Claudio Angeletti

Gender differences in clinical progression of HIV-1-infected individuals during long-term highly active antiretroviral therapy

Objective: To assess gender differences in the long-term clinical, virological and immunological outcomes during highly active antiretroviral therapy (HAART). Methods: This longitudinal observational multicentre study followed 2460 HIV-infected patients who had begun a protease inhibitor-based regimen for a median period of 43 months. Outcome measures were virological suppression (< 500 copies/ml), confirmed virological rebound after suppression, and death or new AIDS-defining illness (ADI). Results: At baseline, 690 female patients (28.0%) had significantly lower age, higher prevalence of heterosexual contact and lower prevalence of intravenous drug use as risk factors for HIV infection compared with males. Furthermore, females had a lower number of AIDS-defining illnesses, higher CD4 cell counts and lower viral loads. No gender differences were reported in terms of proportion of patients achieving viral suppression or exhibiting rebound after achieving viral suppression. Female patients experienced reduced clinical progression during follow-up compared with males (P = 0.008) by Kaplan–Meier analysis; however this difference was not significant in an adjusted analysis. In a multivariate model, the interaction between gender and risk factor for HIV or viral load showed that female drug users and female patients with a baseline HIV RNA viral load of 104–105 copies/ml had a favourable clinical outcome compared with males (P = 0.035 and P = 0.015, respectively). Conclusion: No differences were found between genders in terms of virological and immunological outcomes during long-term HAART. Nevertheless, a lower risk of clinical progression was reported among female patients with intermediate baseline viral load than in males.

Accuracy of Immunodiagnostic Tests for Active Tuberculosis Using Single and Combined Results: A Multicenter TBNET-Study

Background The clinical application of IFN-γ release assays (IGRAs) has recently improved the diagnosis of latent tuberculosis infection. In a multicenter study of the Tuberculosis Network European Trialsgroup (TBNET) we aimed to ascertain in routine clinical practice the accuracy of a novel assay using selected peptides encoded in the mycobacterial genomic region of difference (RD) 1 for the diagnosis of active tuberculosis in comparison with tuberculin skin test (TST), QuantiFERON-TB GOLD In-Tube (Cellestis Ltd., Carnegie, Australia) and T-SPOT.TB (Oxfordimmunotec, Abingdon, UK). Principal Findings 425 individuals from 6 different European centres were prospectively enrolled. We found that sensitivity of the novel test, TST, QuantiFERON-TB GOLD In-Tube and T-SPOT.TB was respectively 73.1%, 85.3%, 78.1%, and 85.2%; specificity was respectively 70.6%, 48.0%, 61.9% and 44.3%; positive likelihood ratios were respectively 2.48, 1.64, 2.05, and 1.53; negative likelihood ratios were respectively 0.38, 0.31, 0.35, 0.33. Sensitivity of TST combined with the novel test, QuantiFERON-TB GOLD In-Tube and T-SPOT.TB increased up to 92.4%, 97.7% and 97.1%, respectively. The likelihood ratios of combined negative results of TST with, respectively, the novel test, QuantiFERON-TB GOLD In-Tube and T-SPOT.TB were 0.19, 0.07 and 0.10. Conclusions The assay based on RD1 selected peptides has similar accuracy for active tuberculosis compared with TST and commercial IGRAs. Then, independently of the spectrum of antigens used in the assays to elicit mycobacterial specific immune responses, the novel test, IGRAs, and the TST do not allow an accurate identification of active tuberculosis in clinical practice. However, the combined use of the novel assay or commercial IGRAs with TST may allow exclusion of tuberculosis.

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

Interferon-&ggr; 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-&ggr; 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-&ggr; 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).

Late presenters in an HIV surveillance system in Italy during the Period 1992-2006

Objectives:The objectives of this study are to describe trends over time from 1992 to 2006 in the number of newly diagnosed HIV-infected individuals in Modena (Italy) and to describe their clinical and immunological characteristics. We also identify risk factors associated with presenting at late stages of HIV disease. Methods:All new HIV diagnoses with at least 1 CD4+ cell count and known stage of HIV disease were included. Using multivariate logistic regression models, we examined factors associated with being a late presenter, defined as individuals presenting with CD4+ cell count <200 cells per microliter or AIDS within 3 months of their HIV-positive test. A quantile regression model was used to examine changes in CD4+ cell count at presentation and trends over time. Results:Of 844 newly diagnosed individuals included in analyses, 332 (39%) were late presenters, and this proportion remained constant over time (P = 0.106). Older age, male sex, and foreign born were the only determinants of being a late presenter. Persons newly diagnosed in 2002-2006 were less likely to present with an advanced clinical status. Discussion:A substantial proportion of new HIV diagnoses are still at advanced stages of disease. In particular, foreign-born and heterosexual males still represent the largest part of AIDS presenters. Efforts are needed to encourage HIV testing and reduce the proportion who first seek HIV care at such a late stage.

The Effect of Age on Response to Therapy With Peginterferon α Plus Ribavirin in a Cohort of Patients With Chronic HCV Hepatitis Including Subjects Older Than 65 Yr

OBJECTIVES:In many industrialized countries HCV infection is characterized by an increasing prevalence during ageing; however, data on the efficacy of treatment among older patients are scarce. This study was set up to evaluate the effect of age on the treatment of chronic HCV hepatitis with peginterferon α plus ribavirin.METHODS:We retrospectively reviewed medical records of 153 adult patients with chronic HCV hepatitis treated with combination therapy; 30 of them (19.6%) were 65 years of age or older.RESULTS:In multivariable analysis, age groups ≥40 years had similar odds of achieving sustained virologic response (P = 0.71) and significantly lower odds of sustained response compared with younger patients (odds ratio [OR] 0.16, 95% confidence interval [CI] 0.05–0.59, P = 0.006; OR 0.13, 95% CI 0.03–0.49, P = 0.002; OR 0.21, 95% CI 0.05–0.91, P = 0.037 for patients aged 40–49 years, 50–64 years, and older than 64 years, respectively). The effect of age was present in the 74 patients infected with genotype 1 or 4 (P = 0.04), while among the 79 patients with genotype 2 or 3 sustained virologic response rates were relatively uniform, with no statistically significant differences.CONCLUSIONS:The probability of good response to combination treatment with peginterferon α plus ribavirin is decreased for patients aged more than 40 years infected with genotype 1 or 4, but patients aged more than 65 had a similar rate of response to those aged 40–64 years. Combination treatment may be safely extended to elderly patients with no major contraindications.

Kaposi's sarcoma in transplant and HIV-infected patients: an epidemiologic study in Italy and France.

Background. A follow-up study was conducted in Italy and in France to compare the epidemiology of Kaposi’s sarcoma (KS) between human immunodeficiency virus (HIV)-infected people and transplant recipients. Methods. In all, 8,074 HIV-positive individuals (6,072 from France and 2,002 HIV-seroconverters from Italy) and 2,705 Italian transplant recipients (1,844 kidney transplants, 702 heart transplants, and 159 liver transplants) were followed-up between 1970 and 2004. Standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were computed to estimate the risk of KS, as compared to sex- and age-matched Italian and French populations. Incidence rate ratios (IRRs) were used to identify risk factors for KS. Results. A 451-fold higher SIR for KS was recorded in HIV-infected subjects and a 128-fold higher SIR was seen in transplant recipients. Significantly increased KS risks were observed in HIV-infected homosexual men (IRR=9.7 in France and IRR=6.7 in Italy vs. intravenous drug users), and in transplant recipients born in southern Italy (IRR=5.2 vs. those born in northern Italy). HIV-infected patients with high CD4+ cell counts and those treated with antiretroviral therapies had reduced KS risks. In relation to duration of immunosuppression, KS occurred earlier in transplant patients than in HIV-seroconverters. Conclusions. This comparison highlighted that the risk of KS was higher among HIV-infected individuals than in transplant recipients, and that different co-factors are likely to influence the risk of KS. Moreover, the early KS occurrence in transplant recipients could be associated with different patterns of progressive impairment of the immune function.

Epidemiological aspects of major opportunistic infections of the respiratory tract in persons with AIDS: Europe, 1993-2000.

Objective(s): To describe the epidemiology of Pneumocystis carinii pneumonia (PCP), pulmonary tuberculosis (PTB) and recurrent bacterial pneumonia (RBP) as AIDS-defining illnesses (ADI) in Europe. Design: Analysis of AIDS surveillance data collected in the World Health Organization European region by EuroHIV, Saint Maurice, France. Methods: Adult AIDS cases notified between 1993 and 2000 were studied. Since AIDS diagnosis may be constituted by up to four concurrent illnesses, polytomous logistic regression odds ratios (OR) and 95% confidence intervals (CI) were computed. Time trends and correlates of PCP, PTB or RBP were assessed. Results: There were 181 296 ADI among the 142 447 AIDS cases included in this study. PCP was the commonest ADI in western Europe (17.8%) and PTB (20.4%) was the commonest ADI in eastern Europe. Within western Europe, PTB was more common in the south than in the north (OR, 1.5) and increased steadily over time. RBP increased until 1998 (from 1.9% to 3.7%) and thereafter declined. Young age was associated with an excess risk for PTB and, in comparison with heterosexuals, homosexual men were at higher risk for PCP (OR, 1.3). Injecting drug users (IDU) (OR, 2.8; 95% CI, 2.6–3.1) and recipients of blood (OR, 1.7; 95% CI, 1.4–2.2) were at increased risk for RBP. Conclusions: This analysis highlighted the continuing importance of PCP and the increasing importance of PTB as an ADI in western Europe, and it emphasized the need to investigate more thoroughly the vast epidemic of AIDS-associated PTB in eastern Europe. IDU and recipients of blood should be considered as target groups for vaccination against RBP.

Effective highly active antiretroviral therapy in patients with primary HIV-1 infection prevents the evolution of the avidity of HIV-1-specific antibodies

Objective:To evaluate if the administration of highly active antiretroviral therapy (HAART) during primary HIV infection (PHI) may affect the antibody avidity evolution. Methods:In 13 subjects with symptomatic PHI, of whom 8 initiated HAART at diagnosis, the Avidity Index (AI) and Western blot evolution patterns were analyzed on serial serum/plasma samples for 1 year. In 4 patients, who subsequently interrupted HAART, additional specimens were analyzed. Results:At diagnosis, the range of HIV viremia was 0.003 to 38 × 106 copies/mL. In untreated patients, viremia reached the set point in 4 to 6 months, whereas in treated patients, early suppression of viremia was observed, remaining undetectable during therapy. At diagnosis, the median AI was low in untreated (0.42, range: 0.33 to 0.43) and treated (0.44, range: 0.40 to 0.72) patients. At 3, 6, and 12 months, the AI progressively increased in untreated patients, whereas it remained <0.80 in all treated patients. In the 4 patients interrupting HAART, the AI increased after therapy interruption to greater than 0.80 in ≤6 months. The Western blot pattern transiently/partially reversed during HAART in 2 patients. Conclusions:Antibody avidity maturation takes place only in the presence of ongoing viral replication. These results may have relevant implications in understanding the complex mechanism of maturation of the immune response to HIV.

underevaluation of Hiv-1 Plasma Viral Load by a Commercially Available Assay in a Cluster of Patients Infected With Hiv-1 A/g Circulating Recombinant Form (crf02)

The authors studied the correlation and agreement of commercially available assays in detection and quantification of the HIV-1 intersubtype A/G circulating recombinant form CRF02. The assays under comparison were Bayer Versant HIV-1 RNA, version 3.0; Roche Amplicor HIV-1 Monitor, version 1.5 (standard procedure); and Organon Teknika NucliSens HIV-1 RNA QT. Plasma samples from 114 patients infected with CRF02 were tested by the three assays under standard conditions. Although correlation among the assays was high and statistically significant for subtype B and CRF02, in the latter instance, NucliSens measured average viral load values (3.29 +/- 0.71 log(10) copies/mL) about 4 and >8 times lower than those obtained by Versant (3.90 +/- 0.90 log(10) copies/mL) and Amplicor (4.22 +/- 1.05 log(10) copies/mL), respectively. Furthermore, in a statistically significant percentage of CRF02-harboring samples, NucliSens produced viral load values undetectable or 1 log(10) lower than those obtained in Versant and Amplicor assays. Altogether, these data underline a low performance of NucliSens in detecting and quantifying viremia in plasma samples harboring the CRF02. These results are potentially important as global distribution of new HIV-1 subtypes is expanding, and recombinant strains, particularly CRF02, are emerging and becoming highly prevalent.

Comparison of LCx with Other Current Viral Load Assays for Detecting and Quantifying Human Immunodeficiency Virus Type 1 RNA in Patients Infected with the Circulating Recombinant Form A/G (CRF02)

ABSTRACT LCx was compared to other assays in measuring human immunodeficiency virus type 1 (HIV-1) CRF02 viremia. LCx showed significant but low correlation with the other methods. Values of <2.60 log10 cp/ml were observed in 29.6% of specimens with LCx and in only 14.8% with bDNA and PCR, suggesting suboptimal performance of LCx with CRF02.