Chapter 173 HIV/AIDS
Naturopathic Medical Principles and Practice
• A diagnosis of human immunodeficiency virus–positive (HIV+) infection is most commonly made after a positive test for HIV antibodies by enzyme-linked immunosorbent assay (ELISA); it is confirmed via Western blot analysis.
• An acute onset (acute antiretroviral syndrome) resembles common influenza. Most persons experience this syndrome 2 to 6 weeks after initial infection; it often goes undiagnosed as HIV owing to its similarity to the flu. Signs and symptoms can include fever, lymphadenopathy, skin rash, pharyngitis, myalgia, arthralgia, headache, diarrhea, and oral ulcerations. Laboratory findings might include leukopenia, thrombocytopenia, and elevated transaminases.
• An insidious onset may manifest as an acquired immunodeficiency syndrome (AIDS)–associated opportunistic infection (OI) or as unexplained progressive fatigue, weight loss, fever, diarrhea, or generalized lymphadenopathy.
• AIDS is diagnosed after positive serology and either a CD4+ T-cell count at or below 200/mm3 or the presence of a designated AIDS-indicator condition (from the Centers for Disease Control and Prevention [CDC] guidelines of 2008). Primary infection is also characterized by a high level of virus production, high concentrations of viral particles and RNA in plasma, and a rapid and steep decline in CD4+ T-helper cells. Peak viral titers can reach 107 virons per milliliter during this phase. Viral production can range up to 10 billion copies per day. After the initial viremia, high levels of viral p24 antigen appear.
• Groups at high risk for contracting HIV include injection drug users, homosexual and bisexual men, hemophiliacs and others receiving transfused blood or other blood products (highest risk to recipients before May 1985, when regular screening of the blood supply began), regular sex partners of people in the aforementioned groups, heterosexual people with greater than one sex partner in the past 12 months, and those who have had unprotected sex during the previous 6 months.
HIV has been described as a retrovirus containing two single strands of RNA. It enters the body via the transfer of body fluids and subsequently binds to and infects CD4-expressing cells of the human immune system (T-helper lymphocytes, blood monocytes, tissue macrophages, Langerhans cells in the skin, and microglial and multinucleated cells in the central nervous system). AIDS is a secondary syndrome resulting from long-term HIV infection. AIDS is defined by one or more of the following: levels of CD4+ cells, the presence of certain specific indicator conditions, or secondary malignancies known to be associated with HIV. Many theories exist as to what causes AIDS, ranging from HIV to multifactorial (environmental and infectious) assaults on the immune system. In this science’s infancy, there is no definitive answer, but current medical thinking is that AIDS is caused by HIV.
This chapter is written for the naturopathic physician, although conventionally trained physicians and other holistic practitioners may find the perspective, treatment principles, and some of the treatment suggestions helpful. The field of HIV/AIDS medicine is rapidly changing. HIV/AIDS was first reported to the CDC only in 1981, and it has since exploded into an international pandemic. Highly active antiretroviral drug therapy (HAART), introduced in 1996, is the use of multiple drugs in combination with the goal of decreasing viral load and increasing CD4+ T-cell counts. Although this innovation resulted in a dramatic slowing in the death rate from AIDS, with it came complicated drug side effects, drug interactions, and unique symptoms that require frequent follow-up between the patient and physician and affect the quality of life of individuals on those regimens.
Studies indicate that more than 70% of HIV+ persons are using some form of complementary/alternative medicine (CAM) in their treatment, resulting in improvements in their quality of life and better outcomes.1 The goal of this chapter is to help the physician better understand the condition and to appropriately guide this affected population with unique and complicated health issues.
Two types of HIV have been identified. HIV-1 is found throughout the world. The majority of infections in the United States are caused by HIV-1. HIV-2 was first identified in West Africa in 1986 and has been found to have a genetic sequence approximately 50% similar to HIV-1. HIV-2 is considered less virulent than HIV-1 and shows lower rates of sexual and perinatal transmission and a lower viral load with a slower rate of CD4 cell decline. This results in a slower rate of disease progression in infected people.2 Research shows that the virus is mutating, and multiple subtypes or clades are spreading throughout the world.1 The existence of multiple clades raises the theoretical possibility that a single individual could become infected with multiple subtypes of the virus. Research has not conclusively demonstrated the existence of a “superinfection,” but the possibility of this phenomenon would significantly enhance virulence as well as increase resistance to present treatments.
Existing research has failed to isolate an intact HIV entity; although fragments believed to belong to the HIV virus have been isolated and identified. Despite this shortcoming, the virus is believed to consist of a bilayer lipid envelope covered with envelope glycoproteins (gp120 receptor and gp41 transmembrane), a viral core containing two single strands of RNA and the reverse transcriptase enzyme, and structural core proteins (p24 capsid protein and p18 matrix protein). It is believed that HIV binds to CD4-expressing cells of the immune system and, through a series of steps, replicates itself and incorporates its genome into the host cell’s genome.
The various classes of antiretroviral medications have been developed to interrupt viral replication during various steps in this process. The key to understanding the mechanisms of action of the various medications is to understand those steps. Fusion is the process by which the HIV particle contacts and binds to the target cell. This occurs through the interaction of the viral gp120 and gp41 transmembrane proteins with CD4 and chemokine receptors on the cell’s membrane. Fusion inhibitors are designed to inhibit this process by altering the cellular receptor sites. Transcription occurs when the viral reverse transcriptase enzyme translates the viral RNA into a double strand of DNA. Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) are designed to disrupt this process.
Integration occurs when the double strand of proviral DNA migrates to the cell’s nucleus and is inserted into the host’s chromosome via the integrase enzyme. The provirus is then permanently integrated into the host DNA. It can remain essentially dormant (equilibrium of viral production and destruction) or become activated and initiate the production of large chains of new viral RNA subunits independent of the host cell’s replication process. Integrase inhibitors prevent the integrase enzyme from inserting the viral DNA into the host DNA. After a period of normal cell function, the infected cell becomes activated, initiating transcription of the proviral DNA into mRNA, which is then translated in the cytoplasm to produce long chains of viral polypeptides. Cleavage occurs when the protease enzyme cuts up these viral polypeptides. The pieces are then joined together to form new retroviruses. Protease inhibitors block the action of the protease enzyme and thereby prevent the reassembly of new viral polypeptides. Packaging is a poorly understood step in this process, where the new RNA viruses are wound up tightly and encapsulated into new viral particles. Budding occurs when the HIV nucleocapsid containing the new viral RNA moves to the host cell’s membrane and binds to the inside of the membrane. It is then enveloped by the membrane as it leaves the cell.
HIV has been found in body fluids and tissues that contain lymphocytes. This includes blood and blood products, semen, vaginal fluids, breast milk, cerebrospinal fluid, synovial fluid, pleural fluid, amniotic fluid, and infected tissues. It has also been found in small amounts in saliva, tears, feces, and urine. According to the CDC, the only documented cases of transmission are via blood, semen, vaginal secretions, breast milk, and transplanted organs from an infected person. Variables affecting transmission rates include the infectivity of the source partner (higher viral load), the presence of sexually transmitted diseases (STDs) (especially with ulcerations), and the type of contact (increased risk with anal intercourse and vaginal intercourse during menses because blood is present).
The most significant routes of transmission are via sexual contact (vaginal, anal, and less frequently oral intercourse); intravenous drug use (sharing contaminated needles and syringes); transfusion of blood or blood products (highest risk prior to May 1985 when screening of the blood supply in the United States for HIV began); and from an HIV-infected mother to her baby (before or during birth or through breastfeeding). Transmission can also potentially occur via percutaneous needlestick, mucous membrane exposure, or exposure of infected fluid into an open wound. Studies show the risk of seroconversion following a needlestick from an HIV+ source to be 0.25% per exposure. They also show that there have been no known seroconverters following splash exposure. The CDC has identified one documented case of transmission from acupuncture.
There is no evidence that HIV can be transmitted via air, water, insects, or dried body fluids. Universal infection control precautions as developed by the CDC should always be employed by health care workers to minimize the risk of HIV transmission in the health care setting. Always assume that all blood and body fluids are potentially hazardous and that all patients are potentially infected.3
Both the humoral and cellular immune systems have a role in the body’s response to HIV infection. The humoral response involves the initial production of transient IgM antibodies to viral core and envelope proteins. Permanent IgG antibodies are subsequently established (this may take several weeks) to core p24 and envelope gp160, gp120, and gp41, corresponding to the resolution of clinical symptoms. The development of these IgG antibodies results in a rapid decrease in circulating virons and p24 antigen titers. Seroconversion occurs when the body starts making antibodies to HIV antigens and those antibodies become detectable by conventionally used laboratory tests (enzyme-linked immunoassays and Western blot analysis).
There is a window of time between initial infection (when patients remain antibody-negative or seronegative as measured by ELISA tests) and when seroconversion (antibody-positive or seropositive by ELISA) occurs. The length of this window varies depending on the individual and can range from 10 to 14 days to 6 months. The cellular immune response is characterized by the elevation of various cytokines (including interferons and tumor necrosis factor), CD4+ lymphopenia, and CD8+ lymphocytosis. Cytotoxic T cells reduce the plasma viremia, whereas natural killer (NK) cells may be involved with killing infected T cells.
Assuming no antiretroviral treatment, a typical scenario of HIV infection might unfold as follows: Within 2 to 3 weeks of initial infection with the virus, an acute retroviral syndrome occurs. Recovery and seroconversion usually follow in 2 to 3 weeks. After recovery from the initial acute syndrome, HIV plasma concentrations decline to a viral “set point” and equilibrium is established between the production and destruction of CD4+ cells. The level of viral replication after acute infection and seroconversion coupled with the CD4+ count is predictive of long-term prognosis. A lower level of replication with a higher CD4+ count indicates a longer asymptomatic course. Conversely, a higher level of replication with lower CD4+ counts generally indicates a shorter asymptomatic course. Over time, a gradual decline in T-cell numbers begins with a concurrent gradual increase in the amount of virus in the body. This period can last 5 to 15 years. Eventually there are not enough T cells for the body’s immune system to function properly. This is when the risk of OIs increases, with the ultimate result being death.4
Box 173-1 lists the CDC’s 2008 revised surveillance case definition of AIDS for adults and adolescents (13 years of age or older). It creates stages of HIV infection based on CD4+ cell counts/percentages and/or clinical symptoms. The primary criterion used is positive serology (i.e., positive for antibodies to HIV via ELISA and Western blot testing and/or positive HIV antigen detection via polymerase chain reaction [PCR] or other specific HIV antigen test). Given a positive serology, a diagnosis of stage 3 HIV or AIDS is given when CD4+ counts fall below 200/mm3 (<14%), any of the noted AIDS-defining conditions occurs, or both.5
From Schneider E, Whitmore S, Glynn KM, et al. Revised surveillance case definitions for HIV infection among adults, adolescents, and children aged <18 months and for HIV infection and AIDS among children aged 18 months to <13 years United States, 2008. Morbidity Mortality Weekly Report, 2008, Dec 5; 57(RR10);1-8.
Clinically, patients tend to be susceptible to certain complications (both infectious and noninfectious) on the basis of their CD4+ cell counts.6 Although there is always individual variation, these data are helpful in predicting probable clinical presentations. Generally a higher viral load represents a greater risk for complications and should always be factored into any such consideration.
• When the CD4+ cell count is greater than 500/mm3, a patient could manifest acute retroviral syndrome, candidal vaginitis, persistent generalized lymphadenopathy (PGL), Guillain-Barré syndrome, myopathy, or aseptic meningitis.
• When the CD4+ count is between 200 and 500/mm3, possible complications include pneumococcal or other bacterial pneumonia, pulmonary tuberculosis, herpes zoster, oropharyngeal candidiasis/thrush, cryptosporidiosis (self-limited), Kaposi sarcoma, oral hairy leukoplakia, cervical and anal dysplasia/cancer, B-cell lymphoma, anemia, mononeuritis multiplex, idiopathic thrombocytopenic purpura, Hodgkin’s lymphoma, or lymphocytic interstitial pneumonitis.
• When the CD4+ count is below 200/mm3, complications might include Pneumocystis jirovecii pneumonia, disseminated histoplasmosis and coccidioidomycosis, miliary/extrapulmonary tuberculosis, progressive multifocal leukoencephalopathy (PML), wasting, peripheral neuropathy, HIV-associated dementia, cardiomyopathy, vacuolar myelopathy, progressive polyradiculopathy, or non-Hodgkin’s lymphoma.
Box 173-2 lists the most recent CDC guidelines for HIV testing.7 Standard serologic testing for the presence of HIV begins with an ELISA test using recombinant antigens to measure antibodies to HIV in the blood.8 If this test is positive, it is repeated on the same blood sample. If it is positive a second time, a Western blot test (using electrophoresis to detect antibodies to specific HIV proteins) is used for confirmation.9 Together, these tests have a sensitivity and specificity approaching 100%.
• Annual screening (minimally) for persons in high-risk groups (includes injection-drug users and their sex partners, persons who exchange sex for money or drugs, sex partners of HIV-infected persons, and men who have sex with men or heterosexual persons who themselves or whose sex partners have had more than one sex partner since their most recent HIV test)
Data from Branson BM, Handsfield HH, Lampe MA, et al. Revised recommendations for HIV testing of adults, adolescents, and pregnant women in health-care settings. Morbidity Mortality Weekly Report, 2006, Sept 22;55(RR14):1-17.
A number of rapid HIV tests have been developed and are currently approved for use by the U.S. Food and Drug Administration (FDA). They all use similar technology to detect antibodies and vary in category assigned by the Clinical Laboratory Improvement Amendments (CLIA) from “waived” to “moderately complex.” Options include OraQuick Advance, Uni-Gold Recombigen, Reveal G-3, MultiSpot Rapid Test, Clearview Stat-Pak, Clearview Complete, and Vitros. Additionally, Home Access Health Corp. (www.HomeAccess.com) produces a kit where the specimen is self-obtained at home and mailed in for analysis. Results are available in 1 or 5 days depending on the price paid. These tests use either whole blood, serum, plasma, or oral fluids and have sensitivity and specificity rates of 99% to 100%.10,11 If an ELISA test is negative and risk factors suggest likely infection, the test should be repeated at 6-week, 3-month, and 6-month intervals. There is no reason to repeat if one of those tests comes back positive.
Although routine testing is now recommended, HIV testing remains voluntary. Testing recommendations should be discussed with each individual patient and informed consent (either written or verbal) obtained prior to testing. Patients have the right to opt out should they wish to do so. Risk screening should be incorportated into routine primary care and risk reduction counseling offered as applicable. All states require that newly diagnosed cases of HIV/AIDS be reported to local health departments and that providers have case reporting forms available.
Initiation of care of an HIV+ patient should begin with a standard medical history including a detailed diet history, exercise patterns, and a complete review of systems. A number of additional historical details should be obtained as well (Box 173-3).
• Dates of infection and subsequent diagnosis, as well as probable source of infection (IV drug use, sexual contact, transfusion). If date of infection is unknown, the naturopathic physician should determine if there was any history of acute retroviral syndrome. Additionally, past and current risk factors for HIV exposure should be determined. This information helps to estimate overall health and vital force and long-term prognosis.
• History of other sexually transmitted diseases. This information should include date and duration of infection as well as therapies (efficacy, adverse reactions, and duration of treatment). Particular infections to screen for include syphilis, gonorrhea, Chlamydia, herpes simplex (all types), hepatitis (A, B, and C or E), and HPV (skin, genital, or anal).
• Chronologic history of HIV-related problems including history of OIs or cofactor viruses/infections (mononucleosis, EBV, molluscum contagiosum, CMV, or yeast infections—vaginal, gastrointestinal, skin), skin rashes or other lesions, oral lesions or tongue coating, lymphadenopathy, fevers, night sweats, weight loss, diarrhea, anorexia, fatigue, malaise, shortness of breath, or cough.
• The initial physical examination must be both comprehensive and appropriately focused as directed by the history. In addition, all patients should have particularly thorough examinations of the mouth and throat, skin, and genitalia. If a full pelvic examination and Pap smear cannot be done on a new female patient at the initial evaluation, these should be scheduled for shortly thereafter.
CMV, cytomegalovirus; EBV, Epstein-Barr virus; HAART, highly active antiretroviral drug therapy; HIV, human immunodeficiency virus; HPV, human papillomavirus; IV, intravenous; OI, opportunistic infection.
Basic initial screening tests for all HIV+ patients should include a complete blood count (CBC) and a fasting serum chemistry panel (to monitor liver, kidney, and pancreatic function; electrolytes; blood proteins; glucose; and lipids). The baseline serum albumin level can serve as an independent predictor of prognosis in HIV+ women.12 Additional testing should include a urinalysis, screening for STDs (syphilis, Chlamydia, gonorrhea, herpes simplex), hepatitis (A, B, and C), toxoplasmosis, tuberculosis, and varicella (if unknown history of chickenpox or shingles). An optional test is glucose-6-phosphate dehydrogenase (based on risk factors).11 Female patients should have regular Pap smears with initial testing for human papillomavirus (HPV), because there is a significant increase in cervical cancer rates in HIV+ women.13 A recent development is the use of the anal Pap smear in male patients engaging in anal sex. Anal squamous cell cancer is similar to cervical cancer in that it is caused by HPV infection and rates are increased in HIV+ men as compared with the general population. Currently, there is some controversy about the use of this test, with no clear consensus on whether to make it part of routine screening. Studies are ongoing.11
HIV-specific testing includes measurement of viral load and T-cell counts as part of the initial evaluation and then at 3- to 6-month intervals. The viral load test detects the presence of viral RNA in the plasma or DNA in white blood cells (WBCs) and uses PCR branched-chain DNA (bDNA) or nucleic acid sequence–based amplification technology. A number of viral load tests exist with varying levels of sensitivity. The most sensitive test currently available detects virus to 20 copies per cubic millimeter of plasma.14 Below any specific test’s threshold, the viral load is deemed “undetectable.” This means that the virus may exist in concentrations in the blood below the ability of the given test to detect. Additionally, note that these assays are not reflective of viral presence or concentration in body compartments beyond the blood (e.g., tissues, cerebrospinal fluid, breast milk). This is an important point for patients to understand, as they can still infect others even if the virus is “undetectable” according to the test they were given.
Other key tests involve T-cell counts. CD4+ helper cells and CD8+ suppressor cells are quantified (absolute numbers and relative percentages), along with the CD4:CD8 ratio. This information is used to stage HIV, predict susceptibility to various OIs, and monitor response to antiretroviral therapy. Many factors can influence CD4+ cell counts, including total WBCs, acute infection, certain medications (e.g., corticosteroids, interferon), as well as other medical conditions. There are also seasonal and diurnal variations in these counts.
Resistance to antiretroviral medications is a growing problem in treatment-naive patients and remains a problem in patients currently undergoing this therapy. Therefore, resistance testing is now recommended at the time of diagnosis as part of baseline screening as well as before changing therapy owing to failure of a current regimen. Two types of tests are available: genotypic and phenotypic. There are advantages and disadvantages to each, but in general this testing can help to identify antiviral medications that the patient might be either resistant or susceptible to and thereby allow the physician to formulate the most effective medication regimen.11
The medical understanding and treatment of HIV/AIDS continue to evolve. AIDS is a complex, multifactorial disease that has both immunodeficiency and autoimmune inflammatory aspects involving virtually every system of the body. HIV enters the body and infects CD4+-expressing cells of the immune system. It inserts itself into cellular DNA and can lie dormant indefinitely. Those cells can be activated for the reproduction and multiplication of HIV virions by antigens, oxidative stress, proinflammatory cytokines, and overstressed liver detoxification and immune systems.
Up-to-date resources should always be consulted prior to making any management decisions. The AIDS information website, administered by the U.S. Department of Health and Human Services (www.aidsinfo.nih.gov/) provides an excellent resource for determining the most up-to-date conventional treatment guidelines as well as information on prevention, FDA-approved and investigational drugs, clinical trials, and vaccinations. Another fine resource is the Johns Hopkins AIDS website (www.hopkinsguides.com). Their HIV guide provides detailed information on the diagnosis and management of HIV and its associated OIs, medications, and resistance. Johns Hopkins University School of Medicine/Knowledge Source Solutions LLC also publishes a helpful text called the Medical Management of HIV Infection, 2009-10, 15th ed, by JG Bartlett, JE Gallant, and PA Pham. It can be ordered on the website. The best resource for patient education is www.thebody.com/index.shtml. This site contains valuable information on signs, symptoms, treatments, and future possibilities, all from a patient-centered perspective.
The naturopathic medical management of HIV and AIDS revolves around a number of treatment principles that should guide the physician in helping patients to optimize their health, slow disease progression, improve their quality of life, and improve immune function.
A resource specifically geared toward complementary practitioners is AIDS and Complementary and Alternative Medicine, Current Science and Practice by Standish, Calabrese, and Galantino, published by Churchill Livingstone in 2002.
In the area of HIV, naturopathic physicians should lead the effort to optimize integrated care. A holistic provider who identifies advantages of all available treatments and encourages positive relationships with all available providers creates a unique and trusting relationship with patients who have often experienced lifetimes of fear, discrimination, victimization, and abuse. Naturopathic medicine offers an important opportunity to empower HIV+ patients.
One of the first priorities is to ensure that each HIV+ patient has a complete care-providing team beginning with a conventional Western medicine HIV specialist. HIV specialists ensure the accessibility of HAART when appropriate and have the greatest familiarity with the multitude of signs, symptoms, adverse reactions, and other issues unique to the HIV+ population. A growing body of literature reports that HIV+ patients have better objective indices of health (low viral load and high CD4 counts), better compliance with medications, and better long-term survival when they work with HIV specialists.15,16
The specialist’s obligations constitute a full-time job, precluding many other aspects of care that have demonstrated efficacy for the overall health of HIV+ patients. Additional providers can support HIV+ patients with general health and lifestyle promotion, specific nutrient and other nondrug recommendations, social services, psychoneuroimmunologic support, counseling, personal empowerment, and end-of-life care. In fact, although naturopathic physicians might be legally able to prescribe prophylactic antimicrobial therapy and HAART in a growing number of states, the greater need is to provide nondrug holistic care in the areas just mentioned.
Complement and Enhance the Positive Effects of Conventional Medical Treatment and Minimize the Negative Effects
One of the paradigms of natural/preventative/holistic medicine is to minimize the need for higher-force (drug, surgery, radiation) interventions. This goal remains valid in the care of patients with HIV, but there are no therapies known to be as effective as HAART in suppressing viral load or increasing CD4 T-lymphocyte cell numbers. CAM providers may be the best practitioners to teach HIV+ patients that there are no realistic “alternatives” to HAART. Risks of OIs and other serious complications increase exponentially when CD4 cell counts drop below 200/µL. The current standard of care is to initiate HAART when the CD4 count drops below 350/µL in asymptomatic patients, those with an AIDS-defining illness (regardless of CD4 count), pregnant women, patients with HIV-associated nephropathy, or hepatitis B coinfection (when treatment of the hepatitis is indicated). HAART initiation may be considered when CD4 cell counts are greater than 350/µL in discordant relationships (one partner is HIV+ and the other HIV–), rapid CD4 decline, advanced age, or high viral load (more than 100,000 copies per milliliter).17 The choice of specific antiretrovirals for either initial regimens or the modification of existing therapy is complex, and there are many factors to consider. Additionally, the guidelines change frequently. The best resource for the most current recommendations is the “Guidelines for the Use of Antiretroviral Agents in HIV-1-infected Adults and Adolescents,” available on the AIDS information website (www.aidsinfo.hih.gov/ContentFiles/AdultandAdolescentGL.pdf). The most recent guidelines were compiled on December 1, 2009.
Some HIV+ patients may never need HAART and others may be resistant to HAART, but the option of HAART should always be considered and should not be discouraged. With or without HAART, there is significant evidence that HIV+ patients receive many benefits from nondrug therapies.18 Naturopathic physicians must actively understand, integrate, and use the entire therapeutic order (most subtle, lower force through most high force, often invasive therapies) to ensure that each patient has the best options to maximize his or her quality of life as well as length of life. Finally, physicians working with HIV must stay current with the global effort to find solutions for this pandemic in order to provide the best possible treatment options to match patients’ short-term needs while also including strategic health goals and future possibilities.
Factors to be considered in the holistic care of HIV+ patients include complications (from immune suppression) of health challenges that existed prior to HIV infection. In addition, the social, psychological, and spiritual challenges that exist with the diagnosis of HIV create a need for health care that extends far beyond the best drug or nutrient necessary for optimal heath. Holistic physicians have a vital role in the care of each patient with HIV.
The majority of HIV+ patients in North America are using HAART. Many of those same patients are also using CAM therapies. Therefore, one of the first priorities of the naturopathic provider should be to ensure that the patient is safe from adverse drug-nutrient interactions. In order to ensure safety, it is necessary to understand the mechanisms of HAART as well as those of common nutrients being used by HIV+ patients.
As a result of the rapidly evolving resistance of HIV to specific drugs, there has been great pressure to quickly develop and approve new medications. As a result, most HAART medications have been generally fast-tracked through the FDA approval process. Therefore, new drugs are typically prescribed as soon as they are approved and usually before the full extent of their adverse reactions are known. As the adverse drug reactions and interactions with HAART are myriad and potentially quite harmful, the clinician is advised to consult up-to-date resources to determine specific issues with each individual medication.
NRTIs were the first class of antiretroviral drugs approved for use in the United States by the FDA. These drugs work during the transcription phase of the HIV life cycle by competitive inhibition of HIV reverse transcriptase (RT), leading to DNA chain termination. Nucleoside (or nucleotide) analogues act as substrates and bind to the active site of the RT enzyme. Then they are added to the new chain of DNA. Once they have been inserted, the normal links between pieces of the chain will not form and the viral chain will be terminated without being inserted into the cell’s DNA.
The NRTIs are fairly well tolerated after introduction (initial mild to severe nausea usually resolves), with minimal long-term adverse effects. Exceptions include AZT and the remaining “D” drugs (DDI and D4T). A common side effect of AZT is bone marrow suppression, leading to macrocytic anemia.19 The D drugs are less commonly used today except in the case of multidrug resistance. They have been associated with mild to severe peripheral neuropathy and, of greater concern, pancreatitis.20 These side effects manifest secondary to neural inhibition of mitochondrial DNA polymerase and reduced mitochondrial DNA content.21 Therefore, patients on D drug therapy should be provided with ample mitochondrial support. Acetyl-L-carnitine, coenzyme Q10 (CoQ10), essential fatty acids (EFAs), α-lipoic acid, and B vitamins have been shown to decrease signs or progression of these side effects when taken in large doses.22–26 Additionally, the thymidine analogues (d4T, ddI, AZT) have been associated with lipoatrophy, also as a result of mitochondrial toxicity. Because the NRTIs have been on the market longer than the other drugs, it is no surprise that they are backed with the greatest amount of research regarding nutrient interactions. Although there are no studies indicating that vitamins or other nutrients deplete AZT, there is evidence that AZT may deplete cellular levels of carnitine, copper, zinc, and vitamin B12.27,28 With the exception of carnitine, these nutrients can be found in a good hypoallergenic multivitamin/multimineral supplement. In addition to deficiency caused by NRTI drugs, carnitine deficiency has been found in HIV+ patients not on HAART. Further, there are many other indications for carnitine in patients with HIV, making this nutrient a high priority for supplementation.
Some nutrients have been found to enhance the efficacy of NRTIs when taken in combination with these drugs, including vitamin E, zinc, and folate.29–31 These nutrients are easily supplemented through a nutritious diet full of whole grains, colorful vegetables and fruits, and a good multivitamin/multimineral supplement.
The second class of HAART comprises the NNRTIs. NNRTIs also affect the transcription process and work by allosterically binding to HIV-1 reverse transcriptase and inhibiting both RNA- and DNA-directed DNA polymerase functions of the RT enzyme.
NNRTI drugs are also fairly well tolerated after introduction, with low long-term toxicity. Other than an initial transient mild to severe skin rash, typical side effects (depending on the specific drug) include insomnia, abnormal dreams, elevated liver enzymes, and gynecomastia (all manageable with naturopathic support).35–37 Resistance to this class of HAART can occur easily if the viral load is unsuppressed, so this type of medication may not be an optimal choice for someone who is inconsistent with taking medications.No nutrients are known to be depleted by NNRTIs or to enhance their efficacy.
Large randomized, double-blind placebo-controlled studies have shown that when used in combination with NRTIs, NNRTIs produce sustained reductions in plasma viral loads and improvements in immunologic responses.38–41 The advantage of this type of protocol is the fewest number of side effects, excellent long-term viral suppression, and ease of dosing (fewer pills).
The third class of HAART is the PIs. PIs intervene during the cleavage part of the viral life cycle by binding competitively to the substrate site of the viral protease (the enzyme responsible for the posttranslational processing), resulting in inhibition of the enzyme and the production of immature virus particles.
Although PIs are effective at viral suppression, they are associated with the greatest number and most significant adverse drug reactions. These include chronic and persistent gastrointestinal (GI) abnormalities; lipodystrophy and lipoatrophy; elevations of cholesterol and triglycerides; insulin resistance leading to diabetes; and liver, kidney, and musculoskeletal complaints.
It is essential to realize that NNRTIs and PIs also work by inhibiting cytochrome P450 3A4 enzyme metabolism. Inhibition of this enzyme slows down the metabolic breakdown of the drug and effectively prolongs higher blood levels, which results in better viral suppression. Many foods, nutrients, and botanicals have been known to upregulate this enzyme function, and two have gained noteworthy attention. Some small studies (of fewer than 25 subjects) in healthy HIV-negative (HIV–) individuals as well as in vitro studies have demonstrated that garlic and St. John’s wort decrease NNRTI and PI drug levels. In the human trials, subjects initiated NNRTI or PI therapy to establish the drug levels necessary to suppress viral load. Garlic or St. John’s wort was then introduced at levels typically used for therapeutic effect. Blood levels were then measured and found to be lower than the levels believed to be necessary to maintain optimal viral suppression. Garlic or St. John’s wort was then discontinued and NNRTI or PI blood levels subsequently measured and found to be back in the therapeutic range.42–45 Although these studies certainly do not conclusively demonstrate that garlic and St. John’s wort interfere with HAART viral suppression (small number of participants, single antiretroviral vs. typical multidrug HAART protocol, HIV– vs. HIV+, drug-naive vs. long-term HAART), these therapies should be avoided in patients with HIV on HAART. The lesson learned from these studies is to be intimately aware of the mechanisms of action when adding new nondrug therapies intended for patients on multidrug treatments. The potential for drug-nutrient interactions also should encourage and reinforce the use of the multitude of low-force interventions (e.g., diet, lifestyle, homeopathy, physical medicine, counseling) for conditions commonly treated by garlic or St. John’s wort in order to avoid potentially decreasing NNRTI or PI blood levels and risking increases in drug resistance.
Milk thistle may be considered for the treatment of significant GI and liver complications with PIs. To date, there have been limited studies investigating the drug interactions of this herb. In one with 10 HIV–, drug-naive patients taking milk thistle at 175 mg three times daily, investigators concluded that milk thistle did not significantly alter blood levels of indinavir despite a decrease of as much as 25% in trough levels.46 Another study showed no effect on indinavir levels in healthy subjects.47 Yet another tested cellular uptake of ritonavir in the presence of various herbal substances including milk thistle (silybinin) and found no change in the efflux of ritonavir or any effect on CYP 3A4.48 An in vivo study with coadministration of nifedipine and silymarin in 16 healthy male volunteers concluded that silymarin is not a potent CYP 3A4 inhibitor in vivo.49 Currently there is no evidence suggesting that milk thistle should be avoided by HIV+ patients on HAART, but more studies are necessary. No nutrients are known to be depleted by PIs or to enhance their efficacy. However, if gastrointestinal side effects are present it could lead to micro- and macronutrient deficiencies.
ENF, T-21, or enfuvirtide (Fuzeon), is a fusion inhibitor that was approved by the FDA in 2003. It blocks the fusion of the virus with the target-cell membrane by binding with cell receptor gp41 proteins and thereby preventing the virus from entering the cell. This drug is unique because it is the only HAART medication administered via injection (two subcutaneous injections per day into the upper arm, thigh, or abdomen). Because of its cost and difficulty of use, Fuzeon has served as “last resort” or salvage therapy in heavily treatment-experienced individuals and in the presence of extensive viral resistance and is not designed to be used alone. With the approval of numerous new medications recently, Fuzeon is now rarely used. It is fairly well tolerated with the exception of injection-site irritation, allergic reactions, and an increased risk of bacterial pneumonia. There are no known drug-nutrient interactions of any clinical significance.
MVC, or maraviroc (Selzentry), is a CCR5 inhibitor approved by the FDA in 2007. After HIV binds to CD4 receptors on the T-cell membrane, it then binds to one of two coreceptors, CCR5 or CXCR4. MVC is an antagonist that specifically blocks CCR5 coreceptors and prevents HIV from binding to them so that it cannnot enter the cell. The limitation with this drug is that different viruses may express various coreceptors: CCR5, CXCR4, or both. A relatively expensive test called a tropism assay must be run in any individual in whom the use of MVC is being considered. This test determines whether the specific virus present binds to CCR5, CXCR4, or both types of receptors. MVC will be effective only on a patient with a CCR5-tropic virus. Significant possible side effects include an allergic reaction (rash) and liver toxicity. Other side effects can include cough, fever, cold, muscle/joint pain, stomach pain, and dizziness. If MVC is used, doses of other medications may have to be adjusted (including but not limited to NNRTIs, PIs, oral contraceptives, certain other antimicrobials). Another potential issue is that other cells of the immune system exhibit CCR5 receptors, and MVC may affect them and potentially increase the risk of other infections and cancers. As of the date of writing, this has not been seen in clinical trials.
RAL, or raltegravir (Isentress), was approved by the FDA in 2007 and belongs to this newest class of antiretroviral drugs. Currently several more integrase inhibitors are in development. These drugs disrupt the integrase enzyme, which facilitates the incorporation of HIV DNA into human DNA and thereby prevents viral replication in the T cell. RAL is relatively well tolerated, easy to take, and has demonstrated a remarkable ability to increase CD4 counts and drop viral load to undetectable levels in highly treatment-experienced patients with significant resistance issues. The most common side effects include diarrhea, nausea, headache, and fever. Some other possible issues may include hypersensitivity reaction, anemia, and liver toxicity. No significant nutrient interactions have been identified.
The creation and approval of these fixed-dose combination formulations have allowed the simplification of dosing and significantly decreased the pill burden for patients taking them. Issues, side effects, and interactions for the individual components are applicable to these combinations.
Of these combinations, FTC/TDF and FTC/TDF/EVF are being used quite extensively in the current standard of care. FTC/TDF/RPV was approved by the FDA in August 2011 and has the advantage of replacing EFV with RPV, thereby eliminating the EFV side effects.
The naturopathic standard of incorporating healthy diet and lifestyle practices cannot be overemphasized for HIV+ individuals. These patients are likely to be taking a large number of medications, nutritional supplements, or both, resulting in additional biochemical stress on the body. Therefore, each patient should be clearly encouraged and continually reminded to maintain dietary habits designed to ensure optimal GI health and nutritional intake.
The most important recommendation is to encourage a high intake of filtered or safe water so as to decrease oxidative stress and reduce the toxic load of the HIV and medications.50 These patients should also be encouraged to maintain an optimal intake of protein.51,52 Protein requirements can be as high as 100 to 150 g per day, particularly when patients are experiencing malabsorption and/or diarrhea; it may be necessary to provide supplemental protein to prevent weight loss. Studies using large doses of whey protein and amino acids (L-glutamine, L-arginine) have proved effective in reversing or preventing HIV-induced wasting.53–55 Essential fatty acids have also been found to be deficient in HIV+ patients. Studies have demonstrated that HIV+ patients consuming generous amounts of EFAs have an increased body cell mass and a decreased risk of progression to AIDS.56–58 HIV+ patients and healthy subjects ingesting fruit juices or a fruit-vegetable concentrate on a long-term basis were found to have higher micronutrient and antioxidant levels.59,60 From this it can be concluded that HIV+ patients should be continually encouraged to include colorful vegetables and fruits in their diets to help maintain levels of essential micronutrients and fiber.61,62
HIV+ patients commonly require appetite stimulation, digestive enzyme support, or both to combat the adverse effects of HIV, HAART, and prophylactic antibiotics on the GI system.63,64 Further, with high oxidation already present in the digestive system, all patients should be strongly encouraged to avoid additional GI stressors such as high-sodium, high-fructose corn syrup in processed foods, alcohol, caffeine, fried foods, and cigarette smoke. Raw eggs, unpasteurized milk, undercooked meat or fish, and potentially contaminated foods must also be avoided to decrease the risk of gastrointestinal OIs and parasites.
Naturopathic physicians should exercise extreme caution in considering allergy elimination diets in HIV+ patients owing to the likelihood of nutrient deficiencies, maldigestion, and malabsorption caused by HIV itself and HAART medications. A safer alternative is to recommend replacement of common food allergens one food at a time in order to make sure that patients can maintain replacement diets without decreasing caloric and nutrient intake over time. Removing food vices and irritating foods may be one of the most challenging aspects of moving HIV+ patients toward optimal wellness, because there are so many other higher-priority challenges and a vital need to maintain body mass.
Lifestyle factors should be part of the naturopathic foundation with each HIV+ patient. Aerobic exercise has been demonstrated to provide benefit to individuals with immunodeficiency diseases, particularly through stress alleviation and mood enhancement. HIV+ individuals had increases in CD4, CD8, and NK cells immediately following aerobic exercise, and long-term exercise has demonstrated increases in immune parameters.65,66 HIV+ individuals practicing Tai Qi demonstrated a greater overall perception of health and significant improvements in several measures of physical function as compared with controls.67 Other patients practicing yoga reported increased self-confidence and a quicker return to athletic activities after medical interventions.68
All patients should be encouraged to create an optimal sleeping environment and to sleep 8 to 10 hours each night. Sleep is essential for the repair and rebuilding of tissues and has been demonstrated to increase circulating NK cells and lymphocytes.69,70