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author:("kanuka, Noah")
1.  Immune activation alters cellular and humoral responses to yellow fever 17D vaccine 
The Journal of Clinical Investigation  2014;124(7):3147-3158.
Background. Defining the parameters that modulate vaccine responses in African populations will be imperative to design effective vaccines for protection against HIV, malaria, tuberculosis, and dengue virus infections. This study aimed to evaluate the contribution of the patient-specific immune microenvironment to the response to the licensed yellow fever vaccine 17D (YF-17D) in an African cohort.
Methods. We compared responses to YF-17D in 50 volunteers in Entebbe, Uganda, and 50 volunteers in Lausanne, Switzerland. We measured the CD8+ T cell and B cell responses induced by YF-17D and correlated them with immune parameters analyzed by flow cytometry prior to vaccination.
Results. We showed that YF-17D–induced CD8+ T cell and B cell responses were substantially lower in immunized individuals from Entebbe compared with immunized individuals from Lausanne. The impaired vaccine response in the Entebbe cohort associated with reduced YF-17D replication. Prior to vaccination, we observed higher frequencies of exhausted and activated NK cells, differentiated T and B cell subsets and proinflammatory monocytes, suggesting an activated immune microenvironment in the Entebbe volunteers. Interestingly, activation of CD8+ T cells and B cells as well as proinflammatory monocytes at baseline negatively correlated with YF-17D–neutralizing antibody titers after vaccination. Additionally, memory T and B cell responses in preimmunized volunteers exhibited reduced persistence in the Entebbe cohort but were boosted by a second vaccination.
Conclusion. Together, these results demonstrate that an activated immune microenvironment prior to vaccination impedes efficacy of the YF-17D vaccine in an African cohort and suggest that vaccine regimens may need to be boosted in African populations to achieve efficient immunity.
Trial registration. Registration is not required for observational studies.
Funding. This study was funded by Canada’s Global Health Research Initiative, Defense Threat Reduction Agency, National Institute of Allergy and Infectious Diseases, Bill & Melinda Gates Foundation, and United States Agency for International Development.
doi:10.1172/JCI75429
PMCID: PMC4071376  PMID: 24911151
2.  High Incidence of HIV-1 Infection in a General Population of Fishing Communities around Lake Victoria, Uganda 
PLoS ONE  2014;9(5):e94932.
Background
High HIV-1 incidence rates were reported among persons in fisherfolk communities (FFC) in Uganda who were selected for high risk behaviour. We assessed the incidence of HIV-1 and associated risk factors in a general population FFC to determine population-wide HIV rates.
Methods
A community-based cohort study was conducted among a random sample of 2191 participants aged 18–49 years. At baseline and 12 months post-baseline, data were collected on socio-demographic characteristics and risky behaviors (including number of partners, new partners, condom use, use of alcohol and illicit drug use). Venous blood was collected for HIV serological testing. HIV incidence was calculated per 100 person years at-risk (pyar) and adjusted incidence rate ratios (Adj.IRR) were estimated by multivariable Poisson regression.
Results
Overall follow up at 12 months was 76.9% (1685/2191) and was significantly higher among HIV uninfected persons and those with at least 1 year duration of stay in community. Overall HIV-1 incidence was 3.39/100 pyar (95% CI: 2.55–4.49). Among the 25–29 years who drank alcohol, HIV incidence was 7.67/100pyar (95% CI;4.62–12.7) while it was 5.67/100pyar (95% CI;3.14–10.2) for 18–24 year olds who drank alcohol. The risk of HIV infection was higher among 25–29 years (adj.IRR = 3.36; 95% CI: 1.48–7.65) and 18–24 years (adj.IRR = 2.65; 95% CI: 1.05–6.70) relative to 30+ years. Compared to non-drinkers, HIV incidence increased by frequency of alcohol drinking - occasional drinkers (adj.IRR = 3.18; 95% CI: 1.18–8.57) and regular drinkers (adj.IRR = 4.93; 95% CI: 1.91–12.8).
Conclusion
HIV-1 incidence in general fisherfolk population along L.Victoria, Uganda, is high and is mainly associated with young age and alcohol drinking. HIV prevention and control strategies are urgently needed in this population.
doi:10.1371/journal.pone.0094932
PMCID: PMC4035272  PMID: 24866840
3.  Impact of Intermittent Preventive Treatment With Dihydroartemisinin-Piperaquine on Malaria in Ugandan Schoolchildren: A Randomized, Placebo-Controlled Trial 
Dihydroartemisinin-piperaquine administered at monthly intervals, but not that dosed once a school term, is a remarkably effective measure for the prevention of incidence of malaria, prevalence of parasitemia, and prevalence of anemia in schoolchildren living in a high-transmission setting.
Background. Intermittent preventive treatment (IPT) in schoolchildren offers a promising option for malaria control. However, the optimal drug and dosing regimens for IPT remain to be determined.
Methods. We conducted a randomized, double-blind, placebo-controlled trial in 740 schoolchildren aged 6–14 years living in a setting of high malaria transmission in Uganda. Enrolled children were randomized to dihydroartemisinin-piperaquine (DP) given once a month (IPTm), DP given once a school term (4 treatments over 12 months, IPTst), or placebo and followed for 12 months. The primary outcome was the incidence of malaria over 12 months. Secondary outcomes included parasite prevalence and anemia over 12 months. Analyses were conducted on an intention-to-treat basis.
Results. In the placebo arm, the incidence of malaria was 0.34 episodes per person-year and the prevalence of parasitemia and anemia was 38% and 20%, respectively. IPTm reduced the incidence of malaria by 96% (95% confidence interval [CI], 88%–99%, P < .0001), the prevalence of asymptomatic parasitemia by 94% (95% CI, 92%–96%, P < .0001), and the prevalence of anemia by 40% (95% CI, 19%–56%, P < .0001). IPTst had no significant effect on the incidence of symptomatic malaria or the prevalence of anemia, but reduced the prevalence of asymptomatic parasitemia by 54% (95% CI, 47%–60%, P < .0001).
Conclusions. Monthly IPT with DP offered remarkable protection against clinical malaria, parasitemia, and anemia in schoolchildren living in a high-malaria-transmission setting.
Clinical Trials Registration.  NCT01231880.
doi:10.1093/cid/ciu150
PMCID: PMC4001293  PMID: 24621953
malaria; intermittent preventive treatment; schoolchildren
4.  Lost in Transition: HIV Prevalence and Correlates of Infection among Young People Living in Post-Emergency Phase Transit Camps in Gulu District, Northern Uganda 
PLoS ONE  2014;9(2):e89786.
Objective
Little is known about HIV infection and the related vulnerabilities of young people living in resource-scarce, post-emergency transit camps that are now home to thousands of Internally Displaced Persons (IDPs) following two decades of war in northern Uganda. The objective of this analysis was to assess the prevalence and correlates of HIV infection among young people living in post-conflict transition in Gulu District, northern Uganda.
Methods
In 2010, a cross-sectional demographic and behavioural survey was conducted in two of Gulu District’s sub-counties with 384 purposively selected transit camp residents aged 15 to 29 years. Biological specimens were collected for rapid HIV testing in the field and confirmatory laboratory testing. Multivariable logistic regression identified independent determinants of HIV infection.
Results
HIV prevalence was alarmingly high at 12.8% (95% CI: 9.6%, 16.5%). The strongest determinant of HIV infection among young people was a non-consensual sexual debut (adjusted odds ratio [AOR], 9.88; 95% CI: 1.70–18.06). Residing in Awach sub-county (AOR, 2.93; 95% CI: 1.28–6.68), experiencing STI symptoms in the previous 12 months (AOR, 2.36; 95% CI: 1.43–6.17), and practicing dry sex (AOR, 2.31; 95% CI: 1.04–5.13) were other key determinants of HIV infection.
Conclusions
Study findings contribute to filling an important gap in epidemiological evidence and are useful for planning public health interventions in northern Uganda that effectively target young people in post-conflict transition and support them in the resettlement process. Findings serve to recommend reaching beyond traditional prevention programming in a way more effectively beneficial to young people in post-conflict settings by developing population-specific responses sensitive to local contexts and sufficient to address the underlying causes of the complex risk factors influencing the spread of HIV.
doi:10.1371/journal.pone.0089786
PMCID: PMC3938506  PMID: 24587034
5.  Rheumatic heart disease in Uganda: the association between MHC class II HLA DR alleles and disease: a case control study 
Background
Rheumatic heart disease (RHD), the only long term consequence of acute rheumatic fever, remains a leading cause of morbidity and mortality among young adults in Uganda. An inherited susceptibility to acute rheumatic fever centers around the major histocompatibility class II human leucocyte antigens. However, there is paucity of data from sub-Saharan Africa. This study compares the frequency of HLA class II DR alleles between RHD cases and normal controls in Uganda.
Methods
One hundred ninety-nine participants including 96 established RHD cases aged 5–60 years and 103 age and sex matched normal controls were recruited for participation. DNA was manually extracted from buffy coat samples and HLA analysis was performed. HLA-DR allelic frequency comparison between cases and controls were estimated using conditional logistic regression with 95% confidence intervals. P -values were corrected for multiple hypothesis testing.
Results
199 participants (103 female, 51.8%) completed the study. The mean (SD) age in years for cases and controls were 29.6 (10.2) and 29(18), respectively. After conditional logistic regression and multiple hypothesis testing, HLA-DR1was associated with a decreased risk of RHD (OR = 0.42, CI 0.21-085, P = 0.01, Corrected P value (PC) = 0.09,) while HLA-DR11 was associated with increased risk of RHD (OR = 3.31, CI 1.57-6.97, P = <0.001, Pc < 0.001). No other significant associations were found.
Conclusion
In this first study of HLA genetic susceptibility to RHD in Uganda, HLA- DR1 was more common in normal controls while HLA- DR11 was more common among RHD cases suggesting a disease susceptibility association. In future studies, high resolution HLA analysis and genome wide studies should be carried out to confirm this pattern.
doi:10.1186/1471-2261-14-28
PMCID: PMC3943278  PMID: 24581333
Rheumatic heart disease; HLA-DR1; HLA-DRB11; MHC- major histocompatibility complex
6.  Characterization of Neutrophil Subsets in Healthy Human Pregnancies 
PLoS ONE  2014;9(2):e85696.
We have previously shown that in successful pregnancies increased arginase activity is a mechanism that contributes to the suppression of the maternal immune system. We identified the main type of arginase-expressing cells as a population of activated low-density granulocytes (LDGs) in peripheral blood mononuclear cells and in term placentae. In the present study, we analyzed the phenotype of LDGs and compared it to the phenotype of normal density granulocytes (NDGs) in maternal peripheral blood, placental biopsies and cord blood. Our data reveal that only LDGs but no NDGs could be detected in placental biopsies. Phenotypically, NDGs and LDGs from both maternal and cord blood expressed different levels of maturation, activation and degranulation markers. NDGs from the maternal and cord blood were phenotypically similar, while maternal, cord and placental LDGs showed different expression levels of CD66b. LDGs present in cord blood expressed higher levels of arginase compared to maternal and placental LDGs. In summary, our results show that in maternal and cord blood, two phenotypically different populations of neutrophils can be identified, whereas in term placentae, only activated neutrophils are present.
doi:10.1371/journal.pone.0085696
PMCID: PMC3923728  PMID: 24551035
7.  Sexual Behavior among Persons Living with HIV in Uganda: Implications for Policy and Practice 
PLoS ONE  2014;9(1):e85646.
Introduction
HIV epidemics are sustained and propagated by new cases of infection which result from transmission from infected persons to uninfected susceptible individuals. People living with HIV (PLHIV) play a critical role in prevention if they adopt safer sexual behaviors. This study estimated the prevalence of and factors associated with safer sexual behaviors among PLHIV seeking care from civil society organizations (CSOs).
Methods
In a cross sectional study PLHIV were interviewed about their sexual practices, use of alcohol, HIV status of their regular sexual partners, desire for more children and about their socio-demographic characteristics. We calculated the proportion of PLHIV who abstained and consistently used condoms in the previous twelve months. Independent associations between safer sex and other variables were estimated using adjusted prevalence ratios (aPR) and their 95% confidence intervals (CI).
Results
Of the 939 PLHIV, 54% (508) were either abstaining or using condoms consistently and 291 (31%) desired more children. The prevalence of consistent condom use among the sexually active was 41.3% (300/731). Consistent condom use was higher among PLHIV who: didn't use alcohol (aPR 1.30, CI 1.03–1.63); were educated about re-infection with a new strain of HIV (aPR 1.84, CI 1.08–3.12) and had regular sexual partner who was HIV negative (aPR 1.29, CI 1.05–1.57). Prevalence of abstinence was 22.2% (208/939). Abstinence increased with age from 9.4% among PLHIV <25 years to 40.5% among those >50 years. Abstinence was extremely low (2.5%) among PLHIV who were married.
Conclusions
Effective interventions that reduce alcohol consumption among PLHIV are needed to avert HIV transmission, prevent acquisition of new HIV strains and STIs. In addition, strategies are needed to address needs of PLHIV who desire more children.
doi:10.1371/journal.pone.0085646
PMCID: PMC3900429  PMID: 24465631
8.  Comparison of Methods for Correction of Mortality Estimates for Loss to Follow-Up after ART Initiation: A Case of the Infectious Diseases Institute, Uganda 
PLoS ONE  2013;8(12):e83524.
Background
In sub-Saharan Africa, a large proportion of HIV positive patients on antiretroviral therapy (ART) are lost to follow-up, some of whom are dead. The objective of this study was to validate methods used to correct mortality estimates for loss-to-follow-up using a cohort with complete death ascertainment.
Methods
Routinely collected data from HIV patients initiating first line antiretroviral therapy (ART) at the Infectious Diseases Institute (IDI) (Routine Cohort) was used. Three methods to estimate mortality after initiation were: 1) standard Kaplan-Meier estimation (uncorrected method) that uses passively observed data; 2) double-sampling methods by Frangakis and Rubin (F&R) where deaths obtained from patient tracing studies are given a higher weight than those passively ascertained; 3) Nomogram proposed by Egger et al. Corrected mortality estimates in the Routine Cohort, were compared with the estimates from the IDI research observational cohort (Research Cohort), which was used as the “gold-standard”.
Results
We included 5,633 patients from the Routine Cohort and 559 from the Research Cohort. Uncorrected mortality estimates (95% confidence interval [1]) in the Routine Cohort at 1, 2 and 3 years were 5.5% (4.9%–6.3%), 6.6% (5.9%–7.5%) and 7.4% (6.5%–8.5%), respectively. The F&R corrected estimates at 1, 2 and 3 years were 11.2% (5.8%–21.2%), 15.8% (9.9%–24.8%) and 18.5% (12.3% –27.2%) respectively. The estimates obtained from the Research Cohort were 15.6% (12.8%–18.9%), 17.5% (14.6%–21.0%) and 19.0% (15.3%–21.9%) at 1, 2 and 3 years respectively. Using the nomogram method in the Routine Cohort, the corrected programme-level mortality estimate in year 1 was 11.9% (8.0%–15.7%).
Conclusion
Mortality adjustments provided by the F&R and nomogram methods are adequate and should be employed to correct mortality for loss-to-follow-up in large HIV care centres in Sub-Saharan Africa.
doi:10.1371/journal.pone.0083524
PMCID: PMC3877043  PMID: 24391780
9.  Previously Transmitted HIV-1 Strains Are Preferentially Selected During Subsequent Sexual Transmissions 
The Journal of Infectious Diseases  2012;206(9):1433-1442.
Background. A genetic bottleneck is known to exist for human immunodeficiency virus (HIV) at the point of sexual transmission. However, the nature of this bottleneck and its effect on viral diversity over time is unclear.
Methods. Interhost and intrahost HIV diversity was analyzed in a stable population in Rakai, Uganda, from 1994 to 2002. HIV-1 envelope sequences from both individuals in initially HIV-discordant relationships in which transmission occurred later were examined using Sanger sequencing of bulk polymerase chain reaction (PCR) products (for 22 couples), clonal analysis (for 3), and next-generation deep sequencing (for 9).
Results. Intrahost viral diversity was significantly higher than changes in interhost diversity (P < .01). The majority of HIV-1–discordant couples examined via bulk PCR (16 of 22 couples), clonal analysis (3 of 3), and next-generation deep sequencing (6 of 9) demonstrated that the viral populations present in the newly infected recipient were more closely related to the donor partner's HIV-1 variants found earlier during infection as compared to those circulating near the estimated time of transmission (P = .03).
Conclusions. These findings suggest that sexual transmission constrains viral diversity at the population level, partially because of the preferential transmission of ancestral as opposed to contemporary strains circulating in the transmitting partner. Future successful vaccine strategies may need to target these transmitted ancestral strains.
doi:10.1093/infdis/jis503
PMCID: PMC3466994  PMID: 22997233
10.  Comparison of HIV-related vulnerabilities between former child soldiers and children never abducted by the LRA in northern Uganda 
Conflict and Health  2013;7:17.
Background
Thousands of former child soldiers who were abducted during the prolonged conflict in northern Uganda have returned to their home communities. Programmes that facilitate their successful reintegration continue to face a number of challenges. Although there is increasing knowledge of the dynamics of HIV infection during conflict, far less is known about its prevalence and implications for population health in the post-conflict period. This study investigated the effects of abduction on the prevalence of HIV and HIV-risk behaviours among young people in Gulu District, northern Uganda. An understanding of abduction experiences and HIV-risk behaviours is vital to both the development of effective reintegration programming for former child soldiers and the design of appropriate HIV prevention interventions for all young people.
Methods
In 2010, we conducted a cross-sectional study of 2 sub-counties in Gulu District. A demographic and behavioural survey was interview-administered to a purposively selected sample of 384 transit camp residents aged 15–29. Biological specimens were collected for HIV rapid testing in the field and confirmatory laboratory testing. Descriptive statistics were used to describe characteristics of abduction. Additionally, a gender-stratified bivariate analysis compared abductees’ and non-abductees’ HIV risk profiles.
Results
Of the 384 participants, 107 (28%) were former child soldiers (61% were young men and 39% were young women). The median age of participants was 20 and median age at abduction was 13. HIV prevalence was similar among former abductees and non-abductees (12% vs. 13%; p = 0.824), with no differences observed by gender. With respect to differences in HIV vulnerability, our bivariate analysis identified greater risky sexual behaviours in the past year for former abductees than non-abductees, but there were no differences between the two groups’ survival/livelihood activities and food insufficiency experiences, both overall and by gender. The analysis further revealed that young northern Ugandans in general are in desperate need of education, skills development, and support for victims of sexual violence.
Conclusions
This study persuasively demonstrates that all young people in northern Ugandan have been similarly affected by HIV infection during war and displacement. Post-conflict programme planners must therefore abandon rudimentary targeting practices based on abductees as a high-profile category. Instead, they must develop evidence-based HIV interventions that are commensurate with young people’s specific needs. As such programmes will be less stigmatizing, more oriented to self-selection, and more inclusive, they will effectively reach the most vulnerable young people in northern Uganda.
doi:10.1186/1752-1505-7-17
PMCID: PMC3751706  PMID: 23919329
Child soldiers; HIV/AIDS; Post-conflict programming; Young people; Northern Uganda
11.  High HIV-1 prevalence, risk behaviours, and willingness to participate in HIV vaccine trials in fishing communities on Lake Victoria, Uganda 
Introduction
HIV epidemics in sub-Saharan Africa are generalized, but high-risk subgroups exist within these epidemics. A recent study among fisher-folk communities (FFC) in Uganda showed high HIV prevalence (28.8%) and incidence (4.9/100 person-years). However, those findings may not reflect population-wide HIV rates in FFC since the study population was selected for high-risk behaviour.
Methods
Between September 2011 and March 2013, we conducted a community-based cohort study to determine the population representative HIV rates and willingness to participate (WTP) in hypothetical vaccine trials among FFC, Uganda. At baseline (September 2011–January 2012), a household enumeration census was done in eight fishing communities (one lakeshore and seven islands), after which a random sample of 2200 participants aged 18–49 years was selected from 5360 individuals. Interviewer-administered questionnaire data were collected on HIV risk behaviours and WTP, and venous blood was collected for HIV testing using rapid HIV tests with enzyme-linked immunosorbent assay (EIA) confirmation. Adjusted prevalence proportion ratios (adj.PPRs) of HIV prevalence were determined using log-binomial regression models.
Results
Overall baseline HIV prevalence was 26.7% and was higher in women than men (32.6% vs. 20.8%, p<0.0001). Prevalence was lower among fishermen (22.4%) than housewives (32.1%), farmers (33.1%) and bar/lodge/restaurant workers (37%). The adj.PPR of HIV was higher among women than men (adj.PPR =1.50, 95%; 1.20, 1.87) and participants aged 30–39 years (adj.PPR=1.40, 95%; 1.10, 1.79) and 40–49 years (adj.PPR=1.41, 95%; 1.04, 1.92) compared to those aged 18–24 years. Other factors associated with HIV prevalence included low education, previous marriage, polygamous marriage, alcohol and marijuana use before sex. WTP in hypothetical vaccine trials was 89.3% and was higher in men than women (91.2% vs. 87.3%, p=0.004) and among island communities compared to lakeshore ones (90.4% vs. 85.8%, p=0.004).
Conclusions
The HIV prevalence in the general fisher-folk population in Uganda is similar to that observed in the “high-risk” fisher folk. FFC have very high levels of willingness to participate in future HIV vaccine trials.
doi:10.7448/IAS.16.1.18621
PMCID: PMC3720985  PMID: 23880102
HIV-1; willingness to participate in HIV vaccine trials; fishing communities; Uganda
12.  Asymptomatic Plasmodium Infection and Cognition among Primary Schoolchildren in a High Malaria Transmission Setting in Uganda 
Asymptomatic parasitemia is common among schoolchildren living in areas of high malaria transmission, yet little is known about its effect on cognitive function in these settings. To investigate associations between asymptomatic parasitemia, anemia, and cognition among primary schoolchildren living in a high malaria transmission setting, we studied 740 children enrolled in a clinical trial in Tororo, Uganda. Parasitemia, measured by thick blood smears, was present in 30% of the children. Infected children had lower test scores for abstract reasoning (adjusted mean difference [AMD] −0.6, 95% confidence interval [CI] −1.01 to −0.21) and sustained attention (AMD −1.6 95% CI −2.40 to −0.81) compared with uninfected children. There was also evidence for a dose–response relationship between parasite density and scores for sustained attention. No associations were observed between anemia and either test of cognition. Schoolchildren in high transmission settings may experience cognitive benefits, from interventions aimed at reducing the prevalence of asymptomatic parasitemia.
doi:10.4269/ajtmh.12-0633
PMCID: PMC3752809  PMID: 23589533
13.  Daily acyclovir to prevent disease progression among HIV-1/HSV-2 co-infected individuals: a randomized, double-blinded placebo controlled trial in Rakai, Uganda 
The Lancet infectious diseases  2012;12(6):441-448.
Background
Daily suppression of herpes simplex virus type 2 (HSV-2) reduces plasma HIV-1 concentrations and has been shown to delay HIV-1 disease progression modestly in one clinical trial. We investigated the impact of daily suppressive acyclovir on HIV-1 disease progression in Rakai, Uganda
Methods
In a single site trial, 440 HIV-1, HSV-2 dually infected consenting adults with CD4+ T-cell counts 300-400 cells/μL and not on antiretroviral therapy were randomized 1:1 to receive either acyclovir 400 mg orally twice daily or placebo; participants were followed for 24 months. The primary outcome was CD4 <250 or ART initiation for WHO stage IV disease. Intent-to-treat analysis used Cox proportional hazards (CPH) models, adjusting for baseline log10 viral load (VL), CD4 cell count, gender and age to assess the risk of disease progression. The impact of suppressive HSV-2 treatment by baseline VL was also investigated in a CPH model. This trial is registered with clinicaltrials.gov, number NCT00405821.
Findings
Overall, 110 participants in the placebo arm and 95 participants in the treatment arm reached the primary endpoint (Adj HR 0.75, 95% CI 0.58-0.99; p=0.040). In a sub-analysis stratified by baseline VL quintile, participants with a baseline VL >= 50,000 copies/ml experienced a 38% reduction in HIV disease progression in the treatment compared to placebo arm (Adj HR 0.62, 95% CI 0.43-0.96;p=0.03).
Interpretation
Acyclovir reduced the rate of disease progression by 25%, with the greatest impact occurring among individuals with high baseline VL. Suppressive acyclovir may be warranted among HSV-2/HIV-1 dually infected individuals with viral loads >= 50,000 copies/ml prior to antiretroviral treatment.
doi:10.1016/S1473-3099(12)70037-3
PMCID: PMC3420068  PMID: 22433279
HIV-1; herpes simplex virus; acyclovir; disease progression
14.  Efficiency of CCR5 Coreceptor Utilization by the HIV Quasispecies Increases over Time, But Is Not Associated with Disease Progression 
Abstract
CCR5 is the primary coreceptor for HIV entry. Early after infection, the HIV viral population diversifies rapidly into a quasispecies. It is not known whether the initial efficiency of the viral quasispecies to utilize CCR5 is associated with HIV disease progression or if it changes in an infected individual over time. The CCR5 and CXCR4 utilization efficiencies (R5-UE and X4-UE) of the HIV quasispecies were examined using a pseudovirus, single-round infection assay for samples obtained from known seroconverters from Rakai district, Uganda (n=88). Initial and longitudinal R5-UE values were examined to assess the association of R5-UE with HIV disease progression using multivariate Cox proportional hazard models. Longitudinal samples were analyzed for 35 seroconverters who had samples available from multiple time points. There was no association between initial or longitudinal changes in R5-UE and the hazard of HIV disease progression (p=0.225 and p=0.942, respectively). In addition, R5-UE increased significantly over time after HIV seroconversion (p<0.001), regardless of HIV subtype or the emergence of CXCR4-tropic virus. These data demonstrate that the R5-UE of the viral quasispecies early in HIV infection is not associated with disease progression, and that R5-UE levels increase in HIV-infected individuals over time.
doi:10.1089/aid.2011.0006
PMCID: PMC3292754  PMID: 21663455
15.  The natural history of bacterial vaginosis (BV) diagnosed by Gram stain among women in Rakai, Uganda 
Sexually transmitted diseases  2011;38(11):1040-1045.
Background
Large datasets for investigating vaginal flora change at frequent, repeated intervals are limited and graphical methods for exploring such data are inadequate. We report 2-year weekly vaginal flora changes based on Gram stain using lasagna plots.
Methods
Weekly vaginal flora patterns were evaluated among 211 sexually experienced women with 18 months or more of follow-up in Rakai, Uganda. Vaginal flora swabs were self-collected weekly and categorized by Nugent Gram stain criteria (0–3, normal; 4–6, intermediate; 7–10, BV). Vaginal flora patterns were analyzed as the percentage of weekly observations with BV (longitudinal prevalence) and illustrated by lasagna plots. Characteristics of women were compared across tertiles of longitudinal prevalence of BV.
Results
Ninety-five percent of women had at least 1 episode of BV over 2 years with one-third of women spending over half (52–100%) of their time with BV. Vaginal pH > 4.5 increased with increasing tertiles of longitudinal prevalence of BV (p < 0.001). Weekly fluctuation in vaginal flora states, as measured by a change in flora states from the prior to current visit, was highest in the middle (41.9%) compared to the lower (30.1%) and upper tertiles (27.8%, p < 0.001). HIV status and reported vaginal symptoms did not differ significantly across BV tertiles.
Conclusions
Women exhibited different patterns of vaginal flora changes over time, which could not be described by baseline behaviors. Lasagna plots aided in describing the natural history of BV within and across women and may be applied to future BV natural history studies.
doi:10.1097/OLQ.0b013e3182275499
PMCID: PMC3192988  PMID: 21992981
16.  Incremental Yield of Serial Sputum Cultures for Diagnosis of Tuberculosis among HIV Infected Smear Negative Pulmonary TB Suspects in Kampala, Uganda 
PLoS ONE  2012;7(5):e37650.
Background
Sputum culture is the gold standard for diagnosis of pulmonary tuberculosis (PTB). Although mostly used for research, culture is recommended by the World Health Organization for TB diagnosis among HIV infected smear negative PTB suspects. Even then, the number of sputum samples required remains unspecified. Here, we determined the Incremental Yield (IY) and number of samples required to diagnose an additional PTB case upon second and third serial sputum culture.
Methods/Findings
This was a cross sectional study done between January and March 2011. Serial sputum samples were provided by participants within two days and cultured using Lowenstein Jensen (LJ) and Mycobacteria Growth Indicator Tube (MGIT) methods. A PTB case was defined as a positive culture on either one or both methods. The IY from the second and third serial cultures was determined and the reciprocal of the product of the fractions of IY provided the number of samples required for an additional PTB case. Of the 170 smear negative PTB suspects, 62 (36.5%) met the case definition. The IY of the second sample culture was 12.7%, 23.6% and 12.6% and for the third sample culture was 6.8%, 7.5% and 7.3% with LJ, MGIT and LJ or MGIT, respectively. The number of samples required for an additional PTB case and 95% CI upon the second sample culture were 29.9 (16.6, 156.5), 11.3 (7.6, 21.9) and 20.8 (12.5, 62.7); while for the third sample culture were 55.6 (26.4, 500.4), 35.7 (19.0, 313.8) and 36.1 (19.1, 330.9) by LJ, MGIT and LJ or MGIT respectively.
Conclusions/Significance
Among HIV infected smear negative PTB suspects in Kampala, 93% of PTB cases are diagnosed upon the second serial sputum culture. The number of cultures needed to diagnose an additional PTB case, ranges from 11–30 and 35–56 by the second and third sputum samples, respectively.
doi:10.1371/journal.pone.0037650
PMCID: PMC3358271  PMID: 22629439
17.  Longitudinal changes in vaginal microbiota composition assessed by Gram-stain among never sexually active pre- and postmenarcheal adolescents in Rakai, Uganda 
Study Objective
To describe changes in vaginal microbiota and pH over time among never sexually active adolescents at different menarcheal stages.
Design
A cohort of 49 sexually inexperienced Ugandan adolescents provided weekly self-collected vaginal swabs and behavioral/health information for up to two years. Menarcheal stage was classified as: not experiencing menarche during follow-up (premenarcheal, n=9), achieving menarche during follow-up (perimenarcheal, n=20), and being postmenarcheal (n=20) at enrollment. Vaginal microbiota were characterized as morphotypes of large Gram-positive rods, small Gram-negative or variable rods, and curved Gram-negative rods based on Nugent Gram-stain criteria. Baseline measures were compared using nonparametric tests. Mean changes (β) in morphotypes and pH over time were estimated using longitudinal mixed-effects models.
Results
The baseline median (IQR: interquartile range) Nugent score was 8 (7-8) in premenarcheal, 4.5 (1-8) in perimenarcheal, and 1 (0-3) in postmenarcheal girls (p=0.001). For each respective menarcheal stage, the median counts of (IQR) Gram-positive rods were 0 (0-0), 10 (0-30), and 30 (18-30) (p=0.002) and Gram-negative or variable rods were 30 (30-30), 16 (0.5-30), and 0.5 (0-2.5) (p=0.002) at enrollment. Counts of Gram-positive rods increased (β = 0.259, 95% CI: 0.156, 0.362) and Gram-negative or variable rods decreased (β = -0.201, 95% CI:-0.298,-0.103) significantly over time in premenarcheal girls, but not in other groups. Vaginal pH declined significantly in peri- and postmenarcheal girls only.
Conclusion
Vaginal microbiota composition varied by menarcheal stage at enrollment. Over time, significant changes in vaginal morphotypes occurred in premenarcheal girls, suggesting this may be an important period of transition.
doi:10.1016/j.jpag.2010.07.002
PMCID: PMC2988102  PMID: 20709584
vaginal microbiota; pH; menarche; lactobacilli; bacterial vaginosis; Gram-stain; Nugent score
18.  Effect of Hormonal Contraceptive Use Prior to HIV Seroconversion on Viral Load Setpoint among Women in Rakai, Uganda 
Background
High viral load (VL) setpoint is a marker for rapid HIV progression, but few studies have examined whether use of hormonal contraception (HC) prior to HIV seroconversion affects VL setpoint.
Methods
We determined VL setpoints in 285 HIV seroconverters using blood samples collected six months or more after estimated HIV seroconversion but before disease progression to CD4≤250 or WHO Stage 3 or 4. We used multivariate linear regression to estimate the effect of HC use prior to HIV seroconversion on VL setpoint, and multivariate Cox regression to estimate the hazards ratio of death associated with VL setpoint.
Results
Of 285 women, 42 (15%) reported using HC prior to HIV seroconversion. Mean VL setpoint was 4.49 (SD 0.79) log10 copies/mL among women who used HC prior to HIV seroconversion and 4.47 (SD 0.86) among non-HC users (p=0.88). In multivariate analysis, HC prior to HIV seroconversion was not associated with VL setpoint (+0.11 log10 copies /mL; p=0.47). Higher socioeconomic status was associated with lower VL setpoint (-0.43 log10 copies/mL; p=0.04). VL setpoints above the median were associated with faster time to death (adjHR: 2.54, 95% CI: 1.30-4.98, p-value <0.01).
Conclusions
Use of HC prior to HIV seroconversion was not associated with elevated VL setpoint.
doi:10.1097/QAI.0b013e3181fbcc11
PMCID: PMC3023004  PMID: 21068673
hormonal contraception; viral load setpoint; HIV progression; Uganda
19.  Changes in the Distribution of HIV Type 1 Subtypes D and A in Rakai District, Uganda Between 1994 and 2002 
AIDS Research and Human Retroviruses  2010;26(10):1087-1091.
Abstract
HIV-1 subtype D (HIV-1D) progresses to disease faster and has lower transmissibility than subtype A (HIV-1A). We examined whether these differences could lead to a population level change in the distribution of these subtypes over time. HIV-1 viral RNA was extracted from stored serum samples from HIV-positive subjects participating in a population-based cohort study in Rakai, Uganda in 1994 and 2002. Portions of the viral proteins gag and gp41 were sequenced and subtyped. HIV-1 subtype assignments were generated for 773 subjects in 1994 and 812 subjects in 2002. The change in subtype distribution of the population as a whole as well as quartile age groups were examined for significant changes using a linear model. There was a significant decrease in the proportion of subjects infected with HIV-1D from 70.2% to 62.4% and a significant increase in subjects infected with HIV-1A from 16.7% to 23.3% over the 8-year period (p = 0.005). The most marked changes in proportion of HIV-1D and A were seen in the younger individuals (<25 and 25–30 years; p < 0.05). The percentages of subjects infected with HIV-1C and recombinant subtypes did not change significantly. Over this 8-year period, the overall viral population in this region evolved toward the less virulent HIV-1A strain, most likely as a consequence of the faster disease progression and lower transmissibility of HIV-1D.
doi:10.1089/aid.2010.0054
PMCID: PMC2965693  PMID: 20925575
20.  Disclosure of HIV results among discordant couples in Rakai, -Uganda: A facilitated couple counselling approach 
AIDS care  2010;22(9):1041-1051.
Disclosure of HIV seropositive results among HIV-discordant couples in sub-Saharan Africa is generally low. We describe a facilitated couple counselling approach to enhance disclosure among HIV-discordant couples.
Using unique identifiers, 293 HIV-discordant couples were identified through retrospective linkage of married or cohabiting consenting adults individually enrolled into a cohort study and into two randomized trials of male circumcision in Rakai, Uganda. HIV discordant couples and a random sample of HIV-infected concordant and HIV-negative concordant couples (to mask HIV status) were invited to sensitization meetings to discuss the benefits of disclosure and couple counselling. HIV-infected partners were subsequently contacted to encourage HIV disclosure to their HIV uninfected partners. If the index positive partner agreed, the counsellor facilitated the disclosure of HIV results, and provided ongoing support. The proportion of disclosure was determined.
81% of HIV-positive partners in discordant relationships disclosed their status to their HIV-uninfected partners in the presence of the counsellor. The rates of disclosure were 81.3% in male HIV-positive and 80.2% in female HIV-positive discordant couples. Disclosure did not vary by age, education or occupation.
In summary, disclosure of HIV-positive results in discordant couples using facilitated couple counselling approach is high, but requires a stepwise process of sensitization and agreement by the infected partner.
doi:10.1080/09540121003602226
PMCID: PMC2936701  PMID: 20824557
HIV disclosure; Facilitated couple counselling; Discordant couples
21.  Foreskin surface area and HIV acquisition in Rakai, Uganda (size matters) 
AIDS (London, England)  2009;23(16):2209-2213.
Introduction
Male circumcision reduces HIV acquisition in men. We assessed whether foreskin surface area was associated with HIV acquisition prior to circumcision.
Methods
In two randomized trials of male circumcision, the surface area of the foreskin was measured after surgery using standardized procedures. Nine hundred and sixty-five initially HIV-negative men were enrolled in a community cohort who subsequently enrolled in the male circumcision trials, provided 3920.8 person-years of observation prior to circumcision. We estimated HIV incidence per 100 person-years prior to circumcision, associated with foreskin surface area categorized into quartiles.
Results
Mean foreskin surface area was significantly higher among men who acquired HIV (43.3 cm2, standard error 2.1) compared with men who remained uninfected (36.8 cm2, standard error 0.5, P = 0.01). HIV incidence was 0.80/100 person-years (8/994.9 person-years) for men with foreskin surface areas in the lowest quartile ( ≤26.3 cm2), 0.92/100 person-years (9/975.3 person-years) with foreskin areas in the second quartile (26.4–35.0 cm2), 0.90/100 person-years (8/888.5 person-years) with foreskin area in the third quartile (35.2–45.5 cm2) and 2.48/100 person-years (23/926.8 person-years) in men with foreskin surfaces areas in the highest quartile (>45.6 cm2). Compared with men with foreskin surface areas in the lowest quartile, the adjusted incidence rate ratio of HIV acquisition was 2.37 (95% confidence interval 1.05–5.31) in men with the largest quartile of foreskin surface area.
Conclusion
The risk of male HIV acquisition is increased among men with larger foreskin surface areas.
doi:10.1097/QAD.0b013e328330eda8
PMCID: PMC3125976  PMID: 19770623
foreskin surface area; HIV acquisition; HIV target cells; male circumcision
22.  Circumcision of HIV-infected men: Effects on High Risk Human Papillomavirus Infections in a Randomized Trial in Rakai, Uganda 
The Journal of infectious diseases  2010;201(10):1463-1469.
In Rakai, Uganda, HIV+ men were randomized to immediate (intervention) or delayed circumcision (controls). Penile swabs were assayed for high risk human papillomavirus (HR-HPV) by Roche HPV Linear Array at enrollment and 24 months (intervention n=103, control n=107). Rate ratios (RR) of HR-HPV were estimated by Poisson regression. At 24 months, HR-HPV prevalence was intervention 55.3% and control 71.7% (RR=0.77, 95%CI 0.62–0.97). Multiple HR-HPV infections were intervention 22.4% and controls 42.5% (RR=0.53, 95%CI 0.33–0.83). New HR-HPV genotypes were acquired by 42.0% of intervention and 57.0% of control arm men (RR=0.74, 95%CI 0.54–1.01, p=0.06). Multiple new HR-HPV genotypes were acquired by 9.9% intervention and 24.7% control arm men (RR = 0.40, 95%CI 0.19–0.84, p = 0.01). Circumcision did not affect the acquisition of single HR-HPV infections (RR=1.00, 95%CI 0.65–1.53) or clearance of HR-HPV (RR=1.09, 95%CI 0.94–1.27). Circumcision of HIV+ men reduced the prevalence and incidence of multiple HR-HPV infections.
doi:10.1086/652185
PMCID: PMC2862639  PMID: 20370481
23.  Male circumcision decreases acquisition and increases clearance of high risk human papillomavirus in HIV-negative men: a randomized trial in Rakai, Uganda 
The Journal of infectious diseases  2010;201(10):1455-1462.
Uncircumcised HIV-negative men aged 15-49 years were randomized to immediate circumcision (n=441) or delayed circumcision (n=399). HPV was detected by Roche HPV Linear Array at enrollment, 6, 12 and 24 months. Incident HR-HPV was estimated in men who acquired a new HR-HPV genotype. HR-HPV clearance was determined in men with prior genotype-specific HR-HPV infections. Rate ratios (RR) and 95% confidence intervals (95%CI) of HR-HPV acquisition were estimated by Poisson multiple regression
Enrollment characteristics were comparable between groups. HR-HPV incidence was 19.7/100 py in the intervention (70/355.8 py) and 29.4/100 py (125/424.8 py) in the control arm (RR=0.67, 95%CI 0.51-0.89, p = 0.006.) The incidence of multiple HR-HPV infections was 6.7/100 py in the intervention and 14.8/100 py in control arm (RR = 0.45, 95%CI 0.28-0.73), but there was no significant effect on single infections (RR=0.89, 95%CI 0.60-1.30). HR-HPV incidence was lower in the intervention arm for all genotypes and demographic/behavioral subgroups. The clearance of pre-existing HR-HPV infections was 215.8/100py (205/95 py) in intervention and 159.1/100py (255/160.25 py) in control arm men (adjRR=1.39, 95%CI 1.17-1.64).
Male circumcision reduces the incidence of multiple HR-HPV infections and increases clearance of HR-HPV infections in HIV-uninfected men.
The trial was registered with ClinicalTrials.gov numbers NCT00425984
doi:10.1086/652184
PMCID: PMC2882881  PMID: 20370483
24.  Innate and Adaptive Immune Responses Both Contribute to Pathological CD4 T Cell Activation in HIV-1 Infected Ugandans 
PLoS ONE  2011;6(4):e18779.
HIV-1 disease progression is associated with persistent immune activation. However, the nature of this association is incompletely understood. Here, we investigated immune activation in the CD4 T cell compartment of chronically HIV-1 infected individuals from Rakai, Uganda. Levels of CD4 T cell activation, assessed as co-expression of PD-1, CD38 and HLA-DR, correlated directly to viral load and inversely to CD4 count. Deeper characterization of these cells indicated an effector memory phenotype with relatively frequent expression of Ki67 despite their PD-1 expression, and levels of these cells were inversely associated with FoxP3+ regulatory T cells. We therefore use the term deregulated effector memory (DEM) cells to describe them. CD4 T cells with a DEM phenotype could be generated by antigen stimulation of recall responses in vitro. Responses against HIV-1 and CMV antigens were enriched among the DEM CD4 T cells in patients, and the diverse Vβ repertoire of DEM CD4 T cells suggested they include diverse antigen-specificities. Furthermore, the levels of DEM CD4 T cells correlated directly to soluble CD14 (sCD14) and IL-6, markers of innate immune activation, in plasma. The size of the activated DEM CD4 T cell subset was predictive of the rate of disease progression, whereas IL-6 was only weakly predictive and sCD14 was not predictive. Taken together, these results are consistent with a model where systemic innate immune activation and chronic antigen stimulation of adaptive T cell responses both play important roles in driving pathological CD4 T cell immune activation in HIV-1 disease.
doi:10.1371/journal.pone.0018779
PMCID: PMC3079731  PMID: 21526194
25.  Increasing access to institutional deliveries using demand and supply side incentives: early results from a quasi-experimental study 
Background
Geographical inaccessibility, lack of transport, and financial burdens are some of the demand side constraints to maternal health services in Uganda, while supply side problems include poor quality services related to unmotivated health workers and inadequate supplies. Most public health interventions in Uganda have addressed only selected supply side issues, and universities have focused their efforts on providing maternal services at tertiary hospitals. To demonstrate how reforms at Makerere University College of Health Sciences (MakCHS) can lead to making systemic changes that can improve maternal health services, a demand and supply side strategy was developed by working with local communities and national stakeholders.
Methods
This quasi-experimental trial is conducted in two districts in Eastern Uganda. The supply side component includes health worker refresher training and additions of minimal drugs and supplies, whereas the demand side component involves vouchers given to pregnant women for motorcycle transport and the payment to service providers for antenatal, delivery, and postnatal care. The trial is ongoing, but early analysis from routine health information systems on the number of services used is presented.
Results
Motorcyclists in the community organized themselves to accept vouchers in exchange for transport for antenatal care, deliveries and postnatal care, and have become actively involved in ensuring that women obtain care. Increases in antenatal, delivery, and postnatal care were demonstrated, with the number of safe deliveries in the intervention area immediately jumping from <200 deliveries/month to over 500 deliveries/month in the intervention arm. Voucher revenues have been used to obtain needed supplies to improve quality and to pay health workers, ensuring their availability at a time when workloads are increasing.
Conclusions
Transport and service vouchers appear to be a viable strategy for rapidly increasing maternal care. MakCHS can design strategies together with stakeholders using a learning-by-doing approach to take advantage of community resources.
doi:10.1186/1472-698X-11-S1-S11
PMCID: PMC3059470  PMID: 21410998

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