2012-05-23 19:03:05 UTC

Treating Now Is Best for Chronic Hepatitis C Patients

May 23, 2012

NAME

 

Donald Jensen, MD

Professor of Medicine, University of Chicago Medical Center, IL

NAME

 

Archita P. Desai, MD

Fellow in Section of Gastroenterology, Hepatology and Nutrition University of Chicago Medical Center, IL

 

The prevalence of chronic hepatitis C (CHC) in the U.S. is staggering with an estimated three million individuals affected. The associated burden on the health-care system will increase dramatically throughout the next two decades until the majority of infected individuals are successfully treated.1 With the approval of the first direct-acting antivirals (DAAs), telaprevir and boceprevir, we are now poised to truly impact the course of hepatitis C infection worldwide as sustained virologic response rates have increased from 40 to 70 to 80 percent for patients with genotype 1 infection.

It is almost universal for patients with genotype 1-related CHC to ask the question, “Should I be treated now or wait for better therapy?” This question reflects the knowledge that further advancements in CHC therapy are already underway, such as therapies that purport even higher efficacy rates, combination therapies with fewer adverse events, and interferon-free therapies. In addition, current guidelines have few absolute indications to starting CHC therapy, leaving a large group of patients and their physicians individually weighing the risk and benefits of initiating therapy versus watchful waiting. In the current era of triple therapy for CHC, I would argue treating now is the best course of action for the majority of patients with CHC.

This recommendation is clearest for those patients who cannot wait for improved therapeutic options and includes those with cirrhosis or advanced fibrosis, as the risk of progression of their disease is real and estimated at 4 percent per year. Decompensation not only carries its own morbidity and mortality, but will make future therapy difficult and less beneficial. Those with intractable symptoms due to CHC such as fatigue, and those with extrahepatic manifestations, including cryoglobulinemia, renal disease and dermatologic manifestations, should be treated now regardless of stage of liver disease.

Another group who would benefit from treatment now are the subset of patients who have risk factors associated with faster progression of fibrosis.2 These include patients with initial infection after age 40, male gender, excessive alcohol consumption, hepatitis B virus or HIV co-infection, steatosis, or prolonged immunosuppressed state. Due to a higher rate of progression that is poorly defined, these patients should be treated now.

Patients with CHC whose liver biopsy shows limited portal fibrosis (METAVIR stage 1 and 2) need careful discussion regarding timing of therapy. In this group, I would argue again for treating now if there is no major contraindication. This is largely based on the inaccuracy of liver biopsy and other non-invasive markers for diagnosing cirrhosis. Specifically, we know that blind percutaneous liver biopsies tend to underestimate the stage of fibrosis and can miss cirrhosis in up to 30 percent of cases. Noninvasive tests of liver fibrosis currently available do not accurately stage liver fibrosis in the intermediate range.3

In addition, the negative effects of age on the success of CHC therapy are now being recognized. Preliminary results from the PROPHYSES trial show that CHC patients age 65 and older have lower rates of virologic response even after correcting for factors such as co-morbidities and medication adherence.

In this same vein, patients with co-morbid conditions — such as chronic cardiopulmonary disorders — are another population where treatment now may be beneficial. Specifically, as those with chronic diseases progress in age, they are also more likely to develop other co-morbid conditions and complications that are negative factors for consideration for — or response to — current interferon-based therapy. While one may argue that these patients ought to wait for interferon-free regimens, the promise of interferon-free therapy has yet to be realized and is at least several years away. Thus, waiting for future therapies risks missing a window of opportunity for successful viral eradication with currently available therapy.

In the subset of CHC patients who have normal alanine aminotransferase levels (approximately 30 percent), sometimes referred to as “healthy HCV carriers,” the answer to treat now or wait is less clear.4 The argument to treat now is supported by the fact that most have mild or moderate chronic hepatitis on liver biopsy despite persistently normal biochemical parameters. While fibrosis is usually absent, the long-term prognosis of these patients is not known, especially in those patients with risk factors for progression of liver fibrosis discussed above. Even if eradication of the virus only provides limited benefit to the patient, it would also decrease the risk of viral transmission to the community at large.

In summary, waiting to treat CHC carries several risks. First, the rate of progression of liver fibrosis cannot be accurately predicted on the patient level. While intermittent liver biopsy may help categorize patients, sampling error associated with liver biopsies undermines this method, and other non-invasive methods lack the sensitivity to guide the decision of when to treat CHC. Second, as patients become older, some will inevitably develop medical conditions that make the tolerability of CHC therapy more difficult. In addition, there are no guidelines for how to monitor these patients while awaiting interferon-free therapies. On the other hand, as we refine and gain experience with triple therapy, we are better able to manage side effects and improve success. Finally, while the promise of interferon-free regimens is tangible, many unknowns remain in this nascent field, including time to approval, worldwide availability, costs and insurance coverage of these medications, side-effect profiles, and, importantly, impact of viral resistance and durability of virologic response.

Looking at the current landscape of CHC therapy, we are truly at the dawn of a new era of CHC therapy, heralded not only by the improved efficacy afforded by the addition of DAAs, but also by the new sparked interest in CHC and its eradication. The improved success rates of triple therapy will inevitably support more universal screening, as is being currently advocated for the baby boomer generation.1 If enacted, a large number of patients who warrant therapy will be identified, and we must carefully weigh the risk of “warehousing” these newly diagnosed patients until even better therapies are available. n

Dr. Jensen receives consultant fees from Consensus Medical Communications, Clinical Care Options and Vertex. He also received research support from Abbott, Boehringer Ingelheim, Genentech/Roche, Pharmasset and Tibotec.

Dr. Desai had no conflicts to disclose.

References

1. Ward JW, Lok AS, Thomas DL, El-Serag HB, Kim WR. Report on a single-topic conference on “Chronic Viral Hepatitis-Strategies to Improve Effectiveness of Screening and Treatment.” Hepatology 2012;55:307-15.

2. Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet 1997;349:825-32.

3. Sebastiani G, Alberti A. How far is noninvasive assessment of liver fibrosis from replacing liver biopsy in hepatitis C? J Viral Hepat 2012;19 Suppl 1:18-32.\

4. Puoti C, Bellis L, Guarisco R, Dell’ Unto O, Spilabotti L, Costanza OM. HCV carriers with normal alanine aminotransferase levels: healthy persons or severely ill patients? Dealing with an everyday clinical problem. Eur J Intern Med 2010;21:57-61.

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