VIROLOGICAL EFFICACY OF A REDUCED DOSE OF NEVIRAPINE IN A SMALL COHORT OF SUPPRESSED HIV-1-INFECTED PATIENTS Massimiliano Lanzafame,MD1,2 Emanuela Lattuada,MD2 Giulia Cucchetto,MD2 Stefano Nicolè,MD2 Ercole Concia,Prof2 Sandro Vento,Prof3 1"Diagnosis and Therapy of HIV infection" Simple Unit,G.B. Rossi Hospital,Verona,Italy 2Infectious Diseases Unit, G.B. Rossi Hospital, Verona, Italy 3Department of Internal Medicine, Faculty of Medicine, University of Botswana Correspondence to: : Massimiliano Lanzafame via Strada Romana 11,San Bonifacio (Verona, Italy), CAP 37047 email:firstname.lastname@example.org 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 . REFERENCES 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 fo.nih.gov/Guidelines/GuidelineDetail.aspx?GuidelineID=7 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. 3.European AIDS Clinical Society Guidelines, Jun ,2014. Available at: http://www.eacsociety.org/Guidelines.aspx 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.