BHIVA 2007: Is chronic HCV co-infection sometimes being misdiagnosed as acute HCV in HIV-positive gay men?

Increasing numbers of HIV-positive gay men are being diagnosed with hepatitis C (HCV) co-infection, according to several papers presented last month in Edinburgh at the 13^th Annual Conference of the British HIV Association (BHIVA) with the British Infection Society. However, an observational study from Imperial College and St Mary’s Hospital in London suggests that recent HCV antibody seroconversion does not necessarily mean acute HCV infection; they recommend using HCV viral load measurements (PCR) as the preferred screening method for high-risk individuals.

Treating acute HCV

However, as with HIV infection, there is a difference between being newly diagnosed and recently infected. Unlike HIV, knowing the difference between acute (usually defined as HCV infection acquired in the previous six months) and chronic (usually defined as HCV infection for longer than six months) HCV infection has important treatment implications: HCV is much more likely to be eradicated during the acute stage.

A recent small German study found a 61% sustained virological response (SVR) rate in HIV-positive men who began treatment during acute HCV infection following 24 or 48 weeks treatment with pegylated interferon (and weight-based ribavirin for patients with HCV genotypes 1 or 4).

In contrast, two major international studies have found that 48 weeks’ treatment with pegylated interferon and ribavirin during chronic HCV infection achieves a much lower SVR (up to 40%) of coinfected individuals, although this is much lower for individuals coinfected with HCV genotypes 1 and 4 (the most frequently-seen HCV genotypes amongst recently-diagnosed gay men).

The two London centres with the most experience of treating HCV co-infection reported data on the management and treatment of acute HCV at the conference. Chelsea and Westminster Hospital reported a 66% SVR rate using pegylated interferon and weight based ribavirin for 24 weeks: treatment success was significantly associated with a higher median CD4 percentage at the start of therapy (29% versus 24%; p

Increasing incidence of new HCV diagnoses

Since 2002 a steadily increasing number of HIV-positive gay men in London and Brighton are being diagnosed with HCV co-infection: the vast majority of these infections appear to have been sexually transmitted.

This year’s BHIVA conference saw several presentations on acute and recently diagnosed HCV infection and its treatment in HIV-positive gay men. The Health Protection Agency’s Dr Murad Ruf reported that 389 cases of acute HCV co-infection had been seen in HIV-positive gay men in London and Brighton up to June 2006. Incidence rose from 7 per 1000 person years in 2002 to 12 per 1000 person years in 2006, resulting in an estimated annual incidence of 1.33% per year (95% CI, 0.99-1.78). Put another way, one out of every 83 HIV-positive gay men in London and Brighton is being newly diagnosed with HCV co-infection each year.

Diagnosing acute HCV

Since both centres concluded that timely diagnosis of acute HCV in co-infected individuals is extremely important, given the much higher SVR rates achieved, it is also critical that acute HCV is diagnosed correctly. There is no standard way of diagnosing acute HCV but three factors are usually considered:

• abnormal liver function tests (alanine-aminotrasferase; ALT)
• positive HCV viral load (HCV PCR)
• documented seroconversion for HCV antibodies

Dr Emma Thomson from Imperial College presented data from St Mary’s Hospital on 32 HIV-positive gay men who appeared to present with acute HCV infection. The object was to assess the sensitivity of HCV antibody versus HCV PCR at three-monthly intervals and also to estimate the median time from HCV PCR positivity to HCV antibody seroconversion.

Two men who had not yet seroconverted were initially diagnosed with acute HCV. However, they were excluded from the study when past blood samples tested positive for HCV viral load: they actually had chronic hepatitis C without HCV antibody seroconversion.

The remaining 30 men had a positive PCR test at baseline, but 77% were HCV antibody negative (sensitivity = 23%) and 19% had normal ALT (sensitivity 81%).

After three months, liver function tests were all above the upper limit of normal although 35% still had a negative HCV antibody test (sensitivity = 65%).

HCV antibody sensitivity reached 93% at nine and twelve months. The median time from positive PCR test to antibody seroconversion was 108 days (range 0-433 days). However, three of the men did not develop antibodies at all during the follow-up period (147, 233 and 240 days post positive PCR test, respectively).

HIV-negative individuals tend to produce an antibody response to HCV within six weeks of infection. Here, the median time to development of HCV antibody in HIV-positive gay men with recent HCV infection was more than 15 weeks (108 days) and look longer than six months in almost one-in-four (22%).

This small study suggests, then, that different diagnostic tests for acute HCV infection can vary greatly in sensitivity. In particular, some individuals may never develop an HCV antibody response. Relying on a documented negative to positive HCV antibody test as one of the definitions of acute HCV may result in the possible misdiagnosis of chronic HCV infection as acute HCV infection.

The investigators suggest that this misdiagnosis of chronic HCV infection as acute HCV infection might be one of factors responsible for the lower SVR seen during apparently acute infection in co-infected individuals. They add, however, that “it is likely that disturbance of the cell-mediated immune response is the major determinant of outcome [in treating acute HCV in co-infected individuals].”

They conclude by recommending, “where there is high clinical suspicion of recent hepatitis C infection (e.g. raised ALT levels), HIV-infected patients should be screened for the presence of HCV RNA by RT-PCR. HIV-infected patients diagnosed with acute hepatitis C should have a preceding HCV-RNA test to establish the timing of infection.”