Okay so it’s a bit weird “celebrating” a nasty viral infection, but the emphasis of World Hepatitis Day is to draw people’s attention to hepatitis and as you’ll see in the case of Hepatitis C, there’s actually a lot to celebrate, so please read on…
Lots of patients admitted to hospital have blood tests done, and many of these include liver function tests (LFTs). The LFT is a bit of a misnomer, there is very little to do with liver function in the LFT and more to do with liver damage. Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) are all liver or biliary enzymes that increase if the liver is damaged. If you are lucky your LFT result might come with an albumin which gives you some idea about the liver’s ability produce proteins, which does therefore show how the liver is functioning, but in my opinion “liver function test” is still not a great name.
So a sick patient has their LFT done and the AST and ALT are elevated which prompts the doctors looking after the patient to ask if the patient might have hepatitis. The wise senior in the team tells the junior to do a “hepatitis screen” but what does this actually mean? The “screen” tends to look for the 3 common causes of viral hepatitis’; A, B and C.
The 1st line tests in a hepatitis screen include:
The results came back as: “anti-HAV IgM negative, HBsAg negative, anti-HCV negative”, the junior looked perplexed at the result but saw the Microbiologist on his ward round and asked “Is this a stupid question: why has my patient clinically got hepatitis but not got a positive result?!”
Many doctors request “hepatitis screens” but I often wonder if the results are interpreted correctly as the results the laboratory send out can actually be really confusing. The anti-HAV IgM and HBsAg help to diagnose acute viral hepatitis (A or B respectively) whereas the test for hepatitis C (anti-HCV) is actually a test for chronic Hepatitis C Virus (HCV) or past infection. So if you think the patient has acute hepatitis it is important to remember that a negative anti-HCV test means your patient does not have chronic HCV but could in fact still have acute hepatitis C; the anti-HCV test is not the right test to determine acute hepatitis C! Which one is then, I hear you cry?!! That’s a Hepatitis C Virus PCR of course… which we’ll cover later :-)
So why use the anti-HCV test!?! In order to understand why the test for HCV infection is the antibody test you first have to understand about the virus and the clinical condition it causes.
What is HCV?
Hepatitis C is an RNA virus in the Flavivirus family. There are 7 different genotypes of HCV however 70% of all infections are caused by genotype 1 and 20% by genotype 2.
HCV is a blood borne virus. Transmission is primarily through contact with blood. The most common routes of transmission are through intravenous drug use, transfusion (in the days before routine screening of donated blood in the UK), sexual intercourse and very occasionally vertical transmission from mother to baby or by haemodialysis. Humans are the main reservoir of HCV.
It was known in the 1970s that hepatitis, not due to Hepatitis A Virus or Hepatitis B Virus, could be transmitted through blood transfusions but it took until 1989 before Drs Alter and Houghton published their research that showed the cause as Hepatitis C Virus. Up until that time the risk of developing hepatitis after a blood transfusion in the USA was said to be about 30%... that’s very high!
In my opinion perhaps the most famous person to have HCV infection was Anita Roddick, the founder of the global cosmetics chain The Body Shop. She campaigned to increase awareness about HCV and on her death in 2007 donated her £51 million fortune to charities rather than her family… I expect HCV charities were high up on her donation list. She’s the only person I remember seeing on TV raising awareness of HCV in the UK which is why she sticks in my mind.
It is estimated that 2-3% of the World’s population is infected with HCV; that is 150-230 million people. It is also estimated that there are about 450,000 deaths a year from HCV.
How does Hepatitis C present?
70-80% of cases of HCV infection are asymptomatic. In the remaining 20-30% nausea, vomiting, vague abdominal discomfort and loss of appetite progress over 6-9 weeks until the patient becomes jaundiced. The initial symptoms usually resolve spontaneously. Irrespective of clinical features 75-85% of infections become chronic with up to 20% developing cirrhosis during the next 20-30 years. It has often been called a silent killer because many of those infected do not know they are infected until the damage to their livers has been done. Up to 5% of chronically infected patients eventually die from liver failure or hepatocellular carcinoma.
The lack of acute symptoms, the chronic progressive nature of the infection and the serious adverse outcomes all make HCV a particularly challenging infection to deal with. Patients are often diagnosed too late for traditional treatments to be effective. Many campaigners want to see universal screening for HCV in order to prevent transmission, cirrhosis and hepatocellular carcinoma.
How is HCV infection diagnosed?
Most cases of HCV are diagnosed because a patient has a blood test for another reason that shows an unexpected hepatitis i.e. raised aspartate aminotransferase (AST), alanine aminotransferase (ALT) and bilirubin or jaundice. The Doctors then arrange a test for hepatitis viruses and HCV is identified.
The initial investigation of possible HCV infection is based upon whether the diagnosis is thought to be acute or chronic infection, and involves a combination of an IgG antibody test (anti-HCV) and viral RNA PCR (PCR). A positive IgG antibody means the infection has been present for 8 to 24 weeks; a positive RNA PCR means the virus is replicating and confirms active infection. The table below shows how to interpret the results of these two tests and when to repeat the tests. Did you know it takes at least 12 weeks to rule out infection and 24 weeks to confirm chronic infection?
So a sick patient has their LFT done and the AST and ALT are elevated which prompts the doctors looking after the patient to ask if the patient might have hepatitis. The wise senior in the team tells the junior to do a “hepatitis screen” but what does this actually mean? The “screen” tends to look for the 3 common causes of viral hepatitis’; A, B and C.
The 1st line tests in a hepatitis screen include:
- Hepatitis A IgM (anti-HAV IgM)
- Hepatitis B surface antigen (HBsAg)
- Hepatitis C IgG (anti-HCV)
The results came back as: “anti-HAV IgM negative, HBsAg negative, anti-HCV negative”, the junior looked perplexed at the result but saw the Microbiologist on his ward round and asked “Is this a stupid question: why has my patient clinically got hepatitis but not got a positive result?!”
Many doctors request “hepatitis screens” but I often wonder if the results are interpreted correctly as the results the laboratory send out can actually be really confusing. The anti-HAV IgM and HBsAg help to diagnose acute viral hepatitis (A or B respectively) whereas the test for hepatitis C (anti-HCV) is actually a test for chronic Hepatitis C Virus (HCV) or past infection. So if you think the patient has acute hepatitis it is important to remember that a negative anti-HCV test means your patient does not have chronic HCV but could in fact still have acute hepatitis C; the anti-HCV test is not the right test to determine acute hepatitis C! Which one is then, I hear you cry?!! That’s a Hepatitis C Virus PCR of course… which we’ll cover later :-)
So why use the anti-HCV test!?! In order to understand why the test for HCV infection is the antibody test you first have to understand about the virus and the clinical condition it causes.
What is HCV?
Hepatitis C is an RNA virus in the Flavivirus family. There are 7 different genotypes of HCV however 70% of all infections are caused by genotype 1 and 20% by genotype 2.
HCV is a blood borne virus. Transmission is primarily through contact with blood. The most common routes of transmission are through intravenous drug use, transfusion (in the days before routine screening of donated blood in the UK), sexual intercourse and very occasionally vertical transmission from mother to baby or by haemodialysis. Humans are the main reservoir of HCV.
It was known in the 1970s that hepatitis, not due to Hepatitis A Virus or Hepatitis B Virus, could be transmitted through blood transfusions but it took until 1989 before Drs Alter and Houghton published their research that showed the cause as Hepatitis C Virus. Up until that time the risk of developing hepatitis after a blood transfusion in the USA was said to be about 30%... that’s very high!
In my opinion perhaps the most famous person to have HCV infection was Anita Roddick, the founder of the global cosmetics chain The Body Shop. She campaigned to increase awareness about HCV and on her death in 2007 donated her £51 million fortune to charities rather than her family… I expect HCV charities were high up on her donation list. She’s the only person I remember seeing on TV raising awareness of HCV in the UK which is why she sticks in my mind.
It is estimated that 2-3% of the World’s population is infected with HCV; that is 150-230 million people. It is also estimated that there are about 450,000 deaths a year from HCV.
How does Hepatitis C present?
70-80% of cases of HCV infection are asymptomatic. In the remaining 20-30% nausea, vomiting, vague abdominal discomfort and loss of appetite progress over 6-9 weeks until the patient becomes jaundiced. The initial symptoms usually resolve spontaneously. Irrespective of clinical features 75-85% of infections become chronic with up to 20% developing cirrhosis during the next 20-30 years. It has often been called a silent killer because many of those infected do not know they are infected until the damage to their livers has been done. Up to 5% of chronically infected patients eventually die from liver failure or hepatocellular carcinoma.
The lack of acute symptoms, the chronic progressive nature of the infection and the serious adverse outcomes all make HCV a particularly challenging infection to deal with. Patients are often diagnosed too late for traditional treatments to be effective. Many campaigners want to see universal screening for HCV in order to prevent transmission, cirrhosis and hepatocellular carcinoma.
How is HCV infection diagnosed?
Most cases of HCV are diagnosed because a patient has a blood test for another reason that shows an unexpected hepatitis i.e. raised aspartate aminotransferase (AST), alanine aminotransferase (ALT) and bilirubin or jaundice. The Doctors then arrange a test for hepatitis viruses and HCV is identified.
The initial investigation of possible HCV infection is based upon whether the diagnosis is thought to be acute or chronic infection, and involves a combination of an IgG antibody test (anti-HCV) and viral RNA PCR (PCR). A positive IgG antibody means the infection has been present for 8 to 24 weeks; a positive RNA PCR means the virus is replicating and confirms active infection. The table below shows how to interpret the results of these two tests and when to repeat the tests. Did you know it takes at least 12 weeks to rule out infection and 24 weeks to confirm chronic infection?
Click for larger image
If HCV infection is diagnosed the next step is to perform genotyping on the virus as this dictates how the infection is treated.
How is HCV infection treated?
There has been radical change in the treatment of HCV infection in recent years. In the past HCV has been difficult to treat, regimens included months of Interferon and Ribavirin both of which made patients feel dreadful, and for which compliance was an issue. Success was limited to about 70-80% of those who managed to complete treatment.
This all changed with the discovery of Direct Acting Antivirals (DAAs) which act on HCV-encoded non-structural proteins that are vital to the replication of the virus. They include proteases, nucleoside and non-nucleoside inhibitors, and NS5A protein inhibitors. The Direct Acting Antivirals directly affect the virus and have fewer side effects due to accidental effects on human cells. In addition they are much more effective at eliminating the virus from the patient leading to a Sustained Virological Response (SVR) when the Direct Acting Antivirals are stopped, essentially curing the patient. SVR is defined as an undetectable RNA level 12 weeks following the completion of therapy.
This is an evolving area of medicine at present but eventually final regimens for each genotype of virus and the stage of liver disease will be decided upon. Given the clinical trial nature of the current treatment of Hepatitis C and the extraordinarily high cost of the drugs involved, Hepatitis C is still in the remit of Hepatologists. However it is possible and probable that the treatment of HCV will move in to primary care after the treatment has been started as the actual use of these drugs is pretty straight forward; they are very effective, need little specialist monitoring and are usually well tolerated.
Some experts recommend waiting to see if the patient will clear their HCV infection themselves before starting treatment however there is increasing evidence that early treatment has a higher success rate of achieving an SVR than waiting to see if the patient is going to develop chronic infection. If the patient fails to drop their HCV viral load on PCR at 4 weeks or if they still have detectable viral load at 12 weeks then the British HIV Association (BHIVA) recommend that they should be treated.
The current BHIVA treatment protocols can be found here. Okay so this document looks like a bit of a nightmare to follow, I appreciate that, but in reality there are only five different drugs across all of the 1st line regimens: Sofosbuvir, Velpatasvir, Elbasvir, Grazoprevir and Ribavirin and the treatment duration is 8-12 weeks. Most regimens consist of 2 Direct Acting Antivirals with Ribavirin added if decompensated liver cirrhosis is present. The table below is just the 1st line treatments however there are many 2nd, 3rd, 4th, 5th, 6th etc. lines of treatment!
How is HCV infection treated?
There has been radical change in the treatment of HCV infection in recent years. In the past HCV has been difficult to treat, regimens included months of Interferon and Ribavirin both of which made patients feel dreadful, and for which compliance was an issue. Success was limited to about 70-80% of those who managed to complete treatment.
This all changed with the discovery of Direct Acting Antivirals (DAAs) which act on HCV-encoded non-structural proteins that are vital to the replication of the virus. They include proteases, nucleoside and non-nucleoside inhibitors, and NS5A protein inhibitors. The Direct Acting Antivirals directly affect the virus and have fewer side effects due to accidental effects on human cells. In addition they are much more effective at eliminating the virus from the patient leading to a Sustained Virological Response (SVR) when the Direct Acting Antivirals are stopped, essentially curing the patient. SVR is defined as an undetectable RNA level 12 weeks following the completion of therapy.
This is an evolving area of medicine at present but eventually final regimens for each genotype of virus and the stage of liver disease will be decided upon. Given the clinical trial nature of the current treatment of Hepatitis C and the extraordinarily high cost of the drugs involved, Hepatitis C is still in the remit of Hepatologists. However it is possible and probable that the treatment of HCV will move in to primary care after the treatment has been started as the actual use of these drugs is pretty straight forward; they are very effective, need little specialist monitoring and are usually well tolerated.
Some experts recommend waiting to see if the patient will clear their HCV infection themselves before starting treatment however there is increasing evidence that early treatment has a higher success rate of achieving an SVR than waiting to see if the patient is going to develop chronic infection. If the patient fails to drop their HCV viral load on PCR at 4 weeks or if they still have detectable viral load at 12 weeks then the British HIV Association (BHIVA) recommend that they should be treated.
The current BHIVA treatment protocols can be found here. Okay so this document looks like a bit of a nightmare to follow, I appreciate that, but in reality there are only five different drugs across all of the 1st line regimens: Sofosbuvir, Velpatasvir, Elbasvir, Grazoprevir and Ribavirin and the treatment duration is 8-12 weeks. Most regimens consist of 2 Direct Acting Antivirals with Ribavirin added if decompensated liver cirrhosis is present. The table below is just the 1st line treatments however there are many 2nd, 3rd, 4th, 5th, 6th etc. lines of treatment!
Click for larger image
The main side effects of the Direct Acting Antivirals are headache and malaise but otherwise they are usually very well tolerated.
Patients should have their viral load checked by RNA PCR after 4 weeks of treatment and if it is still detectable checked again at 6 weeks. If the 6 week level has increased treatment should be stopped and specialist advice sought. All patients should also have their FBC, U&Es and LFTs checked at 4 weeks. If they are taking Grazoprevir PLUS Elbasvir then the FBC, U&Es and LFTs should be checked again at 8 and 12 weeks as side effects are more common with these two drugs. Patients, both male and female, taking Ribavirin should be told to use contraception for 6 months and avoid pregnancies as Ribavirin is teratogenic (causing deformity in the foetus) and hangs around in the body for a long time after stopping treatment. At present it is recommended that patients have their viral load checked again 12 weeks following treatment to confirm an SVR.
Direct Acting Antivirals are very effective at treating HCV infection. The current success rate is between 95-99% with a relapse rate of about 1%. The other important thing to remember about HCV is that resistance is unlikely to occur because HCV is an RNA virus and as such it doesn’t have a genetic memory. Therefore after a treatment failure the virus is likely to revert to wild-type therefore it will still be sensitive to the same Direct Acting Antivirals so they could then be used again for treatment.
There is one significant drawback to Direct Acting Antivirals compared to the old treatments for Hepatitis C and that is cost. The old interferon-alpha PLUS Ribavirin cost just £4000 per treatment course (6 months) whereas at present a 12 week course of Sofosbuvir PLUS Ledipasvir costs almost £40,000, that’s a tenfold increase! As of January this year 25,000 patients had been treated in the UK… that’s £1 billion spent on tablets, about 1% of the annual budget for the NHS!! Okay, the cost of managing these patients for cirrhosis or liver transplants in the future would be much higher but the economics of the new Direct Acting Antiviral treatments are tricky to balance.
So there we have it. Our patient’s PCR was positive and because they were anti-HCV negative they were provisionally diagnosed with acute hepatitis C and retested to confirm this in 4 weeks’ time. Fortunately for our patient and many other hepatitis C patients the new treatments for HCV infection are definitely something to celebrate, so Happy World Hepatitis Day… I’m always looking for an excuse to celebrate… now where did I leave that piece of cake…?!
Questions: should Hepatitis C PCR be used as part of a hepatitis screen instead or as well as anti-HCV? Currently it isn't because it is too expensive to use on everybody with abnormal LFTs. Do you think CCGs would fund routine use of PCR?
NB Clinical Commissioning Groups (CCGs) are groups who decide on how healthcare is provided in the UK and pay for their choices.
Patients should have their viral load checked by RNA PCR after 4 weeks of treatment and if it is still detectable checked again at 6 weeks. If the 6 week level has increased treatment should be stopped and specialist advice sought. All patients should also have their FBC, U&Es and LFTs checked at 4 weeks. If they are taking Grazoprevir PLUS Elbasvir then the FBC, U&Es and LFTs should be checked again at 8 and 12 weeks as side effects are more common with these two drugs. Patients, both male and female, taking Ribavirin should be told to use contraception for 6 months and avoid pregnancies as Ribavirin is teratogenic (causing deformity in the foetus) and hangs around in the body for a long time after stopping treatment. At present it is recommended that patients have their viral load checked again 12 weeks following treatment to confirm an SVR.
Direct Acting Antivirals are very effective at treating HCV infection. The current success rate is between 95-99% with a relapse rate of about 1%. The other important thing to remember about HCV is that resistance is unlikely to occur because HCV is an RNA virus and as such it doesn’t have a genetic memory. Therefore after a treatment failure the virus is likely to revert to wild-type therefore it will still be sensitive to the same Direct Acting Antivirals so they could then be used again for treatment.
There is one significant drawback to Direct Acting Antivirals compared to the old treatments for Hepatitis C and that is cost. The old interferon-alpha PLUS Ribavirin cost just £4000 per treatment course (6 months) whereas at present a 12 week course of Sofosbuvir PLUS Ledipasvir costs almost £40,000, that’s a tenfold increase! As of January this year 25,000 patients had been treated in the UK… that’s £1 billion spent on tablets, about 1% of the annual budget for the NHS!! Okay, the cost of managing these patients for cirrhosis or liver transplants in the future would be much higher but the economics of the new Direct Acting Antiviral treatments are tricky to balance.
So there we have it. Our patient’s PCR was positive and because they were anti-HCV negative they were provisionally diagnosed with acute hepatitis C and retested to confirm this in 4 weeks’ time. Fortunately for our patient and many other hepatitis C patients the new treatments for HCV infection are definitely something to celebrate, so Happy World Hepatitis Day… I’m always looking for an excuse to celebrate… now where did I leave that piece of cake…?!
Questions: should Hepatitis C PCR be used as part of a hepatitis screen instead or as well as anti-HCV? Currently it isn't because it is too expensive to use on everybody with abnormal LFTs. Do you think CCGs would fund routine use of PCR?
NB Clinical Commissioning Groups (CCGs) are groups who decide on how healthcare is provided in the UK and pay for their choices.
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