Among the greatest challenges of modern medicine is the need to intermittently stop and synthesize the mass of data that flows from electronic and print media, formal scientific conferences, and small gatherings of focused researchers. In the last decade, few areas have moved forward as quickly as our knowledge of the significance, epidemiology, diagnosis, virology, and treatment of hepatitis C virus infection. A relatively obscure field in the early 1990s has grown up and now holds center stage in HCV-specific symposia and conferences, specialty journals, and even the popular press. Thousands of articles have now been published in peer-reviewed journals, and "experts" abound. It is in this context that TAG's report, Hepatitis C and HCV/HIV Coinfection: A Critical Review of Research and Treatment, was born and has matured. The first edition of this treatise (Marco 2000) represented an admirable effort to summarize the prevailing views of the time, and to "push the envelope" in terms of future research and management of HCV-infected patients. The latest effort was monumentally more difficult. Review articles and consensus statements (often conflicting and sometimes self-serving) are ubiquitous. One might ask why anyone would take on the seemingly thankless task of trying to bring order and perspective out of this chaos. It is a credit to Tracy Swan and her research and writing team that she constantly sought fact versus opinion and tempered controversy with balanced and thoughtful commentary. The outcome is a document that can be understood by the uninitiated and used as an important reference by those experienced in the field.
Each section of the document has a brief summary that catalogs its high points. Within each section is a detailed, reference-rich analysis of the current literature. The key sections of the document include Natural History, Diagnosis, Molecular Virology, Pathogenesis, and Treatment. All sections have been written following consultation with key experts and then validated for accuracy and fairness by others. Therefore, the TAG report on hepatitis C and HIV/HCV coinfection provides an overview with a detailed body of text depending on the level of interest and knowledge of the individual reader.
The Natural History section reveals the wide variety of clinical pathways that infected patients may follow. We now recognize that many infected patients will spontaneously clear this infection without treatment intervention, particularly in the early months and years after infection. Others will maintain a chronic viral infection, but may not develop significant fibrosis in their liver. Unfortunately, many will continue in stepwise fashion from portal fibrosis to portal bridging and finally to cirrhosis. Some who develop cirrhosis will find their course complicated by development of hepatocellular carcinoma, whose incidence seems to be increasing in countries most affected by this epidemic.
The Treatment of HCV section documents the rapid changes in treatment paradigms over recent years. Pegylated interferon use has moved front and center and essentially replaced use of standard interferon products. The goal of pegylation, namely, the alteration of pharmacokinetics leading to increased area under the curve (AUC), has been achieved in two commercially available products that appear to have similar levels of effectiveness in large-scale Phase III clinical trials. Ribavirin is a mainstay of therapy now, though the exact mechanisms of its action remain uncertain. The duration of therapy has now been clearly delineated in terms of genotype. Genotype 2 and 3 patients have high rates of sustained viral response associated with 24 weeks of continuous interferon/ribavirin therapy. Viral kinetic modeling suggests that even shorter treatment cycles may be possible. In contrast, genotype 1 and probably genotype 4 patients need longer therapy and still fail to achieve the optimal outcome more than 50% of the time. These patients remain the great challenge for newer therapeutic interventions. Potent antiviral agents directed against the HCV serine protease, helicase, and RNA-dependent RNA polymerase are under investigation, and some are in human trials. The timeline of development for antiretroviral agents serves as an important guidepost. We must not forget the lessons learned from early monotherapy interventions that led to rapid mutant virus emergence.
HCV/HIV coinfection represents an important and relatively uninvestigated area for research. The rapid progression to cirrhosis in this group leads to a feeling of great urgency. Unfortunately,the research effort invested in this important subgroup -- which may represent 10% of the HCV burden in the United States -- has been blunted by a variety of factors. Pharmaceutical companies did not pursue large trials in coinfected subjects until HCV monoinfection trials leading to licensure were complete. Hepatologists and gastroenterologists remain unfamiliar and uncomfortable with the management of HIV-infected patients, and infectious disease experts remain woefully weak in their understanding of liver disease. Interactions between drugs used for the two diseases are not well characterized; adherence in many clinical trials and in clinical practice is abysmal. Finally, there is a sense of therapeutic nihilism vis-à-vis HCV in the infectious disease community that quickly affects patients. Decrements in sustained viral response in coinfected patients lead many to declare that HCV treatment in genotype 1 patients makes therapeutic intervention a nonviable alternative. It is important, however, to note that FDA has approved interferon monotherapies at rates of efficacy far lower than that observed for coinfected subjects in current treatment trials, and that "cure "rates of 10-20% are still far better than those achieved for other chronic virus infections.
It has been a privilege to participate in the review process during the development of this monograph. I applaud the tireless efforts of the authors to seek data in place of opinion, and to temper opinion with a call for definitive research. It is time for the next jump forward, as the years of directed antiviral therapy for HCV approach.
Kenneth E. Sherman, M.D., Ph.D.
Gould Professor of Medicine
University of Cincinnati College of Medicine
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