Drug Reactions & Lipodystrophy Workshop
Coverage of the First International Workshop in San Diego
It seems like only yesterday that people started reporting odd body changes that seemed to correspond with their new HIV "cocktail therapies." Lipodsystrophy, or fat redistribution syndrome, has now become the greatest concern for people on or considering begining combination therapy. The First International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV, held in San Diego in June 1999, was the first major event held solely to discuss these new body changes.
The workshop's primary objective was to present scientific information in the hopes of creating a definition for these syndromes that researchers and clinicians could use to determine who was being impacted by lipodystrophy.
The majority of the oral presentations provided background information about the different syndromes and theories about their causes. The most interesting presentations were the studies of mitochondrial toxicities by Dr. Kees Brinkman of the Netherlands, and a series about people around the world with lipodystrophy.
Dr. Brinkman gave a presentation that outlined the mitochondrial toxicities resulting from treatment with nucleoside analog reverse transcriptase inhibitors (NRTI). Although there had been previous reports of lipodystrophy in people who had never been on protease inhibitors (PIs), no one had presented a theory on how NRTIs might be linked to lipodystrophy.
Mitochondria are energy producers inside cells and contain DNA for limited protein construction. New mitochondria are created by the division of pre-existing mitochondria. Dr. Brinkman pointed out that mitochondrial DNA is prone to damage and is not able to repair damage. Mitochondrial dysfunction can cause many of the common side effects attributed to NRTIs. These include neuropathy (pain and numbness in hands, arms, feet and legs), myopathy (muscle disease), cardiomyopathy (muscle disease of the heart), liver steatosis (fatty liver), lactic acidosis (an increase in the acidity of blood), pancreatitis (inflammation of the pancreas), and proximal tubular dysfunction (kidney irregularities). Dr. Brinkman suggested that mitochondrial toxicities can occur in anyone who has taken a NRTI as part of their long-term therapy.
Dr. Brinkman noted that although lipodystrophy was first noted after widespread use of PIs, it is found in people who have never used a PI but have been on NRTIs. He also suggested that lipodistrophy might be caused by overlapping toxicities, such as NRTI-induced mitochondrial dysfunction combined with PI-induced toxicity, and that the two might have a synergistic relationship.
Who Is at Risk for Lipodistrophy?
The conference presented intriguing data about the effect of gender, age, disease stage, and duration of therapy on the risk of developing lipodistrophy.
The Gender Effect
Dr. Julian Falutz of the Montreal General Hospital observed the characteristics of people attending his Montreal clinic as well as data from the self-ascertained lipodystrophy syndrome assessment (or SALSA) group. The SALSA cohort consisted of 270 people, 24% of them women. The vast majority of study participants (78%) were on highly active antiretroviral therapy (HAART), and of that group, 98% were on a regimen that contained a PI.
Dr. Falutz reported a difference in lipodystrophy between men and women. Fat loss was seen most often in men, while fat accumulation was more likely to be seen in women. The men were also more likely to have increased levels of blood fats.
Fat accumulation around the waist was seen in 98% of the women and 76% of the men. "Buffalo humps," fat deposits around the back of the neck, were seen in 46% of the women and 37% of the men. And, not surprisingly, increased fat accumulation in the breast was more common in women (74%) than in men (31%).
Fat atrophy, or fat loss, was seen in the arms and legs of 68% of the men and 54% of the women. The most notable difference was in fat loss in the face. Facial fat loss was reported in more than twice as many men (57%) as women (22%). Men also reported a slightly higher rate of fat loss in the buttocks, with 59% of men and 44% of the women reporting this effect.
Increases in triglycerides were reported in 84% of men and 32% of women; increases in cholesterol were seen in 53% of men and 28% of women.
The results from the SALSA cohort also suggested that there was a relationship between a person's body weight at the beginning of the study and their risk for body changes. For the men in the study, 56% of the overweight group reported buffalo humps while only 14% of the underweight group saw the fat accumulation. In the underweight men, 60% experienced facial fat loss, while it was seen only 20% of the overweight men.
The women in the group reported similar occurrences based on weight. Overweight women developed buffalo humps 65% of the time compared to 29% of the underweight women. The heavier women (83%) also experienced fat accumulation in the breast more often than the underweight women (29%).
In the SALSA cohort there was no significant difference in the percentages of men who experienced increased fats or sugars in the blood comparing the overweight and underweight group. There was a difference seen between overweight and underweight women. Underweight women experienced increased cholesterol 71% of the time and increased blood sugars 29% of the time, compared to only 17% and 0% for the overweight women.
Dr. Rodolphe Thiebaut of the University Victor Segalen, Bordeaux presented data that described their findings from the Aquitaine cohort. This study looked at 581 people and observed lipodistrophy in 38%. The study separated people by fat loss (LD1) and fat accumulation (LD2). LD1 was seen in 15% of the people while LD2 was seen in 22.4%. Older people (mean age 42) were more likely to experience lipodistrophy than younger people (mean age 39). People with an AIDS diagnosis (40%) were more likely to have lipodistrophy than someone without an AIDS diagnosis (20%). Lipodistrophy was seen more often in people who had received HAART with a PI (75%) than those who had not received a PI (53%). It is important to note that 53% of the people who had never been on a PI experienced LD! Duration on therapy also corresponded with increased risk of LD.
What's Up With d4T?
The one piece of information from the workshop that created the greatest buzz was the relationship between d4T (an NRTI) and lipodistrophy. This next section summarizes a few of those presentations.
Dr. Andrew Carr of Saint Vincent's Hospital in Sydney presented data collected from 188 people living with HIV. Of this group, 146 were taking a triple combination that included a PI, and 44 were on a double-NRTI combination. The 44 people on the double-NRTI therapy had never been on a PI, and of those, 14 experienced some type of fat loss. While fat loss was seen in both triple and double combinations, it was most often associated with the use of d4T, AZT, hydroxyurea, and the duration of PI therapy. The researchers determined that people on d4T experienced fat loss at much higher rate than people who did not have d4T as a part of their regimen.
Fat accumulation was also seen in this group of people and was most often associated with current d4T therapy, duration of d4T therapy, duration of 3TC therapy, and duration of PI therapy. Dr. Carr also noted that NRTI-lipodystrophy was often accompanied by liver dysfunction.
Dr. Galli of the University of Milan presented information about 188 people who had never been on a PI who were taking two NRTIs. This group included 92 men and 96 women. Body changes were observed in 26% of the women (11 of these 25 women experienced breast enlargement) compared to only 6.5% of the men in the group. This study also reported that fat redistribution was seen in 26% of the people on combinations containing d4T, compared to only 9.4% of people on combinations with AZT.
Health Outpatient Study (HOPS) Cohort
Drs. Douglas Ward and Kenneth Lichtenstein presented information from a database of 1,077 people living with HIV, collected from eight clinics across the United States. In their group of people experiencing lipodystrophy, they also noticed an association with combinations including d4T as well as indinavir (a PI). But they interpreted the data to indicate that the duration of time on both d4T and indinavir were both correlated with the time on a successful well tolerated therapy, which could imply that LD in not caused by any one specific drug.
Where Do We Go From Here?
The last day of the conference was spent in small groups discussing how to define the lipodistrophy syndrome. Most of the discussion focused on the side effects that are common -- fat loss, fat accumulation, increased lipids, and glucose disturbance. The group also noted that data should be collected about the incidence of dry skin and lips, ingrown toenails, hair loss, decreased libido, erectile dysfunction, avascular necrosis of the bone, and chronic diarrhea because these side effects are also often seen with lipodistrophy.
You can view the complete final report on the web by going to http://www.intedpress.com/lipodystrophy
This article was provided by Seattle Treatment Education Project. It is a part of the publication STEP Perspective.