Fernando Pons

Determinants of the clinical expression of amoxicillin-clavulanate hepatotoxicity: A prospective series from Spain†‡

Amoxicillin‐clavulanate (AC) hepatotoxicity has been reported to exhibit a higher predominance of cholestatic types of damage, especially in males. However, the determinants of its clinical expression are unknown. This study prospectively evaluated the profile of AC hepatotoxicity. Data on all cases of hepatotoxicity reported to the Spanish Registry attributed to AC and assessed as definite or probable on the Council for International Organizations of Medical Sciences (CIOMS) scale were collated and compared to published case series. Hepatotoxicity related to amoxicillin‐clavulanate was identified in 69 patients (36 males; mean age 56 years) representing 14% of all cases of hepatotoxicity submitted to the Registry. There was an overall sex distribution and the predominant pattern of lesion was hepatocellular (36%) which occurred at a shorter duration of treatment (P < .03). Mean time lapse between therapy initiation and jaundice onset was 16 days. Late onset of symptoms following end of treatment occurred in half the cases. Multiple logistic regression analysis identified advancing age as the factor associated with the development of cholestatic/mixed type of injury (odds ratio for an age interval for 1 year: 1.045 [95% CI = 1.013–1.078; P = .005). An unfavorable outcome was seen in 7% of patients. In conclusion, age is the most important determinant in the biochemical expression of AC hepatotoxicity; younger age is associated with cytolytic damage and shorter treatment duration, whereas cholestatic/mixed type of damage is related to older age and prolonged AC therapy. (HEPATOLOGY 2006;44:850–856.)

Development and validation of two models for early prediction of response to therapy in genotype 1 chronic hepatitis C.

Early prediction of response to therapy in genotype 1 chronic hepatitis C is difficult. Two predictive models, a pretreatment scoring model (PreT‐SM) and a fourth week of therapy scoring model (4w‐SM) were constructed in a cohort of 104 patients from a single center (estimation cohort) and validated in a cohort of 141 patients from four independent centers (validation cohort). Individual scores were calculated using variables independently associated with sustained virological response (SVR). Baseline viral load, aspartate aminotransferase/alanine aminotransferase ratio, serum cholesterol, and a numerical score for noninvasive estimation of liver fibrosis were included in the PreT‐SM; HCV RNA clearance and PreT‐SM scores were included in the 4w‐SM. Receiver operating characteristic analysis revealed the area under the curve in the estimation cohort and in the validation cohort to be, respectively, 0.856 and 0.847 for the PreT‐SM and 0.908 and 0.907 for the 4w‐SM. Low scores were associated with SVR, high scores with non‐SVR. The best cutoff scores from the PreT‐SM (7 and 9.70) identified, respectively, 36% of patients with SVR and 41% of those with non‐SVR from the validation cohort, with high accuracy (≥90% positive predictive value [PPV] and specificity). Similarly, cutoff scores of 3.20 and 5.60 from the 4w‐SM identified, respectively, 71% of patients with SVR and 53% of those with non‐SVR from the same cohort with high accuracy (PPV and specificity >92%). In conclusion, these models predicted response to therapy before or after 4 weeks of treatment in approximately 60% of genotype 1 patients and may be valuable for the management of this condition. (HEPATOLOGY 2006;43:72–80.)

Complete response under sorafenib in patients with hepatocellular carcinoma: Relationship with dermatologic adverse events

The clinical benefit of sorafenib in patients with hepatocellular carcinoma (HCC) has been undervalued due to the absence of complete responses, even though patients who develop early dermatologic reactions have shown to have a positive outcome. In addition, sorafenib is described as an antiangiogenic drug, but it also acts on immunological cells. Thus, the goal of this study was to assess the complete response rate in a retrospective cohort of HCC patients treated with sorafenib and to describe the profile of the patients who achieve complete response for identifying factors related to this event and their connection with the immunological profile of sorafenib. Ten Spanish centers submitted cases of complete response under sorafenib. The baseline characteristics, development of early dermatologic reactions, and cause of treatment discontinuation were annotated. Radiological images taken before starting sorafenib, at first control, after starting sorafenib, at the time of complete response, and at least 1 month after treatment were centrally reviewed. Of the 1119 patients studied, 20 had been classified as complete responders by the centers, but eight of these patients were excluded after central review. Ten patients had complete disappearance of all tumor sites, and two had just a small residual fibrotic scar. Thus, 12 patients were classified as complete responders (58% HCV, median age 59.7 years, 83.4% Child‐Pugh class A, Eastern Cooperative Oncology Group performance status 0 91.7%, and Barcelona Clinic Liver Cancer stage C 83.3%). The median overall survival and treatment duration were 85.8 and 40.1 months, respectively. All but one patient developed early dermatologic reactions, and seven patients discontinued sorafenib after achieving complete response due to adverse events, patient decision, or liver decompensation. Conclusion: Complete response affects 1% of patients with HCC who are treated with sorafenib. The association of complete response with early dermatologic reactions supports the role of a specific immune/inflammatory patient profile in the improved response to sorafenib. (Hepatology 2018;67:612‐622).

Validation of noninvasive methods to predict the presence of gastroesophageal varices in a cohort of patients with compensated advanced chronic liver disease: Validation of noninvasive methods

The aim was to validate noninvasive methods to predict the presence of gastroesophageal varices (GEV) in patients with suspected compensated advanced chronic liver disease.

Decrease in viral load at weeks 12 and 24 in patients with chronic hepatitis B treated with lamivudine or adefovir predicts virological response at week 48

AIM The aim of our study was to evaluate the decrease in viral load (VL) that is able to predict antiviral treatment response at one year in patients with chronic hepatitis B. METHODS The clinical records of 66 patients, 31 treated with lamivudine (LAM) and 35 treated with adefovir (ADF), were retrospectively reviewed. We measured viral DNA at months 1, 3 and 6. RESULTS The LAM group showed virological response (VR) in 51.6% of patients. Baseline VL was higher in non responders (5.37 +/- 1.16 vs. 7.01 +/- 1.05; p < 0.001). Responders showed a higher percentage of VL decrease at month 3 from baseline (49.2 vs. 38.3%; p = 0.03). We designed a ROC curve and established a cutoff point for decrease of 30% that had 80% of negative predictive value (NPV).The ADF group showed VR in 57.1% of patients. Baseline VL was higher in nonresponders (4.67 +/- 1.22 vs. 5.78 +/- 1.34; p = 0.01). We observed a significant decrease in VL (log) at months 3 (2.6 +/- 1.1 vs. 1.3 +/- 1.3; p = 0.03) and 6 (2.6 +/- 1.2 vs. 1.3 +/- 1.2; p = 0.006). The percentage of decrease of VL from baseline was also statistically significant. We created ROC curves at months 3 and 6, and established the best cutoff points. At month 6 a decrease of 1 log in VL had a NPV of 80%, and a decrease of 20% in VL from baseline had 100% NPV. CONCLUSION The decrease in viral DNA at weeks 12 and 24 can predict VR at one year in patients with chronic hepatitis B treated with LAM or ADF. This could optimize treatment.

Programa de uso compasivo con adefovir dipivoxil en España: valoración de su eficacia y estudio de las resistencias

Fundamento y objetivo El tratamiento prolongado con lamivudina de los pacientes con hepatitis B cronica se asocia a la emergencia de resistencias. Los pacientes con resistencia a la lamivudina presentan una perdida de la respuesta tanto bioquimica como virologica y una mayor progression de la enfermedad hepatica. El adefovir dipivoxil, un analogo de los nucleotidos, es eficaz en el tratamiento de los pacientes con resistencia a la lamivudina. El objetivo de este estudio ha sido evaluar la eficacia, la seguridad y las resistencias del adefovir dipivoxil en pacientes con hepatitis B cronica refractarios al tratamiento con lamivudina. Pacientes y metodo Se ha incluido a 120 pacientes afectados de hepatitis B cronica y refractarios al tratamiento con lamivudina que recibieron tratamiento con adefovir dipivoxil. En 74 de ellos se realizo seguimiento durante 2 anos. En todos los casos se determino el ADN del virus de la hepatitis B por reaccion en cadena de la polimerasa, y en los casos sin respuesta al tratamiento se estudio la presencia de resistencias a adefovir dipivoxil y lamivudina. Resultados A los 2 anos de tratamiento se observo respuesta virologica en el 54,1% de los pacientes, respuesta bioquimica en el 62,2% y eliminacion del antigeno e de la hepatitis B en el 21%. Se detectaron resistencias a adefovir dipivoxil en el 20% de los casos, y las mutaciones detectadas con mayor frecuencia fueron A181V, A181T y N236T. La seguridad del farmaco fue excelente, pues se detecto solo un efecto adverso relacionado con el tratamiento. Conclusiones El tratamiento durante 2 anos con adefovir dipivoxil en monoterapia en pacientes previamente refractarios a lamivudina se asocia a una alta tasa de respuesta bioquimica y virologica, con una seguridad excelente. La tasa de resistencias al adefovir dipivoxil a los 2 anos fue del 20%.