Cost-effectiveness of albumin in the treatment of decompensated cirrhosis in resource-limited healthcare settings.

Background: Human albumin (HA) is an effective adjuvant treatment for patients with cirrhosis developing spontaneous bacterial peritonitis (SBP), hepatorenal syndrome (HRS) and ascites requiring large-volume paracentesis (LVP). However, cost remains a barrier to use, particularly in resource-limited settings. This study aims to assess the cost-effectiveness of HA in patients with cirrhosis with SBP, HRS or ascites requiring LVP in the Indonesian healthcare system as a representative of a resource-limited setting. Methods: Three decision-tree models were developed to assess the cost-effectiveness of (1) antibiotics and HA versus antibiotics alone in patients with SBP, (2) terlipressin and HA versus terlipressin alone in patients with HRS, and (3) LVP and HA versus LVP and gelatine for patients with ascites. Clinical utility and economic inputs were pooled from the available literature. Time horizon was 3 months. Outcomes were expressed as incremental cost-effectiveness ratios (ICER) reported as 2021 IDR per quality-adjusted life year (QALY) (exchange rate June 30, 2021: 1 EUR = 17,245 IDR). Willingness-to-pay thresholds considered were: three times the GDP per capita (199,355,561 IDR/QALY; 11,560 EUR/QALY) and one time the GDP per capita (66,451,854 IDR/QALY; 3853 EUR/QALY). Results: The ICER for antibiotics and HA (versus antibiotics alone) for SBP was 80,562,652 IDR per QALY gained (4672 EUR/QALY). The ICER for terlipressin and HA (versus terlipressin) for HRS was 23,085,004 IDR per QALY gained (1339 EUR/QALY). The ICER for LVP and HA versus LVP and gelatine was 24,569,827 IDR per QALY gained (1425 EUR/QALY). Conclusion: Adjunctive HA may be a cost-effective treatment for SBP, HRS and LVP in resource-limited settings.

Systematic evaluation of augmentation during treatment with ropinirole in restless legs syndrome (Willis-Ekbom disease): results from a prospective, multicenter study over 66 weeks.

The purpose of this study was to evaluate the incidence of augmentation over 66 weeks of treatment with ropinirole in patients with primary restless legs syndrome (RLS). Augmentation is the main complication of long-term dopaminergic treatment of RLS. Despite widespread use of ropinirole in RLS, no studies have prospectively and systematically assessed the incidence of augmentation with its use. The study consisted of 26 weeks of double-blind flexible-dose treatment with ropinirole or placebo, followed by 40 weeks of open-label ropinirole treatment.. Patients had no previous history of augmentation. Potential cases of augmentation were identified with the Structured Interview for the Diagnosis of Augmentation and the Augmentation Severity Rating Scale and through reporting of adverse events. Cases were blindly evaluated by an expert panel using the NIH diagnostic criteria for augmentation. Four hundred and four patients participated in the double-blind study and 269 in the open-label phase, with a discontinuation rate of 42%. IRLS baseline scores improved at the end of the double-blind (DB) phase (mean ± SE) by -15.9 ± 0.76 for ropinirole, by -13.4 ± 0.77 for placebo (P < .05) and by -20.4 ± 0.55 during the open-label phase. The incidence rates of augmentation were 3.5% for ropinirole and <1% for placebo during the DB phase and 3% during the open-label phase. Clinically significant augmentation occurred in 3%, <1%, and 2%, respectively. Discontinuation of treatment occurred in 50% of all patients (7 of 14) with augmentation. The incidence of augmentation was 3.1% higher with ropinirole than with placebo. New patients with first episodes of augmentation continued to cumulate at a stable rate over the duration of this study.

Development and validation of a subjective post sleep diary (SPSD) to assess sleep status in subjects with restless legs syndrome.

OBJECTIVE: To describe the development and psychometric properties of a daily subjective (patient-reported) sleep diary, the Subjective Post Sleep Diary (SPSD), that assesses sleep in relation to Restless Legs Syndrome (RLS). METHODS: In 2008, the SPSD was developed de novo guided by input from 56 individuals in the US with RLS obtained via focus groups and one-on-one cognitive debriefing sessions. The psychometric properties of the SPSD were evaluated among an additional 470 RLS subjects in the US using three different administration routes; the internet only (N=130), an Interactive Voice Response System (IVRS; N=146) only and a hybrid version (internet and/or IVRS; N=194). RESULTS: A 12-item sleep diary assessing the key sleep parameters associated with RLS was developed and shown to have face validity following several rounds of focus groups and cognitive debriefing sessions. The SPSD items had high correlations with other sleep instruments and low correlations with constructs unrelated to sleep, and high known-groups predictive ability. CONCLUSIONS: The Subjective Post Sleep Diary (SPSD) is a short, valid and responsive instrument for measuring RLS-related sleep via the internet, IVRS or a combination of the two modes for US English speakers.

Randomized polysomnography study of gabapentin enacarbil in subjects with restless legs syndrome.

We assessed the efficacy and tolerability of gabapentin enacarbil in the treatment of moderate to severe primary restless legs syndrome and associated sleep disturbance. This was a multicenter, randomized, double-blind, placebo-controlled, 2-period crossover polysomnography study of gabapentin enacarbil 1200 mg or placebo taken once daily. Subjects were randomized 1:1 to a sequence of gabapentin enacarbil:placebo or placebo:gabapentin enacarbil, receiving each treatment for 4 weeks. The primary end point was the mean change from baseline at weeks 4 and 10 (4/10) last observation carried forward in wake time during sleep. The key secondary end point was the mean change from baseline at weeks 4/10 last observation carried forward in periodic limb movements associated with arousal per hour of sleep. Tolerability assessments included adverse events. One hundred thirty-six subjects were randomized (gabapentin enacarbil:placebo, 67; placebo:gabapentin enacarbil, 69), and 114 (gabapentin enacarbil:placebo, 53; placebo:gabapentin enacarbil, 61) completed the study. Gabapentin enacarbil 1200 mg significantly reduced wake time during sleep (mean change from baseline [adjusted mean treatment difference]: -26.0 minutes; P < .0001) and periodic limb movements associated with arousal per hour of sleep (adjusted mean treatment difference: -3.1 periodic limb movements with arousal/hour; P = .002) compared with placebo at weeks 4/10 last observation carried forward. The most commonly reported adverse events were dizziness (gabapentin enacarbil 20%, placebo 2%) and somnolence (gabapentin enacarbil 13%, placebo 2%). Gabapentin enacarbil 1200 mg once daily significantly reduces restless legs syndrome-associated sleep disturbance and periodic limb movements associated with arousal per hour of sleep and is generally well tolerated in adults with moderate to severe primary restless legs syndrome.

Psychometric evaluation and tests of validity of the Medical Outcomes Study 12-item Sleep Scale (MOS sleep).

OBJECTIVE: To validate the psychometric properties of the Medical Outcomes Study (MOS) Sleep Scale in subjects with restless legs syndrome (RLS). METHODS: Data from a clinical trial program involving two Phase III, double-blind, placebo-controlled trials of ropinirole in subjects with moderate-to-severe primary RLS were analyzed. Subjects were assessed on the MOS Sleep Scale at baseline, Weeks 8 and 12. RESULTS: The baseline validation population included 551 subjects on which full longitudinal data are available. Psychometric assessment of four MOS sleep domains revealed satisfactory item convergent validity (r > 0.40) for most items. All domain items in both trials surpassed the standard for item discriminant validity, with no significant floor or ceiling effects. The MOS sleep domain scores showed good internal consistency reliability. Concurrent validity (r = 0.40) was exceeded in correlations between the RLS overall quality-of-life score and sleep problems index II. The clinical validity of the MOS Sleep Scale was demonstrated against self-reported RLS symptoms and clinician-determined severity; changes in MOS Sleep Scale were responsive to improvements in RLS severity, as measured by the Clinical Global Impression-Improvement and Severity-of-Illness scales. CONCLUSION: The MOS Sleep Scale is a reliable, valid tool for assessing changes in the sleep of subjects with moderate-to-severe primary RLS. The somnolence domain failed to relate to clinical severity of RLS, indicating a possible sleep-wake relationship unique to RLS. Use of this scale to evaluate other conditions causing sleep disturbance is supported.

Abacavir and lamivudine fixed-dose combination tablet once daily compared with abacavir and lamivudine twice daily in HIV-infected patients over 48 weeks (ESS30008, SEAL).

BACKGROUND: Abacavir (ABC) and lamivudine (3TC) administered twice daily were compared with an ABC + 3TC fixed-dose combination (Epzicom, Kivexa; EPZ) administered once daily, both in combination with a protease inhibitor (PI) or nonnucleoside reverse transcriptase inhibitor (NNRTI). METHODS: Two hundred sixty HIV-infected subjects with more than 6 months of ABC and 3TC administered twice daily plus a PI or NNRTI with an HIV-1 RNA level less than 400 copies/mL for more than 3 months and a CD4 count greater than 50 cells/mm were randomized 1:1 to ABC + 3TC administered twice daily or EPZ administered once daily. RESULTS: At baseline, median time on ABC and 3TC administered twice daily was 22 months, and median CD4 count and HIV-1 RNA level were 554 cells/mm and <50 copies/mL, respectively. EPZ administered once daily was established as not inferior to ABC + 3TC administered twice daily based on the proportion of nonvirologic failures (confirmed HIV-1 RNA level > or =1265 copies/mL; 90% confidence interval: -3.4 to 6.4; (intent to treat [ITT]: missing [M] = failure [F]). Proportions with an HIV-1 RNA level <50 copies/mL were 81% of those taking EPZ once daily and 82% of those taking ABC + 3TC twice daily at week 48 (ITT: M = F). Virologic failure was rare (2 patients taking the once-daily regimen, 4 patients taking the twice-daily regimen). There was a low incidence of grade 2 through 4 adverse events (AEs) and no drug-related serious AEs or hypersensitivity reactions. CONCLUSIONS: EPZ administered once daily was established as not inferior to ABC + 3TC administered twice daily in a regimen containing an NNRTI or a PI over 48 weeks. A dual-nucleoside backbone of ABC and 3TC administered once or twice daily is effective, durable, and well tolerated.

Induction with abacavir/lamivudine/zidovudine plus efavirenz for 48 weeks followed by 48-week maintenance with abacavir/lamivudine/zidovudine alone in antiretroviral-naive HIV-1-infected patients.

BACKGROUND: The ESS40013 study tested 4-drug induction followed by 3-drug maintenance as initial antiretroviral therapy (ART) to reduce HIV RNA rapidly and then to simplify to an effective yet more convenient and tolerable regimen. METHODS: Four hundred forty-eight antiretroviral-naive adults were treated with abacavir/lamivudine/zidovudine (ABC/3TC/ZDV) and efavirenz (EFV) for the 48-week induction phase. Two hundred eighty-two patients were randomized in a 1:1 ratio to continue ABC/3TC/ZDV+EFV or to simplify to ABC/3TC/ZDV for the 48-week maintenance phase. RESULTS: The baseline median HIV RNA level and CD4 cell count were 5.08 log10 copies/mL (56%>or=100,000 copies/mL) and 210 cells/mm (48% <200 cells/mm), respectively. No significant differences were noted between ABC/3TC/ZDV+EFV and ABC/3TC/ZDV for an HIV RNA level <50 copies/mL (79% vs. 77% [intent to treat (ITT), missing=failure]; P=0.697) or time to treatment failure (P=0.75) at week 96. Drug-related adverse events were more commonly reported for ABC/3TC/ZDV+EFV than for ABC/3TC/ZDV (15% vs. 6%). Improvements in total cholesterol, low-density lipoprotein cholesterol, and triglycerides were observed in the ABC/3TC/ZDV group. Virologic failure occurred in 22 patients during induction and in 24 patients (16 in ABC/3TC/ZDV group and 8 in ABC/3TC/ZDV+EFV group; P=0.134) during maintenance. A greater proportion of patients receiving ABC/3TC/ZDV than ABC/3TC/ZDV+EFV reported perfect adherence at week 96 (88.8% vs. 79.6%; P=0.057). CONCLUSIONS: After induction with ABC/3TC/ZDV+EFV, simplification to ABC/3TC/ZDV alone maintained virologic control and immunologic response, reduced fasting lipids and ART-associated adverse events, and improved adherence.

Pharmacodynamic effects of zidovudine 600 mg once/day versus 300 mg twice/day in therapy-naïve patients infected with human immunodeficiency virus.

STUDY OBJECTIVE: To compare the virologic activity of zidovudine monotherapy administered as 600 mg once/day versus 300 mg twice/day. DESIGN: Phase II, randomized (1:1), open-label study. SETTING: Thirteen medical centers in the United States. PATIENTS: Thirty-two antiretroviral-naive patients infected with human immunodeficiency virus (HIV). INTERVENTION: Patients were administered either zidovudine 600 mg every 24 hours (16 patients) or 300 mg every 12 hours (16 patients) for 13 days. MEASUREMENTS AND MAIN RESULTS: Plasma HIV-1 RNA concentration was measured daily. Study end points were between-group differences in change from baseline of log10-transformed HIV-1 RNA and in rates of viral load decline measured by the slope of HIV-1 RNA over time. At baseline, mean HIV-1 RNA was similar in the once/day and twice/day groups (4.33 and 4.40 log10 copies/ml, respectively). At day 14, a trend toward lower mean reduction in HIV-1 RNA from baseline was observed in the once/day group (-0.585, 95% confidence interval [CI] -0.728 to -0.442 log10 copies/ml) compared with the twice/day group (-0.849, 95% CI -1.067 to -0.630 log10 copies/ml, p=0.056). Viral load reduction also tended to be slower in the once/day group, as indicated by the smaller slope of viral load decline in the once/day group than in the twice/day group during days 1-14 (-0.045 vs -0.065 logic copies/ml/day, p=0.065). Both zidovudine regimens were similarly well tolerated. CONCLUSION: Zidovudine 600 mg once/day has antiviral activity, although less pronounced and more slowly achieved than that seen with zidovudine 300 mg twice/day. No differences were observed between the two treatment groups with respect to safety profile or tolerability