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Serum biochemical markers accurately predict liver fibrosis in
HIV and hepatitis C virus co-infected patients
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Comments from Jules Levin: In the current issue of the journal AIDS, French researchers Poynard and Benhamou report their study findings that a lab based test is preferable and as reliable rather than an invasive biopsy in terms of predicting stage of disease. In the commentary by Soriano, he makes the case that in coinfected patients the biopsy is even less important to be performed. Soriano suggests that since a most HIV acelerates HCV progression most coinfected patients have stage 2 or greater disease and should start therapy. Therefore, he suggests that biopsy may no longer necessary in cmono-infected and coinfected patients. I disagree with SorianoŐs suggestion. First, I think we need further discussion and study of the French lab based non-invasive index of biochemical markers. Second, I think a biopsy is recommended. The biopsy is the preferred diagnostic way to assess the stage of liver disease and provides the doctor and patient with much information. I know of a number of coinfected patients who were pleasantly surprised to find they had stage 1 disease after having a biopsy performed and decided to delay therapy. If a person has a biopsy and finds they are at stage 3 or 4 they may realize itŐs crucial to start therapy and perhaps more importantly the doctor and patient will realize that maintenence therapy with interferon may be necessary. Without a biopsy they would not know this. Therefore, until considerable more evidence is available I think the biopsy is still the gold standard.
Objective: Liver biopsy, the gold standard for assessing hepatitis C virus (HCV)-related fibrosis, is invasive and prone to complications. Our aim was to determine the operating characteristics of a non-invasive index of biochemical markers for the prediction of fibrosis in patients with HIV/HCV co-infection.
Design: In a cross-sectional, cohort study in a French tertiary-care hospital 130 HIV/HCV-co-infected patients with a liver biopsy and serum were tested for markers of liver fibrosis.
Methods: An index incorporating age, sex, [alpha]2-macroglobulin, apolipoprotein A1, haptoglobin, bilirubin, and [gamma]-glutamyl-transpeptidase (GGT), derived using multivariate logistic regression, was compared with liver histology. HIV-specific indices including the CD4 cell count and HIV-RNA load were also constructed. The diagnostic values of the indices were compared using receiver operating characteristic (ROC) curves.
Main outcome measure: Septal fibrosis (F2-F4) by the METAVIR classification.
Results: By multivariate analysis, the most informative markers were [alpha]2-macroglobulin, apolipoprotein A1, GGT, and sex. The area under the ROC curve of the five-marker index was 0.856 ± 0.035; not significantly different from the
HIV-specific indices. On a scale from zero to 1.00, the five-marker index had a positive predictive value of 86% for scores greater than 0.60, and a negative predictive value of 93% for scores of 0.20 or less. These thresholds could
reduce the necessity for liver biopsy by 55% while maintaining an accuracy of 89%.
Conclusion: An index including five biochemical markers accurately predicts significant fibrosis in patients with HIV/HCV co-infection, and may substantially reduce the necessity for liver biopsy. AIDS 2003; 17(5):721-725. Yves Benhamou and Thierry Poynard et al.
COMMENTARY
Treatment of chronic hepatitis C virus infection: we must target
the virus or liver fibrosis?
AIDS 2003; 17(5):751-753. Vincent Soriano et al. Div Infectious Diseases and Hepatology Unit, Hospital Carlos III, Instituto de Salud Carlos III, Madrid, Spain.
Liver disease caused by hepatitis C virus (HCV) infection is currently one of the leading causes of hospitalization and death in HIV-infected patients living in developed countries. At least four circumstances may account for this fact.
First, progression to cirrhosis and end-stage liver disease is accelerated in HIV/HCV-co-infected individuals. Second, the toxicity of antiretroviral drugs is increased in patients with underlying chronic hepatitis C. Third, HCV might have a deleterious effect as a co-factor for HIV disease progression. Finally, the immune recovery seen after beginning antiretroviral therapy might be partly blunted in individuals with HIV/HCV co-infection.
The treatment of chronic hepatitis C has become a major issue in HIV-positive patients Unfortunately, anti-HCV therapy was until recently inefficient in the vast majority of patients (sustained response rates in less than 15-20% using
interferon monotherapy), and was associated with considerable side-effects. In the past few months, the situation has improved with the addition of ribavirin and the availability of a more comfortable (administered once a week) and active form of interferon (pegylated interferon), which have significantly increased the chances of a cure for chronic hepatitis C. Up to 45% of those with HCV genotype 1 and nearly 75% of those with HCV genotypes 2 or 3 can expect the eradication of HCV infection. Whether or not these results may be reproduced in HCV/HIV-co-infected individuals has still to be determined, but trials are in progress to provide an answer to this question.
Liver biopsy permits the staging of hepatic fibrosis in patients with chronic hepatitis C and can exclude other possible causes of liver damage. Patients with significant liver fibrosis (F2-F4) have the greatest chances of progression to end-stage liver disease. Given the relatively poor efficacy of anti-HCV therapy until recently, its high cost and frequent side-effects, treatment was not recommended in patients lacking or with only minimal liver fibrosis (F0 and F1). In this form, liver biopsy was particularly useful to identify patients who might delay therapy given their good prognosis. However, if a decision to delay therapy is taken initially, liver biopsy should be repeated 3-5 years later to
assess whether treatment should commence at that time.
Given that liver biopsy is an expensive procedure, with occasional complications and poor patient acceptance, the search for surrogate markers to replace liver biopsy has been strongly pursued recently. Forns et al. [20] reported a high predictive value of the lack of fibrosis using a model in which four parameters were considered (platelets, [gamma]-glutamyl transpeptidase, age, and cholesterol). The authors validated their formula in a large series of 476 HIV-negative patients with chronic hepatitis C and paired serum and liver biopsies. In this issue of the journal, Myers et al. [21] show that using an index based on age and sex plus five laboratory parameters (total bilirubin, [gamma]-glutamyl transpeptidase, [alpha]-2 macroglobulin, apolipoprotein A1, and haptoglobin), significant liver fibrosis could be predicted in up to 86% of 130 patients with both HIV and HCV infection. The same index, known as
the 'Fibrotest', has already proved to be useful in HIV-negative individuals with chronic hepatitis C [22, 23]. Of note was the fact that adding CD4 cell counts and plasma HIV-RNA levels into the model did not improve its predictive
value. Given that anti-HCV treatment is recommended when at least septal fibrosis (F2) is found in the liver biopsy, the authors conclude that by using their test more than half of the biopsies could have been avoided in their group of HIV/HCV-co-infected patients, before prescribing anti-HCV treatment.
Patients with chronic hepatitis C are often reluctant to undergo a liver biopsy. The procedure is associated with pain in a third of patients, severe complications in 0.3%, and death in 0.03%. Moreover, it should not be assumed that is the gold standard for diagnosing clinically silent cirrhosis, because sampling error reduces the sensitivity of biopsy below 80%. Liver biopsy also adds significant costs, both direct (equipment, observation time in a clinical facility, and time devoted by a clinician and pathologist) and indirect (time away from work and home). Accordingly, it is not surprising that a recent cost-effectiveness analysis concluded that the best strategy in the management of chronic hepatitis C is to offer therapy to all patients without considering liver biopsies. Current treatment with pegylated interferon and ribavirin provides a cure for more than half the patients. Moreover, data derived from HCV kinetic studies have allowed the prediction, as soon as 12 weeks after beginning therapy, of which patient will have the chance of achieving a sustained response and which will not. Consequently, patients who do not show a reduction in plasma HCV-RNA levels of 2 logs or greater at that time may stop therapy, which is associated with significant costs and side-effects.
If routine liver biopsy is now under debate for patients with chronic hepatitis C without HIV co-infection, at least two additional considerations may make liver biopsy even less justifiable in HIV/HCV-co-infected patients. First, the proportion of these patients who have minimal or absent liver fibrosis is rather low (< 5%) when compared with their HIV-negative counterparts. In Table 1 is recorded the proportion of patients with different stages of liver fibrosis
considering the presence or absence of HIV infection. Of note is the fact that nearly half the HIV/HCV-co-infected patients, but only 15% of those who are HCV monoinfected, are cirrhotic (F4) or pre-cirrhotic (F3). Clearly, there is no doubt that HIV accelerates the progression of HCV-related liver fibrosis. Therefore, most patients with HCV/HIV co-infection should be considered as candidates for therapy. Moreover, in those few individuals lacking fibrosis in the liver and deferring therapy, it will be hard to counsel them to repeat biopsies at intervals of 3-5 years.
Another consideration is that complications of liver biopsy in patients with HCV/HIV co-infection seem to occur more frequently than in HIV-negative patients. Major bleeding is the most frequent adverse event, and accounted for up to a 1.6% mortality rate for the procedure in a large study conducted among HIV-positive individuals in the UK.
Currently, many patients with HCV/HIV co-infection are less than 40 years of age, which is a favourable predictor of response to anti-HCV therapy, and at least a quarter of them carry HCV genotype 3, which in addition to being the
best predictor of treatment response, allows the duration of therapy to be limited to 6 months instead of the standard 12 months.
In summary, the greater efficacy of current anti-HCV therapy and the possibility of predicting as early as 12 weeks after beginning therapy who will not respond to treatment, make the request for a liver biopsy unnecessary in most instances. Given the more aggressive course of HCV infection in HIV-positive individuals, treatment should be considered for all co-infected patients, irrespective of the histological findings and based mainly on two particular issues, the CD4 cell count (i.e. patients with low CD4 cell counts show a much poorer response to therapy and develop more side-effects), and the concomitant use of antiretroviral drugs (i.e. didanosine or zidovudine should be avoided whereas ribavirin is used, because they increase the risk of pancreatitis and anaemia, respectively). Apart from in clinical trials, liver biopsies may no longer be requested to make treatment decisions in patients co-infected with HCV and HIV. The current treatment of chronic HCV infection, particularly in HIV-co-infected patients, should pursue the elimination
of the aetiological agent, irrespective of the demonstration of any liver damage.
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