Issues Regarding Treatment
- When to Change
- Side Effects and Toxicity
The abandonment of the "hit early and hit hard" philosophy in AIDS treatment has brought to light many complex issues that must be confronted and repeatedly evaluated as treatment continues. The foundation of HIV treatment is now long-term management of a chronic condition. Treatment is complicated by difficulties for both the patient and practitioner, including drug complications, failure of a regimen due to drug resistance, difficulty in adhering to the treatment protocol due to the number of medications or their toxicity, complexity of the regimen, and lack of definitive data proving the advantage of one type of therapy or drug combination over another. Other issues that must be addressed include not only when to start therapy, but also when to modify therapy, how to modify therapy, and when to stop or withhold therapy.When to Begin HAART.
Unfortunately, no data exist that clearly define when to start antiretroviral therapy. The period of primary HIV infection or "acute HIV syndrome" is often asymptomatic. We do know that when drugs that have unpleasant side effects are given to patients who have no symptoms, poor compliance is the norm and treatment failure is the result. International guidelines vary in these initial recommendations. British guidelines are more conservative than those of the International AIDS Society (British HIV Association 2000; Carpenter 2000; Fisher 1995/2000). After beginning therapy, only 30-50% of patients reach a viral load below 50 copies per cc, the amount required to block drug resistance.
The sobering facts are that the virus develops resistance during therapy and that a resistant virus can be transmitted to another person as a first infection, making initial treatment selection much more difficult. Treatment is now begun later in order to get maximum benefit with the least toxicity. Even without antiretroviral therapy, median survival is approximately 10 years, and persons may remain without symptoms for almost all of that time period. In the United States, for recommendations about when to start treatment, see the section on Diagnosis and Testing. Even using these guidelines, treatment of HIV is sometimes not recommended. The treatment of serious infections and malignancies may take precedence over the treatment of HIV itself.Monitoring of Therapy.
As discussed previously, both CD4 counts and viral load counts are important lab parameters to track during treatment. A minimum of two CD4 counts and two HIV RNA measurements of viral load should be done on two separate clinic visits before beginning or making changes in therapy. There may be intermittently undetectable virus, but this count varies. According to Carpenter (2000), viral load should rapidly decrease after starting therapy. Achieving an early response by weeks 4-8 of therapy usually indicates HIV will be suppressed successfully. Viral load should be checked within 2 months of beginning or changing therapy; then monthly until the goal of levels below detection is reached; and then every 2-3 months.
Transient viral rebound can be seen when vaccinations are given, causing intermittent infections and treatment lapses. Viral load levels should not be used to guide therapy during these times. Steady increases in the CD4 count can take place during the first several years of therapy. Monitoring drug levels in the blood has not been proven to be definitely helpful, although trough (lowest) levels of protease inhibitors do correlate with the success of viral suppression. Drug resistance testing is routinely done, and if resistance develops, the treatment regimen should be changed in some way. It is important to perform drug resistance testing in a lab with meticulous quality control. This drug resistance testing can determine if a drug is not active against the patient's virus. However, a negative test of drug resistance does not guarantee that the drug will be effective against the patient's particular HIV virus.When to Change Therapy.
The usual reasons for making a change in therapy are poor adherence to the regimen, side effects, and drug failure due to the development of drug-resistant strains of HIV. This decision should not be made on the basis of CD4 cell count alone. As drug resistance develops, the viral load steadily rises, and there is most often a decline in CD4 count. Occasionally a "discordant response" occurs, with increasing viral load and CD4 stabilization or even increase. Again, there is no definite evidence from randomized trials to guide the decision in this area. Failure in reaching the target viral load in 8-16 weeks of therapy indicates that a change in therapy and possible nonadherence issues should be discussed with the patient. Not reaching the target viral load in 24-36 weeks of therapy means the entire regimen should be changed. The development of resistance, even if initial therapy was successful, means therapy should be changed. Therapeutic failure is known to occur with all of the existing regimens.Side Effects and Toxicity Related to Therapy.
Adverse effects include toxicity to the mitochondria (which are responsible for producing energy for all bodily functions in all cells) and disorders in fat and glucose (blood sugar) metabolism. These lipid (fat) and glucose metabolism disorders are frequent in patients taking triple therapy, especially if the therapy contains PIs. However, metabolic disorders such as these have also been found in association with the disease process of AIDS and even in the absence of drug therapy. Theoretically, these disorders of lipids and cholesterol-like compounds could lead to increases in heart and vascular disease. Lactic acidosis, a serious metabolic disorder, is found in persons who have taken NRTI drugs for a long time. Also, the large number of pills and frequent dosing requirements are unacceptable to some patients and therefore limit therapeutic choices. Rashes are often seen with NNRTIs drugs.Changing Therapies.
Once a decision is made to modify therapy, the choice of which drugs to select must be made. A drug to which the patient's HIV virus is resistant would not be chosen. A single drug may be changed in the absence of virologic failure (viral load count too high), such as for adverse drug effects or inability to comply with the complex regimen. Virologic failure can also occur with noncompliance to the regimen, and, in this case, it is also acceptable to change one drug to another drug of similar or higher potency. If the patient has persistently high viral load levels, this usually indicates drug resistance. The best approach to this situation is to change all drugs in the regimen. In the case of patients who have had multiple episodes of resistance development and virologic failures, adding one new drug is not beneficial and should be avoided. Six or more drugs recycled from the three different classes may have short-term antiretroviral activity and could be an option. This six-drug regimen is most effective for patients who never received an NNRTI; however, the regimen is complex and riddled with problems of toxicity, compliance, side effects, and cost.Other Treatment Options and Issues
Host Defense Potentiators.
- Host Defense Potentiators
- Drug Holidays
- Single-Drug Therapy
- Natural Killer Cell
- Micronutrient Depletion
Host defense potentiators (HDPs) can restore or augment the responsiveness of the host to lympho-cytokines or other intrinsic bioactive factors that aid in generating an immune response. HDPs, such as hydroxyurea, may be added to an HIV treatment regimen to maximize the potency of the drugs used, while keeping the dose as low as possible. Hydroxyurea has been used for many years in treating certain types of cancers by inhibiting the virus's reproductive cycle, thus suppressing replication. In the treatment of HIV, hydroxyurea inhibits human cell factors that are needed by HIV to reproduce. The efficacy of HDPs in AIDS treatment is still unproven.Drug Holidays.
Time off from a drug regimen may be used for various reasons. There is anecdotal evidence that interrupting therapy in patients near the time of primary infection and while their viral load is still undetectable may reduce the level of viral rebound in therapy cycles to follow. In patients who have failed with all three classes of drugs, a drug "holiday" before starting a multiple drug regimen, such as "mega HAART," may lead to the appearance again of a wild type of virus or nonresistant strain. Theoretically, drug holidays could be used to give patients a rest from the demands of therapy without reverting to the development of clinical disease, assuming viral loads and CD4 cell counts were monitored. All of the approaches that theoretically suggest drug holidays might be useful are so far unproven and are only appropriate for clinical investigational trials.Ineffectiveness of Single-Drug Therapy Cycles.
Treating in cycles of therapy has only been tried with single-drug therapy and has not been successful. Induction/maintenance therapy is started with an intensive phase of drug treatment; when a clinical endpoint is reached, which may be termed "remission," a less intensive maintenance regimen is continued. Trials have been done that have dropped from three or four drugs down to two drugs; however, they were unsuccessful.Natural Killer Cell Function.
A component of the immune system is the natural killer (NK) cell. The function of NK cells is extremely important in protecting against the development or progression of any infection, including HIV. In determining treatment recommendations for AIDS, the CD4 count and viral load are routinely used. However, for a more complete assessment of overall immune function, a measure of NK cell function is also helpful.
Unlike other immune cells that must first obtain information from CD4 helper cells, the NK cell can target and kill antigens both inside and outside of cells without "conferencing" with other immune cells. Acting on their own volition, NK cells can target and kill viruses, cancer cells, bacteria, and many other antigens (Clayman 1989). However, NK cell function can be impaired by the failure of some infected cells to present antigens on their cell surfaces, which signal the NK cell. This disables the NK cell, causing it to not "see" the infected cell directly, thereby diminishing its ability to destroy it. Multitest CMI is especially valuable in this situation when used with an NK function test. A high NK function score of 100 or more lytic units indicates that the NK cells can "see" the infected cells and have the energy to destroy them. A high lytic unit value implies correct NK function, but coupled with a low Multitest CMI score, or anergy, would still indicate immune dysfunction because diminished antigen presentation will blind the NK cells from "seeing" all infected cells that need to be destroyed.
In this way, both tests are used synergistically for a broader evaluation of immune function. Multitest CMI and NK function tests may be considered to be the polygraph test for the efficacy of all AIDS treatment protocols. High CD4 counts and low PCR viral loads are used as immune markers, but they are not always indicators of actual immune function. High CD4 counts and low PCR viral loads without correct immune functioning will not protect you from PCP, CMV, TB, or other opportunistic infections (OI). Actual measurable improvements of immune function may, even with low CD4 cells and high PCR viral loads, offer protection from OI.Micronutrient Depletion.
Direct relationships have been found between various micronutrient levels and transmission and progression of AIDS. Apoptosis, or programmed cell death, is responsible for the death of CD4 cells in AIDS. Recall that CD4 cells are lymphocytes that can fall to dangerously low levels in AIDS patients. An effective therapeutic regimen will slow the apoptotic death of CD4 cells. According to Romero-Alvira et al. (1998), "Anti-apoptotic/antioxidant strategies should be considered, alongside antiviral strategies, in order to design a more efficient therapy for AIDS in the near future."
Both vitamins A and B12 help support CD4 counts. Interestingly, deficiencies in vitamin A increase the rate of vertical transmission of HIV (that is, transmission from mother to child). Vitamin A, vitamin B12, and zinc all affect the progression of HIV to full-blown AIDS. B12 levels relate to the development of AIDS dementia. Vitamin E levels also relate to the symptomatology and progression of HIV (Tang et al. 1997; Patrick 2000).
Selenium is a micronutrient necessary for proper functioning of T-cells. It may also improve the person's response to all infections by affecting interleukin production and the immune response originating from the thymus gland. In general, selenium levels decline as HIV disease progresses (Look 1997). A low level of selenium has been identified as an independent risk factor in predicting death from HIV in both adults and children. Supplementing with selenium benefits by increasing the activity and assisting with the function of helper T-cells (a type of thymus-derived lymphocyte or white cell).
Higher levels of tumor necrosis factor alpha (TNF-alpha) and other cytokines are seen in HIV and are associated with neurologic damage (Seilhean et al. 1997; Bjugstad et al. 1998; Ryan et al. 2001), Kaposi's sarcoma, AIDS wasting syndrome, and increases in viral replication in the host (Mellors et al. 1991). Selenium supplementation decreases some of the effects of TNF-alpha and thus can reduce the likelihood of developing these complications, as well as suppressing the enhancing effects of TNF-alpha on HIV-1 replication (Hori et al. 1997; Tolando et al. 2000). Selenium declines as a result of HAART, yet it reduces zinc deficiencies (Rousseau et al. 2000).
Zinc levels decline more rapidly in females than in males with HIV. Diarrhea and weight loss are common symptoms of zinc deficiency. There is also an associated higher viral load and lower CD4 count in HIV patients with lower zinc levels. Even while undergoing antiviral triple therapy, due to the importance of zinc, HIV patients should be monitored for zinc deficiencies and supplemented when necessary in order to optimize therapeutic success (Wellinghausen et al. 2000). Lower zinc levels are also associated with severe decline in immune status (Rousseau 2000). Additionally, low magnesium levels have been shown to be related to HIV symptoms and progression of the disease process (Skurnick 1996; Patrick 2000).Boosting Glutathione Levels
- Vitamin C and NAC
- Alpha-Lipoic Acid
- Whey Protein
It is now widely understood that AIDS is associated with a deficiency of glutathione that leads to the generation of enormous levels of oxidative stress that damage and kill otherwise healthy cells throughout the body.
As is the case with so many disease processes, AIDS is a disease mediated by oxidative stress and free-radical injury. HIV-induced cellular depletion of glutathione is associated with free-radical injury to numerous immune system components. Thus, improvement of antioxidant status would seem to be helpful in lessening the severity of the disease or disease progression. Several vitamins and other substances act as antioxidants in the body to mitigate oxidative stress and its resulting cellular damage.Vitamin C and NAC.
The antioxidants vitamin C and N-acetyl-cysteine (NAC) are particularly important in maintaining glutathione levels. Studies have shown that healthy glu-tathione levels relate to maintaining adequate lymphocyte function, which dampens HIV viral replication (Aukrust 1996; Herzenberg et al. 1997; Muller 2000). In patients with the most severe disease, supplementation with vitamin C and NAC led to higher intracellular levels of glutathione and significant improvements in CD4 counts and viral load. NAC also counteracted apoptosis (programmed cell death) and helped to maintain the HIV-damaged lymphocyte population (Malorni et al. 1998). NAC is an amino acid containing sulfur, and sulfur is massively lost in HIV-infected patients. Supplementation with NAC is recommended in HIV-positive persons both with and without receiving antiretroviral therapy. A study by Breitkreutz et al. (2000) showed an improvement in immunologic functioning via NK cell and T-cell functions.Alpha-Lipoic Acid.
Alpha-lipoic acid facilitates energy production through cellular respiration. In addition, research has discovered that alpha-lipoic acid plays a truly central role in antioxidant defense. It is an extraordinarily broad-spectrum antioxidant able to quench a wide range of free radicals in both aqueous (water) and lipid (fat) domains. Moreover, alpha-lipoic acid has the remarkable ability to recycle several other important antioxidants, including vitamins C and E , glutathione , and coenzyme Q10, as well as itself. For these reasons, alpha-lipoic acid has been called the universal antioxidant, approaching an "ideal" antioxidant.
In addition to serving as the hub of the body's antioxidant network, alpha-lipoic acid can boost the level of intracellular glutathione. Besides being the body's primary water-soluble antioxidant and a major detoxification agent, glutathione is absolutely essential for the functioning of the immune system. Raising glutathione levels has also been shown to alter the cytokine balance in favor of a Th1 immune response mode (the anticancer and antiviral mode of immune defense) (Peterson et al. 1998).Whey Protein.
Whey is a complete protein derived from milk that contains all essential and nonessential amino acids, along with the highest branched chain amino acid content found in nature. Whey has the highest biological value (BV) of any available protein (104); the next highest BV is for whole egg (100). Whey protein appears to be unique among proteins in its ability to improve immune function, elevate cellular glutathione levels, and extend lifespan.
As noted earlier, scientists have found that decreased glutathione levels were associated with diminished immune function. In particular, they have shown that intracellular glutathione is directly related to the ability of lymphocytes to respond to mitogenic stimulation in animals (such as challenge with sheep red blood cells)--a measure of the humoral immunity that protects us against a variety of diseases from measles and chicken pox to influenza and pneumonia. Scientists have also shown that humoral immune response, which involves the production of antibodies, requires rapid protein synthesis, which, in turn, requires an adequate dietary intake of essential amino acids (all of which are found in abundance in whey protein).
Low levels of glutathione also contribute to the catabolic state of AIDS wasting. The intestinal impairment caused by glutathione deficiency often manifests as inflammatory bowel disease, a common problem in AIDS patients that prevents effective absorption of vital nutrients into the body (Sido 1998). In addition to enhancing immune function, whey protein can help AIDS patients maintain their weight.
Macrophages are another component of the immune system that rely on glutathione. Macrophages are very large immune cells that protect the body by swallowing and destroying foreign particles and cancer cells. The production of a substance called leukotriene C by macrophages is essential for them to reach invading organisms. When glutathione levels are low, production of leukotriene C by macrophages is inhibited.SAMe.
SAMe (S-adenosylmethionine) is the product of a biochemical reaction between adenosine triphosphate (ATP) and methionine. Half of all methionine in the body is used in the liver to make SAMe. SAMe has been compared to ATP in its importance for the body. It is used in many different cellular processes, from replication to biochemical reactions that create melatonin and phosphatidylcholine. SAMe is particularly important for the liver because glutathione is synthesized from it. Glutathione is crucial for liver function. A good portion of liver SAMe is turned into glutathione. Glutathione is the liver's natural antioxidant (Vendemiale et al. 1989).
Apart from raising glutathione levels, SAMe serves as a methyl donor for a host of methylation reactions in the body. In this capacity, it may prevent and reverse liver disease because studies have shown it may be the most effective substance known to regenerate damaged liver tissue. SAMe's ability to regenerate damaged liver tissue is an important consideration because it may offer increased protection against hepatotoxic antiretroviral medications, perhaps even reversing their damage (Friedel et al. 1989; Chawla et al. 1990).
P. carinii is a common opportunistic infection (OI) in HIV. SAMe is required for the growth of this organism. Therefore, AIDS patients who are concerned about this common form of pneumonia may want to avoid SAMe. Merali et al. (2000) lists the inhibition of SAMe uptake and metabolism by P. carinii as a possible target for future therapeutics in associated cases of pneumonia.Proper Dosing of Glutathione-Boosting Nutrients.
As noted earlier, HIV-induced free-radical oxidation occurs in the presence of low levels of glutathione (Eck et al. 1989). Free radicals impair and destroy immune cells, and scientific studies consistently show glutathione deficiency to be a critical factor in the pathogenesis of immune suppression (AIDS). This suggests that supplementation with nutrients to boost cellular glutathione is crucial to protect against a primary mechanism by which HIV destroys immune function. Glutathione-enhancing nutrients are recommended in order of their importance in the following table.Nutrient - Dose
- NACa - 600mg 2 times daily
- Vitamin C (take with NAC) - 1,000mg 3 times daily
- Selenium - 200mcg 3 times daily
- Alpha-lipoic acid - 250mg 2 times daily
- Whey protein isolate - 30-60 grams of powder once daily
- S-Adenosylmethionine (SAMe) - 400-800mg daily
- Glutathione - 500mg 2 times daily
NAC is well tolerated by most people; however, some may be sensitive to it because it is a sulfur-containing compound. It is recommended to consume vitamin C in a dose of 3 times the amount of cysteine to mitigate cysteine's oxidation to cystine. Vitamin C is included in the appropriate dose in the list suggested above. Please remember if your liver is in a weakened state, it may not be able to convert NAC to glutathione. Taking NAC under these conditions may further suppress lymphocyte functions. A solution may be to consume glutathione supplements directly even though they are poorly absorbed and also to detoxify the liver under the guidance of a qualified health care practitioner. NAC can be resumed after liver toxicity has been resolved.
bAnyone taking SAMe should also take, on a daily basis, 800 mcg of folic acid, 500 mcg of vitamin B12, and at least 100 mg of vitamin B6 to protect against excess homocysteine accumulation in the blood.
c Controversy surrounds oral glutathione supplementation as some research has shown that this form of ingestion has not been efficacious, although other research contradicts this. Glutathione is strongly recommended for HIV patients who can afford this relatively expensive supplement.Continued
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