aHIV Unit, Guy's and St Thomas' Hospitals NHS Foundation Trust, London, UK
bLiverpool HIV Pharmacology Group, University of Liverpool, Liverpool, UK.
Received 22 January, 2009
Accepted 6 April, 2009
Correspondence to Michael Aboud, Harrison Wing, 2nd Floor Lambeth Wing, St Thomas' Hospital, London SW4 7RB, UK. E-mail: firstname.lastname@example.org
A 50-year-old African lady who was tested HIV positive in 1996 started antiretroviral therapy in 1998, and she was previously exposed to zidovudine, stavudine, didanosine (DDI), indinavir, saquinavir and nelfinavir.
Her HAART switches since 1998 were for side effects, drug toxicities and/or virologic failure/resistance. The last 4 years she had been on tenofovir (TDF), DDI and boosted fosamprenavir/r (fAMP/r). She had also been on minocycline for a year for acne.
In January 2008, she presented with abdominal distension and discomfort; clinically, she had ascites. Investigation revealed liver cirrhosis and portal vein thrombosis, normal liver function [alanine transaminase (ALT), aspartate transaminase (AST), platelet function, alpha fetoprotein, albumin and clotting time] and raised cancer antigen-125 (CA-125). She was anticoagulated; liver biopsy was deferred. The possibility of a drug-related cause was considered. We switched the regimen in a step-wise manner initially to TDF, DDI and etravirine (ETV) and then to TDF, ETV and boosted darunavir (DRV/r). Minocycline was also discontinued.
Further investigation revealed liver fibrosis/cirrhosis on biopsy, although the exact cause still remains unclear. She remains anticoagulated, and her decompensated cirrhosis is managed in collaboration with the hepatologists.
She remained stable and maintained her HIV viral load at below the level of detection.
ETV therapeutic drug monitoring (TDM) became available about 8 months into her new HAART regimen (TDF, ETV and DRV/r); ETV level was reported to be 3257 ng/ml, which is about 60 times the alleged target concentration on standard dosing [200 mg twice daily (b.i.d.)]. ETV was discontinued immediately. Serial ETV plasma concentration monitoring was performed at weeks 2 and 5 after discontinuation and were 931 and 100 ng/ml, that is, 18 times and twice the target level, respectively (Fig. 1). The half-life of ETV in this patient was estimated using the three data points (WinNonLin; Pharsight, Mountain View, California, USA) and was 237 h. The patient did not experience any adverse event on ETV.
In the presence of normal hepatic function, the half-life of the nonnucleoside reverse transcriptase inhibitors (NNRTIs) are: nevirapine (NVP) 25–30 h and efavirenz (EFV) and ETV 35–40 h. ETV plasma levels are higher in HIV-negative individuals with mild-to-moderate hepatic impairment compared with healthy volunteers . In HIV-positive individuals, hepatitis coinfection increases ETV area under the curve (AUC) at 12 h by about 1.35-fold .
In one study of 103 hepatitis C virus (HCV)/HIV-coinfected individuals who had fibroscan-defined mild-to-moderate (Child–Pugh A and B) cirrhosis, there was a positive correlation between liver stiffness and plasma levels of EFV and NVP; coinfected patients with compensated cirrhosis had higher than normal concentrations of NNRTIs, especially EFV .
Data from the DUET studies indicate that ETV pharmacokinetics do not vary by sex or race. Furthermore at the dose used, there was no clear relationship between pharmacokinetic parameters and efficacy or safety . ETV is metabolized by hydroxylation by cytochrome P450 3A4 (CYP3A4) and the 2C family, followed by glucuronidation. To date, there are no data implicating specific genetic polymorphisms with ETV plasma concentrations. There is a high interindividual variability in ETV plasma levels .
EFV hepatic clearance in African–Americans is lower than in white non-Hispanic individuals . In the 2NN study , lower EFV drug clearance was reported in Thai patients than in non-Asians, as well as a slightly higher rate of antiretroviral drug-associated adverse events.
There is a link between polymorphisms in CYP2B6 and EFV plasma level and central nervous system (CNS) side effects . African–Americans and Hispanics have higher EFV AUC than European–Americans; EFV levels in African–Americans with the CYP2B6 homozygous G516T variant (TT) genotype were approximately three-fold higher than in individuals with the homozygous GG genotype. The same association was found in European–Americans with the TT genotype, although the frequency of this genotype is less than in African–Americans (16.7 versus 6.3%). Individuals with the TT genotype also had more CNS side effects in the first week of treatment with EFV.
Unlike EFV, NVP is metabolized by isoenzymes from both the CYP3A4 and CYP2B families , and polymorphisms in both have been shown to affect NVP levels [9,10].
Exact target ranges for ETV plasma levels have not been determined, and there is significant interpatient and intrapatient variability. ETV levels are mildly elevated in mild-to-moderate hepatic dysfunction. No data exist for severe hepatic dysfunction. This case showed excessive levels and a long half-life in severe liver disease at standard dosing without adverse outcome.
We present case evidence to support the ETV summary of product characteristics (SmPC) recommendation that pending further data, ETV should not be used in severe liver disease or decompensated liver cirrhosis.
1. Schöller-Gyüre M, Kakuda TN, De Smedt G, Woodfall B, Lacheart R, Beets G, et al. Pharmacokinetics of TMC 125 in once and twice-daily regimens in HIV-1-negative volunteers
[poster #A-1428]. In: 47th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC)
; 17–20 September 2007; Chicago, IL.
2. Kakuda TN, Schöller-Gyüre M, Peeters M, Corbett C, De Smedt G, Woodfall BJ, et al. Pharmacokinetics of etravirine are not affected by sex, age, race, treatment duration or use of enfuvirtide in HIV-1 infected patients
[abstract #Tupe0082]. In: XVIIth International AIDS Conference (IAC)
; 3–8 August 2008; Mexico City, Mexico.
3. Barreiro P, Rodriguez-Novoa S, Labarga P. Influence of the stage of liver fibrosis on plasma levels on antiretroviral drugs in HIV-infected patients with chronic hepatitis
[abstract #PL6.2]. In: 8th International Congress on Drug Therapy in HIV Infection (HIV8)
; 12–16 November 2006; Glasgow, Scotland.
4. Tibotec Data on File; data obtained from various analyses in the DUET studies.
5. Pfister M, Labbé L, Hammer SM, Mellors J, Bennett K, Rosenkranz S, et al
, and the AIDS Clinical Trial Group Protocol 398 Investigators. Population pharmacokinetics and pharmacodynamics of efavirenz, nelfinavir, and indinavir: adult AIDS clinical trial group study 398. Antimicrob Agents Chemother 2003; 47:130–137.
6. van Leth F, Phanuphak P, Ruxrungtham K, Baraldi E, Miller S, Gazzard B, et al
, 2NN Study team. Comparison of first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine: a randomised open-label trial, the 2NN Study. Lancet 2004; 363:1253–1263.
7. Haas DW, Wu H, Li H, Bosch RJ, Lederman MM, Kuritzkes D, et al
. MDR1 gene polymorphisms and phase 1 viral decay during HIV-1 infection: an adult AIDS clinical trials group study. J Acquir Immune Defic Syndr 2003; 34:295–298.
8. Erickson DA, Mather G, Trager WF, Levy RH, Keirns JJ. Characterization of the in vitro biotransformation of the HIV-1 reverse transcriptase inhibitor nevirapine by human hepatic cytochromes P-450. Drug Metab Dispos 1999; 27:1488–1495.
9. Rotger M, Colombo S, Furrer H, Bleiber G, Buclin T, Lee BL, et al
. Influence of CYP2B6 polymorphism on plasma and intracellular concentrations and toxicity of efavirenz and nevirapine in HIV-infected patients. Pharmacogenet Genomics 2005; 15:1–5.
10. Owen A, Almond LM, Hartkoorn R, Walsh T, Youle M, Bonington A, et al
. Relevance of drug transporters and drug metabolism enzymes to nevirapine: superimposition of host genotype
[abstract #650]. In: 12th Conference on Retroviruses and Opportunistic Infections (CROI)
; 22–25 February 2005; Boston, MA.