Patients today have access to an arsenal of powerful antiretroviral drugs to decrease the viral load.
Entry inhibitors. Entry inhibitors bind to CCR5 receptors on immune cells, preventing HIV from attaching to them and initiating infection. Example: maraviroc (Selzentry).
Fusion inhibitors. Fusion inhibitors block the gp41 protein on the surface of HIV, which prevents it from fusing with the host cell.62 Example: enfuvirtide (Fuzeon).
Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs/NtRTIs). These medications interfere with HIV’s ability to be imported into the DNA of healthy immune cells by limiting reverse transcription of viral RNA into viral DNA. Examples: abacavir (Ziagen), emtricitabine (Emtriva), lamivudine (Zeffix), tenofovir (Viread), zidovudine (Retrovir).
Non-nucleoside reverse transcriptase inhibitors (NNRTIs). NNRTIs also inhibit reverse transcription of viral RNA. Examples: etravirine (Intelence), efavirenz (Sustiva), nevirapine (Viramune).
Integrase inhibitors. These medications inhibit integrase, an enzyme that facilitates the insertion of viral DNA into the DNA of infected cells.63 Example: raltegravir (Isentress)
Protease inhibitors. These drugs inhibit protease, an enzyme that is used to help assemble HIV after it has been incorporated into host DNA. Examples: atazanavir (Reyataz), fosamprenavir (Lexiva), ritonavir (Norvir), darunavir (Prezista).
A variety of these drugs, and others, are often used in combination to manage HIV; this strategy is referred to as highly active antiretroviral therapy, or HAART. Drug regimens are typically chosen based on a number of factors, including patient tolerability, patient genetic background, and physician experience.
A Landmark Discovery
Antiretroviral drugs do not completely eliminate the virus—a patient receiving HAART can still infect others, for example, through needle sharing or sexual intercourse. However, breakthrough findings emerged in 2011 with the HIV Prevention Trials Network (HPTN) 052 clinical trial, which found that if a heterosexual with HIV initiates antiretroviral treatment early (prior to the advanced stages of the disease), this can reduce the likelihood of sexual transmission to uninfected partners by a staggering 96%. These monumental findings suggest that, in addition to treating HIV infection, antiretroviral drugs may also dramatically decrease the likelihood of transmission of HIV between heterosexual partners if taken early enough. The study compared "early" participants who began antiretroviral treatment immediately at the beginning of the study, versus those who initiated treatment when their CD4+ counts fell to 250 cells/mm³ or less, or when they experienced an AIDS-associated illness.59 As the authors carry out further research, these findings represent a groundbreaking discovery in HIV management.
Challenges of antiretroviral treatment include:
- Drug resistance. Combining protease inhibitors and reverse transcriptase inhibitors into drug "cocktails" has been extremely effective at decreasing viral load in patients with HIV.64 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 (ie, consisting of just one or two drugs, versus a broader combination) can also promote resistance.65-67 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.
- Toxicity/side effects. 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.68 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.
Note: Some preliminary human data indicates milk thistle extract may support liver health in HIV/HCV co-infected patients.69 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.70 More studies are 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.5-7 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.71 Several studies suggest 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.72 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.73
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.74
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 500 mg twice daily.75 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.76,77 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.78 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.79 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.
Note: 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.80,81
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 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.81
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,82-84 and preliminary data with IL-15 and -21 is encouraging.85-87 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.
Growth hormones. 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.88,89 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.88 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.88-90 Prolonged exposure to thymidine analogs, for example, particularly stavudine (d4T), is considered a risk factor for developing lipohypertrophy and lipoatrophy.88
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).88 Mounting evidence suggests growth hormone plays a role in the pathogeneses of these phenomena,89,91,92 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 enhancing the amount of growth hormone may be beneficial for such patients.93 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.94 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.95 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.96
Testosterone. Testosterone has many important functions in the body, including its roles in fat distribution and muscle mass.97-99 However, low testosterone levels are common in patients with HIV.100-102
Low testosterone levels are associated with the loss of lean body mass, lost muscle mass, and an increased incidence of wasting.101,103 In many studies, patients with HIV who received testosterone treatment found that it helped stop the loss of lean body and muscle mass.101 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.104
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.105 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.106 In HIV-infected men with abdominal obesity and low testosterone, taking 10 grams 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.107
DHEA. 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.108 Other data indicates antiretroviral drug therapy may cause a drop in serum DHEA levels.109 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.110
In clinical trials, DHEA treatment has enhanced overall quality of life,111 improved the steroid hormone profile,112 and eased depressive symptoms113 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.
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.114 In fact, the risk reduction for hormone replacement therapy was as strong as that associated with antiretroviral drug use in this trial.