Direct-acting antivirals in hepatitis C virus (HCV)-infected and HCV/HIV-coinfected patients: real-life safety and efficacy.

OBJECTIVES: Clinical trials of all-oral direct-acting antivirals (DAAs) for chronic hepatitis C virus (HCV) infection reported high response rates in HCV/HIV coinfection, similar to those obtained in HCV monoinfection. We evaluated the safety and efficacy of these regimens in a clinical practice setting. METHODS: In this prospective observational study, all the HCV-monoinfected and HCV/HIV-coinfected patients undergoing HCV treatment with all-oral DAA regimens in a routine clinical setting from December 2014 to December 2015 were included in the analysis. Sustained virological response 12 weeks after the end of therapy (SVR12) and reported adverse events (AEs) were evaluated. Resistance-associated variants (RAVs) were analysed in a subgroup of patients at baseline and at the time of viral rebound in those with virological failure. RESULTS: One-hundred and nine patients (51 HCV-infected and 58 HCV/HIV-coinfected) were enrolled in the study. Sixty per cent had cirrhosis and 52% were pegylated interferon and ribavirin (pegIFN/RBV)-experienced. Thirty-six per cent received ombitasvir + paritaprevir/ritonavir + dasabuvir, 25% sofosbuvir + daclatasvir, 16% sofosbuvir + simeprevir, 17% sofosbuvir + ribavirin and 6% sofosbuvir + ledipasvir; ribavirin was used in 57% of subjects. The SVR12 rate was 91% and 96% in HIV-infected and uninfected patients, respectively (P = 0.44). The 4-week HCV viral decline was similar in the two groups. RAVs were found at baseline in 23 of 49 patients and did not affect SVR12. No predictors of SVR12 were identified in our cohort. CONCLUSIONS: Treatment with all-oral DAA combinations of patients infected with HCV and with HCV/HIV under real-life conditions led to high and similar rates of SVR12. Moreover, the historical factors associated with a sustained virological response to pegIFN/RBV were not predictive of the response to all-oral DAAs.

Odontomas: review of the literature and case reports.

Odontomas are one of the most common Odontogenic Tumors of the jaw. The exact etiology of odontomas is unknown. Histologically they are composed of various formations of dental tissue (enamel, dentin, cementum and sometimes pulp). In the WHO classification, they are divided into complex odontoma and compound odontoma. Clinically, odontomas are generally asymptomatic and only in rare cases cause swelling, pain, suppuration or bony expansion. Radiologically, the tumor is initially lucent, but with time, it develops small calcifications, which eventually coalesce to form a radiodense lesion with a lucent rim. Surgical resection is the treatment of choice and there is no recurrence. The aim of this paper is to define the principal characteristics and the treatment of these lesions, based on literature and personal experience.

A martial arts injury: karate induced unilateral haematoma of the adrenal gland.

Adrenal gland haematoma is often a complication of traumatic events. The case is reported of a 45 year old man with unilateral non-symptomatic adrenal gland haematoma caused by a trauma during martial arts practice.

High frequency of non-Hodgkin's lymphoma in patients with HIV-associated Kaposi's sarcoma.

OBJECTIVE: To evaluate, with the support of autopsy findings, the frequency of non-Hodgkin's lymphoma (NHL) among patients with AIDS-associated Kaposi's sarcoma (KS) in comparison with that of AIDS patients with other AIDS-defining diseases. METHODS: The study involved 363 consecutive patients with AIDS who were cared for and died at the Clinic of Infectious Diseases in Milan between May 1984 and December 1992. Clinical records and autopsy data of all of the patients were retrospectively reviewed. Kaplan-Meier product-limit estimates of the time to the development of NHL were calculated for all patients and by specific subgroups. Cox proportional hazards analyses were made to determine the factors associated with the development of NHL. RESULTS: In the majority of cases (82%), KS was diagnosed during life, whereas NHL was diagnosed before death in only 41.6% of cases. Taking the autopsy data into account, the cumulative incidence of the two tumours was 16.8% for KS and 16.5% for NHL. Among the 61 patients in whom KS was the index disease of AIDS, 16 also developed NHL. The probability of developing NHL was significantly higher in patients with KS at AIDS diagnosis than in patients with Pneumocystis carinii pneumonia (PCP), oesophageal candidiasis or other AIDS-related diseases (P = 0.004). Multivariate analysis of the factors associated with the development of NHL (such as sex, age, risk factors, AIDS-defining diseases and CD4+ cell counts) showed that the patients with KS as the index disease of AIDS had a 5.3-fold higher risk of developing NHL than the patients with PCP as the primary manifestation of AIDS. CONCLUSIONS: Our results confirm the higher incidence of malignant lymphoma in patients with AIDS-KS than in patients with other AIDS-related diseases. The importance of autopsy in assessing these data is underlined by the high percentage of NHL diagnosed only after death. These observations may support the hypothesis of a common aetiological agent, or of a common pathway, for the two neoplasms.

Polymerase chain reaction for Toxoplasma gondii DNA in the cerebrospinal fluid of AIDS patients with focal brain lesions.

OBJECTIVE: To study the accuracy of polymerase chain reaction (PCR) for Toxoplasma gondii DNA in the cerebrospinal fluid (CSF) of AIDS patients for the diagnosis of T. gondii encephalitis. PATIENTS: Eighty-two AIDS patients with brain lesions. At autopsy, 19 patients (group A) had toxoplasmic encephalitis and 33 (group B) primary brain lymphoma or other infections. Brain histology was not available for 30 patients; cerebral lesions improved after anti-Toxoplasma therapy in 16 (group C), but there was no improvement in 14 patients (group D). METHODS: T. gondii RH strain was serially diluted in microplate wells. After heat denaturation, nested PCR was performed on diluted tachyzoites and on 10 microliters CSF with primers flanking the B1 repetitive region of T. gondii genome. RESULTS: DNA from one to five tachyzoites was detected in each experiment. PCR was positive in eight (42.1%) out of 19 group A samples, none of the group B samples, 10 (62.5%) out of 16 group C samples and none of the group D samples. Among group A and C patients, PCR was positive in all 11, and in seven out of 24 (29.1%; P < 0.04) patients who had received anti-Toxoplasma therapy for less or more than 1 week at the time of rachicentesis, respectively. CONCLUSIONS: Nested PCR for T. gondii in CSF may improve early differential diagnosis of AIDS-associated focal brain lesions. Higher diagnostic accuracy was achieved when lumbar puncture was performed in the first week of anti-Toxoplasma therapy.

Redistribution of body fat in HIV-infected women undergoing combined antiretroviral therapy.

OBJECTIVES: To investigate the prevalence, metabolic features and risk factors of a particular pattern of fat redistribution (FR), characterized by a progressive enlargement of breast and abdominal girth associated with a wasting of the lower limbs, observed in HIV-infected women treated with combined antiretroviral (ARV) therapy. DESIGN: Cross-sectional study. SETTING: Outpatients attending the Institute of Infectious Diseases, University of Milan, Milan, Italy. PATIENTS AND METHODS: HIV-infected women treated with two or more ARV drugs, observed between December 1997 and February 1998. FR was confirmed by means of a physical examination and dual-energy X-ray absorptiometry (DEXA). The metabolic and endocrinological measurements in patients with FR were compared with those in FR-free women. RESULTS: FR was observed in 32 out of 306 women (10.5%). DEXA revealed more trunk fat (P < 0.01) and less leg fat (P < 0.001) in the patients with FR than in the matched controls. There were no significant differences in laboratory test results between the two groups. All of the FR patients were taking lamivudine-containing regimens; 20 of them were also taking a protease inhibitor (PI). The association of FR with lamivudine-including regimens was statistically significant (P = 0.017). Among the patients taking lamivudine, the risk associated with treatments including PI was 1.8 (95% CI 0.8-3.8, P = 0.12). A total duration of ARV therapy of more than 1000 days was associated with a greater risk of developing FR (OR 10.8; 95% CI 1.4-80.5; P = 0.0207). Stepwise logistic regression analyses indicated that prolonged ARV therapy and a viral load of more than 10000 copies per ml at the beginning of the last ARV regimen were the only variables that significantly and independently correlated with the risk of FR. CONCLUSIONS: The observed body modifications are caused by a redistribution of body fat without fat loss that is apparently not associated with hyperlipidemia, altered glucose metabolism or other endocrinological disorders. The development of FR in patients receiving only reverse transcriptase (RT) inhibitors suggests the presence of a PI-independent mechanism that deserves further investigation.

Man-to-woman sexual transmission of HIV: longitudinal study of 343 steady partners of infected men.

To study incidence and risk factors of heterosexually transmitted HIV infection, we followed a cohort of 343 seronegative women, stable, monogamous partners of infected men whose only risk of acquiring HIV was sexual exposure to the infected partner. Nineteen seroconversions occurred in 529.6 person years (py) of observation, yielding an incidence rate of 3.6 per 100 py. The incidence rate was 7.2 per 100 py among women who did not always use or never used condoms and 1.1 among those who always used them [relative risk (RR) 6.6, 95% confidence interval (CI) 1.9-21.9]. Anal sex was associated with a risk increase in only those women not always using condoms (RR 1.4, 95% CI 0.4-4.8). No seroconversions were observed among 22 women using oral contraceptives. One of the women using intrauterine devices seroconverted. In couples who did not always use condoms, seroconversions occurred more frequently in partners of men with symptomatic diseases, with a low CD4+ cell number (< 400 per mm3) or with a detectable p24 antigen. In couples not always using condoms and where the man had a low CD4+ cell count, the joint presence of blood viral antigens and AIDS symptoms conditioned a fivefold increased risk of seroconversion of the woman (RR 5.4, CI 1.4-20.3). At multivariate analysis, women with longer relationships (> or = 1 year) showed a lower risk of seroconversion (RR 0.3, CI 0.1-0.8), and those partners of men positive for p24 antigen in serum had an increased risk of seroconversion (RR = 4.0, CI 0.1-0.8).

Cardiovascular disease risk factors in HIV-infected patients in the HAART era.

HIV infection is accompanied by disturbances in lipid and glucose metabolism, which are further compounded by changes induced by antiretroviral drugs. There is increasing concern that these changes will lead to an epidemic of cardiovascular disease. Cardiovascular disease will no doubt increase, but current data indicate that the average absolute levels are likely to remain low, although patients with additional risks (smoking, hypertension, diabetes, age, family history, etc.) are certainly more susceptible. The complications of therapy need to be taken into account when deciding on the time of treatment, and reducing risk factors should become a routine aspect of the care of an HIV population that now lives longer as a result of highly active antiretroviral therapy.

Fat redistribution in HIV-infected patients. A new hormonal-immune disorder?

Multidrug antiretroviral regimes in HIV-infected patients may have side effects. The most frequent side effects are changes in fat metabolism and distribution. We describe a particular pattern of fat redistribution (FR), characterized by a progressive enlargement of breast and abdominal girth and fat loss in the lower limbs, which occurs in approximately 10% of HIV-infected women treated with combined antiretroviral therapy. To elucidate the metabolic, endocrine, and immunologic consequences of the observed disturbance, we measured serum lipids, glucose, C-peptide, ACTH, plasma, urinary cortisol, and cytokines IL-2, IFN gamma, Il-4, IL-10, Il-12, and TNF alpha in 36 patients with FR and in a control group without FR. There were no significant differences in hormonal and metabolic laboratory testing between the two groups. Immunology studies showed that in vitro production of TNF alpha and IL-10 was lower and IL-12 production higher in SR patients. Whether or not such immune alterations may be reponsible or be caused by fat redistribution remains to be explained. One year after the follow up, 50% of the patients treated with triple therapy developed lipodystrophy, characterized by weight loss, face-wasting, and hyperglycemia; the remaining 50% remained unchanged. In 13 patients the 3TC withdrawal was followed by improvements of the syndrome in 50% and of lipodystrophy in about 25%. These data suggest that the FR syndrome is frequent in patients treated with 3TC and that it is associated with characteristic changes in the cytokine production.

Immunoendocrinologic abnormalities in human immunodeficiency virus infection.

Alterations in the production of adrenal steroids and a complex pattern of dysregulation in cytokine profiles accompany the progression of HIV infection. Cortisol levels increase in HIV infection, while those of dehydroepiandrosterone (DHEA), a physiologic antagonist of the immunoregulatory activities of cortisol, decrease. A shift from type-1 to type-2 cytokine production is also detected in most patients during disease progression. This shift is summarized as a defective production of interferon gamma (IFN gamma), interleukin-2 (IL), and IL-12 accompained by increased production of IL-4, IL-5, IL-6, and IL-10. IFN gamma and IL-2 are suppressed, while the generation of IL-4 is stimulated by cortisol and pharmacological doses of glucocorticoids (GC). GC and IL-4 stimulate the differentiation of B lymphocytes into IgE-producing plasma cells, the concentration of which augments in HIV infection. Finally, GC induces programmed cell death (PCD) in a variety of different cells, including mature T lymphocytes. Because (1) TH1 but not TH2 undergo rapid Fas-mediated PCD upon antigen-stimulation, and (2) TH2 clones preferentially survive in vitro cell cultures, the progressive shift from type-1 to type-2 cytokine production observed in HIV infection could be at least partially provoked by the increase in the production of cortisol and the reduction of DHEA. Progression of HIV infection to AIDS can be controlled by highly active antiretroviral therapy (HAART); HAART drastically reduces HIV plasma viremia, but is less effective in immune reconstitution. Additionally HAART is associated in a sizable portion of patients by complex lypodistropyc phenomena that often involve the endocrine system.

A comparison of brain biopsy and CSF-PCR in the diagnosis of CNS lesions in AIDS patients.

Twenty patients with AIDS who had intracranial lesions underwent both brain biopsy and cerebrospinal fluid (CSF) examination to compare histological diagnosis with the polymerase chain reaction (CSF-PCR) for the identification of infectious agents. CSF-PCR was performed for herpes simplex virus, varicella zoster virus, cytomegalovirus (CMV), JC virus (JCV), Epstein-Barr virus (EBV), Toxoplasma gondii and Mycobacterium tuberculosis. A definitive diagnosis was obtained by brain biopsy in 14 patients (2 with astrocytoma, 12 with brain infection). CSF-PCR was positive for EBV DNA in 3 of 3 cases of primary cerebral lymphoma, positive for JCV DNA in 6 of 7 biopsy-proven (and one autopsy-proven) cases of progressive multifocal leukoencephalopathy (PML). CSF-PCR was positive for CMV DNA in one biopsy-proven and one autopsy-proven case of CMV encephalitis (the former also had PML) and positive for M. tuberculosis DNA in one case of tuberculous encephalitis. None of the five toxoplasmic encephalitis cases (one definite, four presumptive) were T. gondii DNA positive. There was close correlation between histology and CSF-PCR for CMV encephalitis, PML and PCL. Antitoxoplasma therapy affected the sensitivity of both histological and CSF-PCR methods.

Post-kala-azar dermal leishmaniasis during highly active antiretroviral therapy in an AIDS patient infected with Leishmania infantum.

We report a case of post-kala-azar dermal leishmaniasis (PKDL) in a woman with AIDS which occurred 13 months after a diagnosis of visceral leishmaniasis concomitantly with immunological recovery induced by highly active retroviral therapy. Cytokine pattern at the time of visceral leishmaniasis and PKDL diagnosis was studied and pathogenic implications were discussed.

Body habitus alterations in HIV-infected women treated with combined antiretroviral therapy.

Fat distribution alterations are among the most frequent and unexpected side effects of combined antiretroviral therapy. They may occur in patients receiving protease inhibitor-containing regimens and those treated with combinations of only nucleoside reverse transcriptase inhibitors. The broad spectrum of body fat alterations, which are variably associated with metabolic abnormalities, raises the question as to whether they represent different components of the same syndrome or are manifestations of different pathogenetic mechanisms. Recent clinical evidence is consistent with a higher risk of developing body fat alterations in females. We here report three different aspects of body habitus changes in women treated with various antiretroviral regimens and describe their short-term follow-up. We also discuss the possible pathogenetic implications and the role of different drug classes according to present knowledge.

[Not Available]. / Toxoplasmosi cerebrale nella sindrome da immunodeficienza acquisita.

UNLABELLED: Toxoplasmic encephalitis (TC) is the most common opportunistic infection of the Central Nervous System (CNS) in patients with the acquired immunodeficiency syndrome (AIDS). In order to investigate its clinical course, we reviewed the records of 133 patients with AIDS and central nervous system (CNS) toxoplasmosis treated at the Clinic of Infectious Diseases, University of Milan, between 1987 and 1992. The most common presenting symptoms were headache, confusion, disorientation and fever. Focal neurologic deficits were present in more than half of cases. Median CD4+ cell count at presentation was 65 per cubic millimeter. 25 (19%) out of 133 patients diagnosed with TC had undetectable anti-T. gondii IgG antibodies using an Elisa technique. Enhancing lesions on Computered Tomography (CT) were demonstrated in 119 (90%) patients. Solitary lesions were present in 26 cases; edema was evident in 19 patients. A complete clinica! and neuroradiological improvement after the acute episode was obtained in 126 (95%) of the cases. Adverse drug reactions occurred in 40 (30%) cases. Relapses occurred in 18/92 patients after a median time of 6 months. IN CONCLUSION: TC occurs in advanced stages of human immunodeficiency syndrome, and the absence of anti-T.gondii antibodies does not exclude the diagnosis. The clinical and radiographic response to therapy is usually rapid, but long-term treatment is frequently limited by adverse drug effects.

Prevalence and factors associated with idiopathic hypercalciuria in HIV patients on combination antiretroviral therapy.

Idiopathic hypercalciuria may lead to bone loss via three pathogenic mechanisms described in HIV-negative patients: intestinal hyperabsorption, kidney loss and bone hyperabsorption. We conducted a cross-sectional study in a cohort of 217 HIV-positive antiretroviral-experienced patients, identifying hypercalciuria in 67 patients: the prevalence was 30.9% (95% confidence interval 27.4-37.0). The occurrence of hypercalciuria in subjects with normal values of parathormone may indicate an absorptive form of hypercalciuria. In this sample, other bone turnover markers and T-scores were not related to the condition. The results of this study show a high prevalence of idiopathic hypercalciuria in a group of antiretroviral-experienced patients. The consequences and the exact causes of this metabolic complication are not yet known and further investigation is needed.

First Italian consensus statement on diagnosis, prevention and treatment of cardiovascular complications in HIV-infected patients in the HAART era (2006).

The present document contains recommendations for assessment, prevention and treatment of cardiovascular risk for HIV-infected patients. All recommendations were graded according to the strength and quality of the evidence and were voted on by 73 members of the Italian Cardiovascular Risk Guidelines Working Group which includes both experts in HIV/AIDS care and in cardiovascular and metabolic medicine. Since antiretroviral drug exposure represents only one risk factor, continued emphasis on an integrated management is given. This should include prevention and treatment of known cardiovascular risk factors (such as dyslipidaemia, diabetes, insulin resistance, healthy diet, physical activity, avoidance of smoking), but also rational switch of antiretroviral drugs. A rational switch strategy should consider both metabolic and anthropometric disturbances and effectiveness of antiretroviral regimens.