Plasma trough concentrations of darunavir/ritonavir and raltegravir in older patients with HIV-1 infection.

OBJECTIVES: The aim of the study was to assess plasma concentrations of darunavir/ritonavir and raltegravir in older patients compared with younger patients with HIV-1 infection. METHODS: In this observational, open-label study, adult HIV-infected out-patients aged ≤ 40 years (younger patients) or ≥ 60 years (older patients) and treated with tenofovir/emtricitabine plus darunavir/ritonavir (800/100 mg daily) or raltegravir (400 mg twice daily) were asked to participate. The trough concentrations (Ctrough ) of darunavir/ritonavir and raltegravir were assessed at steady state using a validated high-performance liquid chromatography (HPLC)-tandem mass spectrometry method. RESULTS: A total of 88 HIV-positive patients were enrolled in the study. Forty-six patients were treated with darunavir/ritonavir, and 42 with raltegravir. The geometric mean plasma Ctrough (coefficient of variation) of raltegravir was comparable between the 19 older and 23 younger subjects: 106 ng/mL (151%) and 94 ng/mL (129%), respectively [geometric mean ratio (GMR) 0.85; 95% confidence interval (CI) 0.71-1.57; P = 0.087]. In contrast, the geometric mean plasma Ctrough of darunavir was significantly higher among the 21 older patients [2209 ng/mL (139%)] than among the 25 younger patients [1876 ng/mL (162%); GMR 1.56; 95% CI: 1.22-1.88; P = 0.004]. Similarly, the geometric mean Ctrough of ritonavir was significantly higher among older than among younger individuals. CONCLUSIONS: The mean plasma Ctrough of darunavir and ritonavir was significantly higher in older patients than in younger patients with HIV-1 infection, while the mean plasma level of raltegravir was comparable in the two groups. However, both regimens showed good tolerability in both younger and older subjects.

No correlation between statin exposure and incident diabetes mellitus in HIV-1-infected patients receiving combination antiretroviral therapy.

OBJECTIVES: Recent clinical studies and one meta-analysis have shown a modest but significant increase in the incidence of diabetes mellitus associated with statin exposure, so this correlation was investigated in a cohort of HIV-positive subjects. METHODS: A retrospective cohort study including adult HIV-1-infected patients followed at our Clinic of Infectious Diseases between 2007 and 2014 was performed. RESULTS: We assessed 3170 HIV-positive patients with a median follow-up of 5.2 years. The incidence of diabetes mellitus was 1.2 per 100 person-years and it was not significantly associated with the prescription of statins [hazard ratio (HR) 1.09 per year of statin exposure; 95% confidence interval (CI) 0.7-1.49; P = 0.067], while it was associated with older age, chronic hepatitis C, antiretroviral-naïve vs. antiretroviral experienced condition, high body mass index, and high serum concentration of triglycerides. CONCLUSIONS: In our study, a higher risk of diabetes mellitus was not associated with statin treatment, but with some traditional risk factors.

Subtypes of depressive symptoms and inflammatory biomarkers: An exploratory study on a sample of HIV-positive patients.

Depressive symptoms cause major impairment and may accelerate HIV progression despite the use of antiretroviral medication. The somatic symptoms criteria for HIV infection and depression partially overlap, which can make differential diagnosis challenging. Because of chronic inflammation caused by HIV infection, HIV-positive patients may develop somatic and affective-cognitive symptoms of depression. Inflammation-related depression is primarily characterized with severe somatic symptoms such as fatigue and sleep disturbance. This study sought to explore the patterns of somatic and cognitive-affective depressive symptoms that characterize HIV-positive patients. Our specific aims were (1) to identify subtypes of depressive symptoms in a sample of HIV-positive patients; and (2) to test the subtypes' difference on inflammatory and HIV disease progression biomarkers. HIV-positive men and women (N=102) with and without depressive symptoms were randomly selected from an Italian HIV clinic. Depressive symptoms (PHQ-9), viral load (VL), CD4+, Il-6, TNF-α, and monocytes were assessed. The three subtypes formed using Latent Class Analysis (LCA) identified patients with (1) severe cognitive-affective and somatic depressive symptoms; (2) severe/moderate somatic symptoms; and (3) absent or low depressive symptoms. The subtype with severe/moderate somatic symptoms was characterized with elevated levels of Il-6 and monocytes. No difference on HIV progression biomarkers was found. The subtypes of depressive symptoms might help differentiating depressive symptoms from HIV- and inflammatory-related somatic symptoms. When present, cognitive-affective and/or somatic symptoms cause significant impairment to patients' lives and thus warrant further assessment and treatment.

Evaluation of glomerular filtration rate in HIV-1-infected patients before and after combined antiretroviral therapy exposure.

BACKGROUND: The prevalence and factors associated with an increased risk of renal dysfunction in HIV-infected patients receiving or not receiving antiretroviral therapy (ART) have been poorly evaluated in observational settings. METHODS: Patients in the ICONA Foundation cohort with at least two creatinine values available while still ART-naïve were enrolled in the study. A logistic regression analysis was performed to identify predictors of an estimated glomerular filtration rate (eGFR)<90 mL/min/1.73 m(2) at baseline. The incidence and predictors of a >20% reduction in eGFR from pre-combination ART (cART) levels (or a decrease from ≥90 to <90 mL/min/1.73 m(2) ) were evaluated by Poisson regression. RESULTS: A total of 1505 patients were included in the study; 363 (24%) had eGFR<90 mL/min/1.73 m(2) at baseline. Older patients [odds ratio (OR) 1.58 per 10 years older; P<0.00001], female patients (OR 2.41 vs. male patients; P<0.00001), those who had diabetes and/or hypertension (OR 2.36 vs. neither; P<0.03) and patients with higher baseline CD4 count (OR 1.06 per 100 cells/µL higher; P<0.03) showed a greater risk of eGFR<90 mL/min/1.73 m(2) . Ninety-six patients experienced an eGFR decrease of >20% from pre-cART levels (6.8 per 100 person-years). Older age [relative risk (RR) 1.41 per 10 years older; P=0.005], female gender (RR 2.25 vs. male; P=0.003) and current exposure to didanosine (ddI), tenofovir and protease inhibitors were the major determinants. CONCLUSIONS: We observed a relatively high rate of mild renal dysfunction in the absence of ART. In addition to traditional risk factors such as older age and diabetes/hypertension, female gender and current use of ddI, tenofovir and protease inhibitors were associated with a greater risk of decreased renal function as measured by eGFR.

Abacavir-induced reaction with fever and severe skin rash in a patient tested human leukocyte antigen-B*5701 negative.

The most serious adverse event caused by abacavir is the hypersensitivity reaction, which is usually associated with the presence of the human leukocyte antigen (HLA) subtype B*5701, as shown in recent studies. We describe the case of a 41-year-old Caucasian female patient, who tested HLA-B*5701 negative and developed fever and severe skin rash 10 weeks after the start of abacavir therapy. Similar reports suggest that not all severe abacavir-induced adverse events occur as a result of classic hypersensitivity reactions, and can present also in HLA-B*5701-negative patients.

Human herpesvirus 8 seropositivity and risk of Kaposi's sarcoma and other acquired immunodeficiency syndrome-related diseases.

BACKGROUND: The incidence of Kaposi's sarcoma (KS) is increased severalfold in individuals infected with human immunodeficiency virus-1 (HIV). Human herpesvirus 8 (HHV8) has also been implicated in KS. We investigated several factors that may determine the onset of KS, particularly HHV8 infection in individuals after becoming seropositive for HIV. METHODS: We studied 366 individuals belonging to different HIV-exposure categories (i.e., homosexual activity, intravenous drug use, and heterosexual contact) for whom a negative HIV serologic test and then a positive HIV serologic test were available within a 2-year period. HHV8 antibody testing was performed by use of an immunofluorescence assay on the first serum sample available after the first positive HIV test. Actuarial rates of progression of KS and of other acquired immunodeficiency syndrome (AIDS)-defining diseases were estimated by use of time-to-event statistical methods. All statistical tests were two-sided. RESULTS: Twenty-one of the 366 study participants developed AIDS-related KS, and 83 developed AIDS without KS. One hundred forty (38.3%) participants had detectable anti-HHV8 antibodies. The actuarial progression rate to KS among persons co-infected with HIV/HHV8 was nearly 30% by 10 years after HIV seroconversion. Increasing HHV8 antibody titers increased the risk of developing KS (for seronegative versus highest titer [1:125 serum dilution], adjusted relative hazard [RH] = 51.82; 95% confidence interval [CI] = 6.08-441.33) but not of other AIDS-defining diseases (adjusted RH = 1.14; 95% CI = 0.72-1.80). HHV8-seropositive homosexual men compared with HHV8-seropositive participants from other HIV-exposure categories showed an increased risk of KS that approached statistical significance (adjusted RH = 6.93; 95% CI = 0.88-54.84). CONCLUSIONS: Approximately one third of individuals co-infected with HIV/HHV8 developed KS within 10 years after HIV seroconversion. Progression to KS increased with time after HIV seroconversion. Higher antibody titers to HHV8 appear to be related to faster progression to KS but not to other AIDS-defining diseases.

Recombinant alpha-interferon 2b in the treatment of HIV-related thrombocytopenia.

OBJECTIVE: To assess the efficacy and the mechanism of action of alpha-interferon (alpha-IFN) in the treatment of HIV-related thrombocytopenia. METHODS: Thirteen HIV-positive subjects [nine men and four women with severe thrombocytopenia (platelets, < or = 30 x 10(9)/l)] were treated with alpha-IFN 2b alone at a dose of 3 x 10(6) U three times a week for 5 weeks. Haematological parameters, platelet kinetic and bone-marrow myeloid progenitor cultures [megakaryocyte colony-forming units (CFU-MK); granulocyte macrophage CFU (CFU-GM) and erythroid burst-forming units (BFU-E)] were evaluated before and after treatment in responsive subjects. RESULTS: Seven out of 13 subjects showed a partial response (platelets, 50-149 x 10(9)/l) after alpha-IFN 2b therapy. Platelet survival as evaluated by 111In-oxine significantly increased, while platelet turnover showed a slight but not statistically significant increase after treatment. The growth of bone-marrow myeloid progenitor cells decreased after alpha-IFN 2b therapy, again without statistical significance. CONCLUSION: alpha-IFN 2b may increase the platelet count in HIV-positive subjects with severe symptomatic thrombocytopenia by prolonging platelet survival. The immunomodulatory and antiviral action of this drug may be responsible for prolonged platelet survival.

Incidence of Kaposi's sarcoma and HHV-8 seroprevalence among homosexual men with known dates of HIV seroconversion. Italian Seroconversion Study.

OBJECTIVES: To evaluate temporal trends of Kaposi's sarcoma (KS) and of the KS-related human herpesvirus (HHV-8) among homosexual men who seroconverted for HIV between 1984 and 1997. METHODS: The study participants were 387 homosexual men. Changes over a period of time were assessed by estimating KS incidence rates per 1000 person-years for the periods 1984-1989, 1990-1992, 1993-1995, and 1996-1997. The proportional incidence of KS as the AIDS-defining disease for the same periods was also calculated. To evaluate a cohort effect of calendar period, Kaplan-Meier curves were used to estimate the risk of KS by period of HIV seroconversion [i.e. before 1990 (median year of seroconversion) versus later]. Relative hazards for the four periods were estimated using competitive-risks models. We also estimated HHV-8 seroprevalence over the study period. RESULTS: Forty-eight participants developed KS. Between 1984 and 1995, the incidence rate of KS per 1000 person-years increased from 3.9 to 32.8, whereas the proportional incidence decreased from 33.3 to 24.3%. The risk of developing KS after HIV seroconversion did not change when comparing the seroconversion periods (i.e. before 1990 versus later). HHV-8 seroprevalence also remained stable. The rates of KS and the relative hazards dramatically decreased after 1995. CONCLUSIONS: Although KS incidence rates increased up to 1995, the proportional incidence decreased, due to the higher increase in rates of other AIDS-defining diseases. The finding that the risk of developing KS after HIV seroconversion remained stable over time is consistent with the stable trend of HHV-8 seroprevalence. The dramatic decrease in KS incidence rates after 1995 coincides with combined antiretroviral therapy.

Impaired telomerase activity in uninfected haematopoietic progenitors in HIV-1-infected patients.

BACKGROUND: Haematopoietic progenitor cells (HPC) of HIV-1-infected patients are severely compromised in their replication and clonogenic capacities, and show an enhanced propensity to apoptosis, despite the lack of productive or latent HIV-1 infection. OBJECTIVE: To investigate telomerase enzyme levels in CD34+ HPC isolated from HIV-1-infected patients, because the absence of telomerase activity has been found to be correlated with a diminished replication potential. METHODS: Telomerase levels were measured by a PCR-based telomeric repeat amplification protocol. CD34+ HPC isolated from the peripheral blood of 11 HIV-1-infected patients were compared with CD34+ HPC isolated from peripheral blood (nine subjects) or bone marrow (six subjects) from 15 healthy donors. Telomerase levels were also studied in normal HPC after exposure to either gp120 or transforming growth factor (TGF)-beta1. RESULTS: CD34+ HPC isolated from either peripheral blood or bone marrow from healthy donors expressed a high level of telomerase activity. On the contrary, CD34+ HPC isolated from HIV-1-seropositive patients did not express any detectable telomerase activity in nine patients, and a clearly reduced enzymatic activity in two patients. Furthermore, telomerase activity in normal CD34+ HPC exposed to recombinant gp120 was significantly reduced, and to a higher extent than in CD34+ HPC exposed to recombinant TGF-beta1. CONCLUSIONS: This is the first study to demonstrate severely impaired telomerase activity in uninfected CD34+ HPC isolated from HIV-1-infected patients. The mechanism underlying this impairment probably involves the interaction of HIV-1 envelope glycoprotein gp120 with the cell membrane. These results may add to our understanding of the pathogenesis of the lesion of the HPC compartment.

Insights into the reasons for discontinuation of the first highly active antiretroviral therapy (HAART) regimen in a cohort of antiretroviral naïve patients. I.CO.N.A. Study Group. Italian Cohort of Antiretroviral-Naïve Patients.

OBJECTIVE: To evaluate the frequency of discontinuation of the first highly active antiretroviral regimen (HAART) and the factors predictive of discontinuing for toxicity and failure in a population-based cohort of HIV-positive individuals in Italy, naïve from antiretrovirals at enrolment. METHODS: The study population consisted of individuals who initiated HAART and had at least one follow-up visit. The primary end-points were discontinuation of any component of HAART for drug toxicity and discontinuation for failure. Survival analyses were performed to identify predictive factors for reaching the two end-points. RESULTS: Eight hundred and sixty-two individuals initiated HAART; in 727 of them (84.3%) this consisted of two nucleoside reverse transcriptase inhibitors (NRTI) and one protease inhibitor (PI). Over a median follow-up of 45 weeks, 312 patients (36.2%) discontinued therapy: 182 (21.1%) discontinued due to toxicity, 44 (5.1%) due to failure. The probability of discontinuing HAART at 1 year was 25.5% [95% confidence interval (CI), 21.9-28.9] due to toxicity and 7.6% (95% CI, 4.9-1 0.3) due to failure. Independent factors associated with discontinuation for toxicity were: gender [relative hazard (RH) = 0.51; 95% CI, 0.32-0.80 for men versus women], type of treatment (indinavir-containing regimens, RH = 1.94; 95% CI, 1.10-3.41 and ritonavir-containing regimens, RH = 3.83; 95% CI, 2.09-7.03 versus hard-gell saquinavir) and time spent on treatment (RH = 0.89; 95% CI, 0.80-0.98 for each additional month). Discontinuation due to failure was independently associated with the most recent HIV-RNA (RH = 3.20; 95% CI, 1.74-5.88 for log10 copies/ml higher), and with type of treatment (indinavir-containing regimens, RH = 0.21; 95% CI, 0.06-0.78 and ritonavir-containing regimens, RH = 0.23; 95% CI, 0.04-1.26 versus hard-gell saquinavir). CONCLUSIONS: If the current HAART regimen caused no toxicity, less than 10% of naïve patients discontinue their first HAART regimen because of failure after 1 year from starting therapy.

Antibodies against full-length Tat protein and some low-molecular-weight Tat-peptides correlate with low or undetectable viral load in HIV-1 seropositive patients.

BACKGROUND: The efficacy of a specific humoral response to transactivating Tat protein was studied in a group of HIV-1 seropositive drug addicts, who had previously received a similar course of anti-retroviral treatment with two reverse transcriptase inhibitors. OBJECTIVES: The aim of the study was to evaluate the meaning of an immune response to Tat protein in HIV-1 seropositive patients with different levels of HIV-1 RNA viremia. STUDY DESIGN: The study analyzed the presence of anti-Tat antibody reacting either with full-length Tat or with individual overlapping Tat-peptides (Tat(6-14), Tat(11-24), Tat(36-50), Tat(46-60), Tat(56-70) and Tat(65-80)), in a group of HIV-1 seropositive subjects with different peripheral blood viral loads. Plasma samples were examined by immunoenzymatic assay for the presence of anti-Tat IgG antibody and for the quantification of peripheral blood (plasma) viral load by branched DNA assay. RESULTS: The large majority of HIV-1 patients showed detectable levels of serum IgG to full-length-Tat, and the anti-Tat antibody level presented an inverse correlation with viral load magnitude. The analysis of antibody levels against individual overlapping Tat-peptides clearly showed that an undetectable viral load was significantly associated with the presence of a high antibody concentration against Tat(6-14), Tat(36-50) and Tat(46-60) (P=0.002, P=0.027 and P<0.001, respectively). CONCLUSION: In HIV-1-infected patients, a strong humoral immune response against HIV-1 Tat protein is inversely correlated to peripheral blood viral load and, in particular, a high level of antibody against Tat peptides containing amino acid residues 6-14 (Tat(6-14)), 36-50 (Tat(36-50)) and 46-60 (Tat(46-60)) is associated with an undetectable plasma viral load. These findings may help to tailor anti-HIV-1 Tat-containing vaccines.

Pentamidine isethionate as treatment and secondary prophylaxis for disseminated cutaneous leishmaniasis during HIV infection: case report.

Leishmaniasis is emerging as a common and serious opportunistic infection in HIV-infected patients in endemic areas (such as Mediterranean countries), and may occur with various clinical presentations, ranging from typical visceral forms to atypical cases, including cutaneous disease. Although pentavalent antimony compounds have been the mainstay of antileishmanial treatment for half a century, new drugs seem today reliable, including liposomal amphotericin B and pentamidine isethionate. However, the most effective therapy is still unknown. An HIV-infected i.v. drug abuser patient with a very uncommon disseminated cutaneous leishmaniasis, following an initial visceral disease, is described. Primary and recurrent visceral forms of protozoan infection have been treated with liposomal amphotericin B, while pentamidine isethionate was successfully employed as treatment for subsequent cutaneous relapse and as secondary prophylaxis.

Evaluation of three different commercial procedures for quantifying human immunodeficiency virus type-1 RNA levels.

A branched DNA method for the quantification of human immunodeficiency virus type 1 (HIV-1) RNA levels (Quantiplex HIV RNA 2.0) was compared with a reverse transcriptase-coupled polymerase chain reaction method (Amplicor HIV-1 Monitor) and a nucleic acid sequence-based assay (Nuclisens HIV-1 QT) in plasma samples from a group of HIV-1 seropositive patients. We found a high correlation between Nuclisens and Quantiplex (r = 0.89; p < 0.001) and between Amplicor and Quantiplex (r = 0.94; p < 0.001), a shift of RNA viral load to higher Nuclisens and Amplicor values compared with the Quantiplex results and a significant positive correlation (rS = 0.60; p < 0.001) between the p24 antigen level and the RNA viral load determined with the Quantiplex assay. We also found higher sensitivities of the Nuclisens and the Amplicor procedures compared with the Quantiplex assay. The total sensivity of the Quantiplex assay in our study was 70% whereas that of the p24 antigen was only 29%.

Prevalence of diabetes mellitus, hyperinsulinaemia and metabolic syndrome among 755 adult patients with HIV-1 infection.

Metabolic complications of antiretroviral therapy in HIV-infected patients include insulin resistance, diabetes mellitus, dyslipidaemia and lipodystrophy syndrome. Metabolic syndrome is an aggregation of central obesity with glucose and lipid metabolism alterations that confers an increased risk of cardiovascular disease, which reproduces the antiretroviral-associated metabolic and morphological abnormalities. In this study, we report the prevalence of diabetes mellitus, hyperinsulinaemia and metabolic syndrome among 755 adult patients with HIV-1 infection referred to our outpatients unit. The prevalence of diabetes mellitus and metabolic syndrome was 4.5% and 9.1%, respectively. A longer exposure to antiretroviral therapy and a diagnosis of lipodystrophy syndrome were significantly associated with both metabolic disturbances.

Merkel cell carcinoma in a human immunodeficiency virus-infected patient.

In the general population, Merkel cell carcinoma (MCC) is a very rare neuroendocrine primary skin cancer, known for its high propensity for local recurrence and distant metastases. Treatment for this neoplasm is individualized on the grounds of clinical staging at presentation, and may include surgical excision, radiotherapy and chemotherapy. Several studies suggest that MCC occurs more frequently and with a more aggressive course in immunocompromised patients such as organ transplant recipients and those infected with human immunodeficiency virus (HIV). A case of this cutaneous malignancy, characterized by a short-term local recurrence and systemic fatal spread in spite of surgical treatment, radiotherapy and chemotherapy, is described in a patient with advanced HIV infection.

Thymopentin (TP-5) therapy during lymphadenopathy syndrome (LAS/ARC): preliminary report.

Persistent generalized lymphadenopathy during HIV infection is now a well classified syndrome featuring multiple chronic lymph node enlargement frequently associated with further symptoms (diarrhea, nocturnal sweating, loss of weight, fever): it is invariably accompanied by serious alterations of the cell-mediated immunity including lymphopenia, reduced number of helper lymphocytes in circulation, inversion of the helper/suppressor ratio, lower proliferative response in vitro and deficient delayed skin sensitivity tests. Minor opportunistic infections are also more frequent, the most widespread being chronic oral candidiasis. Whenever several of these signs are associated in a single patient, especially if the immunitary deficit is severe, an immunomodulating treatment is indicated to improve the lymphocyte functionality and finally to modify any evolutive tendency. The Authors give the preliminary results of a pilot study carried out on 12 patients with LAS/ARC treated with Thymopentin at a dosage of 50 mg by intra muscular injection on alternate days for cycles of 30 days. Compared with 14 untreated patients, the subjects receiving therapy showed a more stable immunological picture, and improvement in subjective symptoms and a better therapeutic response to minor opportunistic infections.

Disseminated histoplasmosis with atypical cutaneous lesions in an Italian HIV-infected patient: another autochtonous case.

Disseminated histoplasmosis is recognized as a common AIDS-defining opportunistic disease in endemic areas (Americas, Africa, East Asia), while it is rarely described in Europe, usually in individuals returning from endemic regions, or following endogenous reactivation of a latent infection imported long before from overseas countries. However, reports of autochtonous cases in Europe suggest the possible, endemic presence of Histoplasma capsulatum in some European regions, such as the South of France or the Po valley in Italy. A case of disseminated histoplasmosis with atypical, papular and ulcerate skin lesions in an Italian HIV-infected patient, without history of travels outside his native region, is described. Our patient represents the fifth autochtonous case of AIDS-associated histoplasmosis described in Italy.

[Thoracic manifestations of AIDS (acquired immunodeficiency syndrome)]. / Manifestazioni toraciche dell'AIDS (sindrome da immunodeficienza acquisita).

AIDS (acquired immunodeficiency syndrome) seems to be related to human immunodeficiency virus (HIV) and is characterized by severe T-helpers lymphocyte dysfunction. Many of the AIDS patients (47-70%) develop pulmonary manifestations, both infectious and neoplastic, in the course of their disease. In the Department of Infectious Diseases of our Hospital are studied many patients HIV+. Every year 246 seropositive new patients have been discovered. Among them we have studied 25 subjects with respiratory disease, by chest radiographs; successively, according to clinical picture, we have performed thoracic computed tomography, Gallium scintigraphy, fiberoptic bronchoscopy with transbronchial biopsy (TBB), bronchoalveolar lavage (BAL); the majority of these patients (68%) had AIDS, only 28% had ARC and 4% had PGL. In our experience, the diagnosed diseases were mainly infections (92%), and most frequently (52%) due to Pneumocystis carinii, alone or in association with other etiologic agents. We have not found pathognomonic radiographic abnormalities, but chest X-ray evaluated with clinical and laboratory data, may often be useful to obtain diagnostic indications and in order to determine a more specific and aggressive diagnostic approach.