Impact of prerelease methadone on mortality among people with HIV and opioid use disorder after prison release: results from a randomized and participant choice open-label trial in Malaysia

Opioids are responsible for 70% of the years of healthy life lost annually to substance use [1]. In 2016, an estimated 26.8 million people worldwide were living with an opioid use disorder (OUD) [2]. Injection of opioids with contaminated equipment remains a key driver of the HIV/AIDS pandemic in many regions [3]. Punitive drug policies have resulted in high rates of incarceration among people with OUD, many of whom are people with HIV (PWH). An estimated 3.8% of people in prison worldwide are HIV-positive [4], and one third to one half of the global prison population are people who inject drugs [5]. Given the high prevalence of HIV and OUD in prison populations, the provision of humane and evidence-based HIV and substance use disorder treatment in prisons is both a human rights and public health imperative [6]. In many countries, however, prisons are not equipped to provide such services [7]. Nor do many coordinate transitional services for postrelease continuity of care. Consequently, discontinuation of treatment, relapse to substance use, and viral rebound often occur in people with OUD and HIV following prison release [8]. This combination of significant treatment needs and structural barriers to care before and after prison release contributes to the overall high global mortality in people released from correctional facilities [9, 10].

In addition to the health risks many people encounter when they leave prison, people with OUD and HIV face risks related to these conditions. Drug overdose is the most common preventable cause of death in people with OUD and in people released from prison worldwide [9, 11]. Even after long periods of abstinence during incarceration, relapse to opioid use after prison release approaches 90% among those with OUD and contributes substantially to mortality that occurs during the immediate postrelease period [10, 12‐14]. The share of postrelease deaths attributable to HIV in the U.S. and other high-income countries has declined [15]. Linkage to care postrelease, however, remains suboptimal [16], and even in the U.S., HIV may supersede drug overdose as the leading cause of postrelease death in people with HIV [17]. Studies of postrelease mortality in middle-income countries, where HIV prevalence in prisons is higher, have concluded similarly that people with HIV are at substantial risk for HIV-related opportunistic infections and HIV-related death after prison release [18, 19]. This study was conducted in Malaysia, where HIV prevalence is significantly higher among men in prison compared with men in the general population, and most incarcerated men with HIV also meet criteria for OUD [20, 21]. Given the high burden of medical and psychiatric comorbidities in this population, mortality risk may be high [20‐23].

Maintenance with opioid agonist therapies (OAT) like methadone or buprenorphine are the most effective strategies for treating OUD [24]. Evidence shows that OAT reduces non-prescribed opioid use, overdose, mortality, and injection-related HIV risk behaviors and improves health and social functioning [25‐29]. Moreover, OAT that is started within prison increases linkage and retention to OAT in the community postrelease [30‐38]. Two large retrospective cohort studies from Australia and England showed that prerelease OAT was associated with lower all-cause mortality in the four weeks postrelease [14, 39]. Additionally, OAT improves HIV-related health outcomes, including initiation of antiretroviral therapy (ART), ART adherence, and viral suppression, which is the single-largest contributor to decreasing HIV-related mortality [40].

In this study, we estimated the effect of prerelease methadone initiation on postrelease mortality in men with HIV and OUD. Our hypothesis, based on formative work in Malaysia [41, 42] and studies of prerelease methadone in Kyrgyzstan [43] and the U.S. [32], was that starting methadone within prison would reduce postrelease mortality by decreasing opioid overdose and increasing engagement in HIV care and adherence to ART. To test this hypothesis, we linked national death records to data from an open-label trial of prerelease methadone conducted with imprisoned and soon-to-be-released men with OUD and HIV in Malaysia. This study is, to our knowledge, the first to examine postrelease mortality and the possible survival benefits of prerelease OAT in this population.

The postrelease mortality rate was extraordinarily high (71.1 deaths per 1000 PY) in this sample of men with OUD and HIV. Although few studies provide an opportunity for direct comparison, studies in populations with one or more of these risk factors have documented far lower mortality rates. For comparison, mortality among released prisoners globally is estimated at about 10 deaths per 1000 person-years [9, 57]. Mortality rates lower than ours also have been observed in people with HIV who use opioids (28.6 deaths per 1000 PY), released prisoners with untreated OUD in Australia (36.7 deaths per 1000 PY) [14] and Taiwan (26 deaths per 1000 PY) [58], and even in released prisoners with HIV in French Guiana (33.8 deaths per 1000 PY) [18] and the U.S. (28.6 deaths per 1000 PY) [59]. Only one study, a cohort of men with HIV released from prisons in Indonesia, documented higher mortality rates (215 deaths per 1000 PY), but was based on a relatively small sample [19]. Elevated mortality rates in our study and the Indonesian cohort are unsurprising, perhaps, given the combined risk of OUD, HIV, and prison release in these cohorts.

The few existing studies of prerelease methadone that have examined postrelease mortality have generally shown some survival benefit, which stands in contrast to our study that failed to detect a postrelease survival benefit. Two large cohort studies in Australia and England, both with very little PWH, concluded that prerelease OAT increased survival, but only in the first postrelease month [14, 39]. A three-arm randomized trial in the US showed one postrelease death in each of the two groups treated with methadone (immediately before or after prison release) compared to six deaths in a group that received neither [32]. In one other trial in the U.S. examining within-prison methadone, postrelease mortality was negligible [31]. The hypothesized pathway through which within-prison methadone would reduce postrelease mortality is through increasing postrelease methadone treatment, though incomplete data limited our ability to conduct an as-treated analysis accounting for post-release methadone receipt.

Our study differs from prior research on prerelease methadone and postrelease mortality in that it included only people with HIV. This difference in inclusion criteria alongside critical differences in social and epidemiological context in Malaysia versus higher-income settings may explain in part why we did not detect any postrelease survival benefit from prerelease methadone. The benefits of prerelease methadone have mainly been demonstrated in high-income countries where life expectancy for people with HIV is higher and OAT effectively prevents relapse to opioids and overdose [30‐34], which is the leading cause of postrelease mortality in these settings [9]. By contrast, our sample was drawn from a prison population with numerous HIV-related health risks and perhaps fewer risks related to opioid use. In Malaysia, while non-fatal overdose among people who use opioids is common [23], rates of fatal overdose are unknown, as are the relative contributions of HIV and opioid-related mortality in this population. For men with OUD and HIV released from prison in Malaysia, the risk of death associated with advanced HIV disease may supersede the risks associated with opioid use disorder, treated or not.

We cannot exclude overdose as a cause of death due to possible underreporting, yet no cases of fatal overdose were reported in our data. Our findings are consistent, however, with the theory that inadequately treated HIV, not overdose, is the primary contributor to postrelease mortality in this population. Moreover, given that most of the participants in this study selected methadone, those at highest risk for overdose may have selected a protective treatment. As further evidence, baseline CD4⁺ T-lymphocyte count strongly predicted mortality, and most causes of death recorded by pronouncing physicians identified some underlying infectious etiology, many of which represented AIDS-defining illnesses. Thus, in incarcerated persons leaving prison, untreated HIV may serve as a more proximal risk for death. Finally, we did not observe markedly higher mortality rates in the period immediately after release, as would be expected if deaths were caused by opioid overdose [10].

While evidence from other settings has shown that OAT can improve HIV treatment outcomes [40], this may not have occurred in our sample. Reasons may include that despite initiating methadone in prison, participants may not have adhered to it or may have discontinued it postrelease. Additionally, linkage to HIV care postrelease may have been poor due to structural barriers. In some high-income settings, postrelease linkage to ART has been found to be low [60], and this is also likely to be the case in Malaysia, where the number of people with HIV receiving treatment is low despite ART being fully subsidized [61]. Provider discrimination may play a role: more than half of sampled Malaysian HIV care providers in one study were unwilling to start ART in patients who injected drugs or were recently released from prison, even at very low CD4⁺ T-cell counts [62, 63]. In addition to stigma and discrimination, the intersection of poorly treated HIV and other medical and social vulnerabilities, such as untreated tuberculosis or chronic diseases, lack of housing, and food insecurity, may increase risk of death. Improving access to quality care for HIV and other medical comorbidities as well as social services for people who use drugs in Malaysia will be a crucial step to reducing health disparities in this population [62].

Factors related to methadone implementation also may explain why we failed to detect an impact of prerelease methadone on postrelease mortality in this study. First, participants allocated to methadone may not have reached an optimal dose before release for reasons including inability to tolerate the titration schedule or being released early before completion of the titration [42]. An as-treated analysis defining treatment as receipt of at least 60 mg of methadone prerelease, however, also was consistent with a null effect; other studies have suggested that optimal doses to engage persons released from prison should receive higher dosages in excess of 80mg [42, 43]. Second, some participants allocated to receive methadone may not have been linked successfully to methadone treatment after release, and some participants not allocated to receive prerelease methadone may have initiated community methadone treatment postrelease. A main study limitation is the absence of complete data on methadone utilization postrelease. Fourth, because the study was not powered to detect survival differences, absence of evidence for a treatment effect could be due to low power. Fifth, selection bias among non-randomized participants due to factors omitted in our adjustment strategy could have biased our estimates toward a null treatment effect. We did not, however, detect an effect in the subsample of randomized participants, where selection bias was not an issue, though our power to detect an effect in this subsample was lower. Finally, we were unable to distinguish deaths that occurred in the community from deaths that may have occurred in prison among participants who were reincarcerated during the postrelease observation period. It should be noted that methadone could have positively impacted other health and social outcomes in our sample including potentially by reducing injection drug use, but this was not the focus of this analysis. Implementation challenges as well as barriers and facilitators to postrelease retention in this trial have been previously reported [44, 46].

Of interest, pre-incarceration alcohol use, reported by 19.2% of participants, was predictive of postrelease mortality. In people with HIV, alcohol use is associated with increased mortality [64]. Alcohol use also has been implicated in overdose deaths in people who use opioids [23, 65], and in the deaths of people receiving methadone for opioid use disorder [66, 67]. One promising intervention meriting further investigation is extended-release naltrexone, which has been associated with improved postrelease HIV treatment outcomes separately in people with opioid and alcohol use disorders [68, 69].

In men with HIV and opioid use disorder in Malaysia, mortality after prison release is high and mainly attributable to HIV/AIDS. Prerelease methadone that has been shown elsewhere to improve health outcomes related to substance use and HIV was not associated with a mortality benefit in this study, which may be due to study limitations as well as an epidemiological context in which advanced and poorly managed HIV superseded opioid-related fatalities as the predominant driver of mortality. Improving patient access to ART and ensuring continuation of ART postrelease is urgently needed to reduce mortality among men with HIV and opioid use disorder in Malaysia. Future research should continue to explore promising biomedical interventions (including patient preferences for and use of long-acting injectable agents for OUD and HIV), behavioral interventions (including peer navigation), and structural interventions (including targeting provider discrimination, lowering barriers to treatment entry, and collocating services) to improve HIV and OUD treatment outcomes in this population.