TreatmentUpdate40: February 1993
Sean Hosein

Like AZT, ddI and d4T, the new anti-viral drug 3TC (Lamivudine) belongs to the class of drugs called nucleoside analogues. In lab experiments with cells 3TC reduces the production of viruses inside HIV-infected cells. In other experiments the drug also blocks the activity of hepatitis B virus. 3TC is thought to work by interfering with the activity of the viral enzyme RT (reverse transcriptase). Without RT new viruses cannot be made. There may also be other ways 3TC can block viral replication. As with AZT, 3TC must first be converted to its anti-viral form before it can block virus production. Experiments with cells have found that the concentration of the anti-viral form of 3TC remains high inside cells for a prolonged period of time. It is thus likely that the drug may only need to be taken two or three times daily. Results from experiments with cells and HIV suggest that 3TC is less toxic than AZT. Combinations of 3TC and AZT have greater anti-viral effect than AZT alone. Similar results have also been seen in experiments with 3TC and ddC or ddI according to Dr. Charles Penn, Glaxo Group Research, UK.

Results from Human Studies

3TC is undergoing human testing in North America and the EC. In results from those studies it has been found that 75 to 80% of the drug is absorbed when given orally. When the dose of 3TC given is continuously increased, less of the drug is absorbed. It is not yet clear if this is due to poor absorption in the intestine or the type of capsules in which the drug is packaged. Taking 3TC with meals delays but does not reduce the absorption of the drug. When given orally, the concentration of 3TC in the blood reaches levels at which viral activity should be reduced. Severe bone marrow toxicity has happened at doses of 12 and 20 mg/kg/day. Headache appears to be the most common side effect reported by subjects. Headaches do not get worse when the dose of 3TC is increased. Subjects have tolerated the drug for over 1 year of use. As the current human studies of 3TC do not have a control group (given placebo or AZT) it is difficult to assess the true impact of 3TC on people with HIV infection. The use of 3TC may have caused some subjects to gain weight and, perhaps, increased energy as well. The drug may also have caused some subjects to have increases in their CD4+ cell counts, but this is not at all certain. Data on subjects given the drug for at least 6 months suggest that HIV resistance to 3TC has not developed.

Trials to Start in May or June '93

The trials which will start in late Spring 1993 will assess the effects of 3TC at high doses (8 mg/kg/day) and at low doses (4mg/kg/day) against AZT 600 mg/day and combinations of AZT and 3TC. These trials will take place in North America. A trial of 3TC to test its anti-hepatitis B activity in humans is planned in Alberta later this year (personal communication, G. Brown, MD, Glaxo Canada Inc.).

References:

1. van Leeuwen R, Lange JMA, Hussey EK, et al. The safety and pharmacokinetics of a reverse transcriptase inhibitor, 3TC, in patients with HIV infection:a phase I study. AIDS 1992:6(12):1471-1475.

2. Penn C. Evaluation of 3TC for treatment of human immunodeficiency virus type 1 infection (symposium). In: Program and abstracts of the 32nd Interscience Conference on Antimicrobial Agents and Chemotherapy (Anaheim). Washington, DC:American Society for Microbiology, 1992:3.

3. Katlama C, Ingrand D, Tubiana R, et al. A phase I/II study of 3TC (GR109714X) (abstract 559). In: Program and abstracts of the 32nd Interscience Conference on Antimicrobial Agents and Chemotherapy (Anaheim). Washington, DC:American Society forMicrobiology, 1992:204.

4. Pluda J, Ruedy J, Levitt N, et al. A phase I/II study of 3TC (GR109714X) (abstract 560). In: Program and abstracts of the 32nd Interscience Conference on Anhmicrobial Agents and Chemotherapy (Anaheim). Washington, DC:American Society for Microbiology, 1992:204.

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