Evolution of illicit opioid use among people with HIV infection in St Petersburg, Russia, in the period 2004-2015.

OBJECTIVES: In the late 1990s, when the current Russian opioid epidemic began, illicit opioids used in Russia consisted almost exclusively of heroin. The type of opioids used has evolved in the early 21st Century. The objective of this study was to describe the evolution of illicit opioid use among people living with HIV (PLWH) reporting recent opioid use in St Petersburg, Russia. METHODS: We examined baseline data from four research studies conducted in the period 2004-2015 that included PLWH who used opioids [Partnership to Reduce the Epidemic Via Engagement in Narcology Treatment (PREVENT; 2004-2005; n = 17), HIV Evolution in Russia-Mitigating Infection Transmission and Alcoholism in a Growing Epidemic (HERMITAGE; 2007-2010; n = 281), Linking Infectious and Narcology Care (LINC; 2013-2014; n = 119) and Russia Alcohol Research Collaboration on HIV/AIDS (Russia ARCH; 2012-2015; n = 121)] and reported recent use of heroin and other opioids. RESULTS: Although these studies spanned more than a decade, the participants represented similar birth cohorts; the mean age was 24.5 years in 2004 and 33.3 years in 2014. The use of opioid types, however, evolved across cohorts, with the use of any illicit drug other than heroin increasing from 6% [95% confidence interval (CI) 000.2, 29%] in PREVENT (2004-2005) to 30% (95% CI 25, 36%) in HERMITAGE (2007-2010) to 70% (95% CI 61, 78%) in LINC (2013-2014) to 77% (95% CI 68, 84%) in ARCH (2012-2015). Any heroin use consistently decreased over the 10-year period in the cohorts, from 100% (95% CI 80, 100%) in 2004-2005 to 54% (95% CI 44, 63%) in 2012-2015. CONCLUSIONS: Among PLWH who use opioids in St Petersburg, Russia, illicit use of opioids other than heroin appears to be more common than heroin use.

[Anhedonia, depression, anxiety, and craving in opioid dependent patients stabilized on oral naltrexone or naltrexone implant]. / Angedoniia, depressiia, trevoga i vlechenie k upotrebleniiu narkotikov u patsientov s opioidnoi zavisimost'iu pri kursovom lechenii peroral'noi ili implantiruemoi formoi naltreksona.

AIM: To assess the relationship between long-term naltrexone treatment and anxiety, depression and craving in opioid dependent individuals. MATERIAL AND METHODS: Opioid dependent patients (n=306) were enrolled in a three cell (102ss/cell) randomized, double blind, double dummy, placebo-controlled 6-month trial comparing extended release implantable naltrexone with oral naltrexone and placebo (oral and implant). Monthly assessments of affective responses used a Visual Analog Scale for opioid craving, the Beck Depression Inventory, Spielberger Anxiety Inventory, and the Ferguson and Chapman Anhedonia Scales. Between-group outcomes were analyzed using mixed model analysis of variance (Mixed ANOVA) and repeated measures and the post hoc Tukey test. RESULTS AND CONCLUSION: Anhedonia, depression, anxiety, and craving for opiates were elevated at baseline but gradually reduced to normal within the first 1-2 months for patients who remained in treatment and did not relapse. There were no significant between-group differences prior to treatment dropout as well as between those who relapsed and who continued on naltrexone. CONCLUSION: These data do not support concerns that naltrexone treatment of opioid dependence precipitates anhedonia, depression, anxiety or craving for opiates.

CONSTRUCTION OF MOSAIC HBC PARTICLES PRESENTING CONSERVATIVE FRAGMENTS OF M2 PROTEIN AND HEMAGGLUTININ OF INFLUENZA A VIRUS.

Virus-like HBc particles formed as a result of the self-assembly of the nuclear antigen of the hepatitis B virus can be used as a highly immunogenic carrier for the presentation of foreign epitopes when creating recombinant vaccines. We use this vehicle to create influenza vaccines based on the conservative antigens of the influenza virus, the extracellular domain of the transmembrane protein M2 (M2e) and the fragment of the second subunit of hemagglutinin (HA2). Presentation on the surface of HBc particles should improve the immunogenicity of these peptides. Using genetic engineering techniques, we obtained a fusion protein in which the HA2 sequence is attached to the N-terminus of the HBc antigen, and the M2e peptide is included in the immunodominant loop region exposed on the surface of HBc particle. The hybrid protein expressed in Escherichia coli and purified under denaturing conditions formed virus-like HBc particles after refolding in vitro. Refolding of this protein in the presence of a previously denatured HBc antigen carrying no inserts resulted in formation of mosaic virus-like particles. The developed method will allow construction of mosaic HBc particles carrying different target epitopes of the influenza virus by combining the corresponding modified HBc proteins, which opens the possibility of creating vaccines with a wider spectrum of protection.

[A double-blind randomized placebo-controlled study of the efficacy of the combined treatment with naltrexone and guanfacine for relapse prevention in opiate dependence].

OBJECTIVE: Authors studied the effect of α-2-adrenoreceptor agonist guanfacine on replace prevention in opiate addicts. MATERIAL AND METHODS: Three hundred and one recently detoxified opiate addicts were randomized under the double-blind double-dummy conditions into one of four treatment groups: naltrexone 50 mg/day+guanfacine 1 mg/day (N+G), naltrexone+guanfacine placebo (N+GP), naltrexone placebo+guanfacine (NP+G), and double placebo (NP+GP). The primary outcome was retention in treatment. The secondary outcomes were perceived stress (Perceived Stress Scale) and craving. RESULTS: At the end of six months, 20 (26.7%) patients in the N+G group and 15 (19.7%) (p=0.26 to N+G) in N+GP group were retained in treatment compared to 5 (6.7%) in the NP+G group (p=0.002 to N+G group and p=0.017 to N+GP group) and 8 (10.7%) in the double placebo group (p=0.013 to N+G group). There is no significant difference in retention between the N+G group and N+GP group at the end of treatment. CONCLUSION: Guanfacine had significant craving and stress reducing effect. Naltrexone was more effective than placebo for relapse prevention in opioid dependent patients. The efficacy of the combination of naltrexone and guanfacine was comparable to naltrexone alone. Guanfacine moderately reduced both stress and craving.

[Factors influencing recovery in patients with hemoblastoses and candidemia].

UNLABELLED: aim: To study the factors influencing the results of treatment for candidemia (CE) in patients with blood system tumors. SUBJECTS AND METHODS: The investigation enrolled patients with hemoblastoses and CE. 30-day all-cause mortality was analyzed. RESULTS: In an 8-year period (2006-2013), CE was diagnosed in 55 patients (median age, 50 years); there was a preponderance of patients with lymphomas (47%) and acute leukemias (27%). The causative agents of CE were C. albicans (38%), C. parapsilosis (17%), C. krusei (11%), C. guilliermondii (11%), C. lusitaniae (6%), C. tropicalis (6%), C. glabrata (3%), C. famata (3%), C. pelliculosa (3%), and C. kefyr (2%). 30-day all-cause mortality was 43.6%. Recovery was statistically significantly more frequently seen following removal of a central venous catheter (67% versus 13%; p=0.004; odds ratio (OR), 14); after use of an antifungal drug on day 1 of isolation of Candida spp. from blood cultures (62% versus 13%; p=0.01; OR, 12); and that of echocandin as a first-line agent (86% versus 42%; p=0.005; OR, 8.4). The poor predictors were septic shock (5% recovery rate versus 86% in the patients without this factor; p<0.0001; OR, 0.01), granulocytopenia (42% versus 88%; p=0.001; OR, 0.1); use of amphotericin B as a first-line drug (26% versus 71%; p=0.002; OR, 0.15); hemoblastosis recurrence or resistance (39% versus 73%; p=0.01; OR, 0.24). Multivariate analysis showed the positive impact of antifungal administration on day 1 of isolation of Candida spp. from blood cultures on treatment results (p=0.03; OR, 27). CONCLUSION: High mortality rates were noted in the patients with hemoblastoses and CE. The recovery rates were statistically significantly higher after use of echinocandin as a first-line agent, after that of an antifungal agent on day 1 of positive blood cultures, after removal of a central venous catheter, and hemoblastosis remission.

[Naltrexone implant treatment of polydrug dependence]. / Primenenie implanta naltreksona dlia terapii polinarkomanii.

Objective. Recent studies indicate that naltrexone implant may be one of the effective pharmacological treatments for opiate dependence. However, nowadays many of addicts are polydrug dependent. The aim of the study was to evaluate the effectiveness of naltrexone implant in the treatment of opiate and amphetamine polydrug dependence. Material and methods. A 10-week randomized, double-blind, placebo-controlled trial with 100 patients dependent on opiates and amphetamines has been conducted. Subjects were randomized in 1:1 ratio to either naltrexone implant or identically looking placebo formulation group. Primary outcome measures were retention in the study, proportion of drug-free urine samples and improvement in the Clinical Global Impression (CGI) scale. Results. At week 10, the retention was 52% among patients with naltrexone vs. 28% among patients with placebo implant (p=0.01), and the proportion of drug-free urine samples was 38% vs. 16% (p=0.01), respectively. Fifty-six per cent of patients treated with naltrexone implant showed marked improvement on CGI compared with 14% of patients treated with placebo (p<0.001, NNT=3.95%, CI 2-4). Conclusion. Naltrexone implant administration resulted in higher retention in the treatment, decreased heroin and amphetamine use, and improved clinical condition of patients, providing the first evidence on effective pharmacological treatment of this kind of polydrug dependence.

Factors associated with study attrition among HIV-infected risky drinkers in St. Petersburg, Russia.

BACKGROUND: Participant attrition in HIV longitudinal studies may introduce bias and diminish research quality. The identification of participant characteristics that are predictive of attrition might inform retention strategies. OBJECTIVE: The study aimed to identify factors associated with attrition among HIV-infected Russian risky drinkers from the secondary HIV prevention HERMITAGE trial. We examined whether current injection drug use (IDU), binge drinking, depressive symptoms, HIV status nondisclosure, stigma, and lifetime history of incarceration were predictors of study attrition. We also explored effect modification due to gender. METHODS: Complete loss to follow-up (LTFU), defined as no follow-up visits after baseline, was the primary outcome, and time to first missed visit was the secondary outcome. We used multiple logistic regression models for the primary analysis, and Cox proportional hazards models for the secondary analysis. RESULTS: Of 660 participants, 101 (15.3%) did not return after baseline. No significant associations between independent variables and complete LTFU were observed. Current IDU and HIV status nondisclosure were significantly associated with time to first missed visit (adjusted hazard ratio [AHR], 1.39; 95% CI, 1.03-1.87; AHR, 1.38; 95% CI, 1.03-1.86, respectively). Gender stratified analyses suggested a larger impact of binge drinking among men and history of incarceration among women with time to first missed visit. CONCLUSIONS: Although no factors were significantly associated with complete LTFU, current IDU and HIV status nondisclosure were significantly associated with time to first missed visit in HIV-infected Russian risky drinkers. An understanding of these predictors may inform retention efforts in longitudinal studies.

[Injectable extended-release naltrexone for opioid dependence: an open label study of long-term safety and efficacy].

OBJECTIVE: To evaluate efficacy and safety of injectable extended-release naltrexone (XR-NTX, Vivitrol), an opioid receptor antagonist, in the treatment of opioid dependence, we carried out a 1-year open-label extension study. MATERIAL AND METHODS: The study followed the initial 6-month randomized, double-blind, PBO-controlled investigation of XR-NTX, used in dose 380 mg, as a treatment for opioid dependence. The study was conducted at 13 clinical sites in Russia. The main measurements were monthly urine samples (efficacy) and adverse events (safety). RESULTS AND CONCLUSION: The open-label extension included 114 patients (67 continued on XR-NTX and 47 switched from placebo). Overall, 62.3% (95% CI: 52.7%, 71.2%) of patients completed the extension. Urine testing revealed that 50.9% (41.5%, 60.4%) were abstinent from opioids at all assessments during the 1-year open-label phase. Adverse events were reported by 21.1% of patients. Elevations in liver function tests occurred in 16.7% of patients. No severe adverse events were reported. The data obtained demonstrate the long-term safety and efficacy of XR-NTX in opioid dependent patients.

[Immunogenicity of recombinant proteins including ectodomain of M2 influenza virus A].

Two recombinant proteins with three copies of the ectodomain of the conserved influenza protein M2 (M2e) of influenza viruses were developed: A (H1N1)pdm09, A/Kurgan/05/05 (H5N1), and M2e consensus sequence of the human influenza A virus (H1N1, H2N2, H3N2) based on flagellin and core antigen of hepatitis B (HBc). The first recombinant protein comprised flagellin fused to three tandem copies of M2e, the second preparation was based on non-covalent interaction between M2e peptides and HBc. The immunogenicity of two preparations was comparatively tested. A covalent linkage of flagellin with M2e significant increased the immunogenicity of the target antigen compared with non-covalent interaction M2e and HBc. Flagellin as a protein carrier of M2e induced mainly IgG1 subclass, whereas HBc stimulated more balanced Th1/Th2 response. Our study showed a decrease in the viral titers in lung tissues of immunized mice after lethal challenge of A/PR/8/34 (H1N1). The study revealed a possibility to obtain a vaccine preparation with equal immunogenicity both against human influenza viruses and highly pathogenic avian influenza viruses.

History of intimate partner violence is associated with sex work but not sexually transmitted infection among HIV-positive female drinkers in Russia.

This paper assesses the associations between intimate partner violence (IPV) and sexually transmitted infections (STIs) and sexual risks among HIV-positive female drinkers in St Petersburg, Russia. Survey and STI data were analysed from 285 women in HERMITAGE, a secondary prevention study of HIV-positive heavy drinkers. Logistic and Poisson regression analyses assessed associations of IPV with STI and risky sex. Most women (78%) experienced IPV and 19% were STI positive; 15% sold sex. IPV was not significantly associated with STI, but was with selling sex (adjusted odds ratio = 3.56, 95% confidence interval = 1.02-12.43). In conclusion, IPV is common and associated with sex trade involvement among Russian HIV-positive female drinkers.

[Results of treatment for candidemia in patients with blood system tumors].

AIM: To study the etiology, clinical manifestations, risk factors, and results of treatment for candidemia (CE) in patients with blood system tumors. SUBJECTS AND METHODS: The investigation included the patients with CE and hemoblastoses treated at the Hematology Research Center, Ministry of Health of the Russian Federation, in 2006 to 2012. The diagnosis of CE was established according to the single isolation of Candida spp. from blood cultures and the presence of infection symptoms. RESULTS: Over 7 years, CE was diagnosed in 57 patients aged 17 to 77 years (median age 48 years). Among the patients with CE, there was a preponderance of those with lymphomas (54%) and acute leukemias (30%). The pathogens of CE were C. albicans (33%), C. guilliermondii (26%), C. parapsilosis (12%), C. krusei (8%), C. lusitaniae (5%), C. famata (4%), C. tropicalis (4%), C. glabrata (4%), and C. pelliculosa (4%). The major risk factors were polychemotherapy (85%), granulocytopenia (63%), mucosal Candida spp. colonization (82%), the presence of central venous catheter (CVC) (97%), antibiotics (100%), and glucocorticosteroids (70%). The infection occurred with the intake of an antifungal agent in 33% of the patients; 60% had concomitant infections of other etiology. Antifungal agents were given to 52 (91%) patients. Within 30 days after CE diagnosis, 20 (35%) patients died; of them 12 (60%) patients showed tumor progression concurrent with the infection. The cure rate for CE was significantly higher in the use of echinocandin as a first-line drug (92%), in complete or partial remission in hemoblastosis (90%), CVC removal (76%) and in the administration of an antifungal drug on day 1 of detection of positive blood cultures (75%). The cure rate was significantly lower when septic shock developed and a patient was transferred to an intensive care unit (15%), when amphotericin B was used as a first-line drug (45%), when granulocytopenia occurred (53%), or glucocorticoids were given (55%). CONCLUSION: Candida non-albicans constitute a high proportion among the pathogens of CE. A number of risk factors influencing survival rates in CE have been identified. It is crucial to use echinocandin as a first-line agent as soon as possible after isolation of Candida spp. from blood cultures.

[Injectable extended-release naltrexone for opioid dependence: a double-blind, placebo-controlled, multicentre randomized trial].

UNLABELLED: We aimed to assess the efficacy and safety of an injectable, once monthly extended-release formulation of the opioid antagonist naltrexone (XR-NTX) for treatment of patients with opioid dependence after detoxification. Two hundreds and fifty patients with opioid dependence were enrolled into the double-blind, placebo-controlled, randomized, 24-week trial. Patients aged 18 years or over who had inpatient detoxification and 7 days or more off all opioids were enrolled at 13 clinical sites in Russia. We randomly assigned patients (1:1) to either 380 mg XR-NTX (n=124) or placebo (n=126). Participants also received 12 biweekly counseling sessions. The primary endpoint was the response profile for confirmed abstinence during weeks 5-24 assessed by urine drug tests and self report of non-use. Secondary endpoints were self-reported opioid- free days, opioid craving scores, number of days of retention, and relapse to physiological opioid dependence. IN CONCLUSION: XR-NTX represents a new treatment option. XR-NTX in conjunction with psychosocial treatment was more effective for treatment of opioid dependence compare to psychosocial support and placebo.

[The use of different forms of naltrexone in the treatment of opioid dependence].

The authors compared the results of own studies and foreign publications on the use of different formulations of naltrexone (peroral, implantable, injectable) for the remission stabilization and relapse prevention in patients with opioid dependence. Opioid antagonists, in particular naltrexone, are the unique medication for the specific pharmacotherapy of opioid dependence currently approved in the Russian Federation. The main problem that considerably reduces the efficacy and restricts the use of naltrexone in the treatment of opioid dependence is the problem of compliance. Nevertheless, in the double blind randomized placebo-controlled trials, we have demonstrated the higher efficacy of peroral naltrexone for the remission stabilization compared to analogous foreign publications. It might be explained by the cultural specifics of the family in the Russia Federation, in particular, by the possibility to control the treatment by relatives of the patient. However the possibilities of this control are significantly reduced as the patient gets older. Long-acting depot formulations of naltrexone (implantable and injectable) are more effective than peroral ones that allows to solve the problem of compliance and opens new perspectives in the treatment of opiate dependence.

Effect of 5-HT3 receptor antagonist MDL 72222 on behaviors induced by ketamine in rats and mice.

Phencyclidine and ketamine (but not other NMDA channel blockers, such as memantine) produce psychotomimetic effects. Since unlike memantine, phencyclidine-like compounds show no significant affinity at 5-HT(3) receptors, we investigated if behavioral effects of ketamine could be reduced by 5HT(3) receptor blockade. Ketamine (3-40 mg/kg) produced ataxia, stereotypes and diminished exploratory activity in mice, and reduced prepulse inhibition of acoustic startle response, lowered accuracy in fixed consecutive number and in delayed non-matching-to-sample tasks in rats. The 5HT(3) receptor antagonist MDL 72222 (0.3-3 mg/kg) administration did not reverse any of these deficits and exerted no effects on discriminative stimulus properties of ketamine. In the tail suspension test, both ketamine and MDL 72222 produced anti-immobility effects when given alone (50-66 and 3 mg/kg, respectively) and together (12.5-25 and 1 mg/kg). The present data suggest that 5-HT(3) receptor blockade does not reverse the behavioral deficits of ketamine and may even enhance its certain effects, such as the antidepressant-like action.

Pretreatment with morphine potentiates naloxone-conditioned place aversion in mice: effects of NMDA receptor antagonists.

Acute pretreatment with opioid receptor agonists potentiates behavioral effects of opioid antagonists. This phenomenon was suggested to serve as an acute model of opioid dependence. Since antagonists acting at N-methyl-D-aspartate (NMDA) receptors were repeatedly shown to attenuate development, maintenance, and expression of opioid dependence, the present study evaluated the effects of competitive NMDA receptor antagonist, D-CPPene (SDZ EAA 494; 3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphonic acid), and low-affinity channel blocker, 1-amino-3,5-dimethyl adamantane hydrochloride (memantine), on establishment of naloxone-conditioned place aversion in mice that were pre-exposed to morphine. Morphine (20 mg/kg) pretreatment significantly potentiated the ability of naloxone (0.01-0.3 mg/kg) to produce place aversion. The place aversion produced by naloxone (0.1 mg/kg) was attenuated by D-CPPene (1 and 3 mg/kg but not 0.1 or 0.3 mg/kg) when it was administered 3.5 h after morphine (0.5 h prior to conditioning trial with naloxone) but not 0.5 h prior to morphine. Memantine (1-10 mg/kg) had no effect under any treatment condition (0.5 h prior to morphine, simultaneously with morphine, 2 or 3.5 h after morphine). Thus, the ability of NMDA receptor antagonist to affect development and/or expression of morphine dependence may not be a good predictor of their effects on establishment of morphine-potentiated naloxone-conditioned place aversion.

Motor impairment produced by ethanol and site-selective NMDA receptor antagonists in mice: tolerance and cross-tolerance.

Current perspectives on clinical use of N-methyl-D-aspartate (NMDA) receptor antagonists infer acute and repeated administration schedules for management of different pathological states. Development of tolerance and cross-tolerance between different antagonists may significantly affect their clinical effectiveness. Since ethanol was repeatedly demonstrated to act as NMDA receptor antagonist, ethanol use may also have its impact on the effects of NMDA receptor ligands. Using the rotarod test in mice, the present study evaluated development of tolerance and cross-tolerance between ethanol (3.2 g/kg, p.o.), competitive NMDA receptor antagonist, D-CPPene (5.6 mg/kg, i.p.), and low-affinity NMDA receptor channel blocker, memantine (30 mg/kg, i.p.), that were administered for seven days once a day after the daily rotarod training session. Acute tests with ethanol (0.3, 1, 1.7, 3.2 g/kg), D-CPPene (0.3, 1, 3, 5.6 mg/kg) and memantine (1, 3, 10, 30 mg/kg) revealed that (a) each of these drugs dose-dependently disrupted rotarod performance in drug-naive mice; (b) in ethanol- and D-CPPene-treated mice, tolerance was observed to ethanol and D-CPPene but not to memantine; moreover, effects of memantine were even more pronounced in D-CPPene-treated subjects; and (c) repeated memantine administration decreased acute motor impairing effects of ethanol, D-CPPene and memantine. Thus, the history of ethanol use or abuse may influence pharmacological activity of NMDA receptor antagonists and this effect is dependent on type of the NMDA receptor antagonist applied.

[A cytofluorescence study of the peripheral blood in radiation exposure]. / Tsitofliuorestsentnoe issledovanie perifericheskoi krovi pri radiatstionnom vozdeistvii.

The cytofluorescent probing method has shown that the radiation action under sharp irradiation regime in experimental animals and chronic regime in people influences the level of synthetic processes in lymphocytes and granulocytes of peripheral blood, characterized by alpha-index (RNA/DNA). The correlation has been found between alpha-index, survivability, doses. alpha-Index can be used to estimate the radiation biological effects and radiosensitivity testing.