HIV care continuum characteristics among people with opioid use disorder and HIV in Vietnam: baseline results from the BRAVO study.

BACKGROUND: Little is known about patient characteristics that contribute to initiating antiretroviral therapy (ART) and achieving viral suppression among HIV people with opioid use disorder in Vietnam. The primary objective of this analysis was to evaluate associations between participant characteristics and the critical steps in the HIV care continuum of ART initiation and HIV viral suppression among people with opioid use disorder and HIV in Vietnam. METHODS: We assessed baseline participant characteristics, ART status, and HIV viral suppression (HIV RNA PCR < 200 copies/mL) enrolled in a clinical trial of HIV clinic-based buprenorphine versus referral for methadone among people with opioid use disorder in Vietnam. We developed logistic regression models to identify characteristics associated with ART status and HIV viral suppression. RESULTS: Among 283 study participants, 191 (67.5%) were prescribed ART at baseline, and 168 of those on ART (90%) were virally suppressed. Years since HIV diagnosis (aOR = 1.12, 95% CI 1.06, 1.19) and being married (aOR = 2.83, 95% CI 1.51, 5.34) were associated with an increased likelihood of current prescription for ART at baseline. Greater depression symptoms were negatively associated with receipt of ART (aOR = 0.97, 95% CI = (0.94, 0.9963)). In the HIV suppression model, once adjusting for all included covariates, only receipt of ART was associated with viral suppression (aOR = 25.9, 95% CI = (12.5, 53.8). In bivariate analyses, methamphetamine was negatively correlated with ART prescription (p = 0.07) and viral suppression (p = 0.08). CONCLUSION: While fewer than 90% of participants had received ART, 90% of those on ART had achieved HIV viral suppression at baseline, suggesting that interventions to improve uptake of ART in Vietnam are essential for achieving UNAIDS 90-90-90 goals in people who use heroin in Vietnam. Social determinants of health associated with ART and HIV viral suppression suggest that social support may be a key to facilitating both of these steps in the HIV care continuum.

Opioid use disorder and the COVID 19 pandemic: A call to sustain regulatory easements and further expand access to treatment.

We highlight the critical roles that pharmacists have related to sustaining and advancing the changes being made in the face of the current COVID-19 pandemic to ensure that patients have more seamless and less complex access to treatment. Discussed herein is how the current COVID-19 pandemic is impacting persons with substance use disorders, barriers that persist, and the opportunities that arise as regulations around treatments for this population are eased.

Response to direct-acting antiviral therapy among ongoing drug users and people receiving opioid substitution therapy.

BACKGROUND & AIMS: People who inject drugs (PWID) and are on opioid agonist therapy (OAT) might have lower adherence to direct-acting antivirals (DAAs) against hepatitis C virus (HCV) and, therefore, lower rates of sustained virologic response (SVR). Because of this, we compared the SVR rates to interferon-free DAA combinations in individuals receiving OAT and those not receiving OAT in a real-world setting. METHODS: The HEPAVIR-DAA cohort, recruiting HIV/HCV-coinfected patients (NCT02057003), and the GEHEP-MONO cohort (NCT02333292), including HCV-monoinfected individuals, are ongoing prospective multicenter cohorts of patients receiving DAAs in clinical practice. We compared SVR 12 weeks after treatment (SVR12) in non-drug users and PWID, including those receiving or not receiving OAT. Intention-to-treat and per protocol analyses were performed. RESULTS: Overall, 1,752 patients started interferon-free DAA treatment. By intention-to-treat analysis, 778 (95%, 95% CI 93%-96%) never injectors, 673 (92%, 95% CI 89%-93%) PWID not on OAT and 177 (89%, 95% CI 83%-92%) PWID on OAT achieved SVR12 (p = 0.002). SVR12 rates for ongoing drug users (with or without OAT) were 68 (79%) compared with 1,548 (95%) for non-drug users (p <0.001). Among ongoing drug users, 15 (17%) were lost-to-follow-up, and 3 (3.5%) became reinfected. In the per protocol analysis, 97% never injectors, 95% PWID not on OAT and 95% PWID on OAT achieved SVR12 (p = 0.246). After adjustment, ongoing drug use was associated with SVR12 (intention-to-treat) and OAT use was not. CONCLUSIONS: HCV-infected PWID achieve high SVR12 rates with DAAs whether they are on OAT or not, but their response rates are lower than those of patients who never used drugs. This is mainly attributable to more frequent loss to follow-up. Accounting for active drug use during DAA therapy nearly closed the gap in SVR rates between the study groups. LAY SUMMARY: Patients with hepatitis C virus infection who are on opioid agonist therapy can achieve high cure rates with current treatments. The use of illicit drugs during treatment can drive drop-outs and reduce cure rates. However, hepatitis C can be cured in most of those using drugs who complete treatment and follow-up. Clinical trial number: HEPAVIR-DAA cohort, NCT02057003; GEHEP-MONO cohort, NCT02333292.

The rise of the opioid epidemic and hepatitis C-positive organs: A new era in liver transplantation.

The use of hepatitis C virus (HCV)-positive organs in liver transplantation (LT) has increased in the era of direct-acting antiviral therapy. A rising demand for organs, the increased ability to effectively treat HCV infection in the transplant setting, and an unprecedented increase in HCV-positive donors have all contributed to this trend. A recent abrupt rise in opioid use in the United States has resulted in a surge of injection drug use, transmission of HCV, and opioid-related overdose deaths. Geographical areas most affected by the opioid epidemic have experienced a rapid increase in recovery and utilization of HCV-positive donor organs, in which the proportion of deceased donor LTs in the United States from donors who are HCV positive has increased nearly 2-fold within the last 3 years. The prospect of expanding the organ donor pool with HCV-positive donors and achieving acceptable posttransplant outcomes has generated much interest in the areas of liver, kidney, and thoracic transplantation, including the potential for transplanting organs from HCV positive donors into HCV-negative recipients. Developing strategies to ensure appropriate selection of potential recipients of HCV-positive organs, initiating timely antiviral therapy, and defining associated risks will be critical in achieving optimal posttransplant outcomes in this setting. (Hepatology 2018;67:1600-1608).

Chronic hepatitis C in Swedish subjects receiving opiate substitution therapy--factors associated with advanced fibrosis.

BACKGROUND: Opiate substitution therapy (OST) reduces the risk of death from directly drug-related causes in heroin users, allowing other chronic health problems to emerge. People who inject drugs (PWID) are exposed to hepatitis C virus (HCV), with an associated risk of chronic liver disease. We investigated HCV prevalence and liver-related morbidity in a cohort of OST recipients, and analyzed factors associated with significant hepatic fibrosis. METHODS: All patients registered on 1 April 2008 in 4 clinics providing OST in the 3 largest cities in Sweden were eligible for inclusion. HCV viremic subjects were evaluated for fibrosis stage by liver biopsy, transient elastometry (TE), and/or a biochemical fibrosis index (Göteborg University Cirrhosis Index; GUCI). Factors associated with severity of fibrosis were determined by logistic regression analysis. RESULTS: Out of 524 eligible patients, 277 consented to enrolment. Two hundred and thirty-six subjects (88%) were anti-HCV-positive, and 162 of these were viremic (69%). Significant liver fibrosis (defined as Ishak stages F3-F6, TE value ≥ 8.85 kPa, or GUCI > 0.33) was found in 69 out of 103 (67%) tested viremic patients, and was associated with alcohol intake (p = 0.03), higher body mass index (BMI; p = 0.04), and the presence of anti-HBc antibodies (indicating exposure to hepatitis B virus (HBV); p = 0.02). CONCLUSIONS: Significant liver fibrosis was detected in two-thirds of HCV viremic OST recipients in this cohort, and was associated with alcohol use, high BMI, and exposure to HBV. These findings indicate that the management of HCV and associated risk factors should be emphasized in Swedish OST programs.

Effects of HCV seropositive status on buprenorphine pharmacokinetics in opioid-dependent individuals.

BACKGROUND AND OBJECTIVES: The purpose of this study was to examine the effect of hepatitis C virus (HCV) infection on buprenorphine pharmacokinetics in opioid-dependent, buprenorphine/naloxone-maintained adults. METHODS: A retrospective analysis of buprenorphine pharmacokinetics in HCV seropositive and seronegative buprenorphine/naloxone-maintained individuals (N = 49) was undertaken. RESULTS: Relative to HCV seronegative subjects, HCV seropositive subjects had higher buprenorphine exposure, as demonstrated by elevated buprenorphine AUC and Cmax values (p = .03 and .02, respectively) and corresponding elevations in the metabolites, buprenorphine-3-glucuronide AUC values (p = .03) and norbuprenorphine-3-glucuronide AUC and C24 values (p = .05 and .03, respectively). DISCUSSION AND CONCLUSIONS: HCV infection was associated with higher plasma concentrations of buprenorphine and buprenorphine metabolites. SCIENTIFIC SIGNIFICANCE AND FUTURE DIRECTIONS: Findings suggest the potential for opioid toxicity among HCV-infected patients treated with buprenorphine/naloxone, and possible hepatotoxic effects related to increased buprenorphine exposure. HCV-infected patients receiving buprenorphine may need lower doses to maintain therapeutic plasma concentrations.

Risk of QTc prolongation in a cohort of opioid-dependent HIV-infected patients on methadone maintenance therapy.

BACKGROUND: Concern regarding the QTc interval in human immunodeficiency virus (HIV)-infected patients has been growing in recent years, and cases of prolonged QTc interval and torsades de pointes have been described in HIV-infected patients on methadone therapy. This study aimed to determine the prevalence and factors associated with long QTc interval in a cohort of opioid-dependent HIV-infected patients on methadone maintenance therapy. METHODS: A cross-sectional study was conducted in opioid-dependent HIV-infected patients on methadone maintenance therapy at a drug abuse outpatient center. Patients with any cardiac disease, drug-positive urine test, electrolyte abnormalities, and changes in their antiretroviral therapy (ART) or methadone doses in the last 2 months were excluded. Heart rate and QT interval in lead II were measured using the Bazett formula. RESULTS: Ninety-one patients were included: 58 (63.7%) were men with a median age of 44.5 years and 68 of 91 (74.7%) were on ART. Median methadone dose was 70 mg/day (range 15-250 mg/day) and mean QTc interval was 438 ± 34 ms. Prolonged QTc interval (>450 ms) was documented in 33 of 91(36.3%) patients, and 3 of 91 (3.2%) had QTc >500 ms. On multiple linear regression analysis, methadone doses (P = .005), chronic hepatitis C-induced cirrhosis (P = .008), and being ART-naive (P = .036) were predictive of prolonged QTc. CONCLUSIONS: The prevalence of prolonged QTc interval in opioid-dependent HIV-infected patients on methadone maintenance therapy is high. Risk factors for prolongation of the QTc interval are chronic hepatitis C-induced cirrhosis, higher methadone doses, and being ART-naive. Thus, electrocardiographic monitoring is required to minimize cardiovascular morbidity and mortality in this specific HIV group.

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

BACKGROUND: Opioid dependence is associated with low rates of treatment-seeking, poor adherence to treatment, frequent relapse, and major societal consequences. We aimed to assess the efficacy, safety, and patient-reported outcomes of an injectable, once monthly extended-release formulation of the opioid antagonist naltrexone (XR-NTX) for treatment of patients with opioid dependence after detoxification. METHODS: We did a double-blind, placebo-controlled, randomised, 24-week trial of patients with opioid dependence disorder. Patients aged 18 years or over who had 30 days or less of 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 or placebo by an interactive voice response system, stratified by site and gender in a centralised, permuted-block method. Participants also received 12 biweekly counselling sessions. Participants, investigators, staff , and the sponsor were masked to treatment allocation. The primary endpoint was the response profile for confirmed abstinence during weeks 5­24, 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. Analyses were by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00678418. FINDINGS: Between July 3, 2008, and Oct 5, 2009, 250 patients were randomly assigned to XR-NTX (n=126) or placebo (n=124). The median proportion of weeks of confirmed abstinence was 90·0% (95% CI 69·9­92·4) in the XR-NTX group compared with 35·0% (11·4­63·8) in the placebo group (p=0·0002). Patients in the XR-NTX group self-reported a median of 99·2% (range 89·1­99·4) opioid-free days compared with 60·4% (46·2­94·0) for the placebo group (p=0·0004). The mean change in craving was ­10·1 (95% CI ­12·3 to ­7·8) in the XR-NTX group compared with 0·7 (­3·1 to 4·4) in the placebo group (p<0·0001). Median retention was over 168 days in the XR-NTX group compared with 96 days (95% CI 63­165) in the placebo group (p=0·0042). Naloxone challenge confirmed relapse to physiological opioid dependence in 17 patients in the placebo group compared with one in the XR-NTX group (p<0·0001). XR-NTX was well tolerated. Two patients in each group discontinued owing to adverse events. No XR-NTX-treated patients died, overdosed, or discontinued owing to severe adverse events. INTERPRETATION: XR-NTX represents a new treatment option that is distinct from opioid agonist maintenance treatment. XR-NTX in conjunction with psychosocial treatment might improve acceptance of opioid dependence pharmacotherapy and provide a useful treatment option for many patients. FUNDING: Alkermes.

Hepatitis C viremia and genotype distribution among a sample of nonmedical prescription drug users exposed to HCV in rural Appalachia.

Research has demonstrated that hepatitis C (HCV) genotype distribution varies geographically and demographically. This exploratory study examines HCV viremia, viral concentration, and genotype distribution among anti-HCV positive, rural Appalachian nonmedical prescription drug users. The study population was randomly selected from a pool of 200 anti-HCV positive participants in a longitudinal study. Those randomly chosen were representative of the overall pool in terms of demographics, drug use, and other risk behaviors. Participants were tested serologically for HCV RNA, viral concentration, and genotype, and interview-administered questionnaires examined behavioral and demographic characteristics. Of the 81 participants, 69% tested RNA positive, 59% of which had viral loads exceeding 800,000 IU/ml. Approximately 66% of the RNA positive sample had genotype 1a; types 2b (16%) and 3a (13%) were less common. RNA positive participants were not significantly different than RNA negative participants demographically or behaviorally. Likewise, with the exception of education, genotype 1 participants were not significantly different than those with genotype 2 or 3. The prevalence of active HCV infection highlights a need for prevention and treatment in this population. However, the predominance of genotype 1 may present challenges due to its association with decreased responsiveness to drug treatment, although the novel class of direct-acting antivirals such as telaprevir and boceprevir offer new hope in this regard. The prevalence of genotype 1 may also foreshadow heightened burden of hepatocellular carcinoma and elevated healthcare expenditures. More research is needed to characterize HCV infection and genotype in this population.

Impact of opiate addiction on neuroinflammation in HIV.

To investigate the independent and interactive effects of opiate addiction and HIV on neuroinflammation, we measured microglial/macrophage activation and astrogliosis in multiple regions of human brain. Samples of thalamus, frontal gray matter, and frontal white matter were obtained from 46 individuals categorized as: HIV negatives, HIV-negative opiate addicts, HIV positives, HIV-positive opiate addicts, HIV encephalitis (HIVE), and HIVE opiate addicts. Activated brain microglia/macrophages and astrocytosis were quantified by morphometric analysis of immunohistochemical stains for CD68, HLA-D, CD163, and GFAP. The effects of HIV grouping, opiate addiction, and their interaction on expression of the markers were examined in a series of two-way ANOVAs. In opiate addicts, there was generally higher baseline expression of CD68 and HLA-D in HIV negatives, and lower expression in HIV and HIVE, compared to individuals without opiate abuse. Thus, for these markers, and for GFAP in frontal gray, opiates were associated with attenuated HIV effect. In contrast, for CD163, opiates did not significantly alter responses to HIV, and HIV effects were variably absent in individuals without opiate abuse. The divergent impact that opiate addiction displays on these markers may suggest a generally immunosuppressive role in the CNS, with decreased HIV-associated activation of markers CD68 and HLA-D that potentially reflect neurotoxic pathways, and preservation of CD163, thought to be an indicator of neuroprotective scavenger systems. These results suggest a complex impact of opiates on neuroinflammation in baseline and virally stimulated states.

Change in HIV-HCV risk-taking behavior and seroprevalence among opiate users seeking treatment over an 11-year period and harm reduction policy.

Our purpose was to assess change in HIV and HCV prevalence and risk-taking behaviors among IDUs over a period of time that included changes in French Public Health policy. Risk behavior and biological testing for serostatus were collected from cross-sectional samples of yearly new requests for opiate dependence treatment in Aquitaine, France between 1994 and 2004 (n = 648). Coincident declines in injection equipment sharing and HIV prevalence among injectors were observed, while sexual behavior remained stable. There was a decline in HCV prevalence that was not significant among injectors. After controlling for potential confounding variables, participants enrolled after 1995 were less likely to share injection material and those enrolled after 1999 were less likely to share spoons. Our findings give evidence for behavioral and seroprevalence changes among IDUs over a period of time that included changes in needle access policy.

Association Between Prescription Opioid Therapy for Noncancer Pain and Hepatitis C Virus Seroconversion.

Importance: Initiation of injection drug use may be more frequent among people dispensed prescription opioid therapy for noncancer pain, potentially increasing the risk of hepatitis C virus (HCV) acquisition. Objective: To assess the association between medically dispensed long-term prescription opioid therapy for noncancer pain and HCV seroconversion among individuals who were initially injection drug use-naive. Design, Setting, and Participants: A population-based, retrospective cohort study of individuals tested for HCV in British Columbia, Canada, with linkage to outpatient pharmacy dispensations, was conducted. Individuals with an initial HCV-negative test result followed by 1 additional test between January 1, 2000, and December 31, 2017, and who had no history of substance use at baseline (first HCV-negative test), were included. Participants were followed up from baseline to the last HCV-negative test or estimated date of seroconversion (midpoint between HCV-positive and the preceding HCV-negative test). Exposures: Episodes of prescription opioid use for noncancer pain were defined as acute (<90 days) or long-term (≥90 days). Prescription opioid exposure status (long-term vs prescription opioid-naive/acute) was treated as time-varying in survival analyses. In secondary analyses, long-term exposure was stratified by intensity of use (chronic vs. episodic) and by average daily dose in morphine equivalents (MEQ). Main Outcomes and Measures: Multivariable Cox regression models were used to assess the association between time-varying prescription opioid status and HCV seroconversion. Results: A total of 382 478 individuals who had more than 1 HCV test were included, of whom more than half were female (224 373 [58.7%]), born before 1974 (201 944 [52.8%]), and younger than 35 years at baseline (196 298 [53.9%]). Participants were followed up for 2 057 668 person-years and 1947 HCV seroconversions occurred. Of the participants, 41 755 people (10.9%) were exposed to long-term prescription opioid therapy at baseline or during follow-up. The HCV seroconversion rate per 1000 person-years was 0.8 among the individuals who were prescription opioid-naive/acute (1489 of 1947 [76.5%] seroconversions; 0.4% seroconverted within 5 years) and 2.1 with long-term prescription opioid therapy (458 of 1947 [23.5%] seroconversions; 1.1% seroconverted within 5 years). In multivariable analysis, exposure to long-term prescription opioid therapy was associated with a 3.2-fold (95% CI, 2.9-3.6) higher risk of HCV seroconversion (vs prescription opioid-naive/acute). In separate Cox models, long-term chronic use was associated with a 4.7-fold higher risk of HCV seroconversion (vs naive/acute use 95% CI, 3.9-5.8), and long-term higher-dose use (≥90 MEQ) was associated with a 5.1-fold higher risk (vs naive/acute use 95% CI, 3.7-7.1). Conclusions and Relevance: In this cohort study of people with more than 1 HCV test, long-term prescription opioid therapy for noncancer pain was associated with a higher risk of HCV seroconversion among individuals who were injection drug use-naive at baseline or at prescription opioid initiation. These results suggest injection drug use initiation risk is higher among people dispensed long-term therapy and may be useful for informing approaches to identify and prevent HCV infection. These findings should not be used to justify abrupt discontinuation of long-term therapy, which could increase risk of harms.

Role of mu-opioids as cofactors in human immunodeficiency virus type 1 disease progression and neuropathogenesis.

About one third of acquired immunodeficiency syndrome cases in the USA have been attributed to the use of injected addictive drugs, frequently involving opioids like heroin and morphine, establishing them as significant predisposing risk factors for contracting human immunodeficiency virus type 1 (HIV-1). Accumulating evidence from in vitro and in vivo experimental systems indicates that opioids act in concert with HIV-1 proteins to exacerbate dysregulation of neural and immune cell function and survival through diverse molecular mechanisms. In contrast, the impact of opioid exposure and withdrawal on the viral life cycle and HIV-1 disease progression itself is unclear, with conflicting reports emerging from the simian immunodeficiency virus and simian-human immunodeficiency virus infection models. However, these studies suggest a potential role of opioids in elevated viral production. Because human microglia, astrocytes, CD4+ T lymphocytes, and monocyte-derived macrophages express opioid receptors, it is likely that intracellular signaling events triggered by morphine facilitate enhancement of HIV-1 infection in these target cell populations. This review highlights the biochemical changes that accompany prolonged exposure to and withdrawal from morphine that synergize with HIV-1 proteins to disrupt normal cellular physiological functions especially within the central nervous system. More importantly, it collates evidence from epidemiological studies, animal models, and heterologous cell systems to propose a mechanistic link between such physiological adaptations and direct modulation of HIV-1 production. Understanding the opioid-HIV-1 interface at the molecular level is vitally important in designing better treatment strategies for HIV-1-infected patients who abuse opioids.

Experiences of people with opioid use disorder during the COVID-19 pandemic: A qualitative study.

AIM: To capture pandemic experiences of people with opioid use disorder (OUD) to better inform the programs that serve them. DESIGN: We designed, conducted, and analyzed semi-structured qualitative interviews using grounded theory. We conducted interviews until theme saturation was reached and we iteratively developed a codebook of emerging themes. Individuals with lived experience of substance use provided feedback at all steps of the study. SETTING: We conducted phone or in-person interviews in compliance with physical distancing and public health regulations in outdoor Vancouver parks or well-ventilated indoor spaces between June to September 2020. PARTICIPANTS: Using purposive sampling, we recruited participants (n = 19) who were individuals with OUD enrolled in an intensive community outreach program, had visited one of two emergency departments, were over 18, lived within catchment, and were not already receiving opioid agonist therapy. MEASUREMENTS: We audio-recorded interviews, which were later transcribed verbatim and checked for accuracy while removing all identifiers. Interviews explored participants' knowledge of COVID-19 and related safety measures, changes to drug use and healthcare services, and community impacts of COVID-19. RESULTS: One third of participants were women, approximately two thirds had stable housing, and ages ranged between 23 and 59 years old. Participants were knowledgeable on COVID-19 public health measures. Some participants noted that fear decreased social connection and reluctance to help reverse overdoses; others expressed pride in community cohesion during crisis. Several participants mentioned decreased access to housing, harm reduction, and medical care services. Several participants reported using drugs alone more frequently, consuming different or fewer drugs because of supply shortages, or using more drugs to replace lost activities. CONCLUSION: COVID-19 had profound effects on the social lives, access to services, and risk-taking behaviour of people with opioid use disorder. Pandemic public health measures must include risk mitigation strategies to maintain access to critical opioid-related services.

HIV clinic-based buprenorphine plus naloxone versus referral for methadone maintenance therapy for treatment of opioid use disorder in HIV clinics in Vietnam (BRAVO): an open-label, randomised, non-inferiority trial.

BACKGROUND: UNAIDS recommends integrating methadone or buprenorphine treatment of opioid use disorder with HIV care to improve HIV outcomes, but buprenorphine adoption remains limited in many countries. We aimed to assess whether HIV clinic-based buprenorphine plus naloxone treatment for opioid use disorder was non-inferior to referral for methadone maintenance therapy in achieving HIV viral suppression in Vietnam. METHODS: In an open-label, non-inferiority trial (BRAVO), we randomly assigned people with HIV and opioid use disorder (1:1) by computer-generated random number sequence, in blocks of ten and stratified by site, to receive HIV clinic-based buprenorphine plus naloxone treatment or referral for methadone maintenance therapy in six HIV clinics in Vietnam. The primary outcome was HIV viral suppression at 12 months (HIV-1 RNA ≤200 copies per mL on PCR) by intention to treat (absolute risk difference [RD] margin ≤13%), compared by use of generalised estimating equations. Research staff actively queried treatment-emergent adverse events during quarterly study visits and passively collected adverse events reported during HIV clinic visits. This study is registered with ClinicalTrials.gov, NCT01936857, and is completed. FINDINGS: Between July 27, 2015, and Feb 12, 2018, we enrolled 281 patients. At baseline, 272 (97%) participants were male, mean age was 38·3 years (SD 6·1), and mean CD4 count was 405 cells per µL (SD 224). Viral suppression improved between baseline and 12 months for both HIV clinic-based buprenorphine plus naloxone (from 97 [69%] of 140 patients to 74 [81%] of 91 patients) and referral for methadone maintenance therapy (from 92 [66%] of 140 to 99 [93%] of 107). Buprenorphine plus naloxone did not demonstrate non-inferiority to methadone maintenance therapy in achieving viral suppression at 12 months (RD -0·11, 95% CI -0·20 to -0·02). Retention on medication at 12 months was lower for buprenorphine plus naloxone than for methadone maintenance therapy (40% vs 65%; RD -0·53, 95% CI -0·75 to -0·31). Participants assigned to buprenorphine plus naloxone more frequently experienced serious adverse events (ten [7%] of 141 vs four of 140 [3%] assigned to methadone maintenance therapy) and deaths (seven of 141 [5%] vs three of 141 [2%]). Serious adverse events and deaths typically occurred in people no longer taking ART or opioid use disorder medications. INTERPRETATION: Although integrated buprenorphine and HIV care may potentially increase access to treatment for opioid use disorder, scale-up in middle-income countries might require enhanced support for buprenorphine adherence to improve HIV viral suppression. The strength of our study as a multisite randomised trial was offset by low retention of patients on buprenorphine. FUNDING: National Institute on Drug Abuse (US National Institutes of Health).

Buprenorphine maintenance treatment in patients with opioid use disorder diagnosed with COVID-19.

The current COVID-19 pandemic is impacting individuals with pre-existing opioid use disorder (OUD), many of whom are receiving daily dosed buprenorphine treatment. There is a limited clinical experience with how to manage buprenorphine maintenance in infected individuals. Published guidance considers the possibility of dosage or formulation changes. This case series reports on 10 cases involving individuals with OUD who were receiving daily dosed buprenorphine and contracted COVID-19. It was found that for those with mild-moderate COVID-19 disease, in the absence of significant respiratory symptoms, changes to buprenorphine management including changes to daily dose, were not necessary.

HIV-1 phylodynamic analysis among people who inject drugs in Pakistan correlates with trends in illicit opioid trade.

Pakistan is considered by the World Health Organization to currently have a "concentrated" HIV-1 epidemic due to a rapid rise in infections among people who inject drugs (PWID). Prevalence among the country's nearly 105,000 PWID is estimated to be 37.8% but has been shown to be higher in several large urban centers. A lack of public health resources, the common use of professional injectors and unsafe injection practices are believed to have fueled the outbreak. Here we evaluate the molecular characteristics of HIV-1 sequences (n = 290) from PWID in several Pakistani cities to examine transmission dynamics and the association between rates of HIV-1 transmission with regards to regional trends in opioid trafficking. Tip-to-tip (patristic) distance based phylogenetic cluster inferences and BEAST2 Bayesian phylodynamic analyses of time-stamped data were performed on HIV-1 pol sequences generated from dried blood spots collected from 1,453 PWID as part of a cross-sectional survey conducted in Pakistan during 2014/2015. Overall, subtype A1 strains were dominant (75.2%) followed by CRF02_AG (14.1%), recombinants/unassigned (7.2%), CRF35_AD (2.1%), G (1.0%) and C (0.3%). Nearly three quarters of the PWID HIV-1 sequences belonged to one of five distinct phylogenetic clusters. Just below half (44.4%) of individuals in the largest cluster (n = 118) did seek help injecting from professional injectors which was previously identified as a strong correlate of HIV-1 infection. Spikes in estimated HIV-1 effective population sizes coincided with increases in opium poppy cultivation in Afghanistan, Pakistan's western neighbor. Structured coalescent analysis was undertaken in order to investigate the spatial relationship of HIV-1 transmission among the various cities under study. In general terms, our analysis placed the city of Larkana at the center of the PWID HIV-1 epidemic in Pakistan which is consistent with previous epidemiological data.

COVID19 pandemic and people with opioid use disorder: innovation to reduce risk.

The Covid-19 pandemic is creating a vast and growing number of challenges for all. People with a history of opioid use disorder (OUD) also may be exposed to additional risks. Piedmont one of the areas most severely affected by the Covid-19 pandemic, with large numbers of people infected and related mortality. In the region, specialists responsible for OUD care identified the risk that the existing care system exposed patients to. Teams designed and implemented innovation approaches to enable continuation of care and reduce the inherent system risk to patients with OUD.

"Chasing the pain relief, not the high": Experiences managing pain after opioid reductions among patients with HIV and a history of substance use.

BACKGROUND: Opioid overdose mortality continues to increase in the United States despite significant investments to reverse the epidemic. The national response to-date has focused primarily on reducing opioid prescribing, yet reductions in prescribing have been associated with patients reporting uncontrolled pain, psychological distress, and transition to illicit substances. The aim of this study is to qualitatively explore chronic pain management experiences among PLWH with a history of illicit substance use after long-term opioid therapy reductions or discontinuations. METHODS: We analyzed 18 interviews, stopping upon reaching thematic saturation, with HIV-positive participants with a history of substance use who were enrolled in a longitudinal cohort study to assess the impact of prescribing changes among patients with chronic pain. Participants in this nested qualitative study had been reduced/discontinued from opioid pain relievers (OPRs) within the 12 months prior to interview. Interviews were audio-recorded and transcribed verbatim. Two analysts coded all interviews, interrater reliability was measured, and coding discrepancies discussed. The study took place in San Francisco, California in 2018. RESULTS: Eleven participants were male with a mean age of 55; 8 were African American and 8 were White. All participants were HIV-positive, actively engaged in primary care, and had a lifetime history of illicit substance use. Twelve reported using illicit substances within the past year, including non-prescription opioids/heroin (10), and stimulant use (10). After being reduced/discontinued from their long-term opioid therapy, patients reported developing complex multimodal pain management systems that often included both nonpharmacological approaches and illicit substance use. Participants encountered a range of barriers to nonpharmacological therapies including issues related to accessibility and availability. Participants often reported attempts to replicate their prior OPR prescription by seeking out the same medication and dose from illicit sources and reported transitioning to heroin after exhausting other options. CONCLUSION: After being reduced/discontinued from OPRs, HIV-positive patients with a history of substance use reported experimenting with a range of pain management modalities including nonpharmacological therapies and illicit substance use to manage symptoms of opioid withdrawal and pain. Providers should consider that any change to a patients' long-term opioid therapy may result in experimentation with pain management outside of the medical setting and may want to employ patient-centered, holistic approaches when managing patients' opioid prescriptions and chronic pain.