Causes and risk factors of death among people who inject drugs in Indonesia, Ukraine and Vietnam: findings from HPTN 074 randomized trial.

INTRODUCTION: The HIV Prevention Trials Network (HPTN) 074 study demonstrated a positive effect of an integrated systems navigation and psychosocial counseling intervention on HIV treatment initiation, viral suppression, medication assisted treatment (MAT) enrollment, and risk of death among people who inject drugs (PWID). In this sub-study, we analyzed the incidence, causes, and predictors of death among HIV-infected and uninfected participants. METHODS: The HPTN 074 randomized clinical trial was conducted in Indonesia, Ukraine, and Vietnam. HIV-infected PWID with unsuppressed viral load (indexes) were recruited together with at least one of their HIV-negative injection partners. Indexes were randomized in a 1:3 ratio to the intervention or standard of care. RESULTS: The trial enrolled 502 index and 806 partner participants. Overall, 13% (66/502) of indexes and 3% (19/806) of partners died during follow-up (crude mortality rates 10.4 [95% CI 8.1-13.3] and 2.1 [1.3-3.3], respectively). These mortality rates were for indexes nearly 30 times and for partners 6 times higher than expected in a population of the same country, age, and gender (standardized mortality ratios 30.7 [23.7-39.0] and 5.8 [3.5-9.1], respectively). HIV-related causes, including a recent CD4 < 200 cells/µL, accounted for 50% of deaths among indexes. Among partners, medical conditions were the most common cause of death (47%). In the multivariable Cox model, the mortality among indexes was associated with sex (male versus female aHR = 4.2 [1.5-17.9]), CD4 count (≥ 200 versus < 200 cells/µL aHR = 0.3 [0.2-0.5]), depression (moderate-to-severe versus no/mild aHR = 2.6 [1.2-5.0]) and study arm (intervention versus control aHR = 0.4 [0.2-0.9]). Among partners, the study arm of the index remained the only significant predictor (intervention versus control aHR = 0.2 [0.0-0.9]) while controlling for the effect of MAT (never versus ever receiving MAT aHR = 2.4 [0.9-7.4]). CONCLUSIONS: The results confirm that both HIV-infected and uninfected PWID remain at a starkly elevated risk of death compared to general population. Mortality related to HIV and other causes can be significantly reduced by scaling-up ART and MAT. Access to these life-saving treatments can be effectively improved by flexible integrated interventions, such as the one developed and tested in HPTN 074.

Perspectives of clients and providers on factors influencing opioid agonist treatment uptake among HIV-positive people who use drugs in Indonesia, Ukraine, and Vietnam: HPTN 074 study.

BACKGROUND: Opioid agonist treatment (OAT) is an effective method of addiction treatment and HIV prevention. However, globally, people who inject drugs (PWID) have insufficient OAT uptake. To expand OAT access and uptake, policymakers, program developers and healthcare providers should be aware of barriers to and facilitators of OAT uptake among PWID. METHODS: As a part of the HPTN 074 study, which assessed the feasibility of an intervention to facilitate HIV treatment and OAT in PWID living with HIV in Indonesia, Ukraine, and Vietnam, we conducted in-depth interviews with 37 HIV-positive PWID and 25 healthcare providers to explore barriers to and facilitators of OAT uptake. All interviews were audio-recorded, transcribed, translated into English, and coded in NVivo for analysis. We developed matrices to identify emergent themes and patterns. RESULTS: Despite some reported country-specific factors, PWID and healthcare providers at all geographic locations reported similar barriers to OAT initiation, such as complicated procedures to initiate OAT, problematic clinic access, lack of information on OAT, misconceptions about methadone, financial burden, and stigma toward PWID. However, while PWID reported fear of drug interaction (OAT and antiretroviral therapy), providers perceived that PWID prioritized drug use over caring for their health and hence were less motivated to take up ART and OAT. Motivation for a life change and social support were reported to be facilitators. CONCLUSION: These results highlight a need for support for PWID to initiate and retain in drug treatment. To expand OAT in all three countries, it is necessary to facilitate access and ensure low-threshold, financially affordable OAT programs for PWID, accompanied with supporting interventions. PWID attitudes and beliefs about OAT indicate the need for informational campaigns to counter misinformation and stigma associated with addiction and OAT (especially methadone).

Client and Provider Perspectives on Antiretroviral Treatment Uptake and Adherence Among People Who Inject Drugs in Indonesia, Ukraine and Vietnam: HPTN 074.

HIV-infected people who inject drugs (PWID) have low uptake of HIV services, increasing the risk of transmission to uninfected injection or sexual partners and the likelihood of AIDS-related deaths. HPTN 074 is a vanguard study assessing the feasibility of an integrated intervention to facilitate treatment as prevention to PWID in Indonesia, Ukraine, and Vietnam. We describe barriers to and facilitators of ART uptake and adherence among PWID. We conducted in-depth interviews with 62 participants, including 25 providers and 37 PWID at baseline across all sites. All interviews were recorded, transcribed, translated into English and coded in NVivo for analysis. Matrices were developed to identify emergent themes and patterns. Overall, differences between provider and PWID perspectives were greater than differences in cross-site perspectives. Providers and PWID recognized clinic access, financial barriers, side effects, and lack of information about HIV testing and ART enrollment as barriers to ART. However, providers tended to emphasize individual level barriers to ART, such as lack of motivation due to drug use, whereas PWID highlighted health systems barriers, such as clinic hours and financial burden, fears, and side effects. Providers did not mention stigma as a barrier though their language reflected stereotypes about drug users. The differences between provider and PWID perspectives suggest a gap in providers' understanding of PWID. This misunderstanding has implications for patient-provider interactions that may affect PWID willingness to access care or adhere to ART. Lessons learned from this study will be important as countries with a significant HIV burden among PWID design and implement programs to engage HIV-infected PWID in care and treatment.

Altered Resting-State Network in Adolescents with Problematic Internet Use.

Problematic internet use (PIU) is increasingly recognized as a mental health concern, particularly among adolescents. The resting-state functional connectivity (rsFC) of the triple-network model has been described inconsistently in PIU. Using resting-state fMRI (rsFMRI) and hypothesizing a lower rsFC between default mode (DMN) and central executive networks (CEN) but a higher rsFC within the salience network (SN), this study scrutinized the neural substrates of PIU adolescents. A total of 30 adolescents with PIU and 30 control subjects underwent rsFMRI. The severity of PIU was evaluated by the Internet Addiction Test. Additionally, personality traits as well as emotional and behavioral problems were evaluated by the Temperament and Character Inventory (TCI) and the Strength and Difficulties Questionnaire (SDQ), respectively. Focusing on the DMN, SN, and CEN, we compared rsFC values between PIU and the control. Subsequently, within the combined group of subjects, TCI and SDQ correlation and mediation effects were investigated. Higher rsFC values of the left lateral prefrontal cortex (LPFC(L)) with the left anterior insula (aIns(L)) were observed for PIU than for the control, while rsFCs of the LPFC(L) with the medial PFC (MPFC), LPFC(L), as well as with the right lateral parietal cortex (LP(R)) were lower for PIU. Among these significant group differences, the rsFC between the LPFC(L) and MPFC was mediated by emotional symptoms (standardized ß = -0.12, 95% CI -0.29, -0.0052). The dysfunctional attention switching and incentive salience regulated by the SN were implicated as being a neural correlate of PIU, and this relationship would in part be explained by the emotional dysregulation associated with PIU in adolescents.

Validation study of the Indonesian internet addiction test among adolescents.

BACKGROUND: Internet addiction is a serious problem that can negatively impact both the physical and mental health of individuals. The Internet Addiction Test (IAT) is the most common used instrument to screen internet addiction worldwide. This study sought to investigate the psychometric properties of an Indonesian version of the IAT. METHODS: The IAT questionnaire was made the focus of forward translation, expert panel discussions, back translation, an item analysis (30 subjects), a pilot study (385 subjects), and field testing (643 subjects). Factor structure was analysed by exploratory (EFA) and confirmatory factor (CFA) analyses, whereas reliability was measured with Cronbach's alpha coefficient. RESULTS: Factor analysis revealed that the Indonesian version of IAT, consisted of 3 domains, and had good validity (χ2 p < 0.001; RMSEA = 0.076; CFI = 0.95; SRMR = 0.057, and AIC = 784.63). The Cronbach's alpha score is 0.855. A significant association was also observed between the level of internet addiction with gender (p = 0.027) and the duration of internet use per day (p = 0.001). CONCLUSION: The Indonesian version of IAT provides good validity and reliability in a three-dimensional model. Therefore, it can be utilised as a tool for screening internet addiction in the Indonesian population.

Internet addiction in adolescents: Development and validation of Internet Addiction Diagnostic Questionnaire (KDAI).

Internet addiction (IA) is an emerging behavioral problem that constitutes a major health threat to vulnerable populations, including adolescents. However, there is a paucity of IA screening tools specifically designed for adolescents, especially in Indonesia. Therefore, the current study developed and validated the IA Diagnostic Questionnaire (KDAI) in adolescents while acknowledging local cultural influences. The KDAI was conceived through extensive literature reviews, expert discussions based on Delphi methods, a face validity study, focus group discussion (N = 31) for initial reliability testing, and a recruited pilot study (N = 385) and main study (N = 643) for exploratory and confirmatory factor analyses, respectively. The multi-sample analyses demonstrated that the KDAI model with the best fit and reliability comprised a seven-factor structure, including withdrawal, loss of control, increase of priority, negative consequences, mood modification, salience, and impairment. These factors were scrutinized against domains of IA Test, and concurrent validity was ascertained. Subsequently, a receiver operating characteristic curve and area under the curve determined a cutoff score of 108 to discern adolescents with IA. Taken together, the KDAI displayed excellent psychometric indices and sensitivity as a screening tool for IA in adolescents.

Depressive symptoms and use of HIV care and medication-assisted treatment among people with HIV who inject drugs.

OBJECTIVE: Vietnam, Indonesia, and Ukraine have major burdens of IDU and HIV. We estimated the prevalence of depressive symptoms at baseline among people living with HIV who inject drugs, evaluated associations between depression at baseline and 12-month HIV care outcomes and medication-assisted treatment (MAT), and evaluated the study intervention effect by baseline depression subgroups. DESIGN: HPTN 074 was a randomized study. The study intervention included psychosocial counseling, systems navigation, and antiretroviral treatment (ART) at any CD4+ cell count. METHODS: Moderate-to-severe depression was defined as a Patient Health Questionnaire-9 score of 10 or above. ART and MAT were self-reported. Eligibility criteria were: 18-60 years of age, active IDU, and viral load of at least 1000 copies/ml. Adjusted probability differences (aPD) were estimated using inverse-probability weighting. RESULTS: A total of 502 participants enrolled from April 2015 to June 2016. Median age was 35 years; 85% identified as men. Prevalence of baseline moderate-to-severe depression was 14% in Vietnam, 14% in Indonesia, and 56% in Ukraine. No evident associations were detected between baseline depression and ART, viral suppression, or MAT at 12-month follow-up. The study intervention improved the proportions of people who inject drugs achieving 12-month viral suppression in both the depressed [intervention 44%; standard of care 24%; estimated aPD = 25% (95% confidence interval: 4.0%, 45%)] and nondepressed subgroups [intervention 38%; standard of care 24%; aPD = 13% (95% confidence interval: 2.0%, 25%)]. CONCLUSION: High levels of depressive symptoms were common among people living with HIV who inject drugs in Ukraine but were less common in Vietnam and Indonesia. The study intervention was effective among participants with or without baseline depression symptoms.

Reported Participation Benefits in International HIV Prevention Research with People Who Inject Drugs.

Given ethical concerns about research involving people who inject drugs and those affected by HIV, identifying potential participation benefits is important. We evaluated participant-reported benefits in a trial conducted in Indonesia, Ukraine, and Vietnam that assessed an intervention combining psychosocial counseling and referral for antiretroviral therapy and substance use treatment for HIV-infected people who use drugs. Reported benefits were aggregated into three groups: clinical (antiretroviral therapy, reduced cravings, reduced drug use, lab testing, medical referral, mental health, physical health), social (employment, financial, relationships, reduced stigma), and general (gained knowledge, life improvement). Overall, 438 index participants (90.5%) and 642 injection partners (83.1%) reported at least one benefit. Significantly more index participants who received the study intervention reported at least one benefit versus those who received the standard of care. Clinical trial participation can provide broad direct and indirect benefits for stigmatized populations, which has implications for assessing the ethical appropriateness of studies with such populations.

Designing an Individually Tailored Multilevel Intervention to Increase Engagement in HIV and Substance Use Treatment Among People Who Inject Drugs With HIV: HPTN 074.

People who inject drugs (PWID) face barriers to engagement in antiretro-viral treatment (ART) and medication-assisted treatment (MAT). We detail the design, rapid preparation and adaptation, and systematic implementation of a flexible, individually tailored intervention for PWID in multiple settings: Indonesia, Ukraine, and Vietnam. HPTN 074 integrated systems navigation and counseling to facilitate entry and adherence to ART and MAT. Site-level guidance on the intervention involved in-depth interviews (IDIs) among PWID and their supporters and site-specific document review. IDIs emphasized ART misinformation and importance of social support for adherence. The document review revealed differences in health care system barriers, requiring an intervention that was flexible and tailored enough to address key outcomes. Implementation included regular debriefs for iterative adaptations based on participants' needs, including booster counseling sessions and subsidizing pre-ART testing. HPTN 074 provides a unique framework implementing a flexible and scalable intervention to improve ART and MAT outcomes among PWID across multiple settings.

Development and implementation of participant safety plans for international research with stigmatised populations.

People who inject drugs with high-risk sharing practices have high rates of HIV transmission and face barriers to HIV care. Interventions to overcome these barriers are needed; however, stigmatisation of drug use and HIV infection leads to safety concerns during the planning and conduct of research on such interventions. In preparing to address concerns about safety and wellbeing of participants in an international research study, HIV Prevention Trials Network 074, we developed participant safety plans (PSPs) at each site to supplement local research ethics committee oversight, community engagement, and usual clinical trial procedures. The PSPs were informed by systematic local legal and policy assessments, and interviews with key stakeholders. After PSP refinement and implementation, we assessed social impacts at each study visit to ensure continued safety. Throughout the study, five participants reported a negative social impact, with three resulting from study participation. Future research with stigmatised populations should consider using and assessing this approach to enhance safety and welfare.

Regional differences between people who inject drugs in an HIV prevention trial integrating treatment and prevention (HPTN 074): a baseline analysis.

INTRODUCTION: People who inject drugs (PWID) experience high HIV incidence and face significant barriers to engagement in HIV care and substance use treatment. Strategies for HIV treatment as prevention and substance use treatment present unique challenges in PWID that may vary regionally. Understanding differences in the risk structure for HIV transmission and disease progression among PWID is essential in developing and effectively targeting intervention strategies of HIV treatment as prevention. METHODS: We present a baseline analysis of HIV Prevention Trials Network (HPTN) 074, a two-arm, randomized controlled trial among PWID in Indonesia (n = 258), Ukraine (n = 457) and Vietnam (n = 439). HPTN 074 was designed to determine the feasibility, barriers and uptake of an integrated intervention combining health systems navigation and psychosocial counselling for the early engagement of antiretroviral therapy (ART) and substance use treatment for PWID living with HIV. Discordant PWID networks were enrolled, consisting of an HIV-positive index and their HIV-negative network injection partner(s). Among the enrolled cohort of 1154 participants (502 index participants and 652 network partners), we examine regional differences in the baseline risk structure, including sociodemographics, HIV and substance use treatment history, and injection and sexual risk behaviours. RESULTS: The majority of participants were male (87%), with 82% of the enrolled females coming from Ukraine. The overall mean age was 34 (IQR: 30, 38). Most commonly injected substances included illegally manufactured methadone in Ukraine (84.2%), and heroin in Indonesia (81.8%) and Vietnam (99.5%). Injection network sizes varied by region: median number of people with whom participants self-reported injecting drugs was 3 (IQR: 2, 5) in Indonesia, 5 (IQR: 3, 10) in Ukraine and 3 (IQR: 2, 4) in Vietnam. Hazardous alcohol use, assessed using the Alcohol Use Disorders Identification Test - Alcohol Consumption Questions (AUDIT-C), was prominent in Ukraine (54.7%) and Vietnam (26.4%). Reported sexual risk behaviours in the past month, including having two or more sex partners and giving/receiving money or drugs in exchange for sex, were uncommon among all participants and regions. CONCLUSIONS: While regional differences in risk structure exist, PWID particularly in Ukraine need immediate attention for risk reduction strategies. Substantial regional differences in risk structure will require flexible, tailored treatment as prevention interventions for distinct PWID populations.

Predictive factors for treatment retention in methadone programs in Indonesia.

This article presents the results of a 6-month prospective cohort study of methadone maintenance treatment (MMT) in Indonesia. The study aimed to investigate the predictor variables of retention in MMT in Indonesia. The duration of treatment (in days) was the main outcome of the study. For the study, program, client, social network, and accessibility factors were investigated as potential predictors of retention. The study analyzed the relative weight of each factor in predicting treatment retention. The sample consisted of 178 clients drawn from three participating clinics: Rumah Sakit Ketergantungan Obat and Tanjung Priok in Jakarta and Sanglah in Bali. The 3- and 6-month retention rates were 74.2% and 61.3%, respectively. These rates are comparable with previous studies conducted in developed countries. A survival analysis using a robust estimation for the Cox PH regression found that the strongest predictors of retention were methadone dose followed by an interaction between take-home dose and the experience of the clinic providing this treatment. Other significant predictor variables included age, perceived clinic accessibility, and client's belief in the program. The study concludes that MMT cannot solely rely on the pharmacology for retention but should also promote informed access to take-home doses.