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1.  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.
To assess safety and efficiency of the dorsal slit and sleeve male circumcision (MC) procedures performed by physicians and clinical officers.
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).
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).
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.
PMCID: PMC4326085  PMID: 21627752
Adult male circumcision; HIV; circumcision programs; task shifting; adverse events; safety; Uganda
2.  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.
PMCID: PMC3864385  PMID: 23922373
HIV-1 Subtype; subtype A; subtype D; disease progression; polymerase; replication capacity; amino acid polymorphisms
3.  Marriage and the Risk of Incident HIV infection in Rakai, Uganda 
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.
Longitudinal data from the Rakai Community Cohort Study (RCCS) between 1999 - 2011
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.
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).
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.
PMCID: PMC3897786  PMID: 24419066
Marriage; HIV infection; Uganda
4.  High Frequency of False-Positive Hepatitis C Virus Enzyme-Linked Immunosorbent Assay in Rakai, Uganda 
The prevalence of hepatitis C virus (HCV) infection in sub-Saharan Africa remains unclear. We tested 1000 individuals from Rakai, Uganda, with the Ortho version 3.0 HCV enzyme-linked immunosorbent assay. All serologically positive samples were tested for HCV RNA. Seventy-six of the 1000 (7.6%) participants were HCV antibody positive; none were confirmed by detection of HCV RNA.
PMCID: PMC3840403  PMID: 24051866
hepatitis C virus; ELISA; Africa
5.  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.
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.
PMCID: PMC4241749  PMID: 22516874
HSV-2; HIV; foreskin; T cells
6.  Effects of Medical Male Circumcision (MC) on Plasma HIV Viral Load in HIV+ HAART Naïve Men; Rakai, Uganda 
PLoS ONE  2014;9(11):e110382.
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.
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).
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).
We observed no increase in plasma HIV viral load following MC in HIV-infected, HAART naïve men.
PMCID: PMC4240554  PMID: 25415874
7.  Neurodevelopmental benefits of Anti-Retroviral Therapy in Ugandan children 0–6 Years of age with HIV 
Insufficient data on neurodevelopmental benefits of antiretroviral therapy (ART) in children.
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.
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.
Longer duration on ART is associated with reduction of some neurologic impairment and early diagnosis and treatment of HIV+ children is a priority.
PMCID: PMC4197805  PMID: 25314252
HIV; neurodevelopment; HIV infected children; HIV affected children; ARTs
8.  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.
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.
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.
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).
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.
PMCID: PMC4183701  PMID: 25275513
9.  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.
PMCID: PMC4169210  PMID: 21326076
10.  Incidence of orphanhood before and after implementation of a HIV CARE program in Rakai, Uganda 
Scaling up of HIV care programs in sub-Saharan Africa has resulted in improved survival of HIV-infected adults, but its effect on orphanhood has not been well studied.
To compare the incidence of orphanhood among children <15 years of age before and after implementing HIV care in Rakai, Uganda.
Annual household censuses and surveys were conducted January 2001 to September 2009 in a community cohort, where HIV care including antiretroviral therapy (ART) started in June 2004. Data included parental survival of children aged –14 years, and HIV status from consenting adults aged 15–49 years. The incidence of orphanhood was estimated as the number of new orphans divided by person-years, determined during three time periods: Pre-HIVcare roll-out (January 2001–June 2003) 1–3 years before the advent of HIV care in Rakai program, HIVcare-transition from September2003–May2006, and the Expanded HIVcare period from August2006–September2009. Poisson regression was used to estimate incidence rate ratios (IRR) of orphanhood and 95% confidence intervals, and the Population attributable fraction (PAF) of incident orphanhood due to HIV+ parental status was estimated as pd*(RR-1)/RR.
A total of 20 823, 21 770 and 23 700 children aged 0–14 years were censused at the three periods, respectively. The prevalence of orphanhood significantly declined; 17.2% during Pre-HIVcare roll-out, 16.0% at HIVcare-transition, and 12.6% at Expanded HIVcare period (χ2 for trend, p<0.0001). The incidence of orphanhood also declined significantly with increasing HIV care from 2.10/100py, 1.57/100py and 1.07/100py (χ2 for trend, p<0.0001). The largest declines were observed among children with HIV+ parent(s), 8.2/100pyr, 5.2/100pys and 3.4/100pyr. PAF also declined from 35.3% in the pre-HIVcare to 27.6% in the Expanded HIVcare periods
After the availability of ART there was decline in population attributable fraction of incident orphanhood due to parental HIV+ status, and in the incidence of orphanhood especially among children with HIV-infected parents.
PMCID: PMC4169214  PMID: 22716203
Incidence; orphanhood; HIV care; ART; PAF; Uganda
11.  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.
PMCID: PMC3749432  PMID: 23583487
12.  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.
PMCID: PMC3732529  PMID: 23400966
Human papillomavirus (HPV); male circumcision; Uganda; cervical cancer; sexually transmitted infections; viral shedding; viral load; linear array band intensity; HIV
13.  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.
PMCID: PMC3733512  PMID: 23812240
herpes simplex virus type 2 (HSV-2); human immunodeficiency virus (HIV); immune reconstitution inflammatory syndrome (IRIS); acyclovir; reactivation; Uganda
14.  The Safety and Acceptance of the PrePex Device for Non-Surgical Adult Male Circumcision in Rakai, Uganda. A Non-Randomized Observational Study 
PLoS ONE  2014;9(8):e100008.
To assess the safety and acceptance of the PrePex device for medical male circumcision (MMC) in rural Uganda.
In an observational study, HIV-uninfected, uncircumcised men aged 18 and older who requested elective MMC were informed about the PrePex and dorsal slit methods and offered a free choice of their preferred procedure. 100 men received PrePex to assess preliminary safety (aim 1). An additional 329 men, 250 chose PrePex and 79 chose Dorsal slit, were enrolled following approval by the Safety Monitoring Committee (aim 2). Men were followed up at 7 days to assess adverse events (AEs) and to remove the PrePex device. Wound healing was assessed at 4 weeks, with subsequent weekly follow up until completed healing.
The PrePex device was contraindicated in 5.7% of men due to a tight prepuce or phimosis/adhesions. Among 429 enrolled men 350 (82.0%) got the PrePex device and 79 (18.0%) the dorsal slit procedure. 250 of 329 men (76.0%) who were invited to choose between the 2 procedures chose Prepex. There were 9 AEs (2.6%) with the PrePex, of which 5 (1.4%) were severe complications, 4 due to patient self-removal of the device leading to edema and urinary obstruction requiring emergency surgical circumcision, and one due to wound dehiscence following device removal. 71.8% of men reported an unpleasant odor prior to PrePex removal. Cumulative rates of completed wound healing with the PrePex were 56.7% at week 4, 84.8% week 5, 97.6% week 6 and 98.6% week 7, compared to 98.7% at week 4 with dorsal slit (p<0.0001).
The PrePex device was well accepted, but healing was slower than with dorsal slit surgery. Severe complications, primarily following PrePex self-removal, required rapid access to emergency surgical facilities. The need to return for removal and delayed healing may increase Program cost and client burden.
PMCID: PMC4140666  PMID: 25144194
15.  The Acceptability and Safety of the Shang Ring for Adult Male Circumcision in Rakai, Uganda 
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.
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.
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.
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.
PMCID: PMC3805675  PMID: 23614991
Male circumcision; Shang Ring; Rakai; Uganda
16.  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.
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.
PMCID: PMC3715796  PMID: 23641870
17.  Liver Stiffness Is Associated With Monocyte Activation in HIV-Infected Ugandans Without Viral Hepatitis 
AIDS Research and Human Retroviruses  2013;29(7):1026-1030.
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.
PMCID: PMC3685686  PMID: 23548102
18.  Differential loss of invariant NKT cells and FoxP3+ regulatory T cells in HIV-1 subtype A and subtype D infections 
HIV-1 subtype D is associated with faster disease progression as compared to subtype A. Immunological correlates of this difference remain undefined. We investigated invariant natural killer T cells and FoxP3+ regulatory T cells in Ugandans infected with either subtype. Loss of iNKT cells was pronounced in subtype D, whereas Tregs displayed more profound loss in subtype A infection. iNKT cell levels were associated with CD4 T cell IL-2 production in subtype A, but not D, infection. Thus, these viral subtypes are associated with differential loss of iNKT cells and Tregs that may influence the quality of the adaptive immune response.
PMCID: PMC3683089  PMID: 23403863
HIV-1; viral subtype; AIDS; iNKT cell; CD1d; T regulatory cell
19.  Financial Implications of Male Circumcision Scale-Up for the Prevention of HIV and Other Sexually Transmitted Infections in a Sub-Saharan African Community 
Sexually transmitted diseases  2013;40(7):559-568.
The financial implications of male circumcision (MC) scale-up in sub-Saharan Africa associated with reduced HIV have been evaluated. However, no analysis has incorporated reduction in a comprehensive set of other sexually transmitted infections (STIs), including human papillomavirus, herpes simplex virus type 2, genital ulcer disease, bacterial vaginosis and trichomoniasis.
A Markov model tracked a dynamic population undergoing potential MC scale-up, as individuals experienced MC procedures, procedure-related adverse events, MC-reduced STIs, and accrued any associated costs. Rakai, Uganda was used as a prototypical rural sub-Saharan African community. Monte Carlo microsimulations evaluated outcomes under four alternative scale-up strategies to reach 80% MC coverage among men 15-49, in addition to a baseline strategy defined by current MC rates in central Uganda. Financial outcomes included direct medical expenses only, and were evaluated over 5 and 25 years. Costs were discounted to the beginning of each time period, coinciding with the start of MC scale-up, and expressed in US$2012.
Cost savings from infections averted by MC vary from $197,531 after 5 years of a scale-up program focusing on adolescent/adult procedures to over $13 million after 25 years, under a strategy incorporating increased infant MCs. Over a 5-year period, reduction in HIV contributes to 50% of cost savings, and over 25 years, this contribution rises to nearly 90%.
STIs other than HIV contribute to cost savings associated with MC scale-up. Previous analyses, focusing exclusively on the financial impact through averted HIV, may have underestimated true cost savings by 10-50%.
PMCID: PMC3752094  PMID: 23965771
male circumcision; HIV; HPV; sexually transmitted infections; herpes simplex virus type 2 (HSV-2); bacterial vaginosis; trichomoniasis; cost-effectiveness; Markov; Monte Carlo; Africa; Uganda
20.  Human Papillomavirus Clearance Among Males Is Associated With HIV Acquisition and Increased Dendritic Cell Density in the Foreskin 
The Journal of Infectious Diseases  2013;207(11):1713-1722.
Background. The association between human papillomavirus (HPV) infection and the risk of human immunodeficiency virus (HIV) seroconversion is unclear, and the genital cellular immunology has not been evaluated.
Methods. A case-control analysis nested within a male circumcision trial was conducted. Cases consisted of 44 male HIV seroconverters, and controls were 787 males who were persistently negative for HIV. The Roche HPV Linear Array Genotype Test detected high-risk HPV (HR-HPV) and low-risk HPV (LR-HPV) genotypes. Generalized estimating equations logistic regression was used to estimate adjusted odds ratios (aORs) of HIV seroconversion. In addition, densities of CD1a+ dendritic cells, CD4+ T cells, and CD8+ T cells were measured using immunohistochemistry analysis in foreskins of 79 males randomly selected from participants in the circumcision trial.
Results. HR-HPV or LR-HPV acquisition was not significantly associated with HIV seroconversion, after adjustment for sexual behaviors. However, HR-HPV and LR-HPV clearance was significantly associated with HIV seroconversion (aOR, 3.25 [95% confidence interval {CI}, 1.11–9.55] and 3.18 [95% CI, 1.14–8.90], respectively). The odds of HIV seroconversion increased with increasing number of HPV genotypes cleared (P < .001, by the test for trend). The median CD1a+ dendritic cell density in the foreskin epidermis was significantly higher among males who cleared HPV (72.0 cells/mm2 [interquartile range {IQR}, 29.4–138.3 cells/mm2]), compared with males who were persistently negative for HPV (32.1 cells/mm2 [IQR, 3.1–96.2 cells/mm2]; P = .047), and increased progressively with the number of HPV genotypes cleared (P = .05).
Conclusions. HPV clearance was associated with subsequent HIV seroconversion and also with increased epidermal dendritic cell density, which potentially mediates HIV seroconversion.
PMCID: PMC3636782  PMID: 23345339
human papillomavirus (HPV); male circumcision; HIV; AIDS; Uganda; penile cancer; cervical cancer; sexually transmitted infections
21.  High risk human papillomavirus viral load and persistence among heterosexual HIV-negative and HIV-positive men 
Sexually transmitted infections  2014;90(4):337-343.
High-risk human papillomavirus (HR-HPV) viral load is associated with HR-HPV transmission and HR-HPV persistence in women. It is unknown whether HR-HPV viral load is associated with persistence in HIV-negative or HIV-positive men.
HR-HPV viral load and persistence were evaluated among 703 HIV-negative and 233 HIV-positive heterosexual men who participated in a male circumcision trial in Rakai, Uganda. Penile swabs were tested at baseline and 6, 12 and 24 months for HR-HPV using the Roche HPV Linear Array, which provides a semi-quantitative measure of HPV shedding by hybridization band intensity (graded:1–4). Prevalence risk ratios (PRR) were used to estimate the association between HR-HPV viral load and persistent detection of HR-HPV.
HR-HPV genotypes with high viral load (grade:3–4) at baseline were more likely to persist than HR-HPV genotypes with low viral load (grade:1–2) among HIV-negative men (month 6: adjPRR=1.83, 95%CI:1.32–2.52; month 12: adjPRR=2.01, 95%CI:1.42–3.11), and HIV-positive men (month 6: adjPRR=1.33, 95%CI:1.06–1.67; month 12: adjPRR=1.73, 95%CI:1.18–2.54). Long-term persistence of HR-HPV was more frequent among HIV-positive men compared to HIV-negative men (month 24: adjPRR=2.27, 95%CI: 1.47–3.51). Persistence of newly detected HR-HPV at the 6 and 12 month visits with high viral load were also more likely to persist to 24 months than HR-HPV with low viral load among HIV-negative men (adjPRR=1.67, 95%CI 0.88–3.16).
HR-HPV genotypes with high viral load are more likely to persist among HIV-negative and HIV-positive men, though persistence was more common among HIV-positive men overall. The results may explain the association between high HR-HPV viral load and HR-HPV transmission.
PMCID: PMC4030299  PMID: 24482488
Human papillomavirus (HPV); human immunodeficiency virus (HIV); male circumcision; Uganda; penile cancer; sexually transmitted infections; viral shedding; viral load; linear array band intensity
22.  Male Circumcision and Mycoplasma genitalium Infection in Female Partners: a Randomized Trial in Rakai, Uganda 
Sexually transmitted infections  2013;90(2):150-154.
Previous randomized trial data have demonstrated that male circumcision reduces Mycoplasma genitalium prevalence in men. We assessed whether male circumcision also reduces M. genitalium infection in female partners of circumcised men.
HIV-negative men were enrolled and randomized to either male circumcision or control. Female partners of male trial participants from the intervention (n=437) and control (n=394) arms provided interview information and self-collected vaginal swabs that were tested for M. genitalium by APTIMA transcription-mediated-amplification-based assay. Prevalence risk ratios (PRR) and 95% confidence intervals (95%CI) of M. genitalium prevalence in intervention versus control group were estimated using Poisson regression. Analysis was by intention-to-treat. An as-treated analysis was conducted to account for study-group crossovers.
Male and female partner enrollment sociodemographic characteristics, sexual behaviors, and symptoms of STIs were similar between study arms. Female M. genitalium prevalence at year-two was 3.2% (14/437) in intervention arm and 3.6% (14/394) in control arm (PRR=0.90, 95%CI 0.43–1.89, p=0.78). In an as-treated analysis, the prevalence of M. genitalium was 3.4% in female partners of circumcised men and 3.3% in female partners of uncircumcised men (PRR= 1.01, 95%CI 0.48–2.12, p=0.97).
Contrary to findings in men, male circumcision did not affect Mycoplasma genitalium infection in female partners.
PMCID: PMC4018720  PMID: 24259189
Male circumcision; mycoplasma genitalium; HIV; Uganda; sexually transmitted infections; transmission
23.  Male circumcision reduces penile high-risk human papillomavirus viral load in a randomised clinical trial in Rakai, Uganda 
Sexually transmitted infections  2012;89(3):262-266.
Male circumcision reduces penile high-risk human papillomavirus (HR-HPV) prevalence in randomised trials. The goal of this study was to examine the effect of circumcision on HPV viral load among HPV-infected men in a randomised trial of male circumcision.
In a randomised trial to assess the efficacy of circumcision on HIV acquisition in Rakai, Uganda, HIV-negative men were randomised to immediate (intervention) or delayed (control) circumcision and followed over 24 months. We performed quantitative-PCR HPV viral load assays on penile swabs which tested positive by Linear Array (LA) for six HR-HPV genotypes and estimated viral load in the remaining types by LA signal strength.
At 24 months, circumcision intervention arm men infected with one of the six selected HR-HPV genotypes had a lower viral load and significantly reduced HR-HPV high LA band intensity (PRR=0.61, 95% CI 0.43 to 0.86) compared to infected men in the control arm of the trial. The decreased viral load associated with circumcision was seen among HPV infections acquired after enrolment but not among infections that persisted from trial enrolment to 24 months (p=0.80).
The decreased penile HR-HPV shedding observed among HPV-infected circumcised men may help to explain the protective association observed between circumcision and reduced acquisition of HR-HPV in female partners.
PMCID: PMC3706631  PMID: 23112341
24.  Cost analyses of peer health worker and mHealth support interventions for improving AIDS care in Rakai, Uganda 
AIDS care  2012;25(5):652-656.
A cost analysis study calculates resources needed to deliver an intervention and can provide useful information on affordability for service providers and policy makers. We conducted cost analyses of both a peer health worker (PHW) and a mHealth (mobile phone) support intervention. Excluding supervisory staffing costs, total yearly costs for the PHW intervention was $8,475, resulting in a yearly cost per patient of $8.74, per virologic failure averted cost of $189, and per patient lost to follow-up averted cost of $1025. Including supervisory staffing costs increased total yearly costs to $14,991. Yearly costs of the mHealth intervention were an additional $1046, resulting in a yearly cost per patient of $2.35. In a threshold analysis, the PHW intervention was found to be cost saving if it was able to avert 1.50 patients per year from switching to second-line antiretroviral therapy. Other AIDS care programs may find these intervention costs affordable.
PMCID: PMC3773472  PMID: 22971113
cost analysis; mHealth; community health workers; Uganda; antiretroviral treatment
25.  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

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