Low Level Viremia is Associated With Virologic Failure in a Large Military Cohort Abstract #932 Christie Joya1, Seung Hyun Won2,4, Jason Okulicz3, Timothy Whitman1, Robert Deiss2,4, Christina Schofield5, Julie Pavlin2,4, Brian Agan2,4, Anuradha Ganesan1,2,4 1Walter Reed National Military Medical Center, Bethesda, MD, 2Henry M. Jackson Foundation for Advancement of Military Medicine, Inc., Bethesda, MD, 3Brooke Army Medical Center, San Antonio, TX, 4Infectious Disease Clinical Research Program, Uniformed Services University of the Health Sciences, Bethesda, MD, 5Madigan Army Medical Center, Takoma, WA Abstract Results Results Continued Methods and Materials Background: Current treatment guidelines recommend against antiretroviral therapy (ART) changes until the viral load (VL) is greater than 200 copies/mL (c/mL) on two or more determinations. Whether VLs between 50 and 200 copies, i.e. persistent low level but quantifiable viremia (pLLV) predicts virologic failure (VF) is unclear. We used data from the U.S. Military HIV Natural History Study (NHS), a well-characterized cohort of HIV-infected military members, to examine virologic outcomes and the association of pLLV and VF. Methods: NHS subjects who initiated ART after 1996 were included, if they had two or more viral loads (VLs) measured utilizing an assay with a lower limit of detection of 50 c/mL; for each subject, one VL had to be measured 6-18 months after ART initiation. The NHS definition of ART, which complies with the definitions discussed in the treatment guidelines, was used in this analysis. VF was defined as a viral load ≥200 copies on two separate determinations. Subjects with VLs ranging from 51 to 199 copies in over 25% of their measured values, while receiving ART, were classified as having pLLV. Continuously suppressed subjects were those with VL <50 c/mL on all measurements. Descriptive statistics and chi-square were used to compare individuals with/without VF; variables found significant (p<0.05) in a univariate analysis were used in a multivariate logistic regression analysis. Results: 1675 NHS subjects [95% male, 42% African- American, 39% Caucasian] met our inclusion criteria. 801 (47.8%) subjects were continually suppressed, while 141 (8.4%) had pLLV. Of the 1675 subjects, 430 (25.7%) experienced VF during follow up. In comparison, 51 (36%) of the 141 subjects with pLLV met criteria for VF. In a multivariate analysis, presence of pLLV, younger age at ART initiation, HIV diagnosis prior to 1996, the use of ARV that did not meet the NHS definition (usually mono or dual therapy) before ART initiation, and use of unboosted protease inhibitor (PI) based regimens were associated with VF (table). Conclusion: In this large well characterized cohort with free access to care and limited confounders pLLV was associated with an increased risk of VF. Other factors identified were consistent with prior reports. Our results suggest that subjects with pLLV should be evaluated for their risk of VF including evaluation of medication adherence, adverse effects, and the need for ART modification. Retrospective cohort study Study population: The US Military Natural History Study (NHS), a well-characterized of nearly 6000 HIV-infected enrollees. 1,675 enrollees started ART after 1996 and had ≥at least two VLs, with at least one VL being drawn between 6 and 18 months after starting ART. Definitions: Virologic Failure (VF): having a VL of >1000 copies/mL more than 6 months after ART initiation or a VL of >200 c/mL provided the VL preceding and succeeding it were >50 copies/mL. Continuous Low Level Viremia (cLLV): VL between 50 and 199 copies/mL on more than 25% of measurements after ART initiation Continuous Suppression (CS): VL of <50 copies/mL on all measurements after ART initiation ART: two nucleoside reverse transcriptase inhibitors (NRTI’s), with a third active ARV that is either an integrase strand transfer inhibitor (INSTI), non-nucleoside reverse transcriptase inhibitor (NNRTI), or a protease inhibitor (PI), or triple NRTIs regimen. Statistics: Baseline demographic data were compared using a chi-square test. Risk factors for VF were examined in an adjusted multivariate logistic regression model that included: age at HIV diagnosis, gender, race, era of HIV diagnosis, CD4 count at HIV diagnosis, antiretroviral drug exposure (ARV) prior to ART initiation, CD4 count at ART initiation, type of ART used, tenofovir as part of ART, and AIDS-defining illness prior to ART initiation. 3173 NHS participants initiated ART after 1996 and had ≥ 2 or more VLs recorded Effect OR 95% CI P-value cLLV 1.754 1.112-2.766 0.00157 Gender (referent male) 0.978 0.554-1.728 0.9394 Race (referent Hispanic) African-American Caucasian 1.314 1.044 0.897-1.926 0.704-1.549 0.2063 HIV diagnosis era (referent prior to 1996) 1996-2000 2001-2009 2010-2016 1.135 0.385 0.059 0.665-1.936 0.225-0.660 0.029-0.120 <0.0001 ARV before ART 3.527 2.119-5.871 CD4 count at ART initiation (per 50 cell increase) 1.000 0.999-1.001 0.6695 ART regimen (referent unboosted PI regimen) Boosted PI NNRTI 3NRTI 0.554 0.595 0.469 0.319-0.961 0.354-0.998 0.318-0.691 0.0042 AIDS dx prior to ART initiation 1.466 0.779-2.761 0.2357 Age at ART initiation (for each year increase) 0.949 0.933-0.966 1717 subjects had ≥ one VL measured between 6-18 months of initiating ART 430 subjects met pre-specified criteria for VF Figure 1. Eligibility Criteria All (n=1,675) No (n=1,534) Yes (n=141) P-value Era of HIV diagnosis Prior to 1996 1996-2000 2001-2009 2010-current 224 (13.4%) 254 (15.2%) 744 (44.4%) 453 (27.0%) 190 (13.0%) 214 (14.6%) 647 (44.2%) 412 (28.2%) 34 (16.0%) 40 (18.9%) 97 (45.8%) 41 (19.3%) 0.0252 ARV before ART No Yes 1461 (87.2%) 214 (12.8%) 1282 (87.6%) 181 (12.4%) 179 (84.4%) 33 (15.6%) 0.1880 CD4 count at HIV diagnosis 0-200 201-350 351-500 500+ 123 (7.3%) 342 (20.4%) 465 (27.8%) 612 (36.5%) 102 (6.6%) 322 (21.0%) 422 (27.5%) 566 (36.9%) 21 (14.9%) 20 (14.2%) 43 (30.5%) 46 (32.6%) 0.0027 CD4 count at ART initiation 208 (12.4%) 520 (31.0%) 480 (28.7%) 353 (21.1%) 185 (12.1%) 479 (31.2%) 439 (28.6%) 329 (21.4%) 23 (16.3%) 41 (29.1%) 24 (17.0%) 0.3549 ART regimen Unboosted PI Boosted PI NNRTI PI+NNRTI+NRTI 3NRTI 207 (12.4%) 199 (11.9%) 969 (57.9%) 38 (2.3%) 262 (15.6%) 174 (11.3%) 901 (58.7%) 34 (2.2%) 240 (15.6%) 22 (15.6%) 25 (17.7%) 68 (48.2%) 4 (2.8%) 0.0668 Age at Art initiation 31.4 (13.0) 31.4 (12.9) 31.9 (13.6) 0.6302 * Race, ART on TDF, gender, age at HIV dx, AIDS prior to ART initiation were evaluated and did not have significant differences between groups. Introduction The goal of antiretroviral therapy [ART] is to suppress HIV replication so that drug-resistance mutations are avoided and immunologic outcomes are improved [1].   While HIV RNA levels below 50 copies/mL are generally thought to avoid these risks, levels more than 200 copies/mL lead to virologic failure [VF] [2,3].  The clinical significance of low level viremia [LLV] (i.e. HIV RNA levels between 50 and 200 copies/mL) is not well defined. Well described risk factors for Virologic Failure [VF] include: unbooosted PI regimens, previous use of antiretrovirals [ARV], and younger age [4] A retrospective analysis from the ART cohort found a borderline association between persistent LLV and VF, however, there was no association with clinical outcomes such as AIDS or death, while another retrospective analysis from a Canadian cohort showed that the rates for VF were the same for those with VLs 50-199 as those with VLs of 200-499 c/mL [5,6].   However, Garcia-Grasco looked at subjects with VLs between 51-500 c/mL on two consecutive occasions and failed to demonstrate an association of LLV and an increased risk of VF [7]. The Swiss Cohort showed that only VLs>200 c/mL was associated with VF [8]. The lack of convincing data demonstrating an association between LLV and VF led us to examine this question in the US military Natural History Study Table 2. Factors Associated with Virologic Failure Discussion Virologic Endpoints N (%) (N=1675) Virologic failure No Yes 1245 (74.3%) 430(25.7%) cLLV 1534 (91.6%) 141 (8.4%) Continuously suppressed 874 (52.2%) 801 (47.8%) In the NHS, we observed an independent association between cLLV and VF. Other factors associated with VF are similar to those previously reported including a HIV diagnosis prior to 1996, the use of an unboosted PI regimen, and ARV use prior to ART initiation. Based on our data patients with cLLV should be viewed as at risk for VF. Patient’s with cLLV should be evaluated early to determine the cause of viremia (such as non-adherence, adverse effects, pharmacokinetic issues) as early intervention may decrease the risk of future VF. Table 3. Proportion of NHS participants who met pre-specified virologic criteria Disclaimer Table 1. Baseline Characteristics The contents of this poster publication are the sole responsibility of the authors and do not necessarily reflect the views, opinions or policies of The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., the Uniformed Services University of the Health Sciences (USUHS), the Department of Defense (DoD), or the Departments of the Army, Navy, or Air Force. Mention of trade names, commercial products, or organizations does not imply endorsement by the U.S. Government. Contact Information References Funding Christie Joya, DO Walter Reed National Military Medical Center Bethesda, MD 20889 Email:christie.a.joya.mil@mail.mil Phone: (702) 279-1462 Grabar S, Le Moing V, Goujard C, et al. Clinical outcome of patients with HIV-1 infection according to immunologic and virologic response after 6 months of highly active antiretroviral therapy. Ann Intern Med 2000; 133(6): 401-10. Kieffer TL, Finucane MM, Nettles RE, et al. 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Clin Infect Dis 2013; 57(10): 1489-96. García-Gascó P, Maida I, Blanco F, et al. Episodes of low-level viral rebound in HIV-infected patients on antiretroviral therapy: frequency, predictors and outcome. J Antimicrob Chemother 2008; 61(3): 699-704. Boillat-Blanco N, Darling KE, Schoni-Affolter F, et al. Virological outcome and management of persistent low-level viraemia in HIV-1-infected patients: 11 years of the Swiss HIV Cohort Study. Antivir Ther 2015; 20(2): 165-75. Support for this work was provided by the Infectious Disease Clinical Research Program (IDCRP), a Department of Defense (DoD) program executed through the Uniformed Services University of the Health Sciences. This project has been funded in whole, or in part, with federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), under Inter-Agency Agreement Y1-AI-5072..