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Women's Health Science Advances—Fiscal Year 2015 (first half)

NIAID conducts and supports research to prevent, diagnose, and treat infectious and immunological diseases that affect the health of women and girls.

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HIV/AIDS
Immunology
Infectious Diseases (Other Than HIV/AIDS)

HIV/AIDS

Sex Differences in Response to the First-Line HIV Drug Atazanavir

The first-line HIV therapy atazanavir is commonly used as one of the medications in combination antiretroviral drug regimens because it is a potent, once-daily drug that patients tolerate well. Prior studies have shown sex-related variability in blood concentrations of atazanavir. However, how the body processes the drug over time and the resulting clinical implications had not been determined. NIAID-funded researchers studied atazanavir concentration in the blood of 131 women and 655 men infected with HIV. They found that women cleared atazanavir from their bloodstream 14 percent more slowly than men did, after accounting for differences in body weight. In addition, women with fast clearance of atazanavir and men with slow clearance had worse clinical outcomes, including an inability to tolerate atazanavir and failure to suppress HIV. These outcomes occurred despite patients’ adherence to atazanavir treatment. This study showed that a patient’s sex is an important factor in atazanavir clearance and treatment outcomes.

Reference: Venuto CS, Mollan K, Ma Q et al. Sex differences in atazanavir pharmacokinetics and associations with time to clinical events: AIDS Clinical Trials Group Study A5202. J Antimicrob Chemother. 2014 Dec;69(12):3300-10.

Pre-Exposure Prophylaxis Fails to Prevent HIV Transmission in Study of African Women

The VOICE study, a randomized clinical trial of more than 5,000 reproductive-age women conducted at multiple sites in South Africa, Uganda, and Zimbabwe, was designed to evaluate the safety and effectiveness of three pre-exposure prophylaxis (PrEP) approaches in preventing male-to-female HIV transmission. The approaches tested were tenofovir 1% vaginal gel and oral tablets containing either the antiretroviral drug tenofovir or a combination of tenofovir and another antiretroviral drug, emtricitabine. Final study results showed that, compared with placebo, none of the drug regimens reduced the rate of HIV infection. Most study participants did not use the study products daily and this could explain the results. However, the researchers were not able to rule out differences in exposure to HIV between women who used the study products and those who did not. While the study was underway, the FDA approved PrEP for HIV prevention in high-risk individuals. Nonetheless, these results reaffirm the need for effective and acceptable prevention methods for women who are at high risk for sexual acquisition of HIV and suggest that measures that are more accurate are critical for estimating product use during HIV prevention trials.

Reference: Marrazzo JM, Ramjee G, Richardson BA, et al. Tenofovir-based preexposure prophylaxis for HIV infection among African women. N Engl J Med. 2015 Feb 5;372(6):509-18.

HIV Infection Has a Small but Negative Effect on Cognitive Function in Women

Women represent the majority of HIV-infected individuals worldwide. Although several studies have reported cognitive impairment in women infected with HIV, the sample sizes of previous studies were too small to understand the factors that may affect cognitive function in these women. As part of the Women’s Interagency HIV Study (WIHS), the largest and longest-running study to investigate the impact of HIV on U.S. women, NIAID-funded researchers studied cognitive function in American, urban-dwelling women. To distinguish the effects of HIV versus other factors that could affect cognitive function, the researchers studied socially and demographically similar women who were either HIV-infected (1,019 participants) or uninfected (502 participants). The study participants completed eight different cognitive tests during four semi-annual WIHS visits. The results showed that HIV infection had a very small but significant effect on cognition: HIV-infected women performed worse than uninfected women on tests of verbal learning, delayed recall and recognition, attention, and psychomotor speed (coordinating thinking and physical movement). The factor most strongly associated with cognitive deficit in HIV-infected women was low reading level. HIV-infected women with low education or compromised immune functions were most vulnerable to cognitive deficits. Results of this study will help define how best to treat HIV-infected women in the United States and globally.

Reference: Maki PM, Rubin LH, Valcour V et al. Cognitive function in women with HIV: findings from the Women's Interagency HIV Study. Neurology. 2015 Jan 20;84(3):231-40.

Immunology

Estrogen Increases the Severity of Severe Allergic Reactions

Anaphylaxis is a severe, potentially life-threatening allergic reaction that may occur in response to food, drugs, or unknown foreign substances. Doctors have reported that anaphylaxis is more common in women than in men, but the reason for this sex-dependent disparity is unclear. In a mouse study designed to explore sex differences in the severity of anaphylaxis, NIAID intramural researchers determined that the increased severity of anaphylactic responses in females may be due to higher levels of estrogen. The researchers found that the higher levels of estradiol (one of the three major estrogens) in female mice increased levels of an enzyme that makes a chemical called nitric oxide (NO) in tissues. Production of NO promotes inflammation by increasing the “leakiness” of blood vessels, enabling inflammation-causing cells and molecules to move more readily through the vessel wall and into adjacent tissues. The researchers showed that blocking NO production completely eliminated the increased severity of the anaphylactic response in female mice. These findings provide novel insight into the sex-dependent disparity in anaphylaxis and highlight the relevance of considering sex as a variable in scientific research. In addition, the findings suggest that drugs that inhibit NO production may be effective for treating certain cases of anaphylaxis.

Reference: Hox V, Desai A, Bandara G et al. Estrogen increases the severity of anaphylaxis in female mice through enhanced endothelial nitric oxide synthase expression and nitric oxide production. J Allergy Clin Immunol. 2015 Mar;135(3)729-36.

Immune Cells Amplify Antiviral State in Tissues

First-line responses to viruses are initiated by the innate, or inborn, immune system, which then activates the white blood cells of the adaptive immune system. These cells include specific CD8+ T cells that elicit powerful responses targeted to virus-infected cells. After the infection is cleared, most of the virus-specific CD8+ T cells die but some persist in the body as “memory” cells, ready to begin a rapid response to reinfection with a previously encountered pathogen. There are several types of CD8+ memory T cells.  Resident memory T cells (Trm cells), rather than circulating in the blood, mostly remain in the tissues where the virus was first encountered, such as the skin or mucous membranes, and enhance protection against reinfection at those sites. However, exactly how Trm cells function in the tissues has remained unclear. NIAID-funded researchers found that activated, virus-specific CD8+ Trm cells in the reproductive tract of female mice can initiate and amplify a nonspecific inflammatory response that provides mucosal protection against unrelated viruses. These findings may help scientists understand previously observed associations between viral infections and exacerbated autoimmune or inflammatory diseases. In addition, the results suggest that scientists could use a vaccine to activate pre-existing Trm cells specific for one pathogen as a strategy to improve local immunity against unrelated pathogens.

Reference: Schenkel JM, Fraser KA, Beura LK et al. Resident memory CD8 T cells trigger protective innate and adaptive immune responses. Science. 2014 Oct 3;346(6205): 98-101.

Infectious Diseases (Other than HIV/AIDS)

Including Pregnant Women in Clinical Trials of Antimicrobials and Vaccines

Clinical studies are critical to develop the knowledge base to ensure the safe and effective use of vaccines and antimicrobials in pregnant women and to enable the prevention and treatment of a range of infectious diseases. Until recently, multiple factors have hindered such studies. A series of NIAID conferences on enrolling pregnant women in clinical trials of antimicrobials and vaccines brought together experts from academia, industry, and governmental and non-governmental agencies to develop a consensus on issues such as inclusion and exclusion criteria, adverse events grading, and markers of health and disease for research studies in pregnant women. This resulted in the publication of an editorial and two guidance papers in September 2013 (1-3). Five additional articles were published in 2015 in a special supplement of Clinical Infectious Diseases funded by the Bill & Melinda Gates Foundation (4). Providing these guidelines to the research community may make it easier for investigators looking to conduct clinical research in pregnant women. Additionally, these guidelines may lead to the standardization of data collection approaches and enhance the value of the data produced by future studies.

References:

  1. Beigi R, Jevaji I, and Goldkind S. Research on vaccines and antimicrobials during pregnancy: challenges and opportunities. Vaccine. 2013 Sep 13;31(40):4261-3.
  2. Sheffield J, Munoz F, Beigi R, et al. Research on vaccines during pregnancy: reference values for vital signs and laboratory assessmentsVaccine 2013 Sep 13;31(40):4264-73.
  3. Munoz F, Sheffield J, Beigi R, et al.  Research on vaccines during pregnancy: protocol design and assessments of safety. Vaccine 2013 Sep 13;31(40):4274-9.
  4. Nesin M, Frew PM, and Read J (eds). Including pregnant women in clinical trials of antimicrobials and vaccines. Clin Infect Dis. 2014 Dec 15;59 (Suppl 7):S395-444.
 

See earlier research overviews.

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Last Updated July 08, 2015