HIV treatment isn't a risk factor for liver dysfunction, but HIV infection is

Infection with HIV is associated with an increased risk of hepatic dysfunction, and death related to liver dysfunction, according to the results of a large US study published in the online edition of the Journal of Acquired Immune Deficiency Syndromes.

A lower CD4 cell count and higher viral load were associated with liver disease and liver-related death.

Reassuringly, there was no evidence that antiretroviral therapy increased the risk of adverse liver-related outcomes. Indeed, HIV treatment reduced the risk of death caused by hepatic dysfunction.

“Our study results clearly did not point to ART [antiretroviral therapy] as contributing to risk; in fact risk was reduced with longer duration,” emphasise the investigators.

The advent of effective antiretroviral treatment has transformed the prognosis of many HIV-positive patients.

However, liver disease is an increasingly important cause of serious illness and even death in individuals with HIV.

A number of possible reasons have been identified. There include co-infection with hepatitis B and/or hepatitis C and drug and alcohol misuse. Some anti-HIV drugs can also cause liver-related side-effects.

Investigators from California wanted to establish if HIV-positive patients were more likely to develop hepatic dysfunction or die of liver-related causes than age and sex-matched HIV-negative individuals. The researchers also wished to see if any specific causes were related to liver disease and death caused by hepatic dysfunction in HIV-infected patients.

They therefore designed a study involving 20,755 HIV-positive patients who received care between 1996 and 2008, each of whom was matched with ten HIV-negative controls of the same sex and age who received care over the same period.

Hepatic dysfunction was defined as:

• Diagnosis with liver failure.

• Diagnosis with hepatic encephalopathy.

• Oesophageal varices (if bleeding).

• ALT/AST levels five-times the upper limit of normal if accompanied by elevated ammonia and/or elevated international normalised ratio greater than the upper normal limit.

Deaths were considered as related to hepatic dysfunction if:

• It was within 60 days of diagnosis with hepatic dysfunction.

• If liver failure was mentioned on the death certificate as the primary or secondary cause of death.

The HIV-positive patients were predominantly men (91%), over half were white (51%) and the mean age at start of follow-up was 41 years.

A total of 437 HIV-positive patients were diagnosed with hepatic dysfunction. The incidence was 491 events per 100,000 person years of follow-up. This compared to 755 events in the HIV-negative controls, an incidence of 67 per 100,000 person years.

The investigators calculated that the incidence of liver dysfunction was 6.5 times higher in the HIV-positive patients compared to the controls (p < 0.001).

There were 170 liver dysfunction-related deaths among the HIV-positive patients. This provided an incidence of 188 per 100,000 person years. In contrast, 192 deaths due to the same cause were recorded in the HIV-negative controls, an incidence of 17 per 100,000 person years.

Therefore, incidence of hepatic dysfunction-related death was six times higher (risk ratio 5.9) in the HIV-positive patients than the controls (p < 0.001).

Among the patients with HIV, the most common primary causes noted when hepatic dysfunction was listed as a cause of death included HIV/AIDS (69%) and other liver-related causes (19%).

Immune dysfunction at all levels increased the risk of hepatic dysfunction or death. However, compared to HIV-uninfected individuals it was lowest for those with a CD4 cell count above 500 cells/mm³ and highest for patients with a CD4 cell count below 200 cells/mm³ not taking antiretroviral therapy (adjusted risk ratio, 59.4; 95% CI, 39.3-89.7, p < 0.001).

There was also a consistent relationship between a higher viral load (above 100,000 copies) and an increased risk of hepatic dysfunction and death from such problems.

Analysis was then restricted to the patients with HIV.

The strongest risk factor for hepatic dysfunction was co-infection with hepatitis B and/or C (aRR = 5.3; 95% CI, 4.3-6.4, p < 0.001). Other risk factors included a CD4 cell count below 200 cells/mm³, viral load above 500 copies/ml, alcohol or drug use and diabetes.

Finally the investigators examined whether cumulative antiretroviral use was associated with adverse liver outcomes.

There was no evidence that the use of antiretroviral therapy was associated with hepatic dysfunction. This was the case for regimens based on protease inhibitors and those based on a non-nucleoside reverse transcriptase inhibitor (NNRTI).

For death related to hepatic dysfunction, the investigators found a protective effective of antiretroviral therapy, each year of therapy reducing the risk by 17% (aRR = 0.83; 95% CI, 0.72-0.94, p = 0.004).

“The long-term, cumulative use of ART did not increase risk of either hepatic dysfunction or hepatic dysfunction-related death,” write the authors. They believe this finding is “reassuring, and clinically of great importance in light of calls…to increase the number of HIV-infected individuals on ART.”

The investigators conclude that their findings “suggest that early diagnosis of HIV and subsequent initiation of ART prior to significant CD4 cell count decline may partially mitigate the risk of hepatic dysfunction or hepatic dysfunction-related death.”