Does tenofovir increase efavirenz hepatotoxicity?

Antiretroviral drugs have the potential to cause liver toxicity, especially in hepatitis B virus or hepatitis C virus coinfected patients. Tenofovir is among the few antiretrovirals that are considered nonhepatotoxic, whereas efavirenz can cause liver enzyme elevations ^[1,2]. We report three cases of liver enzyme elevations in persistently hepatitis B virus and hepatitis C virus-negative, HIV-infected patients after the addition of tenofovir to an efavirenz-containing regimen.

Patient 1

A 58-year-old Caucasian man was on virologically successful antiretroviral therapy (zidovudine, lamivudine and efavirenz, respectively) since July 2002. In July 2007, zidovudine was replaced by tenofovir because of lipoatrophy and bone marrow toxicity. Four weeks later, alanine aminotransferase (ALT, normal values <50 IU/l) was 92 IU/l and aspartate aminotransferase (AST, normal values <50 IU/l) was 62 IU/l. Both enzymes had always been within the normal range prior to the switch. Further controls showed ALT 144 IU/l and AST 84 IU/l (after a further 1 month) and ALT 142 IU/l and AST 77 IU/l 3 months after tenofovir introduction. The patient then stopped tenofovir and began didanosine. Three weeks later, ALT was 48 IU/l and AST was 44 IU/l.

Patient 2

A 34-year-old African woman was on zidovudine, lamivudine and abacavir since September 2003. In October 2006, abacavir was replaced by efavirenz because of virological failure. In August 2007, owing to anaemia, zidovudine was stopped and tenofovir was started. In September 2007, ALT and AST (previously normal) were 133 and 199 IU/l, respectively; liver enzyme elevation was confirmed subsequently after 3 weeks (ALT 186 IU/l, AST 146 IU/l). Highly active antiretroviral therapy (HAART) was stopped and, in the beginning of November 2007, ALT and AST were back to normal (36 and 30 IU/l, respectively). The patient is on abacavir, lamivudine and lopinavir/ritonavir since December 2007.

Patient 3

A 30-year-old Caucasian man was on lamivudine, tenofovir and efavirenz since April 2007. In May 2007, ALT and AST (previously normal) were 392 and 225 IU/l,. ART was discontinued and, 40 days later, ALT was 23 IU/l and AST was 29 IU/l, respectively. The patient is on didanosine, lamivudine and nevirapine since December 2007.

No cases of tenofovir-related hepatotoxicity have been reported in the literature, and the drug appears to be well tolerated even in cirrhotic patients ^[1]. In contrast, numerous cases of hepatotoxicity are related to efavirenz use ^[2,3]. Interestingly, in individuals who are slow efavirenz metabolisers, such as those with CYP2B6 loss/diminished-function alleles, efavirenz plasma area under the curve values are highest among patients receiving tenofovir ^[4], and an unexpected development of neuropsychiatric adverse events has been reported following addition of tenofovir to an efavirenz-containing ART regimen ^[5]. We have not measured efavirenz plasma concentrations in our three patients, and therefore we cannot prove whether an increased efavirenz plasma concentration is responsible for the observed rise in aminotransferase levels. Alternatively, hepatotoxicity may be responsible for a highly infrequent tenofovir-related side-effect. Analysis of large databases or pharmacokinetic studies is needed to confirm, extend and explain our observations.