TreatmentUpdate80 - Vol. 8, No. 0; August 1997
Sean Hosein

Since its anti-HIV activity was discovered in 1987, the drug carbovir has undergone much testing. Unfortunately, absorption of carbovir was poor, it caused kidney and heart damage at relatively low doses and poorly penetrated the brain/spinal cord. So researchers at Glaxo-Wellcome turned and twisted the carbovir molecule and came out with the drug 1592, also called abacavir. Once 1592 gets inside T cells it is converted into small amounts of carbovir. These cells seem to be able to withstand low levels of carbovir.

Resistance to other drugs

Results from lab experiments with 1592 suggest that people who have HIV that is resistant to ddC, ddI and 3TC may also have HIV that is resistant to 1592. Indeed, Glaxo-Wellcome scientists stated that:

"it may not be [best] to use [ddC, ddI and 3TC] together [with 1592] in combination therapy."

Combination therapy

In further lab experiments using HIV from PHAs who had never used anti-HIV drugs, researchers found that 1592 was as effective as AZT or ddI. Combinations that looked promising in the lab included 1592 with AZT, nevirapine and the protease inhibitor, "141." When used in combination with 1592, these drugs caused a severe decrease in HIV activity, far better than when they were used alone. Also producing promising results were 1592 in combination with other nukes -- 3TC, d4T ddC and ddI.

Can 1592 affect other viruses?

1592 can block the growth of hepatitis B-infected cells. This drug also has mild anti-CMV activity, although it is not as powerful as ganciclovir (Cytovene). 1592 does not affect herpes viruses nor the one that causes the flu.

Toxicity

AZT is well known for its toxicity to the bone marrow. According to the manufacturer of 1592, "our results show that 1592 is much less toxic than AZT," in short term experiments.

Expanded access

1592 is not yet licensed in Canada. Eighty people will gain access to it through an expanded access programme to begin later this year. The programme has come about thanks to pressure placed on Glaxo-Wellcome by AIDS activists who wanted access to 1592 for more people. However, the company refused to make it easily available to PHAs who might benefit -- such as those who ahd exhausted all their current treatment options. Glaxo-Wellcome claims that there is a limited supply of 1592 at this time. The Canadian HIV Trials Network (CTN) is taking applications for this programme and doctors may obtain information about registration of their patients from the CTN at 1-800-565-1122. Detailed information on the expanded access programme appears on our website.

When to use it

The place for 1592 in the course of anti-HIV therapy is unclear, partly because:

* Glaxo-Wellcome has been testing it in combination with its own drugs

-- AZT, 3TC and "141" for the longest period in people who have never used anti-HIV drugs;

* related drugs (ddC, ddI and 3TC) may already have been taken, this can lead to the creation of HIV that is resistant to 1592 without PHAs ever having used it.

For PHAs who have used these drugs, 1592 is still an option but one which will have to be carefully used depending on their medication hsitory. The good news is that doctors conducting studies using 1592 in combination with other drugs have found increases in CD+ cell counts and decreases in the amount of HIV in the blood. The drug also gets into the brain where it may be usedful in treating or preventing HIV-related brain damage.

REFERENCES:

1. Tisdale M, Alnadaf T and Cousens D. Combination of mutuations in human immunodeficiency virus type 1 reverse transcripatase required for resistance to the carbocyclic nucleoside 1592U89. Antimicrobial Agents and Chemotherapy 1997;41(5):1094-1098.

2. Faletto MB, Miller WH, Garvey EP. Unique intracellular activation of the potent anti-human immunodeficiency virus agent 1592U89. Antimicrobial Agents and Chemotherapy 1997;41(5):1099-1107.

3. Daluge SM, good SS, Faletto MB et al. 1592U89, a novel carbocyclic nucleoside analog with potent, selective anti-human immunodeficiency virus activeity. Antimicrobial Agents and Chemotherapy 1997;41(5):1082-1093.

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Copyright © 1997 - TreatmentUpdate. Reproduced with permission. Reproduction of this article (other than one copy for personal reference) must be cleared through the Editor, The Canadian AIDS Treatment Information Exchange, 555 Richmond St. West, Suite 505, Box 1104, Toronto, ON, M5V 3B1 • Phone: 416-203-7122 • Toll Free: 1-800-263-1638 • Fax: 416-203-8284  http://www.catie.ca