Model explains why HIV prevention dosing differs by sex

3 years ago by in Applied Mathematics, Applied Mathematics

hiv-virusThe human immunodeficiency virus (HIV) is a lentivirus that causes the acquired immunodeficiency syndrome(AIDS), a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive. Without treatment, average survival time after infection with HIV is estimated to be 9 to 11 years, depending on the HIV subtype. Infection with HIV occurs by the transfer of blood, semen, vaginal fluid, pre-ejaculate, or breast milk. Within these bodily fluids, HIV is present as both free virus particles and virus within infected immune cells.

HIV infects vital cells in the human immune system such as helper T cells, macrophages, and dendritic cells. HIV infection leads to low levels of CD4+ T cells through a number of mechanisms, including apoptosis of uninfected bystander cells, direct viral killing of infected cells, and killing of infected CD4+ T cells by CD8 cytotoxic lymphocytes that recognize infected cells. When CD4+ T cell numbers decline below a critical level, cell-mediated immunity is lost, and the body becomes progressively more susceptible to opportunistic infections.

Mathematical model developed by NIH grantees predicts that women must take the antiretroviral medication Truvada daily to prevent HIV infection via vaginal sex, whereas just two doses per week can protect men from HIV infection via anal sex. This finding helps explain why two large clinical trials testing HIV pre-exposure prophylaxis, or PrEP, in women failed to show efficacy. Participants in the VOICE and FEM-PrEP trials of Truvada and tenofovir (another antiretroviral) for HIV prevention were counseled to take one of the medications daily. However, because they actually took the antiretroviral only about 29 percent of the time in VOICE and about 36 percent of the time in FEM-PrEP, the PrEP strategy did not work.

hıv3Angela D. M. Kashuba, Pharm.D., of the University of North Carolina, and colleagues determined what intracellular ratios of active tenofovir and emtricitabine, the drugs that compose Truvada, to the DNA molecules with which they compete are necessary to prevent HIV replication. Next, using data from an early clinical trial in women, the researchers created a mathematical model that predicts these ratios in vaginal, cervical and rectal tissues given standard doses of medication taken 2 to 7 days per week. Then, the scientists calculated the percentage of a study population that would achieve the effective drug-to-DNA-molecule ratio by taking tenofovir or Truvada at each dosing frequency.

The model forecasts that two standard doses per week of Truvada or a daily standard dose of tenofovir would achieve the target ratio in rectal tissue across a study population. A daily standard dose of Truvada would achieve the target ratio in vaginal tissue in more than 75 percent of a study population, according to the model, and in cervical tissue in half of the population. A daily standard dose of tenofovir would achieve the target ratio in cervical and vaginal tissues in less than half of a study population, the model predicts.

Both men and women who are prescribed Truvada for PrEP should take the pill daily as directed, according to Centers for Disease Control and Prevention guidelines.

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