3/02/2009 Opioid Side Effects - Part 2. Nicholas Lintzeris
7/04/2009 Smoking cessation update. Renee Bittoun
2/06/2009 TBA (cancelled)
4/08/2009 Alcohol problems. John Saunders
6/10/2009 Prescription opioids in chronic pain. Dr Alex Wodak & Dr Milton Cohen
1/12/2009 "The great debate" What is drug of first choice in opioid addiction? Dr Nick Lintzeris says oxycodone; Dr Richard Hallinan says buprenorphine; Dr Andrew Byrne says methadone.
ARCHIVE OF SUMMARIES (OTHERS SEARCHABLE ON SITE)
"Opioid Side Effects - Should we be bothered?"
http://www.redfernclinic.com/concord/2009/03/concord-seminar-tues-3rd-february.php4
3/2/09
Comparisons from UK, Victoria and NSW. http://www.redfernclinic.com/concord/2008/02/comparisons-from-uk-victoria-and-nsw.php4
5/2/08
Practising in Addiction Medicine: how not to be sued!http://www.redfernclinic.com/concord/2008/03/subject-practising-in-addiction.php4
18/3/08
Treating the Addicted Brain: Agonists, Antagonists and Modulators. http://www.redfernclinic.com/concord/2008/05/treating-addicted-brain-agonists.php4
20/5/08
Adult ADHD & Substance Use Disorders – Dr Julian Trollor
http://www.redfernclinic.com/concord/2008/07/adult-adhd-substance-use-disorders-dr.php4
22/7/08
Amphetamine/Stimulant Use: Presentations, complications, interventions.
http://www.redfernclinic.com/concord/2007/01/amphetaminestimulant-use-presentations_30.php4
30/1/07
Methadone side effects, separating fact and fiction.
http://www.redfernclinic.com/concord/2008/03/methadone-side-effects-separating-fact.php4
20/3/07
The Interpretation of Urine Toxicology in Dependency Treatment. Principals and Pitfalls.
http://www.redfernclinic.com/concord/2007/05/interpretation-of-urine-toxicology-in.php4
22/5/07
Personality Disorders. 31 July 2007
http://www.redfernclinic.com/concord/2007/07/personality-disorders-31-july-2007.php4
31/7/07
Personality disorders (by Dr Glenys Dore) supplementary notes.
http://www.redfernclinic.com/concord/2008/07/personality-disorders-by-dr-glenys-dore.php4
31/7/07
Withdrawal management and detoxification-with a focus on complicated patients.
http://www.redfernclinic.com/concord/2007/09/withdrawal-management-and.php4
25/9/07
Advances in assessment and treatments for infection with hepatitis C virus (HCV)
http://www.redfernclinic.com/concord/2007/11/advances-in-assessment-and-treatments.php4
20/11/07
Welfare to Work, Implications for your Patients.
http://www.redfernclinic.com/c/2006/06/welfare-to-work-implications-for-your_2495.php4
30/5/06
Dependency issues and pain management - "A Busman's Holiday and Other Stories" http://www.redfernclinic.com/c/2006/08/dependency-issues-and-pain-management_9514.php4
25/7/06
Opioid Maintenance: Back to Basics. Therapeutic lessons from Vioxx and LAAM.
http://www.redfernclinic.com/c/2006/11/opioid-maintenance-back-to-basics_9619.php4
26/9/06
Dependency issues in gaols, juvenile justice and drug courts http://www.redfernclinic.com/c/2006/11/dependency-issues-in-gaols-juvenile_7874.php4
21/11/06
The use of anti-craving drugs for alcohol dependence.
http://www.redfernclinic.com/concord/2008/02/use-of-anti-craving-drugs-for-alcohol.php4
4/2/03
Dental problems in addiction treatment subjects. Does methadone rot teeth? Can we prevent dental decay?
http://www.redfernclinic.com/c/2003/05/dental-problems-in-addiction-treatment_20.php4
20/5/03
Smoking cessation in dependency patients / Therapeutic thresholds in methadone maintenance
http://www.redfernclinic.com/c/2003/09/smoking-cessation-in-dependency_23.php4
23/9/03
29 December 2008
31 July 2008
"The Other Hepatitis" - An Update on Hepatitis B.
Concord Dependency Seminar Tuesday 23 July 2008 "The Other Hepatitis" - An Update on Hepatitis B. Dr Gail Matthews, St Vincents Hospital Darlinghurst
Summary Part 1. Epidemiology, natural history, assessment.
This seminar was titled The Other Hepatitis, reflecting the lower prevalence of Hepatitis B compared with Hepatitis C among people using addiction treatment services, and the lower profile of HBV in the community.
In contrast to the vigorous response in recent years to hepatitis C (HCV) in Australia, the response to hepatitis B (HBV) has lagged behind, despite important recent developments in understanding of HBV, in diagnostic tests and antiviral treatments, and desite its large disease burden, especially chronic liver disease and liver cancer.
There are many contrasts between HBV and HCV. Whereas HCV in Australia consists of two 'epidemics' - an older group of people born overseas in endemic areas and a younger group of injecting drug users - about half the prevalence of HBV is among Australians born overseas in endemic areas, especially China and SE Asia but also the Middle east and Mediterranean. Only 5% of chronic HBV is among IDUs; another 8% among men who have sex with men (MSM) and a staggering 16% among indigenous Australians.
The picture is different for new infections (incidence) of HBV in Australia: 44% of these happen among IDU (showing the importance of catch-up vaccination for non-immune people in this risk group) and 35% are through sexual transmission, disproportionately among MSM, but the majority still through heterosexual sex.
The total number of people in Australia with chronic HCV is fairly reliably estimated to be between 200,000 and 250,000, while estimates for HBV range more widely between 90,000 and 160,000, reflecting in part poor knowledge of HBV and low levels of testing among some of the high risk groups.
HBV is a DNA virus, where HCV is an RNA virus. HCV is essentially blood-to-blood transmission, particularly by unsafe injecting, and rarely by sexual transmission, while HBV is spread by contact with infected body fluids including blood, semen and saliva. HBV is thus sexually transmitted, but also by vertical transmission (mother to child), horizontally (close personal contact especially in childhood eg cuts, sores) and by IDU.
Of people infected with HCV, 20-30% spontaneously clear the virus, usually within 6 months, and regardless of their age at infection, without however developing immunity (ie they can be reinfected with HCV). Few people develop clinically evident acute hepatitis. By contrast, for HBV progression to chronic infection is strongly related to age at infection: 80-90% of children infected perinatally develop chronic HBV, with lower rates (30%) of chronicity after infection under the age of 5 years; only 6% of older children and adults develop chronic HBV. Most adults who are infected with HBV develop clinically evident acute hepatitis.
Unlike HCV where late clearance of the virus is unknown, a small percentage of people with chronic HBV clear the virus and develop immunity each year.
HBV and HVC are similar in that a subset of people develop chronic liver inflammation which may slowly progress to cirrhosis and liver failure in a minority of cases, and which increases the risk of development of hepatocellular carcinoma (HCC).
The diagnostic tests for HBV, and the natural history of the disease, while rather more complicated than for HCV, have become clearer in recent years. Chronic HBV is now though of as having 4 phases, with gradual progression through the first 2 phases "immune tolerant" and "immunoactive" into the third phase called "immune control" and sometimes progression into a fourth phase called "immune escape".
In the "immune tolerant" phase, there are high levels of HBV-DNA in the blood but little inflammation of the liver (so liver enzymes like ALT are low or normal). The body is not really fighting the virus. This phase is prolonged in people who get HBV perinatally (20 years or more) but is usually much shorter in adult infections.
In the "immunoactive" phase, DNA levels and liver inflammation (ALT) tend to fluctuate. The body is fighting the virus and the liver is in the wars. This can go on for many years, and this is when much of the liver damage from HBV develops.
If the body develops "immune control", viral DNA drops to undetectable levels and the liver function tests normalise. This phase can go on for decades and is associated with no progression of liver disease.
Unfortunately in some people HBV escapes from immune control. In the "immune escape" phase, viral DNA is detectable again and the ALT indicates liver inflammation. People in this phase of HBV often have the most seriously progressive disease.
In making a diagnosis of HBV and working out which phase a person is in, 3 types of tests are used: serological tests, liver function tests (especially ALT for inflammation), and viral DNA measurement (in Australia until recently only specialists could order this expensive test).
There are five commonly used serological tests for HBV. The surface antigen (HBsAg) indicates current Hepatitis B infection. It says "you have hep B now". It is found in serum during the incubation period before symptoms, and persists unless antibodies develop to the surface antigen (anti-HBs). Persistence of HBsAg defines chronic HBV and presence of anti-HBs indicates immunity to HBV infection (either by clearance of surface antigen, or by vaccination). Anti-HBs says "you don't have hep B and you can't get it anymore". * Sometimes anti-HBs wanes to undetectable levels in a person who has immunity to HBV, but there is still immune memory and anti-HBs rises to any immune challenge.
(* but see exceptions below)
The HBV core antibody (anti-HBc) develops early after HBV exposure and generally persists for ever: it just indicates previous exposure, and doesn't imply immunity (in this way it resembles HCV antibody). It says "HBV was here - and may still be here".
There are also tests for the HBV "e" antigen and its antibody (HBeAg and anti-HBe). HBeAg is a marker of viral replication and infectivity, and means there are high levels of HBV DNA in the blood. The person with HBeAg is either in the "immune tolerant" or the "immunoactive" phase of HBV. Loss of the HBeAg with appearance of anti-HBe generally indicates that the HBV DNA levels have been suppressed, the so-called "immune control phase" of hepatitis B - in this case the liver function tests will usually be normal.
However absence of HBeAg and presence of anti-HBe also occurs when a person moves into the "immune escape phase", where HBV-DNA levels and the ALT rise again.
Putting these tests together, HBsAg with HBeAg means chronic HBV with high infectivity. HBsAg with anti-HBe generally means low infectivity, undetectable DNA and "immune control" but can point to "immune escape phase", with high HBV-DNA levels and liver inflammation.
HBV is an oncogenic virus, and unlike HCV, can cause hepatocellular carcinoma (HCC) in the absence of cirrhosis. Of all people with chronic HBV, about 30% will go on to cirrhosis, and 5-10% will go on to HCC. Of people with HBV cirrhosis, about 1 in 4 will go on to liver failure within 5 years.
Numerous factors negatively influence HBV natural history and prognosis: host factors (male gender, older age, obesity and diabetes); viral factors (high viral load, genotype C); coinfection (HIV, HCV, hepatitis D); tobacco smoking and alcohol use. Mortality from liver failure or HCC is much higher when there is HIV coinfection.
Primary prevention for HBV depends on screening and vaccination of high risk individuals and universal vaccination of infants. People who may have poor immune response (HIV/haemodialysis patients) or who may be at higher risk (people with existing liver disease, health care workers) should have anti-HBs checked after the usual 3-vaccine course, and may need a booster. People, including infants, who have accelerated HBV vaccination schedules should also have a booster at 12 months. Immunocompetent people generally do not need boosters even if anti-HBs wanes. However, 5-10% of people fail to respond to vaccination, and these people should be advised that they may need passive vaccination with HBV immunoglobulin (HBIG) within 72 hours if they are exposed to HBV.
HBIG should be given to babies of HBsAg mothers within 12 hrs of delivery, and standard vaccination carried out.
The second part of this summmary will present treatment issues and case studies:
http://www.redfernclinic.com/concord/2008/07/other-hepatitis-update-on-hepatitis-b_31.php4
Summary Part 1. Epidemiology, natural history, assessment.
This seminar was titled The Other Hepatitis, reflecting the lower prevalence of Hepatitis B compared with Hepatitis C among people using addiction treatment services, and the lower profile of HBV in the community.
In contrast to the vigorous response in recent years to hepatitis C (HCV) in Australia, the response to hepatitis B (HBV) has lagged behind, despite important recent developments in understanding of HBV, in diagnostic tests and antiviral treatments, and desite its large disease burden, especially chronic liver disease and liver cancer.
There are many contrasts between HBV and HCV. Whereas HCV in Australia consists of two 'epidemics' - an older group of people born overseas in endemic areas and a younger group of injecting drug users - about half the prevalence of HBV is among Australians born overseas in endemic areas, especially China and SE Asia but also the Middle east and Mediterranean. Only 5% of chronic HBV is among IDUs; another 8% among men who have sex with men (MSM) and a staggering 16% among indigenous Australians.
The picture is different for new infections (incidence) of HBV in Australia: 44% of these happen among IDU (showing the importance of catch-up vaccination for non-immune people in this risk group) and 35% are through sexual transmission, disproportionately among MSM, but the majority still through heterosexual sex.
The total number of people in Australia with chronic HCV is fairly reliably estimated to be between 200,000 and 250,000, while estimates for HBV range more widely between 90,000 and 160,000, reflecting in part poor knowledge of HBV and low levels of testing among some of the high risk groups.
HBV is a DNA virus, where HCV is an RNA virus. HCV is essentially blood-to-blood transmission, particularly by unsafe injecting, and rarely by sexual transmission, while HBV is spread by contact with infected body fluids including blood, semen and saliva. HBV is thus sexually transmitted, but also by vertical transmission (mother to child), horizontally (close personal contact especially in childhood eg cuts, sores) and by IDU.
Of people infected with HCV, 20-30% spontaneously clear the virus, usually within 6 months, and regardless of their age at infection, without however developing immunity (ie they can be reinfected with HCV). Few people develop clinically evident acute hepatitis. By contrast, for HBV progression to chronic infection is strongly related to age at infection: 80-90% of children infected perinatally develop chronic HBV, with lower rates (30%) of chronicity after infection under the age of 5 years; only 6% of older children and adults develop chronic HBV. Most adults who are infected with HBV develop clinically evident acute hepatitis.
Unlike HCV where late clearance of the virus is unknown, a small percentage of people with chronic HBV clear the virus and develop immunity each year.
HBV and HVC are similar in that a subset of people develop chronic liver inflammation which may slowly progress to cirrhosis and liver failure in a minority of cases, and which increases the risk of development of hepatocellular carcinoma (HCC).
The diagnostic tests for HBV, and the natural history of the disease, while rather more complicated than for HCV, have become clearer in recent years. Chronic HBV is now though of as having 4 phases, with gradual progression through the first 2 phases "immune tolerant" and "immunoactive" into the third phase called "immune control" and sometimes progression into a fourth phase called "immune escape".
In the "immune tolerant" phase, there are high levels of HBV-DNA in the blood but little inflammation of the liver (so liver enzymes like ALT are low or normal). The body is not really fighting the virus. This phase is prolonged in people who get HBV perinatally (20 years or more) but is usually much shorter in adult infections.
In the "immunoactive" phase, DNA levels and liver inflammation (ALT) tend to fluctuate. The body is fighting the virus and the liver is in the wars. This can go on for many years, and this is when much of the liver damage from HBV develops.
If the body develops "immune control", viral DNA drops to undetectable levels and the liver function tests normalise. This phase can go on for decades and is associated with no progression of liver disease.
Unfortunately in some people HBV escapes from immune control. In the "immune escape" phase, viral DNA is detectable again and the ALT indicates liver inflammation. People in this phase of HBV often have the most seriously progressive disease.
In making a diagnosis of HBV and working out which phase a person is in, 3 types of tests are used: serological tests, liver function tests (especially ALT for inflammation), and viral DNA measurement (in Australia until recently only specialists could order this expensive test).
There are five commonly used serological tests for HBV. The surface antigen (HBsAg) indicates current Hepatitis B infection. It says "you have hep B now". It is found in serum during the incubation period before symptoms, and persists unless antibodies develop to the surface antigen (anti-HBs). Persistence of HBsAg defines chronic HBV and presence of anti-HBs indicates immunity to HBV infection (either by clearance of surface antigen, or by vaccination). Anti-HBs says "you don't have hep B and you can't get it anymore". * Sometimes anti-HBs wanes to undetectable levels in a person who has immunity to HBV, but there is still immune memory and anti-HBs rises to any immune challenge.
(* but see exceptions below)
The HBV core antibody (anti-HBc) develops early after HBV exposure and generally persists for ever: it just indicates previous exposure, and doesn't imply immunity (in this way it resembles HCV antibody). It says "HBV was here - and may still be here".
There are also tests for the HBV "e" antigen and its antibody (HBeAg and anti-HBe). HBeAg is a marker of viral replication and infectivity, and means there are high levels of HBV DNA in the blood. The person with HBeAg is either in the "immune tolerant" or the "immunoactive" phase of HBV. Loss of the HBeAg with appearance of anti-HBe generally indicates that the HBV DNA levels have been suppressed, the so-called "immune control phase" of hepatitis B - in this case the liver function tests will usually be normal.
However absence of HBeAg and presence of anti-HBe also occurs when a person moves into the "immune escape phase", where HBV-DNA levels and the ALT rise again.
Putting these tests together, HBsAg with HBeAg means chronic HBV with high infectivity. HBsAg with anti-HBe generally means low infectivity, undetectable DNA and "immune control" but can point to "immune escape phase", with high HBV-DNA levels and liver inflammation.
HBV is an oncogenic virus, and unlike HCV, can cause hepatocellular carcinoma (HCC) in the absence of cirrhosis. Of all people with chronic HBV, about 30% will go on to cirrhosis, and 5-10% will go on to HCC. Of people with HBV cirrhosis, about 1 in 4 will go on to liver failure within 5 years.
Numerous factors negatively influence HBV natural history and prognosis: host factors (male gender, older age, obesity and diabetes); viral factors (high viral load, genotype C); coinfection (HIV, HCV, hepatitis D); tobacco smoking and alcohol use. Mortality from liver failure or HCC is much higher when there is HIV coinfection.
Primary prevention for HBV depends on screening and vaccination of high risk individuals and universal vaccination of infants. People who may have poor immune response (HIV/haemodialysis patients) or who may be at higher risk (people with existing liver disease, health care workers) should have anti-HBs checked after the usual 3-vaccine course, and may need a booster. People, including infants, who have accelerated HBV vaccination schedules should also have a booster at 12 months. Immunocompetent people generally do not need boosters even if anti-HBs wanes. However, 5-10% of people fail to respond to vaccination, and these people should be advised that they may need passive vaccination with HBV immunoglobulin (HBIG) within 72 hours if they are exposed to HBV.
HBIG should be given to babies of HBsAg mothers within 12 hrs of delivery, and standard vaccination carried out.
The second part of this summmary will present treatment issues and case studies:
http://www.redfernclinic.com/concord/2008/07/other-hepatitis-update-on-hepatitis-b_31.php4
"The Other Hepatitis" - An Update on Hepatitis B [PART II]
Concord Dependency Seminar Tuesday 23 July 2008 "The Other Hepatitis" - An Update on Hepatitis B. Dr Gail Matthews, St Vincents Hospital Darlinghurst
Summary Part 2. Treatment issues and case studies.
Dr Matthews pointed out that HBV is a fluctuating disease, and that for the majority, chronic HBV is never "cured". One might wish for HBsAg seroconversion as a goal of treatment, but this currently impracticable. For this reason it is best to think of and manage HBV as a chronic viral illness like HIV, rather than merely a viral hepatitis.
(Note: the majority of adults after acute infection, and a small percentage of people each year after chronic infection, may spontaneously clear HBV by developing anti-HBs. Usually this amounts to spontaneous "cure", however even then HBV can return in situations of immunocompromise eg HIV infection, chemotherapy).
Overall, about 60% of people with HBV can be managed by regular monitoring and attention to risk factors for disease progression, while 40% need antiviral treatment. However, people can move from one group to the other.
The goals of therapy can be defined in several ways, but the essential aim is virological suppression to allow histological improvement, and prevention of HCC and end stage liver disease.
For HBeAg positive individuals, a desirable end-point is anti-HBe seroconversion, with loss of HBeAg. For HBeAg negative individuals, suppression of viral DNA is the essential aim. For all individuals, normalisation of ALT is a good indicator of reduced hepatic injury.
Current therapeutic agents are divided into two types, immune modulators (alpha interferon) and antiviral agents (nucleoside analogues NAs). The development of pegylated interferons and a wider range of NAs has improved therapeutic options and outcomes.
The two main therapeutic questions are: whether to use an immune modulator vs an antiviral; and whether to use one or two agents (immune modulator plus NA, or two NAs).
The benefits of interferon alpha monotherapy for HBeAg positive patients are clear, with reduced rates of cirrhosis and HCC, and increased survival. The treatment aim is to "push" these people into the "immune tolerant" phase of HBV. The advantages of interferon are the finite duration of treatment, durable treatment response (when it occurs), the high rate of HBeAg loss (around 30%), and loss of HBsAg in 3%-8%. Drug resistance does not develop. Disadvantages include unpleasant side effects, high cost, and lower responses with some genotypes and where there is high-level viraemia.
Combination therapy with lamivudine plus interferon alpha for HBeAg positive patients gave higher end of treatment viral response but no higher rates of viral response, eAg seroconversion or sAg seroconversion, compared with interferon alone (Lau et al NEJM 2005).
Nucleoside analogues for HBV include lamivudine, adefovir, entecavir, telbivudine, tenofovir and emtricitabine (the first 4 are currently licensed for HBV). The archetypal NA, lamivudine, effectively suppresses viral replication, with reduced liver inflammation and improved liver histology. In up to 50% of HBeAg positive people, it also produces seroconversion to anti-HBe ("pushing" into the immune control phase) however this may take as long as 5 years. For people who do not achieve eAg seroconversion (ie do not develop anti-HBe) the therapy must be continued indefinitely, as it must also for people who are eAg negative (in the "immune escape" phase).
Unfortunately, viral resistance to lamivudine develops almost universally with time, especially where there is HIV coinfection. In this situation, alternatives are adefovir, and entecavir; the latter is a more potent suppressor of viral replication, and resistance appears to be less of a problem. It may increasingly be first line therapy for many people.
Nucleosides analogues have the advantages of oral delivery with minimal side effects. Treatment is less expensive than interferon, but not when given long-term. There is potential for multidrug resistant organisms, especially when NAs are used sequentially.
Management of chronic HBV depends on a thorough assessment including liver function, serological markers, HBV DNA, sometimes liver biopsy (or fibroscan), and cofactors for disease progression (HCV/HDV/HIV). People should be vaccinated for HAV, given clear advice on transmission, and problems of alcohol, tobacco, obesity and diabetes dealt with if possible.
Specific treatment is recommended for:
• HBeAg positive people who have elevated ALT, and HBV DNA > 20,000 IU/ml
• HBeAg negative people who have abnormal ALT, HBV DNA > 2,000 IU/ml, and necroinflammation/fibrosis on biopsy
• Cirrhotic patients with any level of measurable HBV DNA
Initial Treatment Strategies
Immune modulators may be preferred for healthy people < 60 years, with no cirrhosis, a baseline HBV-DNA > 1010 copies/mL, and ALT > 2-3 times normal, and who have genotype A or B (the more responsive genotypes)
Nucleoside analogs can be used for any age adult, for any genotype, with or without comorbidity (including cirrhosis with or without decompensation), a baseline HBV-DNA 109 copies/mL and ALT > 5 times normal.
In people with advanced HBV it is important to manage the viral infection aggressively and refer early for transplant assessment. Any patient with cirrhosis should have 6-monthly screening for HCC, using alphafetoprotein (AFP) and abdominal ultrasound (in cases of doubt triple phase CT/MRI). The following groups should also be targeted for HCC screening, regardless of their stage of liver disease: Asian men over 40 years of age; Asian women over 50 years of age; Africans over 20 years of age; and people with a family history of HCC.
Case studies (with apologies to Hanna Barbera)
Barnie is 36. He has a 12 year history of heroin injecting, previous buprenorphine maintenance on several occasions usually of short duration and with subsequent relapse His current BMT episode is 5 months, dose 8mg/day and he keeps using heroin.
He says "I've had hep B and hep C for years." He sometimes shares fits because 'What's the point? I've got both already." He drinks alcohol most days, 30-120g.
He is HCV seropositive and HCV-RNApcr positive; HIV negative and HBsAg positive. His ALT is 72, AST 60, GGT and other liver function tests are normal. After strong advice, he ceases sharing injecting paraphernalia, but he continues drinking most days.
On subsequent testing his ALT remains elevated. His second HCV-RNA pcr test is negative. He remains HBsAg positive, HBeAg positive and Anti-HBe negative. How should he be managed?
Comments: if his HCV-RNA remains negative, he may have ceased reinfecting himself with HCV and cleared the virus. He has "immunoactive" HBV with alcohol as a risk factor. Progressive liver fibrosis can occur in the "immunoactive" phase, and alcohol and periods of HCV infection may have contributed to this. Liver biopsy staging may be helpful here. If he does not have cirrhosis already, could have interferon treatment to try to push him into the "immune control" phase of HBV. He should be strongly encouraged and supported to stop alcohol entirely, and this would be a condition for interferon treatment. An alternative would be long term NA treatment.
Fred is 37 and has been on MMT for 6 years. He has not injected drugs for 5 years, and has practically given up alcohol, which he used to drink regularly 30-80g/day. He smokes 40 roll-your-own cigarettes a day.
He is HCV and HIV seronegative but has HBsAg, with both e antibody and antigen. He thinks he got HBV from injecting, but doesn't know when. His ALT and AST are usually normal or mildly elevated (<80) and other liver tests are normal.
During ketoconazole treatment for toenail tinea his transaminases rose to over 500, with other LFTs normal. He stopped the ketoconazole but his transaminases remained elevated (about twice normal) over the next 2 years. He remained positive for HBsAg, and anti-HBe, and became negative for HBeAg.
Fred is against "western" treatment for his liver, and gets herbal treatments from a homeopath in Victoria who runs a telephone consultancy. The cost of these medications ranges up to $60/month plus $60 for each phone consultation. Fred pays the phone bill.
Comments: when he had both Anti-HBe and HBeAg, he was apparently seroconverting for e antigen, thus follow up showed loss of HBeAg. As his transaminases remained elevated, HBV-RNA testing was subsequently done, showing <2,000 IU and confirming "immune escape" phase. He therefore needs long term nucleoside analog treatment. There is no evidence for the benefit of homeopathic treatment, and this should not distract him from the antiviral treatment which he needs to prevent severe liver damage. His smoking is a risk factor for HBV disease progression.
Pebbles is a 32 year old transsexual who is on BMT for heroin addiction. She has always smoked her heroin and never injected drugs. She was born in Asia: her blood tests show anti-HBc and HBsAg but her liver tests are always normal. She says all her family back home have Hep B. She has anti-HBe and does not have the HBeAg. She asks "I am going to get liver cancer?"
Comments: she was probably infected early in life, and is now in the "immune control" phase of HBV. She is at risk of hepatoma even if she remains in the "immune control" phase, and should be screened every six months after the age of 40, or from now if there is a family history of liver cancer. Although it is unlikely she has cirrhosis on this evidence, it is possible. If liver biopsy or fibroscan showed evidence of cirrhosis she should have hepatoma surveillance.
Dino is 38 and is on MMT. He has cleared HCV, is HIV negative and had a full course of HBV vaccination 6 years ago. After a recent test showing negative for anti-HBc, anti-HBs and HBsAg, he had two more HBV shots, but remained anti-HBs negative 6 months later. He asks “What's the point of me having all these tests & these expensive shots if they don't work?"
Comments: 5-10% of people fail to respond to vaccination, and these people should be advised that they may need passive vaccination with HBIG within 72 hours if they are exposed to HBV. HAV vaccination should be offered if he is not immune.
Betty is a 54 year old injecting drug user on MMT with regular alcohol use (40-60g/day most days). She is HCV and HIV seronegative. Her HBV serology is: anti-HBc positive, anti-HBs negative, HBsAg negative, eAg and anti-HBe also negative. Her ALT and AST are always high, with ALT>AST. Should she have HBV-DNA testing?
Comments: with isolated core antibody, it is most likely she has waned surface antibody, and a challenge with a vaccine may demonstrate this with anti-HBs becoming measurable. It is also possible she has chronic HBV and low level HBV-DNA despite not having measurable surface antigen. However, it is unlikely that such low levels of DNA would cause clinically significant disease. HBV-DNA testing is probably not needed but she should be advised to reduce her alcohol to safe levels and liver tests followed up 6-monthly.
Summary Part 2. Treatment issues and case studies.
Dr Matthews pointed out that HBV is a fluctuating disease, and that for the majority, chronic HBV is never "cured". One might wish for HBsAg seroconversion as a goal of treatment, but this currently impracticable. For this reason it is best to think of and manage HBV as a chronic viral illness like HIV, rather than merely a viral hepatitis.
(Note: the majority of adults after acute infection, and a small percentage of people each year after chronic infection, may spontaneously clear HBV by developing anti-HBs. Usually this amounts to spontaneous "cure", however even then HBV can return in situations of immunocompromise eg HIV infection, chemotherapy).
Overall, about 60% of people with HBV can be managed by regular monitoring and attention to risk factors for disease progression, while 40% need antiviral treatment. However, people can move from one group to the other.
The goals of therapy can be defined in several ways, but the essential aim is virological suppression to allow histological improvement, and prevention of HCC and end stage liver disease.
For HBeAg positive individuals, a desirable end-point is anti-HBe seroconversion, with loss of HBeAg. For HBeAg negative individuals, suppression of viral DNA is the essential aim. For all individuals, normalisation of ALT is a good indicator of reduced hepatic injury.
Current therapeutic agents are divided into two types, immune modulators (alpha interferon) and antiviral agents (nucleoside analogues NAs). The development of pegylated interferons and a wider range of NAs has improved therapeutic options and outcomes.
The two main therapeutic questions are: whether to use an immune modulator vs an antiviral; and whether to use one or two agents (immune modulator plus NA, or two NAs).
The benefits of interferon alpha monotherapy for HBeAg positive patients are clear, with reduced rates of cirrhosis and HCC, and increased survival. The treatment aim is to "push" these people into the "immune tolerant" phase of HBV. The advantages of interferon are the finite duration of treatment, durable treatment response (when it occurs), the high rate of HBeAg loss (around 30%), and loss of HBsAg in 3%-8%. Drug resistance does not develop. Disadvantages include unpleasant side effects, high cost, and lower responses with some genotypes and where there is high-level viraemia.
Combination therapy with lamivudine plus interferon alpha for HBeAg positive patients gave higher end of treatment viral response but no higher rates of viral response, eAg seroconversion or sAg seroconversion, compared with interferon alone (Lau et al NEJM 2005).
Nucleoside analogues for HBV include lamivudine, adefovir, entecavir, telbivudine, tenofovir and emtricitabine (the first 4 are currently licensed for HBV). The archetypal NA, lamivudine, effectively suppresses viral replication, with reduced liver inflammation and improved liver histology. In up to 50% of HBeAg positive people, it also produces seroconversion to anti-HBe ("pushing" into the immune control phase) however this may take as long as 5 years. For people who do not achieve eAg seroconversion (ie do not develop anti-HBe) the therapy must be continued indefinitely, as it must also for people who are eAg negative (in the "immune escape" phase).
Unfortunately, viral resistance to lamivudine develops almost universally with time, especially where there is HIV coinfection. In this situation, alternatives are adefovir, and entecavir; the latter is a more potent suppressor of viral replication, and resistance appears to be less of a problem. It may increasingly be first line therapy for many people.
Nucleosides analogues have the advantages of oral delivery with minimal side effects. Treatment is less expensive than interferon, but not when given long-term. There is potential for multidrug resistant organisms, especially when NAs are used sequentially.
Management of chronic HBV depends on a thorough assessment including liver function, serological markers, HBV DNA, sometimes liver biopsy (or fibroscan), and cofactors for disease progression (HCV/HDV/HIV). People should be vaccinated for HAV, given clear advice on transmission, and problems of alcohol, tobacco, obesity and diabetes dealt with if possible.
Specific treatment is recommended for:
• HBeAg positive people who have elevated ALT, and HBV DNA > 20,000 IU/ml
• HBeAg negative people who have abnormal ALT, HBV DNA > 2,000 IU/ml, and necroinflammation/fibrosis on biopsy
• Cirrhotic patients with any level of measurable HBV DNA
Initial Treatment Strategies
Immune modulators may be preferred for healthy people < 60 years, with no cirrhosis, a baseline HBV-DNA > 1010 copies/mL, and ALT > 2-3 times normal, and who have genotype A or B (the more responsive genotypes)
Nucleoside analogs can be used for any age adult, for any genotype, with or without comorbidity (including cirrhosis with or without decompensation), a baseline HBV-DNA 109 copies/mL and ALT > 5 times normal.
In people with advanced HBV it is important to manage the viral infection aggressively and refer early for transplant assessment. Any patient with cirrhosis should have 6-monthly screening for HCC, using alphafetoprotein (AFP) and abdominal ultrasound (in cases of doubt triple phase CT/MRI). The following groups should also be targeted for HCC screening, regardless of their stage of liver disease: Asian men over 40 years of age; Asian women over 50 years of age; Africans over 20 years of age; and people with a family history of HCC.
Case studies (with apologies to Hanna Barbera)
Barnie is 36. He has a 12 year history of heroin injecting, previous buprenorphine maintenance on several occasions usually of short duration and with subsequent relapse His current BMT episode is 5 months, dose 8mg/day and he keeps using heroin.
He says "I've had hep B and hep C for years." He sometimes shares fits because 'What's the point? I've got both already." He drinks alcohol most days, 30-120g.
He is HCV seropositive and HCV-RNApcr positive; HIV negative and HBsAg positive. His ALT is 72, AST 60, GGT and other liver function tests are normal. After strong advice, he ceases sharing injecting paraphernalia, but he continues drinking most days.
On subsequent testing his ALT remains elevated. His second HCV-RNA pcr test is negative. He remains HBsAg positive, HBeAg positive and Anti-HBe negative. How should he be managed?
Comments: if his HCV-RNA remains negative, he may have ceased reinfecting himself with HCV and cleared the virus. He has "immunoactive" HBV with alcohol as a risk factor. Progressive liver fibrosis can occur in the "immunoactive" phase, and alcohol and periods of HCV infection may have contributed to this. Liver biopsy staging may be helpful here. If he does not have cirrhosis already, could have interferon treatment to try to push him into the "immune control" phase of HBV. He should be strongly encouraged and supported to stop alcohol entirely, and this would be a condition for interferon treatment. An alternative would be long term NA treatment.
Fred is 37 and has been on MMT for 6 years. He has not injected drugs for 5 years, and has practically given up alcohol, which he used to drink regularly 30-80g/day. He smokes 40 roll-your-own cigarettes a day.
He is HCV and HIV seronegative but has HBsAg, with both e antibody and antigen. He thinks he got HBV from injecting, but doesn't know when. His ALT and AST are usually normal or mildly elevated (<80) and other liver tests are normal.
During ketoconazole treatment for toenail tinea his transaminases rose to over 500, with other LFTs normal. He stopped the ketoconazole but his transaminases remained elevated (about twice normal) over the next 2 years. He remained positive for HBsAg, and anti-HBe, and became negative for HBeAg.
Fred is against "western" treatment for his liver, and gets herbal treatments from a homeopath in Victoria who runs a telephone consultancy. The cost of these medications ranges up to $60/month plus $60 for each phone consultation. Fred pays the phone bill.
Comments: when he had both Anti-HBe and HBeAg, he was apparently seroconverting for e antigen, thus follow up showed loss of HBeAg. As his transaminases remained elevated, HBV-RNA testing was subsequently done, showing <2,000 IU and confirming "immune escape" phase. He therefore needs long term nucleoside analog treatment. There is no evidence for the benefit of homeopathic treatment, and this should not distract him from the antiviral treatment which he needs to prevent severe liver damage. His smoking is a risk factor for HBV disease progression.
Pebbles is a 32 year old transsexual who is on BMT for heroin addiction. She has always smoked her heroin and never injected drugs. She was born in Asia: her blood tests show anti-HBc and HBsAg but her liver tests are always normal. She says all her family back home have Hep B. She has anti-HBe and does not have the HBeAg. She asks "I am going to get liver cancer?"
Comments: she was probably infected early in life, and is now in the "immune control" phase of HBV. She is at risk of hepatoma even if she remains in the "immune control" phase, and should be screened every six months after the age of 40, or from now if there is a family history of liver cancer. Although it is unlikely she has cirrhosis on this evidence, it is possible. If liver biopsy or fibroscan showed evidence of cirrhosis she should have hepatoma surveillance.
Dino is 38 and is on MMT. He has cleared HCV, is HIV negative and had a full course of HBV vaccination 6 years ago. After a recent test showing negative for anti-HBc, anti-HBs and HBsAg, he had two more HBV shots, but remained anti-HBs negative 6 months later. He asks “What's the point of me having all these tests & these expensive shots if they don't work?"
Comments: 5-10% of people fail to respond to vaccination, and these people should be advised that they may need passive vaccination with HBIG within 72 hours if they are exposed to HBV. HAV vaccination should be offered if he is not immune.
Betty is a 54 year old injecting drug user on MMT with regular alcohol use (40-60g/day most days). She is HCV and HIV seronegative. Her HBV serology is: anti-HBc positive, anti-HBs negative, HBsAg negative, eAg and anti-HBe also negative. Her ALT and AST are always high, with ALT>AST. Should she have HBV-DNA testing?
Comments: with isolated core antibody, it is most likely she has waned surface antibody, and a challenge with a vaccine may demonstrate this with anti-HBs becoming measurable. It is also possible she has chronic HBV and low level HBV-DNA despite not having measurable surface antigen. However, it is unlikely that such low levels of DNA would cause clinically significant disease. HBV-DNA testing is probably not needed but she should be advised to reduce her alcohol to safe levels and liver tests followed up 6-monthly.
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