New Option for HIV related Facial Lipoatrophy to be approved soon in the US

I had a call with Bioform, the makers of Radiesse yesterday. I am organizing a group of treatment activists to meet with them to discuss their patient assistance program design soon. We still do not know what the cost for HIV related work will be or what the patient assistance program will look like. I am hoping that they will be as easy to work with as Dermik (Sculptra) was.



From FACIALWASTING.ORG:



Radiesse (also called Radiense) is (calcium hydroxylapatite, (CaHA) microspheres suspended in an aqueous polysaccharide gel. Radiance, the newest product in the market, is not approved in the US as a facial filler yet but doctors are using it under an IDE study. It is manufactured by Bioform of Franksville, Wisconsin. In general, calcium hydroxylapatite has safely been used in the body for many applications including dental applications where bone build-up is needed for reconstruction and also in block form for cosmetic applications such as cheek, jaw, cranial and chin implants (hard bony areas). Calcium hydroxylapatite creates a lattice where the surrounding cells can be incorporated from ossification in bony areas to a stable scaffold in which soft tissue can grow. The calcium hydroxylapatite microspheres are suspended in a polysaccharide carrier which holds the microspheres in place until it is resorbed and the collagenation takes place. When injected in soft tissue, away from bone, fibroblasts work by building reportedly a non-scar tissue collagen type, thus creating volume in the treatment area. Its unclear where this material should be injected (dermally or sub dermally) to achieve correction of facial defects. It is being used in small quatities for wrinkle treatment and lip augmentation. It tends to be unforgiving if not applied properly. An allergy test is supposedly not needed. The especulated longevity is 2 to 5 years .



More about a study here: http://dermatology.cdlib.org/102/therapy/HIV/comite.html





INFORMATION FROM THE COMPANY:
*************************************************



RADIESSE® FACT SHEET



WHAT IS RADIESSE



Radiesse is a next-generation, long-lasting product used for soft tissue augmentation.



· Radiesse consists of calcium-based microsphere technology that naturally promotes the growth of a patient’s own collagen.



· Radiesse provides a correction that has been proven to last one year without surgery.



· Radiesse is not permanent and therefore avoids the risks associated with permanent materials.



HOW IT WORKS



Radiesse is an injectable product consisting of tiny calcium-based particles that replace volume loss and also stimulate new collagen growth for long-lasting clinical results.



· Radiesse is gently injected into the skin in very small amounts with a very fine needle. Its exclusive calcium-based microsphere technology contains tiny particles of calcium-based powder that form a scaffold around which the body produces new collagen to naturally restore the fullness and contours of the face. The tiny microspheres gradually break down into calcium and phosphate ions that are naturally absorbed by the body over time.



· Radiesse’s biocompatible composition is harmonious with the body and poses virtually no risk of an allergic reaction.



WHAT IT TREATS



Radiesse is a long-lasting soft tissue augmentation material used to correct facial wrinkles and folds, such as nasolabial folds. It also used to correct facial lipoatrophy (facial wasting) associated with HIV therapy.



WHAT SETS RADIESSE APART



Radiesse is different because it is a next-generation product that is long-lasting.



THE PROOF:



Years of rigorous clinical testing and use by physicians in more than 200,000 patients worldwide demonstrate that Radiesse is safe and effective. Further, clinical studies show that the average Radiesse treatment lasts one year.



WHO STANDS BY RADIESSE:



BioForm Medical is a privately-held medical device company that develops and commercializes injectable implants for soft tissue augmentation.



ML00179-00


********************************************

Radiesse® 12-Month HIV Facial Lipoatrophy

CLINICAL study BACKGROUNDER


Trial Background:
o A multi-site, clinical study examining the safety and efficacy of Radiesse injections for restorative treatment of HIV-associated facial lipoatrophy.

o Conducted by BioForm Medical, Inc., a privately-held medical device company specializing in injectable products for soft tissue augmentation.

o Trial conducted under an Investigational Device Exemption (IDE) granted by the FDA.

Trial Design:
o Conducted at three medical centers in the United States, including two centers in New York City and one in San Francisco.

o 100 patients with HIV-associated facial lipoatrophy were enrolled in the trial.

o All study patients received an injection of Radiesse during initial visit and were seen one month later for touch up injections as necessary.

o Additional follow up conducted at three and six months.



Key Findings:


o Patients were scored by their physician for improved appearance on the Global Aesthetic Improvement Scale (GAIS). Finding 12 months after treatment with Radiesse showed:

· 32 percent of patients’ appearance were Very Much Improved

· 52 percent of patients’ appearance were Much Improved

· 16 percent of patients’ appearance were Improved

· 0 percent of patients’ appearance was Unchanged

· 0 percent of patients’ appearance was Worse



o During the study, patients were asked how treatment with Radiesse had affected their quality of life. At 12-months follow up:

· 100 percent of patients said that treatment with Radiesse had been beneficial

· 99 percent of patients said they were more confident about their appearance after treatment with Radiesse

· 99 percent of patients said they would recommend treatment with Radiesse

· 98 percent of patients said that they felt more attractive after treatment with Radiesse

· 97percent of patients said that they felt their emotional state had improved after treatment with Radiesse



o Radiesse was safe and well tolerated, with no serious device-related adverse events reported. In all 100 patients, Radiesse was proven safe for injection.

Data Publication/ Presentation:
Study results were presented at the recent meetings of the American Society of Plastic Surgery (ASPS) and American Academy of Facial Plastic and Reconstructive Surgery (AAFPRS).



Findings were published in a special supplement of the September 2005 issue of Plastic Surgery Journal.

Current Indications:
Radiesse is currently approved in the U.S. for treatment of the following conditions:

Oral/Maxillofacial Defects
Vocal Fold Insufficiency
Radiographic Tissue Marking

Good News for People in Salvage Therapy: Merck to start its expanded access program for its integrase inhibitor MRK 518

I am very excited about this expanded access of Merck's integrase inhibitor, MRK 518.

I have been taking it for 3 months now with the new protease (Prezista) and have been able to reach undetectable viral load for the first time in 23 years. My CD4 cells have more than doubled from 180 to 440 cells/ml

The response to MRK 518 seems to be faster than most drugs in the past. In a naive study presented this week in Toronto that compared MRK 518 plus Truvada with Sustiva+Truvada, it was seen that MRK 518 can drive viral load down faster than Sustiva, although the Sustiva arm eventually matched the MRK 518 arm at week 24.

So far, no significant side effects have been observed besides an increased in flatulence in some patients.

MRK 518 is taken in one pill twice a day without Norvir ( no need for Norvir boosting is welcomed by many of us!). It seems that it does not have problematic interactions with most drugs since it is not metabolized in the P450 cytochrome in the liver.

I think MRK 518 will be an excellent drug in combination with Prezista and/or Fuzeon for those of us who have run out of options. It may present the first chance for many of us to have undetectable viral load.



NATAP http://natap.org/
_______________________________________________


Expanded Access Program for MK-0518, an Investigational HIV Integrase Inhibitor, Established for Patients with Limited Available Treatment Options

Worldwide Access Program Will Be Conducted Along With Phase III Studies

TORONTO, Aug. 17, 2006 -- A worldwide expanded access program for HIV/AIDS patients with limited or no treatment options was announced today by Merck & Co., Inc., Whitehouse Station, N.J., U.S.A., with respect to its investigational HIV integrase inhibitor, MK-0518, now in Phase III development. Program enrollment will begin in the next few months, pending regulatory review and approvals.

“Making MK-0518 available to those who would like access to this investigational drug but who are unable to participate in the clinical studies underscores our commitment to patients,” said Dr. Peter S. Kim, president, Merck Research Laboratories (MRL).

MK-0518 belongs to a new class of investigational antiretroviral therapy (ART) agents called integrase inhibitors that inhibit the insertion of the HIV viral DNA into human DNA. Integrase is one of three HIV enzymes - reverse transcriptase, protease and integrase - required by the virus to reproduce. Drugs are available that inhibit the functions of the protease and reverse transcriptase enzymes but, to date, there are no approved drugs that target the integration stage of the HIV-1 lifecycle.

Expanded access

“The MK-0518 program is another example of Merck's dedication to people living with HIV/AIDS around the world,” commented Dr. Randi Leavitt, senior director, Infectious Diseases - Clinical Research, MRL and lead coordinator of the expanded access program. “This makes the third expanded access program that Merck has initiated. In mid and late 1990, the Company implemented expanded access programs for two other investigational drugs for treatment of HIV,” Dr. Leavitt explained.

Expanded access is a mechanism supported by regulatory agencies for getting investigational treatment to patients who have a life threatening disease and who cannot be satisfactorily treated with an alternative therapy or available drug. Expanded access programs are not required by regulatory agencies. These
programs are initiated and supported by drug manufacturers in recognition of the promise an unapproved drug may hold for patients facing a life-threatening disease.

MK-0518 expanded access study design

The expanded access program with MK-0518 is a non-comparative, multi-center, open-label, voluntary treatment use study. Investigators will follow patients according to standard of care. The study will continue until approximately three months after MK-0518 has been launched in the local market.

To be eligible to participate, patients must have documented HIV-1 infection, be at least 16 years old, have limited or no treatment options available to them due to resistance or intolerance to multiple anti-retroviral regimens, are not achieving adequate virologic suppression on current regimen and be at risk of clinical or immunologic progression, and be clinically stable. Patients are excluded from the study if they have received MK-0518 in a clinical trial, require any medications prohibited by the protocol, have acute hepatitis due to any cause or clinically significant chronic liver disease, have a condition which the investigator deems will interfere with adherence and safety, or are pregnant.

Patients will receive open-label MK-0518 400 mg twice daily, in addition to optimized background therapy (OBT). Investigators will select the OBT based on the patient's prior treatment history and anti-retroviral resistance testing. OBT will not be provided by Merck. Safety and tolerability of MK-0518 will be monitored.

The program will be managed by a clinical research organization (CRO). The CRO will collect all case report information including serious adverse events and drug-related adverse events that result in Grade 3 or above laboratory toxicity, leading to treatment interruption or discontinuation. No efficacy data will be collected.

About Merck's HIV/AIDS research program

Merck's HIV clinical research program began in 1985. Merck scientists were among the first to discover and develop medicines for the treatment of HIV/AIDS. In 1996, Merck introduced a protease inhibitor, which was followed by the introduction in 1999 of a non-nucleoside reverse transcriptase inhibitor (NNRTI).

In addition to MK-0518, Merck is focused on developing new treatments for millions of individuals who are already infected with HIV, as well as on preventing HIV transmission through the development of a vaccine. Merck also licensed a compound to the International Partnership for Microbicides (IPM) for development as a possible means of preventing HIV infection in women.

Polycythemia, Anabolic Steroids and HIV Wasting

Some HIV positive people need to gain lean body mass and weight but develop polycythemia when using nandrolone or other anabolics, so their doctors refuse to prescribe these important medicines. Polycythemia is an increase in red blood cells and hematocrit that can cause increased blood viscosity, making it more difficult for the heart to pump blood. This can cause heart attackes or strokes, so it is important to know how to manage this problem. Lyckily, only a very small number of people using anabolics have this problem. We still do not know what makes one person more suceptible than other.

I had this problem for 5 months back when I was on Crixivan. For reasons that I do not understand yet, it went away once I stopped Crixivan. I also think using AZT may have a controlling effect on red blood cells.

This first article explains why anabolics increase red blood cells

Anabolic Steroids and Red Blood Cellshttp://www.mesomorphosis.com/articles/llewellyn/steroids-and-red-blood-cells.htm


Dr Scally has been able to write a very good article to teach doctors how to manage the problem

How to Manage Polycythemia Induced by Anabolic Steroids
By Michael C. Scally M.D.

For better formatting , see
http://health.groups.yahoo.com/group/PozHealth/message/16494

Dr. Michael C. Scally a Harvard and MIT trained physician and researcher in private practice in Houston who has written extensively on hormonal issues and HIV.

During the past few years, his focus have been on managing induced hypogonadism (low testosterone production by the body) after anabolic steroid therapy by restoring HPGA (Hypothalamic Pituitary Gonadal Axis) and managing polycythemia (increased red blood count that increases blood viscosity and cardiovascular disease risks.) This takes on particular importance as hormonal therapies become standard of care in HIV. His development of a new therapeutic approach is detailed in this report, and we are very excited to make it available to our readers.

Anabolic Steroid Use in HIV: Managing Androgen Induced Polycythemia and Hypogonadism

Wasting is one of the most common symptoms of human immunodeficiency virus (HIV). Wasting syndrome is widely considered the involuntary loss of 10% of initial body weight, many times in combination with diarrhea, weakness, and fever (Revision of the CDC surveillance case definition for acquired immunodeficiency syndrome. MMWR Morb. Mortal Wkly. Rep. 1987; 36 Supp.l 1). This condition may be attributed from malnutrition, diarrhea, altered metabolism, malabsorption, or hypogonadism associated with HIV infection. Since there is an increased mortality rate of HIV patients suffering with substantial body weight loss, aggressive therapies aimed at retaining lean body mass have been pursued.

One particular modality that has shown to be effective in preserving lean body weight is anabolic androgenic steroid (AAS) or androgen therapy. Multiple studies have evaluated the effects of androgens on combating wasting in HIV+ males. These reports have shown significant improvements in lean body mass up to 5.6 kg over short-term usage. While other HIV associated wasting and retroviral therapies may improve total body weight, androgen therapy has demonstrated an increase in fat free weight without a concurrent increase in fat mass. Unfortunately, therapies utilizing protease inhibitors or dietary counseling for wasting syndrome have found larger increases in fat tissue than improvements in muscle mass, thus granting minimal improvements in immune function and metabolism.

Along with the documentation and dissemination of the benefits of androgen therapy in treating wasting syndrome has come an associated acceptability within the medical community in prescribing these medicines. Research articles discussing the use of androgens in HIV+ patients are becoming more prevalent in the medical literature. A drawback of the increased utilization of androgens, however, are those scenarios where patients are administered these medicines for lengthy durations. Extended, uninterrupted use of androgens has been shown to induce polycythemia. Defined as a chronic myeloproliferative disorder characterized by an increase in hemoglobin concentration and red blood cell (RBC) mass (erythrocytosis), polycythemia increases the risk of thrombosis, post polycythemia myeloid metaplasia, and acute leukemia. Androgens, by increasing the endogenous production of erythropoietin, enhance the body’s rate of erythropoiesis and subsequently hemoglobin and RBC mass. With increased viscosity of the blood and platelets, an increased risk of blood clotting, heart attack, and stroke becomes a primary concern with patients afflicted with polycythemia. In terms of androgens, uninterrupted treatment may potentially do greater harm than good when faced with the possibility of problematic polycythemia secondary to androgen therapy.

The following is a report of problematic polycythemia as a result of long-term androgen therapy in an HIV+ male.

Case

A 46-year old HIV+ male presented with complaints of shortness-of breath, fatigue, excessive sweating and facial erythema. Medical history revealed a record of uninterrupted testosterone administration for the two years prior to presentation. The patient was administered testosterone cypionate, 200 mg IM per week, for two years to help sustain lean muscle mass in the prevention of HIV associated wasting syndrome. Laboratory studies revealed polycythemia but were otherwise unremarkable. An attempt at discontinuation of androgen therapy precipitated problematic hypogonadism exhibited by lethargy, diminished libido, decreased energy, sleep disturbance and depression. Testosterone treatment was restarted and the patient referred for consultation.

On presentation vital signs and weight, 75kg, were within normal limits. Original baseline laboratory studies prior to testosterone administration revealed normal CBC and hormone profile, Table 1.

Table 1.

Test
Hgb (gm/dL)
Hct (%)
RBC (M/uL)
LH(mIU/mL)
T (ng/dL)

Value
15.8
48.2
5.48
3.4
470

Reference

Range
13.2-17.1
38.5-50.0
4.2-5.8
1.5-9.3
241-827


Hgb “ Hemoglobin

Hct “ Hematocrit

LH “ Luteinizing Hormone

T- Total Testosterone

Laboratory values on the consultation presentation are shown in Table 2.

Table 2.

Test
Hgb (gm/dL)
Hct (%)
RBC (M/uL)
LH (mIU/mL)
T (ng/dL)

Value
18.0
60.0
6.09
<0.2
1200


Therapy was directed two-fold towards the androgen-induced polycythemia. First, the elevated Hemoglobin/Hematocrit was addressed by a therapeutic phlebotomy. Secondly, the increased rate of erythropoiesis was normalized by removing the androgen stimulus. In order to avoid the previous problematic hypogonadism upon androgen cessation a medical protocol for hypothalamic-pituitary-testicular axis (HPTA) normalization was administered.

Therapeutic phlebotomy was initiated to restore normal red blood cell indices. The approximate amount of blood volume that needed to be withdrawn to restore normal values can be calculated by the following formula. This use of the formula includes the assumption that whole blood is withdrawn. Also the duration of time over which the blood volume is withdrawn is affected by whether or not concurrent fluid replacement occurs.

CC of Blood Volume Drawn = Wt(kg) x ABV x [Hgbi - Hgbf] / [(Hgbi + Hgbf)/2]

ABV= Average Blood Volume (default = 70)

Hgbi (Hcti) = Hemoglobin initial

Hgbf (Hctf) = Hemoglobin final (desired); or

CC = 75 X 70 X [20-14]/[(20+14)/2] = 75 X 70 X (6/17) = ~1850;

@ 1Unit Whole Blood = ~350 - 450 CC; ~1850/(350 – 450) = ~4 Units

For a final hemoglobin of 14 a therapeutic phlebotomy of ~4 Units whole blood will be

required.

To return the rate of erythropoiesis to normal it is necessary to remove the androgen stimulus to erythropoietin production. In order to avoid the problematic hypogonadism mentioned previously after androgen cessation a medical protocol was administered for HPTA normalization. The protocol consisted of the medications human chorionic gonadotropin (hCG), Clomiphene citrate and Tamoxifen. Treatment takes place over two discrete intervals. The first treatment interval is to initiate the restoration of testicular function while the latter is for the coupling and restoration of the hypothalamus/pituitary and testicles.

The medications were initiated simultaneously at a time when it was expected that the body would be expected to begin endogenous testosterone production. Since the source of the exogenous androgen was depotestosterone (testosterone cypionate) with a known half-life the date to begin the medical protocol can be predicted with some accuracy. hCG 2500 U SC QOD (every other day); Clomiphene Citrate 50MG I PO BID (oral , twice a day); and Tamoxifen 20MG I PO QD (oral, once a day) were administered for 15 days. A satisfactory testosterone level on day 15, typically 350 or greater, is followed by the oral medications for an additional 15 days. This patient had a testosterone level of 423 after the initial treatment interval. Upon completion of the medications and a therapeutic phlebotomy as noted above during this period followed by a two week washout period the patient had the following laboratory values, Table 3.

Table 3.

Test
Hgb (gm/dL)
Hct (%)
RBC (M/uL)
LH (mIU/mL)
T (ng/dL)

Value
14.1
43.5
4.68
7.3
626


Discussion

This case report is not intended to oppose the use of testosterone or any androgen in the treatment/prevention of HIV associated wasting syndrome. On the contrary, these medicines have proven their worth in retaining lean body mass in HIV+ patients. Nevertheless, attention needs to be drawn to the possible complications of long-term, uninterrupted androgen usage. Toxic effects on liver function have been shown to occur from long-term oral androgen usage. While this effect of androgens is usually associated with only orally active 17-alkylated compounds, all medicines in this class have the potential to cause liver abnormalities, especially at higher dosages and long-term, uninterrupted administration. Previous research dictates that negative lipid alterations can occur almost immediately after testosterone administration. Although the suppression of HDL cholesterol by androgens is quickly reversible upon discontinuation, there is speculation as to the increased risk of cardiovascular disease while supplementing with androgens. As described in this case report, extended, uninterrupted usage of androgens can cause secondary polycythemia. Periodic discontinuation of these medicines can be beneficial to the health of the patient in terms of preventing hepatotoxicity, negative alterations in lipid profile, and polycythemia.

Patients administered androgens for muscle wasting conditions, osteoporosis, anemia, or any other disorder not associated with primary hypogonadism should be discontinued from treatment on a periodic basis to ensure safe return of testicular function and prevent side effects linked to long term, continuous usage. Conversely, in cases of primary testicular failure that does not respond to stimulation therapy, indefinite testosterone replacement without cessation may be required.

Therapies utilizing human chorionic gonadotropin and clomiphene citrate have been proposed as treatment modalities for return of testicular and pituitary function, respectively. While this treatment needs to be evaluated in more extensive controlled studies, the medical literature gives credence to the possible benefits of its use . In the case of preventing androgen induced hypogonadism, this treatment option may prove to be very valuable.

If rapid return of testicular and pituitary function post androgen treatment can be achieved, the attendant effects of androgen-induced hypogonadism (AIH); muscle atrophy, increased adiposity, depressed libido, erection dysfunction, lethargy, and depression, that are typically associated with androgen cessation may be avoided. In cases of sustained hypogonadism that can result for almost two years post therapy , progressive decrease in muscle mass, osteoporosis, oligospermia or azoospermia, and severe mood disturbances may result . Periodic discontinuation of androgen treatment would avoid possible complications due to polycythemia, liver hepatotoxicity, and suppressed HDL-C while simultaneously retaining all of the positive benefits gained during androgen therapy. It’s alarming to realize that the beneficial aspects of androgen supplementation can become transient in the face of post-therapy hypogonadism, thus making androgen therapy an insignificant treatment option if ensuing hypogonadism is disregarded. On the other hand, if androgens can be administered in short term durations to avoid associated side effects while retaining lean body mass gains post-therapy, safe and efficacious use can be applied to numerous patient populations.

References


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20. Burge, M.R., et al., Idiopathic hypogonadotropic hypogonadism in a male runner is reversed by clomiphene citrate. Fertil Steril, 1997. 67(4): p. 783-5.

21. Tash, J.A., J.H. McGovern, and P.N. Schlegel, Acquired hypogonadotropic hypogonadism presenting as decreased seminal volume. Urology, 2000. 56(4): p. 669.

22. Ross, L.S., et al., Clomiphene treatment of the idiopathic hypofertile male: high-dose, alternate-day therapy. Fertil Steril, 1980. 33(6): p. 618-23.

23. Tan, R.S. and D. Vasudevan, Use of clomiphene citrate to reverse premature andropause secondary to steroid abuse. Fertil Steril, 2003. 79(1): p. 203-5.

24. Menon, D.K., Successful treatment of anabolic steroid-induced azoospermia with human chorionic gonadotropin and human menopausal gonadotropin. Fertil Steril, 2003. 79 Suppl 3: p. 1659-61.

25. Gazvani, M.R., et al., Conservative management of azoospermia following steroid abuse. Hum Reprod, 1997. 12(8): p. 1706-8.

26. Jarow, J.P. and L.I. Lipshultz, Anabolic steroid-induced hypogonadotropic hypogonadism. Am J Sports Med, 1990. 18(4): p. 429-31.

27. Petak, S.M., et al., AACE Clinical Practice Guidelines for the Evaluation and Treatment of Hypogonadism in Adult Male Patients. Endocrine Practice, 1996. 2(6): p. 440-453.