Frederikke Falkencrone Rønsholt

Persistent Inflammation and Endothelial Activation in HIV-1 Infected Patients after 12 Years of Antiretroviral Therapy

Objective The study investigated markers of inflammation and endothelial activation in HIV infected patients after 12 years of successful combination antiretroviral treatment (cART). Methods Inflammation and endothelial activation were assessed by measuring levels of immunoglobulins, β2-microglobulin, interleukin (IL) 8, tumor necrosis factor α (TNFα), vascular cell adhesion molecule-1 (sVCAM-1), intercellular adhesion molecule-1 (sICAM-1), sE-Selectin, and sP-Selectin. Results HIV infected patients had higher levels of β2-microglobulin, IL-8, TNFα, and sICAM-1 than uninfected controls, and HIV infected patients lacked correlation between platelet counts and sP-Selectin levels found in uninfected controls. Conclusion Discrete signs of systemic and vascular inflammation persist even after very long term cART.

Discrepant coagulation profile in HIV infection: elevated D-dimer but impaired platelet aggregation and clot initiation.

Objectives:In HIV infection, cardiovascular disease (CVD) has emerged as a clinical problem, and elevated D-dimer has been reported. The pathophysiologic mechanisms underlying this remain unclear. We aimed to investigate whether untreated HIV-infected individuals display evidence of functional coagulopathy and whether this was associated with microbial translocation. Design:The study population consisted of 50 HIV-infected untreated individuals and 50 HIV-infected individuals on combination antiretroviral therapy (cART). Groups were matched for age, sex and current CD4+cell count. Methods:Coagulation analyses included D-dimer and the functional haemostatic whole blood tests, thromboelastography (TEG) and platelet aggregation (Multiplate, impedance aggregometry). Microbial translocation was assessed by plasma levels of lipopolysaccharide (LPS). Results:A larger proportion of untreated individuals compared with treated individuals had D-dimer above normal reference range (27.7 vs. 2.2%, P = 0.001). In both treated and untreated individuals, delayed clot initiation with TEG R-time above upper reference range (18 and 28%, respectively, both P < 0.001) and TEG angle below lower reference range [14% (P = 0.004) and 24% (P < 0.001), respectively] was found. In untreated individuals, 64.6% had aggregation response below threshold in at least two of four tests compared with 36.7% in treated individuals (P = 0.010). Untreated individuals with increased D-dimer levels were relatively hypercoagulable by thromboelastography. Furthermore, in untreated patients, a negative association between microbial translocation and platelet aggregation was found. Conclusion:Elevated D-dimer in untreated HIV-infected individuals was confirmed. However, in both untreated and treated individuals, reduced platelet aggregation and clot initiation was found. The impact of reduced platelet function in HIV infection and a potential role of microbial translocation warrant further investigation.

T-cell subset distribution in HIV-1-infected patients after 12 years of treatment-induced viremic suppression.

Objective:Residual immune activation and skewed T cell maturation may contribute to excess comorbidity and mortality in successfully treated HIV-infected patients, and long-term effects of combination antiretroviral therapy (cART) on immune reconstitution remain a debated issue. Quantitative T cell reconstitution and activation and its association with residual viremia in patients with 12 years of viremic suppression were investigated. Design:Blood samples collected cross-sectionally from 71 HIV-infected patients with cART-induced viremic suppression through 12 years were compared with samples from 16 healthy controls. Methods:Several different subsets of naive, memory, and activated T cells were analyzed in fresh whole blood by 6-color flowcytometry, and ultrasensitive quantification of HIV RNA was performed. Results:HIV-infected patients had lower absolute and relative CD4 T cell counts and higher absolute and relative CD8 T cell counts than controls. HIV-infected patients had lower concentrations of naive CD4 cells than controls, but proportions were similar. HIV-infected patients had higher concentrations of CD8+ T cells than controls in all the examined subsets but only a higher proportion of CD8+ cells in the intermediately differentiated and activated subsets. Residual viremia did not correlate to proportions of naive CD4, CD4 recent thymic emigrants, or activated CD8 T cells. Conclusions:This study demonstrated some degree of T cell imbalance even after 12 years of successful cART. Large longitudinal studies are needed to establish whether these discrete changes have clinical relevance.

T Cell Subsets in HIV Infected Patients after Successful Combination Antiretroviral Therapy: Impact on Survival after 12 Years

Objectives Immune activation is decreased by combination antiretroviral therapy (cART) in patients infected with human immunodeficiency virus (HIV), but residual activation remains and has been proposed as a cause of premature aging and death, but data are lacking. We analyzed the relationship between T-cell subsets after 18 months of cART and overall survival during 12 years of follow up. Methods A cohort of 101 HIV infected patients who had undetectable plasma HIV after starting cART was included in 1997–1998. T cell subsets were analyzed by flowcytometry after 18 months of cART. Relation to survival was calculated using Kaplan-Meier curves and multiple Cox regression. Results Seventeen patients died during the observation period. The leading causes of death were non-AIDS cancer and cardiovascular disease. Higher levels of CD8 memory T cells (CD8+,CD45RO+,CD45RA-) showed a significant beneficiary effect on survival, HR of 0.95 (95% confidence interval 0.91–0.99, P = 0.016) when adjusted for age, nadir CD4 count, CD4 count, and AIDS and hepatitis C status. T cell activation was not associated with increased risk of death. Conclusions Larger and longitudinal studies are needed to accurately establish prognostic factors, but overall results seem to suggest that prognostic information exists within the CD8 compartment.

Prevalence of cervical, oral, and anal human papillomavirus infection in women living with HIV in Denmark - The SHADE cohort study

BACKGROUND Women living with HIV (WLWH) have elevated risk of human papillomavirus (HPV) related cancers. OBJECTIVES To assess prevalence, distribution and concordance of cervical, oral, and anal HPV infection, and predictors of oral and anal HPV in WLWH in Denmark. STUDY DESIGN WLWH followed in the Study on HIV, cervical Abnormalities and infections in women in Denmark (SHADE) were enrolled and examined for cervical, oral, and anal HPV infection. Logistic regression models were used to identify predictors of anal and oral HPV. RESULTS A total of 214 of 334 WLWH had sufficient DNA for analysis at all three anatomical sites and were included in analyses. Cervical, oral, and anal high-risk (hr) HPV prevalence were 28.0%, 3.7% and 39.3%. Most frequent i) cervical, ii) oral and iii) anal hrHPV genotypes were i) hrHPV58 (8.4%), 52 (5.1%), 16 (5.1%) and 51 (5.1%); ii) 52 (1.4%) and iii) 51 (9.3%), 58 (8.9%), 16 (7.0%) and 18 (7.0%). Among present cervical, oral, and anal hrHPV genotypes, 6.7%, 12.5% and 17.9% were targeted by the 2-or 4-valent HPV vaccines, whereas 50.0%, 50.0% and 42.9% of hrHPV genotypes were covered by the 9-valent HPV vaccine. Anal HPV infection was predicted by cervical HPV infection (adjusted OR 4.47 (95%CI 2.25-8.89)). CONCLUSION Cervical and anal HPV infection were highly prevalent in WLWH. Non-16/18 hrHPV genotypes were predominant at all anatomical sites. Almost half of all hrHPV infections at the three anatomical sites could have been prevented by childhood/adolescent vaccination with the 9-valent HPV vaccine.