Liver disease causing larger proportion of deaths since introduction of HAART

Deaths from liver-related causes have increased significantly in a large cohort of HIV-positive patients since the introduction of effective antiretroviral, researchers report in the December 2^nd edition of AIDS. The investigators from the large EuroSIDA study found that although the overall death rate from liver-related disease fell after the introduction of potent anti-HIV treatment, there was in fact a significant year-on-year increase in the rate of death once CD4 cell count was controlled for. Coinfection with hepatitis B virus and/or hepatitis C virus and length of exposure to antiretroviral therapy were found to be significantly associated with an increased rate of liver-related death.

The EuroSIDA investigators wished to describe changes over time in rates of death attributable to liver-related causes and to see if any changes in this death rate were due to combination antiretroviral therapy. The records of almost 11,000 patients were included in their analysis. They calculated the death rate due to liver-related causes per 1000 patient years and adjusted their results for factors including CD4 cell count, the presence of hepatitis B and/or hepatitis C coinfection, treatment for hepatitis coinfection, previous AIDS and demographics.

Three broad time periods were considered: the pre-combination therapy era (1994 – 1996); the early combination therapy era (1997 – 1999); and, the late combination therapy era (2000 onwards). Death rate due to liver disease were calculated for each calendar year and controlled for CD4 cell count.

A total of 184 patients (2%) died of liver disease during a total of 52,000 patient years of follow-up. Overall, those dying of liver disease had a lower CD4 cell count (162 cells/mm³ vs 254 cells/mm³, p

In their initial analysis, the investigators found that the death rate from liver-related disease was 3.5 per 1000 patient years of follow-up. This declined by 7% per year with the introduction of effective HIV treatment (p = 0.01).

The investigators found that there was a strong relationship between current CD4 cell count and death rates from liver disease. The death rate from liver disease for patients with a CD4 cell count below 50 cells/mm³ was 14 per 1000 patient years compared to just 1.6 per 1000 patient years for patients with a CD4 cell count above 200 cells/mm³. This relationship was consistent throughout the three treatment eras.

“Clearly the current CD4 cell count was related to the death rate from liver-related disease and will have changed over time due to the introduction of combination antiretroviral therapy”, write the investigators.

After adjusting for current CD4 cell count, the investigators found that there was a year-on-year 13% increase in death due to liver-related causes (p = 0.008). The investigators found that patients with hepatitis B virus had an almost threefold increased risk of death due to liver disease and that amongst patients with hepatitis C virus this risk increased fivefold.

Of the 184 deaths, 30 (16%) involved patients who were infected with hepatitis B virus and 101 (55%) individuals coinfected who were coinfected with hepatitis C virus. A total of 48% of patients died of liver disease without taking combination antiretroviral therapy and an additional 13% of individuals died of liver disease without taking any anti-HIV treatment.

Patients who had initiated treatment with combinations of anti-HIV drugs had a significantly lower death rate attributable than those who had not, 2.8 per 1000 patient years vs 6.2 per 1000 patient years, p

In further analysis, the investigators found that patients who had taken under two years of treatment with combination anti-HIV therapy had a lower rate of liver-related death than patients who had never taken combination therapy (p = 0.008). However, in further analysis, the investigators found that the risk of death increased for each year of combination anti-HIV treatment after the second year. They estimated that each additional year of therapy increased the risk of liver related death by 12%.

“Although death rates from liver-related disease in almost 11,000 patients with HIV appeared to decrease across Europe, this was explained by increases in CD4 cell count after starting combination antiretroviral therapy”, write the investigators. “After taking such increases into account, there has been a significant increase over time in death rate from liver-related disease.”

They go on to explain that patients with similar hepatitis coinfection status and current CD4 cell count had a higher risk of death from liver-related causes in 2004 than in 2000. In addition, “there was an increase in the death rate from liver-related disease with longer exposure to combination antiretroviral therapy.” The investigators explain “this may be due to longer survival in coinfected patients or prolonged treatment with potentially hepatotoxic drugs.”

The investigators emphasise that their findings should be seen within the wider context of the benefits of HIV therapy which “continues to have a major benefit for reducing the risk of AIDS or HIV-related deaths, and in reducing liver-related deaths, and the increased death rate from liver-related disease with longer exposure to combination therapy should be balanced against its many benefits.”