A controlled trial of methadone treatment combined with directly observed isoniazid for tuberculosis prevention in injection drug users

Abstract

Substance abuse is associated with high risk for tuberculosis (TB) and poor adherence to medication regimens. This study compared completion rates for isoniazid (INH) preventive therapy for injection drug users (IDUs) randomly assigned to methadone treatment combined with directly observed preventive treatment (DOPT) versus those assigned to routine TB clinic referral without methadone treatment. One hundred and eleven opioid-dependent patients with latent TB were assigned to one of three 6-month treatment conditions: standard methadone treatment including substance abuse counseling combined with daily INH DOPT (n=37); minimal methadone treatment without counseling, also combined with daily INH DOPT (n=35); or routine care referral to TB clinic for monthly INH supplies without DOPT and without methadone treatment (n=39). INH completion rates were 77.1% for minimal methadone and 59.5% for standard methadone, as compared with only 13.5% for routine care (P<0.0001). Mean duration of INH treatment retention was 5.7, 5.0 and 1.6 months, respectively (P<0.0001). TB incidence at 4-year follow-up was 0 of 54 subjects who completed preventive therapy versus 2 of 57 who failed to complete. One of these two had been assigned to routine care, and the other to minimal methadone. In conclusion, INH retention time and completion rates were significantly improved by methadone treatment combined with observed INH, whether or not substance abuse counseling was provided. The results of this study indicate that methadone treatment offers clear public health benefits when it is used to deliver preventive medical services.

Introduction

While the tuberculosis (TB) epidemic has responded to aggressive prevention and treatment efforts (McKenna et al., 1998), TB continues to be a serious problem. Individuals with substance use disorders, including injection drug users (IDUs), are at particularly high risk. Two major TB risk factors, infection with human immunodeficiency virus (HIV) and homelessness, converge in IDUs and contribute to the high incidence of TB infection in these patients (Reichman et al., 1979, Selwyn et al., 1989a, Selwyn et al., 1989b, CDC, 1995a, Rusen et al., 1999). Risk is even higher among those IDUs who belong to ethnic minority groups and who are indigent (Friedman et al., 1987, Snider and Hutton, 1989, Daley et al., 1992). Tuberculin skin test conversion incidence is as high as 3% per year, even among IDUs in treatment (Durante et al., 1998). In addition to having higher rates of latent TB infection, IDUs are also at greater risk for progression to active TB (Perlman et al., 1995).

Preventive therapy for latent infection is essential to the control of TB and can prevent development of active disease among tuberculin positive individuals (American Thoracic Society, 1992). A commonly used chemoprophylaxis regimen is 6 months of isoniazid (INH), which decreases occurrence of active TB by 60–90% (Ferebee, 1970, Comstock and Woolpert, 1984, CDC, 1990, Pape et al., 1993) and was, at the time of this study, the preventive therapy recommended by the American Thoracic Society and the US Centers for Disease Control and Prevention (Bass et al., 1994). If, however, patients do not complete preventive therapy, they derive less benefit and develop TB at a higher rate (Gourevitch et al., 1998). Chemoprophylaxis completion rates are frequently low, only about half of patients complete the 6 month course (CDC, 1995b). Furthermore, patients with substance use disorders are more likely to miss doses of self-administered TB medications than other TB clinic patients (Combs et al., 1990).

Direct observation of preventive therapy (DOPT) is a technique to improve TB chemoprophylaxis completion rates, yet it may be difficult to provide to high-risk groups such as drug users. For example, only 49% of men in a homeless shelter completed twice weekly INH DOPT (Nazar-Stewart and Nolan, 1992). Even among drug users in residential treatment, DOPT was completed by less than 50% of patients (Foley et al., 1995). Similarly, while directly observed therapy (DOT) for active TB has yielded high completion rates in previously non-compliant patients, (McDonald et al., 1982) completion of DOT is less likely among substance users (Burman et al., 1997, Perlman et al., 1997), including IDUs (Pablos-Maendez et al., 1997, Marco et al., 1998). In a Spanish study of TB treatment that required only twice weekly visits, injection drug use was the main predictor of non-completion (Caminero et al., 1996).

DOPT with IDUs may be more feasible if conducted in settings that patients already attend on an ongoing basis, such as methadone maintenance programs (CDC, 1995a, CDC, 1999). While DOPT is provided in some methadone treatment programs, such services are not universally available. Methadone programs have been shown to be an effective platform for the delivery of a number of health services including primary medical care for conditions such as active TB (Marco et al., 1998, Elk et al., 1993), and HIV disease (Batki, 1988, Selwyn et al., 1989a, Selwyn et al., 1989b, Sorensen, 1991, Goosby et al., 1992, Selwyn et al., 1993, Umbricht-Schneiter et al., 1994, Selwyn, 1996). Since, methadone programs treat large numbers of at-risk patients who attend the clinic daily or almost daily, they are a logical nexus for providing TB prevention services (Brown and Felton, 1989, Haverkos and Lange, 1990). A randomized trial studying the impact of location of TB screening showed that chest radiograph completion by drug users was much higher in a methadone clinic than in a nearby medical clinic (86 vs. 23%) (Umbricht-Schneiter et al., 1994). Completion rates for directly observed INH have been as high as 80–90% in methadone programs (O'Connor et al., 1992, Gourevitch et al., 1998, Snyder et al., 1999), regardless of participants’ drug use (Gourevitch et al., 1996). This contrasts with other settings, where TB medication adherence among substance users has been lower than among non-users (Combs et al., 1990), even with direct observation (Burman et al., 1997, Pablos-Maendez et al., 1997, Perlman et al., 1997). Completion rates are higher in methadone treatment than the average of 66% found in other types of drug treatment settings (CDC, 1993). However, to date there have been no reports of controlled trials to demonstrate that DOPT in methadone programs actually increases completion rates over routine provision of TB preventive therapy without methadone.

Given the high risk and serious public health consequences of incomplete preventive therapy among IDUs, clinical trials are needed to measure the impact of interventions to improve completion rates. The present study is a controlled trial of 6 months of methadone treatment—both with and without substance abuse counseling—combined with directly observed INH, as compared with routine referral to TB clinic to receive monthly INH supplies without direct observation of medication ingestion and without methadone treatment.