[procaare] Does Tenofovir Increase the Risk of Efavirenz-associated Liver Side-effects?

["AIDSMAP" <procaare@healthnet.org>]

Does Tenofovir Increase the Risk of Efavirenz-associated Liver 
Side-effects?
AIDSMAP - Michael Carter, Friday, May 09, 2008
****************

Italian investigators have reported three cases which suggest that 
treatment with tenofovir (Viread) may increase the risk of liver 
side-effects caused by efavirenz (Sustiva). The reports are 
published in the May 11th edition of AIDS.

Some anti-HIV drugs can cause liver toxicities, particularly in 
patients coinfected with hepatitis B virus and/or hepatitis C 
virus. There is no evidence that tenofovir causes liver 
side-effects, but efavirenz can cause elevations in liver enzymes, 
studies showing this happens in approximately 2% of patients. A 
combination including tenofovir and efavirenz is recommended (with 
FTC, emtricitabine, Emtriva) for first-line antiretroviral therapy 
in the latest edition of British HIV treatment guidelines.

However, doctors in northern Italy have observed three cases of 
liver enzyme elevations in patients taking tenofovir with 
efavirenz. None of the three patients was infected with hepatitis B 
or hepatitis C.

The first patient was a 58-year-old Caucasian man who had been 
taking an antiretroviral combination of AZT, 3TC (lamivudine, 
Epivir) and efavirenz since 2002. Although this therapy was 
suppressing his viral load to undetectable levels, the use of AZT 
caused lipoatrophy and bone marrow toxicity. He therefore replaced 
AZT with tenofovir in July 2007. At the time of this treatment 
switch, his ALT and AST liver function tests were normal (below 50 
iu/l). But, four weeks after switching to tenofovir, the patient's 
ALT increased to 92 iu/l and his AST to 62 iu/l. Tests conducted 
one and three months later confirmed further elevations in the 
patient's liver enzymes. Treatment with tenofovir was therefore 
discontinued and the patient switched to ddI (Videx). Three weeks 
later, his ALT (48 iu/l) and AST (44 iu/l) had returned to normal 
levels.

The second case involved a 34-year-old African woman who started 
antiretroviral therapy with AZT, 3TC and abacavir (Ziagen, the 
three drugs can be combined as Trizivir), in September 2003, a 
triple NRTI combination that would now be considered sub-optimal. 
This combination failed to control the patient's viral load and she 
replaced abacavir with efavirenz in October 2006. A further 
treatment change was made in the summer of 2007 when, because of 
anaemia, the woman replaced AZT with tenofovir. A month after this 
switch, the patient's previously normal liver enzymes increased 
dramatically (ALT 133iu/l; AST 199 iu/l) and further increases were 
evident three weeks later. Antiretroviral therapy was stopped, and 
the individual's liver enzymes returned to normal. Since December 
2007 she has been taking 3TC, abacavir and lopinavir/ritonavir 
(Kaletra).

The final case involved a 30-year-old Caucasian man. His liver 
function tests were normal when he initiated anti-HIV therapy with 
a combination of 3TC, tenofovir and efavirenz in April 2007. But by 
May 2007 his ALT level had increased to 392 iu/l and his AST to 225 
iu/l. Anti-HIV drugs were stopped and his liver function returned 
to normal. In December 2007, treatment with 3TC, ddI and nevirapine 
(Viramune) was started.

"No cases of tenofovir-related hepatotoxicity have been reported in 
the literature, and the drug appears to be well tolerated even in 
cirrhotic patients", write the investigators. They note, however, 
the liver side-effects associated with efavirenz use.

There have been reports of tenofovir increasing concentrations of 
efavirenz leading to the development of efavirenz-associated 
neuro-psychiatric side-effects. Although the investigators did not 
measure efavirenz concentrations in their patients, they speculate 
that this could be the reason for the liver enzyme elevations they 
observed.

Alternatively, they suggest that they may have witnessed a cluster 
of very rare tenofovir-associated side-effects and conclude 
"analysis of large databases of pharmacokinetic studies is needed 
to confirm, extend and explain our observations."

Reference

Lattuada E et al. Does tenofovir increase efavirenz hepatotoxicity? 
AIDS 22: 995, 2008.


Online: 
http://www.aidsmap.com/en/news/F459EAFC-6F8F-4AF3-B16D-28CFE436E57A.asp