Massimiliano Lanzafame,MD1,2
Emanuela Lattuada,MD2
Giulia Cucchetto,MD2
Stefano Nicolè,MD2
Ercole Concia,Prof2
Sandro Vento,Prof3
and Therapy of HIV infection" Simple Unit,G.B. Rossi Hospital,Verona,Italy
Diseases Unit, G.B. Rossi Hospital, Verona, Italy
of Internal Medicine, Faculty of Medicine, University of Botswana
Correspondence to: : Massimiliano Lanzafame
via Strada Romana 11,San Bonifacio (Verona, Italy), CAP 37047
email:[email protected]
Fax number:00390458128257
Phone number :00390458128256
"Conflicts of Interest and Source of Funding".None to declare.This study was carried out as part of
our routine work.
RUNNING HEAD:Efficacy of a reduced doseo f nevirapine
Key words:Nevirapine, dose-optimization,pharmacokinetics
The standard treatment of HIV infection is based on triple therapy that allows a potent, effective
and durable response, minimizing the risk of virological failure.1-3Several triple regimens are
available and ranked as first line options in antiretroviral naïve patients.1-3 Once HIV RNA is
suppressed for a certain length of time, a regimen based on only one drug4 or on reduced drug
doses5,6,7 can be employed. Here we report our results in a cohort of 26 fully suppressed HIVinfected patients (Table 1) on nevirapine 400 mg once daily who were switched to nevirapine 200
mg once daily plus two nucleosides All the patients, a part from three who self reduced the dose
of nevirapine, gave a written informed consent. None of the patients had resistance mutations at
baseline, none had ever failed and none had had viral "blips" while treated. Seventeen patients
were male; mean age was 42.1 (25-61) years; mean BMI was 22.6 (17.9-27.5).Two patients were
HCV-coinfected. Twelve patients were on their first antiretroviral regimen, ten on the second and
four on the third (all the switches had been performed to reduce side effects). The patients had
been on nevirapine 400 mg daily for a mean of 70.5 (12-189) months. After a mean 15 (10-40)
months on nevirapine 200 mg daily, the mean number of CD4 T lymphocytes was 630.5/µL (3491042), and HIV RNA was not detectable in any of the 26
patients. We performed a
pharmacokinetics analysis to assess Ctrough of nevirapine; blood samples were collected 24 hours
after the last dose intake and were stored for subsequent measurement of nevirapine plasma
trough levels.8 In fifteen patients Ctroughs at both 400 and 200 mg daily were evaluated, while in
the remaining eleven patients only Ctrough at nevirapine 200 mg daily was measured. At the
standard dose of 400 mg, 11 patients had a Ctrough below the value of 3000 ng/mL which is
regarded as the minimum target trough concentration in patients with nevirapine-susceptible
virus.9After dose reduction the Ctrough of nevirapine was below this value in 14 out of 26
patients. Therefore in our cohort of patients a strategy based on nevirapine dose reduction
maintained virological suppression.
The results of our pharmacokinetic analysis may look
somewhat surprising. The guidelines from US Department of Health and Human Services have
proposed a minimum target trough concentration (Ctrough) of 3000 ng/ml,1 largely on the basis of
the INCAS trial which showed that patients with nevirapine concentrations above 3.4 mg/L (12.7
µM) reached undetectable levels of plasma HIV-1 RNA more rapidly than those who had lower
trough concentrations. These findings were similar to those of an observational cohort study of
189 patients on nevirapine.10However there was no cutoff value below which a statistically
significant increased risk occurred, raising doubts on the use of a trough level for the sole purpose
of predicting virologic failure.11 Our PK data suggest that the relation between nevirapine Ctrough
levels and virological success is questionable in treatment-experienced patients who are already
virally suppressed. Our data ,also ,reinforcing the hypothesis suggesting that lower levels of
antiretroviral drug exposure are required to sustain viral suppression once viral suppression is
achieved than when initiating therapy with high-level viremia12 .
1.Panel on Clinical Practices for the treatment of HIV Infection.Guidelines for the use of
antiretroviral agents in HIV-infected adults and adolescents.Department of health and Human
Services and Henry J.Kaiser Foundation ,May 1, 2014. Available at: http://www.a i d s i n
2. Günthard HF, Aberg JA, Eron JJ,et al. Antiretroviral treatment of adult HIV infection: 2014
recommendations of the International Antiviral Society-USA Panel. JAMA. 2014;312:410-25.
4.Mathis S, Khanlari B, Pulido F, et al. Effectiveness of protease inhibitor monotherapy versus
combination antiretroviral maintenance therapy: a meta-analysis. PLoS ONE 2011;6:e22003.
5.Lanzafame M,Lattuada E,Rigo F,et al. Efficacy of a reduced dose of darunavir/RTV in a cohort of
antiretroviral-naive and experienced HIV-infected patients: a medium follow-up.J Antimicrobial
chemother 2014 (in press).doi:10.1093/jac/dku390
6.Lanzafame M,Lattuada E,Cucchetto G,et al. Efavirenz dose reduction in HIV-infected patients: a
long-term follow-up.AIDS 2014 (in press). DOI:10.1097/QAD.0000000000000482
7. Lanzafame M, Lattuada E, Rigo F,et al. A maintenance dose of atazanavir/ritonavir 200/100 mg
once daily is effective in virologically suppressed HIV-1-infected patients. J Acquir Immune Defic
Syndr. 2013 ;63:e81-2.
8.D’Avolio A, Baietto L, Siccardi M et al. An HPLC-PDA method for the simultaneous quantification
of the HIV integrase inhibitor raltegravir, the new nonnucleoside reverse transcriptase inhibitor
etravirine, and 11 other antiretroviral agents in the plasma of HIV-infected patients. Ther Drug
Monit 2008; 30: 662–669.
9.Veldkamp AI,Weverling GJ, Lange JM,et al. High exposure to nevirapine in plasma is associated
with an improved virological response in HIV-1-infected individuals.AIDS 2001; 15: 1089–95.
10. de Vries-Sluijs TE, Dieleman JP, Arts D,et al. Low nevirapine plasma concentrations predict
virological failure in an unselected HIV-1-infected population. Clin Pharmacokinet 2003;42:599605.
11. Leth FV, Kappelhoff BS, Johnson D,et al.Pharmacokinetic parameters of nevirapine and
efavirenz in relation to antiretroviral efficacy. AIDS Res Hum Retroviruses 2006;22:232-239.
12. Lima VD,Bangsberg DR, Harrigan R,et al. Risk of viral failure declines with duration of
suppression on Highly Active Antiretroviral Therapy irrespective of adherence level. J Acquir
Immune Defic Syndr 2010;55:460–465.