JAIDS Journal of Acquired Immune Deficiency Syndromes:
Epidemiology and Social Science
Changes in the Use of HIV Antiretroviral Resistance Testing in a Large Cohort of U.S. Patients, 1999 to 2006
Buchacz, Kate PhD*; Baker, Rose K MS†; Young, Benjamin MD, PhD‡; Brooks, John T MD*; and the HIV Outpatient Study (HOPS) Investigators
From the *Divisions of HIV/AIDS Prevention, Centers for Disease Control and Prevention, Atlanta, GA; †Cerner Corporation, Vienna, VA; ‡Rose Medical Center and Division of General Internal Medicine, University of Colorado, Denver, CO; and ¶These investigators are listed in an Appendix.
Received for publication May 27, 2009; accepted August 31, 2009.
The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention.
Supported by the Centers for Disease Control and Prevention (contract nos. 200-2001-00133 and 200-2006-18797).
B.Y. is a consultant to Bristol-Myers Squibb Company, Cerner Corporation, Gilead Sciences, GlaxoSmithKline, Hoffman-LaRoche, Merck & Co., Monogram Bioscience, Pfizer, Tibotec Therapeutics and is a member of the speakers' bureaus for GlaxoSmithKline, Merck & Co., Monogram Bioscience, Tibotec Therapeutics. B.Y. has received research funding from Bristol-Myers Squibb Company; Cerner Corporation; Gilead Sciences, GlaxoSmithKline; Hoffman-LaRoche; Merck & Co. B.Y. is not a shareholder (directly purchased) in any pharmaceutical company. R.B. is employed by Cerner Corporation which has performed consulting services on behalf of Allergan, Amgen, Berlex, Boehringer Ingelheim, Bristol-Myers Squibb, Cephalon, Gilead Sciences, GlaxoSmithKline, Merck, Novartis, Roche, Sanofi, Schering-Plough, Serono and Wyeth. All others have no financial disclosures.
Correspondence to: Dr. Kate Buchacz, PhD, Divisions of HIV/AIDS Prevention, Centers for Disease Control and Prevention; 1600 Clifton Road NE Mail Stop-E45; Atlanta, GA 30333 (e-mail: email@example.com).
Introduction: Monitoring antiretroviral (ARV) drug resistance is of growing importance in the management of persons infected with HIV, but few reports document how genotypic and phenotypic resistance testing (GPT) has been used among patients receiving routine outpatient care.
Methods: We studied data from participants in the HIV Outpatient Study seen at 10 HIV clinics in the United States during 1999 to 2006. We restricted analyses to patients whom we considered eligible for GPT (i.e., had a documented HIV viral load >1000 copies/mL). We used multivariable general modeling to evaluate temporal trends in use of GPT among eligible patients and to identify factors associated with being tested during 1999 to 2002 and 2003 to 2006.
Results: Of 5594 active patients, 3995 (71%) were considered eligible for GPT in at least one year during 1999 to 2006 (declining from 50.2% in 1999 to 31.2% in 2006). The fraction of eligible patients receiving GPT increased from 11.2% in 1999 to 31.0% in 2003 (P < 0.001 for trend) and then stabilized at approximately 30% through 2006. Among persons tested, the annual percentage receiving only genotype testing declined over time (90% to 56%), whereas the percentage receiving genotype and phenotype testing increased (5.4% to 39.1%). The annual use of GPT for ARV-naïve patients increased over time and after 2003 exceeded the corresponding rates for ARV-experienced patients. In multivariable analyses, low CD4 count and high HIV viral load were consistently associated with GPT. Compared with other ARV-experienced patients, those who were triple ARV-class experienced were consistently more likely to be tested, whereas ARV-naïve were less likely to be tested during 1999 to 2002 and more likely during 2003 to 2006. In addition, women and heterosexual men (vs. men who have sex with men) and black patients (vs. white) were less likely to be tested during 1999 to 2002, whereas older patients were less likely to be tested during 2003 to 2006.
Discussion: The annual frequency of GPT use has increased almost threefold since 1999. GPT use among ARV-naïve patients has increased coincident with dissemination of recommendations. Although earlier sex and racial/ethnic disparities in testing have waned, older patients were significantly less likely to be tested in recent years.
Highly active combination antiretroviral therapy (cART) improves survival and reduces the rates of AIDS complications among HIV-infected persons,1-3 but emergence of HIV variants with reduced susceptibility to ARV medications can significantly limit the effectiveness and durability of treatment.4-7 Optimizing cART based on the results of genotypic or phenotypic ARV drug resistance testing (GPT) has been associated with better short-term virologic and clinical outcomes8-12 and with improved survival.13 Resistance testing is now generally recommended in the clinical management of HIV infection.12,14-16 Both genotypic and phenotypic resistance tests have been available commercially since the late 1990s. We assessed trends in the use of GPT from 1999 to 2006 in a large longitudinal cohort of HIV-infected patients in routine clinical care and examined the characteristics of patients who were less likely to receive GPT.
The HIV Outpatient Study
The HIV Outpatient Study (HOPS) is an ongoing, longitudinal cohort study of HIV-infected patients in care at HIV-specialty clinics in eight U.S. cities since 1993. The HOPS methodology has been described previously.17 In brief, trained staff abstract patient data, including sociodemographic characteristics, diagnoses, treatments, and laboratory values (including results of ARV resistance testing), from medical records and enter them into an electronic database for central processing and analysis. HIV drug resistance testing is performed at the discretion of the clinician provider. The institutional research review boards of the Centers for Disease Control and the local participating sites approved and have reviewed the ethical conduct of this study yearly.
For this analysis, we examined data from active participants seen at 10 HOPS clinics between January 1, 1999 and December 31, 2006. Participants were considered active if they had at least two HOPS-related encounters documented in the HOPS database (clinic visits, hospitalizations, laboratory measurements but not telephone calls) and at least one of these encounters was in the calendar years of interest. We defined start of observation (baseline date) as the latter of 1/1/1999 or the participant's first visit in the HOPS, and the end of observation was the earlier of last contact or December 31, 2006. We restricted analyses to patients whom we considered eligible for GPT based on a documented (qualifying) HIV viral load greater than 1000 copies/mL. The qualifying HIV viral load was the closest measurement >1000 copies/mL within the 6 months before the date of GPT for those tested and the earliest HIV viral load greater than1000 copies/mL in the year of interest for persons who did not undergo GPT. We determined eligibility by calendar year. A patient could be eligible in multiple years and was included in the analysis in a given period (1999-2002, 2003-2006, or both periods) if he/she was eligible for GPT in 1 or more years during the period.
Independent variables included sex, race, HIV infection risk, year of observation, and baseline values in each period for age, type of health insurance, antiretroviral (ARV) status, and CD4 cell count. We defined the baseline CD4 cell count and the baseline HIV viral load as the values for each that were measured closest to patients' start of observation in the period from among all values available within 6 months before through 7 days after the baseline date. Viral load category of >1000 to <4000 copies/mL was used to capture viral load ‘blips’. Sex and HIV infection risk were combined into a composite variable with the following categories: women, heterosexual men, and men who have sex with men (MSM). Patients were classified as triple-ARV class (TCE) experienced if they had at least 4 months of continuous exposure to each of the major three ARV classes.
We used unadjusted general linear models to evaluate temporal trends (by year) in use of GPT among eligible patients and multivariable general linear models to examine factors associated with receiving GPT during two periods: 1999 to 2002 and 2003 to 2006. A patient could have different values for independent variable (e.g., ARV-naïve or -experienced) and outcome variable (GPT tested or not) from year to year and from period to period. A patient's status as of the first calendar year he/she was eligible was used to summarize population characteristics in the period (Table 1). Each period was analyzed separately, and we accounted for repeated observations per patient within each period in the multivariable analyses of the correlates for GPT. Data were analyzed with SAS version 8.2 (SAS Institute, Cary, NC, USA). Associations with a P < 0.05 were considered significant.
Characteristics of Study Population
Of 8603 patients in the HOPS database as of March 31, 2008, we identified 5594 patients who were active during 1999 to 2006 (excluded n = 3009). Of these, 3995 were eligible for GPT based on a recorded HIV viral load greater than 1000 copies/mL (excluded n = 1599) during 1999 to 2006. The percentage of patients who were eligible for GPT in a given year steadily declined from 50.2% in 1999 to 31.2% in 2006 (Fig. 1). Of the 3995 patients eligible for ARV resistance testing, 1785 (45%) received GPT at least once during those years, 10% twice, and 7% thrice or more times during the observation period.
The 3995 patients eligible for GPT were significantly different (P < 0.05) from the 1599 active patients never considered eligible for GPT during the study period in terms of available baseline CD4 counts (median 341 vs. 421 cells/mm3), baseline log10 HIV viral load (median 4.3 vs. 1.8 copies/mL), sex (78% vs. 82% male), HIV infection risk group (55% vs. 61% were MSM and 13% vs. 10% were intravenous drug users), race (51% vs. 58% were white), and type of insurance (42% vs. 33% were publicly insured). Of the 1599 patients who were never eligible for GPT in the HOPS during the period of interest, 334 (21%) had no baseline HIV viral load documented, and 1087 (68%) had a baseline HIV viral load 1000 copies/mL or less, whereas the remainder (11%) had a baseline HIV viral load greater than 1000 copies/mL (but had no qualifying viral load).
Compared with patients who were eligible for GPT during 1999 to 2002, patients eligible during 2003 to 2006 were older (median age 42 vs. 39 yr), somewhat less likely to be white (50% vs. 52%), more likely to have higher baseline CD4 counts (43% vs. 39% with CD4 ≥ 350 cells/mm3), and higher HIV viral loads (77% vs. 72% with viral load ≥ 4000 copies/mL) (Table 1). Patients may have been followed in one or both periods, and therefore standard statistical tests for these differences were not performed because of nonindependence of the samples.
Trends in USE of GPT Over Time
From 1999 to 2003, the percentage of patients eligible for GPT decreased steadily from 50.2% to 31.2%, whereby the fraction of eligible patients who received GPT each year increased from 11.2% in 1999 to 31.0% in 2003 (P < 0.0001 for trend) and then stabilized at approximately 30% of eligible patients being tested annually from 2003 onward (P = 0.76 for trend from 2003-2006) (Fig. 1). Of patients who received GPT, the annual percentage who received only genotypic testing decreased from 90.4% in 1999 to 56.4% in 2006 (Fig. 2), whereas the annual percentage who received both genotypic and phenotypic testing increased from 5.4% to 39.1% during the same period.
Frequency of GPT increased for both ARV-naïve and -experienced patients through 2003; thereafter, approximately 30% of ARV-experienced patients were receiving GPT each year (Fig. 3). In contrast, the use of GPT among ARV-naïve patients increased further, exceeding GPT rates among ARV-experienced patients (Fig. 3, Table 2).
The increase in GPT among eligible patients during 1999 to 2003 (Fig. 1) was associated with greater use of a combination of genotypic and phenotypic tests among ARV-experienced patients, particularly those with TCE. Indeed, the percentage of ARV-experienced patients who had TCE increased from 31.1% in 1999 to 47.4% in 2006, and the percentage of TCE patients receiving both genotypic and phenotypic testing within the same year increased from 1.2% in 1999 to 20.9% in 2006.
Factors Associated with Receipt of GPT
Given the differences shown in the characteristics of patients eligible for GPT during 1999 to 2002 and 2003 to 2006 (Table 1) and the substantial uptake in resistance testing, we analyzed factors associated with GPT for each period separately. In the multivariable analysis for the period 1999 to 2002, GPT was significantly less likely among women (adjusted relative risk [RR] = 0.73) and heterosexual men (RR = 0.65) versus MSM and among blacks (RR = 0.72) versus whites. Compared with other ARV-experienced patients, GPT was significantly more likely among TCE patients (RR = 1.34) and significantly less likely among ARV-naïve patients (RR = 0.47) (Table 2). In the multivariable analyses for period 2003 to 2006, we found significantly lower likelihood of undergoing GPT among older patients (RR = 0.89 for every 10 yr of age) and higher rates of testing among ARV-naïve patients (RR = 1.81) and TCE patients (RR = 1.68) compared with other ARV-experienced patients. Women tended to remain less likely to be tested (RR = 0.83, P = 0.05) than MSM during 2003 to 2006, whereas heterosexual men were as likely to have undergone testing (RR 1.04, P = 0.65). Lower CD4 cell count and higher HIV viral load were independently associated with increased likelihood of GPT in both periods. Publicly insured patients tended to have somewhat lower rates of GPT in the first period and higher rates of testing in the second period, but these findings were not statistically significant (Table 2).
Laboratory Markers at GPT
The CD4 counts and HIV viral loads of patients who underwent GPT varied by calendar year. Median CD4 count at the time of GPT increased from 223 cells/mm3 in 1999, peaked at approximately 325 cells/mm3 between 2002 and 2004, and then fell to 266 cells/mm3 among patients tested in 2006 (Fig. 4). Correspondingly, the median HIV viral load fluctuated from 4.7 log10 copies/mL in 1999 to 4.3 log10 copies/mL in 2003 and 4.6 log10 copies/mL in 2006.
Our study documents increasing use of HIV resistance testing for clinical management in a demographically diverse population of ARV-naïve and -experienced patients seen at 10 public and private HIV specialty clinics in the U.S. during 1999 to 2006. Whereas the number and fraction of patients eligible for GPT (by our conservative definition) declined over time, the annual use of GPT increased and leveled at approximately 30% of eligible patients being tested in 2003. Notably, the annual rates of GPT for ARV-naïve patients not only increased over time but after 2003 exceeded the corresponding rates for ARV-experienced patients. In more recent years of 2003 to 2006, older HOPS patients remained less likely to receive GPT, but sex and racial/ethnic disparities in testing observed during 1999 to 2002 diminished or were no longer apparent.
Increased transmission of ARV-resistant HIV observed in several U.S. studies18-20 prompted recommendations starting in 2003 that ARV resistance testing be performed for all ARV-naïve patients before they initiate therapy, especially for patients from regions with a higher prevalence of transmitted resistant virus.12,21-23 The increased use of ARV resistance testing in ARV-naïve HOPS patients during our observation period likely reflects response to these recommendations.
The leveling in use of ARV resistance testing among ARV-experienced patients in the period 2003 to 2006 may reflect an overall decrease in the frequency of virologic failures that necessitated resistance testing. The finding is supported by the observed decline in the proportion of HOPS patients eligible for testing (having HIV viral load > 1000 copies/mL) over time and is consistent with previously noted improvements in morbidity and mortality in our and other HIV cohorts in the United States and other industrialized countries.1,2,4 In the HOPS, GPT was used more frequently among patients with advanced disease (lower CD4 count and higher viral load) and among ARV-experienced TCE patients. Over time, use of both genotypic and phenotypic resistance testing became more common, and genotypic testing alone became relatively less frequent. Taken together, these data suggest that HOPS physicians were more likely to fully use resistance testing options to tailor ARV regimens for their patients at higher risk of treatment failure.
We hypothesize that the trends we observed in Figure 4 document multiple historical events in the highly active ARV era. Shortly after the widespread introduction of GPT around 1999 (which at the time was a relatively expensive and more technically complex diagnostic procedure than in more recent years), ARV testing may have been preferentially reserved for patients with more advanced HIV disease. Thereafter, years through 2004 may have represented a “catch-up” period during which the access to testing and cost of testing fell. In 2003, U.S. treatment guidelines first recommended testing both ARV-experienced and ARV-naïve patients, events that led to a greater proportion of healthier patients receiving GPT. The subsequent reversal in CD4 cell count (decreasing) among testers through 2006 at the same time that the number of GPT-eligible patients was declining and the fraction of eligible patients tested stabilized might be explained by growth in the population of patients stably suppressed on ARV therapy and use of GPT for the smaller fraction of patients failing treatment or presenting with late-stage HIV disease.
Despite adjustment for clinical and treatment factors, we observed significant differences in GPT use by sociodemographic factors, but these differences were mostly period specific, more pronounced in the earlier years, and some subsided in the second time period. Although it is encouraging that racial and ethnic disparities in use of GPT were no longer apparent during 2003 to 2006, older patients remained significantly less likely to be tested than younger patients, and women still tended to be less tested than men. This observation may warrant further investigation in light of the fact that similar disparities have been observed in the delivery of other types of HIV care.24
Our study is subject to some limitations. First, our results are derived from a convenience sample of patients who were receiving care at select HIV specialty clinics staffed by experienced HIV care providers. The HOPS physicians ordered resistance testing at their discretion, and therefore it is possible that, in some cases, our criteria for patient eligibility for genotypic and phenotypic testing (e.g., documented viral load >1000 copies/mL) may not have matched the criteria used by the treating physicians. Our present definition was a conservative choice to ensure a definitive indication for GPT in patients who would have had sufficient virus present for the assay to be performed with reliable results from 1999 onward. Second, there were instances of GPT being ordered for which no preceding HIV viral load was documented in the medical records (particularly HIV viral loads measured before first HOPS visit), which could have led us to misclassify and exclude a small fraction of patients as apparently ineligible for GPT. The percentage of patients who received GPT in any given year with no baseline viral load or only viral loads 1000 copies/mL or less and whom we thus excluded from the analysis ranged from 11% to 20% during the study period. Also, the proportion of patients undergoing GPT at their initial HOPS clinic visit, when HIV viral load may not have been available or abstracted, increased steadily from 4.3% in 1999 to 18.1% in 2006.
In conclusion, this analysis documents the increasing use of GPT in a large population of HIV-infected patients receiving routine HIV care in the United States. Use of GPT increased among both ARV-experienced and ARV-naïve patients, reflecting current recommendations. The use of GPT was closely related to the severity of HIV disease. Although initial disparities in the use of GPT by race/ethnicity have waned, older patients remained significantly less likely to have undergone testing with this diagnostic procedure. Addressing remaining disparities is important in view of recent findings from our cohort that use of GPT was independently associated with improved survival among cART-experienced patients.13
The authors thank the thousands of HOPS subjects across the United States for their continued support and participation in the study. They also thank anonymous reviewers for their thoughtful feedback on the analyses and Marcus Durham for assistance in preparation of the figures.
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Appendix. The HIV Outpatient Study (HOPS) Investigators, 2009
The HOPS Investigators currently include the following investigators and sites: John T. Brooks, Kate Buchacz, Marcus Durham, Division of HIV/AIDS Prevention, National Center for HIV, STD, and TB Prevention (NCHSTP), Centers for Disease Control and Prevention (CDC), Atlanta, GA; Kathleen C. Wood, Rose K. Baker, James T. Richardson, Darlene Hankerson, and Carl Armon, Cerner Corporation, Vienna, VA; Frank J. Palella, Joan S. Chmiel, Carolyn Studney, and Onyinye Enyia, Feinberg School of Medicine, Northwestern University, Chicago, IL; Kenneth A. Lichtenstein and Cheryl Stewart, National Jewish Medical and Research Center Denver, CO; John Hammer, Benjamin Young, Kenneth S. Greenberg, Barbara Widick, and Joslyn D. Axinn, Rose Medical Center, Denver, CO; Bienvenido G. Yangco and Kalliope Halkias, Infectious Disease Research Institute, Tampa, FL; Douglas J. Ward and Jay Miller, Dupont Circle Physicians Group, Washington, DC; Jack Fuhrer, Linda Ording-Bauer, Rita Kelly, and Jane Esteves, State University of New York (SUNY), Stony Brook, NY; Ellen M. Tedaldi, Ramona A. Christian, Faye Ruley and Dania Beadle, Temple University School of Medicine, Philadelphia, PA; Richard M. Novak and Andrea Wendrow, University of Illinois at Chicago, Chicago, IL. Cited Here...
HIV susceptibility testing; highly active antiretroviral therapy; prevalence; epidemiology
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