Microsoft Word - JOP_Article 135 Galley Word_final version.docx Page 89 *Corresponding author: Email address: norilyani@iium.edu.my or norilyaninazar@gmail.com @gmail.com Protective Factors for Mortality among HIV- Positive People Who Inject Drugs (PWID) in Malaysia Aida Roziana Ramlan1,2, Nor Ilyani Mohamed Nazar1*, Norny Syafinaz Ab Rahman1, Dzawani Muhamad3, and Suraya Zin1 ABSTRACT Introduction: People who inject drugs (PWID) have long been associated with HIV transmission in the community. In many countries, Methadone Maintenance Therapy (MMT) programme has been regarded as a critical platform to ensure HIV-positive PWID receive appropriate antiretroviral treatment. Despite treatment availability and accessibility in Malaysia, mortality was extensively observed, and the protective factors are still scarcely studied in this population. This study investigated the protective factors for mortality among HIV-positive PWID in Malaysia's two mainstream treatment settings. Method: This was a retrospective cohort study. The data was collected from one HIV Clinic of a tertiary hospital and six (6) MMT programs of primary care clinics in the district of Kuantan, Pahang, from 2006-2019. The patients were categorised into three different subgroups. The mortality was recorded until the end of the study period. The survival rate was analysed using one-way ANOVA, and the associated factors were analysed using Cox proportional hazard regression analysis. Results: In total, 141 records were found to have met the inclusion and exclusion criteria. Fifteen HIV-related mortalities were recorded throughout the study period. There were significant differences in survival years between the MMT-only group versus MMT + ART and the MMT-only group versus the ART-only group (p-value <0.001 and 0.003, respectively). A longer ART duration was significantly associated with improved survival of PWID (HR=0.5, 95% CI=0.28-0.88). Extended duration in MMT program (HR= 0.50, 95% CI=0.33 – 0.78), started on ART (HR= 0.21, 95% CI=0.04 – 0.97) and received ART counselling (HR= 0.13, 95% CI=0.02 – 0.85) were significantly identified as protective factors for mortality among PWID on MMT. Conclusion: Three factors were identified as protective factors for mortality among HIV-positive PWID in Malaysia. Extended retention in the MMT programme, initiation of ART, and regularly receiving HIV-related counselling were the significant factors contributing to reduced mortality rates among the patients. ARTICLE HISTORY: Received: 8 March 2022 Accepted: 14 July 2022 Published: 31 July 2022 KEYWORDS: HIV-positive people who inject drugs, protective factors, mortality rate HOW TO CITE THIS ARTICLE: Ramlan, A. R., Mohamed Nazar, N. I., Ab Rahman, N. S., Muhamad, D. & Zin, S. (2022). Protective Factors for Mortality among HIV-Positive People Who Inject Drugs (PWID) in Malaysia Journal of Pharmacy, 2(2), 89-98. doi: 10.31436/jop.v2i2.135 Authors’ Affiliation: Page 90 Introduction Globally, around 11 million people inject drugs, and approximately 1 in 8 (or 1.4 million) live with HIV (UNODC, 2020). In Malaysia, it was estimated that the number of active PWID population in 2014 was about 153,000 patients, and in the year 2017, the number steadily increased to approximately 156,000 patients. At the end of 2018, it is estimated that 87,041 people were living with HIV (PLHIV) in Malaysia (Hiebert et al., 2020). In the initial years of encounters, PWID has been strongly associated with HIV risk transmission primarily via the sharing of injecting paraphernalia (Cheong et al., 1997, Rusli et al., 1995). However, the country observed gradual changes in the HIV epidemic landscape in the past decade from predominantly PWID to more sexual transmission. The proportion of sexual transmission has increased to more than 90% in 2019 (Suleiman, 2019). Nevertheless, it is still relevant to treat PWID with appropriate treatment or harm reduction modalities (Osornprasop et al., 2018; Reddon et al., 2019). Methadone maintenance therapy has been regarded as a harm reduction approach to preventing HIV transmission from PWID to the community other than needle/syringe exchange programs (NSPs), condom distribution, and outreach programs. Highly active antiretroviral therapy (HAART) is the mainstay treatment among HIV-positive PWID unless contraindicated (Osornprasop et al., 2018; Myers et al., 2012). The initiation of HAART is based on the symptoms or CD4 counts. Starting with an ART regimen is highly recommended in symptomatic patients, especially those already with an opportunistic infection. In asymptomatic patients, the treatment is recommended in patients with a CD4 count of less than 350cell/ml (MOH, 2011). The government has adopted Methadone Maintenance Therapy (MMT) Program since 2006 as one of the harm reduction approaches to reduce the HIV seroprevalence rates. In many countries, MMT has been regarded as one of the essential platforms to ensure that HIV-positive PWID receives appropriate antiretroviral treatment. However, abstinent patients may also enrol on the Infectious Disease Clinic of a public hospital. People who inject drugs have an elevated risk of death, although mortality rates vary across different settings. Any comprehensive approach to improving health outcomes in this group must include efforts to reduce HIV infection and other causes of death, particularly drug overdose (Mathers et al., 2013). There are many predictors of all causes of mortality and premature death among PWID living with HIV AIDS. Among the identified factors were untreated concomitant infectious diseases such as tuberculosis, HIV AIDS and viral hepatitis; developing acute toxicity, especially in the case of overdose; unstable house conditions or homelessness; being sex workers; polydrug users, lack of regular employment, and poor retention rate at a drug substitution treatment (Davis et al., 2017.; Vinh et al., 2021; Zivanovic et al., 2015). Whereas for protective factors, opioid substitution therapy such as MMT and initiation of HAART were found to independently and significantly protect against HIV-related death, drug- related death and death due to other causes (Nosyk et al., 2015). In Malaysia, despite wide treatment accessibility, mortality was still being observed, and the protective factors were still scarcely investigated among the Malaysian population (Ngah et al., 2019; Bazazi et al., 2018; Lubis et al., 2013). This study aimed to investigate the mortality rate and its protective factors among the HIV- positive PWID from the two mainstream treatment settings in Malaysia. Methodology This study was designed as a retrospective cohort. It has received prior ethics committee approval by the Medical Research and Ethics Committee, Ministry of Health Malaysia (NMRR-18-3067-43939). The data was collected from the available patients' records at an Infectious Disease (ID) HIV Clinic of a tertiary hospital (Hospital Tengku Ampuan Afzan or HTAA) and MMT Programs of six (6) Primary Care Clinics in the district of Kuantan, Pahang. The timeframe for the collected data was from 2006-2019 using a data collection form. The patients' records were screened for the inclusion and exclusion criteria. The inclusion criteria include 1) HIV-positive patients diagnosed upon enrolment or at any time during MMT or ID HIV Clinic, 2) Categorised under PWID – used to or still injecting drugs, and 3) Available demographic and baseline data. The data will be excluded if there are prominent missing/incomplete data. The HIV- positive PWID's records were divided into three different categories based on their antiretroviral treatment (ART) / methadone maintenance therapy (MMT) programme; 1) MMT only; 2) MMT + ART, and 3) ART only. All demographic, baseline data, patients' progress and HIV- related mortality were obtained from the medical records and treated strictly. The flow of the data collection process is summarised in Figure 1. The analysis was conducted using SPSS ver 24. The descriptive baseline data was analysed and tabulated. The mortality rate and years of survival were explored using One-way ANOVA, and the associated factors were analysed using Cox proportional hazard regression analysis. Results In total, 141 records were found to have met the inclusion criteria and are appropriate for further analysis. There were 29 (20.6%) patients on MMT only, 41 (29.1%) were receiving MMT +ART, and most of the records retrieved were those receiving ART only, 71 (50.4%). Table 1 summarises the baseline data collection. Page 91 Figure 1: Flow Chart of Data Collection Process. Page 92 Table 1: Patients' Demographic Characteristics. Note:The statistical test used is Fisher's Exact test unless stated otherwise, aOne-Way ANOVA, Independent t-test SD: Standard deviation Mortality and years of survival At the end of the study period, the number of HIV- related mortality was 15 subjects (10.6%). Table 2 compares mortality (death) and years of survival between groups of PWID. The number of fatalities was significant between the MMT-only group and the ART-only group, with a p-value < 0.001 (Fisher's exact test). The mean (SD) survival years were the shortest among the MMT-only group, which was 3.6 (SD=2.7) years. There were significant differences in survival years between the MMT only group versus MMT + ART and MMT only group versus ART only group with p-value <0.001 and 0.003, respectively (Independent t-test). Protective factors for mortality among PWID initiated on ART A total of 14 independent variables were analysed with univariate Cox proportional hazards regression analysis, and only duration on ART was found to be significantly associated with improved survival of PWID (HR=0.5, 95% CI=0.28-0.88). The longer the patient was on ART, the risk of death was found to be reduced by 50%. Table 3 summarises the results. The Protective factors for mortality among patients on MMT Three independent variables were chosen to predict mortality among the MMT subjects in this study. All significant variables were incorporated in the multivariate analysis. The final model showed that the extended duration in MMT program (HR= 0.51, 95% CI=0.33 – 0.78), started on ART (HR= 0.21, 95% CI=0.04 – 0.97) and received ART counselling (HR= 0.13, 95% CI=0.02 – 0.85) were significantly identified as protective factors for mortality among PWID on MMT. The results are tabulated in Table 4. Discussion The mortality rate among HIV-infected PWID High mortality rates among HIV-infected people who inject drugs (PWID) have been well studied. High-risk behaviour of the PWID population who practised needle sharing, unprotected sex and substance abuse, the risk for blood-borne infections, sexually transmitted disease, and a high rate of substance overdose were among the top contributing factors identified (Farhadian et al., 2021). Blood-borne infections mainly include HIV, HBV and HCV. HCV was one of the common co-infection in the Patients' Characteristics Number, n (%) of patients TOTAL 141 MMT only 29 (20.6) MMT+ART 41(29.1) ART only 71(50.4) P-value Gender Male 136 (96.5) 29 (100) 41 (100) 66 (93) 0.124 Female 5 (3.5) - - 5 (7.0) Age 0.221a Mean (SD) years 37 (6.4) 37 (4.1) 34 (4.3) 38 (7.6) Marital status 0.737 Single 69 (48.9) 13 (44.8) 22 (53.7) 34 (47.9) Married 53 (37.6) 12 (41.4) 13 (31.7) 28 (39.4) Divorced 17 (12.1) 3 (10.3) 5 (12.2) 9 (12.7) Widow 2 (1.4) 1 (3.5) 1 (2.4) - Work 0.297 Yes 94 (66.7) 22 (75.9) 29 (70.7) 43 (60.6) No 47 (33.3) 7 (4.9) 12 (29.3) 28 (39.4) Page 93 Table 2: Mortality and years of survival among PWID. aFisher’s Exact test. bOne-Way ANOVA PWID population, and it definitely increases the mortality threshold in this population (Ali et al., 2018; Draper & McCance-Katz, 2005; Mehta et al., 2010; Teoh et al., 2018). From another perspective, suboptimal access to HIV care was also found to lead to mortality in the sub- population [Des Jarlais et al., 2018]. In this study, The patients who were not on ART had the shortest survival rate compared to those treated with ART. This result is consistent with other studies since ART is expected to restore immune function and improve patients’ survival (Hogg et al., 1998; Manosuthi et al., 2021; Trickey et al., 2017). ART initiation as a protective factor for mortality among HIV-positive PWID This study showed that those patients who started with ART have a protective factor towards mortality compared to those without/not started, regardless of their treatment setting (MMT or without MMT). This finding is supported by many other studies emphasising the important role of ART in reducing the mortality rate among the PWID population (Kitahata et al., 2009; Liu et al., 2013; Wood et al., 2008; Zhao et al., 2017). In a study applying multivariable extended Cox regression analyses of all-cause mortality, those receiving ART and having undetectable VL (<50 copies/mL) had a 42% lower all- cause mortality hazard among both men and women as compared to those who did not receive ART (Brattgård et al., 2022; Shoko & Chikobvu, 2019). Those receiving ART but having detectable VL did not have a significantly lower risk of death (Croxford et al., 2017; Elvstam et al., 2021). The duration also plays a significant role in predicting mortality among the HIV PWID without MMT, where the more extended the ART duration resulted in better survival (Bogdanić et al., 2021). The time for ART treatment initiation is also crucial, and the treatment delay has been associated with increased mortality (Ramlan et al., 2019). Extended MMT programme retention as a protective factor for mortality among HIV-positive PWID under the MMT programme In MMT-treated PWID, it was found that other than the initiation of ART, a more extended period of MMT programme retention and attending the ART counselling sessions were the protective factors that have been significantly associated with improved survival and reduced mortality among patients. These findings are coherent with a study in China (Zhao et al., 2013a). PWID who was not in the MMT program had a higher mortality rate than those in the MMT program, although both groups were initiated on ART. Findings in a few other studies supported that enrolment into the opioid-substitution program will improve access to HIV care and facilitate the early initiation of ART (Hogg et al., 2011; Montaner & Wood, 2011; Liu et al., 2013; Mukandavire et al., 2017; Pham et al., 2017). However, from a local study, about 33% of the MMT patients defaulted to the program due to negative perceptions and poor patient satisfaction (Ali et al., 2018), which needs improvement. The low mortality rate among the MMT + ART group indicated that both MMT and ART effectively reduced the mortality rate. Regular Attendance to HIV and ART Counselling Sessions as protective factors for mortality among the HIV-positive PWID The counselling session is prescribed to improve patients’ understanding of the disease and the related treatment. The results from this study are consistent with other studies on the essential roles of counselling sessions in improving medication adherence, treatment outcomes and reducing the rate of mortality among patients (Go et al., 2017; Hussain et al., 2022). Characteristics Number, n (%) of patients TOTAL 141 MMT only 29 (20.6) MMT+ART 41(29.1) ART only 71(50.4) P-value Death 15 8 (53.3) 5 (33.3) 2 (13.3) <0.001 a Survival, mean (SD) years 5.5 (3.5) 3.6 (2.7) 6.6 (3.2) 5.6 (3.6) <0.001b Page 94 Table 3: The Cox proportional hazards regression analysis on protective factors for mortality among PWID initiated on ART. Note:ref = Reference group, HR = Hazard ratio, *significant when p < 0.05 Variables Univariate analysis Multivariate analysis HR HR 95% CI p HR HR 95% CI p Age (years) 1.00 0.87 – 1.14 0.946 Working Yes No (ref) 0.31 0.07 – 1.38 0.123 Married Yes No (ref) 0.50 0.10 – 2.60 0.411 Ever had a positive urine test Yes No (ref) 0.29 0.07 – 1.31 0.108 Ever been detained or prisoned Yes No (ref) 0.39 0.05 – 3.21 0.380 CD4 baseline (cells/mm3) 1.00 0.99 – 1.01 0.593 CD4 post ART (>6 months (cells/mm3) 0.99 0.97 – 1.01 0.388 Start ART from diagnosis (year) 1.14 0.96 – 1.37 0.141 Start ART from the eligible date (year) 1.03 1.01 – 1.05 0.001* 1.00 0.97 – 1.03 0.928 Duration on ART (year) 0.60 0.41 – 0.88 0.008* 0.50 0.28 – 0.88 0.016* Existing OI 1.83 0.35 – 9.48 0.471 OI after ART 4.05 0.78 – 20.90 0.095 HIV related counselling Yes No (ref) 0.10 0.02 – 0.43 0.002* 17.19 0.92 – 320.9 0.06 RVD treatment centre Hospital Health clinic (ref) 0.20 0.04 – 0.92 0.038* 2.00 0.13 – 31.02 0.62 Page 95 Table 4: Cox proportional hazards regression analysis on protective factors for mortality among PWID on MMT. Note:ref = Reference group, HR = Hazard ratio, *significant when p < 0.05 Variables Univariate analysis Multivariate analysis HR HR 95% CI p HR HR 95% CI p Age (year) 1.20 1.06 – 1.38 0.006 Working Yes No (ref) 1.03 0.286 – 3.80 0.960 Married Yes No (ref) 0.51 0.14 – 1.84 0.301 Ever had a positive urine test Yes No (ref) 1.08 0.38 – 3.56 0.903 Ever been detained or prisoned Yes No (ref) 1.53 0.50 – 4.740 0457 Duration on MMT (year) 0.60 0.46 – 0.79 <0.001 0.51 0.33 – 0.78 0.002* MMT dose (mg) 0.99 0.97 – 1.01 0.279 MMT compliance Yes No (ref) 0.69 0.19 – 2.52 0.574 Start ART Yes No (ref) 0.21 0.07 – 0.66 0.008 0.21 0.04 – 0.97 0.046* CD4 baseline (cells/mm3) 1 0.998 – 1.002 0.883 Existing OI 1.592 0.528 – 4.803 0.409 ART counselling Yes No (ref) 0.12 0.03 – 0.56 0.007 0.13 0.02 – 0.85 0.033* Page 96 Conclusion Three factors were identified as protective factors for mortality among HIV-positive PWID in Malaysia. 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