Printer Friendly

Herbal medicine in the management and treatment of HIV-AIDS--a review of clinical trials.

Introduction

Human immunodeficiency virus infection/acquired immunodeficiency syndrome (HIV-AIDS) is a viral infection that effects the human immune system. The HIV virus comprises of two types, HIV-1 and HIV 2, and is a retrovirus that infects and destroys T-cells, macrophages and dendritic cells. HIV-2 is predominant in West Africa, whereas the more virulent HIV-1 is the cause of the majority of infections globally.

Symptomatically, within two weeks of initial infection, infected individuals may experience an influenza-like illness, with associated swelling of lymph nodes and skin rash, which then subsides with no further symptoms. (1) As the disease progresses the individual's immune system becomes suppressed via the reduction of cluster differentiation 4 protein (CD4), which is a glycoprotein found on the surface of immune cells, such as T-helper cells (herein abbreviated CD4 cells), which has an important role in the adaptive immune system. Clinically, HIV infected patients display CD4 cell counts <200/mL blood. (1)

The patient's prognosis includes a higher relative risk of infections, including opportunistic infections and tumour development. HIV transmission is spread primarily via unprotected sexual intercourse, blood transfusions, hypodermic needles, pregnancy, breastfeeding and body fluid exposure to sensitive tissues such as the eyes and tear ducts. At present there is no HIV vaccine available, with anti-retroviral treatment only slowing the progression of the disease. Immune system support appears to be another therapeutic opportunity, with certain herbal medicines appearing useful in the management of the immune system and thus HIV management.

According to the World Health Organization (WHO), traditional medicines, which include herbal medicines, acupuncture, manual therapies, spiritual therapies, exercise, etc., are the most commonly used form of medicines/treatments in many parts of the world. (2) The use of traditional medicine is especially common in developing countries (i.e. Africa, Asia and Latin/South America). In developing countries, an estimated 60 to 90% of the population use traditional medicines which mainly serve their primary healthcare needs. On the other hand, in developed countries (i.e. Australia, Europe and North America) traditional medicine is commonly used in parallel with allopathic medicine (i.e. highly active antiretroviral therapy (HAART)). (2) The use of complementary and 'alternative medicines' is widespread in chronic conditions, including HIV-AIDS infection. Even though herbal medicine is one of the most commonly used traditional medicines, statistics on the utilisation of herbal medicine in the treatment and management of HIV among the Australian population are largely unavailable. According to a US study, 26% of HIV-infected people use herbal medicine as part of their treatment. (3) A European study showed that herbal medicines are used by approximately 25% of HIV infected people. (4)

The primary reason for the use of traditional medicines in the treatment of HIV, especially in developing countries, is the high cost and/or the unavailability of HAART. (5) Herbal medicines are more likely to be used in HIV-AIDS treatment in western countries as an adjunct therapy to support the immune system, reduce the side-effects of medication (for example nausea and depression), reduce viral replication (6) and improve general well-being (i.e. act as an adaptogen). Herbal medicines may function in different ways in HIV infection and associated conditions. In many cases the mechanisms of action are not clear and the whole herbs or specific phytochemicals require further research. (7) Emerging evidence suggests the possibility of immune-modulatory and anti-viral properties conferred by various herbal species and their extracts. There are however concerns related to unsafe or erroneous practices as well as the increasing frequency of claims of a cure when there is insufficient evidence to support such claims. (5) In addition, herbs or their phytochemicals may display adverse effects in conjunction with anti-retroviral drugs and may be contraindicated for use with these medications. A list of commonly used herbs in HIV-AIDS adjunct therapy is shown in Table 1.

Methodology

A review of clinical trials available on the use of herbal medicine in the treatment of HIV-AIDS or in conjunction with conventional anti-retroviral drugs was conducted using PubMed and Google Scholar databases. The journal articles were obtained using respective online journal databases. The selection criteria were restricted primarily to clinical trials examining herbal medicine in HIV-AIDS treatment, and human health surveys of CAM use from 1st January 1980--30th September 2013. In vitro studies were included if they supported the explanations of observations made in the clinical trials to elaborate on the molecular mechanisms and explain the observed efficacy of the particular herbal medicine.

The search terms included the following string of terms in combination;

'HIV' + 'Herb', 'AIDS' + 'Herb', 'HIV' + 'Herbal', 'AIDS' + 'Herbal', 'HIV' + 'AIDS' + 'Herbal', 'HIV' + 'AIDS' + 'Herb'.

Publications were selected if the term(s) appeared in the publication title. Also a number of publications were observed in multiple or all of the search terms and their respective combinations. Duplicates were removed. Results of these search terms can be seen in Table 2.

Herbal medicines reviewed included Western herbal medicine species, Thai, Chinese and also African species. Although there was some language restriction the review attempted to include herbal medicines from publication in languages other than English where the herbal species is found to be clearly identified. Two of the authors read Mandarin (Han character script) and were able to determine the genus and species of some of the herbal medicines used in Chinese medicine treatments. The review also focused on the safety and efficacy of herbal medicine. After research publications and reviews were compiled with respective search terms, only human clinical trials and epidemiological studies were used for the review (PubMed database). With respect to Google Scholar, the search term(s) were required to be included in the title of the article. Articles repeated with different search terms, databases, as well as some studies with no major relevance to HIV-AIDS were deleted from the review. Publications were accessed directly from the publisher websites. Results from studies were examined such as number of observations, type of research design, and major outcomes of the study. A discussion of these results and conclusions was conducted, sometimes using in vitro studies as references to interpret the results shown in the research articles.

Results

As Table 2 depicts, there was a high number of clinical trials repeated for different search terms (42%) that were deleted. Further, there were another 19.7% of publications which had no direct relevance to HIV-AIDS (Table 2) and subsequently deleted from this review. There were 33 clinical studies and epidemiological studies finally selected and tabulated for the review with major outcomes of the research listed (Table 3).

Discussion

Role of herbal medicine in HIV-AIDS treatment

Only a few clinical trials are available on the use of herbal medicine in HIV-AIDS. They are often administered due to their low cost wide availability in third world and developing nations where anti-retroviral drugs are not easily accessed. One issue is the misguided healthcare provided by uneducated and unqualified herbalists' misuse of herbal therapy in the treatment of HIV-AIDS in the third world and developing nations, (8) although this may represent traditional use of the herbal medicines for infection and inflammatory conditions.

In the developed world CAM treatment appears to be widely used in conjunction with HIV conventional treatment such as anti-retroviral drugs. Herbal medicines are used in combination with anti-retroviral drugs to reduce adverse effects of nausea and depression and for immune support/modulation. In the Third World and developing nations, due mainly to the cost of anti retroviral drugs, herbal medicines appear to be more widely used, especially in management of associated conditions such as immune suppression and opportunistic infections. A study in Mexico revealed that of 293 HIV patients, 73.4% used CAM of which 29.7% were herbal products. The correlation of the use of CAM was highest in lower income earners due to the price of anti-retroviral treatment. (9) In Tanzania, due to cost restrictions, HIV sufferers resorted to the use of an array of 75 herbal medicine species, mostly leaf extracts and consumed as decoctions for the treatment of associated infections such as tuberculosis and oral candidiasis. (10) In Uganda, herbal medicine treatment has been observed as a beneficial treatment option for herpes zoster virus (i.e. reduced pain severity) in HIV patients. (11)

Survey of herbal medicine used in treatment of HIV-AIDS in Thailand

A study from Thailand indicated that 31% of the population reported using herbal medicine. With regard to government support for modern treatment, the study showed that people living with HIV tended to seek assistance from health care services for obtaining treatment. However, females living in up-country areas received less modern treatment but found herbal remedies more accessible for treatment. Respondents from provincial towns were found to use herbal remedies more often than those from Bangkok or highly urbanized areas, and the most commonly used herbal remedy (by 21% of respondents) was bitter cucumber (Momordica charantia). (12)

Evaluation of herbal medicines used for treating HIV-AIDS in South Africa

In a descriptive, prospective, follow-up study in South Africa, 33 HIV-positive volunteers (7 men and 26 women between 22 and 43 years of age) were evaluated regarding the effectiveness of commonly used traditional herbal medicines in the management of HIV-AIDS. The study evaluated the treatment efficacy of using herbal medicines by a number of qualitative parameters. The study was conducted over a period of one year. Participants showed significant health improvement: 80% of the patients displayed a better physical appearance, 65% had increased appetite, 70% had disappearance of skin marks/ lesions, 100% had disappearance of urogenital lesions, and 80% of participants had gained body weight, although body composition was not specified. There was a significant decrease in viral loads with a corresponding significant increase by 2.5 fold in CD4 T-cell counts. Over 60% of patients resumed workplace duties. The study strongly suggested the effectiveness of these traditional South African herbal medicines as supplementary or alternative medicine in HIV-AIDS treatment, and the improvement in viral load suggested they had an anti-viral action. The authors suggested the anti-viral activity may be due to the phytochemical composition of Calendula officinalis or Agastache rugosa, (13) which are used traditionally for their anti-spasmolytic and anti-bacterial actions.

Modulation of the immune system with astragalus

Astragaloside II, a key phytochemical present in Astragalus spp., at a concentration of 100nmol/L, has been shown to initiate T-cell activation in primary murine cell culture (in vitro study). The specific mechanism is through the regulation of CD4 cells via 5 protein tyrosine phosphatase activity (regulates phosphorylation state of various signalling molecules), and may be the specific mechanism by which astragalus modulates the immune system during disease, (14) including HIV-AIDS. Astragalus (Astragalus spp.) was traditionally used as a tonic for diabetes and as an adaptogen for 'healing' in Chinese medicine.

Assessment of Immunoxel in treatment of TB among HIV-AIDS patients

The herbal medicine (Immunoxel) was administered with anti-TB therapy (ATT) among HIV-AIDS patients suffering from tuberculosis. Forty patients were divided into two arms of the study; arm A was treated with ATT and arm B with Immunoxel + ATT. Immunoxel comprises of 27 immunological modulating herbal species. These include; aloe (Aloe arborescens), centaury (Erythraea centaurium), parsley root (Petroselinum crispum), rosehip (Rosa laevigata), highbush cranberry fruits (Viburnum opulus), hypericum (Hypericum perforatum), Chinese agrimony (Agrimonia pilosa), sea buckthorn berries (Hippophae rhamnoides), sage (Salvia officinalis), birch leaves (Betula sp.), marigold flower (Calendula officinalis), plantain (Plantago major), Siberian ginseng (Eleutherococcus senticosus), common wormwood (Artemisia absinthium), linden (Tilia cordata), juniper berries (Juniperus communis), rose root (Rhodiola rosea), ground ivy (Glechoma hederacea), oregano (Origanum vulgare), nettle leaf (Urtica dioica), licorice (Glycyrrhiza sp.), coneflower (Echinacea purpurea), wild thyme (Thymus serpyllum), equisetum (Equisetum arvense), wild strawberry (Fragaria vesca), chaga mushroom (Inonotus obliquus) and green tea (Thea sinensis). It was observed that addition of Immunoxel reduced opportunistic infections as well as improved clinical efficacy of ATT. (17) Given the wide array of herbal species it is unspecified which phytochemicals are present and thus possibly active to stimulate the immune system either in isolation or in combination with other phytochemicals.

Long term treatment of paediatric AIDS with herbal remedies in Romania

In Romania, 10 children living with AIDS when treated with natural herbal remedies (Chan Bai San) showed improvement in CD4 count, decrease in mortality rate and good maintenance of quality of life. These health benefits were shown for those who kept taking the herbal medicines for 3 years, without any side-effect of the herbal medicine usage. (18)

Treatment with anti-oxidant herbs

Coupled with immune status, anti-oxidant status appears to be linked with lymphocyte levels in HIV. In a 24-month prospective study of 30 adults with symptomatic HIV and no anti-retroviral therapy, khaki weed Alternanthera pungens (AP) anti-oxidant herbal extract was provided as a tea thrice weekly (AP Group) vs. no tea control (Without AP Group). (1) Venous blood samples revealed reduced oxidative damage (i.e. as evidenced by reduced malondialdehyde concentration and a reduction in advanced oxidation protein end products), significant increase (p < 0.001) of CD4 and CD8 lymphocytes and the lack of biological hepatic and renal toxicity in the AP Group.

Zidovudine (a nucleoside analogue reverse transcriptase inhibitor) was administered before and after an American ginseng extract (Panax quinquefolius) was administered to a study group comprising of 10 healthy volunteers, for two weeks. The study found a decrease in oxidative stress biomarkers (F2-isoprostane ratio = 0.79; 0.72-0.86 at P < 0.001 and 8-hydroxy deoxyguanosine ratio = 0.74; 0.59-0.92 at P = 0.02) after ginseng extract administration. F2-isoprostane is a metabolite produced from the peroxidation of essential fatty acids (EFA) (primarily arachidonic acid), whereas 8-hydroxy-deoxyguanosine is indicative of in vivo DNA oxidative damage. The experiment also reported that ginseng extract did not interfere with pharmacokinetics of zidovudine. (19)

Mental health benefits from herbal medicine treatment of HIV-AIDS

Mental health is also a key issue in HIV-AIDS sufferers, who are often socially stigmatised. A study conducted in Thailand suggested that herbal medicines can improve the mental health aspect of quality of life (QoL) among HIV-AIDS infected subjects. In this study, 132 HIV-positive adults were given a self-administered questionnaire to assess dimensions of physical function (PF) and mental health (MH) in QoL. The data was also collected on the use of herbal medicine and socio demographic and psychosocial characteristics related to HIV. Significantly better MH was observed among herbal medicine users vs. non-users, whereas, herbal medicine did not have a statistically significant association with PF scores. This improvement in MH score was higher among the socially vulnerable population. (20) A placebo effect cannot be ruled out as a clinical trial of specific herbal extracts with standardised phytochemical concentrations is necessary to make a conclusive recommendation on the use of specific herbal medicine extracts in HIV-AIDS.

Action of a derivative of St John's wort (Hypericum perforatum)

An isolated protein fraction, p27(SJ), derived from St John's wort (Hypericum perforatum) (usually prescribed for depression and some anti-viral activity), reduced the transcription of the HIV-1 genome in primary culture of microglia and astrocytes. Trans-Activator of Transcription (Tat) is a protein responsible for the enhanced efficiency of viral transcription (HIV dsDNA) and causes apoptosis in T-cells thus exacerbating HIV disease state. The p27(SJ) is associated with the transcription factor C/EBP[beta] and also Tat, changing their sub-cellular location (accumulation of C/EBPp and Tat in the peri-nuclear cytoplasmic compartment), (6) affecting DNA binding and hence transcriptional activity. (21) In conjunction with conventional medication, herbal medicines proved to regulate transcription factors associated with HIV replication but also modulate immune function in HIV patients. St John's wort traditionally is used for depression but also shows efficacy as an anti-viral, possibly via alteration of cytoplastic location of C/EBP p and also Tat.

Use of traditional herbal medicine with HIV-AIDS patients in South Africa

In a descriptive, prospective and follow-up study of 33 HIV-positive patients, the viral load decreased and CD4 counts increased after the consumption of traditional South African herbal medicines prior to meals in conjunction with conventional anti-retroviral drugs. The patients were able to increase their social activities such as work and had reduced prevalence of AIDS cachexia. (13) This suggests that the combined therapy may be useful for the treatment and management of immune suppression and systemic inflammation during HIV infection.

Use of TCM treatments for HIV-AIDS

Studies have also shown that some TCM herbal formulations are useful in the management of HIV-AIDS related symptoms.

Evaluation of xiaomi granules

One experiment evaluated efficacy of xiaomi granules (M^Ki) Glycyrrhiza glabra, Pinellia ternana, Scutellaria baicalensis, Codonopsis pilosula, Coptis chinensis, Astragalus membranaceus, Coix lacryma jobi var. mayuen, Lithospermum spp.) in 40 HIV-AIDS patients with oral candidiasis. The study had two groups; one treated with xiaomi granules (n = 40) and control group treated with anticandine. In both groups there were improvements in symptoms of: oral greasy-sticky, thirst, asthenia, abdominal distension and anorexia (p<0.05). Compared to the control group, there was significant improvement in symptoms of oral greasy-sticky and thirst in the xiaomi group (p<0.05). Efficacy rates were also much higher in the xiaomi group than in the control group (90.0% vs. 72.5%) and the 11.1% relapse rate in the xiaomi group was lower than the 31% in the control. (16)

Evaluation of Chinese herbal pills

In a double-blind placebo study of 68 HIV-infected outpatients with a CD4 cell count <0.5 x 10(9)/L, a treatment using Chinese herbal pills was investigated for observed changes in HIV-1 RNA plasma loads, CD4, CD8 cell counts and also quality of life scores. The patients taking Chinese herbs reported significantly more gastrointestinal disturbances (79% versus 38%; p = .003) than those receiving placebo, with no difference in HIV disease progression. (22) It is worth noting that the authors stated the baseline levels of both the control and treatment group to be equivalent, even though the median CD4 counts were 25% lower in the treatment group at baseline and the median HIV-1 plasma viral loads 40% lower, creating a known bias in the study.

Evaluation of Zhongyan-4

Another study examined the Chinese herbal combination Zhongyan-4 (ZY-4), ([TEXT NOT REPRODUCIBLE IN ASCII.]); a herbal prescription containing Korean ginseng (Panax ginseng), astragalus (Astragalus membranaceus), goji berry fruit (Lycium barbarum), trichosanthes root (Trichosanthis kirilowii), Chinese violet (Viola mandshurica) and the root of red-rooted sage or danshen (Salvia miltiorrhiza), showed positive results. The randomised double-blind, placebo-controlled study conducted among 72 patients showed a 5% increase in CD4 vs. placebo (24% decrease). (23) The herbs in ZY-4 are all known for their adaptogenic properties. Although the efficacy of ginseng has not been tested as a single prescription in HIV, the ginsenoside Rh2, which is an active phytochemical in ginseng, has been shown to display immunoregulatory and anti-inflammatory properties in CTLL-2 cells; and the CD8(+) cytotoxic T-cell line which have protective effects against viral infection. (24) It was observed that Rh2-B1 stimulated CTLL-2 cell proliferation and also IFN-[gamma] production and thus anti-viral activity, (24) explaining possible anti-viral activity seen in the trial using ZY-4. Sulfated Lycium barbarum polysaccharides (sLBPSs) have been shown to increase cultured chicken peripheral lymphocytes. Further, an in vivo trial using 14-day-old chickens (n=100) vaccinated with Newcastle disease vaccine showed that in the treatment group the chickens injected with the various sLBPSs had significantly higher lymphocytes proliferation and serum antibody titer, (25) conferring immunological modulating capabilities. An ethanolic extract of Viola mandshurica W. Becker (VM) has been shown in the treatment of bronchial asthma in an ovalbumin (OVA) induced asthmatic BALB/c mouse model to have significantly inhibited increases in total immunoglobulin E (IgE) and cytokines IL-4 and IL-13 levels in serum and bronchoalveolar lavage fluid (BALF), and thus may be of benefit for TB-related hypersensitivity of the lungs and bronchus. (26) Several extracts of Salvia miltiorrhiza (Danshen) have been shown to display a neutralising effect on enterovirus 71 induced cytopathic condition in Vero cells, rhabdomyosarcomacells (malignant tumour from striated muscle) and MRC-5 cells in vitro (27) and perhaps be responsible for the anti-viral effect seen in patients treated with ZY-4.

Evaluation of four different combinations of TCM herbs

In a study investigating four different combinations of TCM herbs administered to 60 AIDS or AIDS related complex (ARC) patients who were individually prescribed one of four different combinations of TCM herbs, a decrease in viral load, an increase in CD4 and an increase in T-lymphocyte counts were reported. (15) Using a TCM approach, patients with AIDS or ARC were observed to have 'deficiencies' of the lung or of the spleen and stomach; 'insufficiency' of both the spleen and kidneys, or mental confusion due to phlegm with excessive heat. (15)

Evaluation of Qian-kun-nin

A Chinese herbal formulation known as Qian-kun-nin ([TEXT NOT REPRODUCIBLE IN ASCII.]), which consists of 14 herbs including Coptis chinensis, astragalus (Astragalus membranaceus), jasmine (Jasminum officinale), wolfiporia fungus (Wolfiporia extensa) (syn. Poria cocos), bur-reed (Sparganium stoloniferum), Polygonatum odoratum and Scrophularia buergeriana is traditionally used for its anti-infection, anti-tumour and immune-enhancing properties. In in vitro trials, Qian-kun-nin displayed 'HIV-growth inhibition and immunomodulation' effects. In a single blind pilot study over 24 weeks, this formula significantly decreased plasma virus load at the end of weeks 12 and 24 (p < 0.01), with increased plasma CD4 count (p < 0.01) and with no adverse effects. Plasma virus loads were also measured after four weeks from ceasing treatment, with viral loads still observed to be decreased. These results support claims that 'Qian-Kun-Nin' has the therapeutic potential to treat HIV-positive patients. (28)

One ingredient of Qian-Kun-Nin; astragalus (Astragalus membranaceus) contains triterpene glycosides (e.g., astragalosides I-VII) and acts as an adaptogen and immune modulator. Furthermore, Polygonatum odoratum, contains saponin and flavonoid components which exhibit both anti-diabetic effect and anti-oxidant effects, (29) and is traditionally used as a food by the Nu ethnic minority people of P.R. China. (30) In addition, Scrophularia buergeriana (SB) modulates the immune responses via cytokine production. Traditionally, SB was used for fever and swelling, and in a human T-cell line (MOLT-4 cells), mouse peritoneal macrophages cytokines were increased after exposure to SB extract, via increase in the level of interleukin (IL)-2, IL-4 and interferon (IFN)-[gamma] production. (31) Thus, Qian-Kun-Nin contains herbs that influence CD4 count via immune modulation and cytokine production, which accords with its traditional use.

Impact of herbal medicine on adherence to conventional therapy

Although herbal medicines are seen as CAM therapies in the West, in Third World and developing nations, due to the cost of conventional anti-retroviral drugs, herbal medicines are a mainstay for the management and treatment of HIV-AIDS. Two studies examined the impact of complementary therapy on adherence to conventional therapies (32) and whether the complementary medicine has an impact on adherence to highly active anti-retroviral therapies (HAART) amongst HIV-positive African American women. (33) The study included 366 women who were taking one of the complementary therapies including herbal medicine at enrolment. Women were considered non-adherent if they missed any dose of HAART in 30 days following baseline. According to a logistic regression model of assessment, women on complementary medicine were 1.69 times more likely to report missing their dose of HAART over the last 30 days vs. women not taking complementary medicine. (33) Similarly, Jernewall et. al (32) conducted a study amongst 152 HIV-positive Latino gay and bisexual men. In this the study, those patients using complementary medicines were less likely to attend their doctors' appointments, to follow the advice of the doctors or to adhere to pharmaceutical medicines prescribed. (32)

In a study using a semi-structured interviewer administered questionnaire of South African individuals with HIV infection or AIDS, it was revealed that a large proportion of the population consult with traditional health practitioners. Further, the majority experience negative interactions with anti-retrovirals (ARVs). Interestingly, herbal practitioners (HP) were interviewed, with 20% making a claim that they were able to cure the disease, with 88% manufacturing their own medications as aqueous plant extracts. In addition, of the HP, only 38% had received HIV-AIDS related training, with many believing that only traditional and herbal medicines should be used for HIV-AIDS treatment, while others believe there is no harm in taking both concurrently. (34)

Safety and efficacy of herbs used in HIV AIDS treatment

There are few clinical trials available using herbs in the co-treatment of HIV-AIDS. There are also a number of safety issues regarding co-administration that have been raised in the literature.

Alternanthera pungens

In a study of the use of Alternanthera pungens herbal tea the treatment of HIV, a significant decrease in plasma levels of biomarkers of oxidative stress (p<0.001) (AOPP and MDA) and a significant increase in CD4 and CD8 lymphocytes (p<0.001) were shown. There were no toxicities related to kidney or liver in this 24-month prospective study consisting of 30 adults with symptomatic HIV and not receiving HAART. (1)

Jingyuankang

In a randomised double-blind trial (6 months) on Jingyuankang Capsule (JYK) + Leucogen analog + HAART drugs (n=58) and Leucogen + JYK analog + HAART drugs showed that JK increases leukocyte as effectively as Leucogen tablet. (35) A list of herbs in this formula is found in Table 3.

Chinese herbal pills

Even though the quality of life was improved in many of the studies involving the use of herbal medicines in HIV-AIDS, in some instances it may pose a negative effect. In a placebo-controlled double-blind study of a Chinese herbal medicine (un-named practitioner devised pill comprising of 35 Chinese herbs) which was claimed to reduce the symptoms and also to improve the quality of life for HIV-infected persons over 6 months. A number of the herbal species are also used in Western herbal medicine. The large majority of actions displayed by the list are related to their anti-oxidant action

The formula contained the following herbs: lmgzhr or reishi (Ganoderma lucidum), woad (Isatis tinctoria), Millettia reticulate, astragalus (Astragalus membranaceus), Snow fungus (Tremealla fuciformis), Andrographis (Andrographis paniculata), Japanese honeysuckle (Lonicera japonica), agarwood (Aquilaria agallocha), horny goatweed (Epimedium macranthum), oldenlandia (Oldenlandia diffusa), cistanche (Cistanche salsa), Tibet goji berry (Lycium chinense), sea tangle (Laminaria japonica), dong quai (Angelica sinensis), Japanese knotweed (Polygonum cuspidatum), American ginseng (Panax quinquefolius), schizandra (Schizandra chinensis), Chinese privet (Ligustrum lucidum), Bai Zhu (Atractylodes macrocephala), rehmannia (Rehmannia glutinosa), danshen (Salvia miltiorrhiza), tumeric (Curcuma longa), violet herb (yedoensis), Mandarin orange (Citrus reticulatereticulata), paeonia (Paeonia lactiflora), polygonum (Polygonum multiflorum), eucommia (Eucommia ulmoides), amomum (Amomum villosum), Chinese liquorice (Glycyrrhiza uralensis), self-heal (Prunella vulgaris), cordyceps (Cordyceps sinensis), patchouli plant (Pogostemon cablin), Japanese hawthorn (Crataegus cuneata), Massamedicata fermentata, barley (Hordeum vulgare), rice (Oryza sativa) with fillers such as microcrystalline cellulose (filler), magnesium stearate (anti-adherent), silicon dioxide (desiccant), and gum acacia. Interestingly, gastrointestinal disturbances were the only effect of this Chinese herbal mixture with no significant differences in plasma viral loads, CD4 counts, symptoms, and psychometric parameters or HIV-1 RNA levels. (122)

IGM-1

In a fully-randomised, double-blind placebo, clinic-controlled study reviewing the short-term (12 week) safety and efficacy of a Chinese medicinal herb preparation (IGM-1) to treat HIV, there was revealed no significance differences between the placebo and the Chinese herbal medicine except for some reduction in symptoms (i.e. life satisfaction, perceived health, social function, and mental health). (36) The species present in the Chinese / Kampo medicinal herb preparation included herbs prepared based on AIDS symptomology. Of 31 herbal ingredients in the 650-mg tablet, those present in significant concentration included lingzi or reishi (Ganoderma lucidum), woad (Isatis tinctoria), astragalus (Astragalus membranaceus), andrographis (Andrographis paniculata), Japanese honeysuckle (Lonicera japonica), evergreen wisteria (Milletia reticulata), oldenlandia (Oldenlandia diffusa), and dashi kombu (Laminaria japonica). These herbs have a range of immunomodulating, anti-viral, anti-cancer properties. Even though there was an improvement in symptoms, this alone could not be interpreted as a long term success with the use of this specific Chinese Medicine / Kampo herb formulation as presented for the treatment of HIV. Measures such as 'quality of life' can be subjective and open to bias such as placebo effect. Actual improvements in quantitative parameters such as CD4 counts were not recorded and/or not significant and thus it is unknown whether immune function had been affected or improved.

Oral suspension SH

A study by Kusum et al (37) who examined oral suspension SH, a combination of five 'Chinese herbs', native to Asia, near-Asia and Europe. These herbs, namely licorice (Glycyrrhiza glabra), capillary wormwood (Artemisia capillaris) white mulberry (Morus alba), astragalus (Astragalus membranaceus), safflower (Carthamus tinctorius) were either provided as 5g solid or 30 mL tincture, divided into three doses daily. These herbs have phytochemicals present that display efficacy as anti inflammatory, adrenal tonic, anti-oxidant, anti-viral, immune enhancement, adaptogenic and postprandial. The combination was administered daily in three divided doses post-meal amongst 28 subjects with HIV AIDS. The participants also received sulfamethoxazole/ trimethoprim (antibiotic pharmaceutical selective against Pneumocystis pneumonia in patients with HIV), 400/80 mg after breakfast with treatment provided for 12 weeks. The combination was shown to be safe and showed satisfactory outcomes in terms of viral load, whereas immunological response measured in terms of increase of CD4 cell count did not demonstrate a satisfactory outcome. (37)

Jin Huang

'Jin Huang' a Chinese herbal medicine combination showed no anti-viral effect although patients described a certain 'improvement in personal well-being. (38) Such measures as 'well-being' are subjective and open to bias on the part of the observer, (39) however in the context of the TCM objective to 're-balance' the health status of the patient there is room in the treatment management for a placebo-like effect of the 'qi', an unquantifiable component, similar to vis medicatrix naturae. This re-balancing process is not readily translated into numerical terms, so TCM utilises qualitative descriptions to characterise health status. The formulation of 'Jin Huang' comprises of turmeric (Curcuma longa), artificial calculus bovis (i.e. dried ox gallstones; cholesterol/ bile salts), tien-chi ginseng (Panax notoginseng), mu xiang (Aucklandia lappa), Rheum officinale, fritillaria (Fritillaria cirrhosa), bing pian (Borneolum Syntheticum) as shown in Table 3, and the ingredients' appear to have anti-inflammatory and anti-oxidant actions.

CKBM-A01

Overall, the peer-reviewed literature suggests that except for 'Qian-Kun-Nin', various Chinese herbal medicine formulations showed no, or only limited, effectiveness for the treatment of HIV-AIDS, with some displaying adverse effects. This was also shown in a study on the use of a Chinese medicinal combination known as CKBM-A01, which had no effect on CD4 cell counts or HIV viral loading, but had improvement in cold and flu symptoms suggesting an immune-stimulant effect, but with intermittent diarrhoea observed in over half of the patients, together with skin rashes and increased peristalsis as side effects. (40)

Neem Leaf

A study (41) assessed the efficacy of a neem leaf extract (Azadirachta indica) amongst 60 HIV-AIDS subjects (HIV I or II positive, CD4 cell count <300 cells/[micro]L, and anti-retroviral naive). Traditionally A. indica has been used, amongst other actions, for its anti-viral activity. In a study, the effect of an acetone-water neem leaf extract (IRAB), of 1.0 g daily for 12 weeks, on immunity and viral load were monitored. Of the 60 participants, 50 (83.33%) were compliant. There was significant improvement in CD4 cell count in these 50 patients (p<0.001) at 12 weeks. There was improvement in the erythrocyte sedimentation rate (64 mm/hr at baseline to 16 mm/hr at week 12). There was also a decrease in HIV-AIDS-related pathologies (120 at baseline to 5 at 12 weeks). Further, there was a significant increase in mean bodyweight, haemoglobin concentration and lymphocyte differential count observed. No major adverse effects were reported in the study. (41)

Melaleuca

Two studies evaluated the efficacy of oil derived from the genus melaleuca in fluconazole-refractory (anti-fungal pharmaceutical resistant) oral candidiasis amongst AIDS patients. (42,43) An alcohol-based and alcohol-free melaleuca oral solution was evaluated for two to four weeks amongst AIDS patients with fluconazole-refractory oropharyngeal candidiasis (within mouth cavity) in a prospective, single-centre, open-label study. (42) Twenty-seven participants randomly received either alcohol-based or alcohol-free melaleuca oral solution four times daily at a 1:1 extract ratio. The primary study aim was the resolution of clinical lesions. Evaluation of clinical signs and symptoms of oral candidiasis and quantitative yeast cultures were performed at two and four weeks. At week four, clinical response was demonstrated in 60% of the participants suggesting efficacy in oral candidiasis refractory to fluconazole in AIDS patients. (42) Further, in a prospective, single-centre, open-labelled study (no blinding) which evaluated 12 patients with AIDS and oral candidiasis resistant to fluconazole. (43) The patients were treated using a 15 ml melaleuca oral solution four times a day, administered as a mouth wash, for a period of two to four weeks. The participants were evaluated weekly both clinically and with quantitative yeast cultures. A total of 8 of the 12 patients responded positively in four weeks (2 cured, 6 improved with 4 not responding) to the prescribed therapy. Seven patients showed mycological response. Clinical relapse was not observed amongst cured patients during a follow-up of the cohort after a two to four week period after final evaluation. (43)

American ginseng

Healthy patients consuming 200mg of a ginsenoside enriched American ginseng (Panax quinquefolius) extract for two weeks have been observed to induce phase 2 (i.e. UDP-glucuronosyltransferases, sulfotransferases, N-acetyltransferases, glutathione S-transferases and methyltransferases) and antioxidant enzymes in vitro and thought to increase the clearance of zidovudine, an anti-retroviral drug at a 300 mg dosage. (19) Clearance is thought to be due to increased quinone reductase activity. However two weeks of the P quinquefolius extract intake did not adversely alter zidovudine pharmacokinetics, but was shown to reduce oxidative stress markers, and thus a positive outcome for treatment of HIV-AIDS patients using the extract for its presumed adaptogenic properties. (19)

Micronutrients

Interestingly, in a study of sub-Sahara African HIV positive patients, it was observed that micronutrient deficiencies (i.e. micronutrients including vitamins A, C, and E, p-carotene, selenium, zinc, and food/tea polyphenols) are common. Due to HIV infection, there is an increased generation of reactive oxygen species (ROS). These anti-oxidant nutrients can be provided via an anti-oxidant rich-diet (i.e. fruit and vegetable based diets) or via dietary anti-oxidant supplements and may have a positive effect on CD4 and viral load in HIV positive patients that are ineligible for anti-retroviral therapy. (44)

In a review of HIV-infected individuals, selenium was suggested to be beneficial due to its inhibitory effect in HIV in vitro and for increasing CD4 counts in vivo, and it has been observed as a deficient nutrient in cohorts with HIV infection. (45) Thus, brazil nuts (Bertholletia excelsa), and burdock root (Arctium spp.), which contain higher levels of selenium, may be a beneficial inclusion in the diet of HIV-AIDS sufferers.

Impact of CAM on the pharmacokinetics of conventional medicine

In traditional Western herbal medicine St John's Wort (Hypericum perforatum) is used for the treatment of mild depression and Echinacea spp. for their immunomodulation action.

In a study investigating the safety of the use of echinacea (Echinacea purpurea) and its interaction with etravirine (non-nucleoside reverse transcriptase inhibitor of HIV), patients received 400 mg once daily of etravirine and also E. purpurea root (500 mg every 8 h) over a 14 day period. The etravirine pharmacokinetic parameters such as geometric mean ratio showed that the co-administration of E. purpurea with etravirine was safe and well-tolerated in HIV-infected patients. (46) This observation was also noted in a study of co-administration of E. purpurea with darunavir-ritonavir (protease inhibitor, anti-retroviral drug), but there was a minor decrease in darunavir concentrations, which warranted the monitoring of darunavir concentrations in plasma to ensure the patient was receiving adequate dosage. (47)

Conversely, St John's wort (Hypericum perforatum) has been shown to increase the activity of [beta]-glycoprotein (PgP), which is a trans-membrane protein that excretes xenotoxins (i.e. pharmaceutical compounds or their conjugates) from cells such as anti-viral conjugates, especially indinavir and cyclosporine which are known substrates for cytochrome P450 3A4 (CYP3A4), and which theoretically may pose a threat to the efficacy of an anti-retroviral drug. Another placebo-controlled study also showed utility of St John's wort to increase PgP expression (4.2 fold) from baseline. (48)

The co-administration of Ginkgo biloba extract marginally increased [C.sub.max] (maximal plasma drug concentration in a tested area post-administration) of raltegravir, however there was no effect on raltegravir exposure. The change in [C.sub.max] of raltegravir was considered of minor significance owing to the large inter subject variability of raltegravir. (49)

Thus, some herbal medicines appear to be safe for co-use with anti-retroviral medicine, and provide immune-supportive action in the treatment of HIV-AIDS and present a valuable complementary treatment options for patients, but there are still questions about others due to possible interaction with anti-retroviral drugs and reduction in their efficacy i.e. reduction of [C.sub.max].

Concluding remarks

Herbal medicines are commonly used all over the world in both developing and developed countries, especially in the management of chronic conditions. They are used for the treatment of HIV-AIDS and associated conditions such as opportunistic infections. Emerging evidence suggests some benefits of herbal medicines for immune modulating effects, but there are some concerns related to its use for example the possible reduced efficacy of antiretroviral drugs. Herbal medicines may be suited to immune-support by increasing CD4, rather than treatment of HIV-AIDS. However, there have not been an extensive number clinical trials (i.e. randomised clinical trials) carried out on the utility of herbal medicine as a direct treatment or in combination with anti-retroviral drugs, as revealed in our literature search for this review.

Studies indicate that some herbal medicines (single extracts and combinationformulas) are safe and efficacious however in some instances safety issues arose, especially in relation to the ability of practitioners to administer a phytochemically relevant herbal extract or mixture. There is also the danger of contamination or adulteration with other materials such as heavy metals, pesticides, bacteria or pharmaceutical compounds which is a known concern for Chinese herbal medicines. Some studies showed efficacy of herbs in terms of immunological parameters, viral load and symptomatology however since the studies were not conducted on large populations and were not of a longitudinal cohort design, they are not conclusive enough to create a definitive answer relating to the use of herbal medicines in HIV-AIDS.

The main actions of herbal medicine for the treatment of HIV-AIDS are via immune modulation, anti-oxidant activity and some anti-retroviral activity of isolated fractions. Considering the primary evidence of efficacy from these small trials, and also selected in vitro cell culture, conducting further in vitro for mechanistic understanding, as well as clinical studies may be beneficial and may lead to a clearer recommendation on how and where in the treatment plan to use herbal medicines in HIV-AIDS treatment. Further, standardisation of extracts and validation using double-blind clinical trials are required with formalised complementary treatment protocols co-administered with anti-retroviral drugs.

Another issue that was revealed in this review is the significant incidence of people with HIV-AIDS using herbal medicine and not adhering to conventional medical treatment. This may be due to compliance issues or the availability and cost of modern anti-retroviral drugs. Thus, there is a need to educate patients, as well as herbal medicine practitioners across the globe, of the importance of conventional medicine and the need for extensive study of herb/drug interactions. Chinese herbal medicine, using combinations of up to 40 herbs, gave results suggesting minimal success other than immune supportive functions, as did African herbal medicine. In these traditional systems of medicine, which also appear as art forms rather than scientific practices, the practitioner relies on a static empirical belief system without considering a scientific understanding of the patient's health. Conversely, this is also true of pharmacological intervention of HIV-AIDS. The main focus of traditional systems is to 're-balance' patient health and bodily systems rather than to control or impede viral activity. Similarly, Western herbal medicine, both traditional and modern (as pharmacognosy), appears to be of benefit in immune support rather than 'curing' the condition per se. Clinical trials using phytochemically validated herbal medicines in conjunction with pharmacological intervention such as anti-retrovirals are required to assess potential benefits in such a complex condition which often has many confounding co-morbidities. There is potential for an integrative medicine system, enabling the patient to elect for either single or combined treatment from a pharmacological, pharmacognosy and traditional perspective and to include multiple modalities in the treatment plan which would include the use of herbal medicines.

In conclusion, herbal medicines are widely used in the treatment of HIV-AIDS and associated conditions. There are studies suggesting the safety and a degree of efficacy for some herbal medicines with, some studies suggesting a positive impact on viral load and immunological parameters. Herbal medicines may have great potential in the management of HIV-AIDS however rigorous research is required to determine safety and efficacy.

Conflict of Interest Statement

The authors have no conflict of interest to declare.

References

(1.) Djohan Y, Camara C, Monde A, Koffi G, Niamke G, Dere L, Tiahou G, Djessou P, Sess D. 2009. Interest of antioxidants in the care of the patients infected by the HIV: the experience of long term administration of Alternanthera pungens herb tea. Ann Biol Clin (Paris). 67(5):563-568.

(2.) World Health Organisation (WHO) 2002. Traditional medicine growing needs and potential. WHO Policy Perspectives on Medicines.

(3.) Duggan J, Peterson WS, Schutz M, Khuder S, Charkraborty J. 2001. Use of complementary and alternative therapies in HIV infected patients. AIDS Patient Care STDS. 15(3):159-167.

(4.) Colebunders R, Dreezen C, Florence E, Pelgrom Y, Schrooten W. 2003. The use of complementary and alternative medicine by persons with HIV infection in Europe. Int J STD AIDS. 14(10): 672-674.

(5.) Bodeker G, Carter G, Burford G, Dvorak-Little M. 2006. HIV AIDS: Traditional systems of health care in the management of a global epidemic. J Altern Complement Med. 12(6):563-576.

(6.) Darbinian-Sarkissian N, Darbinyan A, Otte J, Radhakrishnan S, Sawaya BE, Arzumanyan A, Chipitsyna G, Popov Y, Rappaport J, Amini S, Khalili K. 2006. p27(SJ), a novel protein in St John's Wort, that suppresses expression of HIV-1 genome. Gene Ther. 13(4):288-295.

(7.) Lyons, L., Nambiar, D., Hosein, S., Rogers, T. 2005. A Practical Guide to Herbal Therapies for People Living with HIV. (CATIE). Toronto, Ontario, Canada, CATIE.

(8.) Orisatoki, R O., Oguntibeju, OO. (2010). The role of Herbal Medicine use in HIV-AIDS treatment. Archives of Clinical Microbiology 1(3).

(9.) Herrera-Arellano, A., Jaime-Delgado, M., Herrera-Alvarez, S.,

Oaxaca-Navarro, J., Salazar-Martinez, E. 2009. The alternative medicine used as complementary in patients positive for HIV. Rev Med Inst Mex Seguro Soc. 47(6):651-658.

(10.) Kisangau, D.P., Lyaruu, HV., Hosea, KM., Joseph, CC. 2007. Use of traditional medicines in the management of HIV-AIDS opportunistic infections in Tanzania: a case in the Bukoba rural district. J Ethnobiol Ethnomed. 10(3):29.

(11.) Homsy, J., Katabira, E., Kabatesi, D., Mubiru, F., Kwamya, L., Tusaba, C., Kasolo, S., Mwebe, D., Ssentamu, L., Okello, M., King, R. 1999. Evaluating herbal medicine for the management of Herpes zoster in human immunodeficiency virus-infected patients in Kampala, Uganda. J Altern Complement Med. 5(6):553-565.

(12.) Vanlandingham M, Im-Em W, Yokota F. 2006. Access to treatment and care associated with HIV infection among members of AIDS support groups in Thailand. AIDS Care 18(7):637-646.13. Tshibangu, K.C., Worku, ZB., de Jongh, MA., van Wyk, AE., Mokwena, SO., Peranovic, V. 2004. Assessment of effectiveness of traditional herbal medicine in managing HIV-AIDS patients in South Africa. East Afr Med J. 81(10):499-504.

(14.) Wan, C.P., Gao, LX., Hou, LF., Yang, XQ., He, PL., Yang, YF., Tang, W., Yue, JM., Li, J., Zuo, JP 2013. Astragaloside II triggers T cell activation through regulation of CD45 protein tyrosine phosphatase activity. Acta Pharmacol Sin. 34(4):522-530.

(15.) Han, G. 2007. The TCM remedies for treatment of AIDS-a clinical report of 60 cases. J Tradit Chin Med. 27(1):33-6.

(16.) Jiang, F., Wei, SH., Peng, B. 2009. Effect of xiaomi granules in treating 40 patients of HIV-AIDS oral candidiasis. Zhongguo Zhong Xi Yi Jie He Za Zhi. 29(12):m7-m9.

(17.) Arjanova, OV., Prihoda, ND., Yurchenko, LV., Sokolenko, NI., Vihrova, LA., Pylypchuk, VS., Frolov, VM., and Kutsyna, G.A. 2009. Enhancement of efficacy of tuberculosis drugs with Immunoxel (Dzherelo(tm)) in HIV-infected patients with active pulmonary tuberculosis. Immunotherapy 1(4):549-556.

(18.) Tani M, Nagase M, Nishiyama T, Yamamoto T, Matusa R. 2002. The effects of long-term herbal treatment for pediatric AIDS. Am J Chin Med. 30(1):51-64.

(19.) Lee, L.S., Wise, SD., Chan, C., Parsons, TL., Flexner, C., Lietman, PS. 2008. Possible differential induction of phase 2 enzyme and antioxidant pathways by American ginseng, Panax quinquefolius. J Clin Pharmacol. 48(5):599-609.

(20.) Sugimoto, N., Ichikawa, M., Siriliang, B., Nakahara, S., Jimba, M., Wakai, S. 2005. Herbal medicine use and quality of life among people living with HIV-AIDS in northeastern Thailand. AIDS Care 17(2): 252-262.

(21.) Darbinian, N., Popov, Y., Khalili, K., Amini, S. 2008. Creation of a bi-directional protein transduction system for suppression of HIV-1 expression by p27SJ. Antiviral Res. 79(2):136-141.

(22.) Weber, R., Christen, L., Loy, M., Schaller, S., Christen, S., Joyce, CR., Ledermann, U., Ledergerber, B., Cone, R., Luthy, R., Cohen, M.R. 1999. Randomized, placebo-controlled trial of Chinese herb therapy for HIV-1-infected individuals. J Acquir Immune Defic Syndr. 22(1):56-64.

(23.) Wang, J., Yang, FZ., Zhao, M., Zhang, YH., Zhang, YX., Liu, Y., Liu, WM., Wang, FS., Xu, SL., Yu, ZM., Xie, YM., Zhou, XZ., Jiang, TJ. 2006. Randomised double-blinded and controlled clinical trial on treatment of HIV-AIDS by Zhongyan-4. Chin J Integr Med. 12(1), 6-11.

(24.) Lv, S., Yi, PF., Shen, HQ., Zhang, LY., Dong, HB., Wu, SC., Xia, F., Guo, X., Wei, XB., Fu, BD. 2014. Ginsenoside Rh2-B1 stimulates cell proliferation and IFN-[gamma] production by activating the p38 MAPK and ERK-dependent signalling pathways in CTLL-2 cells. Immunopharmacol Immunotoxicol. 36(1):43-51.

(25.) Wang, J., Hu, Y., Wang, D., Liu, J., Zhang, J., Abula, S., Zhao, B., Ruan, S. 2010. Sulfated modification can enhance the immune enhancing activity of lycium barbarum polysaccharides. Cell Immunol. 263(2):219-223.

(26.) Lee, MY, Yuk, JE., Kwon, OK., Kim, HS., Oh, SR., Lee, HK., Ahn, KS. 2010. Anti-inflammatory and anti-asthmatic effects of Viola mandshurica W. Becker (VM) ethanolic (EtOH) extract on airway inflammation in a mouse model of allergic asthma. J Ethnopharmacol. 127(1), 159-164.

(27.) Wu, BW., Pan, TL., Leu, YL., Chang, YK., Tai, PJ., Lin, KH., Horng, JT. 2007. Antiviral effects of Salvia miltiorrhiza (Danshen) against enterovirus 71. Am J Chin Med. 35(1):153-168.

(28.) Zhan L, Y S., Xue YX, Attele AS, Yuan CS. 2000. Effects of qian-kun-nin, a Chinese herbal medicine formulation, on HIV positive subjects: a pilot study. Am J Chin Med. 28(3-4): 305 312.

(29.) Deng, Y., He, K., Ye, X., Chen, X., Huang, J., Li, X., Yuan, L., Jin, Y., Jin, Q., Li, P. 2012. Saponin rich fractions from Polygonatum odoratum (Mill.) Druce with more potential hypoglycemic effects. J Ethnopharmacol. 141(1):228-233.

(30.) Wujisguleng, W., Yujing, L., Chunlin, L. 2012. Ethnobotanical review of food uses of Polygonatum (Convallariaceae) in China. Acta Soc Bot Pol 81(4):239-244.

(31.) Kim, SJ., Park, JS., Myung, NY., Moon, PD., Choi, IY., An, HJ., Kim, NH., Na, HJ., Kim, DH., Kim, MC., An, NH., Kim, IK., Lee, JY., Jeong, HJ., Um, JY., Kim, HM., Hong, SH. 2009. Scrophularia buergeriana regulates cytokine production in vitro. Immunopharmacol Immunotoxicol. 31(2): 246-252.

(32.) Jernewall, N., Zea, MC., Reisen, C.A., Poppen, PJ. 2005. "Complementary and alternative medicine and adherence to care among HIV-positive Latino gay and bisexual men." AIDS Care 17(5): 601-609.

(33.) Owen-Smith, A., Diclemente, R., Wingood, G. 2007. Complementary and alternative medicine use decreases adherence to HAART in HIV-positive women. AIDS Care. 19(5):589-593.

(34.) Walwyn, D., Maitshotlo, B. 2010. The role of South African traditional health practitioners in the treatment of HIV-AIDS: a study of their practices and use of herbal medicines. Southern African Journal of HIV Medicine 11(2).

(35.) Jiang, S.Q., Sun, H.X., Xu, Y.M., Jiang, Y.L., Pei, J.W., Wang, H.L. 2011. Effects of jingyuankang capsules on leukocyte level in AIDS patients. J Tradit Chin Med. 31(1):32-35.

(36.) Burack, J.H., Cohen, MR., Hahn, JA., Abrams, DI. 1996. Pilot randomized controlled trial of Chinese herbal treatment for HIV-associated symptoms. J Acquir Immune Defic Syndr Hum Retrovirol. 12(4): 386-393.

(37.) Kusum, M., Klinbuayaem, V., Bunjob, M., Sangkitporn, S. 2004. Preliminary efficacy and safety of oral suspension SH, combination of five Chinese medicinal herbs, in people living with HIV-AIDS ; the phase I/II study. J Med Assoc Thai. 87(9): 1065-1070.

(38.) Maek-a-nantawat, W, Pitisuttithum, P, Bussaratid, V, Chamnachanan, S, Naksrisook, S, Peonim, W, Thantamnu, N, Muanaum, R, Ngamdee, V. 2003. 6-month evaluation of JinHuang Chinese herbal medicine study in asymptomatic HIV infected Thais. Southeast Asian J Trop Med Public Health. 34(2): 379-384.

(39.) Hrobjartsson, A., Thomsen, AS., Emanuelsson, F., Tendal, B., Hilden, J., Boutron, I., Ravaud, P, Brorson, S. 2013. Observer bias in randomized clinical trials with measurement scale outcomes: a systematic review of trials with both blinded and nonblinded assessors. CMAJ. 185(4): E201-211.

(40.) Maek-a-nantawat, W., Phonrat, B., Dhitavat, J., Naksrisook, S., Muanaum, R., Ngamdee, V., Pitisuttithum, P. 2009. Safety and efficacy of CKBM-A01, a Chinese herbal medicine, among asymptomatic HIV patients. Southeast Asian J Trop Med Public Health. 40(3): 494-501.

(41.) Mbah, A.U., Udeinya, IJ., Shu, EN., Chijioke, CP., Nubila, T., Udeinya, F., Muobuike, A., Mmuobieri, A. Obioma, MS. 2007. Fractionated neem leaf extract is safe and increases CD4+ cell levels in HIV-AIDS patients. Am J Ther. 14(4): 369-374.

(42.) Vazquez, JA., Zawawi, AA. 2002. Efficacy of alcohol based and alcohol-free melaleuca oral solution for the treatment of fluconazole-refractory oropharyngeal candidiasis in patients with AIDS. HIV Clin Trials. 3(5): 379-385.

(43.) Jandourek, A., Vaishampayan, JK., Vazquez, JA. 1998. "Efficacy of melaleuca oral solution for the treatment of fluconazole refractory oral candidiasis in AIDS patients." AIDS. 12(9): 1033-1037.

(44.) Nkengfack, G.N., Torimiro, JN., Englert, H. 2012. Effects of antioxidants on CD4 and viral load in HIV-infected women in sub-Saharan Africa--dietary supplements vs. local diet. Int J Vitam Nutr Res. 82(1): 63-72.

(45.) Stone, CA., Kawai, K., Kupka, R., Fawzi, WW. 2010. Role of selenium in HIV infection. Nutrition Reviews 68(11): 671-681.

(46.) Molto, J., Valle, M., Miranda, C., Cedeno, S., Negredo, E., Barbanoj, MJ., Clotet, B. 2011. Herb-drug interaction between Echinacea purpurea and darunavir-ritonavir in HIV-infected patients. Antimicrob Agents Chemother. 55(1): 326-330.

(47.) Molto, J., Valle, M., Miranda, C., Cedeno, S., Negredo, E., Clotet, B. 2012. Herb-drug interaction between Echinacea purpurea and etravirine in HIV-infected patients. Antimicrob Agents Chemother. 56(10): 5328-5331.

(48.) Hennessy, M., Kelleher, D., Spiers, JP, Barry, M., Kavanagh, P, Back, D., Mulcahy, F., Feely, J. 2002. St Johns wort increases expression of P-glycoprotein: implications for drug interactions. Br J Clin Pharmacol. 53(1): 75-82.

(49.) Blonk, M., Colbers, A., Poirters, A., Schouwenberg, B., Burger, D. 2012. Effect of ginkgo biloba on the pharmacokinetics of raltegravir in healthy volunteers. Antimicrob Agents Chemother. 6(10): 5070-5.

Simon Cichello * [1,2], Surafel Melaku Tegegne [1,3], Hong Yun [4]

[1] School of Life Sciences, La Trobe University, Victoria, Australia

[2] School of Public Health, Kunming Medical University, Yunnan, P.R. China

[3] Bahir Dar University, Amara, Bahir Dar, Ethiopia

[4] The First Affiliated Hospital, College of Medicine, Zhejiang University, P.R. China

* To whom correspondence should be addressed: SCichello@latrobe.edu.au
Table 1: Commonly used herbs in HIV-AIDS treatment

Skin immunity

* Aloe vera (Aloe vera)

Adaptogen

* Ginseng (Panax spp.)

* Withania (Withania somnifera)

Anti-bacterial

* Propolis*

Anti-inflammatory

* Atractylodes (Atractylodes macrocephala)

* Olive tree (Olea europaea)

* Tea tree (Melaleuca alternifolia)

* Turmeric {Curcuma longa)

Anti-viral activity

* Golden Seal (Hydrastis canadensis)

* Biscuit root (Lomatium spp.)

* Neem tree (Azadirachta indica)

* St. John's wort (Hypericum perforatum)

Anti-carcinogen

* Dyer's woad (Isatis tinctoria)

Circulatory stimulant

* Ginger (Zingiber officinale)

* Ginkgo {Ginkgo biloba)

Depurative

* Garlic (Allium sativum)

* Grapefruit seed (Citrus x paradisi)

Diaphoretic

* Boxwood {Buxus sempervirens)

Digestive carminative

* Peppermint (Mentha x piperita)

Expectorant

* Hyssop (Hyssopus officinalis)

Hepatoprotective

* Greater celandine {Chelidonium majus)

* Liquorice {Glycyrrhiza glabra)*

* Milk thistle (Silybum marianum)

* Also denotes anti-viral activity.

Some indications shown above differ from TCM theory.

Adapted from (Lyons et al. 2005).

Table 2: Tabulation of literature search results and differentiation
process

Search Term(s) & Combinations           No . Publications
                                        (Google Scholar)

HIV' + 'Herb'                                  11
AIDS' + 'Herb'                                  4
HIV' + 'Herbal'                                60
AIDS' + 'Herbal'                                4
HIV' + 'AIDS' + 'Herbal'                        3
HIV' + 'AIDS' + 'Herb'                         14
Total Number of Publications                   --
Overlapping or Deleted Publications            --
Reviewed Publications

Search Term(s) & Combinations         No Publications
                                         (PubMed)

HIV' + 'Herb'                               106
AIDS' + 'Herb'                              61
HIV' + 'Herbal'                             449
AIDS' + 'Herbal'                            61
HIV' + 'AIDS' + 'Herbal'                    211
HIV' + 'AIDS' + 'Herb'                      34
Total Number of Publications                --
Overlapping or Deleted Publications         --
Reviewed Publications

Search Term(s) & Combinations           No Clinical Trial
                                      Publications (PubMed)

HIV' + 'Herb'                                   7
AIDS' + 'Herb'                                  1
HIV' + 'Herbal'                                27
AIDS' + 'Herbal'                               18
HIV' + 'AIDS' + 'Herbal'                       12
HIV' + 'AIDS' + 'Herb'                          1
Total Number of Publications                   66
Overlapping or Deleted Publications            33
Reviewed Publications                          33

Table 3: Details and major outcomes of reviewed research articles and
epidemiological studies

Abbreviations: AIDS: Acquired Immunodeficiency
Syndrome; ARC: AIDS-related complex, ART: Anti-
retroviral treatment-therapy, HZ: Herpes zoster
(Shingles), HAART: Highly Active Anti-
Retroviral Therapy, NASE: No adverse side
effects, PVL: plasma viral loads, TB :
Tuberculosis, [up arrow] -[down arrow] :
increase-decrease, PgP: P-glycoprotein.

Author                 Year   Methodology           Subjects

Arjanova et al. (17)   2009   Open label study      A (n = 20) and
                                                    B (n = 20) -
                                                    TB/HIV

Blonk et al. (49)      2012   Open-label,           18 healthy
                              randomised, two-      volunteers
                              period, crossover
                              phase I trial

Burack et al. (36)     1996   Randomised            30 Adults with
                              controlled trial      symptomatic
                                                    HIV

Colebunders            2003   Two questionnaire     European
et al. (4)                    based surveys         population

Djohan et al. (1)      2009   24 month              30 Adults with
                              prospective study     symptomatic
                                                    HIV, no ART

Duggan et al. (3)      2001   Survey (USA           191-HIV
                              based)                positive out-
                                                    patients

Han (15)               2007   Various               60 cases of
                              treatments            AIDS or ARC

Hennessy et            2002   0.15% St John's       n=15 SJW
al. (48)                      Wort, 600 mg          n=7 placebo
                              thrice daily/ 16
                              days

Herrera-               2009   Cross-sectional       293
Arellano et al. (9)           study of HIV
                              patients / survey.

Homsy et al. (11)      1999   Non-randomised,       Phase 1: 52
                              non-placebo           c/c
                              controlled,           Phase 2: 154
                              observational         c/c
                              study (2 phases).
                              Phase 1: 3 mo
                              follow up, Phase
                              2: 3 mo follow up.

Jandourek et           1998   Prospective,          12 patients
al. (43)                      single centre,        with AIDS
                              open-labelled         and oral
                              study                 candidiasis

Jernewall et al (32)   2005   Survey                152 HIV-
                                                    positive
                                                    Latino gay
                                                    and bisexual
                                                    men

Jiang et al. (16)      2009   Open label            n = 40
                              interventional        patients /
                              study (Grp A:         group
                              anticandine,
                              Grp B: xiaomi
                              granules)

Jiang et al. (35)      2011   Randomised            n = 58
                              double-blind trial    Treatment (T)
                              (6 months)            n = 58 Control
                              Jingyuankang          (C)
                              Capsule (Abbrev. JYK)
                              ([TEXT NOT
                              REPRODUCIBLE IN
                              ASCII])

Kisangau et            2007   Semi-structured       30 herbal
al. (10)                      questionnaire         practitioners

Kusum et al. (37)      2004   Open-label study      28

Lee et al. (19)        2008   Pharmacokinetic       10 healthy
                              study                 volunteers

Maek-a-                2003   Prospective open      21
nantawat et                   study (6 month)       asymptomatic
al. (38)                                            HIV patients

Maek-a-                2009   Open-labelled         18
nantawat et                   trial                 asymptomatic
al. (40)                                            HIV patients

Mbah et al. (41)       2007   Interventional        60 HIV-AIDS
                              study                 patients

Molto et al. (47)      2012   Open-label, fixed-    15 HIV
                              sequence study        infected
                                                    patients

Molto et al. (46)      2011   Open-label, fixed-
                              sequence study
                              (4 weeks)

Owen-Smith et          2007   Observational         366 HIV-
al. (33)                      study                 positive,
                                                    mostly
                                                    African-
                                                    American
                                                    women, aged
                                                    18-50 years

Sugimoto et            2005   Survey                132 HIV-
al. (20)                                            positive Thai
                                                    adults

Tani et al. (18)       2002   Long term study       10 children
                              with herbal           with pediatric
                              intervention (year    AIDS
                              1992-2000)

Tshibangu et           2004   12-month              33 HIV-
al. (13)                      follow-up study.      positive
                                                    patients

Vanlandingham          2006   Analysis of data      412 HIV-AIDS
et al. (12)                   collected during      patients
                              the year 2000
Vazquez et al. (42)    2002   Prospective,          27 AIDS
                              single-centre,        patients with
                              open-label study      oral candidias

Walwyn et al. (34)     2010   Semi-structured       Herbal
                              questionnaire         practitioners

Wang et al. (23)       2006   Randomised            72 patients
                              double-blinded        divided into
                              and placebo-          treatment
                              parallel-controlled   (n=36) and
                              trial                 control (n=36)

Weber et al. (22)      1999   Prospective,          68 HIV-
                              placebo-              infected
                              controlled            adults
                              double-blind
                              study (6 mths).

Wujisguleng et         2012   Ethnobotanical        n/a
al. (30)                      review

Zhan et al. (28)       2000   Pilot study, single   8 patients
                              blind placebo
                              study (24 weeks)

Author                 Herbal Species

Arjanova et al. (17)   first-line anti-TB therapy
                       (ATT) or ATT + Immunoxel
                       (Dzherelo), respectively

Blonk et al. (49)      Ginkgo biloba extract +
                       raltegravir

Burack et al. (36)     Preparation of 31 Chinese
                       herbs

Colebunders            Assessed the use of anti-
et al. (4)             retrovirals, complementary or
                       alternative medicines

Djohan et al. (1)      Alternanthera pungens
                       (khaki weed) extract as drink/
                       tea; anti-oxidant containing
                       herbal extract); thrice weekly
                       or placebo

Duggan et al. (3)      Use of various herbal
                       medicines surveyed and
                       recorded

Han (15)               Four different TCM formulae
                       depending on presentation.

Hennessy et            St John's wort {Hypericum
al. (48)               perforatum)

Herrera-               Use of various herbal
Arellano et al. (9)    medicines surveyed and
                       recorded

Homsy et al. (11)      Herbal treatment according
                       to healers' prescriptions

Jandourek et           15ml Tea tree oil
al. (43)               (Melaleuca alternifolia) oral
                       solution four times daily

Jernewall et al (32)   Use of various herbal
                       medicines surveyed and
                       recorded

Jiang et al. (16)      Xiaomi granules([TEXT NOT REPRODUCIBLE
                       IN ASCII]: Glycyrrhiza glabra) ([TEXT NOT
                       REPRODUCIBLE IN ASCII])) Pinellia ternana,
                       Scutellaria baicalensis ([TEXT NOT
                       REPRODUCIBLE IN ASCII]) Codonopsis pilosula
                       ([TEXT NOT REPRODUCIBLE IN ASCII])

                       Coptis chinensis ([TEXT NOT REPRODUCIBLE
                       IN ASCII]) Astragalus membranaceus
                       ([TEXT NOT REPRODUCIBLE IN ASCII]), Coix
                       lacryma-jobi var. mayuen ([TEXT NOT
                       REPRODUCIBLE IN ASCII]), Lithospermum spp.
                       ([TEXT NOT REPRODUCIBLE IN ASCII]) Anticandine
                       (anti-candidiasis pharmaceutical)

Jiang et al. (35)      (T) Jingyuankang Capsule
                       ([TEXT NOT REPRODUCIBLE IN ASCII]
                       Panax ginseng(XM) Astragalus membranaceus
                       ([TEXT NOT REPRODUCIBLE IN ASCII])

                       Ligustrum lucidum ([TEXT NOT REPRODUCIBLE IN
                       ASCII]) Dioscorea opposita ([TEXT NOT
                       REPRODUCIBLE IN ASCII]) Rehmannia glutinosa
                       (root) ([TEXT NOT REPRODUCIBLE IN ASCII])
                       Ammomum sp fruit (MX) Epimedium sp. ([TEXT NOT
                       REPRODUCIBLE IN ASCII]) Angelica sinensis
                       ([TEXT NOT REPRODUCIBLE IN ASCII]) Leucogen
                       analog and HAART drugs (C) Leucogen(Leucogen)
                       and HAART drugs

Kisangau et            Various African herbal
al. (10)               medical species described.

Kusum et al. (37)      Glycyrrhiza glabra
                       Artemisia capillaris
                       Morus alba
                       Astragalus membranaceus
                       Carthamus tinctorius

Lee et al. (19)        300 mg zidovudine
                       orally before and after 2
                       weeks of treatment with
                       American ginseng (Panax
                       quinquefolius) extract 200
                       mg b.i.d.

Maek-a-                Jin Huang comprises of
nantawat et            Curcuma longa, artificial
al. (38)               Calculus bovis, Panax
                       notoginseng, Aucklandia
                       lappa, Rheum. officinale,
                       Fritillaria cirrhosa,
                       Borneolum Syntheticum

Maek-a-                CKBM-A01, a Chinese
nantawat et            herbal medicine formulation
al. (40)               composed of Panax ginseng
                       Schisandra
                       chinensis, Ziziphus jujube,
                       Crataegus pinnatifida,
                       Vigna radiata, Glycine max,
                       Saccharomyces cerevisiae,
                       apple, honey and water

Mbah et al. (41)       Acetone-water Azadirachta
                       indica (neem) leaf extract
                       (IRAB)

Molto et al. (47)      1500mg/d Echinacea
                       purpurea root and 400mg
                       etravirine.

Molto et al. (46)      1500mg/d Echinacea
                       purpurea root and 200mg
                       darunavir-ritonavir (protease
                       inhibitor)

Owen-Smith et          CAM (Chinese herbs,
al. (33)               mushrooms, garlic, ginseng
                       or algae or multivitamins or
                       religious/psychic health or
                       bodywork) use and HAART
                       adherence among HIV+
                       women

Sugimoto et            Herbal medicine
al. (20)

Tani et al. (18)       Chan Bai San--a formulation
                       of 30 herbs undefined

Tshibangu et           Traditional South African
al. (13)               herbal medicines undefined.

Vanlandingham          Bitter Cucumber (Momordica
et al. (12)            charantia) and other species
                       used
Vazquez et al. (42)    Alcohol-based or alcohol-
                       free Melaleuca alternifolia
                       oral solution

Walwyn et al. (34)     Various aqueous plant
                       extracts

Wang et al. (23)       Zhongyan-4 (ZY-4), a
                       Chinese herbal preparation

Weber et al. (22)      4 x 7 pills daily containing a
                       standardised preparation of
                       35 Chinese herbs (listed in
                       text above) versus placebo.

Wujisguleng et         Polygonatum macropodium,
al. (30)               P. cytonema, P filipes

Zhan et al. (28)       Qian-kun-Nin capsules
                       Coptis chinensis
                       Astragalus membranaceus,
                       Gardenia jasminoides,
                       Poria cocos, Sparganium
                       stoloniferum

Author                 Outcomes

Arjanova et al. (17)   Dzherelo had positive impact on the
                       TB drugs and it [down arrow] incidence of new
                       opportunistic infections

Blonk et al. (49)      Although there was marginal
                       increase in [C.sub.max] of raltegravir, it was
                       of minor significance.

Burack et al. (36)     Improvements in quality of life and
                       symptoms

                       No change in CD4+ count

Colebunders            Vitamins/minerals were most
et al. (4)             commonly used followed by
                       homeopathy and herbal products.
                       Complementary medicines are
                       commonly used despite availability
                       of pharmaceutical medicine.

Djohan et al. (1)      [down arrow] oxidative damage, [up arrow] T-
                       CD4 and CD8 lymphocytes (p<0.001)

                       No hepatic and renal toxicity in AP
                       group

Duggan et al. (3)      67% used CAM at some point of
                       time;
                       40% were receiving CAM at the time
                       of survey.
                       Exercise (43%) was the most common
                       CAM used followed by lifestyle
                       changes, dietary supplements,
                       counselling, herbal medications,
                       megavitamins, and prayer therapy.
                       74% used a protease inhibitor
                       medication, 15% used a protease
                       inhibitor sparing regime, and 11% had
                       no current or prior anti-retroviral use.
                       70% of the patients felt improvement
                       in QoL with CAM.

Han (15)               86.7% patients; [down arrow] virus loading;
                       [up arrow] CD4 T lymphocyte count.

Hennessy et            [up arrow] PgP expression (4.2 fold) from
al. (48)               baseline in SJW group, evidenced by
                       rhodamine efflux.
                       PgP efflux was inhibited in both
                       groups by Ritonavir (5 [micro]M).

Herrera-               29.7% using herbal medicine
Arellano et al. (9)    perceived benefit of quality of life

Homsy et al. (11)      Phase 1: HZ super-infection (18% vs.
                       42%, p < 0.02) and keloid formation
                       less common in herbal medicine vs.
                       control.

                       Phase 2: Faster pain resolution with
                       herbal patients vs. control.

Jandourek et           At 2 weeks: 7 improved, none were
al. (43)               cured and 5 were unchanged.
                       At 4 weeks: 8 responded (2 cured
                       and 6 improved), 4 did not respond.
                       7 patients showed mycological
                       response.

Jernewall et al (32)   80% reported to use CAM.
                       Asian CAM and herbal medicines
                       commonly used. Adherence to
                       pharmaceutical treatment was lower
                       in those using CAM.

Jiang et al. (16)      There was improvement in
                       symptoms of oral greasy-sticky,
                       thirsty, asthenia, abdominal
                       distension and anorexia in both
                       the groups. Oral greasy-stickiness,
                       thirsty and relapse rate were better in
                       xiaomi group vs. control group.

Jiang et al. (35)      JYK enhances leukocyte level as
                       effectively as Leucogen tablet (grade
                       I, II leukopenia), > Leucogen (grade
                       III leukopenia). NASE.
                       Note: both groups were on HAART

Kisangau et            Most common HIV-AIDS
al. (10)               opportunistic infections were TB and
                       oral candidiasis

Kusum et al. (37)      Reduction of plasma HIV-1 RNA [down arrow]
                       > 0.5 log (treatment) and follow up
                       period 4-10 (14.2-35.7%). Negative
                       response [up arrow] plasma HIV-1 RNA > 0.5
                       log were 2-4 (0-14.2%).
                       No [up arrow] CD4 cell count.

Lee et al. (19)        Ginsenoside does not alter the
                       pharmacokinetics of zidovudine.
                       [down arrow] oxidative stress biomarkers
                       (F2-isoprostane ratio = 0.79; 0.72-0.86;
                       p<.001; 8-hydroxy-deoxyguanosine
                       ratio = 0.74; 0.59-0.92; p=0.02).

Maek-a-                No changes to viral load or CD4
nantawat et            count
al. (38)
                       Adverse reactions; increased bowel
                       movements, vague taste.

Maek-a-                No significant changes in log viral
nantawat et            load or CD4 cell counts
al. (40)               Adverse reactions; intermittent
                       diarrhoea, skin rash/itching,
                       increased bowel movement

Mbah et al. (41)       50% had significant (159%) increase
                       in mean CD4 cells (p< 0.001).

Molto et al. (47)      Geometric Mean Ratio of etravirine
                       co-administered with E. purpurea =
                       1.07; safe for co-administration.

Molto et al. (46)      Herbal medicine co-administered
                       with darunavir- ritonavir resulted in
                       slight decrease in the concentration
                       of darunavir

Owen-Smith et          Women using CAM were 1.69 times
al. (33)               more likely to report missing HAART
                       doses

Sugimoto et            Significant improvement in mental
al. (20)               health but no effect on physical
                       health.

Tani et al. (18)       Improvement in CD4 counts,
                       mortality rates and quality of life.
                       Treatment showed positive results
                       after 1 to 3 years and dug resistant
                       HIV strains did not emerge

Tshibangu et           Anti-viral activity present
al. (13)

Vanlandingham          74% reported using allopathic
et al. (12)            medicine with 31% reported using
                       herbal treatments (3% overlap)
Vazquez et al. (42)    60% of patients showed clinical
                       response in 4 weeks.

Walwyn et al. (34)     Only 38% had received HIV-AIDS
                       related training

Wang et al. (23)       [up arrow] CD4 count (ZY-4) group (5%) vs. 24%
                       [down arrow] in placebo group. [up arrow]
                       CD(45) RA(+), & CD(8)(+) count, HIV virus load,
                       & [up arrow] b.w.

Weber et al. (22)      Adverse reactions; gastrointestinal
                       disturbances.
                       No sig. [down arrow] HIV-1 RNA level, PVL,
                       CD4 cell counts, psychometric
                       parameters.
                       Median CD4 cell counts ([down arrow] 0.05 x
                       [10.sup.9]/L); both groups.

Wujisguleng et         Eaten as salad, green tea ethanol
al. (30)               extract is used as adaptogen. In
                       TCM P odoratum reinforces "qi",
                       nourishing "yin" and moistening the
                       lungs, strengthening kidney and
                       spleen

Zhan et al. (28)       Sig. [down arrow] plasma virus load week 12 &
                       week 24, & >4 week after cessation
                       of treatment cf. baseline.
                       [up arrow] blood CD4 cell counts, & NASE
COPYRIGHT 2014 National Herbalists Association of Australia
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 2014 Gale, Cengage Learning. All rights reserved.

Article Details
Printer friendly Cite/link Email Feedback
Author:Cichello, Simon; Tegegne, Surafel Melaku; Yun, Hong
Publication:Australian Journal of Herbal Medicine
Article Type:Report
Geographic Code:8AUST
Date:Sep 1, 2014
Words:10767
Previous Article:Inhibition of the poliomyelitis viral--induced cytopathic effect by extracts of moringa oleifera Lam.
Next Article:Herbal medicine usage by paramedical students of Delta State University Abraka, Nigeria.
Topics:

Terms of use | Privacy policy | Copyright © 2019 Farlex, Inc. | Feedback | For webmasters