Screening for Tuberculosis Infection among Migrants: A Cost-Effectiveness Analysis in the Italian Context.

BACKGROUND: Screening of tuberculosis infection (TBI) among migrants from high-incidence countries is a cornerstone of tuberculosis control in low-incidence countries. However, the optimal screening strategy has not been defined yet. METHODS: A quasi-experimental study involving migrants residing in the province of Brescia was carried out that aimed at assessing the completion rate, time to completion, preventive treatment initiation rate, and cost-effectiveness of two strategies for TBI screening. They underwent TBI screening with the IGRA-only strategy (arm 1) or with the sequential strategy (tuberculin skin test, TST, followed by IGRA in case of a positive result-arm 2). The two strategies were compared in terms of screening completion, time to complete the screening process, therapy initiation, and cost-effectiveness. RESULTS: Between May 2019 and May 2022, 657 migrants were evaluated, and 599 subjects were included in the study, with 358 assigned to arm 1 and 237 to arm 2. Screening strategy was the only factor associated with screening completion in a multivariable analysis, with the subjects assigned to the IGRA-only strategy more likely to complete the screening cascade (n = 328, 91.6% vs. n = 202, 85.2%, IRR 1.08, 95% CI (1.01-1.14), p = 0.019). The time to complete the screening process was significantly longer for patients assigned to the sequential strategy arm (74 days vs. 46 days, p = 0.002). Therapy initiation did not significantly differ between the two arms, and cost-effectiveness was higher for the sequential strategy. CONCLUSION: Sequential strategy implementation for TBI screening among migrants may be justified by its higher cost-effectiveness in spite of the lower completion of the screening cascade.

Fragmentation of Healthcare Services as a Possible Determinant of the Low Completion for the Tuberculosis Cascade of Prevention among Asylum Seekers: Results from a Prospective Study with Historical Comparison.

Background: Effective screening for tuberculosis infection (TBI) among asylum seekers (AS) is crucial for tuberculosis (TB) elimination in low incidence countries. Methods: We assessed the proportion of completion of the screening for TBI among asylum seekers with a centralized delivery method compared to the decentralized model previously adopted in the study area (historical control). In the historical model (January 2017 to May 2018) screening of AS was performed at the arrival offering TBI testing (TST followed by IGRA among those positive), radiological investigation, treatment initiation and hospital referral, if needed, at three sites: migrant health clinic, pneumology clinic and infectious diseases department for active disease (decentralized model). In the study model (June 2018, centralized) all steps of screening were performed at a single site, at a minimum of 6 months after arrival. Multivariable Poisson regression analysis, with robust variance, was used to assess variables associated with the completion of screening for infection. Multivariable logistic regression was used to identify factors associated with the diagnosis of TB infection. Results: The intervention approach was offered to 144 AS with an overall 98.6% proportion of completion (98.7% for those with a positive TST). In the historical screening model, 1192 AS were candidates for screening, which was completed by 74.5% of those who started it (44.7% for those resulted TST positive). Major losses (55%) were detected in the TST/CXR-IGRA sequential step, followed by the execution of TST test (25%). The ratio of screening completion was significantly higher in the intervention period (aIRR 1.78, 95% CI 1.68-1.88) and for AS coming from high incidence TB countries (aIRR 1.14, 95% CI 1.04-1.25). Screening after 6 months from arrival and age were associated with TB infection (2.09, 95% CI 1.36-3.2 and 1.14, 95% CI 1.01-1.29). Conclusions: Screening for TBI can be improved by a centralized approach. Higher prevalence of TBI 6 months after arrival could reflect recent (either during travel or in Italy) acquisition of the infection.

Immunological Evolution of a Cohort of HIV-2 Infected Patients: Peculiarities of an Underestimated Infection.

Background: Human Immunodeficiency Virus type 2 (HIV-2) affects a minority of patients in Italy; nevertheless, the increasing migratory flow from higher prevalence areas led to the spread of this virus into our Country. We evaluate clinical, viro-immunological, and therapeutic characteristics of patients with HIV-2 infection and HIV-1/HIV-2 dual-infection and the early treatment impact on overall survival and incidence of AIDS events. Methods: We retrospectively analyzed all HIV-2, and HIV-1/HIV-2 positive patients followed in a large Italian clinic from January 1987 to December 2020. We recorded demographic, viro-immunological, clinical, and therapeutic data. We performed a descriptive analysis followed by a longitudinal analysis to explore the factors associated with the CD4+ lymphocyte trend; lastly, we studied the possible predictors of death and AIDS in our cohort in a multivariable model. Results: 32 subjects were enrolled, 17 (53%) HIV-2 infected and 15 (46.8%) HIV-1/HIV-2 dual-infected; 12 patients were lost to follow up, while 3 died. We found a lack of HIV-2 viremia in 12/32 subjects (37.5%). Most of the patients at baseline had a good viro-immunological profile with HIV-2 RNA <200 copies/ml and CD4+ lymphocyte >200 cell/mcl. We found a CD4+ lymphocyte improvement over time, both in the absolute number (ß 472.61, 95%CI 383.05-562.18, p<0.001) and in percentage (ß 25.28, 95%CI 21.91 - 28.66, p<0.001). Nevertheless, subjects taking cART had CD4+ lymphocyte percentage increase over time, and this trend appeared significantly better than those who did not receive therapy. Lastly, in the multivariable model CD4+, T-cell count increase was negatively associated with AIDS (HR 0.34 95%CI 0.13-0.91, p=0.032). Conclusion: We found a higher prevalence of HIV-1/2 dual infection than in previous observations. Subjects with HIV-2 infection showed a favorable immunological condition at diagnosis, and the benefits of cART in those who received treatment are undiscussed. Moreover, our data suggest a different disease course based on age at diagnosis, as in HIV-1 infections. We encourage starting cART at diagnosis in HIV-2 patients, regardless of CD4+ lymphocyte, because even in the new cART era, CD4+ lymphocyte decrease remains the strongest predictor of death and AIDS also in this population.

Consequences of the COVID-19 pandemic on the continuum of care in a cohort of people living with HIV followed in a single center of Northern Italy.

INTRODUCTION: During the COVID-19 pandemic, hospitals faced increasing pressure, where people living with HIV risked to either acquire SARS-CoV-2 and to interrupt the HIV continuum of care. METHODS: This is a retrospective, observational study. We compared the numbers of medical visits performed, antiretroviral drugs dispensed and the number of new HIV diagnosis and of hospitalizations in a cohort of people living with HIV (PLWH) followed by the Spedali Civili of Brescia between the bimester of the COVID-19 pandemic peak and the bimester of October-November 2019. Data were retrieved from administrative files and from paper and electronic clinical charts. Categorical variables were described using frequencies and percentages, while continuous variables were described using mean, median, and interquartile range (IQR) values. Means for continuous variables were compared using Student's t-tests and the Mann-Whitney test. Proportions for categorical variables were compared using the χ2 test. RESULTS: As of December 31st, 2019, a total of 3875 PLWH were followed in our clinic. Mean age was 51.4 ± 13 years old, where 28% were females and 18.8% non-Italian. Overall, 98.9% were on ART (n = 3834), 93% were viro-suppressed. A total of 1217 and 1162 patients had their visit scheduled at our out-patient HIV clinic during the two bimesters of 2019 and 2020, respectively. Comparing the two periods, we observed a raise of missed visits from 5 to 8% (p < 0.01), a reduction in the number of new HIV diagnosis from 6.4 in 2019 to 2.5 per month in 2020 (p = 0.01), a drop in ART dispensation and an increase of hospitalized HIV patients due to COVID-19. ART regimens including protease inhibitors (PIs) had a smaller average drop than ART not including PIs (16.6 vs 21.6%, p < 0.05). Whether this may be due to the perception of a possible efficacy of PIs on COVID19 is not known. CONCLUSIONS: Our experience highlights the importance of a resilient healthcare system and the need to implement new strategies in order to guarantee the continuum of HIV care even in the context of emergency.

High HIV-1 diversity in immigrants resident in Italy (2008-2017).

The proportion of new diagnoses of HIV infection in immigrants residing in Italy raised from 11% in 1992 to 29.7% in 2018. To investigate the HIV clades circulating in this community a retrospective study was performed in 557 HIV-infected immigrants living in 12 Italian cities. Immigrants originated from East-Europe and Central-Asia (11.7%), North Africa and Middle East (7.3%), South and South-East Asia (7.2%), Latin America and the Caribbean (14.4%), and sub-Saharan Africa (59.4%). More than 87% of immigrants were on antiretroviral therapy (ART), although 26.6% of them were viremic. A 22.0% of immigrants had hepatitis (HBV and/or HCV) and/or tuberculosis. HIV phylogenetic analysis on sequences from 192 immigrants showed the presence of clades B (23.4%), G (16.1%), C (10.4%), A1 (9.4%), F1 (5.2%), D (1.6%) and Circulating Recombinant Forms (CRFs) (33.9%). CRF02_AG represented 72.3% of the total CRFs. Clusters between immigrants and Italian natives were also present. Drug resistance mutations to NRTI, NNRTI, and PI drug classes occurred in 29.1% of ART-treated and in 12.9% of ART-naïve individuals. These data highlight the need for tailored public health interventions in immigrants to avoid spreading in Italy of HIV genetic forms and ART-resistant variants, as well as HIV co-morbidities.

Screening for active and latent tuberculosis among asylum seekers in Italy: A retrospective cohort analysis.

BACKGROUND: The World Health Organization conditionally recommends systematic screening of tuberculosis (TB) and Latent Tuberculosis Infection (LTBI) among asylum seekers (AS) from high-burden countries, but the effectiveness of different screening approaches is controversial. METHODS: We report the results of a retrospective cohort analysis of TB and LTBI screening among consecutive AS in Brescia, Italy during 2015-2016. TB screening was based on symptoms, LTBI screening on the tuberculin skin test (TST). Logistic regression analysis was performed to identify factors associated with screening uptake. RESULTS: Of 2904 registered AS 2567 (88.4%) were evaluated for TB, 62 (2.4%) had symptoms and active TB yield was 155/100,000. Prevalence and incidence TB rates were 545/100,000 persons and 220/100,000 person-years. Questionnaire screening identified 28.6% (4/14) prevalent cases. Of 2303 (89.7%) AS with TST result, the positivity rate was 36.6% (843/2303). Of the 843 candidates for LTBI treatment 413 (49.0%) completed the screening. LTBI treatment was prescribed to 190 (47.9%) of 397 eligible individuals, 10.8% (91) completed treatment. CONCLUSIONS: TB prevalence and incidence rates were high in this AS population, but symptom-based screening performed poorly. LTBI cascade losses were significant and mainly attributable to the defragmentation of the health care system.

Molecular epidemiology and phylogenetic analysis of Hepatitis B virus in a group of migrants in Italy.

BACKGROUND: Hepatitis B virus infection (HBV) is widespread and it is considered a major health problem worldwide. The global distribution of HBV varies significantly between countries and between regions of the world. Among the many factors contributing to the changing epidemiology of viral hepatitis, the movement of people within and between countries is a potentially important one. In Italy, the number of migrant individuals has been increasing during the past 25 years. HBV genotype D has been found throughout the world, although its highest prevalence is in the Mediterranean area, the Middle East and southern Asia. We describe the molecular epidemiology of HBV in a chronically infected population of migrants (living in Italy), by using the phylogenetic analysis. METHODS: HBV-DNA was amplified and sequenced from 43 HBV chronically infected patients. Phylogenetic and evolutionary analysis were performed using both maximum Likelihood and Bayesian methods. RESULTS AND CONCLUSION: Of the 43 HBV S gene isolates from migrants, 25 (58.1 %) were classified as D genotype. Maximum Likelihood analysis showed an intermixing between Moldavian and foreigners sequences mostly respect to Italian ones. Italian sequences clustered mostly together in a main clade separately from all others. The estimation of the time of the tree's root gave a mean value of 17 years ago, suggesting the origin of the tree back to 1992 year. The skyline plot showed that the number of infections softly increased until the early 2005s, after which reached a plateau. Comparing phylogenetic data to the migrants date of arrival in Italy, it should be possible that migrants arrived in Italy yet infected from their country of origin. In conclusion, this is the first paper where phylogenetic analysis and genetic evolution has been used to characterize HBV sub genotypes D1 circulation in a selected and homogenous group of migrants coming from a restricted area of Balkans and to approximately define the period of infection besides the migration date.

Point-of-care screening, prevalence, and risk factors for hepatitis B infection among 3,728 mainly undocumented migrants from non-EU countries in northern Italy.

BACKGROUND: Screening migrants from areas where hepatitis B virus (HBV) infection is endemic is important to implement preventive measures in Europe. The aim of our study was to assess (1) the feasibility of point-of-care screening in a primary care clinic and (2) hepatitis B surface antigen (HBsAg) prevalence, associated risk factors, and its clinical and epidemiological implications in undocumented migrants in Brescia, northern Italy. METHODS: A longitudinal prospective study was conducted from January 2006 to April 2010 to assess HBsAg reactivity and associated risk factors among consenting undocumented migrants who accessed the Service of International Medicine of Brescia's Local Health Authority. Genotyping assay was also performed in HBV DNA-positive patients. RESULTS: Screening was accepted by 3,728/4,078 (91.4%) subjects consecutively observed during the study period, 224 (6%) of whom were found to be HBsAg-positive. HBsAg reactivity was independently associated with the prevalence of HBsAg carriers in the geographical area of provenance (p < 0.001). On the contrary, current or past sexual risk behaviors (despite being common in our sample) were not associated with HBV infection. Half of the HBsAg patients (111/224) had either hepatitis B e-antigen (HBeAg)-positive or -negative chronic HBV infection with a possible indication for treatment. HBV genotypes were identified in 45 of 167 HBV-infected patients as follows: genotype D, 27 subjects; genotype A, 8; genotype B, 5; and genotype C, 5. The geographical distribution of genotypes reflected the geographic provenance. CONCLUSIONS: Our results suggest that point-of-care screening is feasible in undocumented migrants and should be targeted according to provenance. Case detection of HBV infection among migrants could potentially reduce HBV incidence in migrants' contacts and in the general population by prompting vaccination of susceptible individuals and care of eligible infected patients.

Lopinavir pharmacokinetic profiles in HIV-infected patients during rifabutin-based anti-mycobacterial therapy.

OBJECTIVES: To evaluate the pharmacokinetic profile of ritonavir-boosted lopinavir in HIV-infected patients during rifabutin-based anti-mycobacterial therapy. PATIENTS AND METHODS: A longitudinal, cross-over pharmacokinetic evaluation of lopinavir with and without rifabutin in HIV-infected subjects with mycobacterial disease was done. All received lopinavir/ritonavir (400/100 mg twice a day) + an adjusted rifabutin dose of 150 mg every other day. Twelve-hour lopinavir pharmacokinetic sampling occurred at 2 weeks (T1) and 6 weeks (T2) after starting combined therapy and 10 weeks after completion of adjusted rifabutin (T3). Plasma was assayed using an HPLC method; lopinavir plasma concentration-time data were analysed using non-compartmental methods. RESULTS: In 10 patients with complete lopinavir curves at T1, T2 and T3 pharmacokinetic values were, respectively: AUC(0-12), 187.5, 161.8 and 121.1 µg ·â€Šh/mL; C(trough), 13.2, 10.0 and 7.7 µg/mL; C(max), 18.7, 15.9 and 13.3 µg/mL; and apparent oral clearance (CL/F), 0.035, 0.037 and 0.045 L/h/kg. Lopinavir C(trough) and AUC(0-12) were significantly higher at T1 compared with T3 while CL/F remained unchanged throughout. Combined treatment was well tolerated and none of the patients experienced moderate to severe lopinavir-related adverse events. CONCLUSIONS: Lopinavir serum concentrations are not reduced when the drug is administered together with an adjusted dose of 150 mg of rifabutin every other day.

Dead blood under my skin.

The diagnostic attitude of western physicians toward migrants' complaints is often an unstable balance between the obstinate search for exotic tropical diseases and the overappreciation of the cultural dimensions of symptoms. Such attitude may divert attention from organic diseases. The careful assessment of all levels of possible misunderstandings (prelinguistic, linguistic, metalinguistic, cultural, and metacultural) may help the physician to discriminate between illness and disease. The long and difficult itinerary leading to the correct diagnosis of congenital myopathy in a migrant from Senegal is described, together with the barriers encountered by the caring staff.

Forty meals for a drop of blood ...

Increasing migration flow to Western countries poses formidable challenges from the epidemiological, clinical, and cultural standpoints. A case of Dhat syndrome is presented in a young Pakistani male migrant living in Italy, which required integrated medical and cultural approach to be solved after a through diagnostic workout that did not yield any result.

Preterm delivery risk in migrants in Italy: an observational prospective study.

BACKGROUND: Various studies have ascertained different birth outcomes between resident and migrant populations in western countries. Considering preterm delivery (<37 complete weeks of gestation) as a perinatal risk condition, we assessed its rate in migrant and native Italian women who delivered in the main public hospital in Brescia (Italy). METHODS: All migrant puerperas and a random sample of native puerperas hospitalized during the period February to May 2005 were included in the study after informed consent and filled in a self-administered multilanguage questionnaire enquiring about sociodemographic and obstetric data. Additional information including last menstrual period was obtained from personal obstetric records. RESULTS: As many as 471 puerperas entered the study: 366 Italian and 105 migrant women coming from eastern Europe (41.9%), Asia (20%), South America (10.5%), and Africa (27.6%). Of the migrant population, 67 of 105 (63.8%) were at their first delivery in Italy (median interval from arrival: 3.8 y). Gestational age at delivery was assessed for 456 of 471 women (103 migrants and 353 Italians). A total of 36 (7.9%) preterm deliveries were registered: 22 (6.2%) in Italian and 14 (13.6%) in migrant puerperas (p value = 0.015). The highest preterm delivery rate was observed in African women (20.7%), while women from eastern Europe had a similar rate to Italians. In univariate analysis, factors associated to preterm delivery were parity and length of permanence in Italy. We could not demonstrate any correlation with smoking or with a delayed access to antenatal care (first obstetric evaluation after 12 complete weeks of gestation). In multivariate analysis, African origin was the only independent risk factor for preterm delivery [odds ratio (OR) = 3.54; p = 0.018]. CONCLUSIONS: In our setting, preterm delivery occurred more frequently in migrant women, particularly of African origin, and it is not associated to delayed access to antenatal care.

QuantiFERON-TB Gold test in the identification of latent tuberculosis infection in immigrants.

BACKGROUND: The identification and treatment of latent tuberculosis infection (LTBI) among immigrants are an effective strategy for TB control in developed countries. A new test for LTBI identification that uses more specific antigens of Mycobacterium tuberculosis is now commercially available under the brand name of QuantiFERON-TB Gold test. OBJECTIVE: To compare QuantiFERON-TB Gold test to tuberculin skin testing (TST) for the detection of LTBI among immigrants from high endemic TB areas. PATIENTS AND METHODS: Undocumented immigrants attending a district medical center were enrolled if they originated from high endemic TB areas, the time of arrival in Italy was < or = 5 years, had neither active TB disease nor known immunodeficiency status. The TST was applied according to standards and QuantiFERON-TB Gold test was performed following the manufacturer's instructions. RESULTS: Hundred subjects were included in the comparative analysis. TST was positive in 44% of subjects; 15% had a positive QuantiFERON-TB Gold test result. The total agreement between TST and QuantiFERON-TB Gold test was 71%, for a kappa statistics of 0.37; agreement was 100% for TST negative results, but only 34% for TST positive ones. In the multivariate logistic regression analysis, previous BCG vaccination was independently associated with a lower chance of disagreement between the tests. CONCLUSION: The prevalence of LTBI among immigrants was lower when determined by QuantiFERON-TB Gold; this may be a consequence of more specific MTB antigens used. Our results suggest that QuantiFERON-TB Gold may be used as confirmatory test for TST positive immigrants candidate to preventive therapy.

CD4+ T cell evolution and predictors of its trend before and after tenofovir/didanosine backbone in the presence of sustained undetectable HIV plasma viral load.

BACKGROUND: Tenofovir with full-dose didanosine has been associated with paradoxical CD4 + T cell decrease despite virological suppression. We investigated whether tenofovir plus didanosine at a weight-adjusted dosage could be responsible for such an effect, and factors associated with CD4 + T cell count evolution under this combination. METHODS: This was a prospective observational multicohort study (Italian MASTER and Spanish Hospital Carlos III HIV cohorts). Patients with HIV plasma viral load suppression for >/= 6 months who switched to an antiretroviral combination including tenofovir plus didanosine were studied, as long as virological success was maintained. CD4 + T cell count variations over time (slopes) were compared before and after switching to tenofovir plus didanosine using linear mixed models and segmented regression analysis. RESULTS: Annual time-weighted CD4 + T cell count slope did not change significantly after the prescription of tenofovir plus didanosine: it was 14 cells/mm(3) [95% confidence interval (CI) - 7 to 35] from month - 24 to month - 12, 12 cells/mm(3) (95% CI - 14 to 38) from month - 12 to the time of switching, 30 cells/mm(3) (95% CI 5-55) from switching to month + 12 and 15 cells/mm(3) (95% CI - 8 to 39) from month + 12 to month + 24 after switching to tenofovir plus didanosine. No significant change in the slope of the segment after the switch to tenofovir plus didanosine-containing regimens when compared with the segment preceding the intervention was found (CD4 + T cell count slope change: 24 cells/mm(3); 95% CI - 10 to 58). Similar results were obtained using CD4 + T cell percentage over total lymphocytes. The significant independent predictors of lower CD4 + T cell count slope were older age (P = 0.006), lower nadir CD4 + T cell count (P < 0.001) and positive hepatitis C virus antibody (P = 0.03). Moreover, reduced estimated creatinine clearance was an additional independent predictor of lower CD4 + T cell count slope (P = 0.02), but only after excluding nadir CD4 + T cell count. CONCLUSIONS: Tenofovir plus didanosine (weight-adjusted dosage) was not associated with paradoxical CD4 + T cell decrease in our patients maintaining undetectable HIV plasma viral load for a maximum of 24 months after switching. Several factors could explain variability in CD4 + T cell count evolution in these patients.

Chlamydia trachomatis genital infection in migrant female sex workers in Italy.

We have assessed prevalence, incidence, and factors associated with increased risk for Chlamydia trachomatis genital infection among female migrant sex workers in Italy. In a prospective, observational study, women were offered free screening for sexually transmitted diseases and C. trachomatis was tested by a commercial ligase chain reaction assay in endocervical specimens. Of the 101 women tested, 14 (14%) were positive. The odds ratio (OR) for C. trachomatis infection was significantly higher for females under 24 years (OR=4.31), women from Eastern Europe (OR=4.80), and migrants less than 12 months in Italy (OR=4.41). In a multivariate logistic regression model, only origin from Eastern Europe remained independently associated to a higher risk for C. trachomatis infection (OR=6.05). This study provides evidence for high prevalence and incidence of C. trachomatis genital infection in migrant sex workers. Women from Eastern Europe have a significantly higher risk. These data reinforce the need for targeted control interventions.

Clinical experiences with interferon as monotherapy or in combination with ribavirin in patients co-infected with HIV and HCV.

Human immunodeficiency virus (HIV) co-infection accelerates progression of hepatitis C virus (HCV) toward cirrhosis. Thus, with the increase of life expectancy observed after introduction of combination antiretroviral treatment, liver disease is becoming an increasing cause of morbidity and mortality in HIV-infected patients. In addition, HCV co-infection blunts CD4 restoration induced by HAART and increases HAART hepatotoxicity. For all these reasons, anti-HCV treatment is mandatory in HIV seropositives. The perfect treatment of hepatitis C should not only be safe and effective, but it should not have any adverse impact on HIV diseases and concurrent anti-HIV therapy. Two drugs are currently licensed for treatment of HCV: interferon alfa (IFNalpha) and ribavirin. Three hundred and thirty-eight patients have been included in pilot studies on the efficacy and tolerability of IFNalpha monotherapy: 16% showed sustained response and 10% dropped out. No significant adverse impact of IFNalpha monotherapy on HIV diseases or antiretroviral treatment has been observed. IFNalpha and ribavirin in combination have been introduced more recently: only 88 patients were included in pilot studies published as full papers with a 25% sustained response and an 11% rate of drop outs. Anemia and cumulative toxicity with didanosine were the most important side effects of combination treatment, but it did not affect HIV disease progression. Higher rates of sustained response (33%) without increase of side effects have been observed in preliminary experiences with the new long-acting pegylated interferons in combination with ribavirin. The search for the perfect treatment continues.