Long-term intake of Korean red ginseng in HIV-1-infected patients: development of resistance mutation to zidovudine is delayed

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Abstract

We have observed that CD4+ T cell counts in human immunodeficiency virus (HIV)-1-infected patients treated with only Korean red ginseng (KRG) are maintained or even increased for a prolonged period. In the present study, we investigated whether the development of resistance mutations in reverse transcriptase (RT) to zidovudine (ZDV) is delayed by combined therapy with KRG and ZDV. Nested polymerase chain reaction (PCR) and direct sequencing methods were used to define RT codons 41, 67, 70, 210, 215 and 219 of the HIV-1 pol gene in DNA from peripheral blood mononuclear cells (PBMC) samples from 18 patients. Nine of these eighteen patients were in the KRG group and had been treated with KRG for 60±15 months (range: 38–82) and ZDV, and nine were in the control group and had been treated with ZDV only. The patients in the KRG group had been treated with ZDV for 75±24 months, and CD4+ T cell counts were maintained from 239±85 to 234±187 μl−1 (P>0.05) during the study period, whereas the patients in the control group had been treated with ZDV for 51±31 months, and their CD4+ T cell counts decreased from 272±97 to 146±154 μl−1 (P<0.01). In samples within 24 months of ZDV therapy, the overall incidence of 6 resistance mutations to ZDV was 4.2% and 47% in the KRG and control group (P<0.01), respectively. In samples after 24 months of therapy, the incidence was 21.7% and 56.3% in the KRG and control group (P<0.01), respectively. These data suggest that the maintenance of CD4+ T cell counts by ZDV and KRG-intake for a prolonged period might be indirectly associated with delayed development of resistance to ZDV by KRG-intake.

Introduction

Remarkable advances in the treatment of HIV infection have been made with highly active anti-retroviral drug therapy over the last decade, but HIV infection still remains an incurable disease. Drug resistance is probably the most important factor attributing for the failure of treatment today [1]. Consequently, multidrug therapy has been tried over several years, but it can be poorly tolerated and is compromised by toxicity and noncompliance. Immune system-based therapy combined with antiretroviral therapy is needed as an alternative approach for controlling HIV [2].

In Korea, ZDV monotherapy was introduced in early 1991 to treat HIV-infected patients with CD4+ T cell counts of less than 500 μl−1. Although the effects of low dose ZDV monotherapy (400–600 mg/day) were not maintained up to 12 months [3], it was the only antiretroviral therapy until early 1997. Disease progression in patients with ZDV therapy coincides with the emergence of drug-resistant strains having mutation out of RT codon amino acid positions 41, 67, 70, 210, 215 and 219 [4], [5], [6], [7].

Panax ginseng C.A. Meyer is an herbal root, which has been known in China for more than 2000 years [8]. Many scientific investigations have been performed on the active ingredients and their functions since the late 1960s. In regard to antimicrobial effect, Song et al. [9] reported that ginseng treatment reduces bacterial load and lung pathology in chronic Pseudomonas aeruginosa pneumonia in rats. Ginseng is now 1 of 12 medicinal herbs commonly used in America [10]. A double-blind study in normal human volunteers revealed a significant increase in neutrophil function, CD4+ T cell counts and NK-function in individuals taking ginseng compared to those taking placebo [11]. It is particularly interesting that the immunostimulating effect of acidic polysaccharide (Ginsan) from ginseng root is blocked in the presence of anti-interleukin (IL)-2 and anti-IFN-γ [12].

We had an opportunity to try KRG for HIV-1-infected individuals for 6 months beginning in late 1991. Surprisingly, we observed various beneficial effects of KRG-intake (5.4 mg daily) in these individuals including increases in the CD4+, CD8+ T cell counts and body weight, and decrease in soluble CD8 antigen (sCD8) in serum [13]. Thereafter, the study was done consecutively for the same target population although the number of patients was increased and there were some interruptions. Moreover, our data showed that intrapatient amino acid variation between clones in the C2/V3 region of HIV-1 from these patients was inversely correlated with the duration of KRG-intake [14]. Among the patients who were involved in the first KRG trial, some have maintained CD4+ T cell counts for 8 years with KRG-intake only. On the other hand, in patients with ZDV monotherapy, the decrease in CD4+ T cell counts usually occurs within 12 months due to the development of resistance to ZDV. This phenomenon was not observed, however, in the patients treated for a prolonged period with ZDV and KRG in combination.

In the present study, we investigated whether the maintenance of CD4+ T cell count in HIV-1-infected patients treated with ZDV and KRG is associated with the delay of the development of resistance to ZDV.

Section snippets

Patients

This study was approved by the Institutional Review Board of Asan Medical Center of University of Ulsan College of Medicine, and all patients gave their written informed consent before participation. Eighteen patients who were selected from our cohort [13], [14] were divided into a KRG group and a control group. In the KRG group, all nine HIV-1-infected patients had taken KRG for more than 36 months (60±15 months; range: 38–82) and ZDV for more than 18 months. All were asymptomatic at

Change in CD4+ T cell counts

In KRG group, nine patients had been treated with both ZDV and KRG for 75±24 months after initiation of ZDV therapy, and CD4+ T cell counts were well maintained (from 239±85 to 234±187 μl−1; P>0.05). The change of CD4+ T cell counts and development of resistance mutations for patients 1 to 3 was described in detail previously [17] and those in patients 6 and 8 are described (Fig. 2). Patient 9, who received combined therapy with ZDV and KRG as early as 6 months after HIV-1 infection, had a

Discussion

We have observed the maintenance or increase in CD4+ T cell counts in patients treated with KRG since 1991 [13], [14]. Mild but consistent decrease in p24 antigen during KRG-intake was also detected. In particular, the decrease in sCD8 level in serum during KRG-intake was most notable. The decrease in sCD8 was 31.3% from 801 to 550 U/ml during 68 months in KRG group. The decrease in sCD8 was maintained as long as KRG was taken. This finding could probably result in the enhancement or long-term

Acknowledgements

This work was supported by the grant (2000-062) from Asan Institute for Life Sciences and Korean red ginseng was supported by Korea Ginseng via Korean Society of Ginseng (2000). The authors thank Professor Chun Sik Park, University of Ulsan College of Medicine for the critical reading of this manuscript.

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