The philosophy behind the use of modern drugs against invading viruses is simple; they kill the organism. But a virus does not show all the qualities of a living organism until it invades the host cell. This means that viruses are difficult to inactivate chemically and usually require highly toxic agents to do so. 
Once a cell is infected it is difficult to selectively inhibit the virus without harming the cell. Viruses, especially HIV, can exhibit rapid rates of mutation and, through natural selection, are becoming better equipped at infecting host cells and evading immune destruction. This is why many drugs, in particular antibiotics, are becoming less effective. Like humans, plants are also subject to viral infections. It is possible that they have evolved effective and nontoxic antiviral metabolites. Even if this is not the case, the diversity of chemical compounds found in plants far exceeds the human imagination. It is likely that potent anti-viral agents (including ones that can battle HIV) already exist in the plant world, waiting to be discovered. Medicinal plants can also contribute to the fight against viral infections through enhancement of immunity - a vital, and often overlooked aspect of HIV therapy. Improving the immune system is an central aspect of herbal therapy which has no equal in other therapeutic modalities. This methodology forms the basis of the KM1 Herbal Formula trial. 
To date most of the information about the efficacy and safety of many complementary and alternative therapies has largely been generated from anecdotal reports or through the long history of traditional use associated with medical care conducted in the arena of herbal medicine. While the herbs to be used within the formula have by virtue of their long term experience in the clinic been reported to be effective in improving immune function, the combination of herbs in this group of people (people with AIDS) has not yet been explored. The KM1 Herbal Formula trial provides an opportunity to determine the limitations (if any) of the use of the herbal preparation. In particular it will provide important information as to the possible side effects that may arise out of using this treatment. Further, it will give some indication as to any limitations to the duration of use. The conducting of a trial in this manner provides a very strong precedent by providing results through a controlled and statistically invaluable study. In turn, this will also allow reproducible results that can be translated into clinical practice for all people with HIV and AIDS.  

THE AIMS OF THE STUDY  

• To evaluate the safety of a specific formula and dose of a herbal complex. 
• To evaluate the efficacy of a specific formula of a herbal formula when given as an oral preparation. 
• To compare the changes in surrogate markers of immune response (CD4/CD8 and CD4/CD8 ratios) in people continuing standard anti-HIV care and in people who include herbal preparation as treatment. 
• To compare the changes in markers of viral activity P24 antigen/antibody, liver function and urinalysis in people continuing standard anti-HIV care and in people who include herbal preparation as treatment. 
• To evaluate changes in quality of life scores in HIV positive people taking standard antiviral treatment plus or minus the inclusion of the specified herbal formula. 
• To evaluate the frequency and severity of adverse effects of the stated herbal preparation when taken alone or in combination with nucleoside analogues (AZT etc.) used as antiretroviral therapy. 

• Significant increases in CD4 cell counts can be achieved by including the stated herbal preparation in combination with standard forms of AZT/ddI or ddC in people who have had an AIDS diagnosis. 
• Significant improvements in quality of life measures can be achieved by including the stated herbal preparation as a treatment against people with AIDS. 

The herbs used within this study have had a history of use as traditional medications that help stimulate the immune system. 

Echinacea  
Echinacea is one of the most frequently prescribed herbal therapies. It is used as an immune system stimulant. It is considered to be particularly useful in terms of countering the effects of modern lifestyles that have placed the immune system under pressure. The roots of all three species have recently been studied and shown to possess immune enhancing properties in experimental models. These models measured the changes in phagocyte activity, since an increase in phagocytosis is thought to play a central role in immune stimulation1. Much of the use of Echinacea has stemmed from use as an antiviral and antibiotic by the native Indians of America for many centuries. By far the majority of scientific research has been conducted on the Echinacea purperea species, and usually this has been a fresh extract of the whole plant. This research was mostly conducted in Germany. Early research concentrated on its ability to inhibit the enzyme hyaluronidase2,3 which in turn would inhibit the spread of viruses and bacteria, and in conjunction with the observed proliferation of fibroblasts, to facilitate connective tissue regeneration. In other tests it is claimed that the administration of Echinacea purperea raise the proper din levels in humans4 and also to directly increase the levels of phagocyte activity5. In vitro experiments have shown an interferon like antiviral activity 6. Research in the 1980s isolated high molecular weight polysaccharides with pronounced immune stimulant activity 8 and this was thought to be the fundamental substance responsible for its activity. 

Eleutherococcus senticosus  
This is a deciduous herbaceous shrub that is native to eastern Russia, China, Korea and Japan. It is commonly known as Siberian ginseng. Although the use of this herb has been an important component of traditional Chinese herbal medicine, its potential against bacteria and the viral depletion of the immune system was first demonstrated by Russian researchers. The extract contains a diverse group of secondary metabolites known as the eleutherosides. Eleutherosides a, b, 'b1', c, d and e have been chemically isolated. In addition two triterpenois saponins have been found and are also thought to play a part in its biological activity. The observed activity of eleuthrococcus may be due to the combined effect of all of these constituents or it could be due to one only. This remains unclear. Several polysaccharides have been isolated from the root and have been thought to be an immune stimulant, but the exact activity is not well understood. One study however, has concluded that the eleutheroside e, a major constituent, was mainly responsible for increasing resistance to stress and fatigue. In the 1950s, Russian scientists became interested in substances which could improve general health and performance when the body was under stress. In their systematic search for cheaper and more abundant treatments they discovered eleuthrococcus as a substance that was able to increase the body's resistance to noxious influences including infection. Resistance to bacterial infection was shown to be increased in studies that were conducted on mice by prior dosing with eleuthrococcus. Antiviral immunity is also stimulated in animals as well as in the test tube, by administering eleuthrococcus extract. 

Hypericum perforatum (St. john's wort)  
Perhaps the most significant development in herbal treatments of viral infections is the discovery of the antiviral properties of hypericin and pseudo hypericin, which are the major components of St. john's wort. The discovery of non-toxic agents that are derived from the plant extracts and appear to be able to inactivate some viruses may be a promising prospect for the treatment of HIV illness. Considerable interest was generated in 1988 when a study was published which demonstrated that hypericin and pseudo hypericin have potent activity against retroviruses7. Several pharmacologic studies have been published and clinical trials using hypericin or the herb Hypericum have been conducted, with inconclusive results. However many practitioners have now included hypericin into the regimen of treatment against AIDS. Clinical observations reported in 1989 were supportive of the fact that some people appear to do very well when using this treatment and some demonstrated measurable increases in CD4 count8. Animal studies have shown hypericin has the ability to inactivate HIV and that it interferes with the assembly or processing of viral components by an infected cell, significantly decreasing the production of mature viral particles9. Further, there was some evidence to suggest that hypericin is synergistic with AZT in its antiviral activities when studied in animal models8. Other evidence has suggested that hypericin may also: Inhibit PKC (protein kinase complex) with hypericin having stronger activity than pseudohypericin. This suggests that inhibition of PKC may be involved in signal transduction inside the cell and that this in turn may be related to its antiviral effect 10; It has been shown that hypericin is only active against envelope viruses, suggesting that its affinity for lipids may somehow underlie its activity 11. 

Astragalus membranaceus  
This is a Chinese herb, also known as Huang Qi. The root has been mainly used to stop debilitating sweating and to promote healing and tissue repair. Research on animal and humans in China has shown a variety of actions on the immune system 12 and these include: 
1. Increases in phagocytic activity; 
2. Increases in levels of antibodies to the pathogen; 
3. Increases the activity of CD4 Natural Killer Cells (a part of the immune system); 
4. Counteracts the immunosupressive effects of cortisone. 
However many suggest that the antiviral activity of Astragalus is most likely due to increased immunity and natural interferon production. It has been shown to protect mice against parainfluenza virus infection and augments interferon response to viral infection. Astragalus has also been shown to protect against Coxsackie B virus both in test tube and animal studies 12. In clinical studies a prophylactic effect against the common cold was found with a decreased incidence or a shortened duration of infection when compared to a control group12. In other studies patients with low white blood cell counts responded to treatment with Astragalus and cases of chronic persistent hepatitis showed an 86% response rate 12. In summary, Astragalus may be a potentially useful treatment against HIsince reports have indicated it to have properties of being an immune system stimulant. 

Dosage  
The herbs will be dispensed as a herbal formula within a 200 mL amber bottle and the bottles will be clearly labelled with instructions for use. The placebo mixture will look & taste identical to the herbal formula except for different numbers. Dosages of individual herbs have been based upon traditional usage and from other clinical trials. 

The TGA regards all four herbs as safe to use and they are found in many over the counter preparations sold in Australian pharmacies and Health Food specialists. They are also widely used by practitioners. 

The Hypericum preparation is standardised to contain 0.4 mg of total hypericin per mL, since this group of compounds is considered to be the potential antiviral agent. The Eleutherococcus is standardised for eleutheroside E and the daily dose will deliver a dose of eleutheroside E of 1.5 mg. The dosage of the combined formula is within the range normally used in herbal therapy. 

Adverse Reactions  
The side effects of the herbal preparations as per this formula are not fully known but reports have included: 
1. Tingling sensation on tongue; 
2. Bitter taste; 
3. Mild insomnia. 
Beyond this point we do not anticipate serious problems due to the free availability. Any individual who exhibits adverse reactions will be offered the possibility of withdrawing from the study. In all cases where a serious opportunistic illness is shown to exhibit symptoms, the participant will be withdrawn from the study to be treated in an appropriate manner. The overall risks of the study are considered minimal. 

The Formula is manufactured by Mediherb, who are licensed by the Therapeutic Goods Administration to manufacture herbal products for therapeutic use. Mediherb holds license no 47674. Compliance with the code of Good Manufacturing is rated by the TGA as high. 

To date a number of reports have indicated that the use of these preparations may have an impact on either the activity of HIV or act as immune modulators. The use of a combination of these agents may provide the clearest picture yet as to the efficacy of these agents and indeed whether individually or collectively they should be studied in greater depth. 

REFERENCES  
1. Bauer R et al, Arzeneim - forsche:38: 276 1988. 2. Koch E. and Haase H Arzeneim - forsche 2 464 (1952). 3. Busing K.H. Ibid :2:467 (1952). 4. Reissmann G Fol Haemat 85: 125 (1966). 5. Muse J.B. Med Welt p1463 (1983). 6. Wagner H et al Planta Med p 139. 7. Meruelo D et al. Proc. Nat. Acad. Sci. 85:5230 (1988) . 8. James J. AIDS Treatment News 74:1 (1989). 9. Lavie G et al, Proc Nat. Acad. Sci 86:5963 (1989). 10. Tamaoki T. et al. The Biology of Medicine of Signal Transduction Raven Press, 1990. 11. Tang J. et al Antiviral Res 13:313 (1990). 12. Chang H and But P.P. Pharmacology and Applications of Chinese Materia Mediaca. Vol. 2 World Scientific Publishing Co., 1987.