Endogenous retrotransposition activates oncogenic pathways in hepatocellular carcinoma.

LINE-1 (L1) retrotransposons are mobile genetic elements comprising ~17% of the human genome. New L1 insertions can profoundly alter gene function and cause disease, though their significance in cancer remains unclear. Here, we applied enhanced retrotransposon capture sequencing (RC-seq) to 19 hepatocellular carcinoma (HCC) genomes and elucidated two archetypal L1-mediated mechanisms enabling tumorigenesis. In the first example, 4/19 (21.1%) donors presented germline retrotransposition events in the tumor suppressor mutated in colorectal cancers (MCC). MCC expression was ablated in each case, enabling oncogenic ß-catenin/Wnt signaling. In the second example, suppression of tumorigenicity 18 (ST18) was activated by a tumor-specific L1 insertion. Experimental assays confirmed that the L1 interrupted a negative feedback loop by blocking ST18 repression of its enhancer. ST18 was also frequently amplified in HCC nodules from Mdr2(-/-) mice, supporting its assignment as a candidate liver oncogene. These proof-of-principle results substantiate L1-mediated retrotransposition as an important etiological factor in HCC.

Utility of self-report antiretroviral adherence for predicting HIV viral load among persons who inject drugs in Hai Phong Vietnam: assessing differences by methamphetamine use.

ABSTRACTIn resource-limited settings, alternatives to HIV viral load testing may be necessary to monitor the health of people living with HIV. We assessed the utility of self-report antiretroviral therapy (ART) to screen for HIV viral load among persons who inject drugs in Hai Phong Vietnam, and consider differences by recent methamphetamine use. From 2016 to 2018 we recruited PWID through cross sectional surveys and collected self-report ART adherence and HIV viral load to estimate sensitivity, specificity, positive and negative predictive values (PPV, NPV) and likelihood ratios (LR+, LR-) for self-reported ART adherence as a screening test for HIV viral load. We used three HIV viral load thresholds: < 1000, 500 and 250 copies/mL; laboratory-confirmed HIV viral load was the gold standard. Among 792 PWID recruited, PPV remained above 90% regardless of recent methamphetamine use with slightly higher PPV among those not reporting recent methamphetamine use. The results remained consistent across all three HIV viral load thresholds. Our findings suggest that when HIV viral load testing is not possible, self-reported ART adherence may inform decisions about how to prioritize HIV viral load testing among PWID. The high PPV values suggest self-reported high ART adherence indicates likely HIV viral suppression, irrespective of methamphetamine use.

Systematic or Test-Guided Treatment for Tuberculosis in HIV-Infected Adults.

BACKGROUND: In regions with high burdens of tuberculosis and human immunodeficiency virus (HIV), many HIV-infected adults begin antiretroviral therapy (ART) when they are already severely immunocompromised. Mortality after ART initiation is high in these patients, and tuberculosis and invasive bacterial diseases are common causes of death. METHODS: We conducted a 48-week trial of empirical treatment for tuberculosis as compared with treatment guided by testing in HIV-infected adults who had not previously received ART and had CD4+ T-cell counts below 100 cells per cubic millimeter. Patients recruited in Ivory Coast, Uganda, Cambodia, and Vietnam were randomly assigned in a 1:1 ratio to undergo screening (Xpert MTB/RIF test, urinary lipoarabinomannan test, and chest radiography) to determine whether treatment for tuberculosis should be started or to receive systematic empirical treatment with rifampin, isoniazid, ethambutol, and pyrazinamide daily for 2 months, followed by rifampin and isoniazid daily for 4 months. The primary end point was a composite of death from any cause or invasive bacterial disease within 24 weeks (primary analysis) or within 48 weeks after randomization. RESULTS: A total of 522 patients in the systematic-treatment group and 525 in the guided-treatment group were included in the analyses. At week 24, the rate of death from any cause or invasive bacterial disease (calculated as the number of first events per 100 patient-years) was 19.4 with systematic treatment and 20.3 with guided treatment (adjusted hazard ratio, 0.95; 95% confidence interval [CI], 0.63 to 1.44). At week 48, the corresponding rates were 12.8 and 13.3 (adjusted hazard ratio, 0.97 [95% CI, 0.67 to 1.40]). At week 24, the probability of tuberculosis was lower with systematic treatment than with guided treatment (3.0% vs. 17.9%; adjusted hazard ratio, 0.15; 95% CI, 0.09 to 0.26), but the probability of grade 3 or 4 drug-related adverse events was higher with systematic treatment (17.4% vs. 7.2%; adjusted hazard ratio 2.57; 95% CI, 1.75 to 3.78). Serious adverse events were more common with systematic treatment. CONCLUSIONS: Among severely immunosuppressed adults with HIV infection who had not previously received ART, systematic treatment for tuberculosis was not superior to test-guided treatment in reducing the rate of death or invasive bacterial disease over 24 or 48 weeks and was associated with more grade 3 or 4 adverse events. (Funded by the Agence Nationale de Recherches sur le Sida et les Hépatites Virales; STATIS ANRS 12290 ClinicalTrials.gov number, NCT02057796.).

Gender Differences in HIV, HCV risk and Prevention Needs Among People who Inject drug in Vietnam.

We examined gender differences among people who inject drug (PWID) in Hai Phong, Vietnam in term of blood-borne infections, risk behaviors, and access to care. Using respondent-driven-sampling surveys, we recruited 3146 PWID from 2016 to 2018. Inclusion criteria included a positive urine test for heroin and recent injection marks. There were 155 female PWID (4,9%), including 82 at RDS-2016, 32 at RDS-2017 and 38 at RDS-2018. The age mean was 36.3 ± 7.2 years. The majority of female PWID had less than high school education (90.9%) and were unemployed (51.3%). There was no difference in the proportion of HIV and HCV positive by gender. However, women had several significant differences in risk behaviors than men in multivariable logistic regression. Being a woman was independently associated with being unemployed, being a sex worker, having unstable housing, having uses drugs for less than 5 years, more use of methamphetamine, having a partner who ever injected drugs, and less access to methadone treatment. Interventions targeting female PWID are needed, possibly through community organizations and peer educators.

How has the COVID-19 epidemic affected the risk behaviors of people who inject drugs in a city with high harm reduction service coverage in Vietnam? A qualitative investigation.

INTRODUCTION: The COVID-19 outbreak disproportionally affects vulnerable populations including people who inject drugs (PWID). Social distancing and stay-at-home orders might result in a lack of access to medical and social services, poorer mental health, and financial precariousness, and thus, increases in HIV and HCV risk behaviors. This article explores how the HIV/HCV risk behaviors of PWID in Haiphong, a city with high harm reduction service coverage in Vietnam, changed during the early phase of the COVID-19 pandemic, and what shaped such changes, using the risk environment framework. METHOD: We conducted three focus group discussions with peer outreach workers in May 2020 at the very end of the first lockdown, and 30 in-depth interviews with PWID between September and October 2020, after the second wave of infection in Vietnam. Discussions and interviews centered on the impact of the COVID-19 pandemic on their lives, and how their drug use and sexual behaviors changed as a result of the pandemic. RESULTS: The national shutdown of nonessential businesses due to the COVID-19 epidemic caused substantial economic challenges to participants, who mostly were in a precarious financial situation before the start of the epidemic. Unsafe injection is no longer an issue among our sample of PWID in Haiphong thanks to a combination of different factors, including high awareness of injection-related HIV/HCV risk and the availability of methadone treatment. However, group methamphetamine use as a means to cope with the boredom and stress related to COVID-19 was common during the lockdown. Sharing of smoking equipment was a standard practice. Female sex workers, especially those who were active heroin users, suffered most from COVID-related financial pressure and may have engaged in unsafe sex. CONCLUSION: While unsafe drug injection might no longer be an issue, group methamphetamine use and unsafe sex were the two most worrisome HIV/HCV risk behaviors of PWID in Haiphong during the social distancing and lockdown periods. These elevated risks could continue beyond the enforced lockdown periods, given PWID in general, and PWID who are also sex workers in particular, have been disproportionately affected during the global crisis.

L1 retrotransposition is a common feature of mammalian hepatocarcinogenesis.

The retrotransposon Long Interspersed Element 1 (LINE-1 or L1) is a continuing source of germline and somatic mutagenesis in mammals. Deregulated L1 activity is a hallmark of cancer, and L1 mutagenesis has been described in numerous human malignancies. We previously employed retrotransposon capture sequencing (RC-seq) to analyze hepatocellular carcinoma (HCC) samples from patients infected with hepatitis B or hepatitis C virus and identified L1 variants responsible for activating oncogenic pathways. Here, we have applied RC-seq and whole-genome sequencing (WGS) to an Abcb4 (Mdr2)-/- mouse model of hepatic carcinogenesis and demonstrated for the first time that L1 mobilization occurs in murine tumors. In 12 HCC nodules obtained from 10 animals, we validated four somatic L1 insertions by PCR and capillary sequencing, including TF subfamily elements, and one GF subfamily example. One of the TF insertions carried a 3' transduction, allowing us to identify its donor L1 and to demonstrate that this full-length TF element retained retrotransposition capacity in cultured cancer cells. Using RC-seq, we also identified eight tumor-specific L1 insertions from 25 HCC patients with a history of alcohol abuse. Finally, we used RC-seq and WGS to identify three tumor-specific L1 insertions among 10 intra-hepatic cholangiocarcinoma (ICC) patients, including one insertion traced to a donor L1 on Chromosome 22 known to be highly active in other cancers. This study reveals L1 mobilization as a common feature of hepatocarcinogenesis in mammals, demonstrating that the phenomenon is not restricted to human viral HCC etiologies and is encountered in murine liver tumors.

Identification of Four Immune Subtypes Characterized by Distinct Composition and Functions of Tumor Microenvironment in Intrahepatic Cholangiocarcinoma.

BACKGROUND AND AIMS: Intrahepatic cholangiocarcinoma (ICC) is a severe malignant tumor in which the standard therapies are mostly ineffective. The biological significance of the desmoplastic tumor microenvironment (TME) of ICC has been stressed but was insufficiently taken into account in the search for classifications of ICC adapted to clinical trial design. We investigated the heterogeneous tumor stroma composition and built a TME-based classification of ICC tumors that detects potentially targetable ICC subtypes. APPROACH AND RESULTS: We established the bulk gene expression profiles of 78 ICCs. Epithelial and stromal compartments of 23 ICCs were laser microdissected. We quantified 14 gene expression signatures of the TME and those of 3 functional indicators (liver activity, inflammation, immune resistance). The cell population abundances were quantified using the microenvironment cell population-counter package and compared with immunohistochemistry. We performed an unsupervised TME-based classification of 198 ICCs (training set) and 368 ICCs (validation set). We determined immune response and signaling features of the different immune subtypes by functional annotations. We showed that a set of 198 ICCs could be classified into 4 TME-based subtypes related to distinct immune escape mechanisms and patient outcomes. The validity of these immune subtypes was confirmed over an independent set of 368 ICCs and by immunohistochemical analysis of 64 ICC tissue samples. About 45% of ICCs displayed an immune desert phenotype. The other subtypes differed in nature (lymphoid, myeloid, mesenchymal) and abundance of tumor-infiltrating cells. The inflamed subtype (11%) presented a massive T lymphocyte infiltration, an activation of inflammatory and immune checkpoint pathways, and was associated with the longest patient survival. CONCLUSION: We showed the existence of an inflamed ICC subtype, which is potentially treatable with checkpoint blockade immunotherapy.

Antimicrobial protein REG3A regulates glucose homeostasis and insulin resistance in obese diabetic mice.

Innate immune mediators of pathogen clearance, including the secreted C-type lectins REG3 of the antimicrobial peptide (AMP) family, are known to be involved in the regulation of tissue repair and homeostasis. Their role in metabolic homeostasis remains unknown. Here we show that an increase in human REG3A improves glucose and lipid homeostasis in nutritional and genetic mouse models of obesity and type 2 diabetes. Mice overexpressing REG3A in the liver show improved glucose homeostasis, which is reflected in better insulin sensitivity in normal weight and obese states. Delivery of recombinant REG3A protein to leptin-deficient ob/ob mice or wild-type mice on a high-fat diet also improves glucose homeostasis. This is accompanied by reduced oxidative protein damage, increased AMPK phosphorylation and insulin-stimulated glucose uptake in skeletal muscle tissue. Oxidative damage in differentiated C2C12 myotubes is greatly attenuated by REG3A, as is the increase in gp130-mediated AMPK activation. In contrast, Akt-mediated insulin action, which is impaired by oxidative stress, is not restored by REG3A. These data highlight the importance of REG3A in controlling oxidative protein damage involved in energy and metabolic pathways during obesity and diabetes, and provide additional insight into the dual function of host-immune defense and metabolic regulation for AMP.

Gender, homelessness, hospitalization and methamphetamine use fuel depression among people who inject drugs: implications for innovative prevention and care strategies.

Background: The co-occurrence of substance use disorder and mental disorder, known as dual diagnosis, has a distressingly high prevalence among individuals grappling with either of these conditions. Mood disorders, especially depression, constitute a substantial burden for People Who Inject Drugs (PWID) and a significant public health concern in Vietnam. Identifying risk factors for depression in PWID is imperative for the development of targeted interventions. Methods: We enrolled PWID into a cohort using the respondent-driven sampling method. Over a 36-month period, we systematically tracked the emergence of depression and employed multiple imputation in conjunction with a mixed nonlinear model to pinpoint risk factors for depression in this demographic. At inclusion, depression was screened using the PHQ-2 questionnaire, and subsequent episodes of depression were assessed semi-annually using the CES-D8. Results: Three hundred and ninety-one PWID (26.6%) were depressed. Major risk factors for depression included being female, not having a permanent residency, having been hospitalized and using methamphetamine more than weekly. Other risk factors included age, being single, not having a health insurance card and not being on methadone. Limitations: The exclusion of missing visits and social desirability could have led to selection and information biases. In this observational study, confusion biases are possible despite our best efforts. Conclusion: Depression is alarmingly frequent in PWID. In this study taking in account the chronological relationship between sociodemographic and clinical factors and depression, risk factors were identified in this specific setting of low-to-middle income country. The findings highlight the need to develop innovative targeted psychiatric interventions with the help of supporting peers.

Association between recent methamphetamine use, antiretroviral therapy and HIV viral load; a mediation analysis from a cohort of HIV positive persons who inject drugs in Hai Phong, Vietnam.

BACKGROUND: There has been a significant increase in methamphetamine use among persons who use drugs in Vietnam in the last 5-10 years. We examined the degree to which adherence to antiretroviral therapy (ART) mediates the relationship between recent methamphetamine use and unsuppressed HIV viral load among people who inject drugs (PWID) in Hai Phong, Vietnam. METHODS: We recruited PWID from October 2016-October 2018 and enrolled HIV positive PWID into a cohort, with up to three years of total follow-up. We assessed relationships among recent methamphetamine use frequency, ART adherence and unsuppressed HIV viral load. Mediation analysis was used to estimate the total and natural direct effects of recent methamphetamine use on unsuppressed HIV viral load and the indirect effect proportion. RESULTS: We enrolled 792 HIV seropositive PWID into the cohort; approximately 75.9% reported high/perfect ART adherence at baseline and 81.3% were virally suppressed. In mediation analysis, the total effect for the association between methamphetamine use and unsuppressed HIV viral load (1000 copies/mL) was 3.94 (95% CI: 1.95, 7.96); the natural direct effect was 2.14 (95% CI: 1.29, 3.55); the proportion mediated by self-reported ART adherence was 0.444. Similar results were found when examining lower unsuppressed HIV viral load cutpoints of 250 copies/mL and 500 copies/mL. CONCLUSIONS: Methamphetamine use is associated with unsuppressed HIV viral load among PWID despite high levels of ART adherence. Further research is needed to better understand these relationships, with emphasis on potential biological pathways that may interact with ART.

HCV RNA Quantification by a Domestic Commercial Assay: A Case Study among People Who Inject Drugs in Vietnam.

The desired performance of nucleic acid testing (NAT) may vary if used for disease diagnosis or for the evaluation of the therapeutic efficacy of a treatment, although in most cases, the same assay is used. However, these tests may not be affordable in many situations including in low/middle income countries that in response have developed domestic assays. Given the example of HCV NAT among people who inject drugs in Vietnam, we aimed at evaluating a domestic assay versus an FDA- and CE-approved assay. This cross-evaluation revealed that (i) the domestic assay had a poorer sensitivity with a threshold of detection above 104 IU/mL, and (ii) the FDA-approved assay had a percentage of false negative results close to 1%. Together, in the present study, the domestic assay had a performance compatible with diagnosis purposes (given that this population was 70% HCV seropositive) but not compatible with HCV treatment monitoring (given that treatment failures are rare and the observed viremia frequently below the threshold of detection). This study highlights the need for a proper evaluation of HCV RNA domestic assays in order to efficiently contribute to the WHO HCV elimination target by 2030.

A community-based strategy to eliminate hepatitis C among people who inject drugs in Vietnam.

Background: Towards hepatitis C elimination among people who inject drugs (PWID), we assessed the effectiveness of a strategy consisting of a community-based respondent-driven sampling (RDS) as wide screening, a simplified and integrated hospital-based care, and prevention of reinfection supported by community-based organisations (CBO), in Hai Phong, Vietnam. Methods: Adults who injected heroin were enrolled in a RDS survey implemented in two CBO premises. Rapid HIV and HCV tests were done on site, and blood was taken for HCV RNA testing. Those with detectable HCV RNA were referred with CBO support to three public hospitals for 12-week sofosbuvir/daclatasvir, plus ribavirin for patients with cirrhosis. Participants were followed-up 12 weeks post-treatment (SVR12) and 48 weeks after enrolment. The primary endpoint was the rate of undetectable HCV RNA participants at 48 weeks. Findings: Among the 1444 RDS survey participants, 875 had hepatitis C. Their median age was 41 years (IQR 36-47), 96% were males, 36% were HIV-coinfected. Overall, 686 (78.4%) started sofosbuvir/daclatasvirs, and 629 of the 647 (97.2%) patients tested at SVR12 were cured. At week 48 (581/608) 95.6% had undetectable HCV RNA, representing 66.4% of all PWID identified with hepatitis C. The reinfection rate after SVR12 was 4/100 person-years (95% CI: 2-7). Interpretation: Our strategy, involving CBO and addressing all steps from wide HCV screening to prevention of reinfection, stands as a promising approach to eliminate HCV among PWID in low and middle-income countries. Funding: France ANRS|MIE (#ANRS12380). The RDS survey was implemented with grants from the NIDA (#R01DA041978) and ANRS|MIE (#ANRS12353).

Mental Disorders Are Associated With Leukocytes Telomere Shortening Among People Who Inject Drugs.

Premature biological aging, assessed by shorter telomere length (TL) and mitochondrial DNA (mtDNA) alterations, has been reported among people with major depressive disorders or psychotic disorders. However, these markers have never been assessed together among people who inject drugs (PWIDs), although mental disorders are highly prevalent in this population, which, in addition, is subject to other aggravating exposures. Diagnosis of mental disorders was performed by a psychiatrist using the Mini International Neuropsychiatric Interview test among active PWIDs in Haiphong, Vietnam. mtDNA copy number (MCN), mtDNA deletion, and TL were assessed by quantitative PCR and compared to those without any mental disorder. We next performed a multivariate analysis to identify risk factors associated with being diagnosed with a major depressive episode (MDE) or a psychotic syndrome (PS). In total, 130 and 136 PWIDs with and without psychiatric conditions were analyzed. Among PWIDs with mental disorders, 110 and 74 were diagnosed with MDE and PS, respectively. TL attrition was significantly associated with hepatitis C virus-infected PWIDs with MDE or PS (adjusted odds ratio [OR]: 0.53 [0.36; 0.80] and 0.59 [0.39; 0.88], respectively). TL attrition was even stronger when PWIDs cumulated at least two episodes of major depressive disorders. On the other hand, no difference was observed in mtDNA alterations between groups. The telomeric age difference with drug users without a diagnosis of psychiatric condition was estimated during 4.2-12.8 years according to the number of MDEs, making this group more prone to age-related diseases.

A community-based intervention to decrease the prevalence of HIV viremia among people who inject drugs in Vietnam.

Background: In most low-to-middle-income countries, HIV control at the population level among people who inject drugs (PWID) remains a major challenge. We aimed to demonstrate that an innovative intervention can identify HIV-positive PWID in the community who are not treated efficiently, and get them treated efficiently. Methods: Between 2016 and 2020, we implemented an intervention consisting of mass HIV screening of PWID using three annual respondent-driven sampling surveys (RDSS) and a post-intervention evaluation RDSS in community-based organisation (CBO) sites, coupled with peer support to facilitate/improve access to antiretroviral and methadone therapy in Haiphong, Vietnam. The primary outcome was the proportion of identified uncontrolled HIV-positive PWID who achieved viral control. We also estimated the potential effect of the intervention on the proportion of PWID with HIV RNA >1000 copies/mL among all PWID during the study period. Findings: Over the three RDSS, 3150 different PWID were screened, i.e. two-thirds of the estimated population size. They all injected heroin, their median age was of 39 years, 95% were male, 26.5% were HIV-infected, and 78.6% of the latter had HIV RNA ≤1000 copies/mL. Among the 177 PWID identified with an unsuppressed viral load, 73 (41.2%) achieved viral suppression at the final visit. HIV viremia decreased from 7.2% at baseline to 2.9% at the final RDSS (p<0.001). Up to 42% of this observed reduction may be explained by the intervention, in the absence of any external intervention targeting PWID during the study period. Interpretation: Mass community-based screening using RDSS coupled with CBO support is a powerful tool to rapidly identify untreated HIV-positive PWID and (re)link them to care. Funding: NIDA (USA) and ANRS (France).

Alarming Tuberculosis Rate Among People Who Inject Drugs in Vietnam.

BACKGROUND: The tuberculosis (TB) epidemic is not homogeneous in the general population but presents high-risk groups. People who inject drugs (PWID) are such a group. However, TB among PWID remains largely undocumented. Our goal was to assess the prevalence of TB and the risk factors associated with TB among PWID in Vietnam. METHODS: We implemented a cross-sectional survey among 2 community-based cohorts of human immunodeficiency virus (HIV)-positive and HIV-negative PWID in Hai Phong. Participants were screened for TB using questions on TB symptoms. Those who reported any symptom were accompanied by peers to the TB clinic for chest x-ray. If the latter was abnormal, a sputum was collected to perform an Xpert MTB/RIF test. RESULTS: A total of 885 PWID were screened for TB. For both cohorts, most PWID were male (>90.0%), with a median age of 42 years. Beside heroin injection, 52.5% of participants reported smoking methamphetamine, and 63.2% were on methadone. Among HIV-positive PWID (N = 451), 90.4% were on antiretroviral therapy and 81.6% had a viral load <1000 copies/mL. Using a complete-case analysis, the estimated TB prevalence was 2.3% (95% confidence interval [CI], 1.0-4.5) and 2.1% (95% CI, 0.8-4.2) among HIV-positive and HIV-negative people, respectively. Living as a couple, arrest over the past 6 months, homelessness, and smoking methamphetamine were independently associated with TB but not HIV infection. CONCLUSIONS: In the context of very large antiretroviral therapy coverage, this extremely high rate of TB among PWID requires urgent actions.

Assessment of a psychiatric intervention at community level for people who inject drugs in a low-middle income country: the DRIVE-Mind cohort study in Hai Phong, Viet Nam.

BACKGROUND: Access to psychiatric care for people who inject drugs (PWID) is limited/absent and stigmatized in most low-middle-income countries (LMICs). Innovative interventions are needed. We aimed to describe and assess the impact of a community-based psychiatric intervention among PWID in Hai Phong, Vietnam. METHODS: In a cohort study with one year psychiatric follow-up, PWID diagnosed with a psychotic disorder, a major depressive episode, or suicide risk, were recruited from the wider Drug-Related Infections in ViEtnam (DRIVE) project in the city of Hai Phong. The community-based psychiatric intervention included specialized follow-up (free consultations with psychiatrists, free medication, referral to mental health department for hospitalization when necessary) and support from community-based organisations (case management, harm reduction, administrative support, linkage to HIV care, methadone maintenance treatment and mental health support). The main outcome was reduction/remission of symptoms. Access to and retention in psychiatric care, quality-of-life and stigmatization were also measured pre and post-intervention. FINDINGS: Among the 1212 participants screened from March to May 2019, 271 met the inclusion criteria, 233 (86.3%) accepted the intervention and 170 completed the follow-up (72.9%). At inclusion, 80.6% were diagnosed with current depression, 44.7% with psychotic disorder and 42.4% with suicide risk. After a one-year follow-up, these proportions dropped to 15.9%, 21.8%, and 22.9% respectively. Quality-of-life and perceived stigma related to mental health were also significantly improved, while drug use decreased only marginally. INTERPRETATION: Community-based psychiatric interventions are both feasible and efficient in the Vietnamese context. Similar interventions should be implemented and evaluated in other, different LMICs. FUNDING: : This work was supported by grants from NIDA (US) (#DA041978) and ANRS (France) (#13353). The funding agencies had no role in designing the research, data analyses, or preparation of the report.

"Maintaining HIV and HCV prevention and care for people who inject drugs despite COVID-19 in Hai Phong, Vietnam".

BACKGROUND: After the emergence of COVID-19, a one-month strict lockdown was imposed in April 2020 in Vietnam, followed by lighter social distancing restrictions over the year. We investigated whether those measures affected people who inject drugs (PWID) in terms of risk behaviors for HIV and HCV and access to prevention and care in the city of Haiphong, a historic hotspot for HIV and drug use. METHODOLOGY: We carried out a 'before-after' study from 2019 to 2020 using respondent-driven sampling method to enroll PWID. They were interviewed on their socioeconomic situation, drug use and sexual behaviors, relations to care services and tested for drugs and methadone in the urine, for HIV, HCV, and HIV plasma viral load when HIV-positive. Changes following the restrictions were assessed by comparing 'before' to 'after' data. RESULTS: 780 PWID were enrolled. Mean age was 44 years; 94% were male. All were actively injecting heroin 'before', versus 56% 'after'. Among those, frequency of consumption decreased from 24 to 17 days per month. No changes were observed in the frequency and practices of methamphetamine smoking. The proportion of PWID on MMT increased from 68.7% to 75.3%, and that of PWID engaging in risky behaviors related to drug injection decreased from 6.0% to 1.5%. No HIV seroconversions were observed; HCV incidence was 2.6/100 person-years (95% CI [0.7-6.7]). 9% of PWID reported a monthly income of less than 130USD 'before' versus 53% 'after'. CONCLUSION: The case of Hai Phong shows that it is possible, during times of COVID-19 pandemic, to maintain access to harm reduction and care and to prevent HIV and HCV transmission among PWID in a resource-limited setting where severe social distancing restrictions are implemented. Further research is needed to assess the consequences of long-term economic difficulties and the impact of actual spread of SARS-Cov2 that has since emerged in Haiphong.

Development and assessment of a community-based screening tool for mental health disorders among people who inject drugs.

INTRODUCTION: The prevalence of mental health disorders among people who use drugs is high and well documented. This hard-to-reach population faces a very low awareness and access to mental health care, especially in developing countries. The objectives of this study were to design and assess a quick screening tool (QST) that community-based organisations (CBO) could routinely apply to a Vietnamese population of people who inject drugs (PWID), in order to refer them appropriately to mental health specialists. METHODS: We devised a tool that included nine questions covering anxiety, depression, suicide risk and psychotic symptomatology. Its use required no specific background and 2 h training. Specificity and sensitivity of the QST were assessed in a population of 418 PWID recruited via respondent driven sampling, using the Mini International Neuropsychiatric Interview questionnaire plus clinical evaluation as a reference standard. Acceptability was assessed using a self-administered anonymous questionnaire submitted to all CBO members who used the QST. RESULTS: CBO members considered the QST easy to use, relevant and helpful to deal with mental health issues. Area under the curve for detection of any symptom using the QST was 0.770. The maximum sensitivity and specificity were reached with a cut-off of 2 [sensitivity was 71.1% (95% confidence interval 62.4, 78.8), specificity was 75.9% (70.5, 80.7)]. DISCUSSION AND CONCLUSIONS: The QST appeared to be both efficient and well accepted. Given the burden of mental health problems among hard-to-reach PWID in developing countries, community-based screenings such as this one could be a particularly appropriate response.

Long-Term Persistence of Mitochondrial DNA Instability among HCV-Cured People Who Inject Drugs.

People who inject drugs (PWID) are a population exposed to many genotoxicants and with a high prevalence of HCV infection. Direct-acting antiviral (DAA) regimens are now widely used to treat chronic HCV infection. Although side effects to treatment are currently rare, the long-term effects such as suspicions of de novo hepatocellular carcinoma (HCC) occurrence or HCC recurrence and cardiac defects are still up for debate. Given the structure of DAAs, the molecules have a potential mitochondrial DNA (mtDNA) genotoxicity. We have previously reported acute mtDNA toxicity of three DAA regimens among PWID with a strong impact on the rate of mtDNA deletion, less on the quantity of mtDNA copy per cell at sustained viral response at 12 weeks (SVR12). Herein, we report the mtDNA parameters nine months after drug discontinuation. We observed that the percentage of the deleted mtDNA genome increased over time. No exposure to any other genotoxicants during this period was associated with a high deletion percentage, suggesting that the replicative advantage of the deleted molecules outweighed their elimination processes. Such observation calls for longer-term follow-up and may contribute to the molecular basis of subclinical side effects of DAA treatments.

The methamphetamine epidemic among persons who inject heroin in Hai Phong, Vietnam.

AIMS: To describe the current methamphetamine (MA) use epidemic among persons who inject heroin (PWID) in Hai Phong, Vietnam, and consider possibilities for mitigating adverse effects of methamphetamine use. METHODS: This study conducted surveys of PWID in 2016, 2017, and 2018 (N = 1383, 1451, and 1445, respectively). Trained interviewers administered structured interviews covering drug use histories, current drug use, and related risk behaviors. The study used urinalysis to confirm current drug use, and conducted HIV and HCV testing. RESULTS: Participants were predominantly male (95%), mean age of 40, and all reported injecting heroin. Respondents' reports of initiating MA use were rare up through early 2000s but increased exponentially through the mid-2010s. MA use was predominantly "smoking," heating the drug and inhaling the vapor using a pipe; injecting MA was rare. Current (past 30 day) MA use appears to have plateaued in 2016-2018 with 53-58% of participants reporting no use in the last 30 days, 37-41% reporting low to moderate use (1 to 19 days in last 30 days), and 5-7% reporting very frequent use (20 or more days in last 30 days). This plateau reflects a rough balance between new users and individuals ceasing use. CONCLUSIONS: MA use has become a substantial public health problem among PWID in Hai Phong. Initiation into MA use rose exponentially from 2005 to about 2015. Use of MA will likely continue for a substantial number of PWID. Currently, no medication is approved for treating MA disorders in Vietnam. Current psychosocial treatment requires highly trained counselors and months of treatment, so that psychosocial treatment for all PWID with MA disorders is likely beyond the resources available in a middle-income country such as Vietnam. Harm reduction programs implemented by community-based organization staff may provide a way to rapidly address aspects of the current MA epidemic. Such programs could emphasize social support for reducing use where possible and for avoiding escalation of use among persons continuing to use.