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European Study Does Not See Rapid Long-Term Liver Fibrosis in HIV/HCV Coinfected People

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People who are already HIV positive when they acquire hepatitis C virus (HCV) may not experience unusually rapid liver disease progression over the long term, even though the fibrosis progression rate may appear high during the acute stage of infection, according to a European FibroScan study described in the February 15, 2012, issue of Clinical Infectious Diseases.

The past decade has seen an outbreak of presumably sexually transmitted HCV infection among HIV positive gay and bisexual men in Europe, Australia, and the U.S. While a majority of HIV/HCV coinfected people acquire HCV first (e.g., HCV is more easily transmitted via injection drug equipment than HIV), many gay men are infected with HCV after they already have HIV, and regular liver function monitoring enables early diagnosis of acute hepatitis C in this group.

Studies indicates that HIV positive people with chronic hepatitis C tend to experience more aggressive liver disease, on average, than HIV negative people with HCV alone, especially if they have advanced immune deficiency. But the picture is less clear for acute hepatitis C.

Looking at repeated liver biopsies, researchers at Mount Sinai Medical Center in New York City have reported unusually rapid liver disease progression among HIV positive gay men with acute hepatitis C. Several men showed evidence of moderate to severe fibrosis despite being infected with HCV for only a matter of months.

However, several European teams have not observed rapid progression using the transient elastometry or FibroScan method, which uses sound waves to determine liver "stiffness." FibroScan is regarded as less accurate than biopsy, but it is also less expensive, less painful, and many find it more acceptable for repeated evaluations over time.

In the present study, Martin Vogel and fellow investigators with the European AIDS Treatment Network (NEAT) Study Group evaluated liver fibrosis progression using FibroScan among 38 HIV positive men who presented with acute hepatitis C.

Participants had a known course of acute-to-chronic HCV infection or available FibroScan results prior to starting hepatitis C treatment. About three-quarters were enrolled retrospectively based on medical records from 2005 to 2009, with the remainder enrolled prospectively between 2009 and 2011. Date of HCV infection was either reported by the patient, if known, or calculated based on the first elevated alanine transaminases (ALT) measurement.

The researchers selected "conservative cutoffs" to match FibroScan liver stiffness values to corresponding Metavir fibrosis scores, and assumed patients had no fibrosis (stage F0) prior to acute HCV infection:

  • ≤ 6.0 kiloPascals (kPa): Metavir stage F1 (minimal fibrosis);
  • 6.1-9.0 kPa: Metavir F2 (moderate fibrosis);
  • 9.1-12.0 kPa: Metavir F3 (advanced fibrosis);
  • > 12.1 kPa: Metavir F4 (cirrhosis).

These measurements were used to calculate the fibrosis progression rate (FPR) by dividing the difference in fibrosis units by the time of follow-up; a FPR of 1 indicates that fibrosis advances by 1 stage per 1 year of follow-up. The researchers noted that the FPR model "implies that liver fibrosis is a linear process over time, with increasing liver fibrosis finally leading to liver cirrhosis."

Results

  • Over a median follow-up period of 0.4 years, the median fibrosis progression rate was 3.6 Metavir fibrosis units per year.
  • FPR rates were very high during the first months after acute HCV infection.
  • Among patients followed for more than 9 months, however, FPR rates became similar to those reported in prior studies of people with chronic HIV/HCV coinfection (median 0.8 fibrosis units per year).
  • Both duration of follow-up and serum ALT at the time of FibroScan testing had a significant effect on fibrosis progression rates.
    • The higher the ALT level at the time of FibroScan testing, the higher the calculated FPR.
    • The shorter the duration of follow-up from estimated date of acute HCV infection to FibroScan testing, the higher the calculated FPR.
  • In a multivariate analysis, ALT level and duration of follow-up together could explain 92% of the observed variance in fibrosis progression rates.
  • Prolonging follow-up from 1 year to 10 years, the researchers calculated, would reduce the FPR to approximately one-tenth of the starting value.
  • Other potential confounding factors, including duration of antiretroviral therapy and use of any particular antiretroviral drug, were not associated with increased FPR.

"Fibrosis progression after acute hepatitis C virus (HCV) infection in human immunodeficiency virus (HIV)-infected patients with follow-up > 9 months became similar to reported rates from studies in chronic HIV/HCV coinfection, as measured with transient elastometry," the researchers concluded.

"The duration of follow-up and serum alanine transaminase correlated with liver stiffness, and short follow-up resulted in high fibrosis progression rates," they continued. "[W]e did not find any evidence for continuing accelerated fibrosis progression rates after [acute hepatitis C] in HIV-infected participants, which should reassure patients and caregivers regarding the risk of liver cirrhosis after [acute hepatitis C]."

Elevated ALT during acute HCV infection -- which reflects liver inflammation rather than fibrosis -- is associated with higher FibroScan measurements, resulting in higher estimates of fibrosis progression, they explained in their discussion. But as HCV infection becomes chronic and ALT levels decrease, FibroScan scores also fall; with prolonged follow-up, fibrosis progression resembles that of coinfected people with chronic hepatitis C who presumably acquired HCV first.

"Every HIV-infected patient should be advised to consider early treatment for acute HCV if spontaneous clearance does not occur," the study authors recommended. "However, there may be room for delaying treatment among those who prefer to wait for new HCV therapies without the risk of rapidly developing cirrhosis."

The first of a new wave of direct-acting anti-HCV agents have recently become available and are now being tested with interferon and ribavirin in HIV/HCV coinfected patients. But new and potentially better hepatitis C therapies are in the pipeline -- including all-oral, interferon-free regimens -- prompting some patients and providers to adopt a "wait and watch" strategy.

The NEAT findings support this approach, but the Mount Sinai data showing rapid progression suggest that waiting can be risky due to fast progression. Further study is needed to resolve these conflicting findings.

Investigator affiliations: Department of Internal Medicine I, Bonn University, Bonn, Germany; Department of HIV Medicine, Chelsea and Westminster Hospital, London, UK; Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Austria; Center for HIV and Hepatogastroenterology, Duesseldorf Germany; Medical Center for Infectious Diseases, Berlin, Germany

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Reference

M Vogel, E Page, C Boesecke, et al (European AIDS Treatment Network Study Group). Liver Fibrosis Progression After Acute Hepatitis C Virus Infection in HIV-Positive Individuals. Clinical Infectious Diseases 54(4):556-559. February 15, 2012.