Edited by: Steve Bunk
J.L. Eron, S.L. Benoit, J. Jemsek, R.D. MacArthur, J. Santana, J.B. Quinn, D.R. Kuritzkes, M.A. Fallon, M. Rubin, "Treatment with lamivudine, zidovudine, or both in HIV-positive patients with 200 to 500 CD4+ cells per cubic millimeter," New England Journal of Medicine, 333:1662-9, 1995. (Cited in 120 publications through October 1997)
Comments by Joseph Jemsek, Nalle Clinic, Charlotte, N.C.
Among viruses that cause infectious disease, HIV is particularly adept at mutating to survive drug therapy. "That's the strongest argument for combination therapy, because you can corner the drug, as it were, and not allow it to mutate," notes Joseph Jemsek, director of clinical research at the Nalle Clinic in Charlotte, N.C. "The downside is, it's hard to take that many drugs forever."
DOUBLE COMBINATION: The Nalle Clinic's Joseph Jemsek was on the team that pioneered successful combination drug therapy for HIV.
Accordingly, before the trials conducted for this paper, other researchers had tested several dual combinations of drugs in the family to which AZT belongs, that of reverse transcriptase inhibitors. These drugs inhibit a critical growth process of HIV-infected cells, in which enzymes catalyze the formation of DNA using the infected cell's RNA as a template. The drugs that had been tested were generally better in combination than singly, but questions remained concerning safety, tolerance, and efficacy. In such trials, efficacy is gauged by measuring changes in the levels of HIV- 1 RNA and in the numbers of CD4+ T lymphocyte cells that fight the virus.
For this paper's project, 366 patients at 26 sites throughout the United States were randomly assigned to receive one of four oral treatments: AZT plus a placebo, lamivudine (also known as 3TC) plus a placebo, relatively low dosages of the two drugs together, and relatively high dosages of them in combination.
Jemsek says the main significance of this paper was its ground-breaking result: "We were able to show without question that the CD4+ counts and viral loads were both favorably impacted by the use of these two drugs in combination." He adds that while HIV often will mutate to withstand the effects of one drug or the other, these two compounds work in a reciprocal fashion to counteract such mutations. In other words, "a mutation in a strain of the virus against one drug doesn't necessarily sabotage the program, because the antiviral capacity of the other drug is generally effective against that mutant."
These mutations vary from one person to the next, depending in part on the individual's therapeutic history. For example, someone who previously has been treated with AZT might have a mutated strain of the virus to protect it against that drug. Therefore, research since this paper has identified several other dual combinations of the five major reverse transcriptase inhibitors that work well together. But AZT and 3TC remain among the best combinations. Glaxo Wellcome Inc., the Research Triangle Park, N.C.-based company that supported the research team with funds and scientific personnel, has since developed a single pill named Combivir that incorporates both AZT and 3TC.
The latest step, of course, has been to add a protease inhibitor to the double combination. Jemsek is among those who now are testing various combinations of protease agents with reverse transcriptase inhibitors or with other drugs. Although progress has been heartening, he cautions that HIV infection has not yet been utterly reduced from an acute disease to one that is merely chronic and controllable. "Breakthroughs" can still occur, in which the virus mutates months after combination therapy has kept it in check. Sometimes, particularly in patients who are not severely immunocompromised, doctors may decide to withhold the maximum therapeutic potency and the increased side effects of triple combination drugs, continuing instead to monitor the T-cell count and viral load.
"It's easy to sit in the office and say, 'We'll hit the virus with everything we have and suppress it,'" Jemsek reflects, "but there still are a lot of tough issues to deal with."