The basis of cancer is genetic, using hepatitis B virus to illustrate the case

The main theme of this post is to say “the basis of cancer is genetic; the cancerous state is maintained by genes.”

The difference of germ cell mutation and somatic cell mutation  

Speaking of ‘genetic’, many automatically relate that it comes from parents and will pass along to children.  But, that is not the case.  There are two main types of cells: germ cells and somatic cells.  Germ cells are sex cells (gametes) that include sperms and eggs.  Each gamete contains one set of chromosomes (23).  When a boy (sperm) meets a girl (egg); they unite to form zygote (contains 2 sets of chromosomes or 46) which is the very beginning of an embryo.

Thus gamete (either sperm or egg) mutation can pass along to offspring, such as sickle cell anemia, cystic fibrosis or color blindness. Somatic (body) cells mutation will not pass along to offspring, but may cause cancer.

The basis of cancer is genetic                      

One needs to grasp two concepts to understand the story of why the basis of cancer is genetic:                              

(1)  Virus infection may lead to cancer; virus does it by ‘manipulating’ our genes.                                                 

(2)  Mutation of our genes (caused by virus or by chemical agents or radiation) leads to cancer.

Renato Dulbecco first demonstrated a viral infection may lead to cancer 

Dr. Renato Dulbecco

I wrote an obituary of Renato Dulbecco in February 2012 when he died, I called it “Remembrance (which is the obituary for Wall Street Journal): Renato Dulbecco”, to protest WSJ for not having a “Remembrance” for such a medical giant.

http://doctorjytsai.blogspot.com/2012/02/remembrance-renato-dulbecco-1914-2012.html

Dulbecco (at Caltech in 1960s) was the one demonstrated that DNA of a virus can integrate into the chromosomal DNA of the host cell, causing the uncontrolled cell growth, which is the genetic basis of cancer, and for which he was awarded a Nobel Prize in 1975, thus viral genes transform normal cells into cancer cells.

Michael Bishop and Harold Varmus (at UC Medical School at San Francisco in 1975) discovered the origin of so-called ‘cancer gene”, which is not of virus, but of our own gene.

Michael Bishop and Harold Varmus: The concept of proto-oncogene and oncogene 

Dr.Michael Bishop

If a given (human) gene is picked up and transduced/transformed by retrovirus (i.e. when cell is infected by retrovirus) into an oncogene, then this given human gene is called proto-oncogene.

In addition to virus being the culprit to transform a proto-oncogene to oncogene, certain chemical agents or radiation can cause a mutation of a proto-oncogene to become an oncogene, these chemical agents are called carcinogens, which are usually mutagens.

Michael Bishop and Harold Varmus worked on the Rous sarcoma virus (see the story later) in the early 1970s to make this discovery.  Even though the cancer is caused by virus, but the so-called ‘viral oncogenes’ are not truly viral at all but are of human genes in origin.  They discovered the retrovirus genomes are incorporated into the human gene and exploited to wreak havoc.  Michael Bishop and Harold Varmus were honored with Nobel Prizes in Medicine for this pivotal discovery in 1989.

Dr. Harold Varmus

The sequence of nucleotide in an oncogene can be different by only a single nucleotide from the sequence of the corresponding proto-oncogene, which is still normal and healthy.

Since the nucleotides sequence of a gene (DNA) is translated into the amino acid sequence of a protein the gene makes, so the sequence of amino acid of a oncogene protein [made by oncogene] can be different by only a single amino acid from the sequence of the corresponding proto-oncogene protein [made by proto-oncogene].

Dr. Peyton Rous

This is a good example that a single amino acid (among millions) goes astray can wreak havoc to cause cancer or sickle cell anemia.

Peyton Rous started it all 

Peyton Rous was honored with a Nobel Prize in Medicine in 1966, almost 40 years after he first discovered a virus (now bears his name) cause cancer in chicken.  This is the main reason why Michael Bishop and Harold Varmus picked Rous sarcoma virus to work.

A visit by Dr. Chih-Wen Lin whose article in the Journal of Hepatology prompted me to write this article article

Last week our friend, Dr. Chih-Wen Lin came to visit us from Taiwan.  有朋自遠方來，不亦樂乎。.  His article (“Heavy alcohol consumption increases the incidence of hepatocellular carcinoma in hepatitis B virus-related cirrhosis”) in 2013 Journal of Hepatology (see photo) prompted my writing of this article.

Dr. Lin is the Director of the Department of Gastroenterology at E-DA Hospital/I-Shou University in Kao-Hsiung, Taiwan.  Their data showed that the 5-year cumulative incidence of hepatocellular carcinoma (HCC) is 10.7% in alcoholic cirrhotic patients, and the alcoholic cirrhotic patients with concomitant hepatitis B virus (HBV) infection have significantly higher incidence of HCC (36.8%) than those with HBV infection alone or alcoholism alone.

The focus of this post is not to discuss Dr. Lin’s article, but to show you that alcoholic cirrhosis without HBV infection can also lead to HCC (liver cancer).  In fact, cirrhosis from steatohepatitis (the most severe form of fatty liver), hemochromatosis or Wilson disease can also lead to HCC, less frequent though it may be.

The mechanisms of liver cancer-making in hepatitis B and hepatitis C are different                

Up to 90% of patients with hepatocellular carcinoma are known to have chronic liver disease and cirrhosis, hepatitis B infection may be a rare exception; HBV can cause HCC in the absence of cirrhosis, in contrast to HCV-related HCC which is found almost exclusively in patients with cirrhosis.

Hepatitis B virus (a DNA-containing virus) is able to integrate its DNA into the DNA of the host cells to transform it into oncogene, whereas hepatitis C virus (an RNA-containing virus) doesn’t have this ability.

The mechanism of how HCC (liver cancer) is formed is quite heterogeneous and complex, hepatitis B and hepatitis C play a big role, but they are not the sole perpetrators.  Alcohol is an important cofactor in patients with either hepatitis B or C infection with cirrhosis that leads to HCC (liver cancer), the mechanism of which is not clear, or at least unknown to me.  I read somewhere that telomerase is even involved.

Dr. Baruch Blumberg: A towering figure in medicine, a humble scientist and a great man           

It would be remiss of me not to mention Dr. Baruch Blumberg while talking about hepatitis B.  He discovered Australia antigen, later proved to be hepatitis B surface antigen (HBsAg), the origin of hepatitis B infection in mid-1960s, leading to the Nobel Prize in Medicine in 1976. His memoir is “The Hunt for a Killer virus: Hepatitis B”, a fascinating story.

He also made the first hepatitis B vaccine that was used in Taiwan.  His The Lancet article (Nov. 1, 1969) connected hepatitis B related cirrhosis to hepatocellular carcinoma (primary liver cancer).  Another related article was also published on July 5, 1975 Lancet

Medicine is complex                                                                                                                          Like Oppenheimer told his students at U.C. Berkeley, “I can make it clearer, but I cannot make it simpler.”  I am hoping you would paraphrase Enrico Fermi that before you read this article, you’re confused, and after reading this article, you’re still confused, but at a higher level.

Hepatitis B: Dr. Baruch Blumberg: a great scientist and a great man

It would be an inexcusable omission if I do not mention Dr. Baruch Blumberg while talking about hepatitis B.  He discovered Australia antigen, later proved to be hepatitis B surface antigen (HBsAg), the origin of hepatitis B infection in mid-1960s, leading to the Nobel Prize in Medicine in 1976.

Blumbergs celebrating Nobel Prize in 1976

Dr. Baruch Blumberg died on April 5, 2011 (a Tuesday), we read NY Times obituary next day, but LA Times obituary showed up three days later (April 8).  The delay is embarrassing either uninformed or unprepared.  Blumberg is not household name; it took even LA Times three days to come up with an obituary.

Blumberg was a towering figure in medicine, whose study on polymorphism led to the discovery of Australia Antigen (hepatitis B virus).  He helped develop the test to detect the HbsAg to ensure the safety of blood transfusion; he also developed the first hepatitis B vaccine (first used in Taiwan)—truly the first cancer vaccine as preventing hepatitis B also prevents liver cancer.

The detailed story of how the genetic polymorphism research led to the discovery of hepatitis B surface antigen is beyond the scope of this writing.  Dr. Blumberg noticed that a hemophilic patient whose blood reacted with a stuff in the blood of an Australian aborigine; the “stuff” was then called Australia antigen.

D

Dr. Barusch Blumberg

r. Blumberg and his team observed that there was a high prevalence of positive Australia antigen among the institutionalized Down syndrome patients.  They documented a mentally retarded patient, James Bair, who developed hepatitis when his Australia antigen turned from negative to positive, strongly suggested hepatitis (it was then called serum hepatitis) is infectious and Australia antigen is the culprit.

James Bair’s parents allowed, in fact, encouraged Dr. Blumberg to use his real name, as they’re pleased their son had played an important role in the discovery of hepatitis B virus and infection.

Dr. Blumberg wrote a paper about this finding and submitted it to the Annals of Internal Medicine (the official publication of the American College of Physicians to which both Dr. Blumberg and I belong.  I on purposely put Dr. Blumberg and I in the same sentence, how about that :- ); the paper was rejected as it was felt this was just one of the many claims that HBV had been found.  The Annals editor later admitted the rejection was the biggest blunder the journal had made.

The term ‘serendipity” has been used in describing this story, implying “fortunate happening” and “pleasant surprise”.  But, Australia antigen and hepatitis B couldn’t be put together without Dr. Blumberg’s keen insight, relentless pursuit for the answer and intense intellectual passion.  After graduating from Columbia University Medical School, he obtained a PhD in biochemistry from Balliol College, Oxford University.  He studied physics and math before entering the medical school.

Reading his memoir (The Hunt for a killer virus Hepatitis B), I found Dr. Blumberg was such a kind and humble person.  He was as humble as James Watson was arrogant (he mellowed as he aged) and both are great scientists.

He was a co-owner of a farm in western Maryland that supplied beef for a local market. “Shoveling manure for a day is an excellent counterbalance to intellectual work,” he said.

One can only imagine how many millions of lives he saved or will save for generations to come by discovering Australia antigen (HBsAg).   His obituary in NY Times ended like this.

“Well, it is something I always wanted to do,” he said. “This is what drew me to medicine. There is, in Jewish thought, this idea that if you save a single life, you save the whole world, and that affected me.”

It may be a cliché the say many of the great scientists are Jewish.  Blumberg, Richard Feynman and Burton Richter, all came from Far Rockaway High School, a Jewish neighborhood in New York City (borough of Queens).  It is unprecedented that one high school produced 3 Nobel laureates. In fact, two were honored in 1976 (Blumberg and Richter).  Sadly Bernard Madoff was also an alumnus; sadly the school was closed in 2011.

Viral hepatitis: Questions and Answers

I will conduct a session of questions and answers:

Question 1
True story: A couple from Taiwan came to visit their son (who is a physician) and his family in the States.  The daughter-in-law wouldn’t allow them to eat in the same table, lest they would pass along the HBV to her children and herself, as they apparently had “hepatitis B”.  Do you think this daughter-in-law did the right thing to protect her family?

Answer
We do not know the serology status of the parents’ serology, but assume for the worst scenario that they had positive HBsAg and HBeAg with no antibodies, which means they had active viral replication with high infectivity.  The mode of transmission of hepatitis B is through blood/body fluid (viruses are present in blood, saliva, and semen), not the fecal-oral route.  It is perfectly safe to sit down to share the same dish in the same table.

The parents needed education that they cannot share tooth brushes or shaving equipment with others; they need to know how to handle the open wounds.  It is not necessary to have separate plates or cups but if the daughter-in-law so insisted, then it is OK to do so to please her.  Sometime I wonder would she do the same if it were her own parents. 

If one family member has chronic hepatitis B, then the rest of the family members need to take hepatitis B vaccine unless they already have HBs antibody.

Question 2
Rumor had it that the chef in one of your favorite restaurants has hepatitis B, shall you stop patronize the restaurant?

Answer
I am not aware any state law prohibits one with chronic hepatitis B or C to work in a restaurant as there was no evidence that one can get hepatitis B or C from a food handler without direct blood-to-blood contact.  The same is also true that a surgeon with chronic hepatitis B should be allowed to operate.

One may argue that the chef may be tasting the food and put it back to the pan while cooking, I certainly hope no chef (with or without hepatitis B) has this kind of practice.

Question 3
Is hepatitis B a sexually transmitted disease (STD)?

Answer
Yes, hepatitis B virus (HBV) is much more easily transmitted sexually than HIV or hepatitis C virus (HCV).

Although HCV is not efficiently transmitted sexually, the chance is not zero; it can happen, especially among HIV-infected persons.

Mode of transmission for hepatitis B in developed countries, such as USA, is IV drug use, STD and needle sticks, etc., whereas vertical transmission from mother to infant is the predominant way in Asia, including Taiwan.  Let’s not forget some got it from acupuncture.

Blood transfusion has been safe from hepatitis C in USA since 1992 when the test to detect HCV was developed.

Question 4
Vertical transmission: How the pregnant mother passes along the virus to the infant?

Answer
One may assume that HBV was passed from mother to the baby/fetus via placenta; wrong! That was not the case.  Observation has shown that it occurs during the child birth when mother’s body fluid comes in contact with infant’s mucosal membrane.  One study from China says only 3.7% was transmitted in uterus.

The high protective efficacy (95%) when the infant was given vaccine upon birth proves this is the case, if the fetus was infected while still in uterus, then the vaccination upon birth wouldn’t work as well.

Question 5
Why hepatitis A was not covered in your talk?

Answer
There is no such a thing as chronic hepatitis A.  The great majority fully recovered.  That is not to say we don’t have to take hepatitis A seriously.  Fulminant hepatitis A can be fatal, and the incidence of which seemed to be climbing for unknown reason over the past decade or two.

Infection by hepatitis virus triggers an immune response in our body.  When the immune response gets out of hand the killer T lymphocytes attack and destroy the infected liver cells.  Too much immune response is not necessary a good thing.  It is not due to the more virulent virus.

Question  6

What’s diabetes got to do with hepatitis B?

Answer

There were 29 outbreaks of hepatitis B in long-term care facilities in the States from 1996 to 2011, of these 25 involved adults with diabetes receiving assisted blood sugar monitoring.  This prompted Advisory Committee for Immunization Practice (ACIP—part of CDC) to investigate the risk of diabetics getting hepatitis B.

This led to ACIP recommendations in October 2011 that “hepatitis B vaccine should be given to adults with diabetes who are aged 19 through 59 years whether they live in a long-term facility or not.”

The data (of how susceptible ones with diabetes to hepatitis B) for those who are diabetics and are aged ≥60 years is less evident and the vaccination decision is at the discretion of the treating clinician.

Primary hepatitis B infections become chronic more frequently in immunosuppressed persons, such as hemodialysis patients and persons with HIV and diabetes.

(more questions to come!)

Viral hepatitis: The serology (diagnosis) of hepatitis B

How to screen and diagnose hepatitis C
A doctor orders hepatitis C antibody to screen for hepatitis, if positive then orders HCV RNA by PCR, if positive then diagnosis is confirmed, and that’s all there is to it. 

If hepatitis C antibody is positive and yet HCV RNA by PCR is negative, then it is most likely a false positive for hepatitis C antibody; another possibility is that one had hepatitis C and recovered.   This doesn’t happen often; recall about 85% of persons infected with HCV never recovered, thanks to the high mutation rate of the hepatitis C virus (HCV).  Having hepatitis C antibody doesn’t confer immunity or protection again because of the high mutation rate of the virus.  If virus (antigen) keeps changing, then the antibody cannot manage (match) it.

Hepatitis B serology is more complicated
Hepatitis B is a different and a more complicated story.  It has three different antigens: surface antigen (HBsAg), core antigen (HBcAg) and e antigen (HBeAg); each generates its antibody.

Dr. Baruch Blumberg was awarded Nobel Prize in Medicine in 1976 for his discovery of HBsAg as the origin of hepatitis B and for the elucidation of the mechanism of the infectious process.  When the virus invades us, the virus (foreign invader, the antigen) triggers an immune response.  When the battle was won, the body produces antibody and the antigen disappears.

This explains why up to 95% of infants infected with HBV from the mother cannot overcome the infection as the infant’s capability of immune response is not matured yet, whereas 90-95% of the infected adults recover.

HBsAg and HBs antibody
When one overcomes hepatitis B infection, the surface antibody appears and surface antigen (HBsAg) disappears.  HBs antibody confers immunity and protection, which means if one has contact with HBV again, one won’t get infected.

HBcAg and HBc antibody
Hepatitis B core antigen cannot be measured as it is inside the virus.  Hepatitis B core antibody simply means one was infected with HBV (recovered or not); it confers no immunity or protection.

Successful hepatitis B vaccination is confirmed when one develops hepatitis B surface antibody, not hepatitis B core antibody.

HBeAg and HBe antibody
The presence of hepatitis B e antigen signifies active viral replication.  Disappearance of e antigen is the goal of treatment, corresponding to the viral count to be undetectable level.  Discontinuation of therapy can be considered when that happens.

Now let's play a doctor
Armed with serology info, along with the knowledge of liver function and the viral count, one can tell various forms of hepatitis B infection, summarized by the table.

Acute hepatitis B

Positive HBsAg, no HBs antibody yet; hepatitis core antibody IgM may be present (IgM antibody is short lived, IgG antibody is long lasting that shows up later); HBe antigen is present, no HBe antibody yet; liver function is abnormal.

Recovered from hepatitis B

HBsAg disappears and HBs antibody appears, conferring immunity and protection; IgG HBc antibody presents, signifying infection by HBV, conferring no protection; HBeAg disappears and HBe antibody appears, signifying no more active viral replication; liver function normalizes.

HBeAg-positive chronic hepatitis B
HBsAg is still present and no HBs antibody produces, thus no recovery, no immunity; IgG HBc antibody presents, signifying infection by HBV; HBeAg is still present, still active viral replication and no HBe antibody produced; liver function remains abnormal.

HBeAg-negative chronic hepatitis B (a variant due to mutation)
HBsAg is still present and no HBs antibody produced, thus no recovery, no immunity; IgG HBc antibody presents, signifying infection by HBV; HBeAg is negative and HBe antibody positive, and yet active viral replication remains; liver function may or may not be normal.

Successful vaccination with hepatitis B vaccine

Presence of hepatitis B surface antibody confirms the successful vaccination

Inactive carrier

HBsAg is still present and no HBs antibody produced, thus no recovery, no immunity; IgG HBc antibody presents, signifying infection by HBV; HBe Ag disappears and HBe antibody appears, suggesting no active viral replication; liver function is normal.  Inactive carrier may still be able to pass along the virus to others, although the infectivity is relatively low.

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!

Viral hepatitis series: The viral replication, and viral replication only, is the thing

Dr. Liang asked me to give a talk about viral hepatitis at Taiwanese Bible Study last Saturday.  It is a timely talk on account of the recent dramatic success of treating hepatitis C with the direct anti-viral drugs, as Dr. Dienstag (of MGH) claimed “hepatitis C is the only chronic viral infection that can be cured.”  The hepatitis B treatment over the past 10 years is less impressive but certainly not far behind; good news is not lacking.

Katy sent a dispatch to World Journal reporting my talk of viral hepatitis

And of course, the topic was chosen because of the high prevalence of hepatitis B in Taiwan for which Taiwan cannot claim as a “developed” country.  We should take pride in the great contribution of Taiwanese medical profession to the understanding of viral hepatitis and the success of its treatment.

I’ll write a series of articles to cover this complex topic, each with a theme.

Oscar Wilde said “The play, and play only, is the thing”, and I say “The viral replication, and viral replication only, is the thing.”  I cannot over emphasize the importance of viral replication and its implication.

How hepatitis B virus (HBV) or hepatitis C virus (HCV) replicates

All viruses are either DNA or RNA wrapped inside a protein coat.  Once getting into liver cell, the virus removes its protein coat and enters the nucleus, integrating into host DNA, it is a covalent bond—a stronger chemical bond.  No wonder Dr. Baruch Blumberg (who discovered Australia antigen, was later identified as HBsAg) said “We have met the enemy and he is us.” The virus then takes over the “manufacture machinery”, making their own stuff; repackaged and new virion is released from cell.

We can measure the total number of virus in blood by doing a quantitative HBV DNA by PCR (for hepatitis B) or HCV RNA by PCR (for hepatitis C).  High numbers of virus is a reliable marker of active viral replication.

I’ll devote one article to the serology of hepatitis B.  Once the hepatitis B virus invades us, the liver cells mount an immune response, a defense, so to speak.  The foreign invaders, virus, whose various components that can trigger an immune response are called antigens: hepatitis B surface antigen (HBsAg), core antigen (HBcAg) and e antigen (HBeAg).  Having e antigen in the blood signifies active viral replication.

Of all things about hepatitis B or C virus infection, viral replication is the one matters most, everything else is the consequence of it.  Let’s talk about a few things to make a point.

The consequence of active viral replication

Pregnant mother with positive e antigen, active viral replication that is, has 90-95% chance of passing along the virus to the infant, whereas only 30% of the infants infected with the virus if the mother has no HBeAg in the blood.

Chronic hepatitis B patients with positive HBeAg tend to have disease progression, leading to cirrhosis of liver and have higher risk for hepatocellular carcinoma (liver cancer).  Viral replication is the driver for liver injury.

Suppressing viral replication changes the natural history of the disease.  Active viral replication is the main indication of treatment and the goal of treatment is to achieve the sustained viral suppression; call it “cure” if you will.  So the loss of HBeAg or seroconversion (loss of HBeAg and appearance of Hepatitis B e antibody) is a wonderful thing and may be safe to discontinue therapy.

One may not fully recover from hepatitis B by having positive HBsAg (without HBs antibody) and positive HBc antibody, which indicates infection of HBV.  But one can be an inactive carrier, which is defined as no active or progressive liver disease, the liver function should be normal and hepatitis B e antigen should be negative with no active viral replication and hepatitis B e antibody positive.