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Risk of Developing Specific AIDS-Defining Illnesses in Patients Coinfected with HIV and Hepatitis C Virus With or Without Liver Cirrhosis

  1. Antonella d'Arminio Monforte1,
  2. Alessandro Cozzi-Lepri12,
  3. Antonella Castagna2,
  4. Andrea Antinori3,
  5. Andrea De Luca4,
  6. Cristina Mussini5,
  7. Sergio Lo Caputo6,
  8. Massimo Arlotti7,
  9. Giacomo Magnani8,
  10. Gianpietro Pellizzer9,
  11. Franco Maggiolo10,
  12. Massimo Puoti11, and
  13. Icona Foundation Study Groupa
  1. 1Clinic of Infectious and Tropical Diseases, San Paolo Hospital, University of Milan, Rome
  2. 2Department of Infectious Diseases, Istituto Ricerca Clinica Carattere Scientifico San Raffaele Hospital, Milan, Rome
  3. 3Istituto Nazionale Malattie Infettive Lazzaro Spallanzani and Cattolica University, Rome
  4. 4Clinic of Infectious Diseases, Cattolica University, Rome
  5. 5Clinic of Infectious Diseases, Modena University, Modena
  6. 6Department of Infectious Diseases, Santissima Annunziata Hospital, Bagno a Ripoli, Florence
  7. 7Department of Infectious Diseases, Hospital of Rimini, Rimini
  8. 8Department of Infectious Diseases, Hospital of Reggio Emilia, Reggio Emilia
  9. 9Department of Infectious Diseases, Hospital of Vicenza, Vicenza
  10. 10Department of Infectious Diseases, Riuniti Hospital, Bergamo
  11. 11Institute of Infectious Diseases, University of Brescia, Italy
  12. 12Research Department of Infection and Population, Royal Free and University College Medical School, London, United Kingdom
  1. Reprints or correspondence: Dr. Antonella d'Arminio Monforte, Clinic of Infectious and Tropical Diseases, Dept. of Medicine, Surgery and Dentistry, San Paolo University Hospital Milan, via A Di Rudinì 8-20142, Milan, Italy (antonella.darminio{at}unimi.it).
 
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Abstract

Background. There are few data concerning the risk of specific opportunistic diseases in patients with and without hepatitis C virus (HCV) infection. We evaluated the correlation between the occurrence of different AIDS-defining illnesses (ADIs) and chronic HCV infection or HCV-related liver cirrhosis in a large Italian cohort of human immunodeficiency virus (HIV)-infected subjects.

Methods. Subjects were stratified into 2 groups: patients without HCV coinfection and with persistently normal aminotransferase levels and patients with HCV coinfection. The patients with HCV coinfection were stratified according to the diagnosis of liver cirrhosis. The incidences of new ADIs were calculated as the number of events per 1000 person-years of follow-up. The rates in the 2 groups were compared using a Poisson regression model adjusted for potential confounders.

Results. We observed a total of 496 ADIs among 5397 patients with 25,105 person-years of follow-up (50% tested positive for HCV). HCV coinfection was associated with increased risk of developing an ADI (adjusted relative rate [ARR], 2.61; 95% confidence interval [CI], 1.88–3.61), specifically bacterial infection (ARR, 3.15; 95% CI, 1.76–5.67), HIV-related disease (ARR, 2.68; 95% CI, 1.03–6.97), and mycotic disease (ARR, 3.87; 95% CI, 2.28–6.59) but not non-Hodgkin lymphoma (ARR, 0.88; 95% CI, 0.22–3.48). The rate of mycotic infection, bacterial infection, toxoplasmosis, and HIV-related ADI among patients with cirrhosis were significantly higher than that among HIV-monoinfected patients, and the risk was greater than that estimated for HCV antibody-positive patients without cirrhosis.

Conclusions. HIV-related bacterial and mycotic infections are strongly associated with positive HCV serostatus and HCV-related cirrhosis. Clinicians should take into account these data when making decisions on initiation of antiretroviral therapy for HCV-coinfected individuals.

After the introduction of highly active antiretroviral therapy (HAART), a dramatic reduction in human immunodeficiency virus (HIV)-related morbidity and mortality was observed [1, 2], primarily regarding opportunistic diseases [3]. As a consequence, liver diseases have gained importance as a cause of morbidity and death among HIV-infected individuals [4, 5]. Hepatitis C virus (HCV) is the main cause of liver disease in this population, because HIV and HCV share routes of transmission. HIV-HCV-coinfected patients show an increased risk of progression of HCV-related liver dis ease, compared with HCV-monoinfected patients [6, 7]. There are conflicting reports concerning whether HCV infection may alter the course of HIV infection [8, 9]. In the pre-HAART era, several studies suggested a similar survival rate and progression to AIDS for HIV-infected subjects, independent of HCV infection, whereas other studies suggested the opposite [6, 10–12]. After the introduction of HAART, HCV infection has emerged as one of the main diseases affecting the survival of HIV-infected individuals; however, data on the impact of HCV coinfection on HIV disease progression and mortality are highly controversial [13–26].

At present, with the exception of lymphoma, there are few data concerning the risk of specific opportunistic diseases in HCV-infected and -uninfected patients. The study of the association between HCV and risk of cancer were prompted by emerging evidences that HCV may play a role in lymphoproliferation [27, 28]. Several studies of patients not infected with HIV demonstrated that, in southern Europe and Japan, the prevalence of HCV infection is increased among persons with non-Hodgkin lymphoma [29–31], but this observation was not confirmed in other studies [32–34]. To date, the relationship between HIV-HCV coinfection and the risk of HIV-related non-Hodgkin lymphoma has been evaluated in only a few cohort studies in the United States or northern Europe, providing no evidence that the HIV-HCV-coinfected population is at increased risk of lymphoma [35–37].

The aim of this study was to evaluate the risk of different AIDS-defining conditions (including non-Hodgkin lymphoma) in relation to the presence of chronic HCV infection or HCV-related liver cirrhosis in a large Italian cohort of HIV-infected patients.

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Methods

Patient selection and classification. We considered all patients in an Italian cohort of HIV-infected subjects who were enrolled when antiretroviral therapy naive (in the Icona Foundation Study). All patients enrolled in the original cohort (see detailed description elsewhere [38]) are still included in the Icona Foundation Study; enrollments were reopened in 2007, and the plan is to extend patient follow-up for at least an additional 10 years. Patients were defined as being HCV infected from the time of the first test result positive for HCV antibody. Subjects with hepatitis B virus infection (defined by a test result positive for hepatitis B surface antigen on at least 1 occasion during the follow-up) were excluded. Treatment of HCV infection was recorded in the database; there is an entry for all start and stop dates of any drug active against HCV.

We evaluated the incidence of different types of AIDS-defining illnesses (ADIs) according to whether patients (i) had current evidence of HIV infection but not of HCV infection, with recent evidence of normal transaminase levels (alanine aminotransferase level, <40 IU/mL in the past 2 consecutive measurements), or (ii) had previously tested positive for HCV infection. Person-years of follow-up (PYFU) for HIV-monoinfected patients who had recent evidence of a non-HCV-induced alanine aminotransferase level >40 IU/mL were excluded from this analysis; the rationale was to create a control group of HIV-infected patients who were unlikely to have HCV-unrelated liver disease. The second group of patients was further stratified according to whether patients were currently free of cirrhosis or had previously received a diagnosis (histological and/or clinical) of HCV-related liver cirrhosis. Because only a proportion of patients underwent a histological examination, it is possible that a larger number of histological diagnoses of cirrhosis would have been made if all patients were tested, thus resulting in misclassification. To reduce this possible bias, a sensitivity analysis excluding all patients who received a histological diagnosis was performed.

Clinical outcomes. ADIs were diagnosed according to the 1993 Centers for Disease Control and Prevention criteria [39] and were classified a priori into 6 different groups according to etiology: (a) non-Hodgkin lymphoma; (b) viral infection (Kaposi sarcoma, disseminated cytomegalovirus infection, progressive multifocal leukoencephalopathy, disseminated herpes simplex virus infection, cervix carcinoma, and primary brain lymphoma); (c) bacterial infection (Mycobacterium avium complex [MAC] disseminated infection, recurrent bacterial pneumonia, Mycobacterium tuberculosis pulmonary or extrapulmonary infection, and recurrent Salmonella sepsis); (d) HIV-related disease (wasting syndrome and AIDS dementia complex); (e) protozoal infection (Toxoplasma gondii encephalitis); and (f) mycotic infection (esophageal candidiasis, Pneumocystis jirovecii pneumonia [PCP], and Cryptococcus neoformans meningitis). CD4 cell count was not used for the definition of any of the ADIs. We used the Icona Foundation database, the version updated to March 2009, for this analysis.

Statistical analyses. Patients with >1 new diagnosis at the time of the first new ADI after enrollment contributed more than once to the analysis. We used robust standard errors to make inferences to account for nonindependence of events coming from the same patient. We analyzed each end point separately, and we adopted a competing-risk analysis with baseline as the date of enrollment in the Icona Foundation Study and with censoring of patients' follow-up at the end of follow-up if they developed an ADI different from that under analysis. The incidences of new ADIs were calculated as the number of events divided by the PYFU and expressed per 1000 PYFU. The rates in the exposure groups of interest described above (ie, HIV-monoinfected and HCV-coinfected patients) were compared using a Poisson regression model adjusted for several potential confounders, such as year of enrollment; months since first test result positive for HIV; age; mode of HIV infection; current use of HAART (fitted as time dependent); most recent HIV-RNA level, CD4 cell count, and CD4 cell count nadir (all fitted as time dependent); level of education; type of employment; and use of alcohol. To evaluate whether the potential impact of HCV infection on the risk of ADI was different according to whether patients were currently receiving antiretroviral therapy, the interaction between HCV coinfection and antiretroviral therapy was formally tested in the model. The main analysis was repeated using a cause-specific approach censoring patients' follow-up at the date of the competing event [40].

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Results

Study population. We included 5397 patients in the Icona Foundation Study cohort who had been tested at least once for both HCV antibody and hepatitis B surface antigen and had test results negative for hepatitis B surface antigen at any point during the follow-up. Their median year at enrollment was 1998 (range, 1997–2008). Clinical and demographic characteristics of the population at enrollment are presented in Table 1.

Figure 1
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Figure 1

CD4 cell counts at the time of AIDS diagnosis, according to hepatitis C virus antibody (HCV Ab) test result and type of AIDS-defining illness. HIV, human immunodeficiency virus; NHL, non-Hodgkin lymphoma; +, positive for HCV Ab; −, negative for HCV Ab.

Table 1
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Table 1

Characteristics of the 5397 Patients at Enrollment

Overall, the total patient follow-up time of 25,105 PYFU was divided into 12,581 PYFU (50%) in which patients were positive for HCV antibody and 12,524 PYFU (50%) in which patients were negative for HCV antibody. By inclusion criteria, the most recent measurement of alanine aminotransferase level and the value before the current one were both <40 IU/mL in the latter group. By the end of the follow-up, the percentage of time spent receiving anti-HCV treatment was 1.3% (325 of 25,106 PYFU). Repeated HCV antibody testing in our cohort was relatively common, with a mean of 2.25 tests/year (standard deviation, 2.44), with similar intensity of testing across different modes of HIV transmission.

Incidence of ADIs. Overall, we observed a total of 496 ADIs; the types of ADI that occurred in our population, stratified according to our definition of causal etiology, are described in Table 2, which also shows the overall incidence of ADIs (counting only the first event per patient and the crude incidence rates of each type of ADI). Incidence rates were low; mycotic and bacterial infections had the highest incidences (mainly PCP and tuberculosis, respectively), with a rate of 5–6 events per 1000 PYFU, whereas the incidences of non-Hodgkin lymphoma and toxoplasmosis were 5-fold lower. Specifically, the incidence of PCP was 99 events over 27,264 PYFU (3.6 events per 1000 PYFU; 95% confidence interval [CI], 3.0–4.4 events per 1000 PYFU) and that of tuberculosis was 71 events over 27,308 PYFU (2.6 events per 1000 PYFU; 95% CI, 2.0–3.3 events per 1000 PYFU). A description of the median CD4 cell count at the time of diagnosis by specific ADI, according to whether patients were positive for HCV antibody, is shown in Figure 1.

Table 2
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Table 2

Number of AIDS-Defining Illnesses, Person-Years of Follow-up (PYFU), and Overall Rates, According to the Most Frequent Types

Table 3shows the crude risks of developing the different types of ADI according to HCV coinfection. Coinfection with HCV was associated with a 3–5 fold increased risk in bacterial, HIV-related, mycotic, and protozoal infections but not with viral infection or non-Hodgkin lymphoma. However, a tendency toward an increased risk was observed for all ADIs (Table 3). Results were similar when using either the cause-specific or competing-risk approach.

Table 3
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Table 3

Crude Rates of AIDS-Defining Illnesses, According to Hepatitis C Virus (HCV) Infection Status, and Relative Rates (RRs), with Human Immunodeficiency Virus (HIV)-Monoinfected Patients as the Comparator Group

Independent predictors of ADIs. In our analysis, patients with HCV coinfection had a 2-fold greater risk of developing ADI than did those infected with HIV alone (adjusted relative rate [ARR], 2.61; 95% CI, 1.88–3.61; P<.001). Table 4shows the ARR of developing each specific ADI according to HCV infection and a list of other factors that were associated with the study end points independently of HCV status. Current HIV RNA load (ARR, 1.47 per log10copies/mL higher; 95% CI, 1.03–2.10; P=.03) was the only independent predictor of the risk of developing non-Hodgkin lymphoma. A current CD4 cell count <200 cells/µL, compared with >500 cells/µL, was a strong predictor (P<.001) of all types of ADI except non-Hodgkin lymphoma and brain toxoplasmosis; the greatest magnitude of the effect was found for mycotic infection (relative rate [RR], 12.19; 95% CI, 4.83–30.76; Table 4).

Table 4
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Table 4

Adjusted Relative Rates (RRs) of AIDS-Defining Illnesses Calculated from the Fitting of a Poisson Regression Model

Interestingly, a higher current HIV RNA load was strongly associated (P<.001) with all study-defined end points (ARR per log10higher ranged from 1.45 for viral infection to 1.64 for bacterial infection). Older age was associated with greater risk of viral infection (RR, 1.40 per 10 years older; 95% CI, 1.09–1.79; P=.009) and mycotic infection (ARR, 1.25; 95% CI, 1.00–1.62; P=.05). Moreover, patients who acquired HIV via homosexual contacts were at higher risk of developing viral infection than were those who acquired HIV via heterosexual contacts (ARR, 1.97; 95% CI, 1.00–3.46; P=.05), and a longer duration of time from HIV diagnosis was associated with lower risk of mycotic infection (ARR, 0.93 per year longer; 95% CI, 0.89–0.97; P=.0002). Exposure to any anti-HCV treatment was not associated with the risk of any ADI (data not shown). When we investigated the association between HCV coinfection and the risk of PCP and tuberculosis separately, the ARR for comparison of HIV-HCV-coinfected patients with HIV-monoinfected patients was 1.22 (95% CI, 0.50–3.01; P=.66) for PCP and 0.99 (95% CI, 0.38–2.59; P=.98) for tuberculosis.

Association between HCV coinfection and ADIs according to current use of antiretroviral therapy. In the analysis with mycotic infection as end point, in comparison of patients who tested positive for HCV and patients who tested negative, there was a significantly greater risk (P=.008, for interaction) of developing a mycotic ADI among patients who were currently not receiving antiretroviral therapy (RR, 9.08; 95% CI, 3.62–22.75) than among those currently receiving antiretroviral therapy (ARR, 2.26; 95% CI, 1.44–3.55). In contrast, in the case of HIV-related disease, the risk associated with HCV coinfection was greater (P=.02) among patients currently receiving therapy (ARR, 10.26; 95% CI, 3.63–28.96) than among those not receiving antiretroviral therapy (RR, 2.00; 95% CI, 0.70–5.77). For all other ADIs, there was no evidence that the effect associated with testing positive for HCV was different according to current use of antiretroviral therapy.

Risk of ADIs associated with a diagnosis of cirrhosis. Of the 2450 patients who had ever tested positive for HCV antibody during follow-up, 143 patients (6%) received a clinical diagnosis and 10 (0.4%) received a histological diagnosis of cirrhosis, yielding a total of 153 liver-related cirrhosis cases included in the analysis. Of 2976 patients who had no evidence of HCV coinfection at enrollment, 96 had evidence of HCV seroconversion during follow-up, and 4 of these patients (2%) received a diagnosis of cirrhosis. We then compared the risk of ADI in 3 groups: HIV monoinfected patients, HIV-HCV-coinfected patients currently without cirrhosis, and HIV-HCV-coinfected patients currently with cirrhosis. The rates of mycotic infection (ARR, 3.86; 95% CI, 1.59–9.35; P=.003), bacterial infection (ARR, 3.74; 95% CI, 1.40–9.99; P=.009), toxoplasmosis (ARR, 7.38; 95% CI, 1.50–36.37; P=.01), and HIV-related disease (ARR, 4.78; 95% CI, 1.38–16.62; P=.01) among coinfected patients with evidence of cirrhosis were significantly higher than those among HIV-monoinfected patients, and the magnitude of the risk was greater than that estimated for HCV antibody-positive patients without cirrhosis. There was no evidence of exacerbated risk for developing non-Hodgkin lymphoma and viral infection in HCV antibody-positive patients with cirrhosis above that associated with testing positive for HCV only. In a sensitivity analysis performed after exclusion of all patients who underwent a histological examination, results were similar to those of the main analysis (data not shown).

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Discussion

In our large cohort of HIV-infected patients, largely treated with antiretroviral agents, we have observed a low incidence of ADIs, with evidence of a 2-fold increased risk of AIDS among HIV-HCV-coinfected patients, compared with HIV-monoinfected patients. This increased risk was >3-fold for mycotic infection, bacterial infection, and HIV-related disease. There was evidence that a concurrent diagnosis of cirrhosis further increased the risk of these specific ADIs. HCV infection did not show a strong association with the risk of non-Hodgkin lymphoma, viral infection, and toxoplasmosis.

A previous study showed that HCV coinfection was associated with an increased risk of AIDS or CD4+cell count of <200 cells/µL, compared with HIV infection alone [41]. In this study, the number of HCV-coinfected patients was too small to analyze its association with different ADIs. To our knowledge, this is the first study to investigate whether the risk associated with HCV infection may be different according to specific AIDS-defining events and whether it is exacerbated in patients with liver cirrhosis.

Our results have important implications because HCV coinfection is frequent among HIV-infected individuals, especially those who acquired HIV via injection drug use. Up to 45% of the patients enrolled in our study were coinfected with HCV, and 5% of them had received a diagnosis of cirrhosis.

A lot of data have been published on the possible role of HCV to accelerate HIV disease progression, although conflicting evidence remains [13–26, 41]. Six analyses showed an association between HCV and an impaired CD4 cell count recovery during receipt of antiretroviral therapy [13–17]; one showed only a partial impairment in CD4 cell count recovery [18]. An additional study reported a higher risk of AIDS or a CD4 cell count <200 cells/µL in HCV-coinfected persons [41]. In contrast, 8 large studies did not show a significant association between HCV and CD4 cell count recovery or HIV-related mortality [19–26]. Several possible confounders and differences in inclusion criteria might explain these discrepancies; differences in demographic and clinical characteristics of the studied populations, possible competitive events, different HCV subtypes (with possible different pathogenic effects), and other, not recognized factors [40].

HCV is unique in its ability to establish chronic infection in more than two-thirds of those who have contact with it [42]. The inability of the innate and adaptive immune responses to control HCV replication contributes to the development and persistence of chronic HCV infection [42]. It has been demonstrated that HCV is able in vitro to subvert innate immunity and to delay an effective adaptive immune response through several mechanisms [42–46]. In addition, it has been reported that HCV may impair CD4+T cells and related subsets in patients with HCV monoinfection and, more significantly, in patients with HIV-HCV coinfection [47–49]. The higher incidence of bacterial and mycotic infections could thus be linked to specific interactions between HCV and the weak immune response of HIV-infected patients. This hypothesis seems to be confirmed by the fact that this association has been observed in other immunocompromised individuals, such as kidney transplant recipients [50].

In HIV-infected persons, microbial translocation is strongly associated with HCV-related disease progression [51]; this may explain the remarkably high risk of bacterial infections associated with HCV and HCV-related cirrhosis.

The fact that HIV-HCV-coinfected individuals showed an increased risk of HIV-related diseases—namely, wasting syndrome and HIV dementia—is not surprising, because both cachexia and encephalopathy, hallmarkers of wasting syndrome and dementia, may also be related to advanced liver disease. We did not find a significant association between HCV and non-Hodgkin lymphoma, contrary to what has been suggested by other studies, primarily involving HIV-uninfected subjects, although the statistical analysis had limited power [23, 25].

As expected, with the exception of non-Hodgkin lymphoma, both nadir and current CD4 cell counts were strongly associated with the risk of developing all types of ADI. Older patients and homosexual men were at higher risk of viral infection, probably because of the high prevalence of Kaposi sarcoma among the diseases included in the viral infections group [52].

The association with the risk of ADI was independent of the use of antiretroviral therapy. We also investigated the interaction between current antiretroviral therapy, HCV infection, and the occurrence of ADIs, and we found no evidence to support the hypothesis that the increased risk of ADI was different for patients currently receiving antiretroviral therapy than for patients who were still antiretroviral therapy naive or who were undergoing a treatment interruption, apart from the case of mycotic and HIV-related diseases, which are difficult to explain.

We have not systematically evaluated adherence in the cohort. The association between HCV coinfection and poor adherence to HAART is controversial [53, 54], mainly because social and demographic factors are strongly associated with both poor adherence and HCV coinfection. In our study, the association between HCV coinfection and the risk of ADI was independent of social and demographic variables (employment status, level of education, and HIV risk exposure). Nevertheless, we cannot rule out that HIV-monoinfected and HCV-coinfected patients might have been different with regard to other factors that we did not measure.

The main strengths of our study are the large sample size, the number of cofactors studied, and the rigorous coding of the events. Nonetheless, because it is an observational study, selection bias cannot be ruled out, and the reproducibility of these results in other settings would strengthen the robustness of these findings.

In conclusion, we found that HIV-HCV-coinfected patients in our cohort were at a 2-fold increased risk of developing AIDS than were HIV-monoinfected patients. Bacterial and mycotic infections and HIV-related disease are the ADIs more strongly associated with positive HCV serostatus and also with HCV-related cirrhosis. Clinicians should take these data into account in their clinical management of HCV-coinfected patients, in particular when deciding when to start antiretroviral therapy.

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Icona Foundation Study Group

Governing body. M. Moroni (Chair), G. Carosi, R. Cauda, F. Chiodo, A. d'Arminio Monforte, G. Di Perri, M. Galli, R. Iardino, G. Ippolito, A. Lazzarin, F. Mazzotta, R. Panebianco, G. Pastore, and C. F. Perno.

Scientific Secretary. A. d'Arminio Monforte.

Steering Committee. A. Ammassari, A. Antinori, C. Balotta, P. Bonfanti, M. R. Capobianchi, A. Castagna, F. Ceccherini-Silberstein, A. Cozzi-Lepri, A. d'Arminio Monforte, A. De Luca, C. Gervasoni, E. Girardi, S. Lo Caputo, F. Maggiolo, R. Murri, C. Mussini, M. Puoti, and C. Torti.

Epidemiology/Biostatistics and Data Managing Group. A. Cozzi-Lepri, I. Fanti, T. Formenti, and M. Prosperi.

Participating physicians and centers (Italy). M. Montroni, A. Giacometti, A. Costantini, and A. Riva (Ancona); U. Tirelli and F. Martellotta (Aviano-PN); G. Pastore and N. Ladisa (Bari); F. Suter and F. Maggiolo (Bergamo); F. Chiodo, G. Verucchi, and C. Fiorini (Bologna); G. Carosi, G. Cristini, C. Torti, C. Minardi, and D. Bertelli (Brescia); T. Quirino and C. Abeli (Busto Arsizio); P. E. Manconi and P. Piano (Cagliari); E. Pizzigallo and M. Dalessandro (Chieti); G. Carnevale and S. Lorenzotti (Cremona); F. Ghinelli and L. Sighinolfi (Ferrara); F. Leoncini, F. Mazzotta, M. Pozzi, and S. Lo Caputo (Firenze); G. Pagano, G. Cassola, G. Viscoli, A. Alessandrini, and R. Piscopo (Genova); F. Soscia and L. Tacconi (Latina); A. Orani and R. Rossotto (Lecco); D. Tommasi and P. Congedo (Lecce); A. Chiodera and P. Castelli (Macerata); M. Galli, A. Lazzarin, G. Rizzardini, I. Schlacht, A. d'Arminio Monforte, A. L. Ridolfo, A. Foschi, A. Castagna, S. Salpietro, S. Merli, S. Melzi, M. C. Moioli, P. Cicconi, and T. Formenti (Milano); R. Esposito and C. Mussini (Modena); A. Gori and A. Borrello (Monza); N. Abrescia, A. Chirianni, C. M. Izzo, M. De Marco, R. Viglietti, and E. Manzillo (Napoli); C. Ferrari and P. Pizzaferri (Parma); F. Baldelli and G. Camanni (Perugia); G. Magnani and M. A. Ursitti (Reggio Emilia); M. Arlotti and P. Ortolani (Rimini); R. Cauda, M. Andreoni, A. Antinori, G. Antonucci, P. Narciso, V. Tozzi, V. Vullo, A. De Luca, M. Zaccarelli, R. Acinapura, P. De Longis, M. P. Trotta, M. Lichtner, and F. Carletti (Roma); M. S. Mura and G. Madeddu (Sassari); P. Caramello, G. Di Perri, and G. C. Orofino (Torino); E. Raise and F. Ebo (Venezia); and G. Pellizzer and D. Buonfrate (Vicenza).

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Acknowledgments

Financial support. The Icona Foundation Study is supported by unrestricted educational grants from Abbott, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Pfizer, and Janssen-Cilag.

Potential conflicts of interest. All authors: no conflicts.

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Footnotes

  • ↵a Members of the study group are listed at the end of the text.

  • Received December 24, 2008.
  • Revision received April 12, 2009.
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  1. Clin Infect Dis. (2009) 49 (4): 612-622. doi: 10.1086/603557
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