Antioxidants slow or prevent the oxidation of other chemicals: oxidation is a redox (short for oxidation/reduction reaction) chemical reaction that transfers electrons from a substance to an oxidizing agent. These reactions are a natural process and critical to life, but often involve the production of free radicals, which can start damaging chain reactions.

In essence, oxidation is how our bodies "rust."

Oxidative stress occurs when the body’s supply of antioxidants is insufficient to counter the various body processes (including the body’s immune responses to HIV) that generate unstable molecules (free radicals and other reactive oxygen species). Reactive oxygen species (ROS) damage all components of the cell, including proteins, lipids, and DNA.

While these ROS may serve an initial purpose (such as destroying a pathogenic organism like a virus or bacteria, or participating in many different normal body processes such as respiration or energy production) they then can cause cellular damage when they bounce around through the body, picking off electrons (in order to stabilize themselves) and damaging cells and tissues along the way.

Left unchecked, oxidative stress can lead to any number of dangerous conditions, such as cardiovascular disease. It is also though to play a major role in the development of cancer and neurodegenerative diseases (such as Alzheimer's and Parkinson's), as the brain is highly susecptible to damage from oxidative stress, due to its physiology (a high metabolic rate and high levels of polyunsaturated lipids), although it is not clear whether oxidative stress is the cause or consequence of these conditions.

Many studies, all the way back to the pre-HAART era, have shown that oxidative stress is consistently present in HIV disease.

Many different HIV disease processes contribute to oxidative stress: Increased levels of malondialdehyde (a marker for lipid peroxidation, the process in which the fats in cell membranes are damaged by free radicals) have been found in people living with HIV in a number of studies. The increased levels are seen even in early, asymptomatic disease stages. Therefore, much higher than normal levels of antioxidants are needed to quench the high levels of free radicals and reactive oxygen species, stopping the unstable molecules in their tracks (by donating an electron and thus stabilizing them) and preventing downstream body damage. This may be particularly important for the maintenance of immune cells, including both CD4s and CD8s.

The most important intracellular antioxidant is glutahione. Glutathione is also cofactor for the antioxidant enzymes glutathione peroxidase and glutathione transferase.

Research has shown that cellular levels of glutathione begin to decrease within weeks of HIV infection, and go downhill from there. The glutathione decrease may result from a combination of increased oxidative stress in the body and decreased synthesis of glutathione in the liver. The decreased level of glutathione has been shown to be tied to the death of immune cells. Proper glutathione levels are needed for competent lymphocyte function, including the activity of cytotoxic T cells. Even small decreases in cellular levels of glutathione are known to cause significant immune decline.

In addition, the liver uses glutathione for the detoxification of drugs. When levels of glutathione in the liver are too low, its ability to properly break drugs down may be compromised. Optimal levels of glutathione are also necessary for the immune defenses of the lungs, and deficiencies may increase the risk of lung infections.

Researchers believe that restoring glutathione levels can reduce oxidative damage, inhibit HIV stimulation by inflammatory cytokines such as tumor necrosis factor, and block viral production. It may also help restore the function of T cells.

Glutathione is important to immune function in a number of ways, including its effects on the synthesis and turnover of the interleukin-2 (IL-2) receptors that are needed for the use of IL-2, the body's natural growth hormone for T cells.

For all these reasons, restoring and maintaining glutathione levels may be one of the very most important things people with HIV can do for long-term survival.

The nutrients that help to stabilize glutathione levels include alpha-lipoic acid, N-acetyl-cysteine (NAC), glutamine, Vitamin E, and Vitamin C.

In addition to glutathione, there are many other antioxidants in the body that work in different ways and in different places to protect it against oxidative stress, so keeping all the antioxidants at optimal levels is important.

In addition to their possible role in slowing disease progression, a plentiful supply of antioxidants can help to protect against the development of cardiovascular disease, damage to the body caused by elevated blood sugar, and many problems related to mitochondrial damage, as further discussed below.

For anyone seeking protection against all such problems, it is very important to not just focus on one antioxidant: certain antioxidants work in one place in the body, and others in other places.

Some antioxidants, like Vitamin E, are fat-soluble and work predominantly in the fat-containing cell membranes, quenching lipid (fat) peroxyl radicals. Vitamin E is, in fact, the major chain-breaking antioxidant that protects membranes from lipid peroxidation. In other words, you need it to keep your cellular membranes strong and undamaged. However, it has little if any activity against radicals in the aqueous phase (in water - that is, such as the blood, lymph and other fluids).

Vitamin C, on the other hand, is water-soluble and works predominantly in the watery parts of the body, particularly the blood. Vitamin C works both directly as an antioxidant and indirectly, particularly by promoting increases in intracellular glutathione.

Alpha-lipoic acid works in both lipid and aqueous parts of the body. Alpha-lipoic acid also works in partnership with other antioxidants. For example, it has part of its effects working with vitamin E. Each antioxidant works in its own way and may have activity in fat-containing body parts, water-containing body parts, or both, working either singly or in conjunction with other antioxidants.

Conclusion: a broad spectrum of antioxidants is vital to provide protection throughout the body.

This is important because antioxidants at times become oxidized themselves. However, with a broad spectrum of antioxidants, they will work to "recycle" each other.

For example, vitamin C, Coenzyme Q-10, glutathione, and alpha-lipoic acid can recycle vitamin E from its oxidized form back to its reduced form (in which it again becomes an antioxidant).

Vitamin C can be regenerated through reaction with thiol compounds such as glutathione or alpha-lipoic acid. In fact, alpha-lipoic acid works so well in this regard that it has been shown to protect against the symptoms of vitamin E or vitamin C deficiency in animals fed diets deficient in those nutrients.

Remember that a diet that is rich in such nutrients is vital. The fruits, vegetables, legumes, and whole grains that are rich in a broad spectrum of these nutrients are the best possible base for your supplementation program.

Herbs and spices are also an important natural source of antioxidants. For example, curcumin is the pigment that gives turmeric (and the curry powders which contains it) its yellow color. It is a powerful antioxidant that may reduce cancer risk. Animal research has shown that curcumin may not only decrease the risk of developing cancer but may also reduce the spread of already present cancer to other parts of the body. Trials to assess its value as a cancer preventive are ongoing. Curcumin is a natural, non-toxic compound that does not appear to cause any side effects other than gastrointestinal irritation in a small number of people using higher dosages.

Legumes of all kinds are an often forgotten but also important source of antioxidants and should be included frequently in the diet. Combining a diet rich in antioxidants with supplementation of a broad spectrum of these important nutrients is the best approach to ensure that your body has all the weapons it needs to protect itself from the damaging effects that oxidative stress could otherwise cause.

It has been shown that mitochondrial dysfunction may be a cause of:
• fat changes in the body (especially lipoatrophy)
• neuropathy
• myopathy
• pancreatitis
• fatty liver
• white blood cell and platelet decreases and anemia
• (in its severest form) potentially lethal lactic acidosis, a condition in which lactic acid builds up in the blood, sometimes to life-threatening levels.

Research has also shown that:

1. The function of mitochondria (the energy factories inside cells) is affected by nucleoside analogues ("nukes" or NRTIs)...

2. That people with HIV taking antiretrovirals (ARVs) have depletion of mitochondrial DNA (mtDNA, the genetic building block of the mitochondria), and also that ...

3. Depletion of mtDNA is greater in patients with lipoapathy (lipodystrophy-associated fat loss).

Research has also shown that countering oxidative stress may be a key for preventing nuke-caused damage.

While diagnosis of either oxidative stress or mitochondrial problems is mostly done only in research studies (since most of the laboratory assessments that can show these are difficult to do and are not commonly available to individuals), the research evidence that these problems exist in people with HIV is compelling enough for us to believe that everyone living with this disease should be doing whatever is possible to counter them.

Among the most important nutrients for countering mitochondrial stress and the related potential problems are antioxidant vitamins and minerals, amino acids, and fatty acids.

Of particular importance are the nutrients that work together to maintain a healthy level of glutathione and the important enzymes for which it is a cofactor: N-acetyl-cysteine, alpha-lipoic acid, glutamine, selenium, and vitamins C and E. These and the other important antioxidants (including the carotenoids and coenzyme Q-10) are needed to counter the oxidative stress and help reduce the body wide inflammation that HIV infection causes.

Also of great importance is the amino acid carnitine. Acetyl-L-carnitine is a naturally occurring molecule in the body, derived from carnitine. It is involved in the normal transportation of free fatty acids into the mitochondria, and the normal oxidation of free fatty acids. Without carnitine, the mitochondria cannot function properly.

The B vitamins are also crucial nutrients for mitochondrial support. Thiamine (vitamin B-1) and riboflavin (vitamin B-2) are both important for intact mitochondrial function. Thiamine is a coenzyme of pyruvate dehydrogenase, and thiamine deficiency can lead to defective pyruvate metabolism and accumulation of lactate. Riboflavin is converted to flavin mononucleotide and dinucleotide, both serving as necessary cofactors for the electron transport chain. Recent reports suggest dramatic improvement of lactic acidosis after administration of these vitamins. The combination of carnitine, antioxidants and B vitamins may significantly help to counter mitochondrial toxicity and all the problems that can stem from it.

In one study, obesity-prone mice were given a nuke either with or without the antioxidants ascorbate (vitamin C) and alpha-tocopherol (vitamin E). The researchers found that several metabolic changes, including elevated triglycerides and increased lactate production (indicative of mitochondrial damage), occurred in high-dose, nuke-treated animals, and that concurrent treatment with antioxidants prevented the changes.

Studies of gene expression in adipose (fat) tissue also showed the potential value of antioxidant therapy. The expression of genes related to endogenous antioxidant activity was suppressed with high-dose nuke therapy. In addition, nuke therapy was associated with increased expression of TNF mRNA, whose activity promotes oxidative stress, and decreased expression of PPAR gamma, a key transcription factor for adipogenesis (the formation of fat in the body). These alterations in gene expression were prevented by antioxidants.

The bottom line to all of this is that the use of antioxidant nutrients along with nucleoside analogue drugs may well help to prevent the damage the nukes might otherwise cause. The same antioxidants could also help to counter the oxidative stress of HIV disease, in general, in ways that could protect immune cells and slow disease progression.

Kees Brinkman, MD, the pioneering researcher on the theory that mitochondrial toxicity is the main way in which nucleoside analogues harm the body, was also the pioneer in recommending this sort of nutrient combination to counter the toxicity. In one of his studies, serious lactic acidosis was reversed in all those given intravenous doses twice daily of L-carnitine (1000 mg) and B complex (an intravenous solution containing 100 mg thiamine, 20 mg riboflavin, 100 mg niacinamide, 10 mg pyridoxine and 10 mg dexpanthenol). This reversal is particularly impressive since lactic acidosis is generally estimated to be fatal in fifty percent of cases. In Dr. Brinkman’s study, all the patients given these nutrients survived.

A number of other studies and published case reports have also provided support for the idea of reversing mitochondrial dysfunction and the clinical problems that result from it—neuropathy, myopathy, bone marrow suppression (and resulting decreases in red and white blood cells and platelets), pancreatitis, fatty liver, lactic acidosis, and fat loss (lipoatrophy)—with nutrients. For example, based on the findings from a small study, Michael Youle, MD, from the Royal Free Center for HIV Medicine in London, has reported that oral acetyl-L-carnitine improved the symptoms of peripheral neuropathy (numbness, tingling, and pain) and resulted in positive changes seen with nerve biopsies.

A number of case reports from several different physicians have shown reversal of lactic acidosis or its less severe form, symptomatic hyperlactatemia, with nutrients. Most recently, widely respected researchers Grace A. McComsey, MD, and Michael M. Lederman, MD, have reported not only reversal of lactic acidosis, but also the successful resumption of nuke therapy in people with HIV given thiamine and riboflavin. The latter is very important. In any situation where hyperlactatemia or lactic acidosis have developed, it is considered optimal to restart antiretroviral therapy using nuke-sparing regimens. However, this option may not be available for heavily antiretroviral-experienced people with HIV since they may not be able to put together an effective combo without nukes. Thus, an approach that might prevent a recurrence of hyperlactatemia in those who require nuke-based therapy is very desirable.

Drs. McComsey and Lederman report that in two people with HIV who had developed symptomatic hyperlactatemia, the combination of discontinuing antiretroviral therapy and supplementation with thiamine (100 mg daily) and riboflavin (50 mg daily) resulted in elimination of symptoms and a return to normal lactate levels. In both patients, antiretroviral regimens were then restarted (in one, the same regimen as she had previously been on, and in the other, a different combination but one which also contained nukes) and the daily dosing with B vitamins was continued. After almost a year and a half, both people continue to do well on their regimens, with no return of lactate elevations or symptoms.

In an editorial that accompanied the publication of these case reports, Hélène Côté, PhD, and Julio Montaner, MD, internationally respected researchers at Vancouver’s British Columbia Centre for Excellence in HIV/AIDS, supported this approach. They note that nutritional deficiencies are more prevalent in people with HIV and have been associated with accelerated disease progression and with adverse drug effects, and then go on to say that both test tube evidence and anecdotal reports suggest that a number of nutrients, including vitamins B-1 and B-2, L-carnitine, and alpha-lipoic acid (an antioxidant), may be of potential value for reversing mitochondrial dysfunction. While noting that the current randomized clinical trials to evaluate some of these treatments have not yet provided efficacy data, they state that there is no evidence that the administration of these products may lead to serious adverse effects, and that they agree with McComsey and Lederman in cautiously endorsing treatment interruption, NRTI-sparing regimens when feasible, and the use of nutrient supplements for the management of NRTI-associated hyperlactatemia and lactic acidosis.

It seems clear that the better overall approach would be nutrient supplementation given at the beginning of HAART use in order to help prevent mitochondrial damage from the nukes. However, even in those with pre-existing problems, using nutrients in this way might help to reverse or prevent worsening of them, and allow continuation of drugs that might otherwise have to be permanently discontinued.

The most important antioxidants would include vitamin E (800 to 1,200 IU daily), vitamin C (1,000 to 2,000 mg, three times daily with meals), bioflavonoid complex (1 capsule with each meal), carotenoid complex (1 capsule with each meal), selenium (400 to 600 mcg daily, total from all sources, including your multiple), N-acetyl-cysteine (500 mg, two or three times daily), coenzyme Q-10 (100 to 500 mg daily), and alpha-lipoic acid (200 to 400 mg, three times daily).

Also important is supplementation with a B complex formula that provides at least 50 mg of most of the B vitamins, including riboflavin and thiamine (1 capsule with each meal) or a potent multivitamin/ mineral formula that includes the whole B complex in equally potent amounts (as directed, with meals).

Thiamine (vitamin B-1) and riboflavin (vitamin B-2) are both important for intact mitochondrial function. Thiamine is a coenzyme of pyruvate dehydrogenase, and thiamine deficiency can lead to defective pyruvate metabolism and accumulation of lactate - leading to lactic acidosis. Riboflavin is converted to flavin mononucleotide and dinucleotide, both serving as necessary cofactors for the electron transport chain.

Although B₁ and B-2 are the most important of the B complex in terms of mitochondrial support, it should never be forgotten that the B vitamins work together, that deficiencies of several B vitamins and many other nutrients are common in HIV disease, and that one missing link could sabotage the effectiveness of other nutrients. This is why a B complex formula or a multiple containing the whole B complex is so important and should always be given in conjunction with any separate supplementation with individual B vitamins.

Also crucially important is the amino acid carnitine. Carnitine is available in two forms: L-carnitine and acetyl-L-carnitine. There are both over-the-counter and prescription forms of L-carnitine. The brand name of the prescription form is Carnitor.

L-carnitine should be taken in doses of 1000 to 2000 mg, three times per day. Acetyl-L-carnitine (available over the counter) should be taken in doses of 500 to 1000 mg, twice daily. Note that acetyl-L-carnitine will release four times the amount of free carnitine into the bloodstream than an equivalent dose of plain L-carnitine.

If insurance or Medicaid coverage for Carnitor is available, this could provide substantial savings. If it is not, then the over-the-counter L-acetyl-carnitine may be best since it requires lower doses for the same effect.

Lactic acidosis symptoms include: fatigue, nausea, vomiting, abdominal pain, sudden unexplained weight loss, shortness of breath or difficulty breathing (respiratory symptoms), and neurological symptoms (including difficulty moving).

Experts urge anyone experiencing any of the symptoms that can indicate lactic acidosis to contact their physician immediately. Anyone who experiences any of these symptoms along with ascending muscular weakness, a rare but potentially lethal complication, is urged to stop antiretroviral therapy and see their physician immediately.

Acetyl-L-Carnitine Each bottle, 100 capsules. Each capsule, 500 mg of N-acetyl-L-carnitine.

Alpha Lipoic Acid (NYBC) Each bottle 180 capsules. Each capsule, 100 mg of high-grade alpha lipoic acid.

B-Right (Jarrow). Each bottle, 100 capsules of B vitamins.

Carotenoid Complex Ultra Antioxidant (NYBC) 90 capsules. Contains a wide range of carotenoid compounds including alpha and beta carotene, lutein, and lycopene.

E-400 (Jarrow) Each bottle, 250 softgels. Each softgel, 400 IU of vitamin E (d-alpha tocopherol) along with selenium from yeast (100 mcg) and mixed tocopherols.

Famil-E (Jarrow Formulas) Each bottle, 60 softgels. Each softgel, a blend of various forms of vitamin E (tocopherols and tocotrienols) derived from soy bean oil.

L-Carnitine 500 (Jarrow Formulas) Each bottle, 100 tablets. Each tablet, 500 mg carnitine from 750 mg carnitine tartrate (250 mg tartaric acid, 500 mg L-carnitine). This elemental, free-base, non-salt form of L-carnitine should not be confused with the commonly mislabeled tartrate, fumarate, or hydrochloride forms prevalent on the market today. This is the most concentrated form of L-carnitine available.

Methyl B-12 (Jarrow); 100 lozenges / 1000mcg methylcobalamin ea. Suggested usage: dissolve under tongue or chew one 1000 mcg lozenge every 2 or 3 days with a meal.

NAC Effervescent (Hexall/ACC Akut) Each box, 20 wafers. Each wafer, 600 mg NAC. Imported from Germany.

NYBC Super C (NYBC) Formerly named C, Mineral Ascorbates. Each bottle, 180 1000mg tablets

Thiol NAC Ultra Antioxidant (NYBC) Each bottle, 90 tablets, sustained release formula. Each tablet contains 500 mg of NAC, 200 mg of alpha lipoic acid and 250 mg of MSM sulfur.

Q-absorb Co-Q10 (Jarrow Formulas) - Available as 100mg/60 softgels or 30mg/120 softgels