The Next Generation of Human Growth Hormone
How Serostim and Tesamorelin Measure Up
Every Tuesday night for three years I drove to Beverly Hills, sat in a room, and listened to five other middle-aged men discuss their lives. I didn't expect group therapy to last for years. With every passing season, we all got a little older: a few more grey hairs, a pound or two around the middle, another wrinkle. Naturally, we all showed our age -- all of us but Steve.
Steve had been HIV-positive for about 18 years, but it certainly didn't show. He was lean but not skinny. He wore snug-fitting shirts that revealed a naturally fit frame. His cheeks were full, lacking the telltale divots that years of HIV medicine can etch into our faces. In fact, it was the healthy quality of his skin that led me to assume he was in his early 40s.
I was shocked when Steve offhandedly revealed he was 51. Whatever Steve was doing, I thought, I would do the same. One day after group, I cornered Steve in the street and barraged him with questions. Yes, he went to the gym occasionally. Of course, he watched calories. But when I pushed him for more details, he finally confided that his doctor had prescribed him human growth hormone, that he had been injecting himself with a low dose for about seven years, and that growth hormone was why he looked lean and youthful.
Bingo, I thought, that's what I want. I'm a 42-year-old Polish guy who's put on a belly through beer and bad habits. I know what this particular body shape should look like. But when I looked in the mirror I saw something different. I saw a huge barrel belly, an oddly fat neck and jowls. Protruding from this mass was skinny, scrawny arms and legs. I felt like an apple on toothpicks.
I've been HIV-positive for more than 20 years. I've spent 15 of those years on HIV meds. Don't get me wrong, I'm thrilled to be alive. I'm grateful for the meds, but they left their mark on my body. The physical changes from the meds were undeniable. I wasn't just getting older and softer. The shape of my body had changed dramatically and not in a good way. After speaking with Steve, I decided to do something about it.
I did what the pharmaceutical commercials tell me: I asked my doctor if growth hormone was right for me. Oddly, he got a little nervous. You don't really have AIDS wasting, he mumbled, adding that there are a lot of side effects. Instead, he suggested a surgical procedure where my stomach is permanently clamped off by a band that's implanted in the body. This option seemed extreme.
Coincidentally, I heard about an experimental drug called tesamorelin, which supercharged your body to kick up its own natural levels of growth hormone. Soon, I joined a clinical trial of tesamorelin to treat HIV-associated belly fat. Just recently, I completed the year-long trial. Now, I have the unique opportunity to assess how human growth hormone has changed my life.
A Hangover From the AIDS Cocktail
It was around 1996 when the success of the "AIDS cocktail" made headlines. It was a breakthrough. For the first time, HIV medicine was good enough to essentially snuff out the virus and start to save lives. It was a welcomed change of course for a beleaguered patient community. So it almost seemed inconsequential in the very beginning when anecdotes of strange body-shape changes first began to emerge as a side effect of the medicine.
The AIDS cocktail got its name because it combined three different classes of HIV drugs.
One class is the protease inhibitors, of which indinavir is a member. Indinavir is the generic name of the drug and Crixivan is the brand name. Another class is the nucleoside analogs, of which zidovudine and stavudine are members. Stavudine's brand name is Zerit. Zidovudine's brand name is Retrovir, but it's better known as AZT. It's also one ingredient in various combination pills by the names Combivir, Epzicom, and Trizivir.
As body-shape side effects emerged among patients taking the cocktail, the changes sometimes got informally named as AZT butt or Crix belly. It seemed that the nucleoside analogs were associated with fat loss in the buttocks, legs, arms, and cheeks. On the other hand, the protease inhibitors were associated with fat gain in the stomach, jowls, and neck. Another distressing condition was a disfiguring accumulation of fat at the base of the neck called "buffalo hump."
Over time, the anecdotes could not be ignored. As researchers examined the issue more closely, they also found unusually high levels of cholesterol and triglycerides in the blood of patients taking protease inhibitors. The range of conditions baffled doctors, but one thing was clear: the common denominator was fat.
"Fat loss is clearly associated with stavudine and to a lesser extent, zidovudine," said Valerianna Amorosa, M.D. She is chief of Infectious Diseases at the Philadelphia Veterans Hospital in Pennsylvania. Her clinical practice and research focuses on conditions related to HIV, hepatitis C, and obesity. As for the cause of buffalo hump, she said the jury is still out. "We thought it was the protease inhibitors, but I don't think it's that simple any more."
These days, the trend is to distinguish between weight gain and weight loss as separate and distinct conditions. Weight loss in the butt, legs, arms, and cheeks is called lipoatrophy. Weight gain around the belly is called excess visceral adipose tissue, which is abbreviated as VAT. I prefer to use the lowercase vat because it's similar to fat, but still different. Too much vat gives your body an apple shape, with fat growing between internal organs. Garden-variety fat tends to distribute itself more evenly and stays just below the skin where it's less harmful.
Sometimes, it's hard to tell the difference between fat and vat, notes Amorosa. The commonly used body mass index, also called BMI, is not a great indicator of the risks associated with being overweight. Vat is linked to high blood pressure, diabetes, high cholesterol, and high triglycerides. The difference between vat and fat is where the fat lives on the person. "In somebody who has a BMI of 26, but who doesn't have a big belly, who has a relatively flat belly, and has some weight in the trunk or in the bottom, I don't worry as much about them."
High levels of cholesterol and triglycerides or glucose problems are collectively referred to as metabolic syndrome. A surprising study in 2007 found the prevalence of metabolic syndrome among people with HIV is not any higher than that of the general population. Metabolic syndrome, it seems, has less to do with HIV medicine and more to do with beer and bad habits.
For me, feeling like an apple on toothpicks had two causes. First, I had taken AZT and Zerit in the past, which probably led to fat loss in the legs, butt, and little in the cheeks. On the other hand, I also had taken Crixivan, which probably led to some fat gain in the belly. Before the HIV meds, when I gained weight, I got fat all over. Now when I gain weight, it has nowhere to go but my belly.
The Notorious History of Serostim
Steve had been out of the country so I hadn't seen him in a year. I was to meet him for coffee and I wondered if he still looked as young as I remembered. After all, he continued to take the human growth hormone called somatropin. Its brand name is Serostim. When Steve turned the corner and I saw him, once again I was struck by his lean and youthful appearance.
Steve was prescribed Serostim in 2001 after he started on the AIDS cocktail, which caused him debilitating fatigue. With the cocktail, his viral load and T-cells rebounded, but he could barely work. His doctor attempted to treat Steve in different ways, all of which failed to alleviate the fatigue. Then Steve started injecting Serostim.
Steve noticed changes within weeks. His energy came back. He felt better. Eventually, he started working out with a personal trainer. For fatigue, it worked. Then Steve noticed the side effects. "My skin felt less tough, like I was wearing a super moisturizer. My hair stopped falling out," he said. "I lost my gut and it stayed off."
These effects should be no surprise. They were first described in 1990 when the New England Journal of Medicine published research titled "Effects of human growth hormone in men over 60 years old" by Daniel Rudman, M.D. One conclusion was that "diminished secretion of growth hormone is responsible, in part, for the decrease of lean body mass, the expansion of adipose-tissue mass, and the thinning of the skin that occur in old age."
The article sparked an explosion of "anti-aging" clinics and dietary supplements that extolled the age-defying benefits of growth hormone. Growth hormone is a substance that's easily destroyed by stomach acid. This means that supplements taken by mouth don't work. But this hasn't stopped the dietary supplement industry from advertising pseudo "growth hormone" pills.
The legitimate pharmaceutical industry also flourished. Subsequent studies confirmed that growth hormone causes muscles to grow. This ability to grow muscle was the primary reason why in 1996 the Food and Drug Administration (FDA) gave pharmaceutical middle-weight Serono approval to sell Serostim as a treatment for AIDS wasting.
Technically, AIDS wasting is the involuntary loss of more than 10% of body weight, plus more than 30 days of either diarrhea, or weakness and fever. Serostim clearly helps people with wasting. When taken for 12 weeks, people gained lean body mass, improved physical endurance, and reported they felt better in terms of weight and appearance. Unfortunately for Serono, the success of the AIDS cocktail also meant less people got diagnosed with AIDS wasting.
Back in the 1990s, the FDA took a more laissez-faire approach to pharmaceutical marketing practices. With a shrinking market for Serostim, Serono pushed the legal envelope by awarding doctors all-expenses-paid vacations when they prescribed lots of Serostim. The company also developed a quack test so doctors could easily prescribe the drug.
After several federal investigations on behalf of Medicaid, the U.S. government finally sued Serono in 2005 for more than $700 million to recoup Medicaid losses and punish the company for illegally marketing Serostim. The case became the third largest settlement by the federal government in a health care fraud case.
Allegations of fraud extended to pharmacies and AIDS patients as well. Reports surfaced of pharmacies billing an insurance company or Medicaid for Serostim that patients didn't actually use. Those patients then sold the drug back to the dispensing pharmacy in exchange for cash.
Patients also sold their Serostim to a booming black market, where bodybuilders paid top dollar. There's a market for Serostim because it isn't detectable by blood tests. In fact, the market was so profitable that counterfeiters even started selling fake Serostim, some which landed in the needles of legitimate patients.
"Serostim was approved for HIV wasting," said Robin Mathias, an expert on health care fraud. She operates something of a detective agency for large healthcare clients. She notes that it's illegal for Serono to sell "the idea" that Serostim should be prescribed off label. "Of course, a physician can choose to prescribe a drug for an off-label use. But representatives from the pharmaceutical company should not go around telling doctors, 'This is really good for body building.'"
One kit of Serostim -- that's the legitimate version with the special hologram on the box -- contains seven vials called blue tops. Each blue top contains 6.0 milligrams of somatropin, which translate to 18 international units (IU). The black market pays about $7 per IU. The black market asking price for one kit of Serostim is around $500.
To treat AIDS wasting, the official dose of Serostim is 6.0 mg given daily for 12 weeks. To treat excess vat, Serono researchers used 4.0 mg daily for 12 weeks. This dose was tough on patients, many of whom were forced to reduce their dose or stop the drug entirely due to swelling of hands and feet, joint pain, carpal tunnel syndrome, glucose problems, and diabetes.
Steve, on the other hand, hasn't had any problems with Serostim for more than seven years. However, he injects only 6.0 mg twice a week. For Steve, a one-month supply lasts four months. One 12-week supply lasts a year. His energy level has been normal, and he enjoys the side effects, which he said are "looking great, having better skin, better hair, less fat, and more muscle."
"Looking great" is not something the FDA considers when reviewing the evidence of a drug's safety and effectiveness. In 2007, Serono asked the FDA to approve Serostim to treat excess vat. The FDA denied Serono's request, saying there wasn't enough safety and efficacy data to give the green light for vat. Also, the FDA expressed concerns that, once Serostim is stopped, vat comes back. To keep vat levels low, long-term therapy would be needed. And Serono hasn't studied the drug long-term.
With this, the FDA handed Serono a pharmaceutical smack-down, according to HIV treatment advocate Tim Horn who attended an FDA community meeting on Serostim. "In a very matter-of-fact tone," said Horn, "the FDA made it clear that, 'by the time Serono has completed a follow-up study to support a [vat] approval, another drug will have been approved by the agency for this indication.' Obviously the FDA was talking about tesamorelin."
Twelve Months of Tesamorelin
For most of my life, I refused to give in to the idea of exercise. It seemed reserved for vain people. But after turning 40, smoking cigarettes for years, battling back pain and obesity, I began to see exercise not as a tool for vanity, but rather as a means to stay healthy over the long run.
Last year, I made a promise to myself: I will go to the gym at least three times a week, for at least one hour. Come hell or high water. It wasn't easy sticking to this routine over time, but I did. About two months after I started this workout schedule is when I also joined the clinical trial for tesamorelin.
Tesamorelin (pronounced tessa-more-ellen) is an experimental pharmaceutical drug that increases levels of growth hormone. Technically, it's a "releasing factor" or a "proxy" to human growth hormone, which means it stimulates the body's pituitary gland to produce its own growth hormone. When the body makes its own growth hormone, it's called "endogenous." On the other hand, somatropin is artificially produced and then injected into the body, which is called "exogenous."
Beware of dietary supplements that claim to be a "growth hormone releasing factor." Dietary supplements are not regulated by the FDA. As such, makers of these supplements tend to steal catch phrases from legitimate pharmaceutical research and then integrate the language into misleading advertising for their products.
Both tesamorelin and somatropin must be injected by needle, which can be annoying. They also must be refrigerated, so I kept the tesamorelin box hidden in the crisper drawer. First thing every morning, I injected the drug into my abdomen. The first jab is the most difficult. Like my workouts, the injection routine also got easier with time.
Since I was getting to the gym regularly and on growth hormone, I figured it was the best time to hire a personal trainer. Through my gym, I connected with a trainer named Brian. We got along famously. His attitude about fitness was relentlessly optimistic, which offset my cynical beliefs about fitness. Three days a week, he coached me through core-strength and traditional weight training. I handled cardio on my own.
In the first three months of my tesamorelin/exercise regimen, I felt a dramatic relief of pressure from my stomach. I hadn't realized how bloated my stomach had become until it began to shrink. However, I often felt muscle pain, which started in the evenings and continued while I tried to sleep. Sometimes I woke up with cramps in my calves, thighs, and butt. I found stretching, massage, ibuprofen, and L-glutamine supplements helped alleviate this particular kind of muscle pain.
By month six, my belly got flatter and my muscles got bigger. My belly-to-butt ratio improved. Good and bad cholesterol improved, but my high blood pressure didn't budge. Before the study, I felt like I was carrying a 20-pound turkey inside my belly. After six months on the study, the turkey was gone. I went from a waist size of 36 to a waist size of 34.
My mid-section shrank and my legs and arms gained muscle. I looked more proportional and felt more normal. Also, the quality of my skin improved. When I saw my boss in person after six months, she stopped into my office, stared at me for minute, and then said, "You look 10 years younger."
By month nine, the weight loss slowed but the muscle growth continued. On a roll, I decided to quit smoking with a new anti-nicotine drug called Chantix. It makes you a little crazy and depressed, but kills the urge to smoke. Once I stopped the Chantix, I found myself binging on high-carb, high-fat foods. Luckily, my regular workouts helped offset those extra calories.
By month 12 of tesamorelin/exercise, my weight was back to baseline. However, I felt completely different: leaner in the belly and much bigger in the legs, arms, and butt. My absolute weight seemed less important to me because I felt good about how I looked in general. I felt normal.
Still, the last few months on tesamorelin, I experienced some uncomfortable side effects. I felt numbness and tingling in my arms, hands, and fingers. If I slept with one arm under the pillow, that arm immediately fell asleep. The tingling and carpal-tunnel-like symptoms continued sometimes all day. At one point, I cut down my dose of tesamorelin for a couple weeks. The tingling disappeared, but returned once I started again on the higher dose.
How Tesamorelin Stacks Up Against Serostim
It's easy to be impressed by the research on tesamorelin. Several large Phase 3 clinical trials have been completed and they are impressive. People taking 2 mg of tesamorelin lost at least 11% of their vat at week 26. At week 52, people lost up to 18% of their vat. According to the FDA, any vat reduction of at least 8% was good enough.
For perspective, compare the numbers for both tesamorelin and somatropin. After 26 weeks on 2 mg of tesamorelin taken daily, patients lost about 20 square centimeters from their belly when compared to placebo. Most of the effect occurred in the first 13 weeks of treatment. On the other hand, after 12 weeks on 4 mg of somatropin taken daily, patients also lost about 20 square centimeters from their belly when compared to placebo.
In terms of safety, somatropin falls short when compared to tesamorelin. In a 12-week study of somatropin, about one-in-four patients were forced to stop or lower their dose because of intolerable side effects, such as swelling or glucose problems and diabetes. For tesamorelin, side effects were no more common than with placebo and showed no signs of prompting glucose issues.
"We see the advantage in the safety profile," said Andrea Gilpin, vice president of investor relations and communications at Theratechnologies (makers of tesamorelin). Newcomers to the HIV market, the small Canadian biotech plans to file for FDA approval by end of 2008. "We feel we have a good product and just need to take it to the finish line."
But whose finish line? Understandably for Theratechnologies, the end game is FDA approval. But for patients, the predicament of tesamorelin and somatropin is what happens after the drug is stopped. For people who took tesamorelin for 26 weeks and then stopped, they regained nearly all their vat within six months. The same holds true for Serostim, except some unlucky patients gain back vat and get stuck with diabetes.
"What's the endpoint?" said Amorosa about the prospect of growth hormone as a viable treatment for vat. "What happens afterward? Do you leave someone on medication for years?" She noted that growth hormone treatment isn't practical for the majority of people with HIV. Furthermore, she cautioned that tesamorelin has not been compared to intensive diet and exercise.
The Boring Truth About Diet and Exercise
As a kid, I read the novel Flowers for Algernon. The main character, Charly, is the first person to test a medical procedure that improves intelligence. Charly grows smarter, even brilliant at one point after surgery. But with time, he reverts back to his below-average IQ. For me, the prospect of reverting back to my old apple-shaped self within six months is depressing. I wonder, is it better to have lost vat and gained it back, than to never have lost vat at all?
Over the years, a few scattered studies have looked at how exercise affects vat. In 2007, a 16-week clinical trial studied the effects of a supervised high-intensity exercise program on vat, cholesterol, and glucose control among people with HIV. The exercise program consisted of cardio and strength training -- almost identical to the program my trainer Brian had imposed on me.
The study was small, nine people started and only five people finished. But the results were impressive. Researchers saw statistically significant decreases in vat, triglycerides, and improvements for insulin sensitivity. The researchers concluded that a larger study of exercise intervention is justified. Unfortunately, there isn't money to be made from exercise. There is no large exercise organization to lobby for its benefits. So, vat interventions will continue to come in the form of pharmaceutical pills and shots.
To maintain less fat and more muscle, I figure the key is diet and exercise. I plan to continue my three-times weekly workouts with Brian. But calorie restriction has never been easy for me, especially without cigarettes.
"Honestly, the most important thing is not to smoke," said Amorosa. "A lot of people smoke because they want to keep thin. In our patients who have HIV, there's a lot of smoking. It's worse in terms of risk factors for heart attack and everything else. Even if people were to gain five pounds from not smoking, that would be worth it. If they care about their health, that's number one."
At the end of the day, she said, there are two primary issues people should consider. There's the physical issue of being comfortable in your own skin, how you look. The other is the potential for bad health outcomes, like heart disease and diabetes.
So what's a person to do? "It's boring, but it's diet and exercise," said Amorosa. People should adopt healthy eating habits that are sustainable over time. People need to learn exactly what that means. She suggested limiting calories, but especially those from sugar and alcohol. She also suggested that Weight Watchers has a solid track record for long-term weight loss. "Thinking about pharmacologic interventions," said Amorosa, "compare the cost of tesamorelin to the cost of a membership at Weight Watchers."
After a year on tesamorelin, I can say that tesamorelin reduces vat and increases muscle. No question. Is tesamorelin more effective than Serostim? Probably. Tesamorelin certainly is safer -- so far anyway. Does the vat return when treatment stops? Yes, that's what the research says.
What am I going to do without growth hormone? I'm going to choose the relentlessly optimistic attitude about fitness that my trainer drilled into me. I will continue to work out three days a week. As for my Tuesday nights, I quit group therapy. In its place, I've joined Weight Watchers. Maybe it's hokey, but I don't care. For long-term health, it's important to stay as lean as possible. After all, I was blessed enough to survive HIV, the least I can do is take really good care of the rest of me.
Brett Grodeck is the author of The First Year -- HIV: An Essential Guide for the Newly Diagnosed, and a former editor of Positively Aware magazine.
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