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.

Dem Bones—Reports of Abnormal Changes in HIV
by Daniel S. Berger MD

Body habitus and metabolic abnormalities in HIV- infection continue to get great press and headlines—and they should. The alterations in fat redistribution are sometimes gruesome and include various combinations of manifestations, including posterior neck fat pads (buffalo hump), increasing visceral fat (abdominal paunch), loss of fat from extremities, face and buttocks, and increasing breast mass. If one is bored of reading repeated reports of metabolic problems that emphasize insulin resistance and diabetes as well as elevations in cholesterol and triglycerides (and don’t forget the elevations of lactic acid in the blood, a byproduct of biochemical pathways occurring as tissues deprived of oxygen), there is something new to contemplate. Bone mineral loss has been emerging as a new metabolic concern in patients who are HIV infected. Several reports of HIV-positive HAART (regimen) treated patients with bone disorders have come to the surface. One such disease of bone that results in death of bone tissue due to circulation problems is called avascular necrosis. The second reported disorder is osteopenia, or bone thinning that may result in spontaneous bone fractures.
The bony skeleton is an integral part of the human anatomy. Besides the obvious characteristics of movement and support, bone is dynamic, constantly turning over with bone formation and resorption (bone remodeling). Bone also acts as a mineral reservoir, and regulates calcium and phosphate metabolism. When bone is being resorped, calcium is extracted and the bone matrix is destroyed. Conversely, bone formation requires normal levels of calcium, phosphate and vitamin D. Various hormones (calcitonin and parathormone) and several organs (kidney, intestine and brain) are also involved in this process. Up to 15% of our total bone mass turns over each year. A peak in bone mass occurs between ages 20 and 30 years. Equal rates of formation and resorption continue to maintain stable bone mass until near 50 years of age. Thereafter resorption increases over formation and bone density decreases slowly. Certain diseases and certain medications can disrupt this process and results in a loss of bone mass. As of recent, HIV or HIV-negative related therapy is now being called into question as a possible cause for increased bone turnover and/or bone disorders.
Various reports of bone abnormalities being observed began recently. Several studies have been presented at international conferences and in medical journals. One such meeting, the Second International Workshop on Adverse Reactions and Lipodystrophy in HIV, met last fall in Toronto. While the meeting primarily discussed the research relating to fat redistribution, and its associated metabolic complications, several reports of bone demineralization and related bone disorders were presented. Researchers from Washington University School of Medicine presented evidence of elevated bone turnover and an additional study evaluated evidence of the inhibition (stopping) of conversion by protease inhibitors of vitamin D to the more active form [1,25(OH)2 vitamin D3], which is needed for bone formation. Additionally, Dr. David Nolan from the Western Australia HIV cohort showed higher rates of osteopenia (bone thinning) and osteoporosis (increased bone softening and loss of bone tissue) in individuals on protease inhibitors.
Bone mineral loss has been emerging as a new metabolic concern in patients who are HIV infected.In the area of avascular necrosis (death of bone tissue associated with circulation problems), a small group of 14 patients with this disorder was found to have the association of previous Pneumocystis carinii pneumonia infection, prior corticosteroid use (not anabolic steroid use) and low CD4 T-cells (less than 50).
Lastly, Dr. Pablo Tebas recently published a report in AIDS (2000;14:F63-F67) of a study of 112 patients: 64 received protease inhibitors, 36 HIV-positive patients were not exposed to protease inhibitors and 22 HIV negative persons were used as controls. Various tests were performed to assess bone density, including a specialized x-ray scan (DEXA) to detect bone density reduction. The results of the study showed that 50% of the patients from the group of protease inhibitors use had lower bone mineral density. This was compared with the 6% of the HIV negative controls and 11% of the other HIV-positive patients with no prior protease inhibitor use who showed reduced bone density. While the rates of bone disorders reported here are shocking, one should question how the patients were selected for the study. Most HIV treatment clinics have not witnessed bone disorders this high, but do not routinely test for bone density.
Presently and for patients who are on antiviral therapy, there is no cause for alarm. There is no evidence to suggest a need for changing one’s antiviral therapy or regimen. Although there are increasing numbers of patients being reported with bone disorders, most HIV treaters are not observing these complications at these alarming numbers. Also, a cause and effect relationship to antiviral therapy has not been demonstrated, nor do we know of any mechanism for which protease inhibitors can cause bone mineral loss or turn over.
Moreover other causes and factors are associated with bone loss. Avascular necrosis is associated with alcohol abuse, hyperlipidemia (elevated cholesterol and triglycerides), sickle cell disease, systemic lupus erythematosis and the use of anabolic steroids and testosterone. Osteopenia (bone loss) has been associated with prolonged bed rest, severe weight loss, disorders of the parathyroid and thyroid hormone axis as well as medications that include corticosteroids, pentamidine, phenobarbital and ketoconazole. Thus one must take into account these other factors when examining the rates of bone disorders, as well as individual patients.
Thus far, it is not indicated to routinely check for bone densities in HIV-positive patients on treatment. However, if signs or symptoms occur that suggest the possibility of a bone disorder, such as bone pain, which means weakness in a particular bone structure, then appropriate X-rays, MRIs and bone density testing should be done. To be proactive, weight bearing exercises and calcium supplements can be considered, but should be discussed with one’s physician. Lastly, a relatively new class of drugs called biphosphonates reduce bone resorption and are being increasingly used for certain bone thinning diseases, such as osteoporosis.
There is much that needs to be examined to improve our understanding of this relatively new reported complication of HIV. Large controlled studies should be undertaken to better explore the risks of bone loss in HIV-related disease in our patients, as well as studying HIV negative controls on antiviral therapy. Other work should look into the etiology (cause) and possible relationship to various antiviral agents.

The Importance of Sequencing in Treatment Options
by Daniel S. Berger MD
Physicians should constantly consider the sequence for which they use antiviral drugs in their patients (sequencing therapies). HIV positive individuals are living longer with the help of effective treatment, but an increasing number of patients are developing resistance to their regimen. If a patient develops resistance to his or her regimen, the next regimen, one that is not cross resistant and allows for further options, should be well thought out. Thus, the raison d’être for properly sequencing HIV drug treatment allows for the maximum number of options and alternatives to be available for the long term. With the probability of keeping patients on treatment for 20 or more years, antiretroviral drugs must be properly sequenced.
Physicians may need to change a patient’s therapy perhaps as early as 18 months into treatment. While newer drugs become available, sequencing should encompass the specific resistance characteristics of all antiviral agents. For example, patients who have had long experience to the nucleoside class (nukes, or NRTI) and whose virus in resistant to, for example, 3TC may have resistance to other nukes, such as abacavir or Ziagen. Those with high resistance to this class of drug may alternatively be very susceptible to the non-nuke class (NNRTI) or have increased susceptibility to tenofovir (an experimental drug). However, individuals developing resistance to their new NNRTI will likely have cross-resistance to other NNRTIs. Likewise, various protease inhibitors bear cross resistance within their family of drugs. However, using them in a particular order may allow for further use in salvage regimens and in various dual protease inhibitor regimens (two protease inhibitors in the same drug regimen).
For these reasons, changing therapy should be well thought out, not done haphazardly. For highly experienced patients newer drugs should be reserved whenever possible. A basis for changing to another regimen includes treatment failure, but toxicities or intolerance to the current antiviral regimen are also grounds for switching an existing regimen. Pharmaceutical companies are attempting to develop newer drugs, acutely aware of the urgency and marketability of drugs effective against resistant virus. A new protease inhibitor recently approved, Kaletra, is being used in salvage regimens. Three other agents from differing drug classes are in development and key in on resistant virus; they include tenofovir DF, T-20 and DPC-083. These significantly improve our options for patients who need alternatives.
Kaletra (lopinavir/ritonavir or ABT-378/ritonavir) has only been available and on the market for a relatively short period of time. It has been studied in naïve and protease-experienced patients in combination with non-nucleosides. The data holds up regarding the advantages of using this protease inhibitor in certain situations. Being new, Kaletra has not been studied as extensively as other drugs, and regarding sequencing protease inhibitors, it is not quite clear as to where Kaletra should fit in with the overall treatment scheme of individual patients. Questions regarding its appropriate use as first line treatment, and the proper sequencing of this drug because of cross-resistance to other protease inhibitors have been raised. However, it is well tolerated and has become a useful addition to the antiviral armamentarium. Like most new drugs coming to market, the reported studies were designed to get the drug FDA approved. Later studies and further clinical experience will add to our understanding.
Abbott Labs has promoted Kaletra and a post-marketing switch protocol (FDA approved) called PLATO. A switch study generally denotes discontinuing an existing drug therapy and changing to the promoted product. This particular study involves switching patients who are intolerant to other therapies to Kaletra. During the study, Abbott provides Kaletra free-of-charge to the patient, afterwards it becomes the patient’s responsibility to pay for the drug.
While observed for a period of only eight weeks, patients are evaluated for quality-of-life changes. While touted as a “quality-of-life” study, PLATO disregards side effects impacting this very issue, such as lipodystrophy and metabolic complications. While lipodystrophy changes usually arise later, when they do occur, they can have huge quality-of-life consequences. Studies of Kaletra have shown that the drug is associated with hyperlipidemia (increased cholesterol and triglycerides) which are often associated with lipodystrophy. Other symptoms can appear later than eight-weeks of treatment which may affect quality-of-life. But Abbott’s Medical Director of Global Antiviral Marketing Product Development denies that the study was done as a marketing vehicle, simply to get people on their drug, claiming there are “probably cheaper ways to market drugs, such as starter packs and coupons.” However, it is widely known that starter samples and coupons are rarely used for HIV prescriptions of antiviral drug therapy. Many physicians and treatment advocates believe the scientific value of studies are improved by designing conventional longer-term projects that seriously delve into the important issues of quality of life and metabolic complications.
Tenofovir DF (developed by Gilead Sciences) is part of a new class of drugs called nucleotide reverse transcriptase inhibitors. Its active metabolite (duration of drug lasting in the blood stream) has a half life between 10–30 hours and the intracellular half life is equal to or greater than 30 hours, therefore it can be given at convenient once daily dosing. In vitro (test tube) toxicity studies show tenofovir having little effects on the mitochondrial enzymes and not limiting the mitochondrial DNA, predictors of mitochondrial toxicity. Most current schools of thought believe that it is this toxicity to mitochondria that causes lipodystrophy complications in HIV disease.
Also, tenofovir has activity against HIV with various Retrovir (AZT), Videx (ddI), and Hivid (ddC)-associated mutations and shows increased activity against HIV with Epivir (3TC) resistance. Indeed, an earlier study (study 902) demonstrated antiviral effect of this agent; 94% of the study patients had NTRI resistance mutations prior to study. The most recently reported study (study 907) enrolled more than 550 treatment-experienced patients. There was significant viral load reduction observed in this group, who had tenofovir added to their existing drug regimen and 45% achieved viral loads below 400 copies. Thus, once available, tenofovir appears to be an attractive choice for use in antiviral regimens.
Tenofovir is currently available on a compassionate program to patients with CD4 T-cells below 100 count who are failing their regimens (two protease inhibitors or one protease inhibitor and a non-nuke) and for patients with recent (within 90 days) opportunistic complications, the CD4 cells can extend to 200 count for eligibility. Gilead Sciences is on track for submission of its New Drug Application to the FDA by mid-year.
A second-generation non-nuke, DPC-083, developed by DuPont Pharmaceuticals, is continuing in clinical trials. Phase II studies are being conducted in Europe and at only five sites around the US, one being here at NorthStar Medical Center in Chicago. This particular protocol is studying individuals who are failing their first regimen containing a non-nucleoside and is still open for enrollment. As a non-nucleoside, DPC-083 has similar potency to Sustiva (efavirenz) against wild type virus, however it has other significant advantages: the drug is effective for virus that is potentially resistant to Sustiva or Viramune (nevirapine), including against the infamous K103 mutant, and is two to eleven times more potent than Sustiva against other potential resistant virus. It has a long half-life, and is administered once daily. Thus far the drug has been found to be well tolerated and side effects have been found to be of minor severity and of short duration.
DuPont Pharmaceuticals is currently up for sale. We hope that a pharmaceutical company experienced in HIV drug development acquires DuPont and will show the same commitment and ability to develop further antiviral options, and continues to support the HIV community.
T-20 is another novel agent in a new drug class called fusion inhibitors. T-20 blocks the ability of HIV to combine or fuse with the CD4 receptor (T-cell). Preliminary studies have shown that T-20 is effective in patients with resistance to other antiviral agents. Cross-resistance is unlikely due to the unique mechanism of action. Because the chemical structure of this agent is a chain of amino acids, it is easily broken down by stomach acids. Thus the drug needs to be administered by subcutaneous injection. The drug, developed by the small biotech company Trimeris, sold marketing rights to Roche. This larger pharmaceutical company will definitely aid in its faster development and production. T-20 will also become available on a limited compassionate track program (see News Briefs).
New antiviral agents are being developed with resistance in mind. With more drugs becoming available and as we expect to see our patients living to old age, effective drug sequencing becomes even more crucial and we’ll need to conserve as many options for treatment as wholly possible.

Faster Approval of HIV Drugs for Patients with Resistance
by Daniel S. Berger MD

It is finally apparent to government policy makers that an increasing number of HIV positive people are in need of more options to combat resistance to available therapies. The U.S. Food and Drug Administration (FDA) recently held a meeting in Washington, D.C. to consider setting new guidelines for HIV drug development. The FDA heard testimony from HIV clinicians and research experts who addressed the growing need for treatments that would be helpful to those patients dealing with resistance to current HIV drugs. Often antiviral medications fail to suppress HIV replication, ultimately leading to rising viral loads. In other words, medications may no longer remain effective because of the virus’ ability to change into mutant HIV strains resistant to the effect of the medication.
Combination therapy for HIV disease has saved countless lives, however, many more individuals with high levels of mutant virus have resistance to many common treatments. It is these individuals that are at greater risk for HIV progression and complications, and they are often excluded from research studies involving the new more effective therapies. In other words, patients that are in the most need of new treatment do not have access to them. In our practice, there is a growing number of people who are on their second, third, or fourth regimen. These are the individuals who most urgently need access to new drugs.
The FDA indicates a readiness to examine the possibility of allowing faster approval of drugs that are potentially helpful to patients with fewer options. The agency is now considering approval of drugs that demonstrate antiviral effect through the use of shorter clinical trials. This would promote the quicker availability of drugs to patients, especially those who need drugs to stay alive.
By reducing the length of time of research trials, drugs can potentially become available to patients with the greatest need much sooner. However, at the meeting’s conclusion it was still unclear whether the agency has made any decision in regards to this issue. There is uncertainty as to when a decision will actually be made regarding these potential changes in the approval process. But the AIDS Chief, Heidi Jolson, was quoted as saying a decision may be ready next year.
Dr. Heidi Jolson, the director of the Division of Antiviral Drug Products (FDA AIDS Chief) is leaving the FDA. She supports AIDS treatments for approval while appropriately evaluating safety issues. She also supports the various compassionate track pathways. We hope that a suitable individual is found to replace Dr. Jolson upon her departure and that the issue of promoting a faster approval process for HIV drugs to the sickest patients does not get delayed.
HIV Vaccine Study: Conflict with a Pharmaceutical Manufacturer:
Does Remune Have Clinical Utility as a Treatment for HIV Positive Patients?The prestigious Journal of the American Medical Association (JAMA) recently published a controversial article regarding the results of a large-scale clinical trial using an HIV treatment vaccine called HIV-1 Immunogen (brand name Remune). The article described the results of a large multicenter study of 2,527 HIV positive participants. Patients with CD4 counts between 300 and 549 cells received either Remune or placebo (fake medicine). The idea for a treatment vaccine is to boost the immune system of HIV positive individuals by exposing them to viral antigens (HIV proteins). The body’s own immune response against these proteins would hypothetically assist in one’s control of HIV. The study was not a success and was terminated earlier than scheduled by the Data Safety Monitoring Board, an independent group that oversees clinical trials. According to the authors of the JAMA article, the results failed to demonstrate that the addition of the vaccine conferred any effect on HIV progression-free survival and was also associated with a lack of clinical improvement.
Moreover, the strategy for this mode of treatment is a controversial one. HIV infected patients already possess very high turnover of virus in the blood, which should be enough to stimulate an immune response against the virus. Administering more viral proteins in the form of a vaccine to the already present viral burden of an HIV positive person is not a proven way to fight HIV.
The results published in the JAMA article concluded with the lack of substantial effect of the vaccine and was followed with much drama and criticism of the authors by Remune’s manufacturer, Immune Response Corporation. The pharmaceutical company has filed a claim with the American Arbitration Association seeking millions of dollars in damages from the University of California at San Francisco, the affiliation of the lead author of the study. According to Dr. Ronald Moss, vice president of Medical and Scientific Affairs for Immune Response Corp., the purpose of the suit was to have a third party arbitrate and hopefully cause the JAMA authors to incorporate other data that would dispel the already negative view of the product. The University of California has filed a counterclaim against Immune Response, however.
Allegations were made by the manufacturing company that certain details and findings may have been excluded and may have been more positive to their product. These details included data from a subset of 250 randomly assigned patients who had virologic testing done every three months, as opposed to the every six months monitoring done for the more than 2,000 other patients under study. According to Immune Response, of this smaller subgroup of patients, there was some data indicating the presence of HIV specific immunity that was associated with greater decrease in viral load. However, the JAMA authors were not persuaded by Immune Response’s arguments and felt the subset virologic data was not consistent with any significant changes. Additionally, many believe that in a large study of 2,500 people, if the drug was indeed successful it would have been demonstrable in this large patient group.
Other company complaints were the unexpected presence of low HIV-related illnesses and the high rate of changing antiviral therapy occurring during the study, not planned for, nor were guidelines set in the study design, which Immune Response claims altered the results. However in a letter to me dated November 30, 2000, the JAMA authors clearly state they did not leave out any data that should have been published in this manuscript and eventually concluded that the treatment vaccine was ineffective; their objective in presenting the manuscript was to present an accurate assessment of the study. They were also concerned that “new patients were enrolling” in further studies with this agent and “were concerned that selective data improperly analyzed from the study was being sent to investigators to justify the ongoing or newly planned studies.”
Other criticism came from some study investigators and clinicians who did much of the work; the authors James Kahn, et. al., failed to recognize these individuals in the manuscript (the authors claim that the company did not provide the names and the company says that isn’t true). In addition, some of the investigators disagreed with the JAMA authors’ conclusions and interpretation of the study. Consequently, a second manuscript submitted by other lead investigators in cooperation with Immune Response has been accepted for publication in an attempt to refute the present conclusions and offer an additional interpretation of the study. Current JAMA authors plan to also do further analysis of the data. There is much corporate and pharmaceutical money at stake here and so it appears that the controversy will be never ending.
Too often pharmaceutical companies exert much censorship on publication of research because of industry money concerns. There are strong feelings harbored by many physicians that medical research can often be compromised because of the “bottom line.”

Drug Holidays & Lipodystrophy: Ongoing Controversies and Research
by Daniel S. Berger MD

This is the first installment of “The Buzzî, a column that is scheduled to appear in every issue of Positively Aware. I hope to provide our readers with an inside perspective on treatment issues and community concerns that are at times controversial, and commentary on topics being whispered or bandied about by clinicians, researchers or industry. I’d like to thank the editors, Charles Clifton and Enid Vázsquez for asking me to contribute in this way and becoming part of the Positively Aware family and staff.
A “treatment interruptions think tankî recently took place, as 80 researchers from around the world gathered in Chicago. Martin Delaney, founder and executive director of Project Inform (San Francisco), remarked that a major consensus emerged among the attendees, which included many conservatives and old hat researchers. What Martin has been saying for years, most now seem to agree upon—that “life-long treatment with antivirals is not a viable option.î While current treatments have been life saving measures for HIV-positive individuals, it is time for researchers to focus more attention on addressing the drug side effects and toxicities. As an approach to long-term treatment, perhaps treatment interruptions may be part of the solution for patients having to deal with these concerns.
Another issue discussed at this meeting was “reversal of resistance,î which may be accomplished through treatment interruption. Wild type virus, the viral population that is usually present during initial infection with HIV, is stronger and usually dominates over the presence of resistant virus. To invoke the emergence of wild type virus, HIV drug therapy may be placed on hold. As wild type begins to replicate it keeps down resistant strains. This method is now increasingly being investigated.
One example of how reversal of resistance occurs in practice is demonstrated with an anecdotal report. One of my new patients, who came in from another clinic, had viral loads approaching 7 million copies (one of the highest that I’ve ever seen) despite taking a “kitchen sinkî regimen of five antivirals including T-20, a fusion inhibitor, and one of the newest treatment breakthroughs. I stopped all the antiviral medications and placed the client on a six-month strategic treatment interruption (drug holiday). Since restarting treatment with a new drug regimen, the client’s viral load has dropped to very low levels and CD4+ T-cells have tripled. This probably occurred because wild type virus recurred and suppressed the resistant HIV strains. This approach to treatment is investigative. Many safety questions regarding this approach remain unanswered, and individuals should not attempt this without physician guidance.
While Martin tells me not to call these interruptions “drug holidays,î holiday seems to be the “buzzî in the field. And it is increasingly clear that many clients are interested in alternatives to treatment that involve interruptions or holidays. While there remains much uncertainty, if an individual is faced with the pressures of treatment toxicity or multiple failures due to drug resistance, drug holiday or strategic treatment interruption should be on the table as a viable option.
While attending the International Workshop on Lipodystrophy in Toronto, September 2000, it was refreshing to observe more progress in this area. Two institutions presented groundbreaking research regarding genetically engineered rat models of lipodystrophy. The Department of Molecular Genetics, University of Texas at Southwestern Medical Center has genetically engineered mice that are deficient in fat, similar in many ways to the HIV patients who demonstrate lipodystrophy. The NIH Diabetes Branch has also genetically developed a mouse model that lacks various types of adipose (fat) tissue. Because these mice have a high tendency to develop insulin resistance and diabetes, the researchers conclude that it is the lack of fat that results in various metabolic abnormalities that occur with lipodystrophy. Many HIV impacted individuals have lipoatrophy, a condition that refers to a loss of fat from the face, buttocks, and/or extremities. With these fat-redistribution changes, these individuals often have diabetic symptoms as well as elevated cholesterol or triglycerides. Having an animal model to study lipodystrophy should improve our knowledge and lead to further developments in this field.
What drives scientific research at competitive pharmaceutical companies?
During the International Workshop on Lipodystrophy, Jim Lenhard’s group, from the diabetes branch of research at Glaxo-Wellcome, presented results from a recent study. The researchers examined the effects of antioxidant vitamins on metabolic aberrations that occur after treatment with nucleoside reverse transcriptase inhibitors (NRTI, or nukes). In this study mice were the research subjects. The immune competent (HIV-negative) mice were treated with nukes, Retrovir (AZT) or Zerit (d4T) given at 5mg/kg (lower dose) or Zerit at a much higher dose of 50 mg/kg. This resulted in the mice developing many of the metabolic changes associated with lipodystrophy, seen in HIV-treated patients. The abnormalities included elevated lactic acid and lipid levels, as well as increased liver weight. The Zerit treated animals (although at very high doses), developed greater metabolic abnormalities. Subsequently these same study mice were then treated with ascorbate (vitamin C) and tocopherol (vitamin E), which then reversed many of the objective changes. The reversal of metabolic complications of nucleosides by anti-oxidant vitamins holds many implications for further research.
However, during the presentation, many in the largely scientific audience questioned the possibility of marketing bias in the design of the study, since Zerit is a competitor of Glaxo’s product, Retrovir. The mice were indeed treated with higher doses of Zerit than their Retrovir counterparts. The “buzzî included cynicism in regards to the design of the study. However, after discussing the results with Dr. Lenhard, he claimed that the focus of the study was not to place Retrovir against Zerit, but to examine the effects of the vitamins on oxidative stress. Toxicology studies with animals traditionally involve the administration at much higher doses, Lenhard stated, since they metabolize drugs more quickly than humans do. It was crucial to realize the metabolic toxicities of the nucleosides, in order to enable testing the effects of antioxidants against those toxicities.
Finally, a word of caution: while the results show that antioxidant vitamins can potentially be helpful, one should not overstate the conclusions of this study and attempt to take high doses of antioxidants without discussion and supervision by one’s physician. Normal doses of vitamin C are okay and high doses are rarely toxic, however high doses of vitamin E can be toxic—and should not be used as a supplement by people taking Agenerase. While the results of this study are interesting and positive, one should not assume that these effects would be reproducible in HIV-positive humans. Further studies at GlaxoWellcome are being planned.
On the local news front in Chicago, continuing a trend of all too frequent big business takeovers, Advocate Healthcare has assumed control of Illinois Masonic Medical Center. Illinois Masonic was the first hospital in the Chicago area to have a dedicated HIV unit and has long been a pillar of in-patient hospital care for the community. It is a place where HIV-positive patients that needed hospitalization could always depend on for the highest quality care. While many ensuing changes are sure to occur, we hope the quality of care continues.