Micronutrient Supplementation Increases CD4 Count in HIV-Infected Individuals on Highly Active Antiretroviral Therapy: A Prospective, Double-Blinded, Placebo-Controlled Trial

Jon D. Kaiser, MD; Adriana M. Campa, PhD; Joseph P. Ondercin, PA-C; Gifford S. Leoung, MD; Richard F. Pless, PhD; Marianna K. Baum, PhD


J Acquir Immune Defic Syndr. 2006;42(5):523-528. 

In This Article


An increase in CD4 cell count after micronutrient supplementation in HIV-infected persons has previously been reported by Fawzi and colleagues,[23] but this cohort was not receiving HAART. To our knowledge, this investigation is the first trial of micronutrient supplementation to show a significant immunologic benefit in patients taking a stable HAART regimen. Moreover, the robust recuperation of the CD4 cell count (a mean increase of 65 cells/µL) in the micronutrient group occurred after 12 weeks of supplementation, a relatively short period of time compared with the slower reconstitution reported by other cohorts after initiating HAART without micronutrient supplementation; Connick and colleagues2 reported a median increase of 170 cells in 48 weeks, whereas Koletar et al3 reported a much slower rate of increase of 5.9 cells/µL every 8 weeks.

The mechanism of precisely how micronutrient supplementation may increase the CD4 count is presently unknown. Although it is not possible to determine from this study which of the micronutrients or their combination is responsible for the observed immune reconstitution, several of the B vitamins and vitamins C and E have previously been shown to enhance cellular immunity.[31,32] Supplementation of HIV-infected African women with these nutrients significantly improved CD4+, CD8+, and CD3+ cell counts, and this beneficial effect was sustained for a median of 5 years.[23] Moreover, the supplement used in our study included 3 additional antioxidants (acetyl l-carnitine, N-acetyl-cysteine, and alpha lipoic acid). Each of these nutrients has individually been shown to produce positive effects in HIV-infected individuals.[33,34,35,36,37,38,39,40,41,42]

In addition, antioxidant supplementation has previously been associated with a reduction in viral load[23,43] and has been observed to produce a significant decrease in CD4 cell apoptosis.[34] This effect was reported in 2 studies after supplementation with the antioxidant l-carnitine in both symptomatic[33] and asymptomatic HIV-infected patients.[34] The mechanism of action of apoptosis in HIV-infected CD4 cells is believed to result from the effect of HIV itself and from concomitant antioxidant imbalances in host cells.[44,45,46] A correction of these imbalances, leading to a subsequent decrease in the apoptosis rate of CD4 lymphocytes, may be partially responsible for the increases in CD4 cell counts observed in our study.

Because N-acetyl-cysteine was also included in the micronutrient supplement in this study, an additional mechanism of action could be through the replacement of sulfur in the form of N-acetyl-cysteine. Previous studies have shown that sulfur is lost on a massive scale in HIV-infected patients as a consequence of peripheral tissue cysteine catabolism, and this sulfur loss is not ameliorated by HAART.[36] Supplementation of HIV-infected patients with N-acetyl-cysteine for 7 months in placebo-controlled randomized clinical trials resulted in a significant increase in immunological function[35,36,37] and in a release of the chemokines MIP-1alpha, MIP-1beta, and RANTES, which are implicated in blocking the interaction of HIV with the CCR5 receptor38 and in lowering apoptosis.[39,40] Thus, as part of this micronutrient supplement, the N-acetyl-cysteine provided may have contributed toward the observed immunological reconstitution.

Although there was no statistically significant change in the DSP symptoms in this trial, the mean 42% improvement in DSP symptoms in patients taking the micronutrients compared with a 33% improvement in the placebo arm is clinically significant. This finding is in accord with a recently published trial by Hart and colleagues,[41] who showed improvement in DSP symptoms when HIV-infected patients were supplemented with oral acetyl-l-carnitine for 24 months. The improvement in DSP symptoms was accompanied by significant nerve fiber regeneration determined by immunohistochemical staining techniques.[41] The 12-week duration of our study may not have been sufficient to observe a statistically significant change in neuropathy symptoms.

The micronutrient supplement we tested was well tolerated. McComsey et al[47] reported in an uncontrolled clinical trial that antioxidant supplementation with vitamins C and E and N-acetyl-cysteine provided to HIV-infected patients taking HAART was associated with an adverse effect on fasting glucose levels and insulin resistance at 24 weeks. Our study found no such effect. Fasting glucose, insulin, and lipid parameters (as well as aspartate aminotransferase, ALT, and serum creatinine) were not adversely affected after administering this micronutrient formula for 12 weeks.


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