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Abstract Background The risk of HIV-1 related mortality is strongly related to CD4 count. Guidance on optimal timing for initiation of antiretroviral therapy (ART) is still evolving, but the contribution of HIV-1 infection to excess mortality at CD4 cell counts above thresholds for HIV-1 treatment has not been fully described, especially in resource-poor settings. To compare mortality among HIV-1 infected and uninfected members of HIV-1 serodiscordant couples followed for up to 24 months, we conducted a secondary data analysis examining mortality among HIV-1 serodiscordant couples participating in a multicenter, randomized controlled trial at 14 sites in seven sub-Saharan African countries. Methods Predictors of death were examined using Cox regression and excess mortality by CD4 count and plasma HIV-1 RNA was computed using Poisson regression for correlated data. Results Among 3295 HIV serodiscordant couples, we observed 109 deaths from any cause (74 deaths among HIV-1 infected and 25 among HIV-1 uninfected persons). Among HIV-1 infected persons, the risk of death increased with lower CD4 count and higher plasma viral levels. HIV-1 infected persons had excess mortality due to medical causes of 15.2 deaths/1000 person years at CD4 counts of 250 – 349 cells/μl and 8.9 deaths at CD4 counts of 350 – 499 cells/μl. Above a CD4 count of 500 cells/μl, mortality was comparable among HIV-1 infected and uninfected persons. Conclusions Among African serodiscordant couples, there is a high rate of mortality attributable to HIV-1 infection at CD4 counts above the current threshold (200 – 350 cells/μl) for ART initiation in many African countries. These data indicate that earlier initiation of treatment is likely to provide clinical benefit if further expansion of ART access can be achieved. Trial Registration Clinicaltrials.gov (NCT00194519)

We recently reported that the risk of sexually acquired HIV-1 infection is increased significantly by variants in the gene encoding CD101, a protein thought to modify inflammatory responses. Using blood samples from individuals with and without these variants, we demonstrate that CD101 variants modify the prevalence of circulating inflammatory cell types and show that CD101 variants are associated with increased proinflammatory cytokine production by circulating T cells. One category of CD101 variants is associated with a reduced capacity of regulatory T cells to suppress T cell cytokine production, resulting in a reduction in the baseline level of immune quiescence. These data are supported by transcriptomics data revealing alterations in the intrinsic regulation of antiviral pathways and HIV resistance genes in individuals with CD101 variants. Our data support the hypothesis that CD101 contributes to homeostatic regulation of bystander inflammation, with CD101 variants altering heterosexual HIV-1 acquisition by facilitating increased prevalence and altered function of T cell subsets.

Abstract Background To explore adolescent HIV risk perception, HIV vaccine knowledge, willingness to participate in future HIV vaccine clinical trials, and the factors that influence willingness to participate among high school students in Soweto, South Africa, we recruited school-going youth through randomly selected local high schools. All pupils within the selected schools from whom parental consent and child assent could be obtained were eligible for participation. A self-administered, facilitated questionnaire was completed by all participants. Findings Perception of adolescent HIV risk was high. Some misconceptions regarding vaccine research were common, particularly regarding placebo and potential eligibility criteria for prophylactic vaccine trials. Of 240 responses to the willingness item, 84 (35%) indicated they were "probably willing" and 126 (52.5%) that they were "definitely willing to participate". There were no significant differences in willingness by gender, age, school grade, or institution. Factors that were rated as "very important" in determining willingness included receiving current information about HIV research [n = 201 (88.9%)], doing something to honour people who have HIV or have died of AIDS [n = 168 (70.9%)], getting free counselling and testing [n = 167 (70.5)], that participants may receive some protection against HIV infection from the vaccine [n = 160 (70.2%)], and improving motivation to avoid risky behaviour [n = 134 (59%)]. Conclusion Soweto school-going youth report high degrees of willingness to participate in HIV vaccine trials. This may be related to the high levels of adolescent HIV risk perception. Whether hypothetical willingness translates to participation will await data from adolescent HIV vaccine trials.

Abstract Background In the presence of both HIV infection and cervical intraepithelial neoplasia (CIN), the risk of cancer development despite treatment may be greater. We investigated clinical predictors of persistent cytological abnormalities in women who had had a large loop excision of the transformation zone (LLETZ). Methods Women with high grade squamous intraepithelial lesions or worse (HSIL), less severe abnormalities which persisted and any abnormality in women who are HIV-infected, were referred to the colposcopy clinic. HIV infection was ascertained by self-report. A LLETZ was performed on all patients with HSIL or higher on Papanicolaou (Pap) smear or colposcopy, LSIL or higher in patients who are HIV-infected, where the colposcopy is inadequate, and when there was a discrepancy between colposcopy and cytology by one or more grades. Women with abnormal follow-up smears were compared to those with normal smears. We examined the association between abnormal follow-up smears and demographic and clinical predictors using logistic regression Results The median time between LLETZ and first follow-up Pap smear was rather short at 122 days. Persistent cytological abnormalities occurred in 49% of our patients after LLETZ. Predictors of persistence included the presence of disease at both margins and HIV infection. Among the latter, disease at the excision margins and CD4+ cell count were important predictors. In these women, disease at the endocervical margin, both margins, and disease only at the ectocervical margin were associated with increased odds of persistent abnormalities on follow-up cervical smear. Conclusion We showed extremely high risk of cytological abnormality at follow-up after treatment more so in patients with incomplete excision and in the presence of immunocompromise. It remains uncertain whether recurrent CIN is a surrogate marker for invasive cervical cancer.

Abstract The public sector delivery of male circumcision in the only public sector hospital in Soweto, South Africa was examined to gauge local capacity to deliver this procedure as an intervention for prevention of HIV acquisition. During the period from July 1998 to March 2006, approximately 360 procedures were performed per annum. Striking seasonal variations and the relatively few procedures performed may create challenges for program planning, if male circumcision is increased to a level required to have an impact on the incidence of HIV among this population.

BackgroundWhether bacterial vaginosis (BV) and CD101 immunoglobulin-like (Ig-like) variants independently increase HIV risk through mucosal inflammation is not well understood. We evaluated whether the impact of BV on HIV acquisition in women differs by the presence or absence of candidate CD101 Ig-like variants.MethodsWe used data from 2 studies of HIV serodiscordant couples in east (Kenya, Tanzania, and Uganda) and southern (Botswana, South Africa, and Zambia) Africa, which longitudinally assessed HIV acquisition (by ELISA) and BV (by Nugent score ≥7). We used previously generated CD101 sequence data for each case and control participant to create a binary variable indicating the presence/absence of any of 5 CD101 Ig-like variants.ResultsConfirming previously shown results in this cohort, Ig-like variants increased HIV-infection risk (adjusted hazard ratio [aHR], = 2.63; 95% confidence interval [CI], 1.41 to 4.89). BV was associated with 2.5-fold higher HIV-infection risk only in the absence of Ig-like variants (aHR = 2.47; 95% CI, 0.99 to 6.15; P = 0.052), whereas in the presence of Ig-like variants, BV was not associated with higher HIV-infection risk (aHR = 0.87; 95% CI, 0.35 to 2.15; P = 0.765); however, a test for interaction was nonsignificant (P = 0.116).ConclusionsWe hypothesized that both BV and CD101 Ig-like variants facilitate HIV acquisition by augmenting similar genital inflammation pathways. Our findings indicate that inflammatory mucosal effects of Ig-like variants may influence the impact of BV on HIV risk. Host-defined inflammatory pathways may be useful targets for HIV prevention.

Abstract Background We conducted a review of the diagnostic accuracy of clinical examination for the diagnosis of cirrhosis. The objectives were: to identify studies assessing the accuracy of clinical examination in the detection of cirrhosis; to summarize the diagnostic accuracy of reported physical examination findings; and to define the effects of study characteristics on estimates of diagnostic accuracy. Methods Studies were identified through electronic literature search of MEDLINE (1966 to 2000), search of bibliographic references, and contact with authors. Studies that evaluated indicants from physical examination of patients with known or suspected liver disease undergoing liver biopsy were included. Qualitative data on study characteristics were extracted. Two-by-two tables of presence or absence of physical findings for patients with and without cirrhosis were created from study data. Data for physical findings reported in each study were combined using Summary Receiver Operating Characteristic (SROC) curves or random effects modeling, as appropriate. Results Twelve studies met inclusion criteria, including a total of 1895 patients, ranging in age from 3 to 90 years. Most studies were conducted in referral populations with elevated aminotransferase levels. Ten physical signs were reported in three or more studies and ten signs in only a single study. Signs for which there was more study data were associated with high specificity (range 75–98%), but low sensitivity (range 15–68%) for histologically-proven cirrhosis. Conclusions Physical findings are generally of low sensitivity for the diagnosis of cirrhosis, and signs with higher specificity represent decompensated disease. Most studies have been undertaken in highly selected populations.

BackgroundImmune reconstitution inflammatory syndrome (IRIS) in human immunodeficiency virus (HIV)-infected persons beginning antiretroviral therapy (ART) has been incompletely characterized for herpes simplex virus type 2 (HSV-2).MethodsWe evaluated genital ulcer disease (GUD) and HSV-2-associated GUD at quarterly visits or when spontaneously reported at monthly visits in 3381 HIV/HSV-2-coinfected individuals in a placebo-controlled trial of suppressive acyclovir therapy to prevent HIV transmission, 349 of whom initiated ART during the study. Incidence was calculated for months before and after ART initiation, and incidence rate ratios (IRRs) were calculated.ResultsGUD incidence increased from 15.0 episodes per 100 person-years before ART to 26.9 episodes per 100 person-years in the first full quarter after ART initiation (IRR, 1.83;P= .03), and the incidence of HSV-2-associated GUD increased from 8.1 to 19.0 episodes per 100 person-years (IRR, 2.20;P= .02). Subsequently, the incidence of GUD was similar to that before ART, although the numbers were small. Persons receiving suppressive acyclovir had fewer GUD episodes, but the IRR after beginning ART was similar in the acyclovir and placebo groups.ConclusionsInitiation of ART in HIV/HSV-2-coinfected persons is associated with a transient increase in GUD and HSV-2 GUD. Acyclovir reduces the incidence of GUD but does not prevent an increase in GUD incidence during the first quarter following initiation of ART.

BackgroundThe efficacy of condoms for protection against transmission of herpes simplex virus type 2 (HSV-2) has been examined in a variety of populations with different effect measures. Often the efficacy has been assessed as change in hazard of transmission with consistent vs inconsistent use, independent of the number of acts. Condom efficacy has not previously measured on a per-act basis.MethodsWe examined the per-act HSV-2 transmission rates with and without condom use among 911 African HSV-2 and human immunodeficiency virus type 1 (HIV-1) serodiscordant couples followed for an average of 18 months in an HIV prevention study. Infectivity models were used to associate the log10 probability of HSV-2 transmission over monthly risk periods with reported numbers of protected and unprotected sex acts. Condom efficacy was computed as the proportionate reduction in transmission risk for protected relative to unprotected sex acts.ResultsTransmission of HSV-2 occurred in 68 couples, including 17 with susceptible women and 51 with susceptible men. The highest rate of transmission was from men to women: 28.5 transmissions per 1000 unprotected sex acts. We found that condoms were differentially protective against HSV-2 transmission by sex; condom use reduced per-act risk of transmission from men to women by 96% (P < .001) and marginally from women to men by 65% (P = .060).ConclusionsCondoms are recommended as an effective preventive method for heterosexual transmission of HSV-2.

BackgroundA heightened proinflammatory state has been hypothesized to enhance human immunodeficiency virus type 1 (HIV-1) transmission - both susceptibility of HIV-1-exposed persons and infectiousness of HIV-1-infected persons.MethodsUsing prospective data from heterosexual African couples with HIV-1 serodiscordance, we conducted a nested case-control analysis to assess the relationship between cytokine concentrations and the risk of HIV-1 acquisition. Case couples (n = 120) were initially serodiscordant couples in which HIV-1 was transmitted to the seronegative partner during the study; control couples (n = 321) were serodiscordant couples in which HIV-1 was not transmitted to the seronegative partner. Differences in a panel of 30 cytokines were measured using plasma specimens from both HIV-1-susceptible and HIV-1-infected partners. Plasma was collected before seroconversion for cases.ResultsFor both HIV-1-infected and HIV-1-susceptible partners, cases and controls had significantly different mean responses in cytokine panels (P < .001, by the Hotelling T(2) test), suggesting a broadly different pattern of immune activation for couples in which HIV-1 was transmitted, compared with couples without transmission. Individually, log10 mean concentrations of interleukin 10 (IL-10) and CXCL10 were significantly higher for both HIV-1-susceptible and HIV-1-infected case partners, compared with HIV-1-susceptible and HIV-1-infected control partners (P < .01 for all comparisons). In multivariate analysis, HIV-1 transmission was significantly associated with elevated CXCL10 concentrations in HIV-1-susceptible partners (P = .001) and with elevated IL-10 concentrations in HIV-1-infected partners (P = .02).ConclusionsImmune activation, as measured by levels of cytokine markers, particularly elevated levels of IL-10 and CXCL1, are associated with increased HIV-1 susceptibility and infectiousness.

Most reported U.S. zoonotic cases of babesiosis have occurred in the Northeast and been caused by Babesia microti. In Washington State, three cases of babesiosis have been reported previously, which [...]