Challenges of Antiretroviral Treatment
Combining protease inhibitors and reverse transcriptase inhibitors into drug "cocktails" has been extremely effective at decreasing viral load in patients with HIV (Yazdanpanah 2009). As noted earlier, however, HIV can mutate at a rapid rate during cell replication; this can give rise to resistant strains of the virus that do not respond to treatment. Patients can mitigate this risk by adhering to their medication schedules, as non-adherence encourages the development of resistant strains of HIV. Inadequate drug treatment (i.e., consisting of just one or two drugs, versus a broader combination) can also promote resistance (Graham 2010; Lockman 2010; Volberding 2010). Drug resistance tests, which establish whether an HIV strain is resistant to certain medications, can provide guidance for selecting optimal drug combinations for each patient and could be useful for revising combination therapies in cases where treatments begin to fail.
A significant concern with antiretroviral drugs is their high toxicity and negative side effects, which range from nausea and diarrhea to more serious complications, including liver abnormalities* and insulin resistance (Sharma 2011). In many cases, a patient may not be able to tolerate one or more drugs. Moreover, these medications have been found to increase oxidative stress, overwhelming the body's antioxidant supplies. Until less toxic therapies are developed, patients can support their health by optimizing other, more controllable areas of the overall treatment package, such as engaging in moderate physical activity and maintaining optimal nutrition.
*Some preliminary human data indicates that milk thistle extract may support liver health in HIV/HCV co-infected patients (McCord 2008). Additionally, a write-up of a single case involving a man with HIV/HCV co-infection reports eradication of both infections after two weeks of intravenous infusions of silymarin, a group of active constituents from milk thistle (Payer 2010). More study is needed before firm conclusions can be drawn.
Insulin Resistance and other Cardio-Metabolic Abnormalities
Long-term antiretroviral drug therapy has been associated with a number of metabolic side effects, including insulin resistance and diabetes (Escote 2011; Tien 2008; Tebas 2008). Impaired glucose metabolism in antiretroviral-treated HIV patients, in turn, contributes to an increased risk of cardiovascular disease and other major comorbidities. In order to maintain the best quality of life, HIV patients must strive to keep these metabolic risks in check by controlling their glucose levels.
Life Extension recommends the antidiabetic drug metformin to maintain optimal glucose metabolism during healthy aging, as well as in various disease states (Goepp 2010)**. Several studies suggest that metformin effectively combats HAART-associated cardio-metabolic risk as well.
In a year-long trial involving 50 HIV-infected patients who had been treated with antiretroviral drugs for an average of six years and had developed metabolic syndrome, metformin treatment significantly slowed the rate of coronary artery calcification compared to lifestyle modification (Fitch 2011). Moreover, metformin alone significantly improved insulin sensitivity, and, when combined with lifestyle modification, boosted levels of HDL (“good”) cholesterol.
In addition to improving insulin sensitivity, metformin also appears to promote healthy fat distribution, which is typically deregulated in HAART-treated HIV patients. A small, six-month trial in non-diabetic HIV-positive patients revealed that metformin therapy reduced abdominal fat accumulation, lowered blood pressure, and raised HDL cholesterol, supporting the cardio-protective role of the drug in this population (Diehl 2008).
Studies show that though some other diabetic drugs may control insulin sensitivity in HIV patients, they do not reduce overall cardiovascular risk as effectively as metformin. In one investigation involving 37 patients, rosiglitazone tampered insulin resistance similarly to metformin, but only metformin suppressed postprandial lipemia, an independent cardiovascular risk factor (van Wijk 2011).
A small study published in the Journal of the American Medical Association found that metformin was safe and well-tolerated in HIV patients at a dose of 500mg twice daily (Hadigan 2000). This trial further showed that metformin reduced visceral abdominal fat, which poses greater cardio-metabolic risk than subcutaneous abdominal fat, without affecting liver function and causing only mild gastrointestinal discomfort in some patients.
Green coffee extract has recently emerged as a powerful glucose control agent as well**. Unroasted coffee beans, once purified and standardized, produce high levels of chlorogenic acid and other beneficial polyphenols that can suppress excess blood glucose levels. Human clinical trials support the role of chlorogenic acid-rich green coffee bean extract in promoting healthy blood sugar control and reducing disease risk.
Scientists have discovered that chlorogenic acid found abundantly in green coffee bean extract inhibits the enzyme glucose-6-phosphatase that triggers new glucose formation and glucose release by the liver (Henry-Vitrac 2010; Andrade-Cetto 2010). Glucose-6-phosphatase is involved in dangerous postprandial (after-meal) spikes in blood sugar.
In another significant mechanism, chlorogenic acid increases the signal protein for insulin receptors in liver cells (Rodriguez de Sotillo 2006). That has the effect of increasing insulin sensitivity, which in turn drives down blood sugar levels.
In a clinical trial, 56 healthy volunteers, were challenged with an oral glucose tolerance test before and after a supplemental dose of green coffee extract. The oral glucose tolerance test is a standardized way of measuring a person's after-meal blood sugar response. In subjects not taking green coffee bean extract, the oral glucose tolerance test showed the expected rise of blood sugar to an average of 144 mg/dL after a 30 minute period. But in subjects who had taken 200 mg of the green coffee bean extract, that sugar spike was significantly reduced, to just 124 mg/dL—a 14% decrease (Nagendran 2011). When a higher dose (400 mg) of green coffee bean extract was supplemented, there was an even greater average reduction in blood sugar—up to nearly 28% at one hour.
**Metformin and green coffee extract may not be appropriate for patients who are experiencing malabsorption. Patients with malabsorption should consult a qualified healthcare provider before using metformin or green coffee extract.
Cytokines are cell-signaling proteins used by the immune system to orchestrate immunologic activity. By secreting cytokines, cells of the immune system are able to modify the number and/ or activity of other immune cells throughout the body. Cytokines are needed to mediate responses to infection and injury, and to ensure hemostatic immune balance during healthy conditions. During HIV infection, however, cytokine signaling becomes irregular (Diallo 2011; Sirskyj 2008).
CD8+ cytotoxic T-cells are necessary to destroy HIV-infected cells, while CD4+ T-helper cells are necessary to organize defense against pathogens. In late-stage HIV, CD8+ cells become dysfunctional and CD4+ cell numbers decline dramatically, allowing HIV to replicate rampantly and impairing the body’s ability to respond to infections. Thus, upon progression to AIDS, most patients succumb to opportunistic infections. Recent research suggests that suboptimal production and signaling of γ-chain cytokines (IL’s-2, -4, -7, -9, -15, and -21) contributes significantly to immunological failure in HIV infected patients (Sirskyj 2008).
Armed with this knowledge, scientists have begun developing cutting-edge therapies that capitalize on the ability of exogenous recombinant cytokines to reinvigorate immune function lost to HIV infection. Currently, clinical trials with IL-2 and -7 have shown promising results (Martin 2005; Sabbatini 2010; Chahroudi 2010), and preliminary data with IL-15 and -21 is encouraging (Walter 2009; d’Ettorre 2002; Williams 2011). A growing body of evidence indicates that cytokines, especially in combination, may become an important tool in augmenting CD4+ cell populations and CD+8 function in HAART-treated HIV patients.
Moving forward researchers hope to begin assessing efficacy of various combinations of recombinant γ-chain cytokines in HIV patients. Clinical trials are underway; any HIV patient interested in participating in a trial should speak with their healthcare provider(s) and visit www.clinicaltrials.gov to identify trials they may be eligible for.
Hormones: Striking the Right Balance
Hormones appear to have a profound impact on conditions associated with HIV.
Body fat distribution disorders, including lipoatrophy (fat loss in select areas) and lipohypertrophy (fat accumulation in select areas), are common among people with HIV/AIDS (Moreno 2009; Stanley 2009). Lipoatrophy usually occurs in the patient's buttocks, limbs, and face, whereas lipohypertrophy is characterized by visceral fat accumulations, or fat accumulations in the abdomen, mid-upper neck, mammary area, and/or above the pubic region (Moreno 2009). These physical changes can have a negative impact on self-perception and quality of life. Moreover, antiretroviral drug therapy is associated with the development of these conditions, a factor that could dissuade patients from taking their medications (Moreno 2009; Stanley 2009; Sweeney 2007). Prolonged exposure to thymidine analogs, for example, particularly stavudine (d4T), is considered a risk factor for developing lipohypertrophy and lipoatrophy (Moreno 2009).
This disturbance in fat metabolism, commonly referred to as "lipodystrophy syndrome", is associated with various metabolic changes, including insulin resistance and dyslipidemia (excessive amounts of fat in the blood) (Moreno 2009). Mounting evidence suggests that growth hormone plays a role in the pathogeneses of these phenomena (Stanley 2009; Rietschel 2001; Grunfield 2007), and numerous study findings have indicated that using hormone replacement therapy may help to combat these metabolic challenges.
In HIV-infected individuals with accumulations of abdominal fat, an independent association was found between lowered secretions of growth hormone and higher levels of fasting glucose and triglycerides. This suggests that enhancing the amount of growth hormone may be beneficial for such patients (Lo 2009). Additional support for this hypothesis came from a study by Benedini and colleagues, who found that people with HIV who had syndromes of fat accumulation benefited from significant reductions in body fat, as well as increased lean tissue, following growth hormone treatment (Benedini 2008). A review of several randomized controlled trials revealed that the use of growth hormone axis drugs successfully decreases visceral fat tissue mass and increases lean body mass in people who have HIV-associated lipodystrophy (Sivakumar 2011). A review by Leung and Glesby found that analogs of the growth hormone/growth hormone-releasing hormone axis seemed particularly effective at decreasing visceral fat tissue in patients with HIV (Leung 2011).
Testosterone has many important functions in the body, including its roles in fat distribution and muscle mass (Brown 2008; Blouin 2008; Lang 2011). However, low testosterone levels are common in patients with HIV (Rochira 2011; Dobs 2003; Rietschel 2000).
Low testosterone levels are associated with the loss of lean body mass, lost muscle mass, and an increased incidence of wasting (Dobs 2003; Kopicko 1999). In many studies, patients with HIV who received testosterone treatment found that it helped stop the loss of lean body and muscle mass (Dobs 2003). A study of HIV-infected male patients using HAART indicated that sex hormones participate in fat distribution changes, as well as insulin sensitivity, among male patients with HIV-lipodystrophy (Andersen 2007).
The beneficial effects of testosterone treatment in HIV-infected patients have been reported in a number of studies. A systematic review and meta-analysis by Kong and Edmonds found that testosterone therapy increased lean body mass more than placebo, and that a greater increase occurred when the testosterone was administered intramuscularly (Kong 2002). In a review of anabolic steroids for the treatment of weight loss in people with HIV, Johns and associates found a potential relationship between the use of anabolic steroids and small increases in lean body mass and body weight. However, the authors did not formally recommend testosterone treatment due to study limitations, as well as the lack of knowledge regarding potential benefits and adverse effects of long-term anabolic steroid use, target populations for the therapy, and the best regimen (Johns 2005). In HIV-infected men with abdominal obesity and low testosterone, taking 10 g of testosterone each day for 24 weeks corresponded with a greater reduction in total, whole body, and abdominal fat mass, as well as a more substantial increase in lean mass, compared with participants who took a placebo (Bhasin 2007).
Dehydroepiandrosterone (DHEA) is an adrenal steroid hormone that exerts influence within a variety of biological systems either directly, or via its metabolites, which include androgens and estrogens. With respect to the immune system, studies have shown that the number of CD4+ cells correlates positively with serum DHEA levels, and negatively with cortisol levels in HIV patients (Christeff 1997). Other data indicates that antiretroviral drug therapy may cause a drop in serum DHEA levels (TreatmentUpdate 2001). In a study that followed 34 HIV-positive men for nearly three years, lower DHEA, and higher cortisol levels were associated with increasing lipodystrophy severity (Christeff 2002).
In clinical trials, DHEA treatment has enhanced overall quality of life (Abrams 2007), improved the steroid hormone profile (Poretsky 2009), and eased depressive symptoms (Rabkin 2006) in HIV patients. The effects of DHEA administration on CD4+ and CD8+ levels in humans remain unclear, but DHEA treatment does not appear to result in negative outcomes in HIV trials.
Men and women who would like more information about maintaining healthy hormone levels should review Life Extension’s Male Hormone Restoration and Female Hormone Restoration protocols.
Female Hormone Restoration
In a review of patient data from 84 cases of HIV in women older than 40, use of hormone replacement therapy was associated with a strong reduction in risk of death (Clark 1997). In fact, the risk reduction for hormone replacement therapy was as strong as that associated with antiretroviral drug use in this trial.
Developing a Cure
The medical community has not yet found a cure for HIV/AIDS, but a striking case from Berlin may provide valuable insights into potential treatment strategies: Due to a genetic mutation (known as CCR5-delta32), some people do not express chemokine receptor 5 (CCR5), a co-receptor for HIV, on their CD4+ cells. These individuals are naturally resistant to R5 HIV infection. In the Berlin case, a patient with leukemia and HIV received a stem cell transplant from an individual with this mutation (Hütter 2009). Since the stem cell treatment, which occurred several years ago, doctors have not found any evidence of HIV. This finding has prompted further study in an attempt to replicate these results and ultimately develop a cure.
In 2011, Sangamo BioSciences announced a cell-based method for reducing HIV viral load, harnessing the potential therapeutic power of the CCR5 mutation. The process involves the temporary cessation of antiretroviral treatment, the removal of T cells containing the CD4 receptor, and the exposure of these cells to an enzyme to knockout the gene for the CCR5 co-receptor. Following this treatment, the cells are re-introduced into the patient, where they appear to function normally. In preliminary experiments, this method has been found to boost CD4 cell counts in people with HIV and may also be useful for controlling viral load (Ando 2011). One HIV-infected patient in these experiments was able to maintain a controlled viral load even without HAART (Ando 2011).
Numerous other investigations have been carried out to devise a cure, including attempts to produce an HIV vaccine. Kang and colleagues recently developed the SAV001 vaccine, which is now undergoing clinical trials. The SAV001 vaccine is made by genetically modifying the virus so that it is no longer pathogenic. From there, the virus undergoes further deactivation via radiation and chemical treatments. Testing this vaccine in clinical trials will take a few years, but if it proves successful, it will represent one of the greatest developments in the history of HIV/AIDS research.
Building a Healthy Lifestyle – Optimizing Nutritional Status and Staying Active
Optimal nutrition is important for maintaining a healthy immune system and preserving overall general health. However, several factors make this a challenge for people with HIV. Weight loss and malnutrition are common due to complications such as anorexia, changes in metabolism, malabsorption, and chronic diarrhea (Fisher 2001). HIV-related factors such as depression, loss of appetite, impaired taste or smell, or stomach upset (from treatment or from co-infections) may prevent affected individuals from eating enough (Somarriba 2010; Fisher 2001). Even people with HIV who consume adequate diets may experience chronic diarrhea and/or vomiting from drug treatments or opportunistic infections, leading to nutrient loss (Fisher 2001). Combined, these factors can lead to nutrient deficiency, which can impair immune function and lower the body's resistance to infection (Somarriba 2010; Ahoua 2011). New infections, in turn, can further impair nutritional status, creating a vicious cycle that promotes the progression of the disease (Somarriba 2010). Moreover, some individuals with HIV may have increased nutrient requirements for other reasons, including pregnancy, or because they are infants or growing children. These issues underscore the importance of ensuring adequate intake of vitamins and other nutrients to maintain health.
Other steps toward optimal health include maintaining a healthy lifestyle—avoiding the use of illicit drugs, alcohol, and tobacco, as well as engaging in moderate physical activity. In moderation, being active has been found to support immune function, reduce the potential for metabolic abnormalities, and decrease the risk of acute infection (Somarriba 2010). It can also boost muscle mass, which may be useful for countering HIV-related lipodystrophy (Somarriba 2010). Regular physical activity is associated with decreased levels of skeletal muscle inflammatory proteins, as well as reductions in several other important markers of inflammation (Gleeson 2006). These markers bear strong correlations with adverse conditions such as cardiovascular and metabolic diseases (e.g. insulin resistance), underscoring the value of moderate physical activity (Gleeson 2006). Moderate activity can also eliminate obesity. This presents additional health-related benefits, particularly since obesity is associated with impaired immune function, along with a host of other health problems (Gleeson 2006). Prolonged (more than 1.5 hours), high-intensity exercise is not recommended for people with HIV, as it may have an immune-suppressing effect (Gleeson 2007).