Within the past two decades, hepatitis C virus (HCV) has emerged as the second major viral epidemic after HIV. Complications from HCV are becoming one of the most important medical issues facing HIV-positive individuals, and the ramifications of co-infection are considerable on survival and quality of life. According to Centers for Disease Control and Prevention reports, approximately a quarter of the HIV-infected population in the United States is also infected with HCV. HIV/HCV co-infection is found in 50–90% of injection drug users (IDU). As this is a rapidly emerging public health concern, two companion workshops, described below, were organized to examine our current knowledge of basic, behavioral and clinical issues relevant to HIV/HCV co-infection and to identify future research directions.
The goal of the first workshop entitled ‘HIV/Hepatitis C Co-infection: Impact on Nervous System Disease Burden’ was to define the burden of neurological and neuropsychiatric disease in the setting of HIV/HCV co-infection, and identify future research directions in the areas of neuropathogenesis as well as treatment. The invited speakers focused on neuropsychiatric, neurological, virological and treatment-related issues relevant to HIV/HCV co-infection. The goal of the second companion workshop entitled ‘HIV/Hepatitis C Co-infection: Behavioral and Clinical Research in Mental Health and Drug Abuse’ was to build on the most current information and provide a clearer focus for mental health and drug abuse-related research on the behavioral and clinical aspects of HIV/HCV co-infection (i.e. risk and prevention; services; treatment). These meetings (convened in October 2003 in Washington, DC, USA) were sponsored by the National Institute of Mental Health and co-sponsored by the National Institute on Drug Abuse, the National Institute of Neurological Disorders and Stroke and the NIH Office on AIDS Research.
The assembled articles in this special issue resulted from these companion workshops and were recently updated with the latest information. Whereas each meeting had unique areas of emphasis, there were also overlapping areas. To organize the collection and to bring together related articles we have integrated the content of the two meetings into five sections. These include: (i) vulnerable populations; (ii) neurocognitive and neuropsychological studies relating to HIV/HCV co-infection; (iii) neurological and neuropsychiatric complications of HIV/HCV co-infection; (iv) virological studies relating to HCV infection of the central nervous system (CNS); and (v) treatment, treatment services and prevention.
Thomas and Sulkowski introduced the complex interrelationships of HIV/HCV infections, illicit drug use, mental illness and medical care. They discussed the epidemiology of HIV/HCV co-infection and neurocognitive dysfunction and mental illness in HIV/HCV-co-infected patients. HIV and HCV treatment strategies for co-infected patients, which ideally require an integrated approach at a single point of care involving multiple disciplines, were also discussed.
Section I: Vulnerable populations
The papers in this section discussed the epidemiology, among the most vulnerable subpopulations, of HCV and HIV/HCV co-infection. Backus et al. analysed a database from the Department of Veterans Affairs (VA) Immunology Case Registry, the single largest provider of healthcare services in the United States to individuals infected with HIV, and reported an HCV infection rate of 37% in HIV-infected individuals. This high rate of HIV/HCV co-infection can complicate the pharmacological therapy and clinical course of both HIV and HCV infections. In addition, they showed that the high prevalence of substance abuse and psychiatric diagnoses, in particular the high rate of depression, posed an additional challenge. Co-infected patients had a shortened survival, perhaps because IFN-α products may exacerbate or precipitate mental health illness, particularly depression. Injection drug use, considered to be the major risk factor for contracting HCV and HIV, significantly impacts on each disorder's progression and accounts for 60% of new HCV cases and up to 40% of new HIV infections. Des Jarlais et al. noted that although the prevalence and incidence of HCV remains at very high levels among IDU in the inner city, there has been a reduction in both HIV and HCV prevalence, which is temporally associated with the large-scale expansion of syringe exchange programmes. These authors pointed out that even with these trends, HCV infection is still a major problem among IDU, and there is a need for increased efforts to reduce HCV among IDU through syringe exchange, drug abuse treatment programmes and community outreach programmes focusing on HCV education and prevention. Rosenberg et al. discussed their research in the context of the emerging findings that individuals with psychiatric disorders, in particular severe mental illness, frequently associated with a heightened risk of substance use disorder, are at an elevated risk of both HIV and HCV infection. In a multi-site sample of clients with severe mental illness, co-infection was found to be associated with the severity of psychiatric illness, ongoing drug abuse, poverty, urban residence, homelessness, incarceration and racial/ethnic minority group membership. The latter three subpopulations were addressed in greater detail in the final three articles of this section as they relate to HIV/HCV co-infection. Nyamathi et al. explored the health risks of homeless and runaway youth, who are vulnerable to hepatitis and HIV infection because of the high prevalence of injection drug use, non-injection substance use, mental illness, risky sexual practices, the limited use of preventive health services and a lack of knowledge about HCV and HIV and risk-reduction behaviors. They concluded that there is need for youth-centered programmes in an accessible outpatient setting that integrates the concurrent use of primary health services, mental health services, substance abuse treatment, risk reduction, psychotherapeutic interventions and case management to address the adverse effects of co-occurring complications, improve adherence and health outcomes. Weinbaum et al. noted that although limited published data are available regarding HIV/HCV co-infection among US prisoners, there is now increasing evidence that injection drug use and unsafe sexual behaviors have resulted in a greater number of inmates being infected with HCV, hepatitis B virus (HBV) or HIV in the jails and prisons of the United States. The authors discussed the epidemiology of HCV, HBV, HIV and HIV/HCV co-infections among inmates and releasees of correctional facilities, and strategies for the prevention of these infections among incarcerated populations in correctional settings. In view of the disparities in diagnosis, treatment, care access and outcomes of various medical and neuropsychiatric disorders in racial and ethnic minority populations, Estrada reviewed the epidemiology of HIV, HBV and HCV among African-American and Hispanic individuals, and, in particular, IDU. Their data suggest that a comprehensive approach is required to reduce and ultimately eliminate these health disparities, including case management, testing and counseling, clinical treatment and community-based behavioral or structural interventions.
Section II: Neurocognitive and neuropsychological studies relating to HIV/hepatitis C virus co-infection
The articles contained in this section clearly suggest that HIV or HCV mono-infection contribute to subtle neurocognitive and neuropsychological deficits. Furthermore, in-vivo cerebral magnetic resonance spectroscopy studies in patients with hepatitis C and normal liver function have reported elevations in cerebral choline-containing compounds and reductions in N-acetyl aspartate, suggesting that a biological mechanism may underlie the cognitive findings (Forton et al.). However, studies of the neuropsychological and neurocognitive abnormalities of patients in the setting of HIV/HCV co-infection have yielded disparate results. For example, Clifford et al. demonstrated that HIV/HCV co-infection has an adverse impact on the digit symbol measure of neuropsychological function. HCV may also be associated with depressed mood, particularly with somatic depressive symptoms. The authors recognized that confounding contributors, such as substance abuse, mental illness and other medications, to neuropsychological performance are difficult to exclude. Similar effects of HIV/HCV co-infection on neuropsychological performance in the context of drug abuse were presented by Letendre et al. HCV-positive individuals performed worse on neuropsychological testing and were almost twice as likely to be diagnosed as being globally impaired, compared with those who were HCV negative. Using linear regression analysis, it was evident that HCV, HIV, and methamphetamine dependence were independently associated with worse performance, even after adjusting for the CDC stage and antiretroviral drug use. In contrast, studies by Perry et al. found that HCV alone was associated with worse performance on neuropsychological measures, and increased hepatic fibrosis was associated with even poorer performance independent of HIV status. Many patients with HCV complain of fatigue and Kramer et al. addressed the impact of HCV-induced fatigue on the quality of life. In untreated patients with chronic HCV infection, fatigue severity and age, but not neurocognitive dysfunction or hepatic function, were independently associated with impaired health-related quality of life.
Section III: Neurological and neuropsychiatric complications of HIV/HCV co-infection
Weissenborn et al. reviewed neuropsychiatric abnormalities in liver disease, particularly in the context of hepatic encephalopathy. In contrast to patients with hepatic encephalopathy, HCV-infected patients with neuropsychiatric findings did not show motor symptoms or deficits in visual perception, but did show considerable deficits in attention and concentration ability. Goulet et al. reported preliminary data that HIV/HCV-co-infected veterans (who are more likely than mono-infected to be older and of minority status) had a higher prevalence of comorbid conditions (especially alcohol, drug and psychiatric disorders), which may complicate and limit treatment options for HIV and for HCV co-infection. The authors concluded that strategies to improve treatment options for co-infected patients with comorbidities must be developed, and further research is needed to determine the extent to which the treatment of co-occurring conditions influences the rate of successful HCV treatment and related outcomes. On the basis of a retrospective review of medical records, Huckans et al. evaluated demographic risk factors associated with both HIV and HCV infections in a veteran population, and found that veterans with substance use disorders were significantly more likely to be tested for both HCV and HIV infections and to test positive for HCV but not HIV. It was suggested that programmes should be developed that integrate mental health, substance abuse, and medical care in view of the increasing number of HCV and HIV-infected patients, particularly in populations of patients with substance use disorders.
The impact of liver function and HCV serostatus on neurological, neuropsychological and psychiatric abnormalities in an advanced stage, HIV-infected cohort were discussed by Morgello et al. Biochemical indices of liver function correlated with evidence of motor dysfunction but not with neuropsychological and neuropsychiatric disorders. HCV had no relationship to any neurological disorder or symptom complex but was related to neuropsychological and neuropsychiatric abnormalities.
The last three manuscripts in this section focused on the pathophysiology of peripheral neuropathy and extrahepatic complications. Vassilopoulos provided an overview of the extrahepatic immunological complications of hepatitis C infection. In the majority of cases the underlying pathogenetic mechanisms are immune mediated, as evidenced by the presence of circulating autoantibodies (mixed cryoglobulinemia), whereas for others a localized host cellular immune response is indicated (e.g. sialadenitis, lichen planus). Cacoub et al. also reviewed the link between HCV infection, mixed cryoglobulinemia vasculitis and peripheral neuropathy. Treatment strategies for peripheral neuropathy induced by HCV infection were also discussed. The last in the series of articles on peripheral neuropathy was presented by Estanislao et al., who described studies in the context of HIV mono-infection and preliminary available data on HIV/HCV co-infection. Although data on HIV-induced peripheral neuropathy are on firm footing, currently available data are inadequate to suggest that HCV neuropathy impacts on the prevalence of HIV neuropathy. The authors suggested the need for detailed and systematic studies to draw firm conclusions on the potential for synergy between HCV and HIV in the development of peripheral neuropathy.
Section IV: Virological studies relating to hepatitic C virus infection of the central nervous system
The focus of papers in this section is on virological studies related to HCV infection of the CNS. Laskus et al. in a recent study detected negative-strand HCV RNA, which is a viral replicative intermediary, in the macrophages/microglia of autopsy brain tissues of HCV-infected patients. This raises the possibility that HCV infection of the brain could be related to the reported neuropsychological changes. Adair et al. went on to study whether HCV infection affects gene expression in brain tissue using differential display and reverse Northern hybridization. A prominent finding was the downregulation of mitochondrial oxidative phosphorylation genes, some ribosomal protein genes and several genes involved in transcription regulation. Bagaglio et al. examined the compartmentalization of different HCV strains in the plasma, peripheral blood mononuclear cells and cerebrospinal fluid (CSF) of HIV-positive patients in an attempt to identify active HCV replication in the CSF, and clarify whether CSF-derived HCV viral particles are more closely related to those found in plasma or, peripheral blood mononuclear cell samples. The authors described HCV genetic diversification in different compartments, suggesting the possibility that the CSF is an independent site of viral replication and persistence. The demonstration of HCV infection and replication in the CNS compartment is highly significant and may provide a biological basis for the neurocognitive and neuropsychological deficits observed in infected patients.
Section V: Treatment, treatment services and prevention
The set of papers in this section examined challenges associated with treatment, providing treatment services, and prevention strategies for HIV/HCV co-infected patients. Kotoronis et al. provided an overview of the treatment advances for HCV mono-infection and HIV/HCV co-infection, and proposed a treatment algorithm of HCV in HIV co-infection. There has been a rapid evolution in the management of HCV in mono-infected patients. The most effective and generally available treatment for HCV is combination therapy that includes pegylated IFN-α and ribavirin. Although therapeutic advances have been made for HCV mono-infection, treatment intervention in HIV/HCV-co-infected patients has been limited. HIV caregivers and patients have been unwilling to try an additional medication regimen that is associated with many adverse events and drug interactions and in which treatment success is often limited, particularly for genotype 1, which makes up the majority of HCV in co-infected patients. For example, depression and cognitive impairments are frequent and persistent side-effects of interferon treatment (Reichenberg et al.).
The next two papers addressed some of the specific barriers to treatment success (Mehta et al., Wagner et al.). First, Mehta et al. discussed treatment eligibility, the likelihood of success, acceptability, and some important medical factors and barriers that impede treatment progress among IDU. They proposed a framework for better understanding factors that affect the utilization and adherence to HCV therapy in the context of the impact of individual-level, provider-level and structural or environmental-level barriers. The relative importance of these barriers is likely to differ among those infected with HCV alone and HIV/HCV-co-infected individuals, which might suggest useful guidelines for therapeutic decisions among these different populations. Wagner and Ryan noted that, despite the relative success of HCV treatment (approximately 15–40% of co-infected patients can be successfully treated for HCV), very few co-infected patients are actually treated because of the multiple barriers to treatment uptake. They reviewed studies on the medical, behavioral and mental health variables contributing to providers’ assessment of treatment readiness, outcome and adherence that can inform intervention development and policy efforts for improving HCV care in HIV-infected patients. Whereas the development and dissemination of treatments to help drug users manage their infections is urgently needed, there is no doubt that prevention programmes targeted to relevant risks are important and yet there are few studies examining prevention. Noting the very high prevalence of HCV infection among HIV-positive IDU, Hagan et al. emphasized the importance of HCV prevention strategies to control HIV/HCV co-infection. Citing the evidence of the inconsistent effects of HCV prevention programmes (e.g. studies of HCV screening and education, drug treatment or needle exchange), the authors identified strategies to improve the success of various prevention strategies on HCV transmission through larger scale studies that target the multiple, potentially modifiable, influences on HCV incidence and transmission.
The next two papers return to some of the most vulnerable, hard-to-reach and difficult-to-treat subpopulations of HCV and HIV/HCV-infected individuals from treatment viewpoints (see also Section I). Thompson et al. identified the reasons why the homeless and marginally housed are often considered ineligible for treatment. When multidisciplinary efforts are employed towards integrating treatment with ongoing care for homeless individuals, many of these treatment barriers (e.g. concurrent depression, poor adherence) are effectively addressed and significant success can be experienced. Also focusing on an integrated approach, Goldberg et al. proposed their ‘supported medical model’ to integrate self-management skills training for a chronic illness, and enhanced medical case management so that psychiatric and medical care needs of individuals with severe mental illness can be coordinated. Although the authors discussed their model in the context of several other conceptual models (e.g. biopsychological model), there has been surprisingly little research on integrated intervention efficacy to address the global needs of this highly vulnerable population.
The final two articles in this section focus on integrated treatments. First, Kresina et al. presented data on the integration of buprenorphine treatment for opioid addiction to HIV primary care as a new treatment paradigm for IDU to address substance abuse. The authors also discussed integrated buprenorphine–HIV care systems in the context of barriers to the integration of pharmacotherapy as well as the effectiveness of other interventions (e.g. case management, mental health services, directly observed therapies). The other paper on integration examined the rationale for integrated care, conceptual issues behind integration, and the various approaches, such as improved linkages and integrated teams in the same setting, for such care (Willenbring). Although evidence for the success of integration strategies has been based largely on observational demonstration projects, it should be aggressively pursued in a more targeted way to maximize the chances of successful outcomes for populations susceptible to HIV, HCV or HCV/HIV co-infection.
Future research directions
A major goal of both workshops and the resulting proceedings herein was to define critical research gaps in the areas of (i) HIV/HCV co-infection and the impact on nervous system disease burden, and (ii) behavioral and clinical research in mental health and drug abuse in the context of HIV/HCV co-infection. The identification of key research areas helps guide the National Institute of Mental Health, the National Institute on Drug Abuse and the National Institute of Neurological Disorders and Stroke in developing research programmes and initiatives. 1Discussion panels were convened at the end of each of the workshops to identify gaps in the field that needed to be addressed and the most promising research opportunities for the HIV/HCV co-infection research community. These include studies on:
* Epidemiology and the prevention of HIV/HCV: Identify and characterize those populations at elevated risk of HIV/HCV co-infection, determine the incidence and prevalence of HIV/HCV co-infection among those populations, and identify optimal screening and testing strategies. Another important area is to develop and test prevention strategies for HIV/HCV co-infection.
* Pathogenesis of HIV/HCV co-infection: Examine the impact of co-infections on immune dysfunction and HIV progression and the impact of HIV infection on the natural history and pathogenesis of co-infecting pathogens.
* Epidemiology of HCV neurocognitive impairment: Determine the prevalence, qualitative, and quantitative features of HCV neurocognitive impairment compared with neurocognitive effects of HIV or other neurodegenerative diseases and co-factors associated with impairment.
* Pathogenesis of HCV neurocognitive impairment: Determine the mechanisms of neural injury by HCV, including host and viral factors and their interactions.
* Treatment of HIV/HCV: Develop, test and implement treatment strategies for HIV/HCV co-infection that are effective for already-infected individuals and for the recurrence of infection, and ascertain required treatment adherence levels for optimal clinical benefits.
* Impact and treatment of HCV neurocognitive impairment: Determine the impact of HCV neurocognitive impairment on everyday function and quality of life including treatment adherence. Evaluate whether the successful treatment of HCV improves neurocognitive performance and peripheral nervous system functioning and explore specific neuroprotective interventions and treatment beyond that of clearing the virus.
* Barriers to prevention and care of HIV/HCV: Identify and evaluate barriers to the care and prevention of HIV/HCV co-infection, including factors related to patient (medical, neuropsychiatric, substance abuse comorbidities), provider, organizational structure of care and social disorganization (e.g. poverty, homelessness, healthcare system mistrust) and test strategies to overcome these barriers including the treatment of comorbidities.
* Integrated care for HIV/HCV: Develop optimal models of integrated care (individual, programme and systems level) for HIV/HCV co-infection (and associated comorbidities), the effectiveness of coordinated care, and identify the most effective components of an integrated comprehensive multidisciplinary treatment plan.
These aforementioned research questions on HIV/HCV co-infection in a number of different areas represent several research programmes supported by the Center for Mental Health Research on AIDS at the National Institute of Mental Health (http://www.nimh.nih.gov/dahbr.cfm). The importance of HIV/HCV co-infection as a scientific research priority has been described in the National Institute of Health Fiscal Year 2006 Plan for HIV-Related Research from the Office of AIDS Research (http://www.nih.gov/od/oar/public/public.htm). It is hoped that the wide range of issues covered in this supplement will serve to articulate the state-of-the art in the emergent research area of HIV/HCV co-infection and will help to identify scientific opportunities and provide the most promising strategies for moving the field forward.
The authors would like to acknowledge the superb editorial work by Louisa Mott and Daniel Nebel. In addition, the authors acknowledge Dr. Kevin Robertson for providing critical advice regarding several manuscripts in this supplement.
1Discussion panel from the ‘HIV/Hepatitis C Co-Infection: Impact on Nervous System Disease Burden’ meeting was led by Dr Igor Grant and included Drs David Clifford, Douglas Dieterich and Jack Stapleton. Discussion panel from the ‘HIV/Hepatitis C Co-Infection: Behavioral and Clinical Research in Mental Health and Drug Abuse’ meeting was led by Drs Laura Cheever and Adeline Nymathi.
Sponsorship: C.v.d.H. is supported by the following grants UNC Center for AIDS Research (P30-AI50410), UNC AIDS Clinical Trials Unit (AI25868) and the South African CIPRA (5U19AI053217).