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Kaposi's Sarcoma (KS) is a multicentric angioproliferative cancer of endothelial cells (ECs) caused by Human Herpesvirus 8 (HHV8) characterized by clinical heterogeneity depending on the host immune conditions. Despite its incidence has dramatically decreased in developed countries after the introduction of Highly Active Antiretroviral Therapy (HAART), KS remains the most frequent tumor in HIV-infected patients worldwide. Clinical presentation varies from an indolent slowly progressive behavior, generally limited to the skin, to an aggressive and rapidly progressing disease. In more than 50% of cases, the skin lesions are often associated with a more or less important visceral involvement, particularly to the oral cavity and the gastrointestinal tract that are involved in 35% and 40% of cases respectively. A large number of treatments can be used both as local and as systemic therapy. Particularly, HAART represents the first treatment in patients with moderate lesions limited to skin, and it can be sufficient to reduce significantly the size of lesions and, often, the complete disappear in 35% of cases after 3-9 months of treatment. In case of a rapidly progressive disease with extensive cutaneous and/or visceral involvement systemic drugs are used such as the liposomal anthracyclines pegylated liposomal doxorubicin (PLD) and daunorubicin citrate liposome (DNX), the combined treatment adriamycin-bleomycin-vincristine (ABV) and bleomycin-vincristine (BV), Paclitaxel and Interferon-alfa. In patients with limited skin localization, the local treatment can play an important role. Local medical therapy is based on the use of alitretinoin, antineoplastic drugs vincristine, vinblastine and bleomycin and Sodium Tetradecyl Sulfate (STS). In addition to medical therapy, physical treatment, such as cryotherapy and radiotherapy, are also commonly used. [ABSTRACT FROM AUTHOR]

The efficacy of the current HIV therapy has led to increased survival and prolongation of the average life expectancy of people living with HIV (PLWH), as well as the emergence of comorbidities and non-AIDS related cancer. Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. Current evidence suggests that HCC is an important cause of morbidity and mortality in HIV infected patients. In fact, HCC prevalence rate is indeed higher with respect to the general population average. In this paper, we review the diagnostic and therapeutic management of Hepatitis C-related hepatocellular carcinoma in HCV-HIV co-infected patients. Several therapeutic options are available depending on several factors as HCC stage, liver functions, comorbidities and they have been divided into three groups: potentially curative, proven effective but not curative, and unproven or ineffective therapy. In HIV-infected patients, surgical options are preferred compared to non-surgical therapies. Further studies, especially multicenter ones, are needed in order to define the most appropriate, evidence- based therapeutic approach to PLWH suffering from HCC. It also appears necessary to develop appropriate care guidelines for PLWH. [ABSTRACT FROM AUTHOR]

The advent of highly active anti-retroviral therapy (HAART) in the mid-1990s has transformed Human Immunodeficiency Virus (HIV) infection into a chronic disease. HIV-infected patients are living longer and are facing several non-AIDS-associated morbidities related with aging, including diabetes mellitus, cardiovascular disease, osteoporosis, osteopenia and fragility fractures. The prevalence of bone disease is higher among HIV-infected subjects. In addition to traditional risk factors, HAART, chronic inflammation and the virus itself have been suggested to contribute to bone loss in the setting of HIV infection. In the present review, we summarize the current knowledge about risk factors for low bone mineral density in HIV-positive patients as well as current recommendations for fracture screening and treatment in this specific population. [ABSTRACT FROM AUTHOR]

Kaposi's sarcoma (KS) is a multicentric angioproliferative cancer of endothelial origin typically occurring in the context of immunodeficiency, i.e. coinfection with Human Immonodeficiency Virus (HIV) or transplantation. The incidence of KS has dramatically decreased in both US and Europe in the Highly Active Anti-retroviral Therapy (HAART) era. However, KS remains the second most frequent tumor in HIV-infected patients worldwide and it has become the most common cancer in Sub-Saharan Africa. In 1994, Yuan Chang et al discovered a novel γ-herpesvirus in biopsy specimens of human KS. Epidemiologic studies showed that KS-as-sociated herpesvirus (KSHV) or human her-pesvirus-8 (HHV-8) was the etiological agent associated with all subtypes of KS. KS has a variable clinical course ranging from very indolent forms to a rapidly progressive disease. HAART represents the first treatment step for slowly progressive disease. Chemotherapy (CT) plus HAART is indicated for visceral and/or rapidly progressive disease. The current understanding of KS as a convergence of immune evasion, oncogenesis, inflammation and angiogenesis has prompted investigators to develop target therapy, based on anti-angiogenic agents as well as metallopro-teinase and cytokine signaling pathway inhibitors. These drugs may represent effective strategies for patients with AIDS-associated KS, which progress despite chemotherapy and/or HAART. In this review, we focus on the current state of knowledge on KSHV epidemiology, pathogenesis and therapeutic options. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Across Europe, more than one third of patients are diagnosed with HIV infection late. Late presentation for care has been associated with higher risk of clinical progression and mortality. In the present study, we evaluated the prevalence, epidemiological characteristics and survival probability of patients with late and very late presentation, newly diagnosed with HIV infection in Catania, Italy, from 1985 to 2010. PATIENTS AND METHODS: According to the European Consensus definition, Late Presenters (LP) were defined as subjects presenting for care with a CD4+ T-cell count below 350 cells/µl or with an AIDS-defining event, regardless of CD4+ T-cell count; patients with advanced HIV disease (Very Late Presenters) (VLP) were those presenting with a CD4+ T-cell count below 200 cells/µl or with an AIDS-defining event, regardless of CD4+ T-cell count. RESULTS: 620 patients were included in the study. 345 (55.6%) subjects were LP, 35% of them were asymptomatic; 246 (39.7%) were VLP. In univariate analysis, late presentation was related to age (p < 0.001), to heterosexual exposure to HIV infection (70% of heterosexual subjects were LP) (p < 0.005) and to being diagnosed during the calendar period from 1991 to 2000 (p < 0.001). Very late presentation was related to age (p < 0.001), male sex (p < 0.01), heterosexual risk (p < 0.001) and to being diagnosed during the calendar period from 1991 to 2000 (p < 0.001). In multivariate analysis, age (p < 0.0001), being older than 50 years old (p = 0.02), years of diagnosis 1991-1995 (p < 0.005) and 1996-2000 (p < 0.05) in the subgroup of late presenters and age (p < 0.0001), being older than 50 years old (p < 0.005), male sex (p < 0.0001), years of diagnosis 1991-1995 (p < 0.05) and 1996-2000 (p < 0.005) in the subgroup of very late presenters maintained statistical significance. The survival probability within LP and VLP group was statistically lower than no LP/VLP (log rank test p < 0.0005 and p < 0.0001, respectively). For both LP (p < 0.002) and VLP (p < 0.0001), survival probability was significantly lower in the pre-HAART era, in comparison with the period of mono/dual therapy and the HAART era. CONCLUSIONS: More than fifty percent of patients in our setting were diagnosed late with HIV infection and, consequently, treated late. Late and very late presentation were associated with lower survival probability. The implementation of strategies focused on targeted prevention efforts and HIV testing programs appears fundamental to diagnose and treat HIV infection as early as possible. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Anxiety disorders are frequent in HIV-infected individuals, can pre-exist or occur during HIV infection. We evaluated with a self-reported questionnaire whether anxiety is related to HIV clinical status and therapeutic success in a cohort of HIV-positive subjects in Sicily. PATIENTS AND METHODS: We enrolled 251 patients on combination antiretroviral therapy (cART) for at least six months; Self Rating Anxiety State SAS 054 was used to diagnose anxiety and a Z score = = 45 points was considered diagnostic. RESULTS: 47% of patients were diagnosed with anxiety. Patients showing symptoms related to anxiety had experienced a high number of therapeutic switches (fourth line or more). CONCLUSIONS: These data confirm a high prevalence of anxiety symptoms among subjects with HIV infection in Eastern Sicily. Physicians should be aware of the extent of the problem and should be able to adequately manage anxiety in the setting of HIV infection. [ABSTRACT FROM AUTHOR]

AIM: Vitamin D deficiency is very common among HIV-infected subjects. We cross-sectionally evaluated the prevalence and risk factors for hypovitaminosis D in 91 HIV-infected Italian patients. PATIENTS AND METHODS: We studied in a cohort of 91 HIV-infected Italian patients the metabolism of Vitamin D by evaluating the in vitro expression of CYP27B1, CYP24A1 and vitamin D receptor (VDR) by monocytes and macrophages stimulated with the viral envelope protein gp120 or lipopolysaccharide (LPS). RESULTS: The prevalence of vitamin D deficiency (25OHD < 10 ng/ml) and vitamin D insufficiency (25OHD 10-30 ng/ml) was 31% and 57%, respectively. In univariate analysis, female sex (p = 0.01), increasing age (p = 0.05), higher highly sensitive-C reactive protein (p = 0.025), higher parathyroid hormone (PTH) (p = 0.043) and lower BMI (p = 0.04) were associated with vitamin D deficiency. In multivariate analysis, the association was still significant only for PTH (p = 0.03) and female sex (p = 0.03). Monocyte stimulation with LPS (100 ng/ml) or gp120 (1 µg/ml) signif icantly upregulated CYP27B1 mRNA expression. Moreover, gp120 significantly increased VDR mRNA levels. On the contrary, neither LPS nor gp120 modified CYP24A1 levels. Macrophage stimulation with LPS (100 ng/ml) significantly upregulated CYP27B1 and CYP24A1 mRNA expression. When monocytes were cultured in the presence of 25OHD (40 ng/ml) and stimulated with LPS we detected significantly lower levels of 25OHD in the supernatant. CONCLUSIONS: Vitamin D deficiency was very common in our cohort of HIV-infected patients. Chronic inflammation, including residual viral replication, may contribute to hypovitaminosis D, by modulating vitamin D metabolism and catabolism. Systematic screening may help identifying subjects requiring supplementation. [ABSTRACT FROM AUTHOR]

Hypovitaminosis D is a very common disorder, regarding both Western and developing countries. A growing amount of data over the last years have shown vitamin D deficiency to be high prevalent among HIV-positive subjects. In addition to "classic" risk factors, such as female sex, low dietary intake, dark skin pigmentation and low sun exposure, HIV-related factors, including immune activation and anti-retroviral adverse effects, may affect vitamin D status. Even if both protease inhibitors and non-nucleoside reverse transcriptase inhibitors have been associated with low vitamin D levels, available evidences have failed to univocally associate hypovitaminosis D with specific antiretroviral class effects. Low vitamin D is known to have a negative impact not only on bone health, but also on neurocognitive, metabolic, cardiovascular and immune functions. Similarly to the general population, several studies conducted on HIV-infected subjects have associated hypovitaminosis D with a greater risk of developing osteopenia/osteoporosis and fragility fractures. Analogously, vitamin D deficiency has been described as an independent risk factor for cardiovascular disease and metabolic disorders, such as insulin resistance and type 2 diabetes mellitus. Last EACS guidelines suggest to screen for hypovitaminosis D every HIV-positive subject having a history of bone disease, chronic kidney disease or other known risk factors for vitamin D deficiency. Vitamin D repletion is recommended when 25-hydroxyvitamin D levels are below 10 ng/ml. Furthermore, it may be indicated in presence of 25OHD values between 10 and 30 ng/ml, if associated with osteoporosis, osteomalacia or increased parathyroid hormone levels. The optimal repletion and maintenance dosing regimens remain to be established, as well as the impact of vitamin D supplementation in preventing comorbidities. [ABSTRACT FROM AUTHOR]

The natural history of HIV infection has been greatly changed by the introduction of highly active antiretroviral therapy (HAART). As a consequence of improved immune function, the incidence of AIDS-defining cancers (ADCs), such as Kaposi's sarcoma, non- Hodgkin's lymphoma (NHL) and invasive cervical cancer, has significantly declined. On the contrary, non-AIDS-defining cancers (NADCs), such as hepatocellular carcinoma, anal cancer, lung cancer, colorectal cancer and Hodgkin's lymphoma, have gradually emerged as a major fraction of the overall cancer burden. The reasons are still partially unknown. Some of the increased risk may be explained by a high prevalence of cancer risk factors, such as smoking, alcohol consumption, human papilloma virus (HPV) infection and HCV infection among HIV-infected people. The role of immunosuppression in the development of NADCs is controversial, as several studies have not found a clear-cut evidence of an association between the degree of immunosuppression and the development of NADCs. Analogously, the impact of HAART is still not well defined. Future research should focus on the etiology of NADCs, in order to shed light on the pathogenesis of cancer and ultimately to work for prevention; moreover, additional studies should evaluate the best therapeutic approaches to NADCs and the impact of cancer screening interventions among HIV-infected people, in an effort to diagnose cancer at an earlier stage. [ABSTRACT FROM AUTHOR]

HIV-associated neurocognitive disorders are common in HIV-infected individuals, even in the combination antiretroviral therapy (c-ART) era. Several mechanisms are involved in neuronal damage, including chronic inflammation immune activation. Mammalian 2'-5'-oligoadenylate synthetase (OAS) genes are produced in response to interferon (IFN), mainly by monocytes, and exert their antiviral functions by activation of RNase L that degrades viral and cellular RNAs. In this study, we aimed at exploring OAS gene family RNA expression in simian immunodeficiency virus encephalitis (SIVE), in HIV-associated neurocognitive disorders (HAND), and in HIV-associate dementia (HAD). We analyzed three microarray datasets obtained from the NCBI in order to assess the expression levels of OAS gene family network in brain biopsies of macaques with SIVE vs uninfected animals, as well as post-mortem brain of individuals with HAND (on or off ART) vs uninfected controls and three brain regions of HIV-infected individuals with both neurocognitive impairment (HAD) and encephalitis (HIVE). All OAS genes were upregulated both in SIVE and in HAND. OAS expression was significantly higher in high-viremic individuals; increased expression levels persisted in cART subjects when compared to healthy controls. OAS gene network analysis showed that several genes belonging to the type I IFN pathway, especially CXCL10 and IFIT3, were similarly upregulated in SIVE/HAND. Furthermore, we identified a significant upregulation of OAS gene family RNA expression in basal ganglia, white matter, and frontal cortex of HIV-1, HAD, and HAD/HIVE patients compared to healthy subjects. OAS gene family expression is increased in brain sections from individuals with HAND, HAD, and HIVE as well as macaques with SIVE. OAS family expression is likely to be induced by IFN as a consequence of viral replication in the CNS. Its long-term upregulation may contribute to the chronic inflammatory status and neurocognitive impairment we still observe in virologically suppressed individuals on c-ART.

Introduction: Hepatitis C virus (HCV) infection is a common cause of chronic liver disease and hepatocellular carcinoma (HCC). The prevalence of HCC significantly declines among patients achieving a sustained virological response (SVR) after antiviral therapy with pegylated(PEG)-interferon (IFN) and ribavirin. However, up to 5% of patients with SVR may develop HCC., Patients and Methods: We investigated the epidemiological, clinical, biochemical and virological characteristics of a small cohort of patients with chronic hepatitis C (CHC) who developed HCC after being successfully treated with PEG-IFN-α and ribavirin., Results: Between September 2000 and January 2003, 598 patients with CHC underwent a complete course of treatment with PEG-IFN-α and ribavirin; 221 out of 598 (37%) patients obtained a SVR. Throughout the 10-year post-treatment follow up, 13 of 221 ( 5.8% ) SVR patients developed HCC. All 13 patients were male and were affected with Child A liver cirrhosis; in addition, at baseline they were significantly older (p < 0.05) and had higher alpha-fetoprotein levels (p < 0.05) in comparison with those who did not develop HCC. Nine patients (69.3%) developed HCC within the first 3 years after antiviral treatment completion, one patient (7.7%) between 3 and 5 years and 3 subjects (23%) between 5 and 10 years; 12 of 13 had a solitary lesion with a mean diameter of 2.5± 0.5 cm. Eleven cases (84.6%) underwent surgical resection, one (7.7%) received liver transplantation, one (7.7%) received palliative care., Conclusions: The risk of developing HCC after achieving SVR persists in patients with HCV-related cirrhosis. As a consequence, these patients should continue to undergo long-term surveillance for HCC, in order to early detect and treat it.

The introduction of highly active antiretroviral therapy (HAART) has reduced mortality and improved life expectancy of HIV-positive patients. However, increased survival is associated with increased prevalence of comorbidities, such as cardiovascular disease, hepatic and renal disease. Kidney disease, including HIV-associated nephropathy, acute renal failure and chronic kidney disease, represents one of the main causes of morbidity and mortality, especially if associated to other risk factors, i.e. hypertension, diabetes, older age, black race and hepatitis C coinfection. Careful evaluation of renal function may help identifying kidney disease in its early stages. In addition, proper management of hypertension and diabetes is recommended. Even if HAART has changed the natural course of HIV-associated nephropathy, reducing the risk of End-stage Renal Disease (ERDS), some antiretroviral regimens have been related with the development of acute or chronic kidney disease. Further studies are needed to optimize the management of renal disease among HIV-infected patients.

After starting highly active antiretroviral therapy (HAART), HIV-infected patients may experience what is termed immune reconstitution inflammatory syndrome (IRIS). IRIS is characterized by a paradoxical inflammatory response to either previously or recently treated infections or unmasked subclinical infections, when the patient regains the ability to mount a suitable immune response against specific antigens or pathogens. Cryptococcal IRIS (C-IRIS) is thought to be mediated by recovery of Cryptococcus-specific immune responses, resulting in exaggerated host inflammatory responses. In HIV-positive subjects, two distinct modes of presentation of C-IRIS are recognized, "paradoxical" and "unmasking" C-IRIS. "Paradoxical" C-IRIS presents as worsening or recurrence of treated cryptococcal disease following HAART initiation, despite microbiological treatment success. In the "unmasking" form, patients with no prior diagnosis may develop acute symptoms of cryptococcosis, such as meningitis or necrotizing lymphadenopathy, after starting HAART. Here, we present the case of an HIV-positive man, who developed cryptococcal meningitis two months after having started HAART and experienced several meningeal relapses and a "paradoxical" C-IRIS during the following year.