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by Hananja Brice-Ytsma Medical Herbalist (MSc, MNIMH) http://creativecommons.org/licenses/by-nc-nd/2.0/uk/ HIV and herbal medicine The introduction of highly active antiretrovital therapy (HAART) into clinical practice has dramatically changed the development of HIV-related diseases in industrialised countries (Vella 2000) but HIV infection still remains an incurable disease (Wei et al 1995). HAART alone cannot eradicate the virus in the human body (Finzi et al). Drug resistance is probably the most important factor contributing to the failure of treatment today (Richman D 1997). The antiretrovirals have an impact on reducing morbidity and mortality, prolonging lives, improving the quality of life of many people living with HIV (WHO 2002). Many people in developing countries cannot afford the high cost of HAART (Asres et al 2005), it has a limited response in some patients, it has a complicated dosage regimen leading to non-compliance, and is associated with drug toxicity and the emergence of drug resistance (Bonfanti et al 1999). The majority of people living with HIV are using complementary medicine (Ozsoy 1999). In Europe herbal treatments have been the most popular complementary medicine used by HIV infected individuals (Ozsoy 1999). Research has been carried out and is in progress to isolate the active constituents from plants for the prevention of transmission of HIV and treatment of AIDS (Asres et all 2005). Many plants are active against HIV replication at least in vitro, whose significance is not yet clear, and have not been followed up to see their actual clinical usefulness in combating HIV/AIDS(De Clercq 2000). Being a relatively new disease there is no tradition of herbs used for HIV/AIDS. So is there any clinical evidence for use of herbal medicine in HIV positive patients?
Panax ginseng (Korean Red Ginseng KRG)
Panax ginseng is an herbal root that has been known in China for more than 2000 years (Li et al 1973). A study in healthy human volunteers revealed that KRG significantly increases neutrophil, CD4 T cells and NK cell function (Scallione et al 1990). Ginseng was found to increase the cellular immune functions of peripheral blood mononuclear (PBMC) from AIDS patients and normal individuals (See et al 1997). KRG was given for 6 months to HIV-1 infected individuals (5.4mg daily), CD4T cell counts in HIV-1-infected patients treated with only KRG were maintained or even increased for a prolonged period. The development of resistance mutations in RT to zidovudine (ZDV) was delayed by combined therapy with KRG and ZDV (Cho et al 1993). Some of those patients have maintained CD4+ count for 8 years with KRG-intake only (Cho et al 2001). It was suggested that the maintenance of CD4T cell counts by ZDV and KRG intake for a prolonged period might be indirectly associated with delayed development of resistance to ZDV by KRG intake (Cho et al 2001). No details are given on the trial itself, the number of patients involved, the stage of disease, no control, so we cannot draw any conclusion of the above but the initial observation led to the following study done by the same authors. A study investigated whether the maintenance of CD4+ T cell count in HIV1-infected patients treated with ZDV and KRG is associated with the delay of the development of resistance to ZDV (Cho et al 2001). Nine of the 18 pt were in the KRG group, daily dose of 5.4g, and had been treated with KRG for 60 months and ZDV
for more than 18 months, nine were in the control group and been treated with ZDV only. KRG intake was the only significant variable between the two groups. There was no significant difference in clinical stages and demographics between the KRG group and the control group. Maintenance or increase in CD4+ T cell counts in patients treated with KRG was found. Mild but consistent decrease in p24 antigen during KRG-intake was also detected as long as KRG was taken. In Combination with ZDV, the beneficial effects associated with KRG-intake were a decrease in CD4+ T cell count was not detected during at least a few years of therapy. Based on these observations, the authors concluded that KRG intake itself is likely to have beneficial effects in HIV patients. Over the 24 months of treatment, the overall incidence of 6 resistance mutations to ZDV was significantly reduced in the KRG group. The authors conclude that the maintenance of CD4+ T cell counts by ZDV and KRG-intake for a prolonged period might be indirectly associated with delayed development of resistance to ZDV by KRG-intake. The authors recommend KRG intake as early stage as possible to get good prognosis over a long term. The number in this study is very small but well accounted for. There was a significant time scale used. Individuals respond different to the virus and cofactors could lead to earlier development of AIDS. Being such a small number it is difficult to say how valid and reliable the measurements were. The patients and investigators were not blinded. No side effects were reported. The data suggests that the combination of antiretroviral drugs with KRG could be a new therapeutic modality to treat HIV-1 infected patients but larger trials are needed. KRG was tested with ZDV so we cannot draw a conclusion on the combination of other antiretroviral drugs with KRG and that would need to be investigated. Another original study was done to investigate whether this slow progression or maintenance of CD4 T cell over 10 years was affected by KRG intake alone or in combination with HLA factor (Sung et al 2004). Many patients have maintained their CD4 T cell counts for more than 10 years without antiretroviral drugs therapy and prognosis of HIV-1 infected patients has been found to be strongly associated with their HLA alleles. They determined HLA class I in 90 HIV-1 infected patients diagnosed from 1987 to 2001. They were randomly recruited nation-wide however, it is not stated how. At enrolment the patients were asked to return for an interview and for clinical examination and a blood sample every 6 months. Estimating the rate of progression of HIV-1 infection was accomplished by measuring the annual decrease in CD4 T cells. The HLA results were compared with those of a control group, which was comprised of 199 uninfected Korean people drawn for the population. 22 patients were treated with antiretroviral drugs or were monitored for less than 60 months. Changes in the CD4 T cells and correlation among KRG intake, CD4-Tcells and HLA were finally analysed in the 68 out of 90 patients. The median follow up time in the 68 pt was 113.5 months (range 60-164 months. 61 out of the 68 pt were treated with KRG (5.4g per day). A strong correlation was found between KRG intake and annual decrease in CD4 T cells, and between KRG intake and sCD8, together with a significant inverse correlation between HLA prognostic score and annual decrease in CD4 cells. In addition they found that KRG intake alone slows the decrease in CD4 T cells irrespective of HLA prognostic score. Also, a significant decrease in serum sCD8 was found which is an immune activation marker physiologically secreted from CD8T cells. The significant and consistent decrease in serum sCD8 was maintained as long as KRG was taken continuously. Thus the decrease in serum sCD8 may be indicative of a lower level of destruction of CD8 T cells in patients ingesting KRG and suggests that KRG intake is associated with prolonged maintenance of enhanced CD8T lymphocyte activity. The authors concluded that KRG intake independently has beneficial effects on the slow decrease in CD4 T cells and on serum sCD8 levels in HIV- infected patients, although the HLA factor was also significantly associated with the rate of CD4 T cell depletion in the Korean population. The population studied was small, and only seven were not taking KRG, but over a significant amount of time, no side effects are mentioned, patients and
investigators were not blinded so open to systematic bias. To say if the measurements were valid, reliable, and reproducible, one might need a larger group. The paper could point to possible use of KRG, but is difficult to conclude without more rigorous trials. Hypericum perforatum (HP); St John's Wort Hypericum perforatum (HP); St John’s Wort Hypericin or HP is taken commonly by HIV-infected persons (Kassler et al 1991). Hypericin has activity against many HIV in vitro Hudson et al 1991). In 1989 researchers found that two extracts of HP had anti-HIV activity in lab experiments with cells and viruses. Since hypericin is known to exhibit a similar inhibitory property, it is likely to be one of the active constituents of St Johns wort (Taher et al 2002). Hypericin appears to inactivate free virions and interfere with steps in the replicative cycle (Hudson 1991). Hypericin and pseudohypericin display an extremely effective antiviral activity when administered to mice after retroviral infection (Muerelo et al 1988). It was found that relatively small doses of hypericin or pseudohypericin 10-50ug per mouse can prolong survival of HIV infected mice. When the compounds interact with the infection particles shortly after in vivo administration, disease is completely prevented. The compounds can cross the blood-brain barrier (Meruela et al 1988). Initial studies looked promising (James 1989). An uncontrolled study of 26 pt self-administering Hypericum containing herbal extract (Cooper and James 1990) concomitant, used AZT, and other treatment was permitted. All patients were HIV positive, at various stages of the disease, and were taking approximately 1 mg total hypericin per day. They received baseline and 4 monthly checks, including physical examinations, T-cell subsets and p24 antigen. Toxicity was limited to mild reversible liver enzyme elevation in 5 patients, with levels returning to baseline after 1 month without Hypericum. At the end of the 4month study, p24 antigenaemia disappeared in 2 of 6 initially positive patients, both also using AZT. CD4 cell changes differed, depending on AZT usage, in the subgroup of 10 pt who had never taken AZT, none had developed AIDs, the mean CD4 count increased 13% from the base line after 1 month of Hypericum and maintained this increase for 4 months. These increases were not statistically significant. By contrast however, in those using Hypericum and AZT throughout the study, CD4 counts fell significantly after initial mild rise. Details of the patients are minimal and there was no control group; size sample was small and duration short. So, again, a study might not have any significance, however this is the first pointer towards that hp might interfere with the anitiviral AZT and as a consequence lower CD4 count. A study was carried out to assess the toxicity and possible anti-HIV activity of hypericin; there was no CD4 count criteria for entry (Fumer et al 1991). Four different daily dosage levels of hypericin were administered (0.5mg, 2mg, 4mg, 8mg) to cohorts, often HIV-infected men, all HIV positive, no details of what stage of disease, for a period of 12 weeks. No indication is given on the baseline differences between the different groups. Possibly observed toxicities included mild diarrhoea and indigestion, and infrequent itchy rash, and fatigue or depression. An idiosyncratic, reversible elevation of hepatic transaminases was also observed. No early, marked anti-HIV activity was found. The authors concluded that at doses of 2mg per day given to HIV infected individuals, hypericin appears to be safe for the majority of subjects observed so far (Moraleda et al 1993). Duration of treatment was 12 weeks, which might be too short to notice any beneficial effects. However the conclusion that 2 mg was a safe dose for the majority of patients is important to look at.
An open clinical trial with (Steinbeck-Klose and Wernet 1993) 16 HIV patients at various stages of the disease process were treated solely with Hypericum. No statement on recruitment, inclusion or exclusion criteria, and no control group. Standardised extract, 0.8mg total hypericin per week, plus 6 tablets of unspecified strength. Patients showed stable or increasing counts of absolute CD4 values for helper T cells over the 40 months of observation. A significant length of treatment compared to the other trial. This trend was not dependent on the levels of the absolute CD4 count at the beginning of Hypericum treatment. Only 2 of the 16 encountered an opportunistic infection during the 40 months. The other 14 pt remained clinically stable and are active in work and life with a karnoviski-index of 100 (a validated form of measurement). This correlated to the stable values of haemoglobin, leukocytes and platelets. None of the known viral complications due to cytomegalovirus, herpes or Epstein-Barr virus were encountered. No side effects, including photosensitivity, were seen or measured in any of the patients. With such as small study, and the many variables, one cannot conclude any more than that it is of interest, and should be investigated in a more rigorous study. Hypericin can cause moderate to severe phototoxicity in people with HIV. In a phase 1 trial (Gullick et al 1999), the researchers examined the safety and antiviral activity of oral and intravenous hypericin in 30 HIV-positive patients with fewer than 350 CD4+ cells/mm3. Subjects were excluded if they had significant medical illnesses or were taking medication within 1 month of study entry. The study was done in four clinical research units, open label, dose-escalation study of intravenous or oral hypericin. 30 Patients enrolled in to three cohorts, that received intravenous hypericin and one cohort that received oral hypericin. Groups received 0.25 or 0.5mg/kg twice weekly or 0.25mg three times a week intravenously. The oral dose of hypericin was 0.5mg/kg per day (n3). During the trial newly observed toxic effects were observed and a scale for phototoxicity was implemented. The drug used was synthesised by a pharmaceutical company, pure hypericin. None finished the trial because of moderate or severe phototoxicity. They concluded that 0.25mg/kg as the maximum tolerated dose for twice weekly intravenous administration. The toxic reaction was an erythematous rash associated with painful dysesthesias that involved areas exposed to light, consistent with a cutaneous phototoxic reaction. This reaction resolved after discontinuation of hypericin therapy. No clear evidence of antiretroviral activity was observed. The authors concluded Hypericin therapy induced serious cutaneous phototoxicity and lacked demonstrable antiretroviral activity at the doses tested in the study. They also stated that these findings raised concerns about the safety of hypericin, which is available as an herbal preparation and commonly used by HIV-infected patients. They do however say that previous studies of hypericin and Hypericum in both HIV-infected and non-HIV infected patients noted a relative lack of side effects, although the doses were lower and the preparations were less pure than those used in their study. In fact, the doses used are extremely high and near to impossible to achieve when using the whole herb. Hypericin was synthesised by a pharmaceutical company as opposed to coming from the plant itself, and when tried on animals the herb was used. There might be other constituents in the plant contributing to antiviral activity and this should be investigated. What has become clear is that synthesised high doses of hypericin leads to severe phototoxicity, and has no clear effect on the virus. Average doses of hypericin in previous trials were between 1-2mg of hypericin per day. One or the above studies concluded not to give more than 2 mg per day. The dose of hypericin described here is much higher (5-10x). Interaction with antivirals St.John’s wort affects the activity of certain enzymes in the liver and intestines that are used to process the following groups of HIV drugs (protease inhibitors
and non-nucleoside reverse transcriptase inhibitors), speeding the process up and reducing the levels of these anti-HIV drugs to less than ideal levels (Piscitelli et al 2000). In such situations, it is relatively easy for HIV to become resistant to these drugs. Over time this can lead to increased levels of virus in the blood and falling levels of immune system cells and, perhaps, life-threatening infections. According to one study the use of HP can cause significant decrease in indinavir levels in the blood, ranging from 49-99%, in addition to reducing the efficacy of indinavir, such a large drop in the drug’s level may increase the risk of resistance (Piscitelli et all 2000). Doctors have found that HP can reduce levels of nevirapine a non-nuke nevirapine. Conclusion All the above studies are extremely small, and there was a loss of interest once it became apparent that HP cannot be given together with antivirals. However there might still be a role for HP when patients are not on antiviral. KRG could be of benefit, but needs to be investigated with other antivirals. Outcome studies examining the efficacy of herbal medicine among people living with HIV-AIDS are often conducted among small sample sizes with very little follow-up data or time points. It is difficult to conduct clinical studies in chronically ill patients without participants dropping out, typically because studies’ demands, coupled with their illness, become too burdensome. Small trials may cause random error for both positive and negative findings, the treatment duration is not long enough for endpoint outcomes such as mortality or new aids related events. Many studies with small sample sizes reported trends, but did not find statistical significance. Increasing sample sizes in further studies is necessary in order to evaluate the scientific merit of these trends (Power et al 2002). Future trials of herbal medicine should be large and should take into account the clinical outcomes, such as progression to AIDS or AIDS-related illness and quality of life, using longitudinal, controlled designs to accurately assess the safety of such interventions (Power et al 2002). Since studies have demonstrated the relationship between plasma HIV RNA loads, CD4 cell counts, and disease progression in HIV infection, these need to be included. Compatibility and drugs interaction of any sort with conventional antiretrovirals and other drugs commonly administered to AIDS patients should be studied. Many of the anti-HIV natural products have other medicinal values; these types of compounds may also be of interest as they can deal with both the virus and the various disorders that characterise HIV/AIDS.
<a rel="license" href="http://creativecommons.org/licenses/by-nc-nd/2.0/uk/"><img alt="Creative Commons License" style="border-width:0" src="http://i.creativecommons.org/l/by-nc-nd/2.0/uk/88x31.png" /></a><br />This <span xmlns:dc="http://purl.org/dc/elements/1.1/" href="http://purl.org/dc/dcmitype/Text" rel="dc:type">work</span> by <span xmlns:cc="http://creativecommons.org/ns#" property="cc:attributionName">Hananja Brice-Ytsma (MNIMH, MSc)</span> is licensed under a <a rel="license" href="http://creativecommons.org/licenses/by-nc-nd/2.0/uk/">Creative Commons Attribution-Non-Commercial-No Derivative Works 2.0 UK: England & Wales License</a>. references http://creativecommons.org/licenses/by-nc-nd/2.0/uk/ Arris 1997 Against death: The practice of living with AIDS. Australia: Gordone &
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