report TDR [13]NVPCheeseman, et al. among the undiagnosed or untreated. Individuals with TDR seem to have steeper declines in CD4 counts in the first year after infection[6], which may impact immunologic recovery later. Once engaged in HIV care, pre-existing resistance restricts available first-line ARV options and may force providers to select alternative regimens with less favorable dosing intervals or side effect profiles. Adherence may suffer as a result, placing patients at increased risk for accumulating additional resistance mutations over time. Finally, although patients with resistant viruses are benefitting from new ARV classes introduced over the past several years, the current ARV drug development pipeline is relatively limited. One of the new products from that pipeline is raltegravir, the prototype integrase strand-transfer inhibitor (InSTI) that earned Food and Drug Administration (FDA) approval in 2007. Its MPO-IN-28 safety profile, tolerability, and potency when paired with tenofovir/emtricitabine[7] prompted the inclusion of this combination as a preferred first-line regimen in the U.S. Department of Health and Human Services (DHHS) adult HIV treatment guidelines in 2009 2009.[8] This decision is further supported by studies demonstrating an extremely low prevalence of mutations associated with raltegravir resistance in treatment-na?ve patients.[9, 10] Unlike the recommendation to pursue baseline genotypic resistance testing of reverse transcriptase (RT) and protease, the DHHS guidelines specifically noted that pre-treatment Itgb2 integrase resistance testing was not necessary C at least not yet.[8] With the first two documented cases of transmitted InSTI resistance reported in this issue of em Antiviral Therapy /em ,[11, 12] it is only a matter of time before that recommendation changes. But how soon after the introduction of a new ARV class can one expect to see significant circulating resistance? And just how much time do we have before the prevalence of transmitted InSTI resistance reaches a threshold that makes pre-treatment testing necessary? Some historical perspective may help us answer these questions (Table 1). Table 1 Date of first clinical trial publication, U.S. Food and Drug Administration (FDA) approval, and initial report of transmitted drug resistance (TDR) for selected antiretrovirals thead th align=”left” MPO-IN-28 rowspan=”1″ colspan=”1″ Year /th th align=”center” colspan=”5″ rowspan=”1″ Antiretroviral class and agent /th th align=”left” rowspan=”1″ colspan=”1″ Event /th /thead em NRTI /em em NNRTI /em em PI /em em EI /em em InSTI /em hr / 1986ZDVYarchoan, et al. publish first clinical trial [33]1987ZDVFDA approval [34]1993ZDVErice, et al. report TDR [13]NVPCheeseman, et al. publish first clinical trial [17]1995SQVKitchen, et al. publish first clinical trial [21]SQVFDA approval [34]1996NVPFDA approval [34]1997NVPImrie, et al. report TDR [18]1998SQVHecht, et al. report TDR [20]2002ENFKilby, et al. publish first clinical trial [35]2003ENFFDA approval [34]2006RALMarkowitz, et al. publish first clinical trial [36]2007RALFDA approval [34]ENFPeuchant, et al. report TDR [37]2010RALYoung, et al. and Boyd, et al. report TDR [11, 12] Open in a separate window EI, entry inhibitor; ENF, enfuvirtide (T-20); FDA, US Food and Drug Administration; InSTI, integrase strand-transfer inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside/nucleotide reverse transcriptase inhibitor; NVP, nevirapine; PI, protease inhibitor; RAL, raltegravir; SQV, saquinavir; ZDV, zidovudine The first published report of TDR came in 1993, when a young man who presented with acute HIV infection was started on single-agent zidovudine but failed to have any significant response following three months of treatment. After it was learned that one of his likely source partners was receiving MPO-IN-28 zidovudine, retrospective analysis of pre-treatment samples demonstrated the presence of T215Y/F mutations in RT, conferring resistance to the drug.[13] Six years of widespread zidovudine monotherapy following its FDA approval in 1987 led to a high.