Mitochondrial Mayhem

With the passage of time and accumulation of more data, we are learning more about the nature of lipodystrophy and metabolic complications. Still, there were widely varying reports on their incidence at the Retrovirus Conference. Much depends on how the syndrome is defined, but now the question seems to be "Is it one syndrome, or many?" It appears to be much more complicated than initially thought. In one symposia at the Retrovirus Conference, Kathleen Mulligan of UCSF explained, "Because a number of these problems were initially appreciated around the time that protease inhibitors came into widespread use, it was initially assumed that these problems were the result of protease inhibitor use. That assumption might have been premature or at least incomplete." Much of the focus has now been shifted to the toxicity of nucleoside analogs to mitochondrial DNA.

Mitochondria are organelles within cells, small factories responsible for the cellular respiration that powers the cell. Each mitochondrion contains its own DNA, which serves as instructions for the production of some proteins used in cellular respiration. Unfortunately, polymerase gamma, the enzyme responsible for copying mitochondrial DNA, sometimes does not recognize that nucleoside analogs are not real DNA building blocks. When the enzyme uses the nucleoside analogs, there is decreased production of mitochondrial DNA, or production of mutant DNA, which in turn leads to decreased production of mitochondrial proteins. Without these proteins, cellular respiration and energy production drops, and cells may start to malfunction.

This can lead to a range of clinical symptoms, depending upon which cells (and organs) are affected. These include polyneuropathy (seen with ddC, ddI, and d4T); myopathy (AZT); cardiomyopathy (AZT, ddC, ddI); liver problems like steatosis and lactic acidosis (AZT, ddI, d4T); gastrointestinal problems including pancreatitis and vomiting (AZT, ddI, d4T); hematological with pancytopenias (AZT); kidney toxicity such as proximal tubular dysfunction (adefovir); and now apparently, fat cells, leading to lipodystrophy. In a presentation at a community meeting, Dr. Kees Brinkman noted that mitochondrial toxicity causes a related syndrome, multiple symmetrical lipomatosis, in people without HIV.

Drs. Cooper and Carr, who earlier reported on lipodystrophy in patients on protease inhibitors, recently reported a similar syndrome in patients who were only on nucleoside analogs and had developed lactic acidemia (abstract S21). Lactic acid is a waste product when cellular respiration is inadequate, and its accumulation can be quite dangerous, even fatal. What Cooper and Carr found were severe changes in body composition, with fat loss in the periphery, but with perhaps less truncal fat accumulation. In other words, nucleoside analogs may be responsible for fat loss, but not fat accumulation. A number of other studies have suggested that duration of nucleoside analog use may be associated with lipodystophy. Some have similarly associated nucleoside analog use with fat loss in the periphery (arms, legs, buttocks) and face. d4T in particular was singled out, often by Glaxo Wellcome funded studies. But the association with d4T may be an accident of history (most who have used d4T have previously used AZT) or due to the fact that people susceptible to nucleoside analog mitochondrial toxicity may take d4T longer because AZT's toxicity is more immediate. Said Dr. Miles, "people who drop off of AZT because of myopathy and anemia may simply be staying on d4T long enough for this toxicity to become noticeable."

At present, these are just theories. Even so, some clinicians are already using nucleoside-sparing regimens in patients with severe facial wasting. Dr. Cassie Workman from Australia is one, despite the fact that "many people seem to act like not including a nucleoside analog in a combination is blasphemy," she told TI at a recent meeting.

But if indeed nucleoside analogs are to blame for some aspects of lipodystrophy, then why has not the pattern been observed before? Well, indeed many believe it has, as Dr. Donald Kotler has long maintained (see Treatment Issues, March 1999). Now, particularly as people have been surviving longer, the effectiveness of HAART may simply have allowed the effect of mitochondrial toxicity become more noticeable over time.

Back to the GMHC Treatment Issues Spring 2000 contents page.