At
the 15th Conference on Retroviruses and Opportunistic Infections
last month in Boston, researchers with the TICO study reported on the occurrence
of such flares, which they hypothesized might be a form of immune restoration
disease (IRD; also known as immune restoration inflammation syndrome, or IRIS)
that occurs due to increased recruitment of activated
T-cells to the liver as the CD4 cell count increases.
In
the prospective TICO trial, 36 antiretroviral-naive HIV-HBV coinfected patients
in Thailand were randomly assigned to receive tenofovir vs lamivudine vs tenofovir
+ lamivudine, as part of an efavirenz
(Sustiva)-based HAART regimen.
Hepatic flares were defined as ALT > 5 times the upper limit of normal (ULN)
or more than 200 IU/mL above baseline within 12 weeks of starting HAART.
The
researchers measured various immune system cytokines including interleukins (IL)
2, 6, 8, 10, and 18, soluble CD26 and CD30, interferon-inducible protein 10 (IP-10;
also known as CXCL-10), macrophage chemotactic protein 1 (MCP-1), tumor necrosis
factor-alpha (TNF-alpha), and interferon (IFN) alpha and gamma. These levels were
correlated with ALT, HBV viral load, HIV viral load, and CD4 cell count.
Results
•
Of the 36 participants, 8 patients, or 22%, experience hepatic flares ("cases"),
while 28 subjects (78%) did not ("controls").
•
1 individual died due to a severe flare.
•
Cases had significantly higher HBV viral load and ALT levels compared with controls
prior to starting HAART.
•
Cases also had lower pre-treatment CD4 cell counts, and thus experienced greater
gains after starting HAART.
•
Following HAART initiation, IP-10 levels significantly decreased by weeks 8 and
12 in the cases, but there was no significant decrease in the controls over time.
•
Among the cases, soluble CD30 and ALT levels peaked at week 8, but there was no
significant change in the controls.
•
Significant positive correlations were found between levels of ALT and IP-10,
soluble CD30, MCP-1, and IL-18 at week 8.
•
There was a significant increase in soluble CD26 over time in both cases and controls.
•
IL 2, 6, 8, and 10, TNF-alpha, and IFN alpha and gamma were not detectable in
the majority of blood samples from either cases or controls.
Conclusion
Based
on these findings, the researchers concluded, "IP-10 (an activated T-cell
and natural killer cell chemokine) and soluble CD30 (a T-cell activation marker)
play an important role in the pathogenesis of hepatic flare following initiation
of HBV-active HAART in HIV-HBV coinfected patients. Also implicated are markers
of IFN-gamma induction (IL-18) and activity (MCP-1)."
They added that,
"These data support our hypothesis that hepatic flare is a consequence of
IRD."
The investigators plan further research to assess whether this
increased immune activation following HAART initiation leads to HBV clearance
in HIV-HBV coinfected patients.
Monash Univ, Melbourne, Australia; Univ
of Western Australia, Perth, Australia; Natl Ctr for HIV Epidemiology and Clin
Research, Univ of New South Wales, Australia; HIV Netherlands Australia Thailand
Research Collaboration, Bangkok, Thailand; Royal Perth Hospital, Australia; Alfred
Hospital, Melbourne, Australia.
3/04/08
Reference M
Crane, B Oliver, G Matthews, and others. Immunopathogenesis of Hepatic Flares
after Initiation of ART in HIV/HBV-co-infected Individuals. 15th Conference on
Retroviruses and Opportunistic Infections (CROI 2008). Boston, MA. February 3-6,
2008. Abstract 1033.
Hepatitis
Flares in HIV-HBV Coinfected Patients Starting HAART May Be Due to Immune Restoration
Results
