Anna Orani

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.

A Randomized Controlled Trial to Evaluate Antiretroviral Salvage Therapy Guided by Rules-Based or Phenotype-Driven HIV-1 Genotypic Drug-Resistance Interpretation With or Without Concentration-Controlled Intervention: The Resistance and Dosage Adapted Regimens (RADAR) Study

BACKGROUND It is not well defined whether concentration-controlled intervention (CCI) and rules-based human immunodeficiency virus (HIV) type 1 genotype drug-resistance interpretation (GI) or virtual phenotype drug-resistance interpretation (VPI) may improve the outcome of HIV salvage therapy. METHODS In a prospective, randomized, controlled trial, patients were randomized (on a factorial basis) to change treatment after either GI or VPI, and they then were further randomized to the control arm (no CCI) or the CCI arm. Protease inhibitor (PI) and nonnucleoside reverse-transcriptase inhibitor (NNRTI) trough concentration (Ctrough) values were determined at weeks 1, 4, 12, and 24 of the study. RESULTS Among 230 patients, virological benefit (defined by an HIV RNA load of <400 copies/mL at week 24) was not statistically different, either between patients in the GI and VPI arms or between patients in the CCI and control arms. A virological benefit was found for patients in the CCI arm, compared with patients in the control arm, but this benefit was not statistically significant (56.8% vs. 64.3% at week 4 and 63.6% vs. 74% at week 12). Dosage adaptation was possible for only a fraction of patients, because of low rates of treatment adherence or patient refusal to increase dosages. In the logistic regression analysis, independent predictors of virological response at week 24 were a PI Ctrough value and/or an NNRTI Ctrough value in the higher quartiles (or above cutoff levels) and a low number of PIs previously received. Moreover, receipt of a regimen that contained PIs boosted with ritonavir was an independent predictor of virological response. CONCLUSIONS The present study did not support the routine use of CCI for patients undergoing salvage treatment, probably as a result of existing difficulties associated with its clinical application. However, a higher Ctrough value appeared to be correlated with treatment response. No major differences were found between VPI or GI when they are used together with expert advice for the selection of salvage treatment combinations.

Viral interference between hepatitis B, C, and D viruses in dual and triple infections in HIV-positive patients.

Objective:To investigate the reciprocal inhibitory effects of hepatitis B virus (HBV)/hepatitis C virus (HCV)/hepatitis D virus (HDV) infections in naive and previously antiretroviral-experienced HIV-positive patients. Design:This retrospective study involved 72 consecutive patients of the Italian Cohort Naive Antiretroviral cohort: 21 coinfected with HBV/HCV (group 1BC), 18 infected with HBV (group 2B), and 33 infected with HCV (group 3C). Methods:Viral interference between HBV and HCV was assessed by means of the qualitative detection, quantification, and genotyping of each virus; HDV infection was assessed by means of genomic amplification. Results:Univariate analysis showed that HBV DNA was less frequently detected in group 1BC than in group 2B (16 of 21 vs 18 of 18; P = 0.02), their HBV load was significantly lower (median 3.9 vs 5.4 log10 HBV DNA copies/mL; P = 0.002), and they more frequently carried HBV genotype D (12 of 13 vs 4 of 11; P = 0.0071). HCV RNA was less frequently detected in group 1BC than in group 3C (12 of 21 vs 33 of 33; P < 0.0001), and HDV RNA was more frequently detected in group 1BC than in group 2B (9 of 21 vs 2 of 18; P = 0.028). Multivariate analysis of the HBV-infected subjects showed that the risk of HCV coinfection was associated with older age [relative risk 0.28, 95% confidence interval (CI): 0.09 to 0.90; P = 0.033 for every 10 years older] and intravenous drug use (relative risk 73, 95% CI: 2.4 to >999.999; P = 0.013). The only predictor of HBV coinfection in HCV-infected individuals was a lower HCV load (relative risk 0.30, 95% CI: 0.11 to 0.79 for every additional log10 HCV RNA; P = 0.015). Conclusion:HBV and HCV showed alternative dominant replication in the I.Co.N.A. cohort, with HBV having a more unfavorable effect on HCV replication.

Antiviral potency of HAART regimens and clinical success are not strictly coupled in real life conditions: evidence from the MASTER-1 study.

Abstract Purpose: To compare in a real clinical setting the largely unknown midterm clinical effectiveness of two protease inhibitor (PI)-based highly active antiretroviral therapy (HAART) regimens with different potency and tolerability profiles in naïve patients. Method: This study was a multicenter, open-label, randomized trial in naïve patients with less than 400 CD4+ cell count/μL, regardless of viral load. Treatment arms were hard gel capsule saquinavir (HGC-SQV)-based HAART (Arm A), with an expected more favorable tolerability profile, and indinavir (IDV)-based HAART (Arm B), with more potent virologic activity. While viro-immunological surrogate markers and World Health Organization (WHO) grade III toxicity (secondary endpoints) were regularly monitored, primary endpoints of the study were clinical and defined as any AIDS-defining event, AIDS-related death, WHO grade IV toxicity, drop outs, and protocol violations. Results: 262 consecutive patients were enrolled in the study from March 1, 1997 to December 31, 1997, in 24 different Italian clinical centers (132, Arm A; 130, Arm B). After 24 months of follow-up, patients who were enrolled in Arm B showed a significantly higher rate of virological success (75% had viremia below 500 copies/mL, CI = 12.9%, in the on-treatment analysis) and immunological gain (mean CD4+ cell count increase of 274 CD4+ cells/μL, SD = 234) when compared to patients enrolled in arm A (57%, CI = 15.5% and 223 CD4+ cells/μL, SD = 192; p = .0353 and .026, respectively). Despite the significant difference observed in surrogate markers, the number of total primary endpoints did not differ in the two groups (55 out of 132 in Arm A vs. 58 out of 130 person-years in Arm B; p = .86). Conclusion: Our results suggest that, after 24 months of follow-up in a real clinical setting, a PI-based HAART induces significant clinical benefits in naïve patients even in the absence of a complete suppression of viral replication. However, the long-term clinical impact of the possible accumulation of viral mutations in the presence of low-grade viral replication remains to be elucidated.

HIV education and counselling using Facebook: a possible new approach

Almost one third of individuals infected with HIV do not enter health care until late in the course of their infection. This phenomenon, called late presentation, is characterized by individuals who discover their seropositivity when in need of highly active antiretroviral therapy or with an AIDS-defining illness. Late presentation is a major concern, since it is harmful to the infected person and to society as a whole, and it is very costly. Its prevalence ranges from 10% to 45% in Europe. Raising awareness in the general population is crucial and the Internet may be a new way of developing educational and counselling strategies. Social networking sites, such as Facebook, Twitter and MySpace, are well-known Web 2.0 applications (i.e. web sites whose content is mostly driven by the users). Most online information services concerning STDs or HIV operate with a Web 1.0 approach (i.e. information provided by the publisher, with a unidirectional stream). Shifting to Web 2.0 social networking sites may increase the effectiveness of prevention messages. We conducted a multi-centre, prospective communicative intervention involving seven physicians with expertise in infectious diseases (termed “researchers” in what follows) who created their profile on Facebook. It was carried out from December 2009 to May 2010. The researchers created a real profile, which included photographs, lists of interests, contact details and other personal information. They used Facebook like everyone does and had conversations about their personal lives, experiences, emotions and feelings. Chatter concerning STDs and HIV topics were collected as professional messages. The researchers spent at least four hours every week on updating their profiles. They aimed to post replies within one week. We conducted a study in two phases: the first was based on a targeted operation model and was held on Facebook. The objective of this phase was to increase the debate about STDs/HIV. We chose the number of friends and the number of questions that were raised as measures of debate. The target audience was the whole population who use Facebook: neither limitations nor exclusion criteria were defined for the choice of friends, in an attempt to use the social network just as in everyday life. To stimulate the debate, researchers posted messages, links and videos related to STDs/HIV (i.e. video clips from the HIVisible Contest held in Cologne in 2009, or from movies and songs with an AIDS theme; references to newspapers or magazines articles; commentaries to the national campaign launched for the World AIDS day of 2009 or to the Pope’s statements against condom use in Africa). The number of replies was counted by each researcher. Demographic features of friends were collected from their personal pages. The evaluation was through outcome measures. The study was designed to quantify the performance from the user perspective and to measure only the rate of query submission. We are not aware of any previous similar work, so the parameters for measurement were extrapolated from other studies on non-web social networks. The effectiveness of recruitment was measured by the Network Index (the ratio between the number of friends and the number of researchers). The number of questions about STDs/HIV was measured by the Performance Index, a parameter set by analogy with the Network Index, and defined as the ratio between number of messages and the number of researchers. The second phase was based on an open operation model and was held on the official site of the Italian Society of Infectious and Tropical Diseases (SIMIT). The objective of this phase was to analyse the questions and the debates that would develop from the inputs posted by researchers. Topics that needed longer explanation or that were perceived as too personal, were directed from Facebook to specific forums on the SIMIT web site. Technical questions (e.g. concerning new drugs or drug toxicities) were directed to the Expert Online forum, where an Italian physician experienced in the matter would answer. Personal questions (e.g. about risky behaviours or condom use) were directed to a public forum, where the adoption of a nickname could guarantee anonymity. Details about how to log into these forums were explained on the personal pages of the researchers. The researchers were also the coordinators of these forums. During the study period, the number of friends reached 625; demographic features are summarized in Table 1. However, the objective of stimulating debate was not realised. The baseline Network Index was 66 and it increased to a value of 89 at the end of the study. Even though the number of friends increased by 35%, their features reflected mainly those of the researchers, i.e. young women from northern Italy, graduates, who were frequently working in health care as doctors or nurses. Despite the large number of professional postings, professional messages were few and none was followed by a specific debate on the SIMIT forums. The Performance Index was 46 for the personal (private) messages, while it was only three for the professional messages. It was not possible to categorize these messages, because of their small number. Thus the second objective of our study was not realised either. The disappointing outcome of the work is due to some limits inherent in Facebook and to the study design. First, Facebook communication is often a manipulation of the personal virtual image with projections of “Self”, i.e. users sometimes do not write what really happens to them, but manipulate their life experiences to seem nicer, funnier and more appealing. This could lead to unreliable discussions on matters where their image could appear fragile, as in the

Access to treatment for HBV infection and its consistency with 2008 European guidelines in a multicentre cross-sectional study of HIV/HBV co-infected patients in Italy

BackgroundA survey was performed in 2008 to evaluate the profiles of patients with chronic hepatitis B cared for by Italian Infectious Diseases Centers (IDCs).This analysis describes: i) factors associated with access to the anti-HBV treatment in a cohort of HIV/HBV co-infected patients cared for in tertiary centers of a developed country with comprehensive coverage under the National Health System (NHS); ii) consistency of current anti-HBV regimens with specific European guidelines in force at the time of the study and factors associated with the receipt of sub-optimal regimens.MethodsThe study focuses on 374 (87.6%) treated patients at some point in their life out of the 427 tested HIV/HBV positive. It is multicentre, cross-sectional in the design. To account for missing values, a Multiple Imputation method is used.ResultsThree hundred and thirty-four (89.3%) patients were currently treated. The most common current regimen was combination therapy of tenofovir (TDF) plus LAM/FTC (lamivudine/emtricitabine) (n = 235, 70.4%), as part of antiretroviral treatment.In the multivariate analysis, an increased chance of getting treated was independently associated with increasing years since HBV diagnosis (2–10 years, p <0.001; >10 years, p <0.001).Patients consistently treated with European AIDS Clinical Society (EACS) 2008 guidelines were 255 (76.6%), of whom 202 (79.2%) with an indication to an anti-HIV treatment, 30 (11.8%)without an indication, and 21 (8.2%) with cirrhosis. Among the 78 not-consistent patients, LAM mono-therapy (n = 60, 76.9%) was the most common regimen, 34 (56.7%) of them showing HBV DNA load below 1x103 IU/mL.Previous anti-HBV treatment (p = 0.01) and a triple HDV co-infection (p = 0.03) reduced the chance of not-consistent regimens. Conversely, HCV co-infection was independently associated with an increased odds ratio of being inconsistently treated (p = 0.004).ConclusionOur study shows that Italian IDCs treat for HBV infection the vast majority of HIV/HBV co-infected patients with no disparities limiting access to antiviral therapy. In approximately two-thirds of the patients on treatment, anti-HBV regimens are consistent with 2008 EACS guidelines. Finally, our study identifies scenarios in which clinical practice deviates from recommendations, as in case of sub-optimal regimens with effective anti-HBV response.

Once-a-day (QD) vs. Twice-daily (BID) Nevirapine as Simplification in PI-Treated Patients after 2 mos. of BID Induction

To assess the efficacy and the tolerability of once-daily (QD) versus twice-daily (BID) nevirapine (NVP)-based highly active antiretroviral therapy (HAART) in virologically suppressed, HIV-positive patients switched from protease inhibitor (PI)-based HAART. Eligible patients were enrolled in the multicenter trial if HIV RNA levels were <50 copies/mL for ³6 months prior. Patients were switched from a PI to NVP 200 mg BID for 2 months, and then randomized to continue with that regimen (group A) or NVP 400 mg QD (group B) for a further 10 months. Virological efficacy (primary endpoint) and tolerability/toxicity were evaluated according to an intention-to-treat analysis. A total of 126 patients (63 per group) were enrolled. Withdrawals from the study (any reason) numbered 15 in group A and 14 in B, virological failures numbered 5 and 2, respectively, and there were 4 cases of adverse events in each group (all p = NS). Mean alanine aminotransaminase (ALT) and gamma-glutamyl transpeptidase (γ-GT) level increases were significant for the whole cohort (33.2±22.9 to 43.3±29.1, p < 0.001; 57.3±72 to 109±131 U/L, p < 0.0002, respectively), but there were no differences between the two groups. Apparently, no significant differences between the QD and BID NVP groups were found, in terms of virological failures or tolerability/toxicity. The switch to NVP may be safely pursued with a QD schedule.

Switching to nevirapine-based HAART in virologically-suppressed patients: influence of a longer twice-daily induction period on once-a-day dosing

We are conducting a multicenter, randomized, controlled, prospective, open trial to evaluate both the efficacy and toxicity of nevirapine (NVP) (given twice [BID] or once daily [QD]) in virologically-suppressed patients on a PIbased HAART. NVP BID dosing is maintained for 2 months after the switch in both groups.