Coinfection

AIDS 2012: Rapid Liver Disease in HIV+ Men with Acute HCV: The Debate Continues

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Gay and bisexual men who are already HIV positive when they become infected with hepatitis C virus (HCV) may experience unusually rapid and severe liver disease progression, according to a presentation by Daniel Fierer at the XIX International AIDS Conference (AIDS 2012) last month in Washington, DC. Other experts, however, disagree with this conclusion.

Outbreaks of apparently sexually transmitted hepatitis C among HIV positive men who have sex with men (MSM) were first reported in the U.K. about a decade ago, followed by large continental European cities and later Australia and the U.S. as well.

Typically, in HIV negative people, it takes decades for hepatitis C to cause serious liver disease including advanced fibrosis, cirrhosis, and hepatocellular carcinoma. Progression happens somewhat faster in people with HIV, especially those with advanced immune deficiency. But historically most HIV/HCV coinfected people have been injection drug users, and because HCV is easier to transmit than HIV, they typically contract HCV first after they start injecting.

In 2007 Fierer's group at Mt. Sinai School of Medicine in New York City first reported a small number of cases of HIV positive MSM with acute hepatitis C who had liver biopsies revealing extensive fibrosis despite a short period of HCV infection. In contrast to the typical pattern, these men were HIV positive before acquiring sexually transmitted HCV. Fierer's team has continued to describe rapid progression in a growing cohort.

However, other researchers have not observed similar rapid progression using the non-invasive transient elastometry (FibroScan) method rather than biopsies to estimate liver damage.

Rapid Fibrosis Overview

In his invited lecture at AIDS 2012 -- part of an oral session entitled "HCV: A New Era Dawns" -- Fierer reviewed what we know about hepatitis C progression in people with HIV and how it may vary based on order of infection.

Fierer noted that while HCV-related liver disease is among the leading causes of death for people with HIV in the era of effective antiretroviral therapy (ART), progression to liver failure still usually takes decades, and only a minority of HIV/HCV coinfected patients progress to HCV-related liver failure or death.

Concomitant HIV infection accelerates HCV disease progression, but the effect is "modest," shortening the time to fibrosis from about 35 to about 25 years. Studies have found that immunosuppression occurring after HCV infection -- whether due to HIV or kidney transplantation -- mildly accelerates fibrosis, Fierer explained.

However, he continued, a "surprising" amount of liver disease is observed early in MSM with HIV, with liver failure and death occurring just a few years after HCV infection in some patients.

Historically, HCV infection in people with pre-existing immunosuppression has been uncommon, but when it has occurred in patients with hematological malignancies (e.g., leukemia) or kidney or liver transplants (who receive immune-suppressing drugs to prevent organ rejection), rapid progression to cirrhosis has been observed in less than 5 years. Fierer proposed that the same thing may be happening to HIV positive MSM in the sexually transmitted hepatitis C outbreaks of the 2000s.

In Fierer's Mt. Sinai cohort, an analysis published in 2008 found that 9 of 11 men (82%) already had biopsies showing stage 2 (moderate) fibrosis a median of 4 months after HCV diagnosis. Likewise, in 2010 Emmanuel Bottieau and colleaguesreported that 22 of 37 patients (59%) in Belgium had stage 2 or 3 (advanced) fibrosis a median of 7 months after HCV diagnosis, again based on biopsies.

In contrast, studies of HIV negative people with primary HCV infection have not seen such rapid fibrosis, with most patients having stage 0 (absent) or stage 1 (minimal) fibrosis at this early phase.

Fierer's findings have been controversial because other researchers have not observed rapid fibrosis progression in HIV positive MSM with early HCV infection.

In particular, Martin Vogel, Jürgen Rockstroh, and fellow investigators studying the NEAT (European AIDS Treatment Network) cohortsaw very high estimated fibrosis progression rates (nearly 4 Metavir units per year) according to transient elastometry during the first months after HCV infection. But progression rates then fell to match those of people with chronic HIV/HCV coinfection in other studies (less than 1 unit per year).

Fierer ended his presentation with some as yet unpublished data from the Mt. Sinai cohort plus patients seen at Cornell and the University of California San Diego who continued to have persistent HCV infection after the acute phase.

Within this group researchers identified 4 individuals who developed decompensated cirrhosis in 17 months to 6.5 years -- much faster than expected for people with chronic HIV/HCV coinfection:

  • Patient 1 (age 39): CD4 count 53 cells/mm3, initial biopsy - stage 3, second biopsy - stage 4, decompensation at 17 months, underwent liver transplant at 2 years.
  • Patient 2 (age 55): CD4 count 200 cells/mm3, initial biopsy - stage 2, no second biopsy, decompensation at 2.5 years, death at 2.75 years.
  • Patient 3 (age 40): CD4 count 381 cells/mm3, initial biopsy - stage 3, second biopsy - stage 4, decompensation at 3.5 years, still alive at 6.5 years.
  • Patient 4 (age 54): CD4 count 442 cells/mm3, initial biopsy - stage 3, second biopsy - stage 4, decompensation at 6.5 years, death at 7 years.

"What really matters is what order [HIV and HCV] infections happened, and it matters even more how immunocompromised a patient is," Fierer concluded, noting that men with the lowest CD4 counts were the first to experience decompensation in this series.

Asked whether he had seen any patients with high CD4 counts who experienced rapid progression to severe liver disease, Fierer said that while HIV itself plays a role and probably enhances fibrosis, he thinks immunosuppression is what causes rapid fibrogenesis.

The Debate Continues

The latest round of debate between Fierer's group and the NEAT team was published in the June 7, 2012, advance online edition of Clinical Infectious Diseases.

Responding to the NEAT group's report in the February 15, 2012, issue, Fierer and colleagues asserted that the NEAT and Bottieau data "seems to cement that this unexpected outcome [rapid onset fibrosis] is a true consequence of primary HCV infection in HIV-infected men. We disagree, however, that their results using transient elastography demonstrate a sharp decrease in the fibrosis progression rate (FPR) to a clinically unimportant level soon after the primary HCV infection period has waned."

"Transient elastography measures liver stiffness, not fibrosis per se. In patients with new viral hepatitis and in patients with chronic HCV infection, inflammation contributes significantly to the liver stiffness score," they explained. "Patients with biopsies showing as little as stage 0-1 fibrosis but with higher ALT levels had a high rate of spuriously attributed cirrhosis (stage 4). Because Vogel et al did not have liver biopsies of these patients, they could not adjust for this effect, and they thereby vastly overestimated the stage of fibrosis (and therefore the FPR) during early primary HCV infection. Then, when they calculated FPR in the subgroup of just 5 patients who were assessed at later times when inflammation and ALT were much lower, they found a much lower FPR."

Fierer and colleagues reported findings from continued evaluation of their cohort. Analysis of 29 biopsies from HIV positive men with primary HCV infection  showed that "higher histopathological stage of fibrosis was associated with increasing length of HCV infection. These data further reinforce that in HIV-infected men there is rapid onset of fibrosis in the first 1-2 years of primary HCV infection that does not appear to resolve."

"Due to the same short time of follow-up as in the Vogel et al study, we cannot determine from these data the rate at which this fibrosis does or does not continue to accumulate," they continued. "What happens in the subsequent 2-5 years will determine how clinically meaningful these findings end up being."

Unfortunately, liver biopsies are invasive, expensive, and uncomfortable for patients, so do not lend themselves to frequent repetition like the non-invasive, cheaper transient elastometry method.

"We are optimistic that with the continued development of new HCV treatments we may be able cure nearly everyone with HCV infection within 5-10 years -- but that may be too long for some of these patients," Fierer and colleagues concluded.

In a reply in the same issue, Vogel and colleagues countered that they did not claim to detect a sharp decrease in the fibrosis progression rate, but rather showed that the calculated FPR using a linear model most likely overestimated fibrosis progression during acute HCV infection. They also noted that while agreeing that liver inflammation influences transient elastography results, they accounted for this in their analysis, and liver biopsies, too, may be confounded by acute liver inflammation.

"[C]oncordant to the current consensus statement on acute HCV infections in HIV‐infected individuals we recommended that every HIV‐infected patient should be advised to consider early treatment of acute HCV infection if spontaneous clearance did not occur," they wrote. However, they added, "while it is important to raise awareness [of] possible complications of acute HCV infection in HIV‐infected individuals we feel it is timely to inform that fibrosis progression may indeed be lower than previously suggested and patients [will not necessarily] suffer from liver cirrhosis within a year['s] time."

8/14/12

References

DS Fierer. Rapid progression of fibrosis in acute HCV among HIV infected MSM. XIX International AIDS Conference (AIDS 2012). Washington, DC, July 22-27, 2012. Presentation WEAB0101.

DS Fierer, MP Mullen, DT Dieterich, et al. Early-onset Liver Fibrosis Due to Primary Hepatitis C Virus Infection is Higher Over Time in HIV-infected Men (Correspondence). Clinical Infectious Diseases. June 7, 2012 (Epub ahead of print).

M Vogel, E Page, C Boesecke, J Rockstroh, et al. Reply to Fierer et al (Correspondence). Clinical Infectious Diseases. June 7, 2012 (Epub ahead of print).

M Vogel, E Page, C Boesecke, J Rockstroh, et al.  Liver fibrosis progression after acute hepatitis C virus infection in HIV-positive individuals. Clinical Infectious Diseases 54(4):556-559. February 15, 2012