Uy 30/8/07 10:24 Page 957 Antiviral Therapy 12:957–962 HIV genotypic resistance testing to optimize antiretroviral prescribing: is there room for improvement? Jonathan Uy1*, John T Brooks2, Rose Baker2, Mark Hoffman2, Anne Moorman3, Richard Novak1 and the HOPS investigators† 1Section of Infectious Diseases, University of Illinois College of Medicine, Chicago, IL, USA 2Cerner Corporation, Kansas City, MO, USA 3Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA †Participants are listed in the additional file online *Corresponding author: Tel: +1 609 897 4603; Fax: +1 609 897 6068; E-mail: [email protected] Background: Clinical utilization of genotype resistance medication for >6 months after this finding. In 33% of testing is evolving. We examined the extent to which these instances, prescribers reported these actions were HIV care providers requesting genotype resistance tests erroneous oversights. For persons taking the resistant used the information appropriately and the impact of antiretroviral at the time of the genotype test, stopping inappropriate utilization. this medication within 6 months of the test produced Methods: Data from a prospective cohort of HIV-infected greater decreases in viral load (-1.35 versus -0.43 log patients (the HIV Outpatient Study) were used in the copies/ml, P=0.025) and a greater likelihood of analysis. We analysed the frequency with which patients achieving an undetectable viral load (25.3% versus were prescribed any non-nucleoside reverse transcriptase 7.3%, P=0.012) at 9 months. Changes in CD4+ T-cell inhibitor after identification of the K103N mutation in count differed (+22.8 versus -23.0 cells/mm3), but not reverse transcriptase and the frequency of prescription of significantly (P=0.167). nelfinavir after identification of the D30N mutation in Conclusions: Following evidence of definitive resistance HIV protease; the short-term impact of this action on HIV by genotype testing, a substantial fraction of antiretro- viral load and CD4+ T-cell count was assessed. viral prescriptions were continued in error leading to an Results: Among 441 patients demonstrating either attenuated therapeutic response. These data highlight mutation, 18% who were taking the resistant antiretro- the need to consider better systems to manage genotype viral at the time of the test were continued on the resistance testing data in the clinical setting. Introduction Testing pathogens for antimicrobial resistance is a infection and has been incorporated into clinical strategy used widely to manage many infectious treatment guidelines [4]. diseases. Early biological phenotype assays for testing Clinicians’ knowledge and understanding varies resistance of HIV to antiretrovirals (ARVs) were regarding the appropriate utilization of this novel and labour-intensive, unreliable, and impractical for evolving test [5]. Familiarity with HIV genotype resis- routine clinical practice. In the late 1990s, genotype tance assays has increased, current reports are clearer resistance testing became available, and several and easier to read, algorithms to interpret genotype randomized trials [1–3] demonstrated that its use to resistance test results are accessible on the internet [6], guide changes in ARV therapy improved virological and innovative bioinformatic techniques are further outcomes compared with ARV changes without resis- improving genotype interpretation [7]. Still, the scien- tance testing. Subsequent approval by the Food and tific literature is sizeable, technical, and rapidly Drug Administration (FDA) of several genotype resis- changing, thus challenging clinicians’ ability to reach tance assays permitted expansion of the technology, consensus regarding the interpretation of genotype which is now available through most clinical labora- resistance test results. tory services. Genotype resistance testing has become To examine the extent to which care providers part of the standard of care for treatment of HIV requesting genotype resistance tests are using the © 2007 International Medical Press 1359-6535 957 Uy 30/8/07 10:24 Page 958 J Uy et al. information appropriately, and the impact of inappro- incidence of ARV prescription inconsistent with priate utilization on outcomes, we analysed data genotype resistance testing results in two instances collected from a cohort of HIV-infected patients where there is broad agreement that a specific muta- receiving care at a selection of US medical practices tion confers definitive resistance: prescription of any participating in the HIV Outpatient Study (HOPS). We non-nucleoside reverse transcriptase inhibitor analysed the frequency with which patients were (NNRTI) after identification of the K103N mutation prescribed an ARV to which their virus demonstrated in reverse transcriptase and prescription of nelfinavir unequivocal resistance, the circumstances under which (NFV) after identification of the D30N mutation in these apparent inconsistencies occurred, and the the HIV protease. Although continuing NFV in the impact of these inconsistencies on subsequent HIV presence of the D30N mutation might reduce viral viral loads and CD4+ T-cell counts. fitness, this practice also promotes development of additional protease inhibitor resistance mutations Methods that could undermine future treatment options. We defined two categories of inconsistency The HOPS is an ongoing prospective, observational (Figure 1): Mismatch, remaining on an NNRTI or NFV cohort of HIV-infected patients seen at ten HIV- after a genotype resistance test reported a K103N or specialty clinics in seven US cities: Tampa; Washington, D30N mutation, respectively; and Misstart, starting on DC; Oakland; Denver; Chicago; Stony Brook, New an NNRTI or NFV under the same circumstances. York; and Philadelphia [8]. Since 1993, over 8,000 With regard to patients in the first category patients have been enrolled and followed at over (mismatch), to allow for lag time that might have 250,000 visits contributing more than 30,000 person- occurred between reporting and reviewing a genotype years of observation. Data are abstracted from resistance test result and changing a patient’s regimen patients’ medical records and entered directly into an accordingly, we only considered as a mismatch electronic database by trained abstractors. Abstracted prescriptions that continued >6 months after the date information includes basic demographic information, of the test. Patients in whom the ARV was stopped risk factors for HIV infection, and all symptoms, diag- within 6 months of the genotype resistance test result noses, medications and laboratory results. The data are date were considered to have been treated appropri- compiled centrally, regularly controlled for quality, and ately (no mismatch). We evaluated the impact of updated monthly. For genotype resistance testing, all mismatches in this group by comparing quantitative resistance mutations and ARV susceptibility interpreta- HIV RNA levels (viral loads) and CD4+ T-cell counts at tions on the report form are abstracted. The present baseline, defined as the date of the genotype resistance analysis is based on the HOPS database updated as of test result, and at 9 months thereafter between the two March 31, 2005. groups (mismatch versus no mismatch). Baseline values Recognizing that consensus on the interpretation were defined as the values closest in time to the date of of genotypes is evolving, we chose to examine the the genotype resistance test result, and ranged from 180 days before to 7 days after. Nine-month values were defined as the value closest to the date 9 months after the genotype resistance test result within the Figure 1. Algorithm used for defining mismatches and 6–12 month period after the test. misstarts in the HIV outpatients study, 1998–2005 With regard to patients in the second category, we considered as misstarts initiation of treatment with an Resistance mutation present NNRTI or NFV ≥4 weeks after the date that the corre- at first known genotype test sponding resistance mutation was first reported and that continued for ≥7 days. We then reviewed all available genotype resistance tests between the date on which the Off drug to which On drug to which resistant by genotype resistant by genotype resistance mutation was first detected and the date of misstart to determine whether there might have been (6 months) intervening genotype tests indicating the mutation of interest was absent (that is, the virus had reverted to wild type) on the premise that such reversions could have led Drug Drug ‘Mismatch’ stopped continued to the prescribing of an NNRTI or NFV despite the likely permanent significance of archived resistant virus. We ≥ > ( 4 weeks) (Drug later stopped for 4 weeks) could not analyse the clinical impact of misstarts in terms + Drug started or restarted ‘Misstart’ of their impact on subsequent changes in CD4 T-cell count and viral load, because of the difficulties inherent 958 © 2007 International Medical Press Uy 30/8/07 10:24 Page 959 HIV genotypic resistance testing to optimize antiretroviral prescribing in defining valid comparison patients from this dataset Patients in the mismatch group with NNRTI resistance given the large variance in the lengths of time between were significantly more likely to have been infected first reporting of the resistance mutation and the misstart. through high-risk heterosexual activity, have AIDS, have For determining whether an inconsistency with lower baseline CD4+ T-cell counts