ABSTRACT
BACKGROUND: High daily doses of pancreatic enzyme replacement therapy (PERT) were historically associated with risk of fibrosing colonopathy (FC) in people with cystic fibrosis (pwCF), leading to development of PERT dosing guidelines and reformulated products. This study quantified incidence of FC in pwCF treated with PERT following those measures. METHODS: This large prospective cohort study included eligible pwCF enrolled in the Cystic Fibrosis Foundation Patient Registry with ≥1 clinic visit in 2012-2014 and follow-up through 2020. Data on PERT exposure, demographics, and medical history were collected. Clinical data, imaging, and histopathology of suspected cases were examined by an independent adjudication panel of physicians familiar with this complication. RESULTS: Base Study Population included 26,025 pwCF who contributed 155,814 person-years [mean (SD) 6.0 (2.0) years] of follow-up. Over 7.8 years, 29 pwCF had suspected FC; three cases were confirmed by adjudication, 22 cases were confirmed as not FC, and four cases were indeterminate. There were 22,161 pwCF exposed to any PERT, with mean PERT use time of 5.583 person-years and mean daily dose of 8328 U lipase per kg per day. All three confirmed cases and four indeterminate cases of FC occurred during current use of PERT. Incidence rates per 1000 person-years exposed were 0.0242 (95 % CI [0.0050, 0.0709]) for confirmed FC and 0.0566 (95 % CI [0.0227, 0.1166]) for indeterminate or confirmed FC. CONCLUSIONS: The incidence of FC in pwCF is very low in the era of current treatment guidelines and more stringent quality standards for PERT products.
Subject(s)
Cystic Fibrosis , Humans , Cystic Fibrosis/complications , Cystic Fibrosis/diagnosis , Cystic Fibrosis/drug therapy , Incidence , Prospective Studies , Enzyme Replacement Therapy/adverse effects , Enzyme Replacement Therapy/methods , Pancreas/diagnostic imaging , FibrosisABSTRACT
BACKGROUND: Cardiovascular conditions are the most prevalent comorbidity among patients with prostate cancer, regardless of treatment. Additionally, cardiovascular risk has been shown to increase following exposure to certain treatments for advanced prostate cancer. There is conflicting evidence on risk of overall and specific cardiovascular outcomes among men treated for metastatic castrate resistant prostate cancer (CRPC). We, therefore, sought to compare incidence of serious cardiovascular events among CRPC patients treated with abiraterone acetate plus predniso(lo)ne (AAP) and enzalutamide (ENZ), the two most widely used CRPC therapies. METHODS: Using US administrative claims data, we selected CRPC patients newly exposed to either treatment after August 31, 2012, with prior androgen deprivation therapy (ADT). We assessed incidence of hospitalization for heart failure (HHF), ischemic stroke, and acute myocardial infarction (AMI) during the period 30-days after AAP or ENZ initiation to discontinuation, outcome occurrence, death, or disenrollment. We matched treatment groups on propensity-scores (PSs) to control for observed confounding to estimate the average treatment effect among the treated (AAP) using conditional Cox proportional hazards models. To account for residual bias, we calibrated our estimates against a distribution of effect estimates from 124 negative-control outcomes. RESULTS: The HHF analysis included 2322 (45.1%) AAP initiators and 2827 (54.9%) ENZ initiators. In this analysis, the median follow-up times among AAP and ENZ initiators (after PS matching) were 144 and 122 days, respectively. The empirically calibrated hazard ratio (HR) estimate for HHF was 2.56 (95% confidence interval [CI]: 1.32, 4.94). Corresponding HRs for AMI and ischemic stroke were 1.94 (95% CI: 0.90, 4.18) and 1.25 (95% CI: 0.54, 2.85), respectively. CONCLUSIONS: Our study sought to quantify risk of HHF, AMI and ischemic stroke among CRPC patients initiating AAP relative to ENZ within a national administrative claims database. Increased risk for HHF among AAP compared to ENZ users was observed. The difference in myocardial infarction did not attain statistical significance after controlling for residual bias, and no differences were noted in ischemic stroke between the two treatments. These findings confirm labeled warnings and precautions for AAP for HHF and contribute to the comparative real-world evidence on AAP relative to ENZ.
Subject(s)
Ischemic Stroke , Prostatic Neoplasms, Castration-Resistant , Male , Humans , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms, Castration-Resistant/epidemiology , Prostatic Neoplasms, Castration-Resistant/pathology , Androgen Antagonists , Treatment Outcome , Abiraterone Acetate , Nitriles/adverse effectsABSTRACT
BACKGROUND: A post-hoc analysis of the phase-3 LATITUDE study assessed the impact of abiraterone acetate plus prednisone (AA+P) on overall survival (OS) and radiographic progression-free survival (rPFS) in men with metastatic castration-sensitive prostate cancer (mCSPC) and visceral metastases (VM). METHODS: Newly diagnosed mCSPC patients were randomized (1:1) to AA+P and androgen deprivation therapy (ADT) or placebo+ADT. Patients with VM in liver or lungs with or without other soft tissue and bone metastases (based on CT/MRI) at baseline were analyzed, after 51.8 months' median follow-up. Co-primary endpoints, OS and rPFS, were analyzed. RESULTS: Among 1199 patients enrolled, 228 (19%) had VM at baseline (114 each in AA+P and placebo groups), of which 53 (23.2%; AA+P = 29, Placebo = 24) had liver metastases and 117 (51.3%; AA+P = 60, Placebo = 57) had lung metastases. In patients with VM, treatment with AA+P versus placebo showed an improvement in OS (median 55.4 vs 33.0 months; HR = 0.582; 95%CI = 0.406-0.835;P = 0.0029) and rPFS (median 30.7 vs 18.3 months; HR = 0.527; 95%CI = 0.366-0.759;P = 0.0005), comparable to that of patients without VM. AA+P versus placebo in lung metastases patients was associated with greater improvement in OS (HR = 0.60; 95%CI = 0.35-1.04;P = 0.0678) than in liver metastases patients (HR = 0.82; 95%CI = 0.41-1.66;P = 0.5814). AA+P versus placebo showed improvement in rPFS in lung metastases patients (HR = 0.50; 95%CI = 0.29-0.89;P = 0.0157), but not in liver metastases patients (HR = 1.05; 95%CI = 0.53-2.09; P = 0.8970). CONCLUSION: AA+P treatment improved both rPFS and OS in men with mCSPC and visceral disease, especially those with lung metastases. Men with liver metastases had a poorer prognosis and their optimal treatment remains to be defined. REGISTRATION: ClinicalTrials.gov, number NCT01715285.
Subject(s)
Liver Neoplasms , Lung Neoplasms , Neoplasms, Second Primary , Prostatic Neoplasms, Castration-Resistant , Abiraterone Acetate , Androgen Antagonists/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Castration , Humans , Liver Neoplasms/drug therapy , Liver Neoplasms/etiology , Lung Neoplasms/etiology , Male , Neoplasms, Second Primary/etiology , Prednisone/therapeutic use , Prostatic Neoplasms, Castration-Resistant/pathologyABSTRACT
BACKGROUND: This study was conducted based on a request from the European Medicines Agency to generate robust data on domperidone efficacy in children in the relief of symptoms of nausea and vomiting by assessing the effect of a low-dose and short treatment duration. METHODS: In this randomized, double-blind, phase 3 study, children ages 6 months to 12 years with acute gastroenteritis randomly (1:1) received oral domperidone 0.25âmg/kg with oral rehydration therapy (ORT) or matching placebo thrice daily for 2 to 7 days. The proportion of patients with no vomiting episodes (primary endpoint) and patients ages ≥4 years with no nausea episodes (key secondary endpoint) within 48 hours of first treatment administration were evaluated. RESULTS: The study was terminated early following futility analysis. At early termination, 292 patients randomly received domperidone (nâ=â147) or placebo (nâ=â145). The proportion of patients with no vomiting episodes within 48-hours of first treatment administration was similar between domperidone (32.0%) and placebo groups (33.8%). Similarly, there was no significant difference in proportion of patients ages ≥4 years with no nausea episodes within 48 hours of first treatment administration between domperidone (35.7%) and placebo (38.6%). Total 13 patients (domperidone, 3.4% [5/147] vs placebo, 5.5% [8/145]) reported ≥1 treatment-emergent adverse events. No deaths or adverse events of special interest (extrapyramidal symptoms and QT prolongation) were reported. CONCLUSIONS: Low-dose of domperidone with ORT did not significantly differ from placebo in reducing vomiting and nausea episodes in pediatric patients with acute gastroenteritis (AG), and the safety profile was similar between both groups.
Subject(s)
Antiemetics/therapeutic use , Domperidone/therapeutic use , Gastroenteritis/complications , Nausea/drug therapy , Vomiting/drug therapy , Acute Disease , Administration, Oral , Antiemetics/administration & dosage , Child , Child, Preschool , Domperidone/administration & dosage , Double-Blind Method , Europe , Female , Humans , Infant , Male , Nausea/complications , Russia , South Africa , Treatment Outcome , Vomiting/complicationsABSTRACT
Domperidone effects on QTc duration were assessed in a single-center, double-blind, four-way crossover study of 44 healthy participants randomized to one of four treatment sequences consisting of four treatment periods separated by 4-9 days washout. On Day 1 of each 4-day period, participants began oral domperidone 10 or 20 mg q.i.d., matching placebo q.i.d., or single-dose moxifloxacin 400 mg (positive control)/placebo q.i.d. In each period, triplicate 12-lead electrocardiograms were recorded at baseline (30, 20, and 10 minutes predose), 8 timepoints after dosing on Days 1 and 4, and predose on Day 4. In mixed effects models, the largest difference for domperidone in least squares means for change from baseline QTcP versus placebo was 3.4 milliseconds (20 mg q.i.d., Day 4), 90% CI: 1.0-5.9, and <10 milliseconds at all timepoints for both domperidone dosages. Moxifloxacin response confirmed assay sensitivity. Participants achieved expected domperidone plasma exposures. No significant exposure-response relationship was found for QTc increase per ng/mL domperidone (90% CI of the slope estimate included zero at mean Cmax on Day 1 or Day 4). In summary, domperidone at doses up to 80 mg/day did not cause clinically relevant QTc interval prolongation.
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.
Subject(s)
Gastroesophageal Reflux/drug therapy , Gastroesophageal Reflux/pathology , Proton Pump Inhibitors/therapeutic use , Rabeprazole/therapeutic use , Abdominal Pain/chemically induced , Child , Child, Preschool , Diarrhea/chemically induced , Double-Blind Method , Endoscopy, Gastrointestinal , Female , Humans , Infant , Maintenance Chemotherapy/adverse effects , Male , Patient Satisfaction , Proton Pump Inhibitors/adverse effects , Rabeprazole/adverse effects , Respiratory Tract Infections/chemically induced , Severity of Illness Index , Vomiting/chemically inducedABSTRACT
The primary objective was to compare the pharmacokinetics (PK) of rabeprazole granules versus rabeprazole tablets, and assess the effect of food on the PK of rabeprazole granules. Data from three phase 1, open-label, single-dose, randomized, crossover studies in healthy adult participants are presented separately and as a cross-study comparison; study 1: PK of phase 1 rabeprazole granules versus rabeprazole tablets under fasting conditions; study 2: PK of phase 3 rabeprazole granules versus phase 1 rabeprazole granules; study 3: bioequivalence of to-be-marketed rabeprazole granules (sprinkle capsules) versus phase 3 rabeprazole granules; and assessment of the food effect for the to-be-marketed rabeprazole granules. Overall, 123 of 130 participants enrolled completed the studies. The overall plasma exposure as measured by area under the plasma concentration-time curve (AUC) was comparable between rabeprazole granules and tablets; mean peak plasma concentration (Cmax ) was lower for the granules compared with tablets. The plasma elimination half-life was short and independent of formulation. Food intake prior to administration of the to-be-marketed granules delayed the absorption and reduced the estimated parameters for bioavailability by 55% (Cmax ) and 28% (AUCinf ). Rabeprazole was well-tolerated.
Subject(s)
Food-Drug Interactions , Proton Pump Inhibitors/administration & dosage , Proton Pump Inhibitors/pharmacokinetics , Rabeprazole/administration & dosage , Rabeprazole/pharmacokinetics , Adult , Area Under Curve , Belgium , Cross-Over Studies , Drug Compounding , Fasting/blood , Half-Life , Healthy Volunteers , Humans , Metabolic Clearance Rate , Middle Aged , Models, Biological , Postprandial Period , Proton Pump Inhibitors/adverse effects , Proton Pump Inhibitors/chemistry , Rabeprazole/adverse effects , Rabeprazole/chemistry , Tablets , Therapeutic Equivalency , United States , Young AdultABSTRACT
OBJECTIVE: Evaluate the efficacy and safety of rabeprazole in children, 1 to 11 years old, with endoscopically/histologically proven gastroesophageal reflux disease (GERD). METHODS: Children were randomized to 0.5- or 1.0-mg/kg rabeprazole granule formulation for 12 weeks. The dose was further determined by weight: children 6 to 14.9 kg (low-weight cohort) received 5 or 10 mg and children ≥15 kg (high-weight cohort) received 10 or 20 mg. The primary endpoint was endoscopic/histologic healing at week 12 (defined as grade 0 on the Hetzel-Dent classification scale and/or grade 0 on the Histological Features of Reflux Esophagitis scale). RESULTS: Overall, 81% (87/108) achieved endoscopic/histologic healing at week 12 with higher healing in the low-weight cohort (82% [5-mg dose], 94% [10-mg dose]) compared with high-weight cohort (76% [10-mg dose], 78% [20-mg dose]). There was a significant (P < 0.001) decrease in the mean Total GERD Symptoms and Severity score from 19.7 points (baseline) to 8.6 points (week 12), with 26% fewer children reporting GERD symptoms at week 12. The average frequency of symptoms per child decreased from 7.7 (week 1) to 4.7 (week 12). The GERD Symptom Relief score showed that 71% of children felt better, 81% were rated "good to excellent" on the Global Treatment Satisfaction scale by the investigator; 77% were rated "good to excellent" on the Clinical Global Impressions-Improvement scale by the parent/caregiver. The most common (>10%) treatment-emergent adverse events included cough and vomiting (14% each), abdominal pain (12%), and diarrhea (11%). CONCLUSIONS: Rabeprazole was effective and safe in 1- to 11-year-old children with GERD.
Subject(s)
Esophagitis, Peptic/drug therapy , Gastroesophageal Reflux/drug therapy , Proton Pump Inhibitors/therapeutic use , Rabeprazole/therapeutic use , Abdominal Pain/drug therapy , Abdominal Pain/etiology , Body Weight , Child , Child, Preschool , Diarrhea/drug therapy , Diarrhea/etiology , Dose-Response Relationship, Drug , Esophagitis, Peptic/etiology , Female , Gastroesophageal Reflux/pathology , Humans , Infant , Male , Proton Pump Inhibitors/administration & dosage , Proton Pump Inhibitors/adverse effects , Rabeprazole/administration & dosage , Rabeprazole/adverse effects , Severity of Illness Index , Treatment Outcome , Vomiting/drug therapy , Vomiting/etiologyABSTRACT
BACKGROUND: Pancreatic enzyme replacement therapy (PERT) is critical for correction of exocrine pancreatic insufficiency (EPI) in patients with cystic fibrosis (CF). METHODS: This was a randomized, placebo-controlled PERT withdrawal study evaluating the efficacy and safety of PANCREAZE® (pancrelipase) in CF patients with EPI. Participants (n=49) entered an open-label, ≤ 14 day run-in phase, maintained a high-fat diet (100 ± 15 g/day), and received PANCREAZE® (10.5 or 21). Participants with a coefficient of fat absorption (CFA)≥ 80% (n=40) were then randomized (1:1) to receive either PANCREAZE® or placebo during a double-blind, ≤ 7 day withdrawal phase. RESULTS: PANCREAZE® improved fat absorption as shown by significantly lower mean ± SD change in CFA between open-label and double-blind phases for PANCREAZE® (-1.5 ± 5.88%; p<0.001) compared to placebo (-34.1 ± 23.03%). Protein absorption was similarly improved. No unexpected adverse events were reported. CONCLUSIONS: This study demonstrated PANCREAZE® was effective in treating EPI due to CF and was safe and well tolerated.
Subject(s)
Cystic Fibrosis/complications , Exocrine Pancreatic Insufficiency/drug therapy , Gastrointestinal Agents/administration & dosage , Pancreas, Exocrine/drug effects , Pancrelipase/administration & dosage , Adolescent , Adult , Child , Female , Gastrointestinal Agents/adverse effects , Humans , Male , Middle Aged , Pancrelipase/adverse effects , Placebos , Treatment Outcome , Young AdultABSTRACT
BACKGROUND: The pharmacokinetics of rabeprazole after a single oral dose and once-daily administration for 5 consecutive days was characterized in children 1 to 11 years old with gastroesophageal reflux disease (GERD). PATIENTS AND METHODS: The initial 8 patients received rabeprazole sodium (hereafter referred to as rabeprazole) 0.14 mg/kg (part 1); the next 20 patients were randomized to receive 0.5 or 1 mg/kg (part 2) to target concentrations in plasma expected to be safe and effective. Pharmacokinetic parameters of rabeprazole and the thioether metabolite were calculated using noncompartmental methods. Subjective evaluations of GERD severity, rabeprazole short-term effectiveness, palatability, and safety were also characterized. RESULTS: Rabeprazole concentrations increased in a dose-dependent manner. Little or no accumulation was observed after repeated administration. The results suggest that formation of the thioether is an important metabolic pathway in young patients, which is consistent with adults. Plasma area under the concentration-time curve values of rabeprazole and the metabolite were poorly correlated with individual age and body weight. Furthermore, oral rabeprazole clearance values (not adjusted for weight) were similar to historical adult data. However, weight-adjusted values were higher for the pediatric patients, and approximately 2 to 3 times the milligram per kilogram dose of rabeprazole in these children was necessary to achieve comparable concentrations in adults. Subjective evaluations demonstrated an improvement of GERD symptoms in most patients after rabeprazole treatment. CONCLUSIONS: Palatability of the formulation was reported to be good or excellent. Rabeprazole was well tolerated, with no notable differences in safety among the dose groups.
Subject(s)
2-Pyridinylmethylsulfinylbenzimidazoles/pharmacokinetics , Gastroesophageal Reflux/drug therapy , Patient Acceptance of Health Care , Sulfides/blood , 2-Pyridinylmethylsulfinylbenzimidazoles/blood , 2-Pyridinylmethylsulfinylbenzimidazoles/therapeutic use , Age Factors , Area Under Curve , Body Weight , Child , Child, Preschool , Dose-Response Relationship, Drug , Female , Gastroesophageal Reflux/metabolism , Humans , Infant , Male , RabeprazoleABSTRACT
A 'trailing' effect has been commonly observed when azole antifungals are tested against Candida spp. Previous experience with fluconazole indicates that 24-h minimum inhibitory concentration (MIC) values are more compatible endpoints when compared with clinical outcomes. We evaluated the trailing effect of Candida isolates tested with itraconazole in a guinea pig model of systemic candidiasis. Survival and organ burden were only significantly affected by using a higher dose of itraconazole, irrespective of the MIC differences at 24 and 48 h. A fluconazole-resistant strain with susceptible dose-dependent MICs to itraconazole was successfully treated with high-dose itraconazole. Our data suggests that survival and microbiological response depend more on drug dosing than on the trailing phenotype of the isolates.
Subject(s)
Antifungal Agents/pharmacology , Candida albicans/drug effects , Candida albicans/growth & development , Candidiasis/drug therapy , Candidiasis/mortality , Itraconazole/pharmacology , Animals , Antifungal Agents/administration & dosage , Antifungal Agents/therapeutic use , Candidiasis/microbiology , Colony Count, Microbial , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Resistance, Fungal , Fluconazole/pharmacology , Guinea Pigs , Humans , Itraconazole/administration & dosage , Itraconazole/therapeutic use , Microbial Sensitivity Tests , Phenotype , Time Factors , Treatment OutcomeABSTRACT
STUDY DESIGN: Prospective, open-label, randomized, parallel-group study at 80 centers. OBJECTIVE: To demonstrate there is no clinically important additional risk for deep vein thrombosis with perioperative use of epoetin alfa versus standard of care in spine surgery without prophylactic anticoagulation. SUMMARY OF BACKGROUND DATA: Trials of epoetin alfa in orthopedic surgery that demonstrated no additional risk of thrombovascular events included perioperative pharmacologic anticoagulation. METHODS: Subjects received epoetin alfa 600 U/kg subcutaneously once weekly starting 3 weeks before spinal surgery plus standard of care for blood conservation, or standard of care alone. Perioperative anticoagulation therapy was not permitted; mechanical deep vein thrombosis prophylaxis was allowed. Doppler imaging for deep vein thrombosis was done on postoperative day 4 (or day of discharge), or for suspected deep vein thrombosis. Deep vein thrombosis was diagnosed by Doppler result or adverse event report. The criterion for no additional risk of deep vein thrombosis was a 1-sided 97.5% upper confidence limit < or =4% between groups. RESULTS: Of the 680 subjects analyzed (340 in each treatment group), 16 (4.7%) in the epoetin alfa group and 7 (2.1%) in the standard of care group had a diagnosis of deep vein thrombosis either by Doppler or by adverse event report with normal Doppler. The between-group difference was 2.6% (97.5% upper confidence limit, 5.4%). Deep vein thrombosis confirmed by Doppler (4.1% vs. 2.1%), other clinically relevant thrombovascular events (1.5% vs. 0.9%), and all adverse events combined (76.5% vs. 73.2%) occurred with similar frequency in the 2 treatment groups. CONCLUSION: This study documented a higher incidence of deep vein thrombosis and similar rates of other clinically relevant thrombovascular events with epoetin alfa versus standard of care for blood conservation in subjects who did not receive prophylactic anticoagulation before spinal surgery. Antithrombotic prophylaxis should be considered when erythropoietin is used in the surgical setting.
Subject(s)
Erythropoietin/adverse effects , Perioperative Care/adverse effects , Venous Thrombosis/chemically induced , Aged , Anticoagulants/therapeutic use , Elective Surgical Procedures/adverse effects , Epoetin Alfa , Female , Hematinics/adverse effects , Humans , Intention to Treat Analysis , Male , Middle Aged , Patient Selection , Prospective Studies , Recombinant Proteins , Spine/surgery , Ultrasonography, Doppler, Color , Venous Thrombosis/diagnostic imagingABSTRACT
Anemia, a common hematological abnormality in HIV, contributes to decreased quality of life (QOL). This study assessed once-every-2-week epoetin alfa on maintaining QOL and hemoglobin (Hb) in anemic HIV-infected patients in a 24-week, open-label, multicenter study. HIV-infected patients (Hb < or =12 g/dl) received epoetin alfa 40,000 units subcutaneously once weekly, until reaching Hb > or =13 g/dl. Patients then entered a maintenance phase (MP), in which epoetin alfa was administered every other week or at longer intervals. The trial objectives were to determine if QOL, as measured by the Medical Outcomes Study-HIV (MOS-HIV) general health perceptions (GHP) domain and Hb, was maintained. Safety was also assessed. A total of 292 patients were enrolled (72% on HAART). Mean baseline laboratory values were Hb = 10.8 g/dl, CD4(+) count = 280 cells/microl, and HIV RNA = 51,867 copies/ml. In all, 81% of patients reached Hb > or =13 g/dl and 92% reached Hb > or =12 g/dl. QOL was maintained from the beginning (GHP = 44.2 points) to the end of MP (GHP = 43.4 points) with every other week or longer dosing. Mean Hb at the beginning of MP was 13.4 +/- 0.5 g/dl and was 12.8 +/- 1.4 g/dl at study end. Epoetin alfa was well tolerated; adverse events were consistent with those reported in previous studies of epoetin alfa in HIV-infected patients. Although the clinical approach tested in this study is not consistent with current prescribing recommendations, the results confirm the efficacy of prolonged dosing intervals (every 2-4 weeks) in maintaining optimal Hb levels and QOL in anemic HIV-infected patients.
Subject(s)
Anemia/drug therapy , Erythropoietin/administration & dosage , HIV Infections/complications , Hematinics/administration & dosage , Hemoglobins/analysis , Quality of Life , Adult , Aged , CD4 Lymphocyte Count , Epoetin Alfa , Erythropoietin/adverse effects , Erythropoietin/therapeutic use , Female , Hematinics/adverse effects , Hematinics/therapeutic use , Humans , Injections, Subcutaneous , Male , Middle Aged , Recombinant Proteins , Treatment Outcome , Viral LoadABSTRACT
OBJECTIVE: To describe anemia prevalence and correlates with biomarkers and antiretroviral therapy (ART) in HIV/AIDS. METHODS: Multicenter, cross-sectional study; clinical laboratory data collected at single visits, including hemoglobin (Hb), CD4+ count, HIV-1 RNA. Patients receiving care at US physician offices during the year 2000. Main outcome measure was anemia (Hb < 14 g/dL [men]; < 12 g/dL [women]) and marked anemia (Hb < 11 g/dL [men]; < 10 g/dL [women]) prevalence. Multivariable models examined association of anemia prevalence with HIV-1 biomarkers and ART. RESULTS: Among 9690 patients, prevalence of anemia and marked anemia was 36% and 5%, respectively. Among 1721 patients receiving no ART, 39.7% were anemic; among 7252 receiving highly active antiretroviral therapy (HAART), 35.5% were anemic (p = 0.001). Anemia was most prevalent among men (37.3 vs. 32.3%; p = 0.0008), blacks (49 vs. 26% [whites]; p < 0.0001), patients with CD4+ < 200 cells/mm(3) (57 vs. 23% [> or = 500 CD4+]; p < 0.00001), and HIV-1 RNA > 30 000 copies/ml (53 vs. 30% [< 500 copies/ml]; p < 0.00001). Marked anemia was more common in women (6.8 vs. 4.3%; p < 0.0001). Among treated patients, logistic regression analysis controlling for CD4+, HIV-1 RNA, sex, and ethnicity, zidovudine (ZDV)-containing regimens (except combination with saquinavir/ZDV/lamivudine) were associated with increased overall anemia risk (odds ratio, 1.39 : 1.74). No regimen was associated with increased risk for marked anemia. Multivariable logistic regression showed CD4+, sex, and ethnicity more strongly associated with anemia than any ART regimen. CONCLUSION: This large, single-visit, cross-sectional, US-based study shows that anemia remains highly prevalent in HIV-infected patients. Data from this analysis suggest low CD4+ count, black ethnicity, and male sex are consistently strongest correlates of overall anemia; women are significantly more likely to have marked anemia.
Subject(s)
Anemia/epidemiology , Anti-HIV Agents/therapeutic use , HIV Infections/blood , Anemia/etiology , Anti-HIV Agents/administration & dosage , Antiretroviral Therapy, Highly Active , Biomarkers , CD4 Lymphocyte Count , Comorbidity , Cross-Sectional Studies , Drug Therapy, Combination , Female , HIV Infections/epidemiology , HIV-1 , Hepatitis C/epidemiology , Humans , Male , Models, Biological , Prevalence , RNA, Messenger/blood , Risk Factors , United States/epidemiologyABSTRACT
The natural history of anemia related to interferon/ribavirin (IFN/RBV) treatment in patients with human immunodeficiency virus/hepatitis C virus (HIV/HCV) coinfection is not completely understood. The current 8-week, multicenter, observational study characterized anemia over the course of HCV treatment in patients with HIV/HCV coinfection. Eligible HIV/HCV coinfected patients were receiving care in community-based and academic institutions and were on stable antiretroviral therapy and initiating IFN/RBV therapy. Hb, sEPO, reticulocytes, transfusions, laboratory values (e.g., total bilirubin), and IFN and RBV dosages were monitored weekly. Ninety-one patients were analyzed (mean age, 46 years; 71% on HAART) and 53 patients completed the study. Mean Hb decreased significantly (5.0 g/dl) within 1 week of initiating IFN/RBV therapy (p = 0.0002); Hb nadir occurred at a median of 37 days. Maximum Hb decreases of > or =2.0 g/dl occurred in 56 (62%) patients and > or =3.0 g/dl occurred in 45 (49%) patients. Reticulocyte count increased within the first 2 weeks and sEPO peaked at week 3. Mean increase from baseline to week 2 in reticulocyte count and sEPO, respectively, was 1.3% (n = 74) and 45.0 mIU/ml (n = 80) (p < 0.0001 for each parameter), and from baseline to week 8 was 0.9% (n = 48) and 41.0 mIU/ml (n = 52) (p < or = 0.0001 for each parameter). Adverse events (AEs) were the most common reason for study discontinuation (66% of discontinuing patients). Among the 25 patients who discontinued due to AEs, 84% discontinued due to anemia (n = 21). Significant decreases in Hb were observed in HIV/HCV-coinfected patients within 1 week of initiating IFN/RBV therapy. sEPO and reticulocyte increases were blunted in response to anemia; Hb levels did not return to baseline values and anemia was a frequent reason for discontinuing the study.
Subject(s)
Anemia/blood , Antiviral Agents/administration & dosage , HIV Infections/drug therapy , Hepatitis C, Chronic/drug therapy , Interferon-alpha/administration & dosage , Ribavirin/administration & dosage , Adolescent , Adult , Aged , Anemia/chemically induced , Anti-HIV Agents/administration & dosage , Antiretroviral Therapy, Highly Active , Antiviral Agents/adverse effects , Black People/statistics & numerical data , Cell Count , Dose-Response Relationship, Drug , Drug Therapy, Combination , Erythropoietin/blood , Female , HIV Infections/complications , Hemoglobins/analysis , Hepatitis C, Chronic/complications , Hispanic or Latino/statistics & numerical data , Humans , Interferon alpha-2 , Interferon-alpha/adverse effects , Male , Middle Aged , Protease Inhibitors/administration & dosage , Recombinant Proteins , Reticulocytes/cytology , Retrospective Studies , Reverse Transcriptase Inhibitors/administration & dosage , Ribavirin/adverse effects , Time Factors , Treatment Outcome , White People/statistics & numerical data , Zidovudine/administration & dosageSubject(s)
Anemia/drug therapy , Antiviral Agents/adverse effects , Erythropoietin/therapeutic use , Hematinics/therapeutic use , Hepatitis C/drug therapy , Interferons/adverse effects , Ribavirin/adverse effects , Adolescent , Adult , Aged , Anemia/chemically induced , Drug Administration Schedule , Epoetin Alfa , Female , HIV Infections/complications , Hepatitis C/complications , Humans , Male , Middle Aged , Quality of Life , Recombinant ProteinsABSTRACT
OBJECTIVES: In hepatitis C virus (HCV)-infected patients receiving pegylated interferon (PEG-IFN)/ribavirin (RBV) combination therapy, anemia is a well-known side effect. The purpose of this study was to describe the time course and extent of hemoglobin (Hb) changes and the erythropoietic response to PEG-IFN/RBV-induced anemia. METHODS: In this multicenter, observational, 8-wk study, laboratory parameters were measured weekly for 8 wk or until early withdrawal. Primary endpoints included changes in Hb and serum erythropoietin (sEPO) from baseline to week 8; other measures were changes in reticulocytes and RBV dose. The predictive value of baseline factors for maximum Hb decline was assessed. RESULTS: In the 97 evaluable patients, mean Hb decreased from 14.4 +/- 1.4 g/dl (baseline) to 11.9 +/- 1.3 g/dl (week 8). Twenty-one percent of patients withdrew before week 8. The estimated erythropoietic response was lower than that seen in two historic control populations of iron deficiency anemia patients. Mean RBV dose decreased from 986 +/- 190 mg/day (baseline) to 913 +/- 228 mg/day (week 8). Fifty-seven out of 77 (74%) patients who completed the study maintained their initial prescribed RBV dose. Patients maintained on the initial dose of RBV who had a higher baseline Hb and viral load showed a trend toward larger Hb declines. Platelets and white blood cells (WBCs) also declined during the study. CONCLUSIONS: HCV-infected patients receiving PEG-IFN/RBV therapy have reductions in Hb, platelets, and WBCs, possibly due to bone marrow suppression. They also have diminished endogenous sEPO production for their degree of anemia.
Subject(s)
Anemia/blood , Antiviral Agents/administration & dosage , Erythropoietin/blood , Hepatitis C, Chronic/drug therapy , Interferon-alpha/administration & dosage , Polyethylene Glycols , Ribavirin/administration & dosage , Anemia/chemically induced , Antiviral Agents/adverse effects , Dose-Response Relationship, Drug , Drug Therapy, Combination , Female , Hemoglobins/analysis , Humans , Interferon alpha-2 , Interferon-alpha/adverse effects , Male , Middle Aged , Recombinant Proteins , Ribavirin/adverse effectsABSTRACT
This prospective, open-label, multicenter trial evaluated the effects of once-weekly (qw) epoetin alfa on quality of life (QOL) and hemoglobin (Hb) levels in anemic human immunodeficiency virus (HIV)-infected adult receiving antiretroviral therapy. A total of 650 patients with Hb < or = 11 g/dl received epoetin alfa 40,000 U qw subcutaneously, with dose escalation to 60,000 qw if Hb increase was <1 g/dl after 4 weeks. The linear Analog Scale Assessment (LASA) overall QOL score, LASA energy score, and LASA activity score each significantly improved from baseline to final measurement (p < 0.0001 for each parameter). Improvements in the Medical Outcomes Study (MOS)-HIV physical and mental health summary scores were also significant (p < 0.0001), and coincided with Hb increases. Mean Hb increased from baseline to final measurement by 2.5 g/dl (95% CI: 2.3, 2.6 g/dl; p < 0.0001). Objective hematological response rate, defined as a > or = 1 g/dl Hb increase from baseline to week 8, was 86%. Hemoglobin increased significantly in all subgroups of race, zidovudine use, CD4+ cell count, and viral load. Once-weekly epoetin alfa was well tolerated. Once-weekly epoetin alfa is effective in improving QOL and Hb measures.
Subject(s)
Anemia/drug therapy , Erythropoietin/administration & dosage , HIV Infections/complications , Hematinics/administration & dosage , Hemoglobins/analysis , Quality of Life , Adult , Aged , Anemia/etiology , Antiretroviral Therapy, Highly Active , Combined Modality Therapy , Epoetin Alfa , Erythropoietin/therapeutic use , Female , HIV Infections/drug therapy , Hematinics/therapeutic use , Humans , Male , Middle Aged , Recombinant Proteins , Treatment OutcomeABSTRACT
HIV-associated sensory neuropathy (HIV-SN) is the most common neurological complication of HIV infection. Presently, there are no effective therapies for this painful neuropathy. The pathology of HIV-SN is characterized by 'dying back' sensory axonal degeneration and a more modest loss of dorsal root ganglion (DRG) sensory neurons. It has been hypothesized that HIV-SN results from neurotoxicity by secreted viral proteins, such as the HIV envelope glycoprotein gp120. Furthermore, neurotoxicity by dideoxynucleoside (DDX) agents, results in the observed higher incidence of HIV-SN in HIV-infected patients taking these antiretroviral drugs. In this study we show that administration of picomolar amounts of the hormone erythropoietin (EPO) prevents sensory axonal degeneration and in vitro DRG neuronal death by both gp120 and ddC (a neurotoxic DDX drug). Our results suggest that EPO may be useful in the treatment of HIV-SN.
Subject(s)
Erythropoietin/pharmacology , HIV-1/drug effects , Neuroprotective Agents/pharmacology , Polyneuropathies/prevention & control , Animals , Cells, Cultured , Dose-Response Relationship, Drug , Erythropoietin/therapeutic use , Ganglia, Spinal/drug effects , Ganglia, Spinal/physiology , HIV Infections/drug therapy , HIV-1/physiology , Neuroprotective Agents/therapeutic use , Polyneuropathies/virology , Rats , Rats, Sprague-DawleyABSTRACT
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 < or = 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.