Does HIV increase the prevalence, density or risk in patients co-infected with malaria?

The data from surveys are briefly summarized in Table 1 for children up to age 7, Table 2 for adults, and Table 3 for pregnant women and their offspring, but where observations were mainly restricted to the neonatal period and included data on placental parasitization.

Early studies, from 1988 to 1993, on co-infections in humans found relatively small effects of HIV on malaria, except for one report of 95% red cells infected with P. vivax in a patient with AIDS (Katongole-Mbidde, Baruna & Kizito, 1988) and a slightly higher parasite density in HIVP children compared to HIV negative (HIVN) children, though there were no differences in parasite prevalence (Shaffer et al. 1990; Table 1). However, these studies have been criticized (Chandramohan & Greenwood, 1998; French & Gilks, 2000) with some justification for a variety of reasons: failure to assess HIV status in detail, especially whether patients had only been HIVP for a short time (Colebunders et al. 1990; Greenberg et al. 1991, Table 1), small numbers of subjects in some groups, failure to distinguish rural versus urban situations in regard to their malaria and so forth.

Since 1993, evidence for a greater impact of HIV on malaria has accumulated. Three groups, Atzori et al. (1993), Whitworth et al. (2000), and French & Gilks (French & Gilks, 2000; French et al. 2001), observed up to a 3-fold increased risk of parasite prevalence or of malarial fever in HIVP adults (Table 2), though Whitworth et al. and French et al. detected this only as CD4⁺ counts declined to a low level (<200 CD4⁺ cells/μl of blood). Francesconi et al. (2001) found an increased fever risk in HIVP adults with malaria but the differences were not statistically significant (Table 2). Chirenda, Siziya & Tshimanga (2000) (Table 2) also noted a 2-fold increase in mortality but, curiously, the occurrence of severe and complicated malaria did not correlate with a low CD4⁺ count in HIVP adults. Probably the most significant impact of HIV on malaria reported so far comes from a recent study of non-immune HIVP adults in South Africa: the increase in risk for mortality was finally calculated as nearly 7-fold, but there was no difference in parasite density between HIVP and HIVN subjects (Grimwade et al. 2004; Table 2).

Observations on pregnant mothers, sometimes including their new-born children, generally demonstrated an increased risk from malaria, with the exception of an older survey (Allen et al. 1991; Table 3). In HIVP pregnant women 2 to 4-fold increases were noted in the prevalence of malaria (Steketee et al. 1996; Verhoeff et al. 1999) and up to a 4-fold higher density of parasites at delivery. Ladner et al. (2002, 2003) reported a 2-fold increase in incidence, with a particular risk to mothers post-partum, and Van Eijk et al. (2002) reported a similar increase in probability of parasitaemia but malaria was only one of a number of factors involved. In general, the increased risk of high parasitaemia is seen as often in multigravidae as in primagravidae (Steketee et al. 1996; Verhoeff et al. 1999) indicating that HIV hinders the maintenance of immunity. Seropositivity for HIV was also associated with lower birth weights (Ayisi et al. 2003b), higher mortality, a 4-fold greater risk of malaria attacks in new-borns and an increase in the probability of having parasitized placentas (Ticconi et al. 2003). Higher post-natal mortality for HIVP infants born of mothers with placental malaria was detected by Bloland et al. (1995).

The information on children, some of whom were infected from blood transfusions, and who were monitored for varying periods of time, includes many of the earlier, criticized studies in which differences between HIVP and HIVN groups were not significant (see Table 1). However, even more recent studies have not discerned very dramatic effects: Grimwade et al. (2003) observed that parasite density in children was unrelated to HIV status, whereas in another investigation, HIVP children aged from 0·5 to 5 years had lower parasitaemias than HIVN children (Villamor et al. 2003). Kalyesubula et al. (1997) observed HIVP children for up to 4 years but found no significant increase in parasite density and fewer episodes of malaria, although if they did get malaria a higher proportion required hospital treatment. Taha et al. (1994), who monitored children for the first 18 months post-partum, observed no differences between the HIVP and HIVN groups.

HIV and cause of death in malaria-infected patients

The pathology of severe and cerebral malaria (CM) is at least in part immunologically mediated, reflected in profound changes in cytokine patterns (Artevanis-Tsakonas et al. 2003; Clark & Cowden, 2004): for example, the peak of CM tends to occur after a year or two of malaria experience and non-immune adults moving into a malarial area have a higher risk than children, probably from antigenic cross-reactivity between plasmodial and commonly experienced antigens. The role of parasite cytoadherence and of strains with a greater potential for precipitating CM are also important considerations and the relative contributions of these are hotly debated (Clark & Cowden, 2004).

The numbers of admissions for CM over a 5-year period in Uganda did not alter with increasing admissions for AIDS (Müller, Moser & Alexander, 1991) and two early small studies also reported no increased CM with HIV (Simooya, Mwendapole & Sikateyo, 1988; Leaver, Hale & Watters, 1990). However, CM may be too rare an occurrence to give sufficient numbers of cases for a precise comparison in the various studies that have been done (Greenwood, Marsh & Snow, 1991). Only Grimwade et al. (2004) found a very significantly increased risk of mortality in adults, including death in coma, but without an accompanying rise in parasitaemias that is usually assumed to be a predisposing factor for CM (Warrell et al. 1990). If the role of T cells in murine models of CM is any guide there should be less CM rather than more in HIVP patients as CD4⁺ counts decrease (e.g. Marussig, Renia & Mazier, 1996); the immunological evidence in humans points to the same conclusion (see above).

As already mentioned, HIVP neonates are at an increased risk of dying if the mothers had placentas heavily infected with parasites but death was from diseases such as diarrhoea or gastrointestinal disease not malaria (Bloland et al. 1995).

If any patients succumbed to overwhelming parasitaemias this is not reported; most post-mortem findings on AIDS patients do not mention malaria as a cause of death (Lucas et al. 1993; Chakraborty et al. 2002; Kawo et al. 2000). It comes fifth in the list of causes of death from retrospective analysis of hospital records of 3667 HIVP people admitted to hospital in Moshi, Tanzania (Ole-Nguyaine et al. 2004).

Interestingly, in contrast to the somewhat confusing picture in malaria there has been no difficulty in demonstrating that other protozoan parasites are often major contributors to mortality in AIDS: Babesia (Falagas & Klempner, 1996), Toxoplasma, Giardia, Cryptosporidium, Isospora (Curry, Turner & Lucas, 1991) and Leishmania (Olivier et al. 2002).

Antibodies in HIVP patients

In the diseases that lead to AIDS, immunity is thought to be predominantly controlled by cell-mediated responses; in addition to those mentioned above, in developing/tropical countries tuberculosis is probably the most common cause. Thus, as acquired immunity to blood-stage malaria is primarily antibody-mediated one might predict that it will be largely unaffected, particularly as cytokine patterns in HIV are said to be associated with a shift to Th2-type responses (Clerici & Shearer, 1993; Chatt et al. 2002) and it is mainly cell-mediated immunity that is impaired (Kedzierska & Crowe, 2001). Further, B cell polyclonal expansion (Shirai et al. 1992) and total immunoglobulin concentrations can be at higher or at equivalent concentrations in HIVP patients compared to HIVN controls, including antimalarial antibodies (Wabwire-Mangen et al. 1989; Rodriguez et al. 2003). In pregnant women seropositive for HIV, antibody levels to malaria are largely maintained (Ayisi et al. 2003a) until the onset of AIDS when they become significantly lower (Wabwire-Mangen et al. 1989). However, for antibody to be effective older data from passive immunity experiments (Cohen, McGregor & Carrington, 1961) suggest that high concentrations are needed, even against very small doses of parasites (Cohen & Butcher, 1969). People with a good acquired immunity to malaria may have the capacity to continue to generate enough antibody to protect them until other infections bring them down with AIDS, but this would not apply to partially immune subjects.

Acute/inflammatory responses in HIV-infected non-malaria-immune subjects

In the investigations on HIVP children (Table 1) there would have been many who were too young to have acquired immunity to malaria (Nguyen-Dinh et al. 1987; Müller et al. 1990b; Shaffer et al. 1990; Kaleysubula et al. 1997; Grimwade et al. 2003). Although some children had parasitaemias over 25% in one study (Nguyen-Dinh et al. 1987) this did not correlate with HIV and the recent South African report on non-immune adults also indicated little difference in parasite numbers between HIVP and HIVN patients (Grimwade et al. 2004; Table 2). In HIVP adults, decreased lymphocyte IFN-γ secretion in response to malaria antigens (Migot et al. 1996) combined with a rise in Il-10 and/or TGFβ that occurs in acute malaria (Li, Corraliza & Langhorne, 1999; Artevanis-Tsakonas et al. 2003) may add to depression of macrophage activation and thus increased susceptibility. Further, the activation of TGFβ by HIV (Wiercinska-Drapalo et al. 2004) may enhance that generated by malaria (Omer et al. 2003) leading to reduced inflammatory responses; this reinforces the expectation that parasite multiplication in the acute phase would be uncontrolled.

Immunity in pregnancy with HIV

Resistance to malaria declines in mothers in endemic areas during the first pregnancies (Shulman & Dorman, 2003). Cell-mediated responses in the absence of HIV, including IFN-γ production in response to malaria antigen, are depressed (Riley et al. 1989) and the placenta may be highly parasitized. In addition, mothers may carry multiple parasite strains (Beck et al. 2001; see below) and low IFN-γ generation in the parasitized placenta is exacerbated if subjects are HIVP (Moore et al. 2000; Chaisavaneeyakorn et al. 2002). It is not too surprising, therefore, that HIV has an impact in pregnancy, but perhaps more surprising that the differences between HIVP and HIVN mothers are not greater.

Recent data indicate that subsets of parasites adhere to chondroitin sulphate in the placenta (Beeson & Brown, 2004), to which mothers in their first pregnancies lack antibody, but there is no information as yet on this in HIVP mothers.

Declining immunity and new infections

In endemic areas PCR-based diagnostic techniques have revealed that infection with multiple species of Plasmodium may be common (Bruce & Day, 2003), in addition to multiple strains of individual species (Beck et al. 2001; Franks et al. 2001). Persisting chronic infections involving antigenic variation by schizont surface antigens are also characteristic of malaria. Thus, there is a continuing challenge with new species/strains/variants in HIV-infected hosts. Although strain-transcending immunity undoubtedly occurs (Baird, 1994) and non-specific responses to one parasite species suppress a second, both showing evidence of ‘crisis forms’ (Butcher, Mitchell & Cohen, 1978), any new infectious challenges presumably pose a more serious additional threat in immunosuppressed patients.

Immunosuppression and immunostimulation in co-infected hosts

Immunosuppression by malaria to other antigens and infections during both the acute and chronic phases involves a number of mechanisms including haemazoin-induced defective macrophage function (Scorza et al. 1999) and direct parasite action on dendritic cells (Urban & Roberts, 2002). In addition, there is apoptosis of lymphocytes (Balde, Sarthu & Rousshiloun, 1995; Helmby, Junsson & Troye-Blomberg, 2000) and activation of T_reg cells (Hisaeda et al. 2004). All this is compounded by the loss of immunity caused by HIV and in which apoptosis is also prominent (Brenchley et al. 2004).

Equally importantly, malaria infection is a major activator of T cells and macrophages, generating high levels of TNF-α and increased HIV viral load in cells in malarial patients (Hoffman et al. 1999; Tkachuk et al. 2001; Kapiga et al. 2002; Chen et al. 2003). Similarly, CD4⁺ T cells induced increased viral expression in dendritic cells in a transgenic mouse model (Freitag et al. 2001). Surprisingly, in view of these data, Kalyesubula et al. (1997) claimed progression to AIDS was slower in HIVP children than those who were HIVN. Clearly, immune responses in the co-infected host are dynamic and extremely complex and more research is needed, especially as malaria therapy has been used as an HIV treatment (Heimlich et al. 1997), a procedure that most researchers would probably question.