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

Developed in Montréal, 3TC is a chemical 'related' to AZT. Experiments on HIV-infected humans using this drug are underway in North America and in the European Union. In this article we report results from 2 studies looking at safety and anti-HIV effects, as well as the development of viruses resistant to 3TC. Detailed results from a study testing a combination of 3TC and AZT had not been released as we went to press.

* STUDY DETAILS

All 114 subjects were male and had less than 401 CD4+ cells. Researchers randomly assigned 15 subjects to one of 6 groups, each group taking a different dose of 3TC. After each dose, researchers looked for side effects of 3TC. When subjects did not experience toxicity, the researchers increased their dose of 3TC. Subjects took 3TC in "two equal doses every 12 hours". The doses of 3TC used were 1/2 or 1, 2, 4, 8, 12 or 20 mg/kg of body weight/day. Six months after entering the study, subjects taking lower doses were allowed to increase their dose to 8 mg/kg/day, which is about 300 mg/day.

* TOXICITY

The researchers claimed that "3TC was well tolerated" at all doses. Common side effects included:

- diarrhea 69% of subjects - fatigue 56% - headache 49% - coughing 39% - problems sleeping 30% - muscle pain 25% - nausea/vomiting 19%

The researchers stated that many of these symptoms were temporary and "mild". Less than 5% of subjects developed low blood levels of white blood cells and platelets. Others developed high blood levels of liver enzymes. According to the researchers, all these changes were temporary.

* DEATHS, DISEASES AND DROPOUTS

Fourteen subjects stopped taking 3TC mostly "because of [falling] CD4+ cell counts." Five of 11 subjects who developed life-threatening infections or cancers left the study. One subject left because of headaches and 2 subjects died. There were no significant differences between dose groups when researchers looked at who developed AIDS.

* COUNTING CD4+ CELLS AND OTHER LAB TESTS

Before potential subjects received 3TC, doctors made sure that at least 2 CD4+ cell counts were done. They found that statistically significant increases occurred even before subjects received 3TC. In half of the subjects the increase was about 17 cells. CD4+ cell counts reached their highest level during the first 2 months of the study. Half of the subjects had their CD4+ counts return to their pre-study level after receiving 3TC for 12 weeks. Despite using different ways of analyzing data, researchers could not find a link between the dose of 3TC and an increased CD4+ cell count. Researchers also measured production of virus, levels of beta2-microglobulin and neopterin, but again there were no statistically significant links between doses of 3TC and changes in those laboratory measurements.

* HIV RESISTANCE AGAINST 3TC

In other developments, researchers in the laboratory of virologist Mark Wainberg (Montréal) and elsewhere have been studying the long term effect of 3TC on HIV in 39 subjects with less than 301 CD4+ cells. Subjects received various doses of 3TC (as listed earlier). Technicians found HIV resistant to 3TC in blood samples from 13 subjects. Resistance developed in subjects taking low doses (1/2, 1 or 4 mg/kg/day) as well as in subjects taking high doses (8, 12 and 20 mg/ kg/day). Resistance appeared as early as 4 months in some subjects, while in others it appeared in the 10th month of using 3TC. The researchers could not find any link between the dose of 3TC used and the development of resistance. As well there was no connection between the development of HIV resistant to 3TC and declining CD4+ cell counts and the development of life-threatening infections. A number of studies of 3TC are underway. There is an 'open-label' trial where subjects can get 3TC taken orally. Subjects will be randomly assigned to receive either a low dose (150 mg/day) in two divided doses, or 300 mg day, again in a divided dose. Subjects taking the 150 mg dose may also take AZT. Physicians in Canada and the USA interested in enrolling their patients in the open label programme may call 1-800-248-9757 (personal communication, D. Donaldson, Glaxo-Wellcome and D. Maclean).

REFERENCES:

1. van Leeuwen R, Katlama C, Kitchen V, et al. Evaluation of safety and efficacy of 3TC (lamivudine) in patients with asymptomatic or mildly symptomatic Human Immunodeficiency Virus infection: a phase I/II study. Journal of Infectious Diseases 1995;171:1166-1171.

2. Wainberg MA, Solomon H, Gu Z, et al. Development of HIV-I resistance to (-)2'-deoxy-3'-thiacytidine in patients with AIDS and advanced AIDS-related complex. AIDS 1995;9(4):351-357.

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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