Worth the Wait? Should chronic hepatitis C patients be treated now or wait for promising therapies?

June/July 2012 issue of AGA Perspectives

Worth the Wait?
Should chronic hepatitis C patients be treated now or wait for promising therapies?

DONALD JENSEN, MD; ARCHITA P. DESAI, MD; and Gregory T. Everson, MD, debate the risks and benefits of initiating therapy now versus waiting for future treatments.

Donald Jensen,MD
Professor of Medicine,
University of Chicago
Medical Center, IL
Archita P. Desai,MD

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Treating Now Is Best for Chronic Hepatitis C Patients

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 improvedtherapeutic 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 comorbid conditions and complications that are negative factors for consideration for — or response to — current interferon-based therapy.

… waiting for future therapies risks missing a window of opportunity
for successful viral eradication with currently available 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 withliver 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 interferonfree 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 interferonfree 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

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.

Treating Chronic Hepatitis C in 2012: The Argument for Waiting

B efore May 2011, I had one option for treating patients with chronic hepatitis C: the combination of peginterferon (PEGIFN) and ribavirin (RBV). Rates of sustained virologic response (SVR) were approximately 40 percent for hepatitis C virus (HCV) genotype (GT) 1;40 to 60 percent for GTs 4, 5 and 6; and 80 percent for GTs 2 and 3.

From my perspective as a physician, the treatment was validated each time a patient achieved SVR, was cured of HCV, and eliminated or reduced their risk for disease progression.

However, patients had a different perspective. Despite the apparent successes,they — in general — were not happy with PEGIFN/RBV treatment. More than 70 percent of patients were infected with HCV GT 1, the genotype with the lowest rate of SVR, and many suffered through a long course of treatment without achieving their goal of eliminating HCV.

Nearly all patients experienced adverse side effects of treatment, such as flu-like symptoms,neuro-cognitive impairment, mood swings, skin rashes, loss of appetite, alopecia,thyroid disease, autoimmune reactions and altered personal relationships.

Some doubted that treatment with PEGIFN/RBV was worth the aggravation, althoughhad achieved SVR. In general, patients anxiously anticipated the next revolution in HCV treatment — protease inhibitors — hopefully to avoid interferon and its side effects.

In May 2011, two inhibitors of the HCV NS3/4a protease, telaprevir and boceprevir, were approved by the FDA. Combining these drugs with PEGIFN/RBV (triple therapy) improves the rates of SVR from 40 to 75 percent for treatment-naïve patients infected with HCV GT 1. However, patients and providers now have had to deal with side effects of not only PEGIFN/RBV, but also telaprevir and boceprevir.

Rash (telaprevir), anal pain (telaprevir)and anemia (telaprevir and boceprevir)further complicate the management of HCV treatment. Treatment regimens are complicated and the pill burden is high —two (telaprevir) or four (boceprevir) pills every eight hours with meals, in addition to weekly injections of PEGIFN and twice daily dosing of RBV.

Unfortunately, only a subgroup of HCV GT 1 patients responds to triple therapy. Sub-analyses of the telaprevir trials suggest that there are two major determinants of SVR: responsiveness to interferon and stage of fibrosis.1, 2 The likelihood of SVR depends on stage of fibrosis and type of virologic response during a prior course of PEGIFN and RBV (view figure 1 on this page). The best candidates for current triple therapy are relapsers,treatment naïve patients with minimal fibrosis (F0-F2) and partial responders with minimal fibrosis (F0-F2). In contrast, the likelihood of achieving SVR is approximately 50 percent or less for all other patient categories.

In fact, SVR is only 14 percent in cirrhotic null responders to prior PEGIFN/RBV. Although triple therapy is clearly an improvement over PEGIFN/RBV, many patients with HCV GT 1 will not be cured, especially patients with advanced fibrosis or those who are least responsive to interferon.

.

These realities of current triple therapy beg the patient’s question, “Should I wait for future treatments?” Certainly this is a consideration because the emerging future treatments will likely:
-Improve rates of SVR.
-Shorten duration of treatment.
-Have activity against most, if not all,HCV genotypes.
- Reduce dosing frequency.
- Reduce pill burden.
- Improve the patients’ tolerability of the treatment regimen.

Future triple therapy regimens will include PEGIFN/RBV with one of several new direct-acting antiviral agents (DAAs). These regimens will likely increase the rates of both extended rapid virologic response (eRVR)and SVR , reduce pill burden, and decrease side effects compared to telapreviror boceprevir-based triple therapy.

In a phase II study of once-daily TMC-435/PEGIFN/RBV, rates of eRVR ranged from 79 to 86 percent, maximum SVR was 86 percent, and there were no additional side effects beyond those due to PEGIFN/RBV.3 Another phaseII study of once-daily GS-7977 (formerly PSI-7977) with PEGIFN/RBV yielded eRVR and SVR of 91 percent, without additional side effects.4 Future DAAs may also have broader activity against other HCV GTs.

For example, GS-7977 is active againstHCV GTs 2 and 3,5 and both daclatasvir and danoprevir have demonstrated activity against HCV GT 4.

Even more exciting are the early results with IFN-free and QUAD regimens. A pilot study of 24 weeks of once-daily daclatasvir (NS5a inhibitor) plus twicedaily asunaprevir (NS3/4a protease inhibitor) (DUAL DAA therapy), without either PEGIFN or RBV, achieved SVR of 100 percent in 21 Japanese patients infected with HCV GT 1b who were null responders to a prior course of PEGIFN/RBV.6 In a small preliminary study of U.S. patients, 24 weeks of DUAL DAA treatment was ineffective against HCV GT 1a. But, the addition of PEGIFN/RBV to DUAL (QUAD) yielded SVR12 of 100 percent.7 Many DUAL, QUAD, multi-DAA and IFN-free regimens are currently under investigation.

When will these promising treatments become available?

Several are already in phase III of clinical development and some may be available as soon as 2013 or 2014.

The first to conclude phase III testing will likely be triple therapy using the next generation of protease inhibitors (TMC-435, BI-201335) for HCV GT 1 and an interferon-free regimen of a nucleoside NS5b polymerase inhibitor (GS-7977 [formerly PSI-7977]) with ribavirin for HCV GTs 2 and 3. Other DAAs in or nearing phase III development include additional protease inhibitors (danoprevir, asunaprevir, vaniprevir,ABT-450, others), NS5a inhibitors (daclatasvir, others), nucleoside NS5b polymerase inhibitors (mericitibine, others), and non-nucleoside NS5b polymerase inhibitors (many).

Table: Future Regimens-

Speculations on the Availability, Rates of SVR, Duration of Treatment and Tolerability of Future

Regimens for Treatment of Chronic Hepatitis C.

Click To Enlarge

Abbreviations: SVR, sustained virologic response; GT, genotype; SOC, standard of care; P, peginterferon; R, ribavirin; PI-1st, first available inhibitors of the NS3/4a hepatitis C virus (HCV) protease (telaprevir or boceprevir); PI-2nd, next available inhibitors of the NS3/4a HCV protease; NI, nucleoside inhibitors of the NS5b HCV polymerase; 5aI, inhibitors of the NS5a protein; DAA, direct-acting antiviral agents directed against either NS3/4a protease, NS5b polymerase or NS5a protein; LVL, low viral load(typically less then 600,000 IU/mL). The shaded rows represent current SOC for HCV genotypes 2 or 3 (upper shaded row) and HCV genotype 1 (lower shaded row).
1 Year, earliest possible year of FDA approval, but likely to be later.

2 Side effects were arbitrarily graded cumulatively by “+,” based upon one for short-course PR, two for long-course PR, and one for side effects of the DAA.

The anticipated availability, effectiveness and tolerability of future regimens are shown in the table on this page. If these projections are correct, many highly efficacious options for chronic hepatitis C could be available prior to or around the year 2015. Of course, projections are simply unproven speculations — at best,they are educated guesses. Emergence of unexpected toxicity or failure to achieve the projected rates of SVR may withdraw a drug from consideration and delay drug development for chronic hepatitis C.

On the other hand, assuming the drugs are safe and effective, future treatment regimens with a shorter duration, higher chance for SVR and fewer side effects will soon be available.

Patients ask, “Is it safe to wait?”
Their concerns regarding the recommendation to wait for future treatment include the potential for progression of disease, development of cirrhosis, reduction in virologic response to treatment and development of hepatocellular carcinoma.

The stable, early stage patient (F0-F2) should be reassured by the fact that fibrosis progression is slow, around 0.1 fibrosis stage/year.8 Although it is true thatwaiting for three years could increase the stage of fibrosis by 0.3, this degree of change would not likely increase the risk for clinical deterioration or reduce the response to treatment. In contrast, the patient with F3/F4 fibrosis and poor response to PEGIFN/RBV has a greater immediate need for treatment.

Unfortunately, current triple therapy is least effective in this subgroup. But, the F3/F4 patient with normal bilirubin, albumin, international normalized ratio and platelet count should be somewhat reassured by knowing that the risk of clinical deterioration over three and a half years is only 2 percent.9 Unlike Beckett’s Godot,11 the new DAAs are truly coming, and soon. I would suggest that the patient who can wait, and is willing to wait, should consider waiting.

Dr. Everson is a consultant for or has advisory board agreements with Abbott, Bristol-Myers Squibb, Genentech, Gilead, Merck and Vertex. He is an equity member of HepQuant LLC. He received research support from Abbott, Bristol-Myers Squibb, Merck, Gilead, Pfizer, Roche/Genentech,
Vertex and ZymoGenetics

References

http://www.gastro.org/journals-publications/aga-perspectives/AGA_Perspectives_V8N3_Final.pdf


Note From The Editor
This issue heralds a new AGA year and the start of summer. For those of you who attended DDW ® 2012 and the AGA Spring Postgraduate Course, I hope you had a great meeting and enjoyed all that San Diego has to offer. To start the June/July 2012 issue of AGA Perspectives, our bimonthly point/counterpoint pieces discuss whether patients with hepatitis C virus should be treated now or wait for promising new drugs. Gregory Everson advocates for waiting while Donald Jensen and Archita Desai argue that treating now is the better option. To participate in this debate, feel free to join the discussion board online at gastro.org/discuss perspectives.
To continue the liver theme for this issue, Timothy Davern explores the topic of drug-induced liver disease, while my colleague Rohit Loomba explores the topic of who needs a liver biopsy with NAFLD, a condition that affects one-third of the adult U.S. population. Michael Charlton discusses the role of IL28B genotyping in the management of chronic hepatitis C virus infection.

I am also pleased that our international colleagues, Marcus-Alexander Wörns and Peter Galle examine the role of the hepatologist in prescribing treatment for managing hepatocellular carcinoma. (In case you think that keeping up on new developments in liver disease is just for hepatologists, it is worth remembering that liver disease questions make up one-quarter of the American Board of Internal Medicine GI board examination for those of you planning to take your boards for the first time or recertify.)

In this issue, we also feature two articles that focus on education. Brijen Shah and Suzanne Rose report on the newly created AGA Academy of Educators, while Art DeCross discusses his concern that attending physicians may also need some form of capitation on their work hours akin to what their trainees are afforded. (I am sure some of our readers may wish to weigh in with their own views on this topic.) I hope that those of our readers who are active in educating trainees of all levels will join the AGA Academy of Educators. I would also like to encourage our readers to become an AGA fellow if you have not already done so. Visit gastro.org/academyedu to join the academy.

Details on how to apply for AGA fellowship are available at gastro.org/aboutaga/aga-fellows-program.

It is my great pleasure to introduce our new (107th) AGA President, Loren Laine, and to have contributed to the article in this issue of AGA Perspectives.

I would also like to welcome Hashem El-Serag, the new editor-in-chief of Clinical Gastroenterology and Hepatology (CGH), and thank the outgoing CGH editor, Mel Wilcox and his board of editors for their hard work.

Best wishes for a nice summer.