Slow Release Naltrexone Implant vs Oral Naltrexone for Improving Treatment Outcomes in Opioid Addicted Participants with HIV: A Randomised Trial

Abstract

Background: Untreated opioid addiction in persons with HIV is associated with poor outcome. Agonist maintenance is not always available and some do not want it. Slow release naltrexone may be a useful option. Methods: The study was a 48-week trial in which 200 opioid addicted patients starting antiretroviral treatment (ART) for HIV were stratified according to gender, viral load (VL) and CD4 count, and randomized to addiction treatment using a naltrexone implant and oral naltrexone placebo (NI; n=100), or oral naltrexone 50 mg/day and a placebo implant (ON; n=100). Research staff was blinded to group assignment. Primary outcome was plasma VL<400 copies at 24 and 48 weeks. All participants were included in the outcome analyses according to intention to treat principles. Findings: There was no difference between NI and ON in the number of participants with VL<400 copies at week 24 (38 [38%] vs 35 [35%] p=0*77) but more NI than ON participants had a VL<400 copies at week 48 (66 [66%] vs 50 [50%] RR: 1*32 [95% CI: 1*04-1*68] p=0*0451). Regardless of group assignment, those who continued naltrexone at 24 weeks more commonly had VL<400 copies than discontinuers (51 [70 %] vs 22 [30%] RR: 2*89 [95% CI: 1*91-4*38] p<0*0001) with similar findings at week 48 (VL <400 copies (64 [55%] vs 52 [44%] RR: 1*53 [95% CI: 1*21-1*95] p=0*0005). There were seven serious adverse events registered: three deaths in NI (one heart disease, one trauma, one AIDS), and four in ON (two overdoses, one pancreatic cancer, one AIDS). The overdose deaths occurred 9-10 months after the last naltrexone dose. Interpretation: An implant that is approved in the Russian Federation and provides opioid blockade for three months caused no serious adverse events and improved retention and outcome of persons with opioid addiction and HIV. Clinical Trial Number: The trial is registered at ClinicaTrials.gov, NCT02046252. Funding Statement: NIDA Grants: R01 DA026336; K05 DA17009; U10 DA013043; UG1 DA013034; Penn Center for AIDS Research P30 A1045008; Penn Mental Health AIDS Research Center P30 MH097488 Declaration of Interests: Fidelity Capital provided Prodetoxon®) at a reduced price and Prodetoxon placebo at no charge. Dr. Woody is a consultant to BICX102, a company that submitted a grant to NIDA requesting funds to develop and test a similarly-designed implant that could be submitted to the FDA for approval in the U.S. Dr. Krupitsky was a consultant to Alkermes in 2008-2011 and was a consultant for Prodetoxon LTD in 2017. Ethics Approval Statement: The protocol and consents were written in English, translated into Russian, reviewed by bilingual staff in Russia and the U.S, and approved by human subjects’ committees (IRBs) at First Pavlov State Medical University and the University of Pennsylvania. The sponsor and the two IRBs did annual reviews of study progress and reports of adverse events.