Telaprevir and Ribavirin Interaction: Higher Ribavirin Levels Are Not Only Due to Renal Dysfunction during Triple Therapy

A higher incidence of anemia has been observed during the treatment of hepatitis C virus genotype 1 (HCV-1) infection with pegylated alpha interferon (pegIFN-α), ribavirin, and telaprevir. We assessed the impacts that concomitant administration of telaprevir and changes in the glomerular filtration rate have on ribavirin plasma levels. The minimum concentrations of ribavirin in plasma (ribavirin C_min) determined during triple therapy including telaprevir were compared with those observed after telaprevir withdrawal and those observed in the same subjects and in a large cohort during a previous course of pegIFN-α plus ribavirin. Intensive pharmacokinetic sampling for ribavirin was performed at steady state during the triple-therapy phase. Ribavirin levels were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Twenty-seven HCV-1/HIV-coinfected patients were enrolled. The median ribavirin C_min for triple therapy (4.08 μg/ml; range, 2.14 to 5.56 μg/ml) was higher than that observed after telaprevir withdrawal (1.96 μg/ml; range, 0.41 to 3.45 μg/ml) (P < 0.001) and that observed for 125 HCV-1/HIV-coinfected patients treated only with pegIFN-α plus ribavirin (1.65 μg/ml; range, 0.41 to 5.56 μg/ml) (P < 0.001). The estimated glomerular filtration rate (eGFR) decreased >20% from the baseline value in 11 of 27 patients and became normal after telaprevir removal in almost all cases. There was a negative correlation between eGFR and ribavirin clearance (r² = 0.257; P = 0.064) but not the ribavirin area under the concentration-time curve from 0 to 12 h (AUC_0–12) (r² = 0.001; P = 0.455). Thus, there is a significant pharmacokinetic interaction between telaprevir and ribavirin that results in very high ribavirin levels, which explains the excess of toxicity observed with this drug combination. A blockade of the proximal tubular transporters might be implicated in both the increase in plasma creatinine and the high ribavirin levels. (This study has been registered at ClinicalTrials.gov under registration no. {"type":"clinical-trial","attrs":{"text":"NCT01818856","term_id":"NCT01818856"}}NCT01818856.)     

Prevalence of M. tuberculosis infection and tuberculosis disease among HIV-infected people in Spain.

OBJECTIVE: To study the prevalence of Mycobacterium tuberculosis infection (MTBI) and past/current tuberculosis (TB) among human immunodeficiency virus (HIV) infected persons in Spain. DESIGN: Longitudinal study conducted between 2000 and 2003 at 10 HIV hospital-based clinics. Data were drawn from clinical records. Associations were measured using odds ratios (ORs) and their 95% confidence intervals (95%CI). RESULTS: Of the 1242 persons who met the eligibility criteria, most were male (75%), aged <40 years (75%) and unemployed (40%). HIV infection occurred through intravenous drug use (53%), heterosexual sex (29%) and sex between men (16%). In the initial evaluation, 315 subjects had evidence of MTBI: 84 (6.8%) had a history of TB, 23 (1.8%) current TB and 208 (16.8%) latent tuberculosis infection (LTBI). MTBI was associated with male sex, age 30-49 years, contact with a TB case, homelessness, poor education, and negatively with CD4 <100 cells/mm(3). Among subjects with MTBI, past/current TB was associated with retirement/disability (OR 6, 95%CI 1.6-22.5), CD4 <200 cells/mm(3) (OR 9.7, 95%CI 3.8-24.6), viral load >55,000 copies (OR 5.3, 95%CI 1.4-20.0), and negatively, with skilled work (OR 0.4, 95%CI 0.1-1.0) or administrative/managerial/professional work (OR 0.05, 95%CI 0.01-0.4). CONCLUSION: Social context has an impact on the effectiveness of HIV and TB control programmes even in industrialised countries with free access to health care.     

Keys to demographic changes in the new millennium

This article describes the main features of the dynamics of demographic change in the population of Spain during the twentieth century, emphasizing the most recent developments: population ageing, the establishment of a very low fertility regime and the increasing importance of foreign immigration as well as the impact which all these have on the composition of households. Those aspects most directly related to the provision of health and social services is discussed, such as the impact of increased life expectancy on the incidence of illness and handicap in the population, the role of foreign immigration in providing personal services within the family and the health implications of the new model of delayed fertility. Finally, the health implications of population projections for the next 50 years are discussed.     

Hepatitis C virus and human immunodeficiency virus coinfection in Spain

OBJECTIVE AND METHODS: In a cross-sectional study, based on a cohort composed of HIV-infected patients of fifteen tertiary level institutions of Spain, the main data of the entire cohort are described, characteristics of patients with or without hepatitis C coinfection are compared, and the possible association of hepatitis C virus coinfection with socioeconomic, HIV-related, and hepatitis B-related variables is assessed. RESULTS: A total of 4,709 patients are studied. Median of age is 37 years, 78.3% are male. HIV risk behaviours are: parenteral drug use in 63.8% of patients, heterosexual in 22.3%, and homosexual in 10.8%. Serology of hepatitis C is positive in 69.2% of participants. The following variables are associated with increased prevalence of hepatitis C coinfection, both in univariate and in multivariate analysis: HIV risk behaviour, positive anti-HBs, longer time elapsed since HIV infection diagnosis, younger age, lower social status, lower CD4 cell count increase between nadir and last available result, and lower educational level (all P<0.001). Patients with heterosexual behaviour are more frequently coinfected than patients with homosexual behaviour (P<0.001). CONCLUSION: This study highlights that, in Spain, more than two thirds of patients with HIV infection are coinfected with hepatitis C virus.     

Multicenter prospective study of treatment of Brucella melitensis brucellosis with doxycycline for 6 weeks plus streptomycin for 2 weeks.

The effectiveness of treating human brucellosis caused by Brucella melitensis with a 6-week course of doxcycline plus streptomycin for 2 of those weeks was analyzed by a multicenter prospective study of 139 patients. Subjects with central nervous system involvement, endocarditis, or spondylitis were excluded from the study. All but 5 of the 139 patients completed the full treatment schedule and became afebrile in the first week of therapy. Four patients suffered relapses during the follow-up period. Of the five patients who did not complete the treatment, two left because of adverse secondary effects (1.4%), another two left for noncomplicance with the treatment (1.4%), and the remaining patient was considered a therapeutic failure because his symptoms persisted after the first week of therapy (0.7%). We concluded that the combination of doxycycline and streptomycin is an effective treatment for the types of brucellosis included in our study.