Paradigm Shift
Back in 2006, the CEO of Vertex Pharmaceuticals told the investment community and the media that the company's hepatitis C protease inhibitor promised to usher in a new era in hepatitis C treatment due to its potency. He claimed that telaprevir, their experimental drug, could potentially shortening treatment for people with genotype 1 from 48 weeks to only 12 weeks, with very high success rates. These claims were backed by very preliminary data showing that telaprevir was highly potent, reducing hepatitis C viral load to very low -- often undetectable -- levels in a matter of days.
This was hype. The company was clearly and genuinely excited about the drug -- I saw that when I talked with researchers working on it. And justifiably so. But in the annals of drug development, new drugs never look so promising as in the early days of research. As more research gets done, with more people taking the drug for longer periods of time, we start to see the drawbacks, tempering the optimism with the realities of data.
This pattern holds true for telaprevir. In late 2006, Vertex announced data that showed a disturbing, heretofore unseen, side effect -- rashes, in some cases severe enough to warrant discontinuation of treatment (for some drugs, such as the HIV medication nevirapine, rashes can be potentially life-threatening, and so they require carefully monitoring). More recently, the company presented preliminary data at a major scientific meeting this spring analyzing people who took telaprevir in combination with pegylated interferon and ribavirin for 12 weeks, and then were followed up for an additional 20 weeks to assess virological response. A sustained virological response (SVR) -- increased considered tantamount to a cure -- is defined as undetectable viral load 24 weeks after the end of treatment. Some people who achieve undetectable viral loads during treatment experience a viral rebound after treatment -- hence the assessment 24 weeks post-treatment. 20 weeks post-treament is a reasonable proxy for sustained virologic response rates, since in most cases viral rebound seems to happen in the first 12 weeks off treatment.
These preliminary results were discouraging. While the numbers of people studied were small, they indicate that only roughly a third of people undergoing the 12-week course of triple-combination treatment with telaprevir had an undetectable viral load 20 weeks post-treatment. Most likely, telaprevir will require at least 24 weeks of triple-combination treatment in order to achieve high sustained virologic response rates, and the incidence and severity of rashes as a side effect continue to warrant concern.
Further data on telaprevir will become available in the coming months. Telaprevir is still an experimental drug, available only in research studies; Vertex is expected to initiate large phase III studies -- the final phase of research prior to submitting new drugs to FDA for approval -- by 2008. In theory, if Vertex demonstrates that telaprevir is safe and effective, it could be come available by late 2009 or, more likely, 2010. Until then, the only way to obtain this drug is through participation in company-sponsored clinical trials. People wishing to join a clinical trial studying telaprevir -- or any other experimental drug -- should think carefully about the potential risks and benefits, many of which will remain uncertain (i.e., unexpected side effects) until further research has been conducted.
What would a true paradigm change in hepatitis C treatment look like? In my opinion, Joshua Bolger (the Vertex CEO) is correct in asserting that a 12-week course of treatment with very high success rates (say, in the 80-90% range for sustained virological responses among people with genotype 1) would represent a radical transformation -- especially if the medication regimen does not pose too high a risk of side effects. All of the new drugs in development that directly target the hepatitis C virus -- primarily protease inhibitors and polymerase inhibitors -- will only be used as part of combination therapy. In the near future, that means that they will each be added on to pegylated interferon and ribavirin, though many hope that when enough new drugs become available we may be able to eliminate first ribavirin, and ultimately interferon altogether.
Thus, the first wave of new drugs approved to treat hepatitis C will not reduce -- and may potentially increase -- the number and range of side effects that people experience on treatment from pegylated interferon and ribavirin. These side effects are a large deterrent to treatment for many people, and even many of those who initiate treatment find that they need to discontinue when they can't tolerate the side effects. Doctors have become better and more aggressive at managing many of these side effects, and people who have been through treatment have learned and shared many tips and strategies for managing side effects. Still, uptake of hepatitis C treatment remains limited by concern about side effects -- and the addition of a third drug is only likely to add more side effects into the mix.
Nevertheless, the prospect of shortening treatment from 48 weeks to 12 weeks may alter the risk/benefit ratio regarding side effects for people considering treatment. The prospect of having to undergo only 12 weeks of side effects rather than a full year -- while not ideal -- may be the tipping point that shifts many people's willingness to undergo treatment in the first place. Especially if the other side of the risk/benefit ratio -- the likelihood of treatment success -- increases. For people with genotype 1, slightly less than half of people who undergo 48 weeks of treatment will achieve an SVR. Many people, including African Americans and people co-infected with HIV, have a substantially lower prospect of success -- in the 20-25% range. If a new drug, in combination with pegylated interferon and ribavirin, doubled the chances of success (to 80-90% for people with genotype 1 overall, and to at least above 50% and ideally higher for African Americans and people with HIV), I'm betting that many more people would be willing to undergo treatment -- especially a course of treatment only lasting for 12 weeks.
Rates of hepatitis C treatment in the U.S. -- the overall number of people who start treatment each year -- have been relatively flat for several years now, estimated at roughly 100,000 (though this number may be inflated). Yet the need for treatment is increasing -- as people with hepatitis C get older, an increasing number are projected to develop cirrhosis, and mortality rates due to hepatitis C are expected to climb steadily over the next decade. Unless more people are successfully treated, more people will die from hepatitis C-related liver disease -- indeed, the number of deaths due to hepatitis C is projected to exceed the number of HIV-related deaths in the U.S. by the year 2020. The time to act is now.
Other factors limiting the uptake of treatment include the limited number of doctors -- primarily liver disease specialists -- who treat hepatitis C. Much of this is due to the perceived complexity of hepatitis C treatment, particularly with regard to managing side effects, which discourage most primary care physicians from offering treatment to their patients -- instead, they typically refer their patients to a liver disease specialist for evaluation and follow-up. Part of this is also related to the perception that not everyone with hepatitis C should be treated -- the high incidence of side effects, coupled with the relatively modest success rate (and the fairly high cost of treatment), leads many doctors to discourage people from treatment unless absolutely necessary. Necessity is primarily judged by evaluating the degree of liver disease present, as measured by a liver biopsy. Biopsies are specialized procedures not performed in most community health centers or primary care physician offices, requiring referral to a specialist (i.e., a hepatologist or, increasingly, interventional radiologist). Many patients decline or avoid biopsies, in part because they are invasive and often painful procedures. Hence, many do not complete a full evaluation for treatment, or follow up with referrals from their primary care doctors to specialists -- and hence fall through the cracks.
In recent years, many researchers and companies have attempted to develop non-invasive alternatives to liver biopsy as a means of evaluating liver disease. Most of these efforts take the form of blood tests. Debate rages on about the accuracy and value of these tests, but significant progress has been made -- many of these alternate tests have proven very accurate at detecting either very advanced liver disease (i.e. cirrhosis, or very advanced fibrosis) or very minimal liver disease. The former would indicate an immediate need for treatment; the latter would indicate that treatment can be safely deferred. In general, these alternate tests are much less accurate for evaluating people in the middle stages of liver disease -- and for this group, a liver biopsy is still recommended.
The broader use of these blood tests may bridge the gap between primary care physicians and liver disease specialists -- the primary care doctor can offer a blood test as a preliminary evaluation of liver disease to their patients, rather than completely deferring all evaluation to specialists. While the information yielded by these tests is limited, they may provide enough information to encourage people with hepatitis C to take the next steps in considering treatment.
The paradigm shift we envision here -- 12 weeks of treatment with high success rates and tolerable side effects -- may reduce the need for liver biopsy even further. By comparison, people whose strain of hepatitis C belongs to genotype 2 or 3 already have very high success rates after only 24 weeks of treatment, in the 70-90% range (somewhat lower, but still quite high, for people coinfected with HIV). As a result, most doctors do not require a liver biopsy before treating people with these genotypes, because the risk/benefit ratio is so favorable. If new drugs led to a similar or even better risk/benefit ratio for people with genotype 1, the recommendation for liver biopsy as a critical step in treatment evaluation may ultimately disappear. One caveat -- hepatitis C treatment is already quite expensive (around $20,000 - $30,000 for a full 48-week course of pegylated interferon and ribavirin, possibly higher if other drugs are prescribed to manage side effects). Early indications suggest that new drugs marketed to treat hepatitis C will likely be priced quite high, potentially adding to the total cost of treatment. If these drugs are priced sufficiently high, insurers may limit reimbursement for treatment to only those with more advanced liver disease -- hence, reinstating the requirement for liver biopsy (or a suitable alternative) as a cost-saving measure.
Research from people with hepatitis C genotype 2 and 3 has demonstrated that a 12 week course of treatment can result in high sustained virologic response rates. While the current standard of treatment for these genotypes is 24 weeks, many studies have attempted to assess whether shorter courses of treatment -- in the range of 12-16 weeks -- is equally effective. The benefits of shorter durations of treatment would consist of lesser exposure to side effects, as well as cost savings. Many of these studies have focused on people deemed to have a rapid virologic response -- that is, their hepatitis C viral load becomes undetectable within the first four weeks on treatment. The latest research suggests that 24 weeks is still the optimal length of treatment for people with genotype 2 or 3 (and a full 48 weeks of treatment is recommended for people with those genotypes who are also co-infected with HIV). However, a very high number of people completing only 12-16 weeks of treatment in these studies still achieve an SVR (the 24-week recommendation resides in the observation that this length has the highest success rate, though the differences in percentage of SVRs are relatively small). In other words, data from people with genotype 2 and 3 offer compelling proof of concept that -- given sufficiently potent and effective drugs -- many people will only require 12 weeks of treatment to achieve a sustained virologic response. The challenge lies in finding a sufficiently potent and effective drug regimen that achieves this success rate in 12 weeks for people with genotype 1, and especially for people with poorer chances of obtaining an SVR with currently available therapy (again, African Americans and people with HIV in particular).
Lastly, many people with hepatitis C have not been tested or diagnosed, and remain unaware of their infection. While the availability of hepatitis C testing in community settings -- including needle exchange programs -- as well as health departments, substance abuse treatment programs, and even jails and prisons has increased in recent years, less than half of people with hepatitis C -- and perhaps as few as a third of the 3-4 million people chronically infected in the U.S. -- know that they have hepatitis C. Most doctors do not routinely test for hepatitis C, nor do they routinely ask about potential risk factors such as a history of injection drug use. Current guidelines do not recommend routine testing, and general knowledge and awareness of hepatitis C remains limited.
Many advocates are working to change this, by promoting testing and conducting local education and awareness campaigns. The need for a high-profile, national public education campaign to raise the profile of hepatitis C and encourage testing has been a prime agenda item for hepatitis C advocates for many years now. Despite some inroads and progress, lack of sufficient funding has hampered efforts to raise awareness on a national level.
Even national awareness would not automatically translate into increased testing and diagnosis -- particularly for those, such as drug injectors, with high rates of hepatitis C but limited access and utilization of health care. Fortunately, a rapid oral hepatitis C test -- similar to currently available HIV tests that provide results in 20 minutes and do not require drawing blood -- is currently in development and being tested. Ideally, this test would become available in the next year or two, and allow community-based groups and outreach workers to make hepatitis C testing available much more widely in a greater number of settings outside of health care facilities. Assuming the test is sufficiently accurate for widespread use and priced reasonably, the challenge will lie in securing adequate funding to expand community-based testing initiatives, while ensuring that people diagnosed with hepatitis C are connected to medical care. The latter is particularly important, given that the rapid oral test -- like hepatitis C blood tests currently in use -- detects only antibodies to hepatitis C, which indicate that a person has been infected with the virus but not whether they remain chronically infected. Given that roughly 20-30% of people infected with hepatitis C clear the virus on their own (without treatment, thanks to their immune system), follow-up testing that detects whether or not the hepatitis C virus remains present in the blood is necessary for an accurate diagnosis of chronic infection (whether a person currently remains infected -- and should undergo an evaluation for extent of liver disease and potential need for treatment). The follow-up blood test to diagnose chronic (current/active) hepatitis C infection is only available in a doctor's office or clinic -- in general, community-based programs and health departments that operate HIV/STD/hepatitis C testing sites do not provide this test.
I do believe that we are poised on the edge of a paradigm shift in hepatitis C -- though I do not expect this shift to fully arrive until the next decade. For me, this shift would usher in an era of highly effective, well-tolerated, short-term treatment. In turn, this would result in more people seeking treatment -- and a broader range of clinicians, including primary care doctors, offering treatment. Ideally, this new paradigm would encourage more testing and diagnosis, and reduce the stigma of the disease. Ultimately, the combination of all of these factors would dramatically reduce hepatitis C-related mortality and associated suffering from advanced hepatitis C-related liver disease.
I spend a lot of time thinking about what this new paradigm would look like -- and what we have to do to get there -- because I am pessimistic about the prospects for improving the response to hepatitis C among current and former drug users under the current paradigm. I see many signs of progress on local levels -- community-based organizations educating and testing drug injectors, progressive clinicians developing models of multi-disciplinary care to treat people with drug use histories, substance abuse treatment facilities (particularly methadone programs) incorporating hepatitis C into their mission and services, hepatitis C advocates taking on harm reduction and issues related to drug injectors in their work and advocacy. But in terms of reducing disease and mortality, we ultimately need better treatments -- and nobody needs them more than people with histories of drug use. While current and former drug users can be successfully treated for hepatitis C, they are profoundly affected by all of the barriers that I outline above -- fear of side effects, few completing evaluation for treatment, limited access to doctors providing treatment. As we strategize, innovate, and advocate for change and improvement in local responses to hepatitis C among drug users, we must remember that true, broad-scale transformation will almost certainly require a fundamental paradigm shift. New hepatitis C therapies -- or better alternatives to biopsy, or a rapid oral hepatitis C test -- won't guarantee that transformation, but they will facilitate it.
The rest will be up to us. We must all commit to making sure that the paradigm shift, when it comes, benefits everyone -- including current and former drug users, and others at the margins of society and the health care system.
W
