HIV TREATMENT INITIATION AND RETENTION AMONG INDIVIDUALS INITIATED ON INJECTABLE OPIOID AGONIST THERAPY FOR SEVERE OPIOID USE DISORDER: A CASE SERIES

Abstract

Objectives:

Injectable opioid agonist therapy (iOAT) has previously been demonstrated to be an effective treatment option for individuals with a severe opioid use disorder (OUD) who have been unsuccessful on first line therapy (e.g., buprenorphine/naloxone or methadone). Many individuals with severe OUD may also have HIV infection. Despite this, no literature currently exists examining the relationship between antiretroviral therapy (ART) initiation and adherence following iOAT initiation in the outpatient setting.

Methods:

Retrospective case series (n = 3) of HIV-infected individuals with a severe OUD who were refractory to oral opioid agonist treatment and were started on iOAT in a community setting in Vancouver, Canada. Outcomes of interest included: (1) iOAT induction and maintenance dosing schedules; (2) ART adherence demonstrated by change in HIV viral load.

Results:

All three patients initiated and successfully reached iOAT maintenance doses with significant reduction in illicit opioid use. Stable iOAT was associated with increased ART initiation and adherence, and decreased HIV viral loads. Conversely, poor retention or discontinuation of iOAT was associated with reduced adherence to ART and in one patient, increased HIV viral loads.

Conclusions:

The individual cases presented suggest that among individuals with severe OUD and HIV infection, iOAT may improve HIV treatment uptake and retention in care.

Background

Individuals with concurrent HIV infection and severe opioid use disorder (OUD) constitute a substantial public health burden as concomitant disease is associated with high levels of morbidity and mortality (Mathers et al., 2014; May et al., 2015; Parashar et al., 2016). While antiretroviral therapy (ART) has been shown to reduce HIV viral load, increase CD4 counts, and delay progression to AIDS (Hogg et al., 2001), access and adherence to these medications among individuals with a severe OUD can be challenging for a myriad of reasons (e.g., stigma, poverty, psychiatric illness) (Azar et al., 2015; Li et al., 2017; Wood et al., 2008). Treatment of OUD with oral opioid agonist therapy (OAT; e.g, methadone, buprenorphine/naloxone) has demonstrated efficacy in decreasing risk behaviours associated with HIV transmission (Gowing et al., 2011), improving access and adherence to ART (Low et al., 2016), and decreasing mortality when both OAT and ART are taken together (Nosyk et al., 2015). Among individuals unsuccessful on oral OAT, injectable opioid agonist therapy (iOAT), a high intensity treatment involving titrating injection doses of diacetylmorphine or hydromorphone to an individually directed maintenance dose, has demonstrated efficacy in reducing illicit opioid use, improving retention in addiction treatment, and minimizing intersection with the criminal justice system (Oviedo-Joekes et al., 2009, 2016; Lucas et al., 2006). Notably, iOAT utilizing hydromorphone have fewer regulatory barriers to treatment delivery and expansion compared with diacetylmorphine (British Columbia Centre on Substance Use (BCCSU), 2017; Oviedo-Joekes et al., 2016). Individuals attend clinic for 2-3 observed self-injections, using clinic-supplied syringes and site care from nurses, frequently paired with a daily dose of oral OAT such as methadone or Sustained Release Oral Morphine (SROM), a safe and effective alternative to methadone (Hammig et al., 2014; Ferri et al., 2013, Oviedo-Joekes et al., 2009, 2016). The relationship between iOAT and ART initiation and retention however has not yet been described. Accordingly, this study describes three cases of HIV infected individuals who were initiated on iOAT with hydromorphone for the treatment of severe OUD in an outpatient setting in Vancouver, Canada, with subsequent ART initiation or re-initiation. In this study, HIV care was provided by separate providers in focused HIV clinics. Outcomes included: (1) iOAT induction and maintenance dosing schedules; and (2) ART adherence demonstrated by change in HIV viral load. Written consent was obtained for all patients.

Case 1:

A 43-year-old female presented to clinic to access addiction treatment, her substance use met DSM-V criteria for a severe OUD. Her past medical history was notable for HIV (since 2005), hepatitis C (genotype 1a, unknown date of diagnosis), and probable liver cirrhosis indicated by ultrasound. Although she was previously on treatment for HIV, she was on no prescribed medications. Her substance use included injections of 0.25 grams (g) of heroin and unintentional illicit fentanyl (due to contamination of a significant proportion of the heroin supply) four times a day. While she had previously attempted oral opioid agonist treatment with methadone up to 60 mg, she did not have a reduction in heroin/fentanyl use and self-discontinued treatment. She declined treatment with methadone, buprenorphine/naloxone, SROM, and was pre-contemplative about cessation of injection opioids. Given the severity of her OUD and need for stabilization, the patient agreed with her caregivers to initiate injectable hydromorphone. She was started on 20 milligrams (mg) intravenous (IV) twice daily (BID), and titrated to a maintenance dose of 90 mg IV BID (Table 1 – Case 1, Titration #1) based upon current practice for iOAT titration at existing iOAT sites at the time. She remained on treatment for two years with substantial reduction in the frequency of illicit opioid use (from multiple injections per day to injection once every few weeks) and had at least 6 months of abstinence (corroborated by urine toxicology screens negative for fentanyl). Approximately four months after iOAT induction, the patient restarted ART at a specialized HIV clinic with daily delivery and direct observed therapy (DOT) by nurses at the iOAT clinic. Over a nine month period of treatment her HIV viral load (VL) decreased from 69,512 copies per millilitre (mL) to 2,193 copies/mL. Two years after the patient’s initial induction, as a result of increased psychosocial stressors, the patient discontinued iOAT. Her use of heroin and illicit fentanyl increased to injections of up to 1 g daily and shortly after, she discontinued ART. Two months later, she returned to clinic requesting to restart iOAT and was prescribed injectable hydromorphone utilizing a more rapid titration schedule for individuals with severe OUD and proven high opioid tolerance (e.g. injection fentanyl use and recently on iOAT), with options of additional top-up doses if no intoxication is observed after the initial dose (BCCSU, 2017; Table 1 – Case 1, Titration #2). She was also offered oral OAT and preferred SROM, which was initiated at 200 mg daily with stabilization at 400mg daily (the titration of SROM followed clinical experience for the treatment of severe OUD). She also agreed to restart on ART with Triumeq® (dolutegravir/abacavir/lamivudine). As DOT of SROM was already standard practice, her ART was coupled with SROM for DOT at her place of residence by a community pharmacist. She demonstrated good adherence to both treatments, reported improved mood, and decreased heroin/fentanyl injection use to 0.5 g every 3 days. She also completed bloodwork including hepatitis C genotype and viral load, a liver ultrasound, and is preparing for hepatitis C treatment.

Table 1.

iOAT titration schedule and maintenance doses of self-administered IV or IM hydromorphone in two doses daily

	Case 1		Case 1		Case 2		Case 3
	Titration #1		Titration #2
	Dose #1	Dose #2	Dose #1	Dose #2	Dose #1	Dose #2	Dose #1	Dose #2
Titration
Day 1	20	20	45+30*	50+30*	15+30*	45+10*	15+30*	45+30*
Day 2	40	60	80+20*	100	45+30*	50+30*	50+30*	80+20*
Day 3	60	80	100	100	80	80	100	100
Day 4	80	90	-	-	-	-	-	-
Day 5	90	90	-	-	-	-	-	-
Maintenance
Hydromorphone IV	90	90	140	140	60	60	150	150
Oral OAT (SROM)	-		400		600		400

^{^}All doses in milligrams (mg). Doses are at least 3 hours apart with 20 minute post-dose observation period.

^*Top-up doses given 20 minutes later if no signs of intoxication based on clinical judgement by nurse or physician and discussion with patient.

Case 2:

A 30-year-old male was referred by his community provider for consideration of iOAT. He had a recent diagnosis of HIV infection but had not started ART despite outreach attempts by nurses and physicians as he was difficult to locate and rarely presented to clinic. He also had hepatitis C and psychosis for which he was on a monthly zuclopenthixol depot injection. His substance use history met DSM-V criteria for severe OUD with daily injections of illicit fentanyl and heroin (approximately 0.1 g multiple times a day). Previous OAT included methadone and SROM without reduction or periods of abstinence from illicit drug use due to poor medication adherence and difficulty in titrating to an effective maintenance dose. The patient was interested in iOAT as he preferred opioid injections, but agreed for it to be paired with SROM to help mitigate opiate withdrawal during hours of iOAT clinic closure. Both therapies were started following standard initiation protocol and individualized based on clinical response and safety (BCCSU, 2017; Table 1 Case 2). He demonstrated oversedation during the titration at 80 mg IV BID, thus his dose of hydromorphone was decreased to 40 mg IV BID over several days, before gradually titrating back to a maintenance dose of 60 mg IV BID. Over 16 months, he did not miss any iOAT doses and produced urine drug screens consistently negative for fentanyl. Although the health care team continuously engaged with the patient regarding starting ART at all clinical encounters, it was not until one month of iOAT maintenance that he initiated ART. He demonstrated good adherence, and achieved an HIV VL of <40 copies/mL. He also completed bloodwork including hepatitis C genotype, viral load, and a liver ultrasound in preparation for hepatitis C treatment.

Case 3:

A 51-year-old male presented to clinic for iOAT initiation for treatment of his OUD. The patient had HIV infection since 1994, was on ART for numerous years and had an undetectable VL. He began injecting opioids at the age of 19, had multiple previous overdoses and was currently injecting approximately 0.5 g of heroin and illicit fentanyl daily. Despite OAT with both methadone and buprenorphine-naloxone (maximum daily doses of 100 and 16 mg respectively) he experienced ongoing use of heroin and illicit fentanyl. The patient was initiated on injectable hydromorphone following standard protocol up to 100 mg IV BID by day 3 followed by gradual titrations to maintenance at 150 mg IV BID (BCCSU, 2017; Table 1 – Case 4). Over the next 9 months, he demonstrated sub-optimal adherence with iOAT doses (frequently presenting for only one out of two daily iOAT doses, and requiring four iOAT re-titrations due to consecutive missed doses). This was associated with increased illicit fentanyl use, worsened ART adherence, and increase in HIV VL to 1237 copies/mL. To address this, his ART medication (darunavir-cobicistat and emtricitabine-tenofivir) was dispensed for DOT when he would present for iOAT. His adherence to both ART and iOAT subsequently improved, and five months later the patient had an undetectable VL.

Discussion

Though prior studies have demonstrated that OAT improves uptake and adherence to ART among HIV infected individuals (Low et al., 2016), this case series is, to our knowledge, the first to characterize ART treatment among patients newly initiated on iOAT in the outpatient setting. The three cases presented include HIV-infected individuals with severe OUD with limited success in the reduction or cessation of illicit opioids due to challenges with adherence, initiation, or maintenance onto oral OAT. Although the cases described are of limited generalizability and cannot conclude causality, each example demonstrates success with the simultaneous treatment of OUD and HIV.

The use of iOAT can provide an opportunity for the establishment of a therapeutic alliance between a health care provider and patient, many of whom may have experienced multiple barriers to accessing either addiction or HIV treatment as a result of having a substance use disorder, psychiatric comorbidity, and other social vulnerabilities. Indeed, previous evidence has indicated improved treatment retention with iOAT compared with OAT for individuals with OUD refractory to oral therapy (Oviedo-Joekes et al., 2009; Strang et al., 2015). Our findings additionally suggest that for individuals with both severe OUD and HIV infection, engagement in iOAT may assist with stabilizing an individual from an addiction perspective prior to ART initiation.

Given that each iOAT dose is witnessed by a community health care provider, the opportunity exists to couple the administration of iOAT with ART to optimize adherence to both medications and improve treatment outcomes (as demonstrated in Case #3 above). This approach has proven to improve ART uptake and adherence when ART is administered with either methadone or buprenorphine/naloxone (Moatti et al., 2000; Wood et al., 2005). Beyond improving HIV outcomes, stabilization with iOAT also provides the opportunity for health care providers to address other aspects of patient health, including hepatitis C treatment as demonstrated in Case #1 and #2 above (particularly as co-infection is known to increase mortality risk) (May et al., 2015). As such, it may also be beneficial to couple DOT of hepatitis C treatment, ART, and iOAT, as evidence has indicated improved hepatitis C treatment adherence among people on oral OAT with DOT compared to those self-administering treatment (Akiyama et al., 2019).

As iOAT is a specialist-led approach, access to this form of treatment is limited. Where available however, HIV, hepatitis C, and other health screens, (vaccinations, testing for tuberculosis, other sexually transmitted infections… etc.) should be routine, and treatment readily available. Furthermore, simultaneous administration of these medications may improve adherence and treatment outcomes for both OUD and HIV. While further research is needed, the integration of iOAT and HIV care may offer an effective strategy for patients with concurrent HIV and OUD diagnoses.