In 2003, I interviewed Alfred Plechner DVM on his theories and protocols for normalizing endocrine (hypothalamus, pituitary and adrenal) [HPA] and thyroid hormones to normalize immune function in animals with chronic immune dysfunction such as cats with FIV (feline immune deficiency) and pets with allergies, cancer, fatigue and other chronic conditions. Most of this interview is published in two chapters in the "Immune Restoration Handbook."
To recap Plechner's theories, a defect in the Adrenal Cortex limits the amount of cortisol it can produce. Under stimulation from ACTH produced by the Pituitary, Plechner theorized that this causes the Adrenal glands to produce estrogen from the middle adrenal cortex when the adrenals are unable to produce more cortisol. Plechner states that the excess estrogen levels then impairs immune function.
Over a period of several decades, Plechner reports he has successfully treated over 30,000 pets by using a low-dose of thyroid in combination with low-dose cortisol. He has observed improvements in the health and conditions of these animals and frequent remissions of their illnesses. Many aspects of Plechner's work are corroborated by other researchers but the link of immune dysfunction to elevated estrogen levels is not conclusive and has inconsistencies.
For example, I have talked to many persons who have chronic fatigue syndrome and/or multiple food allergies that actually have low rather than high estrogen levels. A search of the scientific literature fails to link elevated estrogen to immune dysregulation such as a predominance of TH2 cytokines (interluken 4, 5 6 and 10) with IL6 being the most consistent and problematic of the TH2 cytokines. In cancer and AIDS, there is substantial research linking high levels of IL-6 and tumor necrosis factor (TNF) to wasting syndrome and HIV progression to AIDS.
In candidiasis, chronic insomnia and CFIDS, elevated plasma levels of IL6 have been widely and consistently reported for several years. Elevated IL-6 is linked to increased replication of HIV, HHV-6, CMV, EBV, herpes and other viruses.
Today, in TV ads to sell new weight loss products (Cortislim Relacore etc), cortisol produced for protective effects from stress is being portrayed as the cause of obesity. The causes of obesity are really complex and involve food allergies and sensitivities along with overeating, liver toxicity, insulin resistance, low levels of serotonin and lack of exercise among other things.
Cortisol has a reputation for being immunosuppressive. Why would anyone with Candidiasis, Cancer, HIV/AIDS, allergies, rheumatism and CFIDS want to use low-dose hydrocortisone or "Cortef"??? Why?
The answer is that like a teeter-totter, the TH1 arm of the immune system is on one side and the TH2 is on the other. When the TH2 arm is over-active, it depresses the TH1 arm. Lowering the TH2 arm of the immune system raises the TH1 arm. In the middle is, in theory, the TH3 balance point with TH3 being the digestive tract. When food allergies and sensitivities develop and a person develops leaky gut syndrome, these conditions will lead to inflammatory reactions by increasing IL-6 and antibody production.
IL-6 is an essential TH2 cytokine needed to support the function of humoral immunity ‚ particularly antibody production, although researchers have reported neuroprotective effects as well. The problem of imbalance occurs when levels of IL-6 do not return to normal and as a result depresses TH1 cytokine function. Several factors appear to contribute to elevated interleukin-6. They are:
1. Chronic infections
2. Chronic oxidative stress and free radicals
4. Toxins in food, water, air and environment
5. Stress from multiple causes ‚ noise, strenuous exercise as in weight lifting, emotional and electromagnetic pollution (microwave, cell phone relay towers, violence on television and movies, rapid scene changes on TVs and computers without EMF blocker screens etc).
Researchers have found that in acute stress, both cortisol and IL-6 levels increase. With lower levels of stress, cortisol and other glucocorticoids reduce IL-6 secretion. IL-6 has been found to stimulate the pituitary to release ACTH, the hormone that then stimulates the adrenals to produce more cortisol. Over time, the body has evolved a unique set of checks and balances to control the effects of stress and immune challenges. It is now very evident that proinflammatory cytokines like TNF and IL-6 influence the functioning of the HPA (Hypothalamus, Pituitary and Adrenal) axis.
There are several components to any successful program to balance the immune system including a hyper allergenic diet and anti-inflammatory supplements including cortisol have a supportive role.
By helping to normalize IL-6 levels, low-dose cortisol along with low dose thyroid therapy has many benefits to offer. Besides reduced food allergies and chemical sensitivities, these benefits include reduced replication of HIV, candidiasis, CMV, HHV-6, CMV, EBV, herpes, less fatigue during the day and more restful sleep at night along with improvements in Natural Killer cell function and macrophage function.
Now, I am about to show you through published scientific research that one of the main side effects of low levels of free cortisol and adrenal exhaustion is elevated levels of interleukin 6. In so doing, I propose that it is elevated IL-6, not estrogen, that was the primary cause of immune dysfunction in Plechner's 30,000 pets that he successfully treated with low dose thyroid and cortisol. The correct use of low dose cortisol may also help restore normal circadian cycles of cortisol (high in the morning and low at night) essential to restore normal sleep patterns.
The use of low-dose cortisol would probably not be needed if we learned how to get the liver to convert cortisone (the inactive form) to the active form of cortisol. In immune-compromised patients, levels of bound cortisol ( called cortisone) will sometimes be high while levels of free cortisol - the active form - will be low. In persons under the stress of chronic infections, the need for free cortisol will be higher than in the normal population. Normal or lower cortisol levels should not necessarily be considered good news for this group while elevated cortisol levels should not necessarily be considered bad news.
An important test is to measure for plasma levels of IL-6. Ask your physician for a "TH2 cytokine panel test." This test will measure IL-6 and other TH2 type cytokines.
Cortisol supplementation can be given and then adjusted up or down to bring IL-6 levels back to the normal reference range which is a desirable goal and will have wide range benefits and symptomatic relief for many chronic conditions of inflammation. There are also several other supplements (i.e. fish oil, some anti-oxidants etc) and other dietary factors that can increase free cortisol levels and help return IL-6 to normal reference ranges.
Geneva, Italy. J. Rheumatology.
Cutolo M et al from the University of Genoa in Italy report in the J Rheumatology April 29, 2002 on a 12 month study involving 41 patients recently diagnosed with polymyalgia rheumatica (PMR). Basically this is a form of rheumatism associated with muscle pain. Patients were monitored for serum cortisol levels, DHEA, androstenedione and IL-6 concentrations at baseline and after 1, 3, 6, 9 and 12 months of glucocorticoid treatment.
They report that "serum concentrations of IL-6 at baseline were significantly higher in PMR patients than in controls. During 12 months of glucocorticoid treatment IL-6 levels dropped significantly at one month; thereafter they remained stable and did not increase again despite tapering of the glucocorticoid dose."
They concluded: "This study found reduced production of adrenal hormones (cortisol, DHEAS) at baseline in patients with active and untreated PMR. The defect seems mainly related to altered adrenal responsiveness to the ACTH stimulation (i.e. increased 17-OHP), at least in untreated patients. The 12 month glucocorticoid treatment of patients reduced the production of inflammatory mediators (i.e. IL-6) in a stable manner that persisted after glucocorticoids were tapered off."
This study validates the use of low-dose anti-inflammatory steroids (cortisol etc) long-term to down regulate an over active TH2 cytokine (i.e. IL-6). Researchers have also found that in humans, injections of IL-6 increases ACTH secretion, but more so in males than in females (1) Since ACTH stimulates the adrenals to produce more cortisol, the use of low-dose cortisol to reduce IL-6 ultimately reduces ACTH that in turn reduces the signals to the Adrenals to produce more cortisol. Thus the HPA axis comes back into balance and helps to restore a normal 24-hour hormonal and cytokine cycle.
1. Differential male and female adrenalä. cortisol responses to interleuken-6 in humans. Silva C et al.; ANN NY Acad Sci 2002 Jun;966:68-72
Straub RH et al report in March 2002 (1)
Straub et al reported that the number of swollen joints correlated inversely with the ratio of serum cortisol to serum IL-6 in rheumatoid arthritis patients. In rheumatoid arthritis and reactive arthritis patients, they found lower levels of ACTH, cortisol, ASD, DHEAS, and 17-OH-progesterone in relation to levels of IL-6 and TNF (tumor necrosis factor). They concluded that the level of cortisol and ACTH are relatively low in relation to levels of IL-6 and TNF in untreated patients with early rheumatoid arthritis and reactive arthritis.
1. Arthritis Rheum, 2002 Mar;46(3): 654-62
Post Traumatic Stress Disorder or PTSD was first brought to my attention after the Vietnam War although media reports state it was first diagnosed after World War II. Interrupted sleep, fatigue, nightmares and uncontrolled nervous reactions to loud noises that bring back reactions to the trauma of past combat experiences are some of the symptoms.
According to an article published in "Neuroimmunomodulation" in 2001 by Baker SDG et al, at the University of Cincinnati College of Medicine, Baker et al report that "Interluken-6 (IL-6) secretion is suppressed by glucocorticoids and stimulated by catecholamines. Patients with PTSD have decreased cortisol and increased catecholamine secretion."
In a study that measured the IL-6 and norepinephrine levels in the Cerebrospinal fluid of PTSD patients vs. healthy controls, the researchers found that "PTSD patients had increased concentrations of IL-6 in their Cerebrospinal fluid." They report that low cortisol secretion in patients with PTSD may account for the elevated IL-6 secretion.
Chronic fatigue syndrome most likely is associated with defects in the hypothalamus, pituitary and adrenal glands or HPA axis. This could involve overactive B cells that produce cytokines (TH2 types ‚ IL-4, 5 6 and 10) and antibodies that are not effective against infections and inflammatory conditions. The cytokines may contribute to daytime fatigue.
Vgontzas An et al report in the journal of "Metabolism" (1) "interluken-6 and tumor necrosis factor are fatigue-inducing cytokines, and the daytime secretion of IL-6 is negatively influenced by the quantity and quality of the previous night's sleep."
The researchers hypothesized that fatigue during the day is caused by increased secretion of IL-6 and tumor necrosis factor (TNF) during the daytime hours. Eleven insomniacs and 11 healthy controls were matched for this study. Patients were tested for 4 days in a sleep laboratory and on the 4th day, plasma levels of IL-6 and TNF were taken during the 24-hour period.
The authors concluded "that chronic insomnia is associated with a shift of IL-6 and TNF secretion from nighttime to daytime, which may explain daytime fatigue." At the same time, the pituitary continues to pump out ACTH that stimulates the adrenals to produce more cortisol until the adrenals become exhausted and are unable to keep up with demand.
1. Chronic insomnia is associated with a shift of inteulukin-6 and tumor necrosis factor secretion from nighttime to daytime. Vgontzas An et al, Metabolism, 2002 Jul;51(7):887-92
Barber MD et al reporting in Nutr Cancer. 2001;40(2):118-24 from Edinburgh, UK that nutritional supplements with fish oil given to pancreatic cancer patients who were losing weight resulted in weight gain. In this study, 20 patients who were wasting away were asked to consume daily a 600-calorie nutritional supplement that contained 2 grams of EPA (eicosapentaenoic acid) derived from fish oil. After 3 weeks of consumption of the fish oil-enriched supplement, they reported "a significant fall in production of IL-6, a rise in serum insulin concentration and a fall in the proportion of patients excreting proteolysis inducing factor." These blood parameter changes were associated with a median weight gain of 1 kg per patient. They stated, "Various mediators of catabolism in cachexia are modulated by administration of a fish oil-enriched nutritional supplement in pancreatic cancer patients. This may account for the reversal of weight loss in patients consuming this supplement."
Note: If using "EPActive" by Jarrow Formulas, it would take 10 capsules daily to reach the level of 2000 mg of EPA (eicosapentaenoic acid).
In an article titled "The Traditional Diet of Greece and Cancer" Simopoulos AP (1) writes that the diet on the island of Crete represents the traditional "Mediterranean diet" prior to 1960. Analysis of the diet shows a number of protective substances including selenium, glutathione, high fiber and antioxidants and Resveratrol from red wine and polyphenols from olive oil and a balanced ratio of omega 6 and omega 3 fatty acids. The Omega 3 (DHA and EPA) fatty acids from fish "exert protective effects against some common cancers, especially cancer of the breast, colon and prostate." The Omega 3 fatty acids suppress "Cox-2, IL-1 and IL-6 gene expression." Other Cox-2 inhibitors (Pharmaceutical or botanical) may also inhibit IL-6.
Note: Cox 2 inhibitors are widely marketed for treatment of arthritis and rheumatoid arthritis.
Treble T et al (2) reports that tumor necrosis factor and Il-6 decreased with dietary fish oil supplementation in healthy men in a dose dependent manner.
In an article published in the Br J Nutr by Wallace FA. Miles and Calder titled "Comparison of the effects of linseed oil and different doses of fish oil on mononuclear cell function in healthy human subjects" the authors report on 3 types of Omega 3 fatty acids and their effects. In Linseed oil also known as flaxseed oil that is high in alpha-linolenic acid, they reported an increase in EPA but not DHA in plasma phospholipids. With fish oil (DHA and EPA) they reported a decrease in IL-6 in a daily dose between .44 and .94 grams daily. That would be 440 to 940 mg daily in healthy adults. It is important to remember that this dose was in a population of healthy adults, not a group of seriously immune compromised patients.
In the study with patients with pancreatic cancer, 2000 mg of EPA was used daily. However, I have read research that both DHA and EPA have similar anti-inflammatory effects and reduce IL-6, (Note: The "Max DHA" product from Jarrow Formulas will provide 2088 mg of DHA/EPA at about 6 capsules daily or 3 twice a day).
It takes about 3600 mg of sardine oil to yield around 2088 mg of a mixture of DHA/EPA and other Omega 3 fatty acids. Six capsules of Jarrow Formula DHA/EPA will yield that exact amount. Based on published research, that level of supplementation should reduce IL-6 plasma concentrations within a few weeks and bring a noticeable improvement in symptoms.
Note: Avoid taking rancid fish oil or rancid flaxseed oil as these can have the opposite effect of actually increasing IL-6 levels. Buying the lowest priced fish oil supplements on the market from mass merchandisers could be detrimental to your health. Fish oil should always be sealed in a dark capsule that prevents entrance of light or sealed in a can (canned sardines are good choice). Also avoid cod liver oil that is bottled in a clear bottle that allows light in and sits on a store shelf. Avoid all fish oil capsules that are "clear." The capsules must be brown or black in color to prevent the entrance of light and prevent rancidity from forming while on the shelf.
Never use flax oil or fish oil that has been long exposed to either light or oxygen (example ‚ a nutritional bar that sits on a store shelf with either flax oil or deodorized sardine oil added should be considered rancid and avoided).
You can tell rancidity by the taste. If it has a fresh taste it is not rancid. If it tastes bitter, sour or flat, it may be rancid or going in that direction. Freezing or refrigeration helps prolong the shelf life of all oils.
Okayama, Japan. Kohno K et al report (1) that when supernatants of Royal Jelly, the food of the Queen Bee, were added to a culture of mouse peritoneal macrophages that were stimulated with lipopolysaccharide, the production of proinflammatory cytokines such as TNF-alpha and IL-6 were efficiently inhibited in a dose-dependent manner without having cytotoxic effects on the macrophages. Macrophages are a type of white blood cell that fight infections in the body. The factors that had this effect in Royal Jelly were not identified and the dose was not mentioned in the abstract. Based on other research, a dose of 1000 to 2000 mg daily should be a good starting point.
My own opinion is that the least processed Royal Jelly is likely to have the most benefits (i.e. fresh Royal Jelly rather than freeze dried). Royal
Jelly should to be kept under refrigeration or sealed in opaque (light resistant) capsules.
1. Royal Jelly inhibits the production of proinflammatory cytokines by activated Macrophages, Kohno K et al; Biosci Biotechnol Biochem. 2004 Jan;68(1):138-45
Chiba Univ. Hayashi N et al in Japan measured the effects of intravenous Omega 3 from fish oil (DHA/EPA) versus Omega 6 (poly unsaturated fatty acids) or PUFAs from vegetable oils on delayed-type hypersensitivity reactions in burned rats. They concluded that the Omega 6 from vegetable oils increased proinflammatory cytokine levels (IL-6, TNF etc) while the Omega 3's from fish oil prevented immunosuppression in burned rats receiving TPN.
The pro cancer effects of high fat diets are widely reported and the fats themselves are almost universally the wrong kind of fats (processed vegetable oils, margarine, hydrogenated fats etc). Compare the high cancer and heart disease rate of the western use of "vegetable oils" to the "Mediterranean diet" that uses olive oil and the Eskimos who eat high fat diets from fish that have little or no heart disease or cancer. The results speak for themselves.
Note: It is evident that under stress conditions, the consumption of these vegetable oils (canola, soybean corn, sunflower, safflower etc) promote inflammatory cytokines (IL-6, TNF etc) and would weaken the immune response against cancer, HIV, HHV-6 etc). The safe oils to use would be palm oil and olive oil, the latter containing 90% monounsaturated fatty acids.
Note on Flaxseed oil: The research I have read thus far suggests that the Omega 3 fatty acids from fish oil are more effective than the alpha linolenic acid from flax seed oil for their suppression of inflammatory cytokines. This does not mean that there are fewer benefits from using fresh flaxseed oil, except that there are more documented benefits from using high quality fish oils. The quality of these oils is critical for obtaining their benefits. If either is rancid, (oxidized), the effects will be the opposite of what is expected.
Copenhagen. Fischer CP et al report (1) that 400 i.u of vitamin E daily inhibited the release of interleuken-6 from contracting human skeletal muscle after 3 hours of knee-extensor exercise. Lipid peroxidation levels did not increase in the group treated with the vitamin E. This was a small controlled study involving 7 volunteers.
Godbout JP et al report in experiments in mice that vitamin E inhibits peroxide formation and interleuken-6 secretion. (2)
1. Vitamin C and E supplementation inhibits the release of interleukin-6 from contracting human skeletal muscle. Fischer CP et al, J Physiol. 2004 May 28 Univ of Copenhagen.
Note: Other researchers report that vitamin C when used in doses above 500 mg daily can increase oxidative stress.
2. Alpha-Tocopherol reduces lipopolysaccharide-induced peroxide radical formation and interleukin-6 secretionä" Godbout JP et al. J Neuroimmunol. 2004 apr;149(1-2):101-9
Researchers Yu WK et al (1) in China found that increases in glucose levels in the blood raised macrophage production of IL-6, TNF and insulin. These conditions are more pronounced in persons with impaired glucose tolerance or have type 1 or 2 diabetes, sepsis or hyperglycemia. What does this say about the stress effects of consuming corn syrup and white sugar found in soda and thousands of processed foods? These simple sugars clearly promote IL-6, TH2 dominance and immune imbalance.
1. World J Gastrolenterol, 2003 Aug;9(8):1824-7
1. Low-dose cortisol ‚ 5 to 10 mg Cortef (Upjohn) taken early 8 or 9am and at 1 or 2 pm only, not later. Do not exceed 20 mg daily without medical supervision. Also use low-dose thyroid ‚ 1/2 grain once or twice daily as prescribed ‚ helps the liver process cortisone into cortisol and detoxify the body. Avoid using cortisol long term without also using thyroid at the same time.
2. Fish oil ‚ DHA and EPA ‚ Sardine and/or Salmon oil. Max DHA from Jarrow Formulas and/or EPActive. Three capsules twice daily should lower IL-6 based on the scientific literature. Fish oil lowers tumor necrosis factor as well as IL-6. Critically needed for all cancer, CFIDS and HIV patients.
3. Avoid vegetable oils high in Omega 6 PUFAS that stimulate the secretion of inflammatory TH2 cytokines. These oils include canola, soybean, corn oil, sunflower and safflower oil primarily. Peanut oil that has 50% monounsaturated fatty acids and is less problematic but the best choices are the oils very high in monounsaturated fatty acids like olive oil ‚ all types even the ultra light have 90% monounsaturated fatty acids. Special strains of safflower oil are also very high in monounsaturated fatty acids and are so labeled. Avoid eating in restaurants where fats of unknown origin are used.
4. Low-Calorie, low glycemic diet normalizes IL-6 while starvation diets do not. Eat small meals 5 times a day ‚ snack only, do not eat large multi course meals. Avoid simple sugars and corn syrup that increases IL-6 levels. Absolutely no canned sodas. Avoid all refined carbohydrates (including white sugar, white flour etc). Avoid large quantities of fruit juices except for cherry and grapefruit ‚ better to eat whole fruit instead, preferably raw.
5. A Hypoallergenic diet reduces stress on the digestive tract and thus IL-6 levels. (Avoid milk, ice cream, soy flour, and gluten from wheat if you are gluten intolerant etc). Note: You can try using cultured milk products (yogurt, kefir) and cultured soy products (Tofu, Miso). Soy milk is usually well tolerated while soy flour causes digestive problems. Consider using fiber and probiotics together daily.
6. Complex carbohydrates (with no added fat or protein) normalize IL-6 and other inflammatory cytokines. For an anti-inflammatory breakfast, consider plain whole grain toast with natural applesauce and tea (green/licorice). Whole grains, fruits and vegetables with little or no oils added and some fish are the ultimate diet for balanced immunity and health.
7. Cox-2 inhibitors, NF-Kappa B inhibitors and anti-oxidants with variable anti-cancer properties [Tumeric, Holy Basil, Skullcap, Green tea, Hu Zhang aka Solomon's Seal (high in Resveratrol), Rosemary, Ginger, Red grapes, Oregano, Hops, raw potatoes - high in catalase ‚ breaks down H2O2 into O2 and H2O]
8. Licorice root. One study suggested that the use of the herb "licorice" helps the liver convert cortisone to cortisol. Should be used in the morning and at noon only. Too much licorice will raise blood pressure. Suggestion: Find an herbal tea with licorice root as the 2nd, 3rd or 4th ingredient mentioned on the label. (e.g. Red Zinger" by Celestial Seasonings")
9. Vitamin E ‚ use "mixed tocopherols" only for best results‚ for adults 400 i.u daily.
10. Royal Jelly ‚ fresh only 1000 mg to 2000 mg daily.
Since January 2002, the NIH has sponsored a study of HIV patients using pulsed or interrupted treatment protocols based on the CD4 counts and not the viral load. Among the group doing the interrupted protocols, they stop taking the drug cocktail when the CD4 counts is over 350 and start taking it again when the CD4 counts drops to 250 or less. The shift from focusing on the viral load back to the CD4 counts is based on the long-term experience that low viral loads are not as good a predictor of survival as are high CD4 counts.
In the last issue of the Journal of Immunity, we discussed the pros and cons of structured treatments interruptions consisting of one week on and one week off vs. one month on and one month off. The NIH Smart Drugs study does not fix a rigid time sequence to use or not use the drugs. It is all based on the CD4 helper T cell counts.
The issue of drug resistance: Since the study will have a control - the "Go Group" that takes the HIV drugs continuously vs. the "Wait Group" that only take the drugs when their CD4 counts drop to 250 or less, the issue of which group is more likely to develop drug resistance will be answered over time. Current widespread assumptions that stopping and starting treatments will lead to viral resistance have not been scientifically proven. We have observed over the past several years that the RT (Reverse Transcriptase) inhibitors are the most likely set of treatments (drugs or herbs) for which viral resistance may develop over time.
Immune-based therapies: Bihari MD has reported for several years that in patients with CD4 counts higher than 300 the use of low dose Naltrexone daily has often kept the CD4 counts high and stabilized for several years without the need or intervention of prescription anti-HIV drugs. The low cost, once daily dose and lack of side effects makes Naltrexone an easy choice to consider among many of the immune-based treatments.
The 20 or more immune-based therapies mentioned in our last newsletter are less likely to be on the list of failed treatments due to viral resistance because immune-based therapies do not attack the virus in an area where viral mutations run rampant.
by Charles Chesson, Ph.D.
Washington DC: In January 2002, the Community Programs for Clinical Research on AIDS (CPCRA) announced the start of the SMART Study (Strategies for Management of Antiretroviral Therapy). The study is being carried out by 16 units in the CPCRA, 5 other sites in the United States, and sites in Australia associated with the Australian National Centre in HIV Epidemiology and Clinical Research (NCHECR). The sponsor of the study is the National Institute of Allergy and Infectious Diseases, a component of the National Institutes of Health.
According to Claire Rappaport, an AIDS activist from San Francisco and a member of the SMART protocol team, "The new anti-HIV drugs have given many people longer, healthier lives, but serious questions remain about how best to use the medications to get the maximum, long-term benefit and to minimize long-term side effects. Clinicians and patients have been making crucial treatment decisions on far too little data."
The study will enroll 6,000 people above the age of 13 over a 3-year period. Participants will be followed for 6 - 9 years to quantify the risks and benefits of two different ways of treating HIV infection. Half of the participants will be randomly assigned to the Viral Suppression or "Go group," a treatment strategy in keeping with the current HIV treatment guidelines for adults and adolescents. In this group, antiretroviral drugs will be used continuously to suppress levels of HIV in the blood to low or undetectable levels.
The other half of the participants will be randomly assigned to the Drug Conservation or "Wait group." In this group, antiretroviral drugs will be used episodically only when the participants' CD4+ T-cell counts drop below 250 cells/mm3; therapy will be discontinued when the CD4+ T-cell count rises above 350 cells/mm3. "This approach of not using antiretroviral medications when CD4+ T-cell counts are higher and when the risks of complications of HIV are low could have the advantage of reducing side effects, drug resistance and cost, while saving antiretroviral medication options for a time when the risk of complications from HIV begins to increase," according to Dr. Wafaa El-Sadr, principal investigator at Harlem Hospital and Columbia University in New York and co-chair of the study.
The SMART study also will gather information on important questions such as differences in body composition and body fat distribution, quality of life and cost effectiveness, drug resistance, and HIV transmission risk, in the two study arms. "The initiation of the SMART study marks an important turning point in HIV research," says James Neaton, Ph.D., principal investigator at the CPCRA Statistical Center at the University of Minnesota in Minneapolis and co-chair of the SMART study team.
"Randomized evidence from large, long-term trials could substantially improve the management of HIV disease. Up until this point, we have relied heavily on the results of shorter-term, randomized trials that measured viral load and on observational studies to guide HIV management decisions. Because people with HIV are living longer and will potentially be on therapy for decades, longer-term trials comparing clinical outcomes are needed to fully understand the impact of HIV treatment decisions."
"A trial of this scope and length will be a challenge," says Dr. El-Sadr. "The SMART study, will address questions that are uppermost in the minds of people with HIV and the clinicians who treat them. While significant advances have been made in the treatment of HIV, after two decades we still do not know for certain that the current method of treating HIV, with continuous therapy to maximally suppress viral load, is the best way to manage HIV in the long-run."
"The CPCRA is uniquely positioned to lead this effort," according to Dr. Fred Gordin of the Veteran's Affairs Medical Center in Washington, D.C. and the CPCRA Group Leader. "The CPCRA network was initiated by the NIH in 1989 to expand research opportunities to communities of color, to women, and to others affected by HIV, such as intravenous drug users. The CPCRA has research sites located in primary care settings in areas of the country hardest hit by the HIV epidemic." Since 1989, the CPCRA has enrolled over 17,000 patients in 19 randomized and 6 observational studies and has contributed data for the development of Public Health Service guidelines for management of a range of opportunistic infections associated with HIV infection.
For more information visit the SMART Study web site at http://www.smart-trial.org/ and the CPCRA web site at http://www.cpcra.org/.