World Hepatitis Day: reason to celebrate

By Paul Sax

After years of intense basic and clinical research, hepatitis C is now curable for the vast majority of the millions of people who have it. The major barrier is access (diagnosis, getting care, and paying for it), because the scientific problem has been solved.

Not only that — but the situation will soon get even better.

For those who haven’t followed this medical miracle closely, here’s a Spark Notes version to bring you up to speed:

Pre-1989: Many blood transfusion recipients, injection drug users, and people with hemophilia have a form of chronic hepatitis, but they test negative for hepatitis A or B. Their infection is cleverly called “non-A, non-B hepatitis,” kind of a placeholder for a future discovery.

1989: A government-industry collaboration discovers the virus that causes “NANB hepatitis” (as it is sometimes further abbreviated). Good thing for that placeholder, because the new virus is called “hepatitis C”, abbreviated “HCV.” A few years later, a reasonably accurate blood test arrives, helping protect the blood supply and also giving us a much better sense of the natural history of HCV (generally slow but progressive liver disease), and finding a vast number of people infected, most of them unaware of it.

1990s: Remarkably, interferon therapy alone sometimes cures hepatitis C. That’s right, cures it. Unlike HIV and hepatitis B, HCV has no phase where it’s integrated into the host genome, so clearance of the virus completely occurs, provided the host and treatment factors are right. That’s the good news, but the rest, not so much: cure rates are terrible (generally <10% for genotype 1, the most common form in the United States), interferon has to be injected three times a week, and, perhaps worst of all, side effects are legion — fatigue, fever, muscle aches, anorexia, depression, irritability — and tend to worsen over the year or so of required therapy.

Late 1990s: Ribavirin — a mysterious antiviral whose mechanism of action still remains unclear — is added to interferon treatment, boosting cure rates up to 30-40% for genotype 1, 70% or higher for genotypes 2 and 3. Cause for celebration? Usually not, for several reasons: ribavirin has its own tricky side effects (hemolytic anemia, for one, and severe teratogenicity), so treatment is even more difficult than with interferon alone. Furthermore, the viral kinetics of successful treatment remain poorly defined, and hence patients are often given months of toxic therapy before it is ultimately stopped for “futility”.

Early 2000s: Attaching polyethylene glycol (PEG) to interferon greatly slows its clearance, so injections are now required only once a week. These “pegylated” forms of interferon plus ribavirin increase cure rates a bit further, as the reduced frequency of injections markedly improves adherence. (They also engender one of the best trade names ever for a drug – what marketing genius thought of Pegasys?) Side effects, alas, are no better. “I feel like I’m slowly killing myself,” says one of my patients, memorably, as he abandons treatment after 36 weeks of fatigue, snapping at his wife and co-workers, and general misery because his blood tests still show a bit of detectable virus – with no guarantee that continuing on to week 48 will cure him.

2011: The first “directly acting antivirals” (DAAs) are approved, the HCV protease inhibitors boceprevir and telaprevir. For patients completing treatment with these drugs — again, in addition to interferon and ribavirin — cure rates for genotype 1 reach 70-80%. Certainly a big improvement, yes, but a few major caveats: first, though the treatment can sometimes (but not always) be shortened to 24 weeks with these three rather than two drugs, interferon and ribavirin side effects remain extremely problematic, with some of them (in particular the cytopenias) made even worse. Second, these first-generation protease inhibitors have their own set of nasty toxicities (anemia, rashes, taste disturbance, diarrhea, pain with defecation — another memorable patient quote: “I feel like I’m shitting glass shards.”) Third, both drugs have a high pill burden and, with telaprevir, stringent food requirements, making adherence extremely challenging.

Given the limitations of interferon (pegylated or not), ribavirin, telaprevir and boceprevir, it’s not surprising that many clinicians and patients decide it’s best to wait for better treatments to come. In fact, the cure rates from clinical trials are huge overestimates of the proportions actually cured in clinical practice, since there is intense clinician and patient self-selection about who should launch into these tough treatments. Meanwhile, research is proceeding rapidly (competition in this field is a good thing) to find other anti-HCV drugs, and several promising early clinical trials results are presented at academic meetings.

The practical culmination of this research finally arrives in late 2013 with the approval of first simeprevir — another protease inhibitor, only given as just one pill a day and with very few side effects — and, a few weeks later, sofosbuvir. The first HCV nucleotide polymerase inhibitor, sofosbuvir is also one pill a day, is highly potent, has few side effects or drug interactions, and is so effective it can help you get a better deal on your car insurance. (That last part was made up, but for the price — $1000 a pill — sofosbuvir better be pretty good.)

Simeprevir and sofosbuvir have been studied together in the COSMOS study and the bottom line is that more than 90% of genotype 1 patients are cured with 12 weeks of therapy. Some of the patients in COSMOS received no ribavirin, and most importantly none received interferon. It’s a small study, yes, and so we can’t take that response rate as applicable to everyone – some very difficult to treat individuals have already failed “SIM-SOF,” as the combination is being called by the HCV cognoscenti. But both in the clinical trial and thus far in clinical practice, this two-pill, once-daily regimen has shockingly few side effects.

So what’s next? How can this happy state of affairs get even better? Within the next 12 months, we’ll have a combination pill that gives HCV treatment as one pill a day. Some patients will be cured in 8 rather than 12 weeks. Other options (here and here) will arrive that have the same astounding cure rates – because a greater than 90% response is the price of entry into this HCV treatment arena. It’s hoped (and expected by many) that these expanded options will bring the cost of HCV therapy down, because that’s the way markets are supposed to work.

More than 90% cured. Sure beats the 9% rate from the interferon-only days.

And that, my friends, is reason to celebrate World Hepatitis Day.

Paul Edward Sax, MD is Clinical Director of the Brigham and Women’s Hospital and Professor of Medicine, Harvard Medical School. He is the editor-in-chief of the Infectious Diseases Society of America’s new peer-reviewed, open access journal, Open Forum Infectious Diseases (OFID).

Open Forum Infectious Diseases provides a global forum for the rapid publication of clinical, translational, and basic research findings in a fully open access, online journal environment. The journal reflects the broad diversity of the field of infectious diseases, and focuses on the intersection of biomedical science and clinical practice, with a particular emphasis on knowledge that holds the potential to improve patient care in populations around the world.

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Image: World Hepatitis Day logo via World Hepatitis Alliance.