Viral resuppression and detection of drug resistance following interruption of a suppressive non-nucleoside reverse transcriptase inhibitor-based regimen.
[en] BACKGROUND: Interruption of a non-nucleoside reverse transcriptase inhibitor (NNRTI)-regimen is often necessary, but must be performed with caution because NNRTIs have a low genetic barrier to resistance. Limited data exist to guide clinical practice on the best interruption strategy to use. METHODS: Patients in the drug-conservation arm of the Strategies for Management of Antiretroviral Therapy (SMART) trial who interrupted a fully suppressive NNRTI-regimen were evaluated. From 2003, SMART recommended interruption of an NNRTI by a staggered interruption, in which the NNRTI was stopped before the NRTIs, or by replacing the NNRTI with another drug before interruption. Simultaneous interruption of all antiretrovirals was discouraged. Resuppression rates 4-8 months after reinitiating NNRTI-therapy were assessed, as was the detection of drug-resistance mutations within 2 months of the treatment interruption in a subset (N = 141). RESULTS: Overall, 601/688 (87.4%) patients who restarted an NNRTI achieved viral resuppression. The adjusted odds ratio (95% confidence interval) for achieving resuppression was 1.94 (1.02-3.69) for patients with a staggered interruption and 3.64 (1.37-9.64) for those with a switched interruption compared with patients with a simultaneous interruption. At least one NNRTI-mutation was detected in the virus of 16.4% patients with simultaneous interruption, 12.5% patients with staggered interruption and 4.2% patients with switched interruption. Fewer patients with detectable mutations (i.e. 69.2%) achieved HIV-RNA of 400 copies/ml or less compared with those in whom no mutations were detected (i.e. 86.7%; P = 0.05). CONCLUSION: In patients who interrupt a suppressive NNRTI-regimen, the choice of interruption strategy may influence resuppression rates when restarting a similar regimen. NNRTI drug-resistance mutations were observed in a relatively high proportion of patients. These data provide additional support for a staggered or switched interruption strategy for NNRTI drugs.
Disciplines :
Immunology & infectious disease
Author, co-author :
Fox, Zoe
Phillips, Andrew
Cohen, Cal
Neuhaus, Jacquie
Baxter, John
Emery, Sean
Hirschel, Bernard
Hullsiek, Kathy Huppler
Stephan, Christoph
Lundgren, Jens
Other collaborator :
Moutschen, Michel ; Université de Liège - ULiège > Département des sciences cliniques > Immunopathologie - Transplantation
Language :
English
Title :
Viral resuppression and detection of drug resistance following interruption of a suppressive non-nucleoside reverse transcriptase inhibitor-based regimen.
Publication date :
2008
Journal title :
AIDS
ISSN :
0269-9370
eISSN :
1473-5571
Publisher :
Lippincott Williams & Wilkins, London, United Kingdom
El-Sadr WM, Lundgren JD, Neaton JD, Gordin F, Abrams D, Arduino RC, et al. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med 2006; 355:2283-2296.
Arduino R. CD4 cell count-guided treatment interruption: be smart and wait for more evidence. Clin Infect Dis 2005; 40:735-737.
Robbins BL, Srinivas RV, Kim C, Bischofberger N, Fridland A. Antihuman immunodeficiency virus activity and cellular metabolism of a potential prodrug of the acyclic nucleoside phosphonate 9-R-(2-phosphonomethoxypropyl)adenine (PMPA), Bis(isopropyloxymethylcarbonyl)PMPA. Antimicrob Agents Chemother 1998; 42:612-617.
Ribaudo HJ, Haas DW, Tierney C, Kim RB, Wilkinson CR, Gulick RM, et al. Pharmacogenetics of plasma efavirenz exposure after treatment discontinuation: an Adult AIDS Clinical Trials Group Study. Clin Infect Dis 2006; 42:401-407.
Taylor S, Boffito M, Khoo S, Smit E, Back D. Stopping antiretroviral therapy. AIDS 2007; 21:1673-1682.
Schweighardt B, Ortiz GM, Grant RM, Wellons M, Miralles GD, Kostrikis LG, et al. Emergence of drug-resistant HIV-1 variants in patients undergoing structured treatment interruptions. AIDS 2002; 16:2342-2344.
Dargere S, Parienti JJ, Verdon R. Treatment resistance after sequential interruption of a nonnucleoside reverse transcriptase inhibitor-based regimen. AIDS 2007; 21:879-880.
Oyugi JH, Byakika-Tusiime J, Ragland K, Laeyendecker O, Mugerwa R, Kityo C, et al. Treatment interruptions predict resistance in HIV-positive individuals purchasing fixed-dose combination antiretroviral therapy in Kampala, Uganda. AIDS 2007; 21:965-971.
US Department of Health and Human Services. Public health service task force recommendations for use of antiretroviral drugs in pregnant HIV-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States. Clinical Guidelines Portal; 2007.
Hawkins D, Blott M, Clayden P, de Ruiter A, Foster G, Gilling-Smith C, et al. Guidelines for the management of HIV infection in pregnant women and the prevention of mother-to-child transmission of HIV. HIV Med 2005; 6:107-148.
Palmer S, Boltz V, Maldarelli F, Kearney M, Halvas EK, Rock D, et al. Selection and persistence of nonnucleoside reverse transcriptase inhibitor-resistant HIV-1 in patients starting and stopping nonnucleoside therapy. AIDS 2006; 20:701-710.
Johnson VA, Brun-Vezinet F, Clotet B, Gunthard HF, Kuritzkes DR, Pillay D, et al. Update of the drug resistance mutations in HIV-1: 2007. Top HIV Med 2007; 15:119-125.
Daniel N, Schneider V, Pialoux G, Krivine A, Grabar S, Nguyen TH, et al. Emergence of HIV-1 mutated strains after interruption of highly active antiretroviral therapy in chronically infected patients. AIDS 2003; 17:2126-2129.
Martinez-Picado J, Morales-Lopetegi K, Wrin T, Prado J, Frost S, Petropoulos CJ, et al. Selection of drug-resistant HIV-1 mutants in response to repeated structured treatment interruptions. AIDS 2002; 16:895-899.
Metzner KJ, Bonhoeffer S, Fischer M, Karanicolas R, Allers K, Joos B, et al. Emergence of minor populations of human immunodeficiency virus type 1 carrying the M184V and L90M mutations in subjects undergoing structured treatment interruptions. J Infect Dis 2003; 188:1433-1443.
Ruiz L, Paredes R, Gomez G, Romeu J, Domingo P, Perez-Alvarez N, et al. Antiretroviral therapy interruption guided by CD4 cell counts and plasma HIV-1 RNA levels in chronically HIV-1-infected patients. AIDS 2007; 21:169-178.
Danel C, Moh R, Chaix ML, Gabillard D, Kouadio B, Toni T, et al. A 2-months-off/4-months-on HAART is clinically not inferior to continuous therapy but leads to unacceptable resistance Rates in african adults with >350CD4/mm3 at first interruption: final results of the TRIVACAN Trial. 15th Conference on Retroviruses and Opportunistic Infections 2008; Session 127:778.
Palmisano L, Giuliano M, Bucciardini R, Fragola V, Andreotti M, Galluzzo C, et al. Determinants of virologic and immunologic outcomes in chronically HIV-infected subjects undergoing repeated treatment interruptions: the Istituto Superiore di Sanita-Pulsed Antiretroviral Therapy (ISS-PART) study. J Acquir Immune Defic Syndr 2007; 46:39-47.
Darwich L, Bellido R, Blanco A, Ruiz L, Esteva A, Cabrera C, et al. Nonnucleoside reverse transcriptase inhibitor (NNRTI) plasma concentrations determine different NNRTI resistance pattern in virological responders during treatment interruptions [abstract number 64]. Antivir Ther 2007; 12(S73).
Arnedo-Valero M, Garcia F, Gil C, Cuila T, Fumero E, Castro P, et al. Risk of selecting de novo drug-resistance mutations during structured treatment interruptions in patients with chronic HIV infection. Clin Infect Dis 2005; 41:883-890.
Metzner KJ, Allers K, Rauch P, Harrer T. Rapid selection of drug-resistant HIV-1 during the first months of suppressive ART in treatment-naive patients. AIDS 2007; 21:703-711.
Simen BB, Huppler Hullsiek K, Novak RM, MacArthur RD, Baxter JD, Huang C, et al. Prevalence of low abundant drug resistant variants by ultra-deep sequencing in chronically HIV-infected antiretroviral naive patients and the impact on virologic outcomes [abstract number 134]. Antivir Ther 2007; 12(S149).
Hare CB, Mellors J, Krambrink A, Su Z, et al. Detection of nonnucleoside reverse transcriptase inhibitor-resistant HIV-1 after discontinuation of virologically suppressive antiretroviral therapy. Clin Infect Dis 2008; 47:421-424.