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Structured treatment interruptions progressively lowered the rate of viral rebound in some HIV-1 infected patients. This approach should be explored as an alternative to continuous antiretroviral therapies. [ABSTRACT FROM AUTHOR]

Background Dolutegravir (DTG) is a next-generation HIV integrase inhibitor (INI) with an increased genetic barrier to resistance with respect to raltegravir (RAL) or elvitegravir (EVG). Few data are available on the durability of DTG-containing regimens. Objectives We aimed at investigating the duration of the DTG-containing regimen, the occurrence of an HIV-1 RNA blip, and factors associated with DTG virological response. Study design From the Antiviral Response Cohort Analysis database, we selected 89 HIV-1-positive four-class-experienced subjects who started DTG after receiving RAL or EVG. Factors associated with durability and virological response were analysed by logistic regression. Results After a median duration of 18.8 [0.4–76.2] months, 79/89 (88.8%) subjects were still on DTG. All subjects remaining on DTG at the end of follow-up had undetectable HIV-1 RNA, compared to 5/10 subjects who discontinued DTG. DTG discontinuation was less frequent in patients who had experienced ≥10 regimens (HR 0.11, p = 0.040). The probability of having an HIV-1 RNA positive value at the last follow-up significantly increased in patients with non-B HIV-1 subtype (HR 5.77, p < .001) and significantly decreased in patients with CD4 nadir >200/μL (HR 0.29, p = 0.038), with more than 10 previous regimens (HR 0.27, p = 0.040), and who harbored virus with IN mutations (HR 0.12, p = 0.023) at DTG start. Conclusions After previous exposure to first-generation INIs, treatment with DTG showed long durability and did not show virological rebound after virological suppression. Subjects infected with a non-B HIV-1 subtype had a greater risk of having detectable HIV-1 RNA at the last observation. [ABSTRACT FROM AUTHOR]

Raltegravir ( RAL) is the only licensed human immunodeficiency virus ( HIV) integrase inhibitor. The factors associated with the virological response to RAL-containing regimens and the prevalence of integrase mutations associated with RAL failure deserve further investigation. From the Antiretroviral Resistance Cohort Analysis database, we selected triple-class-experienced subjects failing their current treatment with complete treatment history available. Selection criteria included HIV- RNA, CD4 count and HIV genotype within 3 months of RAL initiation. Factors associated with 24-week response were analysed; genotypic sensitivity scores ( GSS) and weighted- GSS were evaluated. Virological response was achieved in 74.3% of 105 subjects. Mutations associated with RAL failure were detected in 12/24 subjects with an integrase genotype, with the prevalence of Q148H + G140S. Each extra unit of GSS (p 0.05, OR 2.62; 95% CI 1.00-6.87). was found to be a associated with response. Weighted- GSS had borderline statistical significance (p 0.063, OR 2.04; 95% CI 0.96-4.33) When stratifying for different cut-offs (<1 as reference, 1-1.49, ≥1.5), a borderline significant increase in the probability of response appeared for GSS ≥1.5 (p 0.053, OR 4.00; 95% CI 0.98-16.25). GSS ≥1 showed the highest sensitivity, 82.6%. Receiver operating characteristic curves depicted the widest area under the curve (0.663, p 0.054) of GSS ≥1. Unresponsiveness to RAL-containing regimens among triple-class-experienced subjects was low. The activity of the background regimen was strongly associated with response. Although few integrase genotypes were available at failure, half of these were without integrase resistance mutations. The substantial rate of RAL failure in the absence of known RAL-resistance mutations may be associated with adherence issues and this issue warrants further analysis in longer observations. [ABSTRACT FROM AUTHOR]

Abstract: Background: Increasing the safety in Immunogenetics Labs, in the era of antiretroviral pharmacogenomics, represents an imperative goal. To this purpose, we tested saliva and buccal cells as biological sources of DNA, alternative to peripheral blood, for HLA-B*57:01 genomic typing of HIV positive patients eligible to treatment with abacavir. Methods: Blood, saliva and buccal cells of 20 voluntary donors and 20 HIV positive patients were collected. DNA was extracted with a manual commercial kit and an automated platform. Quality and quantity of DNA was evaluated with different procedures. The suitability and reliability of DNAs for HLA-B*57:01 genotyping was checked at low and high resolution level, using PCR-SSP (sequence specific primers PCR), revPCR-SSO (reverse sequence specific oligonucleotides PCR), bead array and SBT (sequence based typing) techniques. Results: DNA concentrations were qualitatively very good and quantitatively comparable in all the specimens tested with an inferior yield for cotton swabs. Comparing the results of HLA typing with different methodologies, the 100% of reproducibility was achieved. Conclusions: The viral load of buccal epithelial cells or saliva is extremely low. Here we demonstrated that the DNA from these alternative sources is appropriate for HLA-B*57:01 typing. We strongly recommend the use of this procedure to increase the safety in the lab when dealing with infectious samples. [Copyright &y& Elsevier]

The introduction of highly active antiretroviral therapy does not seem to have altered the incidence of progressive multifocal leukoencephalopathy (PML) in HIV infection. Moreover, the occurrence of a HIV-related leukoencephalopathy, called not determined leukoencephalopaties (NDLE), has been reported. As neuropsychological impairment remains highly prevalent in HIV infection, the aim of this study is to describe the neuropsychological profile of PML and NDLE patients, analyzing the time-related changes. Clinical and neuropsychological data from 32 patients (17 PML, 15 NDLE) were compared with two control groups: (1) asymptomatic HIV+ patients without magnetic resonance imaging evidence of leukoencephalopathy; (2) age-/gender-/education-matched healthy subjects. Patients with rapidly worsening PML were significantly impaired on all neuropsychological tests, while PML with more benign course and NDLE groups showed a dysexecutive pattern of impairment. Asymptomatic HIV+ subjects showed mild and isolated cognitive deficits, without functional impact. Cognitive impairment should therefore be considered a key feature from HIV infection diagnosis. [ABSTRACT FROM AUTHOR]

Objectives: Transmitted HIV-1 drug resistance (TDR) can reduce the efficacy of first-line antiretroviral therapy. [ABSTRACT FROM PUBLISHER]

Background Guidelines for kidney function monitoring and antiretroviral drug dosing are available and respectively refer to glomerular filtration rate and creatinine clearance (CrCl). Objective The aim of the study was to compare kidney function estimates vs. measured 24-h CrCl in HIV-infected subjects. Methods A cross-sectional design was used, with comparison of Cockcroft–Gault (CG), original and simplified modification of diet in renal disease (MDRD) equations vs. measured 24-h CrCl. Subjects were HIV-infected, 18–70 years old, without pre-existing kidney disease. Results Results are presented as mean (±standard deviation), unless otherwise stated. The study population consisted of 90 patients, of whom 71% were male, with a mean age of 45 years (±6.5 years). At the time of evaluation, the mean body mass index was 23 (±3.3); mean serum creatinine was 0.91 mg/dL (±0.2 mg/dL); and mean blood urea nitrogen (BUN) was 34.7 mg/dL (±10.6 mg/dL). Differences between paired methods were all significant ( P<0.00001), except between CG and simplified MDRD ( P=0.21; Pearson r=0.81). In univariate analysis, male gender, CD4 nadir, hepatitis B virus coinfection, BUN and current CD4 cell count showed a significant positive correlation ( P<0.2) with the difference between measured 24-h CrCl and either CG or simplified MDRD estimates. In multivariate analysis, only BUN showed a significant positive correlation ( P<0.05). Conclusions Estimates were lower than the measurements of 24-h CrCl. Original MDRD estimates were lower than those with other equations. CG and simplified MDRD estimates showed a satisfactory correlation. [ABSTRACT FROM AUTHOR]

Malaria is a common, life-threatening infection in endemic tropical areas and one that presents a diagnostic challenge to laboratories in most non-endemic countries. A rapid and accurate diagnosis is a prerequisite for effective treatment, especially for the potentially fatal cases of Plasmodium falciparum infection. In the present, multi-centre study, the performances of a rapid diagnostic test (NOW® Malaria) and several, commercial, PCR-based assays (AMS61®, AMS42®, AMS43®, AMS44® and AMS45®) were compared against the results of microscopical examination of bloodsmears (the current 'gold standard'). The subjects were either non-European immigrants (N=135) or international travellers (N=171). There was good concordance between the results of all the detection methods, with kappa values of >0.8. Although the NOW Malaria rapid test was both sensitive (100%) and specific (100%) in detecting P. falciparum infections, it was less specific (93.1%) and sensitive (90.7%) in identifying the other Plasmodium species. The results from the AMS61 assay, designed to detect any malarial infection, generally parallelled those of the microscopy (kappa 5 0.89), giving a specificity of 98.2% and a sensitivity of 91.0%. Although the use of species-specific molecular primers to identify pure infections with P. falciparum and P. vivax gave results that were in good agreement with those of the microscopy, the subjects who had apparently pure infections with P. ovale or P. malariae were always found PCR-negative. Compared with the standard microscopy, both the NOW Malaria test and the PCR-based assays were therefore poor at identifying mixed infections. The NOW Malaria test and the PCR-based assays clearly need to be improved, particularly for the correct identification of infections with Plasmodium spp. other than P. falciparum, including mixed infections. For now, expert microscopy must remain the mainstay of the laboratory diagnosis of malaria. [ABSTRACT FROM AUTHOR]

A new technique was used to simultaneously determine human cytomegalovirus (HCMV)-specific CD4+ and CD8+ T-cells in highly active anti-retroviral therapy (HAART)-naive and HAART-treated patients infected with human immunodeficiency virus (HIV). HIV-infected patients with HCMV infection, but without HCMV disease, showed low numbers of HCMV-specific CD4+ cells and high numbers of CD8+ T-cells, both before and during HAART. HIV-infected patients with HCMV disease had no HCMV-specific CD4+ T-cells and extremely low levels of CD8+ T-cells. Resolution of disease during HAART was associated with rescue of specific CD4+ T-cells and a large increase in the specific CD8+ T-cell count. Thus, HAART does not completely restore the normal immune function. In HIV-infected patients, sustained control of HCMV infection requires high frequencies of specific CD8+ T-cells. [ABSTRACT FROM AUTHOR]

In the present study, 67 patients suspected to be cases of visceral leishmaniasis (VL) were each checked for leishmanial infection by the microscopical evaluation of various biological specimens, in-vitro culture, serology and an assay based on nested PCR. Most (35) of the subjects were immunocompetent (IC) but 32 were immunodeficient (ID) as the result of HIV infection (18 cases), treatment to prevent transplanted organs being rejected (six) or haematological malignancies (eight). Forty-one (61.2%) of the subjects (19 IC subjects, 12 HIV-positive patients, four transplant patients and six patients with malignancies) were considered true cases of VL. For the IC subjects, only the production and microscopical examination of leucocytoconcentrates and cultures of Buffy coats gave sensitivities of< 80%, the results of the other methods showing higher sensitivities and almost perfect agreement with the 'gold-standard' diagnoses. For the ID subjects, however, only the serological tests and the PCR gave reasonable sensitivities (of > 80%). For the initial diagnosis of leishmaniasis in ID patients, IFAT and western blots may be useful, as, among the present ID patients, they gave sensitivities (of 80.9% and 88.2%, respectively) that were almost as high as that for the PCR, and specificities of 100%. In the diagnosis of VL in either IC or ID patients, the assay based on a nested PCR appeared to be particularly reliable, with sensitivities of 88.9% and 95.2%, respectively, and a specificity of 100% in both groups of patients. The testing of bone-marrow aspirates by PCR revealed very few VL cases who were not found positive when samples of their peripheral blood were checked in the same assay. For both IC and ID subjects therefore, the use of the PCRbased method to test samples of peripheral blood (which can be collected much more easily than bone-marrow aspirates and with much less pain for the subject) is recommended. [ABSTRACT FROM AUTHOR]

Objectives: To link local proinflammatory cytokines with HIV related nucleic acids in cervico-vaginal secretions and the factors associated with them.Methods: An observational study on 60 HIV positive women attending the department of obstetrics and gynaecology, University of Pavia, Italy. HIV-1 RNA in plasma, proviral HIV-1-DNA, cell associated and cell free HIV-1 RNA in cervico-vaginal secretions were evaluated by competitive polymerase chain reaction (c-PCR) and reverse transcriptase PCR (cRT-PCR). IL-1beta, IL-6, and TNF-alpha were measured by ELISA in cervico-vaginal lavages. Multiple regression analysis on ordinal categorical variables was used to test for the simultaneous associations of clinical and microbiological variables on quartiles of cytokine concentrations in lavage samples.Results: Proviral HIV-1 DNA, cell associated and cell free HIV-1 RNA were detected in 76.7% (46/60), 70% (42/60), and 71.7% (43/60) of the patients, respectively. IL-1beta concentration was directly correlated with proviral HIV-DNA (Spearman rho = 0.35, p = 0.01) and cell associated HIV-RNA levels (Spearman rho = 0.263, p = 0.05). IL-1beta concentration (153.9 pg/ml) was higher (p<0.05) among women with cytological squamous intraepithelial lesion (SIL) than negative controls (73.4 pg/ml). In women with vaginal infection both IL-1beta (41.7 pg/ml) and IL-6 (10.2 pg/ml) were lower (p<0.05) in comparison to negative controls (144.9 pg/ml and 23.7 pg/ml, respectively). Women receiving stable antiretroviral therapy had significantly lower TNF-alpha (34.4 pg/ml versus 44.4 pg/ml, p = 0.04) and higher IL-6 (24.0 pg/ml versus 1.4 pg/ml, p = 0.004) levels in lavage samples compared to untreated women. The associations between the presence of SIL, antiretroviral treatment, vaginal infection and cytokine concentrations in cervico-vaginal secretions were confirmed in multiple regression analysis.Conclusions: Local immune activation may modulate HIV-1 shedding in cervico-vaginal secretion with possible influence on vaginal physiology and host defence. Pharmacological agents lowering HIV-1 replication cause a shift to a pattern of cytokine production which seems less favourable to the transmission of the disease. [ABSTRACT FROM AUTHOR]

Objective: Lipid disorders associated with the use of protease inhibitors (PI) may be a risk factor for premature atherosclerosis development. The aim of this study is to evaluate the extent of carotid intima media thickness (IMT) among HIV-positive patients treated with PI containing regimens compared to PI-naı¨ve and HIV-negative subjects. Methods: We analysed plasma lipid levels and carotid IMT in 28 HIV-positive patients treated with protease inhibitors (PIs) for a mean of 28.7 months (range 18–43) and in two control groups constituted, respectively, by 15 HIV-positive naı¨ve patients and 16 HIV-negative subjects, that were matched for age, risk factors for HIV infection, cigarette smoke use and CD4+ cell count. Results: PI-treated patients had higher triglyceride, HDL and apo B levels than controls. Carotid IMT was significantly increased in PI-treated patients compared to naı¨ve or HIV-negative subjects. A correlation between cholesterol HDL, triglyceride and ApoB levels and IMT was observed among the entire cohort. Conclusions: Plasma lipid alterations were associated with an increased IMT and intima media thickening was more pronounced in PI-treated patients than in the two control groups. Periodical evaluation of blood lipid profile and, if required, the use of lipid-lowering agents is advisable. Moreover, physicians should address concurrent risk factor for atherosclerosis that can be modified, including smoking, hypertension, obesity and sedentary life-style. [Copyright &y& Elsevier]

7-11 November 2010, Tenth International Congress on Drug Therapy in HIV Infection, Glasgow, UK [ABSTRACT FROM AUTHOR]

An abstract of the article "Smoking, female gender and PI use are associated with decreasing renal function in TDF-containing HAART," by A. Uglietti and colleagues is presented.

PREVALEAT II (PREmature VAscular LEsions and Antiretroviral Therapy II) is an ongoing multicenter, longitudinal cohort study aimed to the evaluation of cardiovascular risk in advanced naïve HIV-infected patients starting their first HAART. It includes all consecutive naïve pts with <200 CD4 cells/ml who start any PI/r-based or NNRTI-based+2 NRTIs regimen. Pts are subjected to epi-aortic vessels ultrasonography, brachial artery flow mediated dilation (FMD), endothelial cytokine inflammatory markers value at time 0 and after 3, 6 and 12 months. Data about independent risk factors for CV disease are taken at time 0. Viral load, CD4+ counts, serum lipid values, glucose, body mass index (BMI) are recorded at every control. We enrolled 47 pts: 76,6% males, 87,2% caucasians, 40,4% cigarette smokers, 10,6% HCV co-infected, 6,4% had lipodystrophy. 29,8% homosexuals, 12,8% drug addicts, 51,1% heterosexuals. At baseline, 23,4% of pts had pathologic BMI, 31,91% had a epi-aortic vessels lesion (IMT and/or plaque), 27,65% had pathologic FMD; ICAM1 was pathologic in 46,80%, VCAM1 in 53,19%, IL-6 in 51,06%, D-dimers in 29,79%, hsCRP in 23,40%. 27 pts completed stage T1 of the study (after 3 months); percentages and significance level of variations are the following: 44,44% had a lesion of the epi-aortic vessels (p=0,28), 48,14% had a pathologic FMD (p=0,08), ICAM1 was pathologic in 59,26% (p=0,30), VCAM1 in 70,37% (p=0,15), IL-6 in 74,07% (p=0,05), D-dimers in 14,81% (p=0,12), hsCRP in 25,92% (p=0,80). 27 pts completed stage T2 of the study (6 months). Percentages and significance level of variations in regard of baseline are the following: 51,85% had a epi-aortic vessels lesion (p=0,462); 25,92% had pathologic FMD (p=0,37). 10 pts completed stage T3 of the study (12 months): 60% had a epi-aortic vessels lesion (p=0,07); 40% had pathologic FMD (p=0,49). No significant change has been showed in the trend of variation of inflammatory cytokines at T2 and T3. Our data, at baseline, evidence that advanced naïve pts show a relevant deterioration of CV conditions in terms of US data, FMD and cytokine markers. At T1, US and FMD seem to further worsen; cytokines, except D-dimers, show a worsening trend, too. At T1 and T2, prevalence of vessel lesion and pathologic FMD is yet higher, with a p value closer to significance level. Further data deriving from the follow-up of missing pts are warranted to better understand the evolution of the CV risk profile in this setting of pts. [ABSTRACT FROM AUTHOR]