PI-based Regimens Research Articles

No increased risk of Kaposi sarcoma relapse in patients with controlled HIV-1 infection after switching protease inhibitor-based antiretroviral therapy.

Our aim was to assess if switching from a protease inhibitors (PI)-based regimen to a PI-free one is associated with an increased risk of Kaposi Sarcoma (KS) relapse among patients living with HIV (PLHIV) with history of KS and controlled HIV replication. In a retrospective analysis of the prospectively collected Dat'AIDS database we selected patients who both had a past KS history and a HIV-1 viral load below 200 copies/mL while being PI-treated. We searched for KS relapses while persistent virological success was maintained for at least 6 months, whether patients kept taking the PI, or switched to PI-free regimen. Among the 216 patients with past KS event and a history of HIV-1 infection efficiently treated by a PI-based regimen, 148 patients (68.5%) later switched to a PI-sparing regimen. Their baseline characteristics were not different from non-switching patients. We described 7 cases of relapse (3.2% of the 216 patients). Five cases of relapse occurred in switching patients (3.4%). The remaining two relapses occurred in PI-treated patients (2.9%). At KS relapse, CD4 cell count was 459 cells/μL (range 225-560) for switching patients, compared with 362 and 136 cells/μL for the other two patients. In this large cohort of PLHIV with a history of KS and ART-controlled HIV replication, KS relapses were described in 3.2% of the patients, and were not more frequent when a PI-containing ART regimen has been switched to a PI-free regimen. Our results do not support a specific effect of PI on KS.

Efavirenz versus Protease Inhibitors in Patients with HIV: A Systematic Review and Meta-Analysis

Efavirenz- and protease inhibitor (PI)-based regimens remain viable options across the globe. We conducted a meta-analysis to compare the effectiveness of efavirenz-based regimens relative to PI-based regimens. EMBASE, PubMed, Cochrane, and clinicaltrials.gov were searched for randomized controlled trials conducted between 1987 and 2018 comparing efavirenz- with PI-based regimens. This was followed by title, abstract, and full-text screens. The quality of selected studies was assessed using the Cochrane risk of bias tool. Meta-analysis of the odds of virological suppression was conducted using the robust variance estimation approach. Fifteen studies met the inclusion criteria and totaled 6712 patients (efavirenz arm = 3339; PI arm = 3373), of which 1610 (24.0%) were females. Follow-up ranged from 24 to 144 weeks. Mean/median age ranged from 33 to 44 years. Mean/median baseline CD4 count ranged from 32 to 557 cells/mL while mean/median baseline viral load ranged from log10 4.5 to log10 5.5 copies/mL. Meta-analysis showed that patients receiving efavirenz-based regimens had 37% higher odds of virological suppression compared to PI-based regimens (odds ratio = 1.37, 95% confidence interval = 1.06-1.77, p = 0.02). The Egger test suggested the presence of publication bias (B = 0.927, t = 2.214, p = 0.033). The main threat to the quality of evidence was attrition bias. Regarding virological suppression, efavirenzbased regimens were more effective than PI-based regimens and, therefore, might be ideal for the management of treatment naïve patients with HIV in settings where NNRTIs and PIs are used.

MM-431: A Comparison Between Daratumumab and Non-Daratumumab-Based Salvage Regimens Used at First Relapse Post-Lenalidomide Maintenance in Multiple Myeloma

Context Lenalidomide maintenance therapy after autologous stem cell transplantation (ASCT) is standard of care for patients with multiple myeloma (MM). However, most patients relapse, and the optimal choice of therapy at first-relapse post-lenalidomide maintenance is not established. Objective To compare the efficacy of salvage therapies at first relapse post-lenalidomide maintenance. Design Retrospective study of consecutive patients with MM seen at Mayo Clinic, Rochester between 1/1/2005–12/31/2016. Setting Tertiary referral center. Patients or Other Participants Two hundred thirteen patients treated with lenalidomide/lenalidomide-dexamethasone maintenance post-ASCT were screened; 136 patients experienced a first relapse. One hundred eighteen patients receiving salvage therapy were included in subsequent analyses. Interventions N/A Main Outcomes Measures The main outcome measure was second progression-free survival (2nd PFS), which was calculated from the start of therapy at first relapse after maintenance until therapy discontinuation. Results The median follow-up was 5.4 (95% CI: 4.9, 5.9) years from diagnosis. The median 2nd PFS was significantly longer in patients treated with daratumumab-based regimens [18.4 (95% CI: 10.9, 25.9) months; n=32] versus patients without daratumumab [8.9 (95% CI: 5.5, 12.3) months; n=86; p=0.006]. Adjusting for age, ISS stage 3, cytogenetic risk, Rd maintenance, and lenalidomide refractoriness at salvage, daratumumab-based therapy was associated with a significantly improved PFS [hazard ratio 0.31 (95% CI: 0.16, 0.61; p=0.001)]. The median 2nd PFS was superior in daratumumab + IMiD (n=16) compared to daratumumab + PI (n=15) [NR versus 1 yr (95% CI: 0.5, 1.5), respectively; p=0.004]. In patients not receiving daratumumab, median 2nd PFS was comparable between PI-based combinations [9.2 (95% CI: 6.6, 11.7) months; n=44], IMiD-based combinations [6.7 (95% CI: 0.82, 12.6) months; n=18; p=0.7], or PI + IMiD-based combinations [11.2 (95% CI: 0, 28.4 months; n=24; p=0.17]. Without daratumumab, there was also no significant difference in median 2nd PFS between patients who received lenalidomide-based combinations [6.7 (95% CI: 0, 15.4) months] compared with pomalidomide-based regimens [20.1 (95% CI: 0, 41.4) months; p=0.5]. Conclusions Daratumumab-based therapies at relapse are associated with improvement in 2nd PFS, and daratumumab-IMiD combination was superior to daratumumab-bortezomib combination. Without daratumumab, there was no significant difference between doublet versus triplet therapies, IMiD-versus PI-based regimens or lenalidomide versus pomalidomide-based combinations.

Treatment patterns and outcomes among nontransplant newly diagnosed multiple myeloma patients in Spain.

Aim: To describe treatment patterns and outcomes in nontransplant newly diagnosed multiple myeloma (NDMM) patients in Spain. Methods: This retrospective study included two cohorts of NDMM patients diagnosed between 1 January2012 to 31 December 2013 and1 April2016 to 31 March2017. Results: Among 113 patients, proteasome inhibitor (PI)+alkylator combinations (49%) and PI-based regimens without an alkylator (30%) were the most common first-line (1L) therapies. Use of PI+immunomodulatory drug-based regimens increased between the cohorts; PI-based regimens without an alkylator/immunomodulatory drug decreased. Use of 1L oral regimens was low but increased over time; use of maintenance therapy was low across both periods. Median 1L duration of treatment was 6.9months. Conclusion: Short 1L duration of treatment and low use of 1L oral regimens and maintenance therapy highlight unmet needs in NDMM.

Changes in lipidomic profile by anti-retroviral treatment regimen: An ACTG 5257 ancillary study.

High cardiovascular disease risk in people living with HIV is partly attributed to antiretroviral therapy (ART). Lipid response to ART has been extensively studied, yet, little is known how small molecule lipids respond to Integrase inhibitor-based (INSTI-based) compared to Protease inhibitor-based (PI-based) ART regimens.Ancillary study to a phase 3, randomized, open-label trial [AIDS Clinical Trial Group A5257 Study] in treatment-naive HIV-infected patients randomized in a 1:1:1 ratio to receive ritonavir-boosted atazanavir (ATV/r), ritonavir-boosted darunavir (DRV/r) (both PI-based), or raltegravir with Tenofovir Disoproxil Fumarate-TDF plus emtricitabine (RAL, INSTI-based).We examined small molecule lipid response in a subcohort of 75 participants. Lipidomic assays of plasma samples collected pre- and post-ART treatment (48 weeks) were conducted using ultra-performance liquid chromatography coupled to time-of-flight mass spectrometry. The effect of ART regimens was regressed on lipid species response adjusting for the baseline covariates (lipids, age, sex, race, CD4 level, BMI, and smoking). Results were validated in the Centers for AIDS Research Network of Integrated Clinical Systems study (N = 16).Out of 417 annotated lipids, glycerophospholipids (P = .007) and sphingolipids (P = .028) had a higher response to ATV/r and DRV/r compared to RAL. The lysophosphatidylcholine (LPCs(16:1),(17:1),(20:3)) and phosphophatidylcholine species (PCs(40:7),(38:4)) had an opposite response to RAL versus ATV/r in the discovery and validation cohort. The INSTI-based regimen had an opposite response of ceramide species ((d38:1), (d42:2)), PCs((35:2), (38:4)), phosphatidylethanolamines (PEs(38:4), (38:6)), and sphingomyelin(SMd38:1) species compared with the PI-based regimens. There were no differences observed between 2 PI-based regimens.We observed differences in response of small molecule lipid species by ART regimens in treatment-naive people living with HIV.

Factors associated with the use and composition of two-drug regimens in a large single-centre HIV cohort.

We aimed to assess the clinical characteristics associated with the use of two-drug regimens (2DRs) and the factors associated with specific antiretrovirals in 2DRs in a large single-centre HIV cohort. Retrospective analysis of demographics, HIV characteristics and AIDS events, antiretroviral prescription, virological failure and genotypic resistance testing, and laboratory results from all adult people with HIV (PWH) prospectively followed at the Hospital Clinic of Barcelona who were receiving a 3DR or a 2DR in January 2020. We assessed factors associated with the probability of receiving 2DRs relative to three-drug regimens (3DRs) using a logistic regression model, controlling for age, sex and year of HIV diagnosis. The same methodology was applied to identify factors associated with the prescription of integrase inhibitor-based regimens or PI-based regimens among PWH receiving 2DRs. There were 3432 (88%) PWH receiving 3DRs and 463 (12%) receiving 2DRs. In the final adjusted model, ≥2 previous virological failures, previous resistance mutations, previous AIDS diagnosis, longer time on current regimen, higher total cholesterol or triglycerides and lower baseline haemoglobin were independent factors associated with 2DRs. The majority of 2DRs included an integrase inhibitor or/and a PI. We identified independent factors associated with the inclusion of integrase inhibitors (lower HDL cholesterol) or PIs (prior AIDS, prior genotypic resistance mutations and lower CD4/CD8 ratio) in the 2DR. In this large single-centre HIV cohort, a worse cardiometabolic status or more archived resistance were key factors associated with inclusion of integrase inhibitors or PIs, respectively, in 2DRs.

Feasibility and clinical relevance of HIV-1 drug resistance testing in patients with low-level viraemia in South Africa.

To determine the feasibility of HIV genotyping at low-level viraemia (LLV) using an in-house assay in a South African population and the prevalence, as well as the clinical relevance, of drug resistance (HIVDR) in this population. We conducted an observational, retrospective, cohort study on patient samples with LLV referred for routine HIVDR testing at a public sector Johannesburg laboratory from August 2017 to October 2018. Genotyping was performed using a nested RT-PCR assay and Sanger sequencing. The genotyping success rate was evaluated for different viraemia categories. Sequences were loaded onto the Stanford HIVdb genotypic resistance tool (version 8.7) for drug resistance interpretation. Plasma samples from 159 HIV-1-infected, treatment-experienced adults with LLV (5-999 copies/mL) were analysed. The in-house assay performed well with an overall success rate of 78.6% (125/159, 95% CI 71.6-84.3). The prevalence of drug resistance mutations in the LLV cohort was 79.2% (99/125, 95% CI 71.2-85.4) with most patients (n = 109, 68.6%) on a PI-based regimen at the time of genotyping. Of 125 sequences obtained, 73.6% (92/125) had ≥1 NRTI mutation while 70.4% (88/125) had ≥1 NNRTI mutation. Major PI mutations, including M46I and V82A, were detected in 7.2% (9/125) of patients. Current South African virological failure guidelines may keep patients on failing regimens for longer than necessary. Our data suggest that genotyping at LLV is feasible and implementation could result in earlier identification and referral of patients requiring third-line regimens.

Evaluation of minor drug-resistant viral variants in patients experiencing virological failure (VF) on a first-line regimen in Fujian Province by high-throughput sequencing

It is largely unknown how frequently minor HIV drug-resistant variants at levels under limit of detection of conventional genotyping are present in patients experiencing virological failure (VF). Further, the clinical implications of minor drug-resistant variants at time of virologic failure are unknown. Fifteen patients experiencing VF on a first-line regimen were evaluated by high-throughput sequencing and compared with the conventional Sanger genotype drug resistance detection method. NRTI drug resistant mutations (DRMs) were detected in a high proportion of subjects, with the most common being M184V and TAMs. Minor resistant mutations accounted for 19.27% of the total drug-resistant mutations in patients with VF. A mean of 1.7 additional mutations per subject were detected by high-throughput sequencing, the difference was statistically significant, and those additional low-abundance drug-resistant mutations increased the genotypic resistance scores in 10 of 11 subjects (90.9%). Among persons experiencing VF, minor variants possessing major PI (protease inhibitor) DRMs were present in a minority of cases, which was also the case in ARV-naive subjects, and suggests PIs may be effective in subjects experiencing VF on subsequent second-line PI-based antiretroviral regimen. The high-throughput sequencing results of mutations between ART failure subjects and treatment naïve subjects were also compared. Three novel mutations were then screened with higher frequencies in the ART failure subjects. It is important to guide the replacement of treatment programs and screening for new drug-resistant mutation sites, and the use of high-throughput sequencing methods can more comprehensively study the characteristics of drug-resistant viral variants of patients experiencing VF on a first-line regimen.

Treatment Sequencing Patterns Observed in Patients Treated Initially with Lenalidomide/Dexamethasone Combination As Frontline Multiple Myeloma Therapy

Introduction: Doublet combinations including lenalidomide (len) and dexamethasone (dex; Ld) are increasingly used to treat frontline (FL) multiple myeloma (MM) patients (pts). Len has also been used as maintenance therapy where strategies increasing len dose with first relapse have been considered (Harousseau JL et al. Blood 2017). Triplet combinations are emerging as standard of care for relapsed/refractory (RR) MM and the treatment paradigm is shifting, with new agents like carfilzomib, ixazomib, elotuzumab, and daratumumab being added to Ld. Although these new combinations have shown improved clinical outcomes in RRMM, most pts ultimately relapse. Thus, treatment decision with each relapse becomes increasingly important to improve survival; the most critical decision may come at first relapse. With earlier len use, better understanding of treatment sequencing patterns of len and its use in clinical practice settings may help optimize treatment strategies in RRMM pts in later lines. We present real-world clinical practice data on treatment sequencing at relapse from len-based FL therapy.Methods: Pts aged ≥18 y with ≥1 diagnosis (International Classification of Diseases [ICD], 9th Revision, codes 203.0x or ICD-10 codes C90.0x), preceded by ≥12 mo (baseline) without a MM claim, were identified from January 1, 2010 in the Explorys electronic medical records US database and followed through the course of available follow-up. FL therapy included all anti-MM treatment received after 1st claim for an anti-MM prescription or administration of anti-MM therapy. The end of a line of therapy (LoT) was defined as the 1st day of a treatment gap of >90 d or initiation of a salvage regimen. LoT escalation was a surrogate for disease progression. Baseline characteristics plus Ld and len monotherapy (mono) patterns of use were summarized using descriptive statistics.Results: 766 FL pts were treated with Ld (466 [61%]) or len mono (300 [39%]). Pts in the 2 cohorts were similar in age and race; males and pts in the US Midwest region (Table) tended to receive Ld vs len mono. Pts on Ld generally had more comorbidities vs pts on len mono. Of 466 pts on Ld, 97% (n=452) had a recorded len dose, of whom 56% (n=253) started len at 25 mg/d and 44% (n=199) at <25 mg/d. Of 253 pts who started len at 25 mg/d, 127 (50%) stopped dex during Ld after a median (IQR) duration of therapy (DoT) of 40 (28-120) d and continued with len mono; 47 (37%) of these pts then had len dose reduced (24 on 15 mg/d, 16 on 10 mg/d, 7 on <10 mg/d). Of the 47 pts with len dose reduced, 22 later switched to second-line (2L) therapy. Proteasome inhibitor (PI)-based regimens (n=8 [36%]) and len with/without dex (n=6 [27%]) were most commonly used in 2L. Of the 199 pts receiving low-dose len with dex, 49% (n=98) stayed on Ld while 51% (n=101) discontinued dex after a median (IQR) DoT of 28 (28-80) d and continued with len mono maintenance. Of 101 pts who discontinued dex, 92% (n=93) had no len dose reduction; of these, 53% (n=49) switched to 2L therapy. A PI-based regimen (27%) and len with/without dex (20%) were the primary 2L treatment choices. Of the 300 pts receiving len mono in FL, 96% (n=289) had a recorded len dose: 80% (n=231) started at <25 mg/d, 20% (n=58) at 25 mg/d. Of 231 pts starting low-dose len, 89% (n=205) had no dex added in FL therapy and 99% (n=202) of those had no len dose increase. Among pts with no len dose increase, 102 had 2L therapy, of whom 16% (n=16) and 46% (n=47) had a PI-based regimen and len with/without dex, respectively, when relapsed from FL treatment. Of 58 pts starting len at 25 mg/d, 74% (n=43) had no dex added; of those, 14% (n=6) had len dose reduced.Conclusions: In real-world clinical practice, about half of pts receiving Ld as FL therapy moved to len mono maintenance therapy; over one-third of these had their len dose reduced. Of pts with reduced len dose, ~50% relapsed and switched treatment in 2L. PI-based regimens and len re-treatment were the most common 2L therapy options after progression on len in FL. Pts on Ld were more likely to progress to 2L if they started treatment with low-dose len. Pts receiving low-dose len were less likely to have len dose increased. Findings suggest the increasing importance of optimizing treatment strategies in RRMM pts who receive len as FL therapy, including use of new triplets, especially for early relapse. Analysis of outcome data is currently ongoing.Study support: Bristol-Myers Squibb [Display omitted] DisclosuresChen:Bristol-Myers Squibb: Employment. Potluri:SmartAnalyst Inc.: Employment; Janssen: Consultancy, Research Funding. Kanakamedala:SmartAnalyst Inc.: Employment. Papademetriou:SmartAnalyst Inc.: Employment. Yasenchak:Bristol-Myers Squibb: Consultancy; Seattle Genetics: Consultancy. Ranjan:SmartAnalyst India Pvt. Ltd: Employment. Bhandari:SmartAnalyst India Pvt. Ltd: Employment. Mann:SmartAnalyst India Pvt. Ltd: Employment. Davis:Bristol-Myers Squibb: Employment.

A Real-World Comparative Analysis of Carfilzomib and Other Systemic Multiple Myeloma Chemotherapies in the US Community Oncology Setting

IntroductionRecently, novel agents have been approved for the treatment of relapsed multiple myeloma (MM). There is a paucity of real-world outcomes data on these novel treatments. The purpose of this retrospective cohort study was to compare time to next treatment (TTNT) between patients who received the most common proteasome inhibitor (PI)-based triplet regimens for relapsed multiple myeloma as their second line of therapy (LOT2).MethodsThe study population consisted of patients who received a carfilzomib (K)-based regimen during the course of treatment for MM between 11/01/2013 and 02/29/2016, were ≥18 years old, were not enrolled in a clinical trial, and had at least 2 visits at a US Oncology Network (USON) clinic. PI-based triplet regimens received by at least 15 patients in LOT2 were considered for this analysis: K+lenalidomide with dexamethasone or prednisone (KRd), bortezomib+lenalidomide with either steroid (VRd), and bortezomib+cyclophosphamide with either steroid (VCyd). Data were captured on lines of therapy (LOT), systemic therapy regimens, and treatment administration dates from the US Oncology Network's iKnowMed® electronic health records (EHR). Treatment sequencing rules were created to define criteria for the advancement of the line of therapy based on the specific regimens, duration of use, and administration dates. TTNT was estimated from date of initiation of LOT2 therapy to the first administration date of the next line of therapy with the Kaplan-Meier method, using log-rank tests for comparison. Death or progression to next treatment were considered failure events. Patients who were lost to follow up or did not experience a failure event during the study period were censored. Hazards ratios (and 95% CIs) were estimated using multivariable Cox regression modeling, adjusting for baseline age, sex, race, geographic region of the practice, number of comorbidities, stage, body mass index (BMI), prior cancer history, performance status, and serum creatinine. A limitation of our real-world data is that a small proportion of LOT indicators may be misclassified due to data inconsistencies. Furthermore, while use of a large geographically dispersed cohort of community-based patients improves generalizability, the results from our data may not be completely generalizable to other community-based practices.ResultsA total of 718 patients received a K-containing regimen at some time (LOT 1 to LOT5) during the course of their MM treatment (Table 1); of these, 156 patients received a LOT2 PI-containing triplet including KRd (n =112; 71.8%), VRd (n = 27; 17.3%), and VCyd (n = 17; 10.9%). Mean baseline age for these 156 patients was 64.8 (SD: 11.3) years. In the KRd group, mean age was 64.7 (SD: 11.6) years, whereas in the VRd and VCyd groups, mean ages were 62.4 (SD: 10.9) and 69.1 (SD: 9.1), respectively. Overall, 57.7% of the study population was male. 64.3% of the KRd group were male, compared to 48.1% of the VRd group and 29.4% of the VCyd group. These PI-based regimen groups were not significantly different across a range of baseline clinical characteristics including number of comorbidities, stage at diagnosis, ECOG, and serum creatinine (Table). Median TTNT was greatest for the KRd group (25.3 months; 95% CI: 19.71-NR), compared to the VRd or VCyd groups (median TTNT for VRd: 10.2 months, 95% CI: 4.24-12.71, and for VCyd: 6.5 months,95% CI: 3.02-12.78; log-rank p<.0001). The adjusted HR for KRd was 0.19 (95% CI: 0.11-0.37), indicating an almost 80% lower risk of progression to next treatment or death among KRd patients, compared to patients who received VRd (referent) in LOT2. Patients receiving VCyd had a similar adjusted risk for progression to next treatment or death, compared to patients receiving VRd (adj. HR: 0.96, 95% CI: 0.43-2.13).ConclusionsOur findings indicate that MM patients who received KRd in LOT2 had significantly improved TTNT, compared to those who received VRd or VCyd. Considering the real-world nature of these data, the median TTNT observed with KRd appears to be consistent with the findings on progression-free survival for KRd in the phase 3 ASPIRE trial (median PFS: ITT population =26.3 months; LOT2 = 29.6 months). These findings confirm the value of KRd as an important therapeutic option for patients with MM at first relapse. [Display omitted] DisclosuresRifkin:McKesson Specialty Health: Employment; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Medhekar:Amgen Inc.: Employment, Equity Ownership. Amirian:McKesson Specialty Health: Employment. Wilson:McKesson Specialty Health: Employment. Boyd:McKesson Specialty Health: Employment. Mezzi:Amgen, Inc.: Employment, Equity Ownership. Panjabi:Amgen Inc.: Employment, Equity Ownership.

PCN60 Healthcare Resource Utilization Burden in the Management of Triple-Class Exposed Patients With Relapsed/Refractory Multiple Myeloma: Results From the ITEMISE Study

Patients with relapsed/refractory multiple myeloma (RRMM) who are triple-class exposed (TCE) to a proteasome inhibitor (PI), immunomodulatory drug, and anti-CD38 antibody have a poor prognosis. Current understanding around management of these patients and associated healthcare resource utilization (HCRU) is limited outside the US. Here, we report findings from the ITEMISE study regarding management, HCRU, and end-of-life (EoL) care for TCE patients with RRMM in Canada and Europe. This study utilized a 3-phase Delphi-like approach consisting of in-depth interviews with 7 hematology experts, the development of a cross-sectional survey fielded to hematologists across Belgium, Canada, France, Germany, Italy, Netherlands, Spain, Sweden, Switzerland, and the UK from August to October 2020, and a final consensus workshop of hematology experts to validate the results. Hematologists considered HCRU post-TCE, including treatment options, outcomes, and the frequency of hospital visits. Pooled survey findings for all countries were analyzed using descriptive statistics including measures of central tendency and spread. 202 hematologists completed the survey (60% from academic hospitals, 38% from public hospitals, and 2% from private practice). An estimated 56% of patients received active treatment post-TCE; most frequently immunomodulatory drug-, anti-CD38 antibody-, or PI-based regimens (received by 23%, 18%, and 15% of patients, respectively). Patients were estimated to have a median of 2 outpatient visits prior to and during the first treatment post-TCE, and 2 unplanned hospitalizations. During EoL care, an estimated 79% of patients received care outside of hospital, with 2 unplanned hospitalizations of 6 bed days per stay. Survey findings indicate the intent to actively treat TCE patients with a range of combination regimens including PIs, immunomodulatory drugs, and anti-CD38 antibodies. The HCRU burden associated with the management of patients post-TCE highlights the significant need for better treatment options to improve patient prognosis, thereby reducing HCRU across Europe and Canada.

Integrase Strand Transfer Inhibitor Start or Switch Impacts Learning in Women With HIV.

Integrase strand transfer inhibitors (INSTIs) are first-line regimens for HIV treatment. We aimed to examine their impact on cognitive performance and depressive symptoms in women with HIV (WWH). Women's Interagency HIV Study, a multisite, prospective, cohort study. WWH who started or switched to INSTI-based antiretroviral therapy (ART) and completed neuropsychological testing and the Center for Epidemiological Studies-Depression (CES-D) scale before and after INSTI start/switch were included in the analyses. Primary outcomes were demographically corrected cognitive domain T-scores. Linear mixed-effects models adjusted for relevant covariates were used to examine effects of start/switch of any INSTI and individual INSTI drugs on cognition and CES-D scores. Six hundred thirty-nine WWH, median age 49 (interquartile range 12) years, 66% Black non-Hispanic, had neuropsychological and CES-D scale data before and after INSTI start/switch. Although 14% started INSTI-based ART, the remainder switched to INSTI-based ART from another regimen. Overall, any INSTI use was associated with poorer learning post-INSTI. Specifically, use of dolutegravir and elvitegravir, but not raltegravir, was associated with poorer learning. In analyses restricted to INSTI switch, any INSTI use, and dolutegravir use, was associated with poorer learning. Among those switching from a PI-based regimen, INSTIs overall and dolutegravir remained associated with poorer learning; switching from a nonnucleoside reverse transcriptase inhibitor to dolutegravir was also associated with poorer learning. INSTI start/switch was not related to depressive symptom changes. INSTI use was associated with poorer learning among WWH. These changes were mainly observed in elvitegravir and dolutegravir users, indicating that the impact of INSTI on cognition in WWH may not be a class effect.

Antiretroviral Therapy Anchor-based Trends in Body Mass Index Following Treatment Initiation Among Military Personnel with HIV.

Weight gain and obesity in people living with HIV have been associated with increased risk for non-AIDS-related comorbidities, and integrase strand transfer inhibitor (INSTI)-based regimens may lead to comparatively more weight gain than other regimens. We evaluated body mass index (BMI) following antiretroviral therapy (ART) initiation among participants in the U.S. Military HIV Natural History Study (NHS). NHS participants with available baseline weight and height data initiating ART from 2006 to 2017 were considered for analysis. Antiretroviral therapy was categorized by anchor class to include INSTIs, non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs). Linear growth-curve modeling was used to predict BMI changes from ART initiation through 2 years of follow-up in participants stratified by baseline BMI (<25 vs ≥25 kg/m2) at ART start and anchor drug class. These models were adjusted for demographic- and HIV-related characteristics. Of 961 NHS participants started on initial ART between 2006 and 2017, 491 men who had available baseline BMI data and were virally suppressed (<200 c/mL) at 1 and 2 years of follow-up were included. Overall, the predicted BMI increased at each time point over 2 years regardless of baseline BMI. There was a trend toward less weight gain for non-INSTI regimens regardless of demographic- or HIV-related factors (-0.65 kg/m2/yr, P = .070). In participants with BMI <25, all regimens were associated with BMI gains except in those with high viral load (≥100,000 copies/mL) started on PI regimens (-1.91 kg/m2/yr, P = .000; n = 13). For those participants with BMI ≥25, only INSTI- and PI-based regimens were significantly associated with increased BMI (INSTI 0.54 kg/m2/y, P = .000; PI 0.39 kg/m2/yr, P = .006). Non-nucleoside reverse transcriptase inhibitors were not associated with weight gain regardless of race- or HIV-related characteristics. African Americans with BMI ≥25 were more likely to gain weight as compared to Whites (0.99 kg/m2/yr, P = .016). Specific anchor drug-based predictions revealed that only INSTI use among African Americans was significantly associated with BMI gains (1.85 kg/m2/yr, P = .007); NNRTI- and PI-related weight change was not significant as compared to Whites. In our cohort of young military members with HIV infection, those with BMI <25 experienced BMI gains across all ART classes. Among those with BMI ≥25, African Americans on INSTI regimens had the greatest BMI gains. Further studies are needed to determine whether NNRTI regimens should be considered in certain individuals at risk for INSTI-associated weight gain.

Extensive drug resistance during low-level HIV viraemia while taking NNRTI-based ART supports lowering the viral load threshold for regimen switch in resource-limited settings: a pre-planned analysis from the SESOTHO trial.

WHO guidelines on ART define the HIV-1 viral load (VL) threshold for treatment failure at 1000 copies/mL. The Switch Either near Suppression Or THOusand (SESOTHO) trial, conducted in Lesotho from 2017 to 2020, found that patients with persistent viraemia below this threshold (100-999 copies/mL) benefit from switching to second-line ART. This pre-planned nested study assesses the prevalence of resistance-associated mutations (RAMs) in SESOTHO trial participants. The SESOTHO trial [registered at ClinicalTrials.gov (NCT03088241)] enrolled 80 persons taking NNRTI-based first-line ART with low-level HIV-1 viraemia (100-999 copies/mL) and randomized them (1:1) to switch to a PI-based second-line regimen (switch) or continue on first-line therapy (control). We sequenced relevant regions of the viral pol gene using plasma samples obtained at enrolment and 36 weeks. RAMs were classified with the Stanford HIV Drug Resistance Database. Sequencing data were obtained for 37/80 (46%) participants at baseline and 26/48 (54%) participants without viral suppression to <50 copies/mL at 36 weeks (21 control participants and 5 switch participants). At baseline, 31/37 (84%) participants harboured high-level resistance to at least two drugs of their current regimen. At 36 weeks, 17/21 (81%) control participants harboured resistance to at least two drugs of their current regimen, while no PI-associated resistance was detected in the 5 switch participants with ongoing viraemia. Among persons with low-level viraemia while taking NNRTI-based first-line ART enrolled in the SESOTHO trial, the majority harboured HIV-1 with RAMs that necessitate ART modification. These findings support lowering the VL threshold triggering a switch to second-line ART in future WHO guidelines.

Trends and factors associated with modification or discontinuation of the initial antiretroviral regimen during the first year of treatment in the Turkish HIV-TR Cohort, 2011\u20132017

BackgroundThere is limited evidence on the modification or stopping of antiretroviral therapy (ART) regimens, including novel antiretroviral drugs. The aim of this study was to evaluate the discontinuation of first ART before and after the availability of better tolerated and less complex regimens by comparing the frequency, reasons and associations with patient characteristics.MethodsA total of 3019 ART-naive patients registered in the HIV-TR cohort who started ART between Jan 2011 and Feb 2017 were studied. Only the first modification within the first year of treatment for each patient was included in the analyses. Reasons were classified as listed in the coded form in the web-based database. Cumulative incidences were analysed using competing risk function and factors associated with discontinuation of the ART regimen were examined using Cox proportional hazards models and Fine-Gray competing risk regression models.ResultsThe initial ART regimen was discontinued in 351 out of 3019 eligible patients (11.6%) within the first year. The main reason for discontinuation was intolerance/toxicity (45.0%), followed by treatment simplification (9.7%), patient willingness (7.4%), poor compliance (7.1%), prevention of future toxicities (6.0%), virologic failure (5.4%), and provider preference (5.4%). Non-nucleoside reverse transcriptase inhibitor (NNRTI)-based (aHR = 4.4, [95% CI 3.0–6.4]; p < 0.0001) or protease inhibitor (PI)-based regimens (aHR = 4.3, [95% CI 3.1–6.0]; p < 0.0001) relative to integrase strand transfer inhibitor (InSTI)-based regimens were significantly associated with ART discontinuation. ART initiated at a later period (2015-Feb 2017) (aHR = 0.6, [95% CI 0.4–0.9]; p < 0.0001) was less likely to be discontinued. A lower rate of treatment discontinuation for intolerance/toxicity was observed with InSTI-based regimens (2.0%) than with NNRTI- (6.6%) and PI-based regimens (7.5%) (p < 0.001). The percentage of patients who achieved HIV RNA < 200 copies/mL within 12 months of ART initiation was 91% in the ART discontinued group vs. 94% in the continued group (p > 0.05).ConclusionART discontinuation due to intolerance/toxicity and virologic failure decreased over time. InSTI-based regimens were less likely to be discontinued than PI- and NNRTI-based ART.

1005. Comparison of Weight Changes in Treatment-Naïve, HIV-Infected Patients Receiving Integrase Inhibitor-Based Therapy Versus Protease Inhibitor-Based Therapy

BackgroundRecent data regarding integrase inhibitor (INSTI) therapy indicate possible association with weight gain. The incidence and degree of weight gain seems to vary by both patient-specific and regimen-related factors, such as nucleoside reverse transcriptase (NRTI) backbone.MethodsThis was a retrospective chart review of previously ART-naïve Indiana University Health LifeCare Clinic patients who started an INSTI- or PI-based regimens from 1/1/13 to 7/31/19. Adult patients without prior ART exposure receiving an INSTI- or PI-based regimen for at least 10 months were included. The primary objective was weight gain at 12 months after starting ART. Subgroup analyses were conducted by INSTI, PI, or NRTI backbone utilized. Statistical testing included Wilcoxon Rank-Sum Test and Chi Square analyses.ResultsThe patient population (N=162) was predominately male and African American with relative immunocompetence, generally achieving viral suppression after 12 months of ART. Patients receiving PI-based therapy were more likely to be Asian American or Hispanic (p=0.04), and to receive a tenofovir disoproxil fumarate (TDF)-based regimen (p=0.0034). No statistically significant difference in weight change was observed between INSTI- and PI-based regimens (median weight gain 5.1 kg vs 3.9 kg, p=0.52). The proportion of obese or overweight patients in the INSTI arm increased significantly as compared to baseline (p=0.00001). Subgroup analyses demonstrated significant increases in weight gain and clinically significant weight gain with tenofovir-based (tenofovir alafenamide and TDF) regimens compared to those with abacavir/lamivudine (p< 0.05).Primary Objective BMI Category Changes by INSTI or PI Agent NRTI Subgroup Analyses ConclusionLack of power makes meaningful interpretation of the results for the primary objective difficult. However, several of the prespecified secondary objectives and subgroup analyses demonstrated clinically significant results related to increased weight gain or BMI category changes with INSTI-, PI-, and tenofovir-based regimens. Checking the patient’s weight at every appointment is considered standard practice at IU Health clinics, but missing values despite qualifying encounters were observed. Further commitment to standardized weighing practices should be a priority at clinics caring for patients living with HIV.Disclosures All Authors: No reported disclosures

1047. Weight change associated with switching to bictegravir/emtricitabine/tenofovir alafenamide in virally suppressed people with HIV

BackgroundIntegrase strand transfer inhibitor (INSTI) associated weight gain has been observed in a number of recent studies but with limited data on bictegravir. Here we examine weight change associated with the switch to co-formulated bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF).MethodsWe performed a retrospective analysis of consecutive PWH attending an academic outpatient clinic who received a prescription for B/F/TAF from 02/07/2018-02/07/2019 and had a baseline HIV RNA < 200 copies/mL prior to starting B/F/TAF. Baseline demographics and clinical parameters were obtained from chart review. Parameters of interest were collected for one year (at a minimum) before and one year after starting B/F/TAF. Linear mixed model analyses were conducted for PWH before/ after switch. Separate analyses were performed examining factors associated with ≥ 10% BMI increase versus < 10% increase.Results156 PWH switching to B/F/TAF were identified, of whom 107 (69%) identified as men, 105 (67%) were African American. Median age was 49 years (IQR 35-57), weight 184 lb (IQR 153-208), and BMI 27.5 (IQR 23-32.3). At time of switch, 3% were underweight, 31% normal weight, 24% overweight, and 41% obese. 74% switched from INSTI-based regimen, 17% from NNRTI- and 16% from PI-based regimens. Of the INSTI, elvitegravir (54.3%) or dolutegravir (41.7%) were most frequently used. 50% were on TAF pre-switch with 28% on tenofovir disoproxil. The mixed model analysis indicated that there was not a significant shift in the mean BMI (P=0.2017) or BMI rate of change over time (P=0.792) after participants switched. 19.2% had ≥ 10% increase in BMI; and when compared to those with < 10% increase, younger age (42.8±13.8 vs. 48.9±13.2 years, P=0.036), switch from a non-PI based regimen (P=0.004), and switch from a TDF containing regimen (36.4% vs. 12.6%, P < 0.001) were associated with greater weight gain.ConclusionOverall, there were no significant changes in BMI between pre and post switch to B/F/TAF time periods; however the majority of PWH switched from an INSTI-based regimen. Analysis of PWH who experienced ≥ 10% increase compared to < 10% BMI increase, indicated that factors including younger age, switch from a non-PI containing regimen and switch from TDF were associated with greater weight gain.Disclosures All Authors: No reported disclosures

The effect of protease inhibitor-based dual antiretroviral regimens on CD4/CD8 ratio during the first year of therapy in ART-naïve patients with HIV-infection.

To assess the effect of protease inhibitor (PI)-based dual therapy on CD4/CD8 ratio during the first year of therapy in antiretroviral therapy (ART)-naïve patients using data from randomized controlled clinical trials. We pooled data from the GARDEL and ANDES studies, both randomized controlled clinical trials that recruited ART-naïve people living with HIV and randomly assigned them to receive PI-based dual therapy (DT) or triple therapy (TT) aiming to compare viral efficacy. We compared median CD4/CD8 ratios and the proportion of patients with CD4/CD8 ratio >1 at 48weeks after ART initiation in both treatment arms using the Mann-Whitney U-test and the χ2 test. We performed subgroup analysis for patients >50years old, with baseline CD4 counts ≤200cells/μL, viral load >100000 HIV RNA copies/mL, and ritonavir-boosted lopinavir-based therapy. We analysed data from 571 patients: 292 on DT and 279 on TT. No differences were observed in CD4/CD8 ratio (0.632 vs. 0.617, P=0.729) or in the proportion of patients with CD4/CD8 ratio >1 (17.9% vs. 19.3%, P=0.678) 48weeks after ART initiation. Subgroup analysis showed no further differences. The impact of PI-based DT regimens on the CD4/CD8 ratio during the first year of treatment for ART-naïve patients is similar to that of TT.

Enhancing current human immunodeficiency virus/hepatitis B and human immunodeficiency virus/hepatitis C virus co-infection management.

Enhancing current human immunodeficiency virus/hepatitis B and human immunodeficiency virus/hepatitis C virus co-infection management.

Impact of Protease Inhibitor-Based Antiretroviral Therapy on Tacrolimus Intrapatient Variability in HIV-Positive Kidney Transplant Recipients

BackgroundHuman immunodeficiency virus (HIV)-positive kidney transplant (KT) recipients have been shown to experience higher rejection rates due in part to drug-drug interactions between antiretroviral therapy (ART) and immunosuppression regimens. High tacrolimus (FK) intrapatient variability (IPV) is associated with inferior outcomes in KT. The purpose of this study was to determine the impact of protease inhibitor (PI)-based ART on FK IPV and graft outcomes. MethodsWe performed a single-center review of HIV-positive KT recipients from 2007 to 2017. Percentage coefficient of variation (%CV = (σ/μ) × 100; σ, median; μ, standard deviation) was calculated for FK IPV. FK IPV at 6 and 12 months, graft function, and immune outcomes in PI-based vs non-PI-based KT recipients were compared. ResultsA total of 23 HIV-positive KT patients were identified, of whom 10 were maintained on PI-based ART. Median IPV for the entire cohort at 6 and 12 months was 35.8% and 41%, respectively. Patients on PI-based regimens were proportionally more likely to experience high IPV at both time points. Median FK IPV was numerically higher at 6 months (37.3% vs 26.8%, P = .11) and significantly higher at 12 months (57.8% vs 30.9%, P = .01) for patients on PI-based regimens. Lastly, inferior graft function was observed in PI-based patients. ConclusionOur data suggest that PI-based ART is associated with a higher degree of FK IPV, which may contribute to worsening graft function. Larger studies are warranted to determine the impact of PI-based ART on FK IPV and graft outcomes in this population.