Viral hepatitis Flashcards
When over half the liver is destroyed, function begins to fail, and you may see jaundice as first sign, as bilirubin cannot be transported into bile. Hepatitis can lead to cirrhosis
What virus families do these viruses belong to?
HAV
HBV
HCV
HAV - hepatovirus
HBV - hepadnavirus
HCV - flavivirus
What virus families do these viruses belong to?
HDV
HEV
Yellow fever
HDV - deltavirus. Required HBV co-infection, as incompelte virus
HEV - orthohepevirus
Yellow fever - flavivirus
Which hepatitis viruses are:
- ssRNA
- dsDNA
HAV HCV HDV HEV YF
HBV
Which hepatitis viruses are transmitted -
- faecal-oral
- blood-borne
- mosquito
- faecal-oral - HAV/HEV
- blood-borne - HBV/ HCV/ HDV
- mosquito - YF
What are other rarer viral causes of hepatitis?
Adenovirus
CMV
EBV
HSV
Which viruses are most associated with cirrhosis and progression to HCC?
HBV
HCV
HAV only has one serotype, and is endemic worldwide. 90% of children have been infected by age 5
What is transmission route?
What is incubation period?
Faecal-oral - poor hygiene/ anal itnercourse
4 weeks
Virus present in stool before symptoms appear
Outbreaks occur in schools/ camps, and near sources of contaminated water. Military will be vaccinated
What is life cycle of HAV?
Ingested in GI tract
Moves to bloodstream - replicates
Enters hepatocytes
Virions excreted into small intestine - appear in faeces
What are symptoms of HAV?
Nausea
Diarrhoea
Fever
Jaundice - more common in adults not previously infected
Has most sudden onset of viral hepatitis viruses
What is management of HAV?
Symptomatic
Vaccinate
Occasionally pooled human normal immunoglobulin
Avoid work/ school for 7 days as potentially infectious
How to diagnose HAV infection?
HAV IgM
HAV
Which at risk groups require vaccination?
Travellers Sewage workers Child day-care MSM IVDU Haemophilia
HEV spreads via faecal-oral route.
Which countries is it more commonly seen in?
From East Africa/ middle east/ Asia
Mexico
How many genotypes of HEV are there?
Genotypes 1/2 - large outbreaks in resource poor countries. Usually contaminated drinking water
Genotypes 3/4 - developing and developed countries. Usually food borne - undercooked food
What are natural reservoirs for HAV?
Chickens Pigs Rabbits Boar Dear
Mostly all asymptomatic
Usually transmitted faecal-oral between humans
But can originate in animals from undercooked pork
HEV infection
What are symptoms?
Which groups need to be wary?
Usually self-limiting mild illness
Pregnancy - may be severe, with up to 20% mortality
Immunosuppressed - 50% becomes chronic infection
How is HEV diagnosed?
Treatment is supportive. Vaccine in development
HEV IgM/ IgG
HEV RNA in blood/ stool
HBV is partially dsDNA virus. Estimated 350million carriers worldwide. Complete HBV virion known as Dane particle.
What are the characteristics of the HBV antigens and antibodies?
HBsAg
HBsAb
HBsAg - envelope antigen of HBV particle, can also occur as free particle in the blood. Indicates infectivity in blood. Part of antigen used to create vaccine
HBsAb - antibody response to HBsAg. Indicates post-vaccination response, and after resolved HBV infection
What are the characteristics of the HBV antigens and antibodies?
HBcAb (total)
HBc IgM
HBcAb - antibody to HB core antigen. Appears early in infection. Includes HBc IgM. Persists for life
HBc IgM - appears in acute HBV infection. Can last for 3 months. Is marker of acute HBV infection (in past 6 months). Can also be seen in those with HBeAg carriers with high viral replication
What are the characteristics of the HBV antigens and antibodies?
HBeAg
HBeAb
HBeAg - antigen derived from HBc. Indicates high transmissibility as indicates high replication and infectivity. It is soluble component secreted by virus core, also expressed on hepatocyte surface as target for host immune response
HBeAb - antibody to HBV core (includes HBeAG/ HBc). This occurs when HBeAg reduces, and is a sign of low-infectivity. HBeAg seroconversion when this antibody produced
What is route of transmission of HBV?
Vertical
Sexual
Blood products/ needles/ dialysis equipment
Tattoo/ accupuncture
How many genotypes are there of HBV?
10 A-J
ADG UK
Over 40 sub-genotypes
What is incubation period of HBV?
6 weeks - 6 months
Median is 2.5 months
HBV infeciton - how does liver damage occur?
Virus does not cause direct damage. Immune mediated damage of hepatocytes.
Virus-specific cytotoxic T-cells attack hepatocytes
As damage increases, signs of hepatitis appear
Immune response slowly becomes effective over period of months, so blood is no longer infectious. But virus remains in liver
Healthy adults with vigorous immune response can clear virus rapidly, but suffer severe illness. 10% cannot clear, and become carriers
What is definition of HBV carrier?
Who is at risk of become chronic carrier HBV?
Detection of HBsAg in blood 6 months after exposure
Immunodeficient - likely to be carrier, but wont suffer much disease
If infected perinatally, have 95% carriage rate
Males more likely to be carrier
What are complications of HBV?
Cirrhosis
HCC - 20-30 years following initial infection
HBeAg is used as marker of infectivity. What other tests help identify infectivity?
HBV DNA load become useful marker, as some virus strains have mutations in e antigen, which results in absence of HBeAg, although viable virion produced. Known as pre-core mutant virus
This therefore means they can be HBeAg neg, and HBeAb positive but could be highly infectious.
What are expected test results in the following conditions?
Acute Hepatitis B
HBsAg HB core antibody (total anti-HBc) HB core IgM (anti-HBcIgM) HBeAb (anti-HBe) HBeAg HB surface antibody (anti-HBs)
Acute Hepatitis B
HBsAg - pos HB core antibody (total anti-HBc) - pos HB core IgM (anti-HBcIgM) - pos HBeAb - neg HBeAg - pos HB surface antibody (anti-HBs) - neg
HBsAg appears in serum during incubation period.
If self-limiting, HBsAg will gradually reduce as HB core IgM is produced. HB core IgM then reduces and is replaced with HB core IgG
If persisting infection, HBsAG remains high. HBeAg begins to icnrease. HB core antibodies are produced, IgM reduces, and is replaced by IgG. But this is ineffective at clearing the virus
What are expected test results in the following conditions?
Past Hepatitis B
HBsAg HB core antibody (total anti-HBc) HB core IgM (anti-HBcIgM) HBeAb (anti-HBe) HBeAg HB surface antibody (anti-HBs)
Past Hepatitis B
HBsAg - neg HB core antibody (total anti-HBc) - pos HB core IgM (anti-HBcIgM) - neg HBeAb - pos HBeAg - neg HB surface antibody (anti-HBs) - pos
What are expected test results in the following conditions?
Hepatitis B carrier low/ high infectivity
HBsAg HB core antibody (total anti-HBc) HB core IgM (anti-HBcIgM) HBeAb (anti-HBe) HBeAg HB surface antibody (anti-HBs)
Hepatitis B carrier high infectivity
HBsAg - pos HB core antibody (total anti-HBc) - pos HB core IgM (anti-HBcIgM) - neg HBeAb - neg HBeAg - pos HB surface antibody (anti-HBs) - neg
Hepatitis B carrier low infectivity
HBsAg - pos HB core antibody (total anti-HBc) - pos HB core IgM (anti-HBcIgM) - neg HBeAb - pos HBeAg - neg HB surface antibody (anti-HBs) - neg
anti-HBs only turns positive upon vaccination, or after approx 36 weeks after infection
What are expected test results in the following conditions?
Hepatitis vaccine response
HBsAg HB core antibody (total anti-HBc) HB core IgM (anti-HBcIgM) HBeAb (anti-HBe) HBeAg HB surface antibody (anti-HBs)
Hepatitis vaccine response
HBsAg - neg HB core antibody (total anti-HBc) - neg HB core IgM (anti-HBcIgM) - neg HBeAb - neg HBeAg - neg HB surface antibody (anti-HBs) - pos
HBV vaccine gives good protection to 90% of people. 10% will not produce protective HB surface antibody.
How many doses are required?
Who is recommended to be vaccinated?
Three injections over 6 months
0, 1, 6 months - routine
0, 1, 2 months - accelerated
Healthcare workers IVDU Transfusion dependent Dialysis patient Sex worker
Now all neonates recommended to be vaccinated
If unvaccinated has needlestick injury, what treatment can be given?
Give HepB vaccination -
- if already immunised - give booster dose
- if not previously immunised - accelerated course 3 injections 3 months
- if vaccine non-responder - boost dose an HBIG
Consider HBIG
Check green book - depends on vaccine status of recipient, and risk form source
What is structure of HBV virion?
not DNA genes
DNA DNA polymerase HBcAg HBsAg with glycoproteins Envelope
What is structure of HBV DNA?
All 10 genotypes (A-J) all contain four long open reading frames (ORFs)
C - core. Encodes HBcAg and HBeAg. Mutations in pre-core region result in lack of HBeAG
S - surface. Encodes pre-S1/ pre-S2/ s region - encode HBsAG
P - polymerase. Encodes DNA polymerase and ribonuclease H. Encompasses 75% of whole genome. Also responsible for reverse transcription.
X gene - encodes polypeptide with several functions
What are possibilities for following serology results HBV?
HBsAg - negative
anti-HBc - positive
anti-HBs - negative
- False-positive anti-HBc, thus susceptible
2 Resolved infection (most common) - not devleoped anti-HBs yet
- “Low level” chronic infection
- passive transfer of maternal anti-HBc – in children up to 3 years of age
What are phases 1-3 (5) of HBV infection?
The progression through these phases of chronic HBV infection can be accompanied by the development of hepatic fibrosis, cirrhosis and HCC formation
Phases related to HBeAg/ HBV DNA levels
Phase 1 - high replicative, low inflammatory state. HBeAg positivity, high viral load, normal aminotransferases
Phase 2 - HBeAg positive chronic hepatitis B phase, fluctuating aminotransferases, high HBV DNA, inflammation on liver biopsy
Phase 3 - HBeAg negative phase, low levels HBV DNA, and normal aminotransferases. If persists, has lower rate of progression towards cirrhosis
What are phases 4-5 (5) of HBV infection?
The progression through these phases of chronic HBV infection can be accompanied by the development of hepatic fibrosis, cirrhosis and HCC formation
Phase 4 - HBeAg negative, representing late immune reactive phase, with periodic fluctuating levels of aminotransferases and HBV DNA. Virus may have nucleotide substitutions in pre-core or basal core promoter region, explaining lack of HBeAg
Phase 5 - HBSag negative phase, HBV DNA usually undetectable
What are advantages of genotyping HBV?
Can locate origin - different genotypes more prevalent certain regions
Tailor treatment to patient
Certain genotypes have different modes of transmission e.g vertical/ horizontal, useful for epidemiology
Genotype influences disease outcomes and development of HCC
Mutation in error prone HBV polymerase creates genetic variability, termed genotype.
What are potential benefits of mutations?
Antiviral drug resistance mutations
Antiviral drug-associated potential vaccine escape mutants
Immune escape mutants - evade B cells
Deletion mutants unable to express non-essential HBV proteins e.g HBeAg
Where are most common HBV genotypes found geogrpahically?
genotype A found in North America, Europe, South-East Africa and India;
genotypes B and C in Asia and Oceania;
genotype D, the most widespread, in North America, North Africa, Europe, the Middle-East and Oceania;
genotype E in West Africa;
genotype F in South America;
genotypes G and H in Central and South America
UK - ADG
Which HBV genotypes are transmitted vertically?
Which HBV genotypes are transmitted horizontally?
Vertical -
A2
B
C
Horizontal - A1 D E F G H I
Which HBV genotypes are more likely to be HBeAg positive?
A2 - early seroconversion
C - late seroconversion
Which HBV genotypes are at higher risk of developing cirrhosis/ HCC?
A1
C
D
F
Which HBV genotypes are more responsive to IFN-alpha?
A1
B
Apart from HBV serology, what are initial tests for someone presenting with suspected HepB?
Do not check initial HBV genotype. Treat first, and if fails, check genotype
HAV Ab
HCV DNA/ Ab
HIV Ab
STIs
Chlamdyia
Gonorrhoea
Syphilis
FBC U+Es LFTs Coag AFP
USS liver/ fibroscan
HBeAg negative chronic HBV, compensated liver disease. What are treatment options?
Wait until it is chronic, as 90% will clear spontaneously
- initial 48-week course of peginterferon alfa-2a as first-line treatment (cannot be continued past this date. So if treatment to continue e.g lifelong, switch to other agent
- Offer entecavir or tenofovir disoproxil as second-line treatment to people with detectable
HBV DNA after first-line treatment with peginterferon alfa-2a.
HBeAg positive chronic HBV, compensated liver disease. What are treatment options?
- initial 48-week course of peginterferon alfa-2a as first-line treatment. NICE guidelines. Other countries suggest straight to tenofovir/ entecavir
- tenofovir disoproxil as second-line treatment to people who do not undergo HBeAg seroconversion or who relapse (revert to being HBeAg positive following seroconversion) after first-line treatment with peginterferon alfa-2a.
- entecavir as an alternative second-line treatment to people who cannot tolerate
tenofovir disoproxil or if it is contraindicated.
Woman diagnosed HBv positive during pregnancy/ breast feeding. What are treatment options?
tenofovir disoproxil in the third trimester to reduce the risk of transmission of HBV to the baby
Avoid peginterferon alfa-2a in pregnancy. Must use contraception if on treatment and not pregnant
What is mechanism of action of:
peginterferon alfa-2a
immunomodulatory - acts by binding to human type 1 interferon receptors. Activation and dimerization of this receptor induces the body’s innate antiviral response by activating the janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway
what is mechanism of action of:
tenofovir
entecavir
tenofovir - NRTI - selectively inhibits viral reverse transcriptase by causing DNA chain termination
entecavir - NRTI - guanosine analgoue, cause DNA chain termination
What is treatment for HBV decompensated liver disease?
- Refer hepatology/ transplant
- pegylated interferon contraindicated
- entecavir first line (if no history lamivudine resistance)
- tenofovir second line (if history lamivudine resistance)
Fibroscan can be used to monitor liver stiffness, as marker of cirrhosis. It assesses large area of liver, so may give better idea of cirrhosis, than liver biopsy
What results indicated liver stiffness measurement (LSM):
Mild
Severe
Cirrhosis
Beware liver elasticity can be influenced by obesity (fatty liver) or alcohol use
Mild - 2.5 -7.5 kPa
Severe - 7.5 - 12.4 kPa
Cirrhosis - >12.5 kPa
Treatment usually initiated if LSM >11.0 kPa. If above 11, this is highly suggestive of cirrhosis, and USS is not required.
If between 6-11, cirrhosis cannot be determined. So biopsy may be required.
Who should be initiated on treatment for HBV?
- Any patient with cirrhosis - regardless of HBV DNA/ ALT levels
- adults aged 30 years and older -
- HBV DNA >2000 IU/ml
- ALT >30 male, >19 female on 2 consecutive tests, conducted 3 months apart - adults younger than 30 years -
- HBV DNA >2000 IU/ml
- ALT >30 male, >19 female on 2 consecutive tests, conducted 3 months apart
- must have necroinflammation or fibrosis on liver biopsy or a transient elastography score greater than 6 kPa.
- if HBV DNA >20 000 treat irregardless
Initial treatment of HBV is peginterferon alfa-2a for 48 weeks.
HBV serology should be checked at 24 weeks. If not improving, what should be done?
Review adherence to treatment
Stop treatment if -
- If HBV DNA level has decreased by less than 2 log10 IU/ml or
- HBsAg is greater than 20,000 IU/ml or
- If do not udnergo HBeAg seroconversion/ relapse
Offer tenofovir second line therapy
Offer entecavir alternative second line if tenofovir not tolerated/ contra-indicated
After completing 48 weeks of treatment for HBV, when can anti-virals been stopped?
No cirrhosis
- stop after 12 months after achieving undetectable HBV DNA and HBsAg seroconversion
Cirrhosis
- Do not stop treatment after achieving undetecable HBV DNA and HBsAg seroconversion
How is HBV managed in pregnancy? Mother/ baby
Mother -
- tenofovir in third trimester to reduce risk transmission to baby
- stop treatment 4-12 weeks after birth, unless meets criteria for long term treatment
- no risk transmitting via breast milk. Can breast feed on anti-virals
Baby -
- HepB immunisation
- HBIG
What is treatment if HBV/HCV co-infected?
peginterferon alfa and ribavirin
What is treatment for HBV/ HDV co-infection?
48-week course of peginterferon alfa-2a if evidence significant fibrosis
Stop treatment after HBsAg seroconversion.
Some patients may be HBsAg positive, but not meet criteria for treatment. If they begin immunomodulating therapy for AI/ atopic disease, there is risk of full HepB infection.
What prophylaxis should be offered?
HBV DNA >2000 IU/ml
HBV DNA < 2000 IU/ml
HBV DNA >2000 IU/ml -
- entecavir or tenofovir
HBV DNA < 2000 IU/ml
- lamivudine if treatment lasting <6 months
- entecavir or tenofovir if treatment lasting >6 months
Start prophylaxis before beginning immunosuppressive therapy and continue for a
minimum of 6 months after HBeAg seroconversion and HBV DNA is undetectable
HBsAg negative
anti-HBc positive
Patient starting immunotherapy for <6 months. What prophylaxis should be offered?
lamivudine
start prophylaxis before beginning immunosuppressive therapy and continue for a minimum of 6 months after stopping immunosuppressive therapy.
HBsAg negative
anti-HBc positive
anti-HBs negative
Patient is not starting immunotherapy.
What treatment should be offered?
monitor HBV DNA monthly and offer prophylaxis (lamivudine) to people whose HBV DNA becomes detectable
HBsAg negative
anti-HBc positive
anti-HBs positive
Patient not starting immunotherapy.
What treatment should be offered?
Do not offer prophylaxis
Monitoring patients with HBV not on treatment.
how often should LFTs be checked?
- immune-tolerant phase (defined by active viral replication and normal ALT levels [less than 30 IU/L in males and less than 19 IU/L in females]). Check every 24 weeks. Check every 12 weeks if rise in ALT
- chronic hepatitis B infection (defined as HBeAg negative on 2 consecutive tests with normal ALT [less than 30 IU/L in males and less than 19 IU/L in females] and HBV DNA less than 2000 IU/ml). Check every 48 weeks
HBV infection, patient has HBeAg seroconversion (produces antibodies to HBeAg)
When should bloods be monitored?
Weeks 4, 12, 24
HBV infected patient, when do bloods need checked in following patients
entecavir
lamivudine
tenofovir
Routine bloods -
week 4
then every 3 months
HBV serology -
week 12
week 24
week 48
In patients with significant fibrosis due to HBV, how often should be monitored for HCC?
Significant fibrosis -
every 6 months with USS/ AFP
no fibrosis -
- if HBV DNA >20 000 - consider USS
- if HBV low, no follow up
Why is HBeAg seroconversion an important marker?
In HBeAg-positive disease, HBeAg seroconversion is a predictor of durable response to antiviral
treatment and can be used as a milestone after which treatment can be stopped
no marker exists for HBeAg negative disease
What are infective causes of acute hepatitis?
Hep A-E
CMV
EBV
HSV
Brucellosis
Leptospirosis
What general advice should be given to someone with acute hepB infection?
Advice for close contacts
HAV vaccination
Avoid sexual intercourse
Avoid alcohol
Avoid sharing razors
HepB vaccination close contacts
Contact trace
When to stop treatment for HBV?
- HBeAg seroconversion, and HBV DNA undetectable - continue treatment for 12 months after this point.
- 50% seroconvert by 5 years
- If HBeAG negative - continuee lifelong treatment to prevent cirrhosis/ HCC
Hepatitis D has small single stranded RNA genome. It is defective virus, and can only multiply in HBV co-infected cell.
What is structure of HDV?
HDV single stranded RNA
HDV Ag
HBsAg acquired when buds from hepatocyte
Once inside hepatocyte, uses host RNA polymerases to replicate
How is HDV infection diagnosed?
HDV antigen
HDV IgM/IgG
HBsAg
What is treatment for HDV infection?
Treat as HBV guidelines
HBV vaccination is reducing incidence of HDV
HepC is +ss RNA virus in hepcivirus genus in falvivididae family. Estimated 185 million worldwide infected
What is transmission route?
Blood
Needles
Tatto/ piercing/ accupuncutre
Dialysis
Uncommon vertical transmission
HCV has six major genotypes, and more than 100 subtypes, due to high error rate in RNA replication by NS5b polymerase.
Which genotypes are prevalent in different geographical distributions?
90% of infections in Europe are genotype 1, 2, 3
(1 + 3 most common)
Americas - genotype 1/2
Northeast/central Africa - genotype 4
Asia - genotype 6
What is significance of HCV genotype?
Predictive of antiviral therapy response
Genotype 1 associated with poor response
Being infected with one genotype does not protect against other. Therefore making vaccine more difficult
How many HCV infected people developed chronic HCV?
What is incubation period?
80% become chronically infected
20% spontaenosuly clear virus by 6 months (90% in HBV)
2-4 months. Mean 7 weeks
What are symptoms of HCV infection?
Most have subclinical infection
25% develop jaundice, as opposed to 90% seen in acute HBV infection
what percentage spontaneously clear HCV?
What percent of those with chronic HCV go on to develop cirrhosis/ HCC?
25% spontaneously clear (90% in HBV)
80% HCV infected will develop cirrhosis
10% will progress to HCC
What tests are used for HCV?
HCV RNA - shows if current infection
HCV Ab - shows if ever had infection or current infection
The goal of treatment is to eradicate the virus, achieve a sustained virological response (SVR), and prevent disease progression
SVR - undetectable HCV RNA in the blood 12 weeks after treatment completion is considered equivalent to a cure
All patients with HCV are eligible for treatment (regardless of fibrosis status). Treatment is Direct Acting Antivirals (DAA)
How long is treatment for?
Initial tests same as HBV
8 - 12 weeks treatment which costs approx £40 000
90% will be cured by end of treatment
What does choice of HCV treatment depend on?
Genotype
Liver disease - Child-Pugh score
If HCV viral load dose not reduce by 4 weeks, then spontaneous clearance unlikely. Consider starting treatment
HCV can become resistant to anti-virals. On stopping treatment this reverses backto “wild-type”. Restarting treatment does not trigger resistance again, because RNA virus cannot store resistance genes
HCV treatment
Non-cirrhotic
Genotype - 1a 1b 2 3 4 5/6
1a sofosbuvir + ledipasvir (8-12 weeks)
1b sofosbuvir + ledipasvir (8-12 weeks)
2 sofosbuvir + ledipasvir
3 sofosbuvir + ledipasvir
4 grazoprevir plus elbasivir
5/6 sofosbuvir + ledipasvir
HCV treatment
Compensated cirrhosis
Genotype - 1a 1b 2 3 4 5/6
1a sofosbuvir + ledipasvir
1b sofosbuvir + ledipasvir
2 sofosbuvir + ledipasvir
3 sofosbuvir + ledipasvir
4 grazoprevir plus elbasivir
5/6 sofosbuvir + ledipasvir
Difference from non-cirrhotic, is all must be 12 weeks treatment
HCV treatment
Decompensated cirrhosis
Genotype - 1a 1b 2 3 4
1a sofosbuvir + ledipasvir + ribavirin
1b sofosbuvir + velpatasvir + ribavirin
2 sofosbuvir + velpatasvir + ribavirin
3 sofosbuvir + velpatasvir + ribavirin
4 grazoprevir + elbasvir + ribavirin
All for 12 weeks
Primary treatment is liver transplant, so should be managed by gastroenterologist
What are four clases of DAA drugs for HCV?
NS3/4A PI
NS5A inhibitor
Nucleotide/ nucleoside NS5B polymerase inhibitor
Non-nucleoside NS5B polymerase inhibitor
Mechanism of action of DAA HCV
NS3/4A PI
Examples
Binds to viral protease inhibiting it
Grazoprevir
Simeprivir
Mechanism of action of DAA HCV
NS5A inhibitor
Examples
Blocks NS5A virus protein required for replication
Elbasvir
Ledipasvir
Velpatasvir
Mechanism of action of DAA HCV
Nucleotide/ nucleoside NS5B polymerase inhibitor
Examples
Prevents HCV replication in hepatocyte
Sofosbuvir
Mechanism of action of DAA HCV
Non-nucleoside NS5B polymerase inhibitor
Examples
Binds to polymerase preventing further viral replication
Dasabuvir
What are most common side effects of DAA HCV?
Fatigue - anaemia
GI symptoms
Headache
Insomnia
HCV treatment, when is HCV RNA levels monitored?
Weeks 2, 4, 8, 12
Assess for SVR - absence of HCV RNA by PCR at 6 months on completing treatment
An increase in viral load from on-treatment nadir of greater than 1 log is indicative of poor adherence and virological breakthrough and treatment will be discontinued. Discontinuation avoids futile therapy
and minimises the development of drug resistance.
HCV +ssRNA virus
RNA contains 10 proteins, what are they?
C - core protein
E1/E2 - envelope proteins
NS2a - envelope protein
NS2, NS3, NS4a, NS4b, NS5a, NS5b -non-structural
What are extraheptaic manifestations of HCV infection?
lichen planus Mixed cryoglobulinaemia Membranoproliferative glomerulonephritis porphyia cutanea tarda pulmonary fibrosis Sjogren's syndrome Thyroid disease
HCV initial investigations before starting treatment
HCV Ab - detectable after 6 weeks (HIV may have false-negative result)
HCV RNA - detectable after few days
Genotype testing
Fibroscan/ USS or liver biopsy
HIV HCV co-infection is associated with faster progression towards cirrhosis.
Must start/ continue HIV ART.
When would you not start HCV DAA?
CD4 count less than 200 cells/mm3, it may be advisable to first initiate antiretroviral therapy and defer HCV therapy until the person is stable on antiretroviral therapy with suppressed HIV RNA levels
Most clinical trials evaluating the efficacy of HCV therapy in persons with HIV have enrolled those with suppressed HIV RNA levels and CD4 counts greater than 200 cells/mm3.
ART will slow HCV progresison towards liver cirrhosis
HIV/ HCV co-infection
What aspects should be considered about drug therapy?
If treatment for both HIV and HCV is indicated, the selected treatment regimens should consider potential drug interactions and whether the recommended duration for persons with HCV monoinfection should be given for a longer duration because of the confection with HIV.
LFTs may raise substantially more if co-infected, and may be attributed to immune reconstitution inflammatory syndrome
Monitoring hepatotoxicity on DAA for HCV.
Up to what level of transaminases is safe?
5x upper limit of normal
However, if develops rising bilirubin, and symptoms such as nausea, weakness. Need to evaluate treatment/ other causes e.g HBV, alcohol,
If blood tests show raised LFTs, then perform more frequent monitoring
HIV/ HCV co-infection
Which ART drugs are contra-indicated?
NRTI
NNRTI
INSTI
PI
CCR5
NRTIs: avoid tenofovir + sofosbuvir
NNRTIs: avoid efavirenz and etravirine
INSTIs: avoid with tenofovir
PIs - avoid all
CCR5 - maraviroc safe
All blood and organ donors need to be screened for infection to prevent transmission
Which tests are performed?
HIV Ag/Ab, RNA
HBsAg, HBV DNA
HCV Ab, HCV RNA
HTLV Ab
CMV IgG
EBV VCA (viral capsid antigen) IgG - only organ donor
Treponema pallidum Ab
Toxoplasma IgG - only organ donor
Travel histroy dependent:
West Nile Virus
Trypanosoma cruzi IgG
Malarial Ab
Individuals who receive blood products, particularly pooled blood products, could have false positive serology tests due to passively acquired antibodies from donor
How to reduce risk of sharp injuries/ BBV exposure?
Treat ever patient as potentially infectious
Training on how to deal with sharps
Sharps bins
Gloves
Mask/ eye shield if splash exposure
Vaccinate HBV
Healthcare worker with HIV.
What are they allowed to do at work?
If viral load >200 copies/ ml, not allowed to practice exposure prone procedures
Healthcare worker with HBV
What are they allowed to do at work?
HBeAg positive - cannot practice exposure prone procedures
HBeAg negative - if HBV DNA >1000 genome copies/ml
HBeAg negative - if HBV DNA <1000 genome copies/ml can return to exposure prone procedures
HCV - RNA undetectable
HIV - RNA <200 copies
Healthcare worker with HCV
What are they allowed to do at work?
Not allowed exposure prone procedure if HCV RNA detectable
Can return to work is sustained virological response to antiviral therapy
Child with CVID given regular immunoglobulin replacement. Which of the following tests cannot be explained by immunoglobulin replacement:
Detectable - CMV IgG EBV VCA IgG HCV IgG Anti-HBc Toxoplasma IgG
HCV IgG
Pooled immunoglobulins contain large variety of immunoglobulins to various organisms, so patient will test positive to lots of organisms.
In UK, blood is screened for HIV, HTLV, HCV, so not expected to be present in immunoglobulin preparations.
CMV/ EBV/ toxoplasma/ HepB core antigen are not routinely screened for, and could appear as passive antigens
What is definition of exposure prone procedure?
Exposure Prone Procedures (EPP) are invasive procedures where there is a risk that injury to the worker may result in the exposure of the patient’s open tissues to the blood of the worker (‘bleed-back’).
These include procedures where the worker’s gloved hands may be in contact with sharp instruments, needle tips or sharp tissues (e.g. spicules of bone or teeth) inside a patient’s open body cavity, wound or confined anatomical space where the hands or fingertips may not be completely visible at all times.
Patient has following results:
HBsAg detected
HBeAG not detected
HBV DNA 10 000 IU/ml
Which of these procedures can they perform?
Arterial cutdown Deep suturing cardiac arrest Laparotomy Repair perineal tear after delivery Venepuncture
Venepuncture
Other procedures are exposure prone procedures. They carry risk of injury to worker, which may result in exposure of patient’s open tissues to the blood of the worker
Can perform EPP once viral load <1000 copies/ml
47 year old with AML about to have stem cell transplant. Blood tests showe:
HBsAg - not detected
anti-HBc - detected
anti-HBs - <10mIU/ml
HBV DNA 340 IU/ml
What is appropriate management?
Accelerated HepB vaccination No anti-viral treatment as HBsAg negative Start adeofvir Start entecavir or tenofovir Start lamivudine
Blood tests suggest previous HBV exposure through infection. This means risk of possible reactivation.
Give 6 monts entecavir or tenofovir
Lamivudine would also be suitable, but resistance develops if used for longer periods such as 6 months
HBsAg positive, with other serology negative.
What are possibilities for this?
False positive HBsAg - need to repeat on another platform, and perform neutralisation
False negative antibody test
Recent vaccination, but nor produced anti-HBs yet
Newly recently acquired HBV infection, and has not yet sero-converted
Patient with immunodeficiency or on chemotherapy - so produces inadequate antibody response. May have been infected at any time
HBsAg positive
HBeAg positive
other serology negative
What is explanation for this?
Acute HBV infection
High viral replication, prior to immune response/ sero-conversion
What is importance of genotyping a virus?
Check inherent resistance before treatment
Assess risk of cirrhosis/ HCC
Assess source of infection - certain genotypes associated with vertical or horizontal transmission
Epidemiological studies
