The trusted source for
healthcare information and
By Maria D. Mileno, MD
Synopsis: Several recent observations add new twists to the intersections between HIV infections and tropical diseases, and to the voracity with which AIDS has taken hold in Africa. The Global AIDS program of the US Centers for Disease Control (CDC) has reported that 34.3 million people are living with HIV, and 70% live in Africa. Many of those regions hardest hit by HIV overlap with malaria in endemic geographic areas. The following material raises concerns for HIV-infected persons who travel to malaria-endemic regions, with cause to reflect upon some possible contributing mechanisms to emerging drug-resistant malaria in Africa.
Sources: Whitworth J, et al. Effect of HIV-1 and increasing immunosuppression on malaria parasitaemia and clinical episodes in adults in rural Uganda: A cohort study. Lancet. 2000;356:1051-1056; Taylor TE, Hoffman IF. Can HIV-1 infections in Africa provide insights into acquired immunity to malaria? Lancet. 2000;356:1046; Anzala AO, et al. Acute sexually transmitted infections increase human immunodeficiency virus Type 1 plasma Type 2 cytokines, and decrease CD4 cell counts. J Infect Dis. 2000;182:459-466; Symposium 3: trimethoprim-sulfamethoxazole prophylaxis for people living with HIV/AIDS in Africa: Efficacy, impact on drug resistant malaria and research ethics. From the 49th Annual Meeting of the American Society of Tropical Medicine and Hygiene, Houston, Texas. October 2000.
Until recently, reports and observations coming out of malaria-endemic regions of the world have shown no particular worsening of malaria among HIV-infected people and no noticeable deterioration of the underlying HIV infection.
However, HIV disease may indeed impair host control of malaria. In one recent study from Entebbe, Uganda, malaria parasite densities in HIV-infected subjects increased as their CD4 counts decreased.1 Another study published in Lancet supported these findings. Four hundred eighty-four HIV-infected and uninfected persons living in rural Uganda were followed every 3 months, and whenever they were sick throughout 8 years. The rate of malaria was 3 times higher in the HIV-infected group. Also, the HIV-infected subjects were nearly twice as likely to be parasitemic compared to those not infected with HIV. The risk for parasitemia and parasite densities increased as CD4 cell counts decreased.
Both disturbing and surprising were the findings of increased plasma HIV-1 RNA in HIV-infected adults who were coinfected with Plasmodium falciparum. These data suggest that episodic malaria in HIV-infected persons may result in increased transmissibility of HIV infection in Africa since higher viral loads are known to increase the chance of both maternal-fetal and sexual HIV transmission.
It is already well documented that concurrent sexually transmitted diseases (STDs), particularly those that ulcerate, are likely to facilitate HIV transmission. An elegant study that looked at proinflammatory cytokines in HIV-infected persons who contracted STDs showed an acceleration of HIV disease progression to AIDS over a 4-year period. This was accompanied by increases in viral load and plasma type 2 cytokine stimulation (IL-4, IL-6, IL-10, and TNF.)
Strong efforts at prophylaxis of opportunistic infections for HIV-infected people living in Africa have been undertaken in attempts to counterbalance the lack of available antiviral medications. In many regions, folic acid antagonists, such as trimethoprim-sulfamethoxazole (Tm/Sxt), are used routinely for prevention of Pneumocystis carinii pneumonia (PCP), and pyrimethamine-sulfadoxine (Fansidar®), a relatively inexpensive analogous combination of folic acid antagonists, has been used widely for weekly prophylaxis of malaria. The potential emergence of Fansidar®-resistant P. falciparum occurring among HIV-infected persons receiving Tm/Sxt for Pneumocystis carinii prophylaxis was addressed in a dynamic symposium at the 49th Annual Meeting of the American Society of Tropical Medicine and Hygiene in Houston, Texas, October 2000. Rapid selection for dihydrofolate reductase (DHFR) mutants was demonstrated in malaria parasites exposed to pyrimethamine. Of 100 individuals who were given weekly pyrimethamine, 8 developed malaria; all 8 harbored DHFR mutants. The discussion that ensued addressed the manner in which this selection process might be further driven by the use of Tm/Sxt for AIDS patients in Africa, particularly among persons with AIDS who require treatment for malaria.
Most bacteria cannot use exogenous folate but must synthesize their own for nucleic acid producton. Tm/Sxt is a unique combination of agents that inhibits 2 sequential steps in bacterial metabolism, hindering bacterial cell replication by preventing both folic acid and nucleic acid synthesis. Sulfamethoxazole competitively inhibits the conversion of paraminobenzoic acid to dihydrofolic acid, and trimethoprim inhibits dihydrofolate reductase. Their mechanism of action is similar against Pneumocystis carinii, with the function of the trimethoprim component being more important. Widespread use of Tm/Sxt could place additional selective pressure on the dihydrofolate reductase enzyme system of P falciparum, favoring mutants in a manner similar to that observed in parasites exposed to pyrimethamine. Thus, the effectiveness of pyrimethamine could be diminshed.
There is a clear need for more information and scientific investigation. Additional observations using PCR to document both viral loads and clinical courses of HIV-infected persons who contract malaria will be extremely important. From an ethical standpoint, PCP prophylaxis in Africa should continue, perhaps with other agents such as atovaquone-proguanil, which likely can prevent both malaria and PCP.
In summary, we now know that HIV-infected individuals who are coinfected with concurrent tropical pathogens may experience an acceleration of their underlying HIV disease and vice versa. The ecology of one serious infectious disease, falciparum malaria, is once again intimately connected to control of the HIV pandemic; PCP prophylaxis may be inducing malaria resistance to other folic acid antagonists such as pyrimethamine. Not to be dismissed is the known potential for transfusion of HIV-infected blood to healthy individuals who become anemic from malaria. Each scenario has particular relevance to the practice of travel medicine. Not only must we concern ourselves with the prevention of HIV infection during travel, but we must be aware of how tropical pathogens such as malaria may affect the HIV-infected traveler. Soon we may also find the very agents we use for prevention of opportunistic infections such as PCP are driving the continued emergence of drug-resistant malaria.
1. French N, Gilks CF. Fresh from the field: Some controversies in tropical medicine and hygiene. HIV and malaria, do they interact? Trans R Soc Trop Med Hyg. 2000;94:233-237.