Alessia Carbone

Use of statins and risk of AIDS-defining and non-AIDS-defining malignancies among HIV-1 infected patients on antiretroviral therapy

Objective:Previous studies have shown that statins use is associated with a lower mortality risk or occurrence of non-Hodgkins lymphoma or non-AIDS-defining malignancies (NADMs) in HIV-positive patients. We evaluated the effect of statin therapy on the occurrence of all AIDS-defining malignancy (ADM) and NADM among HIV-positive patients. Design:A chart study on HIV-1 infected patients attending the Infectious Diseases Department of the San Raffaele Scientific Institute, Italy. Methods:Incident malignancies diagnosed since antiretroviral treatment (ART) initiation until October 2012 among treated patients not taking statins at ART initiation. Statin therapy had to precede cancer diagnosis, if it occurred. Malignancies that occurred before ART or statin initiation were excluded. Follow-up was calculated since ART initiation until the first cancer diagnosis or loss to follow-up or death or last available visit, whichever occurred first. Results are described as median (interquartile range, IQR). Results:Five thousand, three hundred and fifty-seven HIV-1 treated patients were included. During 52 663 person-years, 740 (14%) patients had a history of statin use; 375 malignancies occurred: 12 (1.6%) malignancies (0 ADM; 12 NADM, crude incidence rate, 1.3/1000 person-years) among statin users and 363 (7.9%) malignancies (194 ADM; 169 NADM, crude incidence rate, 8.4/1000 person-years) among non-statin users. By multivariate Fine-Gray regression, statin use was associated with a lower risk of cancer [adjusted hazard ratio (95% confidence interval) for ever use: 0.45 (0.17–0.71)]. Conclusion:Among HIV-1 treated patients, statin use was associated with a lower risk of cancer; the benefit was mainly related to AIDS-defining malignancies. Confirmatory studies are needed to consider the residual confounding likely present in this study.

Cost analysis of initial highly active antiretroviral therapy regimens for managing human immunodeficiency virus-infected patients according to clinical practice in a hospital setting

Objective In the study reported here, single-tablet regimen (STR) versus (vs) multi-tablet regimen (MTR) strategies were evaluated through a cost analysis in a large cohort of patients starting their first highly active antiretroviral therapy (HAART). Adult human immunodeficiency virus (HIV) 1-naïve patients, followed at the San Raffaele Hospital, Milan, Italy, starting their first-line regimen from June 2008 to April 2012 were included in the analysis. Methods The most frequently used first-line HAART regimens (>10%) were grouped into two classes: 1) STR of tenofovir disoproxil fumarate (TDF) + emtricitabine (FTC) + efavirenz (EFV) and 2) MTR including TDF + FTC + EFV, TDF + FTC + atazanavir/ritonavir (ATV/r), TDF + FTC + darunavir/ritonavir (DRV/r), and TDF + FTC + lopinavir/ritoavir (LPV/r). Data were analyzed from the point of view of the Lombardy Regional Health Service. HAART, hospitalizations, visits, medical examinations, and other concomitant non-HAART drug costs were evaluated and price variations included. Descriptive statistics were calculated for baseline demographic, clinical, and laboratory characteristics; associations between categorical variables and type of antiretroviral strategy (STR vs MTR) were examined using chi-square or Fisher’s exact tests. At multivariate analysis, the generalized linear model was used to identify the predictive factors of the overall costs of the first-line HAART regimens. Results A total of 474 naïve patients (90% male, mean age 42.2 years, mean baseline HIV-RNA 4.50 log 10 copies/mL, and cluster of differentiation 4 [CD4+] count of 310 cells/μL, with a mean follow-up of 28 months) were included. Patients starting an STR treatment were less frequently antibody-hepatitis C virus positive (4% vs 11%, P=0.040), and had higher mean CD4+ values (351 vs 297 cells/μL, P=0.004) than MTR patients. The mean annual cost per patient in the STR group was €9,213.00 (range: €6,574.71–€33,570.00) and €14,277.00 (range: €5,908.89–€82,310.30) among MTR patients. At multivariate analysis, after adjustment for age, sex, antibody-hepatitis C virus status, HIV risk factors, baseline CD4+, and HIV-RNA, the cost analysis was significantly lower among patients starting an STR treatment than those starting an MTR (adjusted mean: €12,096.00 vs €16,106.00, P=0.0001). Conclusion STR was associated with a lower annual cost per patient than MTR, thus can be considered a cost-saving strategy in the treatment of HIV patients. This analysis is an important tool for policy makers and health care professionals to make short- and long-term cost projections and thus assess the impact of these on available budgets.

Non-invasive fibrosis biomarkers - APRI and Forns - are associated with liver stiffness in HIV-monoinfected patients receiving antiretroviral drugs.

HIV‐monoinfected patients are susceptible to liver injury by different factors and may develop liver fibrosis, which requires adequate clinical management in terms of therapy and disease monitoring. We aimed to evaluate the presence of liver fibrosis identified by transient elastography (TE), its relationships with indirect biochemical markers [the aspartate aminotransferase/platelet ratio index (APRI), the Forns index and FIB‐4] and its predictive factors in HIV‐monoinfected patients receiving antiretroviral therapy (ART).

Viral rebound after switch to maraviroc/raltegravir dual therapy in highly experienced and virologically suppressed patients with HIV-1 infection

+ 800 mg of ribavirin daily + telaprevir (750 mg/ 8 h) she achieved undetectable HCV-RNA at weeks 4 and 12. Treatment was complicated by severe anaemia, requiring pegy-lated interferon and ribavirin dose reduction and blood transfusion. HCV-RNA remained ,15 IU/L, and she continued on pegylated interferon + ribavirin treatment. HIV-RNA remained undetectable at treatment weeks 4, 8 and 12. Darunavir and telaprevir PK data are shown in Table 1. There were decreases in all darunavir PK parameters when administered with telaprevir for both patients, except for unbound trough concentration in Patient 2. These decreases, ranging from 58% to 97%, were even higher than those previously described in healthy volunteers. 2,3 However, darunavir/ritonavir doses were different in both cases (800/100 mg once daily in our patients and 600/ 100 mg twice daily in healthy volunteers). 2 We also observed decreases in unbound darunavir concentrations in both patients (except for the aforementioned increase in unbound C trough in Patient 2), although the free fraction decreased less than total drug (ranging from 46% to 93%). There are scarce data on daru-navir PK in HIV/HCV-coinfected patients: in a Spanish cohort, dar-unavir once-daily concentrations (total and unbound) were higher than those observed in our two patients, even before telaprevir co-administration. 5 We could not evaluate the impact of darunavir on telaprevir concentrations, as antiretroviral therapy was maintained. However, telaprevir concentrations in our patients were much higher than previously reported in healthy volunteers or HCV-monoinfected patients. 2,3,6 These high telaprevir concentrations in our coinfected patients with advanced fibrosis could partially explain the marked reduction in darunavir levels, although an association between telaprevir exposure and extent of drug interaction with antiretrovirals has not been previously described. Despite the impact of telaprevir co-administration on daruna-vir concentrations (total darunavir C trough was below wild-type virus IC 50 in one patient), HIV-RNA remained undetectable during the 12 weeks of telaprevir therapy. Prolonged HIV suppression prior to starting anti-HCV therapy, preserved antiviral potency of the darunavir-based regimen and interferon anti-HIV effect 7 could have played a role in keeping HIV-RNA undetectable. Having only two patients, we must take into account all the potential confounding factors and the inter-and intra-individual variability , which hamper generalization of our results. However, our results are concordant between both patients. Besides, as PK parameters can be modified with hepatic impairment, it is very important to have data on interaction between telaprevir and darunavir/ ritonavir in …

Plasma fibroblast growth factor 23 and osteocalcin serum levels are associated with cardiovascular risk in HIV-1-infected patients receiving antiretroviral treatment

References 1 Batura D, Gopal Rao G. The national burden of infections after prostate biopsy in England and Wales: a wake-up call for better prevention. J Antimicrob Chemother 2013; 68: 247–9. 2 Hadway P, Barrett LK, Waghorn DJ et al. Urosepsis and bacteraemia caused by antibiotic-resistant organisms after transrectal ultrasonography-guided prostate biopsy. BJU Int 2009; 104: 1556–8. 3 Zani EL, Clark OA, Rodrigues Netto N Jr. Antibiotic prophylaxis for transrectal prostate biopsy. Cochrane Database Syst Rev 2011; issue 5: CD006576. 4 Zaytoun OM, Anil T, Moussa AS et al. Morbidity of prostate biopsy after simplified versus complex preparation protocols: assessment of risk factors. Urology 2011; 77: 910–4. 5 Zaytoun OM, Vargo EH, Rajan R et al. Emergence of fluoroquinoloneresistant Escherichia coli as cause of postprostate biopsy infection: implications for prophylaxis and treatment. Urology 2011; 77: 1035–41. 6 European Association of Urology. Guidelines on Urological Infections. 2013. http://www.uroweb.org/gls/pdf/18_Urologicalinfections_LR.pdf (13 May 2013, date last accessed). 7 Carmignani L, Picozzi S, Spinelli M et al. Bacterial sepsis following prostatic biopsy. Int Urol Nephrol 2012; 44; 1055–63. 8 Williamson DA, Barrett LK, Rogers BA et al. Infectious complications following transrectal ultrasound-guided prostate biopsy: new challenges in the era of multidrug-resistant Escherichia coli. Clin Infect Dis 2013; doi:10.1093/cid/cit193. 9 Patel U, Dasgupta P, Amoroso P et al. Infection after transrectal ultrasonography-guided prostate biopsy: increased relative risks after recent international travel or antibiotic use. BJU Int 2012; 109: 1781–5. 10 Mshana SE, Imirzalioglu C, Hossain H et al. Conjugative IncFI plasmids carrying CTX-M-15 among Escherichia coli ESBL producing isolates at a University hospital in Germany. BMC Infect Dis 2009; 9: 97. 11 Taylor AK, Zembower TR, Nadler RB et al. Targeted antimicrobial prophylaxis using rectal swab cultures in men undergoing transrectal ultrasound guided prostate biopsy is associated with reduced incidence of postoperative infectious complications and cost of care. J Urol 2012; 187: 1275–9.

The use of circulating cathodic antigen rapid test and serology for diagnosis of active Schistosoma mansoni infection in migrants in Italy, a non-endemic country: a cross sectional study

ABSTRACT Diagnosis of schistosomiasis in migrants coming from endemic areas can be difficult, especially in asymptomatic subjects. Light-intensity disease, in fact, may be missed due to the low sensitivity of the stool microscopy and serologic testing cannot distinguish between a resolved infection and an active infection in patients who have been infected and treated in the past, because specific antibodies can persist despite cure. We describe a cross-sectional study conducted on 82 migrants tested for Schistosoma mansoni on single blood (anti-schistosome antibodies, total IgE) and urine [point-of-care (POC) circulating-cathodic-antigen (CCA) test] samples. A positive POC-CCA test (active infection) resulted in two untreated patients with a positive serology while all patients (n = 66) with a past infection showed a negative POC-CCA test. POC-CCA urine test in combination with serology may be helpful in rapidly differentiate active from past S. mansoni infection in migrants coming from endemic areas.

Immortal time bias: authors' reply.

In a recent issue of AIDS, Galli et al. [1] reported that, among HIV-1 individuals receiving combined antiretroviral therapy (cART), statin use is associated with a lower risk of cancer with an adjusted hazards ratio estimated as 0.45 [95% confidence interval (95% CI) 0.17–0.71]. However, their analysis illustrates the well known immortal time bias [2]. As a matter of fact, they defined baseline as time of cART initiation and compared the risk of cancer among those who will initiate statin at a later time versus those who will never initiate statin. Because there is, by construction, a delay between cART initiation and statin initiation, no cancer can be observed in the ‘statin’ group in the first few years after cART initiation as illustrated in the Figure 1 of their article [1]. This is the most likely explanation of the association they described. A correct analysis would have considered statin exposure as a time-dependent covariate. This type of analysis was precisely developed to overcome the issue of immortal time bias [2]. Moreover, adjusting for updated cholesterol values, which might be influenced by statin exposure, is also an error. It is a pity that the review process did not detect these obvious mistakes.

Unboosted atazanavir with lamivudine/emtricitabine for patients with long-lasting virological suppression.

Unboosted atazanavir (ATV) including regimens have been investigated as a ritonavir‐sparing simplification strategy. No data are available on removal of one NRTI in subjects effectively treated with unboosted atazanavir+2NRTIs. We present the 48‐week virological efficacy and safety of unboosted atazanavir plus lamivudine (3TC) or emtricitabine (FTC) (lamivudine/emtricitabine/Reyataz©, LAREY Study).

Efficacy and safety of switching from branded to generic antiretrovirals in virologically suppressed HIV-infected patients

Background Aim of this study was to evaluate the efficacy and the safety of switching from branded to generic antiretrovirals in patients with HIV-RNA <50 copies/mL. Methods Matched-cohort study of patients followed at a single clinical center. Since September 2014, all patients with HIV-RNA <50 copies/mL who were receiving branded lamivudine or zidovudine/lamivudine or efavirenz were switched to the generic compound (switchers) and matched, in a ratio 1:1, for age (±5 years), gender, anti-HCV antibodies, nadir and (±50 cells/μL) baseline CD4+ count (±100 cells/μL), duration of antiretroviral therapy (±1 year), with patients with HIV-RNA <50 copies/mL, on treatment with unavailable generic compounds (non-switchers). Incidence rates (IR) of different outcomes were calculated and compared by Poisson regression model. A confirmed HIV-RNA ≥50 copies/mL defined virological failure; any change in the antiretroviral regimen was defined as treatment discontinuation. Results Four hundred forty patients were switched to generic compounds (268 [61%] on lamivudine, 65 [15%] on zidovudine/lamivudine, 87 [20%] on efavirenz and 20 [4%] on efavirenz and either lamivudine or zidovudine/lamivudine). Over a median follow-up of 15.0 (12.1–15.7) months, virological failure occurred in four switchers (IR: 0.07 [0.02–0.18]/100-person months of follow-up [PMFU]) and in ten non-switchers (IR: 0.20 [0.10–0.35]/100-PMFU) (p = 0.0003), while treatment discontinuation occurred in 118 switchers (IR: 2.05 [1.70–2.44]/100-PMFU) and in 128 non-switchers (IR: 2.37 [1.99–2.81]/100-PMFU) (p = 0.699). Conclusions After more than one year of follow-up, we found no evidence of increased risk of reduced efficacy or increased toxicity after switching from branded to generic lamivudine or zidovudine/lamivudine or efavirenz.

Durability of switch regimens based on rilpivirine or on integrase inhibitors, both in association with tenofovir and emtricitabine, in HIV-infected, virologically suppressed patients

BackgroundSwitch strategies based on rilpivirine/tenofovir/emtricitabine or on an integrase inhibitor (InSTI) plus tenofovir/emtricitabine have never been compared in randomized clinical trials. The main aim of the study was to investigate the durability of these two switch regimens in virologically suppressed, HIV-infected patients.MethodsRetrospective analysis of patients who started rilpivirine or an InSTI (both with tenofovir and emtricitabine) with <50 HIV-RNA copies/mL and had at least one HIV-RNA assessed while receiving the study regimen. Virological failure (VF) was defined as two consecutive measurements of HIV-RNA >50 copies/mL. Treatment failure (TF) was define as either VF or discontinuation of any drug of the regimen. Durability was assessed by the Kaplan-Meier method and compared by Log-rank test. Residual viremia was defined as any detectable HIV-RNA below 50 copies/mL, as assed by a real-time PCR assay.ResultsSix hundred seventy-five patients (466 switched to a rilpivirine-, 209 switched to an InSTI-based regimen [18% dolutegravir, 39% raltegravir, 43% elvitegravir/cobicistat] were included in the analysis.The median (interquartile range, IQR) follow-up in the rilpivirine and in the InSTI group was 16.7 (8.8–22.2) and 10.4 (5.4–19.6) months. The 1-year cumulative probabilities (95%CI) of VF and TF were 0.97% (0.36%–2.62%) and 9.73% (7.21%–13.06%) in the rilpivirine group and 1.83% (0.57%–5.77%) and 8.75% (5.25%–14.4%) in the InSTI group, with no difference between groups (p = 0.328 and 0.209 for VF and TF). The proportion of time spent with residual viremia was comparable in the two groups (9% [IQR 0.5%–49%] and 17% [IQR 0.5%–50%] in the rilpivirine and in the InSTI group, p = 0.087).By the multivariable Cox regression model, TF was independently associated with being on therapy with a protease inhibitor vs. a non-nucleoside reverse transcriptase inhibitor at switch (AHR = 0.52; 95%CI = 0.31–0.90; p = 0.018), baseline total/HDL-cholesterol ratio (AHR = 1.19 per 0.5-units increments; 95%CI = 1.06–1.34; p = 0.004), baseline estimated glomerular filtration rate (AHR = 0.78 per 10-units increments; 95%CI = 0.67–0.90; p = 0.001) and baseline hemoglobin (AHR = 0.78 per 1-unit increments; 95%CI = 0.64–0.94; p = 0.009), but not with treatment group (rilpivirine vs. InSTI).ConclusionsIn our clinical practice, the durability of the two regimens was comparable and both showed a very low probability of VF.