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Only 4% of IDUs Eligible for HCV Therapy, in this study
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"Eligibility for Treatment of Hepatitis C Virus Infection among Young Injection Drug Users in 3 US Cities"
"...Injection drug users (IDUs) constitute the core of the hepatitis C epidemic in the developed world......work on HCV has focused on convenient populations....When restrictive criteria are applied to substance users with HCV infection, however, the proportion that remains eligible for antiviral therapy quickly evaporates....Four-hundred four IDUs [in this study] were drawn from the more than 1 million active IDUs in the United States with HCV infection. Of these 404, only 4% would be offered treatment if those with problem drinking, moderate-to-severe depression, or recent injection drug use are considered ineligible. If this is the best we can do-if the "incredible shrinking" pool of patients depicted in their figure is all we can hope to treat-we will forever remain consigned to treating patients at the peripheries of the epidemic, and the burden of liver disease will continue to rise....."
....can patients with these problems be treated for HCV infection? A growing number of studies suggest that they can. ....The Ryan White CARE Act has provided resources for productive collaboration among providers serving patients with HIV infection.....Cultural and behavioral barriers encumber work with IDUs, whether in research, clinical care, disease prevention, or public health. Nonetheless, until these barriers are overcome, the HCV epidemic will continue to spread unabated, and morbidity and mortality from liver disease will continue to rise...."
Clinical Infectious Diseases March 1 2006;42:669-672
Holly Hagan,1 Mary H. Latka,2 Jennifer V. Campbell,3 Elizabeth T. Golub,4 Richard S. Garfein,5 David A. Thomas,4,5 Farzana Kapadia,2 and Steffanie A. Strathdee,6 for the Study to Reduce Intravenous Exposures Project Teama
1National Development and Research Institutes, Center for Drug Use and HIV Research, 2New York Academy of Medicine, Center for Urban Epidemiologic Studies, New York; 3Public Health-Seattle & King County, HIV/AIDS Epidemiology, Seattle, Washington; 4Johns Hopkins Bloomberg School of Public Health, Department of Epidemiology, and 5School of Medicine, Baltimore, Maryland; and 6University of California at San Diego School of Medicine, Department of Family and Preventive Medicine
(See the editorial commentary by Edlin and Cardin following article below)
Among 404 injection drug users aged 18-35 who tested positive for hepatitis C virus (HCV) RNA, 96% had conditions that are potentially unwarranted contraindications for HCV treatment (e.g., problem drinking, moderate-to-severe depression, and recent drug injection). Restrictive eligibility criteria may deny treatment to a large proportion of patients who could benefit from it... In this sample of HCV RNA-positive IDUs aged 18-35 years, there was a high prevalence of conditions that represent potentially unwarranted contraindications for anti-HCV treatment. In particular, most subjects (89%) had injected drugs recently, and 63% had symptoms of either depression or problem drinking. Thus, the application of multiple exclusion criteria to this population may deny treatment to the vast majority-perhaps 96%-of IDUs with HCV infection... treating young patients may have other important public health and individual benefitsc.
Globally, the prevalence of hepatitis C virus (HCV) infection among injection drug users (IDUs) ranges between 40% and 95%, depending on the underlying characteristics of the sample population, such as time at risk and relative frequency of exposure to HCV through unsafe injection [1]. Successful treatment of chronic HCV infection has steadily advanced in recent years; in 2005, approximately half of HCV-infected patients will recover after receiving combination therapy with pegylated interferon and ribavirin [2].
Treatment of IDUs for HCV infection has been controversial. The principal concerns are that drug use may interfere with their ability to adhere to treatment or that it may increase the risk of reinfection after they have recovered [3]. Interferon treatment is associated with acute depression, and symptoms of depression are highly prevalent among IDUs [4, 5]. Heavy alcohol use is related to severe liver disease in HCV-positive patients, and it can reduce the effectiveness of anti-HCV treatment [6]. Polydrug use, including heavy alcohol consumption, is also relatively common among IDUs [7]. Altogether, IDUs may face a number of obstacles to anti-HCV treatment, and anti-HCV treatment may be received less often by IDUs than by other patient groups [8, 9]. In 2002, the National Institutes of Health consensus on medical management of HCV infection reversed a previous judgment from 1997 [10], and recommended that practitioners "determine on an individual basis whether patients who use drugs or alcohol may be offered treatment" [11, p. 12]. This represented an important step toward providing treatment for HCV infection to a greater proportion of infected persons, but many individual practitioners still choose to apply restrictive criteria, including abstinence from ongoing illicit drug use for 6 months prior to treatment [8, 12]. Previous studies have not examined the potential impact of multiple screening criteria on IDUs' access to treatment. This article assesses eligibility of a sample of young, HCV RNA-positive IDUs for anti-HCV treatment-an important population because young age (defined here as aged 18-35) is associated with higher likelihood of successful treatment outcome [13].
Discussion.
In this sample of HCV RNA-positive IDUs aged 18-35 years, there was a high prevalence of conditions that represent potentially unwarranted contraindications for anti-HCV treatment. In particular, most subjects (89%) had injected drugs recently, and 63% had symptoms of either depression or problem drinking. Thus, the application of multiple exclusion criteria to this population may deny treatment to the vast majority-perhaps 96%-of IDUs with HCV infection.
Considering the degree to which these criteria may restrict access to treatment, there is remarkably little evidence to support their use in screening patients for eligibility. A review of anti-HCV treatment experiences among active or former IDUs reported that studies have consistently shown low rates of reinfection, and treatment completion rates among IDUs are comparable to the rates in other patient populations [8]. Other studies have shown that it may be unnecessary to withhold HCV treatment from patients with symptoms of moderate or severe depression, and pretreatment with antidepressants and monitoring for signs of acute depression may improve treatment safety [17]. A relatively large proportion of IDUs with HCV infection (50%-80%) may be willing to undergo treatment [18], which suggests that patient reluctance is not a major barrier. Heavy alcohol use may represent a more important contraindication to HCV treatment, because it appears to decrease response to therapy, but the effect of moderate alcohol use is less clear [19]. Thus, the number of IDUs treated for HCV infection may increase substantially if only those factors empirically shown to affect treatment outcome are considered. Particularly because younger patients are more likely to respond to treatment of HCV infection, factors used in screening for treatment eligibility in this group should be limited to those that clearly reduce the effectiveness of treatment or increase toxicity.
In addition to increasing the likelihood of a sustained virologic response to HCV therapy, treating young patients may have other important public health and individual benefits. Early treatment may substantially shorten the period of infectiousness and, if carried out on a large scale, lower the prevalence of IDUs who are infectious HCV carriers to a meaningful degree. In addition, anti-HCV pharmacotherapy requires regular medical visits over a long-term period-a regimen that may permit the integration of primary medical care or office-based treatment of opiate addiction with buprenorphine [20]. Clearly, cost-benefit analyses of anti-HCV treatment for IDUs should include any health care cost savings due to averted infections and early treatment of other conditions, including substance abuse.
Limitations to the study include the possibility that the patient sample may not be representative of the underlying population of younger, HCV RNA-positive IDUs. Although the sample included a relatively large proportion of white males and may not be representative of IDUs in all US cities, the use of several different recruitment strategies, including targeted street outreach and participant-driven referrals, would tend to reduce recruitment bias. Social desirability bias may have influenced the reporting of alcohol use, although the interviews were administered using computer-assisted self-interview technology. The elevated ALT levels in a large proportion of patients in our sample may have been a consequence of alcohol use rather than an indication of the effects of HCV infection. However, the use of elevated ALT levels to select individuals with a higher probability of response to treatment has been brought into question by recent studies of HCV virologic kinetics [21]. We also did not perform liver biopsies or other tests to determine medical eligibility for treatment, and the single ALT test may not be particularly informative in determining whether active hepatitis infection is present. None of the young IDUs we screened for recruitment were ineligible to join the study because they had not injected drugs in the past 6 months. However, if 6 months' abstinence were a requirement, even fewer than 4% of young IDUs may be eligible for HCV treatment.
Members of the STRIVE project team. Steffanie A. Strathdee, Elizabeth T. Golub, David Thomas, Susan Sherman, Marie Bailey-Kloch, Yvette Bowser, Peter O'Driscoll, Janet Reeves, Marcella Sapun, Dale Netski, McCay Moiforay, Fleesie Hubbard, Coralee Meslin, Karen Yen-Hobelmann, Eddie Poole, David Hudson, Gina Gant, and Eric Hendren, from Johns Hopkins University, Baltimore, Maryland; Mary Latka, Farzana Kapadia, David Vlahov, Micaela Coady, Danielle Ompad, Sebastian Bonner, Joanna Cruz, Sandra DelVecchio, Dirk Jackson, Gregory Malave, Joan Monserrate, Clarisse Miller O'Shea, and Manny Yonko, from the New York Academy of Medicine, New York, New York; Holly Hagan, Jennifer V. Campbell, Eileen Hough, Hanne Thiede, Rong Lee, Susan Nelson, Jef St. De Lore, Kimberly Houk, Sarah Brooks, Carrie Shriver, Hal Garcia-Smith, Jeanette Frazier, Jean Pass, and Paul Swenson, from Seattle-King County Public Health, Seattle, Washington; and Richard S. Garfein, from the University of California, San Diego.
Methods. The Study to Reduce Intravenous Exposures (STRIVE) was a trial of a randomized, controlled, behavioral intervention that aimed to reduce HCV transmission risk behavior and increase health care utilization among HCV-positive, young IDUs in Baltimore, New York, and Seattle. Enrollment occurred from June 2002 to February 2004. To be eligible, participants had to have used injection drugs in the past 6 months, had to test positive for antibodies against HCV, and test negative for antibodies against HIV, and had to be aged 18-35 years. Participants were recruited by referral from other studies that had screened them for antibodies against HCV. At baseline, participants completed questionnaires via computer-assisted self-interview. Depression was measured using the Beck Depression Inventory [14]; a score of >19 indicates moderate-to-severe depression symptoms. Alcohol use was measured using the Alcohol Use Disorders Identification Test (AUDIT) [15]; an AUDIT score of >8 indicates problem drinking. We defined current IDUs as those who had used an injection drug in the 30 days prior to study enrollment. Blood samples were tested for antibodies against HCV with either HCV EIA 3.0 (Ortho) or HCV EIA 2.0 (Abbott), and alanine aminotransferase (ALT) levels and HCV RNA levels were determined with the Cobas Amplicor assay (Roche Diagnostic Systems). The reference ranges used by the 3 local laboratories that performed the tests were used to establish the upper limit of normal for ALT levels. However, because the accepted upper limit of normal may not be a sensitive measure of hepatic injury, Prati et al. [16] have proposed that the "healthy" upper limit of normal for ALT levels be revised as 0.75 times the upper limit of normal for men and 0.63 times the upper limit of normal for women. Therefore, we report the proportion of subjects with elevated ALT levels, showing both the percentage of those whose levels are above healthy limits and the percentage of those whose levels are above normal limits. This analysis estimates the proportion of HCV RNA-positive subjects that may be considered eligible for treatment of HCV infection, assuming that problem drinking, depression, or current drug injection may be used to screen patients, and that some clinicians may only treat patients with elevated ALT levels. These criteria were selected because they appear to reflect general practice; with the exception of alcohol use, none of the criteria have been systematically studied to assess their impact on treatment outcome. This study was approved by institutional review boards at each of the study sites.
Results.
There were 632 eligible subjects enrolled in STRIVE; 404 (64%) were HCV RNA-positive and included in this analysis. Seventy-eight percent were men, and 60% were white. The median age was 26 years (interquartile range, 23-29 years). Heroin injected alone or with cocaine was the injected drug mainly used by subjects. The median number of years since first injection was 6 (interquartile range, 4-9 years). Eighty-four percent of the subjects had never been incarcerated, and 70% had never been in drug treatment of some type. Only 23% reported they were currently enrolled in a drug treatment program. Most participants (65%) injected drugs daily. Two hundred twenty-two (55%) of 404 IDUs scored <19 on the Beck Depression Inventory, and 255 (63%) of 404) scored <8 on AUDIT. Forty-four (11%) of 44/404 had not injected drugs in the previous 30 days.
Figure 1 shows the percentage of IDUs who may be deemed eligible for treatment of HCV infection, as multiple criteria are applied. Three hundred thirty-five (38%) of 404 had ALT levels above the healthy limit, and 279 (69%) of 404 had ALT levels above the normal limit. Thirty-seven percent had low Beck Depression Inventory and AUDIT scores; including only those with elevated ALT levels, this reduced the percentage of eligible subjects to 26%-32%. Of the 11% who had not injected drugs in the previous 30 days, only half would be considered eligible for treatment of HCV infection if the presence of problem alcohol use or depression was also used in screening. Only 4% of all subjects in the study would be considered eligible for anti-HCV therapy on the basis of having ALT levels above normal limits, low AUDIT and Beck Depression Inventory scores, and having not injected drugs in the past 30 days.
Injection Drug Users: The Overlooked Core of the Hepatitis C Epidemic
EDITORIAL
Brian R. Edlin and Michael R. Carden
Center for the Study of Hepatitis C, Weill Medical College of Cornell University and Center for the Study of Hepatitis C, Weill Medical College of Cornell University, New York, New York
Injection drug users (IDUs) constitute the core of the hepatitis C epidemic in the developed world. Four times more prevalent than HIV infection, hepatitis C virus (HCV) has been acquired by at least 5 million Americans and an estimated 170 million people worldwide. In developed countries, people who use illegal drugs by injection are the largest group of persons with HCV infection and the group among whom most new infections occur. Viral transmission is uncontrolled among IDUs, with incidence rates ranging from 16%-42% per year [1-4], and yet, our efforts to control this pandemic have largely ignored the population in whom its biology and epidemiology are being played out with the most devastating effects.
Disease control depends on epidemiology, basic science, treatment, and prevention. In each of these spheres, work on HCV has focused on convenient populations-patients who come to our clinics and offices of their own accord-rather than the more challenged and stigmatized populations in whom the epidemic continues to rage out of control. The ubiquitously quoted estimate of the number of Americans infected with HCV-4 million-was derived from the National Health and Nutrition Examination Survey, a study of the housed, noninstitutionalized, civilian population of the United States [5]. But the populations most severely affected by HCV are poorly captured by this study. Disproportionately low response rates can be expected in government surveys from persons engaged in illegal activities, disclosure of which could result in incarceration or deportation. In addition, the National Health and Nutrition Examination Survey sampling frame, by design, explicitly excluded several large groups known to have high prevalences of injection drug use and HCV infection: people who are homeless, incarcerated, hospitalized, or institutionalized. Available estimates of the sizes and HCV prevalences of these populations suggest that at least a million more Americans have been infected with HCV than estimated by the National Health and Nutrition Examination Survey data [6].
New HCV infections in persons who inject illicit drugs are probably not well-represented in official estimates of HCV incidence in the United States, either. National estimates of the number of new HCV infections-about 30,000 per year-are based on data from cases of acute HCV infection reported to health departments in the 4 US counties (recently expanded to 6) participating in the Sentinel Counties Study of Acute Viral Hepatitis [7]. The calculations rely on the estimate that 1 in 6 new infections come to medical attention. HCV infections in IDUs, however, are rarely symptomatic, and probably <1% come to medical attention and are diagnosed [8, 9]. Thus, the true incidence of HCV infection among IDUs may be even less accurately ascertained by our surveillance system than the prevalence. The official estimates of these numbers tell us about infections in those of us who are stably housed, have nothing to fear from the criminal justice system, and go to the doctor when sick, but tell us little about those at the core of the epidemic.
If epidemiologists overlook IDUs when studying HCV, it is little wonder that basic scientists and treatment researchers do the same. Critical lessons about effective human immune responses to HCV infection can be learned from persons who clear the virus during the acute phase of infection. But although tens of thousands of IDUs in the United States become infected every year, most of our insights about the biology of acute HCV infection have come from less representative but more accessible sources-rare cases of symptomatic acute HCV infection that come to medical attention and occupationally exposed health care workers [10, 11]. And even as considerable progress has been achieved in developing new effective antiviral regimens for HCV infection, persons who inject illegal drugs, even former IDUs receiving methadone maintenance treatment, are routinely excluded from clinical trials of new HCV therapies.
Because, even by official estimates, most HCV transmission in developed countries occurs through the use of contaminated injection equipment during illicit drug injection, one might expect that prevention efforts would, of necessity, focus on stopping transmission among IDUs, even if other clinical or scientific efforts focused on more accessible populations. Most official publications on the prevention and control of HCV infection [12-14], however, have avoided directly recommending the central strategies for preventing bloodborne disease transmission among IDUs: accessible substance abuse treatment, syringe exchange programs, removal of the legal barriers to syringe access and possession, community-based outreach, and HCV testing and treatment programs for IDUs and incarcerated persons [15]. Prisons offer an unparalleled opportunity for HCV prevention and treatment [16], because an estimated 29%-43% of HCV-infected persons in the United States pass through the corrections system annually [17], but the opportunity is almost universally squandered [18]. Despite their centrality in the epidemic, IDUs all too often seem invisible to epidemiologists, basic scientists, clinicians, and public health authorities alike.
One official document that illuminated this blind spot was the 2002 National Institutes of Health consensus statement on the management of HCV [19]. Departing from previous guidelines, this document recommended that drug users be considered for HCV treatment on a case-by-case basis, just like other patients, and that drug use in and of itself not be considered a contraindication. This change was based on the recognition that data did not exist to support the previous recommendation, made in 1997 [20], that drug users not be treated for HCV infection until they had abstained from all illicit drug use for at least 6 months [21]. Nonetheless, few data exist to guide physicians considering treating active drug users for HCV infection outside of special targeted programs [22-38], and most hepatologists still adhere to the old guidelines on this matter. As a consequence, despite the new guidelines, very few drug users have access to treatment for HCV infection [39].
Current treatment regimens for HCV infection appear to eradicate the virus from 50% of patients [40], averting the risk of liver failure or liver cancer [41]. When restrictive criteria are applied to substance users with HCV infection, however, the proportion that remains eligible for antiviral therapy quickly evaporates, as reported by Hagan and her colleagues in this issue of Clinical Infectious Diseases [42]. Four-hundred four IDUs were drawn from the more than 1 million active IDUs in the United States with HCV infection. Of these 404, only 4% would be offered treatment if those with problem drinking, moderate-to-severe depression, or recent injection drug use are considered ineligible. If this is the best we can do-if the "incredible shrinking" pool of patients depicted in their figure is all we can hope to treat-we will forever remain consigned to treating patients at the peripheries of the epidemic, and the burden of liver disease will continue to rise.
But can patients with these problems be treated for HCV infection? A growing number of studies suggest that they can. Reports from Munich [22-24], Oakland [25], Chicago [26], Rhode Island [27], New York [28], Vancouver [29], England [30], France [31], Italy [32], Belgium [33], Dusseldorf [34], Switzerland [35], Austria [36], Norway [37], and Australia [38], reviewed elsewhere [43-45], have suggested that drug users treated for HCV infection can achieve sustained virologic response rates similar to those in other populations, even if they have psychiatric comorbidity, and even if they continue to use drugs while receiving treatment, although more frequent drug use may be associated with less success [25]. Many of these studies, however, reported on small, diverse groups of sometimes highly selected patients recruited and treated in different settings with differing strategies. Data are sparse on the characteristics that distinguish those who can be successfully treated and the programmatic elements that are critical for success. Larger studies that carefully characterize patient and program characteristics and outcomes are needed to provide this information. The need for such research is urgent, in view of the overwhelming prevalence of HCV infection in this population [46, 47], the increasing morbidity and mortality of the disease [48], and the limited access that IDUs have to liver transplantation [49]. In the meantime, these same considerations demand that we use what we know already to expand and replicate existing programs that have been successful [50].
Cultural and behavioral barriers encumber work with IDUs, whether in research, clinical care, disease prevention, or public health. Nonetheless, until these barriers are overcome, the HCV epidemic will continue to spread unabated, and morbidity and mortality from liver disease will continue to rise. Fortunately, experience working effectively with IDUs is available from a relatively large community of professionals serving substance-using populations, including those working in substance abuse treatment, HIV prevention, harm reduction, HIV care, primary medical care, social services, and other areas. Knowledge and experience with HCV infection and its treatment, however, are needed in these circles. Dialogue and collaboration between experts in HCV treatment and practitioners who have experience with IDUs will be needed to bring the unseen core of the HCV epidemic into view, so that progress can be made toward effective prevention of infection and effective treatment and care of those with HCV infection at the core of the epidemic. The Ryan White CARE Act has provided resources for productive collaboration among providers serving patients with HIV infection. Advocacy for the needs of persons with HCV infection may be required to get needed resources allocated to support similar work on HCV. The all-too-frequently overlooked core of the epidemic is the battleground on which efforts to control HCV infection in the developed world will be won or lost.
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