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1.  Family structure effects on early sexual debut among adolescent girls in Rakai, Uganda 
This study assessed the association between household family structure and early sexual debut among adolescent girls, ages 15-19, in rural Rakai District, Uganda. Early sexual debut is associated with detrimental physical, emotional and social outcomes, including increased risk of HIV. However, research on the family's role on adolescents' sexual risk behaviors in sub-Sahara Africa has been minimal and rarely takes into account the varying family structures within which African adolescents develop. Using six rounds of survey data (2001-2008) from the Rakai Community Cohort Study, unmarried adolescent girls (n=1940) aged 15-17 at their baseline survey, were followed until age 19. Parametric survival models showed that compared to adolescent girls living with both biological parents, girls who headed their own household and girls living with step-fathers, grandparents, siblings, or other relatives had significantly higher hazards of early sexual debut before age 16. Adolescent girls were significantly more likely to debut sexually if neither parent resided in the household, either due to death or other reasons. In addition, absence of the living biological father from the home was associated with higher risk of sexual debut, regardless of the biological mother's presence in the home. Our study's findings suggest that family structure is important to adolescent girls' sexual behavior. There is need for research to understand the underlying processes, interactions and dynamics of both low and high risk family structures in order to devise and strategically target interventions targeted for specific types of family structures.
doi:10.1080/17450128.2013.842027
PMCID: PMC4194054  PMID: 25317199
2.  Penile Microbiota and Female Partner Bacterial Vaginosis in Rakai, Uganda 
mBio  2015;6(3):e00589-15.
ABSTRACT
Bacterial vaginosis (BV) is a common vaginal bacterial imbalance associated with risk for HIV and poor gynecologic and obstetric outcomes. Male circumcision reduces BV-associated bacteria on the penis and decreases BV in female partners, but the link between penile microbiota and female partner BV is not well understood. We tested the hypothesis that having a female partner with BV increases BV-associated bacteria in uncircumcised men. We characterized penile microbiota composition and density (i.e., the quantity of bacteria per swab) by broad-coverage 16S rRNA gene-based sequencing and quantitative PCR (qPCR) in 165 uncircumcised men from Rakai, Uganda. Associations between penile community state types (CSTs) and female partner’s Nugent score were assessed. We found seven distinct penile CSTs of increasing density (CST1 to 7). CST1 to 3 and CST4 to 7 were the two major CST groups. CST4 to 7 had higher prevalence and abundance of BV-associated bacteria, such as Mobiluncus and Dialister, than CST1 to 3. Men with CST4 to 7 were significantly more likely to have a female partner with a high Nugent score (P = 0.03). Men with two or more extramarital partners were significantly more likely to have CST4 to 7 than men with only marital partners (CST4 to 7 prevalence ratio, 1.84; 95% confidence interval [CI], 1.16 to 2.92). Female partner Nugent BV is significantly associated with penile microbiota. Our data support the exchange of BV-associated bacteria through intercourse, which may explain BV recurrence and persistence.
IMPORTANCE
Bacterial vaginosis (BV) is sexually associated but not considered a sexually transmitted disease. Our findings suggest that the uncircumcised penis is an important niche for BV-associated genital anaerobes. In addition, we found a link between extramarital sexual relationships and BV-associated bacteria in men, which parallels earlier findings of the association between sexual activity and BV in women. This suggests the sexual transmissibility of BV-associated bacteria. Reducing bacterial exchange by barrier methods and managing carriage of BV-associated bacteria in men may decrease BV persistence and recurrence in women.
doi:10.1128/mBio.00589-15
PMCID: PMC4471566  PMID: 26081632
3.  Correlates of previous couples’ HIV counseling and testing uptake among married individuals in three HIV prevalence strata in Rakai, Uganda 
Global Health Action  2015;8:10.3402/gha.v8.27935.
Background
Studies show that uptake of couples’ HIV counseling and testing (couples’ HCT) can be affected by individual, relationship, and socioeconomic factors. However, while couples’ HCT uptake can also be affected by background HIV prevalence and awareness of the existence of couples’ HCT services, this is yet to be documented. We explored the correlates of previous couples’ HCT uptake among married individuals in a rural Ugandan district with differing HIV prevalence levels.
Design
This was a cross-sectional study conducted among 2,135 married individuals resident in the three HIV prevalence strata (low HIV prevalence: 9.7–11.2%; middle HIV prevalence: 11.4–16.4%; and high HIV prevalence: 20.5–43%) in Rakai district, southwestern Uganda, between November 2013 and February 2014. Data were collected on sociodemographic and behavioral characteristics, including previous receipt of couples’ HCT. HIV testing data were obtained from the Rakai Community Cohort Study. We conducted multivariable logistic regression analysis to identify correlates that are independently associated with previous receipt of couples’ HCT. Data analysis was conducted using STATA (statistical software, version 11.2).
Results
Of the 2,135 married individuals enrolled, the majority (n=1,783, 83.5%) had been married for five or more years while (n=1,460, 66%) were in the first-order of marriage. Ever receipt of HCT was almost universal (n=2,020, 95%); of those ever tested, (n=846, 41.9%) reported that they had ever received couples’ HCT. There was no significant difference in previous receipt of couples’ HCT between low (n=309, 43.9%), middle (n=295, 41.7%), and high (n=242, 39.7%) HIV prevalence settings (p=0.61). Marital order was not significantly associated with previous receipt of couples’ HCT. However, marital duration [five or more years vis-à-vis 1–2 years: adjusted odds ratio (aOR): 1.06; 95% confidence interval (95% CI): 1.04–1.08] and awareness about the existence of couples’ HCT services within the Rakai community cohort (aOR: 7.58; 95% CI: 5.63–10.20) were significantly associated with previous receipt of couples’ HCT.
Conclusions
Previous couples’ HCT uptake did not significantly differ by HIV prevalence setting. Longer marital duration and awareness of the existence of couples’ HCT services in the community were significantly correlated with previous receipt of couples’ HCT. These findings suggest a need for innovative demand–creation interventions to raise awareness about couples’ HCT service availability to improve couples’ HCT uptake among married individuals.
doi:10.3402/gha.v8.27935
PMCID: PMC4461755  PMID: 26058858
HIV counseling; testing; married individuals; Rakai; Uganda
4.  Durable Suppression of HIV-1 after Virologic Monitoring-Based Antiretroviral Adherence Counseling in Rakai, Uganda 
PLoS ONE  2015;10(5):e0127235.
Objectives
HIV viral load is recommended for monitoring antiretroviral treatment and identifying treatment failure. We assessed the durability of viral suppression after viral load-triggered adherence counseling among patients with HIV viremia 6 months after ART initiation.
Design
Observational cohort enrolled in an antiretroviral treatment program in rural Uganda.
Methods
Participants who underwent routine viral load determination every 24 weeks and had at least 48 weeks of follow-up were included in this analysis. Patients with viral loads >400 copies/ml at 24 weeks of treatment were given additional adherence counseling, and all patients were followed to assess the duration of viral suppression and development of virologic failure.
Results
1,841 participants initiating antiretroviral therapy were enrolled in the Rakai Health Sciences Program between June 2005 and June 2011 and were followed with viral load monitoring every 24 weeks. 148 (8%) of patients did not achieve viral suppression at 24 weeks and were given additional adherence counseling. 85 (60%) of these patients had undetectable viral loads at 48 weeks, with a median duration of viral suppression of 240 weeks (IQR 193-288 weeks). Failure to achieve an undetectable viral load at 48 weeks was associated with age <30 years and 24 week viral load >2,000 copies/ml in multivariate logistic regression analysis.
Conclusions
The majority of patients with persistent viremia who were provided adherence counseling achieved robust viral suppression for a median 4.6 years. Access to virologic monitoring and adherence counseling is a priority in resource-limited settings.
doi:10.1371/journal.pone.0127235
PMCID: PMC4444255  PMID: 26011158
5.  Sexual Coercion among Adolescent Women in Rakai, Uganda: Does Family Structure Matter? 
Journal of interpersonal violence  2013;28(6):1289-1313.
Studies on adolescent girls’ vulnerability to sexual coercion in sub-Saharan Africa have focused mainly on individual and partner risk factors, rarely investigating the role the family might play in their vulnerability. This study examined whether household family structure and parental vital status were associated with adolescent girls’ risk of sexual coercion in Rakai, Uganda. Modified Poisson regression was used to estimate relative risk of sexual coercion in the prior twelve months among 1985 unmarried and married adolescent girls aged 15–19 who were participants in the Rakai Community Cohort Study between 2001 and 2008. Among sexually active girls, 11% reported coercion in a given past year. Unexpectedly, living with a single mother was protective against experiencing coercion. 4.1% of never-married girls living with single mothers reported coercion, compared to 7.8% of girls living with biological fathers (adjRR 2.24; 95% CI: 0.98–5.08) and 20% of girls living in step-father households (adjRR 4.73; 95% CI: 1.78–12.53). Ever-married girls whose mothers alone were deceased were more likely to report coercion than those with both parents alive (adjRR 1.56; 95% CI: 1.08–2.30). Protecting adolescent girls from sexual coercion requires prevention approaches which incorporate the family, with particular emphasis on including the men that affect young girls’ sexual development into prevention efforts. Understanding the family dynamics underlying the risk and protective effects of a given household structure might highlight new ways in which to prevent sexual coercion.
doi:10.1177/0886260512468246
PMCID: PMC4415158  PMID: 23295373
6.  HIV Shedding from Male Circumcision Wounds in HIV-Infected Men: A Prospective Cohort Study 
PLoS Medicine  2015;12(4):e1001820.
Background
A randomized trial of voluntary medical male circumcision (MC) of HIV—infected men reported increased HIV transmission to female partners among men who resumed sexual intercourse prior to wound healing. We conducted a prospective observational study to assess penile HIV shedding after MC.
Methods and Findings
HIV shedding was evaluated among 223 HIV—infected men (183 self—reported not receiving antiretroviral therapy [ART], 11 self—reported receiving ART and had a detectable plasma viral load [VL], and 29 self—reported receiving ART and had an undetectable plasma VL [<400 copies/ml]) in Rakai, Uganda, between June 2009 and April 2012. Preoperative and weekly penile lavages collected for 6 wk and then at 12 wk were tested for HIV shedding and VL using a real—time quantitative PCR assay. Unadjusted prevalence risk ratios (PRRs) and adjusted PRRs (adjPRRs) of HIV shedding were estimated using modified Poisson regression with robust variance. HIV shedding was detected in 9.3% (17/183) of men not on ART prior to surgery and 39.3% (72/183) of these men during the entire study. Relative to baseline, the proportion shedding was significantly increased after MC at 1 wk (PRR = 1.87, 95% CI = 1.12–3.14, p = 0.012), 2 wk (PRR = 3.16, 95% CI = 1.94–5.13, p < 0.001), and 3 wk (PRR = 1.98, 95% CI = 1.19–3.28, p = 0.008) after MC. However, compared to baseline, HIV shedding was decreased by 6 wk after MC (PRR = 0.27, 95% CI = 0.09–0.83, p = 0.023) and remained suppressed at 12 wk after MC (PRR = 0.19, 95% CI = 0.06–0.64, p = 0.008). Detectable HIV shedding from MC wounds occurred in more study visits among men with an HIV plasma VL > 50,000 copies/ml than among those with an HIV plasma VL < 400 copies/ml (adjPRR = 10.3, 95% CI = 4.25–24.90, p < 0.001). Detectable HIV shedding was less common in visits from men with healed MC wounds compared to visits from men without healed wounds (adjPRR = 0.12, 95% CI = 0.07–0.23, p < 0.001) and in visits from men on ART with undetectable plasma VL compared to men not on ART (PRR = 0.15, 95% CI = 0.05–0.43, p = 0.001). Among men with detectable penile HIV shedding, the median log10 HIV copies/milliliter of lavage fluid was significantly lower in men with ART—induced undetectable plasma VL (1.93, interquartile range [IQR] = 1.83–2.14) than in men not on ART (2.63, IQR = 2.28–3.22, p < 0.001). Limitations of this observational study include significant differences in baseline covariates, lack of confirmed receipt of ART for individuals who reported ART use, and lack of information on potential ART initiation during follow—up for those who were not on ART at enrollment.
Conclusion
Penile HIV shedding is significantly reduced after healing of MC wounds. Lower plasma VL is associated with decreased frequency and quantity of HIV shedding from MC wounds. Starting ART prior to MC should be considered to reduce male-to-female HIV transmission risk. Research is needed to assess the time on ART required to decrease shedding, and the acceptability and feasibility of initiating ART at the time of MC.
In this prospective cohort study, Aaron Tobian and colleagues examine the associations between male circumcision wound healing, as well as plasma viral load, and HIV shedding from male circumcision wounds.
Editors' Summary
Background
About 35 million people are currently infected with HIV, the virus that causes AIDS by destroying immune system cells, and every year, 2 million more people become HIV-positive. Antiretroviral therapy (ART) can keep HIV in check, but there is no cure for AIDS. Consequently, prevention of HIV acquisition and transmission is an important component of efforts to control the AIDS epidemic. Because HIV is most often spread through unprotected sex with an infected partner, individuals can reduce their risk of becoming HIV-positive by abstaining from sex, by having only one or a few partners, and by using male or female condoms. In addition, three trials undertaken in sub-Saharan Africa a decade ago showed that male circumcision—the surgical removal of the foreskin, a loose fold of skin that covers the head of the penis—can halve the HIV acquisition rate in men. Thus, since 2007, the World Health Organization (WHO) has recommended voluntary medical male circumcision for individuals living in countries with high HIV prevalence as part of its HIV prevention strategy.
Why Was This Study Done?
With the rollout of voluntary medical male circumcision programs, circumcision has become more normative (regarded as acceptable), and HIV-positive men are increasingly requesting circumcision because they want to avoid any stigma associated with being uncircumcised and because circumcision provides health benefits. WHO recommends that, although circumcision should not be promoted for HIV-positive men, voluntary circumcision programs should operate on HIV-positive men if they request circumcision. However, in a trial of circumcision of HIV-infected men, HIV transmission to their female partners increased if the couples had sexual intercourse before the circumcision wound had healed. Moreover, in studies of current male circumcision programs, two-thirds of married men and a third of all men reported that they resumed sexual intercourse before their circumcision wounds had healed. Thus, better understanding of how male circumcision increases HIV transmission to female partners is essential, and improved ways to prevent transmission in the post-surgical period are needed. Here, in a prospective observational study (an investigation that collects data over time from people undergoing a specific procedure), the researchers assess HIV shedding from the penis after circumcision.
What Did the Researchers Do and Find?
The researchers evaluated penile HIV shedding among 223 HIV-infected men (183 men who self-reported not being on ART and 40 men who self-reported being on ART, 29 of whom had no detectable virus in their blood) living in Rakai, Uganda, by examining preoperative and postoperative penile lavage (wash) samples. Viral shedding was detected in 9.3% of the men not on ART before surgery and in 39.3% of these men during the entire study. Relative to baseline, a greater proportion of men shed virus at one, two, and three weeks after circumcision, but a lower proportion shed virus at six and twelve weeks after circumcision. HIV shedding was more frequent among men with a high amount of virus in their blood (a high viral load) than among men with a low viral load. Moreover, the frequency of HIV shedding was lower in visits from men with healed circumcision wounds than in visits from men with unhealed wounds, and in visits from men on ART with no detectable virus in their blood than in visits from men not on ART men. Finally, among men with detectable penile HIV shedding, men on ART with no detectable virus in their blood shed fewer copies of virus than men not on ART.
What Do These Findings Mean?
The findings suggest that healed circumcision wounds are associated with reduced penile HIV shedding in HIV-positive men compared to unhealed circumcision wounds and HIV shedding prior to circumcision In addition, they suggest that a lower HIV viral load in the blood is associated with a decreased frequency and quantity of HIV shedding from circumcision wounds. Because this was an observational study, these findings cannot prove that healed wounds or reduced blood viral load actually caused reduced penile HIV shedding. Moreover, the accuracy of these findings may be affected by the lack of information on ART initiation during follow-up among men not initially on ART and by reliance on ART self-report. Nevertheless, these findings highlight the importance of counseling HIV-positive men undergoing circumcision to avoid sexual intercourse until their circumcision wound heals. In addition, these findings suggest that it might be possible to reduce HIV transmission among HIV-positive men immediately after circumcision by starting these individuals on ART before circumcision. Further research is needed to assess how long before circumcision ART should be initiated and to assess the acceptability and feasibility of initiating ART concurrent with circumcision.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001820.
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, summaries of recent research findings on HIV care and treatment, information on male circumcision for the prevention of HIV transmission, and personal stories about living with HIV/AIDS
Information is available from Avert, an international AIDS charity on many aspects of HIV/AIDS, including information on HIV prevention, on voluntary medical male circumcision for HIV prevention, and on HIV/AIDS in sub-Saharan Africa; Avert also provides personal stories about living with HIV/AIDS
The World Health Organization provides information on all aspects of HIV/AIDS (in several languages), including on voluntary medical male circumcision for HIV prevention
The UNAIDS Fast-Track Strategy to End the AIDS Epidemic by 2030 provides up-to-date information about the AIDS epidemic and efforts to halt it
The Clearinghouse on Male Circumcision for HIV Prevention provides up-to-date information and resources on male circumcision for HIV prevention
doi:10.1371/journal.pmed.1001820
PMCID: PMC4412625  PMID: 25919012
7.  HIV Infection in Uncircumcised Men Is Associated With Altered CD8 T-cell Function But Normal CD4 T-cell Numbers in the Foreskin 
The Journal of Infectious Diseases  2013;209(8):1185-1194.
Background. Human immunodeficiency virus (HIV)–infected (HIV+) men are more susceptible to sexually transmitted infections, and may be superinfected by HIV. We hypothesized that HIV induces immune alterations in the foreskin that may impact the subsequent acquisition/clearance of genital coinfections.
Methods. Foreskin tissue and blood were obtained from 70 HIV-uninfected and 20 HIV+ men undergoing circumcision. T cells were characterized by flow cytometry, immunohistochemistry, and polymerase chain reaction.
Results. There was substantial influx of CD8 T-cells into the foreskins of HIV+ men (108.8 vs 23.1 cells/mm2; P < .001); but foreskin CD4 T-cell density was unchanged (43.0 vs 33.7/mm2; P = .67), despite substantial blood depletion (409.0 vs 877.8 cells/µL; P < .001). While frequencies of foreskin C-C chemokine receptor type 5+ (CCR5+) T cells, T regulatory cells, and T-helper 17 cells were unaltered in HIV+ men, CD8 T-cell production of tumor necrosis factor α (TNFα) was decreased. HIV-specific CD8 T cells were present in the foreskins of HIV+ men, although their frequency and function was reduced compared to the blood.
Conclusions. Foreskin CD4 T-cell density and CCR5 expression were not reduced during HIV infection, perhaps explaining susceptibility to HIV superinfection. Foreskin CD8 T-cell density was increased, but decreased production of TNFα may enhance susceptibility to genital coinfections in HIV+ men.
doi:10.1093/infdis/jit644
PMCID: PMC3969543  PMID: 24277744
circumcision; cytokines; HIV; sexually transmitted infections; T cells
8.  Impact of HIV Subtype on Performance of the Limiting Antigen-Avidity Enzyme Immunoassay, the Bio-Rad Avidity Assay, and the BED Capture Immunoassay in Rakai, Uganda 
Abstract
Previous studies demonstrated that individuals with subtype D HIV infection who had been infected for 2 or more years were frequently misclassified as assay positive using cross-sectional incidence assays. Samples from 510 subjects (212 subtype A, 298 subtype D) who were infected for 2.2 to 14.5 years (median 5.4 years) and were not virally suppressed were tested using an LAg-Avidity enzyme immunoassay (LAg-Avidity EIA), Bio-Rad Avidity assay, and BED capture enzyme immunoassay (BED-CEIA). The performance of these three assays was evaluated using various assay cutoff values [LAg-Avidity EIA: <1.0 OD-n and <2.0 OD-n; Bio-Rad Avidity assay: <40% avidity index (AI) and <80% AI; BED-CEIA: <0.8 OD-n]. The mean LAg-Avidity EIA result was higher for subtype A than D (4.54±0.95 vs. 3.86±1.26, p<0.001); the mean Bio-Rad Avidity assay result was higher for subtype A than D (88.9%±12.5% vs. 75.1±30.5, p<0.001); and the mean BED-CEIA result was similar for the two subtypes (2.2±1.2 OD-n for subtype A, 2.2±1.3 OD-n for subtype D, p<0.9). The frequency of misclassification was higher for individuals with subtype D infection compared to those with subtype A infection, using either the LAg-Avidity EIA with a cutoff of <2.0 OD-n or the Bio-Rad Avidity assay with cutoffs of <40% or <80% AI. No subtype-specific differences in assay performance were observed using the BED-CEIA. Sex and age were not significantly associated with misclassification by any assay. The LAg-Avidity EIA with a cutoff <1.0 OD-n had the lowest frequency of misclassification in this Ugandan population.
doi:10.1089/aid.2013.0169
PMCID: PMC3976571  PMID: 24083837
9.  Effectiveness of an integrated intimate partner violence and HIV prevention intervention in Rakai, Uganda: analysis of an intervention in an existing cluster randomised cohort 
The Lancet. Global health  2014;3(1):e23-e33.
Summary
Background
Intimate partner violence (IPV) is associated with HIV infection. We aimed to assess whether provision of a combination of IPV prevention and HIV services would reduce IPV and HIV incidence in individuals enrolled in the Rakai Community Cohort Study (RCCS), Rakai, Uganda.
Methods
We used pre-existing clusters of communities randomised as part of a previous family planning trial in this cohort. Four intervention group clusters from the previous trial were provided standard of care HIV services plus a community-level mobilisation intervention to change attitudes, social norms, and behaviours related to IPV, and a screening and brief intervention to promote safe HIV disclosure and risk reduction in women seeking HIV counselling and testing services (the Safe Homes and Respect for Everyone [SHARE] Project). Seven control group clusters (including two intervention groups from the original trial) received only standard of care HIV services. Investigators for the RCCS did a baseline survey between February, 2005, and June, 2006, and two follow-up surveys between August, 2006, and April, 2008, and June, 2008, and December, 2009. Our primary endpoints were self-reported experience and perpetration of past year IPV (emotional, physical, and sexual) and laboratory-based diagnosis of HIV incidence in the study population. We used Poisson multivariable regression to estimate adjusted prevalence risk ratios (aPRR) of IPV, and adjusted incidence rate ratios (aIRR) of HIV acquisition. This study was registered with ClinicalTrials.gov, number NCT02050763.
Findings
Between Feb 15, 2005, and June 30, 2006, we enrolled 11 448 individuals aged 15–49 years. 5337 individuals (in four intervention clusters) were allocated into the SHARE plus HIV services group and 6111 individuals (in seven control clusters) were allocated into the HIV services only group. Compared with control groups, individuals in the SHARE intervention groups had fewer self-reports of past-year physical IPV (346 [16%] of 2127 responders in control groups vs 217 [12%] of 1812 responders in intervention groups; aPRR 0·79, 95% CI 0·67–0·92) and sexual IPV (261 [13%] of 2038 vs 167 [10%] of 1737; 0·80, 0·67–0·97). Incidence of emotional IPV did not differ (409 [20%] of 2039 vs 311 [18%] of 1737; 0·91, 0·79–1·04). SHARE had no effect on male-reported IPV perpetration. At follow-up 2 (after about 35 months) the intervention was associated with a reduction in HIV incidence (1·15 cases per 100 person-years in control vs 0·87 cases per 100 person-years in intervention group; aIRR 0·67, 95% CI 0·46–0·97, p=0·0362).
Interpretation
SHARE could reduce some forms of IPV towards women and overall HIV incidence, possibly through a reduction in forced sex and increased disclosure of HIV results. Findings from this study should inform future work toward HIV prevention, treatment, and care, and SHARE's ecological approach could be adopted, at least partly, as a standard of care for other HIV programmes in sub-Saharan Africa.
Funding
Bill & Melinda Gates Foundation, US National Institutes of Health, WHO, President's Emergency Plan for AIDS Relief, Fogarty International Center.
doi:10.1016/S2214-109X(14)70344-4
PMCID: PMC4370228  PMID: 25539966
10.  Evaluation of the safety and efficiency of the dorsal slit and sleeve methods of male circumcision provided by physicians and clinical officers in Rakai, Uganda 
BJU international  2011;109(1):104-108.
Objectives
To assess safety and efficiency of the dorsal slit and sleeve male circumcision (MC) procedures performed by physicians and clinical officers.
Methods
We evaluated the time required for surgery and moderate / severe adverse events (AEs), among circumcisions by trained physicians and clinical officers using sleeve and dorsal slit methods. Univariate and multivariate regression with robust variance was used to assess factors associated with time for surgery (linear regression) and adverse events (logistic regression).
Results
Six physicians and 8 clinical officers conducted 1934 and 3218 MCs, respectively. There were 2471 dorsal slit and 2681 sleeve procedures. The mean duration of surgery was 33 minutes for newly trained providers and decreased to ~20 minutes after ~100 circumcisions. The adjusted mean duration of surgery for dorsal slit was significantly shorter than that for sleeve method (Δ −2.8 minutes, p- <0.001). The duration of surgery was longer for clinical officers than physicians performing the sleeve procedure, but not the dorsal slit procedure. Crude AEs rates were 0.6% for dorsal slit and 1.4% with the sleeve method (p=0.006). However, there were no significant differences after multivariate adjustment. Use of cautery significantly reduced time needed for surgery (Δ − 4.0 minutes, p =0.008), but was associated with higher rates of AEs (adjusted odds ratio 2.13, 95%CI 1.26–3.61, p=0.005).
Conclusions
The dorsal slit resection method of male circumcision is faster and safer than sleeve resection, and can be safely performed by non-physicians. However, use of cautery may be inadvisable in this setting.
doi:10.1111/j.1464-410X.2011.10259.x
PMCID: PMC4326085  PMID: 21627752
Adult male circumcision; HIV; circumcision programs; task shifting; adverse events; safety; Uganda
11.  HIV Type 1 Polymerase Gene Polymorphisms Are Associated With Phenotypic Differences in Replication Capacity and Disease Progression 
Background. Determinants of intersubtype differences in human immunodeficiency virus type 1 (HIV-1) clinical disease progression remain unknown.
Methods. HIV-1 subtype was independently determined for 5 separate genomic regions in 396 HIV-1 seroconverters from Rakai, Uganda, using a multiregion hybridization assay. Replication capacities (RC) in samples from a subset of 145 of these subjects were determined. HIV-1 genomic regions and pol RC were examined for association with disease progression. Amino acid polymorphisms were examined for association with pol RC.
Results. In multivariate analyses, the hazard for progression to the composite end point (defined as a CD4+ T-cell count <250 cells/mm3, antiretroviral therapy initiation, or death) among patients with subtype D pol infection was 2.4 times the hazard for those infected with subtype A pol infection (P = .001). Compared with subtype A pol (the reference group), the hazard for progression to the composite end point for subtype D pol infection with a pol RC >67% (ie, the median pol RC) was significantly greater (HR, 4.6; 95% confidence interval [CI], 1.9–11.0; P = .001), whereas the hazard for progression to the composite end point for subtype D pol infection with a pol RC ≤67% was not significantly different (HR, 2.2; 95% CI, 1.0–4.9; P = .051). Amino acid substitutions at protease positions 62 and 64 and at reverse transcriptase position 272 were associated with significant differences in pol RC.
Conclusions. HIV-1 pol gene intersubtype and RC differences are associated with disease progression and may be influenced by amino acid polymorphisms.
doi:10.1093/infdis/jit425
PMCID: PMC3864385  PMID: 23922373
HIV-1 Subtype; subtype A; subtype D; disease progression; polymerase; replication capacity; amino acid polymorphisms
12.  Marriage and the Risk of Incident HIV infection in Rakai, Uganda 
Objective
Studies suggest that the prevalence of HIV is higher among long term marital/consensual relationships than in the unmarried. We assessed the risk of incident HIV infection by marital status in rural Rakai, Uganda.
Design
Longitudinal data from the Rakai Community Cohort Study (RCCS) between 1999 - 2011
Methods
We estimated HIV incidence per 100 person years (py) in sexually active individuals aged 15-49 with a total of 44,179.6 person years (py) who were never married (females 2,929py, males 4,261py), currently married or in long-term consensual relationships (“currently married females 29,823py, males 21,299py) and previously married (females 3,563py, males 1,475). Poisson multivariable regression was used to estimate the unadjusted and adjusted incident rate ratios (IRRs) and 95% confidence intervals (95% CI) of HIV acquisition.
Results
HIV incidence among currently married persons was 0.93/100py, which was lower than the never married (1.51/100py) and previously married (2.85/100py). The risk of HIV acquisition was significantly lower in the currently married compared to the never married among women (Adj IRR=0.26, 95% CI: 0.16-0.42), but not men (Adj IRR=0.69, 95% CI: 0.31-1.52). HIV incidence was lower among first marriages (0.73/100py) compared to second or higher order marriages (1.38/100py). Multiple sex partners significantly increased the risk of HIV acquisition in both women (Adj IRR=2.53, 95% CI: 1.6, 3.97) and men (Adj IRR=1.77, 95% CI: 1.20-2.60).
Conclusion
Current marriage especially first order marriage was associated with reduced risk of HIV acquisition in women, but not in men, and multiple sex partnerships increased HIV risk for both sexes.
doi:10.1097/QAI.0b013e3182a7f08a
PMCID: PMC3897786  PMID: 24419066
Marriage; HIV infection; Uganda
13.  Impact of asymptomatic Herpes simplex virus-2 infection on T cell function in the foreskin of men from Rakai, Uganda 
AIDS (London, England)  2012;26(10):1319-1322.
SUMMARY
Herpes simplex type 2 (HSV-2) increases the risk of HIV acquisition in men and overall CD4 T cell density in the foreskin. Using tissues obtained during routine male circumcision, we examined the impact of HSV-2 on the function and phenotype of foreskin T cells in Ugandan men. HSV-2 infection was predominantly associated with a compartmentalized increase in CCR5 expression by foreskin CD4 T cells, which may contribute to HIV susceptibility.
doi:10.1097/QAD.0b013e328354675c
PMCID: PMC4241749  PMID: 22516874
HSV-2; HIV; foreskin; T cells
14.  Effects of Medical Male Circumcision (MC) on Plasma HIV Viral Load in HIV+ HAART Naïve Men; Rakai, Uganda 
PLoS ONE  2014;9(11):e110382.
Background
Medical male circumcision (MC) of HIV-infected men may increase plasma HIV viral load and place female partners at risk of infection. We assessed the effect of MC on plasma HIV viral load in HIV-infected men in Rakai, Uganda.
Methods
195 consenting HIV-positive, HAART naïve men aged 12 and above provided blood for plasma HIV viral load testing before surgery and weekly for six weeks and at 2 and 3 months post surgery. Data were also collected on baseline social demographic characteristics and CD4 counts. Change in log10 plasma viral load between baseline and follow-up visits was estimated using paired t tests and multivariate generalized estimating equation (GEE).
Results
Of the 195 men, 129 had a CD4 count ≧350 and 66 had CD4 <350 cells/mm3. Men with CD4 counts <350 had higher baseline mean log10 plasma viral load than those with CD4 counts ≧350 cells/mm3 (4.715 vs 4.217 cps/mL, respectively, p = 0.0005). Compared to baseline, there was no statistically significant increase in post-MC HIV plasma viral loads irrespective of CD4. Multivariate analysis showed that higher baseline log10 plasma viral load was significantly associated with reduction in mean log10 plasma viral load following MC (coef.  = −0.134, p<0.001).
Conclusion
We observed no increase in plasma HIV viral load following MC in HIV-infected, HAART naïve men.
doi:10.1371/journal.pone.0110382
PMCID: PMC4240554  PMID: 25415874
15.  Neurodevelopmental benefits of Anti-Retroviral Therapy in Ugandan children 0–6 Years of age with HIV 
Background
Insufficient data on neurodevelopmental benefits of antiretroviral therapy (ART) in children.
Methods
Prospective study of 329 mothers and children aged 0–6 years to assess neurodevelopment. Results stratified by the maternal (M) and child (C) HIV status (MHIV−/CHIV−, MHIV+/CHIV−, and MHIV+/CHIV+). Gross Motor, Visual Reception, Fine Motor, Receptive and Expressive Language scores assessed by Mullen Scales of Early Learning. Global cognitive function was derived from an Early Learning Composite score (ELC). Standardized Weight and Height for Age z-scores were constructed and the lowest 15% cutoff defined disability. Generalized linear models were used to estimate Prevalence Rate Ratios (PRR) adjusted for the child’s age, weight and height. In HIV-positive children, generalized linear models assessed the impact of ART initiation and duration on neurodevelopment.
Results
Compared to MHIV−/CHIV− children, HIV+ children were more likely to have global deficits in all measures of neurodevelopment except gross motor skills, whereas in MHIV+/CHIV− children, there was impairment in receptive language (adj.PRR=2.67, CI: 1·08, 6.60) and the ELC (adj.PRR=2.94, CI: 1.11, 7.82). Of the children born to HIV positive mothers, HIV+ children did worse than - MHIV+/CHIV− only in Visual Reception skills (adj.PRR=2.86; CI: 1.23–6.65). Of the 116 HIV+ children, 44% had initiated ART. Compared to ART duration of <12 months, ART durations 24–60 months was associated with decreased impairments in Fine Motor, Receptive Language, Expressive Language and ELC scores.
Conclusions
Longer duration on ART is associated with reduction of some neurologic impairment and early diagnosis and treatment of HIV+ children is a priority.
doi:10.1097/QAI.0000000000000295
PMCID: PMC4197805  PMID: 25314252
HIV; neurodevelopment; HIV infected children; HIV affected children; ARTs
16.  HIV Acquisition Is Associated with Increased Antimicrobial Peptides and Reduced HIV Neutralizing IgA in the Foreskin Prepuce of Uncircumcised Men 
PLoS Pathogens  2014;10(10):e1004416.
Background
The foreskin is the site of most HIV acquisition in uncircumcised heterosexual men. Although HIV-exposed, seronegative (HESN) uncircumcised men demonstrate HIV-neutralizing IgA and increased antimicrobial peptides (AMPs) in the foreskin prepuce, no prospective studies have examined the mucosal immune correlates of HIV acquisition.
Methods
To assess the association of foreskin immune parameters with HIV acquisition, antimicrobial peptides and IgA with the capacity to neutralize a primary clade C HIV strain were quantified by blinded investigators, using sub-preputial swabs collected longitudinally during a randomized trial of male circumcision for HIV prevention in Rakai, Uganda.
Results
Participants were 99 men who acquired HIV (cases) and 109 randomly selected controls who remained HIV seronegative. At enrollment, 44.4% of cases vs. 69.7% of controls demonstrated IgA neutralization (adjusted OR = 0.31; 95% CI, 0.16–0.61). IgA neutralization was detected in 38.7% of cases and 70.7% of controls at the last seronegative case visit prior to HIV acquisition and the comparable control visit (adjusted OR 0.21; 95% CI, 0.11–0.39). Levels of the α-defensins and secretory leukocyte protease inhibitor (SLPI) were over ten-fold higher in the foreskin prepuce of cases who acquired HIV, both at enrollment (mean 4.43 vs. 3.03 and 5.98 vs. 4.61 logn pg/mL, P = 0.005 and 0.009, respectively), and at the last seronegative visit (mean 4.81 vs. 3.15 and 6.46 vs. 5.20 logn pg/mL, P = 0.0002 and 0.013).
Conclusions
This prospective, blinded analysis is the first to assess the immune correlates of HIV acquisition in the foreskin. HIV-neutralizing IgA, previously associated with the HESN phenotype, was a biomarker of HIV protection, but other HESN associations correlated with increased HIV acquisition. This emphasizes the importance of prospective epidemiological studies or in vitro tissue studies to define the impact of mucosal parameters on HIV risk.
Author Summary
Randomized trials of male circumcision (MC) for HIV prevention have shown that the foreskin is a major site of HIV acquisition among heterosexual men, but a number of barriers to MC programs mean that many HIV-susceptible men remain uncircumcised. The immune correlates of HIV acquisition in the foreskin are poorly described, and may inform prevention strategies for uncircumcised men. Using swabs collected prospectively during a previous randomized trial of MC for HIV prevention in Uganda, blinded investigators assessed levels of HIV-neutralizing IgA and soluble antimicrobial peptides in the foreskin prepuce of cases who acquired HIV (n = 99) and controls men who did not (n = 109). We show that IgA with the capacity to neutralize HIV was associated with protection against HIV, while levels of α-defensins and secretory leukocyte protease inhibitor (SLPI) were associated with increased acquisition. This is the first study to assess the immune correlates of HIV acquisition in the foreskin. Advantages included its relatively large sample size, rigorous blinding of immune assays, and ability to control for relevant potential confounders.
doi:10.1371/journal.ppat.1004416
PMCID: PMC4183701  PMID: 25275513
17.  The contribution of HIV-discordant relationships to new HIV infections in Rakai, Uganda 
AIDS (London, England)  2011;25(6):863-865.
We determined HIV incidence in the Rakai, cohort before (82/9311) and after (131/13082) the availability of antiretroviral therapy (ART). The proportions of total HIV infections pre- and post-ART were 18.3% and 13.7%, respectively, among identifiable HIV-discordant couples, 23.2% and 26.0%, respectively, in concordant HIV-negative couples, 29.3% and 17.6% in married persons with unknown partner status, and 29.3% and 42.7% in the unmarried. VCT targeting discordant couples is unlikely to have substantial impact in this setting.
doi:10.1097/QAD.0b013e3283448790
PMCID: PMC4169210  PMID: 21326076
18.  “Men are always scared to test with their partners … it is like taking them to the Police”: Motivations for and barriers to couples’ HIV counselling and testing in Rakai, Uganda: a qualitative study 
Introduction
Uptake of couples’ HIV counselling and testing (couples’ HCT) can positively influence sexual risk behaviours and improve linkage to HIV care among HIV-positive couples. However, less than 30% of married couples have ever tested for HIV together with their partners. We explored the motivations for and barriers to couples’ HCT among married couples in Rakai, Uganda.
Methods
This was a qualitative study conducted among married individuals and selected key informants between August and October 2013. Married individuals were categorized by prior HCT status as: 1) both partners never tested; 2) only one or both partners ever tested separately; and 3) both partners ever tested together. Data were collected on the motivations for and barriers to couples’ HCT, decision-making processes from tested couples and suggestions for improving couples’ HCT uptake. Eighteen focus group discussions with married individuals, nine key informant interviews with selected key informants and six in-depth interviews with married individuals that had ever tested together were conducted. All interviews were audio-recorded, translated and transcribed verbatim and analyzed using Nvivo (version 9), following a thematic framework approach.
Results
Motivations for couples’ HCT included the need to know each other's HIV status, to get a treatment companion or seek HIV treatment together – if one or both partners were HIV-positive – and to reduce mistrust between partners. Barriers to couples’ HCT included fears of the negative consequences associated with couples’ HCT (e.g. fear of marital dissolution), mistrust between partners and conflicting work schedules. Couples’ HCT was negotiated through a process that started off with one of the partners testing alone initially and then convincing the other partner to test together. Suggestions for improving couples’ HCT uptake included the need for couple- and male-partner-specific sensitization, and the use of testimonies from tested couples.
Conclusions
Couples’ HCT is largely driven by individual and relationship-based factors while fear of the negative consequences associated with couples’ HCT appears to be the main barrier to couples’ HCT uptake in this setting. Interventions to increase the uptake of couples’ HCT should build on the motivations for couples’ HCT while dealing with the negative consequences associated with couples’ HCT.
doi:10.7448/IAS.17.1.19160
PMCID: PMC4169647  PMID: 25239379
Motivations; barriers couples; counselling; testing; Rakai; Uganda
19.  Evaluation of current rapid HIV test algorithms in Rakai, Uganda 
Journal of virological methods  2013;192(0):25-27.
Rapid HIV tests are a crucial component of HIV diagnosis in resource limited settings. In Uganda, the Ministry of Health allows for both serial and parallel HIV rapid testing using Determine, Stat-Pak and Uni-Gold. In serial testing, a non-reactive result on Determine ends testing. The performance of serial and parallel algorithms with Determine and Stat-Pak test kits was assessed. A cross-sectional diagnostic test accuracy evaluation using three rapid HIV test kits as per the recommended parallel test algorithm was followed by EIA-WB testing with estimates of the performance of serial testing algorithm. In 2520 participants tested by parallel rapid algorithms, 0.6% had weakly reactive result. Parallel testing had 99.7% sensitivity and 99.8% specificity. If Stat-Pak was used as the first screening test for a serial algorithm, the sensitivity was 99.6% and specificity 99.7%. However, if Determine was used as the screening test, sensitivity was 97.3% and specificity 99.9%. Serial testing with Stat-Pak as the initial screening test performed as well as parallel testing, but Determine was a less sensitive screen. Serial testing could be cost saving.
doi:10.1016/j.jviromet.2013.04.003
PMCID: PMC3749432  PMID: 23583487
20.  Male circumcision decreases high-risk human papillomavirus viral load in female partners: a randomized trial in Rakai, Uganda 
Male circumcision (MC) reduces high-risk human papillomavirus (HR-HPV) infection in female partners. We evaluated the intensity of HR-HPV viral DNA load in HIV-negative, HR-HPV-positive female partners of circumcised and uncircumcised men. HIV-negative men and their female partners were enrolled in randomized trials of MC in Rakai, Uganda. Vaginal swabs were tested for HR-HPV genotypes by Roche HPV Linear Array which provides a semi-quantitative measure of HPV DNA by the intensity of genotype-specific bands (graded:1-4). We assessed the effects of MC on female HR-HPV DNA load by comparing high intensity linear array bands (3-4) to low intensity bands (1-2) using an intention-to-treat analysis. Prevalence risk ratios (PPR) of high intensity bands in partners of intervention versus control arm men were estimated using log-binomial regression with robust variance. The trial included 335 women with male partners in the intervention arm and 340 in the control arm. At enrollment, the frequency of HR-HPV high intensity linear array bands was similar in both study arms. At 24 months follow-up, the prevalence of high intensity bands among women with detectable HRHPV was significantly lower in partners of intervention arm (42.7%) than control arm men (55.1%, PRR= 0.78, 95%CI 0.65-0.94, p=0.02), primarily among incident HR-HPV infections (PRR=0.66, 95% CI 0.50-0.87, p=0.003), but not persistent infections (PRR=1.02, 95% CI 0.83-1.24). Genotypes with high HR-HPV band intensity were more likely to persist (adjHR=1.27 95% CI 1.07-1.50), irrespective of male partner circumcision status. MC reduces HR-HPV DNA load in newly infected female partners.
doi:10.1002/ijc.28100
PMCID: PMC3732529  PMID: 23400966
Human papillomavirus (HPV); male circumcision; Uganda; cervical cancer; sexually transmitted infections; viral shedding; viral load; linear array band intensity; HIV
21.  Reactivation of Herpes Simplex Virus Type 2 After Initiation of Antiretroviral Therapy 
The Journal of Infectious Diseases  2013;208(5):839-846.
Background. The association between initiation of antiretroviral therapy (ART) for human immunodeficiency virus (HIV) infection and possible herpes simplex virus type 2 (HSV-2) shedding and genital ulcer disease (GUD) has not been evaluated.
Methods. GUD and vaginal HSV-2 shedding were evaluated among women coinfected with HIV and HSV-2 (n = 440 for GUD and n = 96 for HSV-2 shedding) who began ART while enrolled in a placebo-controlled trial of HSV-2 suppression with acyclovir in Rakai, Uganda. Monthly vaginal swabs were tested for HSV-2 shedding, using a real-time quantitative polymerase chain reaction assay. Prevalence risk ratios (PRRs) of GUD were estimated using log binomial regression. Random effects logistic regression was used to estimate odds ratios (ORs) of HSV-2 shedding.
Results. Compared with pre-ART values, GUD prevalence increased significantly within the first 3 months after ART initiation (adjusted PRR, 1.94; 95% confidence interval [CI], 1.04–3.62) and returned to baseline after 6 months of ART (adjusted PRR, 0.80; 95% CI, .35–1.80). Detection of HSV-2 shedding was highest in the first 3 months after ART initiation (adjusted OR, 2.58; 95% CI, 1.48–4.49). HSV-2 shedding was significantly less common among women receiving acyclovir (adjusted OR, 0.13; 95% CI, .04–.41).
Conclusions. The prevalence of HSV-2 shedding and GUD increased significantly after ART initiation, possibly because of immune reconstitution inflammatory syndrome. Acyclovir significantly reduced both GUD and HSV-2 shedding and should be considered to mitigate these effects following ART initiation.
doi:10.1093/infdis/jit252
PMCID: PMC3733512  PMID: 23812240
herpes simplex virus type 2 (HSV-2); human immunodeficiency virus (HIV); immune reconstitution inflammatory syndrome (IRIS); acyclovir; reactivation; Uganda
22.  The Acceptability and Safety of the Shang Ring for Adult Male Circumcision in Rakai, Uganda 
Objectives
Medical male circumcision (MMC) is recommended for HIV prevention in men. We assessed the acceptability and safety of the Shang Ring device compared to the dorsal slit method.
Methods
HIV-negative, uncircumcised men aged 18 years or older who requested free MMC services in rural Rakai, Uganda were informed about the Shang Ring and dorsal slit procedures and offered a free choice of procedure. Men were followed at 7 days postoperatively to assess adverse events (AEs) related to surgery and to remove the Shang Ring. Wound healing was assessed at 4 weeks postoperatively.
Results
621 men were enrolled, of whom 508 (81.8%) chose the Shang Ring and 113 the dorsal slit. The Shang Ring was provided to 504 men, among whom there were 4 failures of Ring placement (0.8%) which required surgical hemostasis and wound closure. 500 men received the Shang Ring and postoperative surgery-related moderate AEs were 1.0%, compared to 0.8% among dorsal slit recipients. Complete wound healing at 4 weeks was 84% with the Ring and 100% with dorsal slit (p<0001). Resumption of intercourse before 4 weeks was 7.0% with the Ring and 15.0% with dorsal slit (p=0.01.) The mean time for surgery was 6.1 minutes with the Ring and 17.7 minutes with the dorsal slit. Mean time for Ring removal was 2.2 minutes.
Conclusion
The Shang Ring is highly acceptable and safe in this setting, and could improve the efficiency of MMC services. However, back up surgical services are needed in cases of Ring placement failures.
doi:10.1097/QAI.0b013e3182968dda
PMCID: PMC3805675  PMID: 23614991
Male circumcision; Shang Ring; Rakai; Uganda
23.  Behavioral, Biological, and Demographic Risk and Protective Factors for New HIV Infections among Youth, Rakai, Uganda 
Background
Prevalence of HIV infection is considerable among youth, although data on risk factors for new (incident) infections is limited. We examined incidence of HIV infection and risk and protective factors among youth in rural Uganda, including the role of gender and social transitions.
Methods
Participants were sexually experienced youth (15–24 years-old) enrolled in the Rakai Community Cohort Study,1999–2008 (n=6741). Poisson regression with robust standard errors was used to estimate incident rate ratios (IRR) and 95% confidence intervals (CI) of incident HIV infection.
Results
HIV incidence was greater among young women than young men (14.1 vs. 8.3 per 1000 person-years, respectively); this gender disparity was greater among teens (14.9 vs. 3.6). Beyond behavioral (multiple partners and concurrency) and biological factors (sexually transmitted infection (STI) symptoms), social transitions such as marriage and staying in school influenced HIV risk. In multivariate analyses among women, HIV incidence was associated with living in a trading village [adjusted IRR (aIRR) = 1.48; 95% CI: 1.04 to 2.11], being a student (aIRR = 0.22; 95% CI: 0.07 to 0.72), current marriage (aIRR = 0.55; 95% CI: 0.37 to 0.81), former marriage (aIRR = 1.73; 95% CI: 1.01 to 2.96), having multiple partners, and sexually transmitted infection symptoms. Among men, new infections were associated with former marriage (aIRR = 5.57; 95% CI: 2.51 to 12.36), genital ulceration (aIRR = 3.56; 95% CI: 1.97 to 6.41), and alcohol use (aIRR = 2.08; 95% CI: 1.15 to 3.77).
Conclusions
During the third decade of the HIV epidemic in Uganda, HIV incidence remains considerable among youth, with young women particularly at risk. The risk for new infections was strongly shaped by social transitions such as leaving school, entrance into marriage, and marital dissolution; the impact of marriage was different for young men than women.
doi:10.1097/QAI.0b013e3182926795
PMCID: PMC4131841  PMID: 23535293
Youth; Uganda; HIV; Incidence; Risk Factors; Education
24.  Differential Specificity of HIV Incidence Assays in HIV Subtypes A and D-Infected Individuals from Rakai, Uganda 
AIDS Research and Human Retroviruses  2013;29(8):1146-1150.
Abstract
Assays to determine HIV incidence from cross-sectional surveys have exhibited a high rate of false-recent misclassification in Kenya and Uganda where HIV subtypes A and D predominate. Samples from individuals infected with HIV for at least 2 years with known infecting subtype (133 subtype A, 373 subtype D) were tested using the BED-CEIA and an avidity assay. Both assays had a higher rate of false-recent misclassification for subtype D compared to subtype A (13.7% vs. 6.0%, p=0.02 for BED-CEIA; 11.0% vs. 1.5%, p<0.001 for avidity). For subtype D samples, false-recent misclassification by the BED-CEIA was also more frequent in women than men (15.0% vs. 5.6%, p=0.002), and for samples where that had an amino acid other than lysine at position 12 in the BED-CEIA peptide coding region (p=0.002). Furthermore in subtype D-infected individuals, samples misclassified by one assay were 3.5 times more likely to be misclassified by the other assay. Differential misclassification by infecting subtype of long-term infected individuals as recently infected makes it difficult to use these assays individually to estimate population level incidence without precise knowledge of the distribution of these subtypes within populations where subtype A and D cocirculate. The association of misclassification of the BED-CEIA with the avidity assay in subtype D-infected individuals limits the utility of using these assays in combination within this population.
doi:10.1089/aid.2012.0105
PMCID: PMC3715796  PMID: 23641870
25.  Liver Stiffness Is Associated With Monocyte Activation in HIV-Infected Ugandans Without Viral Hepatitis 
AIDS Research and Human Retroviruses  2013;29(7):1026-1030.
Abstract
A high prevalence of liver stiffness, as determined by elevated transient elastography liver stiffness measurement, was previously found in a cohort of HIV-infected Ugandans in the absence of chronic viral hepatitis. Given the role of immune activation and microbial translocation in models of liver disease, a shared immune mechanism was hypothesized in the same cohort without other overt causes of liver disease. This study examined whether HIV-related liver stiffness was associated with markers of immune activation or microbial translocation (MT). A retrospective case-control study of subjects with evidence of liver stiffness as defined by a transient elastography stiffness measurement ≥9.3 kPa (cases=133) and normal controls (n=133) from Rakai, Uganda was performed. Cases were matched to controls by age, gender, HIV, hepatitis B virus (HBV), and highly active antiretroviral therapy (HAART) status. Lipopolysaccharide (LPS), endotoxin IgM antibody, soluble CD14 (sCD14), C-reactive protein (CRP), and D-dimer levels were measured. Conditional logistic regression was used to estimate adjusted matched odds ratios (adjMOR) and 95% confidence intervals. Higher sCD14 levels were associated with a 19% increased odds of liver stiffness (adjMOR=1.19, p=0.002). In HIV-infected individuals, higher sCD14 levels were associated with a 54% increased odds of having liver stiffness (adjMOR=1.54, p<0.001); however, the opposite was observed in HIV-negative individuals (adjMOR=0.57, p=0.001). No other biomarker was significantly associated with liver stiffness, and only one subject was found to have detectable LPS. Liver stiffness in HIV-infected Ugandans is associated with increased sCD14 indicative of monocyte activation in the absence of viral hepatitis or microbial translocation, and suggests that HIV may be directly involved in liver disease.
doi:10.1089/aid.2013.0004
PMCID: PMC3685686  PMID: 23548102

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