Egrifta (Tesamorelin) Gains FDA Approval & Testosterone Remains an Important Mainstay
Published in Positively Aware Jan 2011
Daniel S. Berger, M.D.
There are many hormones that one considers to have important utility within the field of HIV therapeutics. This article will discuss specifically two of them; testosteone, the oldest therapeutic intervention first used to combat wasting now administered more often and in more healthy individuals. Egrifta is the latest hormone recently approved for the treatment of HIV associated abdominal fat accumulation.
To date, there has been much information about testosterone, difficult to cover its’ full particulars and finer points in an article. However, a recent book , “Testosterone, A Man’s Guide” written by Nelson Virgil has excellent detailed information. In contrast, Egrifta, which is growth hormone-releasing factor (GHRH), is the latest hormone making its’ way into the HIV armamentarium; it has only recently been approved as of November 2010. The information we know is very much based on two large phase III trials, for which am proud to have participated in as a lead principle investigator. Its’ development is historic. As the first and only agent to have gained approval to combat a component of lipodystrophy it has shown to reduce fat accumulation, also known as visceral hypertrophy, or increased belly fat. To open this dialogue on these hormones as treatment, it’s important to put it into clinical context. This article will begin with 4 real cases that I’ve recently seen in the exam room at Northstar and will pose as a useful vehicle for this article’s discussion to illustrate salient points. The names have been changed to protect the innocent.
Dustin is a 31 year old attractive healthy guy who is devout in his practice of gay religion: going regularly to the gym (Gay church) and healthy eating, – overall he’s maintaining himself in the best and great shape. He’s not seen a doctor in years but came into my office because particular issues have been bothering him. He stated that ever since he can remember, he seems to have less of a libido than his friends; when he does meet an attractive “hot” man and finds himself in the “position” he has a difficult time maintaining an erection, despite feeling sexually aroused. He also has difficulty gaining weight, though he does all the right things…diet, exercise, protein supplements. He does not have fatigue or depression symptoms.
Mark is a 54 year old college professor, not married, has a girl friend with benefits. Throughout his life he was an ardent athlete staying in shape but now finds himself with less of a desire to go to the gym. He’s noticed that his libido is down, as well. When discussing these issues with his then primary care physician, the doctor who checked on his testosterone (T) levels, told him that it was “normal” for his age. He came to my office looking for a second opinion and stating that he didn’t want a testosterone level that was normal for his age, but rather a more normal testosterone level for any age. He wanted to regain that zest for enjoying all that life has to offer, for which has been dropping off, as of recent.
Doug is a 37 year old HIV-positive man who has been well-controlled on his antiretroviral cocktail, undetectable and with good CD4 counts. He has no other significant problems but noticed that he has become more tired, even early in the day and upon first getting out of bed in the morning. He also notices that he’s been putting on the wrong kind of weight, more fat and less muscle, despite trying his best to exercise. He mentions that he’s not had much desire for sex, and doesn’t consider this too important, but “wouldn’t mind if things were different”.
Mike is HIV-positive and had complaints of low libido, feeling depressed and fatigued. His doctor told him his T levels were “normal”. When he pressed his doctor to tell him what his levels were, his previous doctor said that normals are between 280 and 900 and that he was within the normal, at 330. Mike nearly freaked, but his doctor continued to reassure him. The other important fact is that Mike has noticed that his waist size has been growing, despite the fact that he’s not changed his diet. His doctor reassured him and explains that he is doing well. Mike confides in me saying all he could think of was the fact that the only thing normal about himself was that he didn’t have a soprano voice, nor have developed breast tissue, yet. He finally got a second opinion.
Egrifta, Much Anticipated, Newly Approved
It has long been understood that HIV-positive individuals are prone to develop unusual increases of fat in specific parts of their bodies. Until only recently, there was no product approved for its’ treatment, nor was it clear about what could be done about it.
Egrifta, developed by the Canadian firm Theratechnologies Inc, is also known as tesamorelin or growth hormone-releasing factor. It works by stimulating the body’s own production of growth hormone and leads to oxidation or burning of body fat, specifically visceral or abdominal fat associated with HIV disease, a component that makes up the syndrome of lipodystophy.
Certain medications including the older protease inhibitors such as Crixivan [indinavir], Kaletra (lopinavir/ritonavir) as well as the non-nuke, Sustiva (also a component of Atripla) has been shown in studies to be associated with developing abnormal body fat increases. Some older nucleosides, such as d4t and AZT and also shown to be associated with abnormal body fat changes as well, most often fat loss or lipoatrophy. These agents reduce mitochondrial functioning. Fat tissue is rich mitochondria, which are cellular organs known as metabolic power houses. It is also believed that HIV infection itself can cause the fat and body habitus changes of lipodystrophy. Egrifta, no doubt will become a very important product used for this purpose. It will be marketed by EMD Serono.
What we can expect of treatment with Egrifta is a resultant decrease in 17% to 18% of visceral fat. This effect is indeed significant and easily noticeable by patients who I was seeing as they participated in the clinical trials. I think that when exercise and diet is combined with Egrifta use, the loss of abdominal fat will only be heightened. Additionally, from what I personally observed in the exam room during both trials, patients who had low self esteem from their perceived unsightly appearance and body image became less depressed with treatment. Patients will need to self administer Egrifta daily by subcutaneous injection.
Patients often notice their body habitus changes long before their physicians. Case 4 illustrates how a patient brings it up in the exam room. One doesn’t need to wait till the lipohypertrophy is severe. If the problem is beginning to manifest itself, I believe one can be proactive and consider treatment early to avert worsening of the condition.
Among side effects, Egrifta was generally well tolerated but because it is associated with increased levels of insulin-like growth factor they include mild stiffness of joints, mild swelling of hands or feet, injection site reactions, redness or tenderness at the injection site and there is a slight possibility of reduced or impaired glucose tolerance. However patients with mild diet controlled diabetes did not have worsening glucose levels during the clinical trials. Nevertheless, physicians should monitor their patients on treatment, as appropriate.
Testosterone: Many Important Functions
Testosterone, known as the male sex hormone is important for many physiologic and metabolic functions other than simply improving performance in the bedroom. Low and deficient levels may be associated with fatigue, depression, irritability, bone thinning and in older age individuals, reduced cognitive functions . These are in addition to the more well known problems of low libido and erectile dysfunction. The cases above illustrate various scenarios and Case 3 illustrates a patient complaining of constitutional symptoms that is a typical presentation of low testosterone levels ( in addition to complaints of low libido). When low testosterone levels persist, a syndrome of hypogonadism can develop and includes symptoms of low libido, fatigue, depression, very common in HIV disease. In HIV-positive individuals, serious loss of lean body mass results is defined as Wasting Syndrome. Also, low testosterone levels are also associated with increased abdominal fat. When wasting occurs in persons with HIV-infection, it is associated with more infections, many constitutional symptoms and increased risk of death. Some years ago, we published a study which showed that 25% of individuals with wasting in the era of HAART (the cocktail) may be due to low testosterone levels.
Originally, it was several community-involved HIV specialists that began recognizing the importance of testosterone replacement. Back in the early 90’s, we began offering our patients “physiologic replacement” by injection. In other words, we administered dosages of testosterone that are consistent with what the body should normally have to maintain its’ normal levels and function. This led to much improved sense-of-well-being among our patients and the reduced potential for weight loss and other HIV complications. Eventually, several companies developed testosterone products in the form of gels and studying its’ use in normal (non-HIV infected) men. Low and behold, there is a large prevalence of men who have low levels and whom derive benefits from replacement treatment. I occasionally see young men in their 20’s and 30’s who have a deficiency, never mind that they are HIV-negative. The patient of case 1 is not an uncommon phenomenon.
Although blood levels of testosterone are checked by physicians, many do not understand that these numeric values are relative, because there is a large range of normal quoted by each lab. An individual who may have a value in the normal range, may not be normal for him, since first, he’s developed symptoms. Second, previous levels are not always available to compare. The individuals in Cases 2 and 3 demonstrate that levels may not correlate with symptomatology.
There are two ways that testosterone can be administered: intramuscular injection and topical administration in either gel or cream form. By either route the replacement of testosterone from my experience can show dramatic effects. These include a marked improvement in energy levels, reduced anxiety and depression symptoms, improved libido and self confidence, improved stamina and in the gym, individuals note their improvement in body mass and reduction in fat. Overall there’s a greatly improved sense of well -being.
A common side effect includes increased red blood cell production (hematopoesis) which we treat at Northstar with therapeutic phlebotomy and sometimes need to modify dosing. Other side effects, increased blood pressure, elevated hepatic transaminases or increased liver enzymes, gynecomastia, acne or skin outbreaks, increased appetite and mood swings can also occur. Thus monitoring of side effects is important and includes blood testing for vigilance liver enzymes, blood count, blood pressures, testosterone levels and prostate specific antigen levels. Side effects get detected early and can be easily managed.
There has been concern that testosterone replacement may have a causal relationship to prostate cancer. This has long been myth that is unfounded. Several clinical studies have now been consistent in showing in persons who do develop prostate cancer, lower testosterone levels are associated with a more aggressive cancer; another study demonstrated that testosterone levels did not result in increased levels of prostate specific antigen (PSA), a marker used for the early detection of prostate cancer. It is believed however, that only if there is prostate cancer already present, untreated, testosterone administration may stimulate tumor growth, or worsening of the cancer. Therefore, for patients without prostate cancer, there is no evidence or data that shows testosterone to cause cancer. Several urologists agree that there is no danger of administering testosterone in whom patients were treated for prostate cancer by prostatectomy.
Patients receiving injections are often on testosterone cypionate (Depo-tesosterone) and are on various intervals of treatment and at varying doses. In the injectable form, the intervals and dosing are often chosen based the perceived durability of effect by the patient. In other words, patient will often tell me that at a certain point in time after their injection, they begin to feel its’ effects wearing off. With each administered injection there is a surge of testosterone in the blood that occurs promptly. This surge is associated with individuals feeling great relief from their symptoms of deficiency. However sometimes, testosterone levels in the blood may begin to drop off rapidly after a few weeks and sometimes within only a few days of the injection, and can remain low until the next injection. Additionally, the surge in testosterone levels can stimulate the brain’s biofeedback mechanism, and sensing the high testosterone levels sends a message to the adrenals and testes to shut down its’ own endogenous production, sometimes making it difficult to maintain normal levels. Nevertheless, patients receiving intramuscular injections of testosterone derive very quick relief of symptoms and often prefer this mode of replacement.
Another mode of administration is by transdermal or topical gel or cream. Individuals usually apply the gel to an area of skin every morning and thus, testosterone is absorbed gradually over several hours. This daily therapy often leads to more consistent blood levels that avoids up and down symptoms that are associated with injectable replacement. Two such products are available: Androgel and Testim. Both products are applied similarly. What differentiates them is that the Testim formulation contains a delivery system that allows for higher levels of testosterone absorption and has made it a more efficient replacement overall. The delivery system is a compound that gives Testim a musky aroma, not unlike a musky cologne such as Brut, but dissipates over the course of a few hours. It is my experience that patients often achieve higher levels with Testim. Additionally, individuals who don’t achieve normal testosterone levels with Androgel often respond better with Testim
The development of Egrifta is an important milestone in HIV therapeutics. It provides patients an option to combat visceral adiposity and body image issues. Facial wasting is a different manifestation of lipodystrophy that had already been overcome by effective treatment with Sculptra and Radiesse and is widely administered at Northstar in Chicago and other clinics nationally. Thus together, we have a more rounded line of therapy for various manifestations of lipodysrophy and the psychological ramifications of altered body image. However, dietary measures and exercise should not be overlooked.
In contrast, testosterone deficiency is common among HIV infected individuals and is associated with many daily symptoms. Replacement treatment improves quality of life through improving daily energy levels, reducing depression and helps build body mass, strength and improved cognitive function, in addition to its’ effect on libido. Testosterone treatment has been used by physicians for many years. With mounting evidence for its’ benefits, it is hoped that other physicians who have been reluctant to provide hormonal replacement easily, may feel more comfortable with its’ management and safety. As patients are increasingly living longer healthier lives, they can be empowered with the knowledge of the various treatment modalities, realize their therapeutic options and help themselves achieve an improved quality of life.
Dr. Daniel S. Berger is a leading HIV physician in the U.S. and is Clinical Associate Professor of Medicine at the University of Illinois at Chicago. He is founder and medical director of Northstar Healthcare, the largest private HIV treatment and research center in the Greater Chicago area. Dr. Berger has published extensively in such prestigious journals as The Lancet and The New England Journal of Medicine and serves on the Medical Issues Committee for the Illinois AIDS Drug Assistance Program and the AIDS Foundation of Chicago. Dr. Berger has been honored by Test Positive Aware Network with the Charles E. Clifton Leadership Award.