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Liver Fibrosis Marker Rises in SMART Interrupters and Predicts Non-AIDS Deaths
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16th Conference on Retroviruses and Opportunistic Infections, February 8-11, 2009, Montreal
Mark Mascolini
suspending treatment "is particularly dangerous" in hepatitis virus-coinfected people if hyaluronic acid is high just before the antiretroviral holiday.....Among coinfected SMART interrupters with a study entry hyaluronic acid level above normal, cumulative risk of non-AIDS death came to 37.3% after 48 months, compared with 7.3% in noninterrupters who had either a normal or high baseline hyaluronic acid reading.... Coinfected people with elevated entry hyaluronic acid readings had significantly higher interleukin 6 (IL-6) and D-dimer levels than people with normal hyaluronic acid quotients at entry. An earlier SMART analysis tied elevated IL-6 and D-dimer to all-cause mortality in SMART, and interrupting antiretrovirals led to increases in both IL-6 and D-dimer
Hyaluronic acid, a liver fibrosis marker, rose in SMART trial participants coinfected with HIV and hepatitis B or C virus (HBV or HCV) during the first 6 months after they suspended antiretroviral therapy [1]. Higher hyaluronic acid levels at study entry independently predicted non-AIDS death in HBV- or HCV-coinfected people who interrupted antiretroviral therapy during SMART.
Because liver fibrosis worsens faster in people with lower CD4 counts, Lars Peters and SMART colleagues theorized that hyaluronic acid levels would rise during treatment interruptions in the trial. To test that hypothesis, they analyzed hyaluronic acid concentrations in all SMART participants with measurable HCV RNA or hepatitis B surface antigen and in a control group of people without HCV or HBV. They matched controls to coinfected people according to randomization date, gender, age, treatment group, history of alcohol abuse, and number of follow-up samples available.
Among the 675 coinfected people, 553 (82%) had HCV infection, 110 (16%) had HBV, and 12 (2%) had both. Compared with the control group of people infected only with HIV, coinfected people were more likely to be black (48.4% vs 34.1%), less likely to be taking antiretrovirals at study entry (79.3% vs 85.8%), and less likely to be antiretroviral naive (2.4% vs 4.3%). Coinfected people also had a longer median time since starting antiretroviral therapy (7 vs 6 years). Median SMART entry CD4 count was high and equivalent in coinfected people and controls (580 and 583).
Median follow-up stretched to 33 months in coinfected people and 35 months in HIV-monoinfected controls. During follow-up, 52 coinfected people died, 31 in the treatment interruption group and 21 in the steady-therapy group. An opportunistic disease developed in 29 coinfected people, and 21 had major liver disease progression (17 with cirrhosis and 4 liver-related deaths).
The normal hyaluronic acid range runs from 0 to 75 ng/mL. At study entry, median hyaluronic acid levels were much higher among coinfected people (29.0 ng/mL in interrupters and 30.9 ng/mL in noninterrupters) than in controls (18.8 ng/mL in interrupters and 18.9 ng/mL in noninterrupters). More than 15% of coinfected people had hyaluronic acid quotients above 75 ng/mL at study entry, compared with fewer than 5% of controls.
At study month 6, median hyaluronic acid rose more in coinfected people (to 41.1 and 45.2 ng/mL in interrupters and noninterrupters) than in monoinfected controls (to 25.0 and 22.9 ng/mL in interrupters and noninterrupters). At 6 months, more than 25% of coinfected people had a hyaluronic acid reading above 75 ng/mL, compared with about 6% of control interrupters and 2% of control noninterrupters. These levels did not change appreciably from month 6 to month 24.
Among coinfected SMART interrupters with a study entry hyaluronic acid level above normal, cumulative risk of non-AIDS death came to 37.3% after 48 months, compared with 7.3% in noninterrupters who had either a normal or high baseline hyaluronic acid reading. Initial hyaluronic acid level did not predict risk of opportunistic infection. Among coinfected people with an entry hyaluronic acid level above 75 ng/mL, interrupters had nearly a 4 times higher risk of a non-AIDS death than noninterrupters (hazard ratio 3.8, 95% confidence interval 1.4-10.6, P = 0.009).
Coinfected people with elevated entry hyaluronic acid readings had significantly higher interleukin 6 (IL-6) and D-dimer levels than people with normal hyaluronic acid quotients at entry. An earlier SMART analysis tied elevated IL-6 and D-dimer to all-cause mortality in SMART, and interrupting antiretrovirals led to increases in both IL-6 and D-dimer [2].
Because hyaluronic acid levels rise after antiretroviral interruption, the SMART investigators warned that suspending treatment "is particularly dangerous" in hepatitis virus-coinfected people if hyaluronic acid is high just before the antiretroviral holiday.
References
1. Peters L, the INSIGHT SMART Study Group. Interruption of ART and changes in hyaluronic acid as marker of liver fibrosis progression in Strategies for Management of ART viral hepatitis-co-infected participants and matched controls. 16th Conference on Retroviruses and Opportunistic Infections. February 8-11, 2009. Montreal. Abstract 858.
(Poster online at http://www.retroconference.org/2009/PDFs/858.pdf.)
2. Kuller LH, Tracey R, Belloso W, et al. Activation of inflammatory and coagulation pathways is associated with mortality in patients with HIV infection. PLoS Med. 2008;5(10):e203.
(Article online at http://medicine.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pmed.0050203.)
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