First-line antiretroviral therapy with efavirenz plus tenofovir disiproxil fumarate/emtricitabine or rilpivirine plus tenofovir disiproxil fumarate/emtricitabine: a durability comparison.

OBJECTIVES: The aim of this study was to compare the durabilities of efavirenz (EFV) and rilpivirine (RPV) in combination with tenofovir/emtricitabine (TDF/FTC) in first-line regimens. METHODS: A multicentre prospective and observational study was carried out. We included all patients participating in the Italian Cohort Naive Antiretrovirals (ICONA) Foundation Study who started first-line combination antiretroviral therapy (cART) with TDF/FTC in combination with RPV or EFV, with a baseline viral load < 100 000 HIV-1 RNA copies/mL. Survival analyses using Kaplan-Meier (KM) curves and Cox regression with time-fixed covariates at baseline were employed. RESULTS: Overall, 1490 ART-naïve patients were included in the study, of whom 704 were initiating their first cART with EFV and 786 with RPV. Patients treated with EFV, compared with those on RPV, were older [median 36 (interquartile range (IQR) 30-43) years vs. 33 (IQR 27-39) years, respectively; P < 0.001], were more frequently at Centers for Disease Control and Prevention (CDC) stage C (3.1% vs. 1.4%, respectively; P = 0.024), and had a lower median baseline CD4 count [340 (IQR 257-421) cells/µL vs. 447 (IQR 347-580) cells/µL, respectively; P < 0.001] and a higher median viral load [4.38 (IQR 3.92-4.74) log10 copies/mL vs. 4.23 (IQR 3.81-4.59) log10 copies/mL, respectively], (P = 0.004). A total of 343 patients discontinued at least one drug of those included in the first cART regimen, more often EFV (26%) than RPV (13%), by 2 years (P < 0.0001). After adjustment, patients treated with EFV were more likely to discontinue at least one drug for any cause [relative hazard (RH) 4.09; 95% confidence interval (CI) 2.89-5.80], for toxicity (RH 2.23; 95% CI 1.05-4.73) for intolerance (RH 5.17; 95% CI 2.66-10.07) and for proactive switch (RH 10.96; 95% CI 3.17-37.87) than those starting RPV. CONCLUSIONS: In our nonrandomized comparison, RPV was better tolerated, less toxic and showed longer durability than EFV, without a significant difference in rates of discontinuation because of failures.

Two different patterns of mutations are involved in the genotypic resistance score for atazanavir boosted versus unboosted by ritonavir in multiple failing patients.

OBJECTIVES: The protease inhibitor atazanavir (ATV) can be used either boosted by ritonavir (ATV300/r) or unboosted (ATV400). To date, however, genotypic resistance scores (GRSs) have been developed only for boosted-ATV. We have determined GRS associated with virologic response (VR) for both ATV300/r and ATV400 in highly pre-treated HIV-1 infected patients. PATIENTS AND METHODS: We analyzed the results of genotypic tests available 0-3 months before the initiation of an ATV-containing regimen in 159 patients with HIV-RNA >or= 500 copies/ml (ATV300/r group: 74; ATV400 group: 85) who were enrolled in the CARe study through an Early Access Program. The impact of baseline protease mutations on VR (>or= 1 log(10)copies/ml HIV-RNA decrease at 12-24 weeks) was analyzed using Fisher's exact test. Mutated protease amino acid positions (MPP) with p < 0.20 were retained for further analysis. The GRSs were determined by a step-by-step analysis using the chi(2) test for trend. RESULTS: The GRSs for ATV300/r and ATV400 revealed differing sets of mutations. For ATV300/r, 12 MPPs (10C/I/V + 32I + 34Q + 46I/L + 53L + 54A/M/V + 82A/F/I/T + 84V + 90M - 15E/G/L/V - 69K/M/N/Q/R/T/Y - 72M/ T/V; p = 1.38 x 10(-9)) were the most strongly associated with VR (VR: 100%, 78.3%, 83.3%, 75% and 0% of patients with a score of -2/-1, 0, 1, 2, and >or= 3, respectively); the last three MPPs (I15/H69/I72) were associated with a better VR. For ATV400, nine MPPs (16E + 20I/M/R/T/V + 32I + 33F/I/V + 53L/Y + 64L/M/ V + 71I/T/V + 85V + 93L/M; p = 9.42 x 10(-8)) were most strongly associated with VR (VR: 83.3%, 66.7%, 5.9%, 0% of patients with 0, 1/2, 3, and >or= 4 MPP, respectively). Differences between GRSs for ATV300/r and ATV400 may be due to different ATV drug levels (boosted vs unboosted), favoring different pathways of escape from antiviral pressure. CONCLUSIONS: Both GRSs were independent predictors of response in a multivariable logistic regression model. Nevertheless, cross-validation of these GRSs on different patient databases is required before their implementation in clinical practice.

Depression and the existential domain in the assessment of quality of life in HIV outpatients with the McGill questionnaire.

AIM: The aim of the present study was to further test criterion validity and factorial validity of the McGIll Quality Of Life (MQOL) questionnaire, and to assess its reliability and sensitivity to clinical change in outpatients with HIV infection. METHODS: The authors present a longitudinal study on a consecutive sample of 216 adults treated with HAART at the outpatient facility of an hospital-based tertiary care center in Italy. Patients completed the MQOL and the Beck Depression Inventory (BDI) both at baseline and follow-up assessments. Patients were classified into subgroups (improved, unchanged, worsened) based on change in BDI scores or CD4 count over time. RESULTS: The pattern of correlation between MQOL subscales and the BDI was as hypothesised. A fairly simple factor structure emerged, with a striking resemblance between the factors and the MQOL subscales. The internal consistency of the MQOL and its subscales was high. The test-retest reliability in clinically unchanged patients was satisfactory. Sensitivity to change, as measured by Guyatt responsiveness statistic, was also satisfactory. CONCLUSIONS: This study contributed to building evidence of reliability and validity for the MQOL questionnaire, which may be particularly useful to assess the so-called "existential" aspects of QOL that are particularly relevant for patients infected with HIV.

[Imported dengue in two tertiary Italian hospitals: Use of rapid diagnostic tests]. / Dengue importée dans deux hôpitaux tertiaires en Italie : utilisation des tests de diagnostic rapides.

Dengue fever is growing at a global level both as number of cases and as geographic area of endemicity. Italy is not in endemic area, but the competent vector Aedes albopictus is widespread in this country, so that the possibility of introduction of the infection cannot be ruled out. We retrospectively collected demographic, clinical, and laboratory data about consecutive cases diagnosed in Torino and Negrar-Verona in the period 2010-2015. One hundred thirteen cases of dengue were observed, with an increasing trend during years. The infection was imported mostly from south-east Asia, but the risk appears to be higher in Latin America. More than half of the patients were admitted to the hospital but only one case of severe dengue was observed. Many patients presented after the resolution of symptoms. Rapid diagnostic tests were done in the majority of patients and allowed a diagnosis both in the acute (NS1 antigen) and convalescent (IgMantibodies) phases of the disease. An early diagnosis is paramount to avoid the spreading of the infection.

Increased risk of virologic failure to the first antiretroviral regimen in HIV-infected migrants compared to natives: data from the ICONA cohort.

Migrant and Italian HIV-infected patients (n = 5773) enrolled in the ICONA cohort in 2004-2014 were compared for disparities in access to an initial antiretroviral regimen and/or risk of virologic failure (VF), and determinants of failure were evaluated. Variables associated with initiating antiretroviral therapy (ART) were analysed. Primary endpoint was time to failure after at least 6 months of ART and was defined as: VF, first of two consecutive virus loads (VL) >200 copies/mL; treatment discontinuation (TD) for any reason; and treatment failure as confirmed VL >200 copies/mL or TD. A Poisson multivariable analysis was performed to control for confounders. Migrants presented significantly lower CD4 counts and more frequent AIDS events at baseline. When adjusting for baseline confounders, migrants presented a lower likelihood to begin ART (odds ratio 0.80, 95% confidence interval (CI) 0.67-0.95, p 0.012). After initiating ART, the incidence VF rate was 6.4 per 100 person-years (95% CI 4.8-8.5) in migrants and 2.7 in natives (95% CI 2.2-3.3). Multivariable analysis confirmed that migrants had a higher risk of VF (incidence rate ratio 1.90, 95% CI 1.25-2.91, p 0.003) and treatment failure (incidence rate ratio 1.16, 95% CI 1.01-1.33, p 0.031), with no differences for TD. Among migrants, variables associated with VF were age, unemployment and use of a boosted protease inhibitor-based regimen versus nonnucleoside reverse transcriptase inhibitors. Despite the use of more potent and safer drugs in the last 10 years, and even in a universal health care setting, migrants living with HIV still present barriers to initiating ART and an increased risk of VF compared to natives.

Risk of developing AIDS after primary acute HIV-1 infection.

We enrolled 134 newly human immunodeficiency virus type 1 (HIV-1)-infected subjects in a prospective study to determine the natural history of the infection and evaluate the risk of developing AIDS after acute primary HIV-1 infection (API). Twenty-three patients were observed during an acute primary HIV-1 infection, and 111 were asymptomatic seroconverters. Acute primary HIV-1 infection was more frequently observed in subjects who had acquired the infection through sexual transmission. Intravenous drug users were rarely affected and presented with milder symptomatology. Patients observed with an acute primary HIV-1 infection had a significantly higher risk of developing AIDS than asymptomatic seroconverters (68% at 56 months vs. 20% at 66 months; p = 0.026). Low CD4+ cell counts at the onset of acute illness and delayed seroconversion in enzyme-linked immunosorbent assay (ELISA) were associated with evolution to AIDS in acute seroconverters (p = 0.03 and 0.02, respectively). During the follow-up, patients with an acute illness were more likely to show an early fall of CD4+ cell counts below 200/microliters than asymptomatic seroconverters. The results of this follow-up study suggest the opportunity to study antiviral treatment protocols in patients with API as a possible measure to control disease progression.

Acute HIV-1 infection: clinical and biological study of 12 patients.

We observed 12 patients with acute human immunodeficiency virus type 1 (HIV-1) infection. The clinical syndrome was characterized by fever (all cases), generalized lymphadenopathy (11), arthralgias and myalgias (9), sore throat (9), rash (7), splenomegaly (6), and other less frequent signs and symptoms. All patients had a spontaneous resolution of their symptoms within 5-30 days. Anti-HIV-1 serum antibodies, as measured by enzyme immunoassay (EIA) at the onset of clinical illness, were negative in every patient. HIV antigen (p24), on the contrary, was detectable in nine cases. Western blot IgM and IgG analysis was serially performed: IgMs were positive in nine cases and IgGs in three. The CD4+/CD8+ ratio was low in all patients because CD8+ were remarkably increased and CD4+ slightly reduced. A laterocervical lymph nodes biopsy was performed in four patients. The morphological and immunohistological pattern of the acute HIV-1-related lymphadenopathy did not correspond to any of the typical ones. The envelope virus protein gp120/160 was found in interfollicular and follicular lymphocytes, in endothelial cells, and in interdigitating and dendritic reticulum cells. The p17 and p24 core virus proteins were mainly detected in endothelial, interdigitating, and dendritic reticulum cells, but in only a few lymphocytes. The follow-up suggests a rapid evolution to ARC and AIDS in patients showing an acute symptomatic HIV infection.

Rapid diagnosis of malaria by use of fluorescent probes.

Malaria diagnosis relies on observation of parasites in blood smears and the Giemsa-stained thick blood smear (G-TS) is the reference test. Diagnosis by G-TS in low-density infections requires long periods of observation and experienced microscopists. Examination of Giemsa-stained thin smears enables more reliable differentiation of species but may miss low-grade infections. Fluorescent stains may offer an alternative technique. We compared the Giemsa technique with 4,6-diamidine-2-phenilindolo-propidium iodide (DAPI-PI) stainings in order to evaluate the time required for diagnosis. A Plasmodium falciparum-infected blood specimen was diluted to obtain concentrations ranging from 6192 to 24 parasites/microliters (p/microliter), and thin and thick smears were stained with the two methods. The DAPI-PI proved useful: parasites were easily recognized and their morphology was preserved in thin and thick smears. The method allowed more rapid evaluation of thin smears as compared with Giemsa staining and enabled recognition of parasites in case of low-level parasitemias. The DAPI-PI staining technique may acquire an important role in malaria diagnosis, especially in nonendemic countries where technicians are not experienced with G-TS; in developing countries, it could be used in epidemiologic surveys of populations with low-density parasitemias, for which it enables a fast examination of smears and possibly the identification of parasite species.

Evaluation of the immune response in visceral leishmaniasis.

Detection of parasites in culture or by microscopy is still necessary to make diagnosis of visceral leishmaniasis (VL). Serological methods still need assessment, as they are quick but not very sensitive, especially in immunosuppressed subjects. This paper compares the results obtained with three serological methods (indirect immunofluorescence test (IFAT), direct agglutination test (DAT), and enzyme-linked immunosorbent assay (ELISA) and the specific cell-mediated immune response, evaluated as proliferation and IFN-gamma production by peripheral blood lymphocytes (PBL) following stimulation with heat-killed L. infantum promastigotes. PBL and sera were obtained from 10 healthy donors, 3 VL patients in acute phase, and 3 patients recovering after two glucantim treatment courses. No false positive results were observed with the serological methods. IFAT can be considered the most sensitive and best suited for follow-up, as it allowed a good discrimination between the acute and remission phase. DAT did not discriminate between healthy donors and remission-phase patients, whereas ELISA is unsuited for follow-up, as it did not show any significant difference between remission- and acute-phase patients. Assessment of the cellular response is not recommended for making a diagnosis, because false positive results are frequent. However, a strong cellular response in a patient stands for a successful treatment. IFN-gamma titration is preferable to the proliferation test, because it gives earlier results and does not require the use of radioactive isotopes.

Detection of Pneumocystis carinii by DNA amplification in human immunodeficiency virus-positive patients.

The opportunistic pathogen Pneumocystis carinii (PC) is a frequent cause of a life-threatening pneumonia in human immunodeficiency virus (HIV)-infected individuals and in other immunocompromised hosts. Specimens obtained from 128 bronchoalveolar lavage (BAL) fluid samples from 123 HIV-positive patients with pulmonary disease and undergoing a diagnostic bronchoscopy were evaluated to detect this organism. We have developed a rapid DNA extraction procedure for nested polymerase chain reaction (PCR) using two sets of primers (pAZ102-E, pAZ102-H and P1 = 5'-CTAGGATATAGCTGGTTTTC-3' and P2 = 5'-TCGACTATCTAGCTTATCGC-3'). The results were compared using cytological techniques (direct wet mount, Giemsa, toluidine blue O) and related to the clinical follow-up of patients. The nested PCR had a 91% sensitivity and a 93% specificity. The effect of chemoprophylaxis and the evaluation of the follow-up of patients are discussed. Nested PCR may represent an important additional tool, along with current cytological methods, for the detection of P. carinii; however, at present it cannot replace routine microbiological methods more simple and less expensive.

Intestinal localization of anisakiasis manifested as acute abdomen.

Anisakis pathology is due mainly to two mechanisms: allergic reactions (from isolated urticaria and angioedema to life-threatening anaphylactic shock associated with gastrointestinal symptoms or 'gastroallergic anisakiasis'), and direct tissue damage, due to invasion of the gut wall, development of eosinophilic granuloma, or perforation (gastric or intestinal anisakiasis). Anisakiasis is a misdiagnosed and underestimated cause of acute abdomen: most patients undergo laparotomy, and virtually no cases are diagnosed before surgery. In some cases, diagnosis is obtained accidentally during other pathologic investigations. We report a case of acute abdomen due to terminal ileum involvement. Microscopic examination of the resected segment showed the presence of helminthic sections consistent with larvae of Anisakis spp. A history of raw fish ingestion was recorded. Histopathologic features are illustrated. A short but up-to-date review of the literature on diagnostic devices (particularly imaging and serology), clinical aspects and therapy is presented.

Severe and complicated Falciparum malaria in Italian travelers.

Imported malaria has been an important public health problem in Western countries in the last 20 years, since international travel has become an increasing habit for nonimmune populations and since chemoresistance to most antimalarial drugs has been spreading throughout the world. Moreover, immigration from African and Asian countries has been rapidly increasing, especially in Italy in the last few years. Malaria had been widespread in Italy in the past, but no new autochthonous cases have been reported since 1961. Nonetheless the number of reported cases throughout the country has been steadily growing because of imported malaria1-3 in nonimmune travelers as well as in immigrants from tropical countries. In our experience as well as according to other statistics, the vast majority of patients have Plasmodium falciparum malaria acquired in Africa.4,5 The clinical spectrum of this disease is wide, and severe cases are frequently observed, including a few fatal cases, which, although rare, are highlighted by mass media and impress the public opinion.5-8 The purpose of this study was to examine the clinical spectrum of malaria, with particular interest in severe falciparum malaria, and to define the frequency of this phenomenon and epidemiologic characteristics of patients who experience it as a life-threatening disease.

Intracellular protozoan infection in small intestinal biopsies of patients with AIDS. Light and electron microscopic evaluation.

Small intestinal biopsies of 21 patients with acquired immunodeficiency syndrome (AIDS) with light microscopic findings diagnostic or suspicious for parasite infection were investigated by transmission electron microscopy (TEM). TEM allowed us to identify and specify the genus and species of involved parasites in 16 out of the 21 cases: 7 Cryptosporidium parvum, 5 Enterocytozoon bieneusi and 4 Isospora belli. Cryptosporidium was easily identified on light microscopy (LM), and only slightly influenced by parasite burden in all the 7 cases; TEM confirmed LM diagnosis and made it possible to characterize the parasites as C. parvum. The identification of Microsporidium on LM in our cases was related to the burden of parasite; its presence was certainty identified in 2 cases and suspected in 3. TEM allowed to identify these parasites as E. bieneusi. Intracytoplasmic coccidia could be detected with certainly in semithin sections in all 4 cases, but TEM was always needed to specify the infectious agent as I. belli. In 5 cases the suspicious of protozoan infection on LM (3 microsporidia, 1 intracytoplasmic coccidia and 1 Cryptosporidium) was not confirmed by TEM. Our data suggest that TEM is an appropriate diagnostic tool in this field of pathology and necessary in most of the cases.

Human PBMC proliferative response to Leishmania infantum promastigotes is inhibited by anti-IFN-gamma mAb gamma 123.

PBMC from individuals both exposed and non-exposed to leishmaniae proliferative and produce interferon-gamma (IFN-gamma) following stimulation with Leishmania antigens. We studied the kinetics of the proliferative response of PBMC from non-exposed individuals and from patients recovering from visceral leishmaniasis due to Leishmania infantum, using heat-killed stationary-phase promastigotes of L. infantum as stimulating agent. The kinetics of both groups followed a similar temporal pattern, with higher values in the patient's group. Moreover, we observed that in both groups the activation was dose-dependently inhibited following the addition of gamma 123 anti-IFN-gamma monoclonal antibody. These results indicate the need for IFN-gamma in the activation process of PBMC induced by Leishmania antigens and stress the role of IFN-gamma in the immune response to leishmaniasis. The relevance of the elucidation of the immune response mechanism in human leishmaniasis for therapy and vaccination is briefly discussed.

Unusual eruption of cutaneous metastases from occult gastric carcinoma shortly after HIV-1 infection.

We report a case of eruptive metastases to the skin of the face and neck from a hitherto unknown gastric carcinoma, occurring in a fifty-two-year-old man (a regular blood donor), about six months after he contracted human immunodeficiency virus-1 infection. The eruption, consisting of more than thirty pea-sized cutaneous nodules appeared within about twenty days. The patient complained of epigastric pain and weight loss. Histologic examination showed signet-ring cells of gastric carcinoma metastases. Gastroscopic examination showed a widely infiltrating tumor. No metastases were found elsewhere after a careful screening. Immunologic variables were only slightly altered. This case and a brief review suggest that gastric carcinomas, possibly as well as other coincidental tumors, may present atypically during human immunodeficiency virus-1 infection.

[Imported cases of malaria in Italy 1974-1979]. / Osservazioni sui casi di importazione di malaria in Italia dal 1974 al 1979.

Malaria is not present in Italy in autochthonous form although cases contracted where the disease is endemic are appearing with ever greater frequency. 767 cases, all imported, were reported to the Ministry of Health between '74 and '79. The number of reports, which is increasing steadily and actually doubled from '76 to '77, is examined here in relation to the age of patients, their work and the aetiological agent. Stress is laid on the epidemiological importance of putting into effect all those measures aimed at preventing an ever greater number of patients from malarial zones reactivating an endemic type of infection transmission in Italy, where an anopheles vector is present.

[Multiple cutaneous leishmaniasis after a stay in Central America]. / Leishmaniosi cutanea a lesioni multiple dopo un soggiorno in America Centrale.

Leishmaniasis is a protozoal disease affecting at least 12 millions persons, with 400,000 new cases per year. It is transmitted by a small insect, the phlebotomine sand fly. Clinical syndromes include visceral leishmaniasis and various cutaneous affections. We describe here the case of a patient affected by a multiple lesions New World cutaneous leishmaniasis, after staying in Costa Rica for tourism; we discuss the differential diagnosis and make a short summary of the principles of treatment.

["Markers" of infection with hepatitis A and B viruses among office workers in a heavy industry]. / I "markers" di infezione da virus epatitici "A" e "B" fra gli addetti agli uffici di una grande industria.

The spread of "A" and "B" hepatitis virus in a limited working environment has been evaluated and the main serum "markers" of this infection (HBsAg, anti-HBs, anti-HBc, anti-HAV) have been researched in 187 subjects (males and females) after being taken on by a large company in Northern Italy. This research, carried out again after 8--10 months from hiring, showed a moderate spread of "B"virus in 6,4% of the subjects observed. This finding is probably due to deficient personal hygiene rather than to environmental factors related to work (these may on the contrary condition the spread of "A" virus which, in the cases observed showed insignificant diffusion).

[Hospital costs of patients with AIDS]. / Costo ospedaliero del malato di AIDS.

We carried out a retrospective research into the hospital care cost of 52 AIDS cases we observed in our department, in the period 1984-1988. These patients required an average of 3.2 hospital admissions per year, and 101.3 hospitalization days per year, spending more than one fourth of their life span after their diagnosis of AIDS, in a hospital. The total care cost was Lit. 1,133,614,000, mostly due to the hospital stay (65.0%), but the introduction of expensive drugs will increase the cost of treatment. The average daily cost per patient was Lit. 227,900. Prognosis and cost vary according to the kind of opportunistic infection or neoplasm. The prolongation of hospitalization in consequence of social and economic problems is very frequent. A better accessibility of diagnostic systems, and a development of day-hospital and social services could reduce AIDS patients costs.