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    • Our simulation model provides an independent confirmation of

    2018-11-13

    Our simulation model provides an independent confirmation of the CMV doubling time we estimated. The model derives a proportion of CMV infections diagnosed with an undesirably high CMV viral load when screening the cohort every 7days to be comparable with what we actually observe in our cohort. With this confirmed fixed point in mind, it Mdivi 1 cost is intriguing that our model would predict an unacceptably high proportion of diagnosis being made with an undesirably high CMV viral load had the original estimates of the doubling time in fact been correct. As most transplantation units world-wide are adhering to and are comfortable with the 7day interval, this also indirectly suggest that previous estimates of the CMV doubling time may be too short. We encourage other transplantation units to present the distribution of their diagnostic viral loads and to consider using our simulation model (enclosed as Appendix A) and possibly engage in collaboration with us to further refine this tool.
    Contributions
    Conflicts of Interests
    Role of the Funding Source This study is supported by grant [grant number DNRF126] from the Danish National Research Foundation. The funding source had no involvement in any part of the study design, data collection, data analysis, and interpretation of the data or in the writing of this manuscript.
    Introduction Effective combination antiretroviral therapy (cART) has dramatically changed the clinical course of HIV infection. However, this clinical success requires affordable access to medications, and lifelong adherence. Specific antiretroviral agents may have high rates of adverse drug effects (ADEs), which lead to discontinuation of otherwise effective (i.e., virologically suppressive) treatment regimens in up to 40% of patients within 1year (Durability of first ART regimen and risk factors for modification, interruption or death in HIV-positive patients starting ART in Europe and North America, 2002–2009, 2013). The World Health Organization, the International AIDS Society and the Department of Health and Human Services (Adolescents PoAGfAa, 2014; Gunthard et al., 2014) recommend efavirenz (EFV) containing regimens as initial first line therapy for HIV, due to once daily dosing which promotes compliance, and favorable long term treatment outcomes. In addition EFV came off patent in November 2013, making generic versions of this drug more affordable particularly in resource poor settings (Walensky et al., 2013). However, treatment discontinuation occurs in up to 20% percent of patients on once daily EFV based therapy (Scourfield et al., 2012; Walmsley et al., 2013), due primarily to the ADE\'s associated with EFV: central neuro-psychiatric symptoms, dizziness, lightheadedness, confusion and abnormal dreams, and a higher likelihood of committing suicide than patients on other agents (Katie Mollan et al., 2013; Mollan et al., 2014). The WHO estimates that 16.8 million persons living with HIV in low- and middle-income countries will be using cART by 2016, and it is estimated that the global market share of EFV among non-nucleotide reverse transcriptase inhibitor based regimens will increase from 40% to 63% (Organization WH, 2014). Given the effectiveness of EFV, and its increasing affordability, it is of global public health importance to accurately predict those patients who will tolerate EFV, particularly in light of the expanding use of EFV in resource limited settings (Takuva et al., 2013). EFV undergoes hepatic metabolism catalyzed by cytochromes P450 CYP2B6 (main pathway), and CYP2A6 and CYP3A4 (accessory pathways) (Desta et al., 2007; Telenti and Zanger, 2008). Single nucleotide polymorphisms (SNPs) in CYP2B6, CYP2A6 and CYP3A4 exist that result in loss of function (LOF) or decrease of function (DOF), which associate with slower EFV metabolism and consequently increased drug levels (di Iulio et al., 2009; Arab-Alameddine et al., 2009). Because the risk of EFV associated neuro-psychiatric symptoms is increased in patients with higher plasma concentrations (Marzolini et al., 2001) (Csajka et al., 2003) (Gounden et al., 2010) (Nanzigu et al., 2012; Gutierrez et al., 2005), it is likely that patients who have SNPs in CYP2B6, CYP2A6 and CYP3A4, will have a higher incidence of EFV intolerance. Indeed, in 831 participants from three AIDS Clinical Trials group studies, SNPs in CYP2B6 were associated with an increased likelihood of a CNS adverse effect from EFV (Ribaudo et al., 2010), and in a separate study of 577 patients, SNPs in all three enzymes, CYP2A6, CYP2B6 and CYP3A4, were associated with discontinuation of EFV-based regimens within 12months of initiation (Lubomirov et al., 2011).