Real-life data on potential drug-druginteractions in patients with chronic hepatitis C viral infection undergoing antiviral therapy with interferon-free DAAs in the PITER Cohort Study

Background There are few real-life data on the potential drug-drug interactions (DDIs) between anti-HCV direct-acting antivirals (DAAs) and the comedications used. Aim To assess the potential DDIs of DAAs in HCV-infected outpatients, according to the severity of liver disease and comedication used in a prospective multicentric study. Methods Data from patients in 15 clinical centers who had started a DAA regimen and were receiving comedications during March 2015 to March 2016 were prospectively evaluated. The DDIs for each regimen and comedication were assigned according to HepC Drug Interactions (www.hep-druginteractions.org) Results Of the 449 patients evaluated, 86 had mild liver disease and 363 had moderate-to-severe disease. The use of a single comedication was more frequent among patients with mild liver disease (p = 0.03), whereas utilization of more than three drugs among those with moderate- to-severe disease (p = 0.05). Of the 142 comedications used in 86 patients with mild disease, 27 (20%) may require dose adjustment/closer monitoring, none was contraindicated. Of the 322 comedications used in 363 patients with moderate-to-severe liver disease, 82 (25%) were classified with potential DDIs that required only monitoring and dose adjustments; 10 (3%) were contraindicated in severe liver disease. In patients with mild liver disease 30% (26/86) used at least one drug with a potential DDI whereas of the 363 patients with moderate-to-severe liver disease, 161 (44%) were at risk for one or more DDI. Conclusions Based on these results, we can estimate that 30 - 44% of patients undergoing DAA and taking comedications are at risk of a clinically significant DDI. This data indicates the need for increased awareness of potential DDI during DAA therapy, especially in patients with moderate- to-severe liver disease. For several drugs, the recommendation related to the DDI changes from "dose adjustment/closer monitoring", in mild to moderate liver disease, to "the use is contraindicated" in severe liver disease

Rate and determinants of residual viremia in multidrug-experienced patients successfully treated with raltegravir-based regimens

none15noResidual HIV viremia, defined by low levels of plasma HIV RNA with enhanced-sensitivity assays, may persist even in the presence of successful antiretroviral therapy, but little is known about its determinants. Our objective was to evaluate the rate and determinants of residual viremia in patients who show stable undetectable plasma HIV-1 RNA with conventional assays. Forty-four multidrug-experienced patients with undetectable levels of HIV RNA for at least 2 years under raltegravir-based regimens were evaluated. An ultrasensitive (2.5 copies/ml) real-time PCR method was used to quantify plasma HIV RNA. After 12 months of salvage treatment, 48.3% of the patients had residual viremia between 2.5 and 37 copies/ml. The proportion of patients with plasma HIV RNA below 2.5 copies/ml decreased from 51.7% at 12 months to 30.8% at 24 months. The presence of residual viremia was not associated with levels of viremia before starting raltegravir. Considering CD4 counts, hepatitis B or C virus (HBV or HCV) coinfection, or other demographic characteristics, for the time interval between HIV diagnosis and initiation of antiretroviral therapy, patients with a longer interval (>1 year) were significant less likely to have RNA levels below 2.5 copies/ml at 12 months compared to patients who started therapy within 1 year of HIV diagnosis (28.6% vs. 73.3%, p=0.027). Half of the patients showing undetectable HIV viremia with conventional assays had low-level viremia with ultrasensitive assays, with no predictive role of viroimmunological status at the start of the regimen. The potential influence of the interval between HIV diagnosis and initiation of treatment should be confirmed in subjects with a known date of seroconversion.Baroncelli, Silvia; Pirillo, Maria Franca; Galluzzo, Clementina Maria; Antoni, Anna Degli; Ladisa, Nicoletta; Francisci, Daniela; D'Ettorre, Gabriella; Segala, Daniela; Vivarelli, Angela; Sozio, Federica; Cirioni, Oscar; Weimer, Liliana Elena; Fragola, Vincenzo; Parruti, Giustino; Floridia, MarcoBaroncelli, Silvia; Pirillo, Maria Franca; Galluzzo, Clementina Maria; Antoni, Anna Degli; Ladisa, Nicoletta; Francisci, Daniela; D'Ettorre, Gabriella; Segala, Daniela; Vivarelli, Angela; Sozio, Federica; Cirioni, Oscar; Weimer, Liliana Elena; Fragola, Vincenzo; Parruti, Giustino; Floridia, Marc

No evidence of autoimmune disorders in antiretroviral-experienced HIV-1-infected individuals after long-term treatment with raltegravir

Background: The HIV integrase inhibitor raltegravir (RAL) can exacerbate autoimmune diseasesin genetically predisposed mice. To evaluate whether this may occur in clinical practice, weclinically monitored HIV positive patients treated with RAL and measured a panel ofautoantibodies (auto-Abs) during the first year of RAL treatment.Methods: This was a longitudinal study in 109 antiretroviral-experienced patients who started aRAL-based regimen and were followed up for more than two years. Forty-five of them were testedat baseline (before starting RAL) and after 12 months for the presence of the following auto-Abs:anti-nuclear antibodies (ANA), anti-double-stranded (ds)DNA, anti-smooth-muscle antibodies(ASMA), anti-thyreoglobulin (anti-TG) and anti-thyroid peroxidase (anti-TPO) antibodies, anticardiolipin(anti-CL) IgG and IgM, anti-nuclear extractable antigens (ENA) including anti-SMRNP antigen, anti–Ro (SSA) antigen and anti-La (SSB) antigen.Results: A low rate of clinically relevant autoimmune diseases was observed at study entry (3/109,2.8%, 95%CI = 0.004 – 0.059). No exacerbations were observed during follow-up. During thesecond year of RAL-based therapy a previously healthy patient developed psoriasis. At baseline17/45 (37.8%) patients tested for the presence of auto-Abs were positive. Most subjects (13) werepositive for anti-CL. After 12 months of RAL exposure 9/45 subjects were positive ( 20%, p =0063). A positive correlation was found between HIV-1 RNA and anti-CL antibody concentration(p = 0.010).Conclusions: According to these results, RAL does not promote antibody-mediated immunedisorders at least in the mid-term. A prolonged follow up and an extension of autoAbs’ panel arerecommended to support these results

Response to raltegravir-based salvage therapy in HIV-infected patients with hepatitis C virus or hepatitis B virus coinfection

Objectives To define the impact of coinfection with hepatitis B virus (HBV) or hepatitis C virus (HCV) on viroimmunological response to raltegravir-based salvage regimens that also include new HIV inhibitors such as maraviroc, darunavir and etravirine. Methods We used data from a national observational study of patients starting raltegravir-based regimens to compare virological suppression and CD4 cell change from baseline in patients with and without concomitant HBV or HCV infection. Results Overall, 275 patients (107 coinfected and 168 non-coinfected) were evaluated. Coinfected patients were more commonly former intravenous drug users and had a longer history of HIV infection and higher baseline aminotransferase levels. Both HIV-RNA and CD4 response were similar in the two groups. Mean time to first HIV-RNA copy number &lt;50 copies/mL was 4.1 months (95% CI 3.5–4.6) in non-coinfected patients and 3.9 months (95% CI 3.3–4.5) in coinfected patients (hazard ratio 1.039, 95% CI 0.761–1.418, P = 0.766, log-rank test). The risk of developing new grade 3–4 hepatic adverse events was significantly higher in coinfected patients (hazard ratio 1.779, 95% CI 1.123–2.817, P = 0.009). The two groups of coinfected and non-coinfected patients had similar rates of interruption of any baseline drug (hazard ratio 1.075, 95% CI 0.649–1.781, P = 0.776) and of raltegravir (hazard ratio 1.520, 95% CI 0.671–3.447, P = 0.311). Few AIDS-defining events and deaths occurred. Conclusions Viroimmunological response to regimens based on raltegravir and other recent anti-HIV inhibitors is not negatively affected by coinfection with HBV or HCV. Liver toxicity, either pre-existing or new, is more common in coinfected patients, but with no increased risk of treatment interruption.</br

Response to raltegravir-based salvage therapy in HIV-infected patients with hepatitis C virus or hepatitis B virus coinfection

none22OBJECTIVES: To define the impact of coinfection with hepatitis B virus (HBV) or hepatitis C virus (HCV) on viroimmunological response to raltegravir-based salvage regimens that also include new HIV inhibitors such as maraviroc, darunavir and etravirine. METHODS: We used data from a national observational study of patients starting raltegravir-based regimens to compare virological suppression and CD4 cell change from baseline in patients with and without concomitant HBV or HCV infection. RESULTS: Overall, 275 patients (107 coinfected and 168 non-coinfected) were evaluated. Coinfected patients were more commonly former intravenous drug users and had a longer history of HIV infection and higher baseline aminotransferase levels. Both HIV-RNA and CD4 response were similar in the two groups. Mean time to first HIV-RNA copy number <50 copies/mL was 4.1 months (95% CI 3.5-4.6) in non-coinfected patients and 3.9 months (95% CI 3.3-4.5) in coinfected patients (hazard ratio 1.039, 95% CI 0.761-1.418, P = 0.766, log-rank test). The risk of developing new grade 3-4 hepatic adverse events was significantly higher in coinfected patients (hazard ratio 1.779, 95% CI 1.123-2.817, P = 0.009). The two groups of coinfected and non-coinfected patients had similar rates of interruption of any baseline drug (hazard ratio 1.075, 95% CI 0.649-1.781, P = 0.776) and of raltegravir (hazard ratio 1.520, 95% CI 0.671-3.447, P = 0.311). Few AIDS-defining events and deaths occurred. CONCLUSIONS: Viroimmunological response to regimens based on raltegravir and other recent anti-HIV inhibitors is not negatively affected by coinfection with HBV or HCV. Liver toxicity, either pre-existing or new, is more common in coinfected patients, but with no increased risk of treatment interruption.openWeimer LE; Fragola V; Floridia M; Guaraldi G; Ladisa N; Francisci D; Bellagamba R; Degli Antoni A; Parruti G; Giacometti A; Manconi PE; Vivarelli A; D'Ettorre G; Mura MS; Cicalini S; Preziosi R; Sighinolfi L; Verucchi G; Libertone R; Tavio M; Sarmati L; Bucciardini R on behalf of the ISS-NIA Study GroupWeimer LE; Fragola V; Floridia M; Guaraldi G; Ladisa N; Francisci D; Bellagamba R; Degli Antoni A; Parruti G; Giacometti A; Manconi PE; Vivarelli A; D'Ettorre G; Mura MS; Cicalini S; Preziosi R; Sighinolfi L; Verucchi G; Libertone R; Tavio M; Sarmati L; Bucciardini R on behalf of the ISS-NIA Study Grou

Correction: Real-life data on potential drug-drug interactions in patients with chronic hepatitis C viral infection undergoing antiviral therapy with interferon-free DAAs in the PITER cohort study (PLoS ONE (2017) 12: 2 (e0172159) DOI: 10.1371/journal.pone.0172159)

The graph that appears as Fig 2A is incorrectly duplicated in Fig 2B. Please see the corrected Fig 2 here.(Figure Presented)

New Dietary Tool to Assess Nutritional Deficiencies in a NAFLD Population: A Simple Tool for Primary Care.

Background: Ophthalmic abnormalities are amongst the 5 major criteria for diagnosing autosomal dominant Alagille Syndrome (AS). Embryotoxon, pseudo-papilledema and pigmentary retinopathy being most frequently part of the syndrome. Papilledema with or without intracranial hypertension (ICHT) are rarely described. We report 9 cases of bilateral papilloedema, 4 associated to ICHT at lumbar puncture (LP) , all being diagnosed idiopathic ICHT in children with AS. Methods: We reviewed ophthalmologic examination data from 85 pediatric patients with clinically (n=48) and/or genetically (n=37) proven AS followed in two referring hospitals (UCL St Luc Brussels, n=75; HUG Geneva n=10). Patients were included if data were available before and after liver transplantation (LT). Results: 69 patients fulfilled inclusions criteria. 41 patients (41/69, 59%) of this group had LT of whom 2 developed true papilloedema before LT and 6 after LT (6/41, 14%). One papilloedema, but with normal neurologic exam and a rapid resolution was found in a non-transplanted child (1/28, 3%). Papilloedema resolved spontaneously in 4 patients (2 with pre-transplant onset) (4/69, 6%). In a fifth patient, severe papilloedema without documented ICHT (normal LP) resolved after switching tacrolimus to cyclosporine and adding acetazolamide. In only 4 remaining patients; the ICHT was revealed at LP. In all patients normal neurological exam and cerebral MRI were reported (4/69, 6%). ICHT was treated by steroids alone in one patient, and in the 3 others patients in combination with acetazolamide and a switch from tacrolimus to cyclosporine. Among these 3 patients, ventriculo-peritoneal derivation was ultimately required in 2 for severe progressive visual loss. We detected pseudo-papilloedema in 7 additional children (7/69, 10%); which was persistent and unchanged after LT in n=4. Conclusion: Besides pseudopapilloedema, true papilloedema with or without proven ICHT in a context of AS occurs in probably more patients than expected. A close follow-up of ophthalmologic complications should be implemented for these patients before and/or after LT because the risk of severe and irreversible visual loss

Real-life data on potential drug-drug interactions in patients with chronic hepatitis C viral infection undergoing antiviral therapy with interferon-free DAAs in the PITER Cohort Study

AIM: To assess the potential DDIs of DAAs in HCV-infected outpatients, according to the severity of liver disease and comedication used in a prospective multicentric study. METHODS: Data from patients in 15 clinical centers who had started a DAA regimen and were receiving comedications during March 2015 to March 2016 were prospectively evaluated. The DDIs for each regimen and comedication were assigned according to HepC Drug Interactions (www.hep-druginteractions.org). RESULTS: Of the 449 patients evaluated, 86 had mild liver disease and 363 had moderate-to-severe disease. The use of a single comedication was more frequent among patients with mild liver disease (p = 0.03), whereas utilization of more than three drugs among those with moderate-to-severe disease (p = 0.05). Of the 142 comedications used in 86 patients with mild disease, 27 (20%) may require dose adjustment/closer monitoring, none was contraindicated. Of the 322 comedications used in 363 patients with moderate-to-severe liver disease, 82 (25%) were classified with potential DDIs that required only monitoring and dose adjustments; 10 (3%) were contraindicated in severe liver disease. In patients with mild liver disease 30% (26/86) used at least one drug with a potential DDI whereas of the 363 patients with moderate-to-severe liver disease, 161 (44%) were at risk for one or more DDI. CONCLUSIONS: Based on these results, we can estimate that 30-44% of patients undergoing DAA and taking comedications are at risk of a clinically significant DDI. This data indicates the need for increased awareness of potential DDI during DAA therapy, especially in patients with moderate-to-severe liver disease. For several drugs, the recommendation related to the DDI changes from "dose adjustment/closer monitoring", in mild to moderate liver disease, to "the use is contraindicated" in severe liver disease