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 #
3R01AI058698-05S1
Application #
8072386
Study Section
AIDS Clinical Studies and Epidemiology Study Section (ACE)
Program Officer
Huebner, Robin E
Project Start
2010-06-01
Project End
2011-02-28
Budget Start
2010-06-01
Budget End
2011-02-28
Support Year
5
Fiscal Year
2010
Total Cost
$120,591
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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