Recent events have lowered the cost barrier to antiretroviral therapy in sub-Saharan Africa, where millions of people could benefit from such treatment. In addition to prolonging lives, antiretrovirals could provide a powerful tool for decreasing the spread of the virus. However, cofactors that enhance viral replication or an increase in sexual risk taking could mitigate the benefits of antiretrovirals on HIV-1 transmission. The objective of the proposed research is to define the complex interplay of these factors in order to understand how the introduction of antiretrovirals will influence sexual transmission of HIV-1. We propose a series of studies utilizing genital HIV-1 as a marker for infectiousness in a core transmitter group of women in Mombasa, Kenya. This research will address the following key hypotheses. First, that antiretroviral therapy will produce a rapid and sustained reduction in genital HIV-1 levels. Second, that there are modifiable cof actors that increase genital HIV-1 shedding even in the face of antiretrovirals. These cof actors represent attractive targets to augment the benefits of antiretroviral therapy for reducing HIV-1 infectivity. Finally, we hypothesize that the introduction of antiretrovirals may adversely influence sexual risk, which could offset the benefit of decreased HIV-1 shedding. This hypothesis will be evaluated by measuring changes in the incidence of communicable genital tract infections before and after the introduction of antiretrovirals. One hundred HIV-1 seropositive women will be recruited from an existing cohort. Women initiating long-term antiretroviral therapy will have serial examinations to determine the effects of antiretrovirals, CD4 count, plasma viral load, adherence to therapy, genital tract infections, and hormonal contraceptives on HIV-1 shedding. These studies will help to guide the development of interventions to address infectious, hormonal, immunologic, virologic, and pharmacologic cof actors for HIV-1 infectivity among women on antiretrovirals, and will identify changes in sexual risk that may occur as access to antiretroviral therapy increases. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI058698-02
Application #
7078538
Study Section
AIDS Clinical Studies and Epidemiology Study Section (ACE)
Program Officer
Huebner, Robin E
Project Start
2005-06-15
Project End
2010-02-28
Budget Start
2006-03-01
Budget End
2007-02-28
Support Year
2
Fiscal Year
2006
Total Cost
$548,094
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Graham, Susan M; Chohan, Vrasha; Ronen, Keshet et al. (2016) Genital Shedding of Resistant Human Immunodeficiency Virus-1 Among Women Diagnosed With Treatment Failure by Clinical and Immunologic Monitoring. Open Forum Infect Dis 3:ofw019
Day, Summer; Graham, Susan M; Masese, Linnet N et al. (2014) A prospective cohort study of the effect of depot medroxyprogesterone acetate on detection of plasma and cervical HIV-1 in women initiating and continuing antiretroviral therapy. J Acquir Immune Defic Syndr 66:452-6
Graham, Susan M; Rajwans, Nimerta; Richardson, Barbra A et al. (2014) Elevation of soluble intercellular adhesion molecule-1 levels, but not angiopoietin 2, in the plasma of human immunodeficiency virus-infected African women with clinical Kaposi sarcoma. Am J Trop Med Hyg 91:705-8
Graham, Susan M; Mwilu, Regina; Liles, W Conrad (2013) Clinical utility of biomarkers of endothelial activation and coagulation for prognosis in HIV infection: a systematic review. Virulence 4:564-71
Graham, Susan M; Rajwans, Nimerta; Tapia, Kenneth A et al. (2013) A prospective study of endothelial activation biomarkers, including plasma angiopoietin-1 and angiopoietin-2, in Kenyan women initiating antiretroviral therapy. BMC Infect Dis 13:263
Graham, Susan M; Rajwans, Nimerta; Jaoko, Walter et al. (2013) Endothelial activation biomarkers increase after HIV-1 acquisition: plasma vascular cell adhesion molecule-1 predicts disease progression. AIDS 27:1803-13
Day, Summer L; Odem-Davis, Katherine; Mandaliya, Kishorchandra N et al. (2013) Prevalence, clinical and virologic outcomes of hepatitis B virus co-infection in HIV-1 positive Kenyan women on antiretroviral therapy. PLoS One 8:e59346
Lagace-Wiens, Philippe R S; Duncan, Sarah; Kimani, Joshua et al. (2012) Emergence of fluoroquinolone resistance in Neisseria gonorrhoeae isolates from four clinics in three regions of Kenya. Sex Transm Dis 39:332-4
Graham, Susan M; Jalalian-Lechak, Zahra; Shafi, Juma et al. (2012) Antiretroviral treatment interruptions predict female genital shedding of genotypically resistant HIV-1 RNA. J Acquir Immune Defic Syndr 60:511-8
Graham, Susan M; Masese, Linnet; Gitau, Ruth et al. (2011) Genital ulceration does not increase HIV-1 shedding in cervical or vaginal secretions of women taking antiretroviral therapy. Sex Transm Infect 87:114-7

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