MAXIMIZING THE BENEFITS OF ANTIVIRAL THERAPY FOR HCV: THEADVANTAGES OF TREATING SIDE EFFECTS

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Preface xxiiiRobert G. Gish

Treating Hepatitis C: The State of the Art S1Robert G. Gish

Treatment of chronic hepatitis C has improved significantly, butmore effective and well-tolerated therapies are needed. While newtherapies are being developed, it is important to optimize the use ofcurrently available treatments. Current treatment regimens areassociated with substantial side effects, especially hematologicand neuropsychiatric side effects, that can lead to nonadherence,dose reduction, and treatment discontinuation. Because treatmentadherence is critical to achieving a sustained virologic response,especially in patients who have genotype 1, early recognition andappropriate management of these side effects should lead to im-proved patient outcomes. Pending the availability of new thera-pies, further progress can be made mainly by maximizingbenefits for individuals infected with HCV through appropriate se-lection of patients for antiviral treatment and increasing treatmentadherence through better patient and caregiver education, closerpatient follow-up, and more aggressive management of the side ef-fects that lead to dose reduction or discontinuation. Further clinicaland research efforts are needed to expand treatment to subgroupsof patients previously considered ineligible because of comorbid-ities such as psychiatric and substance-use disorders. Optimummanagement of patients with hepatitis C will involve a larger coop-erative team effort that includes physician specialists from variousdisciplines, including mental health care providers and physicianextenders. Continued efforts are needed to develop novel therapiesand treatment approaches to benefit patients who do not respondto current therapies, to increase our understanding of the naturalhistory and pathology of HCV infection, and to promote publiceducation to better identify infected individuals and improvehepatitis C prevention.

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Adherence to Combination Therapy: Influence onSustained Virologic Response and Economic Impact S11Michael P. Manns

The health care burden of hepatitis C virus (HCV) infection is pro-jected to continue to increase over the next two decades, so im-proving the efficacy of anti-HCV therapy has the potential tosignificantly affect health care utilization associated with the dis-ease. Adherence to standard combination therapy and maintainingthe doses of interferon (IFN) or peginterferon (PEG-IFN) and riba-virin (RBV) are now recognized as critical to maximizing a sus-tained virologic response (SVR) rate, particularly in patientsinfected with genotype 1 and patients who demonstrate an earlyvirologic response. Early identification and management of thetreatment-related side effects that are most likely to result in dosereductions or discontinuation might also play a role in successfuladherence to therapy and achieving an SVR, as side effects are theprimary reason for nonadherance. Educating patients, their familymembers, and their caregivers about the expectations of treatment,side effects, and the importance of maintaining doses and complet-ing therapy is essential to optimizing adherence. Although patientquality of life (QOL) may decrease during treatment, patientsachieving an SVR experience an improved QOL. Cohort economicmodeling studies and available data from recent controlled trialssuggest that PEG-IFN/RBV therapy increases life expectancy andis cost effective compared with standard IFN/RBV, and that theuse of treatment management algorithms based on early virologictesting can substantially reduce antiviral drug costs and further im-prove the cost effectiveness of therapy, as can increased adherenceto PEG-IFN/RBV therapy. Further research will be needed to devel-op optimum and cost-effective treatment strategies for the generalHCV-infected population, particularly patients with comorbidities.

Role of Epoetin Alfa in Maintaining Ribavirin Dose S25Nezam H. Afdhal

Current therapy for the treatment of hepatitis C virus (HCV) infec-tion is standard interferon (IFN) or pegylated interferon (PEG-IFN)in combination with ribavirin (RBV). Hematologic side effects (neu-tropenia, thrombocytopenia, anemia) are a major reason for dosereduction of anti-HCV therapy. Because treatment adherence andmaintenance of IFN or PEG-IFN and RBV doses have been shownto be important in achieving a sustained virologic response, appro-priate management of hematologic side effects might play a sub-stantial role in optimizing treatment outcomes. Neutropenia andthrombocytopenia are usually managed by IFN or PEG-IFN dosereduction; the role of hematopoietic growth factors to amelioratethese side effects needs further evaluation, but some studies suggestgranulocyte colony-stimulating factor (G-CSF) may be useful in themanagement of IFN/PEG-IFN-associated neutropenia. Anemia isprimarily due to RBV-induced hemolytic anemia, but IFN/PEG-IFN also suppresses bone marrow erythroid precursors. Treat-ment-induced anemia has usually been managed by RBV dose

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reduction or discontinuation. However, recent studies suggest thatepoetin alfa can increase hemoglobin levels and facilitate mainte-nance of RBV dosage in patients with chronic hepatitis C who be-came anemic during standard combination therapy. Results of arandomized, double-blind, placebo-controlled trial suggest thatepoetin alfa therapy canmaintain RBV dosage, increase hemoglobinlevels, and improve quality of life in this population. In patients whohave chronic hepatitis C who experience hematologic toxicities dur-ing standard therapy, the use of hematopoietic growth factors suchas epoetin alfa might have the potential to improve treatment adher-ence rates and allow optimal doses of IFN or PEG-IFN and RBV tobe maintained, thereby leading to improved treatment outcomes.

Neuropsychiatric Side Effects of HCV Therapy and TheirTreatment: Focus on IFNa-induced Depression S37Peter Hauser

Psychiatric disorders, particularly depression, and substance-usedisorders (SUDs) are common comorbidities in patients who havechronic hepatitis C virus (HCV) infection. Patients who are infectedwith HCVwho are treated with interferon alfa (IFNa) are also at sig-nificant risk for IFNa-induced depression (incidence, ~20�30%) andother neuropsychiatric side effects that can affect treatment adher-ence, require dose reduction or discontinuation, and impact patientquality of life adversely. Because psychiatric illness and SUD comor-bidities are so common, patients who have hepatitis C should bescreened for these disorders. If these disorders are present, patientsshould be referred to a mental health care provider for appropriatetreatment before therapy with IFNa is considered. Having a coman-agement model of care that involves mental health care providersshould help identify appropriate candidates for IFNa therapy. Ifpreexisting depression responds to antidepressant treatment IFNatherapy can then be initiated. Patients who have other active psy-chiatric disorders can probably be offered IFNa therapy safely withappropriate monitoring andmanagement involving amental healthcare professional; however, there is a paucity of research in this area,and the few published studies have small sample sizes. If depres-sion develops during IFNa therapy, most patients respond to treat-ment with selective serotonin-reuptake inhibitors, often allowingpatients to continue receiving IFNa therapy. In addition to screeningpatients and treating those who have psychiatric disorders beforeIFNa therapy is started, early recognition of psychiatric disordersand neuropsychiatric side effects during IFNa therapy through con-tinued screening and monitoring, with appropriate management,can potentially maximize HCV treatment adherence and possiblyimprove antiviral therapy outcomes.

Future Trends in Managing Hepatitis C S51John G. McHutchison and Anouk T. Dev

Despite recent improvements in the treatment of patients who havechronic hepatitis C, a large proportion of patients do not achieve

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viral clearance. Treatment regimens are also costly, associated withsignificant morbidity, require substantial patient commitment, andare not appropriate for all patients. Therefore, it is important tomaximize and enhance current therapeutic approaches and to in-vestigate new approaches and therapies. Because the ability tomaintain adherence to current treatment is associated with highersustained virologic response rates (particularly in patients infectedwith genotype 1), strategies directed at patients and support staffto promote treatment adherence are important. Other strategiesto enhance current therapy include alternative interferons (IFNs)/cytokines and new IFN delivery systems. Current therapy may alsobe enhanced by new ribavirin (RBV) analogs with an improvedsafety profile or by the addition of other immunomodulatory agentssuch as inosine 5¢-monophosphate dehydrogenase inhibitors, hista-mine dihydrochloride, thymosin alfa 1, and amantadine. Some ofthese agents have demonstrated promising results, although furtherevaluation is required. Greater knowledge of the molecular biologyof the hepatitis C virus (HCV) holds promise for the development oftargeted therapies such as specific inhibitors of HCV polymerase,protease, or helicase, as well as therapeutic vaccines. Other potentialmolecular-based therapies include antisense oligonucleotides, ribo-zymes, and short interfering ribonucleic acid (RNA) molecules.Therapies aimed at reducing or preventing the development of fi-brosis are also under investigation. Multiple-drug regimens willlikely be required to enhance viral clearance and reduce viral resis-tance, while providing greater tolerability.

Index S63

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