Mortality among opiate users: opioid maintenance therapy, age and causes of death

Aims   This study investigates how age of opioid users is related to causes of death prior to, during and after opioid maintenance treatment (OMT), and estimates risks of death from various causes in relation to age.
Design, setting and participants   Data on all opiate dependents in Norway (1997–2003) who applied for and were accepted for OMT ( n  = 3789) were cross-linked with the Norwegian death register. The total observation time was 10 934 person-years.
Findings   A total of 213 deaths was recorded. Of these, 73% were subject to autopsy, and causes of death were known for 208 cases: the overall death rate was 1.9%. Deaths were due to drug overdose (54%), somatic (32%) and traumatic causes (14%). Overdose deaths among all age groups were reduced during OMT but age had a differential effect upon risk when out of treatment. Younger opioid users were at greater risk of overdose before entering treatment; older users were at greater risk after leaving treatment. Older OMT patients were at higher risk of both somatic and traumatic deaths, and deaths during OMT were most likely to be due to somatic causes.
Conclusions   The high rates of overdose prior to and after treatment emphasize the need to provide rapid access to OMT, to retain patients in treatment and to re-enrol patients. The high prevalence among older patients of deaths due to somatic causes has implications for screening, treatment and referral, and may also lead to increased treatment costs.     

The effectiveness of opioid maintenance treatment in prison settings: a systematic review

Aims To review evidence on the effectiveness of opioid maintenance treatment (OMT) in prison and post‐release. Methods Systematic review of experimental and observational studies of prisoners receiving OMT regarding treatment retention, opioid use, risk behaviours, human immunodeficiency virus (HIV)/hepatitis C virus (HCV) incidence, criminality, re‐incarceration and mortality. We searched electronic research databases, specialist journals and the EMCDDA library for relevant studies until January 2011. Review conducted according to Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines. Results Twenty‐one studies were identified: six experimental and 15 observational. OMT was associated significantly with reduced heroin use, injecting and syringe‐sharing in prison if doses were adequate. Pre‐release OMT was associated significantly with increased treatment entry and retention after release if arrangements existed to continue treatment. For other outcomes, associations with pre‐release OMT were weaker. Four of five studies found post‐release reductions in heroin use. Evidence regarding crime and re‐incarceration was equivocal. There was insufficient evidence concerning HIV/HCV incidence. There was limited evidence that pre‐release OMT reduces post‐release mortality. Disruption of OMT continuity, especially due to brief periods of imprisonment, was associated with very significant increases in HCV incidence. Conclusions Benefits of prison OMT are similar to those in community settings. OMT presents an opportunity to recruit problem opioid users into treatment, to reduce illicit opioid use and risk behaviours in prison and potentially minimize overdose risks on release. If liaison with community‐based programmes exists, prison OMT facilitates continuity of treatment and longer‐term benefits can be achieved. For prisoners in OMT before imprisonment, prison OMT provides treatment continuity.     

The effect of time spent in treatment and dropout status on rates of convictions,cautions and imprisonment over 5 years in a primary care‐led methadone maintenance service

Background Methadone maintenance treatment (MMT) in primary care settings is used increasingly as a standard method of delivering treatment for heroin users. It has been shown to reduce criminal activity and incarceration over periods of periods of 12 months or less; however, little is known about the effect of this treatment over longer durations. Aims To examine the association between treatment status and rates of convictions and cautions (judicial disposals) over a 5‐year period in a cohort of heroin users treated in a general practitioner (GP)‐led MMT service. Design Cohort study. Setting The primary care clinic for drug dependence, Sheffield, 1999–2005. Participants The cohort comprised 108 consecutive patients who were eligible and entered treatment. Ninety were followed‐up for the full 5 years. Intervention The intervention consisted of MMT provided by GPs in a primary care clinic setting. Measurements Criminal conviction and caution rates and time spent in prison, derived from Police National Computer (PNC) criminal records. Findings The overall reduction in the number of convictions and cautions expected for patients entering MMT in similar primary care settings is 10% for each 6 months retained in treatment. Patients in continuous treatment had the greatest reduction in judicial disposal rates, similar to those who were discharged for positive reasons (e.g. drug free). Patients who had more than one treatment episode over the observation period did no better than those who dropped out of treatment. Conclusions MMT delivered in a primary care clinic setting is effective in reducing convictions and cautions and incarceration over an extended period. Continuous treatment is associated with the greatest reductions.     

Prevalence and clinical relevance of corrected QT interval prolongation during methadone and buprenorphine treatment: a mortality assessment study

Aims To determine the prevalence of corrected QT interval (QTc) prolongation among patients in opioid maintenance treatment (OMT) and to investigate mortality potentially attributable to QTc prolongation in the Norwegian OMT programme. Participants and setting Two hundred OMT patients in Oslo were recruited to the QTc assessment study between October 2006 and August 2007. The Norwegian register of all patients receiving OMT in Norway (January 1997–December 2003) and the national death certificate register were used to assess mortality. Mortality records were examined for the 90 deaths that had occurred among 2382 patients with 6450 total years in OMT. Design and measures The QTc interval was assessed by electrocardiography (ECG). All ECGs were examined by the same cardiologist, who was blind to patient history and medication. Mortality was calculated by cross‐matching the OMT register and the national death certificate register: deaths that were possibly attributable to QTc prolongation were divided by the number of patient‐years in OMT. Findings In the QTc assessment sample (n = 200), 173 patients (86.5%) received methadone and 27 (13.5%) received buprenorphine. In the methadone group, 4.6% (n = 8) had a QTc above 500 milliseconds; 15% (n = 26) had a QTc interval above 470 milliseconds; and 28.9% (n = 50) had a QTc above 450 milliseconds. All patients receiving buprenorphine (n = 27) had QTc results <450 milliseconds. A positive dose‐dependent association was identified between QTc length and dose of methadone, and all patients with a QTc above 500 milliseconds were taking methadone doses of 120 mg or more. OMT patient mortality, where QTc prolongation could not be excluded as the cause of death, was 0.06/100 patient‐years. Only one death among 3850 OMT initiations occurred within the first month of treatment. Conclusion Of the methadone patients, 4.6% had QTc intervals above 500 milliseconds. The maximum mortality attributable to QTc prolongation was low: 0.06 per 100 patient‐years.     

A randomized clinical trial of methadone maintenance for prisoners: findings at 6 months post-release

AIMS: This study examined the effectiveness of methadone maintenance initiated prior to or just after release from prison at 6 months post-release. DESIGN: A three-group randomized controlled trial was conducted between September 2003 and June 2005. SETTING: A Baltimore pre-release prison. PARTICIPANTS: Two hundred and eleven adult pre-release inmates who were heroin-dependent during the year prior to incarceration. INTERVENTION: Participants were assigned randomly to the following: counseling only: counseling in prison, with passive referral to treatment upon release (n = 70); counseling + transfer: counseling in prison with transfer to methadone maintenance treatment upon release (n = 70); and counseling + methadone: methadone maintenance and counseling in prison, continued in a community-based methadone maintenance program upon release (n = 71). MEASUREMENTS: Addiction Severity Index at study entry and follow-up. Additional assessments at 6 months post-release were treatment record review; urine drug testing for opioids, cocaine and other illicit drugs. FINDINGS: Counseling + methadone participants were significantly more likely than both counseling only and counseling + transfer participants to be retained in drug abuse treatment (P = 0.0001) and significantly less likely to have an opioid-positive urine specimen compared to counseling only (P = 0.002). Furthermore, counseling + methadone participants reported significantly fewer days of involvement in self-reported heroin use and criminal activity than counseling only participants. CONCLUSIONS: Methadone maintenance, initiated prior to or immediately after release from prison, increases treatment entry and reduces heroin use at 6 months post-release compared to counseling only. This intervention may be able to fill an urgent treatment need for prisoners with heroin addiction histories.     

Pilot randomized double blind placebo-controlled study of dexamphetamine for cocaine dependence

Aims To establish the feasibility of conducting a placebo‐controlled clinical trial of dexamphetamine replacement therapy for cocaine dependence and to obtain preliminary data. Design Double‐blind randomized placebo‐controlled trial. Participants Thirty cocaine‐dependent injecting drug users. Intervention Subjects were assigned randomly to receive 60 mg/day dexamphetamine (n = 16) or placebo (n = 14) for 14 weeks. Measurements Immunoassay and mass spectrometric techniques were used to identify cocaine metabolites in urine. Subjects were screened using the Composite International Diagnostic Interview and DSM‐IV. The Opiate Treatment Index, Brief Symptom Inventory, Severity of Dependence Scale and visual analogue craving scales were used to collect pre‐ and post‐self‐report data. Findings Treatment retention was equivalent between groups; however, outcomes favoured the treatment group with no improvements observed in the placebo control group. The proportion of cocaine‐positive urine samples detected in the treatment group declined from 94% to 56% compared to no change in the placebo group (79% positive). While the improvements were not significant between groups, within‐group analysis revealed that the treatment group reduced self‐reported cocaine use (P = 0.02), reduced criminal activity (P = 0.04), reduced cravings (P < 0.01) and reduced severity of cocaine dependence (P < 0.01) with no within‐group improvements found in the placebo group. Conclusions A definitive evaluation of the utility of dexamphetamine in the management of cocaine dependence is feasible and warranted.     

Neonatal outcomes after fetal exposure to methadone and buprenorphine: national registry studies from the Czech Republic and Norway

Background and Aims

Opioid maintenance treatment (OMT) is recommended to opioid‐dependent females during pregnancy. However, it is not clear which medication should be preferred. We aimed to compare neonatal outcomes after prenatal exposure to methadone (M) and buprenorphine (B) in two European countries.

Design

Nation‐wide register‐based cohort study using personalized IDs assigned to all citizens for data linkage.

Setting

The Czech Republic (2000–14) and Norway (2004–13). [Correction added after online publication on 26 April 2018: The Czech Republic (2000–04) corrected to (2000–14).]

Participants

Opioid‐dependent pregnant Czech (n = 333) and Norwegian (n = 235) women in OMT who received either B or M during pregnancy and their newborns.

Measurements

We linked data from health registries to identify the neonatal outcomes: gestational age, preterm birth, birth weight, length and head circumference, small for gestational age, miscarriages and stillbirth, neonatal abstinence syndrome (NAS) and Apgar score. We performed multivariate linear regression and binary logistic regression to explore the associations between M and B exposure and outcomes. Regression coefficient (β) and odds ratio (OR) were computed.

Findings

Most neonatal outcomes were more favourable after exposure to B compared with M, but none of the differences was statistically significant. For instance, in the multivariate analysis, birth weight was β = 111.6 g [95% confidence interval (CI) = ?10.5 to 233.6 and β = 83.1 g, 95% CI = ?100.8 to 267.0] higher after B exposure in the Czech Republic and Norway, respectively. Adjusted OR of NAS for B compared with M was 0.94 (95% CI = 0.46–1.92) in the Norwegian cohort.

Conclusions

Two national cohorts of women receiving opioid maintenance treatment during pregnancy showed small but not statistically significant differences in neonatal outcomes in favour of buprenorphine compared with methadone.

     

HIV risk reduction in outpatient drug abuse treatment: individual and geographic differences.

In the national Drug Abuse Treatment Outcome Studies (DATOS), many clients in outpatient methadone treatment (OMT) and outpatient drug-free (ODF) modalities were admitted with multiple sex and needle-risk behaviors, but they reduced these risks significantly during treatment. Using hierarchical linear model regression analysis, we examined client and treatment program characteristics as predictors of initial risk levels and of reductions over time. Clients who used cocaine frequently before treatment or had antisocial personality disorder entered treatment with elevated risks. In both modalities, cocaine users reduced risky behaviors significantly, but antisocial clients did so only in OMT. Treatment programs located in cities with higher prevalence rates of HIV/AIDS admitted clients with lower baseline levels of risk behavior than found in other cities. OMT programs in lower prevalence cities achieved higher rates of risk reduction than programs in higher prevalence cities. Reduction of sex and needle risks in both the OMT and ODF modalities indicates the importance of outpatient drug abuse treatment to national HIV prevention policy.     

Changes in criminal activity after entering methadone maintenance

The impact of different approaches to methadone maintenance on the level of crime committed by heroin addicts was examined in a cohort of addicts entering methadone treatment. The cohort comprises three groups: 72 subjects (group 1) who were approved for treatment and referred to a long-term programme which tolerated continued illicit drug use in treatment; 159 subjects (group 2) who were referred to an abstinence orientated programme from which clients who continued to use heroin were expelled; and 84 subjects who were rejected as unsuitable or failed to complete the assessment process. Official records of convictions were used to calculate conviction rates in thepre- and post-assessment periods. Differences between groups in conviction rates for drug and property crimes were analysed using Poisson regression. Three variables—age, sex and age of first criminal conviction—were significant predictors of conviction rates and all analyses controlled for these variables. Most of the rejected subjects entered treatment during the study period and it was, therefore, not possible to interpret differences between treated and untreated subjects. Among those who entered treatment, property offence rates actually rose, due to a significant increase in conviction rates in group 2. Subjects in group 1 were retained significantly longer in treatment than those in group 2. Among those who remained in treatment less than 12 months, most offences occurred after leaving treatment. When conviction rates were adjusted for time spent in treatment, the differences between the clinics disappeared. Remaining in treatment in either clinic was associated with a progressive reduction in the rate of convictions; for each year of treatment, the adjusted rate of property offences fell by a factor of 0.69 [95% Cl (0.62, 0.78)]. Retention in treatment, rather than entry to treatment, is the key to reducing the criminal involvement of addicts. Programmes with low retention are less effective in achieving this goal. To be most effective, methadone programmes should be orientated towards encouraging clients to remain in treatment.     

Treatment outcomes among a cohort of African American buprenorphine patients: Follow-up at 12 months

Background: Although buprenorphine/naloxone (bup/nal) is well-established as a safe and effective treatment for opioid use disorders (OUDs), there are few studies reporting 12-month outcomes of patients receiving bup/nal in formerly drug-free outpatient programs. Objectives: To examine 12-month outcomes by bup/nal treatment enrollment status among a cohort of African American patients enrolled in a clinical trial. Methods: This analysis builds upon a randomized trial of 300 opioid-dependent African American bup/nal patients in two outpatient programs in Baltimore, MD. A subset of participants (N = 133, n = 47 female) were tracked for a 12-month follow-up interview. Results: The participants receiving bup/nal at 12 months had significantly fewer opioid-positive urine screens (44% v. 73%) and days of self-reported heroin use (M [SE] = 1.13 [.34] v. 7.12 [1.44]) than the out-of-bup/nal-treatment group (both ps ≤ .001). Similarly, those receiving bup/nal reported significantly fewer days of cocaine use (M [SE] = 0.85 [0.23] v. 2.88[0.75]) and alcohol use (M [SE] = 1.44 [0.38] v. 3.69 [1.04]; both ps<.05). There were no significant differences related to criminal activity, quality of life, and most ASI composite scores. Models adjusting for the baseline value, prior treatment experience, and assigned study condition largely confirmed these findings, except that participants in treatment had fewer days of crime and higher psychological quality of life scores compared to those out-of-treatment. Conclusions: Those receiving bup/nal at 12 months had significantly lower rates of illicit opioid use than those who were not. Approaches to improve bup/nal treatment retention and reengagement of patients with OUD are needed.     

Topiramate for the treatment of methamphetamine addiction: a multi-center placebo-controlled trial

Aims Topiramate has shown efficacy at facilitating abstinence from alcohol and cocaine abuse. This double‐blind, placebo‐controlled out‐patient trial tested topiramate for treating methamphetamine addiction. Design Participants (n = 140) were randomized to receive topiramate or placebo (13 weeks) in escalating doses from 50 mg/day to the target maintenance of 200 mg/day in weeks 6–12 (tapered in week 13). Medication was combined with weekly brief behavioral compliance enhancement treatment. Setting The trial was conducted at eight medical centers in the United States. Participants One hundred and forty methamphetamine‐dependent adults took part in the trial. Measurements The primary outcome was abstinence from methamphetamine during weeks 6–12. Secondary outcomes included use reduction versus baseline, as well as psychosocial variables. Findings In the intent‐to‐treat analysis, topiramate did not increase abstinence from methamphetamine during weeks 6–12. For secondary outcomes, topiramate reduced weekly median urine methamphetamine levels and observer‐rated severity of dependence scores significantly. Subjects with negative urine before randomization (n = 26) had significantly greater abstinence on topiramate versus placebo during study weeks 6–12. Topiramate was safe and well tolerated. Conclusions Topiramate does not appear to promote abstinence in methamphetamine users but can reduce the amount taken and reduce relapse rates in those who are already abstinent.     

Predictors of treatment in acute coronary syndromes in the elderly: Impact on Decision Making and Clinical Outcome After Interventional Versus Conservative Treatment

Background: Management of elderly patients with acute coronary syndromes (ACS) is not standardized and physicians discretion for invasive versus conservative strategies lacks sufficient evidence. The purpose of this analysis was, therefore, to evaluate treatment strategies and outcomes of elderly patients with ACS and to highlight reasons for the treatment decision in a consecutive series of elderly patients. Methods: This is a retrospective analysis of 1,001 elderly patients (>75 years) presenting with ACS. Patients were identified on the basis of their final discharge diagnosis. Baseline data, past medical history, cardiac and noncardiac concomitant diseases, treatment strategy, and adverse outcomes were evaluated, using patient's charts. Various co‐variates were used to determine the association or predictive value of these co‐variates to the invasive versus conservative management of the subjects. Thirty‐day mortality and long‐term survival were assessed either directly or in discharged patients via telephone interview with the patients, the patients' relatives or the primary care physicians. Results: A total of 776 (77.5%) patients were treated invasively and 225 (22.5%) conservatively. Logistic regression analysis revealed that patients with advanced age, Killip class > II, pre‐existing coronary artery disease, prior stroke, pre‐existing renal failure, obesity, non‐ST‐elevation myocardial infarction, prior ACS, and the presence of supraventricular arrhythmias were significantly more likely to undergo conservative treatment. In‐hospital mortality was significantly higher in conservatively treated patients (P < 0.001). Conclusion: In this retrospective analysis, we identified age as the main predictor for a conservative treatment strategy in elderly patients, albeit an invasive strategy was associated with a significantly better outcome. © 2012 Wiley Periodicals, Inc.     

HIV status and participation in HIV surveillance in the era of antiretroviral treatment: a study of linked population‐based and clinical data in rural South Africa

Objective To examine whether HIV status affects participation in a population‐based longitudinal HIV surveillance in the context of an expanding HIV treatment and care programme in rural South Africa. Method We regressed consent to participate in the HIV surveillance during the most recent fieldworker visit on HIV status (based on previous surveillance participation or enrolment in pre‐antiretroviral treatment (pre‐ART) care or ART in the local HIV treatment and care programme), controlling for sex, age and year of the visit (N = 25 940). We then repeated the regression using the same sample but, in one model, stratifying HIV‐infected persons into three groups (neither enrolled in pre‐ART care nor receiving ART; enrolled in pre‐ART care but not receiving ART; receiving ART) and, in another model, additionally stratifying the group enrolled in pre‐ART and the group receiving ART into those with CD4 count ≤200/μl (i.e. the ART eligibility threshold at the time) vs. those with CD4 count >200/μl. Results HIV‐infected individuals were significantly less likely to consent to participate in the surveillance than HIV‐uninfected individuals [adjusted odds ratio (aOR), 0.74; 95% confidence interval, 0.70–0.79, P < 0.001], controlling for other factors. Persons who were receiving ART were less likely to consent to participate (aOR, 0.75, 0.68–0.84, P < 0.001) than those who had never sought HIV treatment or care (aOR, 0.82, 0.75–0.89, P < 0.001), but more likely to consent than persons enrolled in pre‐ART care (aOR 0.62, 0.56–0.69, P < 0.001). Those with CD4 count ≤200/μl were significantly less likely to consent to participate than those with CD4 count >200/μl in both the group enrolled in pre‐ART and the group receiving ART. Conclusion As HIV test results are not made available to participants in the HIV surveillance, our findings agree with the hypothesis that HIV‐infected persons are less likely than HIV‐uninfected persons to participate in HIV surveillance because they fear the negative consequences of others learning about their HIV infection. Our results further suggest that the increased knowledge of HIV status that accompanies improved ART access can reduce surveillance participation of HIV‐infected persons, but that this effect decreases after ART initiation, in particular in successfully treated patients.     

Substance abuse treatment and criminal justice involvement for SSI recipients: results from Washington state

This study examined the association between receiving substance abuse treatment and subsequent criminal justice involvement. The sample consisted of Supplemental Security Income (SSI) recipients in the state of Washington that were determined to be in need of treatment. Fifty-two percent of those clients entered substance abuse treatment during the study period, while 48% did not. Arrests, felony convictions and convictions for less serious crimes were tracked for 8343 adults for one year following the end of an index treatment episode. Results showed that entering treatment was associated with reduced risks for each outcome. In addition, further analyses were conducted just on those entering treatment. Among that subset of the study population, the completion of treatment and having an episode of treatment lasting at least 90 days were both associated with reduced criminal justice risks. These results suggest that efforts to provide substance abuse treatment for SSI recipients have the potential to provide substantial public benefits.     

Using Behavioral Triage in Court-Supervised Treatment of DUI Offenders

In 2008, San Joaquin County, California, implemented a system change where all repeat Driving Under the Influence (DUI) offenders in the largest judicial district (mainly the City of Stockton) are required to participate in a DUI Monitoring Court program. The program follows a behavioral triage system where offenders are placed into one of two tracks. Track 1 (monitoring) is a less intensive system where participants are required to come to court infrequently to report on progress in completing the terms of their probation, including Department of Motor Vehicle (DMV) requirements, to qualify to get their license returned. Track 2 is for participants who demonstrate through their behavior (i.e., behavioral triage) that they are unable to comply with Track 1 requirements and who are assessed as needing drug and alcohol treatment. Track 2 follows a drug court model. All repeat DUI offenders convicted after 2008 (i.e., program participants) and a comparison group of all repeat DUI offenders convicted in the 2 years prior to program implementation were tracked for 18 months from the time of their DUI conviction. DMV data were used to examine new DUI convictions and traffic accidents for both groups. The results showed that program participants had significantly fewer new DUI convictions, accidents related to drug and alcohol consumption, and accidents resulting in injury. Participants were also significantly more likely to comply with court, probation, and DMV requirements, and to regain their driver's licenses. The model implemented by the San Joaquin DUI Monitoring Court showed substantial promise for increasing public safety by reducing drunk driving and traffic accidents.     

Extended‐release injectable naltrexone for opioid use disorder: a systematic review

Aims

To review systematically the published literature on extended‐release naltrexone (XR‐NTX, Vivitrol^®), marketed as a once‐per‐month injection product to treat opioid use disorder. We addressed the following questions: (1) how successful is induction on XR‐NTX; (2) what are adherence rates to XR‐NTX; and (3) does XR‐NTX decrease opioid use? Factors associated with these outcomes as well as overdose rates were examined.

Methods

We searched PubMed and used Google Scholar for forward citation searches of peer‐reviewed papers from January 2006 to June 2017. Studies that included individuals seeking treatment for opioid use disorder who were offered XR‐NTX were included.

Results

We identified and included 34 studies. Pooled estimates showed that XR‐NTX induction success was lower in studies that included individuals that required opioid detoxification [62.6%, 95% confidence interval (CI) = 54.5–70.0%] compared with studies that included individuals already detoxified from opioids (85.0%, 95% CI = 78.0–90.1%); 44.2% (95% CI = 33.1–55.9%) of individuals took all scheduled injections of XR‐NTX, which were usually six or fewer. Adherence was higher in prospective investigational studies (i.e. studies conducted in a research context according to a study protocol) compared to retrospective studies of medical records taken from routine care (6‐month rates: 46.7%, 95% CI = 34.5–59.2% versus 10.5%, 95% CI = 4.6–22.4%, respectively). Compared with referral to treatment, XR‐NTX reduced opioid use in adults under criminal justice supervision and when administered to inmates before release. XR‐NTX reduced opioid use compared with placebo in Russian adults, but this effect was confounded by differential retention between study groups. XR‐NTX showed similar efficacy to buprenorphine when randomization occurred after detoxification, but was inferior to buprenorphine when randomization occurred prior to detoxification.

Conclusions

Many individuals intending to start extended‐release naltrexone (XR‐NTX) do not and most who do start XR‐NTX discontinue treatment prematurely, two factors that limit its clinical utility significantly. XR‐NTX appears to decrease opioid use but there are few experimental demonstrations of this effect.     

Open‐label study of faldaprevir plus peginterferon and ribavirin in hepatitis C virus genotype 1‐infected patients who failed placebo plus peginterferon and ribavirin

Faldaprevir, a hepatitis C virus (HCV) NS3/4A protease inhibitor, was evaluated in HCV genotype 1‐infected patients who failed peginterferon and ribavirin (PegIFN/RBV) treatment during one of three prior faldaprevir trials. Patients who received placebo plus PegIFN/RBV and had virological failure during a prior trial were enrolled and treated in two cohorts: prior relapsers (n = 43) and prior nonresponders (null responders, partial responders and patients with breakthrough; n = 75). Both cohorts received faldaprevir 240 mg once daily plus PegIFN/RBV for 24 weeks. Prior relapsers with early treatment success (ETS; HCV RNA <25 IU/mL detectable or undetectable at week 4 and <25 IU/mL undetectable at week 8) stopped treatment at week 24. Others received PegIFN/RBV through week 48. The primary efficacy endpoint was sustained virological response (HCV RNA <25 IU/mL undetectable) 12 weeks post treatment (SVR12). More prior nonresponders than prior relapsers had baseline HCV RNA ≥800 000 IU/mL (80% vs 58%) and a non‐CC IL28B genotype (91% vs 70%). Rates of SVR12 (95% CI) were 95.3% (89.1, 100.0) among prior relapsers and 54.7% (43.4, 65.9) among prior nonresponders; corresponding ETS rates were 97.7% and 65.3%. Adverse events led to faldaprevir discontinuations in 3% of patients. The most common Division of AIDS Grade ≥2 adverse events were anaemia (13%), nausea (10%) and hyperbilirubinaemia (9%). In conclusion, faldaprevir plus PegIFN/RBV achieved clinically meaningful SVR12 rates in patients who failed PegIFN/RBV in a prior trial, with response rates higher among prior relapsers than among prior nonresponders. The adverse event profile was consistent with the known safety profile of faldaprevir.     

Daily use of the physio dialysis system: Long‐term experience

Background: Hypovolaemia has been implicated as a major causal factor of morbidity during haemodialysis (HD). In order to avoid the appearance of destabilising hypovolaemia a biofeedback control system for intra‐HD blood volume (BV) change modelling has been developed (Hemocontrol?, Hospal Italy). It is based on an adaptive controller incorporated into a HD machine (Integra?, Hospal Italy). The Hemocontrol? biofeedback system (HBS) monitors BV contraction during HD with an optical device; furthermore, HBS modulates BV contraction rates (by adjusting the ultrafiltration rate — UFR) and the refilling rate (by adjusting dialysate conductivity — DC) in order to obtain the desired pre‐determined BV trajectories. Methods: Nineteen patients prone to hypotension (7 males, 12 females, mean age 64.5 ± 3.0 SEM years, on maintenance HD for 80.5 ± 13.2 months) volunteered for the prospective study which aimed to compare the efficacy and safety of bicarbonate HD treatment equipped with HBS, as a whole (HBS), with the gold standard, bicarbonate treatment, equipped with a constant UFR and DC (BD). The study included one period of 6 months of BD always preceding a follow‐up period of HBS treatment ranging from 14 to 30 months (mean 24.0 ± 1.6). Results: The overall occurrence of symptomatic hypotension and muscle cramps was significantly less in HBS treatment. Self‐evaluation of intra‐ and inter‐HD symptoms (the worst score was 0 and the best one 10) did reveal a statistically significant difference, as far as post‐HD fatigue is concerned (6.2 ± 0.2 in HBS vs. 4.3 ± 0.1 in BD treatment, p < 0.0001). No difference between the two treatments was observed when comparing pre‐ and post‐HD lying blood pressure, heart rate, body weights and body weight changes. Conclusions: HBS is an effective treatment. Hypovolaemia‐associated morbidity occurs less in BD treatment than HBS. Furthermore, HBS is a safe treatment in the medium‐term because these results are achieved without potentially harmful changes in blood pressure, body weight and serum sodium concentration.     

Efficacy of extended-release naltrexone in patients with relatively higher severity of alcohol dependence

Background: Because some literature reviews have suggested that naltrexone’s benefit may be limited to less‐severe alcohol dependence, and exclusively to reduction in heavy drinking rather than abstinence, we examined the efficacy of once per month, injectable extended‐release naltrexone (XR‐NTX 380 mg) in patients with relatively higher severity alcohol dependence. Methods: Post hoc analyses examined data from a multicenter, placebo‐controlled, 24‐week randomized trial of XR‐NTX for alcohol dependence (N = 624). We analyzed treatment effects in alcohol‐dependent patients who had higher baseline severity, as measured by: (i) the Alcohol Dependence Scale (ADS) or (ii) having been medically detoxified in the week before randomization. Efficacy was also examined via the relationship between pretreatment severity indices and reporting at least 4 days of lead‐in abstinence prior to treatment—a major predictor of good outcome in the original study. Results: Higher severity alcohol‐dependent patients, defined by the ADS, when receiving XR‐NTX 380 mg (n = 50) compared with placebo (n = 47), had significantly fewer heavy‐drinking days in‐trial (hazard ratio=0.583; p = 0.0049) and showed an average reduction of 37.3% in heavy‐drinking days compared with 27.4% for placebo‐treated patients (p = 0.039). Among those who had a detoxification just prior to randomization, these reductions were 48.9% (XR‐NTX 380 mg; n = 11) and 30.9% (placebo; n = 15) (p = 0.004). Subjects with at least 4 days of pretreatment abstinence (n = 82) versus those without (n = 542) had significantly higher pretreatment ADS scores (p = 0.002) and were more likely to require detoxification prior to randomization (p < 0.001). Patients with lead‐in abstinence experienced significantly better maintenance of initial and 6‐month abstinence. Conclusions: These secondary analyses support the efficacy of XR‐NTX 380 mg in relatively higher severity alcohol dependence for both reduction in heavy drinking and maintenance of abstinence, with implications for the role of adherence pharmacotherapy.