HCV therapeutics: Times are changing

There are few areas in medicine in which the therapeutic landscape is poised to change more rapidly than in that for the therapy of hepatitis C infection. The 20 years after the introduction of interferon-alpha therapy witnessed only two advances in hepatitis C therapy.

First, ribavirin, an agent that had previously been pitched at more viruses than are included in most medical school curricula, was found to reduce the rate of relapse after a course of interferon-alpha therapy. Secondly, conjugation of interferon-alpha to polyethylene glycol was demonstrated to increase the chance of treatment and the tolerability of interferon therapy.

When these two modifications to classical interferon-alpha therapy were combined, a patient with HCV genotype-1 could look forward to a difficult year that resulted in a cure less than half of the time. In this situation, it would be expected that most patents reluctantly accepted therapy when they (and their physicians) came to the conclusion that therapy was required as a last effort to avoid end-stage liver disease or hepatocellular carcinoma.

In these circumstances, patients usually avoided therapy until their liver disease resulted in referral to a hepatologist who generally viewed their problem as a liver rather than a viral disease. We are now entering a new era in which therapeutic advances for HCV will completely change the treatment paradigm. This will be accompanied by much better outcomes for patients and will require a major expansion of the treating community in which HIV physicians will play a much greater role. These shifts will be driven by three major factors.

Success rates will increase

The addition of either of the newly approved HCV protease inhibitors — boceprevir (Victrelis, Schering) or telaprevir (Incivek, Vertex Pharmaceuticals) — to polyethylene glycol-interferon and ribavirin therapy has already increased the prospect of treatment success to about 70% in genotype-1 infection.

With the increased potency of three-agent antiviral regimens, treatment duration has decreased from 1 year to 6 months in most patients, and early assessment of the antiviral response can provide patients with prognostic information that is reliable as to whether a course of therapy is likely to be successful. Taken together, patients can expect treatment to be successful more frequently, and they will likely be inconvenienced for only half as long as before.

Furthermore, clinical trials with newer agents provide strong evidence that treatment success rates are poised to go higher and that courses of therapy will be shorter for many patients — and perhaps, most importantly, will ultimately include neither interferon nor ribavirin. These factors have already increased interest in testing for and treatment of HCV infection.

Initiation not driven by liver biopsy findings

As current therapies are limited in appeal, most patients seek therapy (and most physicians recommend therapy) only when liver disease has progressed to the point that cirrhosis is at hand or established. Although noninvasive approaches are emerging that serum markers or ultrasound are reasonably good at identifying patients with very little liver damage or substantial cirrhosis, liver biopsy is generally needed to provide sufficiently precise information in the middle spectrum of HCV-induced liver disease to make good therapeutic recommendations in most patients.

In addition, if therapy is delayed too long and decompensated cirrhosis has developed, interferon therapy can lead to liver failure and death. These factors have generally drawn hepatologists into the dialogue about whether therapy is indicated and usually keep them involved after therapy is started, if it is started later in the course of HCV-induced liver disease.

Decisions more complicated

Although art and science were involved in deciding when treatment should be recommended and when a patient should go through a course of polyethylene glycol-interferon/ribavirin therapy, the therapeutic landscape was reasonably straightforward once therapy was recommended.

Ribavirin was included in both regimens, and the two interferons differed from each other only in nuance. Thus, the treatment decision was a dichotomous one, and once therapy was started, side effects (though they were often substantial) were well delineated and predictable. In many treatment settings, a physician (usually a hepatologist) gathered the data and made recommendations about whether treatment was recommended, and care was actually delivered by physicians and nurse practitioners who were able to follow relatively simple toxicity management algorithms and manage most serious side effects with dose reduction and referrals to mental health workers for management of depression.

More than 20 directly acting anti-HCV agents are currently in various phases of development. These drugs have different molecular targets, resistance profiles, metabolic profiles, drug interactions and treatment durations — and it is clear that every regimen will require two to four of these new agents. As it becomes easier to decide who to treat, it is likely that more complex decisions will be required once therapy is started.

Decisions, not unlike those that the HIV-treating community has confronted for years, will be brought into the process, and “laminated-card driven” decision-making of the polyethylene glycol-interferon/ribavirin era will be a thing of the past. Decisions about overlapping resistance pathways and about interactions among anti-HCV agents (and between HCV agents and other drugs that patients must take) will be required. Because decisions about treatment duration and futility will be driven by close monitoring of antiviral response, multiple decisions will be required throughout the course of therapy. Although it is clear that these sorts of decisions can be made by hepatologists if they are heavily engaged in HCV therapy, it is likely that the hepatology community will see a further division into a subset of hepatologists who take care of hepatitis most of the time and a much larger subset who focus on transplantation and/or procedures.

Care models in new HCV therapy era

At present, there are approximately 4 million HCV-infected people in the United States, and it is estimated that fewer than 2,000 physicians are responsible for more than 80% of the currently administered antiviral therapy. As the number of those interested in HCV therapy increases and as the threshold to recommend therapy increasingly shifts to earlier stages of liver disease, current HCV treatment communities will become increasingly overrun. With a likely constriction in the number of hepatologists who are actively engaged in HCV therapy, it is clear that physicians from other disciplines will be drawn into HCV therapy.

Due to the complexity of HCV therapy, it will neither be good for patients nor an efficient use of resources to have thousands of generalists provide care to a few patients each. When HIV-1 emerged in the 1980s, AIDS “specialists” initially came from multiple training backgrounds, including internal medicine, infectious diseases, oncology, dermatology and family medicine.

As the field matured, most de novo training eventually became centered on infectious disease training programs. Most of the “primary” care for HIV (and many of us would also argue the best care) is now provided by multidisciplinary teams that are usually coordinated by physicians with infectious disease specialty training. These multidisciplinary teams optimally include those with complementary specialized expertise in the complications of the disease, including oncologists, hepatologists, psychiatrists, neurologists and clinical pharmacologists.

This shift occurred over time and with little explicit coordination or pre-cognition, but it has proved to be an extremely efficient model of care in which outcomes are better than in settings in which HIV care is provided by those with limited experience and expertise.

Rather than to stumble into an analogous model for HCV therapy during the next decade, it is attractive to think that the HIV experience could provide yet another window on the best approach to HCV care. Optimal HCV care will require interactive multidisciplinary teams with specialized expertise. Developing centers of excellence in HCV care should be a priority for the infectious disease community that should occur in anticipation of, rather than in response to, radically changing treatment paradigms.

These centers of excellence should also include hepatologists interested in viral hepatitis in their direction and operation and will need to include translational virologists, liver transplant surgeons, psychiatrists, radiologists with expertise in noninvasive imaging of the liver and clinical pharmacologists. Based on our experience in the medical and operational aspects of HIV infection, the infectious disease community must play a major role in the initial development of these centers, and most of the leaders in this exciting area of medicine should emerge from our training programs.

We’ve applied a lot of what we learned about RNA viruses from antiretroviral drug development to HCV drug discovery. Although it has been a bit slower, some of the lessons of the benefits of closely aligning clinical and translational science in drug development have been introduced into HCV drug development. There is no reason not to apply what we learned about optimal HIV care models to the very similar multidisciplinary landscape of HCV care.

Tremendous benefits will accrue to patients, and what could be more appealing to those of us in infectious diseases than a viral disease that we can actually eradicate — all that remains is to develop a billing code for “virectomy.”

Robert T. Schooley, MD, professor and head in the division of infectious diseases, and vice-chair of the department of medicine at the University of California, San Diego. Disclosure: Dr. Schooley is a member of scientific advisory boards for Gilead Sciences, GlobeImmune, Inhibitex, Johnson & Johnson, Monogram Biosciences, and Santaris. He has consulted for Merck. Research support is provided by Boehringer Ingelheim and Bristol-Myers Squibb.

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