D:A:D study: long-term treatment with tenofovir associated with increased risk of serious liver disease

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Long-term therapy with the antiretroviral drug tenofovir increases the risk of end-stage liver disease and liver cancer, according to data from the D:A:D study published in the online edition of AIDS. Five-year cumulative use of the drug increased the relative risk of serious liver disease by 46%.

The number of cases of end-stage liver disease and liver cancer among tenofovir-treated patients was low (approximately 1.5 cases per 1000 patients each year), but the association between these conditions and exposure to the drug remained robust after taking into account hepatitis B virus- (HBV) and hepatitis C virus- (HCV) infection status.

The relationship between tenofovir and serious liver disease surprised the study’s authors, who call for further research into this finding. As expected, treatment with the so-called “d” group of antiretrovirals, d-4T (stavudine) and ddI (didanosine) also increased the risk of serious liver-related outcomes, as did therapy with fosamprenavir. The investigators call for patients taking “d” drugs and other antiretrovirals associated with liver disease to have intensified monitoring of liver function.


end-stage disease

Final period or phase in the course of a disease leading to a person's death.

hepatitis B virus (HBV)

The hepatitis B virus can be spread through sexual contact, sharing of contaminated needles and syringes, needlestick injuries and during childbirth. Hepatitis B infection may be either short-lived and rapidly cleared in less than six months by the immune system (acute infection) or lifelong (chronic). The infection can lead to serious illnesses such as cirrhosis and liver cancer. A vaccine is available to prevent the infection.

relative risk

Comparing one group with another, expresses differences in the risk of something happening. For example, in comparison with group A, people in group B have a relative risk of 3 of being ill (they are three times as likely to get ill). A relative risk above 1 means the risk is higher in the group of interest; a relative risk below 1 means the risk is lower. 


A disease or infection affecting the brain. HIV-encephalopathy (also called AIDS dementia complex) is the result of damage to the brain by advanced HIV disease.


To do with the liver.

It is well known that most antiretroviral drugs can cause disturbances in liver function. However, such liver-related side effects are usually transient, mild and asymptomatic. Very little is known about the association between individual antiretrovirals and end-stage liver disease (variceal bleeding, hepatic encephalopathy, hepatorenal syndrome or liver transplant) and hepatocellular carcinoma.

Investigators from the D:A:D study into the long-term safety of HIV therapy examined prospective data collected from approximately 45,000 patients who took antiretrovirals between 2004 and 2014. They calculated the incidence of serious liver disease, survival rates after diagnosis with end-stage liver disease/liver cancer and the association between individual antiretroviral drugs and the relative risk of these outcomes. The investigators hypothesised that there would be an association between therapy with “d” drugs and the risk of serious liver disease because these drugs are known to induce fibrosis. Although “d” drugs are now rarely used in richer countries, and are no longer recommended in World Health Organization guidelines, their use has not yet been phased out in resource-limited settings.

The relationship between individual antiretroviral drugs and end-stage liver disease/liver cancer was adjusted to take account of potential confounders, especially those known to influence the risk of liver disease, including age, gender, ethnicity, smoking status, mode of HIV transmission (IDU vs. other) and co-infection with HBV and/or HCV.

Antiretroviral exposure was measured cumulatively in five-year periods as it was hypothesised that risk of liver-related outcomes would increase with longer exposure to therapy.

Half the patients were Caucasian, 74% were men and 45% were men who have sex with men (MSM) risk group. The median age was baseline was 40 years and median CD4 cell count at this time was 434 cells/mm3.

Patients were followed for a median of 8.4 years and a total of 319 incident end-stage liver disease/liver cancer events were recorded. Overall incidence was 1.01 per 1000 person-years of follow-up, which the investigators describe as “low.”

The median age of patients with serious liver disease was 47, the most common mode of HIV acquisition was injecting drug use (54%) and median CD4 cell count was 266 cells/mm3.

Viral hepatitis co-infection was common, with 72% infected with HCV and 40% with HBV. The overwhelming majority (83%) of serious liver events occurred in patients infected with HCV or HBV. The incidence of end-stage liver disease/liver cancer among patients without HCV or HBV was very low (0.19 per 1000 person years).

The most common end-stage liver events were hepatic encephalopathy (43%) and variceal bleeding (27%).

The prognosis of patients diagnosed with serious liver disease was poor. Three-quarters of patients died and the median survival after diagnosis was approximately three months. The one-year mortality rate was 63%.

Several antiretroviral drugs were associated with an increased relative risk of end-stage liver disease/liver cancer. As expected, these included the “d” drugs, with stavudine use increasing the relative risk of serious liver outcomes by 46% (RR, 1.45/5 years; 95% CI, 1.20-2.77) and didanosine by 32% (RR, 1.32/5 years; 95% CI, 1.07-1.63). The protease inhibitor fosamprenavir was associated with a 47% increase in the relative risk of serious liver disease (RR, 1.47/5 years; 95% CI, 1.01-2.15).

A surprising finding was the association between tenofovir therapy and the risk of serious liver-related outcomes. Long-term exposure to tenofovir increased the relative risk of end-stage liver disease/liver cancer by 46% (RR, 1.46/5 years; 95% CI, 1.11-1.93). Tenofovir is also a treatment for HBV, so researchers did a further analysis to see if this could explain their results. However, the association between tenofovir and serious liver events remained robust even when the analysis was limited to patients without viral hepatitis co-infection.

“The tenofovir association remained unchanged after stratifying according to and adjusting for viral hepatitis status,” comment the authors. “Furthermore, a recent D:A:D analysis which investigated predictors of chronic liver enzyme elevation among individuals without viral hepatitis, also confirmed the positive association between cumulative tenofovir use, supporting this observation.”

The authors acknowledge that their research has some possible limitations. They did not collect data on alcohol use, nor was information available on the use of potentially liver-toxic treatments for serious infections such as tuberculosis and PCP pneumonia.

“Whilst the end-stage liver disease/hepatocellular carcinoma incidence was relatively low in this large heterogeneous cohort, and predominantly seen in individuals with viral hepatitis co-infection the prognosis following a diagnosis was very poor,” conclude the authors. “Intensified monitoring of liver function and avoidance of hepatotoxic compounds should hence be considered amongst all with long-term term current or prior d-drug exposure. The unexpected and viral hepatitis independent, tenofovir association calls for further investigations, whilst the use of d-drugs should be avoided, where there are alternatives available.”


Ryom L et al. Use of antiretroviral therapy and risk of end-stage liver disease and hepatocellular carcinoma in HIV-positive persons. AIDS, online edition. DOI: 10.1097/QAD.00000000000001018 (2016).