To the Editor: Guidelines for HIV/hepatitis C virus (HCV)-coinfected patients recommend HCV treatment with pegylated interferon-α (PEG-IFN) plus ribavirin (RBV).1 The adverse effects of IFN/RBV, particularly anemia, may be more common among HIV/HCV-coinfected than HCV-monoinfected patients2 and are often associated with decreased health-related quality of life (HRQOL)3 as well as with discontinuation or dose reduction of RBV.4 This study evaluated the effectiveness of once-weekly (QW) epoetin alfa (epoetin alfa) compared with standard of care (SOC) in correcting anemia, improving HRQOL, and minimizing RBV dose reductions in HIV/HCV-coinfected patients receiving IFN/RBV therapy. This was a 16-week, open-label, randomized, parallel-group, multicenter study in anemic patients with HIV/HCV coinfection receiving IFN/RBV therapy for an anticipated period of ≥16 additional weeks. Key inclusion criteria included patient age of 18 to 75 years and hemoglobin (Hb) ≤12 g/dL or a ≥2-g/dL decrease in Hb after IFN/RBV initiation. Key exclusion criteria included a history of uncontrolled hypertension or seizure disorder, anemia attributable to another cause, and exposure to any epoetin within 3 months. Patients were randomized (1:1 ratio) to receive up to 16 weeks of epoetin alfa (PROCRIT™; Ortho Biotech Products, LP, Bridgewater, NJ) at a dose of 40,000 U subcutaneously QW or SOC (no epoetin alfa). Epoetin alfa dosage was increased to 60,000 U QW after 4 weeks of therapy if Hb had not returned to pre-IFN/RBV levels. Epoetin alfa was discontinued after an additional 4 weeks at 60,000 U QW if Hb had not increased ≥1.0 g/dL from the nadir Hb value. If Hb exceeded 14 g/dL in women or 16 g/dL in men, epoetin alfa was withheld temporarily. The primary end point was to compare the mean change in Hb from baseline (ie, first dose of study drug in epoetin alfa group, day 1 in SOC group) to week 16 in the epoetin alfa group with that in the SOC group. Secondary end points were mean change in RBV dosage, HRQOL scores (measured by modified Short Form-12 [SF-12] Health Survey-Acute; Physical and Mental Health Components [PCS, MCS]),5 and transfusion. Patients were required to complete HRQOL assessments before each visit. Safety assessments included monitoring vital signs, adverse events, alanine aminotransferase (ALT) levels, CD4+ counts, and HIV and HCV viral loads. Efficacy analyses were based on a modified intent-to-treat (MITT) population defined as all patients who had baseline Hb measured and had at least 1 follow-up Hb assessment and, for the epoetin alfa group, received at least 1 dose of epoetin alfa. Safety analysis considered all patients. Missing values were imputed for the efficacy analyses using the last-value-carried-forward technique. Changes in Hb and SF-12 PCS and MCS scores were analyzed within each treatment group using paired t tests and were compared between groups using an analysis of covariance (ANCOVA) model with treatment group as a factor and baseline values as a covariate. RBV dosage changes were assessed by on-treatment analysis and were analyzed using a Wilcoxon signed-rank test to compare between groups. A post hoc analysis of changes in Hb stratified by zidovudine (AZT) status was performed. The incidence of adverse events between groups was compared using the Fisher exact test. Sixty-six patients were randomized (34 to epoetin alfa group and 32 to SOC group). Baseline characteristics were comparable between the 2 groups. Immediately after randomization (day 1/week 0), 14 patients (4 epoetin alfa and 10 SOC) dropped out of the study without baseline or follow-up assessments. Compared with SOC patients included in the MITT analysis, early SOC dropout patients had lower Hb levels at study entry (10.3 vs. 11.5 g/dL; P = 0.03). Thirty epoetin alfa patients and 22 SOC patients were included in the MITT analysis. Twenty (63%) SOC patients and 11 (32%) epoetin alfa patients dropped out during the 16-week study period. The median time between initiation of IFN/RBV and baseline was 50 days (range: 16-306 days) in the epoetin alfa group and 60 days (range: 22-171 days) in the SOC group. Mean baseline Hb (±SE) was 11.1 ± 0.3 g/dL in the epoetin alfa group and 11.5 ± 0.3 g/dL in the SOC group (P = 0.33), and mean increases in Hb from baseline to week 16 were 2.6 ± 0.3 g/dL and 0.2 ± 0.3 g/dL, respectively (P < 0.001). No patient had epoetin alfa withheld because of reaching the upper limit of Hb. Patients receiving epoetin alfa and AZT had a greater mean increase in Hb from baseline to week 16 than those not receiving AZT (3.2 ± 0.4 g/dL [n = 13] vs. 2.1 ± 0.4 g/dL [n = 17]; Fig. 1). For SOC patients, the mean change in Hb was similar in AZT users and nonusers. No transfusions occurred.FIGURE 1: Hemoglobin (Hb) levels by treatment group stratified by zidovudine (AZT) treatment status (modified-intention-to-treat [MITT] population). *P = 0.001 versus standard of care (SOC) receiving AZT (analysis of covariance [ANCOVA]). †P < 0.001 versus SOC not receiving AZT (ANCOVA).Mean RBV doses at initiation of IFN/RBV and at baseline, respectively, were 1047 and 973 mg/d in the epoetin alfa group and 1027 and 982 mg/d in the SOC group. At week 16, 67% of epoetin alfa patients and 45% of SOC patients were receiving RBV doses ≥10.6 mg/kg/d (P = 0.09). The SF-12 PCS score (mean ± SE) increased significantly from baseline to week 16 in the epoetin alfa group (6.0 ± 1.8 points; P = 0.004), whereas the mean increase in the SOC group was not significant (2.2 ± 1.2 points; P = 0.09). The mean increase in the SF-12 MCS scale score was 2.3 ± 2.0 points in the epoetin alfa group and 0.1 ± 1.5 points in the SOC group (P = nonsignificant vs. baseline for both groups). There were no significant differences between groups for mean change from baseline to week 16 in the SF-12 PCS or SF-12 MCS scale score. Epoetin alfa was well tolerated, with most adverse events mild to moderate in severity. Patients treated with epoetin alfa had significantly less fatigue (n = 3 [10%]) compared with those in the SOC arm (n = 9 [38%]) (P = 0.02); there was no other significant difference between groups in the incidence of common adverse events. Four serious adverse events were reported: 1 in the epoetin alfa group (constipation, which was considered unrelated to epoetin alfa) and 3 in the SOC group (chest pain, myocardial infarction, and psychosis). There were no reports of thrombovascular events or antierythropoietin antibodies related to epoetin alfa. In this randomized study, epoetin alfa effectively corrected anemia in HIV/HCV-coinfected patients treated with IFN/RBV, including those taking AZT. The magnitude of Hb increase (mean = 2.6 g/dL) in coinfected patients was similar to that previously observed in IFN/RBV-related anemia in patients with HCV monoinfection.6,7 In contrast to studies in patients with HCV alone, no effect of epoetin on RBV dose was observed.6,7 A significant number of SOC patients dropped out after randomization (10 patients) and before week 16 (20 patients), however, substantially limiting our ability to assess the secondary end point of RBV dose, because patients and investigators may have selectively discontinued study participation in those SOC patients with worse outcomes. Improvements in HRQOL scores were greater in patients receiving epoetin alfa, but the small sample size precluded definitive conclusions. Significantly fewer patients treated with epoetin alfa than SOC reported fatigue as an adverse event. In conclusion, epoetin alfa was effective in correcting anemia and was well tolerated in HIV/HCV-coinfected patients receiving IFN/RBV therapy compared with SOC. Larger, double-blind, placebo-controlled studies as well as studies evaluating alternative criteria for the use of epoetin alfa are warranted to further assess the effects of epoetin alfa on HRQOL, maintenance of RBV dose, and HCV response. ACKNOWLEDGMENTS Coinvestigators include the following individuals: Philip Keiser, MD, University of Texas, Dallas, TX; David Bernstein, MD, North Shore University Hospital, Manhasset, NY; Christine Zurawski, MD, Office of Joel Rosenstock, MD, Atlanta, GA; Coleman Smith, MD, Minnesota Clinical Research Center, St. Paul, MN; Vilma Vega, MD, Infectious Diseases Associates, Sarasota, FL; Daniel Wolde-Rufael, MD, Chase Brexton Health Services, Baltimore, MD; Joseph Jemsek, MD, Jemsek Clinic, Huntersville, NC; Sangik Oh, MD, Beth Israel Deaconess Medical Center, Boston, MA; and Gerald Pierone, MD, Treasure Coast Infectious Disease Consultants, Vero Beach, FL. The authors acknowledge the contributions of Kimberly Marino, Bann-Mo Day, Nicole Slacik, Kevin Smith, and Angela Klopfer of Ortho Biotech Clinical Affairs, LLC. Mark S. Sulkowski, MD* Douglas T. Dieterich, MD† Edmund J. Bini, MD‡ Norbert Bräu, MD§ Daniel Alvarez, MD§ Edwin DeJesus, MD¶ Gerhard J. Leitz, MD# for the HIV/HCV Coinfection Study Group *Viral Hepatitis Center, Johns Hopkins University, Baltimore, MD †Mt. Sinai Medical Center, New York, NY, ‡Veterans' Administration, New York Harbor Healthcare System, New York, NY, §Bronx Veterans' Administration, Medical Center, Bronx, NY, §Drexel University College of Medicine, Philadelphia, PA, ¶IDC Research Initiative, Altamonte Springs, FL, #Ortho Biotech Clinical Affairs, LLC, Bridgewater, NJ
ABSTRACT Objective: The aim of the present study was to evaluate 24‐week maintenance of efficacy and safety of rabeprazole in children with endoscopically proven gastroesophageal reflux disease (GERD). Methods: Children ages 1 to 11 years who achieved endoscopic/histologic healing (defined as grade 0 of the Hetzel‐Dent Classification scale and/or grade 0 of the Histological Features of Reflux Esophagitis scale) in a 12‐week treatment phase were continued on the same dose for an additional 24 weeks during the maintenance phase. The dose was determined by weight: children weighing 6 to 14.9 kg (low‐weight cohort) received 5 or 10 mg and children weighing ≥15 kg (high‐weight cohort) received 10 or 20 mg. Results: Healing was maintained in 90% of children (100% [low‐weight cohort]; 89% [10 mg, high‐weight cohort]; 85% [20 mg, high‐weight cohort]). The Total GERD Symptom and Severity score continued to improve slightly in all of the children across all dose groups ( P = 0.026) during the maintenance phase, except the 10‐mg dose group (low‐weight cohort), which experienced a slight worsening of 3.6 points. Overall, 71% children felt better on the GERD Symptom Relief score ( P < 0.001); 95% of investigators and 92% of parent/caregivers rated “Good to Excellent” on the Global Treatment Satisfaction scale and Clinical Global Impressions Improvement scale, respectively. Overall incidence of treatment‐emergent adverse events was 63%; upper respiratory tract infections (13%) and vomiting (11%) were the most commonly reported (>10%). Conclusions: Rabeprazole was effective in maintaining endoscopic/histologic healing during a 24‐week maintenance period in children with endoscopically proven GERD. The clinical effect and safety profile were largely similar across dose groups.
Anemia and decreased health–related quality of life (HRQL) are common in patients receiving combination therapy of interferon alfa (IFN) and ribavirin (RBV) for chronic hepatitis C virus (HCV) infection. In a randomized, prospective study evaluating the effectiveness of epoetin alfa in maintaining RBV dose, alleviating anemia, and improving HRQL in anemic (Hb ≤ 12 g/dL) HCV–infected patients receiving combination therapy, patients receiving epoetin alfa had significant improvements in HRQL compared with placebo. In this study, 185 patients were randomized to 40,000 units of epoetin alfa subcutaneously weekly or placebo for an 8–week double–blind phase (DBP), followed by an 8–week open–label phase during which all patients received epoetin alfa. To further assess the impact of epoetin alfa on HRQL, post hoc analyses were conducted in the same patient population to compare the HRQL of these patients at randomization with norms of other populations, and to determine the critical relationship between hemoglobin (Hb) levels and HRQL. Mean HRQL scores of anemic HCV–infected patients receiving combination therapy at randomization were significantly lower than those of both the general population and patients who had other chronic conditions. Patients receiving epoetin alfa who had the greatest Hb increases from randomization to the end of the DBP also had the largest improvements in HRQL. Hb improvement was an independent predictor of HRQL improvement in these patients. In conclusion , epoetin alfa provided clinically significant HRQL improvement in HCV–infected patients receiving IFN/RBV therapy. (Hepatology 2004;40:1450-1458.)
lasting >5 min showed a monotonic decline with increasing dose: placebo 3.8, naronapride 12 mg 2.9, naronapride 40 mg 2.1. The difference between placebo and naronapride 40 mg was significant (p=0.0007), as was the dose-response (p=0.0049). The mean duration of acid reflux episodes also showed some reduction with treatment: 0.67 min on placebo; 0.60 min on both naronapride 12 mg and 40 mg. The dose response was significant (p= 0.0057). Conclusions: Treatment with naronapride resulted in a consistent and dose-related decrease in several measures of esophageal acid exposure, including mean % of time with pH<4.0, total number of acid reflux episodes, the mean duration of acid reflux episodes and the number of acid reflux episodes over 5 min duration. Taken together, these findings suggest that naronapride may be effective in the treatment of acid reflux disorders, and further studies are warranted.
