BEING ALIVE; April 1995
Brett Grodeck

After two months of d4T therapy, Alan's count rose from 189 to 237. He had only minor side effects. Alan clearly understands that this small boost in T-cells may not last. He's fully aware that the long-term effects of d4T remain unknown. Nonetheless, he balances these facts against the facts that his count didn't decline further, that the drug is convenient to take, that it doesn't upset his stomach, and that he feels good and pro-active in the fight against the virus.

One More Option

As therapies to combat HIV become more individualized, d4T is one more option for patients. The drug d4T has three names: the street name is d4T, the generic name is stavudine, and the brand name is Zerit. All three names refer to the same virus-fighting compound.

Last June, Bristol-Myers Squibb, the makers of d4T, was granted permission by the Food and Drug Administration (FDA) to market the drug. Through its accelerated approval program, the FDA approved d4T for the treatment of adults with advanced HIV infection who are intole-rant of approved therapies with proven clinical benefit, or who have experienced significant clinical or immunologic deterioration while receiving these therapies. Also, the drug can be prescribed for people whose therapies for treatment or prevention of opportunistic infections would conflict with AZT, ddI, or ddC.

The FDA based its approval of d4T on improvements in laboratory markers such as T-cell counts and p24 antigen levels. The results of clinical trials designed to look at the incidence of opportunistic infections and the probability of death have yet to be analyzed. Without these crucial data, some AIDS activists maintain that the FDA might have jumped the gun and approved d4T too quickly. Company spokespeople, however, promise that the results of key studies will be released this spring. With this new research, the company says it will submit an application for full FDA approval.

What the Research Means

Despite today's limited data, doctors are prescribing d4T. "I welcome it as something else to give to patients who, at this point, have already tried approved antiretrovirals," says Albert Avendaño, M.D., director of health and treatment at the National Association of People with AIDS in Washington, D.C. "I don't think by itself it's a big breakthrough. The future of treatment is combination therapy. However, the drug is still important because there are many people who have tried everything else and need something new right now. It's another important tool that we should use."

"D4T has several attractive features," says Richard B. Pollard, M.D., professor of internal medicine at the University of Texas Medical Branch in Galveston. "It's well-absorbed, and it has a relatively long intercellular half-life, so you don't have to give it as often. Even early on, the side-effect profile of d4T looks to be at least better than ddI. It looks to be at least as active, if not more active, than ddC. I think it's going to be used a lot more as time goes on."

"After five years of clinical testing, d4T has been shown to be a compound that is well-tolerated and effective in terms of virologic and immunologic responses," says Laurie Smaldone, M.D., vice-president of infectious disease clinical research at the Bristol-Myers Squibb Pharmaceutical Research Institute. "Our submission [to FDA for accelerated approval] is based on improvements in CD4 counts and reduction in viral load - all of which were extremely promising. Some preliminary data suggest there's also significant improvement in weight gain and other parameters that show the compound is doing something clinically beneficial for the patient." Prior to FDA approval, more than 13,000 patients received d4T as part of the manufacturer's parallel-track program. As with all approved antiretrovirals, some patients do well and other don't. "When I was first diagnosed, I started on AZT and absolutely could not take it," says David. "I went from there to ddI and took ddI for a couple of years with no problems. I started taking d4T when it became available. I had absolutely no problem taking it. I didn't really see any change in my T-cell count. It didn't increase, but it didn't drop."

Side Effects

In general, d4T appears to produce minimal side effects. In early clinical trials, fewer than 1% of people taking d4T reported reactions such as headache, chills and fever, nausea, vomiting, insomnia, and depression. By far, the most common side effect is a potentially painful condition called peripheral neuropathy, characterized by tingling or numbness in the feet or hands.

"None of the drug-related neuropathies are permanent if the drug is stopped once you develop symptoms," says Robert Murphy, M.D., associate professor of medicine at Northwestern University Medical School in Chicago. "The only significant problem with d4T is neuropathy. This side effect is similar to ddC or ddI, but apparently less so. If patients develop neuropathy, they can generally tolerate a half dose. If you compare d4T to the other three drugs, it's very well tolerated."

The FDA based its approval of d4T on preliminary data of a Phase III, double-blind, randomized clinical trial conducted by Bristol-Myers Squibb. This trial (BMS-019) compared d4T with AZT in patients who had received more than six months of prior AZT therapy and who had T-cell counts between 50 and 500.

The total enrollment was 822 patients, but an interim review of 359 patients was conducted by an independent agency. The interim data revealed that d4T was associated with an immediate rise in T-cell counts of 22 above baseline at 12 weeks. In contrast, the AZT group - who had already been on AZT for a median of 85 weeks - experienced a mean loss of 22 cells during the same 12 weeks. From 22 to 76 weeks, patients receiving d4T had T-cell counts that averaged 30 to 50 cells higher than those who continued taking only AZT. The final results of BMS-019 will be released by the company in May of this year.

What We Don't Know

The long-term effects of d4T alone and in combination have yet to be determined. According to Dr. Pollard, the jury is still out about whether d4T can successfully be combined with AZT. Early test-tube studies suggest that the two should not be used together. However, Dr. Pollard cited reports that suggested that using the two together produced additional antiretroviral activity. Only further research will answer this question. The company, he says, will begin combination tests in the next few months. Dr. Pollard emphasized that combining d4T with ddI or ddC could produce an increased possibility of peripheral neuropathy. To date, nothing but anecdotal reports have been documented about the combination of d4T and 3TC.

Some AIDS activists stress that the lack of research about the drug should be made clear to patients. "We have an obligation to be clear about what we know and what we don't know," says Spencer Cox, member of Treatment Action Group, an AIDS watchdog organization in New York. "It's a matter of honesty and being clear with people. We are dealing with a very high level of uncertainty about d4T. To pretend that we are certain is the worst thing we can do."

For his part, Dr. Murphy acknowledges the lack of long-term research about d4T. "But in the data so far," says Dr. Murphy, "patients who have been on AZT for over a year and then switched to d4T - these patients had higher T-cells, lower viral loads, felt better, and had fewer side effects than the group that remained on AZT alone. In virtually all the indirect ways we have to measure how safe and effective something is, patients taking d4T did better than staying on AZT."

"Many people have already been on AZT for a year, " says Murphy. "What do we do with these people? Now, we have another drug. Whether we combine it, or switch it, it's another way to fight the virus. We know what happens if patients don't take anything - that's been studied intensely." (This article is reprinted from the March/April 1991 issue of Positively Aware. For subscription information, call 312.472.6397)

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