José María Bellón

Sustained virological response to interferon plus ribavirin reduces liver‐related complications and mortality in patients coinfected with human immunodeficiency virus and hepatitis C virus

Human immunodeficiency virus (HIV) infection modifies the natural history of chronic hepatitis C, thus promoting more rapid progression to cirrhosis and end‐stage liver disease. The objective of our study was to determine whether hepatitis C virus (HCV) clearance is associated with improved clinical outcomes in patients positive for HIV and HCV. It was an ambispective cohort study carried out in 11 HIV units in Spain and involved 711 consecutive patients positive for HIV/HCV who started interferon plus ribavirin therapy between 2000 and 2005. We measured sustained virologic response (SVR), i.e., undetectable HCV RNA at 24 weeks after the end of treatment, and clinical outcomes, defined as death (liver‐related or non–liver‐related), liver decompensation, hepatocellular carcinoma, and liver transplantation. Of 711 patients who were positive for HIV/HCV, 31% had SVR. During a mean follow‐up of 20.8 months (interquartile range: 12.2‐38.7), the incidence rates per 100 person‐years of overall mortality, liver‐related mortality, and liver decompensation were 0.46, 0.23, and 0.23 among patients with SVR and 3.12, 1.65, and 4.33 among those without SVR (P = 0.003, 0.028, and <0.001 by the log‐rank test), respectively. Cox regression analysis adjusted for fibrosis, HCV genotype, HCV RNA viral load, Centers for Disease Control and Prevention clinical category, and nadir CD4+ cell count showed that the adjusted hazard ratio of liver‐related events was 8.92 (95% confidence interval, 1.20; 66.11, P = 0.032) for nonresponders in comparison with responders and 4.96 (95% confidence interval, 2.27; 10.85, P < 0.001) for patients with fibrosis grade of F3‐F4 versus those with F0‐F2.Because this was not a prospective study, selection and survival biases may influence estimates of effect. Conclusion: Our results suggest that the achievement of an SVR after interferon‐ribavirin therapy in patients coinfected with HIV/HCV reduces liver‐related complications and mortality. (HEPATOLOGY 2009.)

Impact on weight and height with the use of HAART in HIV-infected children.

Background: There are few data on long-term effects of highly active antiretroviral therapy (HAART) on weight and height in HIV-infected children. Objectives: Our objective was to assess the effect of HAART on the weight and height of HIV-infected children over time in the Madrid cohort, and analyze possible factors associated with the effect. Patients and methods: This was a retrospective study of HIV-infected children starting HAART in 1997 or later. Serial measurements of weight, height and body mass index (BMI) were performed and converted to z-scores using the Spanish revised reference data. Changes from baseline in weight, height and BMI at 12, 24, 36, 48 and 60 months were determined. Associations of z-scores at the last visit with immunologic (CD4% above 25%) and virologic responses (more than 50% of samples below 400 copies/mL), CDC (Centers for Disease Control) clinical category, and the presence and type of lipodystrophy (lipoatrophy or lipohypertrophy) were evaluated. Results: Twelve hundred and twelve children, 97% of them vertically-infected, received HAART starting in 1997 for a median of 71 months (4–102 months). Median age at initiation of HAART was 6 years (1 month–18 years). Thirty-nine percentage were antiretroviral naive and 61% had received NRTI therapy previously. Thirty-two percentage and 53% had CDC class C and immunologic class 3, respectively. At the final evaluation, 24% of children remained on their first combination therapy, 39% on the second and 37% had received at least 3 different HAART regimens. Fifty-one percentage were classified as virologic responders. Thirty-nine percentage of children in this study were diagnosed with lipodystrophy. At baseline, median z-score for weight, height and BMI were −0.45, −0.60 and −0.33, respectively. HAART was associated with significant increases in z-scores of weight and height but not BMI at the different time-points analyzed. Virologic nonresponders had significantly lower z-scores for weight and height but not for BMI. CDC class C was associated with lower z-scores for height. No differences in final measurements were observed for baseline CD4, immunologic response or lipoatrophy. Children with lipohypertophy had a significantly higher BMI at the last visit. Conclusions: HIV-infected children experienced a continued catch-up in weight and height 5 years after starting HAART. Virologic control is related to sustained growth.

Pediatric defibrillation after cardiac arrest: Initial response and outcome

IntroductionShockable rhythms are rare in pediatric cardiac arrest and the results of defibrillation are uncertain. The objective of this study was to analyze the results of cardiopulmonary resuscitation that included defibrillation in children.MethodsForty-four out of 241 children (18.2%) who were resuscitated from inhospital or out-of-hospital cardiac arrest had been treated with manual defibrillation. Data were recorded according to the Utstein style. Outcome variables were a sustained return of spontaneous circulation (ROSC) and one-year survival. Characteristics of patients and of resuscitation were evaluated.ResultsCardiac disease was the major cause of arrest in this group. Ventricular fibrillation (VF) or pulseless ventricular tachycardia (PVT) was the first documented electrocardiogram rhythm in 19 patients (43.2%). A shockable rhythm developed during resuscitation in 25 patients (56.8%). The first shock (dose, 2 J/kg) terminated VF or PVT in eight patients (18.1%). Seventeen children (38.6%) needed more than three shocks to solve VF or PVT. ROSC was achieved in 28 cases (63.6%) and it was sustained in 19 patients (43.2%). Only three patients (6.8%), however, survived at 1-year follow-up. Children with VF or PVT as the first documented rhythm had better ROSC, better initial survival and better final survival than children with subsequent VF or PVT. Children who survived were older than the finally dead patients. No significant differences in response rate were observed when first and second shocks were compared. The survival rate was higher in patients treated with a second shock dose of 2 J/kg than in those who received higher doses. Outcome was not related to the cause or the location of arrest. The survival rate was inversely related to the duration of cardiopulmonary resuscitation.ConclusionDefibrillation is necessary in 18% of children who suffer cardiac arrest. Termination of VF or PVT after the first defibrillation dose is achieved in a low percentage of cases. Despite a sustained ROSC being obtained in more than one-third of cases, the final survival remains low. The outcome is very poor when a shockable rhythm develops during resuscitation efforts. New studies are needed to ascertain whether the new international guidelines will contribute to improve the outcome of pediatric cardiac arrest.

Naïve and memory CD4+ T cells and T cell activation markers in HIV-1 infected children on HAART.

The objective of this study was to investigate the relationship between peripheral blood CD4+ T cell subsets and routine viro‐immunological markers in vertically HIV‐1‐infected children undergoing highly active antiretroviral therapy (HAART). CD4+ and CD8+ T cell subsets were examined by three‐colour flow cytometry. Plasma viraemia was quantified by a standardized molecular assay. A negative correlation between the %CD4+ T cells and both viral load and the %CD8+ T cells was observed. A strong positive correlation between the %CD4 T cells and naïve, CD38+ and non‐activated CD4+ T cell subsets was found, whereas the %CD4 T cells correlated negatively with the numbers of memory, activated and memory‐activated CD4+ T cell subsets. Elevated percentages of CD8 T cells were associated with increased memory and CD4+ CD62L‐T cell subsets, whereas the naïve and CD4+ HLA‐DRCD38+ subsets negatively correlated with the CD8%. Co‐expression of CD62L on memory CD4+ cells and high expression of HLA‐DR (but not of CD38) were associated with high viral load. No association between viral load and naïve CD4+ T cells was observed. Specific CD4+ T cell subsets may be more informative than routine surrogate markers in defining the evolution of HIV infection and immune reconstitution in children.

Hypophosphatemia and phosphate supplementation during continuous renal replacement therapy in children

Severe hypophosphatemia can cause generalized muscle weakness, paralysis of the respiratory muscles, myocardial dysfunction, reduced peripheral vascular resistance, and encephalopathy. Here we conducted a prospective study to determine the incidence of hypophosphatemia in 47 children on continuous renal replacement therapy and to evaluate the efficacy and safety of adding phosphate to the replacement and dialysate solutions of 38 pediatric patients. During continuous renal replacement therapy, 68% of patients were found to have hypophosphatemia, significantly more than the 12% of patients at the beginning of therapy. There was no higher incidence of hypophosphatemia among patients requiring insulin, diuretics, parenteral nutrition, or high doses of vasoactive drugs. In the children to whom phosphate was not added to replacement and dialysate solutions, 85% presented with an incidence of hypophosphatemia and 36% required intravenous phosphate replacement, rates significantly higher than in those patients where phosphate was added to the solutions. Phosphate supplementation did not cause any instability of the mixtures or other complications. We show here that the incidence of hypophosphatemia in children on continuous renal replacement therapy is very high. Further, we show that the addition of phosphate to replacement and dialysate solutions is safe and that it reduces the incidence of hypophosphatemia and the need for intravenous phosphate treatment.

Complications of continuous renal replacement therapy in critically ill children: a prospective observational evaluation study

IntroductionContinuous renal replacement therapy (CRRT) frequently gives rise to complications in critically ill children. However, no studies have analyzed these complications prospectively. The purpose of this study was to analyze the complications of CRRT in children and to study the associated risk factors.MethodsA prospective, single-centre, observational study was performed in all critically ill children treated using CRRT in order to determine the incidence of complications related to the technique (problems of catheterization, hypotension at the time of connection to the CRRT, hemorrhage, electrolyte disturbances) and their relationship with patient characteristics, clinical severity, need for vasoactive drugs and mechanical ventilation, and the characteristics of the filtration techniques.ResultsOf 174 children treated with CRRT, 13 (7.4%) presented problems of venous catheterization; this complication was significantly more common in children under 12 months of age and in those weighing less than 10 kg. Hypotension on connection to CRRT was detected in 53 patients (30.4%). Hypotension was not associated with any patient or CRRT characteristics. Clinically significant hemorrhage occurred in 18 patients (10.3%); this complication was not related to any of the variables studied. The sodium, chloride, and phosphate levels fell during the first 72 hours of CRRT; the changes in electrolyte levels during the course of treatment were not found to be related to any of the variables analyzed, nor were they associated with mortality.ConclusionsCRRT-related complications are common in children and some are potentially serious. The most common are hypotension at the time of connection and electrolyte disturbances. Strict control and continuous monitoring of the technique are therefore necessary in children on CRRT.

Pegylated interferon α2a plus ribavirin versus pegylated interferon α2b plus ribavirin for the treatment of chronic hepatitis C in HIV-infected patients

OBJECTIVES The two currently available types of pegylated interferon (peg-IFN) used to treat hepatitis C have different pharmacokinetic properties. It is unclear how these differences affect response to therapy. We compared the effectiveness and safety of peg-IFN-alpha2a and peg-IFN-alpha2b, both with ribavirin, against chronic hepatitis C virus (HCV) infection in HIV-infected patients. METHODS From the GESIDA HIV/HCV cohort, we analysed patients treated with peg-IFN-alpha2a (n = 315) or peg-IFN-alpha2b (n = 242). The primary endpoint was a sustained virological response (SVR). RESULTS Both groups were well matched in baseline characteristics except for a higher frequency of injection drug users in the peg-IFN-alpha2b group than in the peg-IFN-alpha2a group (85% versus 76%; P = 0.01) and a higher frequency of bridging fibrosis and cirrhosis (F3-F4) in the peg-IFN-alpha2b group than in the peg-IFN-alpha2a group (42% versus 33%; P = 0.04). End-of-treatment response was significantly lower among patients treated with peg-IFN-alpha2b [40% versus 52%; odds ratio (OR), 1.63; 95% confidence interval (95% CI), 1.16-2.29; P < 0.01]. However, no significant differences were found in SVR between patients treated with peg-IFN-alpha2b and those treated with peg-IFN-alpha2a (31% versus 33%; OR, 1.09; 95% CI, 0.75-1.59; P = 0.655). Therapy was interrupted due to adverse events in 33 (14%) patients treated with peg-IFN-alpha2b and 47 (15%) patients treated with peg-IFN-alpha2a. CONCLUSIONS No differences in effectiveness and safety were found between peg-IFN-alpha2b and peg-IFN-alpha2a for the treatment of chronic HCV infection in HIV-infected patients.

Circuit life span in critically ill children on continuous renal replacement treatment: a prospective observational evaluation study.

IntroductionOne of the greatest problems with continuous renal replacement therapy (CRRT) is early coagulation of the filters. Few studies have monitored circuit function prospectively. The purpose of this study was to determine the variables associated with circuit life in critically ill children with CRRT.MethodsA prospective observational study was performed in 122 children treated with CRRT in a pediatric intensive care unit from 1996 to 2006. Patient and filter characteristics were analyzed to determine their influence on circuit life. Data were collected on 540 filters in 122 patients and an analysis was performed of the 365 filters (67.6%) that were changed due to circuit coagulation.ResultsThe median circuit life was 31 hours (range 1 to 293 hours). A univariate and multivariate logistic regression study was performed to assess the influence of each one of the factors on circuit life span. No significant differences in filter life were found according to age, weight, diagnoses, pump, site of venous access, blood flow rate, ultrafiltration rate, inotropic drug support, or patient outcome. The mean circuit life span was longer when the heparin dose was greater than 20 U/kg per hour (39 versus 29.1 hours; P = 0.008), with hemodiafiltration compared with hemofiltration (34 versus 22.7 hours; P = 0.001), with filters with surface areas of 0.4 to 0.9 m2 (38.2 versus 26.1 hours; P = 0.01), and with a catheter size of 6.5 French or greater (33.0 versus 25.0 hours; P = 0.04). In the multivariate analysis, hemodiafiltration, heparin dose of greater than 20 U/kg per hour, filter surface area of 0.4 m2 or greater, and initial creatinine of less than 2 mg/dL were associated with a filter life of more than 24 and 48 hours. Total effluent rate of greater than 35 mL/kg per hour was associated only with a filter life of more than 24 hours.ConclusionCircuit life span in CRRT in children is short but may be increased by the use of hemodiafiltration, higher heparin doses, and filters with a high surface area.

Preserved immune system in long-term asymptomatic vertically HIV-1 infected children

The objective of this study was to study immune system status in long‐term asymptomatic (LTA) HIV‐1‐infected children. A cross‐sectional study was used, involving HIV‐1‐infected children over 7 years of age who were rated into two groups according to their clinical and immunological classification: (a) LTA: 7 asymptomatic HIV‐1‐infected children in A1; (b) Rapid progressor (RP): 14 age‐matched C3 HIV‐1‐infected children. The control group consisted of 17 age‐matched uninfected children. The characterization of CD4+ T‐cell subsets was determined by three‐colour flow cytometry. The proliferative response and cytokine production by activated peripheral blood T‐cells were also measured. IL‐7 levels were measured in serum. Thymic production of T‐cells was quantified by TCR rearrangement excision circles (TRECs). The LTA children showed similar proliferative responses to PHA, PWM and anti‐CD3+ anti‐CD28, but lower responses to tetanus toxoid and streptokinase, in comparison with the controls but always higher responses in comparison with the RP group. The production of TNF‐α and IFN‐γ was similar in the LTA and control groups, and both were higher than the levels in the RP group. The LTA group showed a lower percentage of memory CD4+ T‐cells (CD4+ CD45RO+, CD4+ CD45RA‐CD62L+) than the control and RP groups. The LTA group also showed lower percentages of CD4+ CD7‐ cells than the controls. As for naïve CD4+ T‐cells (CD4+ CD45RA+ CD62L+), CD4+ CD45RA+ and CD4+ CD62L+ cells, the LTA group showed higher values than the control and RP groups. The LTA group showed higher percentages of CD4+ HLA‐DR+ CD38+ than the controls, but lower values than the RP group. In contrast, the LTA group had percentages of CD4+ HLA‐DR‐CD38+ T‐cells higher than both the control and RP groups, whereas CD4+ CD38+ levels were only higher in the LTA group in comparison with the controls. CD4+ HLA‐DR+ CD38‐ and CD4+ HLA‐DR+ cell numbers were lower in the LTA group in comparison with the RP group. We found almost normal values of TRECs and IL‐7 in the LTA group, but lower values in the RP group. Moreover, we found an inverse relation between TREC levels and IL‐7 in plasma from HIV‐infected children. Asymptomatic HIV‐1 infected children have a well preserved immune system similar to that of control uninfected children in spite of HIV‐infection for more than 7 years. Moreover, our results identified new markers of HIV disease, such as TRECs and IL‐7, that could be used to monitor disease.

Identification of liver fibrosis in HIV/HCV-coinfected patients using a simple predictive model based on routine laboratory data

Summary.  We constructed noninvasive models to predict significant fibrosis (F ≥ 2) and advanced fibrosis (F ≥ 3) among human immunodeficiency virus (HIV)/hepatitis C virus (HCV)‐coinfected patients, naïve for anti‐HCV treatment. A total of 296 patients with liver biopsy were randomly assigned to an estimation group (EG = 226; 70%) and a validation group (VG = 70; 30%). We developed the Hospital Gregorio Marañón (HGM)‐1 index, based on platelet count, aspartate aminotransferase (AST) and glucose, to predict F ≥ 2 and the HGM‐2 index, based on platelet count, international normalized ratio, alkaline phosphatase and AST to predict F ≥ 3. The area under the receiver operating characteristic curves (AUROCs) of the HGM‐1 index for the EG and the VG were 0.807 and 0.712 respectively. The AUROCs of the HGM‐2 index for the EG and the VG were 0.844 and 0.815 respectively. With the HGM‐1 index applied to the VG, using best cutoff scores, the negative predictive value (NPV) to exclude F ≥ 2 was 54.5% and the positive predictive value (PPV) to confirm F ≥ 2 was 93.3%. With the HGM‐2 index applied to the VG, using best cutoff scores, the NPV to exclude F ≥ 3 was 92.3, and the PPV to confirm F ≥ 3 was 64.3%. Thus, HGM‐2 accurately predicted F ≥ 3 among HIV/HCV‐coinfected patients. HGM‐1 was less accurate at predicting F ≥ 2.