Variations in Specific Gene May Help Researchers Determine How Well HIV Patients Will Respond to Treatment

HIV patients with a specific variation in a particular gene, MDR1, have better immune responses to antiretroviral therapy than patients with one of two other variations, according to a study published in the Jan. 5 issue of the Lancet, Reuters Health reports. In addition, the variants are linked to differing blood concentrations of the antiretrovirals nelfinavir and efavirenz in patients (Reuters Health, 1/4). According to lead author Amalio Telenti of the University Hospital of Lausanne, Switzerland, these findings may one day allow researchers to render AIDS drugs more effective by tailoring them to the specific genotypes of the MDR1 gene. MDR1 produces a protein known as P-glycoprotein, which can act as a "barrier" that inhibits the absorption of drugs by the intestine, the brain, the nervous system and the uterus. Researchers divided 123 mostly white HIV patients into three groups based on their MDR1 genotype -- TT, CT or CC -- and initiated treatment with either efavirenz or nelfinavir (Agence France-Presse, 1/4). The researchers then measured and compared the amounts of the drugs in the patients' blood and found that individuals with the TT genotype absorbed the drugs faster and had better immune system recovery. Median drug concentrations for patients with TT, CT and CC genotypes were at the 30th, 50th and 75th percentiles respectively. Individuals with the TT genotype also experienced a greater rise in CD4+ T cells six months after initiating treatment: 257 cells/mm3 versus 165 cells/mm3 for people with a CT genotype and 121 cells/mm3 for participants with a CC genotype (Fellay et al., Lancet, 1/5).

Repercussions for Therapy
Talenti said that if researchers could learn how to control P-glycoprotein, they could "boost the rebound" of the body's immune system after HIV infection (Agence France-Presse, 1/4). Researchers believe that P-glycoprotein protects the immune system by preventing toxic substances, including antiretroviral drugs, from entering cells. People with the TT gene variant had a lower expression of P-glycoprotein than those with other variants, which may allow for the increased antiretroviral penetration and better immune recovery (Reuters Health, 1/4). Half of all whites have the CT genotype, while a quarter each have the TT and CC variations. However, about 67% to 83% of black Africans have the CC genotype, with few incidences of the TT variation. "This variation could lead to different patterns of HIV-1 disease evolution and responses to antiretroviral treatment in human populations," the study states. Because the different genotypes appear to affect P-glycoprotein function, drugs would most likely have to be tailored to each genotype to be most effective (Agence France-Presse, 1/4).