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Long-term Tenofovir Use Associated with Increased Risk of Serious Liver Disease


Long-term therapy with the antiretroviral drug tenofovir (Viread, also in several coformulations including Truvada and Atripla) increases the risk of end-stage liver disease and liver cancer, according to data from the D:A:D study published in the January 18 online edition of AIDS. Researchers found that 5-year cumulative use of the drug increased the relative risk of serious liver disease by 46%.

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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) coinfection 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, stavudine (d4T) and didanosine (ddI), also increased the risk of serious liver-related outcomes, as did treatment with fosamprenavir (Lexiva). The investigators call for patients taking "d" drugs and other antiretrovirals associated with liver disease to undergo intensified monitoring of liver function.

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 (characterized by bleeding varices, hepatic encephalopathy, hepato-renal syndrome, or liver transplantation) and hepatocellular carcinoma.

Investigators with the D:A:D study, which evaluates the long-term safety of HIV therapy, examined prospective data collected from approximately 45,000 patients who took antiretrovirals between 2004 and 2014. The researchers calculated the incidence of serious liver disease, survival rates after diagnosis with end-stage liver disease or liver cancer, and the association between individual antiretroviral drugs and the relative risk of these outcomes.

The investigators hypothesized 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 wealthy 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 or liver cancer was adjusted to take account of potential confounders, especially those known to influence the risk of liver disease, including age, sex, race/ethnicity, smoking status, mode of HIV transmission (injection drug use vs other) and coinfection with HBV and/or HCV.

Antiretroviral exposure was measured cumulatively in 5-year periods as it was hypothesized that risk of liver-related outcomes would increase with longer exposure to therapy.

Half the patients were Caucasian, 74% were men, and 45% were in the men who have sex with men (MSM) risk group. The median age at baseline was 40 years and median CD4 T-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 (new) end-stage liver disease or 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 years, the most common mode of HIV acquisition was injection drug use (54%), and the median CD4 count was 266 cells/mm3.

Viral hepatitis coinfection was common, with 72% coinfected with HCV and 40% with HBV. The overwhelming majority (83%) of serious liver events occurred among patients infected with hepatitis C or B. The incidence of end-stage liver disease or 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 3 months. The 1-year mortality rate was 63%.

Several antiretroviral drugs were associated with an increased relative risk of end-stage liver disease or liver cancer. As expected, these included the "d" drugs, with stavudine use increasing the relative risk of serious liver outcomes by 46% (relative risk [RR] 1.45/5 years) and didanosine increasing the risk by 32% (RR 1.32/5 years). The protease inhibitor fosamprenavir was associated with a 47% increase in the relative risk of serious liver disease (RR 1.47/5 years).

A surprising finding was the association between use of tenofovir and the risk of serious liver-related outcomes. Long-term exposure to tenofovir increased the relative risk of end-stage liver disease or liver cancer by 46% (RR 1.46/5 years). Tenofovir is also used as a treatment for hepatitis B, 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 coinfection.

"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 -- another major risk factor for liver disease -- nor was information available on the use of potentially liver-toxic treatments for serious infections such as tuberculosis or 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 coinfection the prognosis following a diagnosis was very poor," concluded 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."



L Ryom, JD Lundgren, S De Wit, et al (D:A:D Study Group). Use of antiretroviral therapy and risk of end-stage liver disease and hepatocellular carcinoma in HIV-positive persons. AIDS. January 18, 2016 (online ahead of print).