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Malaria and HIV

By Bob Huff

July/August 2001

Reprinted from amfAR HIV/AIDS Treatment Directory Online, www.amfar.org.

Depending on how you look at it, malaria has either a lot or very little in common with HIV.

Both diseases kill millions of people each year, and both diseases are scourges of developing nations in Africa, India, Southeast Asia and South America. But HIV is pandemic, spread from person to person by sexual contact in an increasingly mobile world. Malaria is endemic, dependent on a local symbiosis between infected anopheline mosquitoes and humans. The severe symptoms of malaria caused by the tiny parasite Plasmodium falciparum appear within days and bring death to about 15 to 25% of those stricken when great quantities of infected red blood cells are destroyed in a single burst. HIV infection is a slow, insidious process that can take years to deplete immunologically crucial white blood cells. AIDS results in death for nearly all untreated patients.

Both diseases can be transmitted by contaminated blood. In the eighties, some partially blamed the initial spread of HIV in Africa on the transfusion of infected blood to treat malaria-associated anemia. And a study in Brazil has tracked an outbreak of blood-borne malaria among urban HIV-infected intravenous drug users. (Bastos)

The infection rates of both diseases can be reduced by behavior changes, barrier protection (condoms or bed nets) and medical prophylaxis. Vaccine development for both diseases has been slow. But malaria can often be treated and cured with an inexpensive weeklong course of drugs whereas current HIV treatment is a lifelong prospect of daily medication at costs that have so far limited their use in developing countries. Most people who contract HIV or malaria are poor.

With shared geography and demographics, co-infection is common, yet surprisingly few obvious clinical associations between HIV and malaria are reported. Studies are contradictory about the frequency and severity of malaria in HIV-infected people. Malaria does not appear to act as a classic opportunist in immune-compromised hosts. People who have grown up in endemic regions often retain partial immunity to malaria, and there is no solid evidence that this immunity is lost as HIV disease progresses.


HIV, Malaria and Pregnancy

One thing is clear: The two diseases critically intersect in the bodies of pregnant women.

In parts of Africa, severe anemia during pregnancy can be caused by nutritional deficits, hookworm, malaria or HIV disease. Asymptomatic malaria can exacerbate the common mild anemia of pregnancy, and recrudescence of malaria may be more frequent because of the immune suppression normally experienced by pregnant women. Falciparum malaria episodes are associated with low birth weight, fetal distress, premature labor, and an increased number of stillbirths, miscarriages and neonatal deaths. Placental malaria may be associated with an increased frequency of mother-to-child HIV transmission. Acute falciparum malaria during pregnancy is a particularly dangerous condition, since any underlying anemia can be dramatically amplified by red blood cell destruction. (Shulman)

More commonly, however, malaria is asymptomatic during pregnancy and not always easily diagnosed. Research has shown that even such subacute malaria can contribute to anemia and placental infection. A clinical trial in Kenya reported that presumptive treatment of all pregnant women in endemic malarial areas with only two doses of sulfadoxine-pyrimethamine (SP) reduced the incidence of anemia among first-time mothers by 39%. Another study observed a reduction in the incidence of low birth-weight babies from 14% when only symptomatic mothers were treated (fever case management) to 8% when all mothers were treated presumptively. Treatment of all mothers with SP at risk for malaria is now the standard of care in clinical settings in Kenya and elsewhere. (Steketee; Shulman)

The role of HIV in this complex is illuminated by results from a 1994 study conducted in rural hospitals in Malawi. Researchers diagnosed malaria in 56% of first-time mothers with HIV compared to 36% in first-time mothers who were HIV-negative. Among mothers who had previously given birth, the incidence of malaria was 24% for those with HIV and 11% for those without. All mothers had received SP malaria prophylaxis in accordance with Malawi government guidelines. (Verhoeff)

A Kenyan clinical trial compared two-dose SP with monthly dose SP as presumptive malaria treatment during pregnancy. Investigators reported that placental malaria was found in 25% of HIV-positive women who received two-dose SP and in 7% of HIV-negative women on the same regimen. Findings of placental malaria in HIV-positive women dropped to 7% for women who received monthly presumptive SP dosing during the second and third trimesters of pregnancy. (Parise)

A retrospective analysis of children born in a Malawi trial of prenatal malaria chemoprophylaxis reported a sharply increased risk of postnatal mortality when mothers had placental malaria, HIV or both. A normal birth weight baby born to an HIV-infected woman with placental malaria was 2.7 times more likely to die than the child of an HIV-infected woman without placental malaria. This same child was 4.5 times more likely to die than one born to an HIV-negative woman who had placental malaria. The risk of postnatal death increased to nearly 8 times if the infant had a low birth weight. (Bloland)

A heightened risk of HIV transmission with placental malaria could be the result of one or more factors. There may be a disruption of the placental cellular architecture that allows an intermingling of maternal and fetal blood. Another mechanism might be that placental malaria stimulates a local increase of HIV-infected macrophages and other lymphocytes, and these increase the risk of viral transmission. Or placental malaria may simply be a consequence of advanced HIV infection and higher viral load, itself associated with mother-to-child transmission. (Bloland)

To summarize, these findings suggest that women with HIV are at greater risk of having malaria during pregnancy -- a condition that increases the risk of having a sick baby or of passing HIV to the child. Prophylactic treatment lowers the incidence of subacute and placental malaria. It can improve the health of the mother and child and reduce the risk of placental transmission of both malaria and HIV.


Do Malaria Treatments Affect HIV?

Possible answers to this question are raised by a study in Malawi that reported a lowering of plasma HIV levels during SP treatment of acute falciparum malaria. At baseline, 47 HIV-positive men and women with confirmed symptomatic falciparum malaria had a median viral load of 151,000 copies/mL. The baseline median viral load of the control group, consisting of 42 asymptomatic, aparasitic HIV-positive men and women, was 22,000 copies/mL. Twenty-seven malaria subjects and 22 non-malaria subjects completed four weeks of follow-up. After four weeks on treatment, the median viral load of the 27 malaria patients had declined from 191,000 to 120,000 copies/mL. The median viral load of the control group increased slightly. (Hoffman)

A different anti-malarial agent is chloroquine, a drug with immune modulatory qualities that has also been reported to have an inhibitory effect on HIV in vitro. (Pardridge; Savarino) Although conducted before the availability of sensitive viral load assays, a clinical trial that compared chloroquine to AZT in asymptomatic patients reported equivalent reductions in recoverable HIV after 16 weeks. (Sperber) A study in Uganda reported no difference between the incidence (but not the severity) of malarial episodes in children with or without HIV. The authors wondered whether the anti-HIV properties of the chloroquine administered to both groups had confounded their observations. (Kalyesubula) Compounds related to chloroquine are currently being investigated as HIV integrase inhibitors. (Mathe)

Drug-resistant strains of malaria are threatening to cripple efforts to arrest the epidemic. Chloroquine-resistant Plasmodium is widespread in many parts of Southeast Asia and increasingly common in Africa. Resistance to SP has been noted in Tanzania and elsewhere. Chloroquine and SP, as first- and second-line treatments, once offered a cure for about twenty cents per person. The drugs needed to treat resistant strains of malaria cost many times that amount and will not be widely available in poor countries. As with tuberculosis and HIV, the solution to effective treatment of this resistance-prone pathogen may lie in adopting combination therapy with agents that block the Plasmodium life cycle at two crucial points instead of one, thereby multiplying protection against resistance. (White)

Although expensive HIV drugs are not likely to become available soon for everyday treatment in malarial regions, the efficacy of low-cost, short-course antiretroviral therapy to prevent mother-to-child transmission during birth has been established. The use of AZT and nevirapine in pregnancy is growing and could soon become standard of care throughout most of the world. Although pregnant women in endemic malarial regions are routinely prescribed prophylaxis for malaria, no studies have been made of the potential for pharmacologic, toxic and teratologic interactions between these various classes of drugs. (Okereke)


The Immunological Connection

The mechanisms used by the immune system to fight malaria are not fully understood, although it is clear that both humoral and cell-mediated immunity are involved and that various T-cell subsets are important for regulating the immune response. (Troye-Blomberg) HIV too has an intricate relationship with the immune system, and it appears that there may be several points of intersection between the pathogenesis and response to each disease.

Some have suggested that the malarial antigens and pigments released during the burst of red blood cells stimulate cytokines that can activate HIV replication. The investigators in Malawi who noted lower HIV levels in people treated with SP also measured levels of tumor necrosis factor (TNF alpha), a cellular signaling protein or cytokine that has been associated with increased rates of HIV replication. TNF alpha is released in response to anti-malarial immune activation. But during SP malaria treatment, blood levels of TNF alpha decreased. This adds weight to the suggestion that suppressing malarial infection may result in a lowered HIV viral burden. (Hoffman)

Different clinical manifestations of malaria are associated with different states of immune dysregulation. In Ghana, children with cerebral malaria had significantly higher levels of TNF, TNF receptors, and IL-10 (another cellular signaling cytokine) than did those with severe malarial anemia or uncomplicated malaria. (Akanmori)

This picture is further complicated by reports that various common malaria treatments such as quinine and artesunate directly affect TNF levels in vitro. (Ittarat)

Another cytokine that increases during acute malaria is granulocyte colony stimulating factor (G-CSF). (Stoiser) G-CSF stimulates the production of neutrophils (white blood cells that help fight bacterial and fungal infections). A clinical trial of G-CSF versus placebo in AIDS patients reported a significantly lower incidence of bacterial infections for those receiving G-CSF but no difference in HIV viral load. (Kuritzkes)

A connection between HIV and malaria may exist in the way the immune system responds to certain similar molecular features on their structural proteins. An analysis using Western blot antibody diagnostics found overlapping immune reactivity in blood containing HIV antigens and that with P. falciparum antigens. HIV-negative subjects from Papua, New Guinea, an endemic malarial region, reacted positively to certain HIV antigens. Similarly, blood from HIV-positive persons from non-malarious regions reacted positively in immunoblot tests for antibodies to P. falciparum antigen. (Elm)

If HIV infection stimulates an immune response to P. falciparum, it may help explain unexpected findings of decreased malaria mortality in a group of HIV-positive children. Of 121 children with HIV entering a clinic in Kinshasa, Zaire, 41 had malaria. Half of the malaria cases were moderate to severe, and all cases were treated with quinine. None of the 41 children with HIV and malaria died compared to 25 of the 71 children with just HIV. While no one died in the coinfected pediatric population, there was a 14% death rate among HIV-negative children with malaria. The prevalence of malaria at this hospital was the same for children with or without HIV. (Dayachi) These results seem to be contradicted by a later Ugandan study finding that pediatric malaria patients with HIV had more hospitalizations and required more transfusions than those without HIV. (Kalyesubula)

Others have proposed that the immune response to malaria can increase the pool of lymphocytes available for HIV infection, resulting in accelerated progression to AIDS. Whether this actually occurs is not known. Much research still needs to be done to understand the interactions between the immune system and these all-too-common pathogens.


References

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  2. Bastos F., et al. Co-infection with malaria and HIV in injecting drug users in Brazil: a new challenge to public health? Addiction 1999 Aug;94(8):1165-74.

  3. Bloland P., et al. Maternal HIV infection and infant mortality in Malawi: evidence for increased mortality due to placental malaria infection. AIDS 1995, 9:721-6.

  4. Dayachi F., et al. Decreased mortality from malaria in children with symptomatic HIV infection. Int Conf AIDS. 1991 Jun 16-21;7(2):164 (abstract no. W.A.1291).

  5. Elm J., et al. Serological cross-reactivities between the retroviruses HIV and HTLV-1 and the malaria parasite Plasmodium falciparum. P N G Med J 1998 Mar;41(1):15-22.

  6. Hoffman I., et al. The effect of Plasmodium falciparum malaria on HIV-1 RNA blood plasma concentration. AIDS 1999, 13:487-94.

  7. Ittarat W., et al. The effects of quinine and artesunate treatment on plasma tumor necrosis factor levels in malaria-infected patients. Southeast Asian J Trop Med Public Health 1999 Mar;30(1):7-10.

  8. Kalyesubula I., et al. Effects of malaria infection in human immunodeficiency virus type 1-infected Ugandan children. Pediatr Infect Dis J 1997 Sep;16(9):876-81.

  9. Kuritzkes D., et al. Filgrastim prevents severe neutropenia and reduces infective morbidity in patients with advanced HIV infection: results of a randomized, multicenter, controlled trial. AIDS 12(1):65-74, 1998.

  10. Mathe C., et al. Potential inhibitors of HIV integrase. Nucleosides Nucleotides 1999 Apr-May;18(4-5):681-2.

  11. Okereke C. Management of HIV-infected pregnant patients in malaria-endemic areas: therapeutic and safety considerations in concomitant use of antiretroviral and antimalarial agents. Clin Ther 1999 Sep;21(9):1456-96; discussion 1427-8.

  12. Pardridge W., et al. Chloroquine inhibits HIV-1 replication in human peripheral blood lymphocytes. Immunol Lett 1998 Nov;64(1):45-7.

  13. Parise M., et al. Efficacy of sulfadoxine-pyrimethamine for prevention of placental malaria in an area of Kenya with a high prevalence of malaria and human immunodeficiency virus infection. Am J Trop Med Hyg 1998 Nov;59(5):813-22.

  14. Savarino A., et al. The anti-HIV-1 activity of chloroquine. J Clin Virol 2001 Feb;20(3):131-5.

  15. Shulman C., et al. Malaria in pregnancy: its relevance to safe-motherhood programmes. Ann Trop Med Parasitol 1999 Dec;93 Suppl 1:S59-66.

  16. Sperber K., et al. Comparison of hydroxychloroquine with zidovudine in asymptomatic patients infected with human immunodeficiency virus type 1. Clin Ther 1997 Sep-Oct;19(5):913-23.

  17. Steketee R., et al. Impairment of a pregnant woman's acquired ability to limit Plasmodium falciparum by infection with human immunodeficiency virus type-1. Am J Trop Med Hyg 1996;55(1 Suppl):42-9.

  18. Stoiser B., et al. Serum concentrations of granulocyte-colony stimulating factor in complicated Plasmodium falciparum malaria. Eur Cytokine Netw 2000 Mar;11(1):75-80.

  19. Troye-Blomberg M., et al. Immune regulation of protection and pathogenesis in Plasmodium falciparum malaria. Parassitologia 1999 Sep;41(1-3):131-8.

  20. Verhoeff F., et al. Increased prevalence of malaria in HIV-infected pregnant women and its implications for malaria control. Trop Med Int Health 1999 Jan;4(1):5-12.

  21. White N., et al. Averting a malaria disaster. Lancet 1999; 353: 1965-7.


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