TreatmentUpdate60; Volume 7, No. 6 - June 1995
Sean Hosein

AZT and related drugs (ddC, ddI, 3TC, d4T--nucleoside analogues) are supposed to have anti-HIV activity by affecting a key viral enzyme RT (reverse transcriptase). There is also a different group of anti-HIV agents call non-nucleoside drugs that can affect RT, these drugs include nevirapine and L-697,661 (L-697). In laboratory experiments with cells and HIV, the virus becomes quickly resistant to drugs such as nevirapine and L-697. In experiments on HIV-infected humans, researchers confirmed similar results. We now report results from a study where researchers tested combinations of AZT and L-697.

* STUDY DETAILS

Researchers in Frankfurt enrolled 119 subjects (109 men, 10 women) for a study where some subjects received combinations of AZT and L-697. Subjects had CD4+ cell counts ranging between 200 and 500 CD4+ cells, with the average count at about 350 CD4+ cells. No subject used AZT before entering this study nor did any have AIDS. Researchers randomly assigned subjects to one of four groups or 'arms' of the study:

- group 1: L-697 200 mg/8 hours - group 2: L-697 100 mg/8 hours and AZT 100 mg/day (low dose combination) - group 3: L-697 200 mg/8 hours and AZT 100 mg/8 hour (high dose combination) - group 4: AZT 100 mg/8 hours

Each group had 30 subjects, except for the AZT only arm which had 29. Researchers conducted the study for about 1 year. During this time neither doctors nor their subjects were supposed to know which drug or combinations of drugs they received. The researchers could unblind the study after 6 months and subjects who remained in the study could receive the high dose combination (as in group 3) if they wished.

* RESULTS-CD4+ CELLS

Note: the researchers only released data on CD4+ cell counts for the first 6 months of the study.

- L-697: compared to their pre-study values, subjects receiving L-697 alone had declining CD4+ cell counts. By the 6th month of the study, subjects in this group had lost at least 57 CD4+ cells. - Low dose combination: For the first 3 months, the average CD4+ cell count rose as high as 79 cells, after which it fell and was no longer statistically significant. - High dose combination: half the subjects had an increase of 55 CD4+ cells by the 3rd month of the study. After that point, the increase was no longer statistically significant. - AZT: these subjects had statistically significant increases in their CD4+ cell counts during the first 4 months of the study with half of the subjects maintaining an increase of 84 cells. By the 6th month of this study the increase was no longer statistically significant.

* RESULTS-TOXICITY

Subjects in this study experienced a number of side effects. The following differences in side effects among the groups were statistically significant:

- nausea: subjects receiving AZT or combinations of AZT were 2 to 3 times more likely to have nausea than subjects receiving L-697 alone - irritability: 3 subjects taking AZT developed this problem while other subjects did not - 'sleeping problems': 4 subjects in the high dose combination group had this side effect while no other subjects did - rash: 6 subjects in the L-697 group and 3 others in the high dose group reported this side effect

The researchers did note that six serious events occurred in the study, and in brackets we note in which arm of the study they enrolled:

- 2 subjects committed suicide (1 each in the L-697 and AZT groups) - 1 'developed' lymphoma (AZT arm) - 1 developed an abscess near his rectum (low dose combination) - 1 had life-threatening inflammation of his appendix (low dose combination) - 1 subject developed Kaposi's sarcoma (group missing)

* RESISTANCE TO L-697

Researchers tested blood samples taken during the study to check for HIV that had become resistant to L-697. At the start of the study, all HIV infected cells reduced virus production when treated with L-697. By the 2nd month, technicians found that HIV-infected cells had become resistant to L-697. Subjects who received combination therapy (AZT and L-697) had virus that did not become resistant until some time between the 4th and 8th month of the study. Blood samples from subjects receiving AZT alone always had virus that was affected by L-697. Researchers did not check for HIV resistant to AZT.

* BEYOND RESISTANCE

The researchers conducting this study performed sophisticated analyses of viral resistance and tried to understand this event. It appeared that subjects receiving L-697 alone had virus that was 100 times more resistant to the drug than when they entered the study. While that event is interesting, this study did not show that combination therapy reduced the risk of developing life-threatening infections/cancers that are the hallmark of AIDS. L-697,661 is made by Merck, West Point, Pennsylvania, USA.

REFERENCES:

1. Staszewski S, Massari FE, Kober A, et al. Combination therapy with Zidovudine prevents selection of Human Immunodeficiency Virus type 1 variants expressing high-level resistance to L-697,661 a nonnucleoside reverse transcriptase inhibitor. Journal of Infectious Diseases 1995;171:1159-1165.

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Copyright © 1995 - 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