Giorgio Antonucci

Impact of combination antiretroviral therapy on the risk of tuberculosis among persons with HIV infection

ObjectiveTo assess the association between use of different antiretroviral regimens and incidence of tuberculosis among HIV-infected individuals. DesignObservational, multicenter, prospective cohort study. Setting and patientsTwenty-eight infectious diseases hospital units in Italy. A total of 2160 HIV-infected persons were considered for enrolment in a study on the implementation of tuberculosis preventive therapy between 1 May 1995 and 30 April 1996. The 1360 subjects who completed tuberculin screening at base-line were included in this analysis. Information on the use of antiretroviral therapies over time was collected. The median duration of follow-up was 104 weeks and 997 subjects (73.3%) completed the study. Main outcome measureIncidence of active tuberculosis according to different types of antiretroviral therapy. ResultsEighteen cases of tuberculosis were observed with an overall incidence rate of 0.79 per 100 person–years of observation [95% confidence interval (CI), 0.51–1.31]. Tuberculin positivity and low CD4+ lymphocyte count were the only base-line variables independently associated with the risk of tuberculosis. During follow-up, 637 patients took double combination antiretroviral therapy and 387 took triple combination therapy. After adjusting for base-line characteristics of enrolled individuals, the relative hazard of tuberculosis was 0.16 (95% CI, 0.03–0.74) for double combination therapy and 0.08 (95% CI, 0.01–0.88) for triple combination therapy compared with no therapy or monotherapy. ConclusionsCombination antiretroviral therapy significantly reduced the risk of tuberculosis in HIV-infected persons. In industrialized countries, the widespread use of this treatment may determine a decrease in the incidence of HIV-associated tuberculosis, possibly contributing to a reduction in the overall incidence of tuberculosis.

Risk factors for tuberculosis in HIV-infected persons. A prospective cohort study. The Gruppo Italiano di Studio Tubercolosi e AIDS (GISTA).

OBJECTIVE To analyze how demographic, clinical, and laboratory characteristics influence the risk of tuberculosis in human immunodeficiency virus (HIV)-infected individuals; to examine the incidence of tuberculosis associated with change in skin test responsiveness in HIV-infected, tuberculin-negative, nonanergic individuals. DESIGN Multicenter cohort study. SETTING Twenty-three infectious disease units in public hospitals in Italy. SUBJECTS A consecutive sample of 3397 HIV-infected subjects were considered for entry in the study. Of these, 2695 who were followed up for at least 4 weeks were enrolled in the study; 739 subjects (27.4%) were unavailable for follow-up. The median duration of follow-up was 91 weeks. MAIN OUTCOME MEASURE Culture-proven tuberculosis. RESULTS Eighty-three episodes of tuberculosis were observed. Incidence rates of tuberculosis were 5.42 per 100 person-years among tuberculin-positive subjects, 3.00 per 100 person-years among anergic subjects, and 0.45 per 100 person-years among tuberculin-negative nonanergic subjects. In multivariate analysis, being tuberculin-positive (hazard ratio [HR], 9.94; 95% confidence interval [CI], 3.84 to 25.72) or anergic (HR, 3.35; 95% CI, 1.40 to 8.00), or having a CD4+ lymphocyte count less than 0.20 x 10(9)/L (HR, 4.87; 95% CI, 2.35 to 10.11) or between 0.20 and 0.35 x 10(9)/L (HR, 2.35; 95% CI, 1.09 to 5.05) were statistically significantly associated with the risk of tuberculosis. Incidence of tuberculosis increased with decreasing levels of CD4+ lymphocytes in the three groups of subjects with different skin test responsiveness. Skin tests were repeated 1 year after enrollment in 604 tuberculin-negative nonanergic subjects; three case of tuberculosis were observed among the 13 subjects who converted to tuberculin reactivity. CONCLUSIONS Risk of tuberculosis in HIV-infected persons can be more precisely quantified by jointly considering skin test reactivity and CD4+ lymphocyte count. Periodic skin tests in tuberculin-negative nonanergic individuals can be useful in identifying individuals at high risk of active tuberculosis.

Risk Factors and Outcome among a Large Patient Cohort with Community-Acquired Acute Hepatitis C in Italy

BACKGROUND The epidemiology of acute hepatitis C has changed during the past decade in Western countries. Acute HCV infection has a high rate of chronicity, but it is unclear when patients with acute infection should be treated. METHODS To evaluate current sources of hepatitis C virus (HCV) transmission in Italy and to assess the rate of and factors associated with chronic infection, we enrolled 214 consecutive patients with newly acquired hepatitis C during 1999-2004. The patients were from 12 health care centers throughout the country, and they were followed up for a mean (+/- SD) period of 14+/-15.8 months. Biochemical liver tests were performed, and HCV RNA levels were monitored. RESULTS A total of 146 patients (68%) had symptomatic disease. The most common risk factors for acquiring hepatitis C that were reported were intravenous drug use and medical procedures. The proportion of subjects with spontaneous resolution of infection was 36%. The average timespan from disease onset to HCV RNA clearance was 71 days (range, 27-173 days). In fact, 58 (80%) of 73 patients with self-limiting hepatitis experienced HCV RNA clearance within 3 months of disease onset. Multiple logistic regression analyses showed that none of the variables considered (including asymptomatic disease) were associated with increased risk of developing chronic hepatitis C. CONCLUSIONS These findings underscore the importance of medical procedures as risk factors in the current spread of HCV infection in Italy. Because nearly all patients with acute, self-limiting hepatitis C--both symptomatic and asymptomatic--have spontaneous viral clearance within 3 months of disease onset, it seems reasonable to start treatment after this time period ends to avoid costly and useless treatment.

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.

Role of Human Immunodeficiency Virus in Primary Pulmonary Hypertension Case Reports

Previous cases of pulmonary hypertension (PH) in human immunodeficiency virus (HIV) infection have been reported in the literature. The role of HIV in PH is still debatable. The purpose of this report was to analyze whether HIV plays a direct or indirect role in PH pathogenesis. Between February and November 1997, 56 HIV-infected patients with cardiac symptoms and signs were studied by serial color Doppler echocardiography. In four patients (7.1%), PH not related to other well-known associated conditions, was disclosed. In spite of a low serum HIV RNA viral load and a high-efficacy antiretroviral therapy, including a protease inhibitor in two patients, PH developed and worsened. It could be hypothesized that in some patients with an individual immunogenetic predis position, a high secretion of cytokines and endothelin-1 stimulated by an unidentified pathogen different from HIV could lead to PH. Antiretroviral therapy seems not to prevent or reduce right ventricle pressure gradient in PH.

A randomized controlled trial of pegylated interferon-α2a plus adefovir dipivoxil for hepatitis B e antigen-negative chronic hepatitis B

BACKGROUND Pegylated interferon (PEG-IFN)-alpha monotherapy is the current standard of care for short-term antiviral treatment of hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB). We aimed to assess the safety and efficacy of PEG-IFN-alpha plus adefovir dipivoxil (ADV) versus PEG-IFN-alpha monotherapy for compensated HBeAg-negative CHB. METHODS A multicentre randomized controlled trial was performed in eight outpatient hepatology/infectious disease clinics in central Italy. A total of 60 patients (67% male and median age 48 years) with biopsy-proven HBeAg-negative compensated CHB (mean alanine aminotranferase [ALT] levels 3.3 +/-3x the upper normal limit and serum hepatitis B virus [HBV] DNA 5.8 +/-0.9 log(10) IU/ml) were randomized at baseline to receive PEG-IFN-alpha2a 180 microg/week plus ADV 10 mg/day or PEG-IFN-alpha2a monotherapy for 48 weeks. Post-treatment follow-up was for 24 additional weeks. The primary end point was sustained HBV DNA suppression defined as serum HBV DNA<2,000 IU/ml after 24 weeks of post-treatment follow-up. The secondary end point was ALT normalization at the end of follow-up. RESULTS At week 48, HBV DNA was undetectable in 20/30 (67%) in the combination group versus 11/30 (37%) patients in the monotherapy group (P=0.02). ALT normalization was achieved in 17/30 (57%) versus 10/30 (30%) patients, respectively (P=0.03). At week 72, sustained virological response was achieved in 7/30 (23.3%) in the combination group versus 6/30 (20%) patients in the monotherapy group (P=0.75); 5 (16%) patients in each group dropped out because of adverse events or non-compliance. CONCLUSIONS In HBeAg-negative CHB, combination PEG-IFN-alpha2a plus ADV for 48 weeks is safe and resulted in greater on-treatment efficacy than PEG-IFN-alpha2a monotherapy. No difference in sustained virological and biochemical response rates were observed between the two treatment regimens.

Tuberculosis in HIV‐infected persons in the context of wide availability of highly active antiretroviral therapy

Highly active antiretroviral therapy (HAART) greatly reduces the risk of developing tuberculosis for HIV‐infected persons. Nonetheless, HIV‐associated tuberculosis continues to occur in countries where HAART is widely used. To identify the characteristics of HIV‐infected persons who develop tuberculosis in the context of the availability of HAART, the current authors analysed data taken from 271 patients diagnosed, in Italy, during 1999–2000. These patients represent 0.7% of the 40,413 HIV‐infected patients cared for in the clinical units participating in this current study. From the data it was observed that 20 patients (7.4%) had a previous episode of tuberculosis whose treatment was not completed. Eighty-one patients (29.9%) were diagnosed with HIV at tuberculosis diagnosis, 108 (39.8%) were aware of their HIV status but were not on antiretroviral treatment and 82 (30.3%) were on antiretroviral treatment. Patients on antiretroviral treatment were significantly less immunosuppressed than patients with HIV diagnosed concurrently with tuberculosis, or other patients not on antiretrovirals (median CD4 lymphocytes count: 220 cells·mm−3 versus 100 cells·mm−3, and 109 cells·mm−3, respectively). No significant differences in clinical presentation of tuberculosis according to antiretroviral therapy status were recorded. Failure of tuberculosis control interventions (e.g. noncompletion of treatment) and of HIV care (delayed diagnosis of HIV infection and suboptimal uptake of therapy) may contribute to continuing occurrence of HIV‐associated tuberculosis in a country where highly active antiretroviral therapy is largely available. However, a significant proportion of cases occur in patients who are on antiretroviral treatment.

Practice guidelines for the treatment of hepatitis C: Recommendations from an AISF/SIMIT/SIMAST expert opinion meeting

It is increasingly clear that a tailored therapeutic approach to patients with hepatitis C virus infection is needed. Success rates in difficult to treat and low-responsive hepatitis C virus patients are not completely satisfactory, and there is the need to optimise treatment duration and intensity in patients with the highest likelihood of response. In addition, the management of special patient categories originally excluded from phase III registration trials needs to be critically re-evaluated. This article reports the recommendations for the treatment of hepatitis C virus infection on an individual basis, drafted by experts of three scientific societies.

Role of hepatitis C virus (HCV) viremia and HCV genotype in the immune recovery from highly active antiretroviral therapy in a cohort of antiretroviral-naive HIV-infected individuals.

BACKGROUND The roles of hepatitis C virus (HCV) viremia and HCV genotype in the immune response to highly active antiretroviral therapy (HAART) are poorly understood. Our aim was to assess the CD4+ cell count recovery after HAART in human immunodeficiency virus (HIV)-infected patients with HCV viremia and HIV-infected patients who tested negative for HCV antibody (HCV-Ab). We also aimed to assess whether the response to HAART in these patients varied according to HCV genotype. METHODS The analysis focused on 1219 HCV-Ab-negative patients and 284 HCV-viremic patients from a cohort of HIV-infected subjects that includes persons who were antiretroviral naive before initiating HAART after cohort enrollment. HCV RNA load and HCV genotype were determined in plasma specimens obtained and stored during the 6-month period preceding the initiation of HAART. RESULTS The chance of achieving a CD4+ cell count increase of > or = 100 cells/microL from the pre-HAART level tended to be poorer in HCV-viremic patients than in patients who tested negative for HCV-Ab (adjusted relative hazard [RH], 0.82; 95% confidence interval [CI], 0.66-1.01; P = .06). In contrast, a comparison of patients who had a HCV RNA load >1 x 10(6) IU/mL with patients who had a HCV RNA load of 5-1 x 10(6) IU/mL revealed no significant association between HCV RNA load and achievement of an increased CD4+ cell count (adjusted RH, 0.97; 95% CI, 0.75-1.27; P = .83). There was no clear association between HCV genotype and the probability of achieving a CD4+ cell count increase. CONCLUSIONS An association between the presence of HCV-Ab and immune reconstitution after HAART has been shown elsewhere. Results of our large, prospective study support a direct role of HCV viremia in the CD4+ cell count response to HAART. Moreover, our results underline the fact that, in individuals coinfected with HIV and HCV, the goal of treating HCV infection is to eradicate HCV, to both slow the rate of HCV progression and limit potential interference with the response to HAART.

Occult hepatitis B virus infection in a Cohort of HIV-positive patients: Correlation with hepatitis C virus coinfection, virological and immunological features

Background:An evaluation of the prevalence of occult hepatitis B virus (HBV) infection in HIV-positive individuals is important as HBV infection may have an impact on the outcome of the liver disease in these patients.Materials and Methods:Of the 1,593 HIV-positive subjects enrolled in the Italian Cohort Naïve Antiretroviral (ICONA) program, 175 (10.9%) were selected for inclusion in the study on the basis of hepatitis B surface antigen (HBsAg) negativity and antibody to hepatitis B core antigen (anti- HBc) positivity; 101/175 (58%) were also anti-hepatitis C virus (HCV) positive. HBV-DNA was detected in plasma using a highly sensitive PCR assay (detection limit: 2.6 copies/ml). Two different genomic regions were assayed. Quantification was performed by real-time PCR. The HBV genotype was determined in 20 cases with occult HBV infection. Data on the antiretroviral therapy (ART) regimen was obtained in 169 individuals: 53 (31.4%) patients were ART-naive, 46 (27.2%) were under ART without lamivudine or tenofovir, and the remaining 70 (41.4%) were under ART including lamivudine or tenofovir.Results:27/175 (15%) patients had detectable HBV-DNA in their plasma: 21/101 (21%) were anti-HCV positive and 6/74 (8%) were anti-HCV negative. Genotype D was invariably found in the 20 cases analyzed. Occult HBV infection was significantly higher in HCV-coinfected subjects: adjusted OR 5.02, 95% CI 1.31–19.26, p = 0.02. The value was not associated with immune status, HIV load, or ART regimen.Conclusions:In relation to the high prevalence of occult HBV infection, particularly in HIV/HCV-coinfected individuals, it is necessary to clarify the clinical impact of this cryptic infection by monitoring HBV-DNA in plasma using the correct approach. Similarly to HBsAg-positive individuals of the Mediterranean area, HBV genotype D is invariably detected in this cohort of HIV-infected patients with occult HBV infection.