Browsing by Author "Quinn, Thomas C."
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Item Association of Medical Male Circumcision and Antiretroviral Therapy Scale-up With Community HIV Incidence in Rakai,Uganda(American Medical Association, 2016) Kong, Xiangrong; Kigozi, Godfrey; Ssekasanvu, Joseph; Nalugoda, Fred; Nakigozi, Gertrude; Ndyanabo, Anthony; Lutalo, Tom; Reynolds, Steven J.; Ssekubugu, Robert; Kagaayi, Joseph; Bugos, Eva; Chang, Larry W.; Nanlesta, Pilgrim; Mary, Grabowski; Berman, Amanda; Quinn, Thomas C.; Serwadda, David; Wawer, Maria J.; Gray, Ronald H.Randomized trials have shown that medical male circumcision( MMC)reduces maleHIVacquisition by50% to 60%,1-3 and that early initiation of antiretroviral therapy (ART) reduces HIV transmission by more than90%in HIV-discordant couples.4Mathematical modeling suggests that these interventions could mitigate the HIV epidemic in sub- Saharan Africa,5-7 but there is limited empirical evidence for the population-level effects of these interventions on HIV incidence in real-world programs. MMC provides direct protection against male HIV acquisition by removing the foreskin, which is rich in HIV target cells.8-10 The potential effect ofMMCon population-level HIV incidence depends on this biological effect, the level ofMMC coverage, risk profiles ofmenacceptingMMC,and whether behavioral disinhibition occurs following circumcision.Item Determinants of HIV-1 Load in Subjects with Early and Later HIV Infections, in a General-Population Cohort of Rakai, Uganda(Journal of Infectious Diseases, 2004) Gray, Ronald H.; Li, X.; Wawer, Maria J.; Serwadda, David; Sewankambo, Nelson K.; Wabwire-Mangen, Fred; Lutalo, Tom; Kiwanuka, Noah; Kigozi, Godfrey; Nalugoda, Fred; Meehan, Mary P.; Quinn, Thomas C.Human immunodeficiency virus (HIV) type 1 RNA loads were determined for 256 subjects with early (incident) HIV infection and for 1293 subjects with later (prevalent) HIV infection, in a Ugandan cohort. Prevalent infections were classified as latent (0–1 symptoms) and midstage disease ( 2 symptoms), and deaths were ascribed to acquired immunodeficiency syndrome. Among subjects with incident HIV infection, HIV load did not differ by sex, but, among subjects with prevalent HIV infection, it was higher in males than in females. HIV load was highest in subjects (25–29 years old) with incident HIV infection but increased with age in subjects with prevalent HIV infection. Viremia was higher after serconversion than in latency and increased with more advanced disease. Viremia was increased with genital ulcer disease (GUD) in both subjects with incident infection and in those with prevalent infection, and with herpes simplex virus type 2 seropositivity in subjects with incident HIV infection. GUD was consistently associated with higher HIV loads in subjects with incident and those with prevalent HIV infection, suggesting that treatment of GUD might reduce HIV viremia.Item Development and Evaluation of a Clinical Algorithm to Monitor Patients on Antiretrovirals in Resource-Limited Settings using Adherence, Clinical and CD4 Cell Count Criteria(Journal of the International AIDS Society, 2009) Meya, David; Spacek, Lisa A.; Tibenderana, Hilda; John, Laurence; Namugga, Irene; Magero, Stephen; Dewar, Robin; Quinn, Thomas C.; Colebunders, Robert; Kambugu, Andrew; Reynol, Steven J.Routine viral load monitoring of patients on antiretroviral therapy (ART) is not affordable in most resource-limited settings.A cross-sectional study of 496 Ugandans established on ART was performed at the Infectious Diseases Institute, Kampala, Uganda. Adherence, clinical and laboratory parameters were assessed for their relationship with viral failure by multivariate logistic regression. A clinical algorithm using targeted viral load testing was constructed to identify patients for second-line ART. This algorithm was compared with the World Health Organization (WHO) guidelines, which use clinical and immunological criteria to identify failure in the absence of viral load testing.Forty-nine (10%) had a viral load of >400 copies/mL and 39 (8%) had a viral load of >1000 copies/mL. An algorithm combining adherence failure (interruption >2 days) and CD4 failure (30% fall from peak) had a sensitivity of 67% for a viral load of >1000 copies/mL, a specificity of 82%, and identified 22% of patients for viral load testing. Sensitivity of the WHO-based algorithm was 31%, specificity was 87%, and would result in 14% of those with viral suppression (<400 copies/mL) being switched inappropriately to second-line ART.Algorithms using adherence, clinical and CD4 criteria may better allocate viral load testing, reduce the number of patients continued on failing ART, and limit the development of resistance.Item The Effect of Antiretroviral Therapy Initiation on the Vaginal Microbiome in HIV-Infected Women(The Journal of infectious diseases, 2021) Liu, Cindy M.; Packman, Zoe R.; Abraham, Alison G.; Serwadda, David M.; Nalugoda, Fred; Aziz, Maliha; Prodger, Jessica L.; Kaul, Rupert; Kalibbala, Sarah; Gray, Ronald H.; Price, Lance B.; Quinn, Thomas C.; Tobian, Aaron A.R.; Reynolds, Steven J.The impact of antiretroviral therapy (ART) initiation on the vaginal microbiome is unknown. This is of particular importance among women living in sub-Saharan Africa. Understanding this relationship could help elucidate if and how the host immune system interacts with the vaginal microbiome. Methods. The vaginal microbiome of HIV-1/HSV-2-coinfected women (n = 92) in Uganda was evaluated from self-collected vaginal swabs 1 month pre-ART and at 4 and 6 months post–ART initiation. The vaginal microbiome was characterized by 16S rRNA genebased sequencing and quantitative polymerase chain reaction. Vaginal community state types (CSTs) were identified using proportional abundance data. Changes in microbiome composition were assessed with permutational analyses of variance (PerMANOVA).Item Effect of Peer Health Workers on AIDS Care in Rakai, Uganda: A Cluster-Randomized Trial(PloS one, 2010) Chang, Larry W.; Kagaayi, Joseph; Nakigozi, Gertrude; Ssempijja, Victor; Packer, Arnold H.; Serwadda, David; Quinn, Thomas C.; Gray, Ronald H.; Bollinger, Robert C.; Reynolds, Steven J.Human resource limitations are a challenge to the delivery of antiretroviral therapy (ART) in low-resource settings. We conducted a cluster randomized trial to assess the effect of community-based peer health workers (PHW) on AIDS care of adults in Rakai, Uganda. Methodology/Principal Findings: 15 AIDS clinics were randomized 2:1 to receive the PHW intervention (n = 10) or control (n = 5). PHWtasks included clinic and home-based provision of counseling, clinical, adherence to ART, and social support. Primary outcomes were adherence and cumulative risk of virologic failure (.400 copies/mL). Secondary outcomes were virologic failure at each 24 week time point up to 192 weeks of ART. Analysis was by intention to treat. FromMay 2006 to July 2008, 1336 patients were followed. 444 (33%) of these patients were already on ART at the start of the study. No significant differences were found in lack of adherence (,95% pill count adherence risk ratio [RR] 0.55, 95% confidence interval [CI] 0.23–1.35; ,100% adherence RR 1.10, 95% CI 0.94–1.30), cumulative risk of virologic failure (RR 0.81, 95% CI 0.61–1.08) or in shorter-term virologic outcomes (24 week virologic failure RR 0.93, 95% CI 0.65–1.32; 48 week, RR 0.83, 95% CI 0.47–1.48; 72 week, RR 0.81, 95% CI 0.44–1.49). However, virologic failure rates$96 weeks into ART were significantly decreased in the intervention armcompared to the control arm (96 week failure RR 0.50, 95% CI 0.31–0.81; 120 week, RR 0.59, 95% CI 0.22–1.60; 144 week, RR 0.39, 95% CI 0.16–0.95; 168 week, RR 0.30, 95% CI 0.097–0.92; 192 week, RR 0.067, 95% CI 0.0065–0.71). Conclusions/Significance: A PHW intervention was associated with decreased virologic failure rates occurring 96 weeks and longer into ART, but did not affect cumulative risk of virologic failure, adherence measures, or shorter-term virologic outcomes. PHWs may be an effective intervention to sustain long-term ART in low-resource settingsItem 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. KathrynThe 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.Item Failure of immunologic criteria to appropriately identify antiretroviral treatment failure in Uganda(AIDS, 2009) Reynolds, Steven J.; Nakigozi, Gertrude; Newell, Kevin; Ndyanabo, Anthony; Galiwongo, Ronald; Iga, Boaz; Quinn, Thomas C.; Gray, Ron; Wawer, Maria; Serwadda, DavidMost antiretroviral treatment program in resource-limited settings use immunologic or clinical monitoring to measure response to therapy and to decide when to change to a second line regimen. Our objective was to evaluate immunologic failure criteria against gold standard virologic monitoring. Design—Observation cohort Methods—Participants enrolled in an antiretroviral treatment program in rural Uganda who had at least 6 months of follow-up were included in this analysis. Immunologic monitoring was performed by CD4 cell counts every 3 months during the first year, and every 6 months thereafter. HIV-1 viral loads were performed every 6 months. Results—1133 participants enrolled in the Rakai Health Sciences Program antiretroviral treatment program between June 2004 and September 2007 were followed for up to 44.4 months (median follow-up 20.2 months; IQR 12.4–29.5 months). WHO immunologic failure criteria were reached by 125 (11.0%) participants. A virologic failure endpoint defined as HIV-1 viral load (VL) >400 copies/ml on two measurements was reached by 112 participants (9.9%). Only 26 participants (2.3%) experiencedItem Hepatitis B virus and sexual behavior in Rakai, Uganda(Journal of medical virology, 2011) Stabinski, Lara; Reynolds, Steven J.; Ocama, Ponsiano; Laeyendecker, Oliver; Serwadda, David; Gray, Ron H.; Wawer, Maria; Thomas, David L.; Quinn, Thomas C.; Kirk, Gregory D.HIV and hepatitis B virus (HBV) co-infection poses important public health considerations in resource-limited settings. Demographic data and sera from adult participants of the Rakai Health Sciences Program Cohort in Southwestern Uganda were examined to determine HBV seroprevalence patterns in this area of high HIV endemicity prior to the introduction of antiretroviral therapy. Commercially available EIAs were used to detect prevalent HBV infection (positive for HBV core antibody [anti-HBc] and/or positive HBV surface antigen [HBsAg]), and chronic infection (positive for HBsAg). Of 438 participants, 181 (41%) had prevalent HBV infection while 21 (5%) were infected chronically. Fourteen percent of participants were infected with HIV. Fifty three percent showed evidence of prevalent HBV infection compared to 40% among participants infected with HIV (p=0.067). Seven percent of participants infected with HIV were HBsAg positive compared to 4% among participants not infected with HIV (p=0.403). The prevalence of prevalent HBV infection was 55% in adults aged >50 years old, and 11% in persons under 20 years. In multivariable analysis, older age, HIV status and serologic syphilis were significantly associated with prevalent HBV infection. Transfusion status and receipt of injections were not significantly associated with HBV infection. Contrary to expectations that HBV exposure in Uganda occurred chiefly during childhood, prevalent HBV infection was found to increase with age and was associated sexually transmitted diseases (HIV and syphilis.) Therefore vaccination against HBV, particularly susceptible adults with HIV or at risk of HIV/STDs should be a priority.Item Hepatitis E Virus Seroprevalence and Correlates of Anti-HEV IgG Antibodies in the Rakai District, Uganda(The Journal of Infectious Diseases, 2018) Boon, Denali; Redd, Andrew D.; Laeyendecker, Oliver; Engle, Ronald E.; Nguyen, Hanh; Ocama, Ponsiano; Boaz, Iga; Ndyanabo, Anthony; Kiggundu, Valerian; Reynolds, Steven J.; Gray, Ronald H.; Wawer, Maria J.; Purcell, Robert H.; Kirk, Gregory D.; Quinn, Thomas C.; Stabinski, LaraA cross-sectional study was conducted of 500 human immunodeficiency virus (HIV)-infected adults frequency matched on age, sex, and community to 500 HIV-uninfected individuals in the Rakai District, Uganda to evaluate seroprevalence of anti-hepatitis E virus (HEV) IgG antibodies. HEV seroprevalence was 47%, and 1 HIV-infected individual was actively infected with a genotype 3 virus. Using modified Poisson regression, male sex (prevalence ratios [PR] = 1.247; 95% confidence interval [CI], 1.071–1.450) and chronic hepatitis B virus infection (PR = 1.377; 95% CI, 1.090–1.738) were associated with HEV seroprevalence. HIV infection status (PR = 0.973; 95% CI, 0.852–1.111) was not associated with HEV seroprevalence. These data suggest there is a large burden of prior exposure to HEV in rural Uganda.Item Heterogeneity of the HIV epidemic in agrarian, trading, and fi shing communities in Rakai, Uganda: an observational epidemiological study(The lancet HIV, 2016) Chang, Larry W.; Grabowsk, Mary K.; Ssekubugu, Robert; Nalugoda, Fred; Kigozi, Godfrey; Nantume, Betty; Lessler, Justin; Moore, Sean M.; Quinn, Thomas C.; Reynolds, Steven J.; Gray, Ronald H.; Serwadda, David; Wawer, Maria J.Understanding the extent to which HIV burden diff ers across communities and the drivers of lo cal disparities is crucial for an eff ective and targeted HIV response. We assessed community-level variations in HIV prevalence, risk factors, and treatment and prevention service uptake in Rakai, Uganda. Methods The Rakai Community Cohort Study (RCCS) is an open, population-based cohort of people aged 15–49 years in 40 communities. Participants are HIV tested and interviewed to obtain sociodemographic, behavioural, and health information. RCCS data from Aug 10, 2011, to May 30, 2013, were used to classify communities as agrarian (n=27), trading (n=9), or lakeside fi shing sites (n=4). We mapped HIV prevalence with Bayesian methods, and characterised variability across and within community classifi cations. We also assessed diff erences in HIV risk factors and uptake of antiretroviral therapy and male circumcision between community types. Findings 17 119 individuals were included, 9215 (54%) of whom were female. 9931 participants resided in agrarian, 3318 in trading, and 3870 in fi shing communities. Median HIV prevalence was higher in fi shing communities (42%, range 38–43) than in trading (17%, 11–21) and agrarian communities (14%, 9–26). Antiretroviral therapy use was signifi cantly lower in both men and women in fi shing communities than in trading (age-adjusted prevalence risk ratio in men 0·64, 95% CI 0·44–0·97; women 0·53, 0·42–0·66) and agrarian communities (men 0·55, 0·42–0·72; women 0·65, 0·54–0·79), as was circumcision coverage among men (vs trading 0·48, 0·42–0·55; vs agrarian 0·64, 0·56–0·72). Self-reported risk behaviours were signifi cantly higher in men than in women and in fi shing communities than in other community types. Interpretation Substantial heterogeneity in HIV prevalence, risk factors, and service uptake in Rakai, Uganda, emphasises the need for local surveillance and the design of targeted HIV responses. High HIV burden, risk behaviours, and low use of combination HIV prevention in fi shing communities make these populations a priority for intervention. Funding National Institute of Mental Health, the National Institute of Allergy and Infectious Diseases, the National Institute of Child Health and Development, and the National Institute for Allergy and Infectious Diseases Division of Intramural Research, National Institutes of Health; the Bill & Melinda Gates Foundation; and the Johns Hopkins University Center for AIDS Research.Item High Frequency of False-Positive Hepatitis C Virus Enzyme-Linked Immunosorbent Assay in Rakai, Uganda(Clinical infectious diseases, 2013) Mullis, Caroline E.; Laeyendecker, Oliver; Reynolds, Steven J.; Ocama, Ponsiano; Quinn, Jeffrey; Boaz, Iga; Gray, Ronald H.; Kirk, Gregory D.; Thomas, David L.; Quinn, Thomas C.; Stabinski, LaraThe prevalence of hepatitis C virus (HCV) infection in sub- Saharan Africa remains unclear. We tested 1000 individuals from Rakai, Uganda, with the Ortho version 3.0 HCV enzyme-linked immunosorbent assay. All serologically positive samples were tested for HCV RNA. Seventy-six of the 1000 (7.6%) participants were HCV antibody positive; none were confirmed by detection of HCV RNA.Item HIV serologically indeterminate individuals: Future HIV status and risk factors(PLoS ONE, 2020) Mwinnyaa, George; Grabowski, Mary K.; Gray, Ronald H.; Wawer, Maria; Chang, Larry W.; Ssekasanvu, Joseph; Kagaayi, Joseph; Kigozi, Godfrey; Kalibbala, Sarah; Galiwango, Ronald M.; Ndyanabo, Anthony; Serwadda, David; Quinn, Thomas C.; Reynolds, Steven J.; Laeyendecker, OliverIndeterminate HIV test results are common, but little is known about the evolution of indeterminate serology and itssociodemographic and behavioral correlates. We assessed future HIV serological outcomes for individuals with indeterminate results and associated factors in Rakai, Uganda. Methods 115,944 serological results, defined by two enzyme immunoassay (EIAs), among 39,440 individuals aged 15–49 years in the Rakai Community Cohort Study were assessed. Indeterminate results were defined as contradictory EIAs. Modified Poisson regression models with generalized estimating equations were used to assess prevalence ratios (PRs) of subsequent HIV serological outcomes and factors associated with HIV indeterminate results.Item HIV-1 superinfection can occur in the presence of broadly neutralizing antibodies(Vaccine, 2018) Serwanga, Jennifer; Ssemwanga, Deogratius; Muganga, Michael; Nakiboneka, Ritah; Nakubulwa, Susan; Kiwuwa-Muyingo, Sylvia; Morris, Lynn; Redd, Andrew D.; Quinn, Thomas C.; Kaleebu, PontianoSuperinfection of individuals already infected with HIV-1 suggests that pre-existing immune responses may not adequately protect against re-infection. We assessed high-risk female sex workers initially infected with HIV-1 clades A, D or A/D recombinants, to determine if HIV-1 broadly neutralizing antibodies were lacking prior to superinfection. Methods: Six superinfected female sex workers previously stratified by HIV-1 high-risk behavior, infecting virus clade and volunteer CD4 counts were evaluated at baseline (n = 5) and at 350 days post-superinfection (n = 6); one superinfected volunteer lacked pre-superinfection plasma. Retrospective plasmas were assessed for neutralization of a multi-clade panel of 12 HIV-1 viruses before superinfection, and then at quarterly intervals thereafter. Similarly stratified singly infected female sex workers were correspondingly assessed at baseline (n = 19) and 350 days after superinfection (n = 24). Neutralization of at least 50% of the 12 viruses (broad neutralization), and geometric means of the neutralization titers (IC50) were compared before and after superinfection; and were correlated with the volunteer HIV-1 superinfection status, CD4 counts, and pseudovirus clade. Results: Preexisting broad neutralization occurred in 80% (4/5) of the superinfected subjects with no further broadening by 350 days after superinfection. In one of the five subjects, HIV-1 superinfection occurred when broad neutralization was lacking; with subsequent broadening of neutralizing antibodies occuring within 9 months and plateauing by 30 months after detection of superinfection. Clade B and C pseudoviruses were more sensitive to neutralization (13; [87%]); and (12; [80%]) than the locally circulating clades A (10; [67%]) and D (6; [40%]), respectively (p = 0.025). Low antibody titers correlated with clade D viruses and with >500 CD4 T cell counts, but not with the superinfection status. Conclusion: These data demonstrate that HIV-1 superinfection can occur both in the presence, and in the absence of broadly neutralizing antibodies.Item Human Immunodeficiency Virus Acquisition Associated with Genital Ulcer Disease and Herpes Simplex Virus Type 2 Infection: A Nested Case-Control Study in Rakai, Uganda(The Journal of infectious diseases, 2003) Serwadda, David; Gray, Ronald H.; Sewankambo, Nelson K.; Wabwire-Mangen, Fred; Cheng, Michael Z.; Quinn, Thomas C.; Lutalo, Tom; Kiwanuka, Noah; Kigozi, Godfrey; Nalugoda, Fred; Meehan, Mary P.; Morrow, Rhoda A.; Wawer, Maria J.To assess the timing of symptomatic genital ulcer disease (GUD) relative to human immunodeficiency virus (HIV) seroconversion, we studied 248 case subjects who underwent HIV seroconversion and 496 HIV-negative control subjects, at 3 interview visits conducted at 10-month intervals: visit 1, before HIV acquisition; visit 2, after seroconversion; and visit 3, 10 months after detection of seroconversion. Odds ratios (ORs) and 95% confidence intervals (CIs), for HIV acquisition, were estimated by logistic regression. HIV load was measured by RNA–polymerase chain reaction, and herpes simplex virus type 2 (HSV-2) serologic testing used HerpeSelect EIA with Western blot confirmation. The OR of HSV-2 seropositivity associated with HIV acquisition was 1.7 (95% CI, 1.2–2.4). Prevalence of GUD was increased among case subjects, at visits 2 (OR, 3.2; 95% CI, 1.9– 5.3) and 3 (OR, 2.1; 95% CI, 1.1–3.9). HIV load was increased in HSV-2–seropositive case subjects, compared with that in HSV-2–seronegative subjects, at 5 (Pp.04) and 15 (Pp.02) months after seroconversion. HIV acquisition is associated with HSV-2 seropositivity, and GUD is increased after seroconversion. HIV load is increased in HSV-2–positive subjects who seroconverted, suggesting a role for treatment of HSV-2 infection in HSV-2–seropositive, dually infected individuals.Item 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.Item 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.Item Inferring HIV-1 transmission networks and sources of epidemic spread in Africa with deep-sequence phylogenetic analysis(Nature communications, 2019) Ratmann, Oliver tophe Fraser; Grabowski, M. Kate; Hall, Matthew; Golubchik, Tanya; Wymant, Chris; Abeler-Dörner, Lucie; Bonsall, David; Hoppe, Anne; Leigh Brown, Andrew; Oliveira, Tulio de; Gall, Astrid; Kellam, Paul; Pillay, Deenan; Kagaayi, Joseph; Kigozi, Godfrey; Quinn, Thomas C.; Wawer, Maria J.; Laeyendecker, Oliver; Serwadda, David; Gray, Ronald H.To prevent new infections with human immunodeficiency virus type 1 (HIV-1) in sub-Saharan Africa, UNAIDS recommends targeting interventions to populations that are at high risk of acquiring and passing on the virus. Yet it is often unclear who and where these ‘source’ populations are. Here we demonstrate how viral deep-sequencing can be used to reconstruct HIV-1 transmission networks and to infer the direction of transmission in these networks. We are able to deep-sequence virus from a large population-based sample of infected individuals in Rakai District, Uganda, reconstruct partial transmission networks, and infer the direction of transmission within them at an estimated error rate of 16.3% [8.8–28.3%]. With this error rate, deep-sequence phylogenetics cannot be used against individuals in legal contexts, but is sufficiently low for population-level inferences into the sources of epidemic spread. The technique presents new opportunities for characterizing source populations and for targeting of HIV-1 prevention interventions in Africa.Item Liver Stiffness Is Associated With Monocyte Activation in HIV-Infected Ugandans Without Viral Hepatitis(AIDS research and human retroviruses, 2013) Redd, Andrew D.; Wendel, Sarah K.; Grabowski, Mary K.; Ocama, Ponsiano; Kiggundu, Valerian; Bbosa, Francis; Boaz, Iga; Balagopal, Ashwin; Reynolds, Steven J.; Gray, Ronald H.; Serwadda, David; Kirk, Gregory D.; Quinn, Thomas C.; Stabinski, LaraA high prevalence of liver stiffness, as determined by elevated transient elastography liver stiffness measurement, was previously found in a cohort of HIV-infected Ugandans in the absence of chronic viral hepatitis. Given the role of immune activation and microbial translocation in models of liver disease, a shared immune mechanism was hypothesized in the same cohort without other overt causes of liver disease. This study examined whether HIV-related liver stiffness was associated with markers of immune activation or microbial translocation (MT). A retrospective case-control study of subjects with evidence of liver stiffness as defined by a transient elastography stiffness measurement ‡ 9.3 kPa (cases = 133) and normal controls (n = 133) from Rakai, Uganda was performed. Cases were matched to controls by age, gender, HIV, hepatitis B virus (HBV), and highly active antiretroviral therapy (HAART) status. Lipopolysaccharide (LPS), endotoxin IgM antibody, soluble CD14 (sCD14), C-reactive protein (CRP), and D-dimer levels were measured. Conditional logistic regression was used to estimate adjusted matched odds ratios (adjMOR) and 95% confidence intervals. Higher sCD14 levels were associated with a 19% increased odds of liver stiffness (adjMOR = 1.19, p = 0.002). In HIV-infected individuals, higher sCD14 levels were associated with a 54% increased odds of having liver stiffness (adjMOR = 1.54, p < 0.001); however, the opposite was observed in HIV-negative individuals (adjMOR = 0.57, p = 0.001). No other biomarker was significantly associated with liver stiffness, and only one subject was found to have detectable LPS. Liver stiffness in HIV-infected Ugandans is associated with increased sCD14 indicative of monocyte activation in the absence of viral hepatitis or microbial translocation, and suggests that HIV may be directly involved in liver disease.Item 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.Item Pregnancy Does Not Affect HIV Incidence Test Results Obtained Using the BED Capture Enzyme Immunoassay or an Antibody Avidity Assay(PLoS One, 2010) Laeyendecker, Oliver; Church, Jessica D.; Oliver, Amy E.; Mwatha, Anthony; Owen, S. Michele; Donnell, Deborah; Brookmeyer, Ron; Musoke, Philippa; Jackson, J. Brooks; Guay, Laura; Nakabiito, Clemesia; Quinn, Thomas C.; Eshleman, Susan H.Accurate incidence estimates are needed for surveillance of the HIV epidemic. HIV surveillance occurs at maternal-child health clinics, but it is not known if pregnancy affects HIV incidence testing.We used the BED capture immunoassay (BED) and an antibody avidity assay to test longitudinal samples from 51 HIV-infected Ugandan women infected with subtype A, C, D and intersubtype recombinant HIV who were enrolled in the HIVNET 012 trial (37 baseline samples collected near the time of delivery and 135 follow-up samples collected 3, 4 or 5 years later). Nineteen of 51 women were also pregnant at the time of one or more of the follow-up visits. The BED assay was performed according to the manufacturer's instructions. The avidity assay was performed using a Genetic Systems HIV-1/HIV-2 + O EIA using 0.1M diethylamine as the chaotropic agent.During the HIVNET 012 follow-up study, there was no difference in normalized optical density values (OD-n) obtained with the BED assay or in the avidity test results (%) when women were pregnant (n = 20 results) compared to those obtained when women were not pregnant (n = 115; for BED: p = 0.9, generalized estimating equations model; for avidity: p = 0.7, Wilcoxon rank sum). In addition, BED and avidity results were almost exactly the same in longitudinal samples from the 18 women who were pregnant at only one study visit during the follow-up study (p = 0.6, paired t-test).These results from 51 Ugandan women suggest that any changes in the antibody response to HIV infection that occur during pregnancy are not sufficient to alter results obtained with the BED and avidity assays. Confirmation with larger studies and with other HIV subtypes is needed.