3TC: New Treatment Enters Major Trials

This month, two large studies will begin recruiting patients for efficacy trials of 3TC -- the latest antiviral drug in the class (called nucleoside analogs) that includes AZT, ddI, ddC, and d4T. 3TC does not represent a breakthrough, but it may be a limited advance in controlling HIV, one likely to be used in combination with other antivirals.

Background

In dosage and safety trials, 202 patients -- in the U.S., Canada and Europe, at varying levels of immune health -- received varying doses of 3TC. A number of patients received doses that turned out to be too low to be effective. Detailed final data from these early studies is not available. But there are a few clear points:

1. The drug, as measured by T-helper cell increases, reductions in common markers of viral activity, and some reductions in viral burden, does appear to have anti-HIV activity. In some tests, this activity appeared to be on a par with that of other drugs in this class.

2. T-helper cell increases, however, were not large and did not last very long. These increases were less than those historically seen with AZT, ddI, and d4T. There was some apparent stabilization of T-helper levels.

3. 3TC appeared to have a favorable safety profile. Such things as headache, fatigue, and diarrhea were seen, but only to the extent those symptoms are normally seen in people with fairly advanced HIV disease. At the highest dose, there was some suggestion of neutropenia (deficiency of a kind of infection-fighting white cell), but that dose was more than twice the dose to be used in upcoming trials (since higher doses showed no increase in anti-HIV activity). Probably the most important side effect that was not seen was neuropathy -- which has been associated to varying degrees with all other nucleoside analogs, especially ddI, ddC, and d4T.

4. Evidence of drug resistance was seen in some patients at doses below the ones to be used in future trials. Work is currently underway to see if there were changes in viral susceptibility at the higher doses.

New Trials and Compassionate Use.

Because of the limited T-helper increases, the two 3TC trials will mostly use the drug in combination with AZT. Laboratory studies have shown synergy (good interaction) between AZT and 3TC, but not between 3TC and ddI or ddC.

For the same reason, the studies will last only 32 weeks. Glaxo (the manufacturer) is calling these trials "early Phase II/III," looking for evidence such as T-helper increases and antiviral activity as measured by blood tests, rather than relief or prevention of disease symptoms. Further trials may be necessary, depending on what's shown by these two.

The first study (designated 3001 by Glaxo) will have 320 patients in four arms; the study will be blinded so that nobody knows who is receiving what. The different arms will test single drugs against different doses of 3TC in combination. The first arm will receive 600 mg per day of 3TC. The second will receive the standard dose of AZT. The third will receive the same dose of 3TC with AZT. The fourth will receive half as much 3TC with AZT. (In the early trials, antiviral activity was seen at this dose as well as the higher one.) Patients must have 200 to 500 T-helper cells and no history of using AZT, ddI, or ddC. The sites for this study are in: Atlanta; Beverly Hills; Boston; Chapel Hill; Charlotte; Dallas; Los Angeles; Milwaukee; New York City; Pawtucket; Santurce (Puerto Rico); Toledo; and Torrance. (For Canadian cities, see list below.)

(Note: questions have been raised by community groups about the advisability of putting some people on 3TC alone, given its history of producing such short T-helper increases, but the comparative brevity of the study should largely answer those concerns.)

The second study (designated 3002) will have 225 patients in three arms, and will also be blinded (except for the AZT, because all patients will receive it). The arms will test different doses of 3TC in combination against another combination. The first two arms will receive AZT with either 600 mg or 300 mg of 3TC. The third arm will receive AZT with ddC. Patients must have taken AZT for at least 24 weeks, but never have taken ddC or ddI, and have 100 to 300 T-helper cells. The sites for 3002 are: Atlanta; Boston; Dallas; Durham; East Meadow; Hershey; Houston; Los Angeles; Milwaukee; New York City; Poncho (Puerto Rico); and San Francisco.

There will also be sites for both trials in Canada at Ottawa, Montreal, and Toronto.

1-800-TRIALS-A, the national clinical trials information line, will have full details. Glaxo is making special efforts to enroll women, minorities, and IV drug users, and trial sites will provide services such as child care and transportation to help toward this goal.

There is no definite date, but Glaxo is also planning a compassionate use program to start when the trials are up and running. It will be for people with fewer than 100 T-helper cells who have failed on, or are intolerant to, the other nucleoside analogs. The company has no clear idea how many people will meet its criteria, but does not envision a large expanded-access program, because of the early stage of development of the drug.

Additionally, a dose-escalating safety study of 3TC is continuing in Los Angeles and Bethesda, Maryland, for children up to 17 years old, with a larger efficacy trial to follow at some undetermined point. The compassionate-use program will also cover pediatric cases.

It's also worth noting that 3TC has shown activity against the hepatitis-B virus (HBV), and is being, or soon will be, tested for that use in both Europe and the U.S. People co-
infected with HIV and HBV might have an extra reason for considering 3TC trials.

Comment

While nobody can get very excited about another nucleoside analog, and possibly not a very powerful one at that, 3TC does have some advantages. The main one is its apparent lack of side effects, unprecedented among drugs of this class. And, like other nucleosides, 3TC is backed by a large company with the resources to develop it quickly and move it toward approval (which could come late next year); it benefits from the FDA's familiarity with this class of drugs and willingness to license them. Also, the synergy with AZT is encouraging, as AZT is the other nucleoside least associated with neuropathy. AZT plus 3TC may finally offer a workable combination for many people who use other combinations because of this condition.