Immune correlates of HIV exposure without infection in foreskins of men from Rakai, Uganda.

Human immunodeficiency virus (HIV) susceptibility is heterogenous, with some HIV-exposed but seronegative (HESN) individuals remaining uninfected despite repeated exposure. Previous studies in the cervix have shown that reduced HIV susceptibility may be mediated by immune alterations in the genital mucosa. However, immune correlates of HIV exposure without infection have not been investigated in the foreskin. We collected sub-preputial swabs and foreskin tissue from HESN (n=20) and unexposed control (n=57) men undergoing elective circumcision. Blinded investigators assayed swabs for HIV-neutralizing IgA, innate antimicrobial peptides, and cytokine levels. Functional T-cell subsets from foreskin tissue were assessed by flow cytometry. HESN foreskins had elevated α-defensins (3,027 vs. 1,795 pg ml(-1), P=0.011) and HIV-neutralizing IgA (50.0 vs. 13.5% of men, P=0.019). Foreskin tissue from HESN men contained a higher density of CD3 T cells (151.9 vs. 69.9 cells mm(-2), P=0.018), but a lower proportion of these was Th17 cells (6.12 vs. 8.04% of CD4 T cells, P=0.007), and fewer produced tumor necrosis factor α (TNFα) (34.3 vs. 41.8% of CD4 T cells, P=0.037; 36.9 vs. 45.7% of CD8 T cells, P=0.004). A decrease in the relative abundance of susceptible CD4 T cells and local TNFα production, in combination with HIV-neutralizing IgA and α-defensins, may represent a protective immune milieu at a site of HIV exposure.

Field evaluation of five rapid diagnostic tests for screening of HIV-1 infections in rural Rakai, Uganda.

The performance characteristics of HIV rapid diagnostic tests (RDTs) vary by test and by population. We assessed five commercial RDTs in Uganda where all but one RDT (Determine; Abbott Laboratories, Germany) performed close to manufacturer's expectations. Determine had low specificity (85.2%, positive predictive value 67.3%) due to false-positive results with weak-positive bands. Properly trained staff, good quality control programmes and validation of RDTs with laboratories having confirmatory testing capacity may be warranted to assure accuracy in each setting.

Performance of the Euroline Western blot assay in the detection of herpes simplex virus type 2 antibody in Uganda, China and the USA.

Herpes simplex virus type 2 (HSV-2) infection is one of the most common sexually transmitted infections (STIs) worldwide. While glycoprotein G-2 enzyme-linked immunosorbent assays are commonly used for the serological detection of HSV-2 antibodies, they have low specificity in developing countries. The Euroline Western blot (WB) is a commercially available assay that is easy to perform; however, little is known about its performance characteristics. This study evaluated Euroline WB for the detection of HSV-2 antibodies compared with University of Washington Western blot in three geographically different regions: Baltimore, MD, USA; Rakai, Uganda; and Kunming, China. Among the 135 American men attending a STI clinic in Baltimore, MD, 72% (n = 97) were HSV-2-positive by Euroline WB, showing a sensitivity of 97.8% and a specificity of 81.8%. Among the 273 commercial sex workers in Kunming, 62.3% were HSV-2-positive by Euroline WB (sensitivity 96.9%, specificity 89.1%). Among the 437 Ugandans in Rakai, 67.3% were HSV-2-positive by Euroline WB (sensitivity 98.7%, specificity 65.4%). The Euroline WB has a consistently high sensitivity, but specificity varied significantly among the different locations.

Expose of Fallacious Claims that Male Circumcision Will Increase HIV Infections in Africa

Despite over two decades of extensive research showing that male circumcision protects against heterosexual acquisition of HIV in men; and that includes findings from large randomized controlled trials leading to acceptance by the WHO/UNAIDS and the Cochrane Committee; opponents of circumcision continue to generate specious arguments to the contrary. In a recent issue of the Journal of Public Health in Africa; Van Howe and Storms claim that male circumcision will increase HIV infections in Africa. Here we review the statements they use in support of their thesis and show that there is no scientific basis to such an assertion. We also evaluate the statistics used and show that when these data are properly analyzed the results lead to a contrary conclusion affirming the major role of male circumcision in protecting against HIV infection in Africa. Researchers; policy makers and the wider community should rely on balanced scholarship when assessing scientific evidence. We trust that our assessment may help refute the claims by Van Howe and Storms; and provide reassurance on the importance of circumcision for HIV prevention

Aetiology of genital ulcer disease in female partners of male participants in a circumcision trial in Uganda.

HIV acquisition is associated with herpes simplex virus type 2 (HSV-2) infection and genital ulcer disease (GUD). Three randomized control trials demonstrated that male circumcision significantly decreases HIV, HSV-2, human papillomavirus and self-reported GUD among men. GUD is also decreased among female partners of circumcised men, but it is unknown whether male circumcision status affects GUD pathogens in female partners. For the evaluation of GUD aetiology, two separate multiplex assays were performed to detect Haemophilus ducreyi, Treponema pallidum, HSV-1 and HSV-2. Of all the female GUD swabs evaluated, 67.5% had an aetiology identified, and HSV-2 was the primary pathogen detected (96.3%). However, there was no difference in the proportion of ulcers due to HSV-2 or other pathogens between female partners of circumcised men (11/15, 73.3%) compared with uncircumcised men (15/25, 60.0%, P = 0.39). The seroprevalence of HSV-2 is high in this population and therefore most of the detected HSV-2 infections represent reactivation. Since GUD is associated with HIV acquisition and one-third of GUD in this study did not have an aetiological agent identified, further research is needed to better understand the aetiology of GUD in Africa, and its relationship to circumcision and HIV infection.

Routine, single session, indirect laser for proliferative diabetic retinopathy.

AIMS: To evaluate the visual and morphological outcomes of routine, single session, indirect panretinal photocoagulation (PRP) for proliferative diabetic retinopathy, and to examine adverse events related to indirect laser within the first 8 weeks of treatment. METHODS: The case notes of 107 diabetics with proliferative retinopathy undergoing indirect PRP were reviewed retrospectively, and compared with the UK National Diabetic Retinopathy Laser Treatment Audit. Patients who had received PRP previously were excluded. Follow-up data were collected as close as possible to 9 months following the initial laser treatment. RESULTS: Fifteen patients (14.0%) returned with adverse events within the first 8 weeks of indirect PRP. There were two tractional retinal detachments and two new vitreous haemorrhages. One patient with underlying neurotrophic keratopathy developed a persistent epithelial defect. One developed non-progressive macular drag with a one-line drop in Snellen acuity. Three experienced new or exacerbations of preexisting clinically significant macular oedema, which resolved spontaneously. There were two transient choroidal effusions, two transient anterior uveitis, and two transient visual deteriorations without macular oedema clinically. There were no significant differences in the rates of new tractional retinal detachment, vitreous haemorrhage or rubeosis, but our vitrectomy rate was higher (7.5 vs 1.5%, P=0.02, chi2), largely due to our policy of performing vitrectomy early. CONCLUSIONS: Visual and morphological outcomes of routine, single session, indirect PRP for proliferative diabetic retinopathy were not inferior to the outpatient-based national audit, and the incidence of significant PRP-induced adverse events was low.

Evaluation of multiplex real-time PCR for detection of Haemophilus ducreyi, Treponema pallidum, herpes simplex virus type 1 and 2 in the diagnosis of genital ulcer disease in the Rakai District, Uganda.

OBJECTIVE: To develop a real-time PCR assay that reliably and accurately detects the predominant sexually transmitted aetiological agents of genital ulcer disease (GUD) (Haemophilus ducreyi, Treponema pallidum and herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2)) and to assess the use of real-time PCR diagnostic testing in a rural African field site. METHODS: Two multiplex real-time PCR reactions were used to detect H ducreyi/and HSV-1/HSV-2 in ulcer swabs from 100 people with symptomatic genital ulcers in rural Rakai, Uganda. Results were compared with syphilis, HSV-1 and HSV-2 serology. RESULTS: Of 100 GUD samples analysed from 43 HIV positive and 57 HIV negative individuals, 71% were positive for one or more sexually transmitted infection (STI) pathogens by real-time PCR (61% for HSV-2, 5% for T pallidum, 3% for HSV-1, 1% for H ducreyi and 1% for dual H ducreyi/HSV-2). The frequency of HSV in genital ulcers was 56% (32/57) in HIV negative individuals and 77% (33/43) in HIV positive individuals (p = 0.037). Assay reproducibility was evaluated by repeat PCR testing in the USA with 96% agreement (kappa = 0.85). CONCLUSIONS: STI pathogens were detected in the majority of GUD swab samples from symptomatic patients in Rakai, Uganda, by real-time PCR. HSV-2 was the predominant cause of genital ulcers. Real-time PCR technology can provide sensitive, rapid and reproducible evaluation of GUD aetiology in a resource-limited setting.

Performance of two commercial immunochromatographic assays for rapid detection of antibodies specific to human immunodeficiency virus types 1 and 2 in serum and urine samples in a rural community-based research setting (Rakai, Uganda).

Rapid detection of human immunodeficiency virus (HIV) antibodies is of great importance in developing and developed countries to diagnose HIV infections quickly and at low cost. In this study, two new immunochromatographic rapid tests for the detection of HIV antibodies (Aware HIV-1/2 BSP and Aware HIV-1/2 U; Calypte Biomedical Corporation) were evaluated in rural Africa to determine the tests' performance and comparability to commercially available conventional enzyme immunoassay (EIA) and Western blot (WB) tests. This prospective study was conducted from March 2005 through May 2005 using serum and urine from respondents in the Rakai Community Cohort Survey. Nine hundred sixty-three serum samples were tested with the Aware blood rapid assay (Aware-BSP) and compared to two independent EIAs for HIV plus confirmatory Calypte WB for any positive EIAs. The sensitivity of Aware-BSP was 98.2%, and the specificity was 99.8%. Nine hundred forty-two urine samples were run using the Aware urine assay (Aware-U) and linked to blood sample results for analysis. The sensitivity of Aware-U was 88.7% and specificity was 99.9% compared to blood EIAs confirmed by WB analysis. These results support the adoption of the Aware-BSP rapid test as an alternative to EIA and WB assays for the diagnosis of HIV in resource-limited settings. However, the low sensitivity of the Aware-U assay with its potential for falsely negative HIV results makes the urine assay less satisfactory.

Ocular injuries in patients with major trauma.

AIM: To study the epidemiology of ocular injuries in patients with major trauma in the UK, determining the incidence and causes of ocular injuries, and their association with facial fractures. METHODS: A retrospective analysis of the Trauma Audit Research Network database from 1989 to 2004, looking at data from 39,073 patients with major trauma. RESULTS: Of the 39,073 patients with major trauma, 905 (2.3%) patients had associated ocular injuries and 4082 (10.4%) patients had a facial fracture (zygoma, orbit or maxilla). The risk of an eye injury for a patient with a facial fracture is 6.7 times as that for a patient with no facial fracture (95%, confidence interval 5.9 to 7.6). Of the patients with major trauma and an eye injury, 75.1% were men, and the median age was 31 years. 57.3% of ocular injuries were due to road traffic accidents (RTAs). CONCLUSION: The incidence of ocular injuries in patients with major trauma is low, but considerable association was found between eye injuries and facial fractures. Young adults have the highest incidence of ocular injury. RTAs are the leading cause of ocular injuries in patients with major trauma. It is vital that all patients with major trauma are examined specifically for an ocular injury.

Determinants of the impact of sexually transmitted infection treatment on prevention of HIV infection: a synthesis of evidence from the Mwanza, Rakai, and Masaka intervention trials.

Community-randomized trials in Mwanza, Tanzania, and Rakai and Masaka, Uganda, suggested that population characteristics were an important determinant of the impact of sexually transmitted infection (STI) treatment interventions on incidence of human immunodeficiency virus (HIV) infection. We performed simulation modeling of HIV and STI transmission, which confirmed that the low trial impact in Rakai and Masaka could be explained by low prevalences of curable STI resulting from lower-risk sexual behavior in Uganda. The mature HIV epidemics in Uganda, with most HIV transmission occurring outside core groups with high STI rates, also contributed to the low impact on HIV incidence. Simulated impact on HIV was much greater in Mwanza, although the observed impact was larger than predicted from STI reductions, suggesting that random error also may have played some role. Of proposed alternative explanations, increasing herpetic ulceration due to HIV-related immunosuppression contributed little to the diminishing impact of antibiotic treatment during the Ugandan epidemics. The strategy of STI treatment also was unimportant, since syndromic treatment and annual mass treatment showed similar effectiveness in simulations of each trial population. In conclusion, lower-risk behavior and the mature HIV epidemic explain the limited impact of STI treatment on HIV incidence in Uganda in the 1990s. In populations with high-risk sexual behavior and high STI rates, STIs treatment interventions may contribute substantially to prevention of HIV infection.

Burden of infection among heads and non-head of rural households in Rakai, Uganda.

The objective was to determine HIV prevalence, symptomatology and mortality among adult heads and non-heads of households, in order to assess the burden of HIV on households. It was a community study of 11,536 adults aged 15-59, residing in 4,962 households in 56 villages, Rakai district, Uganda. First, 4,962 heads and 6,574 non-heads of households were identified from censuses. Interviews were then used to determine socio-demographic/behavioural characteristics. HIV seroprevalence was diagnosed by two EIAs with Western blot confirmation. The adjusted odds ratio (OR) and 95% confidence intervals (CI) of HIV infection in household heads and non-heads were estimated by multivariate logistic regression. Age-adjusted mortality was also assessed. HIV prevalence was 16.9% in the population, and 21.5% of households had at least one HIV-infected person (<0.0001). HIV prevalence was higher among heads than non-heads of households (21.5 and 13.3%, respectively, OR=1.79; CI 1.62-1.97). Most household heads were males (70.5%), and HIV prevalence was 17.8% among male heads compared with 6.6% in male non-heads of households (OR=2.31; CI 1.65-2.52). Women heading households were predominantly widowed, separated or divorced (64.4%). HIV prevalence was 30.5% among female heads, compared with 15.6% in female non-household heads (OR=1.42; CI 1.15-1.63). Age-adjusted mortality was significantly lower among male household heads than non-heads, both for the HIV-positive (RR=0.68) and HIV-negative men (RR=0.63). Among women, HIV-negative female household heads had significantly higher mortality than HIV-uninfected female non-heads (RR=1.72). HIV disproportionately affects heads of households, particularly males. Mortality due to AIDS is likely to increase the proportion of female-headed households, and adversely affect the welfare of domestic units.

A 10 year retrospective survey of cataract surgery and endophthalmitis in a single eye unit: injectable lenses lower the incidence of endophthalmitis.

AIM: To study the incidence of endophthalmitis following cataract surgery over a 10 year period, and to examine ways in which this may be related to changes in surgical technique. METHODS: All cases of endophthalmitis occurring over a 10 year period within a single ophthalmic unit in the United Kingdom were reviewed, and possible risk factors identified. RESULTS: During the study period, as the technique of extracapsular cataract surgery was replaced by phacoemulsification, there was a commensurate reduction in the incidence of endophthalmitis. Injectable IOLs were associated with the lowest risk of postoperative endophthalmitis (0.028%). CONCLUSIONS: Injectable intraocular lenses do not make contact with the ocular surface and this may result in the observed lower rate of endophthalmitis. This, and the ease with which they can be inserted through small incisions, support their use as the first line method of lens insertion.

Comparison of STD prevalences in the Mwanza, Rakai, and Masaka trial populations: the role of selection bias and diagnostic errors.

OBJECTIVES: To assess bias in estimates of STD prevalence in population based surveys resulting from diagnostic error and selection bias. To evaluate the effects of such biases on STD prevalence estimates from three community randomised trials of STD treatment for HIV prevention in Masaka and Rakai, Uganda and Mwanza, Tanzania. METHODS: Age and sex stratified prevalences of gonorrhoea, chlamydia, syphilis, HSV-2 infection, and trichomoniasis observed at baseline in the three trials were adjusted for sensitivity and specificity of diagnostic tests and for sample selection criteria. RESULTS: STD prevalences were underestimated in all three populations because of diagnostic errors and selection bias. After adjustment, gonorrhoea prevalence was higher in men and women in Mwanza (2.8% and 2.3%) compared to Rakai (1.1% and 1.9%) and Masaka (0.9% and 1.8%). Chlamydia prevalence was higher in women in Mwanza (13.0%) compared to Rakai (3.2%) and Masaka (1.6%) but similar in men (2.3% in Mwanza, 2.7% in Rakai, and 2.2% in Masaka). Prevalence of trichomoniasis was higher in women in Mwanza compared to women in Rakai (41.9% versus 30.8%). Herpes simplex virus type 2 (HSV-2) seroprevalence and prevalence of serological syphilis (TPHA+/RPR+) were similar in the three populations but the prevalence of high titre syphilis (TPHA+/RPR >/=1:8) in men and women was higher in Mwanza (5.6% and 6.3%) than in Rakai (2.3% and 1.4%) and Masaka (1.2% and 0.7%). CONCLUSIONS: Limited sensitivity of diagnostic and screening tests led to underestimation of STD prevalence in all three trials but especially in Mwanza. Adjusted prevalences of curable STD were higher in Mwanza than in Rakai and Masaka.