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Director's Report to the National Advisory Council on Drug Abuse - February, 2006



Research Findings - Research on Medical Consequences of Drug Abuse and Infections: AIDA/HIV/HEP C Co-Infection

Management and Treatment of Injection Drug Users with Hepatitis C Virus (HCV) Infection and HCV/Human Immunodeficiency Virus Coinfection

Injection drug use is the major mode of hepatitis C virus (HCV) transmission in developed countries. Despite this, relatively few current and recovering injection drug users (IDUs) have received HCV treatment. Studies among individuals with a recent history of injection drug use or those receiving drug dependency treatment have provided evidence that these groups can be successfully treated for chronic HCV infection. These studies have provided the impetus to change guidelines for treatment of current and recovering IDUs, with a move toward individualized HCV treatment assessment and the removal of defined periods of illicit drug use abstinence. Strategies to improve access to HCV treatment for current and recovering IDUs include drug dependency treatment education and training for hepatologists and other HCV treatment physicians, HCV treatment education and training for addiction medicine physicians, development of multidisciplinary clinics, and peer-based education and support for individuals considering and receiving HCV treatment. Dore, G.J. and Thomas D.L.M., Semin Liver Dis. 25(1), pp. 18-32, February 2005.

Treating Hepatitis C Virus Infection in Active Substance Users

Although injection drug users represent the majority of new and existing cases of infection with hepatitis C virus (HCV), many lack access to treatment because of concerns about adherence, effectiveness, and re-infection. On the basis of a small but increasing body of evidence showing that injection drug users can undergo treatment for HCV infection successfully, the 2002 National Institutes of Health Consensus Statement on Hepatitis C has recommended that substance users be treated for HCV infection on a case-by-case basis. However, the criteria on which these treatment decisions should be made are unclear. The duration of pretreatment abstinence, concurrent psychiatric illness, intervening drug use, and the potential for injected interferon to cause relapse of drug use may all influence results of treatment for HCV infection. This overview presents preliminary data on the impact of these potential barriers on outcomes of treatment for HCV infection. Sylvestre, D.L. Clin Infect Dis, 40 Suppl 5:S321-4, April 15, 2005.

Prospective Evaluation of Community-acquired Acute-phase Hepatitis C Virus Infection

More than two-thirds of hepatitis C virus (HCV) infections in Western countries are caused by injection drug use, but prospective clinical data regarding the most common mode of HCV acquisition are rare, in part because acute-phase HCV infection is usually asymptomatic. To characterize acute-phase HCV infection, 179 HCV antibody-negative injection drug users were prospectively evaluated; 62 (34%) of these patients had seroconverted. Twenty of the participants who seroconverted had long-term follow-up with consistent monthly sampling before and after seroconversion, allowing detailed study. The first indication of HCV infection was the presence of HCV RNA in serum, which preceded elevation of alanine transaminase levels and total bilirubin levels to equal or greater than 2 times baseline in 45% and 77% of patients, respectively. No subjects had jaundice. The median time from initial viremia to seroconversion was 36 days (range, 32-46 days). In one instance, viremia was detected 434 days before seroconversion. However, in no other case was HCV RNA detected >63 days before seroconversion. In subjects with viral persistence, a stable level of HCV RNA in the blood was noted in some subjects within 60 days after the initial detection of viremia, but in others, it was not apparent until >1 year later. In subjects with long-term viral clearance, HCV became persistently undetectable as early as 94 and as late as 620 days after initial viremia. These data underscore the importance of nucleic acid screening of blood donations to prevent HCV transmission and of long-term follow-up to ascertain whether there is viral persistence, at least among injection drug users. Cox, A.L., Netski, D.M., Mosbruger, T., Sherman, S.G., Strathdee, S., Ompad, D., Vlahov, D., Chien, D., Shyamala, V., Ray, S.C. and Thomas, D.L. Clin Infect Dis. 40(7), pp. 951-958, April 1, 2005.

Epidemiology and Natural History of Hepatitis C Virus Infection in Injection Drug Users: Implications for Treatment

Effective methods to diminish the burden of hepatitis C virus (HCV) infection among injection drug users (IDUs) require consideration of the epidemiology and natural history of both hepatitis C and drug use. Most HCV infections are due to injection drug use, and most IDUs have HCV infection. In addition, HCV infection often occurs with other medical problems, such as human immunodeficiency virus infection and depression, which may complicate its recognition and management. Infection with HCV can be fatal, but usually not until years later, and persons may be unaware of the infection, allowing an individual to infect many others. Effective treatment is available for HCV infection; however, the therapy is prolonged, involving both weekly injections and daily oral medication, and is typically associated with significant adverse effects, such as fatigue, depression, and, rarely, life-threatening complications. Although clearly some IDUs want their HCV infection to be treated, many are unwilling or unable to initiate or sustain treatment with currently available therapies, and IDUs who are treated require considerable, multidimensional support. Solutions to the problem of HCV infection among IDUs must account for these facts. Sulkowski, M.S. and Thomas, D.L. Clin Infect Dis. 40 Suppl 5:S263-269, April 15, 2005.

The Hepatitis C Virus Alternate Reading Frame (ARF) and its Family of Novel Products: The Alternate Reading Frame Protein/F-protein, the Double-frameshift Protein, and Others

The hepatitis C virus (HCV) has an alternate reading frame (ARF) that overlaps the core protein gene. The overlapping reading frame distinguishes HCV from all of its known viral relatives, with the possible exception of GB virus B (GBV-B). The ARF is expressed during natural HCV infections and stimulates specific immune responses. Like several essential genes in other viruses (e.g., the human immunodeficiency virus polymerase) the ARF lacks an in-frame AUG start codon, suggesting that its expression involves unusual translation-level events. In vitro studies indicate that ribosomal frameshifting may be one of several processes that can lead to translation of the ARF. Frameshifting yields chimeric proteins that have segments encoded in the core gene covalently attached to amino acids encoded in the ARF. A consistent nomenclature for the ARF's protein products has yet to be established. The authors propose that all proteins that contain amino acids encoded in the + 1 ARF be called alternate reading frame proteins (ARFPs) and that specific ARFPs, such as the ARFP/F-protein, the double-frameshift protein, and the short form of core + 1, be designated as follows: ARFP/F (ARFP/F-protein), ARFP/DF (double-frameshift), and ARFP/S (short form of core + 1). The roles of ARFPs in the HCV life cycle are not yet known. There is a significant possibility that ARFPs may be responsible for some of the effects attributed to the core protein, given that most studies seeking to define the function of the core protein have employed materials likely to contain a combination of the core protein and ARFPs. The observed effects of the core protein include the induction of liver cancer, transformation of cells, and alterations of immune responses. This article reviews the discovery of ARF, describes the RNA structural elements involved in core/ARF gene expression, discusses possible functions of ARFPs, and considers the potential usefulness of ARFPs in vaccines. The HCV ARF is the focus of a new and rapidly expanding area of research, and the results of many ongoing studies are currently available in abstract form only. The preliminary nature of investigations that have not yet been reviewed by peers is noted in the text. Branch, A.D., Stump, D.D., Gutierrez, J.A., Eng, F. and Walewski, J.L. Semin Liver Dis. 25(1), pp. 105-117, February 2005.

A Framework for Understanding Factors that Affect Access and Utilization of Treatment for Hepatitis C Virus Infection among HCV-mono-infected and HIV/HCV-co-infected Injection Drug Users

Treatment for hepatitis C virus (HCV) is rarely received by injection drug users (IDU), particularly those co-infected with HIV. The authors propose a framework for understanding factors that affect utilization and adherence to HCV therapy among HCV mono-infected and HIV/HCV-co-infected IDU. Provision of treatment requires calculation of risks and benefits including evaluation of a number of time-varying factors that collectively determine a gradient of treatment eligibility, advisability and acceptability, the relative importance of which may differ in co-infected and mono-infected IDU. Treatment eligibility is determined by a number of non-modifiable and modifiable contraindications, the latter of which can change over time rendering patients who were once ineligible eligible. Among those eligible, treatment need can be assessed by liver biopsy and therapy may be deferred in those with no liver disease and started in those with significant liver disease. Among those with moderate disease, further consideration of treatment advisability (medical factors that affect treatment response) and acceptability (individual, provider and environmental barriers) is needed before treatment decisions are made. These factors are dynamic and thus should be continually evaluated even among those who may not initially appear to be ready for treatment. An evaluation of this framework is needed to determine applicability and feasibility. Until then, treatment decisions should be made on an individual basis after careful consideration of these issues by provider and patient and efforts to develop novel strategies for identifying IDU who need treatment most (alternatives to liver biopsy) and multidimensional approaches to deliver treatment for HCV while addressing other factors including HIV infection, depression and drug use should be continued. Mehta, S.H., Thomas, D.L., Sulkowski, M.S., Safaein, M., Vlahov, D. and Strathdee, S.A. AIDS. 19 Suppl 3:S179-S189, October 2005.

Liver Enzyme Values in Injection Drug Users with Chronic Hepatitis C

Liver enzymes fluctuate in chronic hepatitis C virus infection. However, the range that can be attributed to the course of hepatitis C virus (versus an intercurrent cause of hepatitis) is unknown. The aim of this study was to characterize the range of liver enzyme values as a function of the upper limit of normal (ULN) of the assay among persons chronically infected with hepatitis C virus. Patients comprised one thousand and fifty-nine hepatitis C virus chronically infected individuals with < or =5 semi-annual evaluations. Alanine aminotransferase and aspartate aminotransferase levels were prospectively obtained. Potential causes of elevations were examined using serologic testing. Among 1059 individuals, 11,463 enzyme measurements were obtained over 6.5 years, of which 63.5% were <1.25x ULN, 26.5% were 1.25-2.5x ULN, 8.3% were 2.5-5x ULN, and 1.6% were 5-10x ULN; only 0.2% were>10x ULN. Elevations >10x ULN were transient, the alanine aminotransferase/aspartate aminotransferase ratio tended to be different at the time of the elevation compared to before and after and 24% were associated with acute viral hepatitis. On the other hand, subjects with elevations 5-10x ULN tended to have elevated levels throughout follow-up and only 8% were associated with acute viral hepatitis. Authors concluded that liver enzymes fluctuate up to 5x ULN in most hepatitis C virus-infected persons; clinicians should seek alternate explanations for those with higher alanine aminotransferase or aspartate aminotransferase levels, especially among hepatitis C virus-infected persons with greater than 10-fold elevations. Mehta, S.H., Netski, D., Sulkowski, M.S., Strathdee, S.A., Vlahov, D. and Thomas, D.L. Liver Enzyme Values in Injection Drug Users with Chronic Hepatitis C. Dig Liver Dis. 37(9), pp. 674-680, September 2005.

The Effect of HIV Infection on Overdose Mortality

The objectives of this study were to quantify the association of HIV infection with overdose mortality and explore the potential mechanisms. This was a prospective cohort study in which a total of 1927 actively injecting drug users who were HIV seronegative at baseline, of whom 308 later HIV seroconverted, were followed semi-annually for death from 1988 to 2001. Survival analyses using marginal structural and standard Cox models were used to evaluate the effect of HIV infection on the risk of overdose mortality. Results indicated that overdose death rates were higher in HIV-seropositive than HIV-seronegative drug users: 13.9 and 5.6 per 1000 person-years, respectively (P< 0.01). The hazard ratio (HR) was 2.54 [95% confidence interval (CI) 1.47, 4.38] for the marginal structural model and 2.06 (95% CI 1.25, 3.38) for the standard Cox model, both adjusted for demographics, drug injection characteristics, alcohol abuse, substance abuse treatment, and sexual orientation. Adjusting for possible time-varying mediators (i.e. drug use, medical conditions and healthcare access) in extended marginal structural models reduced the effect of HIV on overdose mortality by 30% (HR 1.82, 95% CI 1.01, 3.30). Abnormal liver function was associated with a higher risk of overdose mortality (HR 2.00, 95% CI 1.05, 3.84); adjustment for this further reduced the effect of HIV on overdose mortality. The authors conclude that HIV infection was associated with a higher risk of overdose mortality. Drug use behavior, systematic disease and liver damage associated with HIV infection appeared to account for a substantial portion of this association. The data suggest a group to target with interventions to reduce overdose mortality rates. Wang, C., Vlahov, D., Galai, N., Cole, S.R., Bareta, J., Pollini, R., Mehta, S.H., Nelson, K.E. and Galea, S. AIDS. 19(9), pp. 935-942, June 10, 2005.

Non-fatal Overdose and Subsequent Drug Treatment Among Injection Drug Users

Overdose is a leading cause of death among illicit drug users. Nine hundred twenty-four injection drug users (IDUs) in Baltimore, Maryland, were interviewed to characterize overdose events and determine the circumstances under which they lead to drug treatment. Overall, 366 (39.7%) reported at least one non-fatal drug overdose. Most (96.2%) used heroin on the day of their last overdose and almost half (42.6%) used heroin and alcohol but few (4.1%) used tranquilizers or benzodiazepines. Five percent were in drug treatment when the overdose occurred and 7.1% had been incarcerated 2 weeks prior. One in four IDUs (26.2%) sought drug treatment within 30 days after their last overdose of whom 75% enrolled. Speaking with someone about drug treatment after the overdose was associated with treatment seeking (AOR 5.22; 95% CI: 3.12, 8.71). Family members were the most commonly cited source of treatment information (53.7%) but only those who spoke with spouses, crisis counselors and hospital staff were more likely to seek treatment. Not being ready for treatment (69.6%) and not viewing drug use as a problem (30.7%) were the most common reasons for not seeking treatment and being placed on a waiting list was the most common reason for not subsequently enrolling in treatment (66.7%). Of the IDUs treated by emergency medical technicians, ER staff or hospital staff, only 17.3%, 26.2% and 43.2% reported getting drug treatment information from those sources, respectively. Interventions that provide drug treatment information and enhance motivation for treatment in the medical setting and policies that reduce barriers to treatment entry among motivated drug users are recommended. Pollini, R.A., McCall, L., Mehta, S.H., Vlahov, D. and Strathdee, S.A. Drug Alcohol Depend. November 22, 2005.


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