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.

Chagas disease knocks on our door: a cross-sectional study among Latin American immigrants in Milan, Italy.

OBJECTIVES: We aimed to assess the prevalence and risk factors for Chagas disease (CD) in Latin American immigrants and to evaluate the accuracy of diagnostic tests. Moreover, we offered to all positive subjects a complete free-of-charge clinical/instrumental evaluation as well as benznidazole treatment in order to stage the disease and verify drug tolerability. METHODS: A cross-sectional survey of CD among Latin Americans living in Milan and its metropolitan area was conducted between July 2013 and July 2014. Blood samples were tested for serologic evidence of CD together with a questionnaire covering demographic and clinical-epidemiological information. RESULTS: Forty-eight (9.6%) of the 501 tested subjects were conclusively diagnosed as having CD. The highest prevalence of CD was among those from Bolivia (43/169, 25.4%) and El Salvador (4/68, 5.9%). Older age (adjusted odds ratio (aOR)] 1.05, p =0.004), a Bolivian origin (aOR 8.80; p =0.003), being born in the department of Santa Cruz (aOR 3.72, p =0.047), having lived in mud houses (aOR 2.68; p =0.019), and having an affected relative (aOR 12.77, p =0.001) were independently associated with CD. The ARCHITECT Chagas test showed the highest sensitivity (100%) and specificity (99.8%). Twenty-nine of the subjects with CD (60.4%) underwent disease staging, 10 of whom (35.7%) showed cardiac and/or digestive involvement. Benznidazole treatment was associated with high frequency of adverse reactions (19/27, 70.4%) and permanent discontinuation (8/27, 29.6%). CONCLUSIONS: CD is highly prevalent among Bolivians and Salvadorans living in Milan. Regions with a large Latin American immigrant population should implement programmes of active detection and treatment.

Soluble interleukin-2 receptor decrease in the sera of HIV-infected patients treated with zidovudine.

Laboratory parameters which are modified following administration of zidovudine are becoming increasingly useful in monitoring the efficacy of treatment of early stages of HIV-1 infection. The serum levels of soluble interleukin (sILR)-2 receptor, which have been reported to increase early in HIV-1 infection, were found to be significantly lower in 24 patients being treated with zidovudine than in 69 patients who were not treated, 28 of whom had CD4+ counts greater than 400 x 10(6)/l, and 41 less than 400 x 10(6)/l, respectively (P less than 0.0001). A prospective study group of 33 subjects treated with zidovudine demonstrated a decrease in sIL-2R during therapy (base values 2113 +/- 1131 versus 1444 +/- 728 after 90 days of therapy; P less than 0.0007). The reduction of sIL-2R was greater in those subjects were p24 antigen became negative during treatment. sIL-2R therefore seems to be a useful tool in the monitoring of therapy with zidovudine.

Homozygous delta 32 deletion of the CCR-5 chemokine receptor gene in an HIV-1-infected patient.

BACKGROUND: Recent research has found that entry of non-syncytium-inducing (NSI), monocyte-macrophage-tropic HIV-1 isolates requires binding to both CD4 and CCR5 receptors, and that delta 32/delta 32 homozygous individuals are protected against infection. OBJECTIVE: To analyse the polymorphism of CCR-5 gene in HIV-1-infected and uninfected subjects. DESIGN AND METHODS: CCR-5 sequences were amplified by polymerase chain reaction (PCR) from DNA of peripheral blood mononuclear cells. Samples from 152 HIV-1-infected subjects and 122 uninfected controls were tested for the detection of the 32 base-pair deletion. HIV-1 phenotype was determined by viral isolation and MT-2 evaluation. RESULTS: The wild-type/delta 32 heterozygous and delta 32/delta 32 homozygous conditions were represented in 10.7 and 0.8% of healthy controls and in 9.8 and 0.7% of HIV-1-infected subjects, respectively. Of note, the delta 32/delta 32 deletion of the CCR-5 gene was detected by PCR and sequencing confirmed in a patient with progressive infection harbouring a clade B virus with SI phenotype. CONCLUSIONS: delta 32/delta 32 homozygosity for the CCR-5 gene does not confer absolute protection against HIV-1 infection, suggesting that either macrophage-tropic viral strains could use coreceptors other than CCR-5 or infect independently of the presence of a functional CCR-5 coreceptor. Alternatively, primary infection sustained by T-cell-tropic isolates, although exceptional, may occur.

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.

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.

Persisting HIV-1 replication triggered by acute hepatitis A virus infection.

We report the case of two patients in whom acute hepatitis A was associated with a marked and prolonged increase in human immunodeficiency virus type 1 (HIV-1) viral load. Although in one patient the rise in HIV-1 RNA might also have been related to the interruption of antiretroviral therapy, we also observed a similar pattern in the other patient who had a stable undetectable plasma viraemia prior to acute hepatitis and never received treatment with anti-retrovirals. Our observation supports the hypothesis that immune activation that is induced by acute hepatitis A virus (HAV) infection may trigger HIV-1 replication. This highlights the importance of maintaining antiretroviral therapy throughout the acute phase of hepatitis A and of preventing HAV infection through active immunization.

Frequent detection of antibodies against HTLV antigens in patients with AIDS-related non-Hodgkin lymphoma.

We studied the prevalence of anti-HTLV-I/II antibodies in 22 patients with AIDS-related non-Hodgkin lymphoma (NHL), 453 HIV-1-infected patients without lymphoma (194 of whom were diagnosed as having AIDS), and 6 HIV-1-positive and 75 HIV-1-negative patients with Hodgkin lymphoma. The frequency of serological reactivity against HTLV antigens was significantly higher in the AIDS patients with lymphoma than in those without (8 of 22, 36.4% vs. 20 of 194, 10.3%-p = 0.0027). One of the HIV-1-positive and none of the HIV-1-negative patients with Hodgkin lymphoma showed anti-HTLV-I/II reactivity. Four of the eight seropositive NHL patients showed antibodies directed against HTLV-II recombinant antigens when tested for serological discrimination in a Western blot assay. A PCR study of PBMCs from the only patient with NHL still alive at the time of the study showed HTLV-II-specific sequences in the genomic DNA. These data suggest that HTLV-II or a closely homologous retrovirus infects a high proportion of patients with AIDS-associated NHL.

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.

Still's disease in a patient infected with human immunodeficiency virus type I.

An autoreactive cellular immune response may be a part of HIV-1 infection. This autoimmune phenomenon also includes antibodies to collagen that can be associated to arthritis as a clinical condition. In this paper we describe a case of Still's disease in an adult HIV-1 infected patient who presented a marked amelioration in his condition after 15 days of steroid therapy, as well as an improvement of the arthritis. This rare autoimmune condition, which is connected with the disregulation of the immune system, must be taken into account in HIV-1 infected individuals who present with fever of unknown origin.

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.

[Disseminated histoplasmosis in patients with AIDS. 2 case reports]. / Istoplasmosi disseminata in pazienti affetti da AIDS. Descrizione di due casi.

Histoplasmosis is endemic in some areas of United States and in South America, and generally causes an acute self-limiting respiratory infection. In elderly and immunosuppressed patients the infection can spread through the blood, causing a severe systemic illness. Here we describe two cases of disseminated histoplasmosis in AIDS patients. The first was observed in an Italian woman who had never visited endemic countries, and was recognized only at autopsy; the second was observed in a trans-sexual patient, arrived in Italy from Brazil. Clinical suspicion of histoplasmosis is important in immunocompromised patients of non-endemic areas as symptoms are often aspecific and misdiagnosis is frequent.

Tuberculosis cutis miliaris disseminata due to multidrug-resistant Mycobacterium tuberculosis in AIDS patients.

Two patients with AIDS and disseminated tuberculosis characterized by cutaneous involvement are reported. They developed a maculopapular skin eruption, from which a multidrug-resistant Mycobacterium tuberculosis strain was isolated. In both cases the clinical course was rapidly fatal. Tuberculosis cutis miliaris disseminata should be differentiated from the skin lesions frequently seen in HIV-infected patients, especially from folliculitis. In patients with tuberculosis, the appearance of cutaneous lesions may be due to the haematogenous dissemination of mycobacteria. Therefore, early identification of the causative organism by use of optimal microbiological methods is fundamental.

Clinical and immunological aspects of HIV infection in drug addicts.

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

Lung carcinoma in 36 patients with human immunodeficiency virus infection. The Italian Cooperative Group on AIDS and Tumors.

BACKGROUND: The current study describes the clinicopathologic characteristics of 36 patients with lung carcinoma and human immunodeficiency virus (HIV) infection observed within the Italian Cooperative Group on AIDS and Tumors (GICAT). METHODS: Patients with lung carcinoma and HIV infection collected by the GICAT between 1986-1998 were evaluated retrospectively. As a control group, the authors analyzed 102 patients age < 60 years with lung carcinoma but without HIV infection who were seen at the CRO, National Cancer Institute, Aviano, Italy between 1995-1996. RESULTS: Patients with lung carcinoma and HIV infection were younger (38 years vs. 53 years) and previously smoked more cigarettes per day (40 vs. 20) than the control group. The main histologic subtype was adenocarcinoma. TNM Stage III-IV disease was observed in 53% of the patients. The median CD4 cell count was 150/mm(3). The median overall survival was significantly shorter in the patients with HIV compared with the control group (5 months vs. 10 months; P = 0.0001). CONCLUSIONS: The results of the current study demonstrate that lung carcinoma in the HIV setting affects mainly young individuals with a history of heavy tobacco smoking and a moderately advanced immunodeficiency status. Lung carcinoma is associated with a more adverse outcome in HIV patients and represents the cause of death in the majority of these patients.

Identification of two distinct subsets of long-term nonprogressors with divergent viral activity by stromal-derived factor 1 chemokine gene polymorphism analysis.

Stromal-derived factor (SDF)-1, the natural ligand for CXCR4, is present in a common polymorphic variant defined by a G-->A transition in the 3' untranslated region of the gene. In persons infected with human immunodeficiency virus type 1 (HIV-1), the homozygous genotype (SDF1-3'A/3'A) has been postulated to interfere with the appearance of T-tropic syncytium-inducing strains. The polymorphism of SDF1 was correlated with HIV-1 phenotype, plasma viremia, and unspliced and multiply spliced specific transcripts in 158 virologically characterized HIV-1-infected patients (39 recent seroconverters, 75 typical progressors, and 44 AIDS patients) and in 42 HIV-1-infected long-term nonprogressors (LTNPs). Analysis of SDF1 allele distribution revealed that SDF1-3'A/3'A status is associated with low CD4 cell count (P=.0449) but not with a specific HIV-1 phenotype. In LTNPs, SDF1-+/+ condition defined a subset of persons with lower HIV-1 replication than in heterozygous subjects. The low viral activity in SDF1-+/+ LTNPs suggests that other factors play a major role in vivo in determining the course of HIV-1 infection.

No evidence of a higher risk of progression to AIDS in patients with HIV-1-related severe thrombocytopenia.

The prognostic role of platelet (PLT) counts was evaluated in a cohort of 1,533 HIV-1-infected subjects followed for a median of 21 months. Thrombocytopenia (TCP), defined as a PLT count < or = 100 x 10(9)/L was present at enrollment in 11.2% of cases, with counts < or = 50 x 10(9)/L (severe TCP) in 5.3%. With the subjects with normal PLT counts (PLT >150 x 10(9)/L) as the reference group, the relative risk of developing acquired immunodeficiency syndrome (AIDS) was 0.8 [95% confidence interval (CI) 0.5-1.3, p = 0.4] for subjects with severe TCP, 2.1 (95% CI 1.4-3.1, p = 0.002) for those with PLT counts ranging from 51 to 100 x 10(9)/L (moderate TCP), and 1.6 (95% CI 1.2-2.1, p = 0.0004) for those with borderline PLT values (PLT ranging from 101 to 150 x 10(9)/L). Most of the risk increase associated with moderate TCP and borderline PLT values was explained by a higher prevalence of subjects with an older age and lower CD4+ cell counts. However, at multivariable analysis considering age, sex, risk group, and zidovudine (ZDV) treatment, the risk for subjects with severe TCP remained significantly lower than that for subjects with moderate TCP and borderline values. These results suggest the existence of different types of HIV-1-associated TCP and also suggest that severe TCP (which often arises in the early phases of infection) is not related to disease progression.

Hodgkin's disease in 35 patients with HIV infection: an experience with epirubicin, bleomycin, vinblastine and prednisone chemotherapy in combination with antiretroviral therapy and primary use of G-CSF.

BACKGROUND: The optimal therapeutic approach for patients with Hodgkin's disease and human immunodeficiency virus infection (HD-HIV) is unknown. In an attempt to improve the results previously obtained with EBV (epirubicin, bleomycin and vinblastine) without G-CSF (Cancer 1994; 73: 437-44), in January 1993 we started a trial using chemotherapy (CT) consisting of EBV plus prednisone (EBVP), concomitant antiretroviral therapy (zidovudine, AZT or dideoxinosyne, DDI), and G-CSF. PATIENTS AND METHODS: Up to August, 1997, 35 (30 M/5 F) consecutive previously untreated patients (median age 34, range 21-53 years) with HD-HIV were enrolled in the European Intergroup Study HD-HIV. Their median performance status was 1 (range 1-3). At diagnosis of HD, 26% of the patients had AIDS, 90% had B symptoms at HD presentation and 83% had advanced-stage HD. Patients received E 70 mg/m2 i.v. on day 1, B 10 mg/m2 i.v. on day 1, V 6 mg/m2 i.v. on day 1 and P 40 mg/m2 p.o. from day 1 to day 5 (EBVP). Courses were repeated every 21 days for six cycles. AZT (250 mg x 2/day), or DDI (200 or 300 mg x 2/day) if AZT had been previously used, were given orally from the beginning of CT. G-CSF was given at the dose of 5 mcg/kg/day s.c. from day 6 to day 20 in all cycles. RESULTS: An overall response rate of 91% was observed. There were 74% complete responses (CR) and 17% partial responses (PR). Toxicity was moderate, with grade 3-4 leukopenia and thrombocytopenia in 10 (32%) and three (10%) patients, respectively. The median number of administered cycles was 6 (range 3-6). Twenty-three of 35 patients received AZT and nine patients received DDI. Three (8%) patients had opportunistic infections (OI) during or immediately after CT. The median CD4+ cell count was 219/mm3 (6-812) at HD diagnosis and 220/mm3 (2-619) after the end of combined therapy, and these numbers remained unchanged. Ten of 26 (38%) patients who achieved CR relapsed. Twenty-three patients died of HD progression alone or in association with OI, being the cause of death in 48% and 9% of patients respectively. The median survival was 16 months, with a survival rate of 32% and a disease-free survival of 53% at 36 months. CONCLUSIONS: The combined antineoplastic and antiretroviral treatment is feasible, but HD in HIV setting is associated with a more adverse prognosis than in the general population. Although the CR rate obtained was satisfactory, the relapse rate was high. Furthermore, comparison of the results of our two consecutive prospective studies demonstrated no overall improvement in the current trial with respect to the CR rate and survival.