Depletion and activation of mucosal CD4 T cells in HIV infected women with HPV-associated lesions of the cervix uteri

Background: The burden of HPV-associated premalignant and malignant cervical lesions remains high in HIV+ women even under ART treatment. In order to identify possible underlying pathophysiologic mechanisms, we studied activation and HIV co-receptor expression in cervical T-cell populations in relation to HIV, HPV and cervical lesion status. Methods Cervical cytobrush (n = 468: 253 HIV- and 215 HIV+;71% on ART) and blood (in a subset of 39 women) was collected from women in Mbeya, Tanzania. Clinical data on HIV and HPV infection, as well as ART status was collected. T cell populations were characterized using multiparametric flow cytometry-based on their expression of markers for cellular activation (HLA-DR), and memory (CD45RO), as well as HIV co-receptors (CCR5, alpha(4)beta(7)). Results Cervical and blood T cells differed significantly, with higher frequencies of T cells expressing CD45RO, as well as the HIV co-receptors CCR5 and alpha(4)beta(7)in the cervical mucosa. The skewed CD4/CD8 T cell ratio in blood of HIV+ women was mirrored in the cervical mucosa and HPV co-infection was linked to lower levels of mucosal CD4 T cells in HIV+ women (%median: 22 vs 32;p = 0.04). In addition, HIV and HPV infection, and especially HPV-associated cervical lesions were linked to significantly higher frequencies of HLA-DR+ CD4 and CD8 T cells (p-values < 0.05). Interestingly, HPV infection did not significantly alter frequencies of CCR5+ or alpha(4)beta(7)+ CD4 T cells. Conclusion The increased proportion of activated cervical T cells associated with HPV and HIV infection, as well as HPV-associated lesions, together with the HIV-induced depletion of cervical CD4 T cells, may increase the risk for HPV infection, associated premalignant lesions and cancer in HIV+ women. Further, high levels of activated CD4 T cells associated with HPV and HPV-associated lesions could contribute to a higher susceptibility to HIV in HPV infected women

Reduction of malaria prevalence after introduction of artemisinin-combination-therapy in Mbeya Region, Tanzania: results from a cohort study with 6773 participants

Background: A marked decline in malaria morbidity and mortality has been reported after the introduction of artemisinin-based combination therapy (ACT) in high malaria prevalence countries in Africa. Data on the impact of ACT and on the prevalence of malaria has so far been scarce for Southwest Tanzania. Methods: Between 2005 and 2011, a large general population cohort in the Mbeya Region in the south-west of Tanzania has been surveyed within the EMINI-study (Evaluation and Monitoring of the Impact of New Interventions). Participants were examined once per year, including rapid diagnostic testing for malaria. ACT was introduced in the region according to national guidelines in the time period 2006/2007, replacing sulfadoxine/pyrimethamine as first-line therapy. In four study sites, 6773 individuals who participated in the first two of three consecutive survey visits in the period from 2006 to 2009 were included in this analysis. The prevalence of Plasmodium infection prior to and after the introduction of ACT was compared by logistic regression, with consideration of climatic variability, age, sex, socioeconomic status and bed net use as potential confounders. Results: A significant reduction over time in the prevalence of Plasmodium falciparum infection from 2.5 to 0.3% was shown across the four study sites. The decline was not explained by other factors included in the analysis, therefore, the decline over time most likely reflects the impact of introduction of ACT in the study area. Conclusions: The longitudinal study showed a significant and relevant decline in the prevalence of P. falciparum infection after introduction of ACT, which could not be explained by potential confounders. The data suggests that artemisinin-based combinations are not only an effective instrument for reduction of immediate morbidity and mortality, but also for reduction of transmission rates

Low specificity of determine HIV1/2 RDT using whole blood in south west Tanzania

Objective: To evaluate the diagnostic performance of two rapid detection tests (RDTs) for HIV 1/2 in plasma and in whole blood samples. Methods: More than 15,000 study subjects above the age of two years participated in two rounds of a cohort study to determine the prevalence of HIV. HIV testing was performed using the Determine HIV 1/2 test (Abbott) in the first (2006/2007) and the HIV 1/2 STAT-PAK Dipstick Assay (Chembio) in the second round (2007/2008) of the survey. Positive results were classified into faint and strong bands depending on the visual appearance of the test strip and confirmed by ELISA and Western blot. Results: The sensitivity and specificity of the Determine RDT were 100% (95% confidence interval = 86.8 to 100%) and 96.8% (95.9 to 97.6%) in whole blood and 100% (99.7 to 100%) and 97.9% (97.6 to 98.1%) in plasma respectively. Specificity was highly dependent on the tested sample type: when using whole blood, 67.1% of positive results were false positive, as opposed to 17.4% in plasma. Test strips with only faint positive bands were more often false positive than strips showing strong bands and were more common in whole blood than in plasma. Evaluation of the STAT-PAK RDT in plasma during the second year resulted in a sensitivity of 99.7% (99.1 to 99.9%) and a specificity of 99.3% (99.1 to 99.4%) with 6.9% of the positive results being false. Conclusions: Our study shows that the Determine HIV 1/2 strip test with its high sensitivity is an excellent tool to screen for HIV infection, but that – at least in our setting – it can not be recommended as a confirmatory test in VCT campaigns where whole blood is used

HIV-Testing Algorithm and Exclusion criteria Survey 1.

<p>In Survey 1 we tested 1,889 whole blood specimen and 14,448 plasma specimen with the Determine HIV1/2 RDT. The confirmation algorithm included two different ELISAs and one Western Blot. If both ELISAs were in agreement their result was used as the reference standard result. Samples with discordant ELISA results were retested by Western Blot and the Western Blot result used. Samples with indeterminate Western Blot results were excluded from analysis. Negative RDT results were not directly confirmed, but regarded as true negative if the result of the following survey was also negative. Whole blood results where confirmation by ELISA testing was impossible due to lack of plasma, were regarded as true positive if the result in the next survey was confirmed positive and as false positive if a negative test result in the next survey was confirmed using the above reference algorithm. Results where the true HIV status could not be verified according to the reference algorithm were excluded from this analysis.</p

Association of various factors with false positive Determine RDT results in plasma; uni- and multi-variable log-link binomial regression results adjusted for clustering within household (N = 11732).

<p>PR  =  probability ratio for a false positive result; p  =  p-value; 95% CI  = 95% confidence interval.</p>*<p>covariates were only included in multi-variable model if uni-variable p-value <0.2.</p

Diagnostic Test performance of Determine and STAT-PAK RDT numbers of positive and negative results.

<p>Diagnostic Test performance of Determine and STAT-PAK RDT numbers of positive and negative results.</p

Diagnostic Test performance of Determine and STAT-PAK RDT sensitivity, specificity, predictive values and likelihood ratios.

a<p>Prevalences differ from total population prevalence due to exclusion of participants.</p>b<p>No confidence interval can be calculated if sensitivity  = 100%.</p