Awareness and perception of accuracy of the Undetectable=Untransmittable message (U=U) in Italy: results from a survey among PLWHA, infectious-diseases physicians and people having unprotected sex.

Evidences on the absence of risk of sexual transmission of HIV by persons living with HIV/AIDS (PLWHA) with undetectable plasma HIV-RNA (HIV-RNA <200 copies/ml) led to the worldwide campaign "U = U" (undetectable = untransmittable). The purpose of this study was to evaluate the perceived accuracy of this message among PLWHA, HIV-negative people having unprotected sex (PHUS) and infectious diseases' (ID) physicians in Italy. A nationwide survey has been conducted using three different anonymous questionnaires (for ID physicians, PLWHA and PHUS). A total of 1121 participants filled the questionnaires: 397 PLWHA; 90 physicians; 634 PHUS. Awareness of U = U message has been reported in 74%, 92% and 47% of PLWHA, ID physicians and PHUS, respectively. The perception of accuracy of the U = U message among those aware was reported as high in 80.4%, 79.5% and 67.3% of PLWHA, ID physicians and PHUS, respectively. Physicians perceived that 11% of PLWHA have a high rate of perception of U = U, whereas among PLWHA, only 34% reported definitive positive messages from physicians. Discrepancies between awareness and perception of accuracy of the message U = U in PLWHA and physicians have been found, suggesting still low confidence in the community regarding the message itself.

Evolution of major non-HIV-related comorbidities in HIV-infected patients in the Italian Cohort of Individuals, Naïve for Antiretrovirals (ICONA) Foundation Study cohort in the period 2004-2014.

OBJECTIVES: The management of HIV disease is complicated by the incidence of a new spectrum of comorbid noncommunicable diseases (NCDs). It is important to document changes in the prevalence of NCDs over time. The aim of the study was to describe the impact of ageing on HIV markers and on the prevalence of NCDs in people living with HIV (PLWHIV) in the Italian Cohort of Individuals, Naïve for Antiretrovirals (ICONA) seen for care in 2004-2014. METHODS: Analyses were conducted separately for a closed cohort (same people seen at both times) and an open cohort (all people under follow-up). We used the χ2 test for categorical factors and the Wilcoxon test for quantitative factors to compare profiles over time. RESULTS: The closed cohort included 1517 participants and the open cohort 3668 under follow-up in 2004 and 6679 in 2014. The median age of the open cohort was 41 [interquartile range (IQR) 37-46] years in 2004 and 44 (IQR 36-52) years in 2014. Analysis of the closed cohort showed an increase in the prevalence of some NCDs [the prevalence of dyslipidaemia increased from 75% in 2004 to 91% in 2014, that of hypertension from 67 to 84%, and that of cardiovascular disease (CVD) from 18 to 32%] and a decrease in renal function (5% with eGFR < 60 mL/min per 1.73 m2 in 2004 versus 30% in 2014); the percentage of people in the high-risk group for the Framingham CHD score more than tripled (from 13 to 45%). Results in the open cohort were similar. CONCLUSIONS: The burden of NCDs in our PLWHIV population markedly worsened over a 10-year time-span, which is likely to be a result of the effects of both ageing and HIV infection as well as their interaction. Special attention must be given to the management and prevention of NCDs.

Dynamics and phylogenetic relationships of HIV-1 transmitted drug resistance according to subtype in Italy over the years 2000-14.

Background: Transmitted drug-resistance (TDR) remains a critical aspect for the management of HIV-1-infected individuals. Thus, studying the dynamics of TDR is crucial to optimize HIV care. Methods: In total, 4323 HIV-1 protease/reverse-transcriptase sequences from drug-naive individuals diagnosed in north and central Italy between 2000 and 2014 were analysed. TDR was evaluated over time. Maximum-likelihood and Bayesian phylogenetic trees with bootstrap and Bayesian-probability supports defined transmission clusters. Results: Most individuals were males (80.2%) and Italian (72.1%), with a median (IQR) age of 37 (30-45) years. MSM accounted for 42.2% of cases, followed by heterosexuals (36.4%). Non-B subtype infections accounted for 30.8% of the overall population and increased over time (<2005-14: 19.5%-38.5%, P < 0.0001), particularly among Italians (<2005-14: 6.5%-28.8%, P < 0.0001). TDR prevalence was 8.8% and increased over time in non-B subtypes (<2005-14: 2%-7.1%, P = 0.018). Overall, 467 transmission clusters (involving 1207 individuals; 27.9%) were identified. The prevalence of individuals grouping in transmission clusters increased over time in both B (<2005-14: 12.9%-33.5%, P = 0.001) and non-B subtypes (<2005-14: 18.4%-41.9%, P = 0.006). TDR transmission clusters were 13.3% within the overall cluster observed and dramatically increased in recent years (<2005-14: 14.3%-35.5%, P = 0.005). This recent increase was mainly due to non-B subtype-infected individuals, who were also more frequently involved in large transmission clusters than those infected with a B subtype [median number of individuals in transmission clusters: 7 (IQR 6-19) versus 4 (3-4), P = 0.047]. Conclusions: The epidemiology of HIV transmission changed greatly over time; the increasing number of transmission clusters (sometimes with drug resistance) shows that detection and proper treatment of the multi-transmitters is a major target for controlling HIV spread.

European AIDS Clinical Society Standard of Care meeting on HIV and related coinfections: The Rome Statements.

OBJECTIVES: The objective of the 1st European AIDS Clinical Society meeting on Standard of Care in Europe was to raise awareness of the European scenario and come to an agreement on actions that could be taken in the future. METHODS: Data-driven presentations were given on specific topics followed by interactive panel discussions. RESULTS: In Eastern European countries, the epidemic is largely driven by injecting drug use, in contrast with Western Europe where the infection mainly occurs through heterosexual contact. A high proportion of people living with HIV remain unaware of their infection. Substantial differences exist in Eastern Europe and Central Asia with respect to treatment coverage, regimen availability and continuity of drug supply. In 2012, tuberculosis case notification rates were 5-10 times higher in Eastern Europe compared with Western Europe, with an alarming proportion of newly diagnosed multi-drug-resistant cases. Hepatitis C is widespread in selected geographical areas and risk groups. CONCLUSIONS: The key conclusion from the meeting was that a high-priority group of actions could be identified, including: increasing HIV awareness and testing, improving training for health care providers, ensuring equitable patient access to treatments and diagnostics for HIV and comorbidities, and implementing best practices in infection control and treatment of HIV-infected patients coinfected with tuberculosis and hepatitis C virus, for whom direct acting antiviral treatment. should be considered.

Incidence and factors associated with the risk of sexually transmitted diseases in HIV-infected people seen for care in Italy: data from the Icona Foundation cohort.

OBJECTIVES: The aims of this study were to identify temporal trends in the incidence of sexually transmitted diseases (STDs) in a cohort of HIV-infected people and to evaluate factors associated with the risk of a new STD diagnosis. METHODS: All HIV-infected patients in the Icona Foundation Study cohort enrolled after 1998 were included in this study. STD incidence rates (IRs) were calculated and stratified by calendar period. Predictors of STDs were identified using a Poisson regression model with sandwich estimates for standard errors. RESULTS: Data for 9168 participants were analysed [median age 37.3 (range 18-81) years; 74% male; 30% men who have sex with men (MSM)]. Over 46 736 person-years of follow-up (PYFU), 996 episodes of STDs were observed [crude IR 21.3/1000 PYFU; 95% confidence interval (CI) 20.0-22.6/1000 PYFU]. In multivariable Poisson regression analysis, MSM [rate ratio (RR) 3.03; 95% CI 2.52-3.64 versus heterosexuals], calendar period (RR 1.67; 95% CI 1.42-1.97 for 2008-2012 versus 1998-2002), HIV RNA > 50 HIV-1 RNA copies/mL (RR 1.44; 95% CI 1.19-1.74 versus HIV RNA ≤ 50 copies/mL) and a current CD4 count < 100 cells/µL (RR 4.66; 95% CI 3.69-5.89; P < 0.001 versus CD4 count > 500 cells/µL) were associated with an increased risk of STDs. In contrast, older age (RR 0.82 per 10 years older; 95% CI 0.77-0.89) and being currently on ART (RR 0.38; 95% CI 0.33-0.45) compared with being ART-naïve or on a treatment interruption were associated with a lower risk of developing STDs. CONCLUSIONS: An increase in the incidence of STDs was observed in more recent years. Interventions to prevent STDs and potential spread of HIV should target the younger population, MSM and people currently not receiving ART.

Antiretroviral treatment-based cost saving interventions may offset expenses for new patients and earlier treatment start.

OBJECTIVES: Combination antiretroviral therapy (cART) has become the main driver of total costs of caring for persons living with HIV (PLHIV). The present study estimated the short/medium-term cost trends in response to the recent evolution of national guidelines and regional therapeutic protocols for cART in Italy. METHODS: We developed a deterministic mathematical model that was calibrated using epidemic data for Lazio, a region located in central Italy with about six million inhabitants. RESULTS: In the Base Case Scenario, the estimated number of PLHIV in the Lazio region increased over the period 2012-2016 from 14 414 to 17 179. Over the same period, the average projected annual cost for treating the HIV-infected population was €147.0 million. An earlier cART initiation resulted in a rise of 2.3% in the average estimated annual cost, whereas an increase from 27% to 50% in the proportion of naïve subjects starting cART with a nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimen resulted in a reduction of 0.3%. Simplification strategies based on NNRTIs co-formulated in a single tablet regimen and protease inhibitor/ritonavir-boosted monotherapy produced an overall reduction in average annual costs of 1.5%. A further average saving of 3.3% resulted from the introduction of generic antiretroviral drugs. CONCLUSIONS: In the medium term, cost saving interventions could finance the increase in costs resulting from the inertial growth in the number of patients requiring treatment and from the earlier treatment initiation recommended in recent guidelines.

Variability analysis of 'Persian' acid lime tree selections using agronomic and molecular markers.

'Persian' acid lime (PAL) is the most important triploid commercial citrus crop planted in the world. Little is known about the genetic variability of the selections used in Brazil. Therefore, 25 genotypes originating from the PAL, and three control species, Citrus sunki, C. limon, and C. aurantiifolia, were assessed using inter-simple sequence repeat (ISSR) and inter-retrotransposon amplified polymorphism (IRAP) molecular markers and agronomic traits of the fruit. The dendrograms were designed using the mean Euclidean distance for the physicochemical attributes of the fruit (weight, length, diameter, peel color, peel thickness, number of seeds, juice yield, titratable acidity, soluble solids, and ratio) and the Jaccard distances using the data from the ISSR and IRAP molecular markers. In the physicochemical analysis, the genotypes were grouped according to species. The trait that contributed most to the diversity among accessions was the number of seeds. The 17 ISSR primers produced 69 polymorphic bands in the molecular analysis, and the seven IRAP primers generated 30 polymorphic bands. The markers detected polymorphisms within and among the PALs; two groups were formed within the PALs.

Factors associated with access to antiviral treatment in a multicentre cross-sectional study of patients with chronic hepatitis B in Italy.

A multicentre cross-sectional survey was performed to provide an accurate picture of patients with chronic hepatitis B (CHB) cared for by Italian Infectious Diseases Centers (IDCs). This analysis describes factors associated with access to the treatment of CHB in a country where barriers to treatment are not expected to exist because of comprehensive coverage under the National Health System (NHS). The study was performed in 74 IDCs. The analysis focused on 3305 patients with CHB of 3760 HBsAg-positive patients enrolled from March to September, 2008. To account for missing values, a Multiple Imputation method was used. Treatment was reported in 2091 (63.3%) patients. In the multivariate analysis, an increased chance of getting treatment was independently associated with 10 years increase of age at diagnosis (adjusted odds ratio [aOR] 1.2, 95% confidence interval [CI] 1.1-1.3, P < 0.001), HBeAg positivity (aOR 1.8, 95% CI 1.1-2.8, P < 0.001), cirrhosis (aOR 3.6, 95% CI 2-6.3, P = 0.012), HDV (aOR 1.6, 95% CI 1.02-2.5, P = 0.042) and HIV positivity (aOR 6.5, 95% CI 4-10.8, P < 0.001). Conversely, a decreased chance was associated with female gender (aOR 0.6, 95% CI 0.5-0.7, P < 0.001), immigration (aOR 0.6, 95% CI 0.5-0.9, P = 0.009), alcohol consumption (aOR 0.7, 95% CI 0.5-0.98, P = 0.04) and HCV positivity (aOR 0.5, 95% CI 0.3-0.8, P = 0.005). Our study shows that Italian IDCs treat a high percentage of patients with CHB. Nevertheless, disparities exist which are not related to the severity of disease limiting access to antiviral therapy of CHB, even in a country with a universal healthcare system.

Interferon-γ release assays for the diagnosis of active tuberculosis: a systematic review and meta-analysis.

Interferon-γ release assays (IGRAs) are now established for the immunodiagnosis of latent infection with Mycobacterium tuberculosis in many countries. However, the role of IGRAs for the diagnosis of active tuberculosis (TB) remains unclear. Following preferred reporting items for systematic reviews and meta-analyses (PRISMA) and quality assessment of diagnostic accuracy studies (QUADAS) guidelines, we searched PubMed, EMBASE and Cochrane databases to identify studies published in January 2001-November 2009 that evaluated the evidence of using QuantiFERON-TB® Gold in-tube (QFT-G-IT) and T-SPOT.TB® directly on blood or extrasanguinous specimens for the diagnosis of active TB. The literature search yielded 844 studies and 27 met the inclusion criteria. In blood and extrasanguinous fluids, the pooled sensitivity for the diagnosis of active TB was 80% (95% CI 75-84%) and 48% (95% CI 39-58%) for QFT-G-IT, and 81% (95% CI 78-84%) and 88% (confirmed and unconfirmed cases) (95% CI 82-92%) for T-SPOT.TB®, respectively. In blood and extrasanguinous fluids, the pooled specificity was 79% (95% CI 75-82%) and 82% (95% CI 70-91%) for QFT-G-IT, and 59% (95% CI 56-62%) and 82% (95% CI 78-86%) for T-SPOT.TB®, respectively. Although the diagnostic sensitivities of both IGRAs were higher than that of tuberculin skin tests, it was still not high enough to use as a rule out test for TB. Positive evidence for the use of IGRAs in compartments other than blood will require more independent and carefully designed prospective studies.

Late presentation of HIV infection: a consensus definition.

OBJECTIVES: Across Europe, almost a third of individuals infected with HIV do not enter health care until late in the course of their infection. Surveillance to identify the extent to which late presentation occurs remains inadequate across Europe and is further complicated by the lack of a common clinical definition of late presentation. The objective of this article is to present a consensus definition of late presentation of HIV infection. METHODS: Over the past year, two initiatives have moved towards a harmonized definition. In spring 2009, they joined efforts to identify a common definition of what is meant by a 'late-presenting' patient. RESULTS: Two definitions were agreed upon, as follows. Late presentation: persons presenting for care with a CD4 count below 350 cells/µL or presenting with an AIDS-defining event, regardless of the CD4 cell count. Presentation with advanced HIV disease: persons presenting for care with a CD4 count below 200 cells/µL or presenting with an AIDS-defining event, regardless of the CD4 cell count. CONCLUSION: The European Late Presenter Consensus working group believe it would be beneficial if all national health agencies, institutions, and researchers were able to implement this definition (either on its own or alongside their own preferred definition) when reporting surveillance or research data relating to late presentation of HIV infection.

Suspected transmission of tuberculosis in a maternity ward from a smear-positive nurse: preliminary results of clinical evaluations and testing of neonates potentially exposed, Rome, Italy, 1 January to 28 July 2011.

We report preventive measures adopted after tuberculosis(TB) transmission from a nurse to a newborn assessed in late July 2011. All exposed neonates born between January and July 2011 were clinically evaluated and tested by QuantiFERON TB gold in-tube; newborns testing positive were referred for prophylaxis.Of 1,340 newborns, 118 (9%) tested positive and no other active cases of TB were found. Active surveillance for TB will be continued over the next three years for all those exposed.

Hepatitis C diagnosis and treatment in people who use drugs: mind the gap in the linkage to care.

OBJECTIVE: The objective of this study is to identify a simplified rapid screening and linkage-to-care model for HCV among PWUD. PATIENTS AND METHODS: The study stems from a collaborative project bringing together two local Italian Centers for Drug Addiction and the Hepatology-Infectious Diseases Department of Lazzaro Spallanzani. A research physician analyzed the available medical records seeking to identify HCV and HIV infected patients in care in the addiction centers. Between March 2018 and January 2020 subjects were selected from among a cohort of 720 PWUD in the two Centers' care. The study comprises three steps: first, screening for HCVAb; second, the linkage to care; third, clinical assessment to treatment. The research physician recruited patients for the first two steps directly in their local addiction center. The third step was conducted in the Spallanzani. The characteristics of those subjects who adhered to the three-step study program were then compared to those of the non-adhering PWUD. RESULTS: 194 were known HCVAb positive patients. Of the 505 PWUD in the care of the two Centers eligible for screening, 364 were enrolled in the study. 144 resulted HCVAb positive. 269 were tested for HCVRNA. 101 underwent a full assessment. 96 patients started antiviral therapy with DAA. Patients who refused first step screening were older patients and mainly heroin users; in the second step, almost all the HIV/HCV co-infected patients agreed to a viremia test; in the third step all the HIV/HCV co-infected patients refused HCV treatment. CONCLUSIONS: The study suggests an on-site specialist approach conducted directly in the addiction centers themselves starting from screening; it can bring the goal of HCV PWUD microelimination closer.

Therapeutic strategies and outcomes of MDR and pre-XDR-TB in Italy: a nationwide study.

BACKGROUND: Treatment outcomes in multidrug-resistant TB (MDR-TB) patients are suboptimal in several low-incidence countries.METHODS: The primary outcome measure was the proportion of successfully treated patients in Italy during an 18-year period. Secondary outcomes were treatment outcomes in certain drug-containing regimens and the possibility for the WHO shorter MDR-TB regimen.RESULTS: In the 191 patients included (median age at admission: 33 years; 67.5% male, following drug-resistance patterns were found: MDR-TB in 68.6%, pre-extensively drug-resistant TB (pre-XDR-TB) in 30.4% and XDR-TB in 1.1% patients. The most frequently prescribed drugs were fluoroquinolones in 84.6% cases, amikacin in 48.7%, linezolid in 34.6% and meropenem/clavulanic acid in 29.5%. The median duration of treatment was 18 months. Treatment success was achieved in 71.2% patients, of whom, 44% were cured and 27.2% completed treatment. Treatment success rates did not statistically differ between the MDR- (68.8%) and pre-XDR-TB (77.6%) groups (P = 0.26). Treatment success rates had large variability between North and South of Italy (81.3% vs. 53.3%). Only 22.5% of the cases would have been eligible for shorter MDR-TB regimensCONCLUSION: Our study highlights variability in treatment outcomes in MDR- and pre-XDR-TB patients. Study findings confirmed the potential utility of linezolid and, for patients with limited oral options, meropenem/clavulanic acid and amikacin.

Response to Rv2628 latency antigen associates with cured tuberculosis and remote infection.

Interferon-gamma release assays based on region of difference 1 antigens have improved diagnosis of latent tuberculosis infection (LTBI). However, these tests cannot discriminate between recently acquired infection (higher risk of progression to active tuberculosis) and remote LTBI. The objective of the present study was to evaluate the T-cell interferon-gamma responses to Mycobacterium tuberculosis DosR-regulon-encoded antigens (latency antigens) compared with QuantiFERON TB-Gold In-Tube (QFT-GIT) in subjects at different stages of tuberculosis. A total of 16 individuals with remote LTBI and 23 with recent infection were studied; 15 controls unexposed to M. tuberculosis and 50 patients with active tuberculosis and 45 with cured tuberculosis were also analysed. The results indicated that subjects with remote LTBI showed significantly higher whole-blood interferon-gamma responses to M. tuberculosis latency antigen Rv2628 than did individuals with recent infection, active tuberculosis and controls (p<0.003), whereas no significant differences between these groups were found for other latency antigens tested (Rv2626c, Rv2627c, Rv2031c and Rv2032). The proportion of responders to Rv2628 was five-fold higher among QFT-GIT-positive-individuals with remote infection than among those with recently acquired infection. These data suggest that responses to M. tuberculosis latency antigen Rv2628 may associate with immune-mediated protection against tuberculosis. In contact-tracing investigations, these preliminary data may differentiate recent (positive QFT-GIT results without responses to Rv2628) from remote infection (positive to both tests).

3-mercaptopropionic acid-induced seizures decrease NR2B expression in Purkinje cells: cyclopentyladenosine effect.

Inhibitory mechanism of cerebellum epileptic activity can be involved depending on the intensity and frequency of seizure convulsions. N-methyl-D-aspartate receptors (NMDARs) play key roles in excitatory synaptic transmission and have been implicated in neurological disorders: in cerebellum, they have specific characteristics. NMDARs are heteromeric complexes, and the expression of functional receptors in mammalian cells requires the subunit NR1 (essential) and one NR2 subtype of the four isoforms: NR2A-NR2D. In mature Purkinje cells, the combination of NR1 with NR2B subunits forms functional NMDARs; NR2B subunit may be altered in exocitotoxic events. Cyclopentyladenosine (CPA), an adenosine analogue, administered to rats, for one or more days, increases seizure threshold induced by the convulsant drug 3-mercaptopropionic acid (MP). In this study, we focused on the expression of NR2B in cerebellum after repetitive seizures induced by MP and the effect of adenosine analogue CPA administered alone or previous to MP (CPA + MP). A significant decrease in NR2B in the whole cerebellum was observed after MP and CPA administration with a tendency to recover to normal values in the combined treatment of CPA administered 30 min before MP by Western blot assay. In immunohistochemical studies, NR2B expression was observed and analysed in Purkinje cells. NR2B expression was decreased after MP (55%) and CPA (12%) administration, and CPA injected 30 min before MP led to 28% reduction in Purkinje cells. These results could be related to Purkinje cell damage or alternatively to avoid the excitotoxic effect. Results recorded after CPA + MP treatment seemed involved in decreasing the convulsant MP effect.

A new health care index predicts short term mortality for TB and HIV co-infected people.

BACKGROUND: Using 2004-2007 TB:HIV Study data from Europe and Latin America, we previously generated a health care index (HCI) for TB and HIV co-infected people. With improvements in diagnostic and management practices, we have now updated the HCI with new data.METHODS: We evaluated nine aspects of health care in Cox proportional hazards models on time from TB diagnosis to death. Kaplan-Meier methods were used to estimate the probability of death by HCI quartile.RESULTS: Of 1396 eligible individuals (72% male, 59% from Eastern Europe), 269 died within 12 months. Use of rifamycin/isoniazid/pyrazinamide-based treatment (HR 0.67, 95% CI 0.50-0.89), TB drug susceptibility testing (DST) and number of active TB drugs (DST + <3 drugs (HR 1.09, 95% CI 0.80-1.48), DST + ≥3 drugs (HR 0.49, 95% CI 0.35-0.70) vs. no DST), recent HIV-RNA measurement (HR 0.64, 95% CI 0.50-0.82) and combination antiretroviral therapy use (HR 0.72, 95% CI 0.53-0.97) were associated with mortality. These factors contributed respectively 5, -1, 8, 5 and 4 to the HCI. Lower HCI was associated with an increased probability of death; 30% (95% CI 26-35) vs. 9% (95% CI 6-13) in the lowest vs. the highest quartile.CONCLUSION: We found five potentially modifiable health care components that were associated with mortality among TB-HIV positive individuals. Validation of our HCI in other TB cohorts could enhance our findings.

QuantiFERON-TB Gold and the TST are both useful for latent tuberculosis infection screening in autoimmune diseases.

Screening for active tuberculosis (TB) and latent TB infection (LTBI) is mandatory prior to the initiation of tumour necrosis factor-alpha inhibitor therapy. However, no agreement exists on the best strategy for detecting LTBI in this population. The aim of the present study was to analyse the performance of the tuberculin skin test (TST) and QuantiFERON-TB Gold in-tube (QFT-GIT) on LTBI detection in subjects with immunomediated inflammatory diseases (IMID). The TST and QFT-GIT were prospectively performed in 398 consecutive IMID subjects, 310 (78%) on immunosuppressive therapy and only 16 (4%) had been bacillus Calmette-Guérin (BCG) vaccinated. Indeterminate results to QFT-GIT were found in five (1.2%) subjects. Overall, 74 (19%) out of 393 subjects were TST-positive and 52 (13%) were QFT-GIT-positive. Concordance between TST and QFT-GIT results was good (87.7%): 13 were QFT-GIT-positive/TST-negative and 35 QFT-GIT-negative/TST-positive. By multivariate analysis both tests were significantly associated with older age. Only the TST was associated with BCG vaccination and radiological lesions of past TB. Use of immunosuppressive drugs differently modulated QFT-GIT or TST scoring. Use of the QuantiFERON-TB Gold in-tube, as a screening tool for latent tuberculosis among immunomediated inflammatory disease subjects, is feasible. Until further data will elucidate discordant tuberculin skin test/QuantiFERON-TB Gold in-tube results, a strategy of simultaneous tuberculin skin and QuantiFERON-TB Gold in-tube testing in a low prevalence bacillus Calmette-Guérin vaccinated population, should maximise potentials of latent tuberculosis diagnosis.

A retrospective TBNET assessment of linezolid safety, tolerability and efficacy in multidrug-resistant tuberculosis.

Linezolid is used to treat patients with multidrug-resistant (MDR)/extensively drug-resistant (XDR)-tuberculosis (TB) cases, although clinical data on its safety, tolerability and efficacy are lacking. We performed a retrospective, nonrandomised, unblinded observational study evaluating the safety and tolerability of linezolid at 600 mg q.d. or b.i.d. in MDR/XDR-TB treatment in four European countries. Efficacy evaluation compared end-points of 45 linezolid-treated against 110 linezolid-nontreated cases. Out of 195 MDR/XDR-TB patients, 85 were treated with linezolid for a mean of 221 days. Of these, 35 (41.2%) out of 85 experienced major side-effects attributed to linezolid (anaemia, thrombocytopenia and/or polyneuropathy), requiring discontinuation in 27 (77%) cases. Most side-effects occurred after 60 days of treatment. Twice-daily administration produced more major side-effects than once-daily dosing (p = 0.0004), with no difference in efficacy found. Outcomes were similar in patients treated with/without linezolid (p = 0.8), although linezolid-treated cases had more first-line (p = 0.002) and second-line (p = 0.02) drug resistance and a higher number of previous treatment regimens (4.5 versus 2.3; p = 0.07). Linezolid 600 mg q.d. added to an individualised multidrug regimen may improve the chance of bacteriological conversion, providing a better chance of treatment success in only the most complicated MDR/XDR-TB cases. Its safety profile does not warrant use in cases for which there are other, safer, alternatives.

Diagnostic accuracy of in-house PCR for pulmonary tuberculosis in smear-positive patients: meta-analysis and metaregression.

In-house PCR (hPCR) could speed differential diagnosis between tuberculosis (TB) and nontuberculous mycobacterial disease in patients with positive smears and pulmonary infiltrates, but its reported accuracy fluctuates across studies. We conducted a systematic review and meta-analysis of hPCR sensitivity and specificity for smear-positive TB diagnosis, using culture as the reference standard. After searching English language studies in MEDLINE and EMBASE, we estimated cumulative accuracy by means of summary receiver operating characteristic analysis. The possible influence of hPCR procedures and study methodological features on accuracy was explored by univariate metaregression, followed by multivariate adjustment of items selected as significant. Thirty-five articles (1991 to 2006) met the inclusion criteria. The pooled estimates of the diagnostic odds ratio, sensitivity, and specificity (random-effect model) were, respectively, 60 (confidence interval [CI], 29 to 123), 0.96 (CI, 0.95 to 0.97), and 0.81 (CI, 0.78 to 0.84), but significant variations (mainly in specificity) limit their clinical applicability. The quality of the reference test, the detection method, and real-time PCR use explained some of the observed heterogeneity. Probably due to the limited study power of our meta-analysis and to the wide differences in both laboratory techniques and methodological quality, only real-time PCR also displayed a positive impact on accuracy in the multivariate model. Currently, hPCR can be confidently used to exclude TB in smear-positive patients, but its low specificity could lead to erroneous initiation of therapy, isolation, and contact investigation. As the inclusion of samples from treated patients could have artificially reduced specificity, future studies should report mycobacterial-culture results for each TB and non-TB sample analyzed.

Characterization of regulatory T cells identified as CD4(+)CD25(high)CD39(+) in patients with active tuberculosis.

Forkhead box P3 (FoxP3) is a transcription factor whose expression characterizes regulatory T cells (T(reg)), but it is also present on activated T cells, thus hindering correct T(reg) identification. Using classical markers for T(reg) recognition, discordant results were found in terms of T(reg) expansion during active tuberculosis (TB) disease. Recently CD39 has been shown to be an accurate marker for T(reg) detection. The objectives of this study were: (i) to identify T(reg) expressing CD39 in patients with TB and to compare the results with those obtained by the standard phenotypic markers; (ii) to evaluate if T(reg) are expanded in vitro by exogenous interleukin (IL)-2 or by antigen-specific stimulation; and (iii) to characterize T(reg) function on the modulation of antigen-specific responses. We enrolled 13 patients with pulmonary TB and 12 healthy controls. T(reg) were evaluated by flow cytometry ex vivo and after antigen-specific in vitro stimulation using CD25, FoxP3, CD127 and CD39 markers. Results indicate that CD39(+) cells within the CD4(+)CD25(high) cells have T(reg) properties (absence of interferon-gamma production and transforming growth factor-beta1 release upon stimulation). Ex vivo analysis did not show significant differences between TB patients and controls of T(reg) by classical or novel markers. In contrast, a significantly higher percentage of T(reg) was found in TB patients after antigen-specific stimulation both in the presence or absence of IL-2. Depletion of CD39(+) T(reg) increased RD1-specific responses significantly. In conclusion, CD39 is an appropriate marker for T(reg) identification in TB. These results can be useful for future studies to monitor Mycobacterium tuberculosis-specific response during TB.