HIV and malaria

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HIV and malaria

• Moses R. Kamya M.B.Ch.B, M.Med, MPH, PhD
• Associate Professor, Dept.of Medicine, Makerere
  University, Kampala, Uganda

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Outline

• Background (HIV/Malaria Interactions)
• Prevention of malaria among people with HIV
• CTX, bednets and ART
• Treatment of malaria in people with HIV
• Effect of HIV on response to antimalarial therapy
• Safety of antimalarial regimens in patients
  receiving ART and/or other treatments
• Conclusions and recommendations

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Burden of malaria in Africa

• Over 300 million clinical cases and 1 million
  deaths annually
• Accounts for 25-40 of outpatient visits and
  20-50 of hospital admissions

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Malaria incidence and HIV prevalence in selected
Sub-Saharan African countries
Brentlinger, P. E. et al. Arch Intern Med
20071671827-1836.
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Does HIV increase the risk of malaria?

• Early epidemiological evidence of an effect of
  HIV on malaria in children and non-pregnant
  adults found no interaction
• 7 studies (3 children, 3 adults, 1 both)
• All hospital or clinic based
• Cross sectional or retrospective
• Review in 1998 concluded no convincing nor
  consistent link between the two infections apart
  from in pregnant women

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Rates of clinical malaria at interim visits by
HIV status, CD4 count and WHO stage (Lancet 2000)
Rates of clinical malaria per 100 person years
HIV status
CD4 count
WHO stage
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Prevalence of HIV stratified by Age Group (Kamya
et al. JID 2005)
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Is malaria more severe in HIV infected patients?

• Prospective cohort study among adults presenting
  with fever in an area of unstable malaria
  transmission in South Africa (AIDS 2004)
• 613 episodes of malaria diagnosed
• HIV prevalence 30
• HIV associated with an increased odds of
  severe/complicated malaria (OR2.3, 95 CI
  1.4-3.9)
• HIV associated with an increased odds of death
  (OR7.5, 95 CI 2.2-25.1)
• Prospective cohort study from South Africa (CID
  2005)
• HIV-infected non-immune adults at increased risk
  for severe malaria
• This risk associated with low CD4 count

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What do we know about HIV and malaria in
pregnancy?

• Pregnant women are at increased risk for malaria,
  especially in their first 2 pregnancies
• Most pregnant women with malaria are asymptomatic
  and therefore undetected and untreated
• Compared to HIV-uninfected pregnant women, HIV
  infected pregnant women are at increased risk of
  all of the following
• Symptomatic malaria
• Placental malaria
• Maternal anemia
• Adverse birth outcomes
• HIV alters the typical gravidity-specific pattern
  of malaria risk by shifting the burden to all
  pregnancies
• Estimated that the HIV epidemic results in an
  additional 500,000 to 1 million women per year
  who have malaria during pregnancy

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Influence of malaria on HIV disease

• Parasitemia and clinical malaria associated with
  0.25-0.89 log increase in viral load for 9 weeks
• Treatment of malaria in HIV-infected adults
  associated with decreased viral load (190000 to
  120000 copies/ml), and increased CD4 cell count
  (297 to 447 cells/µL) after 28 days
• Clinical malaria episodes associated with 40
  cell/year more rapid decline in CD4 cell count
• Little information in children with HIV

Kublin, et al, Lancet 2005365233-239 ter
Kuile, et al, Am J Trop Med Hyg 20047141-54
Van Geertruyden, et al, JAIDS 200643363-7
Hoffman, et al, AIDS 199913487-495 Mermin, et
al, JAIDS 200641129-130, Brahmbhatt, et al,
AIDS 2003 17 2539-41 Ayisi, et al, AIDS 2003
17 585-94 Ned, et al, Trends Parisitol 200524
285-91
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Ecologic impact

• Modeling in Kisumu, Kenya, indicated a 2.1
  increase in HIV prevalence and 5.1 in malaria
  Since 1980
• 8,500 excess HIV infections
• 980,000 excess cases of malaria

Korenromp EL, et al, Emerg Infect Dis 2005
111410-1419 Abu-Raddad, et al, Science
20063141603-1606 Nguyen-Dinh, et al, Bull
World Health Org 198765607-613
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Cotrimoxazole prophylaxis

• 25-46 reduction in mortality
• U.S., Europe, Cote dIvoire, Uganda, Zambia,
  Malawi, South Africa
• Reductions in malaria, bacterial and Pneumocystis
  pneumonia, toxoplasmosis, diarrhea, sinusitis
• Saved health system 2.50 per person treated

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Malaria rates in 5 years

• 72 reduction in malaria incidence among all
  participants (even people with CD4 cell count
  gt500)

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Malaria incidence among HIV-infected adults
Malaria per 100 person-years

• 95 reduction in malaria with all 3 interventions

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MU-UCSF Study Design and Objectives

• We compared malaria incidence between two
  parallel cohorts
• HIV infected children
• community-based cohort of healthy children
• Objectives
• To estimate the protective efficacy of CTX and
  ITNs on the incidence of malaria in HIV infected
  children
• To investigate the prevalence of molecular
  markers associated with antifolate resistance in
  incident malaria cases.
• (Kamya et al. AIDS 2007)

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Proportion of patients with fever diagnosed with
malaria
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Effect of TMP/SMX prophylaxis and ITN use on
malaria incidence
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Baseline characteristics of malaria episodes
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High malaria risk in high transmission settings
despite CTX
Following randomization only- CTX
groupControl- RR0.36 (p0.13)
Controlling for breastfeeding
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Strategic use of HIV PIs may be justified to
prevent malaria

• Antiretroviral protease inhibitors (PIs) exert
  antimalarial activity in vitro and in animal
  models
• HIV PIs may protect against malaria.
• Clinical evidence is lacking

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Malaria Treatment in HIV Infected Populations- 3
messages

• Effective regimens are efficacious for treatment
  of malaria in HIV-infected and uninfected
  populations
• new infections are higher in HIV but
  recrudescence is similar between HV HIV-
• Increased treatment failure among HIV-infected
  with low CD4 cell counts
• Lower risk of recurrent malaria due to
  re-infection among HIV-infected on CTX prophylaxis

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To assess the effect of HIV infection on response
to antimalarial therapy

• The trials, conducted between 2002 and 2004 at 7
  sites and included the following treatment arms
• Sulfadoxine-pyrimethamine (SP) chloroquine
• SP amodiaquine (AQ)
• AQ Artesunate

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Associations between HIV and treatment failure
following antimalarial therapy (Kamya et al. JID
2005)
Controlling for age and treatment group
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Increased treatment failure among HIV-infected
with low CD4 cell counts

• HIV associated with delayed clearance time of P.
  falciparum by artemisinin
• HIV with CD4 lt200-300 treated with SP have a
  higher risk of treatment failure compared to
  CD4gt200-300 or HIV-

Birku Y et al. Ethiop Med J 2002 40 Suppl
117-26. Shah SN et al. J Infect Dis 2006
1941519-28. . Van geertruyden JP et al J Infect
Dis 2006 194917-25
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Better response in HIV on TMP/SMX
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Safety of antimalarial regimens in patients
receiving ART, TMP/SMX etc?

• Elevated LFTs in healthy volunteers given AQAS
  and EFV
• AQ levels (AUC, Cmax and half life) were elevated
  with EFV exposure

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Time course for abnormalities in liver-associated
enzyme levels ALT (alanine aminotransferase) AST
(aspartate aminotransferase) ULN (upper limit of
normal) Bars, duration of study drug
administration AQ/AS (amodiaquine artesunate)
EFV (efavirenz)
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Risk of new of worsening adverse events within 14
days of AQAS therapy
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Risk factors for new or worsening adverse events
due to neutropenia
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Conclusions (HIV/malaria interactions)

• HIV-infected adults and children have higher
  rates of clinical malaria and in non-malaria
  endemic areas more severe disease
• Advanced immune suppression is associated with an
  increased incidence of malaria
• Malaria episodes are associated with short term
  increases in viral load and decreases in CD4 cell
  count and may have long-term effects on CD4 cell
  count
• HIV is associated with increased placental
  malaria and poor birth outcomes

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Conclusions/Recommendations 1

• Use of TMP/SMX prophylaxis and ITNs substantially
  reduce the risk of malaria in HIV infected
  children and adults despite a high prevalence of
  molecular markers of antifolate resistance
• No evidence to support differential antimalarial
  treatment policies for HIV infected and
  uninfected patients with uncomplicated malaria
• Effective regimens must be used
• Severely immunosuppressed patients should be
  closely followed for Rx failure

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Conclusions/Recommendations 2

• Among HIV infected people receiving TMP/SMX and
  using ITNs, malaria is rarely the cause of fever,
  and the empiric treatment of all fevers as
  malaria would be misguided.
• Provide routine HIV testing for people with
  malaria

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Conclusions/Recommendations 3

• Malaria prevention programs should target HIV
  infected individuals, HIV prevention and
  treatment programs offer an opportunity to
  deliver malaria prevention
• Integrated interventions for both HIV and malaria
  
• Joint programme planning

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Future Research

• Need to monitor surveillance of higher level
  antifolate resistance-- may impact of the
  protective efficacy of TMP/SMX
• Do ARV drugs prevent malaria in vivo?
• Continued research is needed to establish the
  safety and efficacy of ACT regimens in patients
  receiving ART (PK studies, pharmacovigilance)
• Interactions between malaria and HIV in children,
  the population at greatest risk of malaria, need
  further study

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Thank You