News & Commentary

New-Fill on “Hold” and Open-label for T-20
by Daniel S. Berger, MD
 
New-Fill Use Halted
Over the last several months countless numbers of HIV-positive individuals have had their spirits lifted, their morale boosted and their self-confidence improved. This was because a synthetic product called poly-lactic acid under the trademark New-Fill became available for personal use in the United States. New-Fill reversed many disfiguring facial abnormalities for many individuals; facial lipoatrophy changes are due in part to HIV drugs and HIV disease. Actually New-Fill has proved safe through clinical trials outside the US and has been shown to be effective for HIV-positive individuals with facial lipoatrophy. As a result, many HIV-positive individuals sought out treatment through a limited number of centers that were approved to administer the product. The product’s sale and use was administrated by DAAIR, a respectable buyers club based out of New York City. Further detailed background information regarding New-Fill can be found in my previous article from the September/October 2001 issue of Positively Aware and on the www.AIDSInfosource.com web site.After several months of smooth sailing with primarily trained plastic surgeons, almost by surprise, the FDA interceded and halted its use. A recent comment made by an unnamed HIV practitioner was “it appears that the FDA managed to find a loop hole ‘vehicle’ by which to interfere with personal wishes of individuals who suffer from the devastating facial side effects of antiretroviral therapy.” Clearly it was the FDA themselves whose policy allows treatment for personal use, given that a drug is approved outside the US.The October 26 action of the FDA halted all further distribution of New-Fill in the U.S.; therefore, the buying club DAAIR was in effect ordered to not release any more product for shipment—this included shipping New-Fill to those that had already initiated treatment and were still in the process of having the 3-7 administrations needed for New-Fill to be completely effective. DAAIR is guardedly confident that it can fulfill all shipments of product for those patients previously initiated into treatment with New-Fill prior to October 26th; however, at this time they cannot ship product to anyone who would have started the procedures post 10/26/01.The FDA decision was made by a small group of Directors within the FDA, from such areas as Personal Use and the Division of Compliance. The FDA based their decision to halt distribution of New-Fill on the technical terms of their guidelines of allowing availability. Originally, New-Fill was allowed to be accessed by PWAs under the “personal use guidelines.” These guidelines permit use of drugs not yet approved here (but approved in other countries) and for the treatment of one of several qualifying illnesses determined by the FDA. Persons suffering from these illnesses (such as AIDS) can import a drug into the U.S. for their individual personal use. The FDA then decided, upon further examination, that since New-Fill required the expertise of a trained physician and/or plastic surgeon that it no longer should be considered a personal use drug. Moreover, the FDA maintains that as New-Fill does not remain in full control of the individual utilizing the product, it should be re-categorized as a medical device.The FDA does not allow for medical devices to be imported for personal use—all medical devices must be approved prior to use. The example the FDA gave was as follows: This situation would be similar to an artificial heart that was available in Europe but not yet approved for use in the U.S. The FDA would not allow anyone to import that artificial heart and subsequently would not authorize any surgeon to transplant said device—if that individual wants to access that artificial heart they must travel to Europe and have the procedure done there. The FDA did acknowledge that they would consider a treatment-IND (Investigational New Drug) protocol for New-Fill (a clinical trial)—however, this typically is itself a large administrative burden that can take minimally 3-6 months to complete and is usually done by the sponsoring pharmaceutical company.Many medical specialists can state with confidence that New-Fill indeed is not a “device.” Yes it requires someone to inject the product, but linking this to heart transplant surgery is quite a stretch. The product comes in a vial such as many other drugs and is simply reconstituted with sterile water or saline, like other drugs. It is drawn up in a syringe and injected. This does not require any sophisticated or mechanical devices or apparatus.
New-Fill has been approved for use in France and Mexico. Safety and effect studies performed satisfied the French requirements for approval. Additionally, several studies reported the use among HIV-positive individuals. Those reports were presented at the 2nd International Workshop on Adverse Reactions and Lipodystrophy in HIV in Toronto in September 2000 and the 8th European Conference on Clinical Aspects and Treatment of HIV Infection in October 2001 in Athens.

As mentioned, DAAIR remains guardedly confident that it can fill all necessary prescriptions for product to those that had initiated treatment prior to 10/26/01. DAAIR is looking at various avenues within FDA guidelines and is attempting further inspection of this issue. If the FDA’s edict is left to stand, many affected persons will be wronged and deprived of a procedure that can potentially change their quality of life.

DAAIR is experiencing significant slowdown and problems. During this writing plans are being set up for a meeting with the FDA. In this meeting Martin Delaney of Project Inform, DAAIR management, and I with other interested parties will hope to clear up some of these issues. Additionally, clinical trials with New-Fill for a “lipoatrophy associated HIV disease” indication are on the discussion table. I will try to keep you all posted on the www.AIDSInfosource.com website as well as in further issues of my column in Positively Aware.

T-20, Trimeris/Roche Open Label
Trimeris and Roche teamed up to offer a new open label study for the administration of T-20 to the most needy of HIV positive patients. T-20 is a novel antiviral, first of a new class of fusion inhibitors (blocks fusion of HIV to CD4 T cells). This was not an expanded access program, but an open-label safety study and was severely limited to 168 patients nationwide.
The program was initially announced on 11/07/01 and details of the protocol and its operation posted on the Trimeris web site. Additionally the companies announced that for “the letter distributed to doctors concerning the initiation of the study, visit the following websites: www.rocheusa.com or www.Trimeris.com.” However as a physician who prescribes HIV medications, neither I nor the other physicians in our clinic have ever received such a letter. We have also spoken with several other community-based HIV physicians, none of whom received any letter.

The wire news story announced that a phone line would open at 3 PM EST on November 27th for up to 56 physicians who would be allowed to sign up as investigators and enroll three patients each. The criteria for enrollment was CD4 T cell count <50 cells/mm3 and viral load >10,000. First preference would be given to those with a recent opportunistic event while on an anti-HIV regimen in the last 90 days. However, I attempted to get through by telephone to register, getting a busy signal and at times no response. I kept trying. Finally getting a recorded message that stated, “We’re sorry, enrollment is now full.” We were later told that the program closed in less than 20 minutes of opening.

Alex Dusek, Director of Marketing at Trimeris stated that this was their attempt to “serve the community in the most equitable manner” and “seeking the advice of many other people.” As much as we appreciate the efforts of Trimeris and Roche to increase availability it remains that a majority of advanced patients were not served.

If these were the Rolling Stones tickets that were on a first come first serve basis, I could understand handling it this way. However, unfortunately the honest reality is that many individuals’ lives are at stake. When protease inhibitors were in Phase III of development (1994) a lottery system of patient chart numbers was set up through physicians’ offices and sponsoring pharmaceutical companies. Those programs provided a fair chance for all patients to receive drug. In contrast, the Trimeris/Roche program favored larger institutions that could afford to place a dedicated employee on the phone that day and dial as many times as needed to get connected. We were told that no comment can be made as to whether several institutions or sites enrolled more than 1 physician and potentially took up more than their share of very few spaces.Mr. Dusek of Trimeris reiterated that a complicated manufacturing and production process limits supply. I encourage Trimeris to provide wider availability for patients with limited treatment options. During the recent years of development, T-20 access has been greatly restricted. I hope that without too many delays Trimeris and Roche will offer an expanded access program.
 
Daniel S. Berger, M.D. is Medical Director of Northstar Healthcare and Clinical Assistant Professor of Medicine at the University of Illinois at Chicago and editor of AIDSInfosource (www.aidsinfosource.com) He also serves as medical consultant for Positively Aware. For further inquiries Dr. Berger can be reached at DSBergerMD@aol.com or (773) 296-2400.

God Breast Ye Merry Gentlemen
by Daniel S. Berger MD
 
Old Business
Today writing my usual passionate, intense, buzzful column was a difficult, arduous task. Writing generally comes easy for me. However, I, like many, have been experiencing an unfamiliar character of pain from the recent national tragedy that began in New York City. I have unsuccessfully tried to make sense of the loss of so many and the crumbling of our financial capital. I have received differing perspectives on the events from my sister-in-law who was nearly trapped in her work place. My brother is co-director of the Intensive Care Unit at Bellevue Hospital; he witnessed these events from the hospital windows. His thoughts were that his wife was dead until he found out differently several hours later that day. During the evening he stayed up all night in the hospital so that he was available and prepared to help. Waiting and hoping for survivors, they never arrived. Hearing from him personally on a daily basis made it more real and different than the perspectives provided to me by television. These factors left me shaken, with much difficulty focusing on elective tasks. Also, cancellations of various conventions occurred. Specifically, an important international infectious disease and HIV-focused meeting, the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) was postponed till December. I originally planned to use this column to discuss this (now cancelled) ICAAC meeting.

In regards to the last Buzz, I want to thank everyone who has commented on my article. [See Readers’ Forum] Our office has been bombarded with inquiries from all over the country. The rapid rate and tentacles of news disseminating like wild fire is spectacular. We’ve been truly happy to provide New-Fill treatments for those individuals with facial wasting. The filling treatments have been a tremendous morale booster for patients stricken with this form of lipodystrophy. Thus far there have been no complications and patients are generally gratified with their early results.

Now on to the meat of this article…

Breast is More
Introduction to Gynecomastia, Mastitis, and Breast Fat Accumulation
Some men have developed abnormal enlargement of breast tissue, often referred to as gynecomastia. When this occurs, the ducts and periductal fibrous tissue of the chest increase in size and amount; under the microscope, it resembles those breast tissues that are induced by estrogen, the female sex hormone. No wonder many gay men often call themselves “Mary!” Alveoli and breast milk occur only in rare cases. But fortunately or unfortunately (depending on your point of view) the term gynecomastia often refers to feminization, or as many may say, a queen-like texture. Perhaps a better term is hypertrophy of the male breast. Alternatively, deposits of fat in the pectoral region can give an appearance of abnormal breast accumulation, often seen as a complication of lipodystrophy in HIV disease. Breast fat accumulation bears little relationship to gynecomastia. Finally, some individuals develop an inflammation of their nipple area, known as mastitis, without developing the much-feared womanly breast tissue. Many of these conditions can be treated with varying success.
There are many types of gynecomastia and multiple circumstances in which they occur. It is not the intent of this article to review all of them. If I had to evaluate the entire classification, an entire chapter could be easily written. I will therefore try to stick with HIV-related situations.

The Breast is Yet to Come
(Gynecomastia and Mastitis)
Gynecomastia can come from a variety of origins. An excess of estrogen, the female sex hormone, causes proliferation of female ductal (glandular) tissue and can induce the same growth for the male breast. There is also evidence that androgens (male sex hormones) can cause changes and abnormal breast tissue enlargement. Also, androgens can be converted to estrogenically active metabolites; this is especially seen in abnormal testicular function. So how does this apply to patients who are HIV positive? Well, many HIV-positive individuals have a syndrome called hypogonadism. This condition is associated with increases in production of pituitary gonadotropins (hormones produced by the brain); the pituitary hormone then sends messages to various glands in other parts of the body to either produce or shut off production of various sex hormones. Thus hypogonadism can lead to overproduction of estrogen or underproduction of testosterone, both by the testicles.

Also, many individuals with HIV are being treated with a plethora of hormonal drugs: testosterone, decadorabolin, oxandrin, Anadrol, Androgel, and testosterone creme. Some of these drugs can potentially lead to estrogenically active metabolites and/or affect the message system of various sex hormones. In a majority of instances, these agents improve sexual libido and potency; however, sometimes these same drugs can cause sexual dysfunction, often seen with testicular atrophy and a loss of ejaculation capacity. Thus, over-doing it with these agents can lead to hormonal imbalances and gynecomastia.

In clinical practice my treatment approach to the HIV-positive individual with gynecomastia has varied. Sometimes using a variety of different agents can stimulate the testes to produce its own testosterone. This often improves testicular regeneration and improved quantity of ejaculate. When indicated, anti-estrogen pills can often be helpful.

Another symptom, discomfort and tenderness of one or both nipples, often referred to as mastitis, is frequently seen in the HIV clinic. This also can occur due to hormonal imbalances. Additionally, one should know that “tit play” can exacerbate this condition. Anti-inflammatory medications are helpful and when the nipple is infected may require antibiotic and local treatment.

A Fat Breast is a Happy Breast?
The Breast Fat Accumulation of Lipodystrophy in Males and Females
Fat accumulation has occurred in various areas of the body in HIV-infected individuals. Controversial and debated, research is attempting to identify the cause. Abnormal fat changes may be the result of HIV itself versus specific antiviral therapies. Among HIV specialists and researchers, mitochondrial dysfunction (a specific cellular aberration) is often bandied about as the primary cause of lipodystrophy and fat accumulation. Most individuals are aware of fat accumulation manifesting as “buffalo humps” and “protease paunches,” so why not the breast? Not surprisingly, increased breast size has been reported with both males and females.

My approach to a fatty breast is similar to treating fat accumulation in other body parts. Each person with a problem is approached from an individual patient basis and vantage point. Some patients have more options, including changing one’s antiviral therapy. For example, a stable patient on protease inhibitors who has developed a higher propensity for fat accumulation may benefit from switching to a non-nuke (Sustiva or Viramune). Another option that should be on the table for consideration is treatment with growth hormone (Serostim). Serostim improves the growth of lean body mass while burning body fat. In some individuals it has been shown to decrease or improve fat accumulation syndromes, such as buffalo hump and abdominal visceral (organ) fat buildup. Finally, a recent report from Paris has discussed using a testosterone derivative called Andractim or DTH (dihydrotestosterone) topically for gynecomastia. The report is not clear whether the breast enlargements being treated with this modality is due to fat accumulation or is of hormonal origin.
Conclusion

One would hope that one never has to face breasts against one’s will! However, with the evolving field and treatment of HIV and its related complications, breast tissue can emerge as a challenge for both patients and their physicians. The widespread use of hormonal agents to combat hypogonadism and wasting has added to the frequency of gynecomastia. Alternatively, lipodystrophy has increased fatty breast tissues in some HIV-positive individuals. Patients should be aware of treatment options, as well as the risks of using and over-abusing testosterone. Holidays from hormonal replacement treatment are encouraged and anti-estrogens can improve and avert the onset of gynecomastia. As mentioned in many of my articles, discussing treatments mentioned in this column with your personal physician is always prudent. I encourage comments and questions.

Diary of an HIV Doctor: Life During the Early Years of the Epidemic

by Daniel S. Berger, MD

ACT UP and other AIDS activists were often chaining themselves to various public buildings. They were frequently getting arrested while shouting and attempting to increase public awareness for AIDS. Two Republican presidents refused to demonstrate the slightest cognizance of the rapidly developing national emergency. It was commonplace to see individuals who looked like skeletons, many riddled with KaposiГ•s sarcoma lesions. We were desperate to help patients with opportunistic infections with little or no treatments. Cryptosporidium, PML, toxoplasmosis, CMV encephalitis, CMV retinitis, cryptococcal meningitis and MAC. The year was 1984, 1985, 1986, 1987, 1988, 1989 or 1990.

During this era people like Martin Delaney were busy making drug runs across the border to Tijuana, Mexico to obtain ribavirin. Jim Corti was bringing in compound Q from Shanghai, China. Jim brought in, then illegal, clarithromycin (Biaxin) from Italy by request from me for my patients with MAC (later finally approved by the FDA). Several people in California and Texas were involved with the production of bootleg Hivid (ddC). A Philadelphia research lab was raided of its gp160 treatment vaccine. Also during this heart wrenching time period, Steve Wakfield, then the executive director of TPAN, was often busy visiting many members of the community at the hospital and providing education, support and other valuable services at TPAN. TPAN served an indescribably invaluable service during those days. It was not uncommon for Г’Ask the DoctorВ” night at TPAN to be attended by no less than 100 people. They were thirsty for any advice to result in their ability to help themselves feel better, let alone survive.

Was it really 10 or 12 years ago? Can many HIV-negative community members or the more recently and newly-infected individuals understand what life was like for someone with HIV or AIDS 10 years ago, let alone during the 1980Г•s? How does one begin to attempt sharing with our readers this kind of experience? It may be said that it is unfortunate that most have little frame of reference for life during those times. One could easily have been a Faust fan, selling oneГ•s soul to the devil in return for merely understanding the reasons behind the existence of this epidemic, the reasons why our community had to endure the loss of many of its closest friends and the disappearance of valuable talent.

But letГ•s continue to put things in perspective. In 1987 there was nothing. During 1988 AZT was approved but still nothing available for CMV retinitis, the number one cause of blindness for persons with AIDS. In 1989 IV ganciclovir was approved. HIV doctors were constantly occupied with treating the blood infections that resulted from infected central lines. Long term indwelling central catheters were needed for the administration of drugs to treat CMV retinitis. The ensuing hospitalizations and infections continued to weaken many HIV positive individuals. Life was all about hospitals for many of those infected with HIV.

There was the prevailing hopelessness and a conservative notion of what the standard of care should be. There were many nights of lost sleep, many days of preoccupation and worry. However, as a young HIV treating physician, I could not let my frustration and periods of depression show. I remained stubborn, putting on my most optimistic face mask so that one could continue to provide the necessary hope. I implored patients to obtain alternative sources of treatment. We used AZT combined with bootleg ddC and a chemotherapeutic agent developed from a Chinese cucumber known as compound Q. While compound Q was found to kill HIV infected cells, it had to be administered intravenously. I could not provide Q through the medical office or clinic. Patients organized infusion groups (known as Q groups) at individual homes during many evenings. I needed to be present and supervise the infusions and treat the usual and frequent allergic reactions that may have occurred. I was sure this renegade treatment was effective since it raised T-cells, sometimes even doubling the count, and patients often reported improvement in HIV symptoms. Peter Jennings hosted a special television program on PBS devoted to compound Q treatment featuring Martin Delaney and the late Larry Waits, MD. Project Inform issued a bulletin highlighting the effects and benefits of Q.

Therefore, compassionate track Videx (ddI), illegal ddC (later FDA approved) in combination with AZT and often with Compound Q, NAC or glutathione was more the norm in my practice during those early years. I endured the behind-my-back criticism by peers and other conservatives, but knew I was doing everything I could for a very bleak picture. Viral load testing was not yet discovered. In 1990, Drew Badanish, one of the founding graphic designers of Positively Aware, and another TPAN hero, Steve Whitson, who eventually became Editor of Positively Aware, were some of my heroic patients. They, along with many others who were taking these same combinations, made it to the era of protease inhibitors to talk about it. Many are currently working full time, their loved ones at their side. They can reflect on those interesting times and what was HIV drug therapy in 1990.

Eventually, Zerit (d4T) and Epivir (3TC) were approved, though we knew little of the optimum way of prescibing these new agents. Trials with thymus immune globulin and thymic humoral factors, as a treatment to stimulate T-cell growth and differentiation, came and went. Later we participated in clinical trials for a new class of investigational agents known as non-nucleoside reverse transcriptase inhibitors (nevirapine or Viramune), protease inhibitors, interleukin-2 and Sustiva (efavirenz). As HIV drugs were being added to the national formulary, we saw less illness and less hospitalizations.

Slowly there was more hope.

There is not a day that goes by when I don't think of those times and remember people not forgotten. I am thankful for the many who survived and made it to a new millennium. I am grateful for the support I received from many loyal patients and the same stubbornness and fortitude that many HIV positive individuals maintained through many hard times. I hope that lessons can be learned and safe sex may return to being en vogue. Many of you indeed understand; fortunately many of our readers have survived those tragic times.

Daniel S. Berger, MD is Medical Director for NorthStar Medical Center, Clinical Assistant Professor of Medicine at the University of Illinois at Chicago and Editor of AIDS Infosource (www.aidsinfosource.com). Of recent, he is a medical consultant for Positively Aware and will feature a regular column entitled The Buzz.