A. Di Biagio

Impact of an antimicrobial formulary and restriction policy in the largest hospital in italy

We have analysed the expenditure on antimicrobial drugs in the largest hospital in Italy; over this period, a committee prepared an antibiotic policy document. This formulary lists all antimicrobial drugs available in the hospital. Some drugs were removed from the list and others are only available on special request for a named patient. In the hope of optimising drug utilisation, we included all the reasons for the choice of agent in the document. The introduction of this formulary resulted in an immediate saving and perhaps in the future we shall also observe an improvement in bacterial resistance patterns.

Therapeutical aspects and outcome of HIV/HCV coinfected patients treated with pegylated interferon plus ribavirin in an Italian cohort.

Background:One-third of HIV-infected individuals suffer from chronic hepatitis C virus infection (HCV) in Europe. Recommendations from HCV–HIV International Panel advise current treatment with pegylated interferon plus ribavirin. We assessed the impact of interferon and ribavirin combination in 43 patients between 2002 and 2006.Patients and Methods:All coinfected patients treated for HCV during the 5-year period were included in retrospective data collection. CD4+ T-lymphocyte count, HAART discontinuation, reasons for treatment interruption and factors correlated to sustained virological response (SVR) were monitored.Results:The mean age was 41 ± 6.7 years; the risk factor for coinfection was intravenous drug abuse in 32/43 (74%). The baseline CD4+ T-lymphocytes cell count was > 500 in 51% (22/43). Genotype 3a represented 51% (22/43); 37% were on HAART at baseline (16/43) and half of patients showed high HCV RNA levels (> 800,000 IU/ml). High rates of treatment discontinuation were observed (27/43, 63%), caused by voluntary interruptions in 52% (14/27) and virological failure in 26% (7/27). The overall population had an SVR of 30%; genotypes 3a and 1 had SVR of 38% and 24%, respectively. The SVR was significantly lower in three groups: high HCV RNA viral load (χ2 = 6, p < 0.0025), CD4+ T-lymphocyte historical nadir <350 cells/mm3 (χ2 = 3.26, p < 0.01) and genotype 1 with high viral load (χ2 = 4.8, p < 0.005).Conclusions:Although factors such as HCV viral load rates and genotype 1 have been confirmed to threaten the response to therapy, we observed a significant response rate when patients had a history of CD4+ T-lymphocyte nadir >350 per mm3. The high dropout rates due to voluntary discontinuations complicated the patients’ case management.

Maraviroc intensification for HIV-1-positive immunological non-responders (INRs) despite virological suppression during HAART

7‐11 November 2010, Tenth International Congress on Drug Therapy in HIV Infection, Glasgow, UK

Prevalence of mutations and determinants of genotypic resistance to etravirine (TMC125) in a large Italian resistance database (ARCA).

To evaluate whether etravirine (TMC125) might be effective in patients failing therapy with current nonnucleoside reverse transcriptase inhibitors (NNRTIs), we analysed the prevalence of TMC125 mutations and the possible determinants of genotypic resistance to this drug among sequences reported to a large database in Italy [Antiretroviral Resistance Cohort Analysis (ARCA)].

Factors associated with virological success with raltegravir-containing regimens and prevalence of raltegravir-resistance-associated mutations at failure in the ARCA database

Raltegravir (RAL) is the only licensed human immunodeficiency virus (HIV) integrase inhibitor. The factors associated with the virological response to RAL-containing regimens and the prevalence of integrase mutations associated with RAL failure deserve further investigation. From the Antiretroviral Resistance Cohort Analysis database, we selected triple-class-experienced subjects failing their current treatment with complete treatment history available. Selection criteria included HIV-RNA, CD4 count and HIV genotype within 3 months of RAL initiation. Factors associated with 24-week response were analysed; genotypic sensitivity scores (GSS) and weighted-GSS were evaluated. Virological response was achieved in 74.3% of 105 subjects. Mutations associated with RAL failure were detected in 12/24 subjects with an integrase genotype, with the prevalence of Q148H + G140S. Each extra unit of GSS (p 0.05, OR 2.62; 95% CI 1.00-6.87). was found to be a associated with response. Weighted-GSS had borderline statistical significance (p 0.063, OR 2.04; 95% CI 0.96-4.33) When stratifying for different cut-offs (<1 as reference, 1-1.49, ≥1.5), a borderline significant increase in the probability of response appeared for GSS ≥1.5 (p 0.053, OR 4.00; 95% CI 0.98-16.25). GSS ≥1 showed the highest sensitivity, 82.6%. Receiver operating characteristic curves depicted the widest area under the curve (0.663, p 0.054) of GSS ≥1. Unresponsiveness to RAL-containing regimens among triple-class-experienced subjects was low. The activity of the background regimen was strongly associated with response. Although few integrase genotypes were available at failure, half of these were without integrase resistance mutations. The substantial rate of RAL failure in the absence of known RAL-resistance mutations may be associated with adherence issues and this issue warrants further analysis in longer observations.

Use of maraviroc in clinical practice: a multicenter observational study

Promising research suggest that maraviroc (MVC) has favourable clinical outcome in HIV‐infected patients (pts). Aim of the study is to assess: durability, safety profile and immunovirological recovery in a large MVC‐based cohort.

Observational Study on HIV-Infected Subjects Failing HAART Receiving Tenofovir Plus Didanosine as NRTI Backbone

We evaluated the efficacy of tenofovir (TDF) – and didanosine (ddI)-containing backbones in HIV-infected experienced subjects. We included in the study 245 subjects who started a TDF/ddI-containing HAART with HIV-RNA > 3 log10 cp/ml and an available genotypic resistance test at baseline. At baseline, median CD4 counts and HIV-RNA were 278 cell/mmc and 4.32 log10 cp/ml, respectively. Seventy-four subjects (30.2%) discontinued TDF and/or ddI, 23 of them for drug-related toxicities or intolerance. One-hundred and twenty-six (51.4%) subjects achieved virologic success (HIV-RNA < 50 copies/ml in two consecutive determinations) in a median time of 6.1 months; higher HIV-RNA levels (HR: 0.66, 95% CI: 0.54– 0.79, p < 0.001 for each additional log10 copies/ml), and the total number of mutations either for PI and NNRTI at baseline (HR: 0.87, 95% CI: 0.81–0.92, p < 0.001 for each additional mutation) were both predictors of virologic success. M184V was marginally associated with virologic success (HR: 1.34, 95% CI: 0.94–1.90, p = 0.10 vs no M184V), whilst the number of TAMs was not associated. One-hundred-thirty-three (54.3%) subjects achieved immunologic success (increase of ≥ 100 cells/mm3 from baseline) in a median time of 7.5 months; immunologic success was associated with HIV-RNA levels at baseline (HR: 0.91, 95% CI: 0.79–0.98, p = 0.04 for each additional log10 copies/ml), the total number of mutations either for PI or NNRTI (HR: 0.91, 95% CI: 0.85–0.98, p = 0.01 for each additional mutation) and CD4 count at baseline (HR: 1.11, 95% CI: 1.00–1.23, p = 0.05 for each additional 100 cells/mm3). Results obtained by the on-treatment analyses were comparable. In our study, HAART containing TDF/ddI seem associated with a virologic and immunologic response, when such regimens are chosen according to a genotypic resistance test.

Raltegravir-based therapy in a cohort of HIV/HCV co-infected individuals

The relationship between hepatic tolerance and hepatitis C virus (HCV) co-infection has not been extensively studied in clinical practice. We assessed the efficacy and safety of raltegravir-based therapy in an Italian cohort of HIV/HCV co-infected patients. One hundred and forty patients with HIV/HCV co-infection initiating raltegravir from SCOLTA project (Surveillance Cohort Long-Term Toxicity Antiretrovirals) were examined. Of them, 43 were women, with mean age of 45.4±6.4years; 65 (46%) had undetectable HIV-RNA<50copies/mL and 75 (54%) HIV-RNA≥50copies/mL. According to CDC classification, 49 (35%) were in stage C. Based on Fib4 score at the time of starting raltegravir, patients were classified in class I in 41 cases, class II in 68 and in class III in 31 cases. Globally, the Fib4 score slightly decreased during 24months follow-up, from 2.2 to a value of 1.8. Hepatic adverse events of any grade were observed in 67 patients, of which only 2 cases (3%) had severe liver toxicity (grade 3-4). Only one patient had to discontinue the therapy because of adverse events. According to univariate analysis, being in CDC stage C represented a risk for the development of liver toxicity, with a hazard ratio (HR) of 2.27 (95% CI 1.06-4.84, P=0.033). None of the other variables considered (age, sex, years since detection of HIV and HCV-RNA detectable, years of previous HIV therapy, concomitant therapy with PI or NRTI, CD4+ cell count, Fib4, and transaminases level at baseline) resulted statistically correlated to the outcome. In conclusion, raltegravir-based regimens can be safely used in HCV infected patients; in this study, the hepatic toxicity has been found to be more frequent in patients with an advanced HIV disease (CDC stage C), independently of HIV-RNA suppression at raltegravir initiation.

Efficacy and safety of darunavir and etravirine in an antiretroviral multi-experienced youth with vertically HIV-1 infection

Multiclass-drug resistance, often caused by poor treatment compliance, is a challenging problem in all categories of HIV-infected patients. Selective pressure is higher in youth for both biological and behavioral reasons. We report the case of a 15-year-old Caucasian male, with vertically acquired HIV-1 infection, who failed several lines of antiretroviral therapy and was successfully treated with darunavir/ritonavir and etravirine.

Pregnancy and neonatal outcomes among a cohort of HIV-infected women in a large Italian teaching hospital: a 30-year retrospective study

The primary study objective was to investigate three decades from 1985 to 2014 of changes in pregnancies among HIV-infected women. The secondary objective was to assess risk factors associated with preterm delivery and severe small-for-gestational-age (SGA) infants in HIV-infected women. A retrospective review of deliveries among pregnant HIV-infected women at the University of Genoa and IRCCS San Martino-IST in Genoa between 1985 and 2014 was performed. Univariate and multivariable analyses were used to study the variables associated with neonatal outcomes. Overall, 262 deliveries were included in the study. An increase in median age (26 years in 1985-1994 vs. 34 years in 2005-2014), in the proportion of foreigners (none in 1985-1994 vs. 27/70 (38·6%) in 2005-2014), and a decrease in intravenous drug use (75·2% (91/121) in 1985-1994 vs. 12·9% (9/70) in 2005-2014) among pregnant HIV-infected women was observed. Progressively, HIV infections were diagnosed sooner (prior to pregnancy in 80% (56/70) of women in the last decade). An increase in combined antiretroviral therapy (cART) prescription during pregnancy (50% (27/54) in 1995-2004 vs. 92·2% (59/64) in 2005-2014) and in HIV-RNA <50 copies/ml at delivery (19·2% (5/26) in 1995-2004 vs. 82·3% (53/64) in 2005-2014) was observed. The rate of elective caesarean section from 1985 to 1994 was 9·1%, which increased to 92·3% from 2004 to 2015. Twelve (10·1%) mother-to-child transmissions (MTCT) occurred in the first decade, and six (8·3%) cases occurred in the second decade, the last of which was in 2000. Preterm delivery (<37 weeks gestation) was 5% (6/121) from 1985 to 1994 and increased to 17·1% (12/70) from 2005 to 2014. In univariate and multivariable logistic regression analyses, advancing maternal age and previous pregnancies were associated with preterm delivery (odds ratio (OR) 2·7; 95% confidence intervals (CI) 1-7·8 and OR 2·6; 95% CI 1·1-6·7, respectively). In the logistic regression analysis, use of heroin or methadone was found to be the only risk factor for severe SGA (OR 3·1; 95% CI 1·4-6·8). In conclusion, significant changes in demographic, clinical and therapeutic characteristics of HIV-infected pregnant women have occurred over the last 30 years. Since 2000, MTCT has decreased to zero. An increased risk of preterm delivery was found to be associated with advancing maternal age and previous pregnancies but not with cART. The use of heroin or methadone has been confirmed as a risk factor associated with severe SGA.