Browsing by Author "Tobian, Aaron A. R."

Now showing 1 - 9 of 9
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    Effectiveness of Voluntary Medical Male Circumcision for Human Immunodeficiency Virus Prevention in Rakai, Uganda
    (Clinical Infectious Diseases, 2021) Loevinsohn, Gideon; Kigozi, Godfrey; Kagaayi, Joseph; Wawer, Maria J.; Nalugoda, Fred; Chang, Larry W.; Quinn, Thomas C.; Serwadda, David; Reynolds, Steven J.; Nelson, Lisa; Mills, Lisa; Alamo, Stella; Nakigozi, Gertrude; Kabuye, Geoffrey; Ssekubugu, Robert; Tobian, Aaron A. R.; Gray, Ronald H.; Grabowski, M. Kathryn
    The efficacy of voluntary male medical circumcision (VMMC) for human immunodeficiency virus (HIV) prevention in men was demonstrated in 3 randomized trials. This led to the adoption of VMMC as an integral component of the United States President’s Emergency Plan for AIDS Relief (PEPFAR) combination HIV prevention program in sub-Saharan Africa. However, evidence on the individual-level effectiveness of VMMC programs in real-world, programmatic settings is limited. A cohort of initially uncircumcised, non-Muslim, HIV-uninfected men in the Rakai Community Cohort Study in Uganda was followed between 2009 and 2016 during VMMC scale-up. Self-reported VMMC status was collected and HIV tests performed at surveys conducted every 18 months. Multivariable Poisson regression was used to estimate the incidence rate ratio (IRR) of HIV acquisition in newly circumcised vs uncircumcised men.
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    Immune milieu and microbiome of the distal urethra in Ugandan men: impact of penile circumcision and implications for HIV susceptibility
    (Microbiome, 2022) Galiwango, Ronald M.; Park, Daniel E.; Huibner, Sanja; Onos, Abigail; Aziz, Maliha; Roach, Kelsey; Anok, Aggrey; Nnamutete, James; Isabirye, Yahaya; Wasswa, John Bosco; Male, Deo; Kigozi, Godfrey; Tobian, Aaron A. R.; Prodger, Jessica L.; Liu, Cindy M.; Kaul, Rupert
    Coronal sulcus (CS) anaerobe abundance and IL-8 levels are linked to HIV acquisition, and are dramatically reduced after penile circumcision (PC). The distal urethra may be the site of some HIV acquisition before PC, and presumably most acquisition post PC. We describe the immune milieu and microbiome of the distal urethra in uncircumcised Ugandan men, and define the impact of PC. Participants consisted of HIV-negative, genital symptomfree adult Ugandan men undergoing PC (n = 51). Urethral and coronal sulcus swabs were collected at baseline and at 6- and 12-months post-PC. Soluble immune factors were quantified by multiplex ELISA, and bacterial abundance assessed by 16S rRNA qPCR and sequencing. Results: At baseline, the urethra was enriched compared to the CS for most cytokines (including IL-8 and MIP-1β) and soluble E-cadherin (sE-cadherin, an epithelial disruption marker), although CS levels of IL-1α and IL-1β were higher. Baseline total bacterial abundance was ≥ 20-fold higher in the CS than the urethra (median 27,100 vs. 1200 gene copies/swab, p = 0.001), and anaerobes comprised 58% of CS bacteria vs. 42% of urethral bacteria. PC did not alter urethral IL-8 (median 806 at baseline vs. 1130 pg/ml at 12 months; p = 0.062) and urethral sE-cadherin increased (113,223 vs. 158,385 pg/ml, p = 0.009), despite five- and sevenfold drops in total bacterial and anaerobe abundance after PC, respectively. However, PC dramatically reduced CS levels of sE-cadherin (15,843 vs. 837 pg/ml, p < 0.001) and most cytokines (IL-8; 34 vs. 3 pg/ml, p < 0.001), while reducing total bacterial and anaerobe abundance by 13-fold and 60-fold, respectively (both P ≤ 0.004). Conclusions: The urethra is immunologically rich with characteristics of an HIV-susceptible tissue site. However, PC had no impact on urethral immunology and may have reduced epithelial integrity, despite modest reductions in total bacteria and anaerobes, suggesting that HIV protection from PC is not mediated via immune or microbiome alterations in the urethra.
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    Immunological Signaling During Herpes Simplex Virus-2 and Cytomegalovirus Vaginal Shedding After Initiation of Antiretroviral Treatment
    (Oxford University Press, 2016) Nason, Martha C.; Patel, Eshan U.; Kirkpatrick, Allison R.; Prodger, Jessica L.; Shahabi, Kamnoosh; Tobian, Aaron A. R.; Gianella, Sara; Kalibbala, Sarah; Ssebbowa, Paschal; Kaul, Rupert; Gray, Ronald H.; Quinn, Thomas C.; Serwadda, David; Reynolds, Steven J.; Redd, Andrew D.
    Vaginal proinflammatory cytokine expression during herpes virus reactivation was examined in human immunodeficiency virus infected women before and after initiation of antiretroviral therapy (ART). Vaginal swabs were screened for levels of cytokines interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, tumor necrosis factor (TNF)-α, and interferon- γ. The relative risk (RR) of herpes simplex virus-2 or cytomegalovirus (CMV) shedding being associated with cytokine levels above the median were estimated. Herpes simplex virus-2 shedding was significantly associated with higher levels of IL-6 (RR = 1.4, P = .003) and TNF-α (RR = 1.3, P = .010), whereas CMV shedding was associated with higher IL-6 (RR = 1.3, P = .006) and IL-2 (RR = 1.4, P = .01). The association of viral shedding with higher IL-6 levels suggests that herpes virus reactivation may be playing a role in immune activation after ART initiation.
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    Impact of combination HIV interventions on HIV incidence in hyperendemic fishing communities in Uganda: a prospective cohort study
    (The lancet HIV,, 2019) Kagaayi, Joseph; Chang, Larry W.; Ssempijja, Victor; Grabowski, M. Kate; Ssekubugu, Robert; Nakigozi, Gertrude; Kigozi, Godfrey; Serwadda, David M.; Gray, Ronald H.; Nalugoda, Fred; Sewankambo, Nelson K; Nelson, Lisa; Mills, Lisa A.; Kabatesi, Donna; Alamo, Stella; Kennedy, Caitlin E.; Tobian, Aaron A. R.; Santelli, John S.; Mia Ekström, Anna; Nordenstedt, Helena; Quinn, Thomas C.; Wawer, Maria J.; Reynolds, Steven J.
    Targeting combination HIV interventions to locations and populations with high HIV burden is a global priority, but the impact of these strategies on HIV incidence is unclear. We assessed the impact of combination HIV interventions on HIV incidence in four HIV-hyperendemic communities in Uganda. Methods We did an open population-based cohort study of people aged 15–49 years residing in four fishing communities on Lake Victoria. The communities were surveyed five times to collect self-reported demographic, behavioural, and service-uptake data. Free HIV testing was provided at each interview, with referral to combination HIV intervention services as appropriate. From November, 2011, combination HIV intervention services were rapidly expanded in these geographical areas. We evaluated trends in HIV testing coverage among all participants, circumcision coverage among male participants, antiretroviral therapy (ART) coverage and HIV viral load among HIV-positive participants, and sexual behaviours and HIV incidence among HIV-negative participants. Findings From Nov 4, 2011, to Aug 16, 2017, data were collected from five surveys. Overall, 8942 participants contributed 20 721 person-visits; 4619 (52%) of 8942 participants were male. HIV prevalence was 41% (1598 of 3870) in the 2011–12 baseline survey and declined to 37% (1740 of 4738) at the final survey (p<0·0001). 3222 participants who were HIV-negative at baseline, and who had at least one repeat visit, contributed 9477 person-years of follow-up, and 230 incident HIV infections occurred. From the first survey in 2011–12 to the last survey in 2016–17, HIV testing coverage increased from 68% (2613 of 3870) to 96% (4526 of 4738; p<0·0001); male circumcision coverage increased from 35% (698 of 2011) to 65% (1630 of 2525; p<0·0001); ART coverage increased from 16% (254 of 1598) to 82% (1420 of 1740; p<0·0001); and population HIV viral load suppression in all HIV-positive participants increased from 34% (546 of 1596) to 80% (1383 of 1734; p<0·0001). Risky sexual behaviours did not decrease over this period. HIV incidence decreased from 3·43 per 100 person-years (95% CI 2·45–4·67) in 2011–12 to 1·59 per 100 person-years (95% CI 1·19–2·07) in 2016–17; adjusted incidence rate ratio (IRR) 0·52 (95% CI 0·34–0·79). Declines in HIV incidence were similar among men (adjusted IRR 0·53, 95% CI 0·30–0·93) and women (0·51, 0·27–0·96). The risk of incident HIV infection was lower in circumcised men than in uncircumcised men (0·46, 0·32–0·67). Interpretation Rapid expansion of combination HIV interventions in HIV-hyperendemic fishing communities is feasible and could have a substantial impact on HIV incidence. However, incidence remains higher than HIV epidemic control targets, and additional efforts will be needed to achieve this global health priority. Funding The National Institute of Mental Health, the National Institute of Allergy and Infectious Diseases, the National Institute of Child Health and Development, the National Cancer Institute, the National Institute for Allergy and Infectious Diseases Division of Intramural Research, Centers for Disease Control and Prevention Uganda, Karolinska Institutet, and the Johns Hopkins University Center for AIDS Research.
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    Microbial translocation, the innate cytokine response, and HIV-1 disease progression in Africa
    (National Academy of Sciences, 2009) Redd, Andrew D.; Dabitao, Djeneba; Bream, Jay H.; Charvat, Blake; Laeyendecker, Oliver; Kiwanuka, Noah; Lutalo, Tom; Kigozi, Godfrey; Tobian, Aaron A. R.; Gamiel, Jordyn; Neal, Jessica D.; Oliver, Amy E.; Margolick, Joseph B.; Reynolds, Steven J.; Sewankambo, Nelson K.; Wawer, Maria J.; Serwadda, David; Gray, Ronald H.; Quinn, Thomas C.
    Reports from the United States have demonstrated that elevated markers of microbial translocation from the gut may be found in chronic and advanced HIV-1 infection and are associated with an increase in immune activation. However, this phenomenon’s role in HIV-1 disease in Africa is unknown. This study examined the longitudinal relationship between microbial translocation and circulating inflammatory cytokine responses in a cohort of people with varying rates of HIV-1 disease progression in Rakai, Uganda. Multiple markers for microbial translocation (lipopolysaccharide, endotoxin antibody, and sCD14) did not change significantly during HIV-1 disease progression. Moreover, circulating immunoreactive cytokine levels either decreased or remained virtually unchanged throughout disease progression. These data suggest that microbial translocation and its subsequent inflammatory immune response do not have a causal relationship with HIV-1 disease progression in Africa.
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    Migration and risk of HIV acquisition in Rakai, Uganda: a population-based cohort study
    (The lancet HIV, 2018) Olawore, Oluwasolape; Tobian, Aaron A. R.; Kagaayi, Joseph; Bazaale, Jeremiah M.; Nantume, Betty; Kigozi, Grace; Nankinga, Justine; Nalugoda, Fred; Nakigozi, Gertrude; Kigozi, Godfrey; Gray, Ronald H.; Wawer, Maria J.; Ssekubugu, Robert; Santelli, John S.; Reynolds, Steven J.; Chang, Larry W.; Serwadda, David; Grabowski, Mary K.
    In sub-Saharan Africa, migrants typically have higher HIV prevalence than non-migrants; however, whether HIV acquisition typically precedes or follows migration is unknown. We aimed to investigate the risk of HIV after migration in Rakai District, Uganda. Methods In a prospective population-based cohort of HIV-negative participants aged 15–49 years in Rakai, Uganda, between April 6, 1999, and Jan 30, 2015, we assessed the association between migration and HIV acquisition. Individuals were classified as recent in-migrants (≤2 years in community), non-recent in-migrants (>2 years in community), or permanent residents with no migration history. The primary outcome was incident HIV infection. We used Poisson regression to estimate incidence rate ratios (IRRs) of HIV associated with residence status with adjustment for demographics, sexual behaviours, and time. Data were also stratified and analysed within three periods (1999–2004, 2005–11, and 2011–15) in relation to the introduction of combination HIV prevention (CHP; pre-CHP, early CHP, and late CHP). Findings Among 26 995 HIV-negative people who participated in the Rakai Community Cohort Study survey, 15 187 (56%) contributed one or more follow-up visits (89 292 person-years of follow-up) and were included in our final analysis. 4451 (29%) were ever in-migrants and 10 736 (71%) were permanent residents. 841 incident HIV events occurred, including 243 (29%) among in-migrants. HIV incidence per 100 person-years was significantly increased among recent in-migrants compared with permanent residents, for both women (1·92, 95% CI 1·52–2·43 vs 0·93, 0·84–1·04; IRR adjusted for demographics 1·75, 95% CI 1·33–2·33) and men (1·52, 0·99–2·33 vs 0·84, 0·74–0·94; 1·74, 1·12–2·71), but not among non-recent in-migrants (IRR adjusted for demographics 0·94, 95% CI 0·74–1·19 for women and 1·28, 0·94–1·74 for men). Between the pre-CHP and late-CHP periods, HIV incidence declined among permanent resident men (p<0·0001) and women (p=0·002) and non-recent in-migrant men (p=0·031), but was unchanged among non-recent in-migrant women (p=0·13) and recent in-migrants (men p=0·76; women p=0·84) Interpretation The first 2 years after migration are associated with increased risk of HIV acquisition. Prevention programmes focused on migrants are needed to reduce HIV incidence in sub-Saharan Africa. Funding National Institute of Mental Health, the National Institute of Allergy and Infectious Diseases, the National Institute of Child Health and Development, the National Institute for Allergy and Infectious Diseases Division of Intramural Research, National Institutes of Health; the Centers for Disease Control and Prevention; the Bill & Melinda Gates Foundation; and the Johns Hopkins University Center for AIDS Research.
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    Prevalence and Predictors of Persistent Human Immunodeficiency Virus Viremia and Viral Rebound After Universal Test and Treat: A Population-Based Study
    (The Journal of infectious diseases, 2021) Grabowski, M. Kate; Patel, Eshan U.; Nakigozi, Gertrude; Ssempijja, Victor; Ssekubugu, Robert; Ssekasanvu, Joseph; Ndyanabo, Anthony; Kigozi, Godfrey; Nalugoda, Fred; Gray, Ronald H.; Kalibbala, Sarah; Serwadda, David M.; Laeyendecker, Oliver; Wawer, Maria J.; Chang, Larry W.; Quinn, Thomas C.; Kagaayi, Joseph; Tobian, Aaron A. R.; Reynolds, Steven J.
    UNAIDS targets for human immunodeficiency virus (HIV) epidemic control by 2030 include that 86% of all HIV-positive persons be on antiretroviral therapy (ART) and achieve HIV viral load (VL) suppression [1]. The major policy initiative underpinning this target is universal test and treat (UTT), whereby all HIV-positive persons, irrespective of CD4 count or severity of illness, are immediately prescribed ART [2]. In sub-Saharan Africa, which accounts for more than half of all new HIV diagnoses globally, there has been considerable progress in increasing ART coverage [
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    SARS-CoV-2 seroprevalence among blood donors in Uganda: 2019–2022
    (John Wiley & Sons, Ltd, 2023-05-16) Bloch, Evan M; Kyeyune, Dorothy; White, Jodie L; Ddungu, Henry; Ashokkumar, Swetha; Habtehyimer, Feben; Baker, Owen; Kasirye, Ronnie; Patel, Eshan U.; Grabowski, M. Kate; Musisi, Ezra; Moses, Khan; Hume, Heather A; Lubega, Irene; Shrestha, Ruchee; Motevalli, Mahnaz; Fernandez, Reinaldo E; Reynolds, Steven J; Redd, Andrew D; Wambongo Musana, Hellen; Dhabangi, Aggrey; Ouma, Joseph; Eroju, Priscilla; Lange, Telsa; Fowler, Mary Glenn; Musoke, Philippa; Stramer, Susan L.; Whitby, Denise; Zimmerman, Peter A; McCullough, Jeffrey; Sachithanandham, Jaiprasath; Pekosz, Andrew; Goodrich, Raymond; Quinn, Thomas C; Ness, Paul M.; Laeyendecker, Oliver; Tobian, Aaron A. R.
    Abstract Abstract Background The true burden of COVID‐19 in low‐ and middle‐income countries remains poorly characterized, especially in Africa. Even prior to the availability of SARS‐CoV‐2 vaccines, countries in Africa had lower numbers of reported COVID‐19 related hospitalizations and deaths than other regions globally. Methods Ugandan blood donors were evaluated between October 2019 and April 2022 for IgG antibodies to SARS‐CoV‐2 nucleocapsid (N), spike (S), and five variants of the S protein using multiplexed electrochemiluminescence immunoassays (MesoScale Diagnostics, Rockville, MD). Seropositivity for N and S was assigned using manufacturer‐provided cutoffs and trends in seroprevalence were estimated by quarter. Statistically significant associations between N and S antibody seropositivity and donor characteristics in November–December 2021 were assessed by chi‐square tests. Results A total of 5393 blood unit samples from donors were evaluated. N and S seropositivity increased throughout the pandemic to 82.6% in January–April 2022. Among seropositive individuals, N and S antibody levels increased ≥9‐fold over the study period. In November–December 2021, seropositivity to N and S antibody was higher among repeat donors (61.3%) compared with new donors (55.1%; p = .043) and among donors from Kampala (capital city of Uganda) compared with rural regions ( p = .007). Seropositivity to S antibody was significantly lower among HIV‐seropositive individuals (58.8% vs. 84.9%; p = .009). Conclusions Despite previously reported low numbers of COVID‐19 cases and related deaths in Uganda, high SARS‐CoV‐2 seroprevalence and increasing antibody levels among blood donors indicated that the country experienced high levels of infection over the course of the pandemic.
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    Vaginal Cytomegalovirus Shedding Before and After Initiation of Antiretroviral Therapy in Rakai, Uganda
    (The Journal of infectious diseases, 2015) Gianella, Sara; Redd, Andrew D.; Grabowski, Mary K.; Tobian, Aaron A. R.; Serwadda, David; Newell, Kevin; Patel, Eshan U.; Kalibbala, Sarah; Ssebbowa, Paschal; Gray, Ronald H.; Quinn, Thomas C.; Reynolds, Steven J.
    Vaginal shedding of cytomegalovirus (CMV) DNA was determined longitudinally among 96 women coinfected with human immunodeficiency virus (HIV), herpes simplex virus 2, and CMV starting antiretroviral therapy (ART) during a placebo-controlled trial of HSV-2 suppression with acyclovir in Rakai, Uganda. Vaginal CMV was detected in 75 of 96 women (78.0%) and 379 of 1080 individual visits (35.1%). ART status, higher HIV RNAviral load before ART initiation, and younger age were significantly associated with increased frequency of CMV shedding (P < .01). Compared to pre- ART, CMV shedding peaked from month 2 to month 4 after ART initiation, suggesting possible immune reconstitution inflammatory syndrome. Further studies need to determine the clinical significance of asymptomatic CMV shedding.