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1.  Indices to Measure Risk of HIV Acquisition in Rakai, Uganda 
PLoS ONE  2014;9(4):e92015.
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.
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.
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.
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.
PMCID: PMC3976261  PMID: 24704778
2.  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
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.
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
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
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
PMCID: PMC3942316  PMID: 24595023
3.  High-risk human papillomavirus prevalence is associated with HIV infection among heterosexual men in Rakai, Uganda 
Sexually transmitted infections  2012;89(2):122-127.
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.
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.
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).
The burden of HR-HPV infection is high among heterosexual men in sub-Saharan Africa and most pronounced among the HIV-infected individuals.
PMCID: PMC3640492  PMID: 22628661
4.  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.
PMCID: PMC3932992  PMID: 23169325
Female misreporting; male circumcision scale-up; women group
6.  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].
PMCID: PMC3787836  PMID: 23221430
Herpes Simplex Virus Type-2 (HSV-2); male circumcision; HIV; Uganda; Kenya; sexually transmitted infections
7.  Antiretroviral Drug Susceptibility Among HIV-Infected Adults Failing Antiretroviral Therapy in Rakai, Uganda 
AIDS Research and Human Retroviruses  2012;28(12):1739-1744.
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.
PMCID: PMC3505045  PMID: 22443282
8.  Effect of injectable contraceptive use on response to antiretroviral therapy among women in Rakai, Uganda 
Contraception  2012;86(6):725-730.
There is limited evidence on the effect of injectable contraception on response to antiretroviral therapy (ART).
Using modified Poisson regression, we assessed data from 418 female Ugandan ART initiators to examine the effect of injectable contraceptive use on a composite virologic failure outcome (defined as failure to achieve virologic suppression, switch to second line therapy, or death within 12 months of ART initiation), and also assessed ART adherence.
About 12% of women reported using injectable contraceptives at ART initiation, and their composite virologic failure rates 12 months later were similar to women not using injectable contraceptives at ART initiation (11% vs. 12%, p=0.99). Multivariable Poisson regression suggested no significant differences in virologic failure by injectable contraceptive use at baseline (PRR: 0.85, p=0.71), but power was limited. Adherence to ART increased with time since ART initiation, but did not appear to differ between injectable contraceptive users and non-users.
Consistent with current WHO guidelines, our results suggest no deleterious effect of injectable contraceptive use on response to ART, but power was limited, injectable contraceptive use patterns over time were inconsistent, and additional evidence is needed.
PMCID: PMC3449005  PMID: 22717186
family planning; hormonal contraception; injectable contraception; HIV; antiretroviral therapy; Uganda
9.  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.
PMCID: PMC3626062  PMID: 23097257
behavior changes; behavioral disinhibition; HIV prevention; male circumcision; Rakai; risk compensation
10.  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.
PMCID: PMC3466994  PMID: 22997233
11.  Combination implementation for HIV prevention: moving from evidence to population-level impact 
The Lancet infectious diseases  2013;13(1):65-76.
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.
PMCID: PMC3792852  PMID: 23257232
12.  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.
PMCID: PMC3766571  PMID: 24058908
13.  Human papillomavirus incidence and clearance among HIV-positive and HIV-negative men in Rakai, Uganda 
AIDS (London, England)  2012;26(12):1555-1565.
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.
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.
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).
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).
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.
PMCID: PMC3442933  PMID: 22441255
Human papillomavirus (HPV); HIV; male circumcision; Uganda
14.  Non-enrollment for free community HIV care: findings from a population-based study in Rakai, Uganda 
AIDS care  2011;23(6):764-770.
Improved understanding of HIV-related health-seeking behavior at a population level is important in informing the design of more effective HIV prevention and care strategies. We assessed the frequency and determinants of failure to seek free HIV care in Rakai, Uganda. HIV-positive participants in a community cohort who accepted VCT were referred for free HIV care (cotrimoxazole prophylaxis, CD4 monitoring, treatment of opportunistic infections, and, when indicated, antiretroviral therapy). We estimated proportion and adjusted Prevalence Risk Ratios (adj. PRR) of non-enrollment into care six months after receipt of VCT using log-binomial regression. About 1145 HIV-positive participants in the Rakai Community Cohort Study accepted VCT and were referred for care. However, 31.5% (361/1145) did not enroll into HIV care six months after referral. Non-enrollment was significantly higher among men (38%) compared to women (29%, p=0.005). Other factors associated with non-enrollment included: younger age (15–24 years, adj. PRR=2.22; 95% CI: 1.64, 3.00), living alone (adj. PRR=2.22; 95% CI: 1.57, 3.15); or in households with 1–2 co-residents (adj. PRR=1.63; 95% CI: 1.31, 2.03) compared to three or more co-residents, or a CD4 count >250 cells/ul (adj. PRR=1.81; 95% CI: 1.38, 2.46). Median (IQR) CD4 count was lower among enrolled 388 cells/ul (IQR: 211,589) compared to those not enrolled 509 cells/ul (IQR: 321,754).
About one-third of HIV-positive persons failed to utilize community-based free services. Non-use of services was greatest among men, the young, persons with higher CD4 counts and the more socially isolated, suggesting a need for targeted strategies to enhance service uptake.
PMCID: PMC3722430  PMID: 21293989
HIV; HIV care; enrollment
15.  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.
PMCID: PMC3415936  PMID: 22675216
16.  HIV Type 1 Genetic Variation in Foreskin and Blood from Subjects in Rakai, Uganda 
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.
PMCID: PMC3380386  PMID: 21902587
17.  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.
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.
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.
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.
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.
PMCID: PMC3701515  PMID: 23759123
Intimate Partner Violence; Risk Factors; Cohort; Women; Rakai; Uganda
18.  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.
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
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, number NCT00405821.
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).
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.
PMCID: PMC3420068  PMID: 22433279
HIV-1; herpes simplex virus; acyclovir; disease progression
19.  Male Circumcision Significantly Reduces Prevalence and Load of Genital Anaerobic Bacteria 
mBio  2013;4(2):e00076-13.
Male circumcision reduces female-to-male HIV transmission. Hypothesized mechanisms for this protective effect include decreased HIV target cell recruitment and activation due to changes in the penis microbiome. We compared the coronal sulcus microbiota of men from a group of uncircumcised controls (n = 77) and from a circumcised intervention group (n = 79) at enrollment and year 1 follow-up in a randomized circumcision trial in Rakai, Uganda. We characterized microbiota using16S rRNA gene-based quantitative PCR (qPCR) and pyrosequencing, log response ratio (LRR), Bayesian classification, nonmetric multidimensional scaling (nMDS), and permutational multivariate analysis of variance (PerMANOVA). At baseline, men in both study arms had comparable coronal sulcus microbiota; however, by year 1, circumcision decreased the total bacterial load and reduced microbiota biodiversity. Specifically, the prevalence and absolute abundance of 12 anaerobic bacterial taxa decreased significantly in the circumcised men. While aerobic bacterial taxa also increased postcircumcision, these gains were minor. The reduction in anaerobes may partly account for the effects of circumcision on reduced HIV acquisition.
The bacterial changes identified in this study may play an important role in the HIV risk reduction conferred by male circumcision. Decreasing the load of specific anaerobes could reduce HIV target cell recruitment to the foreskin. Understanding the mechanisms that underlie the benefits of male circumcision could help to identify new intervention strategies for decreasing HIV transmission, applicable to populations with high HIV prevalence where male circumcision is culturally less acceptable.
PMCID: PMC3634604  PMID: 23592260
20.  Efficiency of CCR5 Coreceptor Utilization by the HIV Quasispecies Increases over Time, But Is Not Associated with Disease Progression 
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.
PMCID: PMC3292754  PMID: 21663455
21.  Comparison of a High-Resolution Melting Assay to Next-Generation Sequencing for Analysis of HIV Diversity 
Journal of Clinical Microbiology  2012;50(9):3054-3059.
Next-generation sequencing (NGS) has recently been used for analysis of HIV diversity, but this method is labor-intensive, costly, and requires complex protocols for data analysis. We compared diversity measures obtained using NGS data to those obtained using a diversity assay based on high-resolution melting (HRM) of DNA duplexes. The HRM diversity assay provides a single numeric score that reflects the level of diversity in the region analyzed. HIV gag and env from individuals in Rakai, Uganda, were analyzed in a previous study using NGS (n = 220 samples from 110 individuals). Three sequence-based diversity measures were calculated from the NGS sequence data (percent diversity, percent complexity, and Shannon entropy). The amplicon pools used for NGS were analyzed with the HRM diversity assay. HRM scores were significantly associated with sequence-based measures of HIV diversity for both gag and env (P < 0.001 for all measures). The level of diversity measured by the HRM diversity assay and NGS increased over time in both regions analyzed (P < 0.001 for all measures except for percent complexity in gag), and similar amounts of diversification were observed with both methods (P < 0.001 for all measures except for percent complexity in gag). Diversity measures obtained using the HRM diversity assay were significantly associated with those from NGS, and similar increases in diversity over time were detected by both methods. The HRM diversity assay is faster and less expensive than NGS, facilitating rapid analysis of large studies of HIV diversity and evolution.
PMCID: PMC3421787  PMID: 22785188
22.  Male Circumcision and Herpes Simplex Virus Type 2 Infection in Female Partners: A Randomized Trial in Rakai, Uganda 
The Journal of Infectious Diseases  2011;205(3):486-490.
Male circumcision reduces acquisition of herpes simplex virus type 2 (HSV-2) in men. We assessed whether male circumcision reduces HSV-2 infection among female partners. HSV-2–negative, human immunodeficiency virus–negative female partners of 368 males who were and 372 males who were not randomized to receive male circumcision were enrolled. The incidence of HSV-2 infection among females over a period of 2 years was 6.09 cases per 100 person-years in the intervention arm and 6.32 cases per 100 person-years in the control arm (incidence rate ratio [IRR], 0.96 [95% confidence interval {CI}, .62–1.49]; P = .87). Among female partners of HSV-2–positive males, the incidence of HSV-2 infection was 9.55 cases per 100 person-years in the intervention arm and 11.17 cases per 100 person-years in the control arm (IRR, 0.85 [95% CI, .44–1.67]; P = .62). Contrary to findings in males, male circumcision did not affect HSV-2 acquisition among female partners.
PMCID: PMC3256952  PMID: 22147796
23.  Male Circumcision and Anatomic Sites of Penile High-Risk Human Papillomavirus in Rakai, Uganda 
Male circumcision (MC) reduces penile high-risk human papillomavirus (HR-HPV) on the coronal sulcus and urethra. HR-HPV varies by anatomic site, and it is unknown whether MC decreases HR-HPV on the penile shaft. We assessed the efficacy of MC to reduce HR-HPV on the penile shaft and compared it to known efficacy of MC to reduce HR-HPV on the coronal sulcus. HIV-negative men randomized to receive immediate circumcision (intervention) or circumcision delayed for 24 months (control) were evaluated for HR-HPV at 12 months post-enrollment using the Roche HPV Linear Array assay. Among swabs with detectable beta-globin or HPV, year 1 HR-HPV prevalence on the coronal sulcus was 21.5% in the intervention arm and 36.3% in the control arm men (adjusted prevalence risk ratios (PRR)=0.57, 95%CI 0.39–0.84, p=0.005). On the shaft, year 1 HR-HPV prevalence was 15.5% in the intervention and 23.8% in the control arm (adjusted PRR=0.66, 95%CI 0.39–1.12, p=0.12). Efficacy of MC to reduce HR-HPV on the shaft was similar to efficacy on the coronal sulcus (p=0.52). In a sensitivity analysis in which swabs without detectable beta-globin or HPV were included as HPV negative, prevalence of HR-HPV on the shaft was lower in the intervention arm (7.8%) than control arm (13.6%) (PRR 0.57, 95%CI 0.33–0.99, p<0.05). HR-HPV was more frequently detected on the coronal sulcus than penile shaft among uncircumcised men (36.3% vs 23.8%, respectively, p=0.02) and circumcised men (21.5% vs 15.5%, respectively, p=0.24). MC reduced HR-HPV prevalence on both the coronal sulcus and shaft.
PMCID: PMC3193547  PMID: 21462185
Male circumcision; human papillomavirus (HPV); HIV; Uganda; foreskin; penis; coronal sulcus; penile shaft; cervical cancer; sexually transmitted infections
24.  Traditional Herbal Medicine Use Associated with Liver Fibrosis in Rural Rakai, Uganda 
PLoS ONE  2012;7(11):e41737.
Traditional herbal medicines are commonly used in sub-Saharan Africa and some herbs are known to be hepatotoxic. However little is known about the effect of herbal medicines on liver disease in sub-Saharan Africa.
500 HIV-infected participants in a rural HIV care program in Rakai, Uganda, were frequency matched to 500 HIV-uninfected participants. Participants were asked about traditional herbal medicine use and assessed for other potential risk factors for liver disease. All participants underwent transient elastography (FibroScan®) to quantify liver fibrosis. The association between herb use and significant liver fibrosis was measured with adjusted prevalence risk ratios (adjPRR) and 95% confidence intervals (CI) using modified Poisson multivariable logistic regression.
19 unique herbs from 13 plant families were used by 42/1000 of all participants, including 9/500 HIV-infected participants. The three most-used plant families were Asteraceae, Fabaceae, and Lamiaceae. Among all participants, use of any herb (adjPRR = 2.2, 95% CI 1.3–3.5, p = 0.002), herbs from the Asteraceae family (adjPRR = 5.0, 95% CI 2.9–8.7, p<0.001), and herbs from the Lamiaceae family (adjPRR = 3.4, 95% CI 1.2–9.2, p = 0.017) were associated with significant liver fibrosis. Among HIV infected participants, use of any herb (adjPRR = 2.3, 95% CI 1.0–5.0, p = 0.044) and use of herbs from the Asteraceae family (adjPRR = 5.0, 95% CI 1.7–14.7, p = 0.004) were associated with increased liver fibrosis.
Traditional herbal medicine use was independently associated with a substantial increase in significant liver fibrosis in both HIV-infected and HIV-uninfected study participants. Pharmacokinetic and prospective clinical studies are needed to inform herb safety recommendations in sub-Saharan Africa. Counseling about herb use should be part of routine health counseling and counseling of HIV-infected persons in Uganda.
PMCID: PMC3507824  PMID: 23209545
25.  The natural history of bacterial vaginosis (BV) diagnosed by Gram stain among women in Rakai, Uganda 
Sexually transmitted diseases  2011;38(11):1040-1045.
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.
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.
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.
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.
PMCID: PMC3192988  PMID: 21992981

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