Second National Conference on Human Retroviruses and Related Infections

AZT/3TC combination is promising in treating HIV infection


Results of European trials, reported last November in Glasgow, indicated that the drug 3TC would be useful in treating HIV infection. Data from North American trials, reported last Wednesday at the Second National Conference on Human Retroviruses and Related Infections in Washington, D.C., bolster that belief.

The preliminary results of North American clinical studies of the nucleoside analogs 3TC and AZT (zidovudine) show that the two drugs in combination have a greater effect on surrogate markers of HIV infection than either drug alone or the combination of AZT and ddC (zalcitabine), another nucleoside analog. The surrogate markers studied included CD4 cell count and measurements of virus in the blood as determined by levels of HIV RNA.

Treatment for HIV is usually based on CD4 cell counts and symptoms. Healthy people have CD4 cell counts of 800-1000 cells per ml of blood; a CD4 cell count of 200 or less is commonly used as a diagnostic marker for AIDS.

The two Phase II/III studies included 618 patients in Canada and the United States. One study involved 364 patients who had previously received less than four weeks of AZT therapy. It compared effects of four dosage regimens:
-high-dose (300 mg b.i.d.) 3TC combined with AZT
- low-dose (150 mg b.i.d.) 3TC combined with AZT
- AZT alone
-3TC alone

All four regimens produced a rise relative to baseline in CD4 cell count, with the low-dose combination producing the highest peak at entry (70 cells), but the high-dose combination producing the highest sustained increase (58 cells at 24 weeks). The two single-dose regimens produced the least satisfactory results: 3TC alone produced a 15-cell increase at 24 weeks, while AZT alone produced an 8-cell increase 24 weeks into the study. CD4 cell counts remained above baseline for 52 weeks in combination-therapy patients for whom data is currently available. Decreases in HIV RNA followed a similar pattern, with the high-dose combination regimen producing the best results (a decrease of 1.0 log at 24 weeks).

Nausea/vomiting, headache, and malaise/fatigue were the most commonly reported adverse events. There were no significant differences in the side-effect profiles of patients on any of the three regimens. The second study involved 254 patients who had previously taken AZT. It compared effects of three dosage regimens:
-high-dose (300 mg b.i.d.) 3TC combined with AZT
-low-dose (150 mg b.i.d.) 3TC combined with AZT
- AZT+ddC

In this study, the low-dose 3TC/AZT combination produced the best sustained results (an increase of 32 cells at 24 weeks), and the AZT/ddC combination produced a decrease of 15 cells by 24 weeks. In 3TC/AZT combination-therapy patients for whom data is currently available, CD4 increases were sustained to 52 weeks. Effects on HIV RNA were almost identical for all regimens at the 24-week mark, with the low-dose combination producing the greatest decrease (0.8 log).

Adverse events most commonly reported included nausea/vomiting, abdominal discomfort, and headache. Frequency of adverse events was greater in the higher-dose combination arm.

These studies were not designed to assess development of clinical endpoints such as progression to opportunistic infection or death. Trials involving both adults and children will soon get under way in Vancouver, Toronto, and Montreal, as well as in the U.S.A., to assess these endpoints. Clinical trials investigating the use of 3TC in treating hepatitis B are also scheduled; the drug will be known in these trials as lamivudine.

BioChem Pharma in Laval, Quebec discovered 3TC. The drug is being developed by Glaxo worldwide, and BioChem Therapeutics and Glaxo will co-market it in Canada. According to Michael Grey, president of BioChem Therapeutics, his company will apply by mid-summer for approval to market 3TC.