Multiple switching between the biosimilar adalimumab PF-06410293 and reference adalimumab in patients with active rheumatoid arthritis: a phase 3, open-label, randomised, parallel-group study.

BACKGROUND: An adalimumab biosimilar with an interchangeability designation could increase access to effective treatment for more patients. We aimed to assess the interchangeability of adalimumab biosimilar PF-06410293 (adalimumab-afzb) and reference adalimumab using a multi-switch study design. METHODS: We did an open-label, randomised, parallel-group study at 61 community (n=29), hospital (n=12), and academic (n=20) sites in ten countries (Bulgaria, Bosnia and Herzegovina, Czech Republic, Lithuania, Poland, Russia, Serbia, South Africa, Ukraine, and USA). Eligible patients were aged 18-70 years and met the 2010 American College of Rheumatology-European League Against Rheumatism classification criteria for rheumatoid arthritis for at least 4 months with moderately to severely active rheumatoid arthritis, based on their physician's evaluation. Eligible patients had been receiving methotrexate for at least 12 weeks and been on a stable dose for at least 4 weeks before the first dose of study medication. All patients received subcutaneous reference adalimumab (40 mg/0·4 mL [100 mg/mL] every 2 weeks) for 10 weeks before randomisation. At week 10, patients were randomly assigned (1:1) to either three switches between subcutaneous reference adalimumab (40 mg/0·4 mL [100 mg/mL] every 2 weeks) and adalimumab-afzb (40 mg/0·8 mL [50 mg/mL] every 2 weeks; switching group), or continuous dosing with subcutanous reference adalimumab (40 mg/0·4 mL [100 mg/mL] every 2 weeks; non-switching group) with stratification by bodyweight groups. Patients, investigators, and site personnel were not masked to treatment allocation. Primary endpoints were maximum observed serum concentration (Cmax) and area under plasma concentration-time curve (AUCτ) during weeks 30-32 in the pharmacokinetic population. Interchangeability was based on geometric mean ratios and corresponding 90% CIs within prespecified equivalence margins of 80-125% for both primary endpoints. Safety was analysed in all patients who received at least one dose of adalimumab-afzb or reference adalimumab. This trial is registered with ClinicalTrials.gov, NCT04230213. FINDINGS: Of the 569 patients assessed for eligibility between Jan 13, 2020, and June 22, 2021, 445 were enrolled, and 427 completed the first 10 weeks and were randomly assigned (213 to the switching group and 214 to the non-switching group). Participants had a median age of 56 years (IQR 46-63), 354 (83%) of 427 patients were women and 73 (17%) were men, and 422 (99%) were White. In the pharmacokinetic population (n=380), no clinically meaningful differences were observed in mean steady-state pharmacokinetic parameters between the switching and non-switching groups (geometric mean AUC 2237 µg × h/mL in the switching group and 2125 µg × h/mL in the non-switching group; Cmax 8·21 µg/mL in the switching group and 8·00 µg/mL in the non-switching group). Geometric mean ratios and 90% CIs for AUCτ (105·31, 89·16-124·39) and Cmax (102·56, 89·78-117·17) were within prespecified equivalence margins. No meaningful differences were observed in the proportion of patients who had serious adverse events (three [1%] of 213 patients in the switching group vs eight [4%] of 214 patients in the non-switching group), grade 3 or higher adverse events of special interest, discontinuations due to adverse events (eight [4%] vs nine [4%]), or immunogenic reactions in antidrug antibody-positive patients. No deaths were reported during the study. INTERPRETATION: The risk of multiple switches between reference adalimumab and adalimumab-afzb with respect to diminished efficacy (using pharmacokinetics as a surrogate) or safety is not greater than the risk of using reference adalimumab alone. FUNDING: Pfizer. VIDEO ABSTRACT.

Use of multibiomarker disease activity scores in biosimilarity studies for the treatment of patients with rheumatoid arthritis.

OBJECTIVES: This exploratory analysis investigated the potential use of the multibiomarker disease activity (MBDA) score to support biosimilarity assessments using data from two randomised controlled trials (RCTs) of biosimilar infliximab (IFX-qbtx) and biosimilar adalimumab (ADL-afzb) versus EU-sourced infliximab (Remicade; IFX-EU) and adalimumab (Humira; ADL-EU) reference products, respectively, both conducted in adult patients with active rheumatoid arthritis. METHODS: In one study, patients (N=650) were randomised 1:1 to IFX-qbtx or IFX-EU (3 mg/kg intravenous at weeks 0, 2 and 6, then every 8 weeks). In the other, patients (N=597) were randomised 1:1 to ADL-afzb or ADL-EU (40 mg subcutaneous every other week). All treatments were given with MTX. Mean values of MBDA scores were calculated at baseline (BL), based on the concentrations of 12 serum proteins using the Vectra disease activity algorithm, and at timepoints throughout treatment period 1 (TP1) of the IFX (weeks 6, 14, 30) and ADL (weeks 6, 12, 26) studies. Data were summarised using descriptive statistics for the intent-to-treat population, without imputation for missing data. RESULTS: At BL, mean (±SD) MBDA scores were 61.3 (±12.5) and 58.8 (±13.2) for IFX-qbtx (n=236) and IFX-EU (n=248), respectively, and 57.2 (±14.44) and 58.3 (±15.34) for ADL-afzb (n=292) and ADL-EU (n=293), respectively. Mean MBDA scores were highly comparable between IFX-qbtx and IFX-EU and between ADL-afzb and ADL-EU at all measured timepoints during TP1 in each study. CONCLUSIONS: These RCTs are the first to incorporate MBDA score as an exploratory assessment of biosimilarity. MBDA scores may provide objective, quantitative evidence of biosimilarity using an assessment of disease activity that is independent of the potential subjectivity inherent in joint counts, or in patient or physician global assessments. TRIAL REGISTRATION NUMBERS: NCT02222493 and NCT02480153.

Long-term efficacy, safety, and immunogenicity of the adalimumab biosimilar, PF-06410293, in patients with rheumatoid arthritis after switching from reference adalimumab (Humira®) or continuing biosimilar therapy: week 52-92 data from a randomized, double-blind, phase 3 trial.

BACKGROUND/OBJECTIVE: REFLECTIONS B538-02 is a randomized, double-blind comparative study of the adalimumab (ADL) biosimilar PF-06410293, (ADL-PF), and reference ADL sourced from the European Union (ADL-EU) in patients with active RA. Therapeutic equivalence was demonstrated based on ACR20 responses at week 12 (primary endpoint). We report long-term safety, immunogenicity, and efficacy of ADL-PF in patients who continued ADL-PF treatment throughout 78 weeks or who switched from ADL-EU to ADL-PF at week 26 or week 52. METHODS: Eligible patients (2010 ACR/EULAR RA diagnosis criteria for ≥ 4 months; inadequate response to MTX, ≤ 2 doses non-ADL biologic), stratified by geographic regions were initially randomized (1:1) in treatment period 1 (TP1) to ADL-PF or ADL-EU (40 mg subcutaneously, biweekly), both with MTX (10-25 mg/week). At week 26 (start of TP2), patients receiving ADL-EU were re-randomized to remain on ADL-EU or transition to ADL-PF for 26 weeks. At week 52 (start of TP3), all patients received open-label treatment with ADL-PF for 26 weeks and were followed after last treatment dose to week 92. To evaluate maintenance of response after switching or remaining on ADL-PF, ACR20, DAS28-4(CRP), and other measures of clinical response/remission were assessed through week 78 as secondary endpoints. Three groups were evaluated: biosimilar, week 26 switch, and week 52 switch. RESULTS: Overall, 507 patients participated in TP3. ACR20 response rates at week 52 were 88.4%, 88.2%, and 87.6% for the biosimilar, week 26, and week 52 switch groups, respectively. ACR20 response rates and DAS28-4(CRP) scores were sustained and comparable across groups in TP3. Incidence of treatment-emergent adverse events (AEs) during TP3 and follow-up was 42.6% (biosimilar), 37.0% (week 26 switch), and 50.8% (week 52 switch); 3 (0.6%) patients (all week 52 switch) reported treatment-related serious AEs. ADL-PF was generally well tolerated, with a comparable safety profile across groups. Overall, incidences of patients with anti-drug antibodies in TP3 and follow-up were comparable among groups (46.1%, 46.5%, and 54.2%, respectively). CONCLUSIONS: There were no clinically meaningful differences in safety, immunogenicity, and efficacy for patients who were maintained on ADL-PF for 78 weeks and those who had switched from ADL-EU at week 26 or week 52. TRIAL REGISTRATION: ClinicalTrials.gov , NCT02480153. First posted on June 24, 2015; EU Clinical Trials Register; EudraCT number: 2014-000352-29. Start date, October 27, 2014.

Randomised study of PF-06410293, an adalimumab (ADL) biosimilar, compared with reference ADL for the treatment of active rheumatoid arthritis: results from weeks 26-52, including a treatment switch from reference ADL to PF-06410293.

OBJECTIVE: To investigate the efficacy, safety, immunogenicity and pharmacokinetics of biosimilar adalimumab (ADL) PF-06410293 (ADL-PF; adalimumab-afzb) versus EU-sourced reference ADL (ADL-EU) in patients with active rheumatoid arthritis (RA) on longer-term treatment and after being switched from ADL-EU to ADL-PF. METHODS: In this multinational, double-blind study, patients with active RA were initially randomised to ADL-PF or ADL-EU for 26 weeks (treatment period (TP) 1). At the start of TP2 (weeks 26-52), patients in the ADL-EU arm were blindly re-randomised 1:1 to remain on ADL-EU (ADL-EU/ADL-EU; n=135) or switched to ADL-PF (ADL-EU/ADL-PF; n=134); patients receiving ADL-PF continued blinded treatment (ADL-PF/ADL-PF; n=283). RESULTS: The American College of Rheumatology 20% improvement (ACR20) response rates were comparable between treatment groups at all visits during TP2. At week 52, ACR20 response rates were 82.7% (ADL-PF/ADL-PF), 79.3% (ADL-EU/ADL-EU) and 84.3% (ADL-EU/ADL-PF). Other measures of deep response (ACR50/70, ACR/EULAR-defined remission, EULAR good response, and Disease Activity Score in 28 Joints Based on High-Sensitivity C-Reactive Protein <2.6) and Health Assessment Questionnaire-Disability Index were maintained over TP2 and comparable between groups. Treatment-emergent adverse events were reported in 43.5% (ADL-PF/ADL-PF), 44.4% (ADL-EU/ADL-EU) and 38.3% (ADL-EU/ADL-PF) of patients; there were no clinically meaningful differences in the safety profiles between groups. The percentage of patients who were antidrug antibody positive was comparable overall among ADL-PF/ADL-PF (47.3%), ADL-EU/ADL-EU (54.1%) and ADL-EU/ADL-PF (45.9%). CONCLUSIONS: The similar efficacy, safety, immunogenicity and pharmacokinetics of ADL-PF and ADL-EU, maintained up to week 52, were unaffected by blinded treatment switch from ADL-EU to ADL-PF at week 26. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier: NCT02480153; EudraCT number: 2014-000352-29.

Randomized, Open-Label, Single-Dose, Parallel-Group Pharmacokinetic Study of PF-06410293 (adalimumab-afzb), an Adalimumab Biosimilar, by Subcutaneous Dosing Using a Prefilled Syringe or a Prefilled Pen in Healthy Subjects.

This open-label, single-dose, randomized, parallel-group, 2-arm phase 1 bioequivalence (BE) study assessed the pharmacokinetics (PK), safety, and tolerability of PF-06410293 (ADL-PF), an adalimumab (ADL) biosimilar, following administration by prefilled pen (PFP) or prefilled syringe (PFS). A total of 164 healthy adult subjects were randomized (1:1) to receive ADL-PF (40 mg subcutaneously) in the lower abdomen or upper anterior thigh by PFS or PFP; 163 subjects were included in the primary PK analysis. The concentration-time profiles of the ADL-PF PFS and PFP treatment arms were similar. The 90% confidence intervals for the test/reference ratios of the primary end points (area under the serum concentration-time profile from time 0 to 2 weeks after dosing and maximum observed serum concentration) fell within the 80.00%-125.00% prespecified margin for BE. Comparable numbers of subjects experienced adverse events (AEs) between treatment groups, and injection-site pain was similar at all times and for the 2 injection-site locations. This study demonstrated the BE of ADL-PF following subcutaneous administration using either a PFS or PFP device. ADL-PF by PFS or PFP injection was well tolerated, with the distribution of AEs, including injection-site reactions, being similar between treatment arms.

Interchangeability of Biosimilars: What Level of Clinical Evidence is Needed to Support the Interchangeability Designation in the United States?

A biosimilar is a biologic drug that is "highly similar to a reference (originator) product, with no clinically meaningful differences between the two products in safety, purity, and potency". Regulatory approval of a biosimilar is based on analytical, structural, and functional comparisons with the reference product, comparative nonclinical (in vivo) studies, clinical pharmacokinetics and/or pharmacodynamics, and immunogenicity. In addition, comparative clinical efficacy and safety assessments are usually conducted and, taken together, comprise the "totality of the evidence" supporting biosimilarity. For a biosimilar to meet the additional designation of interchangeability in the United States (US), the applicant must demonstrate that the biological drug can be expected to produce the "same clinical result as the reference product in any given patient" and "if the biological drug is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between the use of the biological drug and the reference product is no greater than the risk of using the reference product without such alternation or switch". The challenges faced in conducting clinical studies to support a designation of interchangeability, as defined in the final interchangeability guidance from the US Food and Drug Administration, are considered. Potential alternative approaches to generating adequate and sufficient clinical data to support a designation of interchangeability are also presented.

A mechanistic pharmacokinetic model with drug and antidrug antibody interplay, and its application for assessing the impact of immunogenicity response on bioequivalence testing.

AIMS: Single-dose pharmacokinetic (PK) studies in healthy subjects have been the design of choice for bioequivalence determination for decades. This preference has been recently extended to PK similarity studies of proposed biosimilars. However, PK similarity studies can be complicated by the effect of immunogenicity response on drug disposition. The impact is exacerbated when there is an imbalance in host-specific immunological characteristics of subjects between the test and reference groups. Such complications remain poorly understood. The purpose of this communication is to show that the impact of immunogenicity response on PK similarity determination can be critical, using adalimumab as an example. METHODS: Data for adalimumab concentrations and immunogenicity response over 10 weeks were obtained from 133 healthy subjects receiving a 40 mg dose of Humira® in a PK similarity study. Also, a population PK model with a mechanistic construct for delineating the interplay between adalimumab disposition and antidrug antibodies response was utilized to estimate via simulation the probability that a PK similarity study would fail in typical study settings. RESULTS: The simulations showed that the immunogenicity response can have a profound impact on the outcome of PK similarity determination. As such, the probability of failing to achieve the similarity conclusion increased to 51.9%, from 13.8% in the absence of immunogenicity response. CONCLUSION: This study provides a model-based framework for better understanding of how a PK similarity study can be optimally designed and for interpretation of the outcome of PK similarity determination when the drug disposition is affected in the presence of immunogenicity response.

Dynamics of circulating TNF during adalimumab treatment using a drug-tolerant TNF assay.

Patients with rheumatoid arthritis (RA) can be successfully treated with tumor necrosis factor (TNF) inhibitors, including the monoclonal antibody adalimumab. Once in remission, a proportion of patients can successfully discontinue treatment, indicating that blocking TNF is no longer required for disease control. To explore the dynamics of circulating TNF during adalimumab treatment, we developed a competition enzyme-linked immunosorbent assay that can quantify TNF in the presence of large amounts of TNF inhibitor, i.e., a "drug-tolerant" assay. In 193 consecutive adalimumab-treated patients with RA, we demonstrated that circulating TNF increased in average of >50-fold upon treatment and reached a stable concentration in time for most patients. A similar increase in TNF was found in 30 healthy volunteers after one dose of adalimumab. This implies that TNF in circulation during anti-TNF treatment is not primarily associated with disease activity. During treatment, TNF was in complex with adalimumab and could be recovered as inactive 3:1 adalimumab-TNF complexes. No quantitative association was found between TNF and adalimumab concentrations. Low TNF concentrations at week 4 were associated with a higher frequency of antidrug antibodies (ADAs) at subsequent time points, less frequent methotrexate use at baseline, and less frequent remission after 52 weeks. Also in healthy volunteers, early low TNF concentrations are associated with ADAs. In conclusion, longitudinal TNF concentrations are mostly stable during adalimumab treatment and may therefore not predict successful treatment discontinuation. However, early low TNF is strongly associated with ADA formation and may be used as timely predictor of nonresponse toward adalimumab treatment.

A practical guide about biosimilar data for health care providers treating inflammatory diseases.

To make informed decisions about the safety, efficacy, and clinical utility of a biosimilar, health care providers should understand the types and be able to analyze data generated from a biosimilar development program. This article reviews the biosimilar guidelines, the biosimilar development process to provide education and context about biosimilarity, and uses examples from infliximab biosimilars to review the terminology and potential types of analyses that may be used to compare potential biosimilars to the originator biologic. A biosimilar is a biologic product that is highly similar to an approved (originator) biologic, notwithstanding minor differences in clinically inactive components, and with no clinically meaningful differences in terms of the safety, purity, and potency of the product. Due to their complex nature and production in living systems, it is not possible to exactly duplicate the approved originator biologic. To ensure biosimilars provide consistent, safe, and effective treatment comparable to the originator biologic, extensive analyses of the potential biosimilar are conducted, including side-by-side analytical, nonclinical, and clinical comparisons. A key goal is to determine whether there are sufficient relevant similarities in chemical composition, biologic activity, and pharmacokinetic aspects between the potential biosimilar and the originator. Regulatory approvals and marketing authorizations for biosimilars are made on a case-by-case and agency-by-agency basis after evaluating the totality of the evidence generated from the entire development program. Understanding how regulatory agencies review data for approval can help health care providers make appropriate decisions when biosimilars become available for use in the treatment of inflammatory diseases, and therefore they should review the literature to gain further information about specific biosimilars.

Assessing the Immunogenicity of Biopharmaceuticals.

Biopharmaceuticals have the potential to raise an immunogenic response in treated individuals, which may impact the efficacy and safety profile of these drugs. As a result, it is essential to evaluate immunogenicity throughout the different phases of the clinical development of a biopharmaceutical, including post-marketing surveillance. Although rigorous evaluation of biopharmaceutical immunogenicity is required by regulatory authorities, there is a lack of uniform standards for the type, quantity, and quality of evidence, and for guidance on experimental design for immunogenicity assays or criteria to compare immunogenicity of biopharmaceuticals. Moreover, substantial technological advances in methods to assess immune responses have yielded higher immunogenicity rates with modern assays, and limit comparison of immunogenicity of biopharmaceuticals outside of head-to-head clinical trials. Accordingly, research programs, regulatory agencies, and clinicians need to keep pace with continuously evolving analyses of immunogenicity. Here, we review factors associated with immunogenicity of biopharmaceuticals, potential clinical ramifications, and current regulatory guidance for evaluating immunogenicity, and discuss methods to assess immunogenicity in non-clinical and clinical studies. We also describe special considerations for evaluating the immunogenicity of biosimilar candidates.

Prevalencia de enfermedades hepáticas en una población rural de alta montaña: estudio clínico, bioquímico y ecográfico / Prevalence of liver diseases in a small rural community isolated in tne mountain heights: clinical, biochemical and ultrasonographic study

En este estudio clínico, bioquímico y ecográfico se evaluó la prevalencia de hepatopatías en Lara, una comunidad rural aislada de alta montaña en Tucumán, provincia con la máxima prevalencia de infección por HAV en niños de Argentina. Lara carece de agua potable, electricidad y cloacas. Se estudiaron 102 habitantes, lo que representa el 41% de la población. El anti-HBc y anti-HCV fueron negativos en todos los casos. Ningún niño presentó anormalidades hepáticas. El 41% de los adultos refirió ingesta alcohólica y el 12% transfusiones. Se observó incremento leve de ALT en 3 casos (6%). La ecografía demostró esteatosis en 8 individuos (16%), litiasis vesicular en 7 (14%), microcalcificaciones en 5 (10%) y quistes de aspecto parasitario en 4 (8%). La prevalencia de infección por HAV en Lara fue de 89% en adultos y 35% en niños, siendo significativamente menor que la de los niños de la ciudad de Tucumán con nivel socioeconómico medio / alto (53%, p = 0.05) o bajo (74%, p = 0.0006). La diferencia fue más evidente en niños menores de 5 años (0%, 53% y 75% respectivamente). La serología para hidatidosis fue positiva en 3/4 individuos con quistes, 2/5 con microcalcificaciones y 17/85 (20%) con ecografía normal, lo que sugiere que la técnica de Elisa utilizada se asocia a frecuentes resultados falsos positivos. El estudio poblacional de Lara demostró una elevada prevalencia de esteatosis, litiasis vesicular e hidatidosis en adultos, ausencia de infección por HBV y HCV, y una baja exposición al HAV en niños, especialmente en menores de 5 años.

The goal of this population-based clinical, biochemical and ultrasonographic study was to assess the prevalence of liver diseases in Lara, a small rural community isolated in the mountain heights of Tucumán, a Province of Argentina with the highest reported rates of HAV infection in children. Inhabitants of Lara lack electricity, potable water and a sewer system. The study included 102 individuals representing 41% of the total population. Anti-HBc and anti-HCV were negative in all cases. No children showed clinical, biochemical or ecographic abnormalities. Among adults, 41% referred alcohol consumption and 12% blood transfusions. Only 3 adults (6%) had mildly elevated ALT. Ultrasound showed steatosis in 8 individuals (16%), gallstones in 7 (14%), parenchymal micro-calcifications in 5 (10%) and parasitic cysts in 4 (8%). Prevalence of HAV infection in Lara was 89% in adults and 35% in children, being significantly lower than that of children of medium/high (53%, p=0.05) and low (74%, p=0.0006) socioeconomic level from the city of Tucumán (control groups). These differences were more marked in children aged <5 years (anti-HAV in 0%, 53% y 75% respectively). Serologic tests for echinoccocal disease were positive in 3/4 individuals with parasitic cysts, 2/5 with micro-calcifications and 17/85 (20%) with normal ultrasound, thus suggesting a high rate of false-positive results of the Elisa test utilized. This study showed that in Lara there is a high prevalence of steatosis, gallstones and equinoccocal disease in adults, absenceof HBV and HCV infection and low exposure to HAV in children especially in those aged <5 years.

Prevalencia de enfermedades hepáticas en una población rural de alta montaña: estudio clínico, bioquímico y ecográfico / Prevalence of liver diseases in a small rural community isolated in tne mountain heights: clinical, biochemical and ultrasonographic study

En este estudio clínico, bioquímico y ecográfico se evaluó la prevalencia de hepatopatías en Lara, una comunidad rural aislada de alta montaña en Tucumán, provincia con la máxima prevalencia de infección por HAV en niños de Argentina. Lara carece de agua potable, electricidad y cloacas. Se estudiaron 102 habitantes, lo que representa el 41% de la población. El anti-HBc y anti-HCV fueron negativos en todos los casos. Ningún niño presentó anormalidades hepáticas. El 41% de los adultos refirió ingesta alcohólica y el 12% transfusiones. Se observó incremento leve de ALT en 3 casos (6%). La ecografía demostró esteatosis en 8 individuos (16%), litiasis vesicular en 7 (14%), microcalcificaciones en 5 (10%) y quistes de aspecto parasitario en 4 (8%). La prevalencia de infección por HAV en Lara fue de 89% en adultos y 35% en niños, siendo significativamente menor que la de los niños de la ciudad de Tucumán con nivel socioeconómico medio / alto (53%, p = 0.05) o bajo (74%, p = 0.0006). La diferencia fue más evidente en niños menores de 5 años (0%, 53% y 75% respectivamente). La serología para hidatidosis fue positiva en 3/4 individuos con quistes, 2/5 con microcalcificaciones y 17/85 (20%) con ecografía normal, lo que sugiere que la técnica de Elisa utilizada se asocia a frecuentes resultados falsos positivos. El estudio poblacional de Lara demostró una elevada prevalencia de esteatosis, litiasis vesicular e hidatidosis en adultos, ausencia de infección por HBV y HCV, y una baja exposición al HAV en niños, especialmente en menores de 5 años.(AU)

The goal of this population-based clinical, biochemical and ultrasonographic study was to assess the prevalence of liver diseases in Lara, a small rural community isolated in the mountain heights of Tucumán, a Province of Argentina with the highest reported rates of HAV infection in children. Inhabitants of Lara lack electricity, potable water and a sewer system. The study included 102 individuals representing 41% of the total population. Anti-HBc and anti-HCV were negative in all cases. No children showed clinical, biochemical or ecographic abnormalities. Among adults, 41% referred alcohol consumption and 12% blood transfusions. Only 3 adults (6%) had mildly elevated ALT. Ultrasound showed steatosis in 8 individuals (16%), gallstones in 7 (14%), parenchymal micro-calcifications in 5 (10%) and parasitic cysts in 4 (8%). Prevalence of HAV infection in Lara was 89% in adults and 35% in children, being significantly lower than that of children of medium/high (53%, p=0.05) and low (74%, p=0.0006) socioeconomic level from the city of Tucumán (control groups). These differences were more marked in children aged <5 years (anti-HAV in 0%, 53% y 75% respectively). Serologic tests for echinoccocal disease were positive in 3/4 individuals with parasitic cysts, 2/5 with micro-calcifications and 17/85 (20%) with normal ultrasound, thus suggesting a high rate of false-positive results of the Elisa test utilized. This study showed that in Lara there is a high prevalence of steatosis, gallstones and equinoccocal disease in adults, absenceof HBV and HCV infection and low exposure to HAV in children especially in those aged <5 years. (AU)

[Prevalence of liver diseases in a small rural community isolated in the mountain heights: clinical, biochemical and ultrasonographic study]. / Prevalencia de enfermedades hepáticas en una población rural de alta montaña: estudio clínico, bioquímico y ecográfico.

The goal of this population-based clinical, biochemical and ultrasonographic study was to assess the prevalence of liver diseases in Lara, a small rural community isolated in the mountain heights of Tucumán, a Province of Argentina with the highest reported rates of HAV infection in children. Inhabitants of Lara lack electricity, potable water and a sewer system. The study included 102 individuals representing 41% of the total population. Anti-HBc and anti-HCV were negative in all cases. No children showed clinical, biochemical or ecographic abnormalities. Among adults, 41% referred alcohol consumption and 12% blood transfusions. Only 3 adults (6%) had mildly elevated ALT. Ultrasound showed steatosis in 8 individuals (16%), gallstones in 7 (14%), parenchymal micro-calcifications in 5 (10%) and parasitic cysts in 4 (8%). Prevalence of HAV infection in Lara was 89% in adults and 35% in children, being significantly lower than that of children of medium/high (53%, p = 0.05) and low (74%, p = 0.0006) socioeconomic level from the city of Tucumán (control groups). These differences were more marked in children aged < 5 years (anti-HAV in 0%, 53% and 75% respectively). Serologic tests for echinoccocal disease were positive in 3/4 individuals with parasitic cysts, 2/5 with micro-calcifications and 17/85 (20%) with normal ultrasound, thus suggesting a high rate of false-positive results of the Elisa test utilized. This study showed that in Lara there is a high prevalence of steatosis, gallstones and equinoccocal disease in adults, absence of HBVand HCV infection and low exposure to HAV in children especially in those aged < 5 years.

Hepatitis C virus and HIV coinfection: clinical management and new strategies.

Approximately one third of all HIV-infected people are coinfected with hepatitis C virus (HCV). The progression from initial HCV infection to cirrhosis of the liver is accelerated in coinfected patients compared with HCV-monoinfected patients. Because of improved therapies for HIV/AIDS, one of the leading causes of death for HIV-infected patients is liver disease. It is therefore important to screen all persons with HIV infection for the presence of HCV and to treat the HCV infection as appropriate. Treatment options need to be tailored to each patient, depending on the severity of liver damage, the HCV genotype, and the willingness of the patient to receive therapy. Current first-line therapy for hepatitis C consists of pegylated interferon plus ribavirin. However, this therapy has only limited success in persons with HCV genotype 1 and in African Americans. In addition, the side effects of anti-HCV therapy can be considerable and require careful management. Improvement or delayed progression of fibrosis should be the main goal of therapy in most patients.