Step Perspective, Volume 5, Number 1; A Publication Of The Seattle Treatment Education Project - February 1993
Laury McKean

How Does it Work?

d4T does not kill the virus, but rather works by interfering with the virus's ability to integrate into the cell's genetic material (i.e. DNA). this has the effect of decreasing the rate of infection to other cells in the body. Under normal conditions, when HIV enters a cell, it is able to integrate itself into the cell's DNA. Once the virus accomplishes this, it is able to reproduce, making many virions (complete viral particles) which in turn go on to infect other cells. when an individual takes d4T, this process is interrupted. d4T, like AZT, ddI, and ddC, is known as a nucleoside analog. It works by acting as a decoy for a newly forming chain of DNA. This decoy causes the premature termination of the DNA, leading to inhibition of reverse transcription. Therefore, like the other nucleoside analogues, d4T has no affect on cells already infected. Preliminary data from animal and human studies indicates that d4T is able to penetrate the blood-brain barrier which is essential in helping to prevent and fight HIV related neurological complications.

What Does the Research Show?

In Vitro Studies

Numerous laboratory studies have confirmed the activity of d4T against HIV in vitro. In the majority of the studies, d4T exhibited a degree of potency similar to that of AZT. One major exception is a study that showed d4T had 100-fold less activity than AZT. another study showed that d4T had similar potency against both HIV-1 and HIV-2, but was about 20-fold less potent than AZT.

Clinical Trials

Clinical trials of d4T in humans began in March of 1989. These initial phase I/II trials focused primarily on safety, but also showed preliminary data on its effectiveness. The trials included two dose-escalating studies, two trials assessing the tolerance to d4T in people who had hematologic intolerance of AZT, and one randomized, dose-ranging trial to assess the safety and antiviral activity of d4T over a range of doses. A total of 259 individuals were involved in these trials, 255 of whom were able to be evaluated.

When these studies began, the first participants were given doses of 2.0 mg/kg/day divided into three to four doses per day. This dose was tolerated well and as a result, other individuals were given doses of 4.0, 8.0, and 12.0 mg/kg/day. However, soon after these doses were started, toxicities were seen, mainly peripheral neuropathy. The trials were then modified to study lower dosages, 0.1 through 2.0 mg/kg/day and the frequency of dosing eventually changed to twice a day.

The antiviral activity of d4T was evaluated based on CD4 counts, serum p24 antigen, as well as other parameters. The studies showed a clear dose response in CD4 counts, with at least 50% of the individuals receiving doses of between 0.5 and 2.0 mg/kg/day experiencing a CD4 increase of at least 10% or 10 CD4 cells.

Changes in p24 antigen levels were assessed for 40 individuals who were p24 antigenemic at entry. Three of these individuals were receiving a dose of 0.1 mg/kg and did not show a response. Six of the 14 individuals (42.9%) receiving 0.5 mg/kg showed a decrease in p24 antigen. Of the seven people receiving 1.0 mg/kg, 85.7% showed a response, and of the 16 individuals receiving 2.0 mg/kg, 87.5% showed a response (no statistically significant difference is evident between these two higher doses). although the number of individuals available for analysis was small, this suggests that there may be greater antiviral activity as the dose of d4T is increased.

although it is not possible at this time, based on the limited data available, to determine the degree of efficacy of d4T in comparison to AZT or ddI, it is apparent that d4T does show efficacy. It should definitely be considered as an option for those individuals unable to take AZT or ddI.

What About Side Effects?

Due to the limited number of people in which d4T has been studied, it is difficult to determine a comprehensive side effect profile. The two major side effects appear to be peripheral neuropathy and liver function enzyme elevations (SGOT and SGPT).

Symptoms of peripheral neuropathy are a tingling or burning sensation, sharp pain, numbness, or weakness, usually in the feet or hands. This side effect occurred in 17% of individuals in the clinical trials. However, for individuals receiving 2 mg/kg per day or less, this figure is probably more like 12%. When symptoms of neuropathy occur, it is important to tell your health care provider as soon as possible because drug-related neuropathy is more likely to b reversible if it is detected early. When symptoms of neuropathy occur, physicians will generally either reduce the dose or discontinue therapy, depending on the severity of symptoms. The symptoms of drug-related neuropathy will gradually decline in most individuals over a period of one to two months when the drug is discontinued or the dose reduced. In the clinical trials, more than 90% of the individuals who experienced d4T related neuropathy were able to resume therapy after their symptoms subsided without further problems.

Peripheral neuropathy is also one of the major side effects of ddI and ddC. It is not clear yet whether individuals who experienced neuropathy with either of these drugs will be at increased risk for developing neuropathy as a side effect of d4T. d4T, ddI and ddC are not always the cause of peripheral neuropathy. It can also be the result of HIV infection itself, excess vitamin B6, vitamin B12 deficiency, cytomegalovirus (CMV) or some of the anti- TB drugs. It is often difficult for physicians to determine the actual cause of peripheral neuropathy. (For some additional information on peripheral neuropathy, please request the STEP fact sheet).

Another potentially serious side effect seen in some individuals taking d4T is elevation of liver enzymes called transaminases (SGOT and SGPT). Liver enzymes are basically proteins that are present in liver cells. When liver inflammation or death of liver cells occur, there is an increase in the blood levels of these enzymes. d4T, which is metabolized by the liver, may cause this cell death or inflammation. Also, many different viruses such as hepatitis A, B or C, cytomegalovirus, and Epstein Barr virus can also cause inflammation leading to elevated liver enzymes. Due to previous or ongoing medical conditions, many individuals with HIV have chronic mild elevation of their liver enzymes. This might be considered "normal" for them, and mild elevations are not cause for great concern. Liver function tests should be monitored frequently in individuals used d4T. As with neuropathy, early detection is important to decrease the chances of permanent damage.

As with the other nucleoside analogues (AZT, ddI and ddC), many individuals may experience nausea and headaches, and a general sense of not feeling well during the first few weeks of therapy. These effects are probably a combination of the body adjusting to the drug and the person's anxiety over beginning a new therapy. However, these effects will gradually subside in nearly all individuals.

There are some other, less common side effects related to d4T. One of these is granulocytopenia. Granulocytopenia is a decreased number of ganulocytes (a type of white blood cell). Other conditions seen in studies which may be related to d4T include anemia, leukopenia, and thrombocytopenia. These decreases in cell counts suggest that d4T may be suppressive to the bone marrow in some individuals, therefore blood work should be monitored closely.

Drug Interactions Laboratory studies have shown that AZT inhibits the activity of d4T. This is probably because the two drugs are so similar to each other. Although the interactions of AZT and d4T have not been studied in people, it is probable that the same effect will be seen. Other laboratory studies have shown that ddI and d4T have synergistic activity. this means that the benefits of drugs used together are greater than simply the sum of their effects. Similar to adding two plus two and coming up with six instead of four. Unfortunately, peripheral neuropathy is the main side effect of both ddI and d4T and the potential for this toxicity may be significantly increased with the use of both drugs. Peripheral neuropathy is also one of the main side effect of ddC. There are studies in progress which will assess the risks and benefits of combining d4T with AZT, ddI or ddC.

Because it is not known yet which drugs will cause adverse reactions if used in combination with d4T, drugs which can cause the same side effects should be used with caution. Close monitoring of blood work is necessary. Other drugs which can cause elevated liver function tests include: diphenylhydantoin, tegretol, valproic acid, flucytosine, ganciclovir, isoniazid, ketoconazole, pentamidine, rifampin, trimethoprim-sulfamethoxazole (TMP-SMX, Bactrim, or Septra), other sulfa drugs, rifabutin, and clofazamine. Other drugs which can cause granulocytopenia include: amphotericin B. ganciclovir, isoniazid, flucytosine, pentamidine, TMP-SMX, other sulfa drugs, and cytotoxic chemotherapy. Drugs which may cause peripheral neuropathy include: amphotericin B, flucytosine, isoniazid, metronidazole (flagyl), disulfiram, TMP-SMX, other sulfa drugs, phenytoin, vincristine, vinblastine, cisplatin, ddI and ddC

Where Can You Get d4T?

d4T is currently available, free of charge, through a parallel track program. Physicians may obtain the drug for individuals meeting the entry criteria by calling the manufacturer (Bristol Myers Squibb) at 1-800-842-8036. Individuals must meet the following entry criteria:

Individuals must be intolerant to both AZT and ddI. Intolerance to AZT is defined as having experienced hematological intolerance (such as anemia), severe nausea or vomiting, or myopathy (muscle weakness, atrophy and elevated CPK). Intolerance to ddI includes pancreatitis and/or elevation of serum pancreatic amylase. Individuals who have experienced ddI-related peripheral neuropathy which has resolved are still eligible, or

Individuals must have failed therapy with AZT and ddI. Failure is defined as either repeated episodes of AIDS-defining conditions while on therapy (including wasting syndrome), CD4 counts of less than or equal to 50 CD4 cells per mm3 or greater than 50% decline, or a greater than 20 point decline in Karnofsky score.

In addition, individuals must be a least 13 years old with a CD4 count of less than 300 cells/mm3, and be available for one follow- up visit per month. Additional laboratory values must also be evaluated for entry. Individuals can not have grade 2 or worse disease-related peripheral neuropathy or drug-related neuropathy which has not resolved.

Individuals who qualify for this program will receive doses of either 20 or 40 mg twice a day (less if the individual weighs less than 70 kg). The use of other antivirals, such as AZT or ddI, is strongly discouraged, but not forbidden.

Who Should Use d4T?

although the parallel track program states that only individuals who are intolerant to or failing other antiviral therapy are eligible, it is not impossible for other individuals to qualify with creative wording of side effects and symptoms. d4T provides a good alternative for those individuals who are truly intolerant to or failing AZT and ddI, but it is still far too early to say which drug will ultimately be the most effective. d4T is not a "miracle drug" and individuals who can take other antivirals which have proven to be effective should avoid trying to sneak into the parallel track just because d4T is the new kid on the block.
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Copyright © 1993 - Seattle Treatment Education Project (STEP) - All rights reserved. Noncommercial reproduction is encouraged. STEP is published four times a year by the Seattle Treatment Education Project, 127 Broadway East, 3rd Floor, Seattle, WA 98102.    Email: step100@aol.com  STEP web page