Addiction, AIDS, and NIDA’s Overseas Program

[[{"type":"media","view_mode":"media_crop","fid":"42464","attributes":{"alt":"© robtek/shutterstock.com","class":"media-image media-image-right","id":"media_crop_3012363809043","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"4604","media_crop_rotate":"0","media_crop_scale_h":"150","media_crop_scale_w":"150","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"float: right;","title":"© robtek/shutterstock.com","typeof":"foaf:Image"}}]]As background for this article, it is worth mentioning that I have had a subscription to National Geographic since I was 8. My grandfather noticed me reading copies that he had in his attic during family visits, so he gave me a subscription as a birthday present, and I’ve renewed it ever since. Opportunities to apply this interest in other cultures to addiction emerged in the 1980s when it became clear that behaviors associated with substance use were contributing to the spread of human immunodeficiency virus (HIV) and that substance abuse treatment can be an important component of a public health approach for reducing these problems. The effect of treatment was particularly strong for methadone maintenance but seemed to apply to other effective treatments as well.¹

The severity, urgency, and scope of the HIV problem led the US government––along with other countries and organizations––to provide funds for training investigators in substance abuse prevention, treatment, and research, and to conduct studies to identify how the virus is transmitted, characteristics of individuals who are affected, and the effect of treatment and prevention on reducing the problem.

The Hubert Humphrey program at the Johns Hopkins University became an important source for research training and meeting international colleagues who were interested in substance abuse and HIV research. Meetings developed by the National Institute on Drug Abuse’s (NIDA) international program, initially led by Patricia Needle and later by Steve Gust, in collaboration with a host country, provided opportunities for US and international researchers to share ideas and develop training and research agendas that included applying for grants.

NIDA program announcements with funding for international research and training and the President’s Emergency Fund for AIDS Research (PEPFAR) created research and training opportunities. The lines of communication made possible by the Humphrey program and NIDA-sponsored international meetings showed that most non-US researchers had access to many treatment resources, but that with few exceptions, they had limited knowledge of research methods and few opportunities for funding. Grant applications typically had a US principal investigator with one or more international partners as co-investigators; topics with the best chance of funding addressed an issue of importance to the “home” country as well as the US.

Brazil

The first chance to participate in these activities was in the early 1990s when Bob Schuster, Director of the NIDA at the time, and Pat Needle invited me to a 3-day meeting in Sao Paulo, Brazil, aimed at the exchange of information and the development of collaborative studies on HIV, substance use, and addiction treatment. At the meeting was Flavio Pechansky, a psychiatrist from Porto Alegre, who had tried to study treatment outcomes in private settings without much success, which he attributed to resistance from psychiatrists about having their patients’ outcomes assessed. He was interested in building an addiction treatment and research program, and the meeting encouraged him to apply to the Humphrey program for a year of addiction research training.

While in the program at Johns Hopkins, he spent time at the Penn/VA addiction treatment and research center, where he was trained to use the Addiction Severity Index and later had it modified for Brazilian culture and translated into Brazilian Portuguese by Felix Kessler, a young psychiatrist who was also interested in addiction treatment and research. This work led to a Fogarty grant to study the spread of HIV among persons addicted to cocaine that showed a 5% annual incidence of HIV infection, mostly due to unprotected sex.² This work resulted in a collaboration between Dr Pechansky and Drs Inciardi and Surratt at the University of Delaware who studied similar problems but in different populations. They later combined their data with ours in a paper that showed a stepwise increase in HIV risk as a function of type of risky behavior, with cocaine inhalers at lowest risk, cocaine-using men who have sex with men (MSM) at higher risk, and MSM who were also injecting at highest risk.³

These findings were not surprising, but completing the work showed that Dr Pechansky and his group could successfully implement research studies and led to his receiving a grant from the Brazilian government to study the prevalence of drunk driving in Brazil. Following this project, his group was 1 of 6 new government-funded addiction treatment and research centers that focused on crack cocaine, a major health and criminal justice problem in Brazil. The center is located near the Federal University of Rio Grande do Sul, has inpatient and outpatient facilities including on-site medical services, and is an outstanding resource for research on crack cocaine and other common substance use disorders.

Russia

The next international opportunity came in the form of an invitation from Pat Needle and the NIDA International Program to participate in a meeting in St Petersburg, Russia. Its purpose was similar to that of the meeting in Brazil, and Dr Needle and Dr Edwin Zvartau, Director of the Valdman Pharmacological Research Institute at Pavlov State Medical University, organized it. About 60 Russian addiction psychiatrists (“narcologists”), social workers, and psychologists that included Dr Evgeny Krupitsky, a psychiatrist who worked with Dr Zvartau and had received research training at Yale, attended.

Presentations and conversations showed that injection heroin use was the main way HIV was being spread, that the prevalence of infection was rising, and that the only pharmacological treatment that had a chance of helping reduce drug use was naltrexone because, unlike in the US and most Western countries, methadone and other agonists were prohibited in Russia.⁴

Another treatment aspect that differed from the US was that Russia has a national health service, which funds over 25,000 inpatient detoxification and residential beds for persons with substance use disorders. Patients are often in residential settings for 3 to 4 weeks, but relapse is high after discharge and recidivism is frequent. The underlying approach is to help patients become free of addicting substances even if it requires many attempts, similar in many ways to what prevailed in the US from the mid 1920s until the late 1960s.

The result was 2 randomized, placebo-controlled trials. The first compared oral naltrexone with usual treatment; the second compared oral naltrexone with placebo, with or without fluoxetine. Adherence in both studies was facilitated by the cultural situation in Russia wherein most patients were 19 to 23 years old and living with their parents. The mothers often brought them to treatment, and part of the design was that the patients consented to allow a close relative or friend to supervise the daily naltrexone dosing. Findings showed a significant effect of oral naltrexone over usual treatment with 42% to 44% of the oral naltrexone group remaining in treatment and not relapsed by 6 months compared with 12% to 14% in the placebo groups. Adding fluoxetine showed a nonsignificant trend toward improved adherence and reduced relapse among female participants but no significant overall effect.^5,6

After these findings were published and we had started a new study that compared oral naltrexone with a naltrexone implant that blocks opioid effects for 2 to 3 months, the Medical Director of Alkermes called, asking about opioid research in Russia.⁷ Alkermes staff had read the naltrexone papers and were interested in exploring the possibility of testing extended-release injectable naltrexone (Vivitrol®) for preventing relapse to opioid dependence, in addition to its existing indication for alcohol dependence. Study details were provided and followed by a site visit where the Alkermes Medical Director was introduced to the Pavlov team. The study resulted in FDA approval of extended-release injectable naltrexone for preventing relapse to opioid dependence.⁸

Ukraine and Georgia

Other collaborations made possible by the Humphrey program were with Sergiy Dvoriak, an addiction psychiatrist from Kiev, Ukraine, and David Otiashvili, an addiction psychiatrist from the Republic of Georgia. Each spent time at the Penn/VA addiction treatment and research center during their fellowship and collaborated on grants to study addiction treatment and HIV risk reduction after returning to their home country.

Ukraine was a particularly important country for scaling up opioid addiction treatment because it had the highest prevalence of HIV infection among all former Soviet States and had recently approved methadone maintenance after having been committed to the Russian model of detoxification and non-agonist rehabilitation. To see if methadone maintenance worked as well in Ukraine as in the US, a collaboration with Dr Dvoriak funded by a NIDA R21 grant compared a short course of methadone maintenance between 25 HIV-positive and 25 HIV-negative opioid-dependent individuals at the AIDS Center in Kiev. Adherence to treatment was excellent with very little opioid and other drug use in both groups, and all but a few continued methadone treatment at the 20-week follow-up.⁹

A supplement to this study involved focus groups to explore factors associated with adherence to antiretroviral medication and found evidence that patients were often harassed by police, but that the police were often afraid of the patients. These findings were published in the article, “We Fear the Police, and the Police Fear Us.”¹⁰ Dr Dvoriak later received a Clinical Trials Network/NIDA fellowship to continue training at the University of Pennsylvania and is now working on a study of extended-release injectable naltrexone in Kiev.

Interactions with Dr Otiashvili during his Humphrey fellowship revealed that the Republic of Georgia, another former Soviet State, had a problem with buprenorphine injecting. Neither buprenorphine nor buprenorphine-naloxone was registered in Georgia, but both were being smuggled into the country from Western Europe. As in Ukraine, the laws changed to allow methadone maintenance; however, take-home doses were not permitted. The prevalence of HIV infection was low, but buprenorphine injecting suggested that it could change. Thus, we applied for and received funding for a study to compare daily observed buprenorphine-naloxone with methadone for opioid-dependent individuals who had injected buprenorphine 10 or more times in the past month.

As in Ukraine, adherence to study medications was excellent and there was very little drug use during treatment.¹¹ An analysis of non-opioid use among study patients was undertaken by Dr Piralishvili, a co-investigator who had completed a CTN/ Investigator fellowship at Penn. As in the outcome study by Otiashvili and colleagues,¹¹ drug use was very low-there was more opioid use but less amphetamine and marijuana use in the methadone group compared with the buprenorphine-naloxone patients.¹²

Conclusion

Other international work whose findings have not been published include a study that compared extended-release injectable naltrexone for preventing relapse with amphetamine dependence in Reykjavik, Iceland, and a study that compared brief counseling with more intensive counseling for methadone-maintained patients in Jakarta, Indonesia.

None of these activities could have been undertaken without NIDA support. This work has been very interesting and seems important, since it has helped expand research capacity into other countries. Findings from the agonist treatment studies suggest that methadone and buprenorphine-naloxone appear to work as well or even better in Ukraine and the Republic of Georgia than in the US and that they can be important contributors to reducing drug use and HIV risk.

The work in Brazil led to the creation of an addiction treatment and research center in Porto Alegre with the potential to advance treatment and research in that country. The Russian studies could probably not have been done, or would have taken much longer, in the US and led to FDA approval of extended-release injectable naltrexone, thus expanding the current treatment options for opioid dependence. Many of these results were not anticipated when these studies were funded which, I guess, is why they qualify as “research.”

Acknowledgment-This work was supported by NIDA grants R21 DA026754, R21 DA021073, R01 DA017317, KO5 DA17009, PA-94-029-FIC-AIDS-FIRCA, and U10 DA13043 (Woody, PI); P50 DA012756 (Pettinati, PI); P60 DA05186l (O’Brien, PI); R01 DA11611, R01 DA11580, U10 D13043, K05 DA17009, and a donation from the Center for Drug and Alcohol Studies of the University of Delaware (Inciardi, PI); and the Department of Veterans Affairs.

Disclosures:

Dr Woody is Professor in the department of psychiatry at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia. DuPont Pharmaceutical provided naltrexone; Gideon Richter provided fluoxetine at reduced cost; Reckitt Benckiser provided Suboxone®; Fidelity Capital provided Prodetoxon at reduced cost; and Alkermes provided Vivitrol® and Vivitrol placebo.

References:

1. Metzger DS, Woody GE, O’Brien CP. Drug treatment as HIV prevention: a research update. J Acquir Immune Defic Syndr. 2011;55(suppl 1):S32-S36.

2. Pechansky F, von Diemen L, Kessler F, et al. Preliminary estimates of HIV prevalence and incidence among cocaine abusers of Porto Alegre, Brazil. J Urban Health. 2003;80:115-126.

3. Pechansky F, Woody G, Inciardi J, et al. HIV seroprevalence rates of Brazilian drug users: an analysis of selected variables based on ten years of data collection. Drug Alcohol Depend. 2006;82(suppl):S109-S113.

4. Krupitsky EM, Zvartau EE, Lioznov DA, et al. Comorbidity of infectious and addictive diseases in St Petersburg and the Leningrad Region, Russia. Eur Addict Res. 2006;12:12-19.

5. Krupitsky EM, Zvartau EE, Masalov DV, et al. Naltrexone for heroin dependence treatment in St Petersburg, Russia. J Subst Abuse Treat. 2004;26:285-294.

6. Krupitsky EM, Zvartau EE, Masalov DV, et al. Naltrexone and fluoxetine for heroin dependence treatment in St Petersburg, Russia. J Subst Abuse Treat. 2006;31:319-328.

7. Krupitsky EM, Zvartau EE, Blokhina E, et al. Randomized trial of long acting sustained release naltrexone implant vs. oral naltrexone or placebo for preventing relapse to opioid dependence. Arch Gen Psychiatry. 2012;69:973-981.

8. Krupitsky E, Nunes EV, Ling W, et al. Injectable extended-release naltrexone for opioid dependence: a double-blind, placebo-controlled, multicenter randomised trial. Lancet. 2011;377:1506-1513.

9. Dvoriak S, Karachevsky A, Chhatre S, et al. Methadone maintenance for HIV positive and HIV negative patients in Kyiv: acceptability and treatment response. Drug Alcohol Depend. 2014;137:62-67.

10. Mimiaga MJ, Safren SA, Dvoryak S, et al. “We fear the police, and the police fear us”: structural and individual barriers and facilitators to HIV medication adherence among injection drug users in Kiev, Ukraine. AIDS Care. 2010;22:1305-1313.

11. Otiashvili D, Piralishvili G, Sikharulidze Z, et al. Methadone and buprenorphine-naloxone are effective in reducing illicit buprenorphine and other opioid use, and reducing HIV risk behavior: outcomes of a clinical trial. Drug Alcohol Depend. 2013;133;376-378.

12. Piralishvili G, Otiashvili D, Sikharulidze Z, et al. Opioid addicted buprenorphine injectors: drug use during and after 12-weeks of buprenorphine-naloxone or methadone in the Republic of Georgia. J Subst Abuse Treat. 2014;50:32-37.