboratorial data

HIV viral load• HIV single infection

• HIV/HTLV coinfection

Test Statisticsa

6345,0006940,000

-,181,856

Mann-Whitney UWilcoxon WZAsymp. Sig. (2-tailed)

HIV-1 viralload

Grouping Variable: HIV/HTLV coinfectiona. HIV/HTLV coinfection

NoYes

HIV

-1 v

iral l

oad

3000000

2000000

1000000

0

-1000000

46435254127032540214829491384391801004751761084075192232148533752945939310436928732833224953793288154093383156749011852717595456463905234355243547122043438530400424376120444259135506423193200124339268229

188

497

431

10541526648166

Laboratorial data

HTLV-1 proviral load

HTLV single infectioCoinfected

HTL

V-1

pro

vira

l loa

d

70

60

50

40

30

20

10

0

-10

270

257

18

Test Statisticsa,b

,4511

,502

Chi-SquaredfAsymp. Sig.

HTLV-1proviral load

Kruskal Wallis Testa.

Grouping Variable: General groupb.

Risk Estimate

1,059 ,592 1,895

1,053 ,626 1,771

,994 ,935 1,057

484

Odds Ratio forOpportunistic infection(sim / não)For cohort General group= CoinfectedFor cohort General group= HIV-1 single infectionN of Valid Cases

Value Lower Upper

95% ConfidenceInterval

OI – HIV/HTLV vs HIV single infection

Opportunistic infection * General group Crosstabulation

Count

27 223 25024 210 23451 433 484

simnão

Opportunisticinfection

Total

CoinfectedHIV-1 single

infection

General group

Total

Chi-Square Tests

,038b 1 ,846,002 1 ,963,038 1 ,846

,883 ,482

,038 1 ,846

484

Pearson Chi-SquareContinuity Correctiona

Likelihood RatioFisher's Exact TestLinear-by-LinearAssociationN of Valid Cases

Value dfAsymp. Sig.

(2-sided)Exact Sig.(2-sided)

Exact Sig.(1-sided)

Computed only for a 2x2 tablea.

0 cells (,0%) have expected count less than 5. The minimum expected count is24,66.

b.

Death – HIV/HTLV vs HIV single infection

HIV/HTLV coinfection * Death Crosstabulation

Count

12 28 4028 372 40040 400 440

YesNo

HIV/HTLV coinfection

Total

Yes NoDeath

Total

Chi-Square Tests

23,276b 1 ,00020,576 1 ,00016,299 1 ,000

,000 ,000

23,223 1 ,000

440

Pearson Chi-SquareContinuity Correctiona

Likelihood RatioFisher's Exact TestLinear-by-LinearAssociationN of Valid Cases

Value dfAsymp. Sig.

(2-sided)Exact Sig.(2-sided)

Exact Sig.(1-sided)

Computed only for a 2x2 tablea.

1 cells (25,0%) have expected count less than 5. The minimum expected count is3,64.

b.

Risk Estimate

5,694 2,616 12,393

4,286 2,369 7,755,753 ,613 ,924440

Odds Ratio for HIV/HTLVcoinfection (Yes / No)For cohort Death = YesFor cohort Death = NoN of Valid Cases

Value Lower Upper

95% ConfidenceInterval

Neurological diseases

Neurological disease * General group Crosstabulation

Count

26 49 49 12425 384 40 44951 433 89 573

YesNo

Neurologicaldisease

Total

CoinfectedHIV-1 single

infectionHTLV single

infection

General group

Total

Neurological diseases

Neurological diagnosis * General group Crosstabulation

Count

25 384 39 4489 23 32

1 1

4 2 15 21

12 45 9 661 2 3

1 11 1

51 433 89 573

AsymptomaticHAM/TSPNeurogenic bladderdysfunctionHAM/TSP & PeripheralneuropathyPeripheral neuropathyDementiaATLOptic neuritis

Neurologicaldiagnosis

Total

CoinfectedHIV-1 single

infectionHTLV single

infection

General group

Total

Neurological disease * General group Crosstabulation

Count

26 49 7525 384 40951 433 484

YesNo

Neurologicaldisease

Total

CoinfectedHIV-1 single

infection

General group

Total

Neurological diseasesHIV/HTLV coinfection vs HIV single infection

Chi-Square Tests

54,995b 1 ,00052,000 1 ,00041,064 1 ,000

,000 ,000

54,881 1 ,000

485

Pearson Chi-SquareContinuity Correctiona

Likelihood RatioFisher's Exact TestLinear-by-LinearAssociationN of Valid Cases

Value dfAsymp. Sig.

(2-sided)Exact Sig.(2-sided)

Exact Sig.(1-sided)

Computed only for a 2x2 tablea.

0 cells (,0%) have expected count less than 5. The minimum expected count is7,89.

b.

Risk Estimate

8,171 4,377 15,256

5,685 3,480 9,287

,696 ,589 ,822

485

Odds Ratio forNeurological disease(Yes / No)For cohort General group= CoinfectedFor cohort General group= HIV-1 single infectionN of Valid Cases

Value Lower Upper

95% ConfidenceInterval

Neurological diseasesHIV/HTLV coinfection vs HTLV single infection

Neurological disease * General group Crosstabulation

Count

26 49 7525 40 6551 89 140

YesNo

Neurologicaldisease

Total

CoinfectedHTLV single

infection

General group

Total

Chi-Square Tests

,217b 1 ,642,084 1 ,772,216 1 ,642

,725 ,386

,215 1 ,643

140

Pearson Chi-SquareContinuity Correctiona

Likelihood RatioFisher's Exact TestLinear-by-LinearAssociationN of Valid Cases

Value dfAsymp. Sig.

(2-sided)Exact Sig.(2-sided)

Exact Sig.(1-sided)

Computed only for a 2x2 tablea.

0 cells (,0%) have expected count less than 5. The minimum expected count is23,68.

b.

Risk Estimate

,849 ,426 1,692

,901 ,582 1,396

1,062 ,824 1,368

140

Odds Ratio forNeurological disease(Yes / No)For cohort General group= CoinfectedFor cohort General group= HTLV single infectionN of Valid Cases

Value Lower Upper

95% ConfidenceInterval

Myelopathy HIV/HTLV coinfection vs HIV single infection

Myelopathy * HIV/HTLV coinfection Crosstabulation

Count

13 2 1538 431 46951 433 484

YesNo

Myelopathy

Total

Yes NoHIV/HTLV coinfection

Total

Chi-Square Tests

95,170b 1 ,00087,019 1 ,00050,349 1 ,000

,000 ,000

94,974 1 ,000

484

Pearson Chi-SquareContinuity Correctiona

Likelihood RatioFisher's Exact TestLinear-by-LinearAssociationN of Valid Cases

Value dfAsymp. Sig.

(2-sided)Exact Sig.(2-sided)

Exact Sig.(1-sided)

Computed only for a 2x2 tablea.

1 cells (25,0%) have expected count less than 5. The minimum expected count is1,58.

b.

Risk Estimate

73,724 16,041 338,838

10,696 7,435 15,389

,145 ,040 ,527

484

Odds Ratio forMyelopathy (Yes / No)For cohort HIV/HTLVcoinfection = YesFor cohort HIV/HTLVcoinfection = NoN of Valid Cases

Value Lower Upper

95% ConfidenceInterval

Myelopathy HIV/HTLV coinfection vs HTLV single infection

Myelopathy * HIV/HTLV coinfection Crosstabulation

Count

13 38 5138 51 8951 89 140

YesNo

Myelopathy

Total

Yes NoHIV/HTLV coinfection

Total

Chi-Square Tests

4,145b 1 ,0423,435 1 ,0644,261 1 ,039

,046 ,031

4,115 1 ,042

140

Pearson Chi-SquareContinuity Correctiona

Likelihood RatioFisher's Exact TestLinear-by-LinearAssociationN of Valid Cases

Value dfAsymp. Sig.

(2-sided)Exact Sig.(2-sided)

Exact Sig.(1-sided)

Computed only for a 2x2 tablea.

0 cells (,0%) have expected count less than 5. The minimum expected count is18,58.

b.

Risk Estimate

,459 ,215 ,979

,597 ,352 1,012

1,300 1,022 1,654

140

Odds Ratio forMyelopathy (Yes / No)For cohort HIV/HTLVcoinfection = YesFor cohort HIV/HTLVcoinfection = NoN of Valid Cases

Value Lower Upper

95% ConfidenceInterval

Peripheral neuropathy HIV/HTLV coinfection vs HIV single infection

Isolated peripheral neuropathy * HIV/HTLV coinfectionCrosstabulation

Count

12 45 5739 388 42751 433 484

YesNo

Isolated peripheralneuropathy

Total

Yes NoHIV/HTLV coinfection

Total

Chi-Square Tests

7,578b 1 ,0066,367 1 ,0126,287 1 ,012

,011 ,009

7,563 1 ,006

484

Pearson Chi-SquareContinuity Correctiona

Likelihood RatioFisher's Exact TestLinear-by-LinearAssociationN of Valid Cases

Value dfAsymp. Sig.

(2-sided)Exact Sig.(2-sided)

Exact Sig.(1-sided)

Computed only for a 2x2 tablea.

0 cells (,0%) have expected count less than 5. The minimum expected count is6,01.

b.

Risk Estimate

2,653 1,295 5,433

2,305 1,284 4,137

,869 ,757 ,997

484

Odds Ratio forIsolated peripheralneuropathy (Yes / No)For cohort HIV/HTLVcoinfection = YesFor cohort HIV/HTLVcoinfection = NoN of Valid Cases

Value Lower Upper

95% ConfidenceInterval

Peripheral neuropathy HIV/HTLV coinfection vs HTLV single infection

Isolated peripheral neuropathy * HIV/HTLV coinfectionCrosstabulation

Count

12 9 2139 80 11951 89 140

YesNo

Isolated peripheralneuropathy

Total

Yes NoHIV/HTLV coinfection

Total

Chi-Square Tests

4,578b 1 ,0323,586 1 ,0584,405 1 ,036

,048 ,031

4,545 1 ,033

140

Pearson Chi-SquareContinuity Correctiona

Likelihood RatioFisher's Exact TestLinear-by-LinearAssociationN of Valid Cases

Value dfAsymp. Sig.

(2-sided)Exact Sig.(2-sided)

Exact Sig.(1-sided)

Computed only for a 2x2 tablea.

0 cells (,0%) have expected count less than 5. The minimum expected count is7,65.

b.

Risk Estimate

2,735 1,063 7,038

1,744 1,111 2,737

,638 ,383 1,061

140

Odds Ratio forIsolated peripheralneuropathy (Yes / No)For cohort HIV/HTLVcoinfection = YesFor cohort HIV/HTLVcoinfection = NoN of Valid Cases

Value Lower Upper

95% ConfidenceInterval

Conclusions

HIV/HTLV coinfection – 10.5%

• HTLV-1 – 70.6%

No differences

• CD4+/CD8+ counts

• HIV viral load

• OI incidence

HIV/HTLV coinfection vs HIV single infection

• Death – OR 5.69 (12/28 vs 28/372)

HAART effects?

Conclusions

HIV/HTLV coinfection vs HIV single infection

• Neurological disease – OR 8.17

Myelopathy – 13/51 (HIV – 2/433)

OR 73.7

Peripheral neuropathy – 12/51 (HIV – 45/433)

OR 2.6

Future prospective

Long term follow up• Asymptomatic HIV/HTLV coinfection

Estimate risk HAM/TSP: 2% to 5%

Higher in coinfected patients?

Neuropsychological assessment

Authors

Marcus Tulius T Silva, MD, PhD – Neurologist Maria José de Andrada-Serpa, MD, PhD – Virologist Beatriz Grinsztejn, MD, PhD – HIV clinic Eliane Berinqué – Statistic Dayse Campos, MSc – Statistic Hugo Rojas, MD – Post-graduated student Ramza Harab, MSc – Biologist Marília Santini, MD, PhD – HIV Clinic Ana Leite, MD, PhD – Neurologist Marco Lima, MD, PhD - Neurologist Abelardo Araújo, MD, PhD - Neurologist

Acknowledged - Financial support

Ministry of Health – BrazilNational Program against Sexual Transmitted Diseases & AIDS

Thank you!

Grazie mille!

Obrigado!marcus@ipec.fiocruz.br