Abstract
Long-acting injectable antiretroviral medications are new to HIV treatment. People with HIV may benefit from a treatment option that better aligns with their preferences, but could also face new challenges and barriers. Authors from the fields of HIV, substance use treatment, and mental health collaborated on this commentary on the issues surrounding equitable implementation and uptake of LAI ART by drawing lessons from all three fields. We employ a socio-ecological framework beginning at the policy level and moving through the community, organizational, interpersonal, and patient levels. We look at extant literature on the topic as well as draw from the direct experience of our clinician-authors.
Avoid common mistakes on your manuscript.
Introduction
Forty years into the HIV pandemic, advances in antiretroviral treatment have dramatically reduced HIV-related morbidity and mortality for people with HIV (PWH) who adhere to daily oral antiretroviral medications (ART) [1]. However, many people do not adhere to the daily regimen and thus the benefits of these advances in treatment have not been sufficient to then the epidemic nor distributed uniformly. Some key populations disproportionately do not reach or maintain the critical milestone of HIV suppression: undetectable viral levels in blood plasma. In 2019, 81.3% of PWH were linked to care within 1 month of their diagnosis, but only 65.5% of those linked to care were virally suppressed by 6 months following diagnosis [2]. This suggests that the other 34.5% of PWH were either not prescribed ART, were not adherent to the regimen, or discontinued treatment.
Long-acting injectable (LAI) formulations of medications may help fill the gap by improving uptake, adherence to, and persistence of treatments and preventives for chronic conditions like HIV. The longer-standing experiences of delivering LAIs for other chronic diseases offer insights into the delivery and use of newly available LAIs for HIV prevention and treatment. The latter is also referred to as long-acting injectable antiretroviral therapy or LAI ART for short. Lessons learned from the longer-standing use of LAIs in the fields of mental health and addiction treatment hold particular relevance given that they treat a population that includes people with HIV (PWH). Moreover, conditions from the three fields strongly overlap with one another and have been studied as a syndemic, with other conditions often grouped in as well [3,4,5]. A large cohort study of HIV-positive adults found that nearly half had a history of substance use disorders (SUDs) [6]. The prevalence of mental health disorders among PWH is several times higher than the general population [7] and, if anything, conditions like depression are underdiagnosed in HIV care [8]. Furthermore, the prevalence of HIV is substantially higher among adults with serious mental illnesses such as psychosis and bipolar disorder than those without mental illness [7]. Drug and alcohol dependence are associated with decreased access to and use of healthcare, reducing the likelihood of being prescribed ART (and adherence once prescribed) [9]. Similarly, untreated mental illness results in worse outcomes for treatment of both HIV infection and SUDs [9].
In January 2021, the US Food and Drug Administration (FDA) approved the first LAI ART, cabotegravir/rilpivirine. We employ a socio-ecological framework to discuss issues surrounding the implementation of LAI medications for all three types of conditions and explore ways to maximize potential benefits for HIV [10]. We start with some background on the current state of LAI ART, followed by a discussion that moves from the policy level through the community, organizational, interpersonal, and patient levels. This commentary’s authors include psychiatrists, addiction specialists, HIV providers, health services researchers, and health policy experts. We draw from our own professional experiences and the extant literature to discuss barriers, facilitators, and issues of costs and ethics related to LAIs in the fields of mental health, SUD, and HIV.
A note about scope: when discussing LAIs in psychiatry to address mental illness, our focus is on anti-psychotic medications and for SUDs, on the treatment of opioid use disorders (OUDs). LAI antipsychotics have the longest history, with the first generation of these medications introduced in 1966, and the first second-generation LAI antipsychotic approved starting in 2003 [11, 12]. The FDA first approved extended-release naltrexone in 2010 for relapse prevention in people with OUD following detoxification [13] and extended-release buprenorphine in late 2017 for those who had initiated treatment with transmucosal (absorbed through mucus membrane) buprenorphine [14].
Background
Current HIV Treatment Landscape
LAI cabotegravir/rilpivirine is currently the only FDA-approved injectable ART for patients who have reached viral suppression using oral medication. Initiating and treating a patient on the regimen currently includes the following steps: (1) assessing the patient for clinical appropriateness, (2) beginning the treatment regimen with an oral version of the injectable regimen (also called a “lead-in period”) to establish tolerability, (3) if tolerated, administering a large initial dose (loading dose), and (4) then providing ongoing smaller subsequent doses at 1–2 month intervals.
An in-depth discussion of potential complications is beyond the scope of this paper, but includes potential drug interactions, the need to switch back to oral medications should the injections be delayed from their regular schedule (called “bridging”), and the risk of viral resistance should treatment delays become too long or frequent. Some infrastructural considerations moving forward include developing the capacity for home-based or point-of-care delivery (e.g., pharmacies or other businesses) of LAI treatments [15]. Also important is the harmonization of tracking records to ease implementation across multiple access sites. Several entities, including the manufacturers of cabotegravir/rilpivirine, have ongoing efforts to increase provider awareness about injectable ART options, as well as to discuss and address potential staffing, tracking, patient counseling, and medication administration needs.
In addition to challenges to ART uptake and adherence outlined at the beginning of the introduction, documented disparities in HIV treatment outcomes include differences by age and among racial/ethnic, sexual, and gender minorities [16]. Individuals facing adverse social and structural barriers (e.g., housing instability) [17, 18], poverty [19], criminal justice involvement [20], HIV-related stigma [21], intimate partner violence [22], and SUDs [23] are at increased risk for suboptimal retention in care and medication adherence. The introduction of LAIs ART, which reduces the need for frequent dosing, increases the potential for discreet treatment, and alleviates “pill fatigue,” thus has the potential to help reduce those disparities. However, LAIs could also introduce new challenges and new barriers for these marginalized groups that must be addressed proactively. Examining lessons learned in implementing LAIs for the treatment of SUDs and mental illness provides opportunities to identify and address such challenges and barriers early in the rollout of LAI ART.
Policy
Cost
LAIs for mental illness and OUD are expensive relative to oral treatments and cost is often a structural barrier. Nevertheless, they have been found to be cost-effective. That the medications are both costly and cost-effective underlines the importance of committing up-front investment to realize the benefits of this intervention and to ensure that costs are distributed equitably.
Anti-psychotic LAI medications are associated with better health outcomes when compared to oral formulations [24]. The higher initial cost for anti-psychotic LAIs is offset by lower subsequent costs for medical care through mechanisms like lower hospitalization rates and shorter inpatient stays [25, 26]. The lower social costs of well-controlled schizophrenia include reduced involvement in the criminal legal system, substance abuse, and violence [27].
The cost of LAI ART and several first-line oral HIV medications is comparable [28]. According to the U.S. Department of Health and Human Services, the monthly average wholesale price of LAI cabotegravir/rilpivirine ranges from $4752 to $7218 depending on the dose, which amounts to $43,308 per year for bi-monthly injections or $57,024 per year for monthly injections (excluding oral lead-in and initiation injections). In comparison, the annual average wholesale price of bictegravir/emtricitabine/tenofovir–one of the most commonly prescribed oral HIV medication combinations—is $48,876 [29]. This formulation is still under patent, and branded versions of antiretrovirals are substantially more expensive than generic versions [30]. Thus, as patents for oral HIV medications continue to expire, the cost differential between LAIs and oral medications will grow. Still, LAIs may remain cost-effective given greater beneficial impacts on adherence and viral suppression [28]. Because youth experience particular challenges adhering to ART for both treatment and prevention [31,32,33], cost analyses should estimate relative cost and benefits specific to young PWH.
There are important distinctions between the potential benefits of LAI ART as compared to LAIs for mental illness and SUD. ART adherence has been estimated at 63.4% worldwide and 74.1% in the U.S. [34, 35]. This adherence rate is higher than estimates for patients taking oral buprenorphine (37.1–41.3%) and among patients with schizophrenia taking antipsychotics (31.5–68.7%) [24, 36]. Given the differences between the medications and the conditions they are intended to treat, the variation in adherence numbers are expected. The types of costs associated with undertreated HIV and undertreated mental illness and SUD also differ. HIV, as distinct from substance use and schizophrenia, is a communicable illness with an estimated, discounted lifetime treatment cost of $420,285 in 2019 U.S. dollars, on average [37]. Poor adherence increases the risk of onward horizontal and vertical transmission, as it increases levels of circulating virus above the level that prevents HIV transmission to sexual partners and from birthing parents to their offspring [38, 39]. For all three specialties, documented costs include hospitalization, whose cost is borne by third-party systems such as public payers. For SUDs and mental illness, additional costs include engagement with the criminal legal system, fatal overdose, and increased risk of victimization from (or perpetration of) violence [40,41,42,43,44,45]. For individuals dually diagnosed with mental illness and SUD, social costs may be compounded.
Insurance Coverage
Medicare considers ART medications a “protected drug class” that must be included in Medicare Part D formularies. However, while some Medicare Advantage plans may opt to cover cabotegravir/rilpivirine under Part D, it will likely be covered more often under the less protected Part B as a physician-administered drug. Additionally, because ART medications are quite costly, insurers may institute cost-containment conditions, including requirements for prior authorization, patient cost sharing, step therapy, and formulary exclusions. These practices can impede appropriate LAI prescribing [46].
Cost-containment practices may vary depending on whether medications are prescribed under the medical benefit for injections administered in the medical provider’s office or under the pharmacy benefit. Utilization management is more common for limiting the use of high-cost medications under a plan’s pharmacy benefit [47]. Although the pharmacy benefit typically covers oral products and self-administered injectables, more provider-administered products are starting to fall under the pharmacy benefit [48].
Experience with insurance coverage for LAI antipsychotic medication delivered at the point of care suggests that when the LAIs are insured under the plans’ medical benefit, providers may have to pay in advance and stockpile the medications before injecting them and then seek reimbursement from third-party payers as they are used. This is considered “buy-and-bill” purchasing. This process can be complicated and cost-prohibitive due to the high up-front costs. This may present a barrier to HIV LAI prescribing, particularly for clinics that cannot afford the high upfront costs that come with cabotegravir/rilpivirine.
PWH who lack public or private insurance, many of whom are undocumented or live in Southern states that have not expanded Medicaid, can receive HIV treatment and wraparound services through the Ryan White HIV/AIDS Program. However, Ryan White covered providers are largely unavailable in rural parts of the country, putting the high-cost HIV medications out of reach for many PWH, whether oral or injectable. A report by the South Carolina Rural Research Center found that 95% of rural U.S. counties lacked a Ryan White provider [49]. A disparity in provider access between urban and rural areas may widen geographic differences in LAI access (which cannot be delivered in the mail like oral pills), leading to disparities in HIV outcomes. This dynamic warrants improvement in rural access to comprehensive HIV care.
The potentially higher costs of LAIs for HIV may dissuade correctional institutions from providing them, and those patients who do access them during incarceration may struggle to do so on release. The period following incarceration is characterized by a disruption of care, including for HIV [50]. PWH with SUD are at particular risk for negative outcomes during reentry, with even a brief incarceration strongly associated with virologic failure among people who use injection drugs [51]. According to a 2015 systematic review, the number of PWH receiving ART while incarcerated varies widely, but on average 65% received it during incarceration, a number that dropped to just 37% following release [52]. LAIs, if administered before release, could help cover the period immediately following re-entry into the community [53]. But policy barriers remain; health coverage during periods of incarceration in the U.S. is complicated by the Federal Medicaid Exclusion Act. Medicaid is not available to otherwise-qualified individuals while incarcerated, except for those who are hospitalized overnight while in custody, necessitating correctional institutions to finance medications themselves. U.S. carceral institutions are also not eligible for 340B pharmaceutical pricing, which substantially increases the costs that they pay for HIV medications compared with those providers that treat these same populations in the community [54]. The situation is not, however, static. Many states have moved to suspend, rather than terminate Medicaid during incarceration, facilitating reinstatement, and some local initiatives work to facilitate access to Medicaid during the transition from incarceration to reentry [55]. In 2019, 90% of state prison systems had at least one prison where buprenorphine, methadone, or naltrexone is available, and 62% have at least one prison that offers all three medications [56].
Community
Stigma and Marginalization of People Living with Specific Health Conditions
Although HIV, mental illness, and SUD are biologically and experientially distinct, all are chronic, highly stigmatized conditions that disproportionately affect populations that have otherwise experienced marginalization. Higher burdens or worse outcomes of these conditions are documented among Black, Latinx, and Indigenous populations, sexual and gender minority communities, people who are incarcerated, and those experiencing poverty [57]. Care of patients with these conditions has historically been fraught, as many clinicians and systems of care have contributed to this stigma, marginalization, and mistreatment [57]. Furthermore, these conditions are not mutually exclusive. It is estimated that 31% (95% CI 28–34%) PWH have moderate-to-severe levels of depression [58] and 25% (CI 95%, 21–30%) have an anxiety disorder [59]; however, the estimated prevalence of psychoses that are treatable with LAIs has only been published in studies with small, non-representative samples of PWH. The literature showing elevated frequencies of substance use in PWH is extensive [60] and, in recent years, has included outbreaks among people who inject opiates [61].
The U.S. has always had a low rate of use of LAI antipsychotics compared to European countries [62]. LAIs in the U.S. have likely been preferentially used in settings where clinicians are concerned about low rates of treatment adherence and persistence and in settings of inadequate treatment infrastructure, comorbid substance abuse, or housing instability. Differences in administration by race have also been identified. Around the year 2000, researchers found LAI antipsychotics to be prescribed to Black patients in the U.S. at higher rates than other patients, regardless of the clinical setting [63, 64]. Although a recent study in a large US county mental health system did not find this difference [65], a recent United Kingdom-based study also found increased LAI use among Black patients [66]. Potential racial differences in the use of LAI antipsychotics contribute to concerns about coercion and ethics, including involuntary treatment and the prioritization of clinical or social goals over patient autonomy [57]. The often legally mandated use of LAI antipsychotics, including for court-ordered treatment and carceral settings, makes navigating these issues more challenging for concerned providers and health systems. The frequent association of LAI antipsychotics with coercion and involuntary treatment is unfortunate given that data supports better outcomes compared with oral antipsychotics, and that LAI formulations can be used in a collaborative manner that improves patient autonomy, satisfaction, and quality of life [67]. We explore issues of coercion further below.
Medical Mistrust
While LAI ART treatment lacks the troubled history of LAI antipsychotics, concerns related to potential coercion and malfeasance remain. Since the beginning of the AIDS pandemic, outreach, prevention, and treatment have faced significant mistrust from the communities most affected. Often rooted in historical and current experiences of racism, homophobia, and stigma [68, 69], medical mistrust and conspiracy beliefs are rational responses to engaging sometimes hostile systems of care that are embedded within larger societies infused with these ideologies [70]. Mistrust in the setting of LAI ART has been perceived as a barrier, particularly for Black patients, and community engagement is critical for effective message development and successful implementation [71]. Principal among these concerns was the idea that HIV itself and later that HIV testing, treatment, and prevention efforts (including needle exchange and condoms) were intended to rid society of unwanted members [72,73,74,75,76,77,78]. Conspiracy beliefs that people were infected with HIV while having blood drawn for HIV testing or that HIV was introduced into African populations through vaccination campaigns, rather than emerging naturally from chimpanzee species, hampered HIV testing campaigns early in the U.S. pandemic [79]. Recent surveys indicate that substantial percentages of Black Americans continue to harbor conspiracy beliefs, though the association of mistrust with preventive behaviors is complex [80].
Organizational
Infrastructure
Infrastructure issues vary between the three specialties. Capacity is critical to administering LAIs and includes addressing needs related to training and staffing, storage, and in some cases, refrigeration [81]. Many mental health providers lack the nursing staff to directly deliver injections. Although some pharmacies work with such providers so that they are set up to administer anti-psychotic LAIs, current partnerships of this kind do not appear to be widespread. Private group practices that do not regularly staff nurses also may pool resources to hire a nurse to administer injections on a set day of the week and to purchase equipment such as refrigerators to store medications [81]. MOUD treatment happens in opioid treatment programs, inpatient/outpatient rehabilitation centers, and primary and psychiatric care clinics in addition to emergency rooms. Most of these settings can offer injections. However, some may lack the refrigeration required to store cabotegravir/rilpivirine. In the HIV context, therefore, healthcare providers may have the capacity to administer LAIs for ART but still need to determine how to address the need for medication storage and more frequent visits among patients on LAIs compared with those on daily oral treatments. The HIV care system also benefits from existing networks of specialty care delivery, such as the Ryan White HIV/AIDS Program and large provider networks (e.g., AIDS Healthcare Foundation) that might facilitate the widescale rollout of LAIs.
The increasing role that pharmacies have played in addressing the COVID-19 pandemic underscores the importance of pharmacies in successful LAI implementation. In the United States, pharmacists already perform injections for a wide variety of medication classes, including antipsychotics and long-acting opioid agonists [82]. To both increase capacity and reduce the time and travel associated with obtaining LAI, providers should identify pharmacies and community-based drugstores that have personnel able to perform injections, and policymakers should consider some manner of financial incentive for LAI administration by pharmacists. Restructuring of clinic schedules, electronic health record systems, and reimbursement structures may facilitate the increased frequency of short visits required for LAI treatment in the HIV context.
Coercive Environments
The use of LAIs differs by specialty when it comes to use in carceral settings. The use of LAI antipsychotics has been explored in some locales and jail settings, where the medication has been set as a condition of supervised release [83]. Involuntary administration of ART is rare in this and other settings. To our knowledge, there are no instances of mandated HIV treatment in carceral settings; hence, individuals who have been mandated or forced to use LAI antipsychotics may struggle to accept or understand the idea of voluntary use of LAI ART. Furthermore, given that institutionalized patients have control over a few other aspects of their daily lives, the ability to accept or refuse a daily medication may be one of the few ways to enact bodily agency. Injection with a treatment that endures in the body for weeks to months relinquishes that control [57, 84].
SUDs are common among people in jails and prisons, including those with HIV [85]. Interest is growing in the use of LAI for SUD in correctional settings, with naltrexone favored over buprenorphine by many leaders in the criminal legal system [86]. Although at least one study has shown naltrexone to support the achievement of HIV viral suppression relative to placebo among PWH following reentry [87], both the requirement for detoxification before naltrexone initiation and the treatment’s mechanism of action can increase the risk of fatal overdose [88]. Given the multiple inequities contributing to the overrepresentation of Black people in correctional facilities, the preference for naltrexone in this setting likely contributes to large disparities in buprenorphine use in this population [89].
The ability to maintain adherence to daily oral medications while still in custody is already facilitated by several key factors: systems of control/coercion, stable housing, food security, access to medication regimens with minimal hurdles, and regular dispensing of medication directly to patients, obviating the need for transportation [90]. For these reasons, ART adherence and HIV viral suppression in the U.S. tend to improve when PWH are incarcerated compared with the periods preceding arrest and following reentry [52]. Hence, shifting patients from oral to LAI formulations may not improve viral suppression in custody. However, institutions with longer average stays may practically benefit from the implementation of LAI ART because medication administration in these settings is often carried out one or more times daily by medical staff (i.e., pill call). The lower personnel costs associated with bimonthly injections relative to daily pill administration may make LAIs more cost-effective than oral formulations, especially in carceral settings with high HIV prevalence.
Short-term incarcerations (< 30 days) pose a risk for HIV treatment disruption, one that may be avoided in patients who are on LAIs before entering a correctional facility [91]. Cabotegravir/rilpivirine injections may be difficult to initiate in jail or short-term treatment settings because of the several-week lead-in regimen. The lead-in will soon be optional, but the requirement for virologic suppression will remain; nevertheless, providers are known to use it off label for treatment-experienced patients who are not fully suppressed. However, if the oral bridge to the LAI formulation could be completed and the first (lead-in) injection administered shortly before release, LAIs for HIV might reduce the likelihood of post-release spikes of HIV viremia. A person’s ability to adhere to medication regimens is tested upon release, as the factors that help maintain it while incarcerated disappear and barriers to stability and routine emerge [91, 92]. For this reason, both individuals nearing reentry and their sex- and drug-using partners in the community may stand to gain the most benefit from LAI ART as they have the potential to maintain viral suppression and reduce forward HIV transmission during a critical period of potential increased risk of HIV transmission [93,94,95]. Analogously, the administration of opioid agonists (methadone and buprenorphine) at release has been shown in observational studies to reduce fatal overdose compared with no treatment [96].
Interpersonal
Providers
Provider perceptions and readiness to prescribe LAIs differ by specialty. Although initial studies of LAI antipsychotics showed a reduction in morbidity resulting from their use, they were not well received by psychiatrists who were concerned about increased side effects and patients’ ability to maintain therapeutic drug levels. Patients’ rights groups also argued that LAIs eliminate patient choice. However, beginning in the 1970s, studies increasingly showed that LAIs reduced relapse rates when compared with oral formulations, leading to the growing acceptance and use in the profession. Internationally, LAIs seem to be preferred to oral medication in some regions due to cultural perceptions that injected medications have greater potency [97].
The training required for providers to treat patients with MOUD, specifically buprenorphine, presents a barrier but does not currently differ between oral versus injectable formulations [98]. Despite guidelines that encourage LAI antipsychotic prescription based on patient preference at all stages of illness, provider misperceptions persist that LAIs are non-first-line agents to be reserved for patients with severe or resistant illness [99]. This misunderstanding creates an unnecessary barrier to access for patients who could benefit from early LAI use.
HIV providers may have the same perception and may not fully appreciate the benefits of prescribing LAI treatment. Finally, many rural settings lack HIV specialists, leading patients to receive care from non-specialists or to travel long distances for HIV care. Non-specialists may feel especially uncomfortable with providing LAIs for ART, and the need to travel long distances for treatment may make frequent clinic-based injections infeasible. Finally, the lack of Ryan White-funded providers in many rural areas means a lack of supportive services that could be marshaled to support consistent LAI use [100].
A significant lack of knowledge about and comfort with prescribing LAIs exists among prescribers. The most common reason patients are not given an LAI is that their provider fails to offer it [101]. As addiction medicine is a subspecialty, providers often lack the training required to address many aspects of OUD assessment and treatment and many patients with OUD never receive this level of care [102]. Provider stigma toward patients with OUD, including concerns about misuse and diversion of MOUD [103], can be as high or higher than among the general public [104]. Providers often overestimate the degree to which their patients are hesitant to try LAIs, which emphasizes the need for guidelines or requirements that providers routinely offer LAIs to patients. Indeed, an effect of direct-to-consumer pharmaceutical advertising is that patients become more proactive in requesting specific medications from providers who do not offer them upfront [105].
Education about the low likelihood of severe side effects, increased efficacy over oral medication, decreased re-hospitalization, and morbidity associated with LAIs over oral medications (especially in non-randomized controlled trials) are important and effective at increasing LAI use in mental health populations; employing these strategies with the rollout of HIV LAIs may help avoid some of these same pitfalls for PWH [81, 106,107,108].
Patient Navigation
Wraparound services have long been available to PWH through the Ryan White HIV/AIDS Program [109], and peer navigation has been shown to be successful, particularly for populations vulnerable to incarceration [110]. Similar services are far less common for people experiencing mental illness and SUDs, and suggests that the rollout of LAIs for PWH may be more successful. This existing model of support for some PWH can be leveraged to include expanded patient navigation services to facilitate linkages, retention, and adherence to LAI ART. Successful approaches to complement patient navigation services include monetary incentives (both for HIV treatment [111] and for abstinence from drugs) for PWH [112] and mobile applications that provide support, motivation, and education regarding ongoing engagement in HIV treatment [113]. The current formulation for LAI ART requires much more frequent visits than the standard of care for patients on oral treatments, which is generally twice per year. The FDA has approved LAI ART for bimonthly injections, though some may continue to choose monthly injections. In either case, additional patient support is warranted.
Patients
Burdens on patient access and the need for patient education are similar between the three specialties. In the clinician-authors experiences’, several factors associated with patient choice regarding LAIs for mental illness and SUD may apply to PWH as well. They include fear of needles, negative associations with injection drug use especially for those in recovery, concerns about control (such as the irreversibility of the injection), coercion, and loss of bodily integrity. The complexity of switching to an LAI regimen also may dissuade patients. Finally, the requirement that LAI ART is administered via gluteal injections may prevent use in transgender and cis-gender women who have or want these implants. As of this writing, anterior thigh injections are pending FDA approval.
Some people who use opioids report that long-acting buprenorphine would be more convenient and discreet than using daily opioid agonist therapy, particularly if the former is made available outside of the pharmacy or drug treatment setting that they associated with their OUD [84, 114, 115]. LAI antipsychotics have historically lasted 1 month, requiring more frequent patient visits than the standard 3-month visit interval for many psychiatric patients [12]. However, newer LAI antipsychotics have an increased duration of action to 3–6 months [12], lowering patient costs associated with more frequent visits and travel. Additionally, LAI antipsychotics have been associated with increases in adherence versus oral medication that range from 13 to 40% [116,117,118]. Rehospitalization, all-cause mortality, and symptoms have been shown to occur less frequently with LAI antipsychotics vs. oral medications [106, 108, 119, 120].
LAI antipsychotics uptake by patients has been supported by collaborative approaches [121] to discussing the option with patients, including addressing patients’ concerns and the stigma associated with LAIs [26, 101]. Integration of OUD treatment into primary care using a collaborative care intervention resulted in improved patient outcomes [122]. Providers also should address patients’ potential concerns about coercion, emphasize how LAIs provide better control over their illness than oral medication, and explain that their recommendation for LAI use is not based on disease severity [123]. The option of LAIs may improve medication uptake by offering more medication options to suit patient preferences.
Much to many providers’ surprise, many patients in clinical trials of cabotegravir/rilpivirine found injectable monthly ART preferable to daily oral ART and well-tolerated [124]. The most commonly reported side effects centered around pain or tenderness at the injection sites that were most commonly mild to moderate and short-lived. A smaller number of patients had more prolonged or more severe reactions at the site of the injection, and even fewer found the reactions sufficiently intolerable to stop taking the injections [125, 126]. Qualitative research into LAI PrEP and ART has consistently shown patient interest in LAI despite side effects, including among racial, sexual, and gender minority groups [127,128,129,130].
Education is particularly important for patients moving to LAIs from oral formulations as the two treatment approaches operate differently at the physiologic level. Low health literacy is distributed among regions and specific groups in the U.S. in a similar pattern to the HIV epidemic [131]. However, age and racial disparities in the continuum of care persist after accounting for health literacy, suggesting that insufficient education is one of several factors at work [132] (Table 1).
Future Considerations
The rollout of a new treatment modality often faces challenges in finding acceptance among medical practitioners and the public. In the case of LAIs for antipsychotics, providers feared that the medications would fail to achieve a therapeutic dose and cause unacceptable side effects. Advocacy groups in the community used terms like “chemical straitjacket”, asserting LAIs would be used to impose treatment upon patients regardless of their preferences [133].
Even once a level of acceptance is achieved, barriers highlighted in this paper must be addressed early to both minimize negative perceptions and ensure access to those patients who have the greatest potential to benefit from long-acting formulations. The populations most affected by the HIV epidemic are also the populations most likely to both lack access to and mistrust the treatment in the first place [134]. Community engagement and effective messaging are critical [71], but are undermined without policies to ensure provider capacity and enough insurance coverage to get the medications to the patients who are asked to adhere to the regimen and told to trust that the system will work for them. This is a critically important objective at a time when medical mistrust is increasing [134]. Otherwise, many of the above challenges also have the potential to negatively impact the rollout of LAI ART and to widen disparities in HIV outcomes.
Cost-effectiveness analyses have proven useful in encouraging policy and health system support for LAI use for the treatment of mental illness. Additional cost-effectiveness analyses of LAI ART could inform recommendations regarding priorities for expanding access to LAIs for ART. However, even if LAIs prove to be cost-effective for the treatment of HIV infection, the potentially higher upfront cost may impede their dissemination. As demonstrated in other contexts, when LAIs are covered as a medical benefit, insurers may implement cost-containment strategies, such as requiring prior authorization or step therapy [46]. Insurance coverage raises several important questions to address moving forward: Will patient cost sharing require a coinsurance based on the expensive list prices for LAIs or will lower cost copayment be allowed? What will be the cost associated with monitoring LAI use over time? Will pharmaceutical company rebates apply to LAIs, as they do for oral medications? The December 2021 FDA approval of cabotegravir for HIV pre-exposure prophylaxis [135]; heightens the urgency of ensuring an equitable and efficient rollout of LAI ART.
Data Availability
N/A.
Code Availability
N/A.
References
Wandeler G, Johnson LF, Egger M. Trends in life expectancy of HIV-positive adults on antiretroviral therapy across the globe: comparisons with general population. Curr Opin HIV AIDS. 2016;11(5):492–500.
Monitoring selected national HIV prevention and care objectives by using HIV surveillance data—United States and 6 dependent areas, 2019. 2021.
Tsuyuki K, Pitpitan EV, Levi-Minzi MA, Urada LA, Kurtz SP, Stockman JK, et al. Substance use disorders, violence, mental health, and HIV: differentiating a syndemic factor by gender and sexuality. AIDS Behav. 2017;21(8):2270–82.
Yellin H, Beckwith C, Kurth A, Liu T, Castonguay B, Patrick R, et al. Syndemic effect of mental illness and substance use on viral suppression among recently-incarcerated, HIV-infected individuals in the CARE+ Corrections study. AIDS Care. 2018;30(10):1252–6.
Bhardwaj A, Kohrt BA. Syndemics of HIV with mental illness and other noncommunicable diseases: a research agenda to address the gap between syndemic theory and current research practice. Curr Opin HIV AIDS. 2020;15(4):226–31.
Hartzler B, Dombrowski JC, Crane HM, Eron JJ, Geng EH, Christopher Mathews W, et al. Prevalence and predictors of substance use disorders among HIV care enrollees in the United States. AIDS Behav. 2017;21(4):1138–48.
Remien RH, Stirratt MJ, Nguyen N, Robbins RN, Pala AN, Mellins CA. Mental health and HIV/AIDS: the need for an integrated response. AIDS. 2019;33(9):1411–20.
Asch SM, Kilbourne AM, Gifford AL, Burnam MA, Turner B, Shapiro MF, et al. Underdiagnosis of depression in HIV: who are we missing? J Gen Intern Med. 2003;18(6):450–60.
Altice FL, Kamarulzaman A, Soriano VV, Schechter M, Friedland GH. Treatment of medical, psychiatric, and substance-use comorbidities in people infected with HIV who use drugs. Lancet. 2010;376(9738):367–87.
The Social-Ecological Model: A Framework for Prevention: Centers for Disease Control; [cited 2022 Jan 27]. Available from: https://www.cdc.gov/violenceprevention/about/social-ecologicalmodel.html.
Crocq MA. A history of antipsychotic long-acting injections in the treatment of schizophrenia. Encephale. 2015;41(1):84–92.
Parmentier BL. Second-generation long-acting injectable antipsychotics: a practical guide. Curr Psychiatry. 2020;19(3):24–32.
Kjome KL, Moeller FG. Long-acting injectable naltrexone for the management of patients with opioid dependence. Subst Abuse. 2011;5:1–9.
United States Food and Drug Administration. FDA approves first once-monthly buprenorphine injection, a medication-assisted treatment option for opioid use disorder [press release]. Silver Spring: United States Food and Drug Administration, 2017.
Bassett IV, Govere S, Millham L, Frank SC, Dladla N, Thulare H, et al. Contraception, HIV services, and PrEP in South African hair salons: a qualitative study of owner, stylist, and client perspectives. J Community Health. 2019;44(6):1150–9.
Centers for Disease Control and Prevention. HIV surveillance report, 2019, vol 32. 2020 Available from: https://www.cdc.gov/hiv/library/reports/hiv-surveillance.html.
Aidala AA, Wilson MG, Shubert V, Gogolishvili D, Globerman J, Rueda S, et al. Housing status, medical care, and health outcomes among people living with HIV/AIDS: a systematic review. Am J Public Health. 2016;106(1):e1–23.
Stanic A, Rybin D, Cannata F, Hohl C, Brody J, Gaeta J, et al. The impact of the housing status on clinical outcomes and health care utilization among individuals living with HIV. AIDS Care. 2021;33(1):1–9.
Pellowski JA, Kalichman SC, Matthews KA, Adler N. A pandemic of the poor: social disadvantage and the US HIV epidemic. Am Psychol. 2013;68(4):197–209.
Teixeira da Silva D, Bachireddy C. To End The HIV Epidemic, Implement Proven HIV Prevention Strategies In The Criminal Justice System, Health Affairs Blog. 2021. https://doi.org/10.1377/hblog20210524.22962.
Rueda S, Mitra S, Chen S, Gogolishvili D, Globerman J, Chambers L, et al. Examining the associations between HIV-related stigma and health outcomes in people living with HIV/AIDS: a series of meta-analyses. BMJ Open. 2016;6(7): e011453.
Machtinger EL, Haberer JE, Wilson TC, Weiss DS. Recent trauma is associated with antiretroviral failure and HIV transmission risk behavior among HIV-positive women and female-identified transgenders. AIDS Behav. 2012;16(8):2160–70.
Mellins CA, Havens JF, McDonnell C, Lichtenstein C, Uldall K, Chesney M, et al. Adherence to antiretroviral medications and medical care in HIV-infected adults diagnosed with mental and substance abuse disorders. AIDS Care. 2009;21(2):168–77.
Zhang W, Amos TB, Gutkin SW, Lodowski N, Giegerich E, Joshi K. A systematic literature review of the clinical and health economic burden of schizophrenia in privately insured patients in the United States. Clinicoecon Outcomes Res. 2018;10:309–20.
Pilon D, Tandon N, Lafeuille MH, Kamstra R, Emond B, Lefebvre P, et al. Treatment patterns, health care resource utilization, and spending in Medicaid beneficiaries initiating second-generation long-acting injectable agents versus oral atypical antipsychotics. Clin Ther. 2017;39(10):1972-85.e2.
Correll CU, Citrome L, Haddad PM, Lauriello J, Olfson M, Calloway SM, et al. The use of long-acting injectable antipsychotics in schizophrenia: evaluating the evidence. J Clin Psychiatry. 2016;77(suppl 3):1–24.
Stahl SM. Long-acting injectable antipsychotics: shall the last be first? CNS Spectr. 2014;19(1):3–5.
Parker B, Ward T, Hayward O, Jacob I, Arthurs E, Becker D, et al. Cost-effectiveness of the long-acting regimen cabotegravir plus rilpivirine for the treatment of HIV-1 and its potential impact on adherence and viral transmission: a modelling study. PLoS ONE. 2021;16(2): e0245955.
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services; 2021.
Neilan AM, Landovitz RJ, Le MH, Grinsztejn B, Freedberg KA, McCauley M, et al. Cost-effectiveness of long-acting injectable HIV preexposure prophylaxis in the United States. Ann Intern Med. 2022. https://doi.org/10.7326/M21-1548.
Hosek SG, Landovitz RJ, Kapogiannis B, Siberry GK, Rudy B, Rutledge B, et al. Safety and feasibility of antiretroviral preexposure prophylaxis for adolescent men who have sex with men aged 15 to 17 years in the United States. JAMA Pediatr. 2017;171(11):1063–71.
Hosek SG, Rudy B, Landovitz R, Kapogiannis B, Siberry G, Rutledge B, et al. An HIV preexposure prophylaxis demonstration project and safety study for young MSM. J Acquir Immune Defic Syndr. 2017;74(1):21–9.
Haberer J, Mellins C. Pediatric adherence to HIV antiretroviral therapy. Curr HIV/AIDS Rep. 2009;6(4):194–200.
Bezabhe WM, Chalmers L, Bereznicki LR, Peterson GM. Adherence to antiretroviral therapy and virologic failure: a meta-analysis. Medicine (Baltimore). 2016;95(15):e3361.
McComsey GA, Lingohr-Smith M, Rogers R, Lin J, Donga P. Real-world adherence to antiretroviral therapy among HIV-1 patients across the United States. Adv Ther. 2021;38(9):4961–74.
Ronquest NA, Willson TM, Montejano LB, Nadipelli VR, Wollschlaeger BA. Relationship between buprenorphine adherence and relapse, health care utilization and costs in privately and publicly insured patients with opioid use disorder. Subst Abuse Rehabil. 2018;9:59–78.
Bingham A, Shrestha RK, Khurana N, Jacobson EU, Farnham PG. Estimated lifetime HIV-related medical costs in the United States. Sex Transm Dis. 2021;48(4):299–304.
Rodger AJ, Cambiano V, Bruun T, Vernazza P, Collins S, Degen O, et al. Risk of HIV transmission through condomless sex in serodifferent gay couples with the HIV-positive partner taking suppressive antiretroviral therapy (PARTNER): final results of a multicentre, prospective, observational study. Lancet. 2019;393(10189):2428–38.
Bavinton BR, Pinto AN, Phanuphak N, Grinsztejn B, Prestage GP, Zablotska-Manos IB, et al. Viral suppression and HIV transmission in serodiscordant male couples: an international, prospective, observational, cohort study. Lancet HIV. 2018;5(8):e438–47.
Ascher-Svanum H, Nyhuis AW, Faries DE, Ball DE, Kinon BJ. Involvement in the US criminal justice system and cost implications for persons treated for schizophrenia. BMC Psychiatry. 2010;10:11.
U.S. Department of Justice, National Drug Intelligence Center. The economic impact of illicit drug use on American Society. Washington, DC: U.S. Department of Justice, National Drug Intelligence Center; 2011.
Florence C, Luo F, Rice K. The economic burden of opioid use disorder and fatal opioid overdose in the United States, 2017. Drug Alcohol Depend. 2021;218: 108350.
Lipsky S, Caetano R, Field CA, Larkin GL. Psychosocial and substance-use risk factors for intimate partner violence. Drug Alcohol Depend. 2005;78(1):39–47.
Boles SM, Miotto K. Substance abuse and violence: a review of the literature. Aggress Violent Behav. 2003;8(2):155–74.
Fazel S, Gulati G, Linsell L, Geddes JR, Grann M. Schizophrenia and violence: systematic review and meta-analysis. PLoS Med. 2009;6(8): e1000120.
Budovich A, Claudio-Saez MM, Hershberger J. Savings on high-cost drugs such as atypical long-acting injectable antipsychotics: switching to billing under the pharmacy benefit in outpatient settings. P T. 2019;44(8):474–96.
Utilization Management Through Medical and Pharmacy Benefit The American Journal of Managed Care. 2020. Available from: https://www.ajmc.com/view/utilization-management-through-medical-and-pharmacy-benefit.
Kaplan DA. How ‘White Bagging’ affects patients, physicians and 340B funding managed healthcare executive. 2021. Available from: https://www.managedhealthcareexecutive.com/view/how-white-bagging-affects-patients-physicians-and-340b-funding.
Vyavaharkar M, Glover S, Leonhirth D, Probst J. HIV/AIDS in rural America: prevalence and service availability. Columbia: South Carolina Rural Health Research Center: University of South Carolina; 2013.
Costa M, Montague BT, Solomon L, Sammartino C, Gutman R, Zibman C, et al. Assessing the effect of recent incarceration in prison on HIV care retention and viral suppression in two states. J Urban Health. 2018;95(4):499–507.
Westergaard RP, Kirk GD, Richesson DR, Galai N, Mehta SH. Incarceration predicts virologic failure for HIV-infected injection drug users receiving antiretroviral therapy. Clin Infect Dis. 2011;53(7):725–31.
Iroh PA, Mayo H, Nijhawan AE. The HIV care cascade before, during, and after incarceration: a systematic review and data synthesis. Am J Public Health. 2015;105(7):e5-16.
Brinkley-Rubinstein L, Rosen DL, Christopher P, Bazerman L, Beckwith CG. Long-acting injectable antiretroviral therapy: an opportunity to improve human immunodeficiency virus (HIV) treatment and reduce HIV transmission among persons being released from prison facilities. Clin Infect Dis. 2017;65(7):1247–8.
Pharmaceuticals in state prisons: how departments of corrections purchase, use, and monitor prescription drugs. The Pew Charitable Trusts; 2017.
Camhi N, Mistak D, Wachino V. Medicaid’s evolving role in advancing the health of people involved in the justice system the Commonwealth Fund. 2020 [cited 2022 Jan 6]. Available from: https://www.commonwealthfund.org/publications/issue-briefs/2020/nov/medicaid-role-health-people-involved-justice-system.
Scott CK, Dennis ML, Grella CE, Mischel AF, Carnevale J. The impact of the opioid crisis on U.S. state prison systems. Health Justice. 2021;9(1):17.
Kates OS. What we know about long-acting injectable antipsychotics can help innovate HIV care. AMA J Ethics. 2021;23(5):E405–9.
Rezaei S, Ahmadi S, Rahmati J, Hosseinifard H, Dehnad A, Aryankhesal A, et al. Global prevalence of depression in HIV/AIDS: a systematic review and meta-analysis. BMJ Support Palliat Care. 2019;9(4):404–12.
Rahmati J, Ahmadi S, Rezaei S, Hosseinifard H, Dehnad A, Shabaninejad H, et al. The worldwide prevalence of anxiety in acquired immune deficiency syndrome patients: a systematic review and meta-analysis. Med J Islam Repub Iran. 2021;35:101.
Wang S-C, Maher B. Substance use disorder, intravenous injection, and HIV infection: a review. Cell Transplant. 2019;28(12):1465–71.
Strathdee SA, Beyrer C. Threading the needle—how to stop the HIV outbreak in rural Indiana. N Engl J Med. 2015;373(5):397–9.
De Risio A, Lang AP. History and therapeutic rationale of long acting antipsychotics. Curr Clin Pharmacol. 2014;9(1):39–52.
Kuno E, Rothbard AB. Racial disparities in antipsychotic prescription patterns for patients with schizophrenia. Am J Psychiatry. 2002;159(4):567–72.
Kreyenbuhl J, Zito JM, Buchanan RW, Soeken KL, Lehman AF. Racial disparity in the pharmacological management of schizophrenia. Schizophr Bull. 2003;29(2):183–93.
Soleman M, Lam N, Woo BK. Ethnic and age disparities in patients taking long-acting injectable atypical antipsychotics. Cureus. 2017;9(10): e1772.
Das-Munshi J, Bhugra D, Crawford MJ. Ethnic minority inequalities in access to treatments for schizophrenia and schizoaffective disorders: findings from a nationally representative cross-sectional study. BMC Med. 2018;16(1):55.
Cusimano J, VandenBerg A. Long-acting injectable antipsychotics and their use in court-ordered treatment: a cross-sectional survey of psychiatric pharmacists’ perceptions. Ment Health Clin. 2020;10(1):18–24.
Bogart LM, Takada S, Cunningham WE. Medical mistrust, discrimination, and the domestic HIV epidemic. In: Ojikutu BO, Stone VE, editors. HIV in US communities of color. Cham: Springer International Publishing; 2021. p. 207–31.
Thomas SB, Quinn SC. The Tuskegee Syphilis Study, 1932 to 1972: implications for HIV education and AIDS risk education programs in the black community. Am J Public Health. 1991;81(11):1498–505.
Myers J, Ball K, Jeffers S, Lawson W. Medical mistrust, HIV-related conspiracy beliefs, and the need for cognitive closure among urban-residing African American women: an exploratory study. J Health Dispar Res Pract. 2018;11(4):138–48.
Jolayemi O, Bogart LM, Storholm ED, Goodman-Meza D, Rosenberg-Carlson E, Cohen R, et al. Perspectives on preparing for long-acting injectable treatment for HIV among consumer, clinical and nonclinical stakeholders: a qualitative study exploring the anticipated challenges and opportunities for implementation in Los Angeles County. PLoS ONE. 2022;17(2): e0262926.
Rubincam C. “It’s natural to look for a source”: a qualitative examination of alternative beliefs about HIV and AIDS in Cape Town, South Africa. Public Underst Sci. 2017;26(3):369–84.
Nattrass N. Understanding the origins and prevalence of AIDS conspiracy beliefs in the United States and South Africa. Sociol Health Illn. 2013;35(1):113–29.
Bohnert AS, Latkin CA. HIV testing and conspiracy beliefs regarding the origins of HIV among African Americans. AIDS Patient Care STDS. 2009;23(9):759–63.
Gilley BJ, Keesee M. Linking ‘White oppression’ and HIV/AIDS in American Indian etiology: conspiracy beliefs among MSMs and their peers. Am Indian Alsk Nativ Ment Health Res. 2007;14(1):44–62.
Brooks RA, Allen VC Jr, Regan R, Mutchler MG, Cervantes-Tadeo R, Lee SJ. HIV/AIDS conspiracy beliefs and intention to adopt preexposure prophylaxis among black men who have sex with men in Los Angeles. Int J STD AIDS. 2018;29(4):375–81.
Bogart LM, Wagner G, Galvan FH, Banks D. Conspiracy beliefs about HIV are related to antiretroviral treatment nonadherence among African American men with HIV. J Acquir Immune Defic Syndr. 2010;53(5):648–55.
Heller J. Rumors and realities: making sense of HIV/AIDS conspiracy narratives and contemporary legends. Am J Public Health. 2015;105(1):e43–50.
Curtis T. The origin of AIDS: a startling new theory attempts to answer the question ‘Was it an act of God or an at of man?’. 19 Mar 1992; pp. 54–9, 61, 106, 8, omitting photos and captions.
Bogart LM, Ransome Y, Allen W, Higgins-Biddle M, Ojikutu BO. HIV-related medical mistrust, HIV testing, and HIV risk in the national survey on HIV in the Black Community. Behav Med. 2019;45(2):134–42.
Lindenmayer JP, Glick ID, Talreja H, Underriner M. Persistent barriers to the use of long-acting injectable antipsychotics for the treatment of schizophrenia. J Clin Psychopharmacol. 2020;40(4):346–9.
Skelton JB, Rothholz MC, Vatanka P. Report of the APhA stakeholder conference on improving patient access to injectable medications. J Am Pharm Assoc. 2017;57(4):e1-12.
Freeman B, Frierson RL. Court-mandated, long-acting antipsychotic medication as a condition of supervised release. J Am Acad Psychiatry Law Online. 2009;37(2):268.
Neale J, Tompkins CNE, Strang J. Prolonged-release opioid agonist therapy: qualitative study exploring patients’ views of 1-week, 1-month, and 6-month buprenorphine formulations. Harm Reduct J. 2019;16(1):25.
Chandler R, Gordon MS, Kruszka B, Strand LN, Altice FL, Beckwith CG, et al. Cohort profile: seek, test, treat and retain United States criminal justice cohort. Subst Abuse Treat Prev Policy. 2017;12(1):24.
Andraka-Christou B, Gabriel M, Madeira J, Silverman RD. Court personnel attitudes towards medication-assisted treatment: a state-wide survey. J Subst Abuse Treat. 2019;104:72–82.
Springer SA, Di Paola A, Azar MM, Barbour R, Biondi BE, Desabrais M, et al. Extended-release naltrexone improves viral suppression among incarcerated persons living with HIV with opioid use disorders transitioning to the community: results of a double-blind, placebo-controlled randomized trial. J Acquir Immune Defic Syndr. 2018;78(1):43–53.
Walley AY, Lodi S, Li Y, Bernson D, Babakhanlou-Chase H, Land T, et al. Association between mortality rates and medication and residential treatment after in-patient medically managed opioid withdrawal: a cohort analysis. Addiction (Abingdon, England). 2020;115(8):1496–508.
Lagisetty PA, Ross R, Bohnert A, Clay M, Maust DT. Buprenorphine treatment divide by race/ethnicity and payment. JAMA Psychiatry. 2019;76(9):979–81.
Meyer JP, Cepeda J, Wu J, Trestman RL, Altice FL, Springer SA. Optimization of human immunodeficiency virus treatment during incarceration: viral suppression at the prison gate. JAMA Intern Med. 2014;174(5):721–9.
Westergaard RP, Spaulding AC, Flanigan TP. HIV among persons incarcerated in the USA: a review of evolving concepts in testing, treatment, and linkage to community care. Curr Opin Infect Dis. 2013;26(1):10–6.
Chan B, Gean E, Arkhipova-Jenkins I, Gilbert J, Hilgart J, Fiordalisi C, et al. Retention strategies for medications for opioid use disorder in adults: a rapid evidence review. J Addict Med. 2021;15(1):74–84.
Khan MR, McGinnis KA, Grov C, Scheidell JD, Hawks L, Edelman EJ, et al. Past year and prior incarceration and HIV transmission risk among HIV-positive men who have sex with men in the US. AIDS Care. 2019;31(3):349–56.
Erickson M, Pick N, Ranville F, Braschel M, Kestler M, Kinvig K, et al. Recent incarceration as a primary barrier to virologic suppression among women living with HIV: results from a longitudinal community-based cohort in a Canadian setting. AIDS Behav. 2020;24(4):1243–51.
Tiruneh YM, Li X, Bovell-Ammon B, Iroh P, Flanigan TP, Montague BT, et al. Falling through the cracks: risk factors for becoming lost to HIV care after incarceration in a southern jail. AIDS Behav. 2020;24(8):2430–41.
Degenhardt L, Larney S, Kimber J, Gisev N, Farrell M, Dobbins T, et al. The impact of opioid substitution therapy on mortality post-release from prison: retrospective data linkage study. Addiction. 2014;109(8):1306–17.
James BO, Omoaregba JO, Okonoda KM, Otefe EU, Patel MX. The knowledge and attitudes of psychiatrists towards antipsychotic long-acting injections in Nigeria. Ther Adv Psychopharmacol. 2012;2(5):169–77.
Opioid Treatment Programs and Related Federal Regulations. Congressional research service: United States Congress; 2019.
Psychosis and schizophrenia in adults: prevention and management. NICE—National Institute of Health and Care Excellence; 2014.
Rural Health Information Hub. 2021. Available from: https://www.ruralhealthinfo.org/toolkits/hiv-aids/1/rural-barriers.
Potkin S, Bera R, Zubek D, Lau G. Patient and prescriber perspectives on long-acting injectable (LAI) antipsychotics and analysis of in-office discussion regarding LAI treatment for schizophrenia. BMC Psychiatry. 2013;13:261.
National Academies of Sciences, Engineering, and Medicine; Health and Medicine Division; Board on Health Sciences Policy; Committee on Medication-Assisted Treatment for Opioid Use Disorder. Medications for opioid use disorder save lives. Washington, DC: National Academies Press; 2019.
Lin LA, Lofwall MR, Walsh SL, Gordon AJ, Knudsen HK. Perceptions and practices addressing diversion among US buprenorphine prescribers. Drug Alcohol Depend. 2018;186:147–53. https://doi.org/10.1016/j.drugalcdep.2018.01.015.
Kennedy-Hendricks A, Busch SH, McGinty EE, Bachhuber MA, Niederdeppe J, Gollust SE, et al. Primary care physicians’ perspectives on the prescription opioid epidemic. Drug Alcohol Depend. 2016;165:61–70.
DeFrank JT, Berkman ND, Kahwati L, Cullen K, Aikin KJ, Sullivan HW. Direct-to-consumer advertising of prescription drugs and the patient-prescriber encounter: a systematic review. Health Commun. 2020;35(6):739–46.
Taipale H, Mittendorfer-Rutz E, Alexanderson K, Majak M, Mehtala J, Hoti F, et al. Antipsychotics and mortality in a nationwide cohort of 29,823 patients with schizophrenia. Schizophr Res. 2018;197:274–80.
Taylor DM, Velaga S, Werneke U. Reducing the stigma of long acting injectable antipsychotics—current concepts and future developments. Nord J Psychiatry. 2018;72(sup1):S36–9.
Tiihonen J, Mittendorfer-Rutz E, Majak M, Mehtala J, Hoti F, Jedenius E, et al. Real-world effectiveness of antipsychotic treatments in a nationwide cohort of 29823 patients with schizophrenia. JAMA Psychiatry. 2017;74(7):686–93.
Ginossar T, Oetzel J, Van Meter L, Gans AA, Gallant JE. The Ryan White HIV/AIDS Program after the Patient Protection and Affordable Care Act full implementation: a critical review of predictions, evidence, and future directions. Top Antivir Med. 2019;27(3):91–100.
Cunningham WE, Weiss RE, Nakazono T, Malek MA, Shoptaw SJ, Ettner SL, et al. Effectiveness of a peer navigation intervention to sustain viral suppression among HIV-positive men and transgender women released from jail: the LINK LA Randomized Clinical Trial. JAMA Intern Med. 2018;178(4):542–53.
Bassett IV, Wilson D, Taaffe J, Freedberg KA. Financial incentives to improve progression through the HIV treatment cascade. Curr Opin HIV AIDS. 2015;10(6):451–63.
Cunningham CO, Arnsten JH, Zhang C, Heo M, Bachhuber MA, Jost JJ, et al. Abstinence-reinforcing contingency management improves HIV viral load suppression among HIV-infected people who use drugs: a randomized controlled trial. Drug Alcohol Depend. 2020;216: 108230.
Nelson KM, Perry NS, Horvath KJ, Smith LR. A systematic review of mHealth interventions for HIV prevention and treatment among gay, bisexual, and other men who have sex with men. Transl Behav Med. 2020;10(5):1211–20.
Larance B, Degenhardt L, Grebely J, Nielsen S, Bruno R, Dietze P, et al. Perceptions of extended-release buprenorphine injections for opioid use disorder among people who regularly use opioids in Australia. Addiction. 2020;115(7):1295–305.
Rolland B, Trojak B, Nourredine M, Bachellier J, Chappuy M, Bendimerad P, et al. Determinants of interest in extended-released buprenorphine: a survey among 366 French patients treated with buprenorphine or methadone. Drug Alcohol Depend. 2021;220: 108492.
Kishimoto T, Hagi K, Nitta M, Leucht S, Olfson M, Kane JM, et al. Effectiveness of long-acting injectable vs oral antipsychotics in patients with schizophrenia: a meta-analysis of prospective and retrospective cohort studies. Schizophr Bull. 2018;44(3):603–19.
Greene M, Yan T, Chang E, Hartry A, Touya M, Broder MS. Medication adherence and discontinuation of long-acting injectable versus oral antipsychotics in patients with schizophrenia or bipolar disorder. J Med Econ. 2018;21(2):127–34.
Song X, El Khoury AC, Brouillette M, Smith D, Joshi K. Treatment discontinuation of long-acting injectables or oral atypical antipsychotics among Medicaid recipients with schizophrenia. J Med Econ. 2019;22(11):1105–12.
Subotnik KL, Casaus LR, Ventura J, Luo JS, Hellemann GS, Gretchen-Doorly D, et al. Long-acting injectable risperidone for relapse prevention and control of breakthrough symptoms after a recent first episode of schizophrenia: a randomized clinical trial. JAMA Psychiatry. 2015;72(8):822–9.
Kishimoto T, Hagi K, Kurokawa S, Kane JM, Correll CU. Long-acting injectable versus oral antipsychotics for the maintenance treatment of schizophrenia: a systematic review and comparative meta-analysis of randomised, cohort, and pre-post studies. Lancet Psychiatry. 2021;8(5):387–404.
Klingberg S, Schneider S, Wittorf A, Buchkremer G, Wiedemann G. Collaboration in outpatient antipsychotic drug treatment: analysis of potentially influencing factors. Psychiatry Res. 2008;161(2):225–34.
Watkins KE, Ober AJ, Lamp K, Lind M, Setodji C, Osilla KC, et al. Collaborative care for opioid and alcohol use disorders in primary care: the SUMMIT Randomized Clinical Trial. JAMA Intern Med. 2017;177(10):1480–8.
Yang Y. Strategies for success: using long-acting injectable medications. Webinar, American Psychiatric Association and SMI Adviser Long-Acting Injectable Center of Excellence. 2020.
Murray M, Antela A, Mills A, Huang J, Jäger H, Bernal E, et al. Patient-reported outcomes in ATLAS and FLAIR participants on long-acting regimens of cabotegravir and rilpivirine over 48 weeks. AIDS Behav. 2020;24(12):3533–44.
Orkin C, Arasteh K, Górgolas Hernández-Mora M, Pokrovsky V, Overton ET, Girard P-M, et al. Long-acting cabotegravir and rilpivirine after oral induction for HIV-1 infection. N Engl J Med. 2020;382(12):1124–35.
Swindells S, Andrade-Villanueva J-F, Richmond GJ, Rizzardini G, Baumgarten A, Masiá M, et al. Long-acting cabotegravir and rilpivirine for maintenance of HIV-1 suppression. N Engl J Med. 2020;382(12):1112–23.
Simoni JM, Beima-Sofie K, Mohamed ZH, Christodoulou J, Tapia K, Graham SM, et al. Long-acting injectable antiretroviral treatment acceptability and preferences: a qualitative study among US providers, adults living with HIV, and parents of youth living with HIV. AIDS Patient Care STDS. 2019;33(3):104–11.
Kerrigan D, Mantsios A, Grant R, Markowitz M, Defechereux P, La Mar M, et al. Expanding the menu of HIV prevention options: a qualitative study of experiences with long-acting injectable cabotegravir as PrEP in the context of a phase II trial in the United States. AIDS Behav. 2018;22(11):3540–9.
Rael CT, Lopez-Ríos J, McKenna SA, Das D, Dolezal C, Abascal E, et al. Transgender women’s barriers, facilitators, and preferences on tailored injection delivery strategies to administer long-acting injectable cabotegravir (CAB-LA) for HIV pre-exposure prophylaxis (PrEP). AIDS Behav. 2021;25(12):4180–92.
Mantsios A, Murray M, Karver TS, Davis W, Margolis D, Kumar P, et al. Efficacy and freedom: patient experiences with the transition from daily oral to long-acting injectable antiretroviral therapy to treat HIV in the context of phase 3 trials. AIDS Behav. 2020;24(12):3473–81.
Baumann KE, Phillips AL, Arya M. Overlap of HIV and low health literacy in the southern USA. Lancet HIV. 2015;2(7):e269–70.
Rebeiro PF, McPherson TD, Goggins KM, Turner M, Bebawy SS, Rogers WB, et al. Health literacy and demographic disparities in HIV Care Continuum Outcomes. AIDS Behav. 2018;22(8):2604–14.
Johnson DA. Historical perspective on antipsychotic long-acting injections. Br J Psychiatry Suppl. 2009;52:S7-12.
Jaiswal J. Whose responsibility is it to dismantle medical mistrust? Future directions for researchers and health care providers. Behav Med. 2019;45(2):188–96.
Scarsi KK, Swindells S. The promise of improved adherence with long-acting antiretroviral therapy: what are the data? J Int Assoc Provid AIDS Care. 2021. https://doi.org/10.1177/23259582211009011.
Acknowledgements
This paper was written with support from the Center for HIV Identification, Prevention, and Treatment Services (CHIPTS) National Institutes of Mental Health (NIMH), and support from the California HIV/AIDS Research Program (CHRP)’s Southern California HIV/AIDS Policy Center. Efforts were also funded by the UCLA Clinical Translational Science Institute (CTSI), the NIMH (K23MH125201), The Friends of Semel Institute for Neuroscience and Human Behavior at UCLA, and the National Institute on Drug Abuse (NIDA). The content of this paper is solely the responsibility of the authors and does not necessarily represent the official views of CHRP, CTSI, The Friends of Semel, NIMH, or NIDA.
Funding
This paper was written with support from the Center for HIV Identification, Prevention, and Treatment Services (CHIPTS) National Institutes of Mental Health (NIMH) Grant MH58107, and support from the California HIV/AIDS Research Program (CHRP)’s Southern California HIV/AIDS Policy Center (Grant No. RP15-LA-007). Enrico G. Castillo and Nina T. Harawa’s efforts were also funded by the UCLA Clinical Translational Science Institute (CTSI) (Grant No. UL1TR0001881), and Enrico G. Castillo’s efforts were additionally funded by the NIMH (Grant No. K23MH125201) and The Friends of Semel Institute for Neuroscience and Human Behavior at UCLA. Chelsea L. Shover’s efforts were also funded by the National Institute on Drug Abuse (NIDA) (Grant No. K01-DA050771). The content of this paper is solely the responsibility of the authors and does not necessarily represent the official views of CHRP, CTSI, The Friends of Semel, NIMH, or NIDA.
Author information
Authors and Affiliations
Contributions
The idea for this article came from NTH. All authors took part in drafting, and revisions made by GGE, AMO, EGC, RJL, AAL, CP, YSY, and NTH. MT and GGE were responsible for literature search efforts.
Corresponding author
Ethics declarations
Conflict of interest
Steven Shoptaw has received clinical support for his research from Gilead Sciences, Inc. Raphael Landovitz serves on the Scientific Advisory Board for Gilead Sciences and Merck, Inc, and received honoraria for symposium presentations at Cepheid and Janssen Pharmaceuticals. Nina T. Harawa has received honoraria for two recent speaking engagements sponsored by Gilead Sciences, Inc. She also is a member of the Scientific Advisory Board for the Black AIDS Institute and a co-investigator, with in-kind support, on a Gilead Sciences-focused on HIV prevention center. The authors have no further conflicts of interest or competing interests to declare.
Ethical Approval
This work did not include human subjects and has not been approved by an institutional review board.
Consent to Participate
N/A.
Consent for Publication
N/A.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Edwards, G.G., Miyashita-Ochoa, A., Castillo, E.G. et al. Long-Acting Injectable Therapy for People with HIV: Looking Ahead with Lessons from Psychiatry and Addiction Medicine. AIDS Behav 27, 10–24 (2023). https://doi.org/10.1007/s10461-022-03817-z
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10461-022-03817-z