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1.  Human Papillomavirus Clearance Among Males Is Associated With HIV Acquisition and Increased Dendritic Cell Density in the Foreskin 
The Journal of Infectious Diseases  2013;207(11):1713-1722.
Background. The association between human papillomavirus (HPV) infection and the risk of human immunodeficiency virus (HIV) seroconversion is unclear, and the genital cellular immunology has not been evaluated.
Methods. A case-control analysis nested within a male circumcision trial was conducted. Cases consisted of 44 male HIV seroconverters, and controls were 787 males who were persistently negative for HIV. The Roche HPV Linear Array Genotype Test detected high-risk HPV (HR-HPV) and low-risk HPV (LR-HPV) genotypes. Generalized estimating equations logistic regression was used to estimate adjusted odds ratios (aORs) of HIV seroconversion. In addition, densities of CD1a+ dendritic cells, CD4+ T cells, and CD8+ T cells were measured using immunohistochemistry analysis in foreskins of 79 males randomly selected from participants in the circumcision trial.
Results. HR-HPV or LR-HPV acquisition was not significantly associated with HIV seroconversion, after adjustment for sexual behaviors. However, HR-HPV and LR-HPV clearance was significantly associated with HIV seroconversion (aOR, 3.25 [95% confidence interval {CI}, 1.11–9.55] and 3.18 [95% CI, 1.14–8.90], respectively). The odds of HIV seroconversion increased with increasing number of HPV genotypes cleared (P < .001, by the test for trend). The median CD1a+ dendritic cell density in the foreskin epidermis was significantly higher among males who cleared HPV (72.0 cells/mm2 [interquartile range {IQR}, 29.4–138.3 cells/mm2]), compared with males who were persistently negative for HPV (32.1 cells/mm2 [IQR, 3.1–96.2 cells/mm2]; P = .047), and increased progressively with the number of HPV genotypes cleared (P = .05).
Conclusions. HPV clearance was associated with subsequent HIV seroconversion and also with increased epidermal dendritic cell density, which potentially mediates HIV seroconversion.
doi:10.1093/infdis/jit035
PMCID: PMC3636782  PMID: 23345339
human papillomavirus (HPV); male circumcision; HIV; AIDS; Uganda; penile cancer; cervical cancer; sexually transmitted infections
2.  High risk human papillomavirus viral load and persistence among heterosexual HIV-negative and HIV-positive men 
Sexually transmitted infections  2014;90(4):337-343.
Objectives
High-risk human papillomavirus (HR-HPV) viral load is associated with HR-HPV transmission and HR-HPV persistence in women. It is unknown whether HR-HPV viral load is associated with persistence in HIV-negative or HIV-positive men.
Methods
HR-HPV viral load and persistence were evaluated among 703 HIV-negative and 233 HIV-positive heterosexual men who participated in a male circumcision trial in Rakai, Uganda. Penile swabs were tested at baseline and 6, 12 and 24 months for HR-HPV using the Roche HPV Linear Array, which provides a semi-quantitative measure of HPV shedding by hybridization band intensity (graded:1–4). Prevalence risk ratios (PRR) were used to estimate the association between HR-HPV viral load and persistent detection of HR-HPV.
Results
HR-HPV genotypes with high viral load (grade:3–4) at baseline were more likely to persist than HR-HPV genotypes with low viral load (grade:1–2) among HIV-negative men (month 6: adjPRR=1.83, 95%CI:1.32–2.52; month 12: adjPRR=2.01, 95%CI:1.42–3.11), and HIV-positive men (month 6: adjPRR=1.33, 95%CI:1.06–1.67; month 12: adjPRR=1.73, 95%CI:1.18–2.54). Long-term persistence of HR-HPV was more frequent among HIV-positive men compared to HIV-negative men (month 24: adjPRR=2.27, 95%CI: 1.47–3.51). Persistence of newly detected HR-HPV at the 6 and 12 month visits with high viral load were also more likely to persist to 24 months than HR-HPV with low viral load among HIV-negative men (adjPRR=1.67, 95%CI 0.88–3.16).
Conclusions
HR-HPV genotypes with high viral load are more likely to persist among HIV-negative and HIV-positive men, though persistence was more common among HIV-positive men overall. The results may explain the association between high HR-HPV viral load and HR-HPV transmission.
doi:10.1136/sextrans-2013-051230
PMCID: PMC4030299  PMID: 24482488
Human papillomavirus (HPV); human immunodeficiency virus (HIV); male circumcision; Uganda; penile cancer; sexually transmitted infections; viral shedding; viral load; linear array band intensity
3.  Male Circumcision and Mycoplasma genitalium Infection in Female Partners: a Randomized Trial in Rakai, Uganda 
Sexually transmitted infections  2013;90(2):150-154.
Objective
Previous randomized trial data have demonstrated that male circumcision reduces Mycoplasma genitalium prevalence in men. We assessed whether male circumcision also reduces M. genitalium infection in female partners of circumcised men.
Methods
HIV-negative men were enrolled and randomized to either male circumcision or control. Female partners of male trial participants from the intervention (n=437) and control (n=394) arms provided interview information and self-collected vaginal swabs that were tested for M. genitalium by APTIMA transcription-mediated-amplification-based assay. Prevalence risk ratios (PRR) and 95% confidence intervals (95%CI) of M. genitalium prevalence in intervention versus control group were estimated using Poisson regression. Analysis was by intention-to-treat. An as-treated analysis was conducted to account for study-group crossovers.
Results
Male and female partner enrollment sociodemographic characteristics, sexual behaviors, and symptoms of STIs were similar between study arms. Female M. genitalium prevalence at year-two was 3.2% (14/437) in intervention arm and 3.6% (14/394) in control arm (PRR=0.90, 95%CI 0.43–1.89, p=0.78). In an as-treated analysis, the prevalence of M. genitalium was 3.4% in female partners of circumcised men and 3.3% in female partners of uncircumcised men (PRR= 1.01, 95%CI 0.48–2.12, p=0.97).
Conclusions
Contrary to findings in men, male circumcision did not affect Mycoplasma genitalium infection in female partners.
doi:10.1136/sextrans-2013-051293
PMCID: PMC4018720  PMID: 24259189
Male circumcision; mycoplasma genitalium; HIV; Uganda; sexually transmitted infections; transmission
4.  Male circumcision reduces penile high-risk human papillomavirus viral load in a randomised clinical trial in Rakai, Uganda 
Sexually transmitted infections  2012;89(3):262-266.
Objectives
Male circumcision reduces penile high-risk human papillomavirus (HR-HPV) prevalence in randomised trials. The goal of this study was to examine the effect of circumcision on HPV viral load among HPV-infected men in a randomised trial of male circumcision.
Methods
In a randomised trial to assess the efficacy of circumcision on HIV acquisition in Rakai, Uganda, HIV-negative men were randomised to immediate (intervention) or delayed (control) circumcision and followed over 24 months. We performed quantitative-PCR HPV viral load assays on penile swabs which tested positive by Linear Array (LA) for six HR-HPV genotypes and estimated viral load in the remaining types by LA signal strength.
Results
At 24 months, circumcision intervention arm men infected with one of the six selected HR-HPV genotypes had a lower viral load and significantly reduced HR-HPV high LA band intensity (PRR=0.61, 95% CI 0.43 to 0.86) compared to infected men in the control arm of the trial. The decreased viral load associated with circumcision was seen among HPV infections acquired after enrolment but not among infections that persisted from trial enrolment to 24 months (p=0.80).
Conclusions
The decreased penile HR-HPV shedding observed among HPV-infected circumcised men may help to explain the protective association observed between circumcision and reduced acquisition of HR-HPV in female partners.
doi:10.1136/sextrans-2012-050633
PMCID: PMC3706631  PMID: 23112341
5.  Cost analyses of peer health worker and mHealth support interventions for improving AIDS care in Rakai, Uganda 
AIDS care  2012;25(5):652-656.
A cost analysis study calculates resources needed to deliver an intervention and can provide useful information on affordability for service providers and policy makers. We conducted cost analyses of both a peer health worker (PHW) and a mHealth (mobile phone) support intervention. Excluding supervisory staffing costs, total yearly costs for the PHW intervention was $8,475, resulting in a yearly cost per patient of $8.74, per virologic failure averted cost of $189, and per patient lost to follow-up averted cost of $1025. Including supervisory staffing costs increased total yearly costs to $14,991. Yearly costs of the mHealth intervention were an additional $1046, resulting in a yearly cost per patient of $2.35. In a threshold analysis, the PHW intervention was found to be cost saving if it was able to avert 1.50 patients per year from switching to second-line antiretroviral therapy. Other AIDS care programs may find these intervention costs affordable.
doi:10.1080/09540121.2012.722600
PMCID: PMC3773472  PMID: 22971113
cost analysis; mHealth; community health workers; Uganda; antiretroviral treatment
6.  Indices to Measure Risk of HIV Acquisition in Rakai, Uganda 
PLoS ONE  2014;9(4):e92015.
Introduction
Targeting most-at-risk individuals with HIV preventive interventions is cost-effective. We developed gender-specific indices to measure risk of HIV among sexually active individuals in Rakai, Uganda.
Methods
We used multivariable Cox proportional hazards models to estimate time-to-HIV infection associated with candidate predictors. Reduced models were determined using backward selection procedures with Akaike's information criterion (AIC) as the stopping rule. Model discrimination was determined using Harrell's concordance index (c index). Model calibration was determined graphically. Nomograms were used to present the final prediction models.
Results
We used samples of 7,497 women and 5,783 men. 342 new infections occurred among females (incidence 1.11/100 person years,) and 225 among the males (incidence 1.00/100 person years). The final model for men included age, education, circumcision status, number of sexual partners, genital ulcer disease symptoms, alcohol use before sex, partner in high risk employment, community type, being unaware of a partner's HIV status and community HIV prevalence. The Model's optimism-corrected c index was 69.1 percent (95% CI = 0.66, 0.73). The final women's model included age, marital status, education, number of sex partners, new sex partner, alcohol consumption by self or partner before sex, concurrent sexual partners, being employed in a high-risk occupation, having genital ulcer disease symptoms, community HIV prevalence, and perceiving oneself or partner to be exposed to HIV. The models optimism-corrected c index was 0.67 (95% CI = 0.64, 0.70). Both models were well calibrated.
Conclusion
These indices were discriminative and well calibrated. This provides proof-of-concept that population-based HIV risk indices can be developed. Further research to validate these indices for other populations is needed.
doi:10.1371/journal.pone.0092015
PMCID: PMC3976261  PMID: 24704778
7.  Knowledge and attitudes towards use of long acting reversible contraceptives among women of reproductive age in Lubaga division, Kampala district, Uganda 
BMC Research Notes  2014;7:153.
Background
Uganda has one of the highest total fertility rates globally and in Sub-Saharan Africa. Her high fertility is mainly attributed to the high unmet need for family planning. Use of Long-acting reversible contraceptives (LARC) is low (13%) in Uganda yet they are the most cost-effective contraceptives. This study aimed to assess the reproductive aged women’s knowledge, attitudes, and factors associated with use of LARC.
Methods
A cross-sectional study was conducted involving 565 women (15–49 years) attending private and public health facilities in Lubaga division, Kampala district. Semi-structured questionnaires were used to measure knowledge, attitudes and factors associated with use of LARC; Intra-Uterine Devices, Implants and Injectables. The outcome variable was current use of LARC. A generalized linear regression model was run in STATA version12.0. Prevalence Risk Ratios for associations between current LARC use and independent factors were obtained and regarded significant at 95% CI with p < 0.05.
Results
Mean age (SD) and current use of LARC was 26.34 (5.35) and 31.7% respectively. Factors associated with current use of LARC were; previous use adj.PRR 2.89; (95% CI 2.29, 3.81), knowledge of implant administration site adj.PRR 1.83; (95% CI 1.17, 2.87), and perception that; male partner decisions positively influence their contraceptive choices adj.PRR 1.49; (95% CI 1.18, 1.88). Contrary, perception that LARC should be used by married women was negatively associated with use of LARC adj.PRR 0.63; (95% CI 0.44, 0.90).
Conclusion
Knowledge about site of administration, previous use of LARC and women’s attitude that male partners’ choice influence their contraceptive decisions were positively associated with current use of LARC. Contrary, the attitude that LARC was for married women was negatively associated with its use. This study suggests a need to strengthen client education about LARC to dispel possible myths and to consider integrating male partner’s decision making in contraceptive choices for women.
doi:10.1186/1756-0500-7-153
PMCID: PMC3985592  PMID: 24636154
Family planning; Long-acting reversible contraceptive (LARC); Injectable; Implant; IUD; Knowledge; Attitudes
8.  Field Evaluation of PIMA Point-of-Care CD4 Testing in Rakai, Uganda 
PLoS ONE  2014;9(3):e88928.
Objective
To assess the accuracy of PIMA Point-of-Care (POC) CD4 testing in rural Rakai, Uganda.
Methods
903 HIV positive persons attending field clinics provided a venous blood sample assessed on site using PIMA analyzers per manufacturer's specifications. The venous samples were then run on FACSCalibur flow cytometry at a central facility. The Bland–Altman method was used to estimate mean bias and 95% limits of agreement (LOA). Sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) were calculated for a CD4 threshold of <350 and <500 cells/uL for antiretroviral eligibility.
Results
There was a high correlation between PIMA and FACSCalibur CD4 counts (r = 0.943, p<0.001). Relative to FACSCalibur, the PIMA POC CD4 had negative mean bias of −34.6 cells/uL (95% LOA: −219.8 to 150.6) overall. The dispersion at CD4<350 cells/uL was 5.1 cells/uL (95% LOA: −126.6 to 136.8). For a threshold of CD4<350 cells/uL, PIMA venous blood had a sensitivity of 88.6% (95%CI 84.8–92.4%), specificity of 87.5% (95%CI 84.9–90.1%), NPV of 94.9% (95%CI 93.1–96.7%), and PPV of 74.4% (95%CI 69.6–79.2%). PIMA sensitivity and PPV significantly increased to 96.1% and 88.3% respectively with increased threshold of 500 cells/uL.
Conclusions
Overall, PIMA POC CD4 counts demonstrated negative bias compared to FACSCalibur. PIMA POC sensitivity improved significantly at a higher CD4 threshold of 500 than a 350 cells/uL threshold.
doi:10.1371/journal.pone.0088928
PMCID: PMC3948619  PMID: 24614083
9.  The Role of Viral Introductions in Sustaining Community-Based HIV Epidemics in Rural Uganda: Evidence from Spatial Clustering, Phylogenetics, and Egocentric Transmission Models 
PLoS Medicine  2014;11(3):e1001610.
Using different approaches to investigate HIV transmission patterns, Justin Lessler and colleagues find that extra-community HIV introductions are frequent and likely play a role in sustaining the epidemic in the Rakai community.
Please see later in the article for the Editors' Summary
Background
It is often assumed that local sexual networks play a dominant role in HIV spread in sub-Saharan Africa. The aim of this study was to determine the extent to which continued HIV transmission in rural communities—home to two-thirds of the African population—is driven by intra-community sexual networks versus viral introductions from outside of communities.
Methods and Findings
We analyzed the spatial dynamics of HIV transmission in rural Rakai District, Uganda, using data from a cohort of 14,594 individuals within 46 communities. We applied spatial clustering statistics, viral phylogenetics, and probabilistic transmission models to quantify the relative contribution of viral introductions into communities versus community- and household-based transmission to HIV incidence. Individuals living in households with HIV-incident (n = 189) or HIV-prevalent (n = 1,597) persons were 3.2 (95% CI: 2.7–3.7) times more likely to be HIV infected themselves compared to the population in general, but spatial clustering outside of households was relatively weak and was confined to distances <500 m. Phylogenetic analyses of gag and env genes suggest that chains of transmission frequently cross community boundaries. A total of 95 phylogenetic clusters were identified, of which 44% (42/95) were two individuals sharing a household. Among the remaining clusters, 72% (38/53) crossed community boundaries. Using the locations of self-reported sexual partners, we estimate that 39% (95% CI: 34%–42%) of new viral transmissions occur within stable household partnerships, and that among those infected by extra-household sexual partners, 62% (95% CI: 55%–70%) are infected by sexual partners from outside their community. These results rely on the representativeness of the sample and the quality of self-reported partnership data and may not reflect HIV transmission patterns outside of Rakai.
Conclusions
Our findings suggest that HIV introductions into communities are common and account for a significant proportion of new HIV infections acquired outside of households in rural Uganda, though the extent to which this is true elsewhere in Africa remains unknown. Our results also suggest that HIV prevention efforts should be implemented at spatial scales broader than the community and should target key populations likely responsible for introductions into communities.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
About 35 million people (25 million of whom live in sub-Saharan Africa) are currently infected with HIV, the virus that causes AIDS, and about 2.3 million people become newly infected every year. HIV destroys immune system cells, leaving infected individuals susceptible to other infections. HIV infection can be controlled by taking antiretroviral drugs (antiretroviral therapy, or ART) daily throughout life. Although originally available only to people living in wealthy countries, recent political efforts mean that 9.7 million people in low- and middle-income countries now have access to ART. However, ART does not cure HIV infection, so prevention of viral transmission remains extremely important. Because HIV is usually transmitted through unprotected sex with an infected partner, individuals can reduce their risk of infection by abstaining from sex, by having one or a few partners, and by using condoms. Male circumcision also reduces HIV transmission. In addition to reducing illness and death among HIV-positive people, ART also reduces HIV transmission.
Why Was This Study Done?
Effective HIV control requires an understanding of how HIV spreads through sexual networks. These networks include sexual partnerships between individuals in households, between community members in different households, and between individuals from different communities. Local sexual networks (household and intra-community sexual partnerships) are sometimes assumed to be the dominant driving force in HIV spread in sub-Saharan Africa, but are viral introductions from sexual partnerships with individuals outside the community also important? This question needs answering because the effectiveness of interventions such as ART as prevention partly depends on how many new infections in an intervention area are attributable to infection from partners residing in that area and how many are attributable to infection from partners living elsewhere. Here, the researchers use three analytical methods—spatial clustering statistics, viral phylogenetics, and egocentric transmission modeling—to ask whether HIV transmission in rural Uganda is driven predominantly by intra-community sexual networks. Spatial clustering analysis uses the geographical coordinates of households to measure the tendency of HIV-infected people to cluster spatially at scales consistent with community transmission. Viral phylogenetic analysis examines the genetic relatedness of viruses; if transmission is through local networks, viruses in newly infected individuals should more closely resemble viruses in other community members than those in people outside the community. Egocentric transmission modelling uses information on the locations of recent sexual partners to estimate the proportions of new transmissions from household, intra-community, and extra-community partners.
What Did the Researchers Do and Find?
The researchers applied their three analytical methods to data collected from 14,594 individuals living in 46 communities (governmental administrative units) in Rakai District, Uganda. Spatial clustering analysis indicated that individuals who lived in households with individuals with incident HIV (newly diagnosed) or prevalent HIV (previously diagnosed) were 3.2 times more likely than the general population to be HIV-positive themselves. Spatial clustering outside households was relatively weak, however, and was confined to distances of less than half a kilometer. Viral phylogenetic analysis indicated that 44% of phylogenetic clusters (viruses with related genetic sequences found in more than one individual) were within households, but that 40% of clusters crossed community borders. Finally, analysis of the locations of self-reported sexual partners indicated that 39% of new viral transmissions occurred within stable household partnerships, but that among people newly infected by extra-household partners, nearly two-thirds were infected by partners from outside their community.
What Do These Findings Mean?
The results of all three analyses suggest that HIV introductions into communities are frequent and are likely to play an important role in sustaining HIV transmission in the Rakai District. Specifically, within this rural HIV-endemic region (a region where HIV infection is always present), viral introductions combined with intra-household transmission account for the majority of new infections, although community-based sexual networks also play a critical role in HIV transmission. These findings may not be generalizable to the broader Ugandan population or to other regions of Africa, and their accuracy is likely to be limited by the use of self-reported sexual partner data. Nevertheless, these findings indicate that the dynamics of HIV transmission in rural Uganda (and probably elsewhere) are complex. Consequently, to halt the spread of HIV, prevention efforts will need to be implemented at spatial scales broader than individual communities, and key populations that are likely to introduce HIV into communities will need to be targeted.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001610.
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
NAM/aidsmap provides basic information about HIV/AIDS, and summaries of recent research findings on HIV care and treatment
Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including information on HIV and AIDS in Uganda and on HIV prevention strategies (in English and Spanish)
The UNAIDS Report on the Global AIDS Epidemic 2013 provides up-to-date information about the AIDS epidemic and efforts to halt it
The Center for AIDS Prevention Studies (University of California, San Francisco) has a fact sheet about sexual networks and HIV prevention
Wikipedia provides information on spatial clustering analysis (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
A PLOS Computational Biology Topic Page (a review article that is a published copy of record of a dynamic version of the article as found in Wikipedia) about viral phylodynamics is available
Personal stories about living with HIV/AIDS are available through Avert, NAM/aidsmap, and Healthtalkonline
doi:10.1371/journal.pmed.1001610
PMCID: PMC3942316  PMID: 24595023
10.  High-risk human papillomavirus prevalence is associated with HIV infection among heterosexual men in Rakai, Uganda 
Sexually transmitted infections  2012;89(2):122-127.
Objectives
Human papillomavirus (HPV) infection causes genital warts, penile cancer and cervical cancer. Africa has one of the highest rates of penile and cervical cancers, but there are little data on high-risk human papillomavirus (HR-HPV) prevalence in heterosexual men. Knowledge of HR-HPV prevalence, risk factors and genotype distribution among heterosexual men is important to establish risk-reduction prevention strategies.
Methods
1578 uncircumcised men aged 15–49 years who enrolled in male circumcision trials in Rakai, Uganda, were evaluated for HR-HPV from swabs of the coronal sulcus/glans using Roche HPV Linear Array. Adjusted prevalence risk ratios (adjPRRs) were estimated using modified Poisson multivariable regression.
Results
HPV prevalence (either high risk or low risk) was 90.7% (382/421) among HIV-positive men and 60.9% (596/978) among HIV-negative men (PRR 1.49, 95% CI 1.40 to 1.58). HIV-positive men had a significantly higher risk of infection with three or more HR-HPV genotypes (PRR = 5.76, 95% CI 4.27 to 7.79). Among HIV-positive men, high-risk sexual behaviours were not associated with increased HR-HPV prevalence. Among HIV-negative men, HR-HPV prevalence was associated with self-reported genital warts (adjPRR 1.57, 95% CI 1.07 to 2.31). Among all men (both HIV negative and HIV positive), HR-HPV prevalence was associated with more than 10 lifetime sexual partners (adjPRR 1.30, 95% CI 1.01 to 1.66), consistent condom use (adjPRR 1.31, 95% CI 1.08 to 1.60) and HIV infection (adjPRR 1.80, 95% CI 1.60 to 2.02). HR-HPV prevalence was lower among men who reported no sexual partners during the past year (adjPRR 0.47, 95% CI 0.23 to 0.94).
Conclusion
The burden of HR-HPV infection is high among heterosexual men in sub-Saharan Africa and most pronounced among the HIV-infected individuals.
doi:10.1136/sextrans-2012-050524
PMCID: PMC3640492  PMID: 22628661
11.  The accuracy of women’s reports of their partner’s male circumcision status in Rakai, Uganda 
AIDS (London, England)  2013;27(4):662-664.
We assessed whether women had accurate knowledge of their partners’ male circumcision (MC) status using survey data (2010–2011) from Rakai, Uganda, and examined characteristics of women who misreported MC status. Among couples in which men were uncircumcised (N=1744), 8.2% women misreported; and among couples where men were confirmed circumcised (N=759), 1.2% women misreported. Younger women were 2.2 times more likely to misreport compared to older women. Misreporting was not associated with other sociodemographics or behavioral characteristics. If women are to act as advocates for MC acceptance, there is a need to educate women, particularly younger women about the nature and recognition of MC.
doi:10.1097/QAD.0b013e32835c557c
PMCID: PMC3932992  PMID: 23169325
Female misreporting; male circumcision scale-up; women group
13.  Herpes Simplex Virus Type-2 (HSV-2) Assay Specificity and Male Circumcision to Reduce HSV-2 Acquisition 
AIDS (London, England)  2013;27(1):147-149.
Three male circumcision (MC) trials which enrolled over 10,000 men of different ages, settings (urban vs. rural), countries (Uganda, Kenya and South Africa), and which utilized different surgical techniques were consistent in showing a 51–60% in reduction in HIV incidence [1–5], and all three trials reported that MC decreased high-risk human papillomavirus (HR-HPV) prevalence by 32–35% [6–8].
doi:10.1097/QAD.0b013e32835aa181
PMCID: PMC3787836  PMID: 23221430
Herpes Simplex Virus Type-2 (HSV-2); male circumcision; HIV; Uganda; Kenya; sexually transmitted infections
14.  HIV-1 envelope replication and α4β7 utilization among newly infected subjects and their corresponding heterosexual partners 
Retrovirology  2013;10:162.
Background
Previous studies suggest that active selection limits the number of HIV-1 variants acquired by a newly infected individual from the diverse variants circulating in the transmitting partner. We compared HIV-1 envelopes from 9 newly infected subjects and their linked transmitting partner to explore potential mechanisms for selection.
Results
Recipient virus envelopes had significant genotypic differences compared to those present in the transmitting partner. Recombinant viruses incorporating pools of recipient and transmitter envelopes showed no significant difference in their sensitivity to receptor and fusion inhibitors, suggesting they had relatively similar entry capacity in the presence of low CD4 and CCR5 levels. Aggregate results in primary cells from up to 4 different blood or skin donors showed that viruses with envelopes from the transmitting partner as compared to recipient envelopes replicated more efficiently in CD4+ T cells, monocyte derived dendritic cell (MDDC) – CD4+ T cell co-cultures, Langerhans cells (LCs) – CD4+ T cell co-cultures and CD4+ T cells expressing high levels of the gut homing receptor, α4β7, and demonstrated greater binding to α4β7 high / CD8+ T cells. These transmitter versus recipient envelope virus phenotypic differences, however, were not always consistent among the primary cells from all the different blood or skin donation volunteers.
Conclusion
Although genotypically unique variants are present in newly infected individuals compared to the diverse swarm circulating in the chronically infected transmitting partner, replication in potential early target cells and receptor utilization either do not completely dictate this genetic selection, or these potential transmission phenotypes are lost very soon after HIV-1 acquisition.
doi:10.1186/1742-4690-10-162
PMCID: PMC3883469  PMID: 24369910
HIV-1; Envelope; Transmission; Receptor; Replication; Alpha4 beta7; Dendritic cells; Langerhans cells; Selection
15.  High Prevalence of Malaria Parasitemia and Anemia among Hospitalized Children in Rakai, Uganda 
PLoS ONE  2013;8(12):e82455.
Background
There is a paucity of data on malaria among hospitalized children in malaria endemic areas. We determined the prevalence, presentation and treatment outcomes of malaria and anemia among children in two hospitals in Rakai, Uganda.
Methods
Children under five years hospitalized in Kalisizo hospital or Bikira health center in Rakai district, Uganda between May 2011 and May 2012 were enrolled and followed-up until discharge, death or referral. Data were collected on social-demographic characteristics, current and past illnesses and clinical signs and symptoms. Blood smears, hemoglobin (Hgb) levels and HIV testing were performed from finger/heel prick blood. The associations between malaria infection and other factors were estimated using log-binomial regression to estimate adjusted prevalence risk ratios (aPRR) and 95% confidence intervals (CIs), controlling for clustering at health facilities.
Results
2471 children were enrolled. The most common medical presentations were fever (96.2%), cough (61.7%), vomiting (44.2%), diarrhea (20.8%), and seizures (16.0%). The prevalence of malaria parasitemia was 54.6%. Children with malaria were more likely to present with a history of fever (aPRR 2.23; CI 1.18–4.24) and seizures (aPRR 1.12; CI 1.09–1.16). Confirmed malaria was significantly lower among girls than boys (aPRR 0.92; CI 0.91–0.93), HIV infected children (aPRR 0.60 CI 0.52–0.71), and children with diarrhea (aPRR 0.76; CI 0.65–0.90). The overall prevalence of anemia (Hgb<10 g/dl) was 56.3% and severe anemia (Hgb<6 g/dL) was 17.8%. Among children with severe anemia 76.8% had malaria parasitemia, of whom 93.1% received blood transfusion. Malaria associated mortality was 0.6%.
Conclusion
There was a high prevalence of malaria parasitemia and anemia among inpatient children under five years. Malaria prevention is a priority in this population.
doi:10.1371/journal.pone.0082455
PMCID: PMC3866122  PMID: 24358185
16.  Antiretroviral Drug Susceptibility Among HIV-Infected Adults Failing Antiretroviral Therapy in Rakai, Uganda 
AIDS Research and Human Retroviruses  2012;28(12):1739-1744.
Abstract
We analyzed antiretroviral drug susceptibility in HIV-infected adults failing first- and second-line antiretroviral treatment (ART) in Rakai, Uganda. Samples obtained from participants at baseline (pretreatment) and at the time of failure on first-line ART and second-line ART were analyzed using genotypic and phenotypic assays for antiretroviral drug resistance. Test results were obtained from 73 samples from 38 individuals (31 baseline samples, 36 first-line failure samples, and six second-line failure samples). Four (13%) of the 31 baseline samples had mutations associated with resistance to nucleoside or nonnucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs, respectively). Among the 36 first-line failure samples, 31 (86%) had NNRTI resistance mutations and 29 (81%) had lamivudine resistance mutations; only eight (22%) had other NRTI resistance mutations. None of the six individuals failing a second-line protease inhibitor (PI)-based regimen had PI resistance mutations. Six (16%) of the participants had discordant genotypic and phenotypic test results. Genotypic resistance to drugs included in first-line ART regimens was detected prior to treatment and among participants failing first-line ART. PI resistance was not detected in individuals failing second-line ART. Surveillance for transmitted and acquired drug resistance remains a priority for scale-up of ART.
doi:10.1089/aid.2011.0352
PMCID: PMC3505045  PMID: 22443282
17.  Assessment of Changes in Risk Behaviors During 3 Years of Posttrial Follow-up of Male Circumcision Trial Participants Uncircumcised at Trial Closure in Rakai, Uganda 
American Journal of Epidemiology  2012;176(10):875-885.
Risk compensation associated with male circumcision has been a concern for male circumcision scale-up programs. Using posttrial data collected during 2007–2011 on 2,137 male circumcision trial participants who were uncircumcised at trial closure in Rakai, Uganda, the authors evaluated their sexual behavioral changes during approximately 3 years' follow-up after trial closure. Eighty-one percent of the men self-selected for male circumcision during the period, and their sociodemographic and risk profiles were comparable to those of men remaining uncircumcised. Linear models for marginal probabilities of repeated outcomes estimate that 3.3% (P < 0.0001) of the male circumcision acceptors reduced their engagement in nonmarital relations, whereas there was no significant change among men remaining uncircumcised. Significant decreases in condom use occurred in both male circumcision acceptors (−9.2% with all partners and −7.0% with nonmarital partners) and nonacceptors (−12.4% and −13.5%, respectively), and these were predominantly among younger men. However, the magnitudes of decrease in condom use were not significantly different between the 2 groups. Additionally, significant decreases in sex-related alcohol consumption were observed in both groups (−7.8% in male circumcision acceptors and −6.1% in nonacceptors), mainly among older men. In summary, there was no evidence of risk compensation associated with male circumcision among this cohort of men during 3 years of posttrial follow-up.
doi:10.1093/aje/kws179
PMCID: PMC3626062  PMID: 23097257
behavior changes; behavioral disinhibition; HIV prevention; male circumcision; Rakai; risk compensation
18.  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
19.  Combination implementation for HIV prevention: moving from evidence to population-level impact 
The Lancet infectious diseases  2013;13(1):65-76.
Summary
The promise of combination HIV prevention—the application of multiple HIV prevention interventions to maximize population-level impact—has never been greater. However, to succeed in achieving significant reductions in HIV incidence, an additional concept needs to be considered—combination implementation. Combination implementation for HIV prevention is defined here as the pragmatic, localized application of evidence-based strategies to realize high sustained uptake and quality of HIV prevention interventions. This review explores diverse implementation strategies including HIV testing and counseling models, task shifting, linkage to and retention in care, antiretroviral therapy support, behavior change, demand creation, and structural interventions and discusses how they could be used in the provision of HIV prevention interventions such as medical male circumcision and treatment as prevention. Only through careful consideration of how to implement and operationalize HIV prevention interventions will the HIV community be able to move from clinical trial evidence to population-level impact.
doi:10.1016/S1473-3099(12)70273-6
PMCID: PMC3792852  PMID: 23257232
20.  A Qualitative Study of Barriers to Enrollment into Free HIV Care: Perspectives of Never-in-Care HIV-Positive Patients and Providers in Rakai, Uganda 
BioMed Research International  2013;2013:470245.
Background. Early entry into HIV care is low in Sub-Saharan Africa. In Rakai, about a third (31.5%) of HIV-positive clients who knew their serostatus did not enroll into free care services. This qualitative study explored barriers to entry into care from HIV-positive clients who had never enrolled in care and HIV care providers. Methods. We conducted 48 in-depth interviews among HIV-infected individuals aged 15–49 years, who had not entered care within six months of result receipt and referral for free care. Key-informant interviews were conducted with 12 providers. Interviews were audio-recorded and transcripts subjected to thematic content analysis based on the health belief model. Results. Barriers to using HIV care included fear of stigma and HIV disclosure, women's lack of support from male partners, demanding work schedules, and high transport costs. Programmatic barriers included fear of antiretroviral drug side effects, long waiting and travel times, and inadequate staff respect for patients. Denial of HIV status, belief in spiritual healing, and absence of AIDS symptoms were also barriers. Conclusion. Targeted interventions to combat stigma, strengthen couple counseling and health education programs, address gender inequalities, and implement patient-friendly and flexible clinic service hours are needed to address barriers to HIV care.
doi:10.1155/2013/470245
PMCID: PMC3766571  PMID: 24058908
21.  Human papillomavirus incidence and clearance among HIV-positive and HIV-negative men in Rakai, Uganda 
AIDS (London, England)  2012;26(12):1555-1565.
Objectives
High-risk human papillomavirus (HR-HPV) infection is the most common sexually transmitted infection. Penile and cervical cancer rates are highest in sub-Saharan Africa. However, little is known about the impact of HIV infection on HR-HPV acquisition and clearance among heterosexual men.
Design
HR-HPV incidence and clearance were evaluated in 999 men (776 HIV-negative and 223 HIV-positive) aged 15–49 who participated in male circumcision trials in Rakai, Uganda.
Methods
Penile swabs were tested for HR-HPV by Roche HPV Linear Array. A Poisson multivariable model was used to estimate adjusted incidence rate ratios (adjIRR) and clearance risk ratios (adjRR).
Results
HR-HPV incidence was 66.5/100 py in HIV-positive men and 32.9/100 py among HIV-negative men (IRR=2.0, 95%CI 1.7–2.4). Incidence was higher with non-marital status (adjIRR=1.7, 95%CI 1.2–2.5), and decreased with age (adjIRR=0.6, 95%CI 0.4–1.0) and male circumcision (adjIRR=0.7, 95%CI 0.6–0.9). HR-HPV clearance was 114.7/100 py for HIV-positive men and 170.2/100 py for HIV-negative men (RR=0.7, 95%I 0.6–0.8). Clearance in HIV-negative men was increased with circumcision (adjRR=1.5, 95%CI 1.3–1.7), HSV-2 infection (adjRR=1.2, 95%CI 1.0–1.4), and symptoms of urethral discharge (adjRR=1.4, 95%CI 1.1–1.7).
Conclusions
HR-HPV is common among heterosexual Ugandan men, particularly the HIV-infected. HIV infection increases HR-HPV acquisition and reduces HR-HPV clearance. Promotion of male circumcision and HPV vaccination is critical in sub-Saharan Africa.
doi:10.1097/QAD.0b013e328353b83c
PMCID: PMC3442933  PMID: 22441255
Human papillomavirus (HPV); HIV; male circumcision; Uganda
22.  The Rates of HIV Superinfection and Primary HIV Incidence in a General Population in Rakai, Uganda 
The Journal of Infectious Diseases  2012;206(2):267-274.
Background. Human immunodeficiency virus (HIV) superinfection has been documented in high-risk individuals; however, the rate of superinfection among HIV-infected individuals within a general population remains unknown.
Methods. A novel next-generation ultra-deep sequencing technique was utilized to determine the rate of HIV superinfection in a heterosexual population by examining two regions of the viral genome in longitudinal samples from recent HIV seroconverters (n = 149) in Rakai District, Uganda.
Results. The rate of superinfection was 1.44 per 100 person years (PYs) (95% confidence interval [CI], .4–2.5) and consisted of both inter- and intrasubtype superinfections. This was compared to primary HIV incidence in 20 220 initially HIV-negative individuals in the general population in Rakai (1.15 per 100 PYs; 95% CI, 1.1–1.2; P = .26). Propensity score matching (PS) was used to control for differences in sociodemographic and behavioral characteristics between the HIV-positive individuals at risk for superinfection and the HIV-negative population at baseline and follow-up. After PS matching, the estimated rate of primary incidence was 3.28 per 100 PYs (95% CI, 2.0–5.3; P = .07) controlling for baseline differences and 2.51 per 100 PYs (95% CI, 1.5–4.3; P = .24) controlling for follow-up differences.
Conclusions. This suggests that the rate of HIV superinfection in a general population is substantial, which could have a significant impact on future public health and HIV vaccine strategies.
doi:10.1093/infdis/jis325
PMCID: PMC3415936  PMID: 22675216
23.  HIV Type 1 Genetic Variation in Foreskin and Blood from Subjects in Rakai, Uganda 
Abstract
The foreskin contains a subset of dendritic cells, macrophages, and CD4+ and CD8+ T cells that may be targets for initial HIV infection in female-to-male sexual transmission of HIV-1. We present analyses comparing HIV-1 sequences isolated from foreskin DNA and serum RNA in 12 heterosexual men enrolled in an adult male circumcision trial performed in Rakai, Uganda. Phylogenetic analysis demonstrated three topologies: (1) little divergence between foreskin and serum, (2) multiple genetic bottlenecks occurring in both foreskin and serum, and (3) complete separation of foreskin and serum populations. The latter tree topology provided evidence that foreskin may serve as a reservoir for distinct HIV-1 strains. Distance and recombination analysis also demonstrated that viral genotypes in the foreskin might segregate independently from the circulating pool of viruses.
doi:10.1089/aid.2011.0176
PMCID: PMC3380386  PMID: 21902587
24.  Trends in HIV counseling and testing uptake among married individuals in Rakai, Uganda 
BMC Public Health  2013;13:618.
Background
Despite efforts to promote HIV counseling and testing (HCT) among couples, few couples know their own or their partners’ HIV status. We assessed trends in HCT uptake among married individuals in Rakai district, southwestern Uganda.
Methods
We analysed data for 21,798 married individuals aged 15-49 years who were enrolled into the Rakai Community Cohort Study (RCCS) between 2003 and 2009. Married individuals were interviewed separately but were retrospectively linked to their partners at analysis. All participants had serologic samples obtained for HIV testing, and had the option of receiving HCT together (couples’ HCT) or separately (individual HCT). Individuals were categorized as concordant HIV-positive if both partners had HIV; concordant HIV-negative if both did not have HIV; or HIV-discordant if only one of the partners had HIV. We used χ2 tests to assess linear trends in individual and couples’ HCT uptake in the entire sample and conducted multinomial logistic regression on a sub-sample of 10,712 individuals to assess relative risk ratios (RRR) and 95% Confidence Intervals (95% CI) associated with individual and couples’ HCT uptake. Analysis was done using STATA version 11.0.
Results
Uptake of couples’ HCT was 27.2% in 2003/04, 25.1% in 2005/06, 28.5% in 2006/08 and 27.8% in 2008/09 (χ2 for trend = 2.38; P = 0.12). Uptake of individual HCT was 57.9% in 2003/04, 60.2% in 2005/06, 54.0% in 2006/08 and 54.4% in 2008/09 (χ2 for trend = 8.72; P = 0.003). The proportion of couples who had never tested increased from 14.9% in 2003/04 to 17.8% in 2008/09 (χ2 for trend = 18.16; P < 0.0001). Uptake of couples’ HCT was significantly associated with prior HCT (Adjusted [Adj.] RRR = 6.80; 95% CI: 5.44, 8.51) and being 25-34 years of age (Adj. RRR = 1.81; 95% CI: 1.32, 2.50). Uptake of individual HCT was significantly associated with prior HCT (Adj. RRR = 6.26; 95% CI: 4.24, 9.24) and the female partner being HIV-positive (Adj. RRR = 2.46; 95% CI: 1.26, 4.80).
Conclusion
Uptake of couples’ HCT remained consistently low (below 30%) over the years, while uptake of individual HCT declined over time. These findings call for innovative strategies to increase demand for couples’ HCT, particularly among younger couples and those with no prior HCT.
doi:10.1186/1471-2458-13-618
PMCID: PMC3702530  PMID: 23816253
Trends; HCT; Uptake; Married; Couples; Rakai
25.  Risk factors for intimate partner violence in women in the Rakai Community Cohort Study, Uganda, from 2000 to 2009 
BMC Public Health  2013;13:566.
Background
Intimate partner violence (IPV) is a significant public health problem. There is a lack of data on IPV risk factors from longitudinal studies and from low and middle income countries. Identifying risk factors is needed to inform the design of appropriate IPV interventions.
Methods
Data were from the Rakai Community Cohort Study annual surveys between 2000 and 2009. Female participants who had at least one sexual partner during this period and had data on IPV over the study period were included in analyses (N = 15081). Factors from childhood and early adulthood as well as contemporary factors were considered in separate models. Logistic regression was used to assess early risk factors for IPV during the study period. Longitudinal data analysis was used to assess contemporary risk factors in the past year for IPV in the current year, using a population-averaged multivariable logistic regression model.
Results
Risk factors for IPV from childhood and early adulthood included sexual abuse in childhood or adolescence, earlier age at first sex, lower levels of education, and forced first sex. Contemporary risk factors included younger age, being married, relationships of shorter duration, having a partner who is the same age or younger, alcohol use before sex by women and by their partners, and thinking that violence is acceptable. HIV infection and pregnancy were not associated with an increased odds of IPV.
Conclusions
Using longitudinal data, this study identified a number of risk factors for IPV. These findings are useful for the development of prevention strategies to prevent and mitigate IPV in women.
doi:10.1186/1471-2458-13-566
PMCID: PMC3701515  PMID: 23759123
Intimate Partner Violence; Risk Factors; Cohort; Women; Rakai; Uganda

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