Viral hepatitis series: The amazing success of hepatitis B and C therapy

(Some of the Power Point slides are taken from Dr. Jules Dienstag’s lecture that I attended in Boston on June 13)

The mainstay of hepatitis B and C treatment has been interferon (or pegylated interferon) and ribavirin over the years, and they can achieve sustained viral suppression (SVR) 40% at best with significant adverse effects and longer duration of therapy needed.  SVR is defined as no virus detectable 3 months after completion of therapy; call it “cure” if you will.

The astonishing effects of direct-acting antivirals (DAA)

The breakthrough came in 2001 for hepatitis B (2011 for hepatitis C) when direct-acting antivirals (DAA) became available.  SVR is close to 100% for hepatitis C, leading Dr. Jules Die stag of MGH to utter “hepatitis C is the only chronic viral infection that can be cured”; that of hepatitis B is less impressive, but not far behind, SVR reaches 80%.

The Power Point slide (below) shows the decline in the need for liver transplant for end-stage liver disease secondary to hepatitis B in USA.  The same benefit will be realized for hepatitis C later as the DAA for it came 10 years after that for hepatitis B did.

Numerous studies have shown that hepatitis C or B therapy and achieving an SVR can slow or even reverse the progression of the liver injury, resulting in dramatic decrease in hepatic decompensation, cirrhosis and hepatocellular carcinoma (liver cancer).

Another fringe benefit of DAA therapy is the resulting SVR will reduce infectivity, decreasing the chance of passing along the virus to others.

Treating e antigen negative chronic hepatitis B is a challenge

Hepatitis B e antigen signifies active viral replication, thus the loss of it or seroconversion (loss of hepatitis B e antigen and the appearance of e antibody) can be treated as an indication of stopping the treatment. 

In the natural history of hepatitis B the disappearance of antigens (surface or e antigen, i.e. viral components) and appearance of antibodies (surface, e and core antibody) suggests one has fully recovered.  Hepatitis B surface antibody confers immunity and protection; hepatitis B core antibody indicates one was infected with the disease, but confers no protection; hepatitis B e antibody is supposed to mean no more viral replication.

But thing is more complicated than it seems; there is a variant of chronic hepatitis B that is e antigen negative due to the mutation of the virus.  Active viral replication and disease progression continues despite negative e antigen.  This variant is more prevalent in Europe and cases have been increased in USA in recent years.  Taiwanese doctors contribute to the understanding of this dreaded hepatitis B variant.

As I mentioned that loss of hepatitis e antigen may indicate it is OK to stop therapy; in case of e antigen negative chronic hepatitis B there is no such a marker, and the therapy may need to continue indefinitely.

Translational research accelerates

The hepatitis C virus was just discovered about 25 years ago (it used to be called non-A non-B).  Like hepatitis B virus, the research of it was initially hampered as it cannot be grown in Lab; this was overcome by recombinant technology.  The amazing details of how hepatitis C virus replicates leading the direct-acting antivirals to target and develop an arsenal of powerful drugs such as NS3/4A protease inhibitor, NS5B polymerase inhibitor and NS5A inhibitor.  This is the perfect example of pharmaceutical companies reap what basic biomedical science sows.

This is unprecedented that the basic science research can be so rapidly “translated” into clinical medicine.  FDA deserves some credit by allowing phase 2 studies of all oral regimens without standard-of-care comparators, thus speeding the drug developments.

In his Perspective ("Curing Chronic Hepatitis C -- The Arc of a Medical Triumph") in NEJM (April 24, 2014), Dr. Raymond Chung of MGH points out a unique characteristic of hepatitis C virus that unlike HIV, it doesn’t replicate by using reverse transcripitase, instead it replicates its genome directly into RNA without traversing a DNA intermediate, so it lacks a latent, nuclear form that defies ready immunologic clearance.  It requires continuous replication for its existence.  This observation helps scientists to design drug to permanently clear the virus.

New hepatitis C drugs owe their success to HIV research

The success of the developments of HIV drugs propels the research of developing drugs against HBV and HCV.  Telaprevir and boceprevir are protease inhibitors for HCV, thwarting the activity of a key viral enzyme.  Saquinavir was the first protease inhibitor for HIV treatment back in 1995.

The concept of the combination of two or more classes of drugs also came from HIV experience.  One recalls Dr. David Ho (who came from Taiwan is his teenager years) was named Time magazine’s Man of the Year in 1996. He was the first to use combination if various HIV drugs to achieve the resounding success.

Examples of combination regimen for hepatitis C are: ledipasvir + sofosbuvir (cure rate approaches 100%); paritaprevir + ritonavir + ombitasvir; sofosbuvir + simeprevir.  Currently sofosbuvir, in combination with ribavirin is recommended for genotype 2 and 3 HCV; genotype 3 remains a challenge.

Contribution of Taiwanese medical profession to the hepatitis B therapy

Taiwanese medical community participated in many clinical trials of treating hepatitis B and C, and often plays a leading role. A 2004 NEJM article shows Lamivudine slows the progress of hepatitis B liver disease (長庚醫院).  However, the use of Lamivudine has been greatly limited because of the development of significant resistance, manifested by resurging viral replication.

National Cheng Kung University Medical College (成功大學醫學院) also played a leading role in a 2006 NEJM article comparing Entecavir and Lamivudine for HBeAg-positive chronic hepatitis B.

Entecavir or Tenofovir is currently recommended for treating chronic HBeAg-positive or HBeAg-negative hepatitis B.  However, Telbivudine is no longer recommended.

The good news and the bad news

The good news is the steady improvement of sustained viral suppression (SVR) in treating hepatitis C. A six-month use of interferon achieved a merely 6% in 1991, reaching 70+ % when DAA arrived in 2011 and 95% last year, news drugs in the pipeline and new combination will promise nearly 100% SVR and the duration of therapy will be truncated to 12, 8 or even 6 weeks.  The landscape is rapidly changing, making one dizzy and confused.

The bad news is the exorbitant costs of new direct-acting antivirals for chronic hepatitis C (see the table).  One of the Power Point slide in my talk bearing a title of “Why developing hepatitis C drug?  Because it is where the money is!”

One slide shows the stock price of Gilead Science, reflecting the success of its DAA.  Another slide shows Achillion making splashing news on NASDAQ; the Janssen (a Johnson & Johnson co) will invest $1.1 billion to the company.

In the end the big insurance companies, such as United Health or Aetna, will negotiate and pay a reduce fees.  WHO is urging the pharmaceutical co to lower the prices so that the less fortunate developing countries can afford the treatment.

Many suits against Gilead Science for the patents of its DAA have been filed.  I am personally less critical of its exorbitant prices, outrageous though it may be $1,000 a pill), as this is a very furiously competitive and risky field, a given drug may enjoy the success for a brief period of time, only to be replaced by another star drug in no time.

Telaprevir and boceprevir have fallen out of favor because of their adverse profiles, especially anemia and neutropenia.  Telbivudine is no longer recommended to treat hepatitis B.

Another argument to condone the high prices of direct-acting antivirals (DAA) is that taking care of one with end-stage liver disease or liver cancer is very expensive and DAA saves life; life is priceless, and only sustained viral suppression saves life!