1 February 2005

Hepatitis C diagnosis and management

1st February 2005

Update by Dr Greg Dore, St Vincent's Hospital, Darlinghurst.

This talk reminded us of the progress made in a disease which was not characterised until about 1980 and which we are still learning about today. Previously largely diagnosed as non-A, non-B hepatitis, it probably started in the 1960s in small numbers of parenterally acquired hepatitis, spreading quickly by the 1970s as injecting became popular in the drug using sub-culture.

Dr Dore showed various graphs indicating the dramatic increase in reported cases, pointing out the important distinction between such reports and true incidence or actual seroconversions. Many 'new' reports are diagnoses of patients whose infection was acquired many years previously. We learned that it is more instructive from a public health perspective to track reports from young people 15 - 22 years of age, where the figure more closely mirrors the true rate of seroconversion. This was rising through the 1990s but recent years have shown slowing and possibly a decline at last, in response to improved harm reduction policies. In reality, however, the actual pool of HCV positive patients continues to expand and is probably now over 200,000 in Australia, mostly from drug use. A small proportion acquired the infection from blood transfusions, haemophilia treatments, surgery, tattoos, body piercing, etc.

Six monthly testing in those at risk seems to be a common recommendation, but Dr Dore emphasised the individual needs. Conveniently, six months is also a reasonable interval for monitoring of disease progression in those who are HCV positive. We were then taken through the practicalities of testing. There are numerous possible approaches to screening/monitoring utilising the several available antibody tests, confirmations and HCV RNA pcr (polymerase chain reaction) which is a viral marker or highly sensitive test for presence of virus in the blood. For antibody tests, false positives occur at approximately 1 in 100 tests, presumably being at low titre in response to non HCV antigens. Thus in low risk groups they are frequent and in our high risk patient they can also occur from time to time. In assessing on-going hepatitis, Dr Dore finds little point in routine serum copper, ceruloplasmin or alpha-1 antitrypsin levels. These are all exceedingly rare and would likely be diagnosed at liver biopsy anyway. However he does advise testing for haemochromatosis using iron studies. He has found abdominal ultrasound examinations of limited use except for some cases of fatty liver.

The more widespread availability of HCV PCR as an indicator of actual virus in the blood has improved our approach to disease staging and to measure treatment responses. Under Medicare, GPs can only order this test if the transaminase levels are NORMAL on TWO occasions (serum can be kept frozen for later test requests). Thus we can reassure a certain proportion of cases (up to 40%) where the virus has become undetectable without specific treatment.

Drawing a parallel with HIV, Dr Dore explained the depressingly low rates of responses to original monotherapy (<20%) and subsequent sequential improvements with longer acting interferon (pegylated) combined with ribavirin in recent years (up to 80% response).

Criteria for biopsy and treatment were discussed in some detail. Persistently elevated liver function tests, >10 years disease duration, >35 years of aged were all relative indications for biopsy and treatment where appropriate. The genotype is also an important factor since types 2 and 3 are more likely to have a response (70-80%) than type 1 (~50%) after 6 month (for genotypes 2 or 3) and 12 months (genotype 1) of treatment. Type 1 appears to be less common in Australia than the USA.

There are worse prognostic features in patients who are overweight and who drink excessively as well as for those with co-existing HIV or hepatitis B. Indicators of more advanced liver disease (cirrhosis) include ALT/AST ratio greater than one, reduced platelet count and multiple spider n�vi. Continued injecting or drinking are not contraindications to treatment unless associated with a chaotic lifestyle, severe depression or untreated psychosis, where compliance is likely to be compromised. It is possible that the prospect of effective treatment with psychosocial supports might be used together as part of a therapeutic endeavour to improve outcomes (and save lives). Once hepatic decompensation occurs then biopsy and treatment are no longer appropriate.

A number of practical clinical issues were addressed, including the possibility of sexual transmission. This appears to be extremely rare, although some American data seem to have been skewed by their methods of collecting it. Dr Dore mentioned the very low risk with common, garden variety "vanilla" sex based on an Italian study of 800 'discordant' couples followed for over ten years. They found virtually no documentable disease transmission (the only few cases of seroconversions were of different genotypes!). However, we were told that there was probably a higher risk in both heterosexual and homosexual intercourse of a less orthodox nature, such as might expose small blood vessels. Hence for monogamous heterosexual couples, condoms are probably not needed but others would need individual assessment.

Next Dr Dore addressed the issue of vertical transmission which occurs in about 5% of cases. He advised a routine test at 18 months by which time maternal antibodies were no longer measurable. In cases of particular concern, PCR viral detection could be done as early as 6 weeks since this avoided the pitfalls of passively acquired antibodies in the absence of infection. For those offspring who unfortunately contracted the virus, yearly liver functions and possibly viral load should be considered until about mid-teenage when more detailed clinical assessment is probably worthwhile, despite the very low prevalence of significant disease activity. The ALT was a slightly better marker of disease activity in children than in adults.

Dr Dore has a pragmatic view of the possible non hepatic manifestations of HCV infection - depression, diabetes, fatigue, rashes, sicca syndrome, etc. Some of these may result from the disease, its treatment or intercurrent physical or mental conditions. We were told that fatigue, while sometimes possibly due to the infection, is more likely to relate to an emotional response to the condition.

Needle stick injuries were discussed from several aspects. A random needle injury had a negligible chance of passing on HCV but from a known subject in a recently used needle the chance of seroconverting is probably around 4%. For a needle used many hours previously by a drug user of unknown HCV status, the chances are therefore lower than this. Dr Dore said that he did not normally recommend courses of antivirals in such circumstances.

All in all this was an illuminating and enjoyable evening. There was lively audience participation.

comments by Andrew Byrne ..

Methadone review article raises more questions than it answers!

The effectiveness of community maintenance with methadone or buprenorphine for treating opiate dependence. Simoens S, Matheson C, Bond C, Inkster K, Ludbrook A. British Journal of General Practice 2005 55:139-146

Dear Colleagues,

It is always gratifying to see dependency subjects covered in mainstream journals. This should raise awareness of effective opioid maintenance and other therapies for addictions amongst front line health workers. However, this 'Review Article' would be more likely to turn interested GPs, nurses or pharmacists away from being involved in addiction treatments.

The authors quote comparative research which consistently shows buprenorphine to be slightly but significantly inferior to methadone in most outcome measures. Yet their contradictory conclusion states: ". the evidence suggests that . buprenorphine may even be more effective than methadone, depending on dose".

While comparisons between methadone and buprenorphine are worth addressing, these authors seem to expect the literature to determine which is 'best'. Few would spend time arguing the general 'superiority' of one antibiotic over another. In doing so they miss the point that neither is used altogether appropriately in the UK (or most other countries). A review article might be expected to address better ways of matching patient to treatment, yet this is largely ignored here despite some useful recent research on the subject, including those with HIV, pregnancy, fast metabolism, etc.

They write further: "There was some evidence that primary care could be an effective setting [for opioid maintenance treatment] but such evidence was sparse". This academic peccadillo also applies to insulin, warfarin or most other pharmacotherapies. Although most research is performed in clinics, few would doubt its extension to community practice. It seems that these authors lack confidence in the Cochrane contributors on the subjects. The lingering doubts expressed by the authors might deny treatment to most of the patient population while we wait for yet more research!

One of the most important messages of this review paper, UK treatment standards, is almost buried towards the end. Exemplifying understatement (and some clumsy English) we are told: "With respect to community maintenance with methadone . higher doses of methadone are more effective. This is important because surveys of current prescribing practices of GPs in the UK suggest that methadone may still be underdosed." [In fact the mean dose in the UK is less than 40mg daily. While this is a good starting level it is only half the 'plateau' dose needed for optimum results.]

Thus the authors (all but one from Aberdeen) avoid properly addressing the scandal of methadone treatment in the UK which continues unaddressed to this day. Dependent citizens may thus drop out of inadequate treatment, relapse to heroin use, overdose or contract viral infections while the medical profession gets a bad name for gross mismanagement of opioid dependency. A similar state of affairs for diabetics, hypertensives or arthritis patients could make an election issue centring on the NHS.

After apparently searching the literature for negative items, our current authors also state: 'higher doses of methadone may increase craving for heroin and decrease subjective wellbeing'. This is based on one very small study which has never been replicated (Curran et al, Addiction 1999 94:665). The findings conflict with 2000 years of recorded experience where additional opioids are generally associated with reduced cravings and increased feelings of well being in the acute situation. The Addiction editor wrote to me that there may indeed have been a statistical error in this study but he declined to allow any correspondence on the matter, leaving its rather outlandish sentiments uncontested in the literature. One assumes that these 'Review Article' authors would have read the reference carefully before quoting its title. John Strang wrote recently that methadone may yet have a 'sting in the tail' without further explanation.

After 40 years of clinical experience methadone is no longer "on trial". The question is why people still express lingering yet unfounded doubts about its safety and effectiveness when used according to established practice guidelines. It appears that buprenorphine is in the same category giving patients and doctors choice at last.

comments by Andrew Byrne ..