Targeted Natural Interventions
Given the deteriorating effects of HIV/AIDS progression on the immune system and nutrient status, it is not surprising that nutritional supplements have been shown to be extremely beneficial in patients with HIV. Taking vitamin supplements lowered the risk of HIV disease progression in several studies.122-126 The use of vitamin supplements has also been associated with improved pregnancy outcomes in HIV-infected pregnant women,122,127 increased appetite in HIV-infected children,128 and better health and survival of children with HIV.129-131
In addition, nutritional supplements have been found to improve comorbidities associated with HIV. In HIV-infected patients being treated for tuberculosis (TB), for example, the consumption of micronutrients (vitamins A, B complex, C, and E, plus selenium) corresponded with a lower risk of TB recurrence and a significantly lower incidence of peripheral neuropathy (a side effect of TB treatment); this treatment also raised CD4+ and CD3+ counts.132 In a recent study of children with HIV, a daily supplement of vitamins A, B complex, C, D, E, and folic acid, plus zinc, iron, and copper (at levels based on recommended daily allowances) corresponded with faster recovery from diarrheal episodes and pneumonia.133
Antioxidants are widely known for their health benefits and may be particularly important for people with HIV. In 1985, Life Extension was among the first organizations to propose that patients with HIV/AIDS would benefit from taking high doses of antioxidants. Since then, many scientific studies have examined a wide range of nutrients and supplements for use in HIV/AIDS.
Under normal circumstances, metabolic processes in the body generate free radicals. At low/moderate concentrations, these reactive oxygen species are not harmful, but instead have a variety of beneficial functions. At high concentrations, however, they become extremely destructive. Normally, the human body keeps these levels in check by neutralizing free radicals with its own natural antioxidant defense system. However, some conditions can boost the production of free radicals and create oxidative stress—a condition in which the body's antioxidant defenses are unable to neutralize the overwhelming quantity of free radicals being produced. This can lead to cellular damage and the development of disease.134
HIV is associated with substantial oxidative stress,135-142 and reactive oxygen species participate in the progression of HIV to AIDS.139 As HIV progresses, antioxidant levels decline.143,144 Compounding this problem further is the fact that various HIV treatments have been shown to increase oxidative stress.141,145-147 Combined, these factors create an unhealthy environment that could be further exacerbated by the inadequate intake or poor absorption of nutrients that are commonly associated with HIV.148,149 Antioxidant micronutrient deficiencies are common among people with HIV.150 Reduced serum levels of vitamins E (a powerful antioxidant) have been associated with a higher risk of developing AIDS.151
Antioxidant supplements have been found to counteract some of the damaging effects associated with HIV. Taking supplements of vitamin E (800 IU per day) and vitamin C (1,000 mg per day) for three months lowered oxidative stress among patients with HIV and produced a trend toward a decrease in viral load.150 High serum levels of vitamin E have been linked with a slower progression of HIV.151 In large study in Tanzania involving 1,075 pregnant women with HIV, taking a daily multivitamin combination consisting of vitamins C (500 mg), E (30 mg), and various B vitamins and folic acid improved CD4, CD3, and CD8 cell counts and lowered the risk of fetal death, low birth weight, preterm birth, and small size for gestational age.127
Other antioxidants have also shown beneficial effects in people with HIV. A study involving 331 AIDS patients found that when patients received supplements including various carotenoids (natural pigments with antioxidant properties), as well as multivitamins and minerals, mortality rates were lower, and CD4 T-cell counts were higher, compared with patients who received the same supplementation without the carotenoids.152 In HIV-infected patients following a stable HAART regimen, the use of broad-spectrum, high-dose micronutrient supplementation with antioxidants corresponded with a 24% increase in CD4 cell count.153 Other important antioxidants that have been highlighted in the HIV literature include:
Glutathione. Glutathione is thought to be an extremely important antioxidant for HIV-infected patients, because it appears to interfere with HIV’s entry into its target cells.154 Glutathione deficiency—a common finding in HIV—is associated with compromised T-cell function and decreased survival.155-156 Some nutrients that offer a host of health benefits also assist in the production of glutathione. One of these is N-acetylcysteine.
N-acetylcysteine. N-acetylcysteine (NAC) is of particular interest for people with HIV/AIDS, because it reinstates glutathione levels and has been found to maintain glutathione concentrations,123,157 improve T-cell counts, and reduce viral load in patients with advanced AIDS.157-159 In many studies, the use of NAC oral supplements has correlated with better quality of life and patient well-being.160 A study involving 81 HIV-infected patients showed that eight weeks of oral NAC supplementation correlated with significant improvements in whole blood glutathione concentrations, as well as increased T-cell glutathione levels.161 NAC is known for exerting antioxidant effects against the activity of glycoprotein 120 (gp120), an HIV protein that induces oxidative stress during the infection of macrophages (a type of white blood cell).162
Green tea. Green tea leaves contain compounds called catechins, which have powerful antioxidant properties. The most abundant catechin in green tea, epigallocatechin gallate (EGCG), has also been found to suppress HIV.163 Kawai and colleagues found that EGCG can bind to T-cells and block the virus from attaching to them.164 When HIV comes into contact with a helper T cell in the human body, gp120 on its surface binds to a CD4 receptor on the surface of the T cell, ultimately leading to infection.165 In several studies, EGCG blocked the attachment of gp120 to CD4 cells with varying degrees of inhibition.164,166 EGCG also appears to lower the risk of HIV transmission—normally, fibrils in human sperm collect HIV viruses and deliver them to target cells. EGCG inhibits this activity and degrades the fibrils, thereby lowering transmission risk.167 EGCG has also been found to inhibit a variety of HIV subtypes at physiologic concentrations without damaging human cells.165 When coupled with other nutrients (vitamin C or lysine), green tea extract inhibited the production of HIV in chronically infected T cells; in latently infected cells, combining the green tea extract with vitamin C and amino acids resulted in significantly greater suppressive action than when any of the three were applied individually.168
Lipoic acid. This powerful antioxidant plays a central role in the defense against free radicals. It also recycles other important antioxidants, including glutathione,169 and decreases intracellular signaling that promotes inﬂammation.170 Taking a 300 mg supplement of alpha-lipoic acid three times per day for six months significantly elevated blood glutathione levels in a group of HIV-infected men and women aged 44‒47 years.171 In the lab, alpha-lipoic acid has been shown to inhibit HIV replication.172 Its ability to scavenge reactive oxygen species has been found to block nuclear factor-kappa B, a transcriptional activator that is instrumental in the regulation of HIV gene expression.173 In a study by Merin and associates, applying alpha-lipoic acid to cells infected with HIV completely stopped “initiation of HIV-1 induction by [tumor necrosis factor-alpha]."174
Carnitine (acetyl-L-carnitine). Acetyl-L-carnitine (ALC), also an antioxidant, boosts immune function and helps the body convert fat into energy. A number of studies have reported positive effects of ALC supplementation in people with HIV, especially its positive impact on the side effects of certain antiretroviral drugs. People with HIV who use the NRTIs zalcitabine, didanosine, or stavudine often experience peripheral neuropathy (peripheral nerve damage) and myopathy (muscle tissue disease). These outcomes have been observed in other NRTIs as well and can discourage patients from adhering to their medication regimens.175 However, ALC may help to mitigate these effects.
ALC is known to be involved with peripheral nerve regeneration.176 In a small study by Osio and associates (n=20), taking 2,000 mg of oral ALC each day for a month led to significant reductions in pain intensity scores among HIV-infected patients taking antiretroviral therapy.177 A larger study involving 90 HIV-positive patients with antiretroviral toxic neuropathy found that taking 500 mg of ALC intramuscularly twice per day for 14 days resulted in statistically significant improvements in weekly mean pain ratings versus placebo. When these patients subsequently took 1,000 mg of oral ALC twice per day for six weeks, symptomatic improvements were observed.178 A cohort study involving 21 HIV patients with NRTI-related neuropathy who were reviewed after receiving acetyl-L-carnitine for a mean of 4.3 years, 13 of the 16 patients who completed the study reported "very much or moderate" symptomatic improvement, and nine were pain-free.179 Hart and associates observed that when HIV-infected patients with antiretroviral toxic neuropathy took ALC treatment, 76% of patients experienced reductions in neuropathic pain.176 In a small study involving 21 participants, receiving 3,000 mg of ALC daily for 24 weeks corresponded with improvements in subjective pain ratings.180 A very small review and meta-analysis of 14 studies that described various analgesics did not find a significant benefit of taking 1 gram of ALC daily in treating HIV-associated sensory neuropathy; the authors pointed out that this review was limited by the small number of eligible studies, as well as the differences in study designs and size, which made comparisons across studies difficult.181
Certain vitamins have amassed a notable amount of clinical evidence to highlight their potential supplemental value in people with HIV.
Vitamin D. Vitamin D has a multitude of important functions within the human body, including its roles in supporting proper immune function, regulating bone metabolism, and maintaining calcium and phosphorus homeostasis.182,183 In people with HIV, vitamin D deficiency is common, as is lower-than-normal bone mineral density.4,184-191 Additionally, people with HIV appear to be at an increased risk of osteopenia and osteoporosis.184,190,192 In a recent review of the medical literature, McComsey and colleagues concluded that HIV infection should be regarded as a risk factor for bone disease.193
Deficient levels of vitamin D in HIV-infected individuals may be due to the virus itself185,190 as well as to the effects of antiretroviral treatment.184,185,189,190,194-197 Tenofovir, for example, is a widely used NRTI that is associated with low bone mineral density,198-201 as well as increased levels of parathyroid hormone (PTH). (Increased PTH levels are associated with decreased bone mineral density).202 Non-nucleoside reverse transcriptase inhibitors (NNRTI) have also been implicated in vitamin D deficiency; one in particular—efavirenz—has been linked to low concentrations of 25-hydroxyvitamin D (the form of vitamin D that is measured to determine vitamin D status in the human body).187,189,203
As people with HIV continue to live longer, bone loss prevention becomes an even more prominent consideration in this aging population.192 Some studies have shown a correlation between vitamin D status and CD4 counts,186,203-206 while others did not find this relationship.187,207 Interestingly, some studies that detected vitamin D deficiencies in HIV patients found that uninfected individuals also had low levels of vitamin D.186,187 In the United States, vitamin D deficiency is highly prevalent in the general population, regardless of HIV status.187
Beta-carotene/vitamin A. Beta-carotene is a plant pigment found in colorful fruits and vegetables and is converted into vitamin A in the body. It plays important roles in human growth, vision, and its support of the immune system. In people with HIV who were given 100,000 IU of vitamin A from beta-carotene daily for four weeks, white blood cell counts rose 66%, and T-helper cells rose slightly. Six weeks after cessation of the beta-carotene treatment, the immune-cell measurements returned to pretreatment levels.208 In a Uganda study involving 181 children with HIV, vitamin A supplementation was associated with significantly lower mortality rates, as well as improvements in chronic diarrhea and persistent cough.129 In another study, 687 children in Tanzania with pneumonia received 400,000 IU of vitamin A at baseline, as well as four months after discharge, and, then eight months after discharge. None of the children showed any signs of vitamin A deficiency when they started treatment. Vitamin A supplementation was associated with a 49% drop in mortality and a 92% decrease in diarrhea-related deaths. Plus, AIDS-related deaths plummeted 68%.130 In a population in South Africa that is not generally vitamin A deficient, children with HIV-infected mothers received 50,000 IU of vitamin A at ages 1 month and 3 months, 100,000 IU at 6 months and 9 months, and then 200,000 IU at 12 months and 15 months; this resulted in a significant reduction in morbidity from diarrheal disease.131 In a U.S. study involving HIV-infected children, the use of vitamin A supplementation prior to influenza vaccination muted the increase of HIV viral load post-immunization.209
Kennedy-Oji and associates observed improved weight retention among South African HIV-infected women with vitamin A supplementation.210 Conversely, vitamin A deficiency in HIV-positive women has been associated with increased mother-to-child transmission of the infection.211 However, the potential value of vitamin A supplements in pregnant women with HIV remains questionable, particularly as some studies have indicated that vitamin A supplementation may increase the HIV load in breast milk212 and may potentially elevate the risk of HIV transmission from mother to child.213 A recent review of studies encompassing 6,517 women with HIV in South Africa, Zimbabwe, Malawi, and Tanzania found that vitamin A supplement use among HIV-infected pregnant women correlated with improved birth weights; although the review found no evidence that vitamin A supplements increase the risk of mother-to-child transmission of HIV, the authors pointed out the moderate quality of scientific evidence in these studies.
B vitamins. B vitamins are responsible for an array of important functions within the body, including proper functioning of the brain and immune system.214,215 A number of reports have documented the beneficial effects of B-vitamin supplementation in people with HIV. In a study involving 281 HIV-infected patients, taking vitamin B6 (more than two times the RDA), vitamin B1 (more than five times the RDA), or vitamin B2 (more than five times the RDA) was independently associated with improved survival.216 In 108 HIV-infected men tracked over an 18-month period, low B12 levels at the beginning of the study were significant predictors of faster disease progression (as determined by CD4 cell count); although the development of B12 deficiency corresponded with a drop in CD4 cell count, the normalization of vitamin B12 levels corresponded with higher CD4 cell counts.217
Compelling evidence has also been accumulating for the following:
Omega-3 fatty acids. Omega-3 fatty acids are essential oils—they are not made in the body and must be consumed from external sources. Their anti-inflammatory and immune-modulating capabilities make them a valuable component of general health218; additionally, they appear to have therapeutic value for people with HIV who suffer from high triglyceride levels. A number of published medical reports have described changes in lipid metabolism, increased levels of serum triglycerides, and low levels of HDL cholesterol in people with HIV; moreover, combination antiretroviral treatment is reported to be a risk factor.219-222 A combination of dieting and omega-3 supplements (6 grams per day) was found to cause a major drop in serum triglycerides and levels of arachidonic acid.223 A small systematic review found that varying doses of omega-3 fatty acids caused significant reductions in triglyceride concentrations in people with HIV who were taking antiretroviral therapy.224 A study involving 48 HIV-infected patients (47 males, one female) with HAART-associated hypertriglyceridemia found that a 12-week course of omega-3 fatty acids (4 grams per day) led to significant reductions in triglyceride levels compared with placebo.225 Wohl and associates found that omega-3 fatty acids (in the form of fish oil supplements), plus dietary and exercise counseling, lowered fasting triglyceride levels in HIV-infected patients with hypertriglyceridemia taking antiretroviral medication; however, the difference was not significant compared with participants who received counseling without the fish oil supplements.226 In other studies of HIV-infected patients with elevated triglyceride levels who were using antiretroviral therapy, omega-3 supplementation was associated with significant decreases in triglycerides.227-229
Whey protein. Whey protein contains all essential and nonessential amino acids, which are important for maintaining an adequate immune system response. Whey is also an important supplement to help boost the body’s synthesis of glutathione, and various therapeutic benefits, including its immune-enhancing properties, make it of great interest to people with HIV.230 In a study involving 41 HIV-infected patients, those who received 40 grams of whey protein each day benefitted from a CD4 count increase of 31 cells/µL, versus the control group, which showed a decline of 5 cells/µL over the same 12-week period.231 Whey protein has been found to improve immune function, elevate cellular glutathione levels, and maintain muscle mass.230,232 Although large randomized controlled trials will impart greater insights into the potential benefits of whey protein in patients with HIV, the results so far are encouraging.233
Lactoferrin. Lactoferrin is derived from whey protein. It has been found to inhibit viruses by binding to viral receptor sites, thus preventing the virus from infecting healthy cells.234 In vitro studies show that lactoferrin is an effective inhibitor of HIV entry.235-237 It may also effectively inhibit initial HIV infection by blocking uptake into epithelial cells and transfer from dendritic cells to CD4+ cells.238
One study that compared 22 asymptomatic and 45 symptomatic patients with HIV to 30 healthy control subjects found that plasma lactoferrin levels were decreased in patients infected with HIV.239 In a six-month trial involving 22 HIV-1-infected children, oral lactoferrin caused a small decrease in viral load and an increase in CD4+ cell numbers; lactoferrin plus antiretroviral therapy was more effective than lactoferrin alone.240
Coenzyme Q10 (CoQ10). CoQ10 is present in all cells of the human body and is essential for proper cell function. Low levels of CoQ10 have been detected in people with HIV, and one study found that the level of CoQ10 deficiency corresponds with the stage of HIV infection.241 CoQ10 supplementation increases a number of immune parameters, including T-cell counts,242,243 an important consideration in HIV. A known antioxidant, it has also been found to contribute to the improvement of antioxidant defenses in HIV-infected men when administered as part of a regimen consisting of various antioxidants.224 In a case study involving a 52-year-old man with HIV, the patient suffered from drug-related skeletal myopathy caused by zidovudine. Daily supplementation of CoQ10 led to recovery, allowing the patient to continue his HIV drug treatment.225 Cherry and associates tested a water-soluble formulation of CoQ10 on cultured rat cells and found that it was effective in preventing neurotoxicity caused by d4T (stavudine; the HIV medication most commonly associated with neuropathy).246 Although studies on the effects of CoQ10 in HIV are limited, findings so far highlight this as a promising area for further study.
Selenium. Selenium is required for proper immune system function247 and facilitates a multitude of antioxidant activities in the body.248,249 It also decreases the effect of inflammatory cytokines, which may reduce the risk of developing neurological damage, Kaposi's sarcoma (a common HIV-associated cancer), and wasting syndrome.250 In people with HIV, selenium deficiency has corresponded with disease progression to AIDS or death.247,250,251 Shor-Posner and colleagues found that, among HIV-infected drug users, low selenium was a significant risk factor for developing mycobacterial disease.252 The HIV-inhibiting effects of selenium have also been observed in human cell cultures.253,254 In human studies, selenium supplementation has been found to reduce the incidence of diarrhea and decrease the number of patient hospitalizations.255,256
Zinc and magnesium. On average, patients with HIV/AIDS who have low zinc levels have a higher viral load and lower T-cell counts.257,258 A U.S. study of 231 HIV-infected adults found that taking zinc supplements every day for 18 months reduced the rate of diarrhea by more than 50% compared with placebo and lowered the risk of immunological failure by 400% (CD4 T cell counts of <200 cells/µL). However, it did not affect viral load, nor did it have an impact on mortality.259,260 In a literature review of six human studies involving 1,009 participants, the use of zinc supplements appeared to decrease opportunistic infection among adults and children with HIV. Only the adults were found to have higher CD4 counts; no adverse events were reported for adults or children from using zinc supplementation.261
Some antiretroviral drugs appear to chelate magnesium post-interaction with integrase. Therefore, supplemental magnesium may ensure that magnesium levels are not depleted.262
Probiotics. The human gut contains naturally growing bacteria that possess an array of beneficial functions; these include their ability to provide essential nutrients to the body, break down foods that are otherwise indigestible, via fermentation reactions, for example, and prevent the growth of harmful pathogens.263,264 However, the gut is largely compromised in patients with HIV. Acute HIV infection is marked by the dramatic depletion of CD4+ cells from the gastrointestinal (GI) tract. The GI tract is believed to be a particularly attractive target for HIV replication because the CD4 cells it contains are primarily CD4+ memory cells, which are preferential targets for HIV replication. (CD4+ "memory" cells are named as such because they "remember" antigens they previously encountered; this allows them to mount a more rapid response in subsequent encounters.) Moreover, the CD4+ cells in the GI tract express substantial amounts of CCR5—a receptor commonly used by HIV to enter and infect cells.265,266 As HIV depletes the gut of immune cells, intestinal epithelial permeability generally increases, and the human host becomes increasingly vulnerable to microbial invasion and disease progression.267
Probiotics are living microorganisms that, when provided in sufficient quantities, impart health benefits. Certain strains of probiotics are associated with reduced inflammation268-270 and permeability,271-273 both of which are of notable interest for patients with HIV. In several studies involving people with HIV/AIDS, consuming probiotics was associated with improvements in CD4 cell counts.274-276 More recently, Hummelen and colleagues found that adding probiotics to micronutrient-fortified yogurt did not boost CD4 cell count after one month, versus the same preparation without the added probiotics; although the added probiotics were well tolerated, and no adverse events were reported.277 Larger clinical studies with longer follow-up periods are needed to fully assess the impact of probiotic supplementation on people with HIV, but results so far are promising.
Reishi extract. Reishi (Ganoderma lucidum, or lingzhi) is a mushroom native to Asia that has been a highly valued part of traditional herbal medicine for centuries.278 It has been used to treat a wide range of health problems and promote long life, but is most commonly used as an immune-enhancing supplement.278,279 Several studies have demonstrated reishi’s immune-potentiating ability.280 A preliminary study included five female monkeys with simian acquired immunodeficiency syndrome, caused by inoculation with a virus that is closely related to HIV, called simian immunodeficiency virus. Three of the monkeys received reishi extract and two received no treatment for one year. Treated monkeys had a higher survival rate (2/3 vs. 0/2) and the surviving monkeys experienced a decrease in viral load and less damage in lymphatic and other tissues.281
Reishi’s active constituents include triterpene compounds and polysaccharides; these constituents are central to reishi’s anti-viral and anticancer effects, as well as reishi’s ability to stimulate immune cells.282-284 Triterpenes and related compounds from reishi have been found to have specific anti-HIV-1 activity.285-287 Reishi also contains proteins, fibers, phenolic compounds, minerals, vitamins, and other potentially beneficial constituents.278,279 Extracts from reishi have been found in laboratory and animal studies to modulate both innate and adaptive immunity, stimulating macrophages, T cells (both CD4+ and CD8+ T lymphocytes, as well as others), B cells, dendritic cells, and natural killer cells, and altering the balance of other chemicals, called cytokines, that regulate immune cell activities.288,289 Both its antiviral and general immune-enhancing properties make reishi extract a good choice for individuals with HIV infection.
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