Prevalence and predictors of malignancies in HIV patients: results of a retrospective multicentric Italian cohort.

We report the sharp reduction in the incidence of AIDS defining cancers in a multicentric, retrospective study carried out since 1991 and involving six Infectious Diseases Units spread across Italy. However, due to the parallel increase in non-AIDS defining cancers, cancer incidence was not reduced. Focusing on predictors of death in HIV-positive patients with neoplastic disease, multivariate models revealed that males as well as drug abusers were independently associated with a poor clinical outcome.

High seroprevalence of HCV in the Abruzzo Region, Italy: results on a large sample from opt-out pre-surgical screening.

PURPOSE: Available estimates of the prevalence of chronic HCV infection in Italy are quite conflicting, varying from 1.5 to 22.5%, with an apparent north to south gradient. As Direct Acting Antivirals are expensive, both National and local governmental Agencies are in urgent need of detailed and reliable estimates of HCV patients to be treated, nationwide and in each district. We investigated the prevalence of anti-HCV antibodies in a large unselected sample of surgical patients providing consent to in-hospital opt-out pre-surgical HCV screening, at two hospitals from the Abruzzo Region, Italy. METHODS: Data were retrieved for 55,533 screened patients (4.1% of the total population in the Abruzzo Region), admitted in the Orthopedic and General Surgery wards of Pescara and Teramo Hospitals from 1999 to 2014. RESULTS: The prevalence of anti-HCV antibodies was 4.4% in the total sample. HCV-positive patients had a mean age of 63.8 ± 19.9 years; 49.2% were males. From 1999 to 2014, the prevalence of HCV antibodies decreased from 5.4% to 4.1%; at both sites, however, two age-related-peaks were evidenced, the first among patients aged 30-49 years, the second among those older than 70 years. Statistical analyses confirmed a significant trend to decrease over time and a higher prevalence in Pescara and among males (all p < 0.01). CONCLUSIONS: Data retrieved from opt-out pre-surgical screening programs may allow inexpensive and easy-to-perform estimates of HCV seroprevalence from large samples of unselected patients with a well-defined provenience, which may turn useful for future treatment resource allocation.

Post-traumatic stress in pregnant women with primary cytomegalovirus infection and risk of congenital infection in newborns.

BACKGROUND: Substantial evidence indicates that perinatal mental disturbances are associated with the risk for negative maternal-newborn outcomes. A neuroendocrine brain-placenta interaction has been described to explain the association between prenatal stress-related disorders and placental abnormalities. Whether these mechanisms may affect the likelihood of mother-to-child transmission (MTCT) of infections has never been investigated. AIMS: To evaluate the role of psychological factors in cytomegalovirus (CMV) MTCT in pregnant women with primary CMV infection. METHOD: A cohort of 276 pregnant women with primary CMV infection underwent assessment of (a) reactive psychopathological symptoms, such as current depressive symptoms and ongoing symptoms of post-traumatic stress disorder; and (b) stable personality traits, such as alexithymia and Type D (distressed) personality. Congenital infection was diagnosed by CMV DNA amplification from blood and/or urine and saliva from newborn at birth. RESULTS: The occurrence of congenital CMV disease in the newborn was independently predicted by post-traumatic stress symptoms during pregnancy. CONCLUSIONS: Our findings suggest that psychological stress-related disturbances may weaken the physical and immunological barrier against the mother-to-fetus transmission of viruses. DECLARATION OF INTEREST: We declare that we have no conflicting interests to disclose. COPYRIGHT AND USAGE: © The Royal College of Psychiatrists 2016. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) license.

May some HCV genotype 1 patients still benefit from dual therapy? The role of very early HCV kinetics.

When treating HCV patients with conventional dual therapy in the current context of rapidly evolving HCV therapy, outcome prediction is crucial and HCV kinetics, as early as 48 hours after the start of treatment, may play a major role. We aimed at clarifying the role of HCV very early kinetics. We consecutively enrolled mono-infected HCV patients at 7 treatment sites in Central Italy and evaluated the predictive value of logarithmic decay of HCV RNA 48 hours after the start of dual therapy (Delta48). Among the 171 enrolled patients, 144 were evaluable for early and sustained virological response (EVR, SVR) prediction; 108 (75.0%) reached EVR and 84 (58.3%) reached SVR. Mean Delta 48 was 1.68 ± 1.22 log10 IU/ml, being higher in patients with SVR and EVR. Those genotype-1 patients experiencing a Delta 48 >2 logs showed a very high chance of success (100% positive predictive value), even in the absence of rapid virological response (RVR). Evaluation of very early HCV kinetics helped identify a small but significant proportion of genotype-1 patients (close to 10%) in addition to those identified with RVR, who could be treated with dual therapy in spite of not reaching RVR. In the current European context, whereby sustainability of HCV therapy is a crucial issue, conventional dual therapy may still play a reasonable role in patients with good tolerance and early prediction of success.

Kinetics of hepatitis C virus RNA decay, quasispecies evolution and risk of virological failure during telaprevir-based triple therapy in clinical practice.

BACKGROUND: The used first generation protease inhibitors may be hampered by virological failure in partially interferon-sensitive patients. AIM: To investigate early hepatitis C virus (HCV)-RNA decay and quasispecies modifications, and disclose viral dynamics underlying failure. METHODS: Viraemia decay at early time-points during telaprevir treatment was modelled according to Neumann et al. (1998). NS3-sequences were obtained by population-sequencing and ultradeep-454-pyrosequencing. RESULTS: 13 treatment-experienced (8 non-responders, 5 relapsers), and two cirrhotic naïve patients, received telaprevir+pegylated-interferon-α+ribavirin. Viraemia decay was biphasic. In all patients, first-phase was rapid and consistent, with a median [interquartile-range] viraemia decay of 2.8 [2.6-3.2]logIU/ml within 48h. Second-phase decay was slower, especially in failing patients: 3/3 showed <1logIU/ml decay between 48h and 2 weeks, and HCV-RNA >100IU/ml at week 2. Only one patient experiencing sustained viral response showed similar kinetics. By pyrosequencing, mutational freeze was observed in all 15 patients within the first 24h, but only in patients with sustained response afterwards. Indeed, 2/2 failing patients showed early resistance, as minor (V36A-T54A: prevalence <26% at 48h) or major (V36M/A-R155K: prevalence, 99.8% at week 2) variants. CONCLUSIONS: Following telaprevir administration, first-phase HCV-RNA decay is consistent with mutational freeze and limited/no viral replication, while second-phase is significantly slower in failing patients (with appearance of resistance), suggesting the usefulness of early HCV-RNA monitoring.

Cost of HAART in Italy: multicentric evaluation and determinants from a large HIV outpatient cohort.

BACKGROUND: As HIV infection turned into a chronic treatable disease, now ranking as one of the most costly in medicine, long-term sustainability of highly active antiretroviral treatment (HAART) expenses became a major issue, especially in countries with universal access to care. Identification of determinants of higher HAART costs may therefore help in controlling costs of care, while keeping high levels of retention in care and viral suppression. METHODS: With this aim, we enrolled a large multicentric sample of consecutive unselected human immunodeficiency virus (HIV) patients followed at five sites of care in Italy, and evaluated annual individual HAART costs in relation to a number of sociodemographic, clinical, and laboratory variables. RESULTS: We enrolled 2,044 patients, including 1,902 on HAART. Mean HAART costs were €9,377±€3,501 (range 782-29,852) per year, with remarkable site-based differences, possibly related to the different composition of local assisted populations. Percentages of patients on viral suppression were homogeneously high across all study sites. The factors identified by cross-validation were line of HAART, diagnosis of acquired immune deficiency syndrome, current CD4 T-cell count, and detectable HIV viremia >50 copies/mL. In the final multivariable model, HAART costs were independently directly associated with more advanced HAART line (P<0.001) and inversely correlated with current CD4 T-cell count (P=0.024). Site of care held independent prediction of higher costs, with marked control of expenses at sites 2 (P=0.001) and 5 (P<0.001). CONCLUSION: Higher costs of HAART were strongly associated with previous treatment failures, detectable HIV viremia, and lower CD4 T-cell count at the time of evaluation, with no correlation at all with sex, age, hepatitis C virus coinfection, and nadir CD4 T-cell counts. Newer drugs, which are typically those associated with high prices, at the time of the analysis were still prevalently prescribed to rescue and maintain viral suppression in patients with more complex treatment history. Further analyses of the contribution of the single drug/regimen to the estimated cost are warranted.

Hepatitis C virus RNA levels at week-2 of telaprevir/boceprevir administration are predictive of virological outcome.

BACKGROUND: Triple therapy with telaprevir/boceprevir + pegylated-interferon+ribavirin can achieve excellent antiviral efficacy, but it can be burdened with resistance development at failure. AIMS: To evaluate kinetics of hepatitis C virus (HCV) RNA decay and early resistance development, in order to promptly identify patients at highest risk of failure to first generation protease inhibitors. METHODS: HCV-RNA was prospectively quantified in 158 patients receiving pegylated-interferon+ribavirin+telaprevir (N = 114) or+boceprevir (N = 44), at early time-points and during per protocol follow-up. Drug resistance was contextually evaluated by population sequencing. RESULTS: HCV-RNA at week-2 was significantly higher in patients experiencing virological failure to triple-therapy than in patients with sustained viral response (2.3 [1.9-2.8] versus 1.2 [0.3-1.7]log IU/mL, p < 0.001). A 100 IU/mL cut-off value for week-2 HCV-RNA had the highest sensitivity (86%) in predicting virological success. Indeed, 23/23 (100%) patients with undetectable HCV-RNA reached success, versus 26/34 (76.5%) patients with HCV-RNA<100 IU/mL, and only 11/31 (35.5%) with HCV-RNA > 100 IU/mL (p < 0.001). Furthermore, differently from failing patients, none of the patient with undetectable HCV-RNA at week-2 had baseline/early resistance. CONCLUSIONS: With triple therapy based on first generation protease inhibitors, suboptimal HCV-RNA decay at week-2 combined with early detection of resistance can help identifying patients with higher risk of virological failure, thus requiring a closer monitoring during therapy.

Prevalence and predictors of malignancies in a polycentric cohort of HIV patients from Italy.

INTRODUCTION: HIV infected patients have a higher risk of developing cancer than the general population. Kaposi's sarcoma, non-Hodgkin's lymphoma, primary CNS lymphoma and invasive cervical cancers are considered as AIDS defining [1]. An increased incidence in recent years has been reported also for other malignancies after the introduction of cART [2,3]. MATERIALS AND METHODS: We performed a retrospective multicentric evaluation of all HIV infected patients with both AIDS and non-AIDS defining neoplasms at six Infectious Disease Units spread throughout Italy since 1991 through 2013. Cases were compared with equal number of controls without neoplasia followed at the same institutions, matched for length of HIV infection. RESULTS: Since 1991, 339 consecutive cases of malignancy were collected from the six convening centres, including approximately an equal proportion of AIDS (51.2%) and non-AIDS defining tumours. Mean prevalence of tumours among centres was 8.3% (r. 6.1%-9.6%). Mean age at tumour diagnosis was significantly lower than in controls (42.6±11.0 vs 46.8±10.6 years, respectively, p<0.0001). As to risk factors for HIV infection, approximately 1/4 (26.1%) of patients were drug abusers, in equal proportion as in controls. A remarkable higher proportion of cancer patients had CD4 T-cell counts <200 c/mmc at time of diagnosis (45.2% vs 13.3%, p<0.0001). Seventy percent of tumours occurred in males; 52.8% of tumour patients were diagnosed with AIDS before and 19.0% at the time of tumour diagnosis. Ninety (28.1%) tumour patients were dead at the time of data collection, a much higher proportion than among cases (12.9%, p<0.0001). Deaths among non-AIDS (20.8%) and AIDS defining tumour patients (35.0%) were significantly different (p=0.005). Predictors of AIDS defining tumours at the time of data collection were: male sex (57.9% vs 40.6%, p=0.004), CD4 T-cell counts <200 c/mmc (63.6% vs 44.1%, p<0.0001), whereas being cART treated at the time of tumour diagnosis was protective (38.0% vs 68.0%, p<0.0001). In the final multivariate model of logistic regression, male sex (OR=2.0, p=0.03) and not being cART treated (OR=2.5, p=0.001) held as independent predictors. CONCLUSIONS: Our retrospection revealed a considerably high proportion of non-AIDS defining tumours, apparently at rise in recent years. We registered high prevalence of tumours in each centre. Absence of cART seemed related with AIDS defining tumours: once more prevention of late presentation appeared the way to avoid worse prognosis in this setting.

Properties and mechanisms of immunoglobulins for congenital cytomegalovirus disease.

Immunoglobulins are one major component of adaptive immunity to external and resident microorganisms, evolving very early in phylogenesis. They help eukaryotes in controlling infections, mainly through their neutralizing activity, which quenches both the cytopathic and inflammatory potential of invading microorganisms. Cytomegalovirus (CMV)-related disease is generally blunted in seropositive subjects with conserved specific humoral responses. CMV-seropositive pregnant women, in accordance with such evidence, suffer little or no fetal damage when reexposed to CMV. Several seminal experiences and early experimental models confirmed that repeated infusions of immunoglobulins, either with hyperimmune or standard preparations, may help to reduce maternal-fetal CMV transmission, as well as to quench fetal disease upon transmission. This review focused on experimental evidence supporting the potential role of immunoglobulins as a tool to control fetal CMV-related disease in pregnant women.

Psychological factors, including alexithymia, in the prediction of cardiovascular risk in HIV infected patients: results of a cohort study.

BACKGROUND: Psychological factors are known predictors of cardiovascular disease in many clinical settings, but data are lacking for HIV infection. We carried out a prospective cohort study to evaluate potential psychological predictors of preclinical and clinical vascular disease in HIV patients. METHODOLOGY/PRINCIPAL FINDINGS: HIV patients were consecutively enrolled. Demographics, viral and immune parameters and traditional cardiovascular predictors were considered; Intima-Media Thickness (c-IMT, continuous measure) and Carotid Plaques (CPs, focal thickening ≥1.5 mm) were investigated by B-mode ultrasonography; depressive symptoms by the Beck Depression Inventory (BDI-II), Type D personality (Distressed Personality or Type D) by the DS14, alexithymia by the Toronto Alexithymia Scale (TAS-20). Vascular outcomes included transient ischemic attacks or stroke, acute coronary syndrome, myocardial or other organ infarction. We enrolled 232 HIV subjects, 73.9% males, aged 44.5±9.9 y, 38.2% with AIDS diagnosis, 18.3% untreated. Mean Nadir CD4 T-cell counts were 237.5±186.2/mmc. Of them, 224 (96.5%) attended IMT measurements; 201 (86.6%) attended both IMT assessment and psychological profiling. Mean follow-up was 782±308 days. Fifty-nine patients (29.4%) had CPs at baseline. Nineteen patients (9.5%) had ≥1 vascular event; 12 (6.0%) died due to such events (n = 4) or any cause. At baseline cross-sectional multivariate analysis, increasing age, total cholesterol, current smoking and Alexithymia score≥50 were significantly associated with both increased cIMT (linear regression) and CPs (logistic regression). At follow-up analysis, log-rank tests and Cox's regression revealed that only older age (p = 0.001), current smoking (p = 0.019) and alexithymia score≥50 (p = 0.013) were independently associated with vascular events. CONCLUSIONS/SIGNIFICANCE: In HIV-infected subjects, the Alexithymic trait emerges as a strong predictor of increased IMT, presence of CPs and vascular events. Such results are preliminary and require confirmation from studies with larger sample size and longer follow-up.

Post-herpetic neuralgia.

BACKGROUND: In spite of the large body of evidence available in the literature, definition and treatment of Post-Herpetic Neuralgia (PHN) are still lacking a consistent and universally recognized standardization. Furthermore, many issues concerning diagnosis, prediction and prevention of PHN need to be clarified in view of recent contributions. OBJECTIVES: To assess whether PHN may be better defined, predicted, treated and prevented in light of recent data, and whether available alternative or adjunctive therapies may improve pain relief in treatment recalcitrant PHN. METHODS: Systematic reviews, meta-analyses, randomized controlled trials, cohort studies and protocols were searched; the search sources included PubMed, Cochrane Library, NICE, and DARE. More than 130 papers were selected and evaluated. RESULTS: Diagnosis of PHN is essentially clinical, but it can be improved by resorting to the many tools available, including some practical and accessible questionnaires. Prediction of PHN can be now much more accurate, taking into consideration a few well validated clinical and anamnestic variables. Treatment of PHN is presently based on a well characterized array of drugs and drug associations, including, among others, tricyclic antidepressants, gabapentinoids, opioids and many topical formulations. It is still unsatisfactory, however, in a substantial proportion of patients, especially those with many comorbidities and intense pain at herpes zoster (HZ) presentation, so that this frequent complication of HZ still strongly impacts on the quality of life of affected patients. CONCLUSION: Further efforts are needed to improve the management of PHN. Potentially relevant interventions may include early antiviral therapy of acute HZ, prevention of HZ by adult vaccination, as well as new therapeutic approaches for patients experiencing PHN.

Acupuncture for the treatment of severe acute pain in herpes zoster: results of a nested, open-label, randomized trial in the VZV Pain Study.

BACKGROUND: Data on the potential efficacy of acupuncture (AC) in controlling intense or very intense pain in patients with Herpes Zoster (HZ) has not been so far adequately assessed in comparison with standard pharmacological treatment (ST) by a controlled trial design. METHODS: Within the VZV Pescara study, pain was assessed in HZ patients on a Visual Analogue Scale (VAS) and by the McGill Pain Questionnaire (MPQ) both at the beginning and at the end of treatment. Response rates, mean changes in pain intensity, differences in total pain burden with an area-under-the-curve (AUC) method over a 1-year follow-up and differences in the incidence of Post-Herpetic Neuralgia (PHN) were evaluated. RESULTS: One hundred and two patients were randomized to receive either AC (n = 52) or ST (n = 50) for 4 weeks. Groups were comparable regarding age, sex, pain intensity at presentation and missed antiviral prescription. Both interventions were largely effective. No significant differences were observed in response rates (81.6% vs 89.2%, p = 0.8), mean reduction of VAS (4.1 +/- 2.3 vs 4.9 +/- 1.9, p = 0.12) and MPQ scores (1.3 +/- 0.9 vs 1.3 +/- 0.9, p = 0.9), incidence of PHN after 3 months (48.4% vs 46.8%, p = 0.5), and mean AUC during follow-up (199 +/- 136 vs 173 +/- 141, p = 0.4). No serious treatment-related adverse event was observed in both groups. CONCLUSIONS: This controlled and randomized trial provides the first evidence of a potential role of AC for the treatment of acute herpetic pain. TRIAL REGISTRATION: ChiCTR-TRC-10001146.

Tinea incognito Caused by Microsporum gypseum in a Patient with Advanced HIV Infection: A Case Report.

The prevalence and the clinical relevance of dermatophytoses in HIV-infected patients are poorly documented, particularly for those caused by tinea incognito. Here, we report a case of widespread facial tinea incognito occurring in an Italian patient with advanced HIV infection, showing both skin and brain lesions. Second-line treatment with liposomal amphotericin B and cotrimoxazole, administered after a microbiological characterization of the skin scrapings, led to complete clearance of all lesions.

Predictors of pain intensity and persistence in a prospective Italian cohort of patients with herpes zoster: relevance of smoking, trauma and antiviral therapy.

BACKGROUND: Herpes zoster (HZ) is a common disease, characterized by rash-associated localized pain. Its main complication, post-herpetic neuralgia (PHN), is difficult to treat and may last for months to years in the wake of rash resolution. Uncertainties remain as to the knowledge of predictors of HZ-related pain, including the role of antiviral therapy in preventing PHN in ordinary clinical practice. This prospective cohort study was aimed at investigating pain intensity at HZ presentation and its correlates, as well as the incidence of PHN and its predictors. METHODS: Patients diagnosed with HZ were consecutively enrolled by a network of Italian General Practitioners and Hospital Units in the health district of Pescara, Italy, over two years. Uncertain cases were referred for microbiological investigation. Data were collected through electronic case report form (e-CRFs) at enrollment and at 1, 3, 6 and 12 months after enrollment. Pain intensity was coded on a five-degree semi-quantitative scale at each time point. PHN was defined as pain of any intensity during follow-up and quantified using an area-under-the-curve (AUC) method. RESULTS: Four hundred and forty-one patients composed the final sample. Mean age was 58.1 years (SD = 20.4 years); 43.5% of patients were males; 7.9% did not receive prescription of antivirals. Intense/very intense pain at presentation was reported by 25.2% of patients and was significantly associated with female gender, older age, cigarette smoking, trauma and/or surgery at HZ site (logistic regression). PHN was diagnosed in 51.2% of patients at one month and in 30.0% of patients at three months. PHN was significantly associated with pain intensity at presentation, age, smoking, trauma and missed antiviral prescription (generalized estimating equations model). The same factors were also independent predictors of the overall pain burden as described by the AUC method (linear regression). CONCLUSIONS: Smoking, traumas and surgery at the HZ site emerged as new predictors of both HZ-related pain intensity and persistence, opening new perspectives in the prevention of HZ-related pain. An independent line of evidence was provided for the efficacy of antiviral therapy in preventing PHN and reducing total pain burden.

Rapidly progressive and fatal EBV-related encephalitis in a patient with advanced HIV-1 infection at presentation: a case report and review of the literature.

Epstein-Barr virus (EBV) has been associated with primary central nervous system lymphoma and other EBV-related malignancies in HIV infected patients, and detection of EBV DNA in cerebrospinal fluid (CSF) by polymerase chain reaction (PCR) has been demonstrated to be a good marker of PCNSL. Conversely, EBV has been rarely associated with encephalitis in HIV patients. Here we describe for the first time the case of an HIV-infected, late presenter Caucasian man, diagnosed with a rapidly progressive diffuse encephalitis at presentation. A very high viral load for EBV was detected in CSF by PCR. The patient died 12 days after the onset of encephalitis in spite of supportive, antiviral and antiretroviral therapy. Our experience would suggest that in profoundly immunosuppressed HIV patients EBV may cause severe encephalitis in the absence of lymphoproliferative disorders.

Rapid prediction of sustained virological response in patients chronically infected with HCV by evaluation of RNA decay 48h after the start of treatment with pegylated interferon and ribavirin.

The combination of pegylated interferons (PEG-IFNs) and ribavirin represents the standard of care for the treatment of chronic HCV-infected patients, yet with a success rate around 50% in genotypes 1 and 4, high costs and side effects. Therefore, early prediction of sustained virological response (SVR) is a relevant issue for HCV-patients. We evaluated the association between SVR and decline of HCV-RNA at 48h in a prospective cohort of 145 HCV-patients treated with PEG-IFNs and ribavirin (males=69.1%; genotypes 1/4=51.0%; HIV-1 coinfected=6.7%). SVR was obtained in 65.5% of patients, while 16.6% experienced relapse and 17.9% no response. The first-phase of HCV-RNA decline clearly differentiated patients with SVR from relapsers and non-responders, independently of genotype (P<0.001). In univariate and multivariate analyses, different infralogaritmic thresholds of HCV-RNA decay at 48h were tested, observing the highest predictive potential at 0.5log: decays above this threshold showed a 76.2% negative predictive value for SVR, whereas decays >0.5log indicated a 6.8 odds ratio (95% C.I.: 2.0-23.2) for SVR after controlling for genotype, baseline viremia, adherence to therapy and HIV coinfection. Decays beyond the 0.5log threshold were also strongly associated with and highly predictive of early virological response (95.0% positive predictive value, P<0.001).

Fatal reactivation of HBV and HDV during a long-lasting interruption of HAART in a patient co-infected with HIV, HCV, HBV and HDV.

Coinfection by the Human Immunodeficiency Virus (HIV) and hepatitis viruses is a frequent condition in drug addicts. In the present study we report on the case of a patient with a history of drug and alcohol abuse who was sequentially infected with HIV, HCV, HBV and HDV. He died of an overwhelming reactivation of HBV and HDV in spite of a recent interferon treatment. HBV and HDV resumed their active replication after over 20 years of complete latency, that is after long-lasting viral undetectability, when the patient deliberately discontinued his last HAART regimen. HBV and HDV reactivated in spite of a relatively preserved immune system and a recent immune stimulatory treatment with pegylated interferon.