Introduction
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Malaria is one of the world's most common and serious
infectious diseases, causing approximately 500 million
clinical cases and 1 million deaths each year (3,000 deaths
per day), 90% of them in sub-Saharan Africa.( 1)
It is estimated that 40% of the world's population lives in
malarious areas.
Because of their low levels of immunity to infection,
children under age 5 are the group most heavily affected by
malaria. In fact, malaria is the leading cause of death
worldwide among children in this age group. Pregnant women
also are particularly vulnerable to malaria. The disease
accounts for approximately 35% of preventable cases of low
birth weight and for 5-10% of infant mortality in sub-Saharan
Africa.( 2)
Malaria is a major cause of maternal anemia, which in turn is
a risk factor for maternal mortality. The cost of malaria
prophylaxis, the need for repeated treatment, and the loss of
productive laborers constitute a significant impact on the
economies of countries in which malaria remains highly
endemic. Malarial infection is estimated to cost sub-Saharan
Africa approximately US$2 billion annually.( 3,
4)
Because there is a great deal of geographic overlap between
high-prevalence areas for malaria and HIV infection (see
Figure 1) there is growing concern among health care
professionals, researchers, and policy makers that the two may
be reinforcing each other, synergistically fueling incidence
of both and complicating treatment efforts.
Figure 1. Areas of High Prevalence for Malaria and HIV
Infection
As with HIV, malaria has been difficult to control because
of emerging drug resistance, poor availability of low-cost
prophylactic drugs, inadequate health care infrastructure, and
lack of a preventative vaccine.( 5,
6,
7,
8)
However, whereas antiretroviral drugs were developed
relatively rapidly after the emergence of HIV, the development
of antimalarial drugs powerful enough to treat resistant
strains has been slow. As the number of malarial and HIV
coinfections has increased, it has become apparent that
antiretrovirals interact with both new and established
antimalarial drugs, complicating treatment efforts for both
infections.( 9)
Malarial and HIV coinfection also results in interactions that
adversely affect the outcome of both conditions.( 10)
This is especially true for pregnant women and infants born to
HIV-infected mothers.( 9)
Understanding the pathogenesis of HIV and malaria, therefore,
is important for determining approaches to treatment and
prevention.
This review focuses on the impact of malarial and HIV
coinfection during pregnancy and infancy and the special
considerations related to simultaneous use of antiretroviral
treatment (ART) and antimalarial therapy. Also included is a
discussion of the administration of malaria treatment and
prophylaxis with cotrimoxazole prophylaxis in HIV-infected
women and children. |
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Malarial
Infection: Background |
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Causes
of Malaria |
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Malaria is caused by parasites that belong to the
genus Plasmodium. Most human malarial infection
is caused by 4 species: Plasmodium falciparum,
Plasmodium vivax, Plasmodium malariae, and
Plasmodium ovale. P falciparum, which is
the prevalent species, causes the most severe disease
and is responsible for most malarial mortality and
morbidity. It is concentrated in sub-Saharan Africa.
P vivax and P ovale can cause relapsing
disease.( 5)
Malarial parasites are transmitted from person to
person by the bite of the female mosquito of the genus
Anopheles. After transmission, the parasites grow
and multiply in the liver. When the parasites mature,
they are released into the blood and infect red blood
cells. After they mature and multiply in a red blood
cell, the cell eventually bursts and releases the
parasites, which go on to infect other cells. Internal
organs, such as the brain, are affected when heavily
infected red blood cells clump together and block
capillary blood flow.( 11)
People may be repeatedly infected with malarial
parasites and, in areas where malaria is endemic, may
develop a partial immunity that reduces the severity of
infection but allows reinfection. Children in these
areas usually develop this immunity by their fifth
birthday. |
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Symptoms
of Malarial Infection |
|
In people who have some acquired immunity, malarial
infection may be asymptomatic. In symptomatic patients,
malarial infection usually manifests with fever,
diarrhea, headache, body aches, vomiting, and other
flulike symptoms. These symptoms typically appear 9-30
days after an infectious mosquito bite. Without
treatment, or with ineffective treatment, infection can
progress rapidly into life-threatening, severe malaria.(
7)
A common manifestation of severe malaria is anemia
caused by the destruction of red blood cells (hemolysis)
by parasites. Other manifestations of severe malaria
include:
- cerebral malaria resulting in abnormal behavior,
seizures, or coma
- pulmonary edema or acute respiratory distress
syndrome
- kidney or liver failure
- thrombocytopenia and abnormalities in blood
coagulation
- rupture of the spleen ( 11,
12)
Organ failure occurs more frequently in adults and
children, whereas severe anemia and cerebral malaria are
the most frequent manifestations in children.
Presentation as respiratory distress in children is life
threatening.( 13)
Even with treatment, 20-40% of patients who develop
severe malaria die.( 12)
Cerebral malaria often results in long-term neurological
damage and developmental delays in those who survive.(
14)
The clinical syndromes of malarial infection and the
severity of illness vary, depending on the whether
infection occurs in an area of stable (high or regular)
transmission or unstable (low or infrequent)
transmission. In general, in areas of unstable
transmission the population has not acquired immunity
and disease is more severe. The various clinical courses
for pregnant women, nonpregnant adults, and children are
outlined in Table 1. Pregnant women and infants are
particularly vulnerable to developing severe malaria
following acute infection. In pregnant women, severe
malaria is more likely to develop during the second and
third trimesters of pregnancy. In these cases, maternal
mortality can be as high as 50% and premature labor is
common. Hypoglycemia is a frequent complication in
pregnant women, especially if the patient is receiving
quinine.( 9)
Bacterial infections may occur after delivery. Malaria
can be transmitted from mother to child, though neonatal
malaria is rare.
Pregnant
Women |
- High risk of developing severe, symptomatic
disease
- High levels peripheral parasitemia
- Low levels of placental infection
- High risk of maternal death
- Significant risk of spontaneous abortion,
low birth weight, infant mortality
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- Infection is usually asymptomatic
- Low prevalence of peripheral parasitemia
- High prevalence of parasitemia of the
placenta
- High prevalence of maternal anemia
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Adults |
- Acute febrile disease, which can result in
cerebral malaria and death
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- Infection is usually asymptomatic
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Children
|
- Severe anemia
- Cerebral malarial, leading to death
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- Chronic infection
- Recurrent parasitemia
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Malaria
Prevention |
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The spread of malaria can be prevented in 4 main
ways:
Vector control, which involves reducing the
mosquito population by killing mosquito larvae or adult
mosquitoes through the use of insecticides or the
destruction of breeding sites. Intensive vector control
efforts in the late 1940s successfully eradicated
malaria in a wide geographic area including the USA,
Europe, and parts of Asia. However, such efforts were
largely unsuccessful in Africa and most of Asia.( 5,
15)
Reducing human-mosquito contact by the use of
bed nets treated with pyrethroid insecticides (known as
insecticide-treated nets or ITNs), protective clothing,
topical repellents, or indoor spraying of insecticides.(
12)
ITNs are very effective at reducing the spread of
malaria. Large-scale use of ITNs (80% coverage or
greater) can effectively stem the spread of infection
for an entire population. Studies have shown that the
use of ITNs reduces mortality rates for children under 5
years of age by more than 20%.( 12)
ITNs are also effective for HIV-infected individuals. In
a study performed in Uganda, ITNs used in conjunction
with ART and cotrimoxazole in HIV-infected individuals
reduced the incidence of malaria 25-fold.( 16)
Preventing the establishment of infection
through the use of intermittent preventative treatment
(IPT) or chemoprophylaxis.
Rapidly and effectively treating those who are
infected in order to reduce the reservoir of infected
people.
There is currently no vaccine for malaria although
several trials are under way. |
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Preventative
Treatment |
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The primary means of preventing malaria among
pregnant women and children, who are particularly
vulnerable to infection, is the use of IPT with
prophylactic antimalarial drugs.
In endemic malarious areas, the use of antimalarial
prophylaxis during pregnancy has been shown to decrease
the incidence of maternal anemia and increase infant
birth weights.( 17)
There is no evidence to support the use of IPT in areas
of low transmission of falciparum malaria. Because
pregnant women are at such high risk of malaria-related
complications during pregnancy, the World Health
Organization (WHO) recommends that all pregnant women in
areas of stable (moderate to high) malaria transmission
receive IPT with at least 2 doses of an effective
antimalarial drug during routine antenatal care (ANC):
at least 1 dose in the second trimester of pregnancy
(after quickening) and at least 1 dose in third
trimester.( 18,
19)
Traditionally, chloroquine has been used for
prophylaxis, but the widespread emergence of chloroquine
resistance and the need for frequent dosing have made
this approach ineffective.( 5)
Currently, most IPT regimens consist of 2 or 3 doses
of sulfadoxine-pyrimethamine (SP), as this regimen has
been found to reduce anemia in pregnant women and
decrease the incidence of low birth weight in infants.(
20,
21,
22,
23)
Ongoing studies are investigating the efficacy of IPT
regimens containing artemisinin derivatives in
combination with other antimalarial drugs.
The recommended IPT regimen is:
- 500 mg sulfadoxine + 25 mg pyrimethamine (1
tablet)
- 3 tablets are given at each dose
IPT-SP doses should not be given more
frequently than once a
month. | |
Malaria prophylaxis given at specific times during
the first year of life also decreases morbidity and
mortality in young children. A study in Senegal found
that seasonal IPT consisting of artesunate and SP given
to children under 5 years of age significantly reduced
the incidence of malaria episodes.( 24)
Similar reductions in the incidence of severe malaria
were achieved in two Tanzanian studies that used an IPT
regimen for children during the first year of life.( 23,
25)
A similar study in Mali using IPT for children during
the high transmission season also demonstrated decreased
transmission.( 26)
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Malaria
Treatment |
|
Malaria is treatable and curable if it is detected
early and if treatment is initiated promptly. Timely
malaria treatment also can be thought of as a prevention
strategy because it reduces malaria transmission.
Malaria treatment is complicated by widespread drug
resistance, which has resulted from suboptimal dosing
and overuse of drugs such as chloroquine. Chloroquine
resistance is so widespread that it is no longer
recommended for first-line treatment of uncomplicated
falciparum malaria in most countries. Resistance to two
other widely used drugs, SP and mefloquine, is
increasing as well.( 5,
27)
Because of increasing resistance, the WHO now recommends
combination treatment based on artemisinin derivatives
for first-line treatment of falciparum malaria in Africa
and Asia.( 28)
Current recommended antimalarial coformulations include:
- artemether + lumefantrine
- amodiaquine + artesunate
- mefloquine + artesunate
- SP + artesunate
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Safety
of Malaria Treatment for Pregnant Women |
|
Because pregnant women are at high risk for
complications of malaria, infected women must be treated
promptly, with highly effective regimens. Unfortunately,
there is inadequate information on the safety of
antimalarial drugs during pregnancy and the effect of
such drugs on the developing fetus. Quinine,
chloroquine, proguanil-pyrimethamine, and SP are
considered to be safe in the first trimester of
pregnancy. Of these, quinine is the most effective, and
it can be used throughout pregnancy. Artemisinin
derivatives are increasingly used during pregnancy, with
no evidence of adverse effects on the pregnancy or the
fetus.( 9)
Current WHO guidelines state that artemisinin
derivatives can be used safely for treatment of
uncomplicated falciparum malaria in the second and third
trimester of pregnancy, and with caution in the first
trimester.( 28,
29)
Other drugs used for combination therapy during
pregnancy include: amodiaquine, chlorproguanil, dapsone,
halofantrine, lumefantrine, and piperaquine; however,
there is not sufficient safety data for any of these
drugs to recommend them for routine use.
Certain antimalarial drugs are not recommended for
use during pregnancy. Primaquine is contraindicated for
use during pregnancy. Tetracycline antibiotics are
contraindicated for use by women who are pregnant or
breast-feeding because of their effects on the
development of infant teeth and bones. Mefloquine was
associated with increased stillbirths in a study in
Thailand but no association was found in a similar study
in Malawi.( 28)
Limited data indicate that most antimalarial drugs
are not secreted in sufficient amounts during
breast-feeding to negatively affect infant welfare.
Dapsone and other tetracyclines are an exception; these
drugs are not recommended for use by women who are
breast-feeding. |
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Safety
of Malaria Treatment for Infants and Children |
|
The lack of pharmacokinetic studies of antimalarial
drugs in children complicates the treatment of infants
and children. The scarcity of suitable pediatric drug
formulations also hinders precise administration by
necessitating that adult-strength tablets be divided
into approximate pediatric dosing units.( 28)
As with adult treatment, the increasing failure of
chloroquine and SP has led to the increasing use of
artemisinin derivatives for pediatric treatment. These
drugs appear to be effective and well tolerated in
children, and the WHO currently recommends their use for
first-line pediatric treatment.( 28)
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Malaria
and HIV: Immunologic and Clinical Interaction |
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The interaction between malaria and HIV infection is
complex and subtle. There are several potential ways in which
malaria and HIV infection could interact: Coinfection could
affect the progression or clinical manifestation of either
condition, infection with either malarial parasites or HIV
could facilitate transmission of the other, coinfection could
affect treatment outcomes, and there may be toxicities or
interactions between the drugs used to treat the different
conditions. First, the effects of malarial infection on the
prevention and treatment of HIV infection will be
examined.
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Effect
of Malaria on HIV |
|
There is ample evidence that acute and chronic
malarial infection has an impact on HIV disease
progression. Early studies in the United States
demonstrated that acute viral infections transiently
increase HIV viral loads and decrease CD4 cell counts.
Acute malarial infection likewise causes a transient
increase in HIV viral load.( 30)
This spike in viral load resolves with effective
antimalarial treatment, and there is no evidence that
such transient episodes have a long-term accelerating
effect on the progression of HIV infection.
Chronic malarial infection also may be associated
with significant increases in HIV viral load,( 31)
and several studies have found that malaria in pregnant
women is associated with higher peripheral and placental
viral load,( 32,
33)
which has lead investigators to postulate a possible
association with increased mother-to-child transmission
of HIV.( 33)
However, no clear relationship between maternal
transmission of HIV and malarial infection has been
found in subsequent studies.( 34,
35,
36,
37)
There is no conclusive evidence that malaria
significantly affects HIV transmission, clinical
progression of HIV infection, or response to ART in
nonpregnant adults.( 28)
Regarding the effect of malaria on HIV transmission, it
is worth noting that malarial infection and the severe
anemia that often results from infection are major
reasons for conducting blood transfusion procedures,
most of them unsafe, in children in tropical countries
and may be significant causes of new pediatric HIV
infections. |
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Effect
of HIV on Malaria |
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By compromising the acquired immunity of adults and
children in endemic areas, HIV infection increases the
incidence of malaria and the clinical severity of
infection. Studies throughout sub-Saharan Africa have
found that coinfection with HIV approximately doubles
the risk of parasitemia and clinical malaria.( 38,
39,
40)
This is especially the case in areas where transmission
is unstable. In areas of high HIV prevalence, it is
estimated that approximately a quarter to a third of
cases of clinical malaria in adults can be attributed to
HIV.( 41)
HIV-infected patients with severe immunosuppression
experience more severe malaria than their noninfected
counterparts, and they require more frequent treatment
for uncomplicated malaria.
The negative interactions between malarial and HIV
infections are most apparent in pregnant women.
HIV-infected pregnant women are more likely than
noninfected pregnant women to acquire malaria.( 41)
Coinfection also makes malaria in pregnancy more severe
by impairing the ability of women to control the
illness, resulting in increased peripheral and placental
parasitemia. This is thought to account for the higher
risk of anemia and severe illness (including central
nervous system involvement) found in coinfected pregnant
women.( 38,
40,
42,
43)
Coinfection also increases the risk of preterm birth,
intrauterine growth retardation, and infant morbidity.(
29,
40,
44,
45)
In some geographic regions, rates of severe anemia among
coinfected women and low birth weights among their
infants exceed 35%.( 45)
Less information is available regarding the effect of
coinfection on the severity of malaria in children. A
recent study in Uganda found that HIV-infected children
<5 years of age had rates of parasitemia that were
1.7-fold higher than those among HIV-uninfected
children.( 46)
However, other cohort studies in infants have not found
similar associations.( 47,
48)
The complications of coinfection in children,
particularly older children, seem to be similar to those
found in adults. These include increased episodes of
clinical malaria, higher levels of parasitemia, and
increased prevalence of severe, malaria-induced central
nervous system disease.( 41)
|
Effect
of HIV on Malaria Treatment |
Coinfection with HIV reduces the efficacy of
malaria treatment. A study in Kenya found that
coinfected patients with CD4 cell counts of
<200 cells/µL who were treated with SP had
significantly lower rates of parasite clearance in
the 28 days following treatment.( 49)
In Ethiopia, coinfected adults who were treated
for uncomplicated malaria with artemisinin were
found to take longer to clear parasites and fever
than their HIV-uninfected counterparts.( 50)
HIV infection also reduces the efficacy of
artemisinin-based malaria treatment. A randomized
controlled trial in Zambia comparing
artemether-lumefantrine with SP for the treatment
of uncomplicated adult malaria found that
immunosuppressed patients receiving either therapy
had a higher frequency of malaria treatment
failure.( 51)
A retrospective study in Uganda found that adults
infected with HIV responded worse to malaria
treatment than their uninfected counterparts in
the 28 days following treatment. Using molecular
genotyping, researchers were able to attribute the
higher levels of treatment failure in HIV-infected
patients to a greater frequency of new infections
rather than a recurrence of existing infection.(
10)
HIV infection in the absence of antiretroviral
treatment also may interfere with the
effectiveness of standard IPT regimens such as
SP.( 20,
52)
Because HIV-infected women may not respond
sufficiently to 2 doses of SP, it is often
recommended that they take 3 doses after
quickening.( 53,
54)
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Antimalarial
and Antiretroviral Drug Interactions |
|
There are currently no documented clinical or
pharmacological interactions between antimalarial drugs
and antiretroviral drugs.( 28)
There are, however, several theoretical interactions of
which clinicians should be aware.
Protease inhibitors and nonnucleoside reverse
transcriptase inhibitors (NNRTIs) are the primary
classes of antiretroviral drugs that have the
pharmacokinetic potential to interact with antimalarial
drugs.( 55,
56)
A Dutch study, in a small number of HIV-infected
individuals taking malaria prophylaxis and protease
inhibitors, found no drug-drug interactions between
nelfinavir or indinavir and mefloquine.( 57)
Because WHO HIV treatment guidelines do not recommend
protease inhibitors for first-line antiretroviral
treatment, potential interactions between protease
inhibitors and antimalarials most likely will remain a
nonissue until these drugs become more readily available
in resource-poor countries.( 28)
Nevertheless, to be prudent, the antimalarial drugs
halofantrine, artemether, and lumefantrine should not be
given to patients receiving antiretroviral treatment
that contains protease inhibitors or the NNRTI
delavirdine. In addition, it has been reported that
nevirapine and efavirenz may reduce the concentrations
of lumefantrine and artemether, thus increasing the risk
of treatment failure. Quinine also may interact with
NNRTIs and protease inhibitors. Additional studies will
be required to determine the magnitude of these
interactions and their potential significance.( 56)
As with other sulfa-containing drugs, the risk of
severe adverse reactions to SP may be increased in
HIV-infected patients. Several fatal reactions have been
reported.( 58)
Both SP and nevirapine are independently associated with
skin and fatal liver toxicity, including severe itching
and Stevens-Johnson syndrome.( 28)
Severe skin reactions occur in approximately 2% of
patients who take nevirapine daily; clinical hepatitis
occurs in 4%. The potential for severe drug reactions
raises questions as to whether these two drugs should be
administered simultaneously or delayed by 1-2 weeks to
ascertain which drug is the causative agent if a
reaction occurs.( 28)
Severe anemia is a common occurrence in both adults and
children with malaria and HIV infection. Antiretroviral
drugs, particularly zidovudine, may exacerbate anemia in
coinfected patients, requiring a change in
antiretroviral regimen.
Malarial and HIV coinfection introduces challenging
issues related to drug interactions. There is a
significant absence of studies on the interaction
between antimalarial and antiretroviral drugs to
determine their synergistic toxicities and the effects
coadministration has on drug concentrations. New
fixed-dosed combination antimalarial drugs and
coformulated HIV drugs are urgently needed, as are
studies of their safety and pharmacokinetic properties,
particularly in pregnant women and
children. |
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Cotrimoxazole
Prophylaxis and Antimalarial Drugs |
|
Current WHO guidelines recommend the use of
cotrimoxazole for the prevention of opportunistic
infections in all HIV-infected adults, except those who
are asymptomatic.( 59)
The implementation of such guidelines has been hindered
by concerns that cotrimoxazole-induced cross-resistance
could reduce the prophylactic and therapeutic benefit of
antimalarial drugs such as SP. However, several recent
studies indicate that cotrimoxazole prophylaxis does not
increase resistance to drugs used for malaria prevention
or treatment.( 28,
60,
61)
|
IPT
in HIV-Infected Pregnant Women |
Although there are no data on the efficacy of
cotrimoxazole in preventing malaria during
pregnancy, the daily use of cotrimoxazole in
nonpregnant HIV-infected adults has been
associated with a 70% reduction in the incidence
of malaria and its complications.( 9)
Cotrimoxazole also has been used effectively to
treat malaria in children.( 62,
63)
Concurrent administration of cotrimoxazole and
SP has been associated with a significant increase
in adverse reactions, and therefore is not
recommended.( 9)
The WHO guidelines currently state that SP and
other sulfa-containing antimalarial drugs should
not be given along with daily cotrimoxazole
prophylaxis in HIV-infected patients who either
have or are at risk of malarial infection, because
cotrimoxazole is likely to have an equivalent
antimalarial effect, while having a much greater
efficacy on a broad range of microbial organisms.(
28)
However, it is worth noting that there are no
published data on the effectiveness of daily
cotrimoxazole for the prevention of malaria and
its effects on malaria-related maternal and birth
outcomes such as anemia and low birth weight.( 64)
Several other factors make the daily use of
cotrimoxazole for malaria prophylaxis by pregnant
women difficult: Most women in resource-poor
settings are diagnosed with HIV late in pregnancy
and, often, there is a significant gap in time
between HIV diagnosis and the initiation of HIV
care and treatment. Also, communication between
HIV care and treatment facilities and antenatal
clinics usually is very poor, making it difficult
to coordinate the initiation of malaria
prophylaxis. Therefore, it is difficult to assure
that an HIV-infected woman who does not receive
standard IPT will receive a sufficient course of
cotrimoxazole prophylaxis.( 64)
| | |
|
Summary |
|
Recognition of the immunologic, infectious, and drug-drug
interactions in malarial and HIV coinfection is essential for
safe and effective treatment and prevention of malaria,
especially during pregnancy and infancy. With both malaria and
HIV infection, careful monitoring for drug resistance is
essential. Coformulated drugs and studies of their
pharmacokinetics and safety are urgently needed, particularly
for pregnant women and infants.
|
Take-Home
Points
|
|
- Malarial and HIV coinfection alters immunologic
responses to both conditions. Although there is little
evidence that malarial infection has long-term effects
on the progression of HIV infection, it is clear that
untreated HIV infection increases susceptibility to
malarial infection and the severity of infection.
Patients who are coinfected with HIV are more likely
to develop anemia and symptomatic malaria.
- There is no evidence that malarial and HIV
coinfection in pregnancy increases the risk of
mother-to-child transmission of HIV.
- HIV-infected pregnant women who also have malaria
are at higher risk of acquiring placental malaria.
Malarial and HIV coinfection increases the risk of
adverse birth outcomes such as severe anemia, low
birth weight, maternal mortality, and infant
mortality. It is therefore crucial that HIV-infected
women receive cotrimoxazole prophylaxis or IPT during
pregnancy.
- The efficacy of IPT is reduced in HIV-infected
pregnant women. HIV-infected pregnant women who are
not receiving cotrimoxazole prophylaxis should have at
least 3 IPT doses after quickening instead of the
standard 2 doses.
- Untreated HIV infection reduces the efficacy of
malaria treatment. Antimalarial treatment is more
likely to fail when patients are severely
immunocompromised.
- Patients with HIV infection who develop malaria
should receive standard antimalarial treatment
regimens. However, treatment or IPT with SP should not
be given to HIV-infected patients receiving
cotrimoxazole prophylaxis.
- There is no clear evidence of clinical
interactions between antimalarial and antiretroviral
drugs. But, because of potential interactions, the
antimalarial drugs halofantrine, artemether, and
lumefantrine should not be given to patients receiving
ART that contains protease inhibitors or the NNRTI
delavirdine.
- Artemisinin-based antimalarial drugs appear to be
safe during pregnancy and for the treatment of infants
and children.
| |
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