Malaria and HIV: The Impact on Pregnant Women and Infants

Causes of Malaria

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.

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.

Table 1. Clinical Syndromes of Malarial Infection

Population Group Areas of Unstable Malaria Transmission (Low Levels of Acquired Immunity) Areas of Stable Malaria Transmission (High Levels of Acquired Immunity) 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 Infection is usually asymptomatic Low prevalence of peripheral parasitemia High prevalence of parasitemia of the placenta High prevalence of maternal anemia Adults Acute febrile disease, which can result in cerebral malaria and death Infection is usually asymptomatic Children Severe anemia Cerebral malarial, leading to death Chronic infection Recurrent parasitemia

Source: Theo Smart. "HIV/Malaria: When Elephants Collide". HIV & AIDS Treatment in Practice. Aidsmap. March 1, 2006. Available at: http://hivinsite.ucsf.edu/InSite?page=pa-hatip-64.

Malaria Prevention

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.

Preventative Treatment

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.

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)

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

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.

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)

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.

Effect of HIV on Malaria

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)

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.

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)

Take-Home Points

1. 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.
2. There is no evidence that malarial and HIV coinfection in pregnancy increases the risk of mother-to-child transmission of HIV.
3. 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.
4. 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.
5. Untreated HIV infection reduces the efficacy of malaria treatment. Antimalarial treatment is more likely to fail when patients are severely immunocompromised.
6. 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.
7. 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.
8. Artemisinin-based antimalarial drugs appear to be safe during pregnancy and for the treatment of infants and children.