Pirates flying on brooms to make sweeps

Pittsburgh Pirates has ten (10) sweeps so far and it is not even the All-Star Game break yet; I think it is the best for all the MLB teams.  We see plenty of brooms around in PNC Park nowadays.  When Pirates went to San Francesco (June 1-3) or Chicago (June 17-18) to sweep the Giants and the White Sox, they didn’t take airplanes; they flew with the brooms.  They also swept White Sox in PNC Park on June 15-16.  If I were a cartoonist; that is what I will draw: Pirates flying on brooms!

 

Pirates may not be witches, but they’re as scary.

 

Pirates flying on brooms on the way to cities to be conquerred

Speaking of the statistics Pirates closer Mark Melancon has had 28 saves, the most in National League and the second most among all MLB closers.  It has been nearly two months since Melancon allowed an earned run.

 

A.J. Burnett

With an ERA of 1.99 Pirates pitcher A.J. Burnett has the second lowest ERA among all MLB pitchers, I think he was the lowest at one time.  Recall Burnett took a $4 million cut to leave Philly to come to Pittsburgh, declining the $12.75 million a year that Philly offered to accept $8.5 million Pittsburgh did.  It is obviously not the money alone, chemistry was involved.

 

At age of 37 Burnett has said this will be his last season and he is going to the All-Star Game for the first time in his 17-year career.

 

The other three Pirates going to the All-Star game are: Pitcher Gerrit Cole, close Melancon and Andrew McCutchen, five years in a row, not seen since the Pirates legend, Roberto Clemente did in 1960-67.

 

On a sad note is that Pirates beloved Josh Harrison just underwent surgery to repair the torn ulnar collateral ligament of his left hand.  He’ll be out of commission for about two months, hopefully will be ready for the off season.

Harrison got hurt slipping onto the plate

 

 

 

Raise the Jolly Roger at PNC Park on July 4th

As of July 6 Pittsburgh Pirates is the second best team among all the 30 Major League Baseball (MLB) teams.

With the winning percentage .585 (14 games above .500), it is only 5 ½ games behind the MLB best, St. Louis Cardinals.  It is the second best of the National Leagues, also beating the best team of American League; Kansas City Royals with the winning percentage .582.

We’re at PNC Park to see the Pirates beat Cleveland Indians on July 4^th.  Next evening Pirates’ Pedro Alvarez had a hilarious game-ending hit at a two-out, 3-2 pitch, beating his father-in-law, who is the interim manager of San Diego Padres.

Let’s Go, Bucs!

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.

The joy of gardening: beauty in the making

While working in the garden, I got a call from Jo, who wanted me to stay well hydrated; I said I am as hydrated as the flowers and vegetable are.  They are healthy and happy, so am I.

Many of the walkways in the garden are being re-routed, as are the water supply system; this is part of the infrastructure of the garden.

Much of the garden work is weeding; how could one derive enjoyment from weeding?  It is part of the process of creating something beautiful.  It is not yet beautiful, but beauty is in the making.  These photos can attest to it.

Suddenly, Last Summer; nay, Suddenly, This Summer.

I watched the movie, “Suddenly, Last Summer” before I came to the States (I still remember the Chinese name of the movie, 夏日痴魂).  It was adopted from a Tennessee Williams’s play; screenplay by Gore Vidal; played by Elizabeth Taylor and Montgomery Clift.
 
But, I am not talking about “Suddenly, Last Summer”, as I just realize Suddenly, This Summer is here.  Summer came early this year and we’re caught late with our late spring planting of snow peas and 冬莪 or 茼蒿; Some Like It Hot; they don’t.  The 冬 of 冬莪 is “winter” and "snow" pea, the name says it all.  They may survive, but not thrive in such a hot weather.

冬莪 or 茼蒿: just planted

 

snow peas

 

春耕

The first photo is the art work of my younger brother a few years ago, showing the evolutionary change of our garden.  The rest were taken today.  The garden grew and changed, the hard work is the same.