Gay Men's Health Crisis "Treatment Issues" Vol. 8, No. 11 - December 1994
Dave Gilden

What is 3TC?

Like AZT, 3TC is a nucleoside analog, a faulty DNA building block. It stops the HIV enzyme reverse transcriptase from producing a complete DNA copy of HIV's genes within a newly infected cell. This step is necessary to insert those genes into the cell's own genetic machinery within the nucleus. 3TC has a particularly low number of side-effects (principally nausea, vomiting and headaches, with little of the bone marrow suppression seen with AZT). Its major problem has been that it does not seem to work as a single agent: resistance to 3TC arises a few weeks after therapy begins as a result of a single mutation in HIV's genes.

This resistance is not absolute. There seems to be some continuing reduction in virus levels in people taking 3TC. More significantly, resistance to 3TC in laboratory tests seems to resensitize HIV to AZT.

The observation that resistance to one drug negates resistance to another has occurred before, with ddI and AZT, but has not been confirmed outside the test-tube. In humans, new mutations occur that can confer co-resistance to both AZT and ddI. Nonetheless, research into 3TC combined with AZT was begun, and Burroughs Wellcome, AZT's manufacturer, signed an option agreement to obtain rights to HIV therapy applications from Glaxo, 3TC's developer.

European Data

The data on 3TC plus AZT presented in Glasgow received a lot of notice, and Glaxo considered them encouraging enough to cancel its agreement with Burroughs Wellcome. With the help of trials now being conducted in North America, Glaxo expects to apply for marketing approval of the combination therapy during the first half of next year. The figures do look intriguing, but at second glance, they lack the power to be convincing.

Reports on two European studies were presented in Glasgow, one for people with little prior history on AZT (AZT-naive) and the other involving people with an average of two years on AZT. At this point, the first study has been much more extensively analyzed than the second.

The AZT-naive study started out with 129 people. The median CD4 cell counts in the first study was 251. This number rose in the combination arm of the study by 80 points after 24 weeks of therapy. At the end of 48 weeks, the median CD4 count was still 45 above baseline, and the month-to-month graph of CD4 count changes indicated hardly any downward trend. The decrease in blood-borne HIV corresponded to the increase in CD4 cells. As measured by the RNA PCR test (see Treatment Issues, November 1994, page 4), virus levels were down 86 percent at week 24 and 91 percent at week 48.

An interesting aspect to this study was that it included an AZT-only comparative arm for the first 24 weeks. This group then switched onto open-label AZT plus 3TC for the next 24 weeks. From the very beginning, the AZT-only people fared more poorly than the people on combination therapy although they too had little or no prior exposure to AZT and presumably the HIV in their bodies was not resistant to the drug. At week 24, the AZT-only people were down a median of seven points in their CD4 counts (at week four they had CD4 counts a median of 34 points above baseline). Their HIV levels were only 36 percent below baseline (the peak decrease, at week two, was 76 percent).

After the second 24 weeks, with the AZT monotherapy group now also on 3TC, CD4 counts were a median of 40 points above their initial values and virus load was down 92 percent from the start of the study. In terms of lab values, the original monotherapy group had caught up with the combination arm through adding 3TC to its regimen.

The concept that 3TC reinforces and even rejuvenates the effect of AZT after the first few months was reinforced by the second study presented at the Glasgow conference. This one involved 223 AZT-experienced volunteers with an average CD4 count of about 250. Participants either remained on AZT alone or followed a regimen of AZT and 3TC at one of two doses (150 mg twice daily or 300 mg twice daily). After 24 weeks, those on either of the combination therapies saw their CD4 cell counts rise by an average of 33 (the peak value was 47 above baseline), while those remaining on AZT lost an average of 21 cells. Data on HIV levels or on CD4 cells past 24 weeks have not yet been released.

The Shrinking Sample Size

Though not extraordinary, the response to AZT/3TC therapy does seem comparatively robust given the results with most other anti-reverse transcriptase combinations and, especially, seems more sustained. But the soundness of the numbers is open to question. This is particularly the case for the data after 24 weeks, which substantiate the "sustained" nature of the response.

In the first study, HIV levels were measured by RNA PCR in only one of the study sites -- for a total of only 36 people at baseline, 31 persons at 24 weeks and just sixteen at 48 weeks. Initial CD4 counts were for 129 trial participants, but the 48-week values represented 72 individuals. In both studies, twelve percent of the participants dropped out in the first 24 weeks, and in the first study, many of the participants had not reached 48 weeks of therapy when the data was analyzed. (These figures were all supplied by Glaxo; the dropout rate in the second 24 weeks of the first study was unavailable at Treatment Issues' press time.)

The actual sizes of the subsets involved in the data analysis were not mentioned in any of the written accounts of the Glasgow reports (including Glaxo and Burroughs Wellcome's press releases) nor were they pointed out in the oral presentations themselves. It is unclear at present whether any bias was introduced by these declining numbers. (To give two examples of how the study findings could have been skewed: the site used for measuring HIV levels might not be representative of the study as a whole or the final results might be biased because the best responders tended to remain in the study while others dropped out.)

In any case, it is hard to draw any definite conclusions on the basis of viral load measurements of sixteen people. The CD4 count data also become weaker as the number of people behind the data shrinks. Any firmer conclusion on the value of the 3TC/AZT combination must await the data from the North American trials, which will be reported at the end of January in a conference in Washington, D.C. These two trials have enrolled a total of about 600 people, with HIV levels measured in 500 of them. They supposedly compare 3TC plus AZT to 3TC plus ddC, AZT alone and 3TC alone. But this data will only be available for the first 24 weeks on therapy. Whatever the new data says, none of the 3TC trials to date have proved large enough to detect any significant improvement in physical symptoms due to therapy. Larger trials intended to collect clinical results will commence early next year. At the same time, Glaxo intends to ready its current analyses for an application for FDA approval of the 3TC/AZT combination.

Whether the modest 30 to 80 CD4 cell count rise observed will translate into clinical improvement is an unresolved question. In trials of other nucleoside analogs, improvements in this range did not help patients in the long run, but these increases did not last for as long as they seem to do with 3TC plus AZT.

Hepatitis B

Of note, 3TC is also being studied as a treatment for chronic hepatitis B. Two small trials, one in the U.S. and one in China, have been completed. In the 100 mg and 300 mg per day arms of the North American trials, 3TC reduced virus levels below detectable amounts after three months of treatment. These results involved 22 people. In eleven of the 22, reduced levels of hepatitis B continued through six months of post-treatment follow-up. Additional studies of 3TC alone and in combination with alpha interferon are now in the planning stages.

3TC Expanded Access

Glaxo operates a large expanded access program that provides 3TC to HIV-positive individuals who have CD4 counts below 300 and are failing or cannot tolerate approved therapies. Those who are coinfected with HIV and hepatitis B might be particularly interested in this program. Glaxo is trying to flag coinfected enrollees for special follow-up. Concomitant use of other drugs such as AZT has been discouraged in the expanded access program but not absolutely prohibited. This policy is undergoing review in light of the 3TC/AZT combination therapy results. People who are interested in 3TC expanded access should have their physicians call Glaxo at 800/248-9757.

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