Being Alive, Los Angeles; May 1998
Michael Mooney

While this condition is most commonly seen in patients on Crixivan, it now appears that this is not a side-effect entirely specific to Crixivan, but may be seen with the usage of any of the available PIs. In addition, the various cocktails of drugs being used today to combat the HIV virus seem to increase the potential for this kind of problem over simpler combos. And, in some cases, the addition of Megace to protease inhibitors seems to aggravate this problem.

There are several noteworthy points to be made about why this might happen. "Crix-belly" in many respects resembles the pot-belly seen in disease states like Cushing's syndrome, alcoholic hepatitis, and heart disease. In these diseases the pot-belly is associated with the development of insulin resistance and is primarily composed of enlarged fat deposits surrounding the visceral organs under the abdominal wall. The potential for liver burden or toxicity induced by many of the common AIDS medications has been documented, and the protease inhibitors are no exception to this. Elevated triglycerides, liver enzymes, and blood glucose, and even diabetes, have all been observed in patients on PI therapy. All of these conditions are symptoms of diminished insulin sensitivity, so it is probable that the PIs' effects on liver metabolism are inducing a state of insulin resistance in patients on PI therapy. Complications of insulin resistance include hyperglycemia and diabetes, and the FDA has recently documented 80+ cases of diabetes caused by PI therapy.

Crixivan Can Lower Testosterone

Additionally, several doctors I have spoken to have told me that they have seen that Crixivan can lower testosterone production and low testosterone production is known to correlate with increased insulin resistance in men.

In contrast, women exhibit insulin resistance when testosterone is elevated. However, low testosterone does correlate with increased visceral fat in studies with HIV-negative women. And in HIV+ pre-menopausal women, low testosterone levels are associated with low body cell mass, and a tendency towards having fat mass that is above normal.

It may be that normalizing a testosterone deficiency while being careful about keeping testosterone blood measurements no higher than mid-normal would be beneficial to HIV+ women, to improve nutrient partitioning away from fat tissue, while lean tissue increases. This is an area that needs more investigation, as not enough has been done to study testosterone and wasting in HIV+ women.

We also know that the anti-retrovirals can cause muscle myopathy, so it can be several things (including low testosterone production) that might add up to a loss of lean body mass, and increase in visceral fat.

While this remains to be proven, one of the things that was presented by Dr. Gorbach from Tufts University when he reviewed the Nutrition for Life Cohort (600 HIV+ men-254 days on PI combos) at the Bethesda NIH conference, was that although people tend to put weight back on with PIs, his data asserts that they regain mostly fat, not lean tissue. Note, fat weight is not correlative with survival, but lean tissue is. Also note, the loss of lean tissue and reciprocal gaining of fat, so that total body weight stays the same, is typical of early stage wasting. This increase in fat mass again suggests an impairment in glucose disposal and insulin sensitivity.

For those who have Crix belly, I would be concerned about any apparent muscle wasting and would recommend having the blood testosterone levels checked, including both free and total testosterone. If total testosterone is low, or in some cases, even mid-normal for men, because of the tendency for HIV+ men to have decreased free testosterone levels, which correlate with a progressive decrease in CD4+ T-cells, a doctor should consider beginning testosterone replacement therapy. (More on what "normal" really means later.) We should also note that free testosterone measurements have been shown to be more correlative with lean body mass than total testosterone in wasting HIV+ men and women.

Women and Testosterone

Studies show that HIV+ women who are losing lean body mass may also need testosterone, but the appropriate dosage of testosterone enanthate injections for women is usually one-tenth to one-twentieth that of men, between 2.5 and 20 milligrams per week. This is something for a doctor to determine by taking blood tests, usually two to three days after the third weekly injection for a representative average level. Some HIV+ women are using testosterone creams that are compounded by a pharmacy like Women's International Pharmacy (800.279.5708). However, testosterone enanthate injections deliver a longer-lasting blood level of testosterone than the creams, which have a relatively short life span in the body. If a cream is used, it is best to apply it two or even three times per day, while the injections are best given once per week, as studies show that testosterone enanthate has a half-life of five days.

I note that I have had several women tell me that while they experience little benefit from a testosterone cream, testosterone injections give them immediate improvements in muscle tone, libido, energy, and feelings of well-being. Others do well on the creams, so I suggest experimentation.

It is also important to note that the women are much more sensitive to side-effects from testosterone, so the physician should monitor a female patient closely for any virilizing side-effects, which include oily skin, acne, peach fuzz, hair loss, and clitoral enlargement, and immediately lower the dose or cease the therapy if these kinds of symptoms start to occur.

"Normal" Testosterone Levels in Men May Not Be Enough

I should also note that finding the correct testosterone dose is not always easy for each individual. Data from studies by researchers like Dr. Judith Rabkin suggest that being HIV+ can mean that the "normal" range for testosterone measurements doesn't necessarily apply to men. In her study with HIV+ hypogonadal men, Dr. Rabkin found that the dose of testosterone enanthate needed to be above 200 mg. every two weeks, in order to get normally healthy quality of life. The dosage she found to be effective was 400 mg every two weeks (which we suggest is best given as 200 mg per week for more consistent blood levels, less peak/trough effect and reduced potential for side-effects). At 400 mg given every two weeks the men's blood testosterone levels averaged about 1100 ng/dl one week after the fourth injection (on a scale where the "normal" range is 300-990 ng/dl).

In private correspondence Dr. Rabkin said that she is not sure whether 300 mg every two weeks would yield a satisfactory result or whether the men would respond satisfactorily if their average levels only reached 800 ng/dl. However, she said that some men did receive benefit at about 700 ng/dl. Remember, the bottom of the "normal" scale was 300, so the "normal" scale didn't seem to apply well to these HIV+ men. Sometimes "normal" is a fairy tale.

Free Testosterone

We assert that the men's apparent need for testosterone at higher than the standard replacement dose of 100 mg. per week (for HIV-negative hypogonadal men) may be the result of hormonal resistance to testosterone. Hormonal resistance appears to happen with several hormones in HIV pathology. However, published studies suggest that the need for higher testosterone doses is most likely caused by elevated sex hormone binding globulins and lowered free testosterone, which is common in HIV. When this is the case, total testosterone measurements do not adequately reflect the person's state of health.

Supplementing testosterone to bring free testosterone levels in the body into an optimal range can be beneficial to hypogonadal men in general, by improving the partitioning of nutrients more towards lean tissue and less toward fat tissue, especially visceral fat.

Exercise

Exercise, too, improves insulin sensitivity, so people with insulin resistance should consider some kind of regular exercise, especially weight-training, which builds lean body mass (while aerobics does not build significant lean body mass).

Nutritional Considerations

I would also suggest altering the diet so that it is balanced toward more protein and less simple (high-glycemic) carbohydrates (less sweets) Also, I would like to note that currently the more progressive nutritionists are recommending that people with insulin resistance moderate the intake of carbohydrates that release into the blood stream quickly, including pasta, breads, and processed grains. These carbohydrates actually are quite calorie dense and can upset insulin metabolism just as much as sweets. At the same time, these people should increase the intake of complex carbohydrates from vegetables, which are more nutrient dense, and less calorie dense, and don't tend to raise blood sugar much and insult the insulin mechanism. While it is best that they should also reduce any excessive intake of fats, I don't advocate a "low fat diet", but a reduction in excess saturated fats, while trying to maintain a healthy moderate intake of essential fatty acids with plenty of omega-3 fatty acids, like those found in fish.

Dietary Supplements

Supplements that have been shown to improve insulin sensitivity include chromium, and I recommend 1,000 micrograms of chromium per day in the polynicotinate or picolinate form, as one recent (non-HIV) study showed that 1,000 mcg. of chromium per day increased insulin sensitivity by about 40% without toxicity.

But the best supplement for improving insulin sensitivity and glucose disposal may be the anti-oxidant called alpha lipoic acid (ALA), at 600-1200 mg per day. Note: ALA improves insulin dependent and non-insulin dependent glucose uptake, and it has been shown to effectively lower blood sugar comparably to insulin itself. I believe this is one very important reason ALA is a must for anyone taking HIV-meds, especially the protease inhibitors. Also note that HIV-nutrition expert Lark Lands, PhD, asserts that ALA is a must for PWHIV because of its effect on improving glutathione production and recycling. (I underline the fact that studies last year at Stanford University showed that glutathione levels were directly correlative with increased survival for people with HIV.)

Carnitine, the prescription drug Carnitor, would also be beneficial in higher doses, about 3-4 grams per day, as it helps to lowers triglycerides, which are generally elevated in this kind of situation. Also worth considering is the supplement called EPA (fish oil), which has been shown to lower triglycerides somewhat in a study with HIV+ men.

And taking a strong multi-vitamin/multi-mineral that includes chromium, vitamins E, A, D and calcium will help improve insulin sensitivity. I recommend taking a supplement that contains doses that are higher than the RDAs, though.

For any loss of muscle, Judy Shabert, MD, MPH, RD asserts that supplementing with high doses of the amino acid l-glutamine, will help reduce the catabolic process of breaking down muscle tissue, and a recent study of wasting HIV patients by Prang showed that this might be true. (See Dr. Shabert's article in the August 1997 issue of POZ magazine.) For frank wasting, HIV+ people are using between 12 and 36 grams per day of l-glutamine. (One tablespoon is 12 grams.) I have friends who have stopped their random diarrhea and improved their lean body mass using these kinds of l-glutamine doses, and in Prang's study wasting and diarrhea were stopped by using 30-40 grams of glutamine per day. Glutamine too, has been shown to have a powerful effect on improving glutathione production.

To reduce the loss of lean body mass, I suggest supplementation with a whey protein powder drink like Sportpharma ProMax, with a tablespoon of l-glutamine added to each serving of protein three times a day. Whey proteins appear to be significantly more effective for improving lean body mass growth than most other proteins. And that's why the medical grade whey protein called OPTIMUNE is currently being studied in an ACTG clinical trial for this effect.

Realize though that while supplements (especially alpha lipoic acid) may help, it would also be wise to investigate the use of the drugs that are prescribed to improve insulin sensitivity. (Ask your doctor about these drugs, which include Metformin.)

I should also note that I know people who have gotten rid of their pot belly simply by switching from Crixivan to another protease inhibitor.

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Michael Mooney, the Director of Research of Program for Wellness Restoration (PoWeR), publishes a quarterly newsletter called Medibolics, that focuses on medical and scientific research regarding therapeutic applications of nutrients, anabolic hormones, and exercise for HIV+ people. For more information, contact Medibolics at P.O. Box #333, 836 N. La Cienega Blvd., West Hollywood, CA 90069, e-mail: mmooney@a.crl.com, website: http://www.medibolics.com.

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