DISCUSSION
OF PATIENT CASE OF 5TH ROUND OF INTERNATIONAL INTERLABORATORY CONTROL PROGRAM
FOR THERAPEUTIC DRUG MONITORING IN HIV INFECTION
Description
of Case
A
27-year old female Caucasian patient with a body weight of 65 kg is diagnosed
with asymptomatic HIV infection in June 2002; her viral load at that time is
100,000 copies/mL and CD4 cell count is 230 cells/mm3. The patient
and physician agree that the patient will start with a regimen containing
zidovudine/lamivudine (Combivir®), 1 tablet q12h, plus efavirenz
600mg q24h.
Four
weeks after start of treatment, the patient complains about extensive dreaming
and tiredness. Her viral load has decreased to 700 copies/mL and CD4 is 300
cells/mm3. A sample for TDM is drawn and analysed (sample A for NNRTIs).
Question
1: please give your advise:
-
The plasma level is normal; continue with this dose
-
The plasma level is high; toxicity can be explained; decrease efavirenz dose to 400mg q24h
-
The plasma level is high, but CNS toxicity usually disappears after the first weeks; continue with this dose.
-
Other: …
Scores
Discussion of question 1
Sample
A contained efavirenz in a concentration of 5.4 mg/L. This is indeed a
relatively high concentration (the median value of 194 subsequent patients
tested in our laboratory for efavirenz was 2.4 mg/L (interquartile range 1.6-3.5
mg/L)
1
}).
Efavirenz plasma levels above 3.5-4.0 mg/L have been associated with increased
CNS toxicity in 2 independent reports
2;3
. From
this information it is clear that answer A is not correct. Answer B appears to
be correct as we have a high efavirenz level associated with toxicity, but for 2
reasons answer C is probably the most correct one. First, it is known from
clinical practice that CNS adverse events slowly diminish after
the
first weeks of treatment. Furthermore, although the patient has a good initial
virological response, the viral load is not yet undetectable, so a dose
reduction appears premature in that respect.
Continuation
of case description
Before the TDM result is known the patient calls the physician and says she wants to stop the efavirenz and asks for another agent with a low pill count. The physician wants to prescribe nevirapine but does not know how to dose this agent in a patient already on efavirenz.
Question 2: how would you dose nevirapine in a patient already on efavirenz?
-
Stop efavirenz. Start with nevirapine 200mg q24h and increase dose to q12h after 14 days
-
Stop efavirenz. Start with nevirapine 200mg q12h because hepatic enzymes are already induced and there is no need for dose escalation.
-
Discontinue all medications for 4 weeks and start with new regimen.
-
Other: ……
Scores
Discussion
of question 2:
This is a difficult question for which we do not have any evidence-based data to select the most appropriate answer. It is known that after discontinuing NNRTIs plasma levels of these agents remain detectable for more than one week. Because the (intracellular) levels of the NRTIs will become undetectable earlier there is a time period in which only plasma levels of the NNRTIs are present. At the same time the virus may escape from the viral suppression caused by the HAART regimen and starts replication at an increased rate. It is not surprising that this is the perfect environment for selection of drug resistance. So answer C is probably not the best approach. When starting nevirapine directly after discontinuing efavirenz (answers A & B), the question remains whether one should start directly with the normal dose of nevirapine (200mg q12h) or first start with 2 weeks of 200mg q24h as is the recommendation for dose escalation of nevirapine in general. Both approaches have their risks. When a patient directly starts with normal dose nevirapine there may be an increased risk of toxicity in the first 2 weeks. When a patient starts with the dose escalation there is a risk for subtherapeutic plasma levels of nevirapine because the liver enzymes may already have been induced by previous treatment with efavirenz. In the absence of any data which of these approaches is most appropriate, one have to weigh the risks for toxicity and virological failure, so both answer A & B may be considered correct.
Continuation
of case description
The patient uses nevirapine for more than 1 year without any problem. Viral load and CD4 response are satisfactory. In June 2003 she comes to the clinic and tells her physician that she is pregnant for 10 weeks now. According to the guidelines at your institute, nevirapine is stopped and replaced by nelfinavir 1,250mg q12h with food. At the next visit, 8 weeks later, a morning trough TDM sample for nelfinavir is drawn (sample A for PIs). Viral load remains undetectable.
Question 3: please give your advise:
-
The nelfinavir plasma level is OK; continue with this dose
-
The nelfinavir plasma level is too low; repeat advice to take nelfinavir with food
-
The nelfinavir plasma level is too low; increase dose to 1,500mg q12h
-
Other: ….
Scores
Discussion
of question 3:
Sample
A for PIs contained nelfinavir 0.245 mg/L which is clearly too low when compared
to population data; answer A is incorrect. The central question in this case is
what is the most appropriate intervention in this situation? Many people think
that TDM is only about dose modifications, but that is only part of the story.
Based on our experience with nelfinavir in a number of studies
4-6
we
think that the most likely explanation of a low nelfinavir level in a patient is
intake of the drug without sufficient amount of food. It is our experience that
just by reporting this low level + the advise to discuss the intake of
nelfinavir with food results in a therapeutic nelfinavir level in half of the
cases. A dose increase to 1,500mg q12h is given to patients who still have a
subtherapeutic nelfinavir level on a second occasion, but this leads to an
imorovement in only around 25% of the subjects
7
.
Therefore, answer B is the most correct intervention.
David
Burger
Nijmegen, October 24, 2003
Reference
List
1.
Burger, D. M., La Porte, C., Van der Ende, M., Miesen, J., and Koopmans,
P. Gender-related differences in efavirenz pharmacokinetics. 4th International
Workshop on Clinical Phamacology of HIV Therapy.March 27-29, 2003, Cannes,
France .
2.
Marzolini C, Telenti A, Decosterd LA, Greub G, Biollaz J, Buclin T.
Efavirenz plasma levels can predict treatment failure and central nervous system
side effects in HIV-1-infected patients. AIDS
2001;15:71-75.
3.
Nunez M, Gonzalez dR, Gallego L, Jimenez-Nacher I, Gonzalez-Lahoz J,
Soriano V. Higher efavirenz plasma levels correlate with development of insomnia.
J
Acquir Immune Defic Syndr
2001;28:399-400.
4.
Burger D, Hugen P, Reiss P, Gyssens I, Schneider M, Kroon F, Schreij G,
Brinkman K, Richter C, Prins J, Aarnoutse R, Lange J, for the ATHENA Cohort
Study Group. Therapeutic
drug monitoring of nelfinavir and indinavir in treatment-naive HIV-1-infected
individuals. AIDS
2003;17:1157-65.
5.
Burger DM, Hugen PW, Aarnoutse RE, Hoetelmans RM, Jambroes M, Nieuwkerk
PT, Schreij G, Schneider MM, Van Der Ende ME, Lange JM. Treatment
failure of nelfinavir-containing triple therapy can largely be explained by low
nelfinavir plasma concentrations. Ther
Drug Monit 2003;25:73-80.
6.
Baede-van Dijk PA, Hugen PWH, Verwey-van Wissen CPWGM, Koopmans PP,
Burger DM, Hekster YA. Analysis
of variation in plasma concentrations of nelfinavir and its active metabolite M8
in HIV-positive patients. AIDS
2001;15:991-98.
7.
Porte, C. J. L. la and Burger D.M. Is nelfinavir (NFV) 1500 mg BID an
effective intervention for patients on NFV 1250 mg BID who have low NFV exposure?
2nd International Workshop on Clinical Pharmacology of HIV Therapy, April 2-4,
2001.Noordwijk, the Netherlands [abstract 6.8]