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31 July 2008

"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.