The use of no single antiretroviral drug could be linked to cryptogenic liver disease in HIV-positive patients receiving care at London’s Chelsea and Westminster Hospital. Investigators told the recent Third International Workshop on HIV and Hepatitis Coinfection that twelve of the hospital’s cohort of 4,500 patients had developed fibrosis without an obvious cause between 2004 and 2007.
Nine of the patients at the Chelsea and Westminsiter Hospital had, however, received treatment with the nucleoside reverse transcriptase inhibitor, ddI (didanosine, Videx), and investigators from Spain, who also presented data to the workshop on cryptogenic liver disease, suggested that ddI was the most likely cause of this condition. Three-quarters of the cases in the Spanish study were in gay men, and the Spanish investigators speculated that these men had been infected with bacteria during anal sex that was transfering to the liver and contributing to the development of liver disease.
Studies have recently reported serious liver disease in HIV-positive individuals without obvious infectious causes, such as hepatitis B or hepatitis C virus, or behavioural risk-factors, such as alcoholism. Doctors in Paris "found a high prevalence of nodular regenerative hyperplasia in HIV-positive patients with cryptogenic liver disease.
Investigators at London’s Chelsea and Westminster Hospital, the largest HIV treatment centre in Europe, therefore conducted a retrospective analysis to identify all cases of cryptogenic liver disease seen in their antiretroviral-treated patients between 2004 and 2007.
A total of 90 patients who underwent liver biopsy were identified, and of these twelve were diagnosed as having cryptogenic liver disease. These twelve patients had a mean age of 45, and median CD4 cell count at the time that cryptogenic liver disease was diagnosed was 261 cells/mm3.
Nine of the patients were men, and all the male patients were Caucasian. Two of the three women were African.
All the patients had received therapy with drugs from the three main classes of antiretrovirals. Information was then gathered on the specific antiretroviral drugs that the patients had received and the duration of therapy with each drug. Fifteen individual antiretroviral drugs had been used: ddI was the most commonly used, having been taken by nine patients for a mean duration of 71 months. AZT was taken by eight patients for a mean duration of 55 months. However, the investigators found that thirteen other anti-HIV drugs from all the three main classes had been taken by the patients with mean duration of therapy lasting between five and 52 months.
The patients were extensively tested for possible causes of liver disease and none could be identified. Nor did the investigators believe that gender, race, or sexual behaviour were risk factors as the condition affected both men and women, as well as Caucasians and Africans.
The investigators concluded that no obvious correlation could be found between cryptogenic liver disease and the use of specific antiretrovirals, although they did acknowledge that ddI was the most frequently used drug and for the longest duration. All patients who could have fibrosis should, the investigators recommend, have regular non-invasive tests to check for fibrosis using Fibroscan and Fibrotest.
Liver disease in Spain and Italy
A study examining the prevalence and risk factors for cryptogenic liver disease in HIV-positive in Spain and Italy was also presented to the workshop. Investigators from Madrid conducted a retrospective study involving 3,200 patients receiving HIV care between 2004 and 2006 at five treatment centres. A total of 32 cases of cryptogenic liver disease were identified, all the patients having persistently abnormal liver function tests with no apparent cause.
The median age of the patients was 36 years, 27 were men, 22 were gay, median CD4 cell count was 260 cells/mm3 and the median duration of antiretroviral therapy was four years.
As in the Chelsea and Westminster study, the most frequently used antiretroviral drug was ddI, the mean duration of therapy with this drug being 44 months.
Liver biopsies were performed on ten patients, leading to the diagnosis of two cases of nodular regenerative hyperplasia.
Termination of therapy with ddI led to clinical and biological improvements in 13 patients twelve months later, with mean ALT levels falling from 75 to 46 IU/ml (p = 0.001). A non-significant improvement was observed, using Fibroscan, in the stage of the patients’ fibrosis.
The investigators speculate that there may have dual causes for the cryptogenic liver disease that they observed. Treatment with ddI was likely the first cause – the investigators believe that the drug may lead to mitochondrial damage in the liver. As the majority of the cases involved gay men, the investigators also suggest that anal intercourse could be leading to exposure to bacteria capable of damaging the liver.
Wong THN et al. Cryptogenic liver disease in HIV infected patients. Is there a link with antiretroviral therapy? Third International Workshop on HIV and Hepatitis Coinfection, abstract 62, Paris, 2007.
Maida I et al. HIV associated hepatopathy - a new clinical condition: prevalence, etiology and outcome. Third International Workshop on HIV and Hepatitis Coinfection, abstract 45, Paris, 2007.