SUMMARY: Lower CD4 cell count and higher hepatitis B virus (HBV) viral load were significant predictors of liver toxicity among HIV/HBV coinfected individuals receiving antiretroviral therapy (ART) in an international study, according to a poster presented at the 17th Conference on Retroviruses and Opportunistic Infections (CROI 2010) last month in San Francisco. These findings support current treatment guidelines recommending earlier ART for HIV positive people with chronic hepatitis B.

By Liz Highleyman

HIV/HBV coinfection is associated with more rapid liver disease progression and increased risk for hepatotoxicity (liver toxicity) in patients receiving combination ART. ART can cause liver injury by a variety of mechanisms including direct drug toxicity, immune reconstitution inflammatory syndrome (IRIS), and development of HBV drug-resistance leading to liver inflammation "flares."

Most studies of hepatotoxicity in HIV/HBV coinfected patients have primarily concentrated on the first year of ART and have looked at people in high-income countries.

Jennifer Audsley and fellow investigators sought to better understand the clinical factors associated with hepatotoxicity in an international cohort of HIV/HBV coinfected patients receiving prolonged ART.

For HIV/HBV coinfected individuals, it is not known how HBV viral load, HBV "e" antigen (HBeAg) status, prolonged ART, or drug resistance influence the risk of hepatotoxicity, the researchers noted as background. However, they hypothesized that long-term ART would be associated with a decrease in the risk of hepatotoxicity.

This prospective longitudinal cohort study enrolled 170 HIV/HBV coinfected participants in the U.S. (the Multicenter AIDS Cohort Study [MACS]), Australia, and Thailand. Most (91%) were men and 64% were older than 40 years. Half were HBeAg positive.

Almost all (92%) had been on ART for more than 1 year (median duration 4.9 years), about 80% had undetectable HIV RNA (< 400 copies/mL), and 17% had a CD4 count below 200 copies/mL. About 70% were taking a NNRTI and 36% were taking a protease inhibitor. About two-thirds were taking antiretroviral dugs with dual activity against both HIV and HBV, mostly tenofovir (Viread) plus lamivudine (3TC; Epivir) and/or emtricitabine (Emtriva).

Patients were followed every 6 months with clinical and laboratory assessments including HBV DNA, HBeAg, CD4 cell count, HIV RNA, and alanine transaminase (ALT). Hepatotoxicity was defined according to ALT levels, using an upper limit of normal (ULN) of 30 IU/L for men and 19 IU/L for women. Significant hepatotoxicity was defined as grade 2 or higher. The median follow-up time was 3.5 years (range 0 to 4.4).

Results

	10.8% of study visits yielded ALT measurements classified as significant hepatotoxicity
	At baseline, the prevalence of significant hepatotoxicity was 13%, and this did not change significantly during follow-up.
	In a univariate analysis, factors significantly associated with significant hepatotoxicity included:
	History of AIDS-defining conditions; HBV DNA > 2000 IU/mL; Being HBeAg positive; Use of lamivudine and/or emtricitabine; ART duration < 12 months; Current CD4 count < 200 cells/mm3 Nadir (lowest-ever) CD4 count < 200 cells/mm3
	In a multivariate analysis controlling for confounding factors, the following remained independent predictors of significant hepatotoxicity:
	HBV DNA > 2000 IU/mL (odds ratio 2.50); Current CD4 count < 200 cells/mm3 (odd ratio 1.88).
	In the controlled analysis, ART duration > 12 months showed a trend toward predicting hepatotoxicity -- contradicting the univariate analysis -- but the association did not reach statistical significance.

Based on these results, the researchers concluded, "CD4 count < 200 cells/[mm3] and HBV DNA > 2000 IU/mL months were significantly associated with an increased risk of significant hepatotoxicity among HIV/HBV coinfected people on long-term HAART."

They added that, "This finding provides further support for current guidelines recommending earlier initiation of HAART in HIV/HBV coinfected patients."

As of the December 2007 revision, U.S. antiretroviral therapy guidelines recommend that all HIV/HBV coinfected individuals who require hepatitis B treatment should receive a complete combination ART regimen. The latest International AIDS Society guidelines state that, "Active HBV coinfection should prompt consideration of initiation of antiretroviral therapy, irrespective of CD4 cell count, since earlier therapy might reduce the rate of liver disease progression."

Monash Univ, Melbourne, Australia; Alfred Hosp, Melbourne, Australia; Johns Hopkins Univ Sch of Med, Baltimore, MD; Natl Ctr in HIV Epi and Clin Res, Sydney, Australia; HIVNAT Res Collaboration, Bangkok, Thailand; Victorian Infectious Diseases Reference Lab, Melbourne, Australia.

3/2/10

Reference
J Audsley, E Seaberg, J Sasadeusz, and others. Factors Associated with Hepatotoxicity in an International HIV/HBV Co-infected Cohort on Long-term HAART. 17th Conference on Retroviruses & Opportunistic Infections (CROI 2010). San Francisco. February 16-19, 2010. (Abstract 691).