LEARNING OBJECTIVES
This activity is designed for specialists in infectious diseases and gastroenterology.
* Recognize the magnitude of the problems of HCV infection and HIV/HCV coinfection
* Describe current standards for HCV treatment and ongoing management
* Describe issues about coinfection that distinguish it from infection with HIV or HCV alone
* Discuss HIV/HCV disease interaction: the impact of HIV on HCV as well as the impact of HCV on HIV
* Discuss issues associated with HAART and hepatotoxicity, including mitochondrial toxicity
* Compare and contrast the disease treatment paradigm of HIV with that of HCV
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ACCREDITATION
Projects In Knowledge is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Projects In Knowledge designates Expert Perspectives (highlights + monograph) for up to 2.0 hours in category 1 credit toward the AMA Physician’s Recognition Award.
DISCLOSURE INFORMATION
The Disclosure Policy of Projects In Knowledge requires that faculty participating in a CME activity disclose to the audience any significant relationship they have with a pharmaceutical or medical equipment company, product, or service that may be mentioned as part of their presentation, as well as any significant relationship with the commercial supporter of the activity. John G. Bartlett, MD, has indicated significant relationships with Glaxo Wellcome Inc, Merck & Co Inc, and DuPont Pharmaceuticals Company. Douglas T. Dieterich, MD, has indicated significant relationships with Schering-Plough, Roche Pharmaceuticals, Gilead Sciences, Glaxo Wellcome Inc, and Bristol-Myers Squibb Company. Mark S. Sulkowski, MD, has indicated significant relationships with Schering Corporation, Roche Pharmaceuticals, and Ortho Biotech. Full faculty disclosures can be found in the Expert Perspectives monograph.
Development of Expert Perspectives was made possible through an unrestricted educational grant from:
Schering Oncology/Biotech.
This activity may include a discussion of therapies that are unapproved for use or investigational, ongoing research, or preliminary data. The opinions expressed here are those of the faculty and do not necessarily reflect those of the sponsor or commercial supporter.
Highlights: Expert Perspectives Development Meeting
March 30–April 1, 2000
INTRODUCTION
Hepatitis C virus (HCV) is one of the most important causes of chronic liver disease in the United States. Overall, there may be 300,000 persons coinfected with HCV and HIV in the United States, representing about 33% of the estimated 1 million persons infected with HIV. HIV coinfection is an important factor in HCV disease progression. Coinfection with HIV is associated with a higher HCV RNA viral load and a more rapid progression of HCV-related liver disease, leading to an increased risk of cirrhosis, decompensated liver disease, hepatocellular carcinoma, and death. Thus, chronic HCV infection acts as an opportunistic pathogen in HIV-infected persons, since both the incidence and the severity of HCV disease are increased.
The use of highly active antiretroviral therapies (HAART) and prophylactic agents for the prevention of opportunistic pathogens has dramatically increased the survival rate among HIV-infected patients. HCV-associated disease will become an increasingly significant cause of morbidity and mortality in this patient population. Strategies to prevent primary HCV infection and modify HCV disease progression are urgently needed for HIV-infected individuals.
BACKGROUND ON HCV INFECTION
Mark Sulkowski, MD, cochair, opened the Expert Perspectives Development Meeting by reviewing the role of HCV as a pathogen. HCV infection causes viral persistence and chronic disease in more than 80% of infected patients, despite broad immunologic responses to viral proteins. These responses may be thwarted by the high rate of mutation, which leads to the generation of a highly variable mixture of closely related genomes. This phenomenon persists and continuously evolves in infected individuals, mainly under the influence of host immune pressures. Even recovery from HCV infection does not protect against subsequent re-exposure to the virus. Nevertheless, HIV/HCV-coinfected patients can be treated effectively with antiretroviral therapy. Interferon alfa-2b/ribavirin combination therapy may represent the first step in the development of effective drug regimens to treat HIV/HCV coinfection.
Dr. Sulkowski stressed that all HIV/HCV patients should be evaluated as candidates for treatment. Such evaluation should include HIV/HCV testing; assessment of comorbidity, alcohol use, and psychiatric disorders; and liver biopsy, where appropriate.
The means by which HCV causes liver injury is not completely understood, noted Nezam Afdhal, MD. There is no association between viral genotype or load and the degree of hepatic inflammation or fibrosis. In patients with HCV infection, iron, fat, and alcohol are critical cofactors that can lead to progressive fibrosis.
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EPIDEMIOLOGY OF HIV AND HCV
Ian T. Williams, PhD, MS, presented data from the Third National Health and Nutrition Examination Survey (NHANES III) revealing that about 3.9 million Americans (1.8% of the population) have been infected with HCV. Of these, approximately 2.7 million (70%) are chronically infected. It has been estimated that 3% of the world population has been infected with HCV. Population-based studies indicate that 40% of chronic liver disease is HCV-related and that it results in 8,000 to 10,000 deaths each year. Since the prevalence of HCV infection is roughly 3-fold higher among persons now between 30 and 49 years of age, the number of deaths due to HCV-related liver disease could increase substantially during the next 10 to 20 years, as this cohort reaches the ages at which complications from chronic liver disease typically occur. Direct and indirect costs associated with HCV-related liver disease in the next 2 decades could exceed $50 billion.
Coinfection with HCV and HIV is common due to shared risk factors for transmission. David Thomas, MD, pointed out that up to 40% of HIV-infected patients are also infected with HCV. Of those who acquired HIV via intravenous drug use, 80% to 90% are infected with HCV. In light of these, Barbara McGovern, MD, highlighted the importance of the joint recommendation by the Infectious Diseases Society of America and the US Public Health Service that all patients with HIV be offered hepatitis C antibody testing.
NATURAL HISTORY OF HCV INFECTION AND BIOPSY
HCV infection, although typically asymptomatic, is potentially life threatening. Rarely identified in the acute phase, an estimated 70% to 85% of acute cases of HCV infection progress to chronic infection, with viremia persisting more than 6 months after acquisition. Fredric Gordon, MD, acknowledged that natural history studies are flawed because of our current inability to identify acute infection, the long duration of the disease before adverse disease results manifest, and the lack of an accurate and well-defined control group. Nevertheless, we currently estimate that 20% to 50% of HCV-infected patients will develop cirrhosis from 20 to 50 years after acquisition. Identifying patients with progressive disease and initiating therapy is critical for preventing cirrhosis. Effective treatment in high-risk populations, such as men of advanced age at acquisition and heavy alcohol users, is essential for decreasing HCV morbidity and mortality.
HIV-infected patients are now living long enough for the impact of HCV on the liver to become apparent. Liver biopsy studies have shown that cirrhosis is present in significantly more patients who are coinfected with HIV and HCV than among patients with HCV alone, even when patients are matched in terms of age, sex, and other risk factors for disease progression. HIV/HCV coinfected patients whose CD4+ cell counts are less than 200/µL are at especially high risk of cirrhosis. The likelihood of liver-related mortality is almost 7-fold greater among individuals who are coinfected with HIV/HCV than among those who are infected with HCV alone. Since infection with HIV increases the rate of progression of HCV-related fibrosis, clinicians need to consider treating coinfected patients for HCV.
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CURRENT STANDARD OF TREATMENT
In the past year, standard treatment for chronic hepatitis C infection has advanced from IFN monotherapy to combination IFN/RBV therapy. Ira Jacobson, MD, stated that sustained response rates have increased from approximately 10% to more than 40%. Since viral genotype is regarded as the single most powerful predictor of sustained response, the duration of therapy should be customized to the genotype. Treatment-naive patients with genotype 1 should be treated with combination therapy for 12 months, whereas 6 months of therapy may suffice for patients with genotype 2 or 3. Researchers have modified the critical time at which to assess whether to continue treatment from the end of 3 months for IFN monotherapy to the end of 6 months for combination therapy. For patients who relapse following a course of IFN monotherapy, data clearly demonstrate that a 6-month course of combination therapy provides a sustained response rate 10 times higher than a repeat course of IFN alone (49% vs 5%). Treating relapsers with HCV genotype 1 for a full year rather than for 6 months offers a notable improvement in outcome, as is the case with treatment-naive patients.
Dr. Jacobson agreed that it is increasingly clear that HIV/HCV coinfection is associated with a rapid progression of HCV-related liver disease. Many clinicians now consider that coinfected patients should be treated more aggressively and approached on an individual basis for consideration of liver biopsy followed by therapy. Preliminary data from trials of combination therapy in HIV/HCV coinfected patients suggest that ribavirin does not interfere with the antiretroviral activity of azidothymidine and d4T, as was originally feared.
The experts agreed that collaboration between hepatologists and infectious disease specialists is essential for optimal patient care. Nezam Afdhal, MD, emphasized the importance of using a team approach to manage the treatment of coinfected patients.
Extending his work on the HIV virus, Alan S. Perelson, PhD, described a biphasic decline of serum HCV RNA using mathematical modeling. The implication for clinical practice is plain: Aggressive treatment can rapidly and profoundly reduce the amount of virus in infected patients, potentially allowing the immune system to clear the virus more efficiently, even if the patient has HCV viremia.
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MAINTENANCE THERAPY
With the addition of ribavirin to IFN therapy, physicians have been able to offer patients with HCV infection a treatment option that provides sustained response rates of more than 40%. Although the primary goal of eradication of the virus may not be achieved, secondary goals of delaying the progression to cirrhosis, decreasing the risk of hepatocellular carcinoma, avoiding the need for liver transplantation, and improving life expectancy are important to the patient. Although the sustained response rates reported are variable in mono- and combination-therapy studies, Fredric Gordon, MD, emphasized that improvement in hepatic histology after treatment is an almost universal finding in IFN-based studies. Researchers have found that sustained responders have the greatest degree of improvement and the highest percentage of patients showing improved histology. Even nonresponders who undergo IFN-based therapy for at least 6 months typically have a lesser degree of inflammation. Dr. Gordon reported the results of a meta-analysis of 5 HCV treatment studies conducted by Poynard, et al, who found that IFN-based treatments have the capability of stabilizing, if not improving, fibrosis. The decision to continue IFN in nonresponders must be individualized and take into consideration the adverse effects of treatment and the pretreatment degree of inflammation and fibrosis, in addition to other risk factors for the progression of disease. The fact that few treatment options for nonresponders exist underscores the need for further studies with new compounds, such as pegylated IFN and interleukin-10, a potentially antifibrotic agent. Until improved agents are available, maintenance IFN therapy is the standard of care, especially in patients with stage 2 or greater fibrosis. Halting fibrosis prior to the onset of cirrhosis should decrease the rates of hepatocellular carcinoma, death, and liver transplantation.
MANAGEMENT OF SIDE EFFECTS
Ira Jacobson, MD, described the adverse events commonly reported with the use of IFN: flu-like symptoms, fatigue, headache, myalgia, irritability, depression, and cytopenia. The 2 major adverse events of ribavirin are the potential for teratogenic complications and hemolytic anemia. Adverse events occurring more frequently with combination therapy than with monotherapy include nausea, rash, dry skin, pruritus, noncardiac chest pain, dry cough, and shortness of breath.
Coleman Smith, MD, discussed the hematologic abnormalities, including anemia, neutropenia, and thrombocytopenia, that occur with IFN and ribavirin. The use of ribavirin is associated with a reversible normochromic and normocytic hemolytic anemia. The decrease in hemoglobin levels usually occurs within 2 to 4 weeks of initiating therapy. Within 4 weeks, reticulocytosis is often noted. In the large IFN/ribavirin registration studies, the majority of patients demonstrated a decrease in hemoglobin levels of 2-3 g/dL. Patients with pretreatment hemoglobin levels of less than 14 g/dL were more likely to experience levels below 10 g/dL and to require dose modification. In contrast, patients receiving IFN alone experienced less of a drop in hemoglobin levels (about 1 g/dL). This drop is not usually clinically important.
Mental illness is a risk factor for the acquisition of HCV and HIV, and psychiatric disorders complicate the treatment of HIV/HCV. Mental illness can decrease patient compliance with treatment. With appropriate psychiatric treatment, Glenn J. Treisman, MD, PhD, reported that coinfected patients can be successfully maintained on therapy for HCV infection. In his opinion, the side effects of treatment, such as depression, are common but manageable with a team approach and the use of specific medications.
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HAART IN THE CONTEXT OF HCV INFECTION
While it is clear that HIV has a negative impact on the natural history of HCV, Dr. Eliot Godofsky emphasized that even complete control of HIV using HAART does not affect HCV viral titers. The potential for hepatotoxicity of antiviral medications in patients infected with chronic viral hepatitis has been a concern. When significant hepatotoxicity does develop in coinfected patients, the following issues should be considered: (1) the potential cause(s) of the abnormality; (2) the possibility of changing antiviral medications in an effort to decrease toxicity while maintaining antiretroviral effect; (3) the prevention of additional hepatotoxicity from other sources; and (4) the necessity of treating the underlying viral hepatitis. Thus, the optimal treatment of viral hepatitis concurrent with HIV is a major challenge to address. The pace of both diseases must be considered, and the priority of treatment must be critically evaluated. Norbert Brau, MD, recommended new HAART regimens and that IFN/ribavirin combination therapy should not be started simultaneously with ART. Combination therapy should be given about 4 weeks before starting ART or vice versa.
STRATEGIES FOR THE MANAGEMENT OF HIV/HCV COINFECTION
While the results of well-designed clinical trials are not yet available for coinfected patients, Dr. Sulkowski, cochair, said that data showing enhanced efficacy of IFN/ribavirin among HIV-uninfected persons are compelling. Combination therapy using IFN/ribavirin therapy, the standard of care for treating HCV infection, may be beneficial for treating HCV/HIV coinfection. However, further work is required to define the appropriate use of IFN/ribavirin for HCV treatment in this population. At this time, the goals of HCV therapy in HIV-infected persons should include: 1) eradicating HCV in patients with adequate immune function; 2) delaying, through maintenance therapy, histologic and disease progression in patients who have advanced fibrosis as determined by liver biopsy; and 3) suppressing HCV-related disease activity to prevent HAART-associated hepatotoxicity (eg, maintenance therapy).
Dr. Jacobson concurred and urged hepatologists and infectious disease specialists to collaborate on the treatment of coinfected patients. In particular, he recommended that decisions regarding when to initiate HCV treatment and how to manage potential hepatotoxicity be made jointly.
Douglas Dieterich, MD, cochair, discussed disease management. He, too, highlighted the importance of a multidisciplinary team for the optimal treatment of coinfected patients. A significant issue for these patients is the concurrent management of HBV infection. Dr. Dieterich reported that IFN is widely used for HBV, as is lamivudine (3TC), a reverse transcriptase inhibitor originally developed for the treatment of HIV. In discussing the side effects associated with ribavirin, Dr. Dieterich focused on anemia, one of the most common. Recombinant human erythropoietin may be effective for treatment of ribavirin-associated anemia while granulocyte colony-stimulating factor (GCSF) may be used for IFN-associated neutropenia and for cytopenias occurring in HIV-infected patients.
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CONCLUSION
Dr. Sulkowski emphasized that treatment with combination therapy with IFN/ribavirin should be considered for the following patient populations: those with stable HIV disease (including adequate CD4 count), with a goal of eradicating the virus; those with advanced liver disease, with a goal of delaying disease progression; and those experiencing HAART-related hepatoxicity, with a goal of pursuing aggressive HIV disease treatment. Biopsy, although recommended, is not a prerequisite for initiation of treatment for coinfected patients. Furthermore, he recommended that a team approach be used. Ideally, the treatment team should be led by an HIV-care provider and may include a gastroenterologist and a psychiatrist. In addition, Dr. Sulkowski stressed the critical need for further controlled clinical trial data and a patient registry to track outcomes.
At the conclusion of the conference, participants commented that the monograph developed from the meeting’s proceedings will help physicians gain a greater level of comfort in treating coinfected patients and a better understanding of the natural history of liver disease in coinfected patients.
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