HIV-RNA--Should You Get
by Jeffrey T. Schouten, MD
Recent research results have significantly changed our understanding of how HIV causes AIDS and may lead to a much better way of assessing prognosis, indications for treatment, and response to treatment. The old theory of HIV infection was that after initial infection there is a latent period during which HIV sits quietly inside of cells awaiting a signal to begin massive replication and destruction of the immune system. In 1993, two studies showed that there is ongoing viral replication in the lymph nodes, even when little or no virus could be measured in the blood or in circulating lymphocytes. Subsequently, other studies have shown that in almost all persons infected with HIV, virus can be found in the blood throughout the course of the infection, and furthermore, that the level of virus in the blood is the best predictor of prognosis yet available. There really is no latent period. HIV can be found in blood cells of all people with HIV infection.
Additionally, these studies have shown that the amount of HIV produced every day is much greater than previously thought, from 100-700 million new viruses per day. Equally surprising are measurements which show that the immune system is producing over a billion CD4 cells per day. The half-life of HIV is only 2 days (50% of the virus produced today is gone in two days). Therefore 98% of the viral load in the body is produced by cells infected within the last week. Also, most of the new virus produced is the result of newly infected cells. Thus, over a period of years there is a massive immune response to the production of large numbers of new viruses. Eventually, the immune system is unable to produce enough CD4 cells to overcome the viral production and the immune system weakens. This is a very dynamic process, not one characterized by a latent period, nor one characterized by a weak immune response.
Quantitative HIV Blood Tests
These new findings have been made possible by the rapid advances the last two years in techniques to accurately quantitate (measure) the number of HIV present in peripheral lymphocytes (and other mononuclear cells, or monocytes) and in the plasma (the cell-free portion of the blood). There are two techniques now readily available to measure HIV levels in the blood; they are the branched DNA test (bDNA) and the quantitative polymerase chain reaction (Q PCR)., Both tests measure HIV RNA. HIV carries its genetic information on two strands of RNA (ribonucleic acid). When HIV enters a cell it transfers its genetic information into the host cell as DNA (deoxyribonucleic acid), using an enzyme called reverse transcriptase. (The drugs AZT, ddC, ddI, d4T, and 3TC all interfere with this enzyme). The genetic information inserted into the host DNA may now be used to produce new virus by copying the information from the DNA back to viral RNA. [The Q PCR and bDNA assays measure specifically the viral RNA and not the messenger RNA (mRNA) which is produced to direct the synthesis of proteins used to build the new viruses, which include two strands of viral RNA.] Both the bDNA and Q PCR measure the amount of HIV RNA present in the plasma or in lymphocytes (and other monocytes). Studies have shown that the plasma HIV RNA is an accurate reflection of intracellular viral production.
Neither of the two methods for measuring HIV are approved by the FDA, although both companies making the tests expect to have FDA approval within a year. Once the FDA has the data which shows the consistency and reliability of these tests, they should be approved. People may obtain an HIV RNA test (Quantitative HIV test) through their physician. However, very few health insurers will pay for the test at this time because it is not yet FDA approved. Generally, Medicare and most state Medicaid programs have refused payment. Some private insurers are reimbursing for these tests. Chiron Corp. makes the bDNA test and the cost is $195. Roche Biomedical Laboratories makes the Q PCR test and the cost is $214. The Q PCR is a more sensitive test but may involve more time to perform in the lab, while the bDNA is not as sensitive, it does not measure viral levels below 10,000/ml, although soon this test may detect levels above 5,000/ml. Both tests have been standardized now so that they are available through many local laboratories. (See phone numbers at the end of this article for more information about getting a test.) Viral HIV levels below 10,000 (104)/ml are considered low, while values above 100,000 (105)/ml are considered high. Changes in HIV RNA levels over time are significant if the change is by a factor of at least 5 (or even 10) or more.
For example, an increase from 3.9 x 105 (390,000/ml) to 6.3 x 105 (630,000/ml) would not be considered significant, while an increase to 4.1 x 106 (4,100,000/m;) would be a significant change. Likewise, a decrease to 2.8 x 104 (28,000/ml) would represent a significant decrease.
Prognostic Value of HIV RNA
HIV RNA has been shown in several studies to be the best predictor of prognosis (time to progression to AIDS). It provides more information than any other marker, including CD4 cell counts. As early as 1989, David Ho measured viral blood levels and found that levels of HIV were much higher than previous estimates. He used a technique requiring viral tissue culture in the lab for three weeks to measure the amount of infectious viral particles in the blood. Persons with symptomatic HIV infection and AIDS had much higher levels of HIV in the plasma and lymphocytes (and other monocytes) than did persons with asymptomatic HIV infection. However this study did not evaluate whether HIV levels could predict which persons would progress to AIDS more rapidly. Many studies were done looking at other surrogate markers to predict prognosis including B2-microglobulin, antibodies to HIV, neopterin, interleukin, TNF, p24 (a viral surface antigen or marker), synctium-inducing (SI) phenotype (an aggressive variant of HIV), and others. However, none of these markers have proven to be sensitive enough to be of much use in clinical practice. Most of these markers are elevated (positive) only in late-stage disease, when CD4 counts are already very low, and are not of much help to predict how quickly CD4 counts will decrease.
Studies conducted at the University of Washington in 1989 by Robert Coombs showed that plasma viremia (virus detected in the plasma) was predictive of a more marked decline in CD4 cell counts and correlated with progression to AIDS. The test used was a viral tissue culture, which is not as sensitive as the newer Q PCR and bDNA, and measured infectious virions, not the total number of HIV virions. This was one of the first studies, though, to show the prognostic value of the presence of HIV in the plasma.
A more recent study has convincingly shown that "plasma HIV-1 RNA is a strong, CD4+ T-cell independent predictor of a rapid progression to AIDS after HIV-1 seroconversion." The researchers compared plasma HIV-1 RNA with p24 antigen, B2-microglobulin, and CD4 cell counts to predict progression to AIDS in a group of 62 men who were part of the Multicenter AIDS Cohort Study (MACS). The authors did not correlate HIV-1 RNA levels with synctium-inducing phenotype. HIV RNA was measured using the bDNA assay (Chiron Corp.), which the authors stated had the "advantage of large sample capacity, speed, reproducibility, and a format similar to an enzyme-linked immunosorbent assay (ELISA)." The HIV RNA test was found to be the "earliest and most powerful predictor of outcome after seroconversion." This study added proof to the concept that the course of HIV infection closely follows blood levels of HIV. Even though the Q PCR can detect lower levels of HIV RNA, the authors found that the bDNA gave values accurate enough to predict the risk of progression to AIDS. The bDNA test was found to be rapid and reproducible. The HIV RNA gave more information than did the CD4 cell counts. For persons with CD4 cell counts above 500 cells/mm3, only 6% developed AIDS within 2 years of infection if there was no detectable HIV RNA in the plasma (<10,000 (104 )genome equivalents/ml), compared to 45% if the HIV RNA was detectable (>10,000 (104 ) genome equivalents/ml). The researchers also found that plasma HIV RNA levels were higher in persons with more advanced disease. This is a significant study because it is the largest study to date which correlates plasma HIV RNA levels soon after infection with later progression to AIDS.
The long-term non-progressor HIV-1 infection studies all found that persons with HIV infection and no deterioration of the immune systems after 10 years had very low to non-detectable levels of plasma HIV. Another study compared HIV RNA levels and syctium-inducing (SI) phenotype in order to predict prognosis. HIV-1 RNA copies were found to be high and stable from the time of initial infection in all persons who progressed to AIDS. Non-progressors were found to have a significant decline in the level of HIV RNA after the initial rise seen after infection. HIV RNA was found to be of greater value in predicting prognosis in persons with the non-SI phenotype. HIV RNA was measured by the Q PCR method in this study. The authors concluded that "a decline in HIV-1 RNA copy numbers during the symptom-free period of infection is strongly associated with delayed onset of AIDS." High values for this study, as in most others, were considered to be above 100,000 (1 x 105)/ml, while low values were considered to be below 10,000 (1 x 104)/ml.
The prognostic value of HIV RNA has been confirmed in other studies as well. David Baltimore and colleagues found that HIV RNA measured in lymphocytes and other mononuclear cells strongly correlated with the future course of disease, and could "have significant clinical utility as a prognostic indicator and as a means to guiding and monitoring antiviral therapies." In this study, HIV RNA provided better prognostic information than did CD4 cell counts. Saag and colleagues measured plasma HIV levels with the Q PCR assay and found that viral levels significantly decreased by as much as 235-fold with antiviral therapy or following resolution of the initial infection. HIV RNA was significantly correlated with stage of disease and CD4 cell counts.
HIV RNA As A Measure of Response to Therapy
HIV RNA provides the quickest, simplest, least expensive and most accurate indicator of response to treatment for HIV. Tests for resistance to antiretroviral drugs (like AZT) are available only through research labs, are expensive and do not directly indicate the effect of a drug on the amount of HIV in the body. Several studies have documented the rapid decrease in HIV RNA levels following antiretroviral therapy. Changes are seen in a few days. This rapid change contributed to the recent understanding of the rapid production and turnover of both HIV and CD4 lymphocytes. In 1991, Saag reported that of 8 patients who had HIV present in the blood (by tissue culture method) prior to AZT, five became tissue culture negative following AZT therapy (follow-up range 15-40 months). There was an average decrease in plasma HIV of over 100 (102 or 2 logs). David Ho reported that treatment with ABT-538, a protease inhibitor, resulted in large decreases in plasma HIV-1 levels within a few days. This study again confirmed that "replication of HIV-1 in vivo is continuous and highly productive, driving the rapid turnover of CD4 lymphocytes." Another study has found that almost complete replacement by drug-resistant strains of HIV can occur as quickly as 14 days.
A study which evaluated HIV RNA levels and resistance to Zidovudine (AZT) produced results which showed that changes in serum HIV RNA levels did not directly follow development of AZT resistance. After decreasing with initial AZT therapy, HIV RNA levels increased within weeks, while AZT resistance took longer to develop. Thus, in this study of 11 patients, apparently other factors occurred which resulted in HIV RNA levels rising even before AZT resistance developed. Drug absorption, metabolism and activation are some of the other factors that may explain these results.
HIV RNA As An Indication for Therapy
Plasma HIV RNA levels clearly predict better than any other markers the risk of progression to AIDS and loss of CD4 cells. Even in persons with CD4 cell counts >500, many people have high levels of HIV (>100,000 or 105). While the Concorde Study and ACTG 019 have not shown a survival benefit from early therapy, it is possible that the subset of persons with high levels of HIV RNA may well benefit from early therapy. The major limitation at this time is the emergence of drug resistance, and the studies of HIV RNA have shown how quickly drug-resistant viruses emerge. Long-term non-progressors all have very low plasma HIV levels, and this should be the goal of any therapy.
HIV RNA As A Possible Indicator For Risk of Maternal-Fetal Transmission of HIV
There is data that the risk of transmission of HIV from mother to child is correlated with the amount of HIV in the mother's blood. Some of this information was presented by Dr. Barbara Weiser at the 34th Interscience Conference on Antimicrobial Agents and Chemotherapy on October 5, 1994. These results remain to be verified. Measuring a mother's blood viral level may explain how AZT reduces the risk of maternal-fetal transmission of HIV in some women. During the study which evaluated the use of AZT in pregnancy, HIV RNA levels were obtained although the results are not yet available.
Most current HIV therapy trials measure HIV RNA levels throughout the course of the trial. Ongoing trials should help determine if lowering HIV RNA levels results in better survival and delayed onset of AIDS. Clearly, high HIV RNA levels correlate with faster progression, whether lowering those levels will slow progression remains to be demonstrated. The new understanding of the large numbers of HIV and CD4 cells produced daily would imply that the immunotherapy will not be as effective as antiviral therapy. However, more research and many trials are needed to better understand the role of the immune system in response to HIV infection and therapy. Long-term non-progressors have an effective immune response which keeps the blood levels of HIV very low. One potential danger is using HIV RNA levels to evaluate new drugs is that effective drugs may be abandoned too soon. Drugs which interfere with viral assembly may result in the replication of defective viruses, it is possible that even though HIV RNA levels do not decrease, the person receiving the drug is benefiting from it.
Current Uses For HIV RNA
HIV RNA may be useful for individuals with intermediate CD4 cell counts who are undecided about initiating antiviral therapy. High levels of HIV RNA are associated with a more rapid progression to AIDS. Although there is no proof that lowering viral levels will change the course of the infection, it seems very likely that the decline in the immune system will be slowed if viral levels are kept low. Also, HIV RNA very accurately tracks the effectiveness of antiviral therapy. It seems reasonable not to continue a drug (or add a new drug), if current therapy is not decreasing HIV RNA levels. Again, no clinical study has been done individualizing therapy based on HIV RNA results. This therapeutic strategy is limited by drug resistance and the limited number of drugs available. Preliminary data from the protease inhibitor studies have shown greater decreases in HIV RNA than with the nucleoside analogs (AZT , ddI, ddC, etc.).
Both the Q PCR and the bDNA tests have been shown to be stable from day to day and the results are reproducible for sample to sample. Relative changes over time are of greater value than one single value. The results are the most direct indicator available of HIV levels in the blood. Although CD4 cell counts are useful in determining risks of opportunistic infections, they are only an indirect indication of HIV levels. It is hoped that, more insurers will begin to reimburse patients for the costs of these new useful tests and the cost will probably decrease because there are several companies competing for this service. Soon, monitoring of HIV RNA will become a routine part of assessing drug effectiveness in clinical practice.
Further Information for Laboratories Performing HIV RNA Tests:
Roche Biomedical Laboratories- Human Immunodeficiency Virus (HIV-1) RNA, Quantitative (Q PCR). 800-872-5727. Cost - $214.
Chiron Corp.- Branched DNA HIV RNA Assay. 800-553-5445 (Nichols Lab, for the nearest local laboratory). Chiron also provides a reimbursement service to assist physicians in insurance claims. 800-775-7533 (M-F, 9-5 Pacific Time). Cost - $195.
Jeffrey Schouten is a general surgeon and co-chair of STEP's Scientific Review Committee.
Ganciclovir for Cytomegalovirus
by Jane Woodward, Pharm D.
Great strides have been gain recently in the treatment and prevention of opportunist disease associated with AIDS. These treatments have allowed people to survive longer with more pronounced immunosuppression. As a result of these changes, there has been a rise in the in incidence of infections caused by cytomegalovirus (CMV), primarily because it is seen only in those people with low CD4 counts (usually <75 - 100 cells/mm3). CMV can occur anywhere, but the most common sites of infection are eye, lungs, and the colon. The most common symptom of CMV retinitis is a decrease in visual acuity. This article will discuss the treatment of CMV retinitis only.
Medications available for the treatment of CMV disease include ganciclovir and foscarnet. Treatment begins with a higher dose of either drug as an "induction" phase that lasts 2-3 weeks. Because this disease will progress in virtually all people even after the induction phase, all people are then given a smaller dose of the same drug as the "maintenance" phase that will continue for the rest of the persons life. At this time, no drug has been approved by the FDA for prevention or prophylaxis of CMV.
Treatment of CMV disease has been limited by the fact that the medications available require intravenous administration, are expensive and fairly toxic. They are also only expected to halt or slow disease progression, not reverse damage already done, and their efficacy wanes with time. This loss of efficacy is often due to resistance of the virus, but could be due to inadequate concentrations of the drug within the eye, especially after prolonged maintenance therapy.1 Of the two drugs available on the market, ganciclovir is often preferred over foscarnet because of its ease of administration and lesser side effect profile. Ganciclovir's main toxicity is suppression of the bone marrow, while foscarnet often causes damage to the kidney and disruption of electrolyte balance.
Most clinicians have recommended initiation of therapy with ganciclovir, although there was some question of this after a trial comparing the two agents was halted early due to a survival advantage seen in people that were given foscarnet (12.6 months with foscarnet; 8.5 months with ganciclovir). This advantage was seen only in people with normal kidney function entering the trial. There was speculation that survival was decreased in the ganciclovir treated group because they were unable to take as much zidovudine due to both drugs causing suppression of the bone marrow from producing white blood cells. In the analysis however, the difference in survival was not accounted for entirely by antiretroviral use, and may have been due to foscarnet's own anti-HIV activity and ability to increase the activity of zidovudine. As was expected, foscarnet-treated people experienced more side effects than those on ganciclovir and were more likely to switch to ganciclovir than vice versa.2 Because of foscarnet's severe toxicity, its survival advantage may not be as important when considering quality of life. Some studies are being conducted with the two drugs used together, not only to see if they increase each other's effectiveness, but also in those people that seem to have two different strains of CMV, each responding differently to each drug.3
Research has also been conducted in other forms of therapy for CMV retinitis, the most successful being delivery of these toxic drugs only to eye tissue or local therapy. This is accomplished by injecting the drug directly into the eye (intravitreous injections) or the use of an implantable pellet that slowly releases the drug into the eye over a period of time. Advantages of local therapy of CMV retinitis with ganciclovir included achieving much higher concentrations of the drug in the eye where it is needed (4.1 mcg/ml with implant, 0.93 mcg/ml with intravenous), avoiding exposure of the body to the toxic effects of the drug, and avoiding use of an indwelling catheter. However, local therapy does not protect the uninfected eye, nor does it protect the rest of the body. Because CMV is a disease that is responsible for damage to many organ systems, the use of local therapy only will always have to be used with caution and frequent monitoring.
Intravitreous injections of both ganciclovir and foscarnet have been investigated, with more experience using ganciclovir. Results of these small trials have been reported and have utilized ganciclovir induction doses of 200 to 400 mcg twice weekly, then maintenance doses of 200 to 400 mcg weekly.4,5 Good response was seen, although progression did occur. One study added on intravitreous ganciclovir injections with intravenous therapy in people that appeared to have CMV retinitis that was resistant to both or either drugs given intravenously. Response was seen in 25 of 30 eyes, although progression occurred in 46% without maintenance intravitreous injections.6 Liposome coated ganciclovir has been used in a few case reports, its advantage being proposed as injections being required less frequently. Complications reported with intravitreal injections of ganciclovir have included retinal hemorrhage or detachment and endophthalmitis, an inflammation of the tissue of the eye.
Of the two forms of local therapy, implantable pellets appear to have more advantages and experience in literature. These devices also achieve much higher levels in the eye than with intravenous therapy, an advantage that may be associated with better efficacy and less development of resistance. Of these devices, most release medication from 4-8 months.
There are three notable trials that evaluated the efficacy of the implantable device. the first implanted 30 devices releasing 2 mcg/hr of ganciclovir in 22 people, most of which had already received intravenous ganciclovir. Ninety percent of these stabilized. Nine cases reactivated and the device was estimated to delay progression of disease on average 133 days.7 The second trial randomized those with non-sight threatening retinitis to receive 1 mcg/hr device immediately, or defer treatment until the disease progressed. There were 30 eyes enrolled in 26 clients. Those who received the device immediately progressed in 226 days compared to 15 days in the group who were assigned to deferred treatment.8 The most recent results were reported on a trial that compared IV ganciclovir to the device in 148 clients. The authors found that the intraocular pellet delayed progression 186 days while IV ganciclovir delayed progression 72 days.9 In all of these studies the device did not protect the other eye, or other organs from CMV disease. Reactivations frequently occurred in eyes with devices that were no longer releasing medication. Complications were similar to intravitreal injections, and most of those had a decrease in their vision immediately after surgery, although most cases resolved within 28 days. A device produced by Chiron will probably be submitted to the FDA for approval later this year.
Perhaps the most notable advance in the treatment of CMV infections came in January of this year with the approval of oral ganciclovir. This drug was approved based on the results of trials that gave all clients induction treatment with IV ganciclovir then randomly assigned them to oral treatment or continued IV ganciclovir as maintenance therapy. Those assigned to oral treatment progressed 5-12 days earlier than those on IV maintenance therapy. Because of this, oral ganciclovir was approved at a dose of 1 gram 3 times daily for use only in people after they have gone through induction therapy with IV ganciclovir and have very stable retinitis10 (product information). Side effects are similar with both forms of this medication. Bone marrow suppression may be less with oral ganciclovir, probably due to lower amounts of drug in the body. Currently, higher doses of oral ganciclovir are being studied; up to 2 grams 3 times daily to improve drug levels and, it is hoped, efficacy.
Oral ganciclovir is also being studied for its utility in preventing CMV infections. Preliminary results of a prophylaxis trial have been presented in meetings this year in 725 HIV+ people with CD4 counts less than 50 cells/mm3 or less than 100 cells/mm3 with an AIDS-defining opportunistic infection. The trial was stopped early because an advantage was seen in the ganciclovir arm. Twenty percent of those treated with ganciclovir developed a CMV infection compared with 39% given placebo. The dose used was the same; 1 gram 3 times daily and similar side effects were seen and mostly involved bone marrow suppression.
There are many concerns about oral ganciclovir and the potential for its expanded use in people living with HIV. The first of these is its absorption, which is very poor from the stomach. Taking the drug with food helps it to be absorbed better, but the concentrations in the body are still less than with those obtained with the IV preparation. These low levels may predispose people to develop infections with viruses likely to be resistant to ganciclovir, limiting options for treatment. Unfortunately, there has been no information from the prophylaxis trial about those that did develop CMV disease despite being on ganciclovir. It is possible that the clients were not absorbing the drug; however, it could also be due to viral resistance.
Investigation of oral ganciclovir also revealed a drug interaction with didanosine (ddI), an antiretroviral commonly used with ganciclovir because it does not have the bone marrow suppressive effects of zidovudine (AZT). The amount of ddI in the body increases and average of 111% when given with ganciclovir, potentially increasing the risk of ddI side effects, especially peripheral neuropathy. It is unclear at this time how this occurs, and if it occurs with IV and oral ganciclovir.
Another important issue with oral ganciclovir is its cost. At doses of 3 grams daily, a month's supply will cost on average $1,400.00, not far from the price most infusion companies charge to administer IV ganciclovir. Although an indwelling catheter and all its potential complications are eliminated with oral ganciclovir, the drawback is also that of adding 12 more 250 mg capsules per day to an already complicated drug regimen.
It is difficult to predict the direction in which treatment and prevention of CMV retinitis are heading in the near future, although it is encouraging that new delivery systems are becoming available. Therapy is seriously limited by the toxicities and limitations of existing drugs, and it appears that newer investigational anti-CMV drugs still cause serious side effects. Cidofovir (HPMPC) is currently being tested and looks promising, although its effects on the kidney may seriously hamper its use. It may be that a combination of different drugs or especially different delivery systems using both local and systemic therapy will be used together to protect and treat the entire body from CMV, not just the eyes.
Jane Woodward is a pharmacist, currently in practice at the University of Washington.
The Integrated Care Clinic for HIV/AIDSbyTai Lahans
It is unfortunate but true that the path of the HIV epidemic has, in many respects, allowed for the emergence of alternative forms of medicine into the mainstream. How can we possibly find the right words to express to our patients the inner conflict of feeling health care providers have over this; feelings that are deeply appreciative for the clients choices and deeply dismayed that there is a need to make them in the first place.
An outcome of this emergence of alternative medicine has been the growing understanding, especially in the treatment of serious chronic illness, that an integration needs to occur. In Seattle, the main forms used to treat chronic illness have been conventional medicine ("allopathy"), naturopathic medicine ("naturopathy"), and Chinese medicine ("acupuncture, Chinese herbal medicine", etc.,). These are the main alternative forms of treatment that are highly systematized with a long history of practice and over the years, many clients have integrated their own care with these three main forms of medicine. Making choices as to what and when and how has been left to them without input or discussion on the part of the many health care providers they are seeing. This has left our clients the responsibility and the burden of knowing as much as they can about treatment strategies and deciding alone when and when not to use these treatments and in what, if any, combinations. It has been a heavy burden to bear when dealing with a potentially serious illness or when, acutely, ill.
For those of us who practice an alternative form of medicine, there are also frustrating constraints that feed into this scenario and hold us back from our chosen path of treating HIV/AIDS clients. We usually cannot bill health insurance for services. This limits what we can offer, and many of us carry a heavy load of chronically ill clients who can no longer pay for our services out of pocket. After developing a long clinical and caring relationship with clients, we cannot follow them if they are hospitalized, effectively cutting off our care in times when continuity of care is crucial. These issues add to the burden for clients and practitioners.
In January, 1995, the Integrated Care Clinic at Bastyr University was begun to address some of these issues. This clinic incorporates several forms of medicine working with the client to find the best way to maintain health. The patient group has been limited to twenty people who visit three times per month for acupuncture, Chinese herbal medicine and naturopathic treatment. Two MD's are present in this shared space clinic to consult about diagnoses from a western point of view and to provide an interface with the patient's allopathic doctors should they not be the ones on staff. Discussions are held regarding the presentation of medical problems and the best possible strategies for intervention. These discussion include an MD, ND, nutritionist, and the Chinese medicine components. They can be with or without the patient depending on many circumstances. They are educational, informative, negotiative, and fluid. The point is to provide choices to clients that are the least toxic and most effective in a given situation.
In this approach, a highly complex treatment plan is generated out of a group intake. The group intake allows everyone to hear the same information at the same time, ask questions pertinent to their form and thus train each other from the start about their area. A team member acts as the interviewer, and the patient appoints one member to be the main communicant, the person they call in an emergency and, in turn, calls all of the others. This is the lead person for that patient. The treatment plan is an evaluation of all health issues; physical exam, blood work and labs, areas of health, Chinese evaluation and how it fits (or doesn't) with the western evaluation, Chinese diagnoses and treatment possibilities, nutritional possibilities and recommendations, psycho-emotional-spiritual information, and a set of negotiated plans that is a meld of this total evaluation. This plan is then presented to the patient by the team for further discussion, questions and negotiation.
Everything, including our process as a team, is presented to the patient as an informative means by which choices can be made. We see choices as the clients'. Therefore, we are working toward patient-centered medicine rather than medicine-centered medicine. It is quite different in approach and requires a certain amount of letting go on the part of individual providers. We never know what choices clients will make. It is often immediately apparent that one form of medicine is better suited to a given problem than another. Sometimes it is not; here we must educate each other which often includes a discussion about why we chose our particular form of medicine over another and often a discussion on the side effects of western drug therapies versus the benefits. This requires trust and an honoring of each other as individuals and as physicians who care about our clients no matter what form of medicine we practice.
These discussions and the evolution of this new practice of medicine are boundary-shattering, difficult, inspiring, a relief (shared sense of responsibility), complex and revolutionary. It is empowering for all concerned. The decisions made as a team with the patient included an at the center are no longer rote or bland or poorly adhered to; they are alive, strong, and deeply meaningful.
Tai Lahans is a co-founder of the Kang Wen Clinic and the Integrated Care Clinic. She is an acupuncturist and Chinese herbalist in practice now for ten years. The Integrated Care Clinic is at the Natural Health Clinic of Bastyr University. Tai Lahans can be reached at her private practice at 206-726-0269 or at the Natural Health Clinic at Bastyr University at 206-632-0354, extension 816.
Psychoneuroimmunology and HIV
by Brad Lichtenstein, ND
The majority of writings in this and other publications focus on biochemical medical treatment for those infected with HIV or resultant opportunistic infections. What is often overlooked are the psychological aspects of HIV infection, or for that matter, the psychological perception of illness and disease. The emerging field of psycho-neuroimmunology examines the interaction between physiological functioning and memory, behavior, or thoughts. Psychoneuroimmunology was founded upon the work of George Solomon, MD who suggested that when evaluating health and disease more than physiological symptoms needed to be considered. His initial work in the mid 1960s centered around behavior and personality patterns in patients with chronic rheumatoid arthritis. Since that time numerous studies have been conducted researching the specific biological influences mood, thought, and behavior may exert upon the body.
One of the most important and influential researchers to document the psychological parameters of health has been Suzanne Kobassa. Her work is paramount for its introduction of the term "hardiness." Hardiness consists of three main parameters. These are: commitment, control, and challenge.2 Commitment involves one's feelings toward work, family, social encounters and self. Those with a sense of commitment experience a sense of purpose within themselves and in what they do; they perceive themselves to be a vital and active participant in their own lives. In opposition to commitment lies alienation; a sense of isolation from the world and in interactions.
Control refers to a sense of power. Those with a high profile of control are able to take an active role in and possess a sense of responsibility for their lives. The attitude of those who possess high levels of control is one of influence; they perceive they can influence the outcome of events affecting them. When control is low, individuals suffer from a sense of helplessness and hopelessness, consumed by a feeling that they are powerless to meet the situation.
Challenge is the ability to view all situations as potentially positive with successful outcomes. Individuals who experience low levels of challenge often perceive any given situation as a threat to their health and well-being. Kobassa examined how stressful life events affect one's health and the frequency of disease. She argues against a direct cause-and-effect relationship between stress and illness. She rejects the notion that stress is to be avoided for one to lead a healthy life. What Kobassa's studies demonstrate is how an individual's personality and coping mechanism directly influence health. She discovered that individuals who possessed high levels of hardiness (having high profiles of these three parameters) suffered fewer illnesses.3 The conclusion here is that events, in and of themselves, cannot be identified as stressful or illness provoking; it is the interpretation the person makes regarding the event that is significant. Those with high hardiness profiles will interpret events as positive, engaging, and challenging. Operating from this vantage point, Kobassa believes, one can greatly impact one's own health.
Kobassa measured and evaluated the individuals in her studies based on patient report, psychoemotional scales, and symptoms. Therefore, the patient's assessment of events and health status could easily be gauged. The frequency of office visits during and following the studies was also assessed. However, direct physiological parameters, blood pressure, cell counts, etc., were not measured.
Keicolt - Glaser and Glaser were instrumental in measuring the direct physiological effects of stress. They evaluated the immune functioning of medical students.4,5,6 Their findings suggested that during periods of stress, in this case examination periods, students had a decrease in NK cell activity. NK cells are involved in non-specific immune surveillance against tumor cells and viruses. Additionally, gamma interferon levels (which aid in the body's ability to produce cells to help fight infection) and blastogenesis (ability of cells to transform to larger, more potent forms upon contact with foreign material) were lower during exam periods. These levels all returned to normal after the stressful event was concluded. However, regardless of the familiarity of the stressful event, that is, no matter how many times the students had taken exams, they continued to have a decrease in immune functioning. Finally, Glaser found that students with a sense of isolation and loneliness (a control parameter) had lower NK cell activity than those students who did not report such feelings. This may be interpreted as suggesting that those who viewed the examination process as threatening and stressful experienced a greater decrease in immune functioning as measured by NK cell activity.
Snyder concluded that not only is the individual's hardiness a factor, but the form stressful events take is of equal relevance.7 In her study, Snyder assessed patient response to a novel antigen--a substance that induces an immune response (along the lines of an allergic reaction)--in the context of stressful events. She reports differences for patients experiencing and defining stress in terms of good versus bad. The group with bad stress, those with repeated daily hassles as opposed to brief and infrequent major stress, had decreased immune function as measured by the proliferation of lymphocytes (B and T cells). The intensity of these daily hassles was of key significance. Like the previous studies, stress levels were measured by patient self report and a variety of mental health scales. Not only is the individual's ability to cope with situations a factor now, but the intensity and frequency of the stressful event is of importance. The works of those studying HIV infection and AIDS in context with Kobassa's hardiness scale has contributed further insights. Although not mentioned in her work, others believe a fourth "C" should be added to the scale, namely community, also classified as social support.8, 9, 10 Community plays a large role for those in a medically challenging situation. This last factor can help foster and maintain the individual's control, commitment and challenge. Support involves the patient's ability to access help in both the emotional and the problem-solving realms. Such behavior would include expression of feelings, emotions, and thoughts, and accessing information from others; such as advice or explanations. Those who demonstrated such behavior were reported to have a longer survival rate after exposure to Pneumocystis Carinii Penumonia (PCP).8 What is now added to the equation is specific behavioral traits, namely the process of accessing and expressing personal information.
At the Center for Biopsychosocial Study of AIDS at the University of Miami, researchers set out to further evaluate the behavioral changes that may affect immunological functioning. They conducted a variety of studies following groups of asymptomatic, healthy gay males for 5-10 weeks prior to and following notification of their HIV-1 antibody status.11, 12, 13 Subjects were divided into intervention and control groups. Measured biological outcomes were evaluated by immunological, endocrinological, and neuropeptide levels for the duration of intervention prior to notification, and immediately after notification as well as follow-up intervals throughout 1 year post notification. Some 24 measures were assessed, including total T cells, B cells, T-helper cell subsets, NK cells subsets, serum IgG, IgA, and IgM, Epstein - Barr virus antibodies, plasma cortisol and beta-endorphin levels. The psychological measures involved hardiness parameters, sexual and health behaviors, affect inventories, etc. The authors admit that controlling for confounding factors (factors not considered or evaluated such as sleep and physical activity levels) and compliance remains problematic. However, their research again yields support for the concepts offered by Kobassa. The individual's ability to cope with a situation, the person's hardiness, and belief system affect immunological, endocrine, and neuropeptide levels.
In all the studies conducted by the Miami group, cognitive or behavioral modification was the main intervention offered. However, in a few studies, the effects of aerobic exercise were also examined. The results strongly indicated that at the time of notification of HIV antibody status, those who participated in the cognitive or behavioral modification or the aerobic exercise protocols experienced less or minimal decrease in immunological parameters. As opposed to control groups, psychological measures for depression post notification were less affected. The authors hypothesize that both the cognitive or behavioral intervention and the aerobic exercise facilitate better coping skills for the individual by acting as a buffer system to anxiety and depression. By offering individuals a method for coping and reframing the situation, the individual can view the information at notification as controllable and as a challenge. Furthermore, by engaging in aerobic conditioning or behavioral restructuring, the individual has been supposedly gaining a sense of commitment to his or her health. These interventions provide the individual with a sense of control, self-esteem, and power. Without these, the authors suggests, a cascade of events occurs which decreases the immunological, endocrine, and neuropeptide functioning of the individual.
Their theory is as follows : control subjects showed anxiety, depression, and isolation leading to activation of the sympathetic nervous system (commonly viewed as the flight or fight system) and CRH (cortisol releasing hormone). This then leads to the increase of peripheral catecholamines and/or cortisol levels. When these levels are elevated, a decrease of positive immune enhancing hormones, peptides and cells occurs by way of negative feedback. These include interleukin-1, interleukin-2, and gamma-interferon to name a few. Once the decrease of positive hormones takes place, what has been found is a decrease in the ability of NK cells to attack foreign material, a decrease in the ratio of CD4 to CD8, and the decline in blastogenesis. The authors propose that when a person has undergone some form of stress management, this cascade fails to become engaged at such an intense level. The parasympathetic nervous system (that system responsible for general relaxation and calmness) then predominates. Thus, no increase in cortisol, peripheral catecholamines, and CRH occurs. An increase in the interleukin and interferon levels follows, as well as an increase in beta-endorphins and met-enkephalin. The final result is immune enhancement with an increase in NK cell activity, increase in CD4 and CD8, and increase in blastogenesis. This, they suggest, may decelerate possible disease progression.
All the above mentioned works have focused upon the individual's personality traits or hardiness. Behavior and emotion have been the means by which these traits are assessed. However, the belief system of the individual plays an integral role in directly impacting one's hardiness and health as defined by Kobassa's challenge parameter. This entails the diagnosis and the meaning it carries. Each individual makes an assessment about their diagnosis, thus giving it power to effect their health. This can best demonstrated by the studies involving "medical hexing" and "voodoo death."
The concept of voodoo death comes from the accounts of individuals who have been cursed by a person or persons they deem to have power over them (such as a witch doctor, tribal leader, or spiritual guide). In these accounts, the process was as follows: an individual presented to a hospital or clinic in the final stages of death. The body was responding as if it was dying, yet no causative agent was found. All that was known was that someone had cursed or accused them, for which the prognosis was death. In one case, the tribal doctor who had "pointed the bone" at one such individual was reluctantly brought to the clinic where the MDs pleaded with him to remove the curse.14 Disgruntled, the tribal doctor revoked the curse. A day later, the man who was dying recovered to his previous full state of health. Other individuals were not as fortunate. Such stories help bring into focus the concept of psychoneuroimmunology or psycho-biological interactions.
As Sanford I. Cohen has discussed in his study of the concept of medical "hexing," voodoo deaths occur daily in our medical profession without much forethought. He describes voodoo death as follows: "So called voodoo or hex death is a classic example of biopsychological interaction. It is a dramatic demise that occurs when a person feels cursed by another believed powerful enough to kill or powerful enough to create a feeling of hopelessness. The victim has to believe that the hex works and that he cannot control it."14
This hexing occurs today in our modern medical practices. The hexing occurs the moment, and possibly before, a patient is given a diagnosis. In order for such a process to happen, the following factors are involved:
So what does all this mean for the individual? Again we return to the connections defined by the field of psychoneuroimmunology, the belief in the connection between psyche and soma. In this model, we are no longer individuals who have a mind or a body; we are mind and body. The thoughts we generate directly affect physiological processes. As discussed previously, if the individual holds to the concept that their diagnosis is fatal, a mood is then generated within. No longer can we hold the view that mood is some ephemeral, esoteric entity that is stored in the psyche. Moods are generated by the assertions one makes about the action. The action here is the diagnosis. If one assesses that this diagnosis is equal to fatality, a mood will then be created. The mood occurs in the body as well as in the psyche. By changing the assessments, asserting control, challenge or commitment, the mood borne from such a place would alter the physiology.
The suggestion here is that the individual and medical profession question their assumptions about the individual's ability to take an active role in the process of health. This involves generating a new approach to diagnosis; one that does not stimulate "hexing" behavior. If one is to view patients in a static, materialistic, Cartesian plane, then a diagnosis is something a patient IS. They ARE cancer. They ARE asthma. They ARE HIV. No other reality exists. If this is in the minds of the physician and patient, what impact does this carry? How does this translate into the patient's view of themselves? If the patient is to dissolve themselves into the diagnosis ("I can no longer perform in this way because I have 'X'"), then from where will the healing come?
As we can clearly infer from the work of the Miami group, those who were taught coping mechanisms were better able to deal with notification of their HIV antibody status. What coping and behavioral strategies offered the individual was the means by which to reframe and re-assess the meaning of the notification. What is being proposed here is that one examine one's belief systems and how one reacts to all situations. For stress is not a concrete and identifiable entity. Yet often we find that we speak as if something that occurred was stressful; "My day was stressful," "That meeting was stressful," etc. However, as Kobassa attempted to demonstrate, the day or meeting itself was not stressful. The belief or perception one holds regarding the meeting or day will elicit a biopsychoemotional reaction in the individual. Therefore, if one can learn ways in which to develop hardiness (commitment, challenge and control), foster community, and reframe one's beliefs about illness, diagnosis, and the infallibility of the medical system one may learn ways in which to create wellness and health at any given moment regardless of one's diagnosis.
One way in which people can begin to address these issues is to seek out trusted support opportunities. This may be in the guise of support groups, friends, or even finding a qualified mental health professional. In an atmosphere of trust, one can learn and practice how to be assertive and expressive. Control is one of the parameters for which many find themselves longing. While control had been defined as a sense of power, by applying all the concepts listed here, the meaning of control is far more specific. Control refers to one's ability to effectively impact one's belief system. The only controllable factor in our lives is the perceptions and meanings we assign to any given situation. By attempting to control HIV, one is making judgments about what HIV is and how it will affect one's life. People live in a place of powerlessness, hopelessness and helplessness. The question arises as to whether or not HIV is something one can actually control. However, by exerting control over one's perception about HIV, one can live in a place of power.
A caveat needs to be offered on the issue of guilt. In no way is the information given here an implication of fault or guilt. One need not read this and decide that one's emotions or ways of thinking are the cause of one's illness. Rather, what is being offered is a way to learn how to better assist the body in healing. This is not a panacea -- a cure-all. Psychoneuroimmunolgy stresses the connection between mind and body. Therefore, working on the body will affect the mind as well. What one believes regarding one's treatment has a significant impact upon one's health. By obtaining insight into one's hardiness level, community, and belief or value system, the possibility for experiencing greater health is offered.
Dr. Lichtenstein is a recent graduate of John Bastyr University now in private practice in Seattle. He can be reached at 206/994-8361
Tuberculosis and HIVby Norma Rolfsen, RN
The annual number of tuberculosis (TB) cases was steadily declining from the early 1950s until the mid-1980s, a trend public health officials expected to continue. However, since 1985 the number of TB cases reported rose dramatically. One of the major factors contributing to this increase is co-infection with HIV. It is hypothesized that other contributing factors include immigration from countries with high TB prevalence, and transmission of TB in congregate care settings, including correctional facilities, homeless shelters, mental health group homes, and other health care facilities. Other factors in the increase of TB are diminished access to care for lower socio-economic groups, and the deterioration of the public health system. An estimated 10-15 million persons in the U.S. have latent TB infection. Tuberculosis is an AIDS defining illness. It has been projected that by the year 2000 TB will be the leading cause of death in people living with HIV.
Tuberculosis is caused by Mycobacterium tuberculosis complex (M.tb), an airborne bacterial infection. It is spread when a person has close prolonged contact with someone who has active symptomatic infectious disease. TB is spread in the air only by coughing, and is not spread by blood, sexual, or other contact. It is important to understand the difference between TB infection and TB disease. The immune system responds to TB infection within two to ten weeks after exposure to someone with contagious disease. For the majority of those with TB infection, the disease becomes dormant once the immune system responds. This is the latent infection stage. In this latent stage, a person is not contagious nor symptomatic. The immunocompetent person with TB infection in the U.S. has a 10% lifetime risk of developing active disease. In those who are HIV-positive, there is an 8-10% yearly risk of developing TB disease. Those with HIV often bypass the dormant stage, directly developing active disease.
It is only during active disease that one is both symptomatic and contagious and symptoms of TB include a persistent cough, night sweats, fever, chills, weight loss, fatigue, sometimes chest pain and coughing of blood. Those with HIV are at greater risk of developing TB outside of the lungs, called extrapulmonary TB. Extrapulmonary TB occurs in one-to two-thirds of TB cases involving HIV. People with extrapulmonary TB are usually not infectious unless there is a draining abscess containing M.tb.
It is vital that clinicians consider TB when diagnosing and treating people with HIV infection. Testing methods include a skin test with PPD (purified protein derivative), chest X-rays, and sputum smears and cultures. The Mantoux test is used to screen for TB infection. A small amount (0.1 milliliters) of PPD is injected just beneath the skin on the forearm. The reaction to the test is read by an experienced health care professional 48-72 hours later. People with HIV, the CDC recommends that the test be considered positive when induration below the skin measures 5mm or greater. Redness or surface swelling does not indicate a positive test. In HIV individuals at high risk for TB infection, 10mm of induration is considered a positive test. This test is of limited usefulness for people with HIV infection because people who are immunocompromised become less able to develop a response to the test. Decreased CD4 counts correlate to decreased response to the PPD and a false negative may result. For this reason, testing with controls, also known as anergy panels, is recommended for people who are HIV positive. Two of three control solutions (candida, mumps, or tetanus toxoid) are injected and read, in the same way as the PPD, in order to determine the body's ability to mount a reaction. These solutions are used in the United States as most people have been exposed to these diseases either by infection or vaccination. People with a positive PPD, regardless of response to the controls, are considered to have TB infection. It is concluded that those with positive controls and negative PPD do not have TB infection. In those with negative controls, and negative PPD, the results may be inaccurate and cannot be used for diagnosis.
Anergy is the term used when the body is unable to mount an immune response. Other factors besides HIV infection may also cause anergy, including acute TB disease, febrile or viral illnesses, oral steroid use, cancer, insulin dependent diabetes, bone marrow disease, use of immunosuppressive drugs, or other conditions. Anergy testing, while recommended by the CDC, remains controversial. TB Monitor (November 1994) quotes David Rose, M.D., Associate Professor of Medicine, and Director of the AIDS Program at Mount Sinai School of Medicine in New York, "It does give us some information. The problem with the test is that it gives us imperfect information and we have to make clinical decisions on the basis of imperfect information." In people with HIV, who have been exposed to TB, or who have developed symptoms, further testing is indicated regardless of PPD status. A chest X-ray and sputum specimens should be obtained. Clinicians should be aware that X-ray changes in those with low CD4 counts do not follow typical patterns. If a sputum smear is positive for mycobacterium (+AFB), the person is potentially infectious, and treatment for TB should begin. Cultures from the sputum specimen may take up to 8 weeks to differentiate M.tb from other organisms. Drug susceptibility tests will also be performed to determine drug efficacy in treating TB. These tests also take several weeks.
Preventive therapy for those who have TB infection, but not active disease, is indicated. Daily Isoniazid (INH) is normally used alone unless INH resistance is known. In HIV-positive persons the daily dose is 300mg for 12 months. Twice weekly dosing for some may be effective. People receiving mycobutin 300mg daily, for MAI prophylaxis, do not need to take INH while on this therapy. However, mycobutin is not used to treat active disease in place of INH.
In HIV-positive persons with active TB disease, 3 to 4 drug therapy is recommended until susceptibility is determined. These drugs are INH, rifampin, pyrazinamide, and/or ethambutol. If the organism is culture sensitive to INH and rifampin, the person will continue only on these two medications. Multiple drug therapy has become standard practice since the emergence of multi-drug resistant TB (MDR TB). MDR TB is an organism resistant to INH and rifampin. MDR TB cases have increased dramatically, particularly in New York City, although few cases have been documented in Seattle-King County.
It is important that clinicians provide education about, and monitoring for, adverse reactions of anti-TB drugs. These include allergic reaction, liver problems; including hepatitis, peripheral neuropathy, and decreased platelet count. In severely immunocompromized people with TB, drug treatment may be less effective due to HIV-related malabsorption. Alcohol use also increases risk for decreased liver function. Anti-TB drugs also interact with numerous other drugs. Rifampin may accelerate metabolism of numerous other drugs including anti-convulsants, digitalis, fluconazole, ketoconazole, oral diabetes agents, and methadone. Peoples receiving methadone may need to have their dose increased by as much as 50%. Rifampin may also cause oral contraceptives and contraceptive implants (e.g., Norplant) to be ineffective. INH interacts with Dilantin and Antabuse.
Drug therapy will continue for a total of 9 to 12 months, or 18 plus months for MDR TB. Sputum cultures should be collected at least monthly until the cultures convert to negative. Other factors to consider when measuring effectiveness of therapy include X-ray improvement and clinical improvement. When there is poor response to treatment due to a failing drug regimen, two new drugs should always be added simultaneously. Adding only one drug may further increase drug resistance.
Many people receiving treatment for TB disease find it difficult to complete the recommended regimen and a full 25% do not do so. Inadequate treatment can lead to disease relapse, ongoing transmission, and development of drug resistance. It is essential that public health departments, and other health care workers take all possible measures to assist people in adherence to drug regimens. This is vital both in treating individuals and controlling the spread of TB. Numerous studies have documented the effectiveness of directly observed therapy (DOT). This means that a health care worker watches the person swallow each dose of medication. DOT should be considered for all people, as clinicians may be inaccurate in predicting adherence. DOT can yield decreased rates of relapse and drug resistance, and is useful in determining treatment failure vs. non-adherence.
To be most effective, clinicians must negotiate treatment plans with the individual and their family or support person(s). The development of a therapeutic rapport between a clinician or outreach worker, and the person may increase the person's ability to understand and choose treatment goals and self-care interventions. Whenever possible, people should work with outreach staff of similar cultural and linguistic backgrounds. Incentives may be used to increase adherence. These may include providing food, transportation, and even housing. Urine tests, to check for the presence of drug metabolites, and/or pill counts may be done. These should also be negotiated with the person. Adherence may also be increased with the use of fixed dose combination drugs, thereby decreasing the number of pills the person must take. Within impoverished communities, at least one study has shown greatly increased adherence when food was given along with the medication regimen. This intervention was shown to be cost effective due to the reduction in transmission of TB in the community.
Suspect TB cases must be reported to the public health department. They should also be consulted when it is noted that a person with TB is unable or unwilling to adhere to treatment. They are able to increase services to enable the person to complete therapy. If this is ineffective, the health department will seek appropriate action even to the detention of an infectious person at risk of spreading TB to the community. Infection control measures must be implemented in all settings where people with TB, or at risk for TB, are seen. Engineering controls should be used to decrease the spread and reduce concentration of airborne TB particles. Isolation rooms, with ventilation systems to maintain negative pressure and exhaust air properly, should be available and maintained appropriately. Filters in ventilation systems and ultra-violet lighting may be effective in conjunction with other infection control practices. Special masks (personal respirators) should be used by people who must leave an isolation setting and by health care workers in areas where there is an increased risk of exposure. Visitors should also wear these masks while the person is considered infectious. All health care workers should be educated about TB transmission, infection, and infection control. Protocols should be developed for PPD screening for workers and volunteers of agencies which serve TB clients, or those at risk.
The first priority in TB control must be identifying and treating those with TB disease. It is essential that those persons who have been in contact with TB are also evaluated. To impact the current trends in TB infection, it is critical that community risk/needs assessments be done to identify each community's high risk groups. Primary care providers must be educated to facilitate early diagnosis and treatment. Public health nurses and outreach workers must be aware of the persons's individual needs, including racial, cultural, language, and economic factors. Community leaders may become involved to assist persons at risk to access the health care system, and assist public health officials to reach those who are at risk.
Norma Rolfsen, RN is the Nursing Coordinator of the Bailey-Boushay House and Seattle/Puget Sound chapter President of Association of Nurses in AIDS Care (ANAC)
Liver Function and HIV-1 Infectionby Vic Hernandez, Dr.P.H.
The liver is one of the largest organs of the body. Located below the diaphragm, it occupies the space in the lower rib cage and upper right abdomen, spanning from front to back. The biliary tree, or gall bladder and biliary tract, are closely associated organs which pass bile from the liver to the digestive tract. Large amounts of blood circulate throughout the liver, entering it from both arterial and portal vessels, emptying almost directly into the inferior vena cava through the hepatic veins. The liver works to cleanse blood of dead blood cells, excess impurities, and transform blood-borne products into biologically active or inactive forms. The liver is like a chemical processing facility. It produces bile, used in fat digestion, and acts like a waste management and recycling depot.
The portal vein drains much of the abdominal organs of blood. Thus products of digestion and metabolism from these organs pass into the liver directly for metabolic processing. These products are processed by the three main types of liver tissues. Hepatic and Kupffer cells provide many of the metabolic transformative functions, while the biliary cells produce bile from digestive nourishment. Kupffer cells remove dead blood cells and microorganisms from circulation, and are important in antibody and bile formation. The hepatic cells perform the majority of the liver's chemicalization functions: processing nutrients from food, transforming blood toxins, metabolizing fat-soluble drugs, and work to facilitate carbohydrate, protein, fat and vitamin metabolism throughout the body.
PWHIVs (people with HIV) may have previous or concurrent liver impairment as a result of injection drug use, hepatitis, alcohol abuse and pharmacological damage from other medications. Because the liver is so important in eliminating infections carried in the blood, low-grade opportunistic infection in PWHIVs constantly pressure the liver to cleanse the blood. Liver stress is also common among HIV+ hemophiliacs. Most people are unaware of liver stress, unless there is liver pain, swelling, symptoms of cirrhosis or, they have blood tests measuring liver function.
Hepatitis is a common form this stress takes. For instance, viral hepatitis has similar transmission vectors as HIV and is seen most often in gay men and intravenous drug users because it is blood-borne. The blood products hemophiliacs infuse may carry many bacterial and viral products from the many donors whose blood is pooled to make clotting factor. Many hemophiliacs have been infected with hepatitis as a result of these pooled blood products in the past. (Currently the risk of hepatitis from blood products is extremely low.) Due to this risk factor, HIV+ hemophiliacs should be aware that liver damage from hepatitis may further impair health. Indeed, hepatitis is the second-most common cause of death among this group of PWHIV.
Caring for the liver is very important for PWHIVs. The metabolic products of HIV and other infections (free radicals, etc.) stress the liver's capacity along with the extra work of processing most medication products a person might be taking. This dual load on the livers shows in elevated enzyme markers in the blood, SGOT and SGPT (laboratory tests that monitor liver function), and may manifest physically as hepatomegaly (enlarged liver) or jaundice (hepatic inability to break down bilirubin with resultant yellowing of skin and eyes). The liver reaches a capacity for handling the toxic effects of disease and medications. This capacity varies from person to person depending upon their medical histories. Not all PWHIV will manifest notable liver stress. Because the liver is important to both blood filtration and drug activities, PWHIV should be aware that relieving stress from the liver will help maintain a more normal physiology during chronic and acute management of HIV disease. This creates a synergistic effect of improving health and normalizes processing of medications.1
Treatment Strategies for Liver Stress
Ingested or injected antibiotics, antivirals, herbal remedies, prophylactic drugs and nutrients pass through the liver where they are processed for excretion or metabolism. Chronic presence in the body of these various substances places a strain on liver function, because liver metabolic pathways can overload, and cannot properly process the onslaught of toxins and metabolites. Poorly processed toxins and metabolites reenter the bloodstream, and consequently can damage other organs and tissues because the liver could not inactivate them or tag them for excretion.
Treatment approaches to HIV/AIDS should revolve around supplementing the liver's processing mechanism and accelerating the transformative processes of hepatic and Kupffer cells handling the increased and chronic drug load. This very simply allows the liver to function as it should, without impairment. More evidence of HIV disease and effects of its management upon liver need to be researched to acquire a more complete picture of liver stress and damage.
There is a long history of herbal hepatic and biliary treatment in western medical history. Most have been tonic, bitter herb medications which promote the flow of bile (cholagogues) and relieve jaundiced conditions. Some of these treatments are chickory, dandelion, wahoo, centaury, mandrake and celandine. Modern pharmaceutical medicine does not provide liver tonics or supportives, and PWHIV's have turned to alternative sources to handle liver stress. Thioctic acid, Silybum marianum (milk thistle), and glycyrrhizin are newer sources of treatment which have proven efficacy in handling liver abnormalities. These treatments are supportive in nature, and affect metabolic pathways in the liver.
Thioctic acid, also known a lipoic acid or alpha-lipoic acid, is a liver protectant nutrient comprised of lipoic acid and fat-soluble thiamine. An essential micronutrient in liver cell metabolic pathways, lipoic acid is rapidly depleted during stress-induced processing. 2,3 People diagnosed with liver cirrhosis, diabetes mellitus, atherosclerosis and polyneuritis have been found to have a reduced level of endogenous lipoic acid. 4,5 Lipoic acid works in catabolic and anabolic pathways with other coenzymes. 6,7 As the liver processes a high toxic load, indicated by elevated liver enzymes in the blood; thioctic acid renders these toxins harmless and opens pathways to accommodate the toxins. Thus liver enzyme levels (SGOT and SGPT) are lowered which reduces strain on the liver that jeopardizes its function. 9 The fat-soluble vitamin thiamine tetrhydrofurfuryl disulfide must be present in complementary amounts to work with and enable lipic acid. 10 Thioctic acid has been used in treatment of alcoholics as a liver protectant. 8,9 Physicians are learning to use it as a therapeutic agent for virally- or drug-induced liver damage, and in the treatment of diabetic neuropathy. 4,5 Additionally, laboratory studies on HIV-infected T-cells treated with thioctic acid showed inhibition of HIV by reducing replication rates of active virus. 10,11
Thioctic acid is manufactured by Cardiovascular Research of Concord, California; and is packaged in capsule form (50 mg/capsule). Supplemental thioctic acid ensures a supply of this micronutrient as the liver demands, and allows efficient processing of blood metabolites. Toxicity has only been documented in animals when fed thioctic acid 1/3(!) of their body weight or more. Two hundred to 250 mg daily is needed to achieve the results desired, lower liver enzyme levels and an easing of stress on the liver. You will observe results (decreases in SGOT and SGPT) within one to two weeks.
This sulfated polysaccharide from licorice roots has been isolated and prepared by Japanese pharmaceutics for 40 as a treatment for chronic liver disease and stomach ulcer treatment. It is available in tablet and I.V. forms. More recently, Japanese researchers have been evaluating glycyrrhizin in HIV therapy. Glycyrrhizin is a multifactorial medication, it acts upon several different molecular systems in improving health. It is a lectin, and has many binding properties which uniquely protects and supports liver cells, disallowing destructive effects of toxins. These binding properties have recently been shown to clump HIV and other fat-coated microorganisms, where they are scavenged by macrophages, and killed. It inhibits inflammatory processes of all sorts, including hepatitis and allergies, all of which produce destructive oxidants in the blood. Thus, glycyrrhizin prevents formation of oxidants and free radicals. Glycyrrhizin acts as an antiviral, an anti-inflammatory and protectant/preventative medication. 12 For the liver, the reduction of free radical oxidants in the bloodstream relieves the depletion of hepatic glutathione used in reducing these oxidants. Restoring glutathione, especially in the liver where it is a major antioxidant, aids in relieving liver stress. 13
Milk thistle (Silybum marianum) is a plant used for centuries as a medicinal agent, known for its abilities to cure jaundice, cleanse the blood and "open up" the liver and gall bladder to proper functioning. It is a common weed in recently abandoned fields, found all across the temperate climates, but originated in western and central Europe. 14 It is available in tincture form, or in tablets where the active agent, silymarin, has been concentrated. It has numerous modes of action on the liver, causing cell regeneration, increasing the vital antioxidant glutathione, increasing tolerance for processing toxins like alcohol, and normalizing drug-induced SGOT and SGPT levels. 15,16,17 Side effects have yet to be uncovered, but since this medicinal has been used for thousands of years without reported untoward effects, therapeutic doses are quite safe.
There are other liver therapies, but these three have significant research and history, as well as anecdotal successes reported by PWHIV. Additionally, they contribute to immune modulation and antiretroviral action, especially glycyrrhizin. 10,12 Thioctic acid and milk thistle are often found in apothecaries and better health food stores. Cardiovascular Research's brand of thioctic acid is formulated with fat-soluble thiamine. You should check other brands to be sure the formulation includes this thiamine derivative. Nutrient-oriented buyer's clubs for PWA's carry all three products; check out Healing Alternatives Foundation in San Francisco(415-626-2316), and DAAIR (212-725-6994) in New York City for supplies and prices; or call the STEP Treatment Hotline to request a listing of various buyers' clubs nationwide.
Vic Hernandez is an HIV/AIDS treatment research consultant.. He is an active member of Direct AIDS Alternative Information Resources (DAAIR) New York City, a non-profit organization formed to support the needs of persons living with HIV/AIDS through the use of natural therapies (particularly nutrients) and minimally toxic drugs.
Culpepper, N. Culpepper's Complete Herbal and English Physician Enlarged. Glenwood IL; Meyerbooks, 1990.
Mowrey, D. Ph.D. New Hope for Liver Health: Milk Thistle. Director Science, Mountain West Institute of Herbal Science. Salt Lake City, Utah.
Shook, E.E. Elementary Treatise in Herbology. Beaumont CA; Trinity Center Press, 1974. Williams, P.L., and Warnick, R., eds. Gray's Anatomy. Edinburgh; Churchill Livingston, 1989.
by Terri Ferreira, R.ph.
Mycobacterium Avium - complex (MAC) is a term referring to two closely related species of mycobacteria, M.avium and M. intracellular. MAC is the most common cause of disseminated bacterial infection in patients with AIDS with a prevalence rate up to 40%. Disseminated mycobacterium avium - complex infection (DMAC) usually occurs in people with advanced HIV whose CD4 and T-lymphocyte counts fall below 100 cells/ml. DMAC is a progressive illness presenting with symptoms of fever, night sweats, weight loss, anorexia, diarrhea and abdominal pain. Signs of disseminated MAC include enlarged lymph nodes, enlarged liver and low blood counts.
The treatment of DMAC was debated over the first decade of the AIDS epidemic due to early multi-drug treatment failures and controversy regarding the impact on morbidity and mortality. Since then, new drugs with increased potency have been introduced and studies have been successful in demonstrating that DMAC contributes to both morbidity and mortality in patients with AIDS. Furthermore, clinical studies have demonstrated that the treatment of DMAC can substantially reduce the impact of the disease by decreasing bacteremia (bacteria in the blood), diminishing symptomology and improving patient survival. In June 1993, the U.S. Public Health Service Task Force responded to the ongoing debate by publishing guidelines on both the prophylaxis and treatment of DMAC for adults and adolescents infected with HIV. These guidelines are current in practice today, although there are clinical trials ongoing to determine optimal drug therapy for DMAC. The remainder of this article will only address the treatment of DMAC. For information regarding prophylactic therapy refer to MMWR Vol. 42, No. RR-9 (June 25, 1993).
The following is a summary of the recommendations made by the task force for the treatment of DMAC:
Table 1 provides information on these drugs including dosing, adverse effects and drug interactions. Unfortunately, all these medications cause gastro-intestinal problems. This presents a dilema for the DMAC patient already suffering abdominal pain. A few of these medications are available as intravenous therapy: ciproflaxin, rifampin, and amikacin, although very costly, for those unable to tolerate oral medications. To further complicate the picture, many people with AIDS fail to adequately absorb drugs. In this case, dosages may need to be increased to achieve efficacy.
The medications used to treat DMAC interact with each other (i.e. additive liver toxicity and with other medications. It is important for people to check with a physician and pharmacist when taking these medications.
Other agents under investigation and/or in clinical trials for the treatment of DMAC include Sparfloxacin (a Fluoroquinolone like Ciprofloxacin): immunomodulatory agents such as recombinant tumor necrosis factor, interleukin-2, interferon-v and liposome encapsulation of drugs.
Terri Ferreira, R.ph. is a Consultant Pharmacist at Evergreen Pharmaceuticals. Currently she is the Consulting Pharmacist for Bailey-Boushay House and other facilities in the Seattle area.
Table 1: Medications for the Treatment of DMAC