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Our current understanding of the human immune response to malaria and HIV leads us to expect that either infection might influence the clinical course of the other. Many other types of infections are associated with at least a transient increase in HIV viral load. Hence, it is logical to expect malaria to do the same and potentially to accelerate HIV disease progression. On the other hand, the control of malaria parasitemia is immune mediated, and this prevents most malarial infections from becoming clinically apparent in semi-immune adults in endemic areas. The immune deficiency caused by HIV infection should, in theory, reduce the immune response to malaria parasitemia and therefore increase the frequency of clinical attacks of malaria.
However, as research evidence emerged from sub-Saharan Africa in the 1980s and 1990s, it soon became clear that malaria is not a typical opportunistic infection. In fact, the interaction between HIV and malaria has proved to be remarkably subtle, and it is only in the past few years that a clearer picture of this association has begun to emerge.
|The Association between HIV and Malaria|
In 1998, a review of clinical studies concluded that the numerous studies published to that date had failed to show any convincing and consistent link between HIV and malaria, with the exception of an increased rate of placental malaria in HIV-infected pregnant women.(1) This review included several cross-sectional, retrospective, and longitudinal studies conducted in urban hospitals or clinics in African children and adults, but many of these studies had potential bias or had small sample sizes. In addition, they did not take into account the wide variation in immunosuppression found at different stages of HIV-1 infection.
Infection with HIV-1 causes progressive cellular immunosuppression, 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.(2) However, laboratory-based studies have found that although some components of the human immune response to Plasmodium falciparum are modified by HIV-1, others are unaffected.(3-5) On the other hand, P falciparum has been shown to stimulate HIV-1 replication through the production of cytokines (interleukin-6 and tumor necrosis factor-alpha) by activated lymphocytes.(6,7) P falciparum also increases the potential reservoir for HIV in the placenta by increasing the number of CCR5+ macrophages.(8) An important study from Malawi showed that HIV-1 plasma viral loads were significantly higher in patients with malaria infection than in those without, and these levels remained higher for up to 10 weeks after treatment.(9) The increases in viral load were greatest in those with clinical malaria, high levels of parasitemia, and relatively high CD4 counts. This study suggests that malaria may speed the progression of HIV disease, and this is supported by a study from Uganda showing increased CD4 cell decline associated with episodes of malaria despite prompt treatment.(10) However, the true clinical impact of malaria on HIV progression remains to be determined.(11)
Clear evidence indicates an interaction between HIV-1 and malaria in pregnancy, causing more peripheral and placental parasitemia, higher parasite densities, more clinical malaria, more anemia, and increased risks of adverse birth outcomes.(12) HIV-infected women remain susceptible to the effects of malaria whether or not they are pregnant. Placental HIV-1 viral load is increased in women with placental malaria, especially those with high parasite densities.(13) However, the effect of malaria on mother-to-child transmission of HIV is unclear because published studies to date have given conflicting findings.(14-16) It has been suggested that the discrepancy might be due to variations in maternal immunocompetence. That is, immunocompromised mothers have deranged chemokine and cytokine profiles, less protective immune responses, and consequently higher parasite densities and viral loads, leading to an increased risk of mother-to-child transmission of HIV.(17)
Studies in men and nonpregnant women show that the underlying epidemiology and intensity of malaria transmission seem to be critical for determining the consequences of coinfection. In areas of stable malaria, transmission is intense and continuous, although seasonal variations may occur. Immunity develops early in life, and young children and pregnant women are at greatest risk of morbidity and mortality from malaria. In these areas, HIV-related immunosuppression may increase rates of malaria infection and clinical malaria disease, but does not increase the rates of severe or complicated malaria.(18-22) The odds of parasitemia and risk of malarial fever increase with decreasing CD4 count and increasing viral load. These findings suggest that HIV infection not only may interfere with parasite control, but also, perhaps more important, may cause the loss of antitoxic immunity, which protects persons with parasitemia from clinical disease. In regions of unstable malaria, transmission is intermittent and less predictable, and epidemics may occur. The disease burden is similar in all age groups because preexisting antimalarial immunity is limited. As a result, malarial fever rates are a direct function of parasite transmission rates. Thus, HIV coinfection has its impact on disease presentation, with an increased risk of complicated and severe malaria and death.(23-25)
Studies of malaria and HIV interactions in children living in areas of stable malaria epidemiology have been inconclusive.(26-31) A study in rural Kwazulu-Natal, an area of unstable malaria, reported that HIV-infected children were more likely to experience severe disease, coma, and death.(32) More data are required to document any significant malaria and HIV interactions in children.
|Response to Treatment and Drug Interactions|
Antimalarial therapy is most effective in individuals who have acquired some immunity to malaria. One would predict, therefore, that the response to therapy would be decreased in immunosuppressed HIV-infected individuals living in regions of stable transmission. Although 2 early studies in the Democratic Republic of Congo (formerly Zaire) found no difference in responses to antimalarial treatment in HIV-infected children compared with uninfected children,(28,29) more recent studies suggested that treatment with artemisinin, sulfadoxine-pyrimethamine (SP), and artemether-lumefantrine was less effective in HIV-infected than in uninfected men and nonpregnant women.(21,33-35) However, investigators in Uganda used molecular genotyping of malaria parasites to demonstrate that the increased clinical treatment failure rate for malaria seen in HIV-infected adults is due to a higher frequency of new infections rather than recrudescence of existing infections.(36)
No information is available on the most effective antimalarial therapy for nonimmune HIV-infected individuals, although case reports of travelers suggest that the effectiveness of chemoprophylaxis may be reduced in this group.
Interactions between antimalarial drugs and antiretroviral drug therapy (ART) mostly involve protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs).(37,38) Most ART guidelines do not consider PIs as part of first-line regimens, but they are included in second-line therapy. The antimalarial drugs halofantrine, artemether, and lumefantrine should not be given to patients receiving PIs (or the NNRTI delavirdine) because of excessive risk of toxicity. For patients receiving other NNRTIs (nevirapine or efavirenz), drug-drug interactions may reduce the concentrations of lumefantrine and artemether, thereby increasing the risk of treatment failure. An interaction may also occur between quinine and NNRTI or PI drugs. However, the magnitude and clinical significance of these potential interactions need further research.(39)
|Public Health Implications of Coinfection|
The association between the 2 infections has important implications. Malaria and HIV-1 are 2 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-1,(40) whereas 300 million to 500 million suffer from malaria each year.(41) Therefore, any interaction between these infections will have a significant public health effect, 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.(18) (This assumes that the frequency, duration, and density of gametocytemia rise in parallel with asexual parasitemia, which is currently unproven.) The increased risk of clinical malaria in HIV-positive subjects could increase the burden on clinical services in areas where HIV-1 is prevalent.
The population-attributable fraction of adult malaria due to HIV-1 would be expected to rise in parallel with HIV-1 prevalence. In a region with an HIV-1 prevalence of 30%, such as parts of southern Africa, the population-attributable fraction could reach 20% for parasitemia and 35% for clinical malaria. However, malaria tends to affect mainly children and pregnant women, especially in rural areas, whereas HIV is more common among sexually active adults in urban centers. This mismatch, coupled with the fact that malaria tends to be more intense in western and eastern Africa whereas HIV predominates in southern Africa, means that the high population-attributable fractions given above will not prevail across the entire continent. Indeed, a computer simulation modeling study estimated that HIV would increase the incidence of clinical malaria and malaria deaths across the continent by <5%.(42) Nevertheless, in regions of unstable malaria in southern Africa, the HIV-attributable increase might reach 28% for clinical malaria and 114% for malaria deaths.
|Implications for Clinical and Public Health Management|
In endemic areas, the most relevant immediate action is to encourage HIV-infected patients to avoid malaria because of their increased risk of infection and clinical disease. Clinicians should advise their HIV-infected patients to avoid mosquito bites, perhaps best achieved by sleeping under an insecticide-impregnated bed net. Alternatives include using mosquito repellents on skin or clothing or sleeping in a room with burning mosquito-repellent coils or tablets. These alternatives are likely to be too expensive for regular use by people living in endemic areas, but may be considered by visiting travelers. Of course, visitors to malaria endemic zones should take prophylaxis, whether they are HIV infected or not. (Please see section on malaria prophylaxis in the chapter Infection and Travel in Patients with HIV Disease.)
The use of antimalarial chemoprophylaxis should be stressed in endemic areas. People living with HIV in such areas may be understandably reluctant to take regular preventive medications, but at-risk groups such as pregnant women and their fetuses are particularly likely to benefit. Intermittent presumptive treatment with at least 3 doses of SP given monthly at routine prenatal clinic visits during the second and third trimesters of pregnancy is the most practical public health approach for preventing malaria-related maternal anemia, low birth weight, and the subsequently higher risk of infant mortality.(43) Clinicians must be aware that HIV infection increases the risk of reinfection with malaria within 28 days of starting antimalarial treatment. Pharmacovigilance and additional evidence about the efficacy and safety of antimalarial drugs in HIV infection are urgently needed.
As a result of studies of cotrimoxazole (trimethoprim-sulfamethoxazole) prophylaxis showing significant reductions in morbidity and mortality among HIV-infected adults,(44,45) daily cotrimoxazole prophylaxis is recommended for all symptomatic adults and children living with HIV in Africa. The antifolate drug combination cotrimoxazole is similar to SP and has a similar effect on malaria parasites. There is a risk that widespread use of cotrimoxazole will hasten the development of resistance to SP in malaria parasites, given some evidence of P falciparum cross-resistance between trimethoprim and pyrimethamine at the molecular level.(46) The World Health Organization recommends that pregnant HIV-infected women should not receive intermittent presumptive treatment with SP if they are already receiving cotrimoxazole prophylaxis.(47) It also follows that HIV-infected individuals receiving cotrimoxazole prophylaxis should be treated with antimalarial drugs other than SP. Some evidence indicates that provision of cotrimoxazole prophylaxis to HIV-infected persons substantially reduces transmission of malaria to other household members.(48)
A recent study in Uganda showed that these antimalarial measures can be successfully implemented for HIV-infected adults in field conditions.(49) The combination of regular cotrimoxazole prophylaxis, provision of ART, and use of insecticide-impregnated bed nets was associated with a 95% reduction in the incidence of febrile episodes of malaria.
The effects of HIV on malaria in adults are now well documented. Malaria infection and fever rates are increased in areas of stable transmission, especially for individuals with low CD4 counts or high viral loads. In areas of unstable transmission, HIV is associated with more severe disease and death. Antimalarial therapy appears to be less effective in HIV-infected than in uninfected adults because of more rapid reinfection. In pregnant women, HIV is associated with more episodes of malaria, more fever, and more adverse birth outcomes. In the other direction, malaria up-regulates HIV transcription transiently during acute episodes and increases the rate of CD4 decline.
Several questions still need to be answered, such as how HIV affects malaria in children, whether the current HIV epidemic is affecting malaria control programs in Africa, and whether improved clinical management of malaria in HIV-1-infected subjects (eg, avoidance of mosquito bites or chemoprophylaxis) slows the progression of HIV disease. We also need to establish whether acute malaria episodes accelerate clinical HIV disease progression and increase transmission. The effects of ART and cotrimoxazole on susceptibility to malaria parasitemia and fever should be studied in a range of endemic settings. We also need more information about pharmacokinetic interactions between antimalarials and antiretrovirals and about the implications of widespread cotrimoxazole use in areas of high malaria prevalence.