AIDS TREATMENT NEWS Issue #212, December 03, 1994
John S. James

We were not at the Second International Congress on Drug Therapy in HIV Infection, in Glasgow, Scotland, where the 3TC results were released on November 20. This article is based on conversations with several people who were there, and on press releases which summarized the data presented.

3TC Background

3TC is a nucleoside analog antiviral -- in the same general class as AZT or ddI -- which has been in human trials as an experimental HIV treatment for several years; in addition, it is also showing promise as a treatment for hepatitis B. Since October 1993 (earlier in Canada), 3TC has been available through an expanded-access program, for persons with T-helper counts under 300 who cannot tolerate, or do not benefit from, approved anti-HIV treatment (AZT, ddI, ddC, or d4T). This program is still open for enrolling new patients; for more information, see below. 3TC is being developed by Glaxo, which licensed rights to the drug in 1990 from BioChem Pharma Inc., a biotechnology company located in Laval, Quebec. Glaxo had discussed development arrangements with Burroughs- Wellcome, but decided to develop the drug itself when the new results were announced.

In laboratory tests, 3TC has been found to be synergistic with AZT, meaning that the two drugs in combination work better than would be expected by adding their separate effects. One theory holds that this is because 3TC reverses HIV's resistance to AZT -- that when the virus has the mutation which makes it resistant to 3TC, it will be susceptible to AZT even if it also has the mutations which normally would confer AZT resistance. But other researchers believe that this proposed mechanism -- reversal of AZT resistance by 3TC -- could not explain the new data, which suggests that the synergy of the two drugs starts immediately, and then is maintained over time. AZT alone does not produce the same immediate improvement, even in AZT-naive patients in whom resistance would not be an issue. (Burroughs-Wellcome, which makes AZT, favors the former theory, while Glaxo, which makes 3TC, favors the latter.) More studies of drug resistance and synergy are now being conducted, and some new information should be available at the Human Retroviruses conference early next year.

3TC results for chronic hepatitis B (in HIV-negative patients) were released recently at a Chicago meeting of the American Association for the Study of Liver Diseases. Hepatitis B viral DNA become undetectable in all 22 patients treated with either 100 mg per day or 300 mg per day of 3TC. But treatment was stopped after 12 weeks in this study, and then the virus returned in 16 of the 22 patients, and remained undetectable in the other six -- five of whom had already failed interferon treatment. (For HIV treatment, at least 300 mg per day of 3TC is likely to be used indefinitely, suggesting that this HIV treatment may also control hepatitis B for those with both infections.)

Historically, an earlier version of 3TC was called BCH-189. BCH-189 is a mixture of equal parts of 3TC and a molecule which is a mirror image of 3TC. The molecule not used in 3TC does have anti-HIV activity, apparently less than that of 3TC, but with a different drug-resistance profile.

The Glasgow Results

The results just presented at Glasgow came from two multi- center trials in Europe.

A French study, involving 129 patients, was presented by Professor Christine Katlama from Paris; it compared 3TC plus AZT to AZT alone, in patients who had never taken AZT, or had taken it for less than four weeks. At entry, volunteers had a T-helper counts from 100 to 400 (median 256). They were randomly assigned to take one of the two drug regimens for 24 weeks, then they were allowed to take the combination for an additional 24 weeks (all 55 patients given the choice of switching to combination therapy chose to do so). The 3TC dose was 300 mg twice daily; the AZT dose was 200 mg three times daily.

Those assigned to start the combination therapy had an average T-helper increase of 80 at week 24, and an average of 49 over their starting value at week 48. The level of plasma HIV RNA was reduced 86 percent at week 24, and 91 percent at week 48. The level of virus in blood cells (determined by a viral culture test, to show how infectious the blood cells were) was reduced 99 percent at week 24, and 99 percent at week 48.

The comparison group, randomly assigned to take AZT alone for the first 24 weeks but then switched to the combination, had an average T-helper count decrease of 7 by week 24. By week 48, after 24 weeks on the combination, they had an average T- helper count increase of 40 above baseline. Plasma HIV RNA was reduced by only 36 percent at week 24, but by week 48 the decrease from baseline was 92 percent. The infectivity of the blood cells was reduced only 11 percent at week 24 (by AZT alone), but reduced 98 percent at week 48 (after 24 weeks on the combination).

How do these results compare with those that might be expected from other combination treatments, such as AZT plus ddI? For T-helper count and plasma HIV RNA, the 24-week improvements are within the range one might expect from other successful combinations. What is important is that they were sustained at 48 weeks, with the patients appearing to be considerably better at that time than when they started. The best results, of course, were in the reduced infectivity of blood cells; but here we do not have similar values from other combination trials for comparison.

A German study, testing the combination in AZT-experienced patients, was presented by Dr. Schlomo Staszewski from Frankfurt. This study compared AZT alone, AZT plus high-dose 3TC (300 mg twice daily, the same dose used in the French study), and AZT plus low-dose 3TC (150 mg twice daily). Like the French study, it required participants to have T-helper count between 100 and 400 at entry (the median entry value was 249 for the AZT-only arm, 232 for the combination of AZT plus high-dose 3TC, and 246 for the combination of AZT plus low-dose 3TC). These patients also had to have at least 24 weeks of prior treatment with AZT, but usually they had much more than that (mean prior AZT use, 24.9 MONTHS for the AZT- only arm, 22.1 months for the high-dose combination arm, and 24.4 months for the low-dose combination arm).

A total of 223 patients were randomly assigned to one of these three treatment arms, and treated for 24 weeks. The 48- week data is not yet available; also, no virology data is available at this time.

At 24 weeks, the T-helper count was 33 above the starting value in the high-dose combination and 36 above starting value with the low-dose combination. In contrast, those on AZT alone had an average T-helper decrease of 21 at week 24.

All of the differences reported above for the French and German studies were statistically significant. And the drop- out rate in both studies was low, 12 percent at week 24 in the French study. The low drop-out rate, plus the fact that no one chose not to go onto the open-label combination treatment at 24 weeks, makes it unlikely that selection bias had much effect on the result. (A high drop-out rate can falsely make a drug look good, since those who find out that they are doing poorly are more likely to leave the study, while those doing well are more likely to stay.) Note: 48- week data was available on only 72 patients of the 129 in the French study. This difference is not due to drop-out, but to the fact that only some of the patients had reached the 48- week point at the time the data was analyzed for presentation at the Glasgow meeting.

These studies were not designed to detect differences in clinical disease progression. In the French study, only one patient in the combination arm had a major opportunistic infection (esophageal candidiasis, which started five days into the study). In the German study there were 42 "progression endpoints," with no statistically significant differences between the arms, but a trend favoring the combination treatment for major opportunistic conditions at least, according to data presented in Glasgow. We have not seen a breakdown on the minor events.

There were no unexpected toxicities of the combination treatment, and no statistically significant differences in side effects between the combination treatment and AZT alone.

Future Results and Studies, and Prospects for Approval

Two additional clinical trials in the U.S. and Canada are now finishing; results should be available early next year. These studies, in patients similar to those in the European trials presented at Glasgow, are comparing the 3TC plus AZT combination not only with AZT alone, but also with 3TC alone, and with AZT plus ddC.

In addition, Glaxo's expanded-access program, for patients with T-helper counts under 300 who cannot successfully use approved treatments, has now enrolled over 6,000 persons. In North America they have been randomly assigned to receive 150 mg or 300 mg twice daily. This program is not expected to provide much information about the effectiveness of the drug, but the long-term experience with a large number of people should help provide assurance that there are no major unexpected toxicities.

In early 1995, Glaxo expects to start large-scale studies to make sure that the positive blood-test results of the 3TC plus AZT combination do translate into slower disease progression and/or longer survival of patients.

Glaxo has also taken the lead in testing 3TC in children in parallel with tests in adults, so that the drug can be approved for pediatric use without the delays which have been a major problem with other HIV drugs. Results of an early clinical trial of 3TC in children were presented as early as June 1993, at the International Conference on AIDS in Berlin.

Assuming that the North American studies which are now finishing confirm the European results, Glaxo is likely to apply for approval for 3TC in early 1995, under the FDA's accelerated-approval regulations. Accelerated approval is intended for just this kind of situation: where a drug has shown good results in blood tests improvements, and long-term "clinical endpoint" trials, designed to confirm delay in disease progression, are underway.

The Expanded Access Program

The expanded-access program for 3TC is still open for enrollment. This program is for patients who have a T-helper count under 300, and cannot successfully use approved antiretrovirals (either because of toxicity, or because those drugs are not working for them).

We do not know the details of what evidence is required that approved drugs have failed. Physicians experienced with the program would have the best information on this.

In the current program, combining the 3TC with AZT or other antiretrovirals is "strongly discouraged" -- but apparently not cause for expulsion from the program. Glaxo is now considering changing the program to allow patients who have progressed on AZT, but are tolerant of it, to use the drugs in combination. We do not know whether or not 3TC could be used in combination with ddI, ddC, or d4T, but cross resistance with ddI and ddC has been reported.

Individuals in North America who would like information on the open label program should have their physicians call 800/248-9757.

[Note: AIDS writer Mark Mascolini, who attended the Glasgow conference, assisted with the research for this article.]

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