The role of the pharmacist within an immune-mediated inflammatory disease unit: Results of a survey of healthcare providers and patients.

OBJECTIVE: To evaluate the importance and need for pharmacists to expand  their role to new activities and to promote and maintain others they already  carried out prior to the implementation of a new Immunemediated Inflammatory Diseases Unit to be created in our hospital; to prioritize the new activities incorporated based on the results obtained. METHOD: This was a single center cross-sectional based on a survey  administered during January 2020 to all clinical healthcare providers due to be part of the new unit, as well as to a sample of patients. It was structured into two categories: actions related to patients' pharmaceutical  care, and actions related to practitioners of the Immune-mediated  Inflammatory Diseases Unit. Each item was assigned a score from 0 to 10,  where 10 indicated maximum interest or need. A prioritization template was  applied to quantify and evaluate each activity and implement the new ones in  order of priority. RESULTS: A total of 90 responses were obtained (30 from patients and 60 from  healthcare workers). An analysis was performed of the median scores of each  of the 20 activities proposed, which ranged between 8 and 10 points. When  comparing the scores obtained, it was observed that more statistically  significant differences were obtained in the pharmacists vs doctors group than  in the pharmacists vs nurses group, or the pharmacists vs patients one. After  prioritization, the first action taken was to implement electronic prescriptions  for outpatients with immune-mediated inflammatory diseases. CONCLUSIONS: The survey revealed the expectations of healthcare providers and patients regarding the role pharmacists should play in the newly created unit and provided an insight into the most valued activities. This information will be useful in prioritizing the implementation of the new activities to be carried out by the unit.

Objetivo: Evaluar el interés y necesidad de que el farmacéutico desarrolle nuevas actividades propuestas, y potenciar o mantener otras que ya se realizaban, antes de que la futura Unidad de Enfermedades Inflamatorias Inmunomediadas inicie su actividad en nuestro hospital. Además, priorizar la incorporación de las nuevas actividades en base a los  resultados obtenidos.Método: Diseño observacional transversal unicéntrico mediante una encuesta  realizada en enero de 2020 a todos los profesionales sanitarios de los servicios  clínicos implicados y a una muestra de pacientes, y estructurada en dos  categorías: Acciones orientadas a la atención farmacéutica al paciente y  Acciones orientadas a los profesionales de dicha Unidad. Cada ítem se puntuó  de 0 a 10, siendo 10 el máximo interés/necesidad. Se aplicó una matriz de  priorización para cuantificar y evaluar cada actividad e implantar las nuevas  por orden de priorización.Resultados: Se completaron 90 encuestas (30 de pacientes y 60 de profesionales). Se analizaron las medianas obtenidas de cada una de las 20  actividades propuestas, alcanzándose valores entre 8 y 10. Se compararon valores: en el grupo de farmacéuticos versus médicos se  obtuvieron más ítems con diferencias estadísticamente significativas que en el grupo farmacéuticos versus enfermería, o farmacéuticos versus pacientes. Tras la priorización, la primera acción fue implantar la prescripción electrónica en pacientes externos con enfermedades inflamatorias inmunomediadas.Conclusiones: La encuesta ha permitido conocer las expectativas de los  profesionales sanitarios y pacientes sobre la actividad del farmacéutico en  dicha Unidad, cuantificar las actividades más valoradas y priorizar la  implantación de nuevas actividades.

Real-World Experience with Two-Drug Regimens in HIV-1-Infected Patients Beyond the Indication of Clinical Trials: 48 Weeks' Results.

Data on two-drug regimens (2DRs) have shown high efficacy and tolerability in treatment-naive and treatment-experienced HIV-1 patients. Current guidelines recommend 2DRs as alternative to three-drug regimens (3DRs) to reduce long-term drug exposure and costs. Nevertheless, real-world experience with 2DR is limited. This study assessed the use of 2DR in routine clinical practice in a tertiary hospital. A retrospective, observational, descriptive study was performed on the use of dual therapy in adult HIV-1 patients. Individuals on antiretroviral treatment (ART) with dolutegravir plus lamivudine or dolutegravir plus rilpivirine who started 2DR between November 1, 2018, and April 30, 2019, were eligible for our study. Follow-up period was 48 weeks. Overall, 112 patients started 2DR; median age was 51 years and 88.4% were men. Most patients (97.3%) were treatment experienced before dual therapy, with 9.6 ± 8.0 years of prior ART on average. Around 96.4% of patients were virologically suppressed before 2DR. Most common reasons to start dual therapy were treatment simplification (49.5%), avoidance of long-term toxicities (21.1%), and intolerance to previous ART (18.3%). The main regimen used in dual therapy was dolutegravir plus lamivudine (98.2%). Only eight patients discontinued dual therapy; the main reason for discontinuation was toxicity. All patients who did not discontinue 2DR were virologically suppressed at week 48. ART simplification saved €130,117.58 during the study period. In our cohort, dual therapy was mainly used for virologically suppressed patients, before availability of the single-tablet 2DR. Switching to a 2DR may be a key option for treatment simplification and avoidance of long-term toxicities. Furthermore, 2DR could provide a more cost-effective alternative to 3DR.

Inhaled bronchodilators use and clinical course of adult inpatients with Covid-19 pneumonia in Spain: A retrospective cohort study.

BACKGROUND: In the current coronavirus health crisis, inhaled bronchodilators(IB) have been suggested as a possible treatment for patients hospitalized. Patients with evidence of Covid-19 pneumonia worldwide have been prescribed these medications as part of therapy for the disease, an indication for which this medications could be ineffective taken on account the pathophysiology and mechanisms of disease progression. OBJECTIVE: The main objective was to evaluate whether there is an association between IB use and length of stay. Primary end points were the number of days that a patient stayed in the hospital and death as a final event in a time to event analysis. Pneumonia severity, oxygen requirement, involved drugs, comorbidity, historical or current respiratory diagnoses and other drugs prescribed to treat coronavirus pneumonia were also evaluated. METHODS: A descriptive, observational, cross-sectional study was performed in this tertiary hospital in Madrid (Spain). Data were obtained regarding patients hospitalized with Covid-19, excluding those who were intubated. The primary and secondary outcomes such as duration of hospitalization and death were compared in patients who received IB with those in patients who did not. RESULTS: 327 patients were evaluated, mean age was 64.4 ± 15.8 years. Median length of hospitalization stay was 10 days. Of them 292 (89.3%) overcame the disease, the remaining 35 died. Patients who had received IB did not have less mortality rate (odds ratio 0.839; 95% CI: 0.401 to 1.752) and less hospitalization period when compared with patients who did not received IB (odds ratio 1.280; 95% CI: 0.813 to 2.027). There was no significant association between IB use and recovery or death. Hypertension and diabetes were the most common comorbidities. The prevalence of chronic respiratory disease in our cohort was low (21.1%). Anticholinergics were the IB more frequently prescribed for Covid-19 pneumonia. Better response in patients treated with inhaled corticosteroids was not observed. CONCLUSION: Off-label indication of inhaled-bronchodilators for Covid-19 patients are common in admitted patients. Taken on account our results, the use of IB for coronavirus pneumonia apparently is not associated with a significantly patient's improvement. Our study confirms the hypothesis that inhaled bronchodilators do not improve clinical outcomes or reduce the risk of Covid-19 mortality. This could be due to the fact that the virus mainly affects the lung parenchyma and the pulmonary vasculature and probably not the airway. More researches are necessary in order to fill the gap in evidence for this new indication.

Cost evolution of biological drugs in rheumatoid arthritis patients in a tertiary hospital: Influential factors on price.

OBJECTIVE: To assess the evolution of cost per patient/year and the cost per patient/year/drug in patients with rheumatoid arthritis (RA) receiving biological treatments. To analyze and quantify the factors influencing this evolution, such as the optimization of the biological drugs, the use of biosimilars, and official discounts and discounts obtained after negotiated procedures. In addition, to assess specific clinical parameters of disease activity in these patients. METHODS: Retrospective, observational study conducted in a Spanish tertiary hospital. Adult patients diagnosed with RA under treatment from 2009 to 2017 were included. RESULTS: 320, 270 and 389 patients were included in 2009, 2013 and 2017, respectively. The patient/year cost decreased from 10,789€ in 2009, 7491€ in 2013 to 7116€ in 2017. In 2017, due to the established competition, discounts of 14% and 29.5% were achieved on etanercept and its biosimilar; 11.5%, 17.8%, 17.9%, 17.3% on adalimumab, certolizumab, golimumab and tocilizumab IV respectively, and 24.6% and 43.1% on infliximab and its biosimilar. The percentage of patients optimized in 2017 was 35.2%. The annual saving in 2017 was 1,288,535€ (830,000€ due to dose optimization and/or administration regimens, 249,666€ corresponding to 7.5% of the official discount and 208,868€ after negotiated procedures). CONCLUSION: The annual cost per patient in RA decreased considerably due to different factors, such as discounts on the purchase of drugs due to official discounts and negotiated procedures, together with the optimization of therapies, the latter being the factor that contributed most to this decrease.

Persistence of biological agents over an eight-year period in rheumatoid arthritis and spondyloarthritis patients.

OBJECTIVE: To calculate the persistence, over a period of eight years, the retention rate of first and second-line of treatment with biological agents in  patients with rheumatoid arthritis, spondyloarthritis and psoriatic arthritis and to compare retention rates of the various drugs for each pathology. METHOD: Retrospective observational study that included patients affected by  rheumatoid arthritis, spondyloarthritis and psoriatic arthritis, who started  treatment with biological agents between January 2009 and December 2012 and followed until December 2016. RESULTS: 132, 87 and 33 patients were included in rheumatoid arthritis, spondyloarthritis and psoriatic arthritis, respectively. The median  retention duration of all biological agents for the first and second-line, was 30.9 months and 14.0 months, respectively for rheumatoid arthritis; 63.06  months and 25.6 months, respectively in spondyloarthritis. Psoriatic arthritis did  not reach the median (> 70 months in first-line) (first line p = 0.002). Individual drug survival in first line: the median retention duration of tocilizumab was 58.3 months, followed by etanercept (p = 0.79) in rheumatoid arthritis. For spondyloarthritis, golimumab and etanercept had greater retention than the other drugs (they did not reach the median): adalimumab was 63.0 months and for infliximab was 50.1 months. In psoriatic arthritis, golimumab,  infliximab and etanercept not reach the median and they had greater retention than adalimumab (59.4 months). Individual drug survival in second  line: tocilizumab was the most persistent drug (median 22.1 months) in  rheumatoid arthritis, and golimumab for spondyloarthritis and psoriatic arthritis. CONCLUSIONS: Tocilizumab and etanercept in rheumatoid arthritis, and golimumab in spondyloarthritis and psoriatic arthritis also, were the most persistent drugs in first-line and second-line treatment.

Objetivo: Calcular y analizar la persistencia global y por medicamento, en  primera y segunda línea de tratamiento, en pacientes con artritis reumatoide, espondiloartritis axial radiográfica y no radiográfica y artritis  psoriásica durante un periodo de ocho años.Método: Estudio retrospectivo observacional de persistencia en pacientes que  iniciaron su terapia con medicamentos biológicos entre enero de 2009 y  diciembre de 2012 en seguimiento hasta diciembre de 2016. Resultados: Se analizaron 132, 87 y 33 pacientes con artritis reumatoide, espondiloartritis y artritis psoriásica, respectivamente. La  persistencia mediana global para los biológicos en primera y segunda línea  fueron: 30,9 meses y 14 meses, respectivamente, en artritis reumatoide; 63,06 meses y 25,6 meses en espondiloartritis. No se alcanzó la persistencia mediana en los ocho años de seguimiento en artritis psoriásica (>  70 meses) (p = 0,002 para la función de supervivencia entre patologías en primera línea). Persistencia mediana alcanzada en primera línea por  medicamento: tocilizumab (58,3 meses), seguido de etanercept (44 meses) en  artritis reumatoide (p = 0,79); en espondiloartritis golimumab y etanercept fueron los más persistentes (no alcanzaron la mediana), seguidos deadalimumab (44 meses) e infliximab (50,1 meses). En artritis psoriásica, golimumab seguido de infliximab y etanercept fueron los más persistentes (no alcanzaron la mediana), y adalimumab (59,4 meses).  Persistencia mediana alcanzada en segunda línea por medicamento: tocilizumab (22,1 meses) en artritis reumatoide. Golimumab fue el más persistente en espondiloartritis y artritis psoriásica (sin alcanzar la mediana).Conclusiones: Tocilizumab y etanercept fueron los medicamentos más persistentes en artritis reumatoide, y golimumab en espondiloartritis y  artritis psoriásica en primera y segunda línea de tratamiento.

Effect of mono/dual antiretroviral therapy on suppression of HCV and HIV during treatment of HCV infection in HIV/HCV-coinfected patients.

OBJECTIVE: Data of hepatitis C treatment with direct-acting antivirals (DAAs) in HIV infected patients are limited to a few number of antiretroviral therapies (ART). The aim of this study was to assess the effectiveness and safety of non-conventional ART as monotherapy or dual therapy (MDT) when combined with DAA. METHODS: Retrospective review of HIV/HCV-coinfected patients treated with DAAs during one year in 3 centers. Sustained virologic response 12 weeks after therapy (SVR) and maintenance of HIV viral suppression were compared between patients receiving triple ART (TT) or MDT. RESULTS: Overall 485 patients were included (359 receiving TT and 126 MDT). HCV SVR was 93.4% (95%CI, 90.8% to 95.3%) in the intention-to-treat analysis without differences between groups: 92.8% on TT vs 95.2% on MDT (p=0.3). HCV virological failure was associated with lower CD4+cell count at baseline (for every 100-cell/µl increment: OR, 0.8; 95%CI, 0.7-0.9; p=0.01) and with liver stiffness (for every 10-unit increment: OR, 1.5; 95%CI 1.2-1.8; p<0.01). HIV-RNA during HCV treatment or 12 weeks after was detectable in 23 patients on TT (6.6%) and 9 (7.2%) patients on MDT (p=0.8). The median (IQR) change in CD4+cell count was not significantly different between the groups: 15 (-55 to 115) in TT vs -12 (-68 to 133) cells/µl in MDT (p=0.8). CONCLUSION: DAAs obtain high rates of SVR among HIV/HCV-coinfected patients independently of whether TT or non-conventional ART is used. Suppression of HIV was maintained in both groups.

Cost evolution of biological agents for the treatment of spondyloarthritis in a tertiary hospital: influential factors in price.

Background Spending on biological agents has risen dramatically due to the high cost of the drugs and the increased prevalence of spondyloarthritis. Objective To evaluate the annual cost per patient and cost for each biological drug for treating patients with spondyloarthritis from 2009 to 2016, and to calculate factors that affect treatment cost, such as optimizing therapies by monitoring drug serum levels, the use of biosimilar-TNF inhibitors, and official discounts or negotiated rebates in biologicals acquired by the pharmacy department. Method Retrospective, observational study in a Spanish tertiary hospital. Main outcome Annual cost per patient and per drug. Factors that influenced the costs and socio-demographic parameters and disease activity. Results A total of 129, 215, and 224 patients were treated in 2009, 2013, and 2016, respectively. The annual cost per patient decreased: EUR11,604 in 2009, EUR8513 in 2013, and EUR7464 in 2016. The introduction of new drugs drives economic competition, leading to total savings per drug, with discounts reaching 5.8, 12.4, 16.7, 17.7, 13.7, and 24.8% for original infliximab, etanercept, adalimumab, ertolizumab, golimumab, and secukinumab, respectively, while rebates for biosimilar infliximab reached 31.90% in 2016. The number of patients with optimized therapies reached 47.5% in 2016, which led to cost savings of EUR798,614, in addition to savings from official discounts and rebates of EUR252,706 and savings from optimized therapies of EUR545,908 in 2016. Conclusion The cost of biological treatments declined after official discounts, negotiated rebates, and optimized therapies, leading to a significant decrease in the annual cost per patient. The greatest contribution to economic savings in biological therapy according to our study was biological therapy optimization.

Analysis of antiretroviral therapy modification in routine clinical practice in the management of HIV infection.

OBJECTIVES: The main goal was to assess the reasons for antiretroviral therapy (ART) change in patients with HIV in a hospital setting in routine clinical practice. The economic impact of ART modification was also analysed. METHODS: Patients with HIV who changed their ART between 24 November and 24 December 2014 were registered. Length of initial therapy, type of ART before and after therapy modification, and reasons for the ART change were analysed. To assess the economic impact, antiretroviral drug costs at the time of the study were recorded. RESULTS: Of a cohort of 3850 patients with HIV, 1976 attended for pharmaceutical care consultation at Hospital Universitario La Paz during the study period. Ninety-two patients (4.7%) had their ART modified. The median length of the previous therapy was 26 months (range 1-144). The most common initial therapy regimen was 2 nucleoside reverse transcriptase inhibitors (NRTI)+1 non-nucleoside reverse transcriptase inhibitor (NNRTI) (29.4%), and the most common one after modification was 2 NRTI+1 integrase strand transfer inhibitor (INSTI) (40.2%). Forty-three modifications were made because of toxicity and adverse effects (46.7%), 25 because of therapy simplification (27.2%), 16 because of treatment failure (17.4%), and 8 because of drug-drug interactions (8.7%). ART costs increased by a mean of €14 (SD €216; range -€528 to +€831) per month per patient after therapy modification at the time of study. CONCLUSIONS: Toxicity and adverse effects were the most common reason for ART alteration in patients with HIV in routine clinical practice in a hospital setting. Better knowledge about factors that motivate these changes may contribute to decreased toxicity and increased treatment success. ART modification had a variable but not very substantial economic impact.

Approaches for understanding and predicting drug interactions in human immunodeficiency virus-infected patients.

INTRODUCTION: Knowledge of drug interactions is vital to maximize antiretroviral efficacy and avoid drug-related toxicities. Treatment of co-morbidities has become a difficult task in HIV-infected individuals because pharmacokinetic and/or pharmacodynamic interactions are common when other medications are prescribed along with antiretroviral agents. AREAS COVERED: This article provides an update of the most relevant drug interactions that occur between antiretroviral agents and other drugs. The article additionally revisits how these drug interactions can be prevented from occurring as well as how they can be managed. EXPERT OPINION: Interactions between antiretrovirals and other drugs are frequent in clinical practice. The most common are those affecting drug metabolism due to induction or inhibition of the CYP450, leading to abnormal drug exposure. It is by this mechanism that most HIV protease inhibitors, non-nucleoside reverse transcriptase inhibitors and maraviroc often interact with other medications. In contrast, nucleoside reverse transcriptase inhibitors and some integrase inhibitors, which do not or only marginally affect CYP450, are relatively free of significant pharmacokinetic interactions, although nucleoside analogs might be involved in some pharmacodynamic interactions.

Simplification from protease inhibitors to once- or twice-daily raltegravir: the ODIS trial.

BACKGROUND: Raltegravir has demonstrated good antiviral activity and safety profile in twice-daily (bid) dosing. However, its long terminal elimination half-life might allow once-daily (qd) administration. METHODS: Consecutive HIV-infected individuals at our clinic under protease inhibitor (PI)-based regimens with plasma HIV-RNA <50 copies/mL for > 24 weeks were invited to replace PIs with raltegravir. Patients were randomly assigned to raltegravir 800 mg qd, 400 mg bid, or twice daily for the first 3 months and then once daily. RESULTS: A total of 222 patients completed 24 weeks of follow-up on raltegravir (149 once-daily arm, 35 twice-daily arm, and 38 twice-daily to once-daily arm). At inclusion, mean CD4+ count was 574±308 cells/µL. Within 24 weeks, 13 (5.9%) patients experienced virological failure: 12 (6.4%) in the once-daily arms, and 1 (2.9%) in the twice-daily arm (P = .18). The rate of virological failure was 16.2% (12/74) in patients with prior nucleoside reverse transcriptase inhibitor (NRTI) resistance but only 0.7% (1/148) in the rest (P < .001). CONCLUSION: A switch from PIs to raltegravir in HIV-infected patients with undetectable plasma HIV-RNA effectively sustains viral suppression, as long as prior NRTI resistance had not been selected. No significant differences were seen when comparing raltegravir twice daily or once daily in this context, although once-daily dosing tended to perform less well.

Influence of a single nucleotide polymorphism at the main ribavirin transporter gene on the rapid virological response to pegylated interferon-ribavirin therapy in patients with chronic hepatitis C virus infection.

The equilibrative nucleoside transporter 1 (ENT1) is the main protein involved in ribavirin cellular uptake. Polymorphisms at the ENT1 gene may influence ribavirin activity as part of hepatitis C virus (HCV) therapy. A retrospective study was conducted in 109 human immunodeficiency virus (HIV)-infected patients who were infected with HCV genotypes 1 or 4 who had received pegylated interferon (pegIFN)-ribavirin. Single nucleotide polymorphisms (SNPs) at the ENT1 gene were examined using TaqMan 5'-nuclease assays. In the study population, allelic frequencies at rs760370 were as follows: A3 (43 [39%] of 109 patients), AG (50 [46%] of 109 patients), and GG (16 [15%] of 109 patients). Achievement of rapid virological response was more frequent in GG carriers than in AA/AG carriers (50% vs 17%, respectively; P = .007). In multivariate analysis, the GG genotype (odds ratio [OR], 15.9; 95% confidence interval [CI], 2.8-92.2; P < .002), a baseline serum HCV-RNA level <600,000 IU/mL (OR, 45.7; 95% CI, 8.7-240.5; P <.001) and a serum ribavirin trough concentration >2.5 µg/mL (OR, 4.8; 95% CI, 1.3-17.1; P < .016) were associated with rapid virological response. When 2 or more of these factors were present, positive and negative predictive values of rapid virological response were 65% and 91%, respectively. In summary, a SNP rs760370A→G at the ENT1 gene influences the chance of rapid virological response to pegIFN-ribavirin therapy in HIV-infected patients with chronic HCV infection due to HCV genotypes 1 or 4, most likely modulating intracellular ribavirin exposure within hepatocytes.

Use of the HCP5 single nucleotide polymorphism to predict hypersensitivity reactions to abacavir: correlation with HLA-B*5701.

OBJECTIVES: To study the correlation between the HLA-B*5701 allele and the single nucleotide polymorphism in HCP5 (rs2395029). PATIENTS AND METHODS: All HIV patients naive for abacavir seen at our institution between September 2007 and December 2008 were prospectively screened for HLA-B*5701. HCP5 rs2395029 genotyping was carried out by allelic discrimination using the TaqMan 5'-nuclease assay. High-resolution HLA class I typing was undertaken using sequence-specific primers. RESULTS: A total of 245 HIV patients were included in the study. A good correlation between HLA-B*5701 and HCP5 was observed (negative and positive predictive values of 100% and 93%, respectively). CONCLUSIONS: The use of HCP5 rs2395029 testing could be as useful as HLA-B*5701 typing to prevent the abacavir hypersensitivity reaction. Given that HCP5 testing is cheaper, less time-consuming and easier to perform than HLA typing, it may confidently replace the latter in clinical settings.

The benefit of simplification from tipranavir/ritonavir 500/200 bid to 500/100 bid guided by therapeutic drug monitoring.

Despite being among the most potent protease inhibitors, the use of tipranavir (TPV) is hampered by a high pill burden and frequent side effects compared with other boosted protease inhibitors. A total of 10 patients receiving TPV/ritonavir (TPV/RTV) 500/200 for longer than 6 months were randomized to stay on the same dosing schedule or switch to TPV/RTV 500/100. Although all patients on TVP/RTV 500/200 remained stable for the next 12 weeks, 3 out of 5 patients who switched doses experienced benefits in terms of reducing aminotransferases and total cholesterol. Fasting triglycerides were also reduced in 2 of them. Plasma HIV-RNA remained undetectable in all patients, despite the observed decline in TPV trough concentrations.

Plasma ribavirin trough concentrations at week 4 predict hepatitis C virus (HCV) relapse in HIV-HCV-coinfected patients treated for chronic hepatitis C.

The influence of ribavirin trough concentrations (RBV C(trough)) on the risk of hepatitis C virus (HCV) relapse was retrospectively analyzed in 99 HIV-HCV-coinfected patients who achieved end-of-treatment response with pegylated alpha interferon plus weight-based RBV. The independent predictors (odds ratio [OR] [95% confidence interval (CI)]) of HCV relapse were RBV plasma C(trough) of <2.5 microg/ml (4.5 [1.3 to 15.5]), baseline serum HCV RNA (2.5 [1.2 to 5.1]), and HCV genotype 1 or 4 (13.3 [2.6 to 66.7]). Monitoring of RBV C(trough) may permit early adjustment of RBV dosage to avoid HCV relapse.

Hepatic safety profile of raltegravir in HIV-infected patients with chronic hepatitis C.

BACKGROUND: Patients with chronic hepatitis C virus (HCV) infection experience antiretroviral-associated liver toxicity more frequently than HIV mono-infected persons. Herein, we report the hepatic safety profile of raltegravir in a relatively large group of HIV/HCV co-infected patients, a population that was poorly represented in the registrational studies. METHODS: Prospective, observational study of all antiretroviral-experienced HIV-infected patients who initiated raltegravir from January 2006 to January 2009 at a reference HIV clinic. Clinical data, laboratory parameters and liver stiffness measured at baseline, week 4 and every 3 months thereafter were collected. Chronic hepatitis C was defined as positive serum HCV-RNA. Grade 1-4 hepatotoxicity was defined following the AIDS Clinical Trials Group definition for liver enzyme elevations (LEEs). A control group of patients who initiated protease inhibitors (PIs) or non-nucleoside reverse transcriptase inhibitors (NNRTIs) was examined similarly. RESULTS: Data from 218 HIV-infected patients on raltegravir were analysed, 126 HIV mono-infected and 92 HIV/HCV co-infected patients. Any degree of LEEs occurred in 10 (7.9%) HIV mono-infected and 23 (25%) co-infected patients (relative risk 3.1; 95% confidence interval 2.9-3.4; P = 0.002). Severe hepatotoxicity (grade 3-4), however, was only seen in 3 (1.4%) patients, all co-infected with HCV. It occurred at months 1, 15 and 15, respectively. In all three subjects other reasons than raltegravir exposure most likely explained LEEs. Multivariate analysis revealed HCV co-infection as the only independent variable associated with any degree of hepatotoxicity on raltegravir (P = 0.03). Finally, the rate of LEEs in patients on raltegravir was lower than in those who were treated with PIs or NNRTIs. CONCLUSIONS: LEEs are less frequent in patients treated with raltegravir than with other antiretroviral drug classes. However, HIV/HCV co-infected patients treated with raltegravir experienced LEEs more frequently than HIV mono-infected persons. In this series, LEEs in patients treated with raltegravir were uniformly mild and no cases of grade 3-4 hepatotoxicity could be directly attributed to the drug. These results reinforce the overall hepatic safety profile of raltegravir.

Rate and timing of hepatitis C virus relapse after a successful course of pegylated interferon plus ribavirin in HIV-infected and HIV-uninfected patients.

Information on the rate and timing of hepatitis C virus (HCV) relapse after treatment with pegylated interferon plus ribavirin is scarce. Among 604 patients treated for chronic hepatitis C, the 386 who were human immunodeficiency virus (HIV) positive attained an end-of-treatment response less frequently and experienced relapse more often than did the 218 who were HIV negative. However, episodes of HCV relapse occurred before week 12 in most cases, regardless of HIV status.

Differences in lopinavir plasma concentrations comparing Kaletra film coated tablets and soft gelatine capsules that result in various lipid abnormalities.

Changes in lipids and lopinavir plasma concentrations were examined in 40 HIV-patients exposed to lopinavir/ritonavir 400/100 mg BID, formulated as tablets and as capsules. Triglycerides and total/HDL-cholesterol ratio were significantly lower with tablets than with capsules. Lopinavir concentrations were higher with tablets than with capsules.

Use of different inhibitory quotients to predict early virological response to tipranavir in antiretroviral-experienced human immunodeficiency virus-infected patients.

Information about the relationship between pharmacological parameters and an early virological response to tipranavir (TPV) is scarce. Human immunodeficiency virus (HIV)-infected patients who had received TPV as part of a salvage regimen were analyzed retrospectively. A virological response was defined as a decline in the HIV RNA level of > or = 1 log unit or to <50 copies/ml between weeks 4 and 12 of therapy. The virtual inhibitory quotient (vIQ) was calculated as the ratio of the TPV plasma trough concentration (C(trough))/virtual change in the 50% inhibitory concentration. Three genotypic inhibitory quotients (gIQs) were calculated by using different TPV resistance mutation scores (from the International AIDS Society-USA [IAS-USA], Randomized Evaluation of Strategic Intervention in Multidrug-Resistant Patients with Tipranavir [RESIST], and Agence Nationale de Recherches sur le Sida et les Hépatites Virales [ANRS] trials). The sensitivities, specificities, positive predictive values (PPVs), negative predictive values (NPVs), and likelihood ratios for a positive result (LHR+) and a negative result (LHR-) [LHR+ = sensitivity/(1-specificity); LHR- = (1-sensitivity)/specificity] were calculated. A total of 57 HIV-infected patients were analyzed. A virological response was achieved by 77% of the patients. TPV resistance mutations, TPV C(trough), vIQs, and gIQs were all significantly associated with a virological response. The vIQ had the best PPV and NPV (97% and 78%, respectively). The values of the LHR+ were 7.8 for vIQ, 3.4 for the RESIST gIQ, 3.3 for the IAS-USA gIQ, 3.1 for the ANRS gIQ, 2.2 for TPV C(trough), and 1.3 for the IAS-USA and RESIST scores. The values of LHR- were 0 for the RESIST score, 0.07 for vIQ, 0.09 for the IAS-USA score, 0.27 for the RESIST gIQ, 0.32 for the IAS-USA gIQ, 0.37 for the ANRS gIQ, and 0.48 for TPV C(trough). HIV-infected patients who initiate a salvage regimen based on TPV may benefit from baseline drug resistance testing and TPV plasma concentration determination, as vIQ is the best predictor of a virological response.

Increase in serum bilirubin in HIV/hepatitis-C virus-coinfected patients on atazanavir therapy following initiation of pegylated-interferon and ribavirin.

Atazanavir use is associated with increases in serum bilirubin. Ribavirin, used to treat hepatitis-C infection, cause hemolysis and may worsen hyperbilirubinemia. We studied HIV/hepatitis-C virus-coinfected patients who initiated hepatitis-C therapy. Hyperbilirubinemia grade 3-4 increased from 9% to 45% after the start of hepatitis-C treatment in patients who used atazanavir concomitantly. Atazanavir use and hemoglobin (Hb) drops were predictors of increases in bilirubin. A substantial proportion of patients under atazanavir-therapy experienced significant hyperbilirubinemia and jaundice following initiation of hepatitis-C therapy.

Usefulness of monitoring ribavirin plasma concentrations to improve treatment response in patients with chronic hepatitis C.

Ribavirin in combination with pegylated interferon alpha is the current standard treatment for chronic hepatitis C. Adequate exposure to ribavirin seems crucial for achieving the best virological response. However, anaemia is a frequent, dose-dependent limiting side effect of ribavirin use. Therefore, therapeutic drug monitoring of ribavirin plasma concentrations could be a useful tool for individualizing ribavirin dosing. Herein, we review the relationship between ribavirin plasma concentrations and both virological response and toxicity, in order to define an optimal therapeutic range for ribavirin.