Sexually transmitted infections in HIV-infected people in Switzerland: cross-sectional study.

Sexually transmitted infections (STI) in HIV-infected people are of increasing concern. We estimated STI prevalence and sexual healthcare seeking behaviour in 224 sexually active HIV-infected people, including men who have sex with men (MSM, n = 112), heterosexual men (n = 65) and women (n = 47). Laboratory-diagnosed bacterial STI were more common in MSM (Chlamydia trachomatis 10.7%; 95% CI 6.2, 18.0%, lymphogranuloma venereum 0.9%; 95% CI 0.1, 6.2%, Neisseria gonorrhoeae 2.7%; 95% CI 0.9, 8.0%, syphilis seroconversion 5.4%; 95% CI 2.0, 11.3%) than heterosexual men (gonorrhoea 1.5%; 95% CI 0.2, 10.3%) or women (no acute infections). Combined rates of laboratory-diagnosed and self-reported bacterial STI in the year before the study were: MSM (27.7%; 95% CI 21.1, 36.7%); heterosexual men (1.5%; 95% CI 0.2, 10.3%); and women (6.4%; 95% CI 2.1, 21.0%). Antibodies to hepatitis C virus were least common in MSM. Antibodies to herpes simplex type 2 virus were least common in heterosexual men. Most MSM, but not heterosexual men or women, agreed that STI testing should be offered every year. In this study, combined rates of bacterial STI in MSM were high; a regular assessment of sexual health would allow those at risk of STI to be offered testing, treatment and partner management.

Impact of IL28B genotype on first-week response to telaprevir-based therapy in HIV-HCV coinfection

BACKGROUND IL28B genotype predicts response to treatment against hepatitis C virus (HCV) with pegylated interferon/ribavirin (PR) and impacts on the outcome of therapy including telaprevir (TVR). This study aimed to determine the influence of the favorable IL28B genotype on early viral kinetics during therapy with TVR/PR in HIV/HCV-coinfected patients. METHODS All HIV/HCV genotype 1-coinfected subjects who received TVR/PR for at least 4 weeks were included from populations prospectively followed in 22 centers throughout Germany, Switzerland and Spain. RESULTS Of the 129 subjects included, 38 (29.5%) presented with IL28B genotype CC and 94 (72.9%) were treatment-experienced. Ninety-six (73.8%) patients showed undetectable plasma HCV-RNA at treatment week (W) 4: 30 (78.9%) of the IL28B-CC carriers and 65 (71.4%) of the non-CC carriers (p=0.377). Among treatment-naïve patients, proportions of undetectable HCV-RNA among IL28B-CC versus non-CC carriers were 8/9 (88.9%) versus 3/9 (33.3%, p=0.016) and 14/17 (82.4%) versus 11/18 (61.1%, p=0.164) at W2 and W4. The decrease of HCV-RNA at W2 and W4 was similar among the IL28B carriers. CONCLUSIONS IL28B genotype does not predict W4 response to TVR/PR in HIV/HCV-coinfected patients, regardless of their treatment history. However, there is evidence of an impact on response during the first weeks in treatment-naïve patients.

Response to LIVint-15-00100

Although AST-to-platelet ratio index (APRI) and FIB-4 have been compared with liver biopsy in patients with hepatitis C virus (HCV), hepatitis B virus (HBV), HIV/HCV co-infection, and HIV/HBV co-infection, Johannessen and Lemoine stress that they have not been validated in HIV mono-infected populations in SSA. However, this is unlikely to occur because liver biopsy does not play a role in HIV management and the procedure carries its own risks for complication. Clinicians using APRI and FIB-4 in this setting should be aware of this limitation and should interpret test results in the context of each patient's clinical scenario. This article is protected by copyright. All rights reserved.

Reduced IFNλ4 activity is associated with improved HCV clearance and reduced expression of interferon-stimulated genes

Hepatitis C virus (HCV) infections are the major cause of chronic liver disease, cirrhosis and hepatocellular carcinoma worldwide. Both spontaneous and treatment-induced clearance of HCV depend on genetic variation within the interferon-lambda locus, but until now no clear causal relationship has been established. Here we demonstrate that an amino-acid substitution in the IFNλ4 protein changing a proline at position 70 to a serine (P70S) substantially alters its antiviral activity. Patients harbouring the impaired IFNλ4-S70 variant display lower interferon-stimulated gene (ISG) expression levels, better treatment response rates and better spontaneous clearance rates, compared with patients coding for the fully active IFNλ4-P70 variant. Altogether, these data provide evidence supporting a role for the active IFNλ4 protein as the driver of high hepatic ISG expression as well as the cause of poor HCV clearance.

A common polymorphism in the NCAN gene is associated with hepatocellular carcinoma in alcoholic liver disease

BACKGROUND & AIMS: The genetic background of alcoholic liver diseases and their complications are increasingly recognized. A common polymorphism in the neurocan (NCAN) gene, which is known to be expressed in neuronal tissue, has been identified as a risk factor for non-alcoholic fatty liver disease (NAFLD). We investigated if this polymorphism may also be related to alcoholic liver disease (ALD) and hepatocellular carcinoma (HCC). METHODS: We analysed the distribution of the NCAN rs2228603 genotypes in 356 patients with alcoholic liver cirrhosis, 126 patients with alcoholic HCC, 382 persons with alcohol abuse without liver damage, 362 healthy controls and in 171 patients with hepatitis C virus (HCV) associated HCC. Furthermore, a validation cohort of 229 patients with alcoholic cirrhosis (83 with HCC) was analysed. The genotypes were determined by LightSNiP assays. The expression of NCAN was studied by RT-PCR and immunofluorescence microscopy. RESULTS: The frequency of the NCAN rs2228603 T allele was significantly increased in patients with HCC due to ALD (15.1%) compared to alcoholic cirrhosis without HCC (9.3%), alcoholic controls (7.2%), healthy controls (7.9%), and HCV associated HCC (9.1%). This finding was confirmed in the validation cohort (15.7% vs. 6.8%, OR=2.53; 95%CI: 1.36-4.68; p=0.0025) and by multivariate analysis (OR=1.840; 95%CI: 1.22-2.78; p=0.004 for carriage of the rs2228603 T allele). In addition, we identified and localised NCAN expression in human liver. CONCLUSIONS: NCAN is not only expressed in neuronal tissue, but also in the liver. Its rs2228603 polymorphism is a risk factor for HCC in ALD, but not in HCV infection.

STARTVerso1: A randomized trial of faldaprevir plus pegylated interferon/ribavirin for chronic HCV genotype-1 infection.

BACKGROUND & AIMS The efficacy and tolerability of faldaprevir, a potent hepatitis C virus (HCV) NS3/4A protease inhibitor, plus peginterferon and ribavirin was assessed in a double-blind, placebo-controlled phase 3 study of treatment-naïve patients with HCV genotype-1 infection. METHODS Patients were randomly assigned (1:2:2) to peginterferon/ribavirin plus: placebo (arm 1, n=132) for 24 weeks; faldaprevir (120 mg, once daily) for 12 or 24 weeks (arm 2, n=259); or faldaprevir (240 mg, once daily) for 12 weeks (arm 3, n=261). In arms 2 and 3, patients with early treatment success (HCV RNA <25 IU/mL at week 4 and undetectable at week 8) stopped all treatment at week 24. Other patients received peginterferon/ribavirin until week 48 unless they met futility criteria. The primary endpoint was sustained virologic response 12 weeks post-treatment (SVR12). RESULTS SVR12 was achieved by 52%, 79%, and 80% of patients in arms 1, 2, and 3, respectively (estimated difference for arms 2 and 3 versus arm 1: 27%, 95% confidence interval 17%-36%; and 29%, 95% confidence interval, 19%-38%, respectively; P<.0001 for both). Early treatment success was achieved by 87% (arm 2) and 89% (arm 3) of patients, of whom 86% and 89% achieved SVR12. Adverse event rates were similar among groups; few adverse events led to discontinuation of all regimen components. CONCLUSIONS Faldaprevir plus peginterferon/ribavirin significantly increased SVR12, compared with peginterferon/ribavirin, in treatment-naïve patients with HCV genotype-1 infection. There do not seem to be any differences in responses of patients given once-daily 120 or 240 mg faldaprevir.

Essentials from the 2015 European AIDS Clinical Society (EACS) guidelines for the treatment of adult HIV-positive persons.

BACKGROUND The European AIDS Clinical Society (EACS) guidelines are intended for all clinicians involved in the care of HIV-positive persons, and are available in print, online, and as a free App for download for iPhone and Android. GUIDELINE HIGHLIGHTS The 2015 version of the EACS guidelines contains major revisions in all sections; antiretroviral treatment (ART), comorbidities, coinfections and opportunistic diseases. Among the key revisions is the recommendation of ART for all HIV-positive persons, irrespectively of CD4 count, based on the Strategic Timing of AntiRetroviral Treatment (START) study results. The recommendations for the preferred and the alternative ART options have also been revised, and a new section on the use of pre-exposure prophylaxis (PrEP) has been added. A number of new antiretroviral drugs/drug combinations have been added to the updated tables on drug-drug interactions, adverse drug effects, dose adjustment for renal/liver insufficiency and for ART administration in persons with swallowing difficulties. The revisions of the coinfection section reflect the major advances in anti-hepatitis C virus (HCV) treatment with direct-acting antivirals with earlier start of treatment in individuals at increased risk of liver disease progression, and a phasing out of interferon-containing treatment regimens. The section on opportunistic diseases has been restructured according to individual pathogens/diseases and a new overview table has been added on CD4 count thresholds for different primary prophylaxes. CONCLUSIONS The diagnosis and management of HIV infection and related coinfections, opportunistic diseases and comorbidities continue to require a multidisciplinary effort for which the 2015 version of the EACS guidelines provides an easily accessable and updated overview.

Transcriptome analysis reveals a classical interferon signature induced by IFNλ4 in human primary cells.

The IFNL4 gene is negatively associated with spontaneous and treatment-induced clearance of hepatitis C virus infection. The activity of IFNλ4 has an important causal role in the pathogenesis, but the molecular details are not fully understood. One possible reason for the detrimental effect of IFNλ4 could be a tissue-specific regulation of an unknown subset of genes. To address both tissue and subtype specificity in the interferon response, we treated primary human hepatocytes and airway epithelial cells with IFNα, IFNλ3 or IFNλ4 and assessed interferon mediated gene regulation using transcriptome sequencing. Our data show a surprisingly similar response to all three subtypes of interferon. We also addressed the tissue specificity of the response, and identified a subset of tissue-specific genes. However, the interferon response is robust in both tissues with the majority of the identified genes being regulated in hepatocytes as well as airway epithelial cells. Thus we provide an in-depth analysis of the liver interferon response seen over an array of interferon subtypes and compare it to the response in the lung epithelium.

Methodologies for the Analysis of HCV-Specific CD4(+) T Cells

Virus-specific CD4(+) T cells play a major role in viral infections, such as hepatitis C virus (HCV). Viral clearance is associated with vigorous and multi-specific CD4(+) T-cell responses, while chronic infection has been shown to be associated with weak or absent T-cell responses. Most of these studies have used functional assays to analyze virus-specific CD4(+) T-cell responses; however, these and other detection methods have various limitations. Therefore, the important question of whether virus-specific CD4(+) T cells are completely absent or primarily impaired in specific effector functions during chronic infection, has yet to be analyzed in detail. A novel assay, in which virus-specific CD4(+) T-cell frequencies can be determined by de novo CD154 (CD40 ligand) expression in response to viral antigens, can help to overcome some of the limitations of functional assays and restrictions of multimer-based methods. This and other current established methods for the detection of HCV-specific CD4(+) T cells will be discussed in this review.

Improvement of platelets after SVR among patients with chronic HCV infection and advanced hepatic fibrosis.

BACKGROUND & AIMS Patients with chronic hepatitis C virus (HCV) infection may develop cirrhosis with portal hypertension, reflected by decreased platelet count and splenomegaly. This retrospective cohort study aimed to assess changes in platelet counts after antiviral therapy among chronic HCV-infected patients with advanced fibrosis. METHODS Platelet counts and spleen sizes were recorded in an international cohort of patients with Ishak 4-6 fibrosis who started antiviral therapy between 1990 and 2003. Last measured platelet counts and spleen sizes were compared to their pre-treatment values (within 6 six months prior to the start of therapy). All registered platelet count measurements from 24 week following cessation of antiviral therapy were included in repeated measurement analyses. RESULTS This study included 464 patients; 353 (76%) had cirrhosis and 187 (40%) attained sustained virological response (SVR). Among patients with SVR, median platelet count, increased by 35 x10(9) /L (IQR 7-62, p<0.001). In comparison, patients without SVR showed a median decline of 17 x10(9) /L (IQR -5-47, p<0.001). In a subgroup of 209 patients, median decrease in spleen size was 1.0 cm (IQR 0.3-2.0) for patients with SVR, while median spleen size increased with 0.6 cm (IQR -0.1-2.0, p<0.001) among those without SVR. The changes in spleen size and platelet count were significantly correlated (R=-0.41, p<0.001). CONCLUSIONS Among chronic HCV-infected patients with advanced hepatic fibrosis the platelet counts improved following SVR and the change in platelets correlated with the change in spleen size following antiviral therapy. These results suggest that HCV eradication leads to reduced portal pressure. This article is protected by copyright. All rights reserved.

Determinants of hepatitis A vaccine immunity in a cohort of human immunodeficiency virus-infected children living in Switzerland

Vaccination in HIV-infected children is often less effective than in healthy children. The goal of this study was to assess vaccine responses to hepatitis A virus (HAV) in HIV-infected children. Children of the Swiss Mother and Child HIV Cohort Study (MoCHiV) were enrolled prospectively. Recommendations for initial, catch-up, and additional HAV immunizations were based upon baseline antibody concentrations and vaccine history. HAV IgG was assessed by enzyme-linked immunosorbent assay (ELISA) with a protective cutoff value defined as ≥10 mIU/ml. Eighty-seven patients were included (median age, 11 years; range, 3.4 to 21.2 years). Forty-two patients were seropositive (48.3%) for HAV. Among 45 (51.7%) seronegative patients, 36 had not received any HAV vaccine dose and were considered naïve. Vaccine responses were assessed after the first dose in 29/35 naïve patients and after the second dose in 33/39 children (25 initially naïve patients, 4 seronegative patients, and 4 seropositive patients that had already received 1 dose of vaccine). Seroconversion was 86% after 1 dose and 97% after 2 doses, with a geometric mean concentration of 962 mIU/ml after the second dose. A baseline CD4(+) T cell count below 750 cells/μl significantly reduced the post-2nd-dose response (P = 0.005). Despite a high rate of seroconversion, patients with CD4(+) T cell counts of <750/μl had lower anti-HAV antibody concentrations. This may translate into a shorter protection time. Hence, monitoring humoral immunity may be necessary to provide supplementary doses as needed.

Hepatitis B und C bei HIV-Koinfektion

Hepatitis B and C virus infections are a leading cause of death in HIV-positive patients. Furthermore, the management of these infections is complicated. Psychosocial problems and comorbidities are frequent barriers to the optimal management of these patients. Furthermore, the rapid changes in treatment strategies particularly in Hepatitis C make it difficult to treat patients outside specialized centers. An improvement in treatment uptake and efficacy can only be achieved through coordinated efforts between private care physicians and specialized centers.

Destruction of lymphoid organ architecture and hepatitis caused by CD4+ T cells

Immune responses have the important function of host defense and protection against pathogens. However, the immune response also causes inflammation and host tissue injury, termed immunopathology. For example, hepatitis B and C virus infection in humans cause immunopathological sequel with destruction of liver cells by the host's own immune response. Similarly, after infection with lymphocytic choriomeningitis virus (LCMV) in mice, the adaptive immune response causes liver cell damage, choriomeningitis and destruction of lymphoid organ architecture. The immunopathological sequel during LCMV infection has been attributed to cytotoxic CD8(+) T cells. However, we now show that during LCMV infection CD4(+) T cells selectively induced the destruction of splenic marginal zone and caused liver cell damage with elevated serum alanin-transferase (ALT) levels. The destruction of the splenic marginal zone by CD4(+) T cells included the reduction of marginal zone B cells, marginal zone macrophages and marginal zone metallophilic macrophages. Functionally, this resulted in an impaired production of neutralizing antibodies against LCMV. Furthermore, CD4(+) T cells reduced B cells with an IgM(high)IgD(low) phenotype (transitional stage 1 and 2, marginal zone B cells), whereas other B cell subtypes such as follicular type 1 and 2 and germinal center/memory B cells were not affected. Adoptive transfer of CD4(+) T cells lacking different important effector cytokines and cytolytic pathways such as IFNγ, TNFα, perforin and Fas-FasL interaction did reveal that these cytolytic pathways are redundant in the induction of immunopathological sequel in spleen. In conclusion, our results define an important role of CD4(+) T cells in the induction of immunopathology in liver and spleen. This includes the CD4(+) T cell mediated destruction of the splenic marginal zone with consecutively impaired protective neutralizing antibody responses.

Investigation of a large community-based outbreak of hepatitis B infection in the United Kingdom

We describe the largest outbreak of hepatitis B virus infection reported to date in the UK. Between July 2001 and December 2005, 237 cases were identified in Avon, South West England. The likely route of transmission was injecting drug use in 44% (104/237) and heterosexual intercourse in 30% (71/237) of cases. A case-control study in injectors showed that injecting crack cocaine [adjusted odds ratio (aOR) 23·8, 95% confidence interval (CI) 3·04-186, P<0·001] and sharing injecting paraphernalia in the year before diagnosis (aOR 16·67, 95% CI 1·78-100, P=0·010) were strongly associated with acute hepatitis B. In non-IDUs number of sexual partners and lack of consistent condom use were high compared to a national sample. We describe the control measures implemented in response to the outbreak. This outbreak has highlighted the problems associated with the low uptake from the national hepatitis B vaccination policy which targets high-risk groups, the difficulties of identifying those at risk of acquiring hepatitis B infection through heterosexual sex, and injecting crack cocaine as a risk factor for hepatitis B.

A significant effect of the KIR ligand HLA-C on fibrosis progression in chronic C hepatitis with or without liver transplantation.

BACKGROUND & AIMS The interaction of KIR with their HLA ligands drives the activation and inhibition of natural killer (NK) cells. NK cells could be implicated in the development of liver fibrosis in chronic hepatitis C. METHODS We analysed 206 non-transplanted and 53 liver transplanted patients, selected according to their Metavir fibrosis stage. Several variables such as the number of activator KIR or the HLA ligands were considered in multinomial and logistic regression models. Possible confounding variables were also investigated. RESULTS The KIRs were not significant predictors of the fibrosis stage. Conversely, a significant reduction of the HLA-C1C2 genotype was observed in the most advanced fibrosis stage group (F4) in both cohorts. Furthermore, the progression rate of fibrosis was almost 10 times faster in the subgroup of patients after liver transplantation and HLA-C1C2 was significantly reduced in this cohort compared to non-transplanted patients. CONCLUSION This study suggests a possible role of KIR and their ligands in the development of liver damage. The absence of C1 and C2 ligands heterozygosity could lead to less inhibition of NK cells and a quicker progression to a high level of fibrosis in patients infected by HCV, especially following liver transplantation. This article is protected by copyright. All rights reserved.