The emerging circumstantial evidence that iron may in crease the rate of progression of HIV infection is worry ing 1 and may impede the international commitment to combat iron deficiency. It is crucial to clarify the role of iron in HIV infections, however, because iron is universally administered to anemic patients and pregnant women, even in areas with high HIV prevalence. Given the implicit ethical dilemmas of studying harmful effects of established health interventions, it has been recommended to assess the effect of iron supplementation on viral load retrospectively, based on historical iron supplementation trials. 2 Viral load is considered a useful proxy for clinical outcomes because it has been shown to be a strong determinant of both vertical 3 and sexual 4 transmission and progression. 5
In 1994, we conducted a randomized, placebo-controlled, double-blind iron supplementation trial in western Kenya. Those with a hemoglobin concentration below 80 g/L were excluded and treated. The effects of iron (60 mg as ferrous dextran twice weekly) on helminth reinfections after treatment were studied among 181 adults. We found that iron supplementation reduced posttreatment reinfection rates 6 but did not increase hemoglobin (A. Olsen, unpublished data). We speculated whether this could be due to increased HIV viral replication and progression of HIV infection but were not able to confirm this, because HIV testing was not included in the protocol. Given the public health importance and the time elapsed since the study was conducted, we were granted ethical permission from the Kenyan National Ethical Review Committee and approval from the Danish Central Medical Ethics Committee to do anonymous HIV testing on repository samples.
Of 181 adults, 45 (24.9%) were found to be HIV infected, based on determination of HIV-1 viral load expressed as genome equivalents (geq) per milliliter. 7 Of these 45, sera were available for 32 (71%) from the 4-month follow-up examination.
The randomization resulted in an equal number of HIV-infected subjects in the placebo and iron groups (Table 1). Similarly, there were no differences in mean age, hemoglobin level, or serum ferritin level between the groups or in the proportion with malaria parasitemia and Schistosoma mansoni infection, whereas more subjects in the iron group had hookworm infection.
As seen in Table 2, however, viral load was higher in the iron group compared with the placebo group at baseline (5.57 vs. 4.93, P = 0.02), despite the baseline equivalence with respect to other variables. Viral load declined by 0.7 log geq/mL between baseline and the 4-month follow-up in both groups combined (P < 0.01), with no difference between the placebo and iron groups (0.6 vs. 0.8 log geq/mL, P = 0.31). Using multiple linear regression analysis, with log viral load at follow-up as a dependent variable and log viral load at baseline as a covariate, while controlling for hookworm and the other baseline variables, did not change the effect of iron supplementation (10B=0.91, 95% confidence interval: 0.24; 3.55). The reason why viral load declined is not clear but could be due to limited quantities and previous handling of these samples, although the effect of season cannot be excluded. 8
As reviewed by Weinberg, 9 iron withholding mechanisms seem to be important to the host defense against viral and other infections. Furthermore, data from in vitro and observational human studies suggest that iron may be harmful in HIV infection 8,10–15 because it may increase viral replication and lead to increased progression of HIV.
Nevertheless, we found that 60 mg of elemental iron twice weekly for 4 months did not increase HIV load. Much higher daily doses of iron are often given to treat anemic patients and for the prevention of anemia among pregnant women, also in countries where HIV prevalence may reach 30% of the adult population. We suggest that the effect of these regimens on HIV load should be assessed through randomized and controlled trials. Such trials could use 60 mg twice weekly as the control intervention.
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