Risk Factors for HIV-1 Infection
Among children aged ≤16 years, 28 of 2312 (1.2%) patients with positive malaria smears were infected with HIV-1 compared to 49 of 2155 (2.3%) patients with negative smears. For these children, a negative malaria smear was associated with increased odds of HIV-1 infection (OR = 1.90, 95% CI: 1.18 to 3.06; P = 0.008) compared to a positive smear, after controlling for age and sex for all 7 sites combined (Table 2). Age and sex were not associated with HIV-1 infection in children. There was no evidence for heterogeneity of odds ratios for the association between malaria and HIV-1 infection among children across the 7 sites (P = 0.38).
Among adults aged >16 years, 50 of 391 (12.8%) patients with positive malaria smears were infected with HIV-1 compared to 220 of 2142 (10.3%) with negative smears. A positive blood smear was associated with a significantly higher odds of HIV-1 infection (OR = 1.41, 95% CI: 1.01 to 1.97; P = 0.04) after controlling for sex and age for all 7 sites combined (Table 2). Sex was not associated with HIV-1 infection in adults. HIV prevalence among adults differed significantly across age quartiles, with the highest prevalence among those aged 30 to 39 years (17.3%) and the lowest prevalence among those aged 17 to 22 years (6.1%, P < 0.001). There was no evidence for heterogeneity of odds ratios for the association between malaria and HIV-1 infection among adults across the 7 sites (P = 0.44).
Diagnosis and Treatment of HIV-1-Infected Patients
Because our study did not change routine patient care activities, clinic records of clinical diagnosis and treatment were frequently missing. However, information on clinical diagnosis and treatment was available for 187 (54%) HIV-1-infected patients (Table 3). HIV-1-infected patients with missing information were similar to those with available information with respect to malaria smear positivity (18% vs. 26%, P = 0.07), female sex (63% vs. 70%, P = 0.17), and median age (27 vs. 29 years, P = 0.15). Of note, HIV infection was not listed as a diagnosis and antiretrovirals were not prescribed for any of the 187 HIV-1-infected patients with available records. However, it is possible that some patients received HIV care at other health facilities. Malaria was the most common stated diagnosis, made in 88 (47%) of all HIV-1-infected patients. Only 43 (49%) of those with a stated diagnosis of malaria had positive malaria blood smears. Other common diagnoses were respiratory tract infection (27%) and gastrointestinal illness (13%). Artemether-lumefantrine, the new standard therapy in Uganda for malaria, was the most commonly prescribed drug in HIV-1-infected patients (34%). Only 42 (45%) of those treated with an antimalarial drug had a positive malaria blood smear. An antimalarial drug, an antimicrobial drug, or both were prescribed to 87% of HIV-1-infected patients, including trimethoprim-sulfamethoxazole in 32 (17%) patients. Twenty-six of these 32 patients were being treated for gastrointestinal illness or respiratory tract infections, suggesting that the drug was not given as prophylaxis against opportunistic infections.
In this cross-sectional study of 7000 Ugandans presenting to government clinics and referred for malaria blood smears, we examined interactions between HIV and malaria. We identified significant but modest associations between malaria blood smear results and risk of HIV-1 infection. Interestingly, these associations differed between age groups, with HIV-1 infection associated with a negative blood smear among children and a positive blood smear among adults. Among HIV-1-infected patients, none had a diagnosis of HIV or AIDS recorded, suggesting that HIV infection was unrecognized. Taken together, these findings suggest that current practices for identifying those at risk for HIV are inadequate and that results from routine malaria evaluation may help identify those who would benefit most from HIV testing.
In sub-Saharan Africa, assessment of febrile illnesses often begins with consideration of malaria. Indeed, malaria is the leading cause of attendance at outpatient clinics in Uganda, accounting for 25% to 40% of all outpatient diagnoses.11,18,21 In Africa, malaria is usually diagnosed on clinical grounds alone, and even when diagnostic tests are performed, patients with negative results are often diagnosed and treated for malaria.22,23 However, treating all fevers as malaria leads to overuse of antimalarials and failure to diagnose other important causes of fever, including HIV and related coinfections.24
Our findings suggest that patients presenting to outpatient clinics with symptoms suggestive of malaria are more likely to have HIV-1 infection than the general Ugandan population. Among individuals in this study who were aged 15 to 49 years, the HIV prevalence was almost twice the population-based estimate for the same age group16 (10.5% vs. 6.3%). In children under 5 years of age, HIV prevalence was almost 3 times the national estimate16 (1.6% vs. 0.5%). However, the increased prevalence of HIV was modest compared to that seen with other HIV-related opportunistic infections, such as tuberculosis.25 A higher prevalence (31% to 33%) of HIV in adults with malaria has been reported in other studies from Africa,5,26 but these studies did not include patients with negative malaria smears and therefore were unable to report on the association between malaria blood smear results and risk of HIV infection.
Interestingly, we observed opposite associations between malaria and HIV-1 infection in children and adults. In children, HIV was more common among those with negative malaria blood smears, whereas in adults HIV infection was more common among those with positive blood smears. All HIV-1-infected patients would be expected to be at increased risk of febrile illnesses, but associations between HIV and malaria may vary across age groups. Malaria immunity develops over years of repeated parasite exposure; therefore, children would be expected to have less acquired malarial immunity than adults at the time of HIV infection. The relative increase in HIV prevalence we observed in children with negative malaria smears may be the result of an increase in the risk of nonmalarial febrile illnesses among HIV-infected children.25 It is also possible that HIV-infected children in this study were more recently exposed to antimalarials than HIV-uninfected children, reducing their probability of having a positive malaria smear. In contrast, the relative increase in HIV prevalence we observed in adults with positive malaria smears is likely due to loss of acquired malaria-specific immunity.2,6,27,28
Malaria was the most common diagnosis observed among HIV-1-infected patients in this study, though more than half of those diagnosed and treated for malaria had negative blood smears, a phenomenon reported in multiple studies from Africa.29,30 Although HIV-1-infected patients in this study were commonly diagnosed with malaria, HIV was not listed as a diagnosis in clinic records, nor was antiretroviral therapy recorded as treatment, suggesting the need to integrate routine HIV testing into outpatient clinics. If the results of this study are validated, knowledge of how malaria smear results predict HIV risk may help identify those who would benefit most from HIV testing. All of the government clinics included in this study offer HIV testing and 3 offer antiretroviral therapy. Thus, integrating HIV testing algorithms for high-risk outpatients referred for malaria smears should be feasible.
In conclusion, we found that associations between HIV and malaria operate differently in adults and children in Uganda. Presentation with malaria is a warning sign for HIV infection in adults, because HIV infection likely diminishes acquired antimalarial immunity. In children, malaria is very common, and a negative malaria smear suggests other causes of fever, including HIV-related infections. We support recommendations by other authors28 that integrated HIV and malaria testing be utilized in the outpatient clinic setting. Further data would be particularly useful in refining such referral strategies.
We thank study participants and families; staffs of the district health facilities; Wilson Kambale, Yoel Lubell, Joaniter Nankabirwa, and Christina Angle for assistance in the field; Regina Nakafeero, Maxwell Kilama, and Felix Jurua for blood smear readings; Heidi Hopkins for making the study feasible; Chris Dokomajilar and Hong Kim for laboratory assistance; and Catherine Tugaineyo, Richard Olugo, and Peter Padilla for administrative support. We thank the Doris Duke Charitable Foundation for financial support.
1. Abu-Raddad LJ, Patnaik P, Kublin JG. Dual infection with HIV and malaria fuels the spread of both diseases in sub-Saharan Africa. Science
2. Slutsker L, Marston BJ. HIV and malaria: interactions and implications. Curr Opin Infect Dis
3. UNAIDS. Report on the Global AIDS Epidemic 2006
. Geneva: Joint United Nations Programme on HIV/AIDS; 2006. UNAIDS/06.20E.
4. Whitworth J, Morgan D, Quigley M, et al. Effect of HIV-1 and increasing immunosuppression on malaria parasitaemia and clinical episodes in adults in rural Uganda: a cohort study. Lancet
5. Van Geertruyden JP, Mulenga M, Mwananyanda L, et al. HIV-1 immune suppression and antimalarial treatment outcome in Zambian adults with uncomplicated malaria. J Infect Dis
6. Patnaik P, Jere CS, Miller WC, et al. Effects of HIV-1 serostatus, HIV-1 RNA concentration and CD4 cell count on the incidence of malaria infection in a cohort of adults in rural Malawi. J Infect Dis
7. Mermin J, Lule J, Ekwaru JP, et al. Effect of co-trimoxazole prophylaxis on morbidity, mortality, CD4-cell count, and viral load in HIV infection in rural Uganda. Lancet
8. Kalyesubula I, Musoke-Mudido P, Marum L, et al. Effects of malaria infection in human immunodeficiency virus type 1-infected Ugandan children. Pediatr Infect Dis J
9. Nguyen-Dinh P, Greenberg AE, Mann JM, et al. Absence of association between Plasmodium falciparum malaria and human immunodeficiency virus infection in children in Kinshasa, Zaire. Bull World Health Organ
10. Greenberg AE, Nsa W, Ryder RW, et al. Plasmodium Falciparum malaria and perinatally acquired human immunodeficiency virus type 1 infection in Kinshasa, Zaire. A prospective, longitudinal cohort study of 587 children. N Engl J Med
11. Font F, Alonso Gonzalez M, Nathan R, et al. Diagnostic accuracy and case management of clinical malaria in the primary health services of a rural area in south-eastern Tanzania. Trop Med Int Health
14. Srikantiah P, Lin R, Walusimbi M, et al. Elevated HIV seroprevalence and risk behavior among Ugandan TB suspects: implications for HIV testing and prevention. Int J Tuberc Lung Dis
15. World Health Organization. Interim Policy on Collaborative TB/HIV Activities
. Geneva: WHO; 2004. WHO/HTM/TB/2004.330, WHO/HTM/HIV/2004.1
16. Uganda HIV/AIDS Sero-Behavioural Survey 2004-05
. Kampala, Uganda: Ministry of Health; 2006.
17. Lindblade KA, Walker ED, Onapa AW, et al. Land use change alters malaria transmission parameters by modifying temperature in a highland area of Uganda. Trop Med Int Health
18. Okello PE, Van Bortel W, Byaruhanga AM, et al. Variation in malaria transmission intensity in seven sites throughout Uganda. Am J Trop Med Hyg
19. Fischer A, Lejczak C, Lambert C, et al. Simple DNA extraction method for dried blood spots and comparison of two PCR assays for diagnosis of vertical human immunodeficiency virus type 1 transmission in Rwanda. J Clin Microbiol
20. Gasasira AF, Dorsey G, Kamya MR, et al. False-positive results of enzyme immunoassays for human immunodeficiency virus in patients with uncomplicated malaria. J Clin Microbiol
21. Ndyomugyenyi R, Magnussen P, Clarke S. Diagnosis and treatment of malaria in peripheral health facilities in Uganda: findings from an area of low transmission in south-western Uganda. Malar J
22. Reyburn H, Ruanda J, Mwerinde O, et al. The contribution of microscopy to targeting antimalarial treatment in a low transmission area of Tanzania. Malar J
23. Barat L, Chipipa J, Kolczak M, et al. Does the availability of blood slide microscopy for malaria at health centers improve the management of persons with fever in Zambia? Am J Trop Med Hyg
24. Talisuna AO, Meya DN. Diagnosis and treatment of malaria. BMJ
25. Laufer MK, van Oosterhout JJ, Thesing PC, et al. Impact of HIV-associated immunosuppression on malaria infection and disease in Malawi. J Infect Dis
26. Kamya MR, Gasasira AF, Yeka A, et al. Effect of HIV-1 infection on antimalarial treatment outcomes in Uganda: a population-based study. J Infect Dis
27. Francesconi P, Fabiani M, Dente MG, et al. HIV, malaria parasites, and acute febrile episodes in Ugandan adults: a case-control study. AIDS
28. Kublin JG, Steketee RW. HIV infection and malaria-understanding the interactions. J Infect Dis
29. Nwanyanwu OC, Kumwenda N, Kazembe PN, et al. Malaria and human immunodeficiency virus infection among male employees of a sugar estate in Malawi. Trans R Soc Trop Med Hyg
30. Njama-Meya D, Clark TD, Nzarubara B, et al. Treatment of malaria restricted to laboratory-confirmed cases: a prospective cohort study in Ugandan children. Malar J
Keywords:© 2007 Lippincott Williams & Wilkins, Inc.
malaria; HIV; Africa; human immunodeficiency virus