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20 November 2007

Advances in assessment and treatments for infection with hepatitis C virus (HCV)

Concord Seminar 20th November 2007

Presenter: Professor Greg Dore, Viral Hepatitis Clinical Research Program, National Centre in HIV Epidemiology and Clinical Research.
Subject: Advances in assessment and treatments for infection with hepatitis C virus (HCV).

Topics: HCV epidemiology; treatment assessment; HCV treatment among methadone patients and current injecting drug users (IDU); strategies to improve HCV treatment outcomes; advances in HCV treatment and new research.

Although there has been a drop in annual HCV notifications in Australia from 15,000 in the mid 1990s to 13,000 recently, it is unsure how much of this reflects a fall in incidence (new infections) and thus a success for existing harm reduction policies. As most HCV infections in injecting drug users (IDU) occur within the first few years of injecting, some more significant indicators may be reductions in new HCV notifications in the 15-19 year age group, and in HCV prevalence in young male IDUs attending needle syringe programs (NSPs) from 2001-2006. Such figures do indeed show a marked reduction, which is reassuring that overall notifications should decline further.

It is possible that the lack of a fall in HCV prevalence in young female IDUs may reflect their "going second" in shared injecting situations, and/or sometimes having older male partners already at higher risk of having HCV.

IDUs still constituted the majority (62%) of all acute or newly acquired infections in Australia (n = 474 in 2006), however this may be an underestimate as the source of infection is reported as unknown in 15%, and sexual in 5% (sexual transmission may occur where sexual practices involve blood but is unlikely in most "vanilla" sexual encounters / relationships). Tattoos account for about 8% and occupational exposure 2.5% of new cases.

Overall HCV seroprevalence in people attending NSP remains high at 65%, and is somewhat higher again (75%) in MMT/BMT populations: ie about 30,000 of the circa 40,000 people in opioid replacement treatment in Australia. Of these, probably about 20,000 (50%) have chronic HCV (RNA-positive), about 10% of the total in Australia, making this an important point of access for HCV treatment.

Mortality among people with HCV in Australia has a bimodal distribution, in the 5th and 8th decades of life, the former largely related to drug-related deaths among IDUs and the latter liver disease-related deaths in people born overseas, in HCV endemic areas. Liver disease-related deaths have risen since 1999, a trend perhaps "unmasked" by a fall of direct drug-related deaths as a result of the "heroin shortage".

With cases of HCV cirrhosis in Australia predicted to rise to 12,000 by 2010, and twice that number by 2020, an aim is to be treating 6,000 people/year for HCV. Since April 2006, when the liver biopsy requirement for interferon-based treatment was dropped, treatment figures have risen from about 2,000 to 3,000/year. Liver biopsy was a major disincentive for many people.

Sustained viral response SVR (persisting absence of viral RNA 6 months after treatment) is usually considered a cure of the viral infection, although not necessarily of the underlying liver damage. Occasional later relapses of HCV may represent reinfection with HCV in IDU. Over the last decade response rates to interferon-based treatment have improved, from about 10% SVR for interferon monotherapy to overall to over 60% SVR for combined pegylated interferon/ribavirin (PEG-IFN/RBV), ranging from 50 – 80% depending on genotype.

Early studies of PEG-IFN·2a/RBV showed benefit of longer treatment (48 versus 24 weeks) and bodyweight-adjusted ribavirin dosing (up to 1200mg/day) for genotype 1, but not for genotypes 2 and 3. While early viral response (EVR) - defined as RNA undetectable or >99% decline in viral load at 12 weeks - increases the chances of SVR for genotype 1 to 72%, failure to achieve EVR almost inevitably predicts treatment failure.

The bottom line for treatment is: 24 weeks PEG-IFN/RBV for genotypes 2 and 3; 48 weeks for genotype 1 if the person achieves EVR at 12 weeks. There is no evidence of any difference in efficacy between PEG-IFN·2a (Roche) and PEG-IFN·2b (Schering-Plough).

Recent analysis suggests that people with genotype 1 who have a Rapid Viral Response (RVR) - HCV RNA undetectable at 4 weeks - may do just as well with 24 weeks as 48 weeks of PEG-IFN·2a/RBV, achieving SVR rates above 80%.

At St Vincent’s Hospital in Darlinghurst, treatment completion rates rose from 55% 2000-02 to 74% in 2003-04, with drops in treatment discontinuations due to both non-response and to toxicity. This appears a trend to improvements in delivery of treatment.

Results of treatment in current injectors are comparable to results among non injectors, and abstinence from IDU is not a pre-condition for subsidised treatment in Australia: nor are stage of fibrosis (was pre-2006); elevated ALT (was pre-2006); the presence of symptoms; low alcohol intake.

There is some evidence of poorer treatment outcomes in people who continue to drink alcohol, but whether this is related to worsened treatment adherence or effects on viral replication is unclear.

The current conditions for subsidised treatment eligibility in Australia (S100 Criteria) are:
· 18 years or older
· No evidence of de-compensated cirrhosis
· Must have chronic HCV infection (>6 months)
· Use double contraception where the patient is either a woman of child-bearing years or their male partner.
· No prior IFN-based HCV treatment

Subsidised treatment costs the patient about A$30/month, (A$5/month for concession card holders) and this is probably as cheap as anywhere in the world.

To be balanced against the curative potential of PEG-IFN/RBV are its toxicity (flu-like symptoms, depression, anaemia, lethargy) and the requirement for contraception during and 6 months following treatment. Apart from treatment eligibility, the stage of liver disease and prognosis the genotype and viral load, presence of co-morbidities, and work and family obligations have to be considered in treatment decision-making. There needs to be at least some treatment willingness and relative socio-behavioural stability, however with persistence and good support people with relative treatment contraindications can often be successfully brought through treatment.

Greg Dore advocates some targeting of individuals with higher risk of progressive disease:
Higher likelihood of cirrhosis is predicted by:
· older age (> 40 years)
· duration of infection > 20 years
· heavy alcohol intake
· HIV or chronic HBV coinfection
· peripheral stigmata of CLD (spider naevi, palmar erythema)
· impaired hepatic synthetic function (low albumin, prolonged PT)
· AST / ALT ratio > 1.0
· AST / platelet ratio > 1.0 (<0.5 very unlikely to have cirrhosis)

At the Byrne Surgery, about 50% of people with chronic HCV met similar criteria for higher risk of HCV progression, and have been specifically targeted for treatment, with 27 people having been treated since 2003. Of 20 liver biopsies among these higher risk people, 18 had at least moderate liver fibrosis.

Although HIV and HBV co-infection are relatively uncommon in people with HCV infection, they are definite indicators of higher risk, and in many cases HCV treatment should be undertaken before HIV or HBV treatment.

Phase II trials suggest benefit from triple therapies of IFN/RBV with protease inhibitors for chronic HCV and Phase II trials are due to start soon.

Acute HCV can be treated with interferon monotherapy, with SVR rates of 80-90% in 3 months treatment, unless there is HIV co-infection or HCV genotype 1 with a high viral load. However, as about 25% of people spontaneously clear the virus (generally in the first 3 months after infection but up to 6 months and even later in a few cases) treatment of acute infection is usually deferred at least 3 months.

Although sustained viral response rates at the Byrne surgery are high (71% overall, 81% for genotype 2/3) this is a case showing that things are not always so effective. This long-term MMT patient received HCV antiviral treatment in the setting of micronodular cirrhosis, Genotype 1a/1b, viral load 360,000 and pre-treatment alcohol use of 30-60g/day. This patient was overweight 105kg, a smoker (10 cigs/day) with shortness of breath on exertion, chronic airflow limitation (not taking medications), hypertension (Enalapril), probable ischaemic heart disease (chest tightness on stress test but no ECG changes; echocardiogram: LVH with moderate dilatation), osteoarthritis (diclofenac prn), a history of peptic ulcer disease (uses omeprazole prn).

Despite these relative contraindications to treatment, this patient ceased drinking alcohol, and started combination treatment with IFN.2a/RBV, achieving rapid viral response (<600 ie qualitative RNA assay) at 5 weeks. RBV dose started with 1200mg/day and reducing to 800mg/day as haemoglobin dropped under 100, and was stopped for 5 weeks when the patient suffered severe nose bleeds (with normal BP 130/80; prothrombin time 1.1 and platelets acceptable at 81). Diclofenac was ceased, and ENT review showed a large vessel on the septum which was cauterised, packed with Chloromycetin for 3 days, with ongoing Vaseline use.

After the patient had stoically endured 36 weeks of IFN.2a/RBV, and in view of the apparent rapid viral response, treatment was stopped at week 36, sadly with a rapid ALT and viral ‘flare’. The patient has since maintained alcohol abstinence and long term low dose interferon treatment is being considered.

Issues arising from this case were the feasibility of treatment of "brittle" patients; drying of the nasal mucosa with the IFN/RBV; the pros and cons of NSAIDS for osteoarthritis in this situation; the possibility of viral escape with the interruption to RBV treatment and the wisdom of the decision to stop treatment early; whether endoscopy might have been done to exclude oesophageal varices before treatment; the benefits of going on the front foot in treating HCV in substance dependent people, who may rise to the challenge by achieving abstinence (in this case alcohol abstinence).

Other questions arising in the second half:

What about treating people with persistently high-normal ALT? A: there is some discussion about whether ALT reference ranges should be lowered, especially for women. A single normal ALT measurement is not helpful, as ALT typically waxes and wanes in chronic HCV, so ongoing monitoring at least is required. Although one would rather have a persistently lowish than a persistently very high ALT, ALT correlates poorly with disease activity, and the duration of HCV is an important consideration in assessing risk of disease progression.

What is the role of abdominal ultrasound in assessing chronic HCV? A: mainly to exclude portal hypertension. Greg Dore often does not order this test. Newer methods for assessing fibrosis/cirrhosis by measuring the echo ‘stiffness’ of the liver may make ultrasound more useful.

Summary by Richard Hallinan, Greg Dore, Andrew Byrne.