The Bay Area Reporter - December 3, 1999
Jeff Getty, ACT/UP Golden Gate Writers Pool

At first, many AIDS patients and their doctors were very skeptical of the new resistance results. Many felt there was something wrong with the resistance assays and that these drugs were simply not fitting into the tests' parameters. For example, d4T might trigger a different unmeasured resistance mechanism which causes the virus to mutate around it. "Cells could be pumping out the drug early," said Dr. Michelle Roland, a University of California, San Francisco researcher at San Francisco General Hospital. Still, the phenotype tests, which actually challenge a patient's virus invitro (in the lab) with various drugs, are indicating that d4T and ddI are effectively killing the bug. If the virus was resistant, then why did it die? One reason could be that the concentration of drug in the test is much higher than what could be achieved in the body. Or it could be simply that the drugs are still potent and could be of some use.

So if the tests are correct and the drugs still have an ability to kill the virus, can we add them to new experimental regimes and expect good results? Dr. Robert Scott, an Oakland clinician with a large AIDS practice thinks it might be worth a try. "These drugs are turning out to be quite resilient," he said. At least one of Scott's patients will be recycling d4T in the coming weeks. Roland and others are reluctant to believe there could be any benefit. But many patients have no options left. "Still, I go ahead and use d4T (in this way) because I have not seen any evidence to say that it will not work," Roland remarked. But recent published findings about d4T and ddI toxicities are quietly taming any enthusiasm for these drugs.

Toxicities and mitochondria dysfunction

Last week, following federal Food and Drug Administration (FDA) toxicity findings, Bristol-Myers Squibb issued warnings that d4T and ddI could cause pancreatitis and death. According to a warning letter which went out to physicians all over the U.S., "Didanosine, stavudine and hydroxyurea should be suspended in patients with suspected pancreatitis. Reinstitution of stavudine and/or hydroxyurea after a diagnosis of confirmed pancreatitis should be undertaken with caution. Didanosine should be permanently discontinued in patients with confirmed pancreatitis." Many longtime AIDS patients recall early episodes of this sometimes fatal problem when these drugs were first released. At the time the patients who experienced problems tended to be only the very sickest and most advanced. Or so it seemed. But the new warnings came on the heels of a couple of deaths involving patients with high T-cells and relatively good health.

Such toxicities should give pause to patients considering recycling either of these drugs, and the news only seems to be getting worse. At a recent workshop on lipodystrophy (the unwanted fat redistribution and that undesirable "AIDS look"), data from past European studies was discussed. Some of these studies implicated d4T as a potential culprit in causing lipid dysfunction. From a report written by Ellen S. Engelson about the workshop, which can be found at www.HIVandHepatitis.com, she summarized Dr. Kathy Mulligan's report as follows: "A study from France (St. Marc et al, 1999), where PIs were introduced later and less frequently than in the U.S., found fat redistribution was associated with d4T. In Italy (Gervasoni et al, AIDS 13:465, 1999) there are also fewer people on PIs, and in a group of women with only 14 percent on PIs, fat redistribution was significantly associated with 3TC and d4T. A study by the U.S. Centers for Disease Control and Prevention (CDC), conducted at eight sites and with 1,077 subjects, found fat redistribution to be associated with d4T and indinavir, age, duration of HIV, lowest CD4 count and the rate of rise in CD4 counts."

What is causing lipodystrophy? The latest theory appeared in an article just published in the Lancet medical journal, (Kees Brinkman et al, Lancet; 354, 1112-15, 1999). In the article endocrinoligists from Amsterdam theorize that NRTI (the family of drugs that includes d4T and ddI) treatment results in the depletion of mtDNA and mtDNA-encoded proteins and dysfunctioning mitochondria. The mitochondria are like little energy-producing furnaces that keep a cell functional and perky. Mitochondria dysfunction could very well be the cause of lipodystrophy, since similar symptoms are seen in patients with inherited mitochondria dysfunction. And in one study mentioned in the Lancet article, mitochondria problems were seen in patients on d4T therapy alone. d4T might not be the only drug that causes this problem, but it seems likely to be a prime suspect at this point.

In the Lancet article there were the usual disclaimers saying that it was still early and more testing needed to be done, etc. Mulligan û a leading expert on the subject û is an endocrinologist who has been following AIDS wasting and other endocrine problems for years. At the lipo workshop, Mulligan was hesitant to condemn d4T outright. She said that it was still too early to point a finger at any of the suspected drugs. But when these potential toxicities are combined with the pancreatitis fatality hazard, and the fact that patients who would consider recycling drugs are most likely late-stage AIDS sufferers, the risks become ever higher.

The company line

According to Bristol-Myers Squibb's Dr. Robert Grosso, associate director of immunology and clinical trials, company genotypic studies showed a reduced ability for d4T and ddI to work in multi-drug resistant virus, but that there did remain some level of efficacy. While he stated that Bristol-Myers Squibb had no official position on d4T recycling and that there were no studies to test the idea, he said, "One should assume that in a regime where there are no other options, it (recycling d4T) might be a good thing." When asked about the company's position on the toxicities, he said they were actively searching through data from previous trials to find more information. "We have started two prospective studies to look at where patients have ended up in terms of lipo. We are looking at patients who were on these drugs for over a year to see if they had lipo changes," he said. BMS will most likely report the findings at the 13th International Conference on AIDS to be held in Durban, South Africa next July.

Finally, Roland has never been known to be a doctor who takes big risks with her patients. Yet she stated that she would prescribe the drugs in no-option situations. Given the recent findings about d4T and ddI (for that matter all the drugs in the NRTI family) it shows just how desperate late-stage patients and their doctors have become. "Our biggest limitation is cross resistance. It's (d4T) not saving the day, you've got a big Bastille, and you need lots of ammo," Roland said. The option to recycle d4T and ddI should be carefully weighed. And certainly any patient who does so should be followed very closely for early signs of drug-related harm.
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