Interaction of HIV and Malaria
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Transcript of Interaction of HIV and Malaria
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Interaction of HIV and Malaria
Malaria Branch
Division of Parasitic Diseases
National Center for Infectious Diseases
SAFER HEALTHIER PEOPLE
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Malaria and HIV disease in sub Saharan Africa
• Malaria and HIV are leading causes of morbidity and mortality, particularly in sub Saharan Africa
• Both diseases are highly endemic and have a wide geographic overlap– A small effect of malaria on HIV or vice-versa could
have substantial population-level implications
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Malaria and HIV disease in sub Saharan Africa
• Background on malaria
• What we do and don’t know:
– Malaria <-> HIV interaction
– Science & program
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Scope of the Malaria Problem:• Malaria is the most common
life-threatening infection– 1 million deaths/yr– 300-500 million infections/yr
• ~90% of these deaths occur in sub-Saharan Africa
• most victims are children <5 yrs
• Pregnant women are also especially vulnerable.
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MALARIA 101
Human Malaria is caused by one of 4 protozoan parasites:
Plasmodium falciparum
Plasmodium vivax
Plasmodium ovale
Plasmodium malariae
Malaria is transmitted through the bite of an infectedfemale Anopheles mosquito
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Liver stage
Sporozoites
Mosquito Salivary Gland
Malaria Life Cycle
Gametocytes
Oocyst
Red Blood Cell Cycle
Zygote
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MALARIA 101 – clinical syndromesChronic Disease
Chronic or Recurrent Asymptomatic
InfectionPlacental Malaria
& AnemiaAnemia
InfectionDuring
Pregnancy
Developmental Disorders
Transfusions
Death
LowBirth weight
IncreasedInfant
Mortality
Acute Disease
Non-severeAcute Febrile
disease
CerebralMalaria
Death
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Effective Malaria Interventions Include:
• Providing prompt access to curative treatment
• Preventing and controlling malaria during pregnancy
• Promoting the use of insecticide-treated mosquito nets shown to reduce all-cause child mortality by 20%-25%
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Malaria Interventions - Costs
• Insecticide-treated mosquito nets: $2.50 -- 5.00
• Malaria treatment: – CQ, SP, AQ, Lap-Dap: $0.10 – 0.50– Artemisinin-combinations: $2.00 or more
• Intermittent Preventive Tx in preg: $0.35
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Early studies – mid/late 1980s
• HIV transmission modes: mosquitoes?
• Does HIV make malaria worse?
• Does malaria make HIV worse?– Malaria is not an “opportunistic infection”– Curious because CD4-dependant immune response is
thought to be important for malaria
• Malarial anemia blood transfusion HIV infection
No
“probably No”
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Recognition of the effect of HIV on malaria in pregnant women
• Malawi study (1987-1991):– During pregnancy, malaria was more common and of higher density in HIV(+) vs. HIV(-) women– These findings were repeated in other studies and countries -Malawi (2 sites), Kenya (3), Rwanda (1)
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Placental parasitemia by HIV status and pregnancy number, Kenya
0
5
10
15
20
25
30
35
40
G1 G2 G3 G1 G2 G3
1-999 1000-9999 >10,000
Parasite density/mm3
% parasitemic
HIV (+) HIV (-)
231 159 197 772 402 479
Total n = 2263Summary RR = 1.63 (1.41-1.89), p<0.001
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Current knowledgeMalaria and HIV interactions
• Does HIV make malaria worse?
• Does malaria make HIV worse?
• Anemia and Blood safety
• Pregnant women and their fetus/newborn
• Non-pregnant adults
• Children
• Program overlap
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Anemia and Blood Safety
• Not much new to report– Remains a serious problem– Despite available technology, universal blood screening is
not yet achieved, especially in some high HIV prevalence settings
– Important unmet needs include:
• anemia prevention
• clarity on best criteria to limit transfusions except when truly needed
• universal and quality-controlled HIV testing
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Pregnant women and their fetus/newborn
• HIV does make malaria in pregnancy worse– More and higher density malaria, more illness, more
anemia, more low birth weight
• Malaria may make HIV worse– Higher HIV viral load
– ? impact on Mother-to-Child Transmission (MTCT)
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HIV-associated Risk of Placental and Peripheral Parasitemia in Pregnant Women
1.27
1.70
2.39
1.60
1.58
0 1 2 3
Placental parasitemia(4 studies)
Primigravidae389 HIV+; 1589 HIV-
Secundigravidae241 HIV+; 774 HIV-
Multigravidae382 HIV+; 1606 HIV-
Total982 HIV+; 4049 HIV-
Peripheral parasitemia(7 studies)2336 HIV+; 8667 HIV-
Relative risk (95% CI)
*
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Hemoglobin Level by HIV Status Malaria and Gravidity
Kisumu, Kenya, 1996 –1999 (N= 4,608)
van Eijk et al, AJTMH, 2001
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HIV and Malaria: Associated Reductions in Mean Birth Weight (grams)
Kisumu, Kenya, 1996-99 (N=2,466)
Primi-gravidae Multi-gravidae
HIV alone 44 (-32-112) 138 (78-199)
Malaria alone 145 (82-209)* 8 (-71-88)
Dual infection 206 (115-298)* 161 (63-259)
*In Primigravidae, both malaria (RR 2.24, p=0.003) and dual infection (3.45, p<0.001) associated with significant increased relative risk of LBW (< 2,500 grams) compared with uninfected women
Ayisi et al, AIDS, 2003
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Effect of HIV on Malaria illness in pregnancy
Kisumu, Kenya, 1996-1999
N=2539 Prevalence RR (95% CI)HIV (24.9%) HIV+ HIV-
Clinical malaria 9.4% 3.1% 3.01 (2.36-3.85)
Hospitalization (all causes)
4.3% 2.7% 1.59 (1.16-2.20)
van van Eijk et al, AIDS, 2003
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Does HIV make Malaria worse?Pregnant women, fetus, and newborn
– In western Kenya, where HIV prevalence in pregnant women exceeds 25%
•HIV accounts for one-quarter of all malaria infections in pregnancy
•HIV contributes to anemia, low birth weight, and poor infant survival (in both HIV+ and HIV- infants)
Nearly one-half of all malarious sub-Saharan African countries have HIV seroprevalence in pregnant women in excess of 10%
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Pregnant women and their fetus/newborn
• HIV does make malaria in pregnancy worse– More and higher density malaria, more illness, more
anemia, more low birth weight
• Malaria may make HIV worse– Higher HIV viral load
– ? impact on Mother-to-Child Transmission (MTCT)
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Malaria’s impact on HIV Replication
• Malaria antigens induce HIV-1 replication in-vitro (Xiao et al, JID, 1998)
• HIV transgenic mouse model -- Murine malaria triggered increased P24 antigen production (Freitag, JID 2001)
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Malaria and HIV viral load in pregnancy
Dar es Salaam, Tanzania (Kapiga et al, JAIDS, 2002): Peripheral viral load >2-fold higher in parasitemic pregnant women
Kisumu, Kenya (Ayisi, in press) Peripheral viral load 1.4-fold higher in parasitemic women (p=0.096); ↑ viral load with ↑ parasite density
Blantyre, Malawi (Victor Mwapasa, 10th CROI, Boston, 2003) Placental viral load 2.4-fold higher in HIV+ women with placental malaria than in those without malaria
Mangochi, Malawi (Tkachuk et al. JID 2001) Significant 3-fold higher CCR5 mRNA expression in placentas of malaria-infected women
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Malaria contribution to HIV-MTCT?Malawian pregnant women (Bloland, AJTMH 1995)
• Malaria and HIV co-infection
– Infants born to dually infected mothers had increased post-neonatal mortality, beyond independent risk associated with exposure to either maternal HIV or placental malaria
– Increased viral load or altered placental architecture increased MTCT?
*MTCT = Mother-to-child transmission
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Malaria contribution to HIV-MTCT?
Bloland et al. >> Infant mortality
Verhoeff et al. << Infant mortality
St Louis et al. No association
Brahmbhatt et al. RR 2.9 (1.1 -7.5)
Inion et al. RR 0.6 (0.2-1.7)
Mwapasa et al. RR 1.2 (0.7-2.3)
Ayisi et al. RR 0.4 (0.3-0.7)
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Placental Malaria & HIV-MTCT Kisumu, Kenya, 1996-1999
Ayisi et al, in press EID
• 512 mother-infant pairs with known perinatal HIV transmission status – 128 women (25%) had placental malaria
– 102 infants (20%) acquired HIV perinatally by 4 months (HIV DNA PCRs).
Ayisi, in press
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Perinatal HIV Transmission by Placental Malaria Density Kisumu, Kenya 1996-
Ayisi et al, in press
0
5
10
15
20
25
30
None 1 - 9,999 >=10,000
Placental malaria density (per µl)
% H
IV t
ran
sm
issio
n
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Potential Immunologic Basis: Effect of Malaria on MTCT
Placental malaria
Low density
High density
Th1 response
HIV replication MTCT
LIF
MIP-1-beta
Block cellular entry HIV
TNF-alpha HIV replication
MTCT
MIP-1-beta = Macrophage Inflammatory Protein-beta; LIF = Leukemia Inhibitory Factor
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Conclusions: Malaria & HIV during pregnancy
• Some clear interactions
– Preventing/managing placental malaria and HIV would reduce maternal anemia and low birth weight
• Some unclear interactions that require characterization
– Will clearing placental malaria affect MTCT ?
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Non-pregnant adults
• HIV with immune compromise (CD4 depletion) does make malaria in adults worse– More malaria, higher density parasitemia, more
illness, more severe disease
– Reduced efficacy of antimalarial therapy?
• Malaria may make HIV worse– Higher HIV viral load
– Impact on clinical illness?; survival?; transmission?
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Non-pregnant adults
• HIV with immune compromise (CD4 depletion) does make malaria in adults worse– More malaria, higher density parasitemia, more
illness, more severe disease
– Reduced efficacy of antimalarial therapy?
• Malaria may make HIV worse– Higher HIV viral load
– Impact on clinical illness?; survival?; transmission?
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Impact of HIV on malaria in non-pregnant adults
• Advanced HIV immunosuppression is associated with higher density parasitemia and more clinical illness in adults– French et al, AIDS 2001; Whitworth et al. Lancet 2000; Francesconi
et al, AIDS 2001.
• Advanced HIV immunosuppression is also associated with poorer response to malaria treatment– Shah S et al, personal communication 2004
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Non-pregnant adults
• HIV with immune compromise (CD4 depletion) does make malaria in adults worse– More malaria, higher density parasitemia, more
illness, more severe disease
– Reduced efficacy of antimalarial therapy?
• Malaria may make HIV worse– Higher HIV viral load
– Impact on clinical illness?; survival?; transmission?
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Malaria contributes to increased HIV Viral Load
• Several intercurrent infections have been shown to increase HIV replication in vivo:– Mycobacterium tuberculosis– Mycobacterium avium complex– Pneumocystis carini– Herpes simplex– STIs?
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Studies of the effect of malaria on HIV RNA levels
• Malawian adults with acute malaria – 7-fold increase in HIV-1 viral load
– Reversible with treatment (in some patients)
– Induction of HIV-1 replication in CD14 macrophages Hoffman, 1999; Pisell, 2002
• Follow-up study in Malawian adults Kublin et al, 2003 Am Soc Trop Med Hyg Mtg
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Clinical & public health significance
• Individual – Brief increase in viral load due to malaria may
worsen clinical prognosis
• Population– Higher viral load associated with higher infectivity– Probability of HIV transmission may be elevated
around a malaria episode, especially during the lag time post-malaria before RNA levels return to baseline
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Infants and Children
• Difficult to study– Low incidence/prevalence of HIV in this group– Already highly susceptible to malaria and HIV-
associated immune deficiency may not make this susceptibility much worse
• Dual Malaria and HIV is associated with poor outcome
– Anemia– Survival?
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Malaria in HIV+ infants Kisumu, Kenya, June 1996-April 2000
• HIV+ infants were not at risk of
– more malaria parasitemia
– higher parasite density
• However, if parasitemic, were at risk to:
– be febrile
– have severe anemia
– have splenomegaly
– be admitted to the hospitalSource: van Eijk et al, unpublished
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Hemoglobin in infants by HIV status and malaria
Kisumu, Kenya, June 1996-April 2000
8
9
10
11
12
13
0 4 8 12 16 20 24 28 32 36 40 44 48Age (weeks)
Mea
n h
emo
glo
bin
(g
/dl)
Not infected (reference)
HIV only (Diff= 0.33, P<0.01)
Malaria only (Diff= 0.50, P<0.01)
Dual infection (Diff= 1.07, P<0.01)
Source: van Eijk et al, AJTMH, 2002
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Post-neonatal Infant mortalityby maternal HIV-status and placental malaria
Kisumu, Kenya, June 1996-July 2001, N=866
A: No infection (N=96)
B: placental malaria only (N=117)
D: HIV only (N=494)
C: Dual infection (N=159)
Days
4003002001000
Cu
mu
lativ
e S
urv
iva
l
1.0
.9
.8
A
B
C
D
Source: van Eijk et al, unpublished
A vs C or D: P<0.01
A vs B: P=0.06
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Malaria and HIV biologic interactions– summary 2004
• HIV-associated immunosuppression contributes to more and worse malaria and it’s consequences in adults, pregnant women, and children.
• Malaria contributes to stimulus of HIV replication and possibly(?) to its consequences: disease progression, transmission in adults, and MTCT.
• Co-infection with Malaria and HIV in pregnant women contributes to anemia, low birth weight,and their risk for poor infant survival.
• Malarial anemia in children too frequently requires blood transfusion and may still lead to HIV transmission
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Malaria & HIV program overlap• Population overlaps
– Anemic children; pregnant women; adults with CD4
• Intervention overlaps– Diagnostics– Treatments: complexity and costs of Tx, resistance
•Protease inhibitors block endothelial CD36 binding of malaria-infected red blood cells
•OI prophylaxis with co-trimoxazole (an antimalarial)– HIV-infected persons need malaria prevention
• Site of activity overlaps– GFATM and Country Coordinating Mechanisms– Antenatal clinics; under-5 clinics; communities, VCT
sites? ARV delivery systems
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Malaria & HIV program overlap• Recommendations for coordinated program action
– Jointly strengthen health service delivery: • Laboratories•Antenatal and delivery care
– ITNs & IPT for malaria; VCT & MTCT prevention•Child care – anemia prevention
• Specific Interventions– ITN distribution with ARV delivery– Use highly efficacious antimalarials in HIV+ persons with
malaria infection– HIV+ persons on cotrimoxazole for OI prophylaxis who
get malaria should receive highly effective antimalarials