| |
HCV/HIV Coinfection: challenges & strategies for care & treatment
|
| |
| |
Clinical Infectious Diseases April 2005 Supplement
Financial support. National Institutes of Health
This report put together by Jules Levin includes discussion from CID regarding
--The burden of HCV disease in HIV & how HIV adversely affects HCV
--The challenges to providing care & treatment to coinfected individuals and to current & former injection drug users (IDUs)
--strategies for addressing these challenges. The experiences of implementing programs to address these challenges at three clinics are discussed in this article.
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. As well, recent reports and studies include observations of sexual transmission of HCV among men who have sex with men. Sex partners, heterosexual or homosexual, of IDUs are also at risk for HCV infection.
HIV Worsens HCV
HIV infection may complicate hepatitis C care. HIV infection modifies the natural history of HCV infection, reducing the ability of the host to clear or resolve HCV infection. Clearance of HCV viremia occurs less often in persons coinfected with HIV than in HIV-uninfected persons and occurs less frequently in those with low CD4 lymphocyte counts. Patients coinfected with HCV and HIV have higher levels of HCV RNA and more rapid progression of cirrhosis to end-stage liver disease and death than do HCV-monoinfected persons. Liver disease due to HCV infection has become a major cause of morbidity and mortality among persons living with HIV infection. In addition, HCV coinfection increases the frequency of drug-induced hepatotoxicity in HIV-infected persons, thus complicating the medical management of HIV infection. HIV-coinfected patients are less likely than are HCV-monoinfected persons to achieve a sustained virological response to treatment for HCV infection, although combination therapy with pegylated IFNs and ribavirin have improved treatment outcomes in this population. HIV-infected IDUs with chronic HCV infection should be considered to be candidates for anti-HCV therapy, especially given their higher risk of progression to end-stage liver disease and the higher risk of liver toxicity after beginning antiretroviral therapy. However, this decision should be considered in the wider context of the patient's presentation, including stable antiretroviral therapy, ongoing psychosocial needs (nutrition, housing, and support), underlying psychiatric diagnoses, immunologic status (CD4 lymphocyte count), and the education and motivation of the patient. This is clearly an area in need of further study.
Integrating Treatment for Hepatitis C Virus Infection into an HIV Clinic: there are three examples of care/treatment programs outlined in this article. An entirepublished study report appearing at the end of the report is devoted to the model clinic program in Oakland. This study is one of several approaches to integrating care & treatment. THE PROGRAM STARTED IN 2000: clinician education, integration of liver & HIV clinics, HCV nurse specialist, addressing systemic barriers (performing liver biopsies). INITIAL RESULTS: of our initial 12 patients, 6 discontinued treatment for various reasons (1 of them, infected with HCV genotype 1, nevertheless achieved sustained virological response after 27 weeks of therapy). The patients who completed therapy all achieved sustained virological response. Long-term follow-up information is available for only 2 patients, who are free of HCV after 18 months. See further discussion at end of this article. "The program described here has resulted in promising early results of treatment for HCV infection".
"..it is essential to find strategies to provide successful care and treatment to this patient population given the high burden of disease & health consequences of the disease..at Boston Medical Center 50% of HIV-infected patients have HCV and where liver disease now accounts for 50% of all deaths among HIV-HCV-coinfected patients..." It is roundly thought that hepatitis is the leading cause of hospitalization & death among HIV-infected individuals.
IDUs who are found to have chronic HCV infection should be assessed for the presence and degree of liver disease and evaluated for treatment for HCV. This evaluation should include determining the need for substance abuse services, psychiatric care, and social support and an effort to engage the patient in primary care.
Patient-Provider relationship
Caring for drug users presents special challenges to the health-care team and requires patience, experience, and tolerance. Comorbid psychiatric conditions are common, including major depression, anxiety disorders, posttraumatic stress disorder, and bipolar disorders. In addition, many drug users have had negative experiences with the health-care system and its providers. IFN therapy has a number of reversible neuropsychiatric adverse effects, including impairment in concentration, depression, insomnia, and irritability. Successful treatment for hepatitis C requires a trusting relationship with a health care provider who can help patients anticipate, plan for, and endure the difficulties of therapy for HCV infection. Patients must work at adhering to the regimen, physicians must be responsive to patients' experiences of adverse effects, and both parties must be able to communicate openly about their expectations and frustrations. Physician-patient relationships that support this kind of collaboration are based on mutual trust and respect and take time to develop. Drug users often believe that the health care they receive is judgmental and condescending, unresponsive to their needs, and delivered without respect. For their part, persons actively using drugs may fail to follow through with medical advice, appointments, and prescribed medication. These problems can lead to a dynamic of mistrust and lack of cooperation between the patient and provider.
Education about prevention of HCV infection
Education and counseling aimed at reducing the transmission of HCV and other bloodborne pathogens are integral components of all health-care services for IDUs. The primary goal of prevention education and counseling for patients who continue to inject drugs is to support safer injection practices.
Screening and testing for HCV infection
A comprehensive health care program for IDUs should include strong linkages with hepatitis C prevention services, including community-based programs of counseling and testing for HCV, so that IDUs infected with HCV can be identified and their entry into care facilitated. Screening services should be available either on-site or by referral in all public programs and institutions serving illicit drug users, including public health clinics and hospitals, syringe exchange and HIV prevention programs, substance-abuse treatment programs, correctional institutions, programs for high-risk youth, HIV counseling and testing sites, sexually transmitted disease clinics, mental health clinics, and psychiatric hospitals. Regardless of where HCV testing occurs, counseling and testing provide a critical opportunity to connect IDUs to comprehensive medical and social services addressing other core issues, such as primary care, untreated mental health conditions, housing, and hunger.
Vaccination against HAV and HBV
HAV and HBV are important public health concerns for IDUs infected with HCV, because of the increased risk of severe liver disease due to superimposed chronic HBV infection or acute HAV infection. Vaccinations against HAV and HBV are recommended for persons at high risk, including IDUs and persons with HCV infection. Thus, vaccination strategies for HAV and HBV are an important component of hepatitis C care.
Substance-abuse treatment and hepatitis C care
Hepatitis C care also requires providing access to treatment for substance use and abuse. Numerous treatment modalities for substance dependence have demonstrated effectiveness. Therapy with opioid agonists, including methadone maintenance treatment, has been shown to diminish and often eliminate opioid use and reduce transmission of many infections, including HIV. The recent approval of buprenorphine makes office-based pharmacotherapy for opioid addiction possible. Physicians who complete a defined training can apply for a waiver to the Drug Addiction Treatment Act of 2000 and prescribe buprenorphine to opioid-dependent patients. This new treatment modality not only expands the accessibility of pharmacotherapy for opioid dependence but also mitigates the stigma associated with receiving substance-abuse treatment by integrating it into routine general medical practice.
Care for hepatitis C must also address the risks of alcohol use.
Mental health assessment, monitoring, and treatment
Patients should be screened for depression and other mental health problems before beginning treatment with IFN, treated if necessary, and monitored for these problems during treatment for HCV. Strong linkages with mental health services, whether on-site or within the community, are a vital component of comprehensive health programs for IDUs and are particularly important during treatment for hepatitis C. Past episodes of depression or other psychiatric disorders are not absolute contraindications to treatment for HCV infection. Persons with psychiatric histories may adhere to and complete treatment for HCV infection at rates as high as those of other patient groups [92, 93], if their mental health status is closely monitored and treated. Some authors have recommended prophylactic antidepressant therapy before beginning treatment for HCV in patients thought to have a high risk of depression.
Among injection drug users, psychological and psychiatric barriers to readiness for treatment for hepatitis C virus (HCV) infection include mood and anxiety disorders, cognitive deficits, temperament disorders, and personality vulnerabilities, as well as ongoing drug use. Many aspects of these barriers can be overcome with direct treatment or social support. To establish effective treatment for HCV infection in this population of patients, it is essential that the patient and providers develop a rapport that allows for active communication. It is also important that the patient make an effort to adhere to the treatment requirements and that the patient receive the appropriate evaluation and management of treatable barriers.
"HEPATITIS C VIRUS INFECTION AND SUBSTANCE ABUSE: MEDICAL MANAGEMENT AND DEVELOPING MODELS OF INTEGRATED CARE"
Clinical Infectious Diseases April 2005
Guest Editors: Victoria Cargill, MD, MSCE Thomas F. Kresina, PhD
HCV/HIV COINFECTION CARE & TREATMENT BARRIERS AT BOSTON MEDICAL CENTER
Financial support. National Institutes of Health
"...this population (at Boston Medical Center, see study below) of coinfected patients is often socially deprived and concurrently struggling with poverty and a chaotic lifestyle. In addition, they have multiple medical issues, including HIV disease, which at all times remains the priority of care...."
Here is an excerpt from the text of the article with brief list of barriers to care & treatment experienced at Boston Medical College discussed in the published study below. Below is a more extensive discussion of these barriers & how they can be addressed:
one of the main challenges is access to care... Reflects physician practive and inability of patients to navigate the health-care system and pay for services.... only 22% had levels of HCV RNA checked..
lack of insurance.... 49% of coinfected patients did not have adequate health insurance
--nonadherence with clinic visits,
--active psychiatric disease,
--ongoing injection drug or alcohol use,
--advanced HIV disease,
--late evaluation of patients...decompensated liver disease: at the Boston Medical Center, 13% of coinfected patients are not diagnosed with HCV until they already have decompensated liver disease
--comorbid medical illness
Many of these barriers to treatment are potentially modifiable, leading to the possibility that, with appropriate interventions, treatment rates may be increased.
--IDUs are able to adhere to treatment with IFN and have a low risk of reinfection
-- Strategies to limit hazardous alcohol drinking must be the first priority for these patients, both to minimize the impact of alcohol on the progression of liver disease and to maximize treatment efficacy
-- Psychiatric adverse effects occur in >20% of patients treated for HCV infection, with a higher incidence in those with a preexisting psychiatric history....pretreatment of psychiatric conditions may allow for subsequent successful treatment with IFN for many patients
--weight reduction may improve efficacy of treatment
--anemia and leucopenia can occur before & during treatment for HCV: these conditions can be treated
--Overcoming patients' fears of treatment with IFN; patient education and peer support programs: an individual patient's perception of IFN is frequently based on the treatment experience of peers: a proportion of those patients who initially decline treatment with IFN will later accept treatment after ongoing education
-- Supporting patients through the adverse effects of treatment: antidepressant therapy; addressing anemia, thyroid abnormalities, neutrophil count decreases...
--it's important address alcohol use because alcohol can accelerate HCV disease progression & adversely affect response to therapy
--DIRECT OBSERVED THERAPY (DOT): is used to treat HCV at The Miriam Hospital, Brown University School of Medicine, providence, Rhode Island. Directly observed therapy (DOT) is an effective approach for the treatment of tuberculosis among substance users. We have adapted this model to treat human immunodeficiency virus infection. Our experience suggests that community-based, modified DOT should be explored further as a means to treat infectious diseases and chronic medical illnesses for persons with drug dependence; it may be especially pertinent for the treatment of hepatitis C virus infection. DOT can both optimize adherence and provide a way to offer psychosocial support and linkages to social, addiction, psychiatric, and other services, to help address many of the challenges faced by persons with substance abuse disorders.
Boston Medical Center approach: Multidisciplinary Team
--educate primary care physicians and nurses about the need for early evaluation of HCV infection in HIV-infected patients
--all coinfected patients will be automatically referred for evaluation for HCV infection at the time they enter the HIV program or at annual follow-up
--patient education
--use case management and substance abuse counseling: patients receive ongoing education about HCV infection at each subsequent clinic visit
--psychiatrist who sees all patients with active psychiatric issues and follows patients during treatment with IFN
--Patients receive reminder calls about clinic appointments
--Spanish-speaking provider
To date, our endeavors to treat HCV infection in an urban population of patients coinfected with HCV and HIV have been largely unsuccessful. We believe that this is attributable to the medical and social complexity of this patient group. At each stage of the evaluation and treatment process, we have encountered specific challenges, and, as it evolves, our clinic is attempting to develop a comprehensive approach to address all of these issues.
Given the high burden of liver disease in this population and the fact that hepatitis C is increasingly a disease of IDUs, it is essential that specific strategies be developed, such as the team approach to patient care. It is possible that evaluating and treating hepatitis C earlier in the course of HIV infection, before initiation of treatment for HIV, may facilitate treatment with IFN. This will require education of providers and patients and earlier referral to specialized clinics. Directly observed therapy, whereby IFN is administered by the clinic or provider, may reduce concern about the handling of needles and improve adherence. Linkages to psychiatric care and substance abuse programs may also facilitate the treatment of patients with more complex needs.
However, there remains a need for more effective and tolerable treatment for hepatitis C if we are to make a significant impact on the burden of HCV-related liver disease in this population.
Challenges in the Treatment of Patients Coinfected with HIV and Hepatitis C Virus: Need for Team Care
Clinical Infectious Diseases April 2005
Catherine A. Fleming,1,3 Sheila Tumilty,1 Jessica E. Murray,2 and David Nunes1
1Department of Medicine, Boston Medical Center, Boston University School of Medicine, and 2Department of Epidemiology, Boston University School of Public Health, Boston, and 3Medical Service, Veterans Administration Boston Healthcare System, West Roxbury, Massachusetts
We estimate that only one-third of patients coinfected with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) are eligible for therapy for HCV with interferon (IFN) and ribavirin, and, of those who are eligible, two-thirds decline treatment. To date we have initiated treatment with IFN and ribavirin for 8% of coinfected patients evaluated, and <1% of patients have had a sustained virological response. During this process, we have identified many problems that significantly limit our ability to initiate and complete treatment with IFN in this population and have categorized these difficulties into 4 main challenges. They include
access to care,
contraindications or barriers to treatment,
patients' reluctance to start treatment with IFN,
and the low tolerability of treatment.
If patients coinfected with HCV and HIV are to be treated for hepatitis C in greater numbers, these issues will need to be addressed.
INTRODUCTION
Hepatitis C virus (HCV) infection has been increasingly recognized as a major cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma worldwide.
Because of the common modes of transmission of HIV and HCV, coinfection occurs in A 30% of all HIV-infected persons, and, among injection drug users (IDUs), the proportion of coinfection can be as high as 90%.
More effective management of HIV infection has resulted in significant improvements in quality of life, fewer opportunistic infections, and prolonged survival [4]. As a result, chronic diseases such as HCV infection have become significant contributors to morbidity and mortality among HIV-infected persons [5]. This is especially true for urban patients engaging in injection drug use, among whom the burden of coinfection is highest.
Combination therapy with pegylated IFN and ribavirin is the current standard of care for chronic HCV infection, with rates of sustained response of A 50%. Much of the information about treatment for HCV infection has been determined from clinical trials with strict enrollment criteria, and the proportion of HCV-infected and HIV-HCV-coinfected patients eligible for, and able to tolerate, IFN-based treatment is largely unknown.
There is a relative paucity of data on the treatment of patients with HIV coinfection; however, initial studies suggest that rates of response to treatment with pegylated IFN and ribavirin are lower in HIV-HCV-coinfected patients.
The barriers to the treatment of HIV-HCV-coinfected patients are substantial, and as a result, the recent National Institutes of Health (NIH) Consensus Conference recommended that HIV-HCV-coinfected patients be assessed for treatment for HCV infection and that treatment be initiated on a case-by-case basis.
At Boston Medical Center, where A 50% of the HIV-infected patients are coinfected with HCV and where liver disease now accounts for 50% of all deaths among HIV-HCV-coinfected patients, we established a designated coinfection clinic to evaluate coinfected patients for treatment for HCV infection. Here, we describe our results in initiating and completing antiviral treatment for HCV infection in HCV-infected patients coinfected with HIV and outline the main challenges to treatment in this population.
METHODS
Boston Medical Center is an inner-city hospital that provides care for >1000 HIV-infected patients, of whom A 50% are coinfected with HCV. In response to the significant morbidity and mortality due to HCV-related liver disease that emerged in this population in the late 1990s, we established a clinic specifically for patients coinfected with HIV and HCV. The coinfection clinic aims to evaluate HCV disease in HIV-infected patients and to treat HIV-HCV-coinfected patients with IFN and ribavirin. From its outset in January 2000, this clinic has used a
multidisciplinary approach and is staffed by a
--hepatologist,
--an infectious disease specialist,
--a psychiatrist,
--a dedicated nurse, and
--substance abuse counselors with direct access to specialists in other fields.
In February 2002, we reviewed the records of all patients attending the coinfection clinic, assessing eligibility for IFN-based therapy, whether patients subsequently commenced treatment with IFN, and the outcome of treatment if commenced.
In addition to the cohort of patients followed in the coinfection clinic, the Hepatitis and AIDS Liver Outcomes (HALO) Study cohort was established at Boston Medical Center in August 2000 to prospectively evaluate the natural history of HIV and HCV infection in an inner city population. Approximately 80% of patients attending the coinfection clinic are enrolled in this study, and the demographics of the study population closely represent those of the clinic. Patients complete a detailed questionnaire at the time of enrollment, and a chart review and physical examination are done. Patients are seen yearly for a follow-up questionnaire, chart review, and physical examination.
Institutional review board approval for the studies outlined here were obtained from Boston University School of Medicine, and guidelines for human experimentation of the US Department of Health and Human Services and Boston University School of Medicine were followed.
RESULTS
To date, we have evaluated 260 patients in the coinfection clinic; however, we estimate that we have seen <50% of the HIV-HCV-coinfected patients receiving primary care at Boston Medical Center. Two hundred seventy-four coinfected patients have been enrolled in the HALO study and are being followed annually.
Patient demographics
At baseline, 116 (42%) of the 274 patients in the HALO study have less than a high school education, 98 (36%) are homeless, and only 60 (22%) are employed for pay. With regard to substance use, 226 (82%) are past or current users of heroin, and 131 (48%) have used injection drugs in the past 6 months. Sixty-seven (24%) have ongoing hazardous drinking, as determined by the Alcohol Use Disorders Identification Test questionnaire (defined as a score of >8). This patient population also has significant concurrent morbidity: 117 (43%) of the 274 patients have ongoing psychiatric disease for which they are receiving treatment, 49 (23%) of the 212 patients for whom complete laboratory data were available have a CD4 cell count of <200 cells/mm3, and 15 (7%) have a Child-Pugh score of >7, indicative of advanced liver disease.
Barriers to treatment
By means of a standardized evaluation of HCV infection, we found that 44 (30%) of the 149 HIV-HCV-coinfected patients attending the coinfection clinic who completed the assessment were eligible for treatment with IFN and ribavirin and that 105 (70%) were ineligible [11]. The factors leading to ineligibility included nonadherence with clinic visits (24 patients [23%]), active psychiatric disease (22 patients [21%]), ongoing injection drug or alcohol use (24 patients [23%]), advanced HIV disease (14 patients [13%]), decompensated liver disease (13 patients [12%]) and comorbid medical illness, which included cardiac and renal disease and refractory anemia (8 patients [8%]). We do not classify lack of medical insurance as a specific barrier to treatment, although we rely on programs for indigent patients run by the pharmaceutical companies to obtain medications for those patients who do not qualify for Medicaid.
The reluctance of patients to embark on a course of treatment with IFN is a significant barrier in our clinic population. In our original study, of the 44 patients who were found to be eligible for therapy for HCV infection, 28 (64%) decided not to proceed with treatment. Reasons for not starting treatment included unstable social circumstances, concern about potential adverse effects of treatment, concern about ability to work while receiving IFN and ribavirin, and worry about potential relapse of injection drug use when required to self-inject. Six patients did not return to clinic after discussing therapy, and 3 relocated, again highlighting the difficulty of establishing a long-term intervention in this patient population. However, patients with non-genotype 1 disease were significantly more likely to commence treatment with IFN; 8 (53%) of 15 eligible patients infected with HCV of genotype 2 or 3 proceeded with treatment, compared with 8 (26%) of 29 patients infected with HCV genotype 1. This result suggests that the perception that treatment for HCV infection is effective may contribute significantly to overcoming patient reluctance.
Multiple coexisting barriers
In the eligibility studies conducted to date, each patient was assumed to have only one condition rendering them ineligible for treatment. We studied the issue of multiple coexisting barriers to treatment with IFN in the HALO study and found that, of the 274 coinfected patients enrolled, only 33 (12%) were eligible for treatment by standard criteria; 82 (34%) of 241 ineligible patients had 2 conditions that rendered them ineligible, and 52 (22%) had >3 such conditions. This result is not surprising, given the interrelationships between drug and alcohol use, psychiatric disease, clinic nonattendance, and poor social supports; however, it suggests that, for a significant proportion of coinfected patients, these barriers may be insurmountable, and it reiterates the need to proactively evaluate all medical and social issues in this patient population.
Outcomes of treatment
To date, 21 patients attending the coinfection clinic have commenced IFN-based therapy, representing only 8% of the 260 patients referred to us. Of the 21 patients who started therapy, 4 are currently undergoing treatment, and 8 have completed the prescribed course. Nine patients prematurely discontinued treatment, 4 because of acute psychiatric illness; 4 because of medical complications, including refractory anemia, lactic acidosis, pneumonitis, and retinal hemorrhage; and 1 patient because of loss to follow-up. Four of the patients who were unable to complete the course of treatment with IFN had a relapse of injection drug use. Of the 8 patients who completed the prescribed course of treatment, 5 did not have a virological response to treatment, 1 had an end-of-treatment response, and 2 patients had a sustained virological response; both had non-genotype 1 disease. We have therefore successfully treated 2 patients, representing <1% of coinfected patients referred to our clinic.
AUTHOR DISCUSSION
Despite having a designated clinic and standardized evaluation, only 30% of coinfected patients with chronic HCV infection are eligible for therapy, and, of the eligible patients, two-thirds decline treatment.
To date we have initiated treatment with IFN and ribavirin for 8% of the 260 coinfected patients evaluated, and 2 patients (< 1%) have had a sustained virological response.
During this process, we have identified many problems that significantly limit our ability to initiate and complete treatment with IFN and have categorized these difficulties into 4 main challenges. These problems stem from the fact that this population of coinfected patients is often socially deprived and concurrently struggling with poverty and a chaotic lifestyle. In addition, they have multiple medical issues, including HIV disease, which at all times remains the priority of care.
Challenges to Treatment for HCV in Coinfection
Access to care
We estimate that only a small proportion of HIV-HCV-coinfected patients have been referred for evaluation of or received treatment for HCV infection, and one of the main challenges is access to care. This fact likely reflects both physician practice and the ability of patients to navigate the health-care system and pay for services. In a recent report of 300 HCV-and HIV-coinfected patients attending 3 Veterans Administration outpatient clinics, only 22% had levels of HCV RNA checked, and, of the 65 patients suitable for treatment, only 3% had started treatment with IFN. Although that study did not explore the reasons for the low rates of treatment, the fact that the majority of patients had not had their level of HCV RNA checked suggests that they had never had a specific medical evaluation of their HCV disease.
Lack of insurance has also been cited as an important issue in gaining access to care for HCV infection. In a recent meeting presentation, lack of insurance was the most common reason cited by patients with new diagnoses of HCV infection for not seeking medical care. In another presentation from the same meeting, 49% of coinfected patients did not have adequate health insurance, and this was perceived to be the main barrier to treatment for 22%. Our reliance on programs for indigent patients run by pharmaceutical companies for those patients not qualifying for Medicaid is further complicated by the frequent need for hematopoietic growth factors to facilitate treatment in this population.
Overcoming barriers to eligibility for treatment for HCV infection
The main reasons that coinfected patients evaluated at our clinic were not eligible for treatment with IFN were nonadherence with clinic visits, active psychiatric disease, ongoing injection drug or alcohol use, advanced HIV disease, decompensated liver disease, and comorbid medical illness. Many of these barriers to treatment are potentially modifiable, leading to the possibility that, with appropriate interventions, treatment rates may be increased.
Approximately 90% of HIV-HCV-coinfected patients have a history of injection drug use, and, among our patient population, >30% are actively using injection drugs. There are limited data on the feasibility of treating chronic HCV infection in patients with ongoing injection drug use. Backmund et al. treated 50 IDUs enrolled in a detoxification program and found an overall rate of sustained response of 36%. In a recently reported 5-year follow-up study of 27 former IDUs who had a sustained virological response to treatment with IFN, 33% had relapsed drug use; however, only 1 had evidence of HCV reinfection [16]. These studies demonstrate that IDUs are able to adhere to treatment with IFN and have a low risk of reinfection, and they suggest the possibility of successfully treating HCV infection in patients who have recently used injection drugs and are engaged in programs of treatment for drug abuse. The recently published NIH guidelines also recommend that ongoing injection drug use need not be a contraindication to treatment and that patients should be evaluated on a case-by-case basis.
Alcohol is an important cofactor in the progression of HCV-related liver disease, although the threshold above which alcohol results in accelerated liver disease has not been determined. In addition, ongoing alcohol use adversely affects response to treatment, and abstinence is recommended during treatment with IFN [6]. Alcohol use is very prevalent in this population; A 20% of our patient population meets the criteria for hazardous drinking. Strategies to limit hazardous drinking must be the first priority for these patients, both to minimize the impact of alcohol on the progression of liver disease and to maximize treatment efficacy. To date there are no studies looking at the ability of problem drinkers to successfully embark on treatment with IFN.
Psychiatric adverse effects occur in >20% of patients treated for HCV infection, with a higher incidence in those with a preexisting psychiatric history. Active psychiatric conditions are therefore a relative contraindication to treatment for HCV infection. However, pretreatment of psychiatric conditions may allow for subsequent successful treatment with IFN for many patients. In a recent study, 16 patients with preexisting psychiatric conditions were treated with IFN. Patients were monitored closely during the course of treatment; 38% had a sustained virological response, and 18% did not complete therapy. Psychiatric symptoms remained stable in all, suggesting that with close supervision, patients with psychiatric illness may be safely treated for HCV infection.
Other barriers that are amenable to intervention include anemia and leukopenia, because epoetin-_ and granulocyte colony-stimulating factors have allowed for the successful treatment of these conditions. HIV disease has also been perceived as a barrier; however, with highly active antiretroviral therapy, this too is potentially modifiable. Furthermore, there is a growing belief that weight reduction may improve efficacy of treatment as well as limit the adverse effect of steatosis on HCV-related liver disease. However, as discussed earlier, many patients have multiple, interrelated barriers to treatment, and it remains to be seen whether intensive intervention will allow the safe administration of IFN in this population of HIV-HCV-coinfected patients.
Overcoming patients' fears of treatment with IFN
Even among patients who are considered to be appropriate candidates for treatment with IFN, acceptance of treatment is low in this urban HIV-HCV-coinfected population. Although several studies have suggested that many HCV-infected patients decline treatment with IFN, there has been no research into the reasons for this or the ability of an educational program to surmount this problem [23]. Sixty-four percent of eligible patients in our study declined treatment for a variety of reasons, and we have observed that an individual patient's perception of IFN is frequently based on the treatment experience of peers. However, we have also noticed that a proportion of those patients who initially decline treatment with IFN will later accept treatment after ongoing education. It remains to be seen whether patient education and peer support programs can facilitate successful treatment of this population with IFN.
Supporting patients through the adverse effects of treatment
There are limited data on the tolerability of IFN and ribavirin in treating HIV-HCV-coinfected patients; however, our experience has been that this treatment is poorly tolerated. The adverse effects can be divided into those described among patients with HCV infection alone and complications that are newly recognized in coinfected patients.
"Flulike" symptoms develop in the majority of patients. Neuropsychiatric changes due to IFN occur in up to 50% of treated patients and range from irritability and insomnia to depression and suicide. Pretreatment with a selective serotonin reuptake inhibitor may be beneficial, and both citalopram and paroxetine have been shown to be effective [20, 25]. Hematological changes during treatment are common. The neutrophil count decreases by an average of 1300-1600 cells/_L, and this effect may be increased in HIV-infected patients, particularly those receiving zidovudine. Lymphopenia may be associated with a decrease in CD4 cell count; however, the CD4 cell percentage is typically unchanged, and no additional risk for opportunistic infections has been observed. Anemia is also common, primarily because of ribavirin-induced hemolysis. Administration of epoetin-_ may reverse the anemia, allowing for significantly higher ribavirin doses to be maintained. Thyroid abnormalities have been observed, and exacerbations of other autoimmune disorders may occur. Nonspecific symptoms, including fatigue, malaise, anorexia, weight loss, skin rash, and reversible alopecia, can occur at any stage of therapy.
HIV-HCV-coinfected patients may have a higher incidence of adverse effects related to treatment with IFN, and completing treatment for HCV infection frequently requires the addition of granulocyte colony-stimulating factor, epoetin-_, and an antidepressant in addition to antiretroviral and anti-HCV treatment. In addition, there is an increasing recognition of complications of treatment with IFN and ribavirin specific to HIV-coinfected patients, notably pancreatitis, lactic acidosis, and weight loss. Perez-Olmeda et al. [8] reported the outcomes of treatment with pegylated IFN and ribavirin among 68 coinfected patients. They observed 5 cases of pancreatitis, all in patients taking concomitant didanosine. Two patients developed an asymptomatic increase in lactic acid levels; both were taking didanosine and stavudine. These events likely reflect the interactions between ribavirin, a guanosine nucleoside analogue, and nucleoside reverse-transcriptase inhibitors. Ribavirin inhibits inosine-5-monophosphate dehydrogenase, resulting in an increase in the intracellular conversion of didanosine to its active metabolite and increased toxicity, including mitochondrial toxicity, which is implicated in lactic acidosis and pancreatitis. It is therefore currently recommended that didanosine not be combined with ribavirin. In addition, body weight decreased by an average of 4.6 kg from baseline, exceeding what has previously been described for HIV-uninfected patients. Although these observations are very preliminary, it is possible that the significant weight loss may represent a form of the lipoatrophy syndrome and may also result from the interaction of ribavirin and nucleoside analogues, possibly stavudine, used to treat HIV infection. As discussed above, 8 of the 21 patients treated at the coinfection clinic at Boston Medical Center have been unable to complete treatment because of treatment-related adverse effects, and those patient who completed treatment did so despite experiencing at least one significant adverse event.
Boston Medical Center Approach
In an effort to increase eligibility for treatment with IFN, we have adopted several strategies and have evolved into a multidisciplinary team. First, we have attempted to educate primary care physicians and nurses about the need for early evaluation of HCV infection in HIV-infected patients. In a clinic in which 50% of the deaths from HIV infection are due to liver disease, 13% of patients referred to us already have decompensated liver disease. In an attempt to evaluate patients earlier during the course of their HCV disease, we are revising the referral process, so that all coinfected patients will be automatically referred for evaluation for HCV infection at the time they enter the HIV program or at annual follow-up. We focus initially on patient education, and all patients meet with a nurse for at least one visit, focusing on education about HCV infection and specifically discussing substance use and social issues. We have access to case management and substance abuse counseling, and patients receive ongoing education about HCV infection at each subsequent clinic visit. We have a dedicated psychiatrist who sees all patients with active psychiatric issues and follows patients during treatment with IFN. Patients receive reminder calls about clinic appointments, and a Spanish-speaking provider has recently joined this team to improve communication with our sizeable population of Spanish-speaking patients. As this clinic evolves, it remains to be seen whether this team approach will improve our ability to successfully treat HCV infection in this population.
Integrating Treatment for Hepatitis C Virus Infection into an HIV Clinic
Clinical Infectious Diseases, april 2005
Kathleen A. Clanon, Juergen Johannes Mueller, and Michael Harank
Alameda County Medical Center, Oakland, California
In the United States, one-third of human immunodeficiency virus (HIV)-infected patients are also coinfected with hepatitis C virus (HCV). Of 228 coinfected patients whose charts were reviewed in our 2000 study, only 2 had received therapy with interferon. To address low rates of treatment, in 2001 we implemented a program to shift the primary responsibility for oversight of care for HCV-infected patients from the liver clinic to HIV primary care clinicians and to provide education and support regarding adherence to patients. Critical elements of the program include education of HIV clinicians with regard to treatment for HCV infection, establishment of a coinfection clinic in the HIV clinic, assignment of a full-time Registered Nurse for monitoring and support of patients undergoing treatment for HCV infection, and development of a weekly peer group for the coinfected patients. Preliminary treatment results for patients in the program suggest that this approach has promise for improving outcomes of treatment among coinfected patients.
HCV AND HIV COINFECTION
In the United States, 150,000-300,000 people are infected with both HIV and hepatitis C virus (HCV), representing 15%-30% of all HIV-infected persons and 5%-10% of HCV-infected persons. Some estimates of coinfection are even higher (>75%) among selected at-risk populations, such as injection drug users. As overall HIV-related mortality has declined, liver disease has become an increasingly significant cause of morbidity and death among HIV-infected patients. In 1999, >50% of the mortality among HIV-infected patients in the United States was due to liver failure, and the primary cause of liver failure in this population is HCV-related decompensation.
Treatment of HCV infection has improved markedly during the last few years, first with the introduction of combination therapy with ribavirin and IFN-_ and now with the availability of pegylated IFN. However, treatment for coinfected patients has lagged behind, in terms of both numbers treated and success rate for those who undergo treatment. Immunologic impairment associated with HIV disease is likely the primary cause of the poorer treatment outcomes seen in the coinfected group, and optimal management of HIV disease is the only available strategy to address that issue. However, improvements can likely be made in the access to and support for therapy for HCV infection among coinfected patients. Adherence to difficult treatment regimens is a focus of research and resources in sites offering care for HIV-infected persons, and this experience can be used to address the challenges of therapy for HCV infection, including how to engage patients in decision-making about treatment, how to address patients' concerns about new treatments, and how to support patients in adhering to difficult treatment protocols.
ASSESSING COMMUNITY-BASED COINFECTION CARE
In 2000, the quality management advisory body of a publicly funded HIV care consortium in Alameda County, California, identified increasing numbers of liver disease-related deaths among network patients as a critical quality care issue. Anecdotal concerns about care for HCV-infected patients and disagreement about the appropriate standard of care among coinfected patients also surfaced in the community providers' HIV Journal Club. Finally, a local testing initiative for HCV among high-risk injection drug users had resulted in increased concern and questions about the infection from the local organized patient groups. These concerns resulted in a cooperative project among local providers of care for HIV-infected patients to review the state of care for HCV-HIV-coinfected patients, identify probable causes for any deficiencies, and develop an interim community standard of care based on local experts' best assessment of the current data.
Funds were identified from local government and pharmaceutical companies to do the community assessment, which was conceived in 3 parts: a chart review, focus groups with patients, and interviews with health-care providers. At the same time, an advisory group, which included HCV experts and practitioners who treat HIV-infected patients, was brought together to develop a local community consensus about appropriate workup and treatment algorithms for coinfected patients.
Chart review results
The chart review was done in late 2000 and included 929 patients in care with the network or one of its community partners (S. O'Brien, personal communication). HCV coinfection was present in 228 patients (25% of the total). Four HCV quality-of-care indicators were reviewed. Screening for HCV in the HIV-infected population was nearly 100%; however, counseling regarding cessation of alcohol abuse was rarely documented, only 12% of patients had received vaccinations against hepatitis A virus (HAV) and hepatitis B virus (HBV), and only 2 patients had ever received treatment with IFN for HCV infection. Similar deficits were identified at a multisite Department of Veterans Affairs study in 2002.
In 36% of charts reviewed, the reasons for not pursuing therapy with IFN and ribavirin could not be identified from chart notes. Providers' assessment of active substance abuse (16%) or a history of noncompliance with visits or treatment (12%) were the 2 most frequently identified reasons.
Provider interviews and patient focus group
Both providers who treat HIV-infected patients and gastrointestinal or liver specialists were interviewed to identify common concerns about and/or barriers to care for HCV-infected patients. Providers of care for HIV-infected patients reported knowledge deficits about HCV and fear about complications of treatment with IFN and ribavirin. Providers of care for HCV-infected patients identified lack of experience with and data about treatment for coinfected patients, as well as pessimism about treatment outcome, as reasons not to recommend treatment for HCV infection to patients coinfected with HIV. In addition, the clinicians perceived liver biopsies as being dangerous, as a result of earlier publications (not supported by later data) that suggested higher mortality rates in HIV-positive patients.
Costs of work-up and treatment were identified by both sets of providers as a barrier to care. Although patient assistance programs through pharmaceutical companies exist, they require significant staff knowledge and time to be used successfully (authors' unpublished data). Availability of liver consultation for uninsured and Medicaid patients was extremely limited (3 h twice a month at the already overburdened local public hospital), resulting in many months' delay in getting expert consultation. Communication between primary care and liver clinics was paper based, slow, and too unreliable to allow for coordination and monitoring of a complex treatment regimen.
Barriers identified in patient focus groups held in April 2001 included lack of knowledge about HCV and fear of side effects of treatment for HCV infection. Some patients were concerned that self-injecting IFN might trigger relapse of injection drug use. Patients in 1 group were asked to evaluate some possible treatment support models, which were drawn from the experience of a local successful treatment program for HCV monoinfection (D. L. Sylvestre, personal communication). They believed that availability of injections in the doctor's office, nursing advice for management of adverse effects, and peer support from people who had had treatment were desirable components of a program of treatment for HCV infection.
DESIGN OF THE NEW PROGRAM
On the basis of the information gathered in the assessment phase and consultation with Dr. Diana Sylvestre, a local expert in treatment for HCV infection, a 3-pronged approach to reducing barriers to care was implemented, including education of clinicians, integration of gastrointestinal expert care into the HIV primary care site, and the hiring and training of a nurse specialist in HCV.
Clinician education
Clinician knowledge deficits were addressed in 3 venues. Three Journal Clubs were held, with joint attendance by liver specialists and providers who treat HIV-infected patients, in which data regarding coinfection were reviewed and a protocol about who should be treated was developed. "Mini-residencies" were arranged with a local clinic that treats a high volume of HCV-infected patients, in which HIV clinicians spent time in a monoinfection clinic, reviewed patient management models, and saw first-hand how clinical and social problems were addressed. Regular case conferences were begun in which liver and HIV specialists shared information about patient treatment in the course of discussing individual patients. The outcome of this education program has been a successful transition of primary responsibility for overseeing treatment with IFN and ribavirin from the liver specialists to the HIV primary care clinicians.
Integration of liver and HIV clinics
We noted that, within the program's institution, referrals from HIV clinic to liver clinic had a dismal completion rate, with <10% of referred patients keeping appointments (authors' unpublished data). This problem was addressed in 2001, when a monthly coinfection session was established in the HIV clinic. The nursing and support staff resources of the HIV clinic were engaged to get patients and laboratory results to this special coinfection session. More than 70% of the patients scheduled for the coinfection clinic are seen.
HCV nurse specialist
The experience of the coinfection clinic demonstrated the complexity of treating coinfected patients and highlighted the critical role of a single dedicated case manager or nurse in counseling and following the patients as they considered, decided on, and then began treatment. Because the HIV clinicians were new to treatment for HCV infection and because the resource of the liver specialist was limited, we hired and cross-trained an HCV/HIV nurse specialist to act as the coordinating staff member. The nurse who was hired was experienced in HIV care. A mini-residency was arranged for him with the local HCV clinic so that he could have hands-on experience with treatment for HCV infection. He was then assigned responsibility for developing a counseling protocol covering the basics of HCV and its treatment, establishing a program of vaccination against HAV and HBV for coinfected patients, establishing and running the weekly support and education group, and providing preteaching about side effects and support for their mitigation for those undergoing therapy with IFN and ribavirin.
Addressing systemic barriers
Both patients and providers were reluctant to pursue liver biopsy, and we debated its necessity. Our review of the literature suggested that it was important and safe, particularly for patients infected with HCV genotype 1. Availability of the procedure at our county hospital was poor, with a wait of many months. In 2003, our gastrointestinal specialists agreed to do biopsies in the HIV clinic, with use of portable ultrasound guidance and recovery in the treatment area of the clinic. HIV clinic nurses were trained in procedures of care during recovery for patients after biopsy. To date, we have done 20 biopsies with no complications, good rates of showing up for the procedure, and good patient reports of the experience.
EXPERIENCE WITH THE PROGRAM TO DATE
Counseling and education
The cohort of patients with coinfection were initially counseled by the HCV nurse with regard to nonmedication aspects of management of HCV infection, including cessation of alcohol and drug use, diet, vaccination against HAV and HBV, and avoidance of hepatotoxic medications. The need for pretreatment biopsies was discussed with them in detail. The options and potential complications of treatment with IFN and ribavirin were also addressed, and any questions were answered. Most patients were initially hesitant about starting treatment. During the counseling and education process, patients were screened for absolute contraindications to treatment for HCV infection. Once willing and appropriate candidates were identified, they were referred to the coinfection clinic and simultaneously enrolled in the newly established weekly education and support group.
Peer support and education group
The support group started in February 2002 with 15 members. Weekly meetings are 2 h long and include an education session, followed by participants' exchanges of experiences. In the initial meetings, monoinfected and coinfected patients from outside the site who had already undergone therapy were recruited to act as mentors and sources of information. Initial topics included lengthy discussions about expected adverse effects and possible interventions to treat them. Patients became quite knowledgeable and participated more and more with pointed questions, brought in their own researched information, and began to seriously consider treatment. Once the first patient started and did well on the medications without any serious adverse effects, more patients were willing to start, in a positive "snowball effect" mediated through the exchange of experiences in the support group. Within 4 months, 6 patients were undergoing treatment.
Treatment results and lessons learned
The number of patients who have been treated through the program and who have been followed for at least 6 months after treatment is still small, so treatment outcomes may be biased. Since the program began, 15 patients have started treatment with ribavirin and IFN at the project site, 6 discontinued treatment before finishing therapy, and 7 are evaluable for sustained virological response (at least 6 months after completion of therapy). Thirteen are infected with HCV genotype 1; the rate of sustained virological response is 40% in this population, for which rates of 20% have been reported in the literature. Patients infected with HCV genotypes 2 and 3 (2 total) cleared HCV as expected. In summary, of our initial 12 patients, 6 discontinued treatment for various reasons (1 of them, infected with HCV genotype 1, nevertheless achieved sustained virological response after 27 weeks of therapy). The patients who completed therapy all achieved sustained virological response. Long-term follow-up information is available for only 2 patients, who are free of HCV after 18 months.
Since initiation of the program, experience has highlighted several clinical "pearls" that have guided evolution of our program treatment protocols. First, aggressive management of adverse effects and maintaining maximum doses of IFN and ribavirin throughout the treatment course is the strategy most likely to result in sustained virological response. This has been demonstrated among monoinfected patients. The literature suggests, not surprisingly, that cytopenias are common among coinfected patients undergoing therapy. We have adjusted our protocol to start treatment with epoetin-_ when hemoglobin levels decrease to <10 g/dL and now often start treatment with epoetin before commencing therapy for HCV infection. This strategy has allowed us to avoid reduction of ribavirin doses for our later-treated patients. Other expected complications, including neutropenia and depression, we also treat aggressively. All patients with a history of depression or a moderately high depression score on a standard screening test (Centers for Epidemiologic Studies depression scale) are treated with selective serotonin reuptake inhibitors before treatment for HCV infection is started.
Next, water is the best tool for management of symptoms. Patients are instructed to drink at least 3 L of water daily, which reduces pain, fatigue, and headaches and obviates the need for supplementary pain medications for almost all patients.
Finally, patients' CD4 cell counts invariably decrease during treatment for HCV infection and persist at low levels for 1-6 months after therapy is stopped. Like others, we have seen no morbidity associated with this decrease, but it is upsetting to patients, and counseling about this issue before starting therapy has become part of our pretreatment educational checklist. Of interest, we noted that for patients not undergoing HAART but with detectable HIV loads, the HIV loads almost invariably became undetectable during treatment for HCV infection. The anti-HIV effect of ribavirin plus IFN might be considered an additional benefit of treatment for HCV infection.
SUMMARY
HCV coinfection affects a large percentage of patients with HIV and is a significant and growing cause of morbidity and mortality. HIV-infected patients, particularly those who are uninsured, may experience difficulties in gaining access to or following through with care for HCV infection in the specialty referral model. In this example, barriers to care for HCV-infected patients who were attending the HIV clinic, supervised by the HIV primary clinicians, were assessed, and a program was developed to address them. Additional resources were made available, in the form of hands-on educational experiences for the HIV clinicians in care for HCV-infected patients, as well as time the gastrointestinal clinicians spent on additional teaching and holding conferences regarding cases while the HIV clinicians were gaining experience with treatment for HCV infection. Most costly, and most valuable, has been the assignment of a full-time registered nurse to manage cases and monitor the patients who are considering, moving toward, and undergoing therapy.
The program described here has resulted in promising early results of treatment for HCV infection, suggesting that aggressive medical and social support of patients during therapy for HCV infection may have an effect on rates of sustained virological response reported among coinfected patients. As results of large cohort studies become available, understanding how patients were supported during treatment may give clues to how we can maximize results for our HIV-HCV-coinfected patients.
|
|
| |
|
|
|
