6 курс / Кардиология / Kartikeyan_HIV and AIDS-Basic Elements and Properties
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to be taken with food. The drug should be stored at room temperature. Its side effects are nausea, vomiting, diarrhea, and rhinorrhoea. Skin rash may be serious in rare cases. The combination of darunavir with RTV can increase blood levels of cholesterol and triglycerides. Since darunavir belongs to the sulfa group of drugs, history of allergy to sulfa drugs should be elicited from patients. Darunavir may interact with antitubercular drugs, antifungals, antiarrhythmics, several antihistaminics, sedatives, anticholesterol drugs, and drugs used for treatment of erectile dysfunction and migraine (Fact Sheet 450, 2006).
Fosamprenavir (FPV) – The adult dose is 700 mg twice daily (or) 700 mg twice daily with 100 mg RTV once daily (or) 700 mg once daily with 100 mg RTV twice daily. There are no food restrictions. The drug is reported to cause nausea, vomiting, diarrhoea, skin rash, circumoral paresthesia, and abdominal pain (Fact Sheet 401, 2006).
[G] PROTEASE INHIBITORS UNDER DEVELOPMENT
BRECANAVIR (GW640385, VX-385) has shown activity against wild strains of HIV and strains that are already resistant to current PIs. If used in a relatively low dose that would reduce side effects, it will be boosted with RTV. The side effects are mild to moderate; the most common is skin rash (Fact Sheet 440, 2006).
APPENDIX 5
ATTACHMENT AND FUSION INHIBITORS
Attachment inhibitors prevent HIV from attaching to the host cell. Fusion inhibitors block the ability of HIV to enter host cell by blocking the merging (fusion) of the virus with the host cell membrane. This prevents the HIV from entering and infecting human immune cells (NIAID, 2005). These drugs may prevent infection of a host cell by free virus in the blood stream or by contact with an infected cell. Most of these drugs are administered by injections or intravenous infusions because they are destroyed by the action of digestive acids (Fact Sheet 460, 2006).
Enfuvirtide (ENF, T-20)
The first fusion inhibitor enfuvirtide was approved for use as an ARV drug in the United States by the FDA in 2003. When HIV infects a human cell, it attaches itself to the cell and fuses with the cell membrane. Enfuvirtide stops this process of fusion and thus prevents infection of human cells by HIV. This drug has been studied in adults and children over 6 months of age. It is recommended only when the other ARV drugs are not effective. The drug does not exhibit
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cross-resistance with any other ARV drug (Fact Sheet 461, 2006). It is expensive and requires parenteral administration. It is therefore, not suitable for use in situations with resource limitations (WHO, 2003a).
Dose – The adult dose is 90 mg per injection given subcutaneously, twice daily. For children, the dose is based on their body weight. The drug cannot be administered orally because it is destroyed by digestive acids (Fact Sheet 461, 2006).
Side Effects – Almost everyone develops skin reactions at the site of injection. These reactions may manifest as slight erythema, itching, swelling, pain, hardened skin, or hard lumps. Each reaction might last up to 1 week (Fact Sheet 461, 2006). Other side effects include headache, dyspnoea, pneumonia, chills and fever, skin rash, haematuria, vomiting, pain and numbness in feet or legs, dizziness, insomnia, and hypotension (Fact Sheets 401 & 461, 2006).
Drug Interactions – Enfuvirtide may increase the blood levels of tipranavir and RTV. There are very few known interactions with other ARV drugs. Enfuvirtide has not been studied for interactions with all drugs or dietary supplements. Health care personnel should elicit history of use of medications or dietary supplements from patients (Fact Sheet 461, 2006).
ATTACHMENT AND FUSION INHIBITORS UNDER DEVELOPMENT
AMD 070 blocks the CXCR4 receptor on CD4 T-lymphocytes to inhibit HIV fusion.
AK 602 is being developed by Kumamoto University, Japan and is in early human trials. It blocks the CCR5 receptor on CD4 T-lymphocytes to inhibit HIV fusion.
BMS-378806 is an attachment inhibitor that attaches to gp120 and prevents attachment of HIV.
MARAVIROC (MVC, UK-427–857) blocks the CCR5 receptor on CD4 cells to inhibit HIV fusion (Fact Sheet 461, 2006).
VICRIVIROC (SCH-417690, formerly called Schering-D) blocks the CCR5 receptor on CD4 cells. Phase III trials were discontinued due to poor virologic control in patients who had never received ARV treatment. The study is likely to be repeated at a higher dose of the drug (Fact Sheet 461, 2006).
TNA-355 is a genetically engineered monoclonal antibody that blocks the CD4 receptor. It may be administered by intravenous infusion or as a twicemonthly injection.
INCB 9471 is in Phase I trials in healthy volunteers.
PRO 140 and PRO 542 block fusion by binding to a receptor protein on the surface of CD4 cells.
SIFURVITIDE is being developed in China and human trials are to begin soon (Fact Sheet 461, 2006).
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APPENDIX 6
MISCELLANEOUS DRUGS
NUCLEOTIDE ANALOGUE RTI (NTRTI)
TENOFOVIR or tenofovir disoproxil fumarate (TDF) – The adult dose is 300 mg orally, once daily. There are no food restrictions, but the drug is to be taken 2 hours before, or 1 hour after ddI. The side effects are usually mild and include nausea, vomiting, and loss of appetite. The drug should not be co-administered with 3TC and ABC unless additional ARV drugs are included in the regimen (Fact Sheet 401, 2006). The dose of the drug may vary if ARV drugs are combined. TDF, with or without emtricitabine, reduces infection rate in high-risk groups but its prophylactic use may accelerate emergence of drug resistance. TDF has reportedly been misused as a “party” pill by uninfected individuals who planned to engage in high-risk activity (Sepkowitz, 2006). The prevalence of resistance to TDF has increased from about 5 per cent before 1996 to at least 15 per cent between 1996 and 2003 (Masquelier et al., 2005).
INTEGRASE INHIBITORS
Once the reverse transcriptase enzyme changes the HIV’s genetic code from a single strand to a double strand, the double strand gets inserted into the genetic code of the host cell with the help of integrase enzyme. Integrase inhibitors block the action of integrase enzyme. Gilead 9137 (JTK-303), discovered by Japan Tobacco and now licensed to Gilead Sciences, has shown promising results in early studies. MK-0518 is moving to advanced stage of human trials (Fact Sheets 402 & 470, 2006).
ANTISENSE DRUGS
These are “mirror images” of part of the genetic code of HIV that lock on to the virus to prevent it from functioning. HGTV43 an “antisense” therapy that aims to produce CD4 T-lymphocytes that resist infection by HIV. VRX496 is another “antisense” drug. Both are under trial (Fact Sheets 470 & 480, 2006).
HYDROXYUREA
Hydroxyurea does not act on HIV directly, but enhances the action of ddI and d4T. When taken in the dose of 300 mg twice daily, hydoxyurea showed the best results in terms of tolerability and reduction of viral load. Since the drug blocks an enzyme produced by human cells, HIV cannot develop resistance to it. Hydroxyurea can slow down mutations in HIV so that it takes much longer for resistance to develop to other ARV drugs. It has been approved as an antimalignancy drug by the FDA (USA), but not as an ARV drug. Hydroxyurea is also
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effective in sickle cell anemia. The most serious side effect of hydroxyurea is pancreatitis that caused some deaths. Other side effects include nausea, vomiting, diarrhoea, weight gain, hair loss, peripheral neuropathy, and changes in skin colour. Since the drug can damage the bone marrow causing anaemia and neutropenia, hydroxyurea should not be co-administered with ZDV because both drugs can damage the bone marrow. Hydroxyurea can increase the side effects of ddI, cause serious birth defects, and reduce gains in CD4 cell counts (Fact Sheet 479, 2006).
MATURATION INHIBITORS
This group of drugs prevents maturation of internal structures in new virions. BEVIRIMAT (PA457), the first maturation inhibitor, has shown ARV activity and will probably be a once-a-day drug (Fact Sheet 470, 2006).
ZINC FINGER INHIBITORS (OR ZINC EJECTORS)
The inner core of HIV (the nucleocapsid) is held together by structures called “zinc fingers”. Zinc finger inhibitors (or zinc ejectors) are drugs that can break apart these structures and prevent HIV from functioning. Since it is believed that the nucleocapsid core cannot mutate very easily, a drug that works against the zinc fingers might be effective for a long time. However, zinc fingers are not exclusive to HIV and zinc finger inhibitors could have serious side effects. AZODICARBONAMIDE (ADA) has been tested but there are no recent reports on its development (Fact Sheet 470, 2006).
MICROBICIDES
Technically microbicides are not intended to be used as part of ARV treatment. Microbicides are anti-HIV substances that could reduce the risk of HIV infection during vaginal or anal intercourse. Ideally, microbicides should be used in addition to condoms. Currently, the only available effective tools for HIV prevention are male and female condoms that need cooperation of the male partner. But in situations where male partners object to use of condoms, microbicides could reduce the risk of HIV transmission. Use of these products can be controlled by women without the need for cooperation from the male partner. Women might be able to use some products without their partners’ knowledge. It is estimated that microbicides have the potential to prevent about 2.5 million HIV infections within 3 years, if they worked only 60 per cent of the time and used by only 20 per cent of women in 73 low-income countries. In addition, microbicides may prevent some other STIs besides HIV. However, success of microbicides depends on people remembering to use them correctly and consistently during each act of coitus. Microbicides can be incorporated in gels, foams, creams, thin films, or vaginal pessaries. The possible mechanisms of
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action include immobilising the virus, creating a barrier between the virus and epithelial cells, and preventing HIV from reproducing and establishing infection after it has entered the body. So far, no anti-HIV microbicide has been approved. Microbicides closest to approval are Carraguard, cellulose sulphate gel (also being studied as a contraceptive), PRO 2000 Gel, BufferGel, and Savvy (Fact Sheet 157, 2006).
IMMUNE THERAPIES IN DEVELOPMENT
Concept of Immune Restoration
“Immune restoration” is repairing the damage done to the immune system. A healthy immune system has a full range of CD4 T-lymphocytes that can fight different pathogens, including opportunistic organisms. The first CD4 cells that HIV attacks are the ones that specifically fight HIV. It is believed that increases in CD4 cell counts after ARV therapy is indicative of immune restoration. But, the new CD4 cells are probably copies of the existing types of CD4 cells. If some types of CD4 cells were lost, they do not reappear immediately. This could leave some gaps in the body’s immune defences. Immune restoration explores ways to fill these gaps (Fact Sheet 481, 2006).
When HIV enters the blood stream through any one of the routes of transmission, it is attracted by lymphocytes that have matured in thymus and bear CD4 receptors on their surface. It was believed that the thymus shrinks and stops maturation of lymphocytes to CD4 cells by the age of 20 years. Recent research reveals that thymus continues working, may be up to the age of 50 years. If the viral load is under control for a few years as a result of effective ARV therapy, the thymus might make new CD4 cells that could fill these gaps and restore the immune system. Older persons with HIV infection might need hormonal stimulation of thymus or thymus transplantation (Fact Sheet 481, 2006).
Approaches for Immune Restoration
Cell Expansion: The non-infected cells from the HIV-infected patient are multiplied in vitro and then infused back into the body (Fact Sheet 481, 2006).
Cell Transfer: Transfusing immune cells from patient’s HIV-negative twin or relative (Fact Sheet 481, 2006).
Cytokines: Cytokines are the body’s chemical messengers that support the immune response (Fact Sheet 481, 2006). Some immunomodulators use cytokines to increase the strength of the immune response to HIV (Fact Sheet 402, 2006). Cytokines under trials include – Ampligen, a form of interferon; Interleukin-2 (IL-2, Aldesleukin, Proleukin); Multikine, a mixture of several cytokines; and Bay 50–4798, a modified recombinant form of IL-2. Interleukin-7 is being developed as a general immune system booster. Tumour necrosis factor-alpha is an immune
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system protein that is overproduced in immune disorders. A TNF-alpha blocker (that blocks this protein) is under trial (Fact Sheet 480, 2006).
Gene Therapy: Gene therapy attempts to make the bone marrow cells immune to HIV infection. These genetically changed cells would then travel to the thymus and mature to form CD4 cells (Fact Sheet 481, 2006). Gene therapies under study include – M 870 that makes T-lymphocytes resist infection by HIV; genetically modified CD4 and CD8 cells that block attachment of HIV; RRz2, a ribozyme that attacks tat gene of HIV; and VRX 496, a genetic factor that infects T-lymphocytes and attacks genetic code of HIV (Fact Sheet 480, 2006). Also being studied are Mifepristone (VGX410, RU486) that interferes with the viral protein vpr; and BI-201, an antibody designed to block HIV’s tat gene (Fact Sheet 470, 2006).
Immunotherapy: HRG 214, a genetically engineered group of antibodies to HIV, is being studied for use as a passive immunotherapeutic agent. Dermavir, a novel immunotherapeutic agent that can be applied to the skin, is under study (Fact Sheet 481, 2006).
Other Immune Modulators: Immunitin (HE 2000), an immune regulating hormone has showed promising results in strengthening the humoral immune response. AVR 118 has showed promising results against AIDS-related wasting and anorexia. TH 9507, a growth hormone inducer, is being studied for treatment of visceral fat accumulation in lipodystrophy. Murabitide, that uses fragments of bacteria to stimulate the overall immune response, is being studied by Dr. Georges Bahr in France. Reservatrol is a chemical found in several plants and skin of red grapes. It protects plants against pathogens. It is being studied for immune boosting properties in HIV-infected persons. Reticulase, a nucleic acid, has shown increases in CD4 and CD8 cell counts, fewer opportunistic infections and weight gain in placebo-controlled studies. No toxic side effects have been reported so far. Reticulase is administered by subcutaneous injection. Zenapax (Dachzumab, anti-CD25) is being studied by National Institutes of Health, USA to reduce the viral load beyond what ARV therapy can achieve (Fact Sheet 480, 2006).
Dehydroepiandrosterone (DHEA): This is the steroid hormone produced by the adrenal glands. DHEA can be transformed in the body to testosterone, oestrogen, or other steroids. In normal adults, levels of the hormone decrease steadily after peaking at the age of about 20 years. HIV patients with lipodystrophy have very low levels of DHEA. A clinical trial is studying the effects of DHEA supplementation in HIV-infected individuals (Fact Sheet 724, 2006). Technically DHEA is not part of ARV treatment.
CHAPTER 17
TRADITIONAL ETHNOMEDICINAL SYSTEMS AND ALTERNATIVE THERAPIES
Abstract
Alternative therapies are tried by many HIV-infected persons on the assumption that these may enhance immune function, prevent, or treat various conditions. Alternative therapies usually presuppose that each individual possess an innate healing capacity and aim to restore strength and balance to the weakened system by using different modalities. Formal systems of traditional medicine are regulated by health authorities in many countries. But, unconventional non-formal therapies are not subjected to controls and patients may be vulnerable to exploitation by unscrupulous practitioners. Patients may not disclose their use of alternative therapies since they expect their doctors to taunt them for using such treatments. This leads to loss of opportunity to monitor benefits, side effects, and drug interactions. Health providers should acquire basic knowledge of alternative therapies, set aside prejudices, and facilitate open discussion since ridiculing these treatments will not prevent patients from trying them, but may stop patients from informing them. Combination of modern medicine with traditional or alternative therapies need not be discouraged unless they are expensive or interfere with prescribed treatment.
Key Words
Acupuncture, Acupressure, Alternative medicine, Ayurveda, Complementary medicine, Herbal medicine, Holistic treatments, Homoeopathy, Jamu, Koryo, Moxibustion, Serotonin syndrome, Siddha medicine, Traditional Chinese medicine, Unani-Tibb, Yoga.
17.1 – INTRODUCTION
Many different forms of healing have emerged in different parts of the world. Though the term “Western medicine” is applied to allopathy, which emerged in Western Europe during the 19th century, different medical systems, such as chiropractic, homoeopathy, and naturopathy have emerged in Europe and the United States (Tan, 2000a).
According to allopathic concepts, infectious diseases can be treated with medicines that act as “bullets”, targeting the infectious organisms and killing them. Traditional ethnomedical systems are very complicated, often overlapping with religion and philosophy, and embedded in people’s daily activities. The basic
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concepts of traditional ethnomedical systems are very different from those of Western medicine (allopathy) or Western naturopathy. Often, the human body is considered to be a microcosm of nature, with attributes similar to those of our environment. Individuals may be classified as “hot” or “cold” in terms of body type or personality. Illnesses are considered to be consequence of imbalances and healing techniques are means to restore the original balance. There is much overlap among traditional medical systems. Massage and use of natural products (derived from plants, animals, and minerals) is found in these systems. Dietary restrictions and fasting are also employed with the aim of “detoxifying” the body (Tan, 2000a).
HIV/AIDS care continues to be dominated by allopathic medicine, which centres on the germ theory. For people living with HIV/AIDS, traditional medical systems offer a bewildering variety of products and healing techniques that can be immediately tapped for treating symptomatic ailments such as pain, diarrhoea, nausea, and cough. For example, use of ginger is a remedy for nausea. Nausea can also be controlled by applying pressure on a Chinese acupuncture point called nei-guan on the wrist. These medical systems are potentially useful in strengthening the immune system and dealing with stress. Very little is being done about tapping traditional medicine for HIV/AIDS. It is unfortunate that many of those involved in HIV/AIDS care are sceptic about the role of traditional medicine. Such attitudes may lead to complete rejection of alternative forms of health care (Tan, 2000a).
Prior to the advent of the HIV epidemic, few people were familiar with the immune system. Now, the general public is curious about methods of bolstering immune system. Many HIV-infected persons use other systems of medicine or try alternative therapies in the belief that these may enhance immune function, prevent or treat various conditions. Alternative medicine has been variously called “natural”, “complementary”, “holistic”, and by numerous other appellations, which refer to particular modality or tradition (www.lifepositive.com). These therapies may be considered “complementary” when used with conventional medicine, and “alternative” when taken instead of conventional medicine (McKnight & Scott, 1997). Alternative therapies usually assume that each individual possess an innate healing capacity and the objective is to restore strength and balance to weakened system by using a variety of modalities, such as detoxification, foods, and herbs, which are tailor-made for the individual’s constitution and condition (www.lifepositive.com). The results of clinical trials in Western allopathic medicine reveal that simple lifestyle changes related to food and exercise can boost the immune system. Such discoveries are not new in traditional medical systems (Tan, 2000a).
17.2 – TYPES OF “ALTERNATIVE” THERAPIES
Formal Systems: These include Ayurveda, Siddha, Unani-Tibb, traditional Chinese medicine, and Homoeopathy. Traditional ethnomedical systems are “holistic” by nature – they aim to treat the whole individual rather than a specific disease or symptom. They address not only the physical aspect of the patient but
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also the mind and the spirit (www.lifepositive.com). Jamu, the traditional system of medicine practiced for centuries in Indonesia, is being developed by the Government of Indonesia into a safe and effective option (Chaudhury & Rafei, 2003). Koryo is the traditional system of medicine in People’s Republic of Korea, where health care is provided free of cost. Koryo is combined with modern medicine in University medical curricula (Chaudhury & Rafei, 2003).
Holistic Treatments: These rely on the individual’s interaction with the environment. Holistic treatments include yoga, herbal therapies, aromatherapy, reiki, and meditation.
Combination Therapy: Many practitioners have developed protocols for HIVinfected patients, using a mixture of herbal medicines, homoeopathy, acupuncture, nutrition, exercise, and massage (McKnight & Scott, 1997). Combination of allopathic drugs and traditional Chinese medicine are a common practice in China. However, the potential for drug–herb interactions remains to be investigated (Li et al., 2003).
17.3 – INTRICACIES
Frequency of Use: A survey in South Australia found that 52 per cent of adults had used at least one complementary medicine in the previous year, and 57 per cent had not told their doctor about their use of these products (ADRAC, 2005). Considering the frequency of use of other systems of medicine, it is necessary to conduct formal clinical investigations of these therapies with an open view (Golleridge & Riley, 1996). Though the medical profession has not ratified their use, formal systems of traditional ethnomedicine have enjoyed centuries of acceptance and credibility in the countries of their origin (McKnight & Scott, 1997).
Scientific Studies: Though a review of clinical studies on antimicrobial effects of several “natural” therapies has been published (Golleridge & Riley, 1996), very little information is available on interaction of other alternative treatments with modern orthodox medicine used in HIV-infected persons (McKnight & Scott, 1997). Some alternative therapies treat the whole person, not an illness. Moreover, the treatment is not standardised for a particular disease or condition. For a particular disease (as diagnosed by allopathic medicine), the prescribed treatment in traditional medicine would be based on the concepts of “imbalance in humours”, “disturbances in energy flow”, and “temperament” of the patients. It is difficult to evaluate the mechanism of action of traditional medicines because their classification systems and concepts, such as “hot” and “cold” have no equivalents in Western allopathic medicine (Tan, 2000a). Practitioners of traditional medicines usually dispense extracts that may contain multiple active ingredients and certain other agents that modify or alter action of the active ingredient or reduce its adverse effects. In clinical trials of these medicines, purified active ingredients may be administered by a different route and therefore results obtained may not be comparable. Since most alternative
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therapies are inexpensive and cannot be patented, it is difficult to find a sponsor to pay for the clinical trials (Fact Sheet 700, 2006).
Controls: Formal systems of traditional medicine, such as Ayurveda, Unani-Tibb, Chinese medicine, and Homoeopathy are open to scrutiny by the health authorities and their respective Councils. On the other hand, unconventional non-formal therapies such as aromatherapy, reiki, and meditation are not subjected to controls and patients may be vulnerable to exploitation by unscrupulous practitioners, who may have a vested interest in sustaining the credibility of their occupation. The popularity of these non-formal therapies can change rapidly (McKnight & Scott, 1997). Unregulated complementary medicines, including those obtained through the Internet may be contaminated with other drugs such as steroids, or with toxic heavy metals such as lead, mercury, or arsenic (ADRAC, 2005).
17.4 – ROLE OF THE PHYSICIAN
Many HIV-infected patients are unwilling to disclose their use of alternative therapies since they expect their doctors to mock or ridicule the use of such treatments. Thus, the opportunity to monitor benefits, side effects, and drug interactions is lost. Hence, the treating family physician or specialist should set aside such prejudices so that patients can freely disclose whether they use alternative therapies (McKnight & Scott, 1997). Basic knowledge of these therapies is essential for providers since ignoring or rejecting these treatments will not prevent patients from trying them, but may stop patients from informing their providers. Open discussion about realistic treatment and choices should be promoted. Combination of modern medicine with alternative therapies need not be discouraged unless they are expensive or interfere with prescribed treatment (Scott & Irvine, 1997).
17.4.1 – Dos and Don’ts for Health Care Providers
●Elicit history of use of alternative medicines from patients.
●Collect information about the therapy from persons administering the therapy and from persons who have undergone the treatment recently and in the past.
●Enquire about merits, demerits, side effects, costs, benefits experienced, and duration of time for benefits to accrue.
●Inform patients that currently, health insurance does not reimburse the cost of alternative therapy.
●Enquire about formal training and expertise of alternative medicine practitioner (www.lifepositive.com).
17.5 – AYURVEDA
Ayurveda (Sanskrit: ayu = life; veda = knowledge) originates from the Vedic times. It is believed that this system of medicine is being practised since 12th century BC (Chaudhury & Rafei, 2003). Atharvaveda has 114 hymns on treatment of diseases (Bannerman et al., 1983). Ayurveda is based on the theory of three humours