May 12, 1998 ANN ARBOR---Researchers in the University of Michigan HIV/AIDS Program and the U-M School of Public Health have discovered mutations in the genetic make-up of a type of pneumonia that is the most common severe opportunistic infection in people with AIDS.
The results are reported in the May 1998 issue of the journal AIDS.
The genetic mutations occurred in significantly larger numbers among patients who were taking medication that has proven very successful in preventing pneumocystis carinii pneumonia. The study's authors believe this could signal the emergence of resistance to these medications---called sulfa drugs. Sulfa has proven to be the most effective and widely used drug for preventing and treating pneumocystis, but it does fail in some cases.
"The importance of this study is that it documents mutations in pneumocystis in HIV/AIDS patients," says Powell Kazanjian, M.D., associate professor of internal medicine and director of the HIV/AIDS Program in the U-M Health System. "It is possible that the mutations may lead to resistance to sulfa in pneumocystis."
Kazanjian conducted the study in collaboration with Steven Meshnick, Ph.D., M.D., professor of epidemiology, U-M School of Public Health.
Researchers extracted DNA from the medical specimens of 27 patients who had been treated for pneumocystis between January 1991 and April 1997. Twenty of the patients had AIDS and the other seven were non-HIV-infected patients with compromised immune systems. Samples were obtained from the U-M, Indiana University Medical Center and Ann Arbor Veterans Administration Hospital.
Investigators examined the pneumocystis gene that is targeted by sulfa drugs and found a significantly higher incidence of mutation in patients who were taking sulfa drugs (71 percent) compared with those who weren't (15 percent). All of the mutations occurred in patients with AIDS.
The mutations occurred at two amino-acid positions. Kazanjian and Meshnick believe these two mutation points may be involved in sulfa binding. The same types of genetic mutations have been previously documented to be associated with resistance to sulfa in certain strains of meningitis, streptococcus and malaria.
The study authors say it was not possible to determine what caused the mutations or if the mutations represented actual resistance. Kazanjian and Meshnick are currently conducting a larger study to further investigate these findings. Follow-up studies to determine if resistance is occurring, Kazanjian says, will examine what effect larger sulfa doses have on these mutations, what is causing the mutations and exactly how the mutations might interfere with sulfa.
Kazanjian and Meshnick say study results indicate that the mutations are a recent occurrence. The research team found no evidence of mutations in any of the samples prior to 1995.
Sulfa targets pneumocystis at the genetic level, interrupting the synthesis of folic acid, which is responsible for cell division.
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