Nelfinavir concentrations are significantly higher in HIV/HCV co-infected patients with cirrhosis

Stephen Taylor, for HIV i-Base

One of the most potentially useful applications of therapeutic drug monitoring is to individualise dosing in certain patient populations. HIV infected patients with hepatitis or chronic hepatitis C represent one such growing group. Dr Mario Regazzi from Pavia, Italy presented some of the first pharmacokinetic data on nelfinavir (NFV, Viracept) concentrations and its metabolite M8 in HIV/HCV co-infected patients with and without cirrhosis [1].

This study investigated 42 HIV-positive/HCV-negative individuals and 24 HIV-positive/HCV-positive patients without cirrhosis and 14 HIV-positive/HCV-positive patients with cirrhosis confirmed by biopsy. All patients were at steady state for NFV treatment, which was part of their antiretroviral regimen. Dosages were either 1,250mg BD or 750mg BD. More than seven plasma samples per patient were obtained and analysed for NFV and M8 using validated assays. The pharmacokinetic parameters are given in the Table 1 below.

Table 1: Pharmacokinetc parameters

NFV HIV+/HCV HIV+/HCV+ without cirrhosis HIV+/HCV+ with cirrhosis
n PK parameters n PK parameters n PK parameters
Cmax (mg/mL) 25 5.2±2.2 15 7.7±3.4 12 10.6±6.3
Tmax (h 25 2.7±1.0 15 3.3±0.8 12 3.4±1.4
Ctrough (mg/mL) 25 2.3±1.2 15 3.5±2.7 12 7.2±3.2
AUC 0-24 (mg.h/mL)* 50 60.44±17.05 29 104.55±37.75 14 168.49±88.95
CL/F (L/h/kg) 50 0.66±0.24 29 0.43±0.17 14 0.30±0.12

As can be seen the HIV-positive/HCV-positive with and without cirrhosis had a significantly lower “oral clearance” of NFV compared to HIV-positive/HCV-negative individuals (65% and 35% lower p<0.05) this manifested as a 155% and 58% higher AUC in cirrhotic and non-cirrhotic patients respectively.

Interestingly even the HCV-negative individuals in this study had an AUC 0-24 hours (normalised for a dose of 2,500mg a day) greater than the patients taking NFV in the Dutch ATHENA Cohort [2] (47.6mg.h/mL in the ATHENA cohort vs 60.4 mg.h/mL in the HIV positive/HCV negative Italian cohort).

This presentation generated much debate at the meeting as how this data should be interpreted; some individuals suggested that NFV doses should be reduced to prevent long-term toxicities. A contrasting view was put forward by Charles Flexner of John Hopkins University, USA, who postulated that these patients with hepatic impairment might do virologically very well using NFV, as patient failures with NFV are often driven by non-suppression rather than toxicity. Also he claimed that work by his group presented at last year’s meeting suggested that NFV toxicity with regard to diarrhoea was not dose dependent but an idiosyncratic response. Other members of the audience urged caution at maintaining patients’ NFV concentrations at potentially supra-therapeutic concentrations for prolonged periods of time.


  1. Regazzi MB, Villani P, Zucchi P et al. Clinical pharmacokinetics of nelfinavir and its metabolite M8 in HIV/HCV co-infected patients with and without cirrhosis Abs 14 : P 3.5
  2. Burger D, Hugen WH, Droste J et al therapeutic drug monitoring (TDM) of indinavir (IDV) in treatment -naïve patients improves therapeutic outcome after 1 year; results from ATHENA

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