Effects of malaria and human immunodeficiency virus co-infection during pregnancy.
In sub-Saharan Africa, human immunodeficiency virus (HIV) and malaria are among the leading causes of morbidity and mortality during pregnancy. The HIV pandemic has been superimposed on the longstanding malaria pandemic, where P. falciparum malaria is consistently one of the major causes of infant and child mortality. The high prevalence of both HIV and malaria infection in Africa is an indication that interactions between the two could have substantial effects on populations.
Approximately, one million pregnancies per annum are thought to be complicated by coinfection with malaria and HIV in sub-Saharan Africa. (1) Both maternal malaria and HIV infections have been separately associated with maternal anaemia, infant low birth weight, maternal and infant morbidity and mortality. (2,3) HIV-associated risk of maternal malaria affects women of all gravidities, thus attenuating or even eliminating the decrease in malaria parasitaemia normally seen in HIV-negative multigravidae. (4) The coinfection of malaria and HIV increases the risk of congenital malaria by significantly increasing placental parasite density. (5)
The prevalence of maternal anaemia and incidence of low birthweight are both higher in pregnancies affected by HIV/malaria coinfection than in pregnancies affected by malaria or HIV alone. In the presence of coinfection, anaemia prevalence and low birthweight incidence may both exceed 35% in some subgroups. (6)
With the inception of the Roll Back Malaria partnership in 1998, there was the recognition that previous gradual declines in malaria mortality had been reversed during the 1990's, and that interactions between malaria and HIV could be one contributor. (7) As HIV spreads, it interacts with other infectious diseases, facilitated by the increase in numbers of immuno-suppressed individuals, and its clinical course can be altered by other infections.
High rates of antenatal attendance by pregnant women in Africa suggest that the effects of HIV and malaria during pregnancy could be approached through a "programme partnership" for improved antenatal care. Joint programming to strengthen antenatal care, including access to HIV diagnosis and antiretroviral drugs for PMTCT, in addition to IPT, distribution of ITNs, and improved malaria case management, could have significant impact and long-term benefits for women and children.
The current recommendation of WHO for all pregnant women living in areas of stable Plasmodium falciparum transmission is the use of insecticide-treated nets (ITN) and intermittent preventive treatment for malaria, along with antenatal HIV testing and antiretroviral therapy if indicated. (8)
As the prevalence of malaria and HIV continues to increase, it is imperative to expound on salient issues involved in malaria-HIV co-infection. Therefore, this review elucidates the interactions of malaria and HIV in pregnant women and possible interactions of sulphadoxine-pyrimethamine and antiretroviral drugs. These elements will provide background information that will enhance or facilitate the attainment of currently available interventions such as intermittent preventive treatment of malaria in pregnancy with sulfadoxine-pyrimethamine.
A HIV prevalence of over 1% among pregnant women has been considered an indicator of a generalised epidemic. (9) In Africa, estimated 40 million people are infected with HIV, resulting in an annual mortality of over 3 million (10), whereas over 500 million clinical Plasmodium falciparum infections occur every year with more than a million malaria-associated deaths. (11) Across the world, over 2 million HIV-infected women are pregnant each year, over 90% of them in developing countries, while close to 600,000 women die each year from complications of pregnancy and childbirth, the majority of them also in resource-poor areas. (10) Approximately, 1 million pregnancies each year is complicated by malaria and-HIV co-infection in sub-Saharan Africa. (12) The HIV/AIDS epidemic intersects with the problem of maternal mortality in many circumstances. Almost half of the 42 million people living with HIV are women in their reproductive years. Infection rates in pregnant women range from below 1% to over 40% in different countries. The highest rates are still in Africa, although prevalence in some Asian countries has risen considerably. Studies in pregnant women suggest that in several parts of Africa the prevalence of HIV now exceeds 25%. (13,14)
In Nigeria the prevalence rate of HIV/AIDS in adults aged 15-49 years is 3.9% (range 2.3-5.6%); while the estimated number of women aged 15 years and above living with HIV is 1.6 million. (15)
HIV AND PREGNANCY
The extent of the contribution of HIV/AIDS to maternal mortality is difficult to quantify, as the HIV status of pregnant women is not always known. HIV infection and AIDS-related deaths have become one of the major causes of maternal mortality in many resource-poor settings.
Maternal morbidity and mortality caused by anaemia, postpartum haemorrhage, puerperal sepsis, ectopic pregnancy, early abortion, bacterial pneumonia, urinary tract infection, oral and recurrent vaginal thrush and other infections may be more severe in women infected with HIV. (16)
HIV is also a major indirect cause of maternal mortality by an increased susceptibility to opportunistic infections such as Pneumocystis carinii pneumonia, tuberculosis and malaria. Anaemia may be much more frequent and severe in HIV-infected women, and especially so where pregnancy is complicated by malaria. (17,18)
HIV-infected pregnant women are at higher risk of anaemia because erythropoiesis may be suppressed by opportunistic infections, zidovudine, and HIV itself. (19,20) HIV-related anaemia is an independent risk factor for poor outcomes in HIV infection, and maternal anaemia is an important contributor to maternal mortality. (21,22) Capacity for diagnosis and case management of anaemia in HIV-infected pregnant women must be enhanced where both malaria and HIV are prevalent.
Appropriate antiretroviral therapy started in pregnancy could reverse the toll of HIV-related maternal mortality. Without such efforts and increased HIV prevention, the gains achieved by safe motherhood programmes will be lost in the future. (23)
Maternal dietary deficiencies may exacerbate the progression of HIV. Vitamin A deficiency has been shown to be associated with more rapid disease progression in HIV-infected women, increased rates of transmission of HIV from mother to child and higher levels of viral load in breast milk. A study in a general population in Nepal showed that supplementation with vitamin A or beta carotene reduced maternal mortality by 44%. (24) In Tanzania, multivitamin supplementation, but not vitamin A alone, resulted in significant increases in CD4, CD3 and CD8 counts. (25)
Data available from developed countries suggest that pregnancy does not accelerate the progression of HIV disease. (18) However, an association between adverse maternal outcomes and pregnancy in HIV-infected women has been reported, with AIDS and anaemia being the major causes of post-pregnancy mortality. (26)
HIV increases the risk of malaria in women of all gravidities (4,27,28), although the mechanism of this association is unclear. The standard recommended intermittent therapy regimens of 3 doses of sulfadoxine-pyrimethamine given at intervals of at least 4 weeks may be insufficient to clear parasitaemia in these women and may need to be reassessed. (29,30) Given the role of malaria as a potential cause of maternal mortality, the association of a higher prevalence of disease in HIV-infected women, the anaemia associated with both diseases and the potential interaction, appropriate control strategies are needed.
CO-INFECTION OF HIV AND MALARIA IN PREGNANCY
Effect of HIV on Malaria
Malaria and HIV-1 are two of the most common infections in sub-Saharan Africa and, to a lesser extent, in other developing countries. It is estimated that 38 million Africans are infected with HIV-110 whereas 300 million to 500 million suffer from malaria each year. (31) Therefore, any interaction between these two infections will be of public health significance, even if the statistical effect is modest. On a population basis, an increased prevalence of malaria and increased parasite density in HIV-infected individuals could lead to increased malaria transmission affecting both HIV-positive and -negative individuals. (32)
The control of malaria parasitemia is immune mediated, and this prevents most malaria infections from becoming clinically apparent in semi-immune adults in endemic areas, including pregnant women. The immune deficiency caused by HIV infection should, in theory, reduce the immune response to malaria parasitemia and, therefore, lead to an increased frequency of clinical attacks of malaria. An impaired opsonic activity of antibodies has been reported in multigravid women coinfected with HIV and malaria as in comparison to those without HIV. (33) Thus, the possible basis of interaction between HIV and malaria is linked to cellular-based immune responses to both HIV and malaria.
Infection with HIV-1 causes progressive cellular immuno-suppression, and any resulting impairment in the immune response to malaria might be associated with failure to prevent infection or to suppress parasitemia and clinical disease. (34) However, laboratory-based studies have found that some components of the human immune response to Plasmodium falciparum are modified by HIV-1, but that others are unaffected. (35,36) HIV infection in pregnancy is associated with higher rates of clinical malaria, higher parasite densities (both peripheral and placental). (6) However, the fraction of febrile illness attributable to malaria is lower in HIV infected adults (37), indicating the need for confirmation of malaria infection in HIV patients. The HIV-associated risk of malaria affects all gravidities is consistently greater in multigravidae. (6) HIV and malaria are independently associated with mild-to-moderate anaemia in pregnancy, increased risk of stillbirth, preterm delivery, low birth weight and fetal growth restriction. (6,38) HIV-1 infected malaria patients have a slower haematological recovery after parasite clearance. (39)
The effect of co-infection is greater in patients with advanced HIV disease and a suppressed immune function. The use of insecticide-treated bed nets and cotrimoxazole prophylaxis drastically reduces the incidence of malaria in HIVinfected individuals. (40) In a study to determine risk of death, it was reported that HIV-infected women were approximately 22 times more likely to die than HIV-uninfected women. There was a similar risk for those with malaria. Women co- infected with HIV and malaria had the greatest risk of death compared with those with only HIV infection or malaria infection. (41)
HIV-1 epidemic by increasing malaria parasite biomass in sub-Saharan Africa, may also increase the emergence of anti-malarial drug resistance, potentially affecting the health of the whole populations in countries endemic for both diseases.39 HIV-positive patients are almost twice as likely to be infected with malaria in comparison to HIV-negative persons. (6) HIV has been shown to increase the risk of malaria infection and the development of clinical malaria, with the greatest impact in immuno-suppressed persons. (42,43) Thus, the odds of parasitemia and risk of the malarial fever increase with decreasing CD4 count and increasing viral load. (44,45) For individuals who have acquired immunity through natural exposure to malaria, HIV-related immuno-suppression is associated with only a modest increase in clinical malaria, which may be explained in part by more frequent non-malaria febrile episodes (27,37), but as the level of immuno-suppression increases, there is an apparent loss of anti-disease immunity acquired over the years of living in a malaria-endemic area, which protects persons with parasitemia from clinical disease. The impaired ability to control P. falciparum infection has been attributed to the impaired opsonic phagocytic clearance of malaria parasites, especially in multigravid women (33,46), and reduced levels of specific antibodies associated with protection against malaria in pregnancy. (47)
Studies have shown that HIV-infected women experience consistently more peripheral and placental malaria, higher parasite densities, and more febrile illnesses, severe anemia, and adverse birth outcomes than HIV-uninfected women, particularly in multigravidae. (33,48) The impact of HIV on malaria is on disease presentation, with an increased risk of complicated and severe malaria and death. (48-50)
In the presence of HIV infection, placental malaria appears to be independent of the number of pregnancies, so that the risk of placental malaria is similar in HIV-infected multigravidae and HIV-negative primigravidae. HIV also increases the risk of malaria crossing the placenta and affecting the foetus. (51)
Despite the recommendation by the World Health Organisation of at least 3 therapeutic doses of Sulfadoxine-Pyrime-thamine (SP) during the second and third trimesters of pregnancy for women infected with HIV to prevent malaria during pregnancy (8), in practice, many of these women receive fewer doses of SP than recommended or even no treatment. Thus, the consequences might be particularly severe among the HIV-positive pregnant population. (52) The estimated risk of severe adverse reactions to SP (when given monthly or less often) is 0%-6.3%. (12) Passive surveillance for severe adverse events associated with SP and trimethoprim-sulfamethoxazole in Malawi found that life-threatening reactions (including Stevens-Johnson syndrome) occurred infrequently. (53) Rates were highest in HIV-positive adults (4.9/100,000 SP exposures). Fatal adverse reactions to SP were estimated to be 0.11 deaths/100,000 SP exposures. (54)
Effect of Malaria on HIV
Maternal malaria has been associated with a two-fold higher HIV-1 viral concentrations. Malaria has been shown to induce HIV-1 replication in vitro (55) and in vivo. (56) Transient and repeated increases in HIV viral load resulting from recurrent co-infection with malaria may be an important factor in promoting the spread of HIV in sub-Saharan Africa. (41)
Kublin et al (56) reported that malaria, especially if frequent, unrecognised, inadequately treated, or untreated, might lead to sufficient elevation of viral loads in HIV-infected adults to result in increased rates of HIV transmission and disease progression. An almost one-log elevation in HIV viral load occurs during a febrile malaria episode. (41,56) The transient elevation in viral load associated with malaria infection can be reversed with effective malaria treatment. Malaria prevention and control may prove to be beneficial in reducing HIV transmission and slowing progression to AIDS.
Although the increase in HIV load is reversible with prompt and effective treatment of malaria, outside of clinical studies, asymptomatic malaria infection as seen in pregnant women living in malaria endemic areas are likely to go undetected and untreated. Without prompt malaria treatment or with treatment failure, increase in viral load might be sustained for longer periods. Thus, antimalarial measures might be important for HIV-infected people who are not yet eligible for antiretroviral therapy. (56)
The effect on HIV viral load increases with the severity of malaria, whereby patients with fever and high parasitaemia have a significant increase in viral load. Another finding is that the effect of malaria on viral load elevations is most marked in patients with CD4 cell counts above 300 cells/[micro]L and remained elevated above baseline after malaria treatment. (41) Since the elevation in viral load results from stimulating the replication of the virus in response to the activation of T cells, the more T cells activated the more the replication of viral particles. This also explains why the increase in viral load is higher in individuals with higher CD4 counts than in those with lower CD4 count. Malaria-associated increase in viral load could lead to increased transmission of HIV and more rapid disease progression, with substantial public health implications. (41)
Plasmodium falciparum has been shown to stimulate HIV-1 replication through the production of cytokines (IL-6 and TNF-alpha) by activated lymphocytes. (55,57) It has also been shown to increase the potential reservoir for HIV in the placenta by increasing the number of CC chemokine receptor 5(+) macrophages. (58)
CC chemokine receptor 5(+) macrophages (CCCR5+) are cells targeted by HIV for infection and their accumulation in the placenta in response to malaria parasitaemia in the placenta increases the reservoir of HIV in the placenta, thereby increasing the risk of vertical transmission of HIV. The study by Tkachuk et al (58) showed that placentas of malaria-infected women contain 3 times as much CCCR5+ cells as placentas of women without malaria. By immunohistochemistry, CCCR5+ maternal macrophages were seen in placentas from malaria-infected women but not in placentas from malaria-uninfected women. Thus, malaria infections increase the potential reservoir for HIV in the placenta by increasing the number of HIV target cells.
HIV-1 plasma viral loads are significantly higher in patients with malaria infection than in those without, and these levels remain higher for up to 10 weeks after treatment. Those with increases in viral load were greatest in those with clinical malaria, high parasitemia, and relatively high CD4 counts. (56) Placental HIV-1 viral load is increased in women with placental malaria, especially those with high parasite densities. (59)
Effect of Malaria on mother to child transmission of HIV infection
Without intervention, it is estimated that 25-45% of the HIVinfected women will transmit infection to their children. In 15-30%, this occurs in the intrauterine and intrapartum period and the remainder is due to breastfeeding depending on breastfeeding practices and duration. (14)
The notion that MTCT can virtually be eliminated through effective voluntary testing and counselling, access to antiretroviral therapy, safe delivery practices, and the widespread availability and safe use of breast-milk substitutes (10) should include prevention and treatment of malaria infection during pregnancy. This is because placental malaria increases the risk of mother-to-child-transmission (MTCT) of HIV. (60)
Some studies investigating the effect of placental malaria on mother-to-child HIV-1 transmission showed conflicting results, possibly reflecting a complex balance between placental malarial immune responses and stimulation of HIV-1 viral replication. Ayouba et al (61) showed that binding of a recombinant P. falciparum adhesion to chondroitin sulfate A proteoglycans increases HIV-1 replication in the human placental cell line, BeWo. Thus suggesting that placental malaria could increase the risk of HIV-1 transmission in utero. Brahmbhatt et al (60) reported an increased risk of MTCT of HIV in mothers coinfected with malaria and HIV. However, Msamanga et al (62) reported a lack of association between placental malaria and infant HIV-1 status at birth.
The likelihood of mother-to-child-transmission (MTCT) of HIV is increased by increases in the viral load and also by placental malaria infection. Malaria infection during pregnancy increases risks of MTCT in the intrauterine and intrapartum period as well as during the breastfeeding period, presumably by increasing HIV viral load. Rates of perinatal HIV transmission are higher among HIV-infected mothers with more advanced disease. (63)
Viral exposure in utero and/or HIV induced failure of the maternal immune system to adequately support the development of competent infant immune capacity may result in diminished capacity of the infant to control common infections. (64,65) Of concern in cases in which HIV exposure has compromised fetal immune development is that vaccines given in early childhood may not be immunogenic. This suspicion has been confirmed by the decreased bacille Calmette-Guerin (BCG) scar formation66 and the increased rate of morbidity and mortality (67) among uninfected children born to HIV infected mothers.
To prevent mother-to-child transmission of HIV and/or progression of maternal HIV infection during pregnancy, several different regimens of antiretroviral therapy are now available.
DAILY CO-TRIMOXAZOLE: Alternative to IPTp with SP
Cotrimoxazole (trimethoprim-sulfamethoxazole) has been used effectively to treat malaria in children, and daily use of co-trimoxazole by non-pregnant HIV-infected adults has been associated with reductions of over 70% in the incidence of febrile malaria parasitaemic syndromes. (68,69) The World Health Organization recommends daily co-trimoxazole as an alternative to IPT with SP for immuno-compromised HIV-infected women and that pregnant HIV-infected women should not receive intermittent preventive treatment with SP if they are already receiving cotrimoxazole prophylaxis. (8)
There has been the fear that large-scale use of cotrimoxazole for prophylaxis of opportunistic infections in HIV-positive patients, although of possible benefit in reducing the incidence of malaria, may increase the risk of development of resistance in malaria parasites to SP (used for IPTp). (70) This fear was allayed by the recent report that daily cotrimoxazole prevents malaria and reduced the incidence of anti-folate resistant P. falciparum. (71) The lack of association between co-trimoxazole prophylaxis and development of SP resistance may be due to the difference in the locus associated with trimethorprim resistance in the dihydrofolate gene of P. falciparum and the loci associated with pyrimethamine resistance. (72)
Concurrent administration of SP and co-trimoxazole has been associated with a substantially increased incidence of severe adverse cutaneous and/or hepatic reactions in HIVinfected patients, and is therefore, not recommended.6 Operational constraints resulting from late diagnosis of HIV may limit the use of daily co-trimoxazole for malaria prophylaxis. Women who are not diagnosed with HIV until after the first antenatal visit may not present for HIV care until late pregnancy, especially where HIV care is not offered at the antenatal clinic itself. In many settings, prescription of co-trimoxazole may also be contingent on clinical and/or laboratory staging, which may introduce further delays in initiation of cotrimoxazole prophylaxis. If co-trimoxazole is not begun until the third trimester, malaria-related maternal anaemia and fetal growth retardation may already have developed.
Many HIV-infected people are intolerant of cotrimoxazole because of its sulfonamide component. (73,74) The risk of adverse reactions to co-trimoxazole in HIV-infected people has been estimated at 26*3 per 100 person-years, increasing substantially with advancing immunosuppression. The likelihood of adverse reactions also appears to vary by sex and race, and may be higher in women. (73)
Initiation of daily antiretroviral regimens may influence the timing of co-trimoxazole initiation and the interpretation and management of adverse drug reactions. Hypersensitivity reactions to nevirapine are common and clinically indistinguishable from reactions to co-trimoxazole. Therefore, clinicians commonly stagger their introduction by 2-4 weeks, so that adverse reactions may be correctly ascribed to the offending drug. (75) Therefore, some women who present in late pregnancy for HIV treatment may receive antiretrovirals first, because of the urgency of reducing HIV viral load before delivery, while co-trimoxazole initiation is delayed, sometimes until the postpartum period. Addition of zidovudine to co-trimoxazole prophylaxis may accentuate the adverse haematological consequences (anaemia and neutropenia) of co-trimoxazole prophylaxis, thus increasing the risk of maternal anaemia. (76)
The risk of co-infection with malaria is high among pregnant women infected with HIV living in malaria-endemic areas. Infection of a pregnant woman with HIV has been associated with more peripheral and placental parasitemia, higher parasite densities and more clinical malaria. On the other hand, malaria infection in a HIV-infected pregnant woman is associated with an increase in viral load. The co-infection of HIV and malaria, therefore, enhance the impact of each disease on the pregnant woman such as maternal anaemia, increased risk of adverse birth outcomes, increase in the burden of maternal and infant mortality and increased risk of mother to child transmission of HIV.
The chemoprophylaxis option adopted to adequately protect a HIV-infected pregnant woman from malaria infection requires the knowledge of her level of immunosuppression. For those that are not yet immuno-compromised, the combination of IPT with SP, antiretroviral therapy along with the use of ITN is adequate in protecting against malaria infection. For the immunocompromised pregnant women, the option is daily cotrimoxazole, antiretroviral therapy and use of ITN.
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Corresponding author: Dr. Wellington A. Oyibo, WHO/TDR Malaria Specimen Bank Collection Site Tropical Diseases Research Laboratory (TDRL) Department of Medical Microbiology and Parasitology College of Medicine, University of Lagos, Lagos, Nigeria Tel: 234-8035374004 e-mail: firstname.lastname@example.org
Wellington A. Oyibo  and Chimere O. Agomo [1,2]  WHO/TDR Malaria Specimen Bank Collection site, Department of Medical Microbiology and Parasitology, College of Medicine of the University of Lagos, Nigeria  Malaria Research Laboratory, Nigerian Institute of Medical Research, P.M.B. 2013 Yaba, Lagos, Nigeria
Table 1. WHO guidelines for PMTCT drug regimens in resource-limited settings Pregnancy Labour After After birth: birth: infant mother Recommended AZT after single dose AZT+3TC single dose 28 weeks nevirapine; for seven nevirapine; AZT+3TC days AZT for seven days Alternative AZT after single dose -- single dose (higher risk of 28 weeks nevirapine; nevirapine; drug resistance) AZT for seven days Minimum -- single dose AZT+3TC single dose (less effective) nevirapine; for seven nevirapine AZT+3TC days Minimum (less -- single dose -- single dose effective higher nevir apine nevirapine risk of drug resistance)