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SUMMARYBackground: Throughout Europe, differences in satisfaction with HIV-care of people living with HIV (PLHIV) persist, despite a tendency towards harmonisation of policy and management.Methods: A European sample of 1,549 PLHIV responded to an anonymous questionnaire assessing demographic background, general health, mental health, sexual health, and HIV-service provision. We compared the results across 3 regions: Western, Southern and Central/Eastem Europe.Results: PLHIV differed in several socio-demographic variables (gender, migrant status, sexual orientation, and financial situation) as well as specific psychosocial aspects (HIV-related discrimination, satisfaction with sexual and reproductive health (SRH) services in HIV-care settings, and complaints about service provision). Using multivariate analysis, a predictive model for satisfaction with SRH services in HIV clinics was developed, resulting into region of residence, and participants' satisfaction with their own health status as significant predictors.Conclusions: Better integration of SRH services in HIV-care should be encouraged. Service providers should be trained and encouraged to discuss SRH issues with their patients to create a supportive environment, free of discrimination. More time should be allocated to discuss SRH issues with individual patients.Key words: sexual and reproductive health, HIV-care, EuropeINTRODUCTIONHIV continues to be a public health problem in Europe. In the European Economic Area (EEA) - European Union Member States, Norway, Iceland, and Liechtenstein - and Switzerland, 28,038 new HIV cases were reported in 2011, a rate of 5.7 per 100,000 population (1). The four countries with the highest rates were Estonia, Latvia, Belgium, and the United Kingdom, with rates above 10 per 100,000 population. The predominant mode of transmission of HIV in the EU/EEA-region and Switzerland is sex between men, accounting for 39% (10,855 cases) of the HIV-diagnoses reported in 2011, followed by heterosexual transmission excluding individuals originating from countries with generalised epidemics (23%). For 19% of the newly diagnosed cases in 2011, the transmission mode was unknown (1). While trends towards stronger harmonisation of HIV policy and management across Europe have been observed, there are indications that evidence-based policies, programmes and services are still implemented differently in European countries (2). This may have an impact on patients' satisfaction with health care services. A recent review gathered evidence on perceived service quality of HIV-services. Several factors were found to improve patient's satisfaction. They were either related to individual health care provider (i.e. knowledge, caring and respectful attitude, communication skills, and information provision) or to organisations (responsive and flexible services) (3).In this article we present a subset analysis using data from a European public health project on sexual and reproductive health needs of people living with HIV (PLHIV) in 14 European countries. Details on the study design and overall results are described elsewhere (4). Here we compare socio-demographic variables, measures of satisfaction with sexual and reproductive health services delivered in HIV clinics, and perceived levels of HIV-related discrimination across three European regions. The identified critical differences in HIV-service provision could inform HIV policy makers and service providers to improve care.MATERIALSAND METHODSProceduresThe research was carried out in a network of 17 HIV treatment and research centres in 14 European countries between March and October 2007. A self-administered, anonymous questionnaire was developed including questions on demographic background characteristics, general health related aspects, mental health, sexual health, and HIV-service provision. It was translated into 12 languages, and was distributed to consecutive patients at the collaborating sites. …

Background Before Pre-Exposure Prophylaxis (PrEP) was officially recommended and made available, a few surveys among gay and bisexual men, and persons living with HIV/AIDS (PLWHA), identified an informal use of antiretrovirals (ARVs) for PrEP among HIV-negative individuals. Before PrEP availability in Italy, we aimed to assess whether PLWHA in Italy shared their ARVs with HIV-negative individuals, whether they knew people who were on PrEP, and describe the level of awareness and discussion on this preventive measure among them and people in their close circle. Methods Two anonymous questionnaires investigating personal characteristics and PrEP awareness, knowledge, and experience were proposed to HIV specialists and their patients on ARVs in a one-week, cross-sectional survey (December 2013–January 2014). Among PLWHA, a Multivariable Logistic Regression analysis was conducted to identify factors associated with PrEP discussion with peers (close circle and/or HIV associations), and experience (use in close circle and/or personal ARV sharing). Results Eighty-seven specialists in 31 representative Infectious Diseases departments administered the questionnaire to 1405 PLWHA. Among specialists, 98% reported awareness, 65% knew the dosage schedule, and 14% had previously suggested or prescribed PrEP. Among PLWHA, 45.6% were somehow aware, discussed or had direct or indirect experience of PrEP: 38% “had heard” of PrEP, 24% were aware of studies in HIV-negative individuals demonstrating a risk reduction through the use of ARVs, 22% had discussed PrEP, 12% with peers; 9% reported PrEP use in close circle and 1% personal ARV sharing. Factors predictive of either PrEP discussion with peers or experience differed between men and women, but across all genders were mainly related to having access to information, with HIV association membership being the strongest predictor. Conclusions At a time and place where there were neither official information nor proposals or interventions to guide public policies on PrEP in Italy, a significant number of PLWHA were aware of it, and approximately 10% reported PrEP use in their close circle, although they rarely shared their ARVs with uninfected people for this purpose. Official policies and PrEP availability, along with implementation programs, could avoid risks from uncontrolled PrEP procurement and self-administration practices. Electronic supplementary material The online version of this article (10.1186/s12879-017-2819-5) contains supplementary material, which is available to authorized users.

Objectives Hepatitis B (HBV) infection, which is prevalent worldwide, is also frequently seen in patients with rheumatoid arthritis (RA). The Italian Society of Rheumatology (SIR) and the Italian Society of Infectious and Tropical Diseases (SIMIT) endorsed a national consensus process to review the available evidence on HBV management in RA patients and to produce practical, hospital-wide recommendations. Methods The consensus panel consisted of infectious disease consultants, rheumatologists and epidemiologists and used the criteria of the Oxford Center for Evidence-based Medicine to assess the quality of the evidence and the strength of their recommendations. Results A core-set of statements has been developed to help clinicians in the management of patients with RA and HBV infection. Vaccination and prophylaxis of RA patients treated with biological drugs have been also discussed. Conclusions HBV infection is not rare in clinical practice; a screening for HBV in all patients with early arthritis is not universally accepted, while it is considered mandatory before starting any immunosuppressive or hepatotoxic treatment. In fact, a specific risk, associated with the use of biologic treatments, exists for patients with HBV infection, although longitudinal studies of viral reactivation are generally reassuring. RA patients with HBV infection should be referred to the hepatologist and correctly classified into active or inactive carriers. Patients with active hepatitis B should undergo antiviral treatment before starting immunosuppressive treatments. Occult HBV carriers should be monitored or receive prophylaxis on the basis of the risk of reactivation associated with the administered treatment.

AIM To evaluate the impact of the Glu167Lys (E167K) transmembrane 6 superfamily member 2 (TM6SF2) variant on the biochemical and morphologic expression of liver lesions in human immunodeficiency virus (HIV)/ hepatitis C virus (HCV) co-infected patients. METHODS The study comprised 167 consecutive patients with HIV/ HCV coinfection and biopsy-proven chronic hepatitis. A pathologist graded liver fibrosis and necroinflammation using the Ishak scoring system, and steatosis using Kleiner's scoring system. Patients were genotyped for TM6SF2 E167K (rs58542926) by real-time Polymerase chain reaction. The 167 patients, 35 therapy-naive and 132 receiving ART, were prevalently males (73.6%), the median age was 40.7 years and the immunological condition good (median CD4+ cells/mm3 = 505.5). RESULTS The 17 patients with the TM6SF2 E167K variant, compared with the 150 with TM6SF2-E/E, showed higher AST (P = 0.02) and alanine aminotransferase (P = 0.02) and higher fibrosis score (3.1 ± 2.0 vs 2.3 ± 1.5, P = 0.05). In a multivariate analysis, TM6SF2 E167K was independently associated with severe fibrosis. The same analysis showed that HCV-genotype 3, present in 42.2% of patients was an independent predictor of severe steatosis. The association of TM6SF2 E167K with severe steatosis, absent for the whole group of 167 patients, was re-evaluated separately for HCVgenotype 3 and non-3 patients: No factor was independently associated with severe steatosis in the HCV-genotype-3 subgroup, whereas an independent association was observed between severe steatosis and TM6SF2 E167K in non-3 HCV genotypes. No association between the TM6SF2 E167K variant and severe liver necroinflammation was observed. CONCLUSION In HIV/HCV coinfection the TM6SF2 E167K variant is an independent predictor of severe fibrosis, but appears to be independently associated with severe steatosis only for patients with a non-3 HCV genotype.

HIV-1 mucosal transmission in genital epithelia occurs through infection of Langerhans cells and subsequent transinfection of CD4+ T cells. We previously reported that the vasodilator neuropeptide calcitonin gene-related peptide (CGRP), secreted upon activation of sensory peripheral neurons that innervate all mucosal epithelia, significantly inhibits transinfection. To investigate the association between CGRP and HIV-1 during infection, we evaluated circulating CGRP levels in HIV-1-infected patients. Plasma was obtained from combination antiretroviral therapy (cART)-naive or cART-treated patients with primary/acute (PHI) or chronic (CHI) HIV-1 infection, as well as from individuals who naturally control HIV-1 infection, namely exposed seronegatives (ESNs), elite controllers (ECs), and long-term nonprogressors (LTNPs). CGRP plasma levels were measured using an enzyme immunoassay. Compared with healthy HIV-1-negative controls, CGRP plasma levels significantly decreased in PHI patients and even further in CHI patients, but remained unchanged in ESNs, ECs, and LTNPs. Moreover, CGRP plasma levels were restored to baseline upon cART in both PHI and CHI. Finally, CGRP plasma levels directly correlated with CD4+ T cell counts and inversely with viral loads. Altogether, CGRP could serve as a novel diagnostic plasma biomarker for progression of HIV-1 infection. Moreover, administration of CGRP to cART-naive HIV-1-infected patients, to compensate for CGRP decline, could help controlling on-going HIV-1 infection.

In routine clinical practice, hepatitis C virus-infected patients can prematurely discontinue the prescribed regimen for several reasons. The aim of our study was to investigate sustained virological response (SVR12) rates in patients who prematurely discontinued directly acting antiviral (DAA) regimens and to assess the shortest effective duration of DAA able to lead to SVR12. We retrospectively collected the SVR rates of patients, registered in the NAVIGATORE-Lombardia Network database from January 2015, who discontinued DAAs before the predefined end of treatment. Overall, we included 365 patients, males were the majority (213, 58.4%), mean age was 60.5years, and 53 (14.5%) patients were HIV-co-infected. Liver cirrhosis was observed in 251 (68.8%) subjects, and the most represented genotypes were 1b (n=168, 46%) and 3 (n=59, 16.2%). DAA was discontinued a median of 1 (IQR 1–4) weeks before the predefined EOT, with 164 (44.9%) patients stopping DAAs at least 2weeks before the planned schedule. In patients with F0–F3 liver fibrosis, lower rates of SVR12 were observed in patients treated for

Multiple direct-acting antiviral (DAA)-based regimens are currently approved that provide one or more interferon-free treatment options for hepatitis C virus (HCV) genotypes (G) 1–6. The choice of a DAA regimen, duration of therapy, and use of ribavirin depends on multiple viral and host factors, including HCV genotype, the detection of resistance-associated amino acid (aa) substitutions (RASs), prior treatment experience, and presence of cirrhosis. In regard to viral factors that may guide the treatment choice, the most important is the infecting genotype because a number of DAAs are genotype-designed. The potency and the genetic barrier may also impact the choice of treatment. One important and debated possible virologic factor that may negatively influence the response to DAAs is the presence of baseline RASs. Baseline resistance testing is currently not routinely considered or recommended for initiating HCV treatment, due to the overall high response rates (sustained virological response >90%) obtained. Exceptions are patients infected by HCV G1a when initiating treatment with simeprevir and elbasvir/grazoprevir or in those with cirrhosis prior to daclatasvir/sofosbuvir treatment because of natural polymorphisms demonstrated in sites of resistance. On the basis of these observations, first-line strategies should be optimized to overcome treatment failure due to HCV resistance.

This study analysed the impact of PNPLA3 variants on liver histology of 168 HIV/hepatitis C virus (HCV)-coinfected patients who were naïve for HCV treatment. A athologist unaware of the patients' condition graded liver fibrosis and necroinflammation (Ishak) and steatosis (Kleiner). Patients were tested for PNPLA3 variants and genotyped for the PNPLA3 rs738409 C to G variant underlying the I148M substitution. All were hepatitis B surface antigen negative and stated no alcohol abuse. The mean age was 40.6 (37.6-44.1) years, 72.6% were males, 42% had HCV genotype 3, 38.9% HCV genotype 1 and 79.2% were receiving highly active antiretroviral therapy. The 79 patients with the PNPLA3 p.148I/M or M/M variants more frequently showed severe steatosis (score 3-4) than the 89 with PNPLA3 p.148I/I (43% vs. 24.7%, p 0.001), whereas no difference was observed in the degree of necroinflammation or fibrosis. Compared with 112 patients with lower scores, 56 with severe steatosis showed higher body mass index (p 0.03), higher rate of HCV genotype 3 (55.6% vs. 35.2%, p 0.01), PNPLA3 p.148I/M or M/M (60.7% vs. 39.3%, p 0.01) and lower CD4(+) cells/mm(3) (514.00 (390.5-673.0) vs. 500.00 (399.0-627.0); p 0.002). At multivariate analysis, body mass index (p 0.01), HCV genotype 3 (p 0.006), CD4(+) cell count (p 0.005) and PNPLA3 p.148I/M or M/M variants (p 0.01) were found to be independent predictors of severe liver steatosis. The PNPLA3 p.148 I/M or M/M variants and CD4(+) cell count were the only independent predictors of severe steatosis in patients with HCV non-3 genotypes. This is the first study to show that among HIV/HCV-coinfected patients the PNPLA3 p.148I/M or M/M variant have substantially less impact on steatosis for those with HCV genotype 3 than non-genotype 3.

Background and aim: Antibodies against hepatitis B core antigen (anti-HBc) are found in 14–44% of patients with HIV infection, but it is still unclear whether hepatitis B virus (HBV) vaccination should be recommended for HIV-positive subjects with isolated anti-HBc (IAHBc). We examined the rate of anamnestic and primary responses (ARs and PRs) and associated factors in a group of HIV-infected patients with an IAHBc profile. Methods: This prospective study recruited 25 HIV-positive patients with anti-HBc alone who were vaccinated against HBV infection. Those without an AR (anti-hepatitis B envelope antigen [anti-HBs] levels of 10 but

Background: Hepatocellular carcinoma (HCC) is increasingly prevalent in people living with HIV. Systemic inflammation is a prognostic factor requiring validation in HIV-associated HCC. Aims: Using a multi-centre database of consecutive HCC cases, we investigated the prognostic role of a panel of inflammatory markers, including neutrophil to lymphocyte ratio (NLR), using univariate and multivariate survival analyses. Results: Fifty-nine patients with HIV-associated HCC secondary to hepatitis C (69%) or B virus infection (32%) were identified. The median survival was 22 months. A raised NLR independently predicted patients' survival and was correlated with advanced Barcelona Clinic Liver Cancer stage (p = 0.003) and poor performance status (p < 0.001) but not with HIV RNA or CD4 counts. Conclusion: Systemic inflammation, as measured by NLR, is a prognostic determinant associated with adverse pathological features of malignancy, but not coexisting HIV infection, suggesting a tumour-promoting role of the innate immune response that warrants further investigation in mechanistic studies.

Objective: This is the first study to analyze the impact of the rs35761398 variant of the CNR2 gene leading to the substitution of GLN (Q) of codon 63 of the cannabinoid receptor 2 (CB2) with ARG (R) on the clinical presentation of chronic hepatitis in HIV/HCV coinfected patients. Methods: Enrolled in this study were 166 consecutive HIV/HCV coinfected patients, naïve for HCV treatment. A pathologist unaware of the patients’ condition graded liver fibrosis, necroinflammation (Ishak) and steatosis. All patients were screened for the CB2 rs35761398 polymorphism. Results: Of the 166 HIV/HCV coinfected patients, 72.9% were males, 42.5% were infected with HCV-genotype-3 and 60.2% had been intravenous drug users. The median age was 40.6 years and the immunological condition good (median CD4+cells/mm3= 507, IQR: 398.0–669.5). Thirty-five (21.1%) patients were naive for ART and 131(78.9%) were on ART. The CB2-RR variant was detected in 45.8% of patients, QR in 38.6% and QQ in 15.7%. Patients with CB2-RR showed a necroinflammation score (HAI) ≥9 more frequently than those with CB2-QQ or CB2-QR (32.9% vs. 11.5% and 14.1%, respectively, p≤0.001). In the multivariate analysis, the CB2-RR variant (p = 0.03) and liver fibrosis were both identified as independent predictors of the entity of liver necroinflammation (p = 0.0001). Conclusion: This study shows interesting interplay between the CB2-RR variant and liver necroinflammation in chronic hepatitis patients with HIV/HCV coinfection, an observation of clinical value that coincides with the interest in the use of the CB2 agonists and antagonists in clinical practice emerging from the literature.

Objectives To evaluate the plasma trough concentrations ( C trough ) of dolutegravir and rilpivirine used in combination with simeprevir and sofosbuvir in HIV/hepatitis C virus (HCV)-coinfected patients with liver cirrhosis. Virological efficacy and safety of both ART and anti-HCV therapy were assessed. Patients and methods A prospective observational study in HIV/HCV-coinfected patients with liver cirrhosis on ART with dolutegravir plus rilpivirine and treated with simeprevir plus sofosbuvir (±ribavirin) was conducted. Dolutegravir, rilpivirine, GS-331007 (sofosbuvir metabolite) and simeprevir C trough were evaluated with a validated HPLC method at anti-HCV treatment baseline and weeks 2 and 4. Geometric means were calculated to summarize C trough values. Results Twelve patients were evaluated: 75% were males and the median (IQR) age was 53 (53-55) years. All patients were Child-Pugh stage A, except one who was stage B. The geometric mean (95% CI) of C trough of rilpivirine and dolutegravir did not change between baseline and week 4 ( P = 0.654 and P = 0.268, respectively), with corresponding overall values of 135 (102-177) and 1357 (970-1897) ng/mL. The overall geometric mean (95% CI) of GS-331007 and simeprevir C trough was 370 (268-512) and 2537 (1569-4101) ng/mL, respectively, without significant variation between weeks 2 and 4 ( P = 0.643 and P = 0.179, respectively). All patients completed anti-HCV treatment, achieving sustained virological response. All but two patients maintained undetectable HIV-RNA up to post-treatment week 24. Conclusions Dolutegravir and rilpivirine C trough appeared not to be affected by concomitant treatment with simeprevir plus sofosbuvir in these HIV/HCV-coinfected patients with liver cirrhosis, supporting the use of this antiretroviral regimen in this setting.

Aim: To evaluate changes in liver histology in patients with human immunodeficiency virus/hepatitis C virus coinfection non-responders to a suboptimal Interferon + Ribavirine regimen. Materials and methods: We investigated 49 patients with two sequential liver biopsies: 18 were non-responders to Interferon + Ribavirine treatment (Group hepatitis C virus Rx) administered after the 1st liver biopsy who underwent a 2nd liver biopsy after a median period of 3.92 year and 31 were patients who remained untreated for hepatitis C virus disease (Group hepatitis C virus untreated) after the 1st liver biopsy because of refusal and underwent a 2nd liver biopsy after a median period of 5.05-years. Most patients in both groups were under highly active antiretroviral therapy. At the time of 1st liver biopsy similar degrees of necro-inflammation, fibrosis and steatosis were observed in both groups. Changes in liver lesions between 1st and 2nd liver biopsys were adjusted for different intervals between liver biopsys by a mathematic formula. Results: Liver fibrosis did not change in 88.9% of patients in Group hepatitis C virus Rx and in 77.4% in Group hepatitis C virus untreated. A marked deterioration in liver fibrosis was observed in 5 (16%) patients in Group hepatitis C virus untreated and in none in Group hepatitis C virus treated. Necro-inflammation and steatosis remained substantially unchanged in both groups. Conclusion: Liver histology remained substantially unchanged in human immunodeficiency virus/hepatitis C virus patients non-responder to anti-hepatitis C virus therapy over 4 years observation, suggesting an effective anti-hepatitis C virus early treatment for all hepatitis C virus/human immunodeficiency virus coinfected patients who can reasonably tolerate therapy. Keywords: HIV/HCV coinfection, HIV infection, HIV/HCV coinfection liver histology, Liver fibrosis

Different HCV subtypes may naturally harbor different resistance selection to anti-NS5a inhibitors. 2761 sequences retrieved from the Los Alamos HCV database were analyzed in the NS5a domain 1, the target of NS5a inhibitors. The NS5a resistance-associated polymorphisms (RAPs) were more frequently detected in HCV G1b compared to G1a. The prevalence of polymorphisms associated with cross-resistance to compounds in clinical use (daclatasvir, DCV, ledipasvir, LDV, ombitasvir, and OMV) or scheduled to come into clinical use in the near future (IDX719, elbasvir, and ELV) was higher in G1b compared to G1a (37/1552 (2.4%) in 1b sequences and 15/1209 (1.2%) in 1a isolates, p = 0.040). Interestingly, on the basis of the genotype-specific resistance pattern, 95 (6.1%) G1b sequences had L31M RAP to DCV/IDX719, while 6 sequences of G1a (0.5%) harbored L31M RAP, conferring resistance to DCV/LDV/IDX719/ELV (p < 0.0001). Finally, 28 (2.3%) G1a and none of G1b isolates harbored M28V RAP to OMV (p < 0.0001). In conclusion, the pattern of subtype-specific resistance selection in the naturally occurring strains may guide the treatment option in association with direct acting antivirals (DAAs) targeting different regions, particularly in patients that are difficult to cure, such as those with advanced liver disease or individuals who have failed previous DAAs.

Supplemental Digital Content is available in the text, The extent of mixed hepatitis C virus (HCV) genotype in different compartments (plasma and peripheral blood mononuclear cell, PBMC) and possible association with treatment efficacy in HIV/HCV coinfected patients remains to be unknown. The objective of this study was to elucidate the frequency of mixed genotype infection (MG), its profile in different compartments during anti-HCV treatment, and the possible influence of different genotypes on the response rate. The compartmentalization of HCV population was investigated by next-generation sequencing in 19 HIV/HCV coinfected patients under anti-HCV treatment with peginterferon/ribavirin (P–R). Ten individuals were nonresponder (NR) or relapser (RE) to P–R treatment and 9 had a sustained virological response (SVR). Eleven/nineteen (58%) patients had MG in plasma compartment. Ten or 12 patients infected by a difficult to treat genotype (DTG) 1 or 4 as dominant strain, had an MG, whereas only 1/7 individuals infected by easy to treat genotype (ETG) harbored a mixed genotype, P = 0.006. HCV–RNA was more frequently detected in PBMC of NR (10/10) than in those of SVR (5/9), P = 0.032. Mixed genotype infection was detected in 6/15 (40%) PBMC-positive cases and was not associated with P–R treatment response. By multivariate analysis, MG in plasma samples was the most important viral factor affecting the treatment response (P = 0.0237). Detection of MG in plasma of HIV/HCV coinfected patients seems to represent the major determinant of response to P–R treatment. This finding may have important clinical implication in light of the new therapeutic approach in HIV/HCV coinfected individuals suggesting that combination treatment with direct acting antivirals could be less effective in MG.

Summary The introduction of first-generation protease inhibitors for the treatment of chronic hepatitis C in subjects infected with hepatitis C virus (HCV) genotype 1 has significantly improved the sustained virological response (SVR) rate. As liver cirrhosis reduces the probability of achieving SVR, current guidelines discourage response-guided therapy in cirrhotic patients. We report the first case of a cirrhotic woman with chronic HCV and HIV co-infection achieving virological response after an ultra-short course of therapy. A 40-year-old HIV/HCV co-infected woman with compensated liver cirrhosis was treated with anti-HCV triple therapy containing telaprevir plus pegylated interferon and ribavirin. Baseline plasma HCV RNA was 3.6 log IU/ml and transaminases were within the normal range. She harboured IL28B rs12979860C/C alleles. Ten days after starting therapy, the patient stopped treatment because of mild anorexia and nausea. Virological response was detected at treatment discontinuation and was maintained up to 24 weeks. This case describes an unexpected SVR after a 10-day course of antiviral therapy in a cirrhotic HIV/HCV co-infected woman presenting positive predictive factors for a response (low viral load, IL28B genotype). Nonetheless, there is no evidence to suggest a shorter duration of treatment in this subset of patients.

"OBJECTIVES: To define differences in liver histology between HIV\/HCV coinfection . and HCV monoinfection, and to investigate possible causative factors.. METHODS: Liver biopsies (LBs) from 440 consecutive HIV\/HCV-coinfected patients. (Group HIV\/HCV) and 374 consecutive HCV-monoinfected patients (Group HCV) were. evaluated for necroinflammation and fibrosis (Ishak) by a pathologist unaware of . the clinical and laboratory data. All patients were HBsAg-negative, with no. history of alcohol abuse and naïve to anti-HCV treatment. At LB, 78.4% of. patients in Group HIV\/HCV were on an antiretroviral regimen.. RESULTS: HIV\/HCV-coinfected patients compared to the HCV-monoinfected patients. were younger (p < 0.0001), more frequently males (p < 0.0001), and had HCV. genotype 3 (p < 0.0001); they showed a good immunological condition (CD4+ cell. count: 518 ± 166 cells\/mm(3)). Patients in Group HIV\/HCV more frequently showed a. fibrosis score ≥4 (27.5 vs. 20.6%, p < 0.05) and a necroinflammation score ≥9. (25.9 vs. 13.4%; p < 0.0001). The prevalence of patients with fibrosis score ≥4. was significantly higher in older age classes in both Group HIV\/HCV (p < 0.005). and Group HCV (p < 0.05). A necroinflammation score ≥9 was significantly higher. in older age classes only in Group HIV\/HCV (p < 0.05). A multivariate analysis. for Group HIV\/HCV revealed that the patient age and nadir of CD4+ cell count were. independently associated to higher degrees of fibrosis, the patient age and. antiretroviral treatment were associated to higher degrees of necroinflammation, . and HCV genotype 3 was associated to higher degrees of steatosis.. CONCLUSION: The data suggest a need for early anti-HCV treatment in both. HCV-monoinfected and HIV\/HCV-coinfected patients."

This prospective study evaluated the effect of long-term highly active antiretroviral therapy (HAART) on human papillomavirus-related cervical disease in clinically stable HIV-positive women on unchanged therapy and those switching to HAART because of virological worsening. Only the clinically stable (P= 0.00004) and HAART-treated women in the same group (P= 0.0009) showed a reduction in lesions, thus suggesting that strict preventative regimens for invasive lesions are also needed in the HAART era.

Background & Aims HIV-monoinfected patients are susceptible to liver injury by different factors and may develop liver fibrosis, which requires adequate clinical management in terms of therapy and disease monitoring. We aimed to evaluate the presence of liver fibrosis identified by transient elastography (TE), its relationships with indirect biochemical markers [the aspartate aminotransferase/platelet ratio index (APRI), the Forns index and FIB-4] and its predictive factors in HIV-monoinfected patients receiving antiretroviral therapy (ART). Methods Seventy-two HIV-monoinfected patients underwent TE and were evaluated using APRI, Forns and FIB-4. The clinical, immunological, virological and other biochemical characteristics were evaluated at the time of TE, together with their history of ART. Results Seven patients (10%) had liver stiffness (LS) values predicting cirrhosis, and 12 (17%) had values predicting significant or advanced fibrosis. Higher indirect biochemical scores of liver fibrosis were significantly associated with higher LS values [APRI rs = 0.4296 (P

Objectives: We analyzed clinical progression among persons diagnosed with HIV at the time of an AIDS-defining event, and assessed the impact on outcome of timing of combined antiretroviral treatment (cART). Methods: Retrospective, European and Canadian multicohort study.. Patients were diagnosed with HIV from 1997-2004 and had clinical AIDS from 30 days before to 14 days after diagnosis. Clinical progression (new AIDS event, death) was described using Kaplan-Meier analysis stratifying by type of AIDS event. Factors associated with progression were identified with multivariable Cox regression. Progression rates were compared between those starting early (

IntroductionThere seem to be no published data concerning the clinical impact of populations of hepatitis B virus (HBV) in the hepatic and extrahepatic compartments of HIV-infected people with severe acute hepatitis.Case presentationA 26-year-old Caucasian man presenting to our hospital with clinical symptoms suggesting acute hepatitis was found to have an acute hepatitis B profile upon admission. He developed fatal fulminant hepatitis and was found to be heavily immunocompromised due to HIV-1 infection. He had a high plasma HBV and HIV load, and analysis of the partial pre-S1/pre-S2 domain showed the presence of mixed infection with D and F genotypes. Analysis of the point mutations within this region revealed the presence of HBV strains with amino acid substitutions at the immunodominant epitopes involved in B or T cell recognition. A homogeneous population of a pre-core mutant strain harbouring the A1896G and A1899G affecting HBeAg expression was invariably found in the liver tissue, plasma and peripheral blood mononuclear cells despite active HBeAg secretion; it was the dominant strain in the liver only, and was characterised by the presence of two point mutations in the direct repeat 1 domain involved in HBV replication activity. Taken together, these mutations are indicative of a highly replicative virus capable of evading immune responses.ConclusionThis case report provides clinical evidence of a possible association between the rapid spread of highly replicative escape mutants and the development of fulminant hepatitis in a heavily immunocompromised patient. Virological surveillance of severe acute hepatitis B may be important in establishing an early treatment strategy involving antiviral drugs capable of preventing liver failure, especially in individuals for whom liver transplantation is not accepted as a standard indication.

Objectives: The purpose of this study was to evaluate the steady-state pharmacokinetics of amprenavir and ritonavir in HIV-infected patients with different degrees of hepatic impairment. Methods: HIV-positive patients receiving fosamprenavir/ritonavir ( 700/100 mg twice daily) were included. Patients were classified into three groups: ( i) chronic hepatitis; ( ii) liver cirrhosis; ( iii) normal liver function. Serial blood samples for steady-state amprenavir and ritonavir pharmacokinetics (> 14 days on treatment) were collected in the fasting state before the morning dose ( C-trough) and then 1, 2, 3, 4, 6, 8, 10 and 12 h after drug intake. Amprenavir and ritonavir plasma concentrations were determined by HPLC. Results: Twenty-one HIV-infected patients were included. Seven had chronic hepatitis, eight had liver cirrhosis and six patients were in the control group. Amprenavir AUC(0-12), AUC(0-1), C-max and C-ss were increased by 50% to 60% in the cirrhotic group when compared with controls, whereas CL/F was decreased by 40%. Patients with chronic hepatitis showed a significant increase in AUC(0-12), C-max and C-ss values when compared with controls. Ritonavir pharmacokinetics was different only in cirrhotic patients when compared with controls. Liver function parameters at weeks 4, 12 and 24 were not different from baseline in any of the groups. Overall, a significant correlation between amprenavir AUC(0-12) and total bilirubin values on the day of pharmacokinetic analysis was found ( r = 0.64, P = 0.003). Conclusions: On the basis of these data and also of data available in the literature, it seems reasonable to adapt the dose of fosamprenavir and/or ritonavir exclusively in the presence of adverse events, possibly related to protease inhibitors ( i. e. liver toxicity), in subjects with high drug plasma levels. Therapeutic drug monitoring is advised in the management of these patients.

Serum IL-7 levels correlate with T-cell depletion in HIV-infected individuals. In some patients, we observed that serum IL-7 decreases upon progression to AIDS, suggesting a role for IL-7 in T-cell maintenance in sporadic cases. Interestingly, IL-7 levels were significantly lower in stable long-term non-progressors (LTNP) than in patients who lost the LTNP status in a 3-year follow-up (P < 0.001), indicating that the serum IL-7 concentration might be a valuable marker for maintenance of the LTNP state.

Methods HIV pos women (N = 410) were followed since 1995 in a longitudinal study. Each one undergo periodic (6–12 months) colposcopy, PAP smear, biopsy if needed, and cervical sampling for HPV testing. HIV related parameters (CD4, HIV-RNA, ART) are recorded and related to cervical disease. HPV typing is performed by reverse hybridisation assays, viral load by in-house real time PCR and viral expression by E6/E7 mRNA detection. The Mann-Whitney rank sum test for non-parametric data and the association between discrete variables by Chi-square test of Fisher exact test were applied.

Background. The role of human papillomavirus (HPV) load and the importance of multiple-strain HPV infections as biomarkers for the development of cervical disease were evaluated in human immunodeficiency virus (HIV)‐positive women. Methods. A total of 108 samples were analyzed, 64 of which were obtained from 16 HIV-positive women who underwent surgical resection of the cervical cone for treatment of a histologically confirmed high-grade cervical intraepithelial neoplasm (cases) and 44 of which were obtained from 22 HIV-positive women who had high-risk HPV but a negative colposcopy result (controls). Each patient underwent periodic examinations at 6‐ 12-month intervals that included colposcopy, Papanicolaou testing, biopsy (if indicated), and cervical brushing for HPV testing. Viral typing was performed by reverse dot-blot hybridization and quantification of viral load by in-house real-time PCR and commercial assays. Results. Analysis of the cervical-brush samples collected when high-grade squamous intraepithelial lesions were diagnosed revealed that all cases had HPV loads that were significantly higher than those of controls (P p and , by PCR and the Hybrid Capture 2 index [Digene], respectively). Decreasing concentrations .0004 P p .0003 of HPV load were observed when comparing samples obtained before and after treatment ( ). The number P ! .0001 and type of HPV strains that were detected were not statistically different between cases and controls. Conclusions. The significantly higher HPV load detected in women with high-grade cervical dysplasia, as well as the dramatic decrease in the load after surgical removal of the lesion, suggest that HPV load is a possible prognostic marker of high-grade SIL.

Chronic hepatitis C virus (HCV) is an independent risk factor for antiretroviral-related hepatotoxicity, but little is known about the frequency of severe liver toxicity in patients with HIV-HCV coinfection first treated for HCV (pretreated). The aim of this prospective study of 105 patients was to compare the incidence of progression to severe antiretroviral-related liver toxicity in 66 patients pretreated (36 with interferon-alpha [IFNalpha], 30 with IFNalpha plus ribavirin), and 39 patients not pretreated. The subjects could choose whether to receive anti-HCV therapy. Severe liver toxicity was defined as alanine aminotransferase (ALT) level > or =5-times the upper limit of normal in patients with normal baseline levels and > or =3.5-times in those with increased baseline levels. The authors also estimated the hepatotoxicity-related risk of discontinuing antiretroviral therapy. During antiretroviral therapy, 10 subjects (9.5%) experienced severe hepatotoxicity: 4 of 66 pretreated patients and 6 of 39 untreated patients (24-month survival: 94% +/- 2.9% vs. 85% +/- 5.8%). After adjusting for baseline CD4 cell counts, ALT levels, histologic scores, HCV and HIV viremia, HCV genotype (genotype 1 in 29% of pretreated patients and 20% of patients not pretreated), and previous anti-HCV therapy, the risk of discontinuing anti-HIV treatment was significantly higher in the anti-HCV untreated patients (RR = 10.4; 95% CI: 1.6-66; p =.0127) and in those with increased baseline ALT levels (RR = 1.014; 95% CI: 1.006-1.021; p =.0005). The authors' data suggest that previous treatment of chronic active HCV is an independent factor associated with a decrease of severe liver toxicity as the result of a subsequent antiretroviral regimen. The authors also confirm that the baseline level of ALT is an important prognostic factor for increased liver damage during antiretroviral therapy.

To evaluate the usefulness of a real-time PCR for Leishmania DNA in the diagnosis and follow-up of patients with human immunodeficiency virus type 1 (HIV-1) and Leishmania coinfection, Leishmania DNA levels were measured in whole peripheral blood from 25 HIV-infected patients with clinical features suggestive of visceral leishmaniasis. Leishmania DNA was detected in 10 of 25 patients with microscopically confirmed visceral leishmaniasis and in none of those without this disease. Following treatment with liposomal amphotericin B, a clinical response was observed in 9 of 10 patients, in association with significantly decreased parasite loads. Seven patients relapsed clinically a median of 110 days after the end of treatment, in association with substantial increases in Leishmania DNA levels. Leishmania DNA levels correlated with the clinical course of visceral leishmaniasis, and their measurement at diagnosis and during and after treatment seems to be useful in the clinical management of HIV-infected patients with this disease.

Human herpesvirus oesophagitis in human immunodeficiency virus positive patients is caused by cytomegalovirus and herpes simplex virus; no cases of oesophagitis and oesophagobrochial fistula as a result of varicella zoster virus (VZV) have been reported to date. This report describes the case of a patient with a 2–3 mm deep oesophageal ulcer whose viral culture was positive for VZV. The patient was treated with acyclovir with resolution of the symptomatology. After the end of the induction treatment, because of the onset of fever and fits of coughing during eating, the patient underwent oesophagography, which showed an ulcer with an oesophagobronchial fistula in the middle and lower third of the oesophagus. This case report stresses the role of VZV infection as a possible cause of oesophagobronchial fistula, a rare but benign condition in patients with AIDS.

Fourteen patients with AIDS and toxoplasmic encephalitis, who could not be treated with the standard regimen of pyrimethamine and a sulfonamide due to a previous history of bone marrow suppression and severe allergic reactions to sulfonamides, were treated with oral clindamycin and pyrimethamine. All 14 patients received a 100 mg loading dose of pyrimethamine orally followed by 50 mg/day plus clindamycin orally (600-900 mg q8h). The duration of primary treatment ranged from 6 to 8 weeks. All patients also received folinic acid (15 mg/day orally). Maintenance therapy consisted of 25 mg/day of pyrimethamine and clindamycin (300 mg q6h or 450 mg q8h). A complete or partial clinical or neuroradiological response was observed in all patients at the end of two months of primary therapy. Ten of 14 patients showed complete resolution of clinical signs, and 8 of 14 patients showed complete resolution of neuroradiologic signs. All 14 patients continued the maintenance regimen, and although there were no relapses, symptoms that had not resolved by the end of the second month of acute therapy tended to remain unchanged.

month later. One week later uterine bleeding restarted; repeated for a four-month history of meno-metrorrhagia and sub- sequent anaemia; thereafter, she received a combined blood examinations were normal as before. During this oral contraceptive with resolution of the haemorrhage. second episode of meno-metrorrhagia soluble inter- Ten months later, while she was still taking an oral con- leukin-2 receptor

In opiate addicts specific and unspecific immune responses were examined, before and after methadone treatment. Anomalous immune responses were characterized by compromised cellular immunity (functional deficits of polymorphonuclear leukocytes and T-lymphocytes) in association with efficient production of antibodies. After methadone treatment an elevation of leukocyte functions was noted. The presence of elevated titres of circulating immune complexes observed in all the patients tested could bring about a functional exhaustion of neutrophils. The defects of cellular immunity can be considered important risk factors in the pathogenesis of infectious diseases in addicts.

Eighteen infants born to anti-HIV-positive mothers were tested bimonthly for immunoglobulin M (IgM) anti-HIV by Western blot and HIV p24 antigen (Ag) by enzyme-linked immunosorbent assay (ELISA) in order to determine the role of these markers in the early diagnosis of HIV infection. Twelve healthy infants were also studied as a control group. In 11 out of 18 children (61.1%) an IgM response was demonstrable, in 13 out of 18 (72.2%) IgM anti-HIV and/or p24 antigen (Ag) were detected. Two patterns of IgM response were identified: a precocious IgM positivity (group of five children positive at birth) and a later appearance of IgM, always within the third month (six cases). Early p24 antigenemia occurred in one infant. Three out of four children who developed antigenemia after birth were symptomatic within the sixth month. No clinical or immunological abnormalities were found among the three children who were persistently negative for both IgM anti-HIV and p24 Ag. Serial IgM anti-HIV and p24 Ag testing may be helpful in the early identification of HIV-infected patients.

Intravenous drug users (IVDUs) account for more than 64% of the total AIDS cases in Italy. The IVDUs' seropositivity rate is greater than 70% in Milan and greater than 50% in the main cities of Italy. The first evidence of seropositivity in this population dates back to 1979. In a cohort study performed in Milan the rate of progression to overt AIDS among IVDUs was 6% in 3 years (1984-1987). At presentation, more than 75% of the subjects had CD4+ cell counts higher than 400/mm3 (mean 631, median 528, mode 465). These values are significantly higher than those observed in the same population in New York, the only American city with HIV-infection spread comparable to that observed in Milan. The probability of having CD4+ cell counts lower than 400, 300, and 200/mm3 in relation to the length of follow-up was, respectively, 50, 40, and 2% after 36 months from presentation. At the same end point, subjects presenting less than 400 CD4+ cells at entry had 30% probability of falling under 200 cell/mm3. The pattern of CD4+ cells, as much as the low percentage of yearly progression to overt AIDS, is probably related to the recent, even if rapid, spread of infection among IVDUs in Italy. The clinical features of overt AIDS present some differences between IVDUs and other at-risk groups. Among U.S. IVDUs with AIDS, Kaposi's sarcoma is infrequent (2.9% vs 27.7% in homosexual men) while mycotic infections such as deep candidiasis and cryptococcosis are significantly more frequent. The same pattern has been observed in our case file in Milan: esophageal candidiasis represents the most frequent cause of diagnosis of overt AIDS. Mycotic infections, overall, are more frequent than in U.S. IVDUs. The increased rate of mycotic infections among IVDUs might be justified by altered functions of nonspecific immunity, such as PMNL killing and phagocytosis of Candida albicans spores, impaired in HIV-infected IVDUs, but generally normal in infected subjects belonging to the other at-risk groups.

Thirty-one AIDS patients were typed for HLA A, B, C, and DR antigens. We confirmed that frequency of B35 is significantly higher in patients than in controls. No significant frequency differences in other HLA antigens were found. The analysis of HLA distribution in AIDS patients by risk categories suggests that B35 is a major risk factor, primarily mainly for patients belonging to the category of intravenous (IV) drug addicts.

Summary We describe a case of pulmonary candidiasis in a 26-year old drug-addict who had been recently submitted to a porto-caval by pass operation. This opportunistic infection appeared after an injection of heroin. The same patient was also found to suffer from a severe cellular immune response defect. No opportunistic fungal infections were observed, despite the frequent use of intravenous heroin, in a group of 20 parenteral drug addicts. The latter patients, however, were showing only minor abnormalities of their immunological status. Although in this case the main cause of the disease may have been the injection of heroin contaminated with the infecting organism, other important factors contributing to the development of opportunistic mycoses seem to be a reduced microbicidal capacity of the polymorphonuclear leukocytes and an impaired cell-mediated immunity.

The prevalence of human immunodeficiency virus (HIV) antibodies and the symptoms induced [persistent generalized lymphadenopathy (PGL), AIDS-related complex (ARC), acquired immunodeficiency syndrome (AIDS)] was evaluated in several groups of intravenous (IV) drug abusers in three large Italian cities (Milan, Bologna, and Rome). The earliest evidence of seropositivity in sera collected from patients with acute viral hepatitis dates back to 1979 in Milan and to 1981 in Bologna with peaks in 1983 in both cities. In two groups of IV drug addicts on methadone-maintenance treatment at assistance centers, the prevalence of seropositivity differed sharply between Rome (33.3%) and Milan (69.3%) in 1985. Rates of seroconversion were also found to be higher in Milan than in Bologna and Rome. When a population of IV drug abusers voluntarily attending centers for surveillance of AIDS and/or ARC were investigated, high levels (range 55.2-81.5%) of seropositivity were found in the three cities. ARC prevalence among seropositives was very high (range 48.1-64.2% in 1985) in the three cities. The evolution rate to AIDS in Milan was higher among those attending a center for AIDS surveillance (7.4%) than among those attending an assistance center for methadone treatment (0.9%). These data are compatible with the hypothesis that virus infection among IV drug abusers originated in and then spread widely in Northern Italy (Milan first and then Bologna). Both the first appearance and subsequent spread of virus infection are in keeping with the reported occurrence of AIDS cases in the corresponding three regions of Milan, Bologna, and Rome.

Options for human immunodeficiency virus-1-infected women who are already receiving antiretroviral medications when they become pregnant include the continuation or discontinuation of the therapy during the first trimester. These two strategies are compared in terms of plasma human immunodeficiency virus viral load and CD4 cell count.Seventy women who attended the II Department of Obstetrics and Gynecology were identified. Four different periods for laboratory evaluations were decided: presuspension, suspension, second trimester, and third trimester.Thirty-two women (46%) discontinued antiretroviral therapy; 38 women (54%) did not. Whereas plasma HIV virus viral load and CD4 cell count did not significantly vary during pregnancy in patients who did not interrupt the therapy, these two variables were influenced significantly by the discontinuation of treatment (P.001 for both). Human immunodeficiency virus viral load increased during the suspension period and regressed promptly to basal levels as soon as the therapy was reintroduced. A transitory decrease in CD4 cell count was also documented, but the recovery tended to be slower.The suspension of combination antiretroviral therapy during the first trimester of pregnancy transiently corresponds to an increase in human immunodeficiency virus viral load and a decline of CD4 cell count.

Excerpt The therapy for cryptococcal meningitis in patients with the acquired immunodeficiency syndrome (AIDS) is still unsatisfactory. Although other populations generally respond well to treatmen...

To the Editor.— In patients with the acquired immunodeficiency syndrome (AIDS)- or human immunodeficiency virus (HIV)-related disorders, mucocutaneous manifestations caused by herpesvirus are frequent,1and may present with unusual clinical features.2Chronic anogenital ulcers due to herpes simplex virus (HSV), severe dermatomal herpes zoster (HZ), and protracted forms of varicella and vesiculobullous eruptions due to cytomegalovirus have all been described.3-5The purpose of this article is to illustrate a peculiar form of disseminated ecthymatous varicella zoster virus (VZV) infection in two patients with AIDS, which was characterized by necrotic cutaneous lesions and a prolonged course. Report of Cases.—Case 1. —A 35-year-old bisexual man with a history of varicella during childhood and condylomata acuminata for one year was found to be seropositive to HIV in May 1986, when he was hospitalized forPneumocystis cariniipneumonia and oral candidiasis. He developed cerebral toxoplasmosis in June 1986, and noted