Interferon-free regimens improve portal hypertension and histological necroinflammation in HIV/HCV patients with advanced liver disease.

BACKGROUND: HIV/HCV co-infected patients show accelerated fibrosis progression and higher risk for complications of portal hypertension (PHT). AIM: To assess the effects of interferon-free therapy on portal pressure, liver histology and plasma biomarkers in HIV/HCV-coinfected patients with PHT. METHODS: Twenty-two patients with paired hepatic venous pressure gradient (HVPG) measurements prior and after successful treatment (SVR) with interferon-free regimens were included. Liver stiffness was assessed by transient elastography and biopsies were scored according to METAVIR. Plasma biomarkers were determined by ELISA. RESULTS: Overall, HVPG decreased from 10.7 ± 4.1 mmHg at baseline to 7.4 ± 4.2 mmHg after HCV treatment (Δ:-3.3 ± 2.7 mmHg; p < 0.001). In patients with clinically significant PHT (HVPG≥10 mmHg, n = 11), HVPG decreased from 14.1 ± 2.9 to 10.4 ± 3.9 mmHg (Δ:-3.7 ± 3.3 mmHg; p = 0.004) and a haemodynamic response (HVPG decrease ≥10%) was observed in 73%. In 64% of patients with subclinical PHT (HVPG 6-9 mmHg, n = 11), portal pressure normalised at SVR. Mean liver stiffness decreased from 20.8 kPa to 11.5 kPa (Δ:-8.8 ± 7.4 kPa; p < 0.001). Fifty percent (7/14) of patients with cirrhosis were re-classified as METAVIR ≤F3 and all patients with decompensated cirrhosis improved their Child-Pugh stage. After successful HCV treatment, 39% still had persistent histological necroinflammatory activity (METAVIR A1), which correlated with less HVPG response and more steatosis. While most biomarkers improved with SVR, METAVIR A1 patients had significantly higher plasma levels of fibrogenic (PDGF, TGF-ß) and angiogenic (VEGF, Angiopoietin1) biomarkers. CONCLUSIONS: Interferon-free therapy reduces PHT and halts histological necroinflammatory activity in the majority of HIV/HCV-coinfected patients after SVR, which may lead to re-compensation of liver function in cirrhosis. Biomarkers could identify patients with persisting hepatic necroinflammation.

Predictors for and coverage of influenza vaccination among HIV-positive patients: a cross-sectional survey.

OBJECTIVES: Influenza vaccination is recommended for HIV-infected patients, but limited data about vaccination rates are available. The aim of this study was to evaluate the coverage of and predictors for influenza vaccination among HIV-positive patients. METHODS: All HIV-positive patients who visited the HIV out-patient department of the University Hospital of Vienna, Austria, between June and August 2015 were asked to participate in this survey by completing a questionnaire. RESULTS: A total of 455 HIV-positive patients completed a questionnaire, with 359 male and 96 female participants with a mean age of 46 years. The influenza vaccination rate for the previous season (2014/2015) was 11.9% [n = 54/455; 95% confidence interval (CI) 9.2-15.2%]. Older age was significantly associated with a positive influenza vaccination status. Obtaining information through a medical consultation or receiving a direct recommendation for vaccination by a physician had a significant impact on vaccination behaviour. The probability of being vaccinated against influenza was about 13 times higher among patients who received a recommendation for vaccination by their family physician or by their HIV specialist (P < 0.001). Important reasons for declining vaccination were fear of side effects (39%), not considering influenza as a severe disease (36%) and reasons related to HIV: 17% were worried that the vaccine could worsen the course of HIV infection and 16% believed vaccination would fail because of their compromised immune system. CONCLUSIONS: A low influenza vaccination rate of 11.9% was detected in this HIV-positive cohort. The most effective impact for a positive vaccination status was direct recommendation of the influenza vaccine by the attending physician.

Low tetanus, diphtheria and acellular pertussis (Tdap) vaccination coverage among HIV infected individuals in Austria.

Current management guidelines of HIV infected adults include recommendation to immunization against common vaccine preventable diseases. This effort is hindered by the scarce knowledge regarding the immunization status of this especially vulnerable patient group. This study analyzed the serostatus for pertussis, diphtheria and tetanus of more than 700 HIV infected individuals residing in Austria. These individuals were representative for the Austrian HIV cohort regarding sex, age, transmission risk and HIV progression markers. Overall, 73.6% were on suppressive HAART, mean CD4 cell count was 603c/µl. Seropositivity was 84% for diphtheria, 51% for tetanus and 1% for pertussis. Migrants had a lower chance of tetanus seropositivity (OR 0.30 (CI 0.21 to 0.43)). Increase in CDC classification were associated with increased diphtheria seropositivity (OR 1.42 (CI 1.02 to 1.98)) and a CD4 nadir<200c/µl was associated with increased pertussis seropositivity (OR 12.2, 95% CI 1.2 to 121). Importantly due to the well preserved immune status of nearly all participants vaccination would be feasible in the majority of the seronegative patients. In patients with a CD4 count>200c/µl, 95% lacked seroprotection to at least one of the antigens included in the triple vaccine Tdap and could be vaccinated. Thus, a proactive approach would largely reduce the number of patients at risk for these vaccine-preventable diseases.

High need for MMR vaccination in HIV infected adults in Austria.

Current guidelines recommend screening for HIV infected patients susceptible for vaccine preventable diseases and offering of immunization. However, data regarding the vaccination coverage among this group are largely missing. This study analyzed the serostatus for Measles, Mumps and Rubella of more than 700 HIV infected patients residing in Austria. These patients were representative for the Austrian HIV cohort regarding sex, age, transmission risk and HIV progression markers. 73.6% were on suppressive HAART, mean CD4 cell count was 603c/µl. Seronegativity was 8.4% for Measles, 33.4% for Mumps and 18.8% for Rubella. In total, out of the 713 HIV infected adults analyzed, almost half (47.8%) would require MMR vaccination. In a multivariate analysis migration was significantly associated with seronegativity for Measles (OR 0.5, CI 0.27-0.9) and Mumps (OR 0.57, CI 0.39-0.81). Importantly due to the well preserved immune status of nearly all participants vaccination would be feasible in the majority of the seronegative patients. Thus, a proactive approach would largely reduce the number of patients at risk for vaccine-preventable diseases.

Viral determinants predicting hepatitis B surface antigen (HBsAg) seroclearance in HIV-/HBV-coinfected patients.

The aim of this retrospective study was the identification of clinically useful viral determinants for the prediction of hepatitis B surface antigen (HBsAg) seroclearance and sustained virological response in hepatitis B virus/human immunodeficiency virus (HBV-/HIV)-coinfected patients receiving HBV-active combined antiretroviral therapy (cART). Quantification of HBsAg, HBeAg and HBV DNA before and after initiation of HBV-active cART in a cohort of 59 HIV-/HBV-coinfected patients was performed. Calculations of receiver operating characteristics (ROC) and Kaplan-Meier analysis were used for the identification of predictors of HBsAg seroclearance for HBeAg-positive [HBeAg(+); n = 36] and HBeAg-negative [HBeAg(-);n = 23] patients. HBeAg(+) patients with an HBsAg on-treatment decline ≥ 1 log IU/mL per year achieved higher HBsAg loss rates (P = 0.0294), whereas the quantification of HBeAg had no predictive value for HBsAg seroclearance. Among HBeAg(-) patients, a pretreatment baseline cut-off level of HBsAg ≤ 100 IU/mL was highly predictive for HBsAg seroclearance. No significant influence of the HBV genotype on HBsAg seroclearance was observed among the entire cohort. Quantitative determination of HBsAg provides a clinically useful viral parameter for the prediction of HBsAg seroclearance both in HBeAg(+) and HBeAg(-) HIV-/HBV-coinfected patients receiving HBV-active cART.

A comprehensive and quantitative analysis of the major specificities in rabbit antithymocyte globulin preparations.

Antithymocyte globulin (ATG) preparations are used for treatment and prevention of graft rejection episodes, graft versus host disease and aplastic anemia. The immunomodulatory and immuosuppressive properties of ATGs are mediated by their interaction with a large variety of antigens expressed on immune and nonimmune cell populations. We have conducted a comprehensive analysis on antibody specificities contained in rabbit ATGs in clinical use, ATG-Fresenius (ATG-F) and Thymoglobulin (THG). We have used retroviral expression cloning to identify novel ATG antigens and demonstrate that together with ATG antigens described earlier, these molecules account for the majority of ATG antibodies directed to human cells. Moreover, we have employed cell lines engineered to express antigens at high levels to quantify the antibodies directed to each ATG antigen. We have used cell lines expressing the T cell receptor complex, CD2 and CD28 to remove antibodies to these antigens from ATG preparations and demonstrate that this treatment abrogated the ability of ATGs to induce activation and forkhead box P3 expression in T cells. Comprehensive information and differences on the antigens targeted by ATG-F and THG as well as novel approaches to assess their functional properties are the basis for a better understanding of their immunomodulatory capacities and might eventually translate into improved ATG-based regimen.

Therapy and prophylaxis of opportunistic infections in HIV-infected patients: a guideline by the German and Austrian AIDS societies (DAIG/ÖAG) (AWMF 055/066).

INTRODUCTION: There was a growing need for practical guidelines for the most common OIs in Germany and Austria under consideration of the local epidemiological conditions. MATERIALS AND METHODS: The German and Austrian AIDS societies developed these guidelines between March 2010 and November 2011. A structured Medline research was performed for 12 diseases, namely Immune reconstitution inflammatory syndrome, Pneumocystis jiroveci pneumonia, cerebral toxoplasmosis, cytomegalovirus manifestations, candidiasis, herpes simplex virus infections, varizella zoster virus infections, progressive multifocal leucencephalopathy, cryptosporidiosis, cryptococcosis, nontuberculosis mycobacteria infections and tuberculosis. Due to the lack of evidence by randomized controlled trials, part of the guidelines reflects expert opinions. The German version was accepted by the German and Austrian AIDS Societies and was previously published by the Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (AWMF; German Association of the Scientific Medical Societies). CONCLUSION: The review presented here is a translation of a short version of the German-Austrian Guidelines of opportunistic infections in HIV patients. These guidelines are well-accepted in a clinical setting in both Germany and Austria. They lead to a similar treatment of a heterogeneous group of patients in these countries.

Clinical findings and management of imported cutaneous leishmaniasis: report of 14 cases from Austria.

BACKGROUND: The management of cutaneous leishmaniasis in non-endemic countries is challenging due to the wide variety of clinical manifestations and little information available on treatment modalities for travellers. METHODS: Retrospective analysis and follow-up investigation in patients with imported cutaneous leishmaniasis managed at the General Hospital Vienna from 2004 to 2010. RESULTS: In total, 14 patients with cutaneous leishmaniasis were analyzed. The time to diagnosis ranged between weeks and several months and up to four consultations were necessary before diagnosis was accomplished. Histological investigations performed in all patients were diagnostic for CL in 8 (57%) patients. PCR analyses were performed in 12 patients and were positive in 10 (83%) patients. All six patients with negative histological results for CL tested positive in the PCR analysis. Treatment regimens applied included systemic therapy with liposomal amphotericin B, miltefosine, or fluconazole, and local therapy with cryotherapy, paromomycin ointment, photodynamic therapy, surgery, and various combinations. CONCLUSIONS: The present analysis strongly suggests that awareness of CL among physicians and travellers remains low and highlights the need to harmonize diagnostic and treatment guidelines for cutaneous and mucosal leishmaniasis in European travellers. Diagnostic outcome can be improved by combining histology and PCR in patients with suspected cutaneous leishmaniasis.

Five-year on-treatment efficacy of lamivudine-, tenofovir- and tenofovir + emtricitabine-based HAART in HBV-HIV-coinfected patients.

Data on the efficacy of lamivudine (LAM)-, tenofovir (TDF)- and emtricitabine (FTC)-based antiretroviral therapy (HAART) in HBV-HIV coinfection are limited. We completed a retrospective analysis of HBV-HIV-coinfected patients treated at the Medical University of Vienna. One-hundred and ten coinfected patients were included, with 57% being initially HBV e-Antigen (HBeAg) positive. Baseline HBV load was significantly higher in HBeAg+ than in HBeAg- patients (5962 ± 3663 vs 20 ± 19 × 10(6) IU/mL; P < 0.0001). Over a median observation period of 83 month (range: 26-183), 87% received HAART and 91% showed a suppression of HBV replication. After 5 years of continuous treatment, HBeAg seroconversion was achieved in 21% of LAM-, 50% of TDF- (P = 0.042 vs LAM) and in 57% of TDF + FTC (P = 0.008 vs LAM)-treated patients, respectively. HBsAg loss after 5 years was found in 8% (LAM), 25% (TDF; P = 0.085 vs LAM) and 29% (TDF + FTC; P = 0.037 vs LAM) of HBeAg+ patients. In HBeAg- patients, HBsAg loss was achieved in 11% (LAM), 27% (TDF; P = 0.263 vs LAM) and 36% (TDF + FTC; P = 0.05 vs LAM), respectively. Pretreatment CD4+ counts did not influence rates of HBeAg seroconversion and of HBsAg loss. Patients with HBsAg loss had lower baseline HBV-DNA levels and higher AST/ALT levels than patients without HBsAg loss. Transient HAART-related hepatotoxicity was found in 32% (Grade I: 21%; II:7%; III:2%; IV:0%). Most HBV-HIV-coinfected patients achieve complete suppression of HBV replication despite high baseline viremia. TDF-based HAART leads to high rates of HBeAg seroconversion and HBsAg loss after 5 years of continuous exposure. One-third of HBV-HIV-coinfected patients may experience transient HAART-related hepatotoxicity.

Clinical Challenges in the Management of Leishmania/HIV Coinfection in a Nonendemic Area: A Case Report.

We report on a 37-year-old male HIV-positive patient with generalized cutaneous leishmaniasis undiagnosed for several years. Upon presentation, visceral leishmaniasis was diagnosed in addition to cutaneous manifestation of the disease. Over a period of three years, several different treatment regimens including liposomal amphotericin B, liposomal amphotericin B with miltefosine, liposomal amphotericin B with interferon, and pentamidine combined fluconazole and allopurinol were applied until Leishmania PCR from blood turned negative. This case supports the necessity of multidrug combinational and sequential therapy over a very prolonged period of time in severely immunosuppressed patients infected with Leishmania and highlights the tremendous individual but also economic burden of this disease.

Interaction of antithymocyte globulins with dendritic cell antigens.

The polyclonal rabbit antithymocyte globulins (ATGs), Thymoglobulin and ATG-Fresenius S, are widely used for prevention and therapy of allograft rejection and graft versus host disease. Dendritic cells (DC) govern immune responses and thus the interaction of ATGs with these cells could potentially contribute to the clinical effects of ATG therapy. Currently there is little information on the DC-antigens targeted by ATGs. In this study we have used a new methodology to identify DC surface antigens recognized by ATGs. By screening an eukaryotic expression library generated from DC with ATGs we could identify several novel ATG antigens including CD81, CD82, CD98, CD99 and CD147. Furthermore, we engineered cells to express previously described ATG antigens and probed them with Thymoglobulin and ATG-Fresenius S. Our results demonstrated strong binding to some but not all of these molecules. We show that previously described antigens and antigens identified in this study account for around 80% of the DC reactivity of ATGs. Analysis of molecules induced by ATG-DC interaction are more in support for an activation of these cells by ATGs than for a specific induction of a tolerogenic DC phenotype.

Methotrexate-induced primary cutaneous diffuse large B-cell lymphoma with an 'angiocentric' histological morphology.

A patient with a 25-year history of rheumatoid arthritis and a 3-year history of methotrexate treatment developed a generalized papular rash. The papules rapidly became necrotic and then resolved, leaving a depressed scar. The rapid course of lesion development and regression was reminiscent of pityriasis lichenoides. Histology revealed a nodular infiltrate composed of a mixture of pleomorphic large B cells positive for CD20, CD30 and CD79a, and of small T cells positive for CD3 and CD4. The T cells had a striking angiocentric distribution, with some of the vessels exhibiting fibrinoid necrosis of the vessel wall reminiscent of lymphomatoid granulomatosis. However, B cells were consistently negative for Epstein-Barr virus (EBV) antigen expression. A thorough examination excluded involvement of organs other than the skin. Thus, this patient was classified as having a rare form of an EBV-negative primary cutaneous T-cell-rich B-cell lymphoma in association with methotrexate treatment.